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The invention relates to liquid compositions for use with hair removal devices comprising a silicone polyether block copolymer comprising from 1% to 50%, by weight of polyethylene oxide, from 20% to 90% by weight of polypropylene oxide and from 1% to 20%, by weight of silicone for improved lubrication.

1. A composition dispensing hair removal device, said device comprising a composition comprising from about 0.1% to about 60% by weight of a silicone polyether block copolymer wherein said silicone polyether block copolymer comprises from about 1 to about 50%, by weight of polyethylene oxide, from about 20% to about 90% by weight of polypropylene oxide and from about 1% to about 20%, by weight of silicone. 2. The device according to claim 1, wherein said silicone polyether block copolymer comprises from about 1% to about 30%, by weight of polyethylene oxide, from about 20% to about 80% by weight of polypropylene oxide and from about 1 to about 20%, by weight of silicone. 3. The device according to claim 1, wherein said silicone polyether block copolymer comprises from about 15% by weight of silicone. 4. The device according to claim 1, wherein said silicone polyether block copolymer has a molecular weight of from about 10000 to about 19000. 5. The device according to claim 1, wherein said silicone polyether block copolymer has a molecular weight of from about 10000 to about 15000. 6. The device according to claim 1, wherein said silicone polyether block copolymer has a ratio of polyethylene oxide to polypropylene oxide of from about 2.0 to about 0.1. 7. The device according to claim 6, wherein said silicone polyether block copolymer has a ratio of polyethylene oxide to polypropylene oxide of from about 0.6 to 0.25. 8. The device according to claim 1, wherein said composition further comprises from about 0.1% to about 8% by weight of a water soluble polymer and preferably wherein the ratio of said water soluble polymer to said silicone block copolymer is from about 1:5 to about 5:1. 9. The device according to claim 8, wherein said water soluble polymer is selected from polyethylene oxide, polyvinyl pyrrolidone, polyacrylamide, polyhydroxymethacrylate, polyvinyl imidazoline, polyethylene glycol, polyvinyl alcohol, polyhydroxyethymethacrylate, guars, celluloses, modified celluloses and mixtures thereof. 10. The device according to claim 5, wherein said water soluble polymer is polyethylene oxide having an average molecular weight of at least about 300000. 11. The device according to claim 10, wherein said polyethylene oxide has an average molecular weight of from about 1 million to about 5 million. 12. The device according to claim 1, wherein said composition further comprising from about 0.1% to about 8%, by weight of the lubricating material of a copolymer of polyethylene oxide and polypropylene oxide. 13. The device according to claim 1 wherein said composition comprises from about 0.1% to about 5% of a thickening agent and at least about 30% by weight of water. 14. The device according to claim 1, wherein said device comprises a handle connected to a hair removal head, wherein said handle comprises a cavity for housing said composition disposed within said handle and an actuator adapted to displace said composition from said cavity to a fluid dispensing member. 15. The device according to claim 10, wherein said fluid dispensing member comprises an elongated contact region forming at least one dispensing orifice. 16. The device according to claim 11, wherein said elongate elastomeric contact region forms a one way valve, preferably selected from a flap valve, a slit valve, a duckbill valve and a combination thereof. 17. A personal care composition comprising from about 40% to about 95% by weight of water, about 1% to about 6% by weight of a volatile post foaming agent and from about 0.1% to about 60% by weight of silicone polyether block copolymer wherein said silicone polyether block copolymer comprises at comprises from about 1 to about 50%, by weight of polyethylene oxide, from about 20% to about 90% by weight of polypropylene oxide and from about 1 to about 20%, by weight of silicone.

The invention relates to liquid compositions for use with hair removal devices comprising a silicone polyether block copolymer comprising from 1% to 50%, by weight of polyethylene oxide, from 20% to 90% by weight of polypropylene oxide and from 1% to 20%, by weight of silicone for improved lubrication.1. A composition dispensing hair removal device, said device comprising a composition comprising from about 0.1% to about 60% by weight of a silicone polyether block copolymer wherein said silicone polyether block copolymer comprises from about 1 to about 50%, by weight of polyethylene oxide, from about 20% to about 90% by weight of polypropylene oxide and from about 1% to about 20%, by weight of silicone. 2. The device according to claim 1, wherein said silicone polyether block copolymer comprises from about 1% to about 30%, by weight of polyethylene oxide, from about 20% to about 80% by weight of polypropylene oxide and from about 1 to about 20%, by weight of silicone. 3. The device according to claim 1, wherein said silicone polyether block copolymer comprises from about 15% by weight of silicone. 4. The device according to claim 1, wherein said silicone polyether block copolymer has a molecular weight of from about 10000 to about 19000. 5. The device according to claim 1, wherein said silicone polyether block copolymer has a molecular weight of from about 10000 to about 15000. 6. The device according to claim 1, wherein said silicone polyether block copolymer has a ratio of polyethylene oxide to polypropylene oxide of from about 2.0 to about 0.1. 7. The device according to claim 6, wherein said silicone polyether block copolymer has a ratio of polyethylene oxide to polypropylene oxide of from about 0.6 to 0.25. 8. The device according to claim 1, wherein said composition further comprises from about 0.1% to about 8% by weight of a water soluble polymer and preferably wherein the ratio of said water soluble polymer to said silicone block copolymer is from about 1:5 to about 5:1. 9. The device according to claim 8, wherein said water soluble polymer is selected from polyethylene oxide, polyvinyl pyrrolidone, polyacrylamide, polyhydroxymethacrylate, polyvinyl imidazoline, polyethylene glycol, polyvinyl alcohol, polyhydroxyethymethacrylate, guars, celluloses, modified celluloses and mixtures thereof. 10. The device according to claim 5, wherein said water soluble polymer is polyethylene oxide having an average molecular weight of at least about 300000. 11. The device according to claim 10, wherein said polyethylene oxide has an average molecular weight of from about 1 million to about 5 million. 12. The device according to claim 1, wherein said composition further comprising from about 0.1% to about 8%, by weight of the lubricating material of a copolymer of polyethylene oxide and polypropylene oxide. 13. The device according to claim 1 wherein said composition comprises from about 0.1% to about 5% of a thickening agent and at least about 30% by weight of water. 14. The device according to claim 1, wherein said device comprises a handle connected to a hair removal head, wherein said handle comprises a cavity for housing said composition disposed within said handle and an actuator adapted to displace said composition from said cavity to a fluid dispensing member. 15. The device according to claim 10, wherein said fluid dispensing member comprises an elongated contact region forming at least one dispensing orifice. 16. The device according to claim 11, wherein said elongate elastomeric contact region forms a one way valve, preferably selected from a flap valve, a slit valve, a duckbill valve and a combination thereof. 17. A personal care composition comprising from about 40% to about 95% by weight of water, about 1% to about 6% by weight of a volatile post foaming agent and from about 0.1% to about 60% by weight of silicone polyether block copolymer wherein said silicone polyether block copolymer comprises at comprises from about 1 to about 50%, by weight of polyethylene oxide, from about 20% to about 90% by weight of polypropylene oxide and from about 1 to about 20%, by weight of silicone.

A method for in vivo, ex vivo and in vitro regeneration of cartilage and collagen. In vivo, ex vivo and in vitro regeneration and de novo formation of articular cartilage and collagen by intermittently applied hydrostatic pressure. The application of external interval loading consisting of repeated periods of applied hydrostatic pressure followed and interrupted by periods of recovery. The application of the intermittent hydrostatic pressure at physiological levels 5-10 MPA for an interval of 4 hours followed by a recovery period up to about 20 hours, said pressure applied to the cartilage cells in vitro, explants of cartilage ex vivo and in vivo to cartilage that remains intact within to joint space of diarthrotic joints. The interval loading results in the selective inhibition of matrix degrading enzymes, pro-inflammatory cytokines and chemokines that attract inflammatory cells into the joint cavity and in selective decrease of gene expression of growth factors that are inhibitory to type II collagen expression.

1. A method of treating diseased, aged or injured osteoarthritic cartilage using pressure treated chondrocytes, said chondrocytes releasing a lowered level, when compared to non-treated osteoarthritic chondrocytes, of at least one protein selected from the group consisting of: (i) matrix metalloproteinase-2 (MMP-2); (ii) interleukin-6 (IL-6); and (iii) macrophage chemottractant protein-1 (MCP-1); wherein said regenerated levels of aggrecan in pressure treated osteoarthritic chondrocytes are increased to levels between 4 and 7%, wet weight, when compared to pathological levels between 0.1% and 1%, wet weight, of non-treated osteoarthritic chondrocytes; and wherein said regenerated levels of collagen type II in pressure treated osteoarthritic chondrocytes are increased to levels between 10% and 20%, wet weight, when compared to pathological levels between 1% and 10%, wet weight, of non-treated osteoarthritic chondrocytes. 2. The pressure treated osteoarthritic chondrocytes of claim 1 which are human osteoarthritic chondrocytes. 3. The pressure treated osteoarthritic chondrocytes of claim 2 in a culture medium. 4. The pressure treated osteoarthritic chondrocytes of claim 1 having a lowered level of MMP-2. 5. The pressure treated osteoarthritic chondrocytes of claim 1 having a lowered level of MMP-2, IL-6, and MCP-1. 6. The pressure treated osteoarthritic chondrocytes of claim 2 having a lowered level of MMP-2. 7. The pressure treated osteoarthritic chondrocytes of claim 2 having a lowered level of MMP-2, IL-6, and MCP-1. 8. The pressure treated osteoarthritic chondrocytes of claim 3 having a lowered level of MMP-2. 9. The pressure treated osteoarthritic chondrocytes of claim 3 having a lowered level of MMP-2, IL-6, and MCP-1. 10. The pressure treated osteoarthritic chondrocytes of claim 1 further releasing an increased level of FGF (fibroblast growth factor) when compared to osteoarthritic chondrocytes not treated with pressure. 11. A preparation of pressure treated osteoarthritic chondrocytes isolated from a diseased, aged or injured osteoarthritic cartilage, having increased production of: aggrecan from levels of between 0.1% and 1%, wet weight, of osteoarthritic chondrocytes not treated with pressure, to regenerated levels of aggrecan between 4% and 7%, wet weight; and type II collagen from levels of between 1% and 10%, wet weight, of osteoarthritic chondrocytes not treated with pressure, to regenerated levels of between 10 and 20%, wet weight. 12. The pressure treated osteoarthritic chondrocytes of claim 11 wherein said regeneration and pressure treatment is performed under intermittently applied hydrostatic pressure of between about 0.5 MPa and about 30 MPa, applied at a frequency of about 0.1 Hz to about 10 Hz, for a period of about 1 to about 8 hours, followed with a constant atmospheric pressure applied for a period of about 16 to 23 hours, wherein said period of hydrostatic pressure and said period of constant atmospheric pressure are repeated for about 4 to about 100 days. 13. The pressure treated osteoarthritic chondrocytes of claim 11 wherein, before pressure treatment, levels of between 0.1% and 1%, wet weight, of aggrecan and levels of between 1% and 10%, wet weight, of type II collagen are measured in injured, diseased or aged metabolically inactive osteoarthritic chondrocytes isolated from a diseased, aged or injured osteoarthritic cartilage before pressure treatment and wherein said levels of between 4% and 7%, wet weight, of aggrecan and levels of between 10% and 20%, wet weight, of type II collagen are regenerated levels measured in said regenerated and said pressure activated chondrocytes after the regeneration and pressure treatment. 14. The pressure treated osteoarthritic chondrocytes of claim 13 wherein said injured, degenerated or aged metabolically inactive osteoarthritic chondrocytes are submitted to said regeneration and pressure treatment for a number of repetitions and such a period of time that is needed for said levels of aggrecan or Type II collagen to reach said regenerated levels. 15. The pressure treated osteoarthritic chondrocytes of claim 12 wherein said intermittently applied hydrostatic pressure is between about 1 MPa and about 20 MPa and is applied at a frequency of about 1 Hz. 16. The pressure treated osteoarthritic chondrocytes of claim 15 wherein said intermittently applied hydrostatic pressure is between about 5 MPa and about 10 MPa, applied at a frequency of about 1 Hz. 17. The pressure treated osteoarthritic chondrocytes of claim 14 wherein said intermittently applied hydrostatic pressure is applied for a period of about 4 hours and is followed with a period of about 20 hours of constant atmospheric pressure and wherein said period of hydrostatic pressure and said period of constant atmospheric pressure are repeated for about 7 to about 30 days. 18. The pressure treated osteoarthritic chondrocytes of claim 11 wherein said chondrocytes are human osteoarthritic chondrocytes. 19. The pressure treated osteoarthritic chondrocytes of claim 18 wherein said chondrocytes are autologous.

A method for in vivo, ex vivo and in vitro regeneration of cartilage and collagen. In vivo, ex vivo and in vitro regeneration and de novo formation of articular cartilage and collagen by intermittently applied hydrostatic pressure. The application of external interval loading consisting of repeated periods of applied hydrostatic pressure followed and interrupted by periods of recovery. The application of the intermittent hydrostatic pressure at physiological levels 5-10 MPA for an interval of 4 hours followed by a recovery period up to about 20 hours, said pressure applied to the cartilage cells in vitro, explants of cartilage ex vivo and in vivo to cartilage that remains intact within to joint space of diarthrotic joints. The interval loading results in the selective inhibition of matrix degrading enzymes, pro-inflammatory cytokines and chemokines that attract inflammatory cells into the joint cavity and in selective decrease of gene expression of growth factors that are inhibitory to type II collagen expression.1. A method of treating diseased, aged or injured osteoarthritic cartilage using pressure treated chondrocytes, said chondrocytes releasing a lowered level, when compared to non-treated osteoarthritic chondrocytes, of at least one protein selected from the group consisting of: (i) matrix metalloproteinase-2 (MMP-2); (ii) interleukin-6 (IL-6); and (iii) macrophage chemottractant protein-1 (MCP-1); wherein said regenerated levels of aggrecan in pressure treated osteoarthritic chondrocytes are increased to levels between 4 and 7%, wet weight, when compared to pathological levels between 0.1% and 1%, wet weight, of non-treated osteoarthritic chondrocytes; and wherein said regenerated levels of collagen type II in pressure treated osteoarthritic chondrocytes are increased to levels between 10% and 20%, wet weight, when compared to pathological levels between 1% and 10%, wet weight, of non-treated osteoarthritic chondrocytes. 2. The pressure treated osteoarthritic chondrocytes of claim 1 which are human osteoarthritic chondrocytes. 3. The pressure treated osteoarthritic chondrocytes of claim 2 in a culture medium. 4. The pressure treated osteoarthritic chondrocytes of claim 1 having a lowered level of MMP-2. 5. The pressure treated osteoarthritic chondrocytes of claim 1 having a lowered level of MMP-2, IL-6, and MCP-1. 6. The pressure treated osteoarthritic chondrocytes of claim 2 having a lowered level of MMP-2. 7. The pressure treated osteoarthritic chondrocytes of claim 2 having a lowered level of MMP-2, IL-6, and MCP-1. 8. The pressure treated osteoarthritic chondrocytes of claim 3 having a lowered level of MMP-2. 9. The pressure treated osteoarthritic chondrocytes of claim 3 having a lowered level of MMP-2, IL-6, and MCP-1. 10. The pressure treated osteoarthritic chondrocytes of claim 1 further releasing an increased level of FGF (fibroblast growth factor) when compared to osteoarthritic chondrocytes not treated with pressure. 11. A preparation of pressure treated osteoarthritic chondrocytes isolated from a diseased, aged or injured osteoarthritic cartilage, having increased production of: aggrecan from levels of between 0.1% and 1%, wet weight, of osteoarthritic chondrocytes not treated with pressure, to regenerated levels of aggrecan between 4% and 7%, wet weight; and type II collagen from levels of between 1% and 10%, wet weight, of osteoarthritic chondrocytes not treated with pressure, to regenerated levels of between 10 and 20%, wet weight. 12. The pressure treated osteoarthritic chondrocytes of claim 11 wherein said regeneration and pressure treatment is performed under intermittently applied hydrostatic pressure of between about 0.5 MPa and about 30 MPa, applied at a frequency of about 0.1 Hz to about 10 Hz, for a period of about 1 to about 8 hours, followed with a constant atmospheric pressure applied for a period of about 16 to 23 hours, wherein said period of hydrostatic pressure and said period of constant atmospheric pressure are repeated for about 4 to about 100 days. 13. The pressure treated osteoarthritic chondrocytes of claim 11 wherein, before pressure treatment, levels of between 0.1% and 1%, wet weight, of aggrecan and levels of between 1% and 10%, wet weight, of type II collagen are measured in injured, diseased or aged metabolically inactive osteoarthritic chondrocytes isolated from a diseased, aged or injured osteoarthritic cartilage before pressure treatment and wherein said levels of between 4% and 7%, wet weight, of aggrecan and levels of between 10% and 20%, wet weight, of type II collagen are regenerated levels measured in said regenerated and said pressure activated chondrocytes after the regeneration and pressure treatment. 14. The pressure treated osteoarthritic chondrocytes of claim 13 wherein said injured, degenerated or aged metabolically inactive osteoarthritic chondrocytes are submitted to said regeneration and pressure treatment for a number of repetitions and such a period of time that is needed for said levels of aggrecan or Type II collagen to reach said regenerated levels. 15. The pressure treated osteoarthritic chondrocytes of claim 12 wherein said intermittently applied hydrostatic pressure is between about 1 MPa and about 20 MPa and is applied at a frequency of about 1 Hz. 16. The pressure treated osteoarthritic chondrocytes of claim 15 wherein said intermittently applied hydrostatic pressure is between about 5 MPa and about 10 MPa, applied at a frequency of about 1 Hz. 17. The pressure treated osteoarthritic chondrocytes of claim 14 wherein said intermittently applied hydrostatic pressure is applied for a period of about 4 hours and is followed with a period of about 20 hours of constant atmospheric pressure and wherein said period of hydrostatic pressure and said period of constant atmospheric pressure are repeated for about 7 to about 30 days. 18. The pressure treated osteoarthritic chondrocytes of claim 11 wherein said chondrocytes are human osteoarthritic chondrocytes. 19. The pressure treated osteoarthritic chondrocytes of claim 18 wherein said chondrocytes are autologous.

Methods and compositions are provided for the treatment and diagnosis of diseases related to hyperglycemic conditions, including diabetes, insulin resistance, and the like. Genetic polymorphisms are shown to be associated with disease susceptibility, and their detection is used in the diagnosis of a predisposition to these conditions. The corresponding proteins are useful as targets for therapeutic intervention.

1. A method of treating or preventing the onset of type 2 diabetes in an individual, the method comprising: administering to said individual an inhibitor of CD44. 2. The method of claim 1, wherein the CD44 is expressed on adipose tissue macrophages or adipocytes. 3. The method of claim 1, wherein said inhibitor inhibits CD44 binding to one or more cognate ligands. 4. The method of claim 3, wherein the ligand is osteopontin. 5. The method of claim 3, wherein the ligand is hyaluronic acid. 6. The method of claim 3, wherein the inhibitor is an antibody or fragment thereof. 7. The method of claim 3, wherein the inhibitor is an analog of a CD44 ligand. 8. The method of claim 1, wherein the inhibitor reduces expression of CD44. 9. The method of claim 8, wherein the inhibitor is an antisense oligonucleotide. 10. The method of claim 8, wherein the inhibitor is an RNAi nucleic acid. 11. The method of claim 1 wherein the inhibitor reduces CD44 signaling activity. 12. A method of diagnosing a susceptibility to type 2 diabetes mellitus (T2D) in an individual, comprising determining the presence or absence of a polymorphic allele in a biological sample from said individual, wherein the at least polymorphic allele genetically linked to one or more of CD44, SPP1 and HDC loci, and wherein presence of the allele is indicative of a susceptibility to type 2 diabetes mellitus. 13. The method of claim 12, wherein the polymorphic allele comprises a single nucleotide polymorphism. 14. The method of claim 13, wherein the single nucleotide polymorphism is within an intron or exon of the CD44, SPP1 or HDC loci. 15. The method of claim 13, wherein the single nucleotide polymorphism is within a regulatory region associated with the CD44, SPP1 or HDC loci. 16. The method of claim 14, wherein the SNP is selected from the polymorphisms set forth in SEQ ID NO:1-12. 17. The method of claim 12, further comprising treating said individual with the method set forth in any one of claims 1-11. 18. The method of claim 12, wherein the increased susceptibility is characterized by a relative risk (RR) or odds ratio (OR) of at least 1.2. 19. The method of claim 12, wherein said biological sample is a genetic sample. 20. The method of claim 19, wherein the genetic sample comprises mRNA or a cDNA derived therefrom. 21. A method of diagnosing insulin resistance in an individual, comprising quantitating serum levels of CD44 in said individual. 22. A kit for assessing susceptibility to type 2 diabetes mellitus in an individual, the kit comprising reagents for selectively determining the presence or absence of at least one polymorphic allele in a biological sample from said individual, wherein the polymorphic allele is selected from the polymorphisms set forth in SEQ ID NO:1-12, and wherein the presence of the at least one SNP indicates susceptibility to type 2 diabetes. 23. The kit according to claim 22, comprising probes that specifically bind to at least one sequence set forth in SEQ ID NO:1-12. 24. The kit according to claim 22, further comprising reagents for selectively determining the presence or absence of additional polymorphic alleles associated with a predisposition to type 2 diabetes. 25. The kit according to claim 23, comprising an array of probes that selectively bind to polymorphic alleles associated with a susceptibility to type 2 diabetes.

Methods and compositions are provided for the treatment and diagnosis of diseases related to hyperglycemic conditions, including diabetes, insulin resistance, and the like. Genetic polymorphisms are shown to be associated with disease susceptibility, and their detection is used in the diagnosis of a predisposition to these conditions. The corresponding proteins are useful as targets for therapeutic intervention.1. A method of treating or preventing the onset of type 2 diabetes in an individual, the method comprising: administering to said individual an inhibitor of CD44. 2. The method of claim 1, wherein the CD44 is expressed on adipose tissue macrophages or adipocytes. 3. The method of claim 1, wherein said inhibitor inhibits CD44 binding to one or more cognate ligands. 4. The method of claim 3, wherein the ligand is osteopontin. 5. The method of claim 3, wherein the ligand is hyaluronic acid. 6. The method of claim 3, wherein the inhibitor is an antibody or fragment thereof. 7. The method of claim 3, wherein the inhibitor is an analog of a CD44 ligand. 8. The method of claim 1, wherein the inhibitor reduces expression of CD44. 9. The method of claim 8, wherein the inhibitor is an antisense oligonucleotide. 10. The method of claim 8, wherein the inhibitor is an RNAi nucleic acid. 11. The method of claim 1 wherein the inhibitor reduces CD44 signaling activity. 12. A method of diagnosing a susceptibility to type 2 diabetes mellitus (T2D) in an individual, comprising determining the presence or absence of a polymorphic allele in a biological sample from said individual, wherein the at least polymorphic allele genetically linked to one or more of CD44, SPP1 and HDC loci, and wherein presence of the allele is indicative of a susceptibility to type 2 diabetes mellitus. 13. The method of claim 12, wherein the polymorphic allele comprises a single nucleotide polymorphism. 14. The method of claim 13, wherein the single nucleotide polymorphism is within an intron or exon of the CD44, SPP1 or HDC loci. 15. The method of claim 13, wherein the single nucleotide polymorphism is within a regulatory region associated with the CD44, SPP1 or HDC loci. 16. The method of claim 14, wherein the SNP is selected from the polymorphisms set forth in SEQ ID NO:1-12. 17. The method of claim 12, further comprising treating said individual with the method set forth in any one of claims 1-11. 18. The method of claim 12, wherein the increased susceptibility is characterized by a relative risk (RR) or odds ratio (OR) of at least 1.2. 19. The method of claim 12, wherein said biological sample is a genetic sample. 20. The method of claim 19, wherein the genetic sample comprises mRNA or a cDNA derived therefrom. 21. A method of diagnosing insulin resistance in an individual, comprising quantitating serum levels of CD44 in said individual. 22. A kit for assessing susceptibility to type 2 diabetes mellitus in an individual, the kit comprising reagents for selectively determining the presence or absence of at least one polymorphic allele in a biological sample from said individual, wherein the polymorphic allele is selected from the polymorphisms set forth in SEQ ID NO:1-12, and wherein the presence of the at least one SNP indicates susceptibility to type 2 diabetes. 23. The kit according to claim 22, comprising probes that specifically bind to at least one sequence set forth in SEQ ID NO:1-12. 24. The kit according to claim 22, further comprising reagents for selectively determining the presence or absence of additional polymorphic alleles associated with a predisposition to type 2 diabetes. 25. The kit according to claim 23, comprising an array of probes that selectively bind to polymorphic alleles associated with a susceptibility to type 2 diabetes.

The present invention for the first time discloses a novel small molecular weight enamel matrix polypeptide which is at least 80%, such as 90% identical to the amino acid sequence as shown in SEQ ID NO: 1 (MPLPPHPGHP GYINFSYEVL TPLKWYQNMI RHPYTSYGYE PMGGWLHHQI IPWSQQTPQ SHA) (TRAP63), a homologue, analogue, or a pharmaceutically acceptable salt thereof. The present invention further discloses a pharmaceutical composition consisting of an enamel matrix polypeptide which is at least 80%, such as 90% identical to the amino acid sequence as shown in SEQ ID NO: 1, a homologue, analogue, or a pharmaceutically acceptable salt thereof, and a suitable pharmaceutical carrier, which further can consist of one or more enamel matrix polypeptides selected from the group of enamel matrix polypeptides which correspond to: a. SEQ ID NO: 2, b. SEQ ID NO: 3 and c. SEQ ID NO: 4.

1. An enamel matrix polypeptide which is at least 80%, such ac 90% identical to the amino acid sequence as shown in SEQ ID NO: 1 (TRAP63), a homologue, analogue, or a pharmaceutically acceptable salt thereof, and which stimulates the tissue formation phase of a wound healing process. 2. A pharmaceutical composition comprising an enamel matrix polypeptide according to claim 1, and a suitable pharmaceutical carrier 3. A pharmaceutical composition according to claim 2, further comprising one or more enamel matrix polypeptides selected from the group of enamel matrix polypeptides which correspond to: a. SEQ ID NO: 2 (TRAP43), b. SEQ ID NO: 3 (TRAP45), and c. SEQ ID NO: 4 (LRAP56), which stimulates the tissue formation phase of a wound healing process 4. A pharmaceutical composition comprising an acid-extraction of enamel proteins and/or polypeptides derived from developing mammalian tooth buds, which is at least 2× enriched in an enamel matrix polypeptide, which is at least 80%, such as 90% identical to the amino acid sequence as shown in SEQ ID NO: 1 (TRAP63), a homologue, analogue, or a pharmaceutically acceptable salt thereof, which stimulates the tissue formation phase of a wound healing process. 5. A pharmaceutical composition comprising an enamel matrix polypeptide which is at least 80%, such as 90% identical to the amino acid sequence as shown in SEQ 10 NO: 1 (TRAP63), a homologue, analogue, or a pharmaceutically acceptable salt thereof, which stimulates the tissue formation phase of a wound healing process, which composition consists of all isolated enamel polypeptides and/or proteins with a molecular weight (M.W.)<7 kDa, derivable from a defined amount of developing mammal tooth buds, and a suitable pharmaceutical carrier. 6. A process for producing an enamel matrix polypeptide which is at least 80% identical to the amino acid sequence as shown in SEQ 10 NO: 1 (TRAP63), a homologue, analogue, or a pharmaceutically acceptable salt thereof, which stimulates the tissue formation phase of wound healing process, comprising: a. Isolating the enamel proteins present in a defined amount of developing animal tooth buds, and b. Removing any protein with a molecular weight (M.W.) >8 kDa from said isolate. 7. A process according to claim 6, wherein the enamel polypeptides are isolated from human, porcine, bovine, rat, mouse and/or sheep developing tooth buds. 8. A pharmaceutical composition comprising proteins with a molecular weight (M.W.) >7 kDa, wherein said composition is produced according to the process of claim 6. 9. A pharmaceutical composition according to claim 2, comprising at least one of said enamel polypeptides produced by synthesis in vitro. 10. A pharmaceutical composition according to claim 2, comprising at least one of said enamel polypeptides that is a purified recombinant polypeptide fragment. 11. A pharmaceutical composition according to claim 2, wherein at least one of said enamel polypeptides is synthetically and/or chemically altered. 12. A pharmaceutical composition according to claim 2, comprising at least one of said enamel polypeptides produces by synthesis in vivo. 13. A pharmaceutical composition according to claim 9, wherein the pharmaceutically acceptable carrier is selected from the group consisting of PGA and PEG. 14. A pharmaceutical composition according to claim 2, further comprising EMO. 15. (canceled) 16. A method of accelerating onset of wound healing comprising administering an enamel matrix polypeptide according to claim 1 to a subject suffering from a wound, in an amount sufficient to accelerate onset of wound healing. 17. A method of accelerating wound healing, comprising administering an enamel matrix polypeptide according to claim 1 to a subject suffering from a wound in an amount sufficient to accelerate wound healing. 18. A method of treating an inflammatory condition, comprising administering a therapeutically effective amount of an enamel matrix polypeptide according to claim 1 to a subject suffering from an inflammatory condition. 19. A method of promoting periodontal soft tissue generation, comprising administering, to a subject in need of such treatment, an enamel matrix polypeptide according to any claim 1 in an amount sufficient to promote periodontal soft tissue regeneration 20. A method of stimulating angiogenesis, comprising administering an enamel matrix polypeptide to a subject in an amount sufficient to generate angiogenesis. 21. (canceled) 22. (canceled)

The present invention for the first time discloses a novel small molecular weight enamel matrix polypeptide which is at least 80%, such as 90% identical to the amino acid sequence as shown in SEQ ID NO: 1 (MPLPPHPGHP GYINFSYEVL TPLKWYQNMI RHPYTSYGYE PMGGWLHHQI IPWSQQTPQ SHA) (TRAP63), a homologue, analogue, or a pharmaceutically acceptable salt thereof. The present invention further discloses a pharmaceutical composition consisting of an enamel matrix polypeptide which is at least 80%, such as 90% identical to the amino acid sequence as shown in SEQ ID NO: 1, a homologue, analogue, or a pharmaceutically acceptable salt thereof, and a suitable pharmaceutical carrier, which further can consist of one or more enamel matrix polypeptides selected from the group of enamel matrix polypeptides which correspond to: a. SEQ ID NO: 2, b. SEQ ID NO: 3 and c. SEQ ID NO: 4.1. An enamel matrix polypeptide which is at least 80%, such ac 90% identical to the amino acid sequence as shown in SEQ ID NO: 1 (TRAP63), a homologue, analogue, or a pharmaceutically acceptable salt thereof, and which stimulates the tissue formation phase of a wound healing process. 2. A pharmaceutical composition comprising an enamel matrix polypeptide according to claim 1, and a suitable pharmaceutical carrier 3. A pharmaceutical composition according to claim 2, further comprising one or more enamel matrix polypeptides selected from the group of enamel matrix polypeptides which correspond to: a. SEQ ID NO: 2 (TRAP43), b. SEQ ID NO: 3 (TRAP45), and c. SEQ ID NO: 4 (LRAP56), which stimulates the tissue formation phase of a wound healing process 4. A pharmaceutical composition comprising an acid-extraction of enamel proteins and/or polypeptides derived from developing mammalian tooth buds, which is at least 2× enriched in an enamel matrix polypeptide, which is at least 80%, such as 90% identical to the amino acid sequence as shown in SEQ ID NO: 1 (TRAP63), a homologue, analogue, or a pharmaceutically acceptable salt thereof, which stimulates the tissue formation phase of a wound healing process. 5. A pharmaceutical composition comprising an enamel matrix polypeptide which is at least 80%, such as 90% identical to the amino acid sequence as shown in SEQ 10 NO: 1 (TRAP63), a homologue, analogue, or a pharmaceutically acceptable salt thereof, which stimulates the tissue formation phase of a wound healing process, which composition consists of all isolated enamel polypeptides and/or proteins with a molecular weight (M.W.)<7 kDa, derivable from a defined amount of developing mammal tooth buds, and a suitable pharmaceutical carrier. 6. A process for producing an enamel matrix polypeptide which is at least 80% identical to the amino acid sequence as shown in SEQ 10 NO: 1 (TRAP63), a homologue, analogue, or a pharmaceutically acceptable salt thereof, which stimulates the tissue formation phase of wound healing process, comprising: a. Isolating the enamel proteins present in a defined amount of developing animal tooth buds, and b. Removing any protein with a molecular weight (M.W.) >8 kDa from said isolate. 7. A process according to claim 6, wherein the enamel polypeptides are isolated from human, porcine, bovine, rat, mouse and/or sheep developing tooth buds. 8. A pharmaceutical composition comprising proteins with a molecular weight (M.W.) >7 kDa, wherein said composition is produced according to the process of claim 6. 9. A pharmaceutical composition according to claim 2, comprising at least one of said enamel polypeptides produced by synthesis in vitro. 10. A pharmaceutical composition according to claim 2, comprising at least one of said enamel polypeptides that is a purified recombinant polypeptide fragment. 11. A pharmaceutical composition according to claim 2, wherein at least one of said enamel polypeptides is synthetically and/or chemically altered. 12. A pharmaceutical composition according to claim 2, comprising at least one of said enamel polypeptides produces by synthesis in vivo. 13. A pharmaceutical composition according to claim 9, wherein the pharmaceutically acceptable carrier is selected from the group consisting of PGA and PEG. 14. A pharmaceutical composition according to claim 2, further comprising EMO. 15. (canceled) 16. A method of accelerating onset of wound healing comprising administering an enamel matrix polypeptide according to claim 1 to a subject suffering from a wound, in an amount sufficient to accelerate onset of wound healing. 17. A method of accelerating wound healing, comprising administering an enamel matrix polypeptide according to claim 1 to a subject suffering from a wound in an amount sufficient to accelerate wound healing. 18. A method of treating an inflammatory condition, comprising administering a therapeutically effective amount of an enamel matrix polypeptide according to claim 1 to a subject suffering from an inflammatory condition. 19. A method of promoting periodontal soft tissue generation, comprising administering, to a subject in need of such treatment, an enamel matrix polypeptide according to any claim 1 in an amount sufficient to promote periodontal soft tissue regeneration 20. A method of stimulating angiogenesis, comprising administering an enamel matrix polypeptide to a subject in an amount sufficient to generate angiogenesis. 21. (canceled) 22. (canceled)

The present invention relates to methods for evaluating and/or predicting the outcome of a clinical condition, such as cancer, metastasis, AIDS, autism, Alzheimer's, and/or Parkinson's disorder. The methods can also be used to monitor and track changes in a patient's DNA and/or RNA during and following a clinical treatment regime. The methods may also be used to evaluate protein and/or metabolite levels that correlate with such clinical conditions. The methods are also of use to ascertain the probability outcome for a patient's particular prognosis.

1. A computer-based genomic sequence analysis system comprising: a memory storing at least two genomic sequence datasets including: a tumor sequence dataset comprising genomic sequence strings of a tumor tissue sample of a patient; and a matched normal dataset comprising genomic sequence strings of a normal tissue sample of the same patient; and a sequence analysis engine coupled with the memory and configured to: simultaneously and synchronously read a tumor sequence string from the tumor sequence dataset and a matched normal sequence string from the matched normal sequence dataset; wherein the tumor sequence string is incrementally synchronized with the matched normal sequence string based on a given genomic position; identify a genomic alteration associated with the given genomic position according to a probability derived from reads of the tumor sequence string and of the matched normal sequence string; and store the genomic alteration in a device memory. 2. The system of claim 1, wherein the genomic alteration comprises a genomic variant. 3. The system of claim 2, wherein the genomic variant comprises a somatic variant. 4. The system of claim 2, wherein the genomic variant comprises a germline variant. 5. The system of claim 1, wherein the genomic alteration comprises a single nucleotide polymorphism. 6. The system of claim 1, wherein the genomic alteration comprises an alteration selected from the group consisting of: an allele-specific copy number, a loss of heterozygosity, a structural rearrangement, a chromosomal fusion, and a breakpoint. 7. The system of claim 1, wherein the tumor sequence dataset comprises a tumor BAM file. 8. The system of claim 1, wherein the matched normal dataset comprises a normal BAM file. 9. The system of claim 1, wherein the at least two dataset comprises more than two datasets. 10. The system of claim 9, wherein the more than two datasets comprises related sequencing datasets. 11. The system of claim 9, wherein the more than two datasets include at least one relapse dataset. 12. The system of claim 1, wherein sequence analysis engine is further configured to simultaneously read and synchronize a third dataset with the tumor dataset and matched normal dataset. 13. The system of claim 1, further comprising a genome browser configured to display the genomic alteration in relation to the tumor sequence dataset and the matched normal sequence dataset. 14. The system of claim 1, wherein the memory is configured to store the at least two sequencing data sets as files within a file system. 15. The system of claim 1 wherein identification of a genomic alteration uses pile-ups of the genomic reads that overlap every common genomic location between the tumor sequence strings and the normal sequence strings. 16. The system of claim 1 wherein the given genomic positions for the tumor sequence strings and the normal sequence strings is based on a reference genome. 17. The system of claim 1 wherein the probability is determined by maximizing joint likelihood of both tumor and germline genotypes. 18. The system of claim 17 wherein maximizing the joint likelihood includes deriving a probability from patient data as defined by P(D g ,D t ,G g ,G t |α,r)=P(D g |G g)P(G g |r)P(D t |G g ,G t,α)P(G t |G g)  (1) P(D 1 g,D 1 t,G 1 g,G 1 t┤|α,r)=P(D 1 g┤|G 1 g)P(G 1 g┤|r)P(D 1 t┤|G 1 g,G 1 t,α)P(G 1 t┤|G 1 g)  (2) where r is an observed reference allele, α is a fraction of normal contamination, where tumor and germline genotypes are defined by Gt=(t1, t2) and Gg=(g1,g2), where t1, t2, g1, g2ε{A, T, C, G}, and where tumor and germline sequence data are defined as a set of reads Dt={dt 1, dt 2 . . . , dt n} and Dg={dg 1,dg 2 . . . , dg n}, respectively, with the observed bases dt i, dg iε{A, T, C, G}. 19. The system of claim 18 wherein a probability of germline alleles given a germline genotype is modeled as a multinomial over four nucleotides: P  ( D g | G g ) = n ! n A !  n T !  n G !  n C !  ∏ i n   P  ( d g i | G g ) , where n is the total number of germline reads at the genomic position and nA, nG, nC, nt are reads supporting each observed allele, and a probability of tumor alleles given a tumor genotype is modeled as a multinomial over four nucleotides: P  ( D t | D t , G g , α ) = n ! n A !  n T !  n G !  n C !  ∏ i n   P  ( d t i | G t , G g , α ) , where n is the total number of germline reads at the genomic position and nA, nG, nC, nt are patient data reads supporting each observed allele.

The present invention relates to methods for evaluating and/or predicting the outcome of a clinical condition, such as cancer, metastasis, AIDS, autism, Alzheimer's, and/or Parkinson's disorder. The methods can also be used to monitor and track changes in a patient's DNA and/or RNA during and following a clinical treatment regime. The methods may also be used to evaluate protein and/or metabolite levels that correlate with such clinical conditions. The methods are also of use to ascertain the probability outcome for a patient's particular prognosis.1. A computer-based genomic sequence analysis system comprising: a memory storing at least two genomic sequence datasets including: a tumor sequence dataset comprising genomic sequence strings of a tumor tissue sample of a patient; and a matched normal dataset comprising genomic sequence strings of a normal tissue sample of the same patient; and a sequence analysis engine coupled with the memory and configured to: simultaneously and synchronously read a tumor sequence string from the tumor sequence dataset and a matched normal sequence string from the matched normal sequence dataset; wherein the tumor sequence string is incrementally synchronized with the matched normal sequence string based on a given genomic position; identify a genomic alteration associated with the given genomic position according to a probability derived from reads of the tumor sequence string and of the matched normal sequence string; and store the genomic alteration in a device memory. 2. The system of claim 1, wherein the genomic alteration comprises a genomic variant. 3. The system of claim 2, wherein the genomic variant comprises a somatic variant. 4. The system of claim 2, wherein the genomic variant comprises a germline variant. 5. The system of claim 1, wherein the genomic alteration comprises a single nucleotide polymorphism. 6. The system of claim 1, wherein the genomic alteration comprises an alteration selected from the group consisting of: an allele-specific copy number, a loss of heterozygosity, a structural rearrangement, a chromosomal fusion, and a breakpoint. 7. The system of claim 1, wherein the tumor sequence dataset comprises a tumor BAM file. 8. The system of claim 1, wherein the matched normal dataset comprises a normal BAM file. 9. The system of claim 1, wherein the at least two dataset comprises more than two datasets. 10. The system of claim 9, wherein the more than two datasets comprises related sequencing datasets. 11. The system of claim 9, wherein the more than two datasets include at least one relapse dataset. 12. The system of claim 1, wherein sequence analysis engine is further configured to simultaneously read and synchronize a third dataset with the tumor dataset and matched normal dataset. 13. The system of claim 1, further comprising a genome browser configured to display the genomic alteration in relation to the tumor sequence dataset and the matched normal sequence dataset. 14. The system of claim 1, wherein the memory is configured to store the at least two sequencing data sets as files within a file system. 15. The system of claim 1 wherein identification of a genomic alteration uses pile-ups of the genomic reads that overlap every common genomic location between the tumor sequence strings and the normal sequence strings. 16. The system of claim 1 wherein the given genomic positions for the tumor sequence strings and the normal sequence strings is based on a reference genome. 17. The system of claim 1 wherein the probability is determined by maximizing joint likelihood of both tumor and germline genotypes. 18. The system of claim 17 wherein maximizing the joint likelihood includes deriving a probability from patient data as defined by P(D g ,D t ,G g ,G t |α,r)=P(D g |G g)P(G g |r)P(D t |G g ,G t,α)P(G t |G g)  (1) P(D 1 g,D 1 t,G 1 g,G 1 t┤|α,r)=P(D 1 g┤|G 1 g)P(G 1 g┤|r)P(D 1 t┤|G 1 g,G 1 t,α)P(G 1 t┤|G 1 g)  (2) where r is an observed reference allele, α is a fraction of normal contamination, where tumor and germline genotypes are defined by Gt=(t1, t2) and Gg=(g1,g2), where t1, t2, g1, g2ε{A, T, C, G}, and where tumor and germline sequence data are defined as a set of reads Dt={dt 1, dt 2 . . . , dt n} and Dg={dg 1,dg 2 . . . , dg n}, respectively, with the observed bases dt i, dg iε{A, T, C, G}. 19. The system of claim 18 wherein a probability of germline alleles given a germline genotype is modeled as a multinomial over four nucleotides: P  ( D g | G g ) = n ! n A !  n T !  n G !  n C !  ∏ i n   P  ( d g i | G g ) , where n is the total number of germline reads at the genomic position and nA, nG, nC, nt are reads supporting each observed allele, and a probability of tumor alleles given a tumor genotype is modeled as a multinomial over four nucleotides: P  ( D t | D t , G g , α ) = n ! n A !  n T !  n G !  n C !  ∏ i n   P  ( d t i | G t , G g , α ) , where n is the total number of germline reads at the genomic position and nA, nG, nC, nt are patient data reads supporting each observed allele.

The present invention relates to a microorganism having a reduced fatty acid degradation capacity and expressing a recombinant alkane oxidase, a method for oxidizing an alkyl, comprising a contacting the alkyl with an aqueous solution comprising the inventive cell.

1. A microorganism having a reduced fatty acid degradation capacity and expressing a recombinant alkane oxidase. 2. The microorganism according to claim 1, wherein the expressed recombinant alkane oxidase is selected from the group consisting of a rubredoxin-dependent alkane oxidase, a cytochrome P450 enzyme, a xylene monooxygenase, a methane monooxygenase, and variants thereof. 3. The microorganism according to claim 1, wherein the fatty acid degradation capacity is reduced due to deletion of a gene encoding an enzyme selected from the group consisting of a fatty acid importer, a fatty acid-CoA ligase, an acyl-CoA dehydrogenase, a 2,4-dienoyl-CoA reductase, an enoyl-CoA hydratase and a 3-ketoacyl-CoA thiolase. 4. The microorganism according to claim 1, wherein the microorganism is a prokaryotic or a lower eukaryotic cell. 5. The microorganism according to claim 1, wherein the microorganism expresses a recombinant alcohol dehydrogenase. 6. The microorganism according to claim 1, wherein the microorganism expresses a recombinant transaminase. 7. The microorganism according to claim 6, wherein the microorganism expresses a recombinant amino acid dehydrogenase. 8. A method for oxidizing an alkyl, comprising a) contacting the alkyl with an aqueous solution comprising the microorganism according to claim 1. 9. The method according to claim 8, further comprising b) contacting the aqueous solution from a) with a water-immiscible organic solvent. 10. The method according to claim 9, wherein b) is carried out following completion of the alkyl oxidation. 11. (canceled) 12. The method according to claim 8, wherein the alkyl is a compound represented by the formula H—(CH2)x—R, wherein x is 1 to 30, and R is any chemical group. 13. The method according to claim 8, wherein the alkyl is a linear alkane. 14. The method according to claim 9, wherein the water-immiscible organic solvent is a water-immiscible fatty acid or fatty acid ester. 15. The microorganism according to claim 1, wherein the microorganism is a bacterial cell. 16. The microorganism according to claim 1, wherein the microorganism is E. coli. 17. The microorganism according to claim 7, wherein the recombinant amino acid dehydrogenase is an alanine dehydrogenase.

The present invention relates to a microorganism having a reduced fatty acid degradation capacity and expressing a recombinant alkane oxidase, a method for oxidizing an alkyl, comprising a contacting the alkyl with an aqueous solution comprising the inventive cell.1. A microorganism having a reduced fatty acid degradation capacity and expressing a recombinant alkane oxidase. 2. The microorganism according to claim 1, wherein the expressed recombinant alkane oxidase is selected from the group consisting of a rubredoxin-dependent alkane oxidase, a cytochrome P450 enzyme, a xylene monooxygenase, a methane monooxygenase, and variants thereof. 3. The microorganism according to claim 1, wherein the fatty acid degradation capacity is reduced due to deletion of a gene encoding an enzyme selected from the group consisting of a fatty acid importer, a fatty acid-CoA ligase, an acyl-CoA dehydrogenase, a 2,4-dienoyl-CoA reductase, an enoyl-CoA hydratase and a 3-ketoacyl-CoA thiolase. 4. The microorganism according to claim 1, wherein the microorganism is a prokaryotic or a lower eukaryotic cell. 5. The microorganism according to claim 1, wherein the microorganism expresses a recombinant alcohol dehydrogenase. 6. The microorganism according to claim 1, wherein the microorganism expresses a recombinant transaminase. 7. The microorganism according to claim 6, wherein the microorganism expresses a recombinant amino acid dehydrogenase. 8. A method for oxidizing an alkyl, comprising a) contacting the alkyl with an aqueous solution comprising the microorganism according to claim 1. 9. The method according to claim 8, further comprising b) contacting the aqueous solution from a) with a water-immiscible organic solvent. 10. The method according to claim 9, wherein b) is carried out following completion of the alkyl oxidation. 11. (canceled) 12. The method according to claim 8, wherein the alkyl is a compound represented by the formula H—(CH2)x—R, wherein x is 1 to 30, and R is any chemical group. 13. The method according to claim 8, wherein the alkyl is a linear alkane. 14. The method according to claim 9, wherein the water-immiscible organic solvent is a water-immiscible fatty acid or fatty acid ester. 15. The microorganism according to claim 1, wherein the microorganism is a bacterial cell. 16. The microorganism according to claim 1, wherein the microorganism is E. coli. 17. The microorganism according to claim 7, wherein the recombinant amino acid dehydrogenase is an alanine dehydrogenase.

Compositions containing one or more metal phosphites and prohexadione calcium are suitable for providing micronutrients for plant health and growth regulation when applied to agricultural crops.

1. A method of treating agricultural crops, comprising: applying a composition to a crop, wherein the composition comprises prohexadione calcium and one or more metal phosphites in aqueous solution; wherein the one or more metal phosphites are selected from the group consisting of zinc phosphite, manganese phosphite, magnesium phosphite, calcium phosphite, iron phosphite and copper phosphite. 2. The method of claim 1, wherein applying the composition comprises applying the composition at a rate to provide an amount of prohexadione calcium that is efficacious for growth regulation of the crop. 3. The method of claim 1, wherein applying the composition comprises applying an aqueous solution comprising 0.02-6.0 lbs of one or more of the metal phosphites, measured on a metal basis, for every 1.0 lb of prohexadione calcium. 4. The method of claim 1, wherein applying the composition comprises applying an aqueous solution comprising 1.0-4.0 lbs of calcium as calcium phosphite for every 1.0 lb of prohexadione calcium. 5. The method of claim 1, wherein applying the composition comprises applying the composition to provide 0.2-3.0 lbs/acre of prohexadione calcium and 0.01-1.5 lbs/acre of one or more of the metal phosphites, measured on a metal basis. 6. The method of claim 1, wherein applying the composition comprises applying the composition using a broadcast application method. 7. The method of claim 6, wherein the broadcast method of application is selected from the group consisting of boom spray and air blaster. 8. The method of claim 1, wherein applying the composition comprises applying the composition comprising prohexadione calcium, one or more metal phosphites and one or more additional components selected from the group consisting of dyes, stabilizers, buffers, conditioners, surfactants, preservatives, organic materials, fertilizers other than metal phosphites, plant growth regulators other than prohexadione calcium, herbicides, fungicides and insecticides, in aqueous solution. 9. The method of claim 1, wherein applying the composition comprises applying the composition to apple trees. 10. A composition for treatment of agricultural crops, comprising: prohexadione calcium; and one or more metal phosphites; wherein the one or more metal phosphites are selected from the group consisting of zinc phosphite, manganese phosphite, magnesium phosphite, calcium phosphite, iron phosphite and copper phosphite. 11. The composition of claim 10, wherein the composition is an aqueous solution comprising 1-10% by weight of one or more of the metal phosphites, measured on a metal basis, and 1-25% by weight of prohexadione calcium. 12. The composition of claim 10, wherein at least one of the metal phosphites is calcium phosphite. 13. The composition of claim 10, wherein the composition is a free-flowing solids composition comprising 1-97% by weight of one or more of the metal phosphites by total weight, and 3-99% by weight of prohexadione calcium. 14. The composition of claim 13, wherein at least one of the metal phosphites is calcium phosphite. 15. The composition of claim 13, wherein the free-flowing solids composition is granular. 16. The composition of claim 13, further comprising one or more additional components selected from the group consisting of flow agents, fillers and desiccants. 17. The composition of claim 10, wherein the composition comprises 0.02-6.0 lbs of one or more of the metal phosphites, measured on a metal basis, for every 1.0 lb of prohexadione calcium. 18. The composition of claim 17, wherein the composition comprises 1.0-4.0 lbs of calcium as calcium phosphite for every 1.0 lb of prohexadione calcium. 19. A composition for treatment of agricultural crops, comprising: prohexadione calcium; and calcium phosphite. 20. The composition of claim 19, wherein the composition is an aqueous solution comprising 1-10% by weight of calcium as calcium phosphite and 1-25% by weight of prohexadione calcium. 21. The composition of claim 19, wherein the composition is a free-flowing solids composition comprising 2-40% by weight of calcium phosphite, and 3-40% by weight of prohexadione calcium. 22. The composition of claim 19, wherein the composition comprises 0.02-6.0 lbs of calcium as calcium phosphite for every 1.0 lb of prohexadione calcium. 23. The composition of claim 19, further comprising one or more metal phosphites selected from the group consisting of zinc phosphite, manganese phosphite, magnesium phosphite, iron phosphite and copper phosphite. 24. The composition of claim 19, further comprising one or more additional components selected from the group consisting of flow agents, fillers, desiccants, dyes, stabilizers, buffers, conditioners, surfactants, preservatives, organic materials, fertilizers other than metal phosphites, plant growth regulators other than prohexadione calcium, herbicides, fungicides and insecticides.

Compositions containing one or more metal phosphites and prohexadione calcium are suitable for providing micronutrients for plant health and growth regulation when applied to agricultural crops.1. A method of treating agricultural crops, comprising: applying a composition to a crop, wherein the composition comprises prohexadione calcium and one or more metal phosphites in aqueous solution; wherein the one or more metal phosphites are selected from the group consisting of zinc phosphite, manganese phosphite, magnesium phosphite, calcium phosphite, iron phosphite and copper phosphite. 2. The method of claim 1, wherein applying the composition comprises applying the composition at a rate to provide an amount of prohexadione calcium that is efficacious for growth regulation of the crop. 3. The method of claim 1, wherein applying the composition comprises applying an aqueous solution comprising 0.02-6.0 lbs of one or more of the metal phosphites, measured on a metal basis, for every 1.0 lb of prohexadione calcium. 4. The method of claim 1, wherein applying the composition comprises applying an aqueous solution comprising 1.0-4.0 lbs of calcium as calcium phosphite for every 1.0 lb of prohexadione calcium. 5. The method of claim 1, wherein applying the composition comprises applying the composition to provide 0.2-3.0 lbs/acre of prohexadione calcium and 0.01-1.5 lbs/acre of one or more of the metal phosphites, measured on a metal basis. 6. The method of claim 1, wherein applying the composition comprises applying the composition using a broadcast application method. 7. The method of claim 6, wherein the broadcast method of application is selected from the group consisting of boom spray and air blaster. 8. The method of claim 1, wherein applying the composition comprises applying the composition comprising prohexadione calcium, one or more metal phosphites and one or more additional components selected from the group consisting of dyes, stabilizers, buffers, conditioners, surfactants, preservatives, organic materials, fertilizers other than metal phosphites, plant growth regulators other than prohexadione calcium, herbicides, fungicides and insecticides, in aqueous solution. 9. The method of claim 1, wherein applying the composition comprises applying the composition to apple trees. 10. A composition for treatment of agricultural crops, comprising: prohexadione calcium; and one or more metal phosphites; wherein the one or more metal phosphites are selected from the group consisting of zinc phosphite, manganese phosphite, magnesium phosphite, calcium phosphite, iron phosphite and copper phosphite. 11. The composition of claim 10, wherein the composition is an aqueous solution comprising 1-10% by weight of one or more of the metal phosphites, measured on a metal basis, and 1-25% by weight of prohexadione calcium. 12. The composition of claim 10, wherein at least one of the metal phosphites is calcium phosphite. 13. The composition of claim 10, wherein the composition is a free-flowing solids composition comprising 1-97% by weight of one or more of the metal phosphites by total weight, and 3-99% by weight of prohexadione calcium. 14. The composition of claim 13, wherein at least one of the metal phosphites is calcium phosphite. 15. The composition of claim 13, wherein the free-flowing solids composition is granular. 16. The composition of claim 13, further comprising one or more additional components selected from the group consisting of flow agents, fillers and desiccants. 17. The composition of claim 10, wherein the composition comprises 0.02-6.0 lbs of one or more of the metal phosphites, measured on a metal basis, for every 1.0 lb of prohexadione calcium. 18. The composition of claim 17, wherein the composition comprises 1.0-4.0 lbs of calcium as calcium phosphite for every 1.0 lb of prohexadione calcium. 19. A composition for treatment of agricultural crops, comprising: prohexadione calcium; and calcium phosphite. 20. The composition of claim 19, wherein the composition is an aqueous solution comprising 1-10% by weight of calcium as calcium phosphite and 1-25% by weight of prohexadione calcium. 21. The composition of claim 19, wherein the composition is a free-flowing solids composition comprising 2-40% by weight of calcium phosphite, and 3-40% by weight of prohexadione calcium. 22. The composition of claim 19, wherein the composition comprises 0.02-6.0 lbs of calcium as calcium phosphite for every 1.0 lb of prohexadione calcium. 23. The composition of claim 19, further comprising one or more metal phosphites selected from the group consisting of zinc phosphite, manganese phosphite, magnesium phosphite, iron phosphite and copper phosphite. 24. The composition of claim 19, further comprising one or more additional components selected from the group consisting of flow agents, fillers, desiccants, dyes, stabilizers, buffers, conditioners, surfactants, preservatives, organic materials, fertilizers other than metal phosphites, plant growth regulators other than prohexadione calcium, herbicides, fungicides and insecticides.

A composition for detecting hepatitis B virus cccDNA includes an upstream primer having the DNA sequence set forth in SEQ ID NO. 1, a downstream primer having the DNA sequence set forth in SEQ ID NO. 2, and a TaqMan probe having the DNA sequence set forth in SEQ ID NO. 3. A qualitative and absolute quantification kit for detecting hepatitis C virus cccDNA includes an extraction agent for HBV DNA; an ATP-Dependent DNase; an upstream primer having DNA sequence set forth in SEQ ID NO. 1; a downstream primer having DNA sequence set forth in SEQ ID NO. 2; a TaqMan probe having DNA sequence set forth in SEQ ID NO. 3; EvaGreen fluorescent dyes; a PCR DNA polymerase; and a digital PCR DNA polymerase.

1. A composition for detecting hepatitis B virus cccDNA, comprising an upstream primer having the DNA sequence set forth in SEQ ID NO. 1, a downstream primer having the DNA sequence set forth in SEQ ID NO. 2, and a TaqMan probe having the DNA sequence set forth in SEQ ID NO. 3. 2. A qualitative and absolute quantification kit for detecting hepatitis B virus cccDNA comprising an extraction agent for HBV DNA; an ATP-Dependent DNase; an upstream primer having DNA sequence set forth in SEQ ID NO. 1; a downstream primer having DNA sequence set forth in SEQ ID NO. 2; a TaqMan probe having DNA sequence set forth in SEQ ID NO. 3; EvaGreen fluorescent dyes; a PCR DNA polymerase; and a digital PCR DNA polymerase. 3. The qualitative and absolute quantification kit for detecting hepatitis C virus cccDNA of claim 1, wherein the extraction agent for HBV DNA includes a cell lysate, a Tris saturated phenol, a mixture of phenol:chloroform:isoamyl alcohol=25:24:1, anhydrous ethanol, 75% ethanol, and TE buffer.

A composition for detecting hepatitis B virus cccDNA includes an upstream primer having the DNA sequence set forth in SEQ ID NO. 1, a downstream primer having the DNA sequence set forth in SEQ ID NO. 2, and a TaqMan probe having the DNA sequence set forth in SEQ ID NO. 3. A qualitative and absolute quantification kit for detecting hepatitis C virus cccDNA includes an extraction agent for HBV DNA; an ATP-Dependent DNase; an upstream primer having DNA sequence set forth in SEQ ID NO. 1; a downstream primer having DNA sequence set forth in SEQ ID NO. 2; a TaqMan probe having DNA sequence set forth in SEQ ID NO. 3; EvaGreen fluorescent dyes; a PCR DNA polymerase; and a digital PCR DNA polymerase.1. A composition for detecting hepatitis B virus cccDNA, comprising an upstream primer having the DNA sequence set forth in SEQ ID NO. 1, a downstream primer having the DNA sequence set forth in SEQ ID NO. 2, and a TaqMan probe having the DNA sequence set forth in SEQ ID NO. 3. 2. A qualitative and absolute quantification kit for detecting hepatitis B virus cccDNA comprising an extraction agent for HBV DNA; an ATP-Dependent DNase; an upstream primer having DNA sequence set forth in SEQ ID NO. 1; a downstream primer having DNA sequence set forth in SEQ ID NO. 2; a TaqMan probe having DNA sequence set forth in SEQ ID NO. 3; EvaGreen fluorescent dyes; a PCR DNA polymerase; and a digital PCR DNA polymerase. 3. The qualitative and absolute quantification kit for detecting hepatitis C virus cccDNA of claim 1, wherein the extraction agent for HBV DNA includes a cell lysate, a Tris saturated phenol, a mixture of phenol:chloroform:isoamyl alcohol=25:24:1, anhydrous ethanol, 75% ethanol, and TE buffer.

The disclosure provides an oral composition for reducing serum cholesterol, serum lipids, body fat, or atherogenic index or for prophylaxis or treatment of atherosclerosis, cardiovascular or cerebrovascular diseases, comprising a highly bsh active bacteria, isolate or supernatant thereof; wherein the highly bsh active bacteria degrades >50 μmol glycodeoxycholic acid (GDCA)/gram/hour and >2 μmol taurodeoxycholic acid (TDCA)/gram/hour when measured over 1 hour and 5 hours, respectively, or degrades >65 μmol GDCA/g/hr and >7 μmol TDCA/g/hr when measured over 30 minutes.

1. An oral composition comprising a highly bsh active bacteria, isolate or supernatant thereof; wherein the highly bsh active bacteria degrades >50 μmol GDCA/gram/hour and >2 μmol TDCA/gram/hour when measured over 1 hour and 5 hours, respectively; or >65 μmol GDCA/g/hr and >7 μmol TDCA/g/hr when measured over 30 minutes. 2. The oral composition of claim 1, wherein the highly bsh active bacteria degrades >300 μmol GDCA/g/hr and >40 μmol TDCA/g/hr when measured over 30 minutes. 3. The oral composition of claim 1, wherein the highly bsh active bacteria degrades >2000 μmol GDCA/g/hr and >500 μmol TDCA/g/hr when measured over 30 minutes. 4. The oral composition of claim 1, wherein the highly bsh active bacteria degrades >15000 μmol GDCA/g/hr and >2000 μmol TDCA/g/hr when measured over 30 minutes. 5. The oral composition of claim 1, wherein the bacteria is Lactobacillus, Bifidobacteria, Pediococcus, Streptococcus, Enterococcus, or Leuconostoc. 6. The oral composition of claim 5, wherein the Lactobacillus reuteri is Lactobacillus reuteri (NCIMB 701359), Lactobacillus reuteri (NCIMB 701089), Lactobacillus reuteri (ATCC 55148), Lactobacillus reuteri (ATCC 23272), Lactobacillus reuteri (NCIMB 702655), Lactobacillus reuteri (LMG 18238), Lactobacillus reuteri (CCUG 32271), Lactobacillus reuteri (CCUG 32305), Lactobacillus reuteri (CCUG 37470), Lactobacillus reuteri (CCUG 44001) or Lactobacillus reuteri (CCUG 44144). 7. The oral composition of claim 1, wherein the concentration of bacteria is 106-1012 CFU/gram. 8. The oral composition of claim 1, wherein the highly bsh active bacteria are grown under fermentation conditions comprising a carbon source, a nitrogen source, a pH of 4-7 and a harvest time of 6 to 24 hours. 9. The oral composition of claim 8, further comprising a reducing agent. 10. The oral composition of claim 1, wherein the bacteria are immobilized in a polymer or are encapsulated in polymeric semi permeable microcapsules or nanocapsules. 11. The oral composition of claim 1, wherein the composition is lyophilized, heat dried, spray dried, prepared wet, or flash frozen in a cryoprotectant solution. 12. The oral composition of claim 11, wherein the composition is lyophilized with lyoprotectants comprising (a) 0.2 to 10% maltodextrin and 0.05 to 0.33% yeast extract, (b) 0.05 to 10% inulin and 0.05 to 0.33% yeast extract, (c) 0.05 to 10% inulin, (d) 0.2 to 10% maltodextrin and 0.01 to 0.1% cysteine or (e) 0.05 to 10% inulin and 0.01 to 0.1% cysteine. 13. The oral composition of claim 11, wherein the composition is stored in liquid, wherein the liquid storage conditions comprise a final preservative solution comprising 2.5-10% growth media, 50-99.99% yogurt or other fermented milk, 50-99.99% culture supernatant or 5% MRS solution. 14. The oral composition of claim 11, wherein the cryoprotectant solution comprises a final concentration of (a) 0.2-10% maltodextrin and 0.05 to 0.33% yeast extract, (b) 0.05 to 10% inulin, (c) 0.5M Trehalose, (d) 0.5M sucrose or fructose, (e) 0.5M lactose, (f) 0.5M maltose, (g) 50-99.99% spent media, (h) 0.2-10% maltodextrin and 0.01 to 0.1% cysteine or (i) 0.05% to 10% inulin and 0.01 to 0.1% cysteine. 15. The oral composition of claim 1, wherein the composition further comprises a triglyceride lowering agent, an agent for increasing HDL or limiting HDL decrease, a cholesterol lowering agent, an agent for preserving bsh activity, an agent for modulating adipokines or hormones of obesity, a hypoglycemic agent, a therapeutic for reducing the pro-inflammatory cytokines IL-1α/β, IL-2, IL-15, IL-3, IL-6, IL-8, IL-12, IL-17, IFN-gamma, TNF-alpha, or for increasing the level of the anti-inflammatory cytokines IL-1ra, IL-9, IL-10, IL-11, vitamin B12, conjugated linoleic acid (CLA), reuterin or reutericyclin. 16. A method for lowering serum cholesterol of an animal comprising administering the oral composition of claim 1 to the animal in need thereof. 17. The method of claim 16, for reducing atherosclerotic risk factors of the animal, wherein the atherosclerotic risk factors are selected from serum homocystine, fibrinogen, C-reactive protein, lipoprotein(a), uric acid, matrix metallopeptidase 9 (MMP-9), plasminogen activator inhibitor-1 (PAI-1) or its antigen, tissue plasminogen activator (tPA), TNF alpha, IL-6, P-selectin, monocyte chemotactic protein-1 (MCP-1), soluble CD40 ligand (sCD40L), inter-cellular adhesion molecule 1 (ICAM-1), myeloperoxidase (MPO), adiponectin, leptin, lipoprotein-associated phospholipase A, and insulin. 18. A method for reducing the atherogenic index of an animal comprising administering the oral composition of claim 1 to the animal in need thereof, wherein atherogenic index (AI) is calculated by at least one of the following equations: AI=Log(Triglycerides/HDL-C) or AI=TC-HDL-C/HDL-C. 19. A method for increasing or limiting the reduction of serum high density lipoproteins (HDL-C) of an animal, for decreasing serum triglycerides of the animal, or for producing and delivering vitamin B12, conjugated linoleic acid (CLA), reuterin or reutericyclin to the animal, comprising administering the oral composition of claim 1 to the animal in need thereof. 20. A method for prophylaxis or treatment of atherosclerosis or a degenerative disorder caused by atherosclerosis in an animal, for lowering total body fat or treating obesity or pre-obesity in an animal, for prophylaxis or treatment of metabolic disease or disorder in an animal or for prophylaxis or treatment of a liver disease or disorder associated with high serum or hepatic lipid and triglyceride concentrations, hepatic inflammation, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), non-alcoholic steatohepatitis (NASH), liver cirrhosis, liver steatosis, liver fibrosis, abnormally high serum ALT, AST, GGT, or Alk-P levels, Epstein-Barr virus, hepatitis, autoimmune hepatitis, hepatic granulomatus disease, cholangitis, hepatocellular cancer, cholangiocarcinoma or metabolic liver disease in an animal, comprising administering the oral composition of claim 1 to the animal in need thereof. 21. A process for preparing a highly bsh active bacteria comprising growing bsh-producing bacteria in media comprising a carbon source, a nitrogen source, and a pH of 4 to 7 and harvesting the bacteria after 6 to 24 hours. 22. The process of claim 21, wherein the media further comprises a reducing agent 23. The process of claim 21, further comprising lyophilizing the free or microencapsulated bacteria with lyoprotectants, wherein the lyoprotectants comprise (a) 0.2 to 10% maltodextrin and 0.05 to 0.33% yeast extract, (b) 0.05 to 10% inulin and 0.05 to 0.33% yeast extract, (c) 0.05 to 10% inulin, (d) 0.2 to 10% maltodextrin and 0.01 to 0.1% cysteine or (e) 0.05 to 10% inulin and 0.01 to 0.1% cysteine. 24. The process of claim 21, further comprising storing the highly bsh active free or microencapsulated bacteria under liquid storage conditions, wherein the liquid storage conditions comprises a final preservative solution comprising 2.5-10% growth media, 50-99.99% yogurt or other fermented milk, 50-99.99% culture supernatant or 5% MRS solution. 25. The process of claim 21, further comprising flash freezing the composition in cryoprotectant solution at less than −80 Degrees Celsius, wherein the cryoprotectant solution comprises a final concentration of (a) 0.2-10% maltodextrin and 0.05 to 0.33% yeast extract, (b) 0.05 to 10% inulin, (c) 0.5M Trehalose, (d) 0.5M sucrose or fructose, (e) 0.5M lactose, (f) 0.5M maltose, (g) 50-99.99% spent media, (h) 0.2-10% maltodextrin and 0.01 to 0.1% cysteine or (i) 0.05 to 10% inulin and 0.01 to 0.1% cysteine.

The disclosure provides an oral composition for reducing serum cholesterol, serum lipids, body fat, or atherogenic index or for prophylaxis or treatment of atherosclerosis, cardiovascular or cerebrovascular diseases, comprising a highly bsh active bacteria, isolate or supernatant thereof; wherein the highly bsh active bacteria degrades >50 μmol glycodeoxycholic acid (GDCA)/gram/hour and >2 μmol taurodeoxycholic acid (TDCA)/gram/hour when measured over 1 hour and 5 hours, respectively, or degrades >65 μmol GDCA/g/hr and >7 μmol TDCA/g/hr when measured over 30 minutes.1. An oral composition comprising a highly bsh active bacteria, isolate or supernatant thereof; wherein the highly bsh active bacteria degrades >50 μmol GDCA/gram/hour and >2 μmol TDCA/gram/hour when measured over 1 hour and 5 hours, respectively; or >65 μmol GDCA/g/hr and >7 μmol TDCA/g/hr when measured over 30 minutes. 2. The oral composition of claim 1, wherein the highly bsh active bacteria degrades >300 μmol GDCA/g/hr and >40 μmol TDCA/g/hr when measured over 30 minutes. 3. The oral composition of claim 1, wherein the highly bsh active bacteria degrades >2000 μmol GDCA/g/hr and >500 μmol TDCA/g/hr when measured over 30 minutes. 4. The oral composition of claim 1, wherein the highly bsh active bacteria degrades >15000 μmol GDCA/g/hr and >2000 μmol TDCA/g/hr when measured over 30 minutes. 5. The oral composition of claim 1, wherein the bacteria is Lactobacillus, Bifidobacteria, Pediococcus, Streptococcus, Enterococcus, or Leuconostoc. 6. The oral composition of claim 5, wherein the Lactobacillus reuteri is Lactobacillus reuteri (NCIMB 701359), Lactobacillus reuteri (NCIMB 701089), Lactobacillus reuteri (ATCC 55148), Lactobacillus reuteri (ATCC 23272), Lactobacillus reuteri (NCIMB 702655), Lactobacillus reuteri (LMG 18238), Lactobacillus reuteri (CCUG 32271), Lactobacillus reuteri (CCUG 32305), Lactobacillus reuteri (CCUG 37470), Lactobacillus reuteri (CCUG 44001) or Lactobacillus reuteri (CCUG 44144). 7. The oral composition of claim 1, wherein the concentration of bacteria is 106-1012 CFU/gram. 8. The oral composition of claim 1, wherein the highly bsh active bacteria are grown under fermentation conditions comprising a carbon source, a nitrogen source, a pH of 4-7 and a harvest time of 6 to 24 hours. 9. The oral composition of claim 8, further comprising a reducing agent. 10. The oral composition of claim 1, wherein the bacteria are immobilized in a polymer or are encapsulated in polymeric semi permeable microcapsules or nanocapsules. 11. The oral composition of claim 1, wherein the composition is lyophilized, heat dried, spray dried, prepared wet, or flash frozen in a cryoprotectant solution. 12. The oral composition of claim 11, wherein the composition is lyophilized with lyoprotectants comprising (a) 0.2 to 10% maltodextrin and 0.05 to 0.33% yeast extract, (b) 0.05 to 10% inulin and 0.05 to 0.33% yeast extract, (c) 0.05 to 10% inulin, (d) 0.2 to 10% maltodextrin and 0.01 to 0.1% cysteine or (e) 0.05 to 10% inulin and 0.01 to 0.1% cysteine. 13. The oral composition of claim 11, wherein the composition is stored in liquid, wherein the liquid storage conditions comprise a final preservative solution comprising 2.5-10% growth media, 50-99.99% yogurt or other fermented milk, 50-99.99% culture supernatant or 5% MRS solution. 14. The oral composition of claim 11, wherein the cryoprotectant solution comprises a final concentration of (a) 0.2-10% maltodextrin and 0.05 to 0.33% yeast extract, (b) 0.05 to 10% inulin, (c) 0.5M Trehalose, (d) 0.5M sucrose or fructose, (e) 0.5M lactose, (f) 0.5M maltose, (g) 50-99.99% spent media, (h) 0.2-10% maltodextrin and 0.01 to 0.1% cysteine or (i) 0.05% to 10% inulin and 0.01 to 0.1% cysteine. 15. The oral composition of claim 1, wherein the composition further comprises a triglyceride lowering agent, an agent for increasing HDL or limiting HDL decrease, a cholesterol lowering agent, an agent for preserving bsh activity, an agent for modulating adipokines or hormones of obesity, a hypoglycemic agent, a therapeutic for reducing the pro-inflammatory cytokines IL-1α/β, IL-2, IL-15, IL-3, IL-6, IL-8, IL-12, IL-17, IFN-gamma, TNF-alpha, or for increasing the level of the anti-inflammatory cytokines IL-1ra, IL-9, IL-10, IL-11, vitamin B12, conjugated linoleic acid (CLA), reuterin or reutericyclin. 16. A method for lowering serum cholesterol of an animal comprising administering the oral composition of claim 1 to the animal in need thereof. 17. The method of claim 16, for reducing atherosclerotic risk factors of the animal, wherein the atherosclerotic risk factors are selected from serum homocystine, fibrinogen, C-reactive protein, lipoprotein(a), uric acid, matrix metallopeptidase 9 (MMP-9), plasminogen activator inhibitor-1 (PAI-1) or its antigen, tissue plasminogen activator (tPA), TNF alpha, IL-6, P-selectin, monocyte chemotactic protein-1 (MCP-1), soluble CD40 ligand (sCD40L), inter-cellular adhesion molecule 1 (ICAM-1), myeloperoxidase (MPO), adiponectin, leptin, lipoprotein-associated phospholipase A, and insulin. 18. A method for reducing the atherogenic index of an animal comprising administering the oral composition of claim 1 to the animal in need thereof, wherein atherogenic index (AI) is calculated by at least one of the following equations: AI=Log(Triglycerides/HDL-C) or AI=TC-HDL-C/HDL-C. 19. A method for increasing or limiting the reduction of serum high density lipoproteins (HDL-C) of an animal, for decreasing serum triglycerides of the animal, or for producing and delivering vitamin B12, conjugated linoleic acid (CLA), reuterin or reutericyclin to the animal, comprising administering the oral composition of claim 1 to the animal in need thereof. 20. A method for prophylaxis or treatment of atherosclerosis or a degenerative disorder caused by atherosclerosis in an animal, for lowering total body fat or treating obesity or pre-obesity in an animal, for prophylaxis or treatment of metabolic disease or disorder in an animal or for prophylaxis or treatment of a liver disease or disorder associated with high serum or hepatic lipid and triglyceride concentrations, hepatic inflammation, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), non-alcoholic steatohepatitis (NASH), liver cirrhosis, liver steatosis, liver fibrosis, abnormally high serum ALT, AST, GGT, or Alk-P levels, Epstein-Barr virus, hepatitis, autoimmune hepatitis, hepatic granulomatus disease, cholangitis, hepatocellular cancer, cholangiocarcinoma or metabolic liver disease in an animal, comprising administering the oral composition of claim 1 to the animal in need thereof. 21. A process for preparing a highly bsh active bacteria comprising growing bsh-producing bacteria in media comprising a carbon source, a nitrogen source, and a pH of 4 to 7 and harvesting the bacteria after 6 to 24 hours. 22. The process of claim 21, wherein the media further comprises a reducing agent 23. The process of claim 21, further comprising lyophilizing the free or microencapsulated bacteria with lyoprotectants, wherein the lyoprotectants comprise (a) 0.2 to 10% maltodextrin and 0.05 to 0.33% yeast extract, (b) 0.05 to 10% inulin and 0.05 to 0.33% yeast extract, (c) 0.05 to 10% inulin, (d) 0.2 to 10% maltodextrin and 0.01 to 0.1% cysteine or (e) 0.05 to 10% inulin and 0.01 to 0.1% cysteine. 24. The process of claim 21, further comprising storing the highly bsh active free or microencapsulated bacteria under liquid storage conditions, wherein the liquid storage conditions comprises a final preservative solution comprising 2.5-10% growth media, 50-99.99% yogurt or other fermented milk, 50-99.99% culture supernatant or 5% MRS solution. 25. The process of claim 21, further comprising flash freezing the composition in cryoprotectant solution at less than −80 Degrees Celsius, wherein the cryoprotectant solution comprises a final concentration of (a) 0.2-10% maltodextrin and 0.05 to 0.33% yeast extract, (b) 0.05 to 10% inulin, (c) 0.5M Trehalose, (d) 0.5M sucrose or fructose, (e) 0.5M lactose, (f) 0.5M maltose, (g) 50-99.99% spent media, (h) 0.2-10% maltodextrin and 0.01 to 0.1% cysteine or (i) 0.05 to 10% inulin and 0.01 to 0.1% cysteine.

We describe herein a cell-based multiplexing technique called detectable cell barcoding (DCB). In DCB, each individual sample is labeled with a different DCB signature that distinguishes each sample by one or both of detected intensity or type of detection characteristic. The samples are then combined and analyzed for a detectable characteristic of interest (e.g., presence of an analyte). By employing multiple distinct DCB labels at varying concentrations, one can perform multiplex analyses on up to hundreds or thousands (or more) of cell samples in a single reaction tube. DCB reduces reagent consumption by factors of 100-fold or more, significantly reduces data acquisition times and allows for stringent control sample analysis.

1-21. (canceled) 22. A kit comprising at least one detectable cell barcode (DCB) label in a form that is optimized to DCB label multiple cell samples according the method of claim 1, wherein said at least one DCB label is pre-measured into aliquots, wherein each of said aliquots comprises a different amount of said at least one DCB label that will distinguishably DCB mark starting cell samples in a multiplex DCB assay. 23. The kit of claim 22, wherein said at least one DCB label comprises a cell binding moiety. 24. The kit of claim 23, wherein said cell binding moiety is selected from one or both of a covalent cell binding moiety and a non-covalent cell binding moiety. 25. The kit of claim 22, wherein said at least one DCB label is in a liquid composition. 26. The kit of claim 22, wherein said at least one DCB label is in a dry composition. 27. (canceled) 28. (canceled) 29. The kit of claim 22, wherein said aliquots are provided in a multi-well strip or multi-well plate. 30. The kit of claim 22, wherein said kit comprises multiple distinct DCB labels. 31. The kit of claim 22, wherein said kit further comprises reagents for performing a DCB assay, wherein said reagents are selected form one or more of from the group consisting of: buffers for reconstitution and/or dilution of said at least one DCB label, buffers for labeling cell samples with said at least one DCB label, wash buffers, DCB labeling control cells, DCB labeling control beads, fluorescent beads for flow cytometer calibration, one or more detectable binding agents specific for detection of a cellular characteristic of interest, analyte detection control reagents, and combinations thereof. 32. The kit of claim 31, wherein said one or more detectable binding agents comprises an analyte-specific antibody. 33. The kit of claim 32, wherein said analyte is a specific isoform of a protein. 34. The kit of claim 31, wherein said analyte detection control reagents comprises one or more of: a non-specific isotype control antibody, a positive analyte control sample, a negative analyte control sample, and combinations thereof. 35. The kit of claim 22, wherein said DCB label comprises a fluorescent dye. 36. The kit of claim 22, wherein said DCB label comprises a mass label. 37. The kit of claim 24 wherein said covalent cell binding moiety is selected from the group consisting of: amine-reactive groups, thiol-reactive groups, hydroxyl reactive groups, aldehyde-reactive groups, isothiocyanate groups, amino groups, haloacetyl groups, maleimides, succinimidyl esters, thiols, aldehydes, hydrazides, azides, sulfonyl halides, and combinations thereof. 38. The kit of claim 30, wherein each of said multiple distinct DCB labels can be distinguished from one another based on fluorescence emission wavelength, fluorescence polarization, fluorescence lifetime, light scatter, mass, molecular mass, or combinations thereof. 39. The kit of claim 31, wherein said one or more detectable binding agents comprises a DNA binding agent. 40. The kit of claim 31, wherein said one or more detectable binding agents comprises a detectable catalytic activity. 41. The kit of claim 33, wherein said specific isoform is the phosphorylated isoform of a protein. 42. The kit of claim 30, wherein said aliquots comprise ready-made combinations of said multiple distinct DCB labels that will distinguishably DCB mark starting cell samples in a multiplex DCB assay. 43. The kit of claim 22, wherein said DCB label is pre-measured into three or more aliquots.

We describe herein a cell-based multiplexing technique called detectable cell barcoding (DCB). In DCB, each individual sample is labeled with a different DCB signature that distinguishes each sample by one or both of detected intensity or type of detection characteristic. The samples are then combined and analyzed for a detectable characteristic of interest (e.g., presence of an analyte). By employing multiple distinct DCB labels at varying concentrations, one can perform multiplex analyses on up to hundreds or thousands (or more) of cell samples in a single reaction tube. DCB reduces reagent consumption by factors of 100-fold or more, significantly reduces data acquisition times and allows for stringent control sample analysis.1-21. (canceled) 22. A kit comprising at least one detectable cell barcode (DCB) label in a form that is optimized to DCB label multiple cell samples according the method of claim 1, wherein said at least one DCB label is pre-measured into aliquots, wherein each of said aliquots comprises a different amount of said at least one DCB label that will distinguishably DCB mark starting cell samples in a multiplex DCB assay. 23. The kit of claim 22, wherein said at least one DCB label comprises a cell binding moiety. 24. The kit of claim 23, wherein said cell binding moiety is selected from one or both of a covalent cell binding moiety and a non-covalent cell binding moiety. 25. The kit of claim 22, wherein said at least one DCB label is in a liquid composition. 26. The kit of claim 22, wherein said at least one DCB label is in a dry composition. 27. (canceled) 28. (canceled) 29. The kit of claim 22, wherein said aliquots are provided in a multi-well strip or multi-well plate. 30. The kit of claim 22, wherein said kit comprises multiple distinct DCB labels. 31. The kit of claim 22, wherein said kit further comprises reagents for performing a DCB assay, wherein said reagents are selected form one or more of from the group consisting of: buffers for reconstitution and/or dilution of said at least one DCB label, buffers for labeling cell samples with said at least one DCB label, wash buffers, DCB labeling control cells, DCB labeling control beads, fluorescent beads for flow cytometer calibration, one or more detectable binding agents specific for detection of a cellular characteristic of interest, analyte detection control reagents, and combinations thereof. 32. The kit of claim 31, wherein said one or more detectable binding agents comprises an analyte-specific antibody. 33. The kit of claim 32, wherein said analyte is a specific isoform of a protein. 34. The kit of claim 31, wherein said analyte detection control reagents comprises one or more of: a non-specific isotype control antibody, a positive analyte control sample, a negative analyte control sample, and combinations thereof. 35. The kit of claim 22, wherein said DCB label comprises a fluorescent dye. 36. The kit of claim 22, wherein said DCB label comprises a mass label. 37. The kit of claim 24 wherein said covalent cell binding moiety is selected from the group consisting of: amine-reactive groups, thiol-reactive groups, hydroxyl reactive groups, aldehyde-reactive groups, isothiocyanate groups, amino groups, haloacetyl groups, maleimides, succinimidyl esters, thiols, aldehydes, hydrazides, azides, sulfonyl halides, and combinations thereof. 38. The kit of claim 30, wherein each of said multiple distinct DCB labels can be distinguished from one another based on fluorescence emission wavelength, fluorescence polarization, fluorescence lifetime, light scatter, mass, molecular mass, or combinations thereof. 39. The kit of claim 31, wherein said one or more detectable binding agents comprises a DNA binding agent. 40. The kit of claim 31, wherein said one or more detectable binding agents comprises a detectable catalytic activity. 41. The kit of claim 33, wherein said specific isoform is the phosphorylated isoform of a protein. 42. The kit of claim 30, wherein said aliquots comprise ready-made combinations of said multiple distinct DCB labels that will distinguishably DCB mark starting cell samples in a multiplex DCB assay. 43. The kit of claim 22, wherein said DCB label is pre-measured into three or more aliquots.

An olfaction processor (OLP) ( 100 ) that generates RAW data ( 35 ) including content data ( 139 d ) relating to chemical substances is provided. The OLP ( 100 ) includes a generator ( 130 ) that generates the RAW data ( 35 ). The chemical substances include at least one of compounds, molecules, and elements. The generator ( 130 ) includes a conversion unit ( 131 ) that converts intensity variations, which show detected chemical substances included in data from at least one sensor that detects an amount that changes due to presence of at least one of the chemical substances, to the content data ( 139 d ) by mapping onto a frequency space where a plurality of frequencies have been respectively assigned to a plurality of specified chemical substances.

1. A system including a generator that generates first data including content data relating to chemical substances, wherein the chemical substances include at least one of compounds, molecules, and elements, and the generator comprises a conversion unit that converts intensity variations showing detected chemical substances included in data from at least one sensor that detects an amount that changes due to presence of at least one of the chemical substances, to the content data by mapping onto a frequency space where a plurality of frequencies have been respectively assigned to a plurality of specified chemical substances. 2. The system according to claim 1, wherein the plurality of chemical substances are divided into a plurality of groups and a plurality of sub-bands are assigned respectively to the plurality of groups, and the conversion unit converts the intensity variations showing detected chemical substances to intensity variations of frequencies included in any of the sub-bands. 3. The system according to claim 2, wherein the content data is data for transmitting information for analyzing odors and/or information that relates to odors, and the plurality of groups includes groups divided according to functional groups. 4. The system according to claim 3, wherein the plurality of groups further includes an inorganic group and an unclassified group. 5. The system according to claim 3, further comprising sensors that obtain environmental information including at least temperature and humidity, and the generator comprises a supplementary information adding unit that obtains the environmental information of when the first data is generated and includes the environmental information in the first data as the environmental information of when the first data was generated. 6. The system according to claim 3, wherein the at least one sensor includes left and right sensors with different detection characteristics relating to direction, and the conversion unit includes a function that maps left and right intensity variations showing detected chemical substances included in data from the left and right sensors onto left and right frequency spaces respectively. 7. The system according to claim 1, further comprising a convertor converting the first data to data on a time region. 8. The system according to claim 7, further comprising an interface that outputs the data on a time region using images and/or sounds. 9. The system according to claim 7, further comprising an interface for recording the data on a time region and/or transferring the data on a time region to the outside. 10. The system according to claim 1, further comprising a compression apparatus that generates compressed data produced by compressing the first data. 11. The system according to claim 10, wherein the plurality of chemical substances are divided into a plurality of groups and a plurality of sub-bands are assigned respectively to the plurality of groups, and in the first data, intensity variations showing detected chemical substances have been converted to intensity variations of frequencies included in any of the sub-bands, and the compression apparatus includes a compression control unit that changes compression conditions according to the sub-band. 12. The system according to claim 11, wherein the content data is data for transmitting information for analyzing odors and/or information that relates to odors, and the plurality of groups includes groups divided according to functional groups, and the compression control unit reduces a data amount of the compressed data by deleting sub-bands assigned to groups not related to odors out of the plurality of groups or increasing a compression ratio by using an irreversible compression method. 13. The system according to claim 10, further comprising an interface for recording the compressed data and/or transferring the compressed data to the outside. 14. The system according to claim 1, further comprising: a capture unit that generates static data from the first data; and a recognition apparatus that recognizes a specified substance based on the static data. 15. The system according to claim 14, further comprising: a library including a plurality of patterns for recognition where chemical substances included in a plurality of substances have been mapped onto the frequency space, and a recognition engine that refers to the library, carries out pattern recognition on the static data, and outputs substances that have been recognized. 16. The system according to claim 15, wherein the plurality of chemical substances are divided into a plurality of groups and a plurality of sub-bands are assigned respectively to the plurality of groups, and in the first data, intensity variations showing detected chemical substances have been converted to intensity variations of frequencies included in any of the sub-bands, and the recognition engine carries out pattern recognition in sub-band units. 17. The system according to claim 14, further comprising a communication interface for communication with the outside, wherein the recognition apparatus outputs the static data or data for carrying out pattern recognition on the static data via the communication interface and obtains information relating to a recognized substance. 18. The system according to claim 14, further comprising an interface for carrying out a specified action that depends on a recognized substance. 19. The system according to claim 1, wherein the at least one sensor includes a spectrometry-type sensor whose sensitivity, resolution, and/or selectivity is controlled according to setting conditions, and the system further comprises a preprocessor that sets the setting conditions at preliminary detection conditions that scan a wider range using the spectrometry-type sensor, carries out preliminary analysis based on results of preliminary detection, and changes the setting conditions based on substances analyzed by the preliminary analysis. 20. The system according to claim 19, wherein the preprocessor periodically sets the preliminary detection conditions and carries out the preliminary analysis. 21. The system according to claim 1, wherein the at least one sensor includes a plurality of sensors of different types, and the conversion unit includes a function that maps intensity variations showing detected chemical substances included in data from respective sensors in the plurality of sensors onto the frequency space together. 22. The system according to claim 1, further comprising a reproduction apparatus for supplying a device driver with odor data based on the content data of the first data, wherein the device driver includes a function that converts the odor data to a combination of a plurality of odor sources that are used in an odor generating apparatus. 23. The system according to claim 22, further comprising sensors that obtain environmental information including at least temperature and humidity, wherein the first data includes the environmental information of when the first data was generated, and the reproduction apparatus includes a first compensation unit that obtains environmental information for a time of reproduction from the sensors that obtain environmental information, compares the obtained environmental information with the environmental information of when the first data was generated, and converts the content data of the first data to odor data suited to the obtained environmental information. 24. The system according to claim 22, wherein the reproduction apparatus includes a second compensation unit that obtains information relating to chemical substances during reproduction based on intensity variations showing detected chemical substances included in data from the at least one sensor, compares the obtained information with the content data of the first data, and converts the content data of the first data to the odor data suited to the obtained information relating to chemical substances. 25. The system according to claim 22, wherein the reproduction apparatus includes a reconstruction unit that converts the content data of the first data to the odor data based on characteristics of the human sense of smell. 26. The system according to claim 1, further comprising at least one chip in which circuits including at least the generator are integrated. 27. A system comprising: an interface that receives first data including content data where intensity variations showing chemical substances, which include at least one of compounds, molecules, and elements, have been mapped onto a frequency space where a plurality of frequencies have been respectively assigned to specified chemical substances; and a reproduction apparatus that supplies odor data based on the content data of the first data to a device driver, wherein the device driver includes a function that converts the odor data to a combination of a plurality of odor sources that are used in an odor generating apparatus. 28. The system according to claim 27, further comprising an interface that obtains environmental information at a time of reproduction that includes at least temperature and humidity from sensors that obtain environmental information, wherein the first data includes environmental information of when the first data was generated, and the reproduction apparatus includes a first compensation unit that obtains environmental information for a time of reproduction from the sensor, compares the obtained environmental information with the environmental information of when the first data was generated, and converts the content data of the first data to odor data suited to the obtained environmental information. 29. The system according to claim 27, further comprising an interface that obtains information, which relates to chemical substances at a time of reproduction and includes intensity variations showing chemical substances at a time of reproduction, from a sensor detecting an amount that changes according to presence of the chemical substances, wherein the reproduction apparatus includes a second compensation unit that obtains the information relating to chemical substances at the time of reproduction, compares the obtained information with the content data of the first data, and converts the first data to odor data suited to the obtained information relating to chemical substances. 30. The system according to claim 27, wherein the reproduction apparatus includes a reconstruction unit that converts the first data to the odor data based on characteristics of the human sense of smell. 31. The system according to claim 27, wherein the system is integrated into at least one chip. 32. A method of generating first data including content data relating to chemical substances, wherein the chemical substances include at least one of compounds, molecules, and elements, the method comprising converting intensity variations showing detected chemical substances included in data obtained from at least one sensor that detects an amount that changes due to presence of at least one of the chemical substances, to the content data by mapping onto a frequency space where a plurality of frequencies have been respectively assigned to a plurality of specified chemical substances. 33. The method according to claim 32, wherein the plurality of chemical substances are divided into a plurality of groups and a plurality of sub-bands are assigned respectively to the plurality of groups, and the step of converting includes converting the intensity variations showing detected chemical substances to intensity variations of frequencies included in any of the sub-bands. 34. The method according to claim 32, further comprising obtaining environmental information of when the first data is generated from sensors that obtain environmental information including at least temperature and humidity and including the obtained environmental information in the first data as environmental information of when the first data was generated. 35. The method according to claim 32, wherein the at least one sensor includes left and right sensors with different detection characteristics relating to direction, and the converting includes mapping intensity variations showing detected chemical substances included in the data from the left and right sensors onto left and right frequency spaces respectively. 36. The method according to claim 32, further comprising converting the first data to second data on a time region. 37. The method according to claim 32, further comprising generating compressed data produced by compressing the first data. 38. The method according to claim 32, wherein the at least one sensor includes a spectrometry-type sensor whose sensitivity, resolution, and/or selectivity is controlled according to setting conditions, and the method further comprises setting the setting conditions at preliminary detection conditions that scan a wider range using the spectrometry-type sensor, carrying out preliminary analysis based on results of preliminary detection, and changing the setting conditions based on substances analyzed by the preliminary analysis. 39. The method according to claim 32, wherein the at least one sensor includes a plurality of sensors of different types, and the converting includes mapping intensity variations showing the detected chemical substances included in data from respective sensors in the plurality of sensors onto the frequency space together. 40. A method of testing, investigating, or diagnosing, comprising: a method according to claim 32; a step of capturing static data from the first data; and a step of recognizing a specified substance based on the static data. 41. A method of generating odors, comprising: receiving first data including content data produced by mapping intensity variations showing chemical substances including at least one of compounds, molecules, and elements onto a frequency space where a plurality of frequencies have been respectively assigned to a plurality of specified chemical substances; supplying odor data to a device driver based on the content data of the first data; and converting, by the device driver, the odor data to a combination of a plurality of odor sources that are used in an odor generating apparatus. 42. The method according to claim 41, further comprising obtaining, from sensors, environmental information at a time of reproduction that includes at least one of temperature and humidity; and comparing the obtained environmental information at the time of reproduction to environmental information of when the first data was generated and converting the content data of the first data to odor data suited to the obtained environmental information at a time of reproduction. 43. The method according to claim 41, further comprising obtaining information, which relates to chemical substances at a time of reproduction and includes intensity variations showing chemical substances at the time of reproduction, from a sensor detecting an amount that changes according to presence of a chemical substance; and comparing the obtained information related to chemical substances at the time of reproduction to the content data of the first data and converting the first data to odor data suited to the obtained information related to chemical substances at the time of reproduction. 44. The method according to claim 41, further comprising converting the content data of the first data to the odor data based on characteristics of the human sense of smell. 45. A program for causing a computer to function as an apparatus that generates first data including content data relating to chemical substances, wherein the chemical substances include at least one of compounds, molecules, and elements, and the apparatus that generates comprises a conversion unit that converts intensity variations showing detected chemical substances included in data from at least one sensor that detects an amount that changes due to presence of at least one of the chemical substances, to the content data by mapping onto a frequency space where a plurality of frequencies have been respectively assigned to a plurality of specified chemical substances.

An olfaction processor (OLP) ( 100 ) that generates RAW data ( 35 ) including content data ( 139 d ) relating to chemical substances is provided. The OLP ( 100 ) includes a generator ( 130 ) that generates the RAW data ( 35 ). The chemical substances include at least one of compounds, molecules, and elements. The generator ( 130 ) includes a conversion unit ( 131 ) that converts intensity variations, which show detected chemical substances included in data from at least one sensor that detects an amount that changes due to presence of at least one of the chemical substances, to the content data ( 139 d ) by mapping onto a frequency space where a plurality of frequencies have been respectively assigned to a plurality of specified chemical substances.1. A system including a generator that generates first data including content data relating to chemical substances, wherein the chemical substances include at least one of compounds, molecules, and elements, and the generator comprises a conversion unit that converts intensity variations showing detected chemical substances included in data from at least one sensor that detects an amount that changes due to presence of at least one of the chemical substances, to the content data by mapping onto a frequency space where a plurality of frequencies have been respectively assigned to a plurality of specified chemical substances. 2. The system according to claim 1, wherein the plurality of chemical substances are divided into a plurality of groups and a plurality of sub-bands are assigned respectively to the plurality of groups, and the conversion unit converts the intensity variations showing detected chemical substances to intensity variations of frequencies included in any of the sub-bands. 3. The system according to claim 2, wherein the content data is data for transmitting information for analyzing odors and/or information that relates to odors, and the plurality of groups includes groups divided according to functional groups. 4. The system according to claim 3, wherein the plurality of groups further includes an inorganic group and an unclassified group. 5. The system according to claim 3, further comprising sensors that obtain environmental information including at least temperature and humidity, and the generator comprises a supplementary information adding unit that obtains the environmental information of when the first data is generated and includes the environmental information in the first data as the environmental information of when the first data was generated. 6. The system according to claim 3, wherein the at least one sensor includes left and right sensors with different detection characteristics relating to direction, and the conversion unit includes a function that maps left and right intensity variations showing detected chemical substances included in data from the left and right sensors onto left and right frequency spaces respectively. 7. The system according to claim 1, further comprising a convertor converting the first data to data on a time region. 8. The system according to claim 7, further comprising an interface that outputs the data on a time region using images and/or sounds. 9. The system according to claim 7, further comprising an interface for recording the data on a time region and/or transferring the data on a time region to the outside. 10. The system according to claim 1, further comprising a compression apparatus that generates compressed data produced by compressing the first data. 11. The system according to claim 10, wherein the plurality of chemical substances are divided into a plurality of groups and a plurality of sub-bands are assigned respectively to the plurality of groups, and in the first data, intensity variations showing detected chemical substances have been converted to intensity variations of frequencies included in any of the sub-bands, and the compression apparatus includes a compression control unit that changes compression conditions according to the sub-band. 12. The system according to claim 11, wherein the content data is data for transmitting information for analyzing odors and/or information that relates to odors, and the plurality of groups includes groups divided according to functional groups, and the compression control unit reduces a data amount of the compressed data by deleting sub-bands assigned to groups not related to odors out of the plurality of groups or increasing a compression ratio by using an irreversible compression method. 13. The system according to claim 10, further comprising an interface for recording the compressed data and/or transferring the compressed data to the outside. 14. The system according to claim 1, further comprising: a capture unit that generates static data from the first data; and a recognition apparatus that recognizes a specified substance based on the static data. 15. The system according to claim 14, further comprising: a library including a plurality of patterns for recognition where chemical substances included in a plurality of substances have been mapped onto the frequency space, and a recognition engine that refers to the library, carries out pattern recognition on the static data, and outputs substances that have been recognized. 16. The system according to claim 15, wherein the plurality of chemical substances are divided into a plurality of groups and a plurality of sub-bands are assigned respectively to the plurality of groups, and in the first data, intensity variations showing detected chemical substances have been converted to intensity variations of frequencies included in any of the sub-bands, and the recognition engine carries out pattern recognition in sub-band units. 17. The system according to claim 14, further comprising a communication interface for communication with the outside, wherein the recognition apparatus outputs the static data or data for carrying out pattern recognition on the static data via the communication interface and obtains information relating to a recognized substance. 18. The system according to claim 14, further comprising an interface for carrying out a specified action that depends on a recognized substance. 19. The system according to claim 1, wherein the at least one sensor includes a spectrometry-type sensor whose sensitivity, resolution, and/or selectivity is controlled according to setting conditions, and the system further comprises a preprocessor that sets the setting conditions at preliminary detection conditions that scan a wider range using the spectrometry-type sensor, carries out preliminary analysis based on results of preliminary detection, and changes the setting conditions based on substances analyzed by the preliminary analysis. 20. The system according to claim 19, wherein the preprocessor periodically sets the preliminary detection conditions and carries out the preliminary analysis. 21. The system according to claim 1, wherein the at least one sensor includes a plurality of sensors of different types, and the conversion unit includes a function that maps intensity variations showing detected chemical substances included in data from respective sensors in the plurality of sensors onto the frequency space together. 22. The system according to claim 1, further comprising a reproduction apparatus for supplying a device driver with odor data based on the content data of the first data, wherein the device driver includes a function that converts the odor data to a combination of a plurality of odor sources that are used in an odor generating apparatus. 23. The system according to claim 22, further comprising sensors that obtain environmental information including at least temperature and humidity, wherein the first data includes the environmental information of when the first data was generated, and the reproduction apparatus includes a first compensation unit that obtains environmental information for a time of reproduction from the sensors that obtain environmental information, compares the obtained environmental information with the environmental information of when the first data was generated, and converts the content data of the first data to odor data suited to the obtained environmental information. 24. The system according to claim 22, wherein the reproduction apparatus includes a second compensation unit that obtains information relating to chemical substances during reproduction based on intensity variations showing detected chemical substances included in data from the at least one sensor, compares the obtained information with the content data of the first data, and converts the content data of the first data to the odor data suited to the obtained information relating to chemical substances. 25. The system according to claim 22, wherein the reproduction apparatus includes a reconstruction unit that converts the content data of the first data to the odor data based on characteristics of the human sense of smell. 26. The system according to claim 1, further comprising at least one chip in which circuits including at least the generator are integrated. 27. A system comprising: an interface that receives first data including content data where intensity variations showing chemical substances, which include at least one of compounds, molecules, and elements, have been mapped onto a frequency space where a plurality of frequencies have been respectively assigned to specified chemical substances; and a reproduction apparatus that supplies odor data based on the content data of the first data to a device driver, wherein the device driver includes a function that converts the odor data to a combination of a plurality of odor sources that are used in an odor generating apparatus. 28. The system according to claim 27, further comprising an interface that obtains environmental information at a time of reproduction that includes at least temperature and humidity from sensors that obtain environmental information, wherein the first data includes environmental information of when the first data was generated, and the reproduction apparatus includes a first compensation unit that obtains environmental information for a time of reproduction from the sensor, compares the obtained environmental information with the environmental information of when the first data was generated, and converts the content data of the first data to odor data suited to the obtained environmental information. 29. The system according to claim 27, further comprising an interface that obtains information, which relates to chemical substances at a time of reproduction and includes intensity variations showing chemical substances at a time of reproduction, from a sensor detecting an amount that changes according to presence of the chemical substances, wherein the reproduction apparatus includes a second compensation unit that obtains the information relating to chemical substances at the time of reproduction, compares the obtained information with the content data of the first data, and converts the first data to odor data suited to the obtained information relating to chemical substances. 30. The system according to claim 27, wherein the reproduction apparatus includes a reconstruction unit that converts the first data to the odor data based on characteristics of the human sense of smell. 31. The system according to claim 27, wherein the system is integrated into at least one chip. 32. A method of generating first data including content data relating to chemical substances, wherein the chemical substances include at least one of compounds, molecules, and elements, the method comprising converting intensity variations showing detected chemical substances included in data obtained from at least one sensor that detects an amount that changes due to presence of at least one of the chemical substances, to the content data by mapping onto a frequency space where a plurality of frequencies have been respectively assigned to a plurality of specified chemical substances. 33. The method according to claim 32, wherein the plurality of chemical substances are divided into a plurality of groups and a plurality of sub-bands are assigned respectively to the plurality of groups, and the step of converting includes converting the intensity variations showing detected chemical substances to intensity variations of frequencies included in any of the sub-bands. 34. The method according to claim 32, further comprising obtaining environmental information of when the first data is generated from sensors that obtain environmental information including at least temperature and humidity and including the obtained environmental information in the first data as environmental information of when the first data was generated. 35. The method according to claim 32, wherein the at least one sensor includes left and right sensors with different detection characteristics relating to direction, and the converting includes mapping intensity variations showing detected chemical substances included in the data from the left and right sensors onto left and right frequency spaces respectively. 36. The method according to claim 32, further comprising converting the first data to second data on a time region. 37. The method according to claim 32, further comprising generating compressed data produced by compressing the first data. 38. The method according to claim 32, wherein the at least one sensor includes a spectrometry-type sensor whose sensitivity, resolution, and/or selectivity is controlled according to setting conditions, and the method further comprises setting the setting conditions at preliminary detection conditions that scan a wider range using the spectrometry-type sensor, carrying out preliminary analysis based on results of preliminary detection, and changing the setting conditions based on substances analyzed by the preliminary analysis. 39. The method according to claim 32, wherein the at least one sensor includes a plurality of sensors of different types, and the converting includes mapping intensity variations showing the detected chemical substances included in data from respective sensors in the plurality of sensors onto the frequency space together. 40. A method of testing, investigating, or diagnosing, comprising: a method according to claim 32; a step of capturing static data from the first data; and a step of recognizing a specified substance based on the static data. 41. A method of generating odors, comprising: receiving first data including content data produced by mapping intensity variations showing chemical substances including at least one of compounds, molecules, and elements onto a frequency space where a plurality of frequencies have been respectively assigned to a plurality of specified chemical substances; supplying odor data to a device driver based on the content data of the first data; and converting, by the device driver, the odor data to a combination of a plurality of odor sources that are used in an odor generating apparatus. 42. The method according to claim 41, further comprising obtaining, from sensors, environmental information at a time of reproduction that includes at least one of temperature and humidity; and comparing the obtained environmental information at the time of reproduction to environmental information of when the first data was generated and converting the content data of the first data to odor data suited to the obtained environmental information at a time of reproduction. 43. The method according to claim 41, further comprising obtaining information, which relates to chemical substances at a time of reproduction and includes intensity variations showing chemical substances at the time of reproduction, from a sensor detecting an amount that changes according to presence of a chemical substance; and comparing the obtained information related to chemical substances at the time of reproduction to the content data of the first data and converting the first data to odor data suited to the obtained information related to chemical substances at the time of reproduction. 44. The method according to claim 41, further comprising converting the content data of the first data to the odor data based on characteristics of the human sense of smell. 45. A program for causing a computer to function as an apparatus that generates first data including content data relating to chemical substances, wherein the chemical substances include at least one of compounds, molecules, and elements, and the apparatus that generates comprises a conversion unit that converts intensity variations showing detected chemical substances included in data from at least one sensor that detects an amount that changes due to presence of at least one of the chemical substances, to the content data by mapping onto a frequency space where a plurality of frequencies have been respectively assigned to a plurality of specified chemical substances.

Semen and sperm cell processing and preservation systems, and methods of producing a mammal and methods of producing mammalian embryos are disclosed. The present invention is directed to sperm cell preservation, fertilization, and insemination, maintaining or enhancing sperm quality and addressing one or more sperm cell characteristics, such as viability, motility, functionality, fertilization rates, and pregnancy rates. Further, sperm cell characteristics may be addressed within the context of various collection, handling, separation, storage, transportation, usage, fertilization, or insemination techniques.

1-53. (canceled) 54. A method of producing a non-human mammalian embryo comprising: obtaining cryopreserved sperm cells; thawing the cryopreserved sperm cells; sorting the thawed sperm cells; cryopreserving the sorted sperm cells; thawing the twice cryopreserved sperm cells; fertilizing at least one egg with the thawed, twice cryopreserved sperm cells; and producing a non-human mammalian embryo. 55. The method of claim 54, further comprising the step of producing a non-human mammal from the at least one fertilized egg. 56. The method of claim 54, further comprising the step of inseminating at least one female of a species of the non-human mammal said thawed, twice cryopreserved sperm cells. 57. The method of claim 54, wherein the step of inseminating a female comprises inseminating a superovulated female with the thawed, twice cryopreserved sperm cells. 58. The method of claim 54, wherein the step of fertilizing further comprises fertilizing the at least one egg in vitro. 59. The method of claim 54, further comprising the step of transferring the at least one fertilized egg to a recipient female. 60. The method of claim 54, further comprising the step of obtaining at least one egg of a superovulated female of a species of the mammal and wherein the step of fertilizing includes fertilizing the at least one egg in vitro. 61. The method of claim 60, wherein the step of fertilizing the at least one egg in vitro further comprises fertilizing more than one egg in vitro. 62. The method of claim 60, further comprising the step of transferring the at least one fertilized egg to a recipient female. 63. The method of claim 54, further comprising the step of establishing at least one sperm sample from the sperm cells. 64. The method of claim 63, wherein the step of establishing at least one sperm sample further comprises establishing at least one sperm sample of the thawed sperm cells, and in that the second cryopreserving step includes cryopreserving the at least one sperm sample. 65. The method of claim 63, wherein the step of establishing at least one sperm sample further comprises establishing a sample of the sperm cells capable of fertilizing at least one egg of the female non-human mammal. 66. The method of claim 63, wherein the step of establishing at least one sperm sample further comprises establishing a sample of the sperm cells capable of fertilizing at least one egg of a superovulating female non-human mammal. 67. The method claim of 63, wherein the step of establishing at least one sperm sample further comprises establishing a sample of the sperm cells capable of fertilization in vitro of at least one egg. 68. The method of claim 63, further comprising the step of producing an offspring from the sperm sample. 69. The method of claim 54, further comprising the step of fertilizing a plurality of eggs of a female non-human mammal. 70. The method of claim 54, further comprising the step of producing at least one animal of a pre-selected sex from the cryopreserved processed sperm cells. 71. The method of claim 54, wherein the twice cryopreserved sperm cells have a pre-selected sex. 72. The method of claim 54, wherein the twice cryopreserved sperm cells include a sperm sample selected from the group consisting of: a straw, a pellet, an insemination dose, and a prepared sperm sample.

Semen and sperm cell processing and preservation systems, and methods of producing a mammal and methods of producing mammalian embryos are disclosed. The present invention is directed to sperm cell preservation, fertilization, and insemination, maintaining or enhancing sperm quality and addressing one or more sperm cell characteristics, such as viability, motility, functionality, fertilization rates, and pregnancy rates. Further, sperm cell characteristics may be addressed within the context of various collection, handling, separation, storage, transportation, usage, fertilization, or insemination techniques.1-53. (canceled) 54. A method of producing a non-human mammalian embryo comprising: obtaining cryopreserved sperm cells; thawing the cryopreserved sperm cells; sorting the thawed sperm cells; cryopreserving the sorted sperm cells; thawing the twice cryopreserved sperm cells; fertilizing at least one egg with the thawed, twice cryopreserved sperm cells; and producing a non-human mammalian embryo. 55. The method of claim 54, further comprising the step of producing a non-human mammal from the at least one fertilized egg. 56. The method of claim 54, further comprising the step of inseminating at least one female of a species of the non-human mammal said thawed, twice cryopreserved sperm cells. 57. The method of claim 54, wherein the step of inseminating a female comprises inseminating a superovulated female with the thawed, twice cryopreserved sperm cells. 58. The method of claim 54, wherein the step of fertilizing further comprises fertilizing the at least one egg in vitro. 59. The method of claim 54, further comprising the step of transferring the at least one fertilized egg to a recipient female. 60. The method of claim 54, further comprising the step of obtaining at least one egg of a superovulated female of a species of the mammal and wherein the step of fertilizing includes fertilizing the at least one egg in vitro. 61. The method of claim 60, wherein the step of fertilizing the at least one egg in vitro further comprises fertilizing more than one egg in vitro. 62. The method of claim 60, further comprising the step of transferring the at least one fertilized egg to a recipient female. 63. The method of claim 54, further comprising the step of establishing at least one sperm sample from the sperm cells. 64. The method of claim 63, wherein the step of establishing at least one sperm sample further comprises establishing at least one sperm sample of the thawed sperm cells, and in that the second cryopreserving step includes cryopreserving the at least one sperm sample. 65. The method of claim 63, wherein the step of establishing at least one sperm sample further comprises establishing a sample of the sperm cells capable of fertilizing at least one egg of the female non-human mammal. 66. The method of claim 63, wherein the step of establishing at least one sperm sample further comprises establishing a sample of the sperm cells capable of fertilizing at least one egg of a superovulating female non-human mammal. 67. The method claim of 63, wherein the step of establishing at least one sperm sample further comprises establishing a sample of the sperm cells capable of fertilization in vitro of at least one egg. 68. The method of claim 63, further comprising the step of producing an offspring from the sperm sample. 69. The method of claim 54, further comprising the step of fertilizing a plurality of eggs of a female non-human mammal. 70. The method of claim 54, further comprising the step of producing at least one animal of a pre-selected sex from the cryopreserved processed sperm cells. 71. The method of claim 54, wherein the twice cryopreserved sperm cells have a pre-selected sex. 72. The method of claim 54, wherein the twice cryopreserved sperm cells include a sperm sample selected from the group consisting of: a straw, a pellet, an insemination dose, and a prepared sperm sample.

Compositions and methods for reducing susceptibility to infectious disease in bees using RNA interference technology, and more particularly, prevention and treatment of viral infections in honeybees such as Israel acute paralysis virus (IAPV) by feeding of pathogen-specific dsRNA. Further, multiple-pathogen specific dsRNA is disclosed.

1. A method for increasing the tolerance of a honeybee to a disease caused by a bee pathogen, comprising feeding the bee an effective amount of a bee-ingestible composition comprising a double stranded ribonucleic acid (dsRNA) comprising an RNA sequence capable of hybridizing to an mRNA transcript encoding a polypeptide or a RNA target sequence of at least one bee pathogen, thereby increasing the tolerance of the honeybee to the disease. 2. The method of claim 1, wherein the at least one bee pathogen is selected from the group consisting of: Acute Bee Paralysis Virus (ABPV), Kashmir Bee Virus (KBV), Sacbrood virus (SBV), Black queen cell virus (BQCV), Kakugo virus (KV), Deformed wing virus (DWV) and Israel acute paralysis virus (IAPV). 3. The method of claim 1, wherein the dsRNA comprises an RNA sequence that is capable of hybridizing to an mRNA transcript encoding a polypeptide or a RNA target sequence of two or more bee pathogens. 4. The method of claim 1, wherein the isolated dsRNA comprises an RNA sequence that is complementary to a nucleic acid comprising a nucleotide sequence as set forth in SEQ ID NOs: 24, 47, 49, 50 or 51. 5. The method of claim 1, wherein the dsRNA is selected from the group consisting of siRNA, shRNA and miRNA. 6. The method of claim 1, wherein the bee-ingestible composition is in solid form. 7. The method of claim 1, wherein the bee-ingestible composition is in liquid form. 8. The method of claim 1, wherein the bee-ingestible composition comprises a protein. 9. The method of claim 1, wherein the honeybee is a member of a colony, and wherein providing the bee-ingestible composition to the honeybee increases the tolerance of the colony to the disease. 10. A bee-ingestible composition comprising a double stranded ribonucleic acid (dsRNA) comprising an RNA sequence complementary to a nucleic acid comprising a nucleotide sequence that is highly homologous to a nucleotide sequence of at least one bee virus. 11. The bee-ingestible composition of claim 10, wherein the at least one bee virus is selected from the group consisting of: Acute Bee Paralysis Virus (ABPV), Kashmir Bee Virus (KBV), Sacbrood virus (SBV), Black queen cell virus (BQCV), Kakugo virus (KV), Deformed wing virus (DWV) and Israel acute paralysis virus (IAPV). 12. The bee-ingestible composition of claim 10, wherein the dsRNA comprises an RNA sequence that is complementary to a nucleotide sequence that is highly homologous to a nucleotide sequence of two or more bee viruses. 13. The bee-ingestible composition of claim 10, wherein the dsRNA comprises an RNA sequence that is complementary to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 24, 47, 49, 50 and 51. 14. The bee-ingestible composition of claim 10, wherein the composition is in solid form. 15. The bee-ingestible composition of claim 10, wherein said composition is in liquid form. 16. The bee-ingestible composition of claim 10, wherein the composition comprises a protein. 17. The bee-ingestible composition of claim 10, wherein the composition comprises a carbohydrate or sugar supplement. 18. The bee-ingestible composition of claim 10, wherein the dsRNA is selected from the group consisting of siRNA, shRNA and miRNA. 19. A nucleic acid construct comprising a promoter operably linked to a nucleic acid encoding the dsRNA of claim 10. 20. The nucleic acid construct of claim 19, wherein the dsRNA comprises an RNA sequence that is complementary to SEQ ID NO: 24.

Compositions and methods for reducing susceptibility to infectious disease in bees using RNA interference technology, and more particularly, prevention and treatment of viral infections in honeybees such as Israel acute paralysis virus (IAPV) by feeding of pathogen-specific dsRNA. Further, multiple-pathogen specific dsRNA is disclosed.1. A method for increasing the tolerance of a honeybee to a disease caused by a bee pathogen, comprising feeding the bee an effective amount of a bee-ingestible composition comprising a double stranded ribonucleic acid (dsRNA) comprising an RNA sequence capable of hybridizing to an mRNA transcript encoding a polypeptide or a RNA target sequence of at least one bee pathogen, thereby increasing the tolerance of the honeybee to the disease. 2. The method of claim 1, wherein the at least one bee pathogen is selected from the group consisting of: Acute Bee Paralysis Virus (ABPV), Kashmir Bee Virus (KBV), Sacbrood virus (SBV), Black queen cell virus (BQCV), Kakugo virus (KV), Deformed wing virus (DWV) and Israel acute paralysis virus (IAPV). 3. The method of claim 1, wherein the dsRNA comprises an RNA sequence that is capable of hybridizing to an mRNA transcript encoding a polypeptide or a RNA target sequence of two or more bee pathogens. 4. The method of claim 1, wherein the isolated dsRNA comprises an RNA sequence that is complementary to a nucleic acid comprising a nucleotide sequence as set forth in SEQ ID NOs: 24, 47, 49, 50 or 51. 5. The method of claim 1, wherein the dsRNA is selected from the group consisting of siRNA, shRNA and miRNA. 6. The method of claim 1, wherein the bee-ingestible composition is in solid form. 7. The method of claim 1, wherein the bee-ingestible composition is in liquid form. 8. The method of claim 1, wherein the bee-ingestible composition comprises a protein. 9. The method of claim 1, wherein the honeybee is a member of a colony, and wherein providing the bee-ingestible composition to the honeybee increases the tolerance of the colony to the disease. 10. A bee-ingestible composition comprising a double stranded ribonucleic acid (dsRNA) comprising an RNA sequence complementary to a nucleic acid comprising a nucleotide sequence that is highly homologous to a nucleotide sequence of at least one bee virus. 11. The bee-ingestible composition of claim 10, wherein the at least one bee virus is selected from the group consisting of: Acute Bee Paralysis Virus (ABPV), Kashmir Bee Virus (KBV), Sacbrood virus (SBV), Black queen cell virus (BQCV), Kakugo virus (KV), Deformed wing virus (DWV) and Israel acute paralysis virus (IAPV). 12. The bee-ingestible composition of claim 10, wherein the dsRNA comprises an RNA sequence that is complementary to a nucleotide sequence that is highly homologous to a nucleotide sequence of two or more bee viruses. 13. The bee-ingestible composition of claim 10, wherein the dsRNA comprises an RNA sequence that is complementary to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 24, 47, 49, 50 and 51. 14. The bee-ingestible composition of claim 10, wherein the composition is in solid form. 15. The bee-ingestible composition of claim 10, wherein said composition is in liquid form. 16. The bee-ingestible composition of claim 10, wherein the composition comprises a protein. 17. The bee-ingestible composition of claim 10, wherein the composition comprises a carbohydrate or sugar supplement. 18. The bee-ingestible composition of claim 10, wherein the dsRNA is selected from the group consisting of siRNA, shRNA and miRNA. 19. A nucleic acid construct comprising a promoter operably linked to a nucleic acid encoding the dsRNA of claim 10. 20. The nucleic acid construct of claim 19, wherein the dsRNA comprises an RNA sequence that is complementary to SEQ ID NO: 24.

Novel compositions including bepotastine besilate are provided such as sorbitol-free compositions, compositions including at least about 0.008% w/v benzalkonium chloride, and compositions including hydroxypropylmethyl cellulose E15 LV.

1-58. (canceled) 59. A method of treating at least one of rhinitis, mucosal inflammation associated with rhinitis, sinusitis, rhinosinusitis, and symptoms associated with rhinitis, mucosal inflammation associated with rhinitis, sinusitis, and/or rhinosinusitis in a patient in need of such treatment, the method comprising nasally administering a pharmaceutical composition comprising a pharmaceutically acceptable salt of bepotastine at a concentration ranging from 0.5% w/v to 8.00% w/v in aqueous solution to the patient in need thereof, in a dose regimen effective to treat at least one of rhinitis, mucosal inflammation associated with rhinitis, sinusitis, rhinosinusitis, and symptoms associated with rhinitis, mucosal inflammation associated with rhinitis, sinusitis, and/or rhinosinusitis. 60. The method of claim 59 wherein bepotastine in the composition administered is at a concentration ranging from 2.00% w/v to 4.00% w/v and administration is from 1 time a day to 4 times a day. 61. The method of claim 59 wherein bepotastine in the composition administered is at a concentration of either 3.00% w/v or 4.00% w/v and administration is either 1 time a day or is at more than 12 hour intervals. 62. The method of claim 59 wherein the dose regimen is effective to treat allergic rhinitis. 63. The method of claim 59 wherein the composition administered comprises dibasic sodium phosphate heptahydrate at a concentration of 0.10% w/v to 1.00% w/v; sodium chloride at a concentration of 0.9% w/v with 0.5% bepotastine, 0.4% w/v with 2.00%-3.00% bepotastine, 0.3% w/v with 4.00% bepotastine, 0.2% w/v with 6.00% bepotastine, 0.1% w/v with 8.00% bepotastine; edetate disodium at a concentration of 0.005% w/v to 0.100% w/v; benzalkonium chloride at a concentration of 0.002% w/v to 0.200% w/v; and one of either: a blend of microcrystalline cellulose and carboxymethyl cellulose (AVICEL®) at a concentration of 0.5% w/v to 2.5% w/v and polyoxyethylene (20) sorbitan monooleate (polysorbate 80) at a concentration of 0.005% w/v to 0.050% w/v, or HPMC E15 LV at a concentration of 0.01% w/v to 1.00% w/v, citric acid monohydrate at a concentration of 0.10% w/v to 1.00% w/v, and a taste-making agent at a concentration of 0.01% w/v to 1.00% w/v. 64. The method of claim 59 wherein the composition administered comprises dibasic sodium phosphate heptahydrate at a concentration of 0.70% w/v, sodium chloride at a concentration of 0.30% w/v, edetate disodium at a concentration of 0.020% w/v, benzalkonium chloride at a concentration of 0.020% w/v, and one of either: AVICEL® at a concentration of 2.00% w/v and polysorbate 80 at a concentration of 0.015% w/v, or HPMC at a concentration of 0.10% w/v, citric acid monohydrate at a concentration of 0.10% w/v, and sucralose at a concentration of 0.10% w/v. 65. The method of claim 59 wherein the pharmaceutically acceptable salt of bepotastine is besilate. 66. The method of claim 63 wherein AVICEL® is AVICEL® CL-611. 67. The method of claim 63 wherein HPMC is HPMC E15 LV.

Novel compositions including bepotastine besilate are provided such as sorbitol-free compositions, compositions including at least about 0.008% w/v benzalkonium chloride, and compositions including hydroxypropylmethyl cellulose E15 LV.1-58. (canceled) 59. A method of treating at least one of rhinitis, mucosal inflammation associated with rhinitis, sinusitis, rhinosinusitis, and symptoms associated with rhinitis, mucosal inflammation associated with rhinitis, sinusitis, and/or rhinosinusitis in a patient in need of such treatment, the method comprising nasally administering a pharmaceutical composition comprising a pharmaceutically acceptable salt of bepotastine at a concentration ranging from 0.5% w/v to 8.00% w/v in aqueous solution to the patient in need thereof, in a dose regimen effective to treat at least one of rhinitis, mucosal inflammation associated with rhinitis, sinusitis, rhinosinusitis, and symptoms associated with rhinitis, mucosal inflammation associated with rhinitis, sinusitis, and/or rhinosinusitis. 60. The method of claim 59 wherein bepotastine in the composition administered is at a concentration ranging from 2.00% w/v to 4.00% w/v and administration is from 1 time a day to 4 times a day. 61. The method of claim 59 wherein bepotastine in the composition administered is at a concentration of either 3.00% w/v or 4.00% w/v and administration is either 1 time a day or is at more than 12 hour intervals. 62. The method of claim 59 wherein the dose regimen is effective to treat allergic rhinitis. 63. The method of claim 59 wherein the composition administered comprises dibasic sodium phosphate heptahydrate at a concentration of 0.10% w/v to 1.00% w/v; sodium chloride at a concentration of 0.9% w/v with 0.5% bepotastine, 0.4% w/v with 2.00%-3.00% bepotastine, 0.3% w/v with 4.00% bepotastine, 0.2% w/v with 6.00% bepotastine, 0.1% w/v with 8.00% bepotastine; edetate disodium at a concentration of 0.005% w/v to 0.100% w/v; benzalkonium chloride at a concentration of 0.002% w/v to 0.200% w/v; and one of either: a blend of microcrystalline cellulose and carboxymethyl cellulose (AVICEL®) at a concentration of 0.5% w/v to 2.5% w/v and polyoxyethylene (20) sorbitan monooleate (polysorbate 80) at a concentration of 0.005% w/v to 0.050% w/v, or HPMC E15 LV at a concentration of 0.01% w/v to 1.00% w/v, citric acid monohydrate at a concentration of 0.10% w/v to 1.00% w/v, and a taste-making agent at a concentration of 0.01% w/v to 1.00% w/v. 64. The method of claim 59 wherein the composition administered comprises dibasic sodium phosphate heptahydrate at a concentration of 0.70% w/v, sodium chloride at a concentration of 0.30% w/v, edetate disodium at a concentration of 0.020% w/v, benzalkonium chloride at a concentration of 0.020% w/v, and one of either: AVICEL® at a concentration of 2.00% w/v and polysorbate 80 at a concentration of 0.015% w/v, or HPMC at a concentration of 0.10% w/v, citric acid monohydrate at a concentration of 0.10% w/v, and sucralose at a concentration of 0.10% w/v. 65. The method of claim 59 wherein the pharmaceutically acceptable salt of bepotastine is besilate. 66. The method of claim 63 wherein AVICEL® is AVICEL® CL-611. 67. The method of claim 63 wherein HPMC is HPMC E15 LV.

A tag database establishment section converts, based on information such as an amino acid sequence of an identified peptide and m/z of a peak, a sequence tag indicating a partial sequence and information related to the tag into a database and creates a tag database. When MS2 spectrum information is obtained by measuring a target peptide, a sequence tag acquisition section executes, on the tag database, a search based on coincidence of the m/z of the peak and the like and extracts a sequence tag with high reliability. A peptide identification section performs, based on an amino acid sequence of the sequence tag, m/z of a precursor ion, and the like, a search by a sequence tag search method taking into account a post-translational modification or a variation and identifies a peptide.

1. A mass spectrometric data analyzing apparatus that identifies, based on MSn spectrum data collected by executing an MSn analysis (n is an integer equal to or larger than 2) on a test sample, a target peptide in the test sample, the mass spectrometric data analyzing apparatus comprising: a) a tag database establishment section for establishing a sequence tag database in advance obtaining, from an amino acid sequence of a known peptide and MSn spectrum information, a sequence tag, which is a partial amino acid sequence, and spectrum peak information corresponding to the sequence tag; b) a sequence tag acquisition section for acquiring a sequence tag of the target peptide by collating peak information extracted from a measured MSn spectrum obtained for the test sample with information in the sequence tag database; and c) a peptide identification section for identifying a peptide by performing a database search in the sequence tag database or in a protein database using, as search conditions, the sequence tag for the target peptide obtained by the sequence tag acquisition section and mass of a precursor ion deriving from the target peptide. 2. The mass spectrometric data analyzing apparatus according to claim 1, wherein the tag database establishment section stores information indicating that an amino acid sequence of a sequence tag is subjected to a post-translational modification or a variation in association with the sequence tag when an amino acid sequence of a sequence tag is subjected to a post-translational modification or variation. 3. The mass spectrometric data analyzing apparatus according to claim 1, wherein the peptide identification section performs a database search with an additional condition that a peptide is subjected to a post-translational modification or a variation equivalent to a difference between mass of a precursor ion deriving from the target peptide and mass of a precursor ion stored in the sequence tag database when there is a difference between mass of a precursor ion deriving from the target peptide and mass of a precursor ion stored in the sequence tag database. 4. The mass spectrometric data analyzing apparatus according to claim 2, wherein the peptide identification section performs a database search with an additional condition that a peptide is subjected to a post-translational modification or a variation equivalent to a difference between mass of a precursor ion deriving from the target peptide and mass of a precursor ion stored in the sequence tag database when there is a difference between mass of a precursor ion deriving from the target peptide and mass of a precursor ion stored in the sequence tag database. 5. The mass spectrometric data analyzing apparatus according to claim 3, wherein the peptide identification section distinguishes, when there is a difference between mass of a precursor ion deriving from the target peptide and mass of a precursor ion stored in the tag database, whether the difference is present in an amino acid sequence portion corresponding to the sequence tag, and the peptide identification section performs, when the difference is present in the amino acid sequence portion corresponding to the sequence tag, the database search after correcting the amino acid sequence of the sequence tag to be subjected to a post-translational modification or a variation equivalent to the difference. 6. The mass spectrometric data analyzing apparatus according to claim 4, wherein the peptide identification section distinguishes, when there is a difference between mass of a precursor ion deriving from the target peptide and mass of a precursor ion stored in the tag database, whether the difference is present in an amino acid sequence portion corresponding to the sequence tag, and the peptide identification section performs, when the difference is present in the amino acid sequence portion corresponding to the sequence tag, the database search after correcting the amino acid sequence of the sequence tag to be subjected to a post-translational modification or a variation equivalent to the difference. 7. A mass spectrometric data analyzing method for identifying, based on MSn spectrum data collected by executing an MSn analysis (n is an integer equal to or larger than 2) on a test sample, a target peptide in the test sample, the mass spectrometric data analyzing method comprising: a) a tag database establishment step for establishing a sequence tag database in advance by obtaining, from an amino acid sequence of a known peptide and MSn spectrum information, a sequence tag, which is a partial amino acid sequence, and spectrum peak information corresponding to the sequence tag; b) a sequence tag acquisition step for acquiring a sequence tag of the target peptide by collating peak information extracted from a measured MSn spectrum obtained for the test sample with information in the sequence tag database; and c) a peptide identification step for identifying a peptide by performing a database search in the sequence tag database or in a protein database using, as search conditions, the sequence tag for the target peptide obtained in the sequence tag acquisition step and mass of a precursor ion deriving from the target peptide. 8. The mass spectrometric data analyzing method according to claim 7, wherein, in the tag database establishment step, when an amino acid sequence of a sequence tag is subjected to a post-translational modification or a variation, information indicating to that effect is stored in association with the sequence tag. 9. The mass spectrometric data analyzing method according to claim 7, wherein, in the peptide identification step, when there is a difference between mass of a precursor ion deriving from the target peptide and mass of a precursor ion stored in the tag database, a database search is performed with an additional condition that a peptide is subjected to a post-translational modification or a variation equivalent to the difference. 10. The mass spectrometric data analyzing method according to claim 8, wherein, in the peptide identification step, when there is a difference between mass of a precursor ion deriving from the target peptide and mass of a precursor ion stored in the tag database, a database search is performed with an additional condition that a peptide is subjected to a post-translational modification or a variation equivalent to the difference. 11. The mass spectrometric data analyzing method according to claim 9, wherein in the peptide identification step, when there is a difference between mass of a precursor ion deriving from the target peptide and mass of a precursor ion stored in the tag database, it is distinguished whether the difference is present in an amino acid sequence portion corresponding to the sequence tag, and when the difference is present in the amino acid sequence portion corresponding to the sequence tag, the database search is performed after the amino acid sequence of the sequence tag is corrected to be subjected to a post-translational modification or a variation equivalent to the difference. 12. The mass spectrometric data analyzing method according to claim 10, wherein in the peptide identification step, when there is a difference between mass of a precursor ion deriving from the target peptide and mass of a precursor ion stored in the tag database, it is distinguished whether the difference is present in an amino acid sequence portion corresponding to the sequence tag, and when the difference is present in the amino acid sequence portion corresponding to the sequence tag, the database search is performed after the amino acid sequence of the sequence tag is corrected to be subjected to a post-translational modification or a variation equivalent to the difference.

A tag database establishment section converts, based on information such as an amino acid sequence of an identified peptide and m/z of a peak, a sequence tag indicating a partial sequence and information related to the tag into a database and creates a tag database. When MS2 spectrum information is obtained by measuring a target peptide, a sequence tag acquisition section executes, on the tag database, a search based on coincidence of the m/z of the peak and the like and extracts a sequence tag with high reliability. A peptide identification section performs, based on an amino acid sequence of the sequence tag, m/z of a precursor ion, and the like, a search by a sequence tag search method taking into account a post-translational modification or a variation and identifies a peptide.1. A mass spectrometric data analyzing apparatus that identifies, based on MSn spectrum data collected by executing an MSn analysis (n is an integer equal to or larger than 2) on a test sample, a target peptide in the test sample, the mass spectrometric data analyzing apparatus comprising: a) a tag database establishment section for establishing a sequence tag database in advance obtaining, from an amino acid sequence of a known peptide and MSn spectrum information, a sequence tag, which is a partial amino acid sequence, and spectrum peak information corresponding to the sequence tag; b) a sequence tag acquisition section for acquiring a sequence tag of the target peptide by collating peak information extracted from a measured MSn spectrum obtained for the test sample with information in the sequence tag database; and c) a peptide identification section for identifying a peptide by performing a database search in the sequence tag database or in a protein database using, as search conditions, the sequence tag for the target peptide obtained by the sequence tag acquisition section and mass of a precursor ion deriving from the target peptide. 2. The mass spectrometric data analyzing apparatus according to claim 1, wherein the tag database establishment section stores information indicating that an amino acid sequence of a sequence tag is subjected to a post-translational modification or a variation in association with the sequence tag when an amino acid sequence of a sequence tag is subjected to a post-translational modification or variation. 3. The mass spectrometric data analyzing apparatus according to claim 1, wherein the peptide identification section performs a database search with an additional condition that a peptide is subjected to a post-translational modification or a variation equivalent to a difference between mass of a precursor ion deriving from the target peptide and mass of a precursor ion stored in the sequence tag database when there is a difference between mass of a precursor ion deriving from the target peptide and mass of a precursor ion stored in the sequence tag database. 4. The mass spectrometric data analyzing apparatus according to claim 2, wherein the peptide identification section performs a database search with an additional condition that a peptide is subjected to a post-translational modification or a variation equivalent to a difference between mass of a precursor ion deriving from the target peptide and mass of a precursor ion stored in the sequence tag database when there is a difference between mass of a precursor ion deriving from the target peptide and mass of a precursor ion stored in the sequence tag database. 5. The mass spectrometric data analyzing apparatus according to claim 3, wherein the peptide identification section distinguishes, when there is a difference between mass of a precursor ion deriving from the target peptide and mass of a precursor ion stored in the tag database, whether the difference is present in an amino acid sequence portion corresponding to the sequence tag, and the peptide identification section performs, when the difference is present in the amino acid sequence portion corresponding to the sequence tag, the database search after correcting the amino acid sequence of the sequence tag to be subjected to a post-translational modification or a variation equivalent to the difference. 6. The mass spectrometric data analyzing apparatus according to claim 4, wherein the peptide identification section distinguishes, when there is a difference between mass of a precursor ion deriving from the target peptide and mass of a precursor ion stored in the tag database, whether the difference is present in an amino acid sequence portion corresponding to the sequence tag, and the peptide identification section performs, when the difference is present in the amino acid sequence portion corresponding to the sequence tag, the database search after correcting the amino acid sequence of the sequence tag to be subjected to a post-translational modification or a variation equivalent to the difference. 7. A mass spectrometric data analyzing method for identifying, based on MSn spectrum data collected by executing an MSn analysis (n is an integer equal to or larger than 2) on a test sample, a target peptide in the test sample, the mass spectrometric data analyzing method comprising: a) a tag database establishment step for establishing a sequence tag database in advance by obtaining, from an amino acid sequence of a known peptide and MSn spectrum information, a sequence tag, which is a partial amino acid sequence, and spectrum peak information corresponding to the sequence tag; b) a sequence tag acquisition step for acquiring a sequence tag of the target peptide by collating peak information extracted from a measured MSn spectrum obtained for the test sample with information in the sequence tag database; and c) a peptide identification step for identifying a peptide by performing a database search in the sequence tag database or in a protein database using, as search conditions, the sequence tag for the target peptide obtained in the sequence tag acquisition step and mass of a precursor ion deriving from the target peptide. 8. The mass spectrometric data analyzing method according to claim 7, wherein, in the tag database establishment step, when an amino acid sequence of a sequence tag is subjected to a post-translational modification or a variation, information indicating to that effect is stored in association with the sequence tag. 9. The mass spectrometric data analyzing method according to claim 7, wherein, in the peptide identification step, when there is a difference between mass of a precursor ion deriving from the target peptide and mass of a precursor ion stored in the tag database, a database search is performed with an additional condition that a peptide is subjected to a post-translational modification or a variation equivalent to the difference. 10. The mass spectrometric data analyzing method according to claim 8, wherein, in the peptide identification step, when there is a difference between mass of a precursor ion deriving from the target peptide and mass of a precursor ion stored in the tag database, a database search is performed with an additional condition that a peptide is subjected to a post-translational modification or a variation equivalent to the difference. 11. The mass spectrometric data analyzing method according to claim 9, wherein in the peptide identification step, when there is a difference between mass of a precursor ion deriving from the target peptide and mass of a precursor ion stored in the tag database, it is distinguished whether the difference is present in an amino acid sequence portion corresponding to the sequence tag, and when the difference is present in the amino acid sequence portion corresponding to the sequence tag, the database search is performed after the amino acid sequence of the sequence tag is corrected to be subjected to a post-translational modification or a variation equivalent to the difference. 12. The mass spectrometric data analyzing method according to claim 10, wherein in the peptide identification step, when there is a difference between mass of a precursor ion deriving from the target peptide and mass of a precursor ion stored in the tag database, it is distinguished whether the difference is present in an amino acid sequence portion corresponding to the sequence tag, and when the difference is present in the amino acid sequence portion corresponding to the sequence tag, the database search is performed after the amino acid sequence of the sequence tag is corrected to be subjected to a post-translational modification or a variation equivalent to the difference.

The present invention provides liposomes that are useful for delivery of bioactive agents such as therapeutics. Among others, the liposomes of the invention are capable of delivering their payload at sites of increased secretory phospholipase A2 (sPLA2) activity, because phospholipase A2 (PLA2) will hydrolyse lipids of the liposome. Thus, the liposomes of the invention may e.g. be used in relation to cancer therapy. Another aspect of the invention is a liposomal formulation comprising the liposome of the invention. Still another aspect is a method of producing a liposomal formulation of the invention.

1. A liposome comprising between 25% and 45% (mol/mol) of an anionic lipid, less than 1% cholesterol (mol/mol) and a therapeutic agent selected from the group consisting of small molecule antitumour agents, antibiotics, antifungals, and anti-inflammatory agents wherein the liposome has been exposed to a divalent cation at a concentration between 0.1 mM and 1 mM. 2. The liposome of claim 1, wherein the anionic lipid is selected from a group consisting of PI (phosphatidyl inositol), PS (phosphatidyl serine), DPG (bisphosphatidyl glycerol), PA (phosphatidic acid), PEOH (phosphatidyl alcohol), and PG (phosphatidyl glycerol). 3. The liposome of claim 2, wherein the anionic lipid is phosphatidyl glycerol. 4. The liposome of claim 1, further comprising a hydrophilic polymer selected from the group of PEG [poly(ethylene glycol)], PAcM [poly(N-acryloylmorpholine)], PVP [poly(vinylpyrrolidone)], PLA [poly(lactide)], PG [poly(glycolide)], POZO [poly(2-methyl-2-oxazoline)], PVA [poly(vinyl alcohol)], HPMC (hydroxypropylmethylcellulose), PEO [poly(ethylene oxide)], chitosan [poly(D-glucosamine)], PAA [poly(aminoacid)], polyHEMA [Poly(2-hydroxyethylmethacrylate)] and co-polymers thereof. 5. The liposome of claim 4, wherein the polymer is PEG with a molecular weight between 100 Da and 10 kDa. 6. The liposome of claim 4, wherein polymer is conjugated to the head group of phosphatidyl ethanolamine. 7. The liposome of claim 6, wherein the amount of polymer-conjugated lipid is between 2.5% and 7.5% (mol/mol). 8. The liposome of claim 1, further comprising an uncharged phospholipid selected from the group consisting of PC (phosphatidyl choline) and PE (phosphatidylethanolamine). 9. The liposome of claim 1, comprising no cholesterol. 10. The liposome of claim 1, wherein the alkyl chains of the lipids are C18 saturated chains. 11. The liposome of claim 1, wherein the therapeutic agent is a small molecule antitumour agent selected from the group consisting of anthracyclin derivatives, cisplatin, oxaliplatin, carboplatin, doxorubicin, paclitaxel, 5-fluoruracil, exisulind, cis-retinoic acid, suldinac sulphide, methotrexate, bleomycin and vincristine. 12. The liposome of claim 11, wherein the therapeutic agent is oxaliplatin or cisplatin. 13. The liposome of claim 1, wherein the liposome is a Large Unilamellar Vesicle (LUV). 14. The liposome of claim 13, wherein the liposome has a diameter between 80 and 120 nm. 15. The liposome of claim 1, wherein at least one of the lipids in the liposome is a substrate for sPLA2. 16. A liposome of any of claim 1, further comprising between 0.1 mM and 1 mM of a divalent cation. 17. The liposome of claim 16, wherein the divalent cation is Ca2+. 18. The liposome formulation comprising liposomes according to claim 17. 19. The liposome formulation of claim 18, wherein the Poly Dispersity Index is 0.20 or less. 20. A method for the preparation of a liposomal formulation according to claim 18 comprising the steps of: a. preparing a lipid mixture by dissolving selected lipids in an organic solvent b. hydrating the product of step a) with an aqueous hydration solvent so as to form liposomes; and c. removing the organic solvent of step a) either before addition of the aqueous hydration solvent or after the addition of the aqueous hydration solvent. 21. The method of claim 20, wherein organic solvent is removed before addition of hydration solvent. 22. The method of claim 20 further comprising a step of sonicating the liposomal formulation to produce liposomes of a certain size. 23. The method of claim 20, wherein the hydration solvent comprises a divalent cation at a concentration between 0.1 mM and 1 mM. 24. The method of claim 20 further comprising a step of changing the exterior water phase to another exterior water phase comprising a divalent cation at a concentration 0.1 mM and 1 mM. 25. The method of claim 20, wherein the divalent cation is Ca2+.

The present invention provides liposomes that are useful for delivery of bioactive agents such as therapeutics. Among others, the liposomes of the invention are capable of delivering their payload at sites of increased secretory phospholipase A2 (sPLA2) activity, because phospholipase A2 (PLA2) will hydrolyse lipids of the liposome. Thus, the liposomes of the invention may e.g. be used in relation to cancer therapy. Another aspect of the invention is a liposomal formulation comprising the liposome of the invention. Still another aspect is a method of producing a liposomal formulation of the invention.1. A liposome comprising between 25% and 45% (mol/mol) of an anionic lipid, less than 1% cholesterol (mol/mol) and a therapeutic agent selected from the group consisting of small molecule antitumour agents, antibiotics, antifungals, and anti-inflammatory agents wherein the liposome has been exposed to a divalent cation at a concentration between 0.1 mM and 1 mM. 2. The liposome of claim 1, wherein the anionic lipid is selected from a group consisting of PI (phosphatidyl inositol), PS (phosphatidyl serine), DPG (bisphosphatidyl glycerol), PA (phosphatidic acid), PEOH (phosphatidyl alcohol), and PG (phosphatidyl glycerol). 3. The liposome of claim 2, wherein the anionic lipid is phosphatidyl glycerol. 4. The liposome of claim 1, further comprising a hydrophilic polymer selected from the group of PEG [poly(ethylene glycol)], PAcM [poly(N-acryloylmorpholine)], PVP [poly(vinylpyrrolidone)], PLA [poly(lactide)], PG [poly(glycolide)], POZO [poly(2-methyl-2-oxazoline)], PVA [poly(vinyl alcohol)], HPMC (hydroxypropylmethylcellulose), PEO [poly(ethylene oxide)], chitosan [poly(D-glucosamine)], PAA [poly(aminoacid)], polyHEMA [Poly(2-hydroxyethylmethacrylate)] and co-polymers thereof. 5. The liposome of claim 4, wherein the polymer is PEG with a molecular weight between 100 Da and 10 kDa. 6. The liposome of claim 4, wherein polymer is conjugated to the head group of phosphatidyl ethanolamine. 7. The liposome of claim 6, wherein the amount of polymer-conjugated lipid is between 2.5% and 7.5% (mol/mol). 8. The liposome of claim 1, further comprising an uncharged phospholipid selected from the group consisting of PC (phosphatidyl choline) and PE (phosphatidylethanolamine). 9. The liposome of claim 1, comprising no cholesterol. 10. The liposome of claim 1, wherein the alkyl chains of the lipids are C18 saturated chains. 11. The liposome of claim 1, wherein the therapeutic agent is a small molecule antitumour agent selected from the group consisting of anthracyclin derivatives, cisplatin, oxaliplatin, carboplatin, doxorubicin, paclitaxel, 5-fluoruracil, exisulind, cis-retinoic acid, suldinac sulphide, methotrexate, bleomycin and vincristine. 12. The liposome of claim 11, wherein the therapeutic agent is oxaliplatin or cisplatin. 13. The liposome of claim 1, wherein the liposome is a Large Unilamellar Vesicle (LUV). 14. The liposome of claim 13, wherein the liposome has a diameter between 80 and 120 nm. 15. The liposome of claim 1, wherein at least one of the lipids in the liposome is a substrate for sPLA2. 16. A liposome of any of claim 1, further comprising between 0.1 mM and 1 mM of a divalent cation. 17. The liposome of claim 16, wherein the divalent cation is Ca2+. 18. The liposome formulation comprising liposomes according to claim 17. 19. The liposome formulation of claim 18, wherein the Poly Dispersity Index is 0.20 or less. 20. A method for the preparation of a liposomal formulation according to claim 18 comprising the steps of: a. preparing a lipid mixture by dissolving selected lipids in an organic solvent b. hydrating the product of step a) with an aqueous hydration solvent so as to form liposomes; and c. removing the organic solvent of step a) either before addition of the aqueous hydration solvent or after the addition of the aqueous hydration solvent. 21. The method of claim 20, wherein organic solvent is removed before addition of hydration solvent. 22. The method of claim 20 further comprising a step of sonicating the liposomal formulation to produce liposomes of a certain size. 23. The method of claim 20, wherein the hydration solvent comprises a divalent cation at a concentration between 0.1 mM and 1 mM. 24. The method of claim 20 further comprising a step of changing the exterior water phase to another exterior water phase comprising a divalent cation at a concentration 0.1 mM and 1 mM. 25. The method of claim 20, wherein the divalent cation is Ca2+.

The invention relates to the combination of a sulforaphane precursor, an enzyme capable of converting the sulforaphane precursor to sulforaphane, an enzyme potentiator, and a milk thistle extract or powder. The invention also relates to the combination of a sulforaphane or a derivative thereof and a milk thistle extract or powder. The invention also relates to the combination of a broccoli extract or powder and a milk thistle extract or powder. The invention provides compositions and methods relating to these combinations.

1-14. (canceled) 15. An orally administrable composition comprising a broccoli extract or powder and a milk thistle extract or powder. 16. The orally administrable composition of claim 15, wherein the broccoli extract or powder comprises glucoraphanin in an amount of about 1 to about 75% w/w. 17. The orally administrable composition of claim 15, wherein the broccoli extract or powder comprises myrosinase. 18. The orally administrable composition of claim 15, further comprising an enzyme potentiator. 19. The orally administrable composition of claim 15, wherein the enzyme potentiator comprises ascorbic acid. 20. The orally administrable composition of claim 15, wherein the composition comprises an enteric-coated dosage form. 21. The orally administrable composition of claim 15, comprising a milk thistle extract comprising silymarin. 22. The orally administrable composition of claim 15, comprising a milk thistle extract comprising silibinin. 23. The orally administrable composition of claim 15, further comprising one or more additional components selected from the group consisting of: quercetin, an aminosugar, a glycosaminoglycan, avocado/soybean unsaponifiable, a vitamin, coffee fruit, magnesium, silymarin, proanthocyanidins, ursolic acid, curcumin, phytosterols, phytostanols, and S-adenosylmethionine (SAMe). 24. A method of treating, preventing, reducing the occurrence of, decreasing the symptoms associated with, and/or reducing secondary recurrences of, a disease or condition associated with the liver, prostate, brain, lung, kidneys, colon, breast, esophagus, pancreas, or ovaries in a subject in need thereof, comprising administering to the subject the orally administrable composition of claim 15. 25. A method of increasing glutathione levels in a subject, comprising administering to the subject in need thereof the orally administrable composition of claim 15. 26. A method of treating, preventing, reducing the occurrence of, decreasing the symptoms associated with, and/or reducing secondary recurrences of a non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof, comprising administering to the subject in need thereof the orally administrable composition of claim 15. 27. An orally administrable composition comprising sulforaphane or a derivative thereof and a milk thistle extract or powder. 28. The orally administrable composition of claim 27, comprising a milk thistle extract comprising silymarin. 29. The orally administrable composition of claim 27, comprising a milk thistle extract comprising silibinin. 30. The orally administrable composition of claim 27, further comprising one or more additional components selected from the group consisting of: quercetin, an aminosugar, a glycosaminoglycan, avocado/soybean unsaponifiable, a vitamin, coffee fruit, magnesium, silymarin, proanthocyanidins, ursolic acid, curcumin, phytosterols, and phytostanols. 31. A method of treating, preventing, reducing the occurrence of, decreasing the symptoms associated with, and/or reducing secondary recurrences of, a disease or condition associated with the liver, prostate, brain, lung, kidneys, colon, breast, esophagus, pancreas, or ovaries in a subject in need thereof, comprising administering to the subject the orally administrable composition of claim 27. 32. A method of increasing glutathione levels in a subject, comprising administering to the subject in need thereof the orally administrable composition of claim 27. 33. A method of treating, preventing, reducing the occurrence of, decreasing the symptoms associated with, and/or reducing secondary recurrences of a non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof, comprising administering to the subject in need thereof the orally administrable composition of claim 27.

The invention relates to the combination of a sulforaphane precursor, an enzyme capable of converting the sulforaphane precursor to sulforaphane, an enzyme potentiator, and a milk thistle extract or powder. The invention also relates to the combination of a sulforaphane or a derivative thereof and a milk thistle extract or powder. The invention also relates to the combination of a broccoli extract or powder and a milk thistle extract or powder. The invention provides compositions and methods relating to these combinations.1-14. (canceled) 15. An orally administrable composition comprising a broccoli extract or powder and a milk thistle extract or powder. 16. The orally administrable composition of claim 15, wherein the broccoli extract or powder comprises glucoraphanin in an amount of about 1 to about 75% w/w. 17. The orally administrable composition of claim 15, wherein the broccoli extract or powder comprises myrosinase. 18. The orally administrable composition of claim 15, further comprising an enzyme potentiator. 19. The orally administrable composition of claim 15, wherein the enzyme potentiator comprises ascorbic acid. 20. The orally administrable composition of claim 15, wherein the composition comprises an enteric-coated dosage form. 21. The orally administrable composition of claim 15, comprising a milk thistle extract comprising silymarin. 22. The orally administrable composition of claim 15, comprising a milk thistle extract comprising silibinin. 23. The orally administrable composition of claim 15, further comprising one or more additional components selected from the group consisting of: quercetin, an aminosugar, a glycosaminoglycan, avocado/soybean unsaponifiable, a vitamin, coffee fruit, magnesium, silymarin, proanthocyanidins, ursolic acid, curcumin, phytosterols, phytostanols, and S-adenosylmethionine (SAMe). 24. A method of treating, preventing, reducing the occurrence of, decreasing the symptoms associated with, and/or reducing secondary recurrences of, a disease or condition associated with the liver, prostate, brain, lung, kidneys, colon, breast, esophagus, pancreas, or ovaries in a subject in need thereof, comprising administering to the subject the orally administrable composition of claim 15. 25. A method of increasing glutathione levels in a subject, comprising administering to the subject in need thereof the orally administrable composition of claim 15. 26. A method of treating, preventing, reducing the occurrence of, decreasing the symptoms associated with, and/or reducing secondary recurrences of a non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof, comprising administering to the subject in need thereof the orally administrable composition of claim 15. 27. An orally administrable composition comprising sulforaphane or a derivative thereof and a milk thistle extract or powder. 28. The orally administrable composition of claim 27, comprising a milk thistle extract comprising silymarin. 29. The orally administrable composition of claim 27, comprising a milk thistle extract comprising silibinin. 30. The orally administrable composition of claim 27, further comprising one or more additional components selected from the group consisting of: quercetin, an aminosugar, a glycosaminoglycan, avocado/soybean unsaponifiable, a vitamin, coffee fruit, magnesium, silymarin, proanthocyanidins, ursolic acid, curcumin, phytosterols, and phytostanols. 31. A method of treating, preventing, reducing the occurrence of, decreasing the symptoms associated with, and/or reducing secondary recurrences of, a disease or condition associated with the liver, prostate, brain, lung, kidneys, colon, breast, esophagus, pancreas, or ovaries in a subject in need thereof, comprising administering to the subject the orally administrable composition of claim 27. 32. A method of increasing glutathione levels in a subject, comprising administering to the subject in need thereof the orally administrable composition of claim 27. 33. A method of treating, preventing, reducing the occurrence of, decreasing the symptoms associated with, and/or reducing secondary recurrences of a non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof, comprising administering to the subject in need thereof the orally administrable composition of claim 27.

The present invention provides compositions and systems for delivery of nanocarriers to cells of the immune system. The invention provides vaccine nanocarriers capable of stimulating an immune response in T cells and/or in B cells, in some embodiments, comprising at least one immunomodulatory agent, and optionally comprising at least one targeting moiety and optionally at least one immunostimulatory agent. The invention provides pharmaceutical compositions comprising inventive vaccine nanocarriers. The present invention provides methods of designing, manufacturing, and using inventive vaccine nanocarriers and pharmaceutical compositions thereof. The invention provides methods of prophylaxis and/or treatment of diseases, disorders, and conditions comprising administering at least one inventive vaccine nanocarrier to a subject in need thereof.

1-386. (canceled) 387. Nanoparticles formed of polymer or lipid having a diameter of between 40 nm and 400 nm, having incorporated therein T cell antigens, the nanoparticles having bound to or present on the surface B cell antigen, preferably in a density activating B cell receptors, and/or having immunomodulatory agents incorporated therein. 388. The nanoparticles of claim 387 having bound to or present on the surface an agent or material targeting the nanoparticles to secondary lymphoid tissue or cells therein. 389. The nanoparticles of claim 387 comprising a targeting agent for a molecule selected from the group consisting of CD11b, CD169, mannose receptor, DEC-205, CD11c, and CD21/35. 390. The nanoparticles of claim 387 comprising an immunomodulatory agent selected from the group consisting of specific and non-specific immunostimulants. 391. The nanoparticles of claim 390 wherein the immunomodulatory agent non-selectively targets the nanoparticles to secondary lymphoid tissue or cells therein, wherein the agent is selected from the group consisting of an adjuvant, hydrophilic polymer like polyethylene glycol or amphiphilic polymer, emulsion and liposome associated with the nanoparticles. 392. The nanoparticles of claim 387 wherein the targeting agent is selected from molecules specifically binding to targets on cells in the lymphoid tissue. 393. The nanoparticles of claim 392 wherein the targeting agent targets dendritic cells, macrophages, T cells or B cells. 394. The nanoparticles of claim 387 wherein the T cell antigen is a toll-like receptor agonist. 395. The nanoparticles of claim 387 comprising an immunomodulatory agent selected from the group consisting of CpG peptides, cholera toxin, squalene, phosphate adjuvants, tetrachlorodecaoxide, monophosphoryl lipid A, saponines, imidazoquinoline, CD40 agonists, cytokines, and complement receptor agonists. 396. The nanoparticles of claim 387 wherein the B or T cell antigen is selected from the group consisting of proteins, carbohydrates, glycoproteins, lipoproteins, lipids, nucleic acid, metals and inorganic molecules. 397. The nanoparticles of claim 396 wherein the antigen is selected from the group consisting of infectious disease antigens, degenerative disease antigens, cancer antigens, atopic disease antigens, autoimmune disease antigens, allergens, and alto or xeno antigens. 398. The nanoparticles of claim 397 wherein the B-cell antigen is a small molecule addictive substance or toxin. 399. The nanoparticles of claim 398 wherein the B-cell antigen is nicotine, the immunomodulatory agent is a toll-like receptor agonist, and the nanoparticles are formed of polymer, wherein the nicotine is optionally conjugated to the polymer. 400. The nanoparticles of claim 387 wherein the B cell antigens are of bacterial, viral, protozoan, parasite or fungal origin. 401. The nanoparticles of claim 400 wherein the bacterial antigen is selected from the group consisting of diptherial antigens and tetanus antigens and the viral antigen is selected from the group consisting of adenoviral and vesicular stomatitis viral peptides. 402. The nanoparticles of claim 387 wherein the T cell antigen is a self antigen, cancer antigen or allergenic peptide. 403. The nanoparticles of claim 388 comprising agents targeting dendritic cells, lymph node macrophages, T cells or B cells. 404. The nanoparticles of claim 387 comprising polymer having incorporated therein T cell antigen in combination with an immunomodulatory agent, and having B cell antigen on the surface of the nanoparticles. 405. The nanoparticles of claim 387 formed of a hydrophobic polymer or having a hydrophobic core. 406. The nanoparticles of claim 387 formed of a biodegradable polymer. 407. The nanoparticles of claim 406 wherein the polymer is selected from the group consisting of polymers of lactic acid, glycolic acid, polyethylene glycol, polyoxyethyleneoxide, copolymers and block copolymers thereof. 408. The nanoparticles of claim 387 comprising polymeric nanoparticles comprising antigen and targeted to phagocytic cells, in liposomes or emulsions, in combination with adjuvant. 409. The nanoparticles of claim 387 wherein one or more of the antigens, immunomodulatory agents or targeting agents is covalently bound to the nanoparticles or polymers forming the nanoparticles. 410. The nanoparticles of claim 387 wherein the nanoparticles comprise hydrophilic polymer or lipid on the surface, preferably conjugated to hydrophobic polymer within the nanoparticles. 411. A method of making the nanoparticles of claim 387 comprising forming the nanoparticle with at least a T cell antigen incorporated therein, either in combination with an immunomodulatory agent or having B cell antigen on the surface. 412. A method of therapeutically or prophylactically treating an individual in need thereof comprising administering an effective amount of the nanoparticles of claim 387 to elicit an immune response. 413. The method of claim 412 wherein the individual is in need of vaccination. 414. The method of claim 412 wherein the individual has or is at risk of developing a degenerative disease, an infectious disease, cancer, an atopic disease, an autoimmune disease, an allergy, an addiction, or a metabolic disease. 415. A nanoparticle comprising molecules selected from the group consisting of T cell antigens, B cell antigens, and immunomodulatory agents, wherein the nanoparticle is targeted to dendritic cells, lymph node macrophages, T cells or B cells. 416. A nanoparticle comprising B cell antigens on its surface in a density activating B cell receptors and an immunomodulatory agent. 417. A nanoparticle comprising molecules selected from the group consisting of T cell antigens, B cell antigens, and immunomodulatory agents, wherein the nanoparticle forms by self-assembly.

The present invention provides compositions and systems for delivery of nanocarriers to cells of the immune system. The invention provides vaccine nanocarriers capable of stimulating an immune response in T cells and/or in B cells, in some embodiments, comprising at least one immunomodulatory agent, and optionally comprising at least one targeting moiety and optionally at least one immunostimulatory agent. The invention provides pharmaceutical compositions comprising inventive vaccine nanocarriers. The present invention provides methods of designing, manufacturing, and using inventive vaccine nanocarriers and pharmaceutical compositions thereof. The invention provides methods of prophylaxis and/or treatment of diseases, disorders, and conditions comprising administering at least one inventive vaccine nanocarrier to a subject in need thereof.1-386. (canceled) 387. Nanoparticles formed of polymer or lipid having a diameter of between 40 nm and 400 nm, having incorporated therein T cell antigens, the nanoparticles having bound to or present on the surface B cell antigen, preferably in a density activating B cell receptors, and/or having immunomodulatory agents incorporated therein. 388. The nanoparticles of claim 387 having bound to or present on the surface an agent or material targeting the nanoparticles to secondary lymphoid tissue or cells therein. 389. The nanoparticles of claim 387 comprising a targeting agent for a molecule selected from the group consisting of CD11b, CD169, mannose receptor, DEC-205, CD11c, and CD21/35. 390. The nanoparticles of claim 387 comprising an immunomodulatory agent selected from the group consisting of specific and non-specific immunostimulants. 391. The nanoparticles of claim 390 wherein the immunomodulatory agent non-selectively targets the nanoparticles to secondary lymphoid tissue or cells therein, wherein the agent is selected from the group consisting of an adjuvant, hydrophilic polymer like polyethylene glycol or amphiphilic polymer, emulsion and liposome associated with the nanoparticles. 392. The nanoparticles of claim 387 wherein the targeting agent is selected from molecules specifically binding to targets on cells in the lymphoid tissue. 393. The nanoparticles of claim 392 wherein the targeting agent targets dendritic cells, macrophages, T cells or B cells. 394. The nanoparticles of claim 387 wherein the T cell antigen is a toll-like receptor agonist. 395. The nanoparticles of claim 387 comprising an immunomodulatory agent selected from the group consisting of CpG peptides, cholera toxin, squalene, phosphate adjuvants, tetrachlorodecaoxide, monophosphoryl lipid A, saponines, imidazoquinoline, CD40 agonists, cytokines, and complement receptor agonists. 396. The nanoparticles of claim 387 wherein the B or T cell antigen is selected from the group consisting of proteins, carbohydrates, glycoproteins, lipoproteins, lipids, nucleic acid, metals and inorganic molecules. 397. The nanoparticles of claim 396 wherein the antigen is selected from the group consisting of infectious disease antigens, degenerative disease antigens, cancer antigens, atopic disease antigens, autoimmune disease antigens, allergens, and alto or xeno antigens. 398. The nanoparticles of claim 397 wherein the B-cell antigen is a small molecule addictive substance or toxin. 399. The nanoparticles of claim 398 wherein the B-cell antigen is nicotine, the immunomodulatory agent is a toll-like receptor agonist, and the nanoparticles are formed of polymer, wherein the nicotine is optionally conjugated to the polymer. 400. The nanoparticles of claim 387 wherein the B cell antigens are of bacterial, viral, protozoan, parasite or fungal origin. 401. The nanoparticles of claim 400 wherein the bacterial antigen is selected from the group consisting of diptherial antigens and tetanus antigens and the viral antigen is selected from the group consisting of adenoviral and vesicular stomatitis viral peptides. 402. The nanoparticles of claim 387 wherein the T cell antigen is a self antigen, cancer antigen or allergenic peptide. 403. The nanoparticles of claim 388 comprising agents targeting dendritic cells, lymph node macrophages, T cells or B cells. 404. The nanoparticles of claim 387 comprising polymer having incorporated therein T cell antigen in combination with an immunomodulatory agent, and having B cell antigen on the surface of the nanoparticles. 405. The nanoparticles of claim 387 formed of a hydrophobic polymer or having a hydrophobic core. 406. The nanoparticles of claim 387 formed of a biodegradable polymer. 407. The nanoparticles of claim 406 wherein the polymer is selected from the group consisting of polymers of lactic acid, glycolic acid, polyethylene glycol, polyoxyethyleneoxide, copolymers and block copolymers thereof. 408. The nanoparticles of claim 387 comprising polymeric nanoparticles comprising antigen and targeted to phagocytic cells, in liposomes or emulsions, in combination with adjuvant. 409. The nanoparticles of claim 387 wherein one or more of the antigens, immunomodulatory agents or targeting agents is covalently bound to the nanoparticles or polymers forming the nanoparticles. 410. The nanoparticles of claim 387 wherein the nanoparticles comprise hydrophilic polymer or lipid on the surface, preferably conjugated to hydrophobic polymer within the nanoparticles. 411. A method of making the nanoparticles of claim 387 comprising forming the nanoparticle with at least a T cell antigen incorporated therein, either in combination with an immunomodulatory agent or having B cell antigen on the surface. 412. A method of therapeutically or prophylactically treating an individual in need thereof comprising administering an effective amount of the nanoparticles of claim 387 to elicit an immune response. 413. The method of claim 412 wherein the individual is in need of vaccination. 414. The method of claim 412 wherein the individual has or is at risk of developing a degenerative disease, an infectious disease, cancer, an atopic disease, an autoimmune disease, an allergy, an addiction, or a metabolic disease. 415. A nanoparticle comprising molecules selected from the group consisting of T cell antigens, B cell antigens, and immunomodulatory agents, wherein the nanoparticle is targeted to dendritic cells, lymph node macrophages, T cells or B cells. 416. A nanoparticle comprising B cell antigens on its surface in a density activating B cell receptors and an immunomodulatory agent. 417. A nanoparticle comprising molecules selected from the group consisting of T cell antigens, B cell antigens, and immunomodulatory agents, wherein the nanoparticle forms by self-assembly.

The present invention provides a method for providing alpha-1 antitrypsin (α1-AT) to a subject, in particular a method for treating or preventing a disorder or disease associated with α1-AT deficiency in the subject, wherein the method comprises providing, subcutaneously, a therapeutically or prophylactically effective amount of α1-AT to the subject. Also provided is a composition and article of manufacture comprising α1-AT, in particular a formulation suitable for subcutaneous administration of α1-AT.

1. A method for treating or preventing a disorder or disease associated with α1-AT deficiency in a subject, the method comprising administering, subcutaneously, a therapeutically or prophylactically effective amount of α1-AT to the subject. 2. A method for treating or preventing a disorder or disease associated with α1-AT deficiency in a subject, the method comprising: a) determining a therapeutically or prophylactically effective amount of α1-AT based on a dosing regimen comprising intravenously administered α1-AT; and b) administering, subcutaneously, a dose of at least about 120% of the therapeutically or prophylactically effective amount of α1-AT to the subject. 3. An α1-AT formulation suitable for subcutaneous administration. 4. The formulation of claim 3, wherein the formulation is a lyophilized formulation to be reconstituted prior to administration. 5. A method for treating or preventing a disorder or disease associated with α1-AT deficiency in a subject, the method comprising administering, subcutaneously, a composition comprising a therapeutically or prophylactically effective amount of an α1-AT to the subject, wherein α1-AT is administered in combination with one or more reagents. 6. The method of claim 5, wherein the one or more reagents is a hyaluronidase. 7. The method of claim 6, wherein the composition is a pharmaceutical composition comprising α1-AT and a hyaluronidase, wherein the composition is suitable for subcutaneous administration to the subject. 8. An article of manufacture comprising an α1-AT formulation for subcutaneous administration. 9. The article of claim 8 further comprising a hyaluronidase. 10. The article of claim 8, wherein the formulation further comprises a hyaluronidase.

The present invention provides a method for providing alpha-1 antitrypsin (α1-AT) to a subject, in particular a method for treating or preventing a disorder or disease associated with α1-AT deficiency in the subject, wherein the method comprises providing, subcutaneously, a therapeutically or prophylactically effective amount of α1-AT to the subject. Also provided is a composition and article of manufacture comprising α1-AT, in particular a formulation suitable for subcutaneous administration of α1-AT.1. A method for treating or preventing a disorder or disease associated with α1-AT deficiency in a subject, the method comprising administering, subcutaneously, a therapeutically or prophylactically effective amount of α1-AT to the subject. 2. A method for treating or preventing a disorder or disease associated with α1-AT deficiency in a subject, the method comprising: a) determining a therapeutically or prophylactically effective amount of α1-AT based on a dosing regimen comprising intravenously administered α1-AT; and b) administering, subcutaneously, a dose of at least about 120% of the therapeutically or prophylactically effective amount of α1-AT to the subject. 3. An α1-AT formulation suitable for subcutaneous administration. 4. The formulation of claim 3, wherein the formulation is a lyophilized formulation to be reconstituted prior to administration. 5. A method for treating or preventing a disorder or disease associated with α1-AT deficiency in a subject, the method comprising administering, subcutaneously, a composition comprising a therapeutically or prophylactically effective amount of an α1-AT to the subject, wherein α1-AT is administered in combination with one or more reagents. 6. The method of claim 5, wherein the one or more reagents is a hyaluronidase. 7. The method of claim 6, wherein the composition is a pharmaceutical composition comprising α1-AT and a hyaluronidase, wherein the composition is suitable for subcutaneous administration to the subject. 8. An article of manufacture comprising an α1-AT formulation for subcutaneous administration. 9. The article of claim 8 further comprising a hyaluronidase. 10. The article of claim 8, wherein the formulation further comprises a hyaluronidase.

Provided herein are steroid containing compositions suitable for providing therapeutically effective amounts of at least one steroid to individuals. Also provided herein are compositions comprising testosterone and/or testosterone derivatives suitable for providing therapeutically effective and safe amounts of testosterone over periods of time. Further provided are methods of treating andro- and/or testosterone deficiency in individuals by administering to the individuals compositions described herein.

1. A pharmaceutical composition comprising (i) a therapeutically effective amount of one or more testosterone C2-C13 alkyl ester; and (ii) at least one pharmaceutically acceptable carrier; the pharmaceutical composition releasing about 80% or less of the testosterone C2-C13 alkyl ester after 30 minutes in an aqueous medium. 2. The pharmaceutical composition of claim 1, wherein the testosterone C2-C13 alkyl ester is testosterone undecanoate. 3. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises about 10 mg to about 1000 mg of testosterone C2-C13 alkyl ester. 4. The pharmaceutical composition of claim 1, wherein a single dose of the pharmaceutical composition provides a mean plasma Cmax of testosterone that is about 19 ng/mL or less upon oral administration. 5. The pharmaceutical composition of claim 1, wherein a single dose of the pharmaceutical composition provides a mean plasma Cmax of dihydrotestosterone that is about 4.5 ng/mL or less upon oral administration. 6. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition provides a testosterone mean plasma Cmax at steady state of about 1300 ng/dL or less. 7. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition provides a testosterone mean plasma Cmin at steady state of about 200 ng/dL or more. 8. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition provides with administration to an individual a ratio of a testosterone equivalent dose to a mean steady state testosterone Cmax, the ratio being about 500×106 mL or less. 9. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition provides, with oral administration to an individual, a difference between a mean plasma Cmax of testosterone at steady state and a mean plasma Cmin of testosterone at steady state that is about 16 ng/mL or less. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition provides, with oral administration to an individual, a difference between a mean plasma Cmax at steady state and a mean plasma Cmin at steady state of testosterone C2-C13 alkyl ester that is about 275 ng/mL or less. 11. The pharmaceutical composition of claim 1, wherein a single dose of the pharmaceutical composition provides a mean plasma concentration of testosterone after 1 hour that is about 150 ng/dL or less upon oral administration. 12. The pharmaceutical composition of claim 1, wherein a single dose of the pharmaceutical composition provides a mean plasma concentration of testosterone after 2 hours that is about 500 ng/dL or less upon oral administration. 13. The pharmaceutical composition of claim 1, wherein the at least one pharmaceutically acceptable carrier comprises at least one hydrophilic carrier. 14. The pharmaceutical composition of claim 13, wherein the hydrophilic carrier is a hydrophilic triglyceride. 15. The pharmaceutical composition of claim 14, wherein the hydrophilic triglyceride is a polyoxylated castor oil, or a polyoxylated hydrogenated castor oil. 16. The pharmaceutical composition of claim 1, wherein the at least one pharmaceutically acceptable carrier comprises at least one lipophilic carrier. 17. The pharmaceutical composition of claim 1, wherein the at least one lipophilic carrier is selected from the group consisting of a monoglyceride, a diglyceride, a Vitamin E compound, a trigliceride, a fatty acid, polyoxylated fatty acid, polyoxylated triglyceride, polyoxylated vegetable oil, and a combination thereof. 18. A delayed release oral dosage form comprising (i) a therapeutically effective amount of one or more testosterone C2-C13 alkyl ester; and (ii) at least one pharmaceutically acceptable carrier; wherein a single dose of the delayed release oral dosage form provides a mean plasma Cmax of testosterone that is at least 5% lower than the mean plasma Cmax of testosterone that is provided by a single dose of an immediate release oral dosage form having an identical amount of the testosterone C2-C13 alkyl ester. 19. The delayed release oral dosage form of claim 18, wherein the testosterone C2-C13 alkyl ester is testosterone undecanoate. 20. The delayed release oral dosage form of claim 18, wherein the pharmaceutical composition comprises about 10 mg to about 1000 mg of testosterone C2-C13 alkyl ester. 21-44. (canceled)

Provided herein are steroid containing compositions suitable for providing therapeutically effective amounts of at least one steroid to individuals. Also provided herein are compositions comprising testosterone and/or testosterone derivatives suitable for providing therapeutically effective and safe amounts of testosterone over periods of time. Further provided are methods of treating andro- and/or testosterone deficiency in individuals by administering to the individuals compositions described herein.1. A pharmaceutical composition comprising (i) a therapeutically effective amount of one or more testosterone C2-C13 alkyl ester; and (ii) at least one pharmaceutically acceptable carrier; the pharmaceutical composition releasing about 80% or less of the testosterone C2-C13 alkyl ester after 30 minutes in an aqueous medium. 2. The pharmaceutical composition of claim 1, wherein the testosterone C2-C13 alkyl ester is testosterone undecanoate. 3. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises about 10 mg to about 1000 mg of testosterone C2-C13 alkyl ester. 4. The pharmaceutical composition of claim 1, wherein a single dose of the pharmaceutical composition provides a mean plasma Cmax of testosterone that is about 19 ng/mL or less upon oral administration. 5. The pharmaceutical composition of claim 1, wherein a single dose of the pharmaceutical composition provides a mean plasma Cmax of dihydrotestosterone that is about 4.5 ng/mL or less upon oral administration. 6. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition provides a testosterone mean plasma Cmax at steady state of about 1300 ng/dL or less. 7. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition provides a testosterone mean plasma Cmin at steady state of about 200 ng/dL or more. 8. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition provides with administration to an individual a ratio of a testosterone equivalent dose to a mean steady state testosterone Cmax, the ratio being about 500×106 mL or less. 9. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition provides, with oral administration to an individual, a difference between a mean plasma Cmax of testosterone at steady state and a mean plasma Cmin of testosterone at steady state that is about 16 ng/mL or less. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition provides, with oral administration to an individual, a difference between a mean plasma Cmax at steady state and a mean plasma Cmin at steady state of testosterone C2-C13 alkyl ester that is about 275 ng/mL or less. 11. The pharmaceutical composition of claim 1, wherein a single dose of the pharmaceutical composition provides a mean plasma concentration of testosterone after 1 hour that is about 150 ng/dL or less upon oral administration. 12. The pharmaceutical composition of claim 1, wherein a single dose of the pharmaceutical composition provides a mean plasma concentration of testosterone after 2 hours that is about 500 ng/dL or less upon oral administration. 13. The pharmaceutical composition of claim 1, wherein the at least one pharmaceutically acceptable carrier comprises at least one hydrophilic carrier. 14. The pharmaceutical composition of claim 13, wherein the hydrophilic carrier is a hydrophilic triglyceride. 15. The pharmaceutical composition of claim 14, wherein the hydrophilic triglyceride is a polyoxylated castor oil, or a polyoxylated hydrogenated castor oil. 16. The pharmaceutical composition of claim 1, wherein the at least one pharmaceutically acceptable carrier comprises at least one lipophilic carrier. 17. The pharmaceutical composition of claim 1, wherein the at least one lipophilic carrier is selected from the group consisting of a monoglyceride, a diglyceride, a Vitamin E compound, a trigliceride, a fatty acid, polyoxylated fatty acid, polyoxylated triglyceride, polyoxylated vegetable oil, and a combination thereof. 18. A delayed release oral dosage form comprising (i) a therapeutically effective amount of one or more testosterone C2-C13 alkyl ester; and (ii) at least one pharmaceutically acceptable carrier; wherein a single dose of the delayed release oral dosage form provides a mean plasma Cmax of testosterone that is at least 5% lower than the mean plasma Cmax of testosterone that is provided by a single dose of an immediate release oral dosage form having an identical amount of the testosterone C2-C13 alkyl ester. 19. The delayed release oral dosage form of claim 18, wherein the testosterone C2-C13 alkyl ester is testosterone undecanoate. 20. The delayed release oral dosage form of claim 18, wherein the pharmaceutical composition comprises about 10 mg to about 1000 mg of testosterone C2-C13 alkyl ester. 21-44. (canceled)

The present invention relates to a mixture comprising (i) one or a plurality of 1,2-alkane diols with 5 through 8 carbon atoms and (ii) one or a plurality of ammonium-, sodium- or potassium-R alk -sarcosinates, wherein the structural element R alk represents alkanoyl, alkenoyl or alkadienoyl with 12 through 22 carbon atoms, and optionally (iii) one or a plurality of sodium- or potassium-C10-C16-alkyl-sulfoacetates. The invention further relates to particular compositions and cosmetic preparations, in particular body care products, containing said mixture or composition and methods of production thereof. The present invention further relates to the use of said mixture as solubilizer and for increasing the transparency or decreasing the turbidity of a preparation containing one or a plurality of further organic substances.

1-21. (canceled) 22. A method of increasing the solubility of pane or a plurality of organic substances, decreasing the turbidity of a preparation containing one or a plurality f organic substances, increasing the transparency of a preparation containing one or a plurality of organic, substances, wherein the organic substances have in each a log KOW value, the range from 1 through 12, comprising the step of: mixing the one or more organic substances with a solubilizer mixture comprising: (i) one or more 1,2-alkane diols co uprising 5-8 carbon atoms, (ii) one or more ammonium-, sodium- or potassium-Ralk-sarcosinates, wherein Ralk is alkanoyl, alkenoyl or alkadienoyl comprising 12-22 carbon atoms, and (iii) optionally one or more sodium- or potassium-C10-C16-alkyl-sulfoacetates. 23. A method of improving the solubilizing action of a surfactant, comprising the step of mixing a 1,2-alkane diol having 5-8 carbon atoms or a mixture of 1,2-alkane diols having 5-8 carbon atoms with the surfactant, wherein the surfactant is selected from the group consisting of sodium oleoyl sarcosinate, sodium lauryl sulfoacetate and mixtures thereof. 24. The method of claim 23, wherein in a mixture of sodium oleoyl sarcosinate and sodium lauryl sulfoacetate, the weight ratio is from 10:1 to 1:4. 25. The method of claim 24, wherein the weight ratio is from 4:1 to 1:2. 26. The method of claim 22, wherein the preparation is dispersion and/or an emulsion.

The present invention relates to a mixture comprising (i) one or a plurality of 1,2-alkane diols with 5 through 8 carbon atoms and (ii) one or a plurality of ammonium-, sodium- or potassium-R alk -sarcosinates, wherein the structural element R alk represents alkanoyl, alkenoyl or alkadienoyl with 12 through 22 carbon atoms, and optionally (iii) one or a plurality of sodium- or potassium-C10-C16-alkyl-sulfoacetates. The invention further relates to particular compositions and cosmetic preparations, in particular body care products, containing said mixture or composition and methods of production thereof. The present invention further relates to the use of said mixture as solubilizer and for increasing the transparency or decreasing the turbidity of a preparation containing one or a plurality of further organic substances.1-21. (canceled) 22. A method of increasing the solubility of pane or a plurality of organic substances, decreasing the turbidity of a preparation containing one or a plurality f organic substances, increasing the transparency of a preparation containing one or a plurality of organic, substances, wherein the organic substances have in each a log KOW value, the range from 1 through 12, comprising the step of: mixing the one or more organic substances with a solubilizer mixture comprising: (i) one or more 1,2-alkane diols co uprising 5-8 carbon atoms, (ii) one or more ammonium-, sodium- or potassium-Ralk-sarcosinates, wherein Ralk is alkanoyl, alkenoyl or alkadienoyl comprising 12-22 carbon atoms, and (iii) optionally one or more sodium- or potassium-C10-C16-alkyl-sulfoacetates. 23. A method of improving the solubilizing action of a surfactant, comprising the step of mixing a 1,2-alkane diol having 5-8 carbon atoms or a mixture of 1,2-alkane diols having 5-8 carbon atoms with the surfactant, wherein the surfactant is selected from the group consisting of sodium oleoyl sarcosinate, sodium lauryl sulfoacetate and mixtures thereof. 24. The method of claim 23, wherein in a mixture of sodium oleoyl sarcosinate and sodium lauryl sulfoacetate, the weight ratio is from 10:1 to 1:4. 25. The method of claim 24, wherein the weight ratio is from 4:1 to 1:2. 26. The method of claim 22, wherein the preparation is dispersion and/or an emulsion.

The present invention relates to stable emulsifiable concentrates comprising an oil adjuvant and at least one member selected from the group consisting of herbicidally active 2-[4[(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionic acid derivatives and quinoline derivative safeners and to the use thereof as a pesticide.

1. An emulsifiable concentrate comprising: a) a herbicidally effective amount, preferably 1 to 30% by weight, of at least one herbicide; b) optionally, an amount, which is effective for antagonism of a herbicide, of at least one safener; c) 5 to 80%, preferably 25 to 70%, by weight of at least one oil adjuvant, wherein said oil adjuvant comprises an oil of vegetable or animal origin, or a mineral oil, alkyl esters thereof or mixtures of those oils and oil derivatives; d) an amount of at least one water-immiscible solvent sufficient to keep the AI and safener in solution in the presence of the adjuvant, preferably 5 to 70% by weight, more preferably 25 to 60% by weight; and e) an emulsifying surfactant system in an amount sufficient to form an oil-in-water emulsion when the formulation is added to water, preferably between 1 and 30% by weight; with the proviso that a) comprises a herbicidally effective amount of at least one compound of formula I wherein Hal is halogen Q is oxygen or sulfur, R is hydrogen, an alkali metal ion, or a quaternary C1-C4-alkylammonium group, a C1-C6-alkyl group which is straight-chain or branched-chain, and which is unsubstituted or substituted by halogen, cyano, C1-C4-alkoxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, carbamoyl or di-C1-C4-alkylcarbamoyl, a C3-C6-cycloalkyl group, a C3-C6-alkenyl group, which is straight-chain or branched-chain, and is unsubstituted or substituted by halogen, a C3-C6-alkynyl group, which is straight-chain or branched-chain, and is unsubstituted or substituted by halogen, a group wherein R1 and R2 separately are each a C1-C4-alkyl group, or together form a 4- or 5-membered methylene chain, which can be substituted by C1-C4-alkyl; and/or b) comprises an amount, which is effective for antagonism of a herbicide, of at least one quinoline derivative safener; wherein the emulsifiable concentrate has a pH when diluted to 1% concentration in distilled water in the range of 4.5 to 8.0, preferably 5.0 to 7.0; and wherein the emulsifiable concentrate contains less than 2.5%, preferably less than 2.0%, water. 2. The emulsifiable concentrate of claim 1 comprising a herbicidally effective amount of a compound of formula I. 3. The emulsifiable concentrate of claim 2 wherein the compound of formula I is clodinafop-propargyl. 4. The emulsifiable concentrate of claim 1 wherein the oil adjuvant comprises a methyl ester of a plant oil. 5. The emulsifiable concentrate of claim 3 wherein the oil adjuvant comprises a methyl ester of canola oil. 6. The emulsifiable concentrate of claim 1 wherein the emulsifying surfactant system comprises at least one non-ionic surfactant. 7. The emulsifiable concentrate of claim 1 comprising b) at least one safener selected from the group consisting of quinoline derivatives; benoxacor; dichlormid; fenchlorazole-ethyl; fenclorim; flurazole; fluxofenim; furilazole; isoxadifen-ethyl; mefenpyr, an alkali metal, alkaline earth metal, sulfonium or ammonium cation of mefenpyr, mefenpyr-diethyl and oxabetrinil. 8. The emulsifiable concentrate of claim 7 wherein the safener comprises a quinoline derivative. 9. The emulsifiable concentrate of claim 8 wherein the quinoline derivative comprises at least one member selected from the group consisting of cloquintocet; an alkali metal, alkaline earth metal, sulfonium or ammonium cation of cloquintocet; and cloquintocet-mexyl. 10. The emulsifiable concentrate of claim 9 wherein the safener comprises cloquintocet-mexyl. 11. The emulsifiable concentrate of claim 1 wherein the herbicide comprises cloquintocet-mexyl and the safener comprises cloquintocet-mexyl. 12. The emulsifiable concentrate of claim 1 wherein the pH is in the range of from 5.0 to 7.0. 13. The emulsifiable concentrate of claim 1 wherein the water content is less than 2.0% by weight. 14. The emulsifiable concentrate of claim 1 further comprising at least one member selected from the group consisting of co-herbicides, fungicides, insecticides, acaricides and nematicides. 15. The emulsifiable concentrate of claim 1 further comprising at least one member selected from the group consisting of chemical stabilizers, viscosity controlling agents, thickeners, binders, tackifiers, fertilizers and anti-foam agents 16. A pesticidal composition obtained by diluting an emulsifiable concentrate according to claim 1 in a suitable amount of water to form an oil-in-water emulsion. 17. The pesticidal composition of claim 16 further comprising at least one member selected from the group consisting of co-herbicides, fungicides, insecticides, acaricides, and nematicides 18. A method for the selective control of weeds in crops of useful plants, which method comprises treating the useful plants, their seeds or seedlings or the crop area thereof with a pesticidal composition according to claim 16. 19. The method according to claim 18 wherein the crops of useful plants are selected from the group consisting of maize, cereals, rice and soybeans. 20. The method according to claim 19 wherein the crops of useful plants are cereals. 21. The method according to claim 20 wherein the crop of useful plants is wheat or barley.

The present invention relates to stable emulsifiable concentrates comprising an oil adjuvant and at least one member selected from the group consisting of herbicidally active 2-[4[(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionic acid derivatives and quinoline derivative safeners and to the use thereof as a pesticide.1. An emulsifiable concentrate comprising: a) a herbicidally effective amount, preferably 1 to 30% by weight, of at least one herbicide; b) optionally, an amount, which is effective for antagonism of a herbicide, of at least one safener; c) 5 to 80%, preferably 25 to 70%, by weight of at least one oil adjuvant, wherein said oil adjuvant comprises an oil of vegetable or animal origin, or a mineral oil, alkyl esters thereof or mixtures of those oils and oil derivatives; d) an amount of at least one water-immiscible solvent sufficient to keep the AI and safener in solution in the presence of the adjuvant, preferably 5 to 70% by weight, more preferably 25 to 60% by weight; and e) an emulsifying surfactant system in an amount sufficient to form an oil-in-water emulsion when the formulation is added to water, preferably between 1 and 30% by weight; with the proviso that a) comprises a herbicidally effective amount of at least one compound of formula I wherein Hal is halogen Q is oxygen or sulfur, R is hydrogen, an alkali metal ion, or a quaternary C1-C4-alkylammonium group, a C1-C6-alkyl group which is straight-chain or branched-chain, and which is unsubstituted or substituted by halogen, cyano, C1-C4-alkoxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, carbamoyl or di-C1-C4-alkylcarbamoyl, a C3-C6-cycloalkyl group, a C3-C6-alkenyl group, which is straight-chain or branched-chain, and is unsubstituted or substituted by halogen, a C3-C6-alkynyl group, which is straight-chain or branched-chain, and is unsubstituted or substituted by halogen, a group wherein R1 and R2 separately are each a C1-C4-alkyl group, or together form a 4- or 5-membered methylene chain, which can be substituted by C1-C4-alkyl; and/or b) comprises an amount, which is effective for antagonism of a herbicide, of at least one quinoline derivative safener; wherein the emulsifiable concentrate has a pH when diluted to 1% concentration in distilled water in the range of 4.5 to 8.0, preferably 5.0 to 7.0; and wherein the emulsifiable concentrate contains less than 2.5%, preferably less than 2.0%, water. 2. The emulsifiable concentrate of claim 1 comprising a herbicidally effective amount of a compound of formula I. 3. The emulsifiable concentrate of claim 2 wherein the compound of formula I is clodinafop-propargyl. 4. The emulsifiable concentrate of claim 1 wherein the oil adjuvant comprises a methyl ester of a plant oil. 5. The emulsifiable concentrate of claim 3 wherein the oil adjuvant comprises a methyl ester of canola oil. 6. The emulsifiable concentrate of claim 1 wherein the emulsifying surfactant system comprises at least one non-ionic surfactant. 7. The emulsifiable concentrate of claim 1 comprising b) at least one safener selected from the group consisting of quinoline derivatives; benoxacor; dichlormid; fenchlorazole-ethyl; fenclorim; flurazole; fluxofenim; furilazole; isoxadifen-ethyl; mefenpyr, an alkali metal, alkaline earth metal, sulfonium or ammonium cation of mefenpyr, mefenpyr-diethyl and oxabetrinil. 8. The emulsifiable concentrate of claim 7 wherein the safener comprises a quinoline derivative. 9. The emulsifiable concentrate of claim 8 wherein the quinoline derivative comprises at least one member selected from the group consisting of cloquintocet; an alkali metal, alkaline earth metal, sulfonium or ammonium cation of cloquintocet; and cloquintocet-mexyl. 10. The emulsifiable concentrate of claim 9 wherein the safener comprises cloquintocet-mexyl. 11. The emulsifiable concentrate of claim 1 wherein the herbicide comprises cloquintocet-mexyl and the safener comprises cloquintocet-mexyl. 12. The emulsifiable concentrate of claim 1 wherein the pH is in the range of from 5.0 to 7.0. 13. The emulsifiable concentrate of claim 1 wherein the water content is less than 2.0% by weight. 14. The emulsifiable concentrate of claim 1 further comprising at least one member selected from the group consisting of co-herbicides, fungicides, insecticides, acaricides and nematicides. 15. The emulsifiable concentrate of claim 1 further comprising at least one member selected from the group consisting of chemical stabilizers, viscosity controlling agents, thickeners, binders, tackifiers, fertilizers and anti-foam agents 16. A pesticidal composition obtained by diluting an emulsifiable concentrate according to claim 1 in a suitable amount of water to form an oil-in-water emulsion. 17. The pesticidal composition of claim 16 further comprising at least one member selected from the group consisting of co-herbicides, fungicides, insecticides, acaricides, and nematicides 18. A method for the selective control of weeds in crops of useful plants, which method comprises treating the useful plants, their seeds or seedlings or the crop area thereof with a pesticidal composition according to claim 16. 19. The method according to claim 18 wherein the crops of useful plants are selected from the group consisting of maize, cereals, rice and soybeans. 20. The method according to claim 19 wherein the crops of useful plants are cereals. 21. The method according to claim 20 wherein the crop of useful plants is wheat or barley.

Methods of administering immunoconjugates that bind to FOLR1 are provided. The methods comprise administering an anti-FOLR1 immunoconjugate to a person in need thereof, for example, a cancer patient, at a therapeutically effective dosing regimen that results in minimal adverse effects.

1. A method for treating a human patient having an FOLR1-expressing cancer comprising administering to the patient an immunoconjugate which binds to FOLR1 polypeptide, wherein the immunoconjugate is administered at a dose of about 3.0 to about 7 milligrams (mg) per kilogram (kg) of body weight of the patient, wherein the kilograms of body weight of the patient are adjusted to adjusted ideal body weight (AIBW). 2. (canceled) 3. (canceled) 4. (canceled) 5. The method of claim 1, wherein the immunoconjugate is administered at a dose of about 5.0 mg/kg. 6. The method of claim 1, wherein the immunoconjugate is administered at a dose of about 6.0 mg/kg. 7. The method of claim 1, wherein the immunoconjugate is administered at a dose of about 6.5 mg/kg. 8. The method of claim 1, wherein the immunoconjugate is administered once every three weeks. 9. The method of claim 1, wherein the immunoconjugate is administered once every week. 10. A method for treating a human patient having an FOLR1-expressing cancer comprising administering to the patient an immunoconjugate which binds to FOLR1 polypeptide, wherein the immunoconjugate is administered at a dose of about 3.0 to about 7 milligrams (mg) per kilogram (kg) of body weight of the patient, and wherein the administration produces a Cmax of about 110-160 μg/mL. 11. (canceled) 12. A method for treating a human patient having an FOLR1-expressing cancer comprising administering to the patient an immunoconjugate which binds to FOLR1 polypeptide, wherein the immunoconjugate is administered at a dose of about 3.0 to about 7 milligrams (mg) per kilogram (/kg) of body weight of the patient, and wherein the administration produces an AUC0-24 of no more than 2700 hr·μg/mL. 13. The method of claim 1, wherein the immunoconjugate comprises an antibody or antigen-binding fragment thereof that comprises the CDRs of SEQ ID NOs: 6-9, 11, and 12. 14. (canceled) 15. (canceled) 16. (canceled) 17. (canceled) 18. The method of claim 1, wherein the immunoconjugate is IMGN853. 19. (canceled) 20. The method of claim 1, wherein said cancer is selected from the group consisting of ovarian, brain, breast, uterine, endometrial, pancreatic, renal, and lung cancer. 21. (canceled) 22. (canceled) 23. (canceled) 24. (canceled) 25. (canceled) 26. (canceled) 27. (canceled) 28. (canceled) 29. (canceled) 30. (canceled) 31. (canceled) 32. (canceled) 33. The method of claim 1, wherein the administration results in a decrease in tumor size. 34. (canceled) 35. (canceled) 36. The method of claim 1, wherein the administration results in decreased ocular toxicity. 37. (canceled) 38. (canceled) 39. (canceled) 40. A method for treating a human patient having an FOLR1-expressing cancer comprising administering to the patient an effective dose of an immunoconjugate which binds to FOLR1 polypeptide, wherein the administration produces an AUC0-24 of no more than 2741 hr·μg/mL. 41. (canceled) 42. (canceled) 43. (canceled) 44. (canceled) 45. (canceled) 46. (canceled) 47. (canceled) 48. (canceled) 49. (canceled) 50. (canceled) 51. (canceled) 52. (canceled) 53. (canceled) 54. (canceled) 55. (canceled) 56. (canceled) 57. (canceled) 58. (canceled) 59. (canceled) 60. (canceled) 61. (canceled) 62. (canceled) 63. (canceled) 64. (canceled) 65. (canceled) 66. (canceled) 67. (canceled) 68. A method for treating a human patient having a FOLR1-expressing cancer comprising administering to the patient an immunoconjugate which binds to FOLR1 polypeptide, wherein the immunoconjugate is administered once a week for three weeks on a four-week schedule. 69. The method of claim 68, wherein the immunoconjugate is administered on days 1, 8, and 15 of a four-week schedule. 70. (canceled) 71. (canceled) 72. (canceled) 73. (canceled) 74. (canceled) 75. The method of claim 68, wherein the immunoconjugate is administered at a dose of about 1.5 to about 6 mg/kg. 76. (canceled) 77. (canceled) 78. (canceled) 79. (canceled) 80. (canceled) 81. (canceled) 82. (canceled) 83. (canceled) 84. (canceled) 85. (canceled) 86. (canceled) 87. (canceled) 88. (canceled) 89. (canceled) 90. (canceled) 91. (canceled) 92. A method for treating a human patient having an FOLR1-expressing cancer comprising administering to the patient an immunoconjugate which binds to FOLR1 polypeptide, wherein the immunoconjugate is administered at a dose of about 1 to about 7 milligrams (mg) per kilogram (kg) of body weight of the patient, wherein the kilograms of body weight of the patient are adjusted to adjusted ideal body weight and wherein the immunoconjugate is administered once a week for three weeks on a four-week schedule. 93. The method of claim 92, wherein the immunoconjugate is administered on days 1, 8, and 15 of the four-week schedule. 94. The method of claim 92, wherein the immunoconjugate is administered at a dose of about 1.1 mg/kg. 95. The method of claim 92, wherein the immunoconjugate is administered at a dose of about 1.8 mg/kg. 96. The method of claim 92, wherein the immunoconjugate is administered at a dose of about 2.5 mg/kg. 97. The method of claim 92, wherein the immunoconjugate is administered at a dose of about 3.3 mg/kg. 98. (canceled) 99. (canceled) 100. (canceled) 101. (canceled) 102. (canceled) 103. (canceled) 104. (canceled) 105. (canceled) 106. (canceled) 107. (canceled) 108. (canceled) 109. (canceled) 110. (canceled) 111. (canceled) 112. (canceled) 113. (canceled) 114. (canceled) 115. (canceled) 116. (canceled) 117. (canceled) 118. (canceled) 119. (canceled) 120. (canceled) 121. (canceled) 122. (canceled) 123. (canceled) 124. (canceled) 125. (canceled) 126. (canceled) 127. (canceled) 128. The method of claim 92, wherein the immunoconjugate is administered at a dose of about 2.8 mg/kg. 129. The method of claim 92, wherein the immunoconjugate is administered at a dose of about 3.0 mg/kg. 130. The method of claim 92, wherein the immunoconjugate is administered at a dose of about 3.75 mg/kg. 131. (canceled) 132. (canceled) 133. The method of claim 92, wherein the immunoconjugate is administered at a dose of about 2.0 mg/kg.

Methods of administering immunoconjugates that bind to FOLR1 are provided. The methods comprise administering an anti-FOLR1 immunoconjugate to a person in need thereof, for example, a cancer patient, at a therapeutically effective dosing regimen that results in minimal adverse effects.1. A method for treating a human patient having an FOLR1-expressing cancer comprising administering to the patient an immunoconjugate which binds to FOLR1 polypeptide, wherein the immunoconjugate is administered at a dose of about 3.0 to about 7 milligrams (mg) per kilogram (kg) of body weight of the patient, wherein the kilograms of body weight of the patient are adjusted to adjusted ideal body weight (AIBW). 2. (canceled) 3. (canceled) 4. (canceled) 5. The method of claim 1, wherein the immunoconjugate is administered at a dose of about 5.0 mg/kg. 6. The method of claim 1, wherein the immunoconjugate is administered at a dose of about 6.0 mg/kg. 7. The method of claim 1, wherein the immunoconjugate is administered at a dose of about 6.5 mg/kg. 8. The method of claim 1, wherein the immunoconjugate is administered once every three weeks. 9. The method of claim 1, wherein the immunoconjugate is administered once every week. 10. A method for treating a human patient having an FOLR1-expressing cancer comprising administering to the patient an immunoconjugate which binds to FOLR1 polypeptide, wherein the immunoconjugate is administered at a dose of about 3.0 to about 7 milligrams (mg) per kilogram (kg) of body weight of the patient, and wherein the administration produces a Cmax of about 110-160 μg/mL. 11. (canceled) 12. A method for treating a human patient having an FOLR1-expressing cancer comprising administering to the patient an immunoconjugate which binds to FOLR1 polypeptide, wherein the immunoconjugate is administered at a dose of about 3.0 to about 7 milligrams (mg) per kilogram (/kg) of body weight of the patient, and wherein the administration produces an AUC0-24 of no more than 2700 hr·μg/mL. 13. The method of claim 1, wherein the immunoconjugate comprises an antibody or antigen-binding fragment thereof that comprises the CDRs of SEQ ID NOs: 6-9, 11, and 12. 14. (canceled) 15. (canceled) 16. (canceled) 17. (canceled) 18. The method of claim 1, wherein the immunoconjugate is IMGN853. 19. (canceled) 20. The method of claim 1, wherein said cancer is selected from the group consisting of ovarian, brain, breast, uterine, endometrial, pancreatic, renal, and lung cancer. 21. (canceled) 22. (canceled) 23. (canceled) 24. (canceled) 25. (canceled) 26. (canceled) 27. (canceled) 28. (canceled) 29. (canceled) 30. (canceled) 31. (canceled) 32. (canceled) 33. The method of claim 1, wherein the administration results in a decrease in tumor size. 34. (canceled) 35. (canceled) 36. The method of claim 1, wherein the administration results in decreased ocular toxicity. 37. (canceled) 38. (canceled) 39. (canceled) 40. A method for treating a human patient having an FOLR1-expressing cancer comprising administering to the patient an effective dose of an immunoconjugate which binds to FOLR1 polypeptide, wherein the administration produces an AUC0-24 of no more than 2741 hr·μg/mL. 41. (canceled) 42. (canceled) 43. (canceled) 44. (canceled) 45. (canceled) 46. (canceled) 47. (canceled) 48. (canceled) 49. (canceled) 50. (canceled) 51. (canceled) 52. (canceled) 53. (canceled) 54. (canceled) 55. (canceled) 56. (canceled) 57. (canceled) 58. (canceled) 59. (canceled) 60. (canceled) 61. (canceled) 62. (canceled) 63. (canceled) 64. (canceled) 65. (canceled) 66. (canceled) 67. (canceled) 68. A method for treating a human patient having a FOLR1-expressing cancer comprising administering to the patient an immunoconjugate which binds to FOLR1 polypeptide, wherein the immunoconjugate is administered once a week for three weeks on a four-week schedule. 69. The method of claim 68, wherein the immunoconjugate is administered on days 1, 8, and 15 of a four-week schedule. 70. (canceled) 71. (canceled) 72. (canceled) 73. (canceled) 74. (canceled) 75. The method of claim 68, wherein the immunoconjugate is administered at a dose of about 1.5 to about 6 mg/kg. 76. (canceled) 77. (canceled) 78. (canceled) 79. (canceled) 80. (canceled) 81. (canceled) 82. (canceled) 83. (canceled) 84. (canceled) 85. (canceled) 86. (canceled) 87. (canceled) 88. (canceled) 89. (canceled) 90. (canceled) 91. (canceled) 92. A method for treating a human patient having an FOLR1-expressing cancer comprising administering to the patient an immunoconjugate which binds to FOLR1 polypeptide, wherein the immunoconjugate is administered at a dose of about 1 to about 7 milligrams (mg) per kilogram (kg) of body weight of the patient, wherein the kilograms of body weight of the patient are adjusted to adjusted ideal body weight and wherein the immunoconjugate is administered once a week for three weeks on a four-week schedule. 93. The method of claim 92, wherein the immunoconjugate is administered on days 1, 8, and 15 of the four-week schedule. 94. The method of claim 92, wherein the immunoconjugate is administered at a dose of about 1.1 mg/kg. 95. The method of claim 92, wherein the immunoconjugate is administered at a dose of about 1.8 mg/kg. 96. The method of claim 92, wherein the immunoconjugate is administered at a dose of about 2.5 mg/kg. 97. The method of claim 92, wherein the immunoconjugate is administered at a dose of about 3.3 mg/kg. 98. (canceled) 99. (canceled) 100. (canceled) 101. (canceled) 102. (canceled) 103. (canceled) 104. (canceled) 105. (canceled) 106. (canceled) 107. (canceled) 108. (canceled) 109. (canceled) 110. (canceled) 111. (canceled) 112. (canceled) 113. (canceled) 114. (canceled) 115. (canceled) 116. (canceled) 117. (canceled) 118. (canceled) 119. (canceled) 120. (canceled) 121. (canceled) 122. (canceled) 123. (canceled) 124. (canceled) 125. (canceled) 126. (canceled) 127. (canceled) 128. The method of claim 92, wherein the immunoconjugate is administered at a dose of about 2.8 mg/kg. 129. The method of claim 92, wherein the immunoconjugate is administered at a dose of about 3.0 mg/kg. 130. The method of claim 92, wherein the immunoconjugate is administered at a dose of about 3.75 mg/kg. 131. (canceled) 132. (canceled) 133. The method of claim 92, wherein the immunoconjugate is administered at a dose of about 2.0 mg/kg.

A whitening dentifrice composition, free from peroxide whitening agents, includes a blue coloring agent, a zinc core shell silica (Zn-CSS) particle, and an orally acceptable vehicle including a non-aqueous solvent and water. The blue coloring agent includes at least one of a blue pigment and a blue dye and has a blue to blue-violet color with a hue angle in the CIELAB system ranging from 200 degrees to 320 degrees. The Zn-CSS particle includes a silica core, and a surface of the silica core etched with a metal silicate, which is a silicate of zinc ion and optionally a monovalent metal ion.

1. A whitening dentifrice composition comprising: a blue coloring agent comprising at least one of a blue pigment and a blue dye, wherein the blue coloring agent has a blue to blue-violet color with a hue angle in the CIELAB system ranging from 200 degrees to 320 degrees; a zinc core shell silica (Zn-CSS) particle, wherein the Zn-CSS particle comprises a silica core, and a surface of the silica core etched with a metal silicate, wherein the metal silicate is a silicate of zinc ion and optionally a monovalent metal ion; and an orally acceptable vehicle comprising a non-aqueous solvent and water, wherein the whitening dentifrice composition is free from peroxide whitening agents and oxidants. 2. The whitening dentifrice composition of claim 1, wherein the zinc ion is present in an amount of from 0.01 to 1 weight %, based on the total amount of the whitening dentifrice composition. 3. The whitening dentifrice composition of claim 1, wherein the surface of the silica core of the Zn-CSS particle is represented by the following formula: (SiO2)p[Oo*Mn +Znm 2+Hh + ].qH2O wherein O* is oxygen in the silicate form; M is a monovalent metal ion; Zn is divalent zinc ion; p, o, n, m, h and q are the atomic percentages of each component; and the total charge of each core shell silica particle is zero. 4. The whitening dentifrice composition of claim 1, wherein the non-aqueous solvent is present in an amount from 25 to 95 weight % and water is present in an amount from 3 to 30 weight %, based on the total amount of the whitening dentifrice composition. 5. The whitening dentifrice composition of claim 1, wherein the non-aqueous solvent is in present in an amount from 3 to 50 weight % and water is present in an amount from 25 to 70 weight %, based on the total amount of the whitening dentifrice composition. 6. The whitening dentifrice composition of claim 1, wherein the blue coloring agent is a blue dye present in an amount of from 0.02 to 2 weight %, based on the total amount of the whitening dentifrice composition. 7. The whitening dentifrice composition of claim 1, wherein the blue coloring agent comprises at least one of FD&C Blue#1, FD&C Blue #2, D&C Blue #4, CI Food Blue 5, and Acid Blue 1. 8. The whitening dentifrice composition of claim 1, wherein the blue coloring agent is a blue pigment present in an amount of from 0.01 to 0.075 weight %, based on the total amount of the whitening dentifrice composition. 9. The whitening dentifrice composition of claim 1, wherein the blue coloring agent comprises at least one of a violet pigment #1 through to violet pigment #56 and pigment blue 1 through to pigment blue 83, as listed in the Color Index International. 10. The whitening dentifrice composition of claim 1, wherein the blue coloring agent is a blue pigment #15 or a blue pigment #5. 11. The whitening dentifrice composition of claim 1, wherein the whitening dentifrice composition provides a greater whitening benefit for the blue coloring agent than a comparative dentifrice composition that is identical to the whitening dentifrice composition of claim 1, except that the comparative dentifrice composition either has core shell silica with no zinc (CSS) or has no core shell silica. 12. The whitening dentifrice composition of claim 11, wherein the greater whitening benefit comprises at least one of greater initial whitening benefit and a longer-lasting whitening benefit. 13. The whitening dentifrice composition of claim 1, wherein the non-aqueous solvent comprises glycerin, sorbitol, xylitol, propylene glycol, polyols, ketones, aldehydes, carboxylic acids or salts thereof, amines, or mixtures thereof. 14. A method for whitening a tooth surface comprising contacting the whitening dentifrice composition of claim 1 with the tooth surface. 15. A use of a zinc core shell silica (Zn-CSS) particle as a tooth whitening enhancing agent in a whitening dentifrice composition, wherein the whitening dentifrice composition further comprises: a blue coloring agent comprising at least one of a blue pigment and a blue dye, wherein the blue coloring agent has a blue to blue-violet color with a hue angle in the CIELAB system ranging from 200 degrees to 320 degrees; and an orally acceptable vehicle comprising a non-aqueous solvent and water, wherein the Zn-CSS particle comprises a silica core, and a surface of the silica core etched with a metal silicate, wherein the metal silicate is a silicate of Zinc ion or Zinc ion and a monovalent metal ion, and wherein the whitening dentifrice composition is free from peroxide whitening agents and oxidants.

A whitening dentifrice composition, free from peroxide whitening agents, includes a blue coloring agent, a zinc core shell silica (Zn-CSS) particle, and an orally acceptable vehicle including a non-aqueous solvent and water. The blue coloring agent includes at least one of a blue pigment and a blue dye and has a blue to blue-violet color with a hue angle in the CIELAB system ranging from 200 degrees to 320 degrees. The Zn-CSS particle includes a silica core, and a surface of the silica core etched with a metal silicate, which is a silicate of zinc ion and optionally a monovalent metal ion.1. A whitening dentifrice composition comprising: a blue coloring agent comprising at least one of a blue pigment and a blue dye, wherein the blue coloring agent has a blue to blue-violet color with a hue angle in the CIELAB system ranging from 200 degrees to 320 degrees; a zinc core shell silica (Zn-CSS) particle, wherein the Zn-CSS particle comprises a silica core, and a surface of the silica core etched with a metal silicate, wherein the metal silicate is a silicate of zinc ion and optionally a monovalent metal ion; and an orally acceptable vehicle comprising a non-aqueous solvent and water, wherein the whitening dentifrice composition is free from peroxide whitening agents and oxidants. 2. The whitening dentifrice composition of claim 1, wherein the zinc ion is present in an amount of from 0.01 to 1 weight %, based on the total amount of the whitening dentifrice composition. 3. The whitening dentifrice composition of claim 1, wherein the surface of the silica core of the Zn-CSS particle is represented by the following formula: (SiO2)p[Oo*Mn +Znm 2+Hh + ].qH2O wherein O* is oxygen in the silicate form; M is a monovalent metal ion; Zn is divalent zinc ion; p, o, n, m, h and q are the atomic percentages of each component; and the total charge of each core shell silica particle is zero. 4. The whitening dentifrice composition of claim 1, wherein the non-aqueous solvent is present in an amount from 25 to 95 weight % and water is present in an amount from 3 to 30 weight %, based on the total amount of the whitening dentifrice composition. 5. The whitening dentifrice composition of claim 1, wherein the non-aqueous solvent is in present in an amount from 3 to 50 weight % and water is present in an amount from 25 to 70 weight %, based on the total amount of the whitening dentifrice composition. 6. The whitening dentifrice composition of claim 1, wherein the blue coloring agent is a blue dye present in an amount of from 0.02 to 2 weight %, based on the total amount of the whitening dentifrice composition. 7. The whitening dentifrice composition of claim 1, wherein the blue coloring agent comprises at least one of FD&C Blue#1, FD&C Blue #2, D&C Blue #4, CI Food Blue 5, and Acid Blue 1. 8. The whitening dentifrice composition of claim 1, wherein the blue coloring agent is a blue pigment present in an amount of from 0.01 to 0.075 weight %, based on the total amount of the whitening dentifrice composition. 9. The whitening dentifrice composition of claim 1, wherein the blue coloring agent comprises at least one of a violet pigment #1 through to violet pigment #56 and pigment blue 1 through to pigment blue 83, as listed in the Color Index International. 10. The whitening dentifrice composition of claim 1, wherein the blue coloring agent is a blue pigment #15 or a blue pigment #5. 11. The whitening dentifrice composition of claim 1, wherein the whitening dentifrice composition provides a greater whitening benefit for the blue coloring agent than a comparative dentifrice composition that is identical to the whitening dentifrice composition of claim 1, except that the comparative dentifrice composition either has core shell silica with no zinc (CSS) or has no core shell silica. 12. The whitening dentifrice composition of claim 11, wherein the greater whitening benefit comprises at least one of greater initial whitening benefit and a longer-lasting whitening benefit. 13. The whitening dentifrice composition of claim 1, wherein the non-aqueous solvent comprises glycerin, sorbitol, xylitol, propylene glycol, polyols, ketones, aldehydes, carboxylic acids or salts thereof, amines, or mixtures thereof. 14. A method for whitening a tooth surface comprising contacting the whitening dentifrice composition of claim 1 with the tooth surface. 15. A use of a zinc core shell silica (Zn-CSS) particle as a tooth whitening enhancing agent in a whitening dentifrice composition, wherein the whitening dentifrice composition further comprises: a blue coloring agent comprising at least one of a blue pigment and a blue dye, wherein the blue coloring agent has a blue to blue-violet color with a hue angle in the CIELAB system ranging from 200 degrees to 320 degrees; and an orally acceptable vehicle comprising a non-aqueous solvent and water, wherein the Zn-CSS particle comprises a silica core, and a surface of the silica core etched with a metal silicate, wherein the metal silicate is a silicate of Zinc ion or Zinc ion and a monovalent metal ion, and wherein the whitening dentifrice composition is free from peroxide whitening agents and oxidants.

Systems and methods are described relating to accepting an indication of a schedule for administration of a memory-dampening agent to an individual and presenting an indication of an artificial sensory experience at least partly based on the accepting an indication of the schedule for administration of the memory-dampening agent to an individual.

1-76. (canceled) 77. A system, comprising: an accepter module; and a presenter module configured for presenting an indication of an artificial sensory experience at least partly based on accepting an indication of a schedule for administration of a memory-dampening agent to an individual. 78. The system of claim 77, wherein the accepter module comprises: a schedule accepter module. 79. The system of claim 77, wherein the accepter module comprises: an administration accepter module. 80. The system of claim 77, wherein the accepter module comprises: a dose accepter module. 81. The system of claim 77, wherein the presenter module configured for presenting an indication of an artificial sensory experience at least partly based on accepting an indication of a schedule for administration of a memory-dampening agent to an individual comprises: an algorithm utilizer module. 82. The system of claim 81, wherein the algorithm utilizer module comprises: a contraindication utilizer module. 83. The system of claim 77, wherein the presenter module configured for presenting an indication of an artificial sensory experience at least partly based on accepting an indication of a schedule for administration of a memory-dampening agent to an individual comprises: a history presenter module. 84. The system of claim 77, wherein the presenter module configured for presenting an indication of an artificial sensory experience at least partly based on accepting an indication of a schedule for administration of a memory-dampening agent to an individual comprises: a data presenter module. 85. The system of claim 77, wherein the presenter module configured for presenting an indication of an artificial sensory experience at least partly based on accepting an indication of a schedule for administration of a memory-dampening agent to an individual comprises: a reference tool presenter module. 86. The system of claim 77, wherein the presenter module configured for presenting an indication of an artificial sensory experience at least partly based on accepting an indication of a schedule for administration of a memory-dampening agent to an individual comprises: an output device presenter module. 87. The system of claim 86, wherein the output device presenter module comprises: a user interface presenter module. 88. The system of claim 86, wherein the output device presenter module comprises: a mobile device presenter module. 89. The system of claim 77, wherein the presenter module configured for presenting an indication of an artificial sensory experience at least partly based on accepting an indication of a schedule for administration of a memory-dampening agent to an individual comprises: a third party presenter module. 90. The system of claim 89, wherein the third party presenter module comprises: a health care provider presenter module. 91. The system of claim 89, wherein the third party presenter module comprises: a selective presenter module. 92. The system of claim 77, wherein the presenter module configured for presenting an indication of an artificial sensory experience at least partly based on accepting an indication of a schedule for administration of a memory-dampening agent to an individual comprises: a prescription presenter module. 93. The system of claim 92, wherein the prescription presenter module comprises: an effect presenter module. 94. The system of claim 93, wherein the effect presenter module comprises: a desired effect presenter module. 95. The system of claim 93, wherein the effect presenter module comprises: an adverse effect presenter module. 96. The system of claim 92, wherein the prescription presenter module comprises: a recommender module. 97. The system of claim 77, further comprising: a profile accepter module. 98. The system of claim 97, wherein the profile accepter module comprises: a time representation accepter module. 99. The system of claim 97, wherein the profile accepter module comprises: a dose representation accepter module. 100. The system of claim 97, wherein the profile accepter module comprises: a curve accepter module. 101. The system of claim 97, wherein the profile accepter module comprises: a bioavailability profile accepter module. 102. The system of claim 97, wherein the profile accepter module comprises: a model accepter module. 103. The system of claim 102, wherein the model accepter module comprises: a physiological accepter module. 104. The system of claim 102, wherein the model accepter module comprises: an in vitro model accepter module. 105. The system of claim 102, wherein the model accepter module comprises: a software output accepter module. 106. The system of claim 97, wherein the profile accepter module comprises: an information accepter module. 107. The system of claim 97, wherein the profile accepter module comprises: an attribute accepter module. 108. The system of claim 107, wherein the attribute accepter module comprises: a history accepter module. 109. The system of claim 107, wherein the attribute accepter module comprises: a group accepter module.

Systems and methods are described relating to accepting an indication of a schedule for administration of a memory-dampening agent to an individual and presenting an indication of an artificial sensory experience at least partly based on the accepting an indication of the schedule for administration of the memory-dampening agent to an individual.1-76. (canceled) 77. A system, comprising: an accepter module; and a presenter module configured for presenting an indication of an artificial sensory experience at least partly based on accepting an indication of a schedule for administration of a memory-dampening agent to an individual. 78. The system of claim 77, wherein the accepter module comprises: a schedule accepter module. 79. The system of claim 77, wherein the accepter module comprises: an administration accepter module. 80. The system of claim 77, wherein the accepter module comprises: a dose accepter module. 81. The system of claim 77, wherein the presenter module configured for presenting an indication of an artificial sensory experience at least partly based on accepting an indication of a schedule for administration of a memory-dampening agent to an individual comprises: an algorithm utilizer module. 82. The system of claim 81, wherein the algorithm utilizer module comprises: a contraindication utilizer module. 83. The system of claim 77, wherein the presenter module configured for presenting an indication of an artificial sensory experience at least partly based on accepting an indication of a schedule for administration of a memory-dampening agent to an individual comprises: a history presenter module. 84. The system of claim 77, wherein the presenter module configured for presenting an indication of an artificial sensory experience at least partly based on accepting an indication of a schedule for administration of a memory-dampening agent to an individual comprises: a data presenter module. 85. The system of claim 77, wherein the presenter module configured for presenting an indication of an artificial sensory experience at least partly based on accepting an indication of a schedule for administration of a memory-dampening agent to an individual comprises: a reference tool presenter module. 86. The system of claim 77, wherein the presenter module configured for presenting an indication of an artificial sensory experience at least partly based on accepting an indication of a schedule for administration of a memory-dampening agent to an individual comprises: an output device presenter module. 87. The system of claim 86, wherein the output device presenter module comprises: a user interface presenter module. 88. The system of claim 86, wherein the output device presenter module comprises: a mobile device presenter module. 89. The system of claim 77, wherein the presenter module configured for presenting an indication of an artificial sensory experience at least partly based on accepting an indication of a schedule for administration of a memory-dampening agent to an individual comprises: a third party presenter module. 90. The system of claim 89, wherein the third party presenter module comprises: a health care provider presenter module. 91. The system of claim 89, wherein the third party presenter module comprises: a selective presenter module. 92. The system of claim 77, wherein the presenter module configured for presenting an indication of an artificial sensory experience at least partly based on accepting an indication of a schedule for administration of a memory-dampening agent to an individual comprises: a prescription presenter module. 93. The system of claim 92, wherein the prescription presenter module comprises: an effect presenter module. 94. The system of claim 93, wherein the effect presenter module comprises: a desired effect presenter module. 95. The system of claim 93, wherein the effect presenter module comprises: an adverse effect presenter module. 96. The system of claim 92, wherein the prescription presenter module comprises: a recommender module. 97. The system of claim 77, further comprising: a profile accepter module. 98. The system of claim 97, wherein the profile accepter module comprises: a time representation accepter module. 99. The system of claim 97, wherein the profile accepter module comprises: a dose representation accepter module. 100. The system of claim 97, wherein the profile accepter module comprises: a curve accepter module. 101. The system of claim 97, wherein the profile accepter module comprises: a bioavailability profile accepter module. 102. The system of claim 97, wherein the profile accepter module comprises: a model accepter module. 103. The system of claim 102, wherein the model accepter module comprises: a physiological accepter module. 104. The system of claim 102, wherein the model accepter module comprises: an in vitro model accepter module. 105. The system of claim 102, wherein the model accepter module comprises: a software output accepter module. 106. The system of claim 97, wherein the profile accepter module comprises: an information accepter module. 107. The system of claim 97, wherein the profile accepter module comprises: an attribute accepter module. 108. The system of claim 107, wherein the attribute accepter module comprises: a history accepter module. 109. The system of claim 107, wherein the attribute accepter module comprises: a group accepter module.

The subject invention relates to a novel gene referred to herein as DSM-2. This gene was identified in Sterptomyces coelicolor A3. The DSM-2 protein is distantly related to PAT and BAR. The subject invention also provides plant-optimized genes encoding DSM-2 proteins, DSM-2 can be used as a transgenic trait to impart tolerance in plants and plant cells to the herbicides glufosinate and bialaphos. One preferred use of the subject genes are as selectable markers. The use of this gene as a selectable marker in a bacterial system can increase efficiency for plant transformations. Use of DSM-2 as the sole selection marker eliminates the need for an additional medicinal antibiotic marker (such as ampicillin resistance) during cloning. Various other uses are also possible according to the subject invention.

1. A transgenic plant cell comprising a polynucleotide that encodes a protein that has phosphinothricin acetyltransferase activity, wherein said polynucleotide hybridizes under conditions of 6×SSC at 65° C. with the full complement of a nucleic acid probe that encodes SEQ ID NO:2. 2. The cell of claim 1 wherein said probe comprises a sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:3. 3. The cell of claim 1 wherein said protein has at least 95% sequence identity with the amino acid sequence of SEQ ID NO:2. 4. A vector comprising a promoter operable in a plant cell, and a polynucleotide operably linked to said promoter, wherein said polynucleotide encodes a protein that has phosphinothricin acetyltransferase activity, and wherein said polynucleotide hybridizes under conditions of 6×SSC at 65° C. with the full complement of a nucleic acid probe that encodes the amino acid sequence of SEQ ID NO:2. 5. A method of selecting for a plant cell of claim 1 wherein said method comprises providing a vector of claim 4 to a plurality of plant cells, and growing said plurality of cells in a concentration of a herbicide that permits cells that express said polynucleotide to grow while killing or inhibiting the growth of cells that do not comprise said vector, wherein said herbicide comprises phosphinothricin. 6. The method of claim 5 wherein said herbicide is selected from the group consisting of bialophos and glufosinate. 7. The method of claim 5 wherein said method further comprises identifying and regenerating transformed plant cells. 8. A plant comprising a plurality of cells of claim 1. 9. A seed of a plant of claim 8. 10. A plant cell of claim 1 wherein said cell further comprises an insect-resistance gene derived from an organism selected from the group consisting of Bacillus thuringiensis, Photorhabdus, and Xenorhabdus. 11. A plant cell of claim 1 wherein said cell further comprises a second herbicide-resistance gene. 12. The plant of claim 8 where said plant produces said protein. 13. The plant of claim 12 wherein said protein comprises SEQ ID NO:2. 14. A method of using a phosphinothricin-resistance gene as a resistance marker in plant cells, said method comprising the steps of subjecting a plurality of plant cells to transformation with a vector of claim 4, culturing the cells in a medium, exposing the cells to phosphinothricin, and determining whether cells are resistant to the phosphinothricin. 15. A process for generating phosphinothricin resistant plant cells, plants, and their propagates wherein said method comprises transforming plant cells with the vector of claim 4, and regenerating the transformed plant cells to plants that produce propagates. 16. A process for the production of a phosphinothricin-resistant plant wherein said method comprises incorporating into the genome of the plant a vector of claim 4, and selecting for phosphinothricin resistance. 17. A process for the production of a plant cell that is tolerant to the herbicidal activity of a glutamine synthetase inhibitor including phosphinothricin or a compound with a phosphinothricin moiety, wherein said method comprises the step of incorporating into the nuclear genome of a starting plant cell a recombinant DNA comprising: a) a promoter recognized by a polymerase of said starting plant cell, and b) a coding region comprising a DNA fragment from a Streptomyces coelicolor A3 microorganism that produces said glutamine synthetase inhibitor, wherein said DNA fragment encodes a protein with acetyltransferase activity to said glutamine synthetase inhibitor. 18. A process for producing a plant that is tolerant to the herbicidal activity of a glutamine synthetase inhibitor including phosphinothricin or a compound with a phosphinothricin moiety, which comprises the steps of a) producing a plant cell of claim 1, and b) regenerating a plant from said cell, said plant comprising said polynucleotide in its nuclear genome. 19. A process for protecting a group of cultivated plants in a field by destroying weeds wherein said plants have incorporated into the genome of their cells a vector of claim 4, wherein said weeds are destroyed by application of a herbicide comprising a glutamine synthetase inhibitor as an active ingredient. 20. A process for producing a pure culture of transformed plant cells that have a foreign DNA incorporated into their nuclear genome, said method comprising the steps of: i) transforming starting plant cells in a plant cell culture with a foreign DNA, said foreign DNA comprising: a) a promoter recognized by the polymerases of said starting plant cell, and b) a coding region comprising a DNA fragment from a Streptomyces coelicolor A3 microorganism that produces a glutamine synthetase inhibitor, including phosphinothricin or a compound with a phosphinothricin moiety, wherein said DNA fragment encodes a protein with acetyltransferase activity to said glutamine synthetase inhibitor; and ii) selecting the transformed plant cells by applying to the plant cell culture said glutamine synthetase inhibitor at a sufficient concentration to kill the untransformed plant cells. 21. A method of producing a synthetic protein having phosphinothricin acetyltransferase activity, wherein said method comprises modifying a protein comprising SEQ ID NO:2 to produce a variant protein, and assaying said variant protein for said activity. 22. The method of claim 21 wherein said method comprises modifying a polynucleotide selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:3 to create a plurality of modified polynucleotides, and using said modified polynucleotides in a gene shuffling procedure. 23. The method of claim 21 wherein said method comprises modifying a polynucleotide selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:3 by error-prone PCR. 24. The method of claim 21 wherein said method comprises modifying at least one polynucleotide that encodes at least one of said amino acid sequences. 25. A bacterial cell other than Streptomyces wherein said cell comprises a vector of claim 4. 26. A method of selecting for a plant cell comprising a vector of claim 4, wherein said method comprises a) providing said vector to a plurality of plant cells; and b) growing said plurality of cells in a concentration of a herbicide that permits cells that express said polynucleotide to grow while killing or inhibiting growth of cells that lack said vector, wherein said herbicide comprises phosphinothricin. 27. The method of claim 26 wherein said expression cassette is present in a low copy number binary vector. 28. The method of claim 26 wherein said herbicide is selected from the group consisting of bialophos and glufosinate. 29. The method of claim 26 wherein said method is used in an expression system selected from the group consisting of a bacterial expression system, a plant cell culture expression system, an algal expression system, an animal cell expression system, a viral expression system, a fungal expression system, and a yeast expression system. 30. The method of claim 29 wherein said expression system is a Pseudomonas fluorescens expression system. 31. The transgenic plant cell of claim 1 wherein said cell further comprises a herbicide resistance gene selected from the group consisting of AAD-1 and AAD-12. 32. The process of claim 19 wherein said plants further comprise a glyphosate resistance gene and said process further comprises applying glyphosate to said field. 33. The process of claim 19 wherein said plants further comprise an imidazolinone resistance gene and said process further comprises applying an imidazolinone herbicide to said field. 34. The process of claim 19 wherein said plants further comprise a herbicide resistance gene selected from the group consisting of AAD-1 and AAD-12 and said process further comprises applying 2,4-D to said field. 35. The process of claim 19 wherein said plants further comprise an AAD-1 herbicide resistance gene and said process further comprises applying an aryloxy phenoxy propionate herbicide to said field. 36. The process of claim 19 wherein said plants further comprise an AAD-12 herbicide resistance gene and said process further comprises applying a pyridyloxyacetate herbicide to said field. 37. A method of selecting or distinguishing an individual plant or a group of crop plants containing a DSM-2 gene from a population of plants of the same species not containing the gene. 38. The method of claim 37 comprising applying glufosinate or bialaphos to the collection of plants. 39. The method of claim 37 wherein said method is practiced in a greenhouse, a growth chamber, or a field. 40. A method of controlling at least one weed in a field, said method comprising planting in said field seed of at least one transgenic plant of claim 12, said plant comprising a heterologous polynucleotide that encodes an enzyme conferring resistance a glutamine synthetase inhibiting herbicide, and a second heterologous polynucleotide encodes an enzyme conferring resistance to at least one other herbicide; said method further comprising applying to at least a portion of said field a first herbicide selected from the group consisting of glufosinate, phosphinothricin and bialaphos; and applying said at least one other herbicide to said at least a portion of said field. 41. The method of claim 40 wherein said herbicides are applied sequentially or concurrently. 42. The method of claim 40 wherein said first herbicide is a glutamine synthethse inhibiting herbicide. 43. The method of claim 40 wherein said at least one other herbicide is selected from the group consisting of 2,4-D, acetochlor, acifluorfen, alloxydim, amidosulfuron, aminopyralid, atrazine, beflubutamid, bispyribac, butafenacil, cafenstrole, carfentrazone, chlorimuron, chlorotoluron, cinidon-ethyl, clethodim, clodinafop, clomazone, cloproxydim, clopyralid, cloransulam, cyanazine, cyclosulfamuron, cycloxydim, cyhalofop, daimuron, dicamba, diclofop, dichlorprop, diclosulam, diflufenican, dimethenamid, diquat, dithiopyr, diuron, ethalfluralin, fenoxaprop, flazasulfuron, florasulam, fluazifop, flucarbazone, flufenacet, flufenican, flufenpyr, flumetsulam, flumiclorac, flumioxazin, fluroxypyr, fluthiacet, fomesafen, foramsulfuron, glufosinate, glyphosate, halosafen, halosulfuron, haloxyfop, imazamethabenz, imazamox, imazapic, imazapyr, imazaquin, imazethapyr, imazosulfuron, iodosulfuron, ioxynil, isoxaben, isoxaflutole, lactofen, linuron, MCPA, mecoprop, mefenacet, mefluidide, mesosulfuron, mesotrione, metamifop, metazachlor, metosulam, metribuzin, MSMA, napropamide, nicosulfuron, norflurazon, oryzalin, oxadiazon, oxyfluorfen, paraquat, pebulate, pendimethalin, penoxsulam, picloram, picolinafen, pinoxaden, primisulfuron, profoxydim, propanil, pyraflufen, pyrazosulfuron, pyribenzoxim, pyriminobac, pyrithiobac, pyroxasulfone, pyroxsulam, quinclorac, quinmerac, quizalofop, rimsulfuron, saflufenacil, sethoxydim, simazine, sulcotrione, sulfentrazone, sulfometuron, tefuryltrione, tembotrione, tepraloxydim, terbacil, thiazopyr, thidiazuron, thiencarbazone, thifensulfuron, thiobencarb, topramezone, tralkoxydim, triasulfuron, tribenuron, triclopyr, trifloxysulfuron, trifluralin, triflusulfuron, and tritosulfuron. 44. A method of detecting whether a plant comprises a polynucleotide of claim 8 wherein said method comprises collecting a sample from said plant and assaying said sample for the presence of said polynucleotide. 45. The method of claim 44 wherein said method comprises assaying said sample for the presence of a protein encoded by said polynucleotide. 46. The method of 44 wherein said method comprises using a PCR primer or probe to detect for the presence of said polynucleotide. 47. The method of claim 44 wherein said method comprises using an antibody to detect for the presence of said protein. 48. The plant of claim 8 wherein said plant further comprises an insect-resistance gene derived from an organism selected from the group consisting of Bacillus thuringiensis, Photorhabdus, and Xenorhabdus. 49. The plant of claim 8 wherein said plant further comprises a gene for an agronomic trait selected from the group consisting of fungal resistance, stress tolerance, increased yield, improved oil profile, improved fiber quality, viral resistance, delayed ripening, cold tolerance, and salt tolerance. 50. A method of controlling at least one weed in a field, said method comprising growing at least one plant of claim 8 in said field, and applying a glutamine synthetase inhibiting herbicide to at least a portion of said field. 51. The method of claim 50, further comprising herbicides glufosinate, bialaphos, and phosphinothricin. 52. The method of claim 50 wherein said plant is resistant to a herbicide selected from the group consisting of glyphosate, glufosinate, 2,4-D, quizalofop, imazethapyr, chlorsulfuron, dicamba, mesotrione, isoxaflutole, and butafenacil. 53. The method of claim 24 wherein said plant is a monocot. 54. The method of claim 53 wherein said monocot is selected from the group consisting of corn, rice, wheat, barley, rye, sugarcane, warm and cool-season turf grass, oats, sorghum, and pasture grasses. 55. The method of claim 24 wherein said plant is a dicot. 56. The method of claim 37 wherein said DSM-2 gene functions as a selectable marker and said method is practiced in a greenhouse, a growth chamber, or in a field. 57. The plant of claim 12 wherein said polynucleotide has codon usage for increasing expression in the plant. 58. A transgenic soybean plant comprising a polynucleotide that encodes a protein that has phosphinothricin acetyltransferase activity, wherein said polynucleotide hybridizes under conditions of 6×SSC at 65° C. with the full complement of a nucleic acid probe that encodes SEQ ID NO:2. 59. A transgenic corn plant comprising a polynucleotide that encodes a protein that has phosphinothricin acetyltransferase activity, wherein said polynucleotide hybridizes under conditions of 6×SSC at 65° C. with the full complement of a nucleic acid probe that encodes SEQ ID NO:2. 60. A method of using a polynucleotide to produce a transgenic plant of claim 58 or 59, wherein said polynucleotide has codon usage for increasing expression in the plant. 61. A method of using a protein to convey herbicide tolerance to a plant, wherein said method comprises integrating a polynucleotide into a crop plant, wherein said polynucleotide encodes said protein and said protein has phosphinothricin acetyltransferase activity, wherein said polynucleotide hybridizes under conditions of 6×SSC at 65° C. with the full complement of a nucleic acid probe that encodes SEQ ID NO:2, and wherein expression of said polynucleotide and production of said protein render said plant tolerant to a phosphinothricin herbicide.

The subject invention relates to a novel gene referred to herein as DSM-2. This gene was identified in Sterptomyces coelicolor A3. The DSM-2 protein is distantly related to PAT and BAR. The subject invention also provides plant-optimized genes encoding DSM-2 proteins, DSM-2 can be used as a transgenic trait to impart tolerance in plants and plant cells to the herbicides glufosinate and bialaphos. One preferred use of the subject genes are as selectable markers. The use of this gene as a selectable marker in a bacterial system can increase efficiency for plant transformations. Use of DSM-2 as the sole selection marker eliminates the need for an additional medicinal antibiotic marker (such as ampicillin resistance) during cloning. Various other uses are also possible according to the subject invention.1. A transgenic plant cell comprising a polynucleotide that encodes a protein that has phosphinothricin acetyltransferase activity, wherein said polynucleotide hybridizes under conditions of 6×SSC at 65° C. with the full complement of a nucleic acid probe that encodes SEQ ID NO:2. 2. The cell of claim 1 wherein said probe comprises a sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:3. 3. The cell of claim 1 wherein said protein has at least 95% sequence identity with the amino acid sequence of SEQ ID NO:2. 4. A vector comprising a promoter operable in a plant cell, and a polynucleotide operably linked to said promoter, wherein said polynucleotide encodes a protein that has phosphinothricin acetyltransferase activity, and wherein said polynucleotide hybridizes under conditions of 6×SSC at 65° C. with the full complement of a nucleic acid probe that encodes the amino acid sequence of SEQ ID NO:2. 5. A method of selecting for a plant cell of claim 1 wherein said method comprises providing a vector of claim 4 to a plurality of plant cells, and growing said plurality of cells in a concentration of a herbicide that permits cells that express said polynucleotide to grow while killing or inhibiting the growth of cells that do not comprise said vector, wherein said herbicide comprises phosphinothricin. 6. The method of claim 5 wherein said herbicide is selected from the group consisting of bialophos and glufosinate. 7. The method of claim 5 wherein said method further comprises identifying and regenerating transformed plant cells. 8. A plant comprising a plurality of cells of claim 1. 9. A seed of a plant of claim 8. 10. A plant cell of claim 1 wherein said cell further comprises an insect-resistance gene derived from an organism selected from the group consisting of Bacillus thuringiensis, Photorhabdus, and Xenorhabdus. 11. A plant cell of claim 1 wherein said cell further comprises a second herbicide-resistance gene. 12. The plant of claim 8 where said plant produces said protein. 13. The plant of claim 12 wherein said protein comprises SEQ ID NO:2. 14. A method of using a phosphinothricin-resistance gene as a resistance marker in plant cells, said method comprising the steps of subjecting a plurality of plant cells to transformation with a vector of claim 4, culturing the cells in a medium, exposing the cells to phosphinothricin, and determining whether cells are resistant to the phosphinothricin. 15. A process for generating phosphinothricin resistant plant cells, plants, and their propagates wherein said method comprises transforming plant cells with the vector of claim 4, and regenerating the transformed plant cells to plants that produce propagates. 16. A process for the production of a phosphinothricin-resistant plant wherein said method comprises incorporating into the genome of the plant a vector of claim 4, and selecting for phosphinothricin resistance. 17. A process for the production of a plant cell that is tolerant to the herbicidal activity of a glutamine synthetase inhibitor including phosphinothricin or a compound with a phosphinothricin moiety, wherein said method comprises the step of incorporating into the nuclear genome of a starting plant cell a recombinant DNA comprising: a) a promoter recognized by a polymerase of said starting plant cell, and b) a coding region comprising a DNA fragment from a Streptomyces coelicolor A3 microorganism that produces said glutamine synthetase inhibitor, wherein said DNA fragment encodes a protein with acetyltransferase activity to said glutamine synthetase inhibitor. 18. A process for producing a plant that is tolerant to the herbicidal activity of a glutamine synthetase inhibitor including phosphinothricin or a compound with a phosphinothricin moiety, which comprises the steps of a) producing a plant cell of claim 1, and b) regenerating a plant from said cell, said plant comprising said polynucleotide in its nuclear genome. 19. A process for protecting a group of cultivated plants in a field by destroying weeds wherein said plants have incorporated into the genome of their cells a vector of claim 4, wherein said weeds are destroyed by application of a herbicide comprising a glutamine synthetase inhibitor as an active ingredient. 20. A process for producing a pure culture of transformed plant cells that have a foreign DNA incorporated into their nuclear genome, said method comprising the steps of: i) transforming starting plant cells in a plant cell culture with a foreign DNA, said foreign DNA comprising: a) a promoter recognized by the polymerases of said starting plant cell, and b) a coding region comprising a DNA fragment from a Streptomyces coelicolor A3 microorganism that produces a glutamine synthetase inhibitor, including phosphinothricin or a compound with a phosphinothricin moiety, wherein said DNA fragment encodes a protein with acetyltransferase activity to said glutamine synthetase inhibitor; and ii) selecting the transformed plant cells by applying to the plant cell culture said glutamine synthetase inhibitor at a sufficient concentration to kill the untransformed plant cells. 21. A method of producing a synthetic protein having phosphinothricin acetyltransferase activity, wherein said method comprises modifying a protein comprising SEQ ID NO:2 to produce a variant protein, and assaying said variant protein for said activity. 22. The method of claim 21 wherein said method comprises modifying a polynucleotide selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:3 to create a plurality of modified polynucleotides, and using said modified polynucleotides in a gene shuffling procedure. 23. The method of claim 21 wherein said method comprises modifying a polynucleotide selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:3 by error-prone PCR. 24. The method of claim 21 wherein said method comprises modifying at least one polynucleotide that encodes at least one of said amino acid sequences. 25. A bacterial cell other than Streptomyces wherein said cell comprises a vector of claim 4. 26. A method of selecting for a plant cell comprising a vector of claim 4, wherein said method comprises a) providing said vector to a plurality of plant cells; and b) growing said plurality of cells in a concentration of a herbicide that permits cells that express said polynucleotide to grow while killing or inhibiting growth of cells that lack said vector, wherein said herbicide comprises phosphinothricin. 27. The method of claim 26 wherein said expression cassette is present in a low copy number binary vector. 28. The method of claim 26 wherein said herbicide is selected from the group consisting of bialophos and glufosinate. 29. The method of claim 26 wherein said method is used in an expression system selected from the group consisting of a bacterial expression system, a plant cell culture expression system, an algal expression system, an animal cell expression system, a viral expression system, a fungal expression system, and a yeast expression system. 30. The method of claim 29 wherein said expression system is a Pseudomonas fluorescens expression system. 31. The transgenic plant cell of claim 1 wherein said cell further comprises a herbicide resistance gene selected from the group consisting of AAD-1 and AAD-12. 32. The process of claim 19 wherein said plants further comprise a glyphosate resistance gene and said process further comprises applying glyphosate to said field. 33. The process of claim 19 wherein said plants further comprise an imidazolinone resistance gene and said process further comprises applying an imidazolinone herbicide to said field. 34. The process of claim 19 wherein said plants further comprise a herbicide resistance gene selected from the group consisting of AAD-1 and AAD-12 and said process further comprises applying 2,4-D to said field. 35. The process of claim 19 wherein said plants further comprise an AAD-1 herbicide resistance gene and said process further comprises applying an aryloxy phenoxy propionate herbicide to said field. 36. The process of claim 19 wherein said plants further comprise an AAD-12 herbicide resistance gene and said process further comprises applying a pyridyloxyacetate herbicide to said field. 37. A method of selecting or distinguishing an individual plant or a group of crop plants containing a DSM-2 gene from a population of plants of the same species not containing the gene. 38. The method of claim 37 comprising applying glufosinate or bialaphos to the collection of plants. 39. The method of claim 37 wherein said method is practiced in a greenhouse, a growth chamber, or a field. 40. A method of controlling at least one weed in a field, said method comprising planting in said field seed of at least one transgenic plant of claim 12, said plant comprising a heterologous polynucleotide that encodes an enzyme conferring resistance a glutamine synthetase inhibiting herbicide, and a second heterologous polynucleotide encodes an enzyme conferring resistance to at least one other herbicide; said method further comprising applying to at least a portion of said field a first herbicide selected from the group consisting of glufosinate, phosphinothricin and bialaphos; and applying said at least one other herbicide to said at least a portion of said field. 41. The method of claim 40 wherein said herbicides are applied sequentially or concurrently. 42. The method of claim 40 wherein said first herbicide is a glutamine synthethse inhibiting herbicide. 43. The method of claim 40 wherein said at least one other herbicide is selected from the group consisting of 2,4-D, acetochlor, acifluorfen, alloxydim, amidosulfuron, aminopyralid, atrazine, beflubutamid, bispyribac, butafenacil, cafenstrole, carfentrazone, chlorimuron, chlorotoluron, cinidon-ethyl, clethodim, clodinafop, clomazone, cloproxydim, clopyralid, cloransulam, cyanazine, cyclosulfamuron, cycloxydim, cyhalofop, daimuron, dicamba, diclofop, dichlorprop, diclosulam, diflufenican, dimethenamid, diquat, dithiopyr, diuron, ethalfluralin, fenoxaprop, flazasulfuron, florasulam, fluazifop, flucarbazone, flufenacet, flufenican, flufenpyr, flumetsulam, flumiclorac, flumioxazin, fluroxypyr, fluthiacet, fomesafen, foramsulfuron, glufosinate, glyphosate, halosafen, halosulfuron, haloxyfop, imazamethabenz, imazamox, imazapic, imazapyr, imazaquin, imazethapyr, imazosulfuron, iodosulfuron, ioxynil, isoxaben, isoxaflutole, lactofen, linuron, MCPA, mecoprop, mefenacet, mefluidide, mesosulfuron, mesotrione, metamifop, metazachlor, metosulam, metribuzin, MSMA, napropamide, nicosulfuron, norflurazon, oryzalin, oxadiazon, oxyfluorfen, paraquat, pebulate, pendimethalin, penoxsulam, picloram, picolinafen, pinoxaden, primisulfuron, profoxydim, propanil, pyraflufen, pyrazosulfuron, pyribenzoxim, pyriminobac, pyrithiobac, pyroxasulfone, pyroxsulam, quinclorac, quinmerac, quizalofop, rimsulfuron, saflufenacil, sethoxydim, simazine, sulcotrione, sulfentrazone, sulfometuron, tefuryltrione, tembotrione, tepraloxydim, terbacil, thiazopyr, thidiazuron, thiencarbazone, thifensulfuron, thiobencarb, topramezone, tralkoxydim, triasulfuron, tribenuron, triclopyr, trifloxysulfuron, trifluralin, triflusulfuron, and tritosulfuron. 44. A method of detecting whether a plant comprises a polynucleotide of claim 8 wherein said method comprises collecting a sample from said plant and assaying said sample for the presence of said polynucleotide. 45. The method of claim 44 wherein said method comprises assaying said sample for the presence of a protein encoded by said polynucleotide. 46. The method of 44 wherein said method comprises using a PCR primer or probe to detect for the presence of said polynucleotide. 47. The method of claim 44 wherein said method comprises using an antibody to detect for the presence of said protein. 48. The plant of claim 8 wherein said plant further comprises an insect-resistance gene derived from an organism selected from the group consisting of Bacillus thuringiensis, Photorhabdus, and Xenorhabdus. 49. The plant of claim 8 wherein said plant further comprises a gene for an agronomic trait selected from the group consisting of fungal resistance, stress tolerance, increased yield, improved oil profile, improved fiber quality, viral resistance, delayed ripening, cold tolerance, and salt tolerance. 50. A method of controlling at least one weed in a field, said method comprising growing at least one plant of claim 8 in said field, and applying a glutamine synthetase inhibiting herbicide to at least a portion of said field. 51. The method of claim 50, further comprising herbicides glufosinate, bialaphos, and phosphinothricin. 52. The method of claim 50 wherein said plant is resistant to a herbicide selected from the group consisting of glyphosate, glufosinate, 2,4-D, quizalofop, imazethapyr, chlorsulfuron, dicamba, mesotrione, isoxaflutole, and butafenacil. 53. The method of claim 24 wherein said plant is a monocot. 54. The method of claim 53 wherein said monocot is selected from the group consisting of corn, rice, wheat, barley, rye, sugarcane, warm and cool-season turf grass, oats, sorghum, and pasture grasses. 55. The method of claim 24 wherein said plant is a dicot. 56. The method of claim 37 wherein said DSM-2 gene functions as a selectable marker and said method is practiced in a greenhouse, a growth chamber, or in a field. 57. The plant of claim 12 wherein said polynucleotide has codon usage for increasing expression in the plant. 58. A transgenic soybean plant comprising a polynucleotide that encodes a protein that has phosphinothricin acetyltransferase activity, wherein said polynucleotide hybridizes under conditions of 6×SSC at 65° C. with the full complement of a nucleic acid probe that encodes SEQ ID NO:2. 59. A transgenic corn plant comprising a polynucleotide that encodes a protein that has phosphinothricin acetyltransferase activity, wherein said polynucleotide hybridizes under conditions of 6×SSC at 65° C. with the full complement of a nucleic acid probe that encodes SEQ ID NO:2. 60. A method of using a polynucleotide to produce a transgenic plant of claim 58 or 59, wherein said polynucleotide has codon usage for increasing expression in the plant. 61. A method of using a protein to convey herbicide tolerance to a plant, wherein said method comprises integrating a polynucleotide into a crop plant, wherein said polynucleotide encodes said protein and said protein has phosphinothricin acetyltransferase activity, wherein said polynucleotide hybridizes under conditions of 6×SSC at 65° C. with the full complement of a nucleic acid probe that encodes SEQ ID NO:2, and wherein expression of said polynucleotide and production of said protein render said plant tolerant to a phosphinothricin herbicide.

A process for producing oligosaccharides from lignocellulosic biomass, having the following steps: a) pre-treating the biomass in a pre-treatment reactor ( 1 ) in order to provide an effluent containing a pre-treated substrate; b) enzymatic hydrolysis of the pre-treated substrate contained in the effluent from step a) in a reactor, in the presence of cellulases such that a hydrolysate containing glucose, cellulases and water is produced; c) removing at least a portion of the hydrolysate from step b) comprising a liquid fraction; d) reducing the water content of said portion of the hydrolysate in step c) such that the liquid fraction of the hydrolysate has a water content of less than 65% by weight with respect to the total weight of the liquid fraction; e) incubating the hydrolysate from step d) at a temperature in the range 40° C. to 70° C. for the time necessary to produce an effluent enriched in oligosaccharides.

1. A process for the production of oligosaccharides from lignocellulosic biomass, comprising at least the following steps: a) pre-treating the biomass in a pre-treatment reactor in order to provide an effluent containing a pre-treated substrate; b) carrying out an enzymatic hydrolysis of the pre-treated substrate contained in the effluent obtained from step a) in a reactor, in the presence of cellulases in a manner such that a hydrolysate containing glucose, cellulases and water is produced; c) removing at least a portion of the hydrolysate obtained from step b) comprising a liquid fraction; d) reducing the water content of said portion of the hydrolysate removed in step c) in a manner such that the liquid fraction of the hydrolysate has a water content of less than 65% by weight of water with respect to the total weight of the liquid fraction of the hydrolysate; e) incubating the hydrolysate obtained from step d) at a temperature in the range 40° C. to 70° C. for the time necessary to produce an effluent enriched in oligosaccharides. 2. The process according to claim 1 in which in step d), the hydrolysate removed in step c) is concentrated by evaporation at a temperature of less than 90° C. 3. The process according to claim 1 in which in step d), glucose is added to the hydrolysate removed in step c). 4. The process according to claim 1 in which in step d), a membrane separation of the hydrolysate removed in step c) is carried out in order to separate at least a portion of the water of the liquid fraction. 5. The process according to claim 1 in which in step d), the hydrolysate removed in step c) is separated into at least a first portion and a second portion, the first hydrolysate portion is concentrated at a temperature of more than 90° C. and the concentrated hydrolysate portion is mixed with the second hydrolysate portion. 6. The process according to claim 1, in which a solid/liquid separation of the effluent obtained from step a) is carried out in order to recover a liquid fraction containing sugars and a solid fraction containing the pre-treated substrate, said solid fraction being sent to step b). 7. The process according to claim 6, in which the hydrolysate is treated in step d) as a mixture with the liquid fraction. 8. The process according to claim 6, in which the liquid fraction is mixed with the effluent enriched in oligosaccharides obtained from step e). 9. The process according to claim 1, in which the effluent obtained from step e) comprises sophorose and/or gentiobiose. 10. A process for the production of cellulases from lignocellulosic biomass, comprising a process for the production of oligosaccharides according to claim 1 and the following additional steps: f) sending at least a portion of the hydrolysate enriched in oligosaccharides to a reactor containing a culture medium and microorganisms which are capable of producing cellulases; and g) culturing the mixture in order to produce an effluent enriched in cellulases. 11. The process for the production of cellulases according to claim 10, in which the microorganism used in step f) is from the genus Trichoderma reesei. 12. The process for the production of cellulases according to claim 10, in which step g) is carried out in semi-continuous mode. 13. The process for the production of cellulases according to claim 10, in which a solid/liquid separation of the effluent obtained in step g) is carried out in a manner such that a liquid fraction containing cellulases is recovered and said liquid fraction is recycled to the reactor of step b). 14. A process for the production of alcohols, solvents or organic acids, alone or as a mixture, comprising the steps of the process for the production of cellulases according to claim 10 and in which a portion of the hydrolysate obtained from step b) is sent to a fermentation reactor comprising microorganisms in order to produce a fermentation must comprising alcohols and/or solvents. 15. A process for the production of alcohols, solvents or organic acids, alone or as a mixture, comprising the steps of the process for the production of cellulases according to claim 10 and in which a portion of the effluent obtained from step a) is sent to a unit for simultaneous hydrolysis and fermentation. 16. The process according to claim 14, in which ethanolic fermentation is carried out in order to produce ethanol as the major alcohol. 17. The process according to claim 14, in which butylic fermentation is carried out in order to produce n-butanol alone or as a mixture with acetone or iso-propanol.

A process for producing oligosaccharides from lignocellulosic biomass, having the following steps: a) pre-treating the biomass in a pre-treatment reactor ( 1 ) in order to provide an effluent containing a pre-treated substrate; b) enzymatic hydrolysis of the pre-treated substrate contained in the effluent from step a) in a reactor, in the presence of cellulases such that a hydrolysate containing glucose, cellulases and water is produced; c) removing at least a portion of the hydrolysate from step b) comprising a liquid fraction; d) reducing the water content of said portion of the hydrolysate in step c) such that the liquid fraction of the hydrolysate has a water content of less than 65% by weight with respect to the total weight of the liquid fraction; e) incubating the hydrolysate from step d) at a temperature in the range 40° C. to 70° C. for the time necessary to produce an effluent enriched in oligosaccharides.1. A process for the production of oligosaccharides from lignocellulosic biomass, comprising at least the following steps: a) pre-treating the biomass in a pre-treatment reactor in order to provide an effluent containing a pre-treated substrate; b) carrying out an enzymatic hydrolysis of the pre-treated substrate contained in the effluent obtained from step a) in a reactor, in the presence of cellulases in a manner such that a hydrolysate containing glucose, cellulases and water is produced; c) removing at least a portion of the hydrolysate obtained from step b) comprising a liquid fraction; d) reducing the water content of said portion of the hydrolysate removed in step c) in a manner such that the liquid fraction of the hydrolysate has a water content of less than 65% by weight of water with respect to the total weight of the liquid fraction of the hydrolysate; e) incubating the hydrolysate obtained from step d) at a temperature in the range 40° C. to 70° C. for the time necessary to produce an effluent enriched in oligosaccharides. 2. The process according to claim 1 in which in step d), the hydrolysate removed in step c) is concentrated by evaporation at a temperature of less than 90° C. 3. The process according to claim 1 in which in step d), glucose is added to the hydrolysate removed in step c). 4. The process according to claim 1 in which in step d), a membrane separation of the hydrolysate removed in step c) is carried out in order to separate at least a portion of the water of the liquid fraction. 5. The process according to claim 1 in which in step d), the hydrolysate removed in step c) is separated into at least a first portion and a second portion, the first hydrolysate portion is concentrated at a temperature of more than 90° C. and the concentrated hydrolysate portion is mixed with the second hydrolysate portion. 6. The process according to claim 1, in which a solid/liquid separation of the effluent obtained from step a) is carried out in order to recover a liquid fraction containing sugars and a solid fraction containing the pre-treated substrate, said solid fraction being sent to step b). 7. The process according to claim 6, in which the hydrolysate is treated in step d) as a mixture with the liquid fraction. 8. The process according to claim 6, in which the liquid fraction is mixed with the effluent enriched in oligosaccharides obtained from step e). 9. The process according to claim 1, in which the effluent obtained from step e) comprises sophorose and/or gentiobiose. 10. A process for the production of cellulases from lignocellulosic biomass, comprising a process for the production of oligosaccharides according to claim 1 and the following additional steps: f) sending at least a portion of the hydrolysate enriched in oligosaccharides to a reactor containing a culture medium and microorganisms which are capable of producing cellulases; and g) culturing the mixture in order to produce an effluent enriched in cellulases. 11. The process for the production of cellulases according to claim 10, in which the microorganism used in step f) is from the genus Trichoderma reesei. 12. The process for the production of cellulases according to claim 10, in which step g) is carried out in semi-continuous mode. 13. The process for the production of cellulases according to claim 10, in which a solid/liquid separation of the effluent obtained in step g) is carried out in a manner such that a liquid fraction containing cellulases is recovered and said liquid fraction is recycled to the reactor of step b). 14. A process for the production of alcohols, solvents or organic acids, alone or as a mixture, comprising the steps of the process for the production of cellulases according to claim 10 and in which a portion of the hydrolysate obtained from step b) is sent to a fermentation reactor comprising microorganisms in order to produce a fermentation must comprising alcohols and/or solvents. 15. A process for the production of alcohols, solvents or organic acids, alone or as a mixture, comprising the steps of the process for the production of cellulases according to claim 10 and in which a portion of the effluent obtained from step a) is sent to a unit for simultaneous hydrolysis and fermentation. 16. The process according to claim 14, in which ethanolic fermentation is carried out in order to produce ethanol as the major alcohol. 17. The process according to claim 14, in which butylic fermentation is carried out in order to produce n-butanol alone or as a mixture with acetone or iso-propanol.

The presently disclosed subject matter provides a novel approach for the treatment, prevention, and diagnosis of Cap-Snatching virus infections, particularly all classes of human influenza, including pandemic influenza. The methods involve the use of constructs for RNA-interference (RNAi).

1. An expression vector comprising a polynucleotide coding sequence operably linked to a constitutive promoter, wherein the polynucleotide coding sequence encodes a precursor RNAi construct, wherein the precursor RNAi construct comprises an mRNA molecule comprising: (a) a 5′ methylguanosine cap leader; (b) an 8 to 12 nucleotide sequence immediately downstream from the methylguanosine cap leader; and (c) an RNAi sequence immediately downstream from the 8 to 12 nucleotide sequence; wherein the mRNA molecule does not comprise a ribosomal binding site. 2. The expression vector of claim 1, wherein the RNAi sequence is targeted to a transcript of the Cap-Snatching virus to inhibit replication of the Cap-Snatching virus. 3. The expression vector of claim 1, wherein the RNAi sequence is targeted to a sequence to activate one or more host cell response mechanisms against the Cap-Snatching virus. 4. The expression vector of claim 1, wherein the RNAi sequence targets host response transcripts to repress host responses during viral infection. 5. The expression vector of claim 1, wherein the RNAi sequence modulates a host immune response to prevent sepsis or cytokine storm. 6. The expression vector of any one of claims 1 to 5, wherein the RNAi sequence is selected from the group consisting of an siRNA, an shRNA, a piRNA, an endo-siRNA, and an ra-siRNA. 7. The expression vector of any one of claims 1 to 6, wherein the expression vector is a DNA vector or a lentiviral expression vector. 8. The expression vector of any one of claims 1 to 7, wherein the Cap-Snatching virus is selected from the group consisting of an influenza virus, a hantavirus, a Rift Valley Fever virus, and a Cap-Snatching hemorrhagic virus. 9. The expression vector of any one of claims 1 to 7, wherein the Cap-Snatching virus is an influenza virus, and wherein the RNAi sequence is targeted to an influenza virus transcript. 10. The expression vector of claim 9, wherein the RNAi sequence is an siRNA sequence selected from the group consisting of: SEQ ID NOS: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40. 11. The expression vector of any one of claims 9 to 10, wherein the expression vector is a lentiviral expression vector, and wherein the lentiviral expression vector targets host epithelial airway cells but does not integrate into host epithelial airway cell DNA. 12. The expression vector of claim 11, wherein the host epithelial airway cell is a human epithelial airway cell. 13. A method of treating or preventing a Cap-Snatching virus infection in a subject in need thereof, the method comprising administering to the subject a prophylactically or therapeutically effective amount of a pharmaceutically acceptable composition comprising the expression vector of any one of claims 1 to 12. 14. The method of claim 13, wherein Cap-Snatching virus infection is an influenza infection, and wherein the RNAi sequence is targeted to an influenza virus transcript. 15. The method of claim 14, wherein the RNAi sequence is an siRNA sequence selected from the group consisting of: SEQ ID NOS: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40. 16. The method of any of claims 14 to 15, wherein the expression vector is a lentiviral expression vector, and wherein the lentiviral expression vector targets host epithelial airway cells but does not integrate into host epithelial airway cell DNA. 17. The method of claim 16, wherein the pharmaceutically acceptable composition is administered to airway epithelial cells of the subject. 18. The method of claim 17, wherein the pharmaceutically acceptable composition is administered to nasal or intrapulmonary airway epithelial cells of the subject by direct topical application or by inhalation. 19. The method of claim 18, wherein the pharmaceutically acceptable composition is administered by inhalation and is formulated as an aerosol. 20. The method of any one of claims 13 to 19, wherein the subject is a human subject. 21. The method of any one of claims 13 to 19, wherein the subject is a mammalian subject. 22. The method of any one of claims 13 to 19, wherein the subject is an avian subject. 23. A method of diagnosing a Cap-Snatching virus infection in a subject, the method comprising: (a) obtaining a biological sample from the subject, wherein the biological sample comprises cells suspected of being infected with a Cap-Snatching virus; (b) introducing a first expression vector into the cells, wherein the first expression vector comprises a first polynucleotide coding sequence operably linked to a constitutive promoter, wherein the first polynucleotide coding sequence encodes an expression product capable of producing a detectable signal, and further wherein the detectable signal is produced from the expression product in the cells; (c) obtaining a first measurement of the detectable signal produced from the expression product in the cells; (d) introducing a second expression vector into the cells, wherein the second expression vector comprises a polynucleotide coding sequence encoding a precursor RNAi construct, wherein the precursor RNAi construct comprises an mRNA molecule comprising: (i) a 5′ methylguanosine cap leader; (ii) a 8 to 12 nucleotide sequence immediately downstream from the methylguanosine cap leader; and (iii) an RNAi sequence immediately downstream from the 8 to 12 nucleotide sequence, wherein the RNAi sequence is targeted to the expression product that produces a detectable label; and (e) obtaining a second measurement the detectable signal produced from the expression product in the cells; wherein a decrease in the detectable signal from the first measurement to the second measurement is indicative of a Cap-Snatching virus infection in the subject. 24. The method of claim 23, wherein the expression product that produces a detectable label is Green Fluorescent Protein (GFP). 25. The method of any one of claims 23 to 24, wherein the RNAi sequence is selected from the group consisting of an siRNA, an shRNA, a piRNA, an endo-siRNA, and an ra-siRNA. 26. The method of any one of claims 23 to 25, wherein the expression vector is a DNA vector or a lentiviral expression vector. 27. The method of any one of claims 23 to 26, wherein the Cap-Snatching virus is selected from the group consisting of an influenza virus, a hantavirus, a Rift Valley Fever virus, and a Cap-Snatching hemorrhagic virus. 28. The method of any one of claims 23 to 26, wherein the Cap-Snatching virus is an influenza virus. 29. The method of claim 26, wherein the cells comprise airway epithelial cells suspected of being infected with an influenza virus. 30. The method of any one of claims 23 to 29, wherein the subject is a human subject. 31. The method of any one of claims 23 to 29, wherein the subject is a mammalian subject. 32. The method of any one of claims 23 to 29, wherein the subject is an avian subject.

The presently disclosed subject matter provides a novel approach for the treatment, prevention, and diagnosis of Cap-Snatching virus infections, particularly all classes of human influenza, including pandemic influenza. The methods involve the use of constructs for RNA-interference (RNAi).1. An expression vector comprising a polynucleotide coding sequence operably linked to a constitutive promoter, wherein the polynucleotide coding sequence encodes a precursor RNAi construct, wherein the precursor RNAi construct comprises an mRNA molecule comprising: (a) a 5′ methylguanosine cap leader; (b) an 8 to 12 nucleotide sequence immediately downstream from the methylguanosine cap leader; and (c) an RNAi sequence immediately downstream from the 8 to 12 nucleotide sequence; wherein the mRNA molecule does not comprise a ribosomal binding site. 2. The expression vector of claim 1, wherein the RNAi sequence is targeted to a transcript of the Cap-Snatching virus to inhibit replication of the Cap-Snatching virus. 3. The expression vector of claim 1, wherein the RNAi sequence is targeted to a sequence to activate one or more host cell response mechanisms against the Cap-Snatching virus. 4. The expression vector of claim 1, wherein the RNAi sequence targets host response transcripts to repress host responses during viral infection. 5. The expression vector of claim 1, wherein the RNAi sequence modulates a host immune response to prevent sepsis or cytokine storm. 6. The expression vector of any one of claims 1 to 5, wherein the RNAi sequence is selected from the group consisting of an siRNA, an shRNA, a piRNA, an endo-siRNA, and an ra-siRNA. 7. The expression vector of any one of claims 1 to 6, wherein the expression vector is a DNA vector or a lentiviral expression vector. 8. The expression vector of any one of claims 1 to 7, wherein the Cap-Snatching virus is selected from the group consisting of an influenza virus, a hantavirus, a Rift Valley Fever virus, and a Cap-Snatching hemorrhagic virus. 9. The expression vector of any one of claims 1 to 7, wherein the Cap-Snatching virus is an influenza virus, and wherein the RNAi sequence is targeted to an influenza virus transcript. 10. The expression vector of claim 9, wherein the RNAi sequence is an siRNA sequence selected from the group consisting of: SEQ ID NOS: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40. 11. The expression vector of any one of claims 9 to 10, wherein the expression vector is a lentiviral expression vector, and wherein the lentiviral expression vector targets host epithelial airway cells but does not integrate into host epithelial airway cell DNA. 12. The expression vector of claim 11, wherein the host epithelial airway cell is a human epithelial airway cell. 13. A method of treating or preventing a Cap-Snatching virus infection in a subject in need thereof, the method comprising administering to the subject a prophylactically or therapeutically effective amount of a pharmaceutically acceptable composition comprising the expression vector of any one of claims 1 to 12. 14. The method of claim 13, wherein Cap-Snatching virus infection is an influenza infection, and wherein the RNAi sequence is targeted to an influenza virus transcript. 15. The method of claim 14, wherein the RNAi sequence is an siRNA sequence selected from the group consisting of: SEQ ID NOS: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40. 16. The method of any of claims 14 to 15, wherein the expression vector is a lentiviral expression vector, and wherein the lentiviral expression vector targets host epithelial airway cells but does not integrate into host epithelial airway cell DNA. 17. The method of claim 16, wherein the pharmaceutically acceptable composition is administered to airway epithelial cells of the subject. 18. The method of claim 17, wherein the pharmaceutically acceptable composition is administered to nasal or intrapulmonary airway epithelial cells of the subject by direct topical application or by inhalation. 19. The method of claim 18, wherein the pharmaceutically acceptable composition is administered by inhalation and is formulated as an aerosol. 20. The method of any one of claims 13 to 19, wherein the subject is a human subject. 21. The method of any one of claims 13 to 19, wherein the subject is a mammalian subject. 22. The method of any one of claims 13 to 19, wherein the subject is an avian subject. 23. A method of diagnosing a Cap-Snatching virus infection in a subject, the method comprising: (a) obtaining a biological sample from the subject, wherein the biological sample comprises cells suspected of being infected with a Cap-Snatching virus; (b) introducing a first expression vector into the cells, wherein the first expression vector comprises a first polynucleotide coding sequence operably linked to a constitutive promoter, wherein the first polynucleotide coding sequence encodes an expression product capable of producing a detectable signal, and further wherein the detectable signal is produced from the expression product in the cells; (c) obtaining a first measurement of the detectable signal produced from the expression product in the cells; (d) introducing a second expression vector into the cells, wherein the second expression vector comprises a polynucleotide coding sequence encoding a precursor RNAi construct, wherein the precursor RNAi construct comprises an mRNA molecule comprising: (i) a 5′ methylguanosine cap leader; (ii) a 8 to 12 nucleotide sequence immediately downstream from the methylguanosine cap leader; and (iii) an RNAi sequence immediately downstream from the 8 to 12 nucleotide sequence, wherein the RNAi sequence is targeted to the expression product that produces a detectable label; and (e) obtaining a second measurement the detectable signal produced from the expression product in the cells; wherein a decrease in the detectable signal from the first measurement to the second measurement is indicative of a Cap-Snatching virus infection in the subject. 24. The method of claim 23, wherein the expression product that produces a detectable label is Green Fluorescent Protein (GFP). 25. The method of any one of claims 23 to 24, wherein the RNAi sequence is selected from the group consisting of an siRNA, an shRNA, a piRNA, an endo-siRNA, and an ra-siRNA. 26. The method of any one of claims 23 to 25, wherein the expression vector is a DNA vector or a lentiviral expression vector. 27. The method of any one of claims 23 to 26, wherein the Cap-Snatching virus is selected from the group consisting of an influenza virus, a hantavirus, a Rift Valley Fever virus, and a Cap-Snatching hemorrhagic virus. 28. The method of any one of claims 23 to 26, wherein the Cap-Snatching virus is an influenza virus. 29. The method of claim 26, wherein the cells comprise airway epithelial cells suspected of being infected with an influenza virus. 30. The method of any one of claims 23 to 29, wherein the subject is a human subject. 31. The method of any one of claims 23 to 29, wherein the subject is a mammalian subject. 32. The method of any one of claims 23 to 29, wherein the subject is an avian subject.

Methods and associated apparatus involving designing a ligand ab initio that will bind to a binding site of a macromolecular target, or of identifying a modification to a ligand for improving the affinity of the ligand to a binding site of a macromolecular target, comprising using information about non-bonding, intra-molecular or inter-molecular atom to atom contacts extracted from a database of biological macromolecules to identify favoured regions adjacent to the binding site for particular atom types and modifying a candidate ligand to increase the intersection between atoms of the candidate ligand and the favoured regions. One or more steps of the methods may be performed by a computer.

1. A method for designing a ligand ab initio that will bind to a binding site of a macromolecular target, or of identifying a modification to a ligand for improving the affinity of the ligand to a binding site of a macromolecular target, comprising: a) identifying a target list of atoms forming the surface of the target binding site; b) identifying each atom, hereinafter referred to as a theta atom, in the target list, as a particular theta atom type; c) extracting from a structural database of biological macromolecules, information about non-bonding, intra-molecular or inter-molecular atom to atom contacts, where the first atom in a contacting pair of atoms is of a particular theta atom type and the opposing, second atom of the pair, hereinafter referred to as an iota atom, is of a particular iota atom type, said information comprising spatial and/or contextual data about the iota atom relative to the theta atom, and said data collected for a plurality of contacts of the given theta atom type from the said database is hereinafter referred to as a theta contact set; d) for each theta atom identified in the target list in b), superimposing in or around the target binding site data relating to a given iota atom type, or a predetermined group of related iota atom types, from the corresponding theta contact set extracted in c); e) combining and/or parsing the superimposed data in such a way as to predict one or more favoured regions of the binding site where the given iota atom type, or the predetermined group of related iota atom types, has high theoretical propensity; and f) with a candidate ligand notionally docked into the binding site, comparing the type and position of one or more of the atoms of the candidate ligand with the predicted favoured regions for the respective iota atom types, to identify a modification to the candidate ligand, in terms of alternate and/or additional candidate ligand atoms, that will produce a greater intersection between the alternate and/or additional candidate ligand atoms and the respective iota atom type favoured regions, leading to an improvement in the affinity of the modified candidate ligand to the binding site compared to the unmodified candidate ligand; wherein each non-bonding intra-molecular or inter-molecular contact in the database is defined as a contact between opposing residues of a protein fold or between opposing monomer units of a macromolecular fold or between two interacting macromolecular partners and is specifically between a theta atom on one side of the fold or first interacting partner and an iota atom on the opposing side or second interacting partner; in an instance where the following condition is satisfied: s−Rw≦t, where s is the separation between the two atoms of the contact, Rw is the sum of the van de Waals radii of the two atoms of the contact, and t is a predetermined threshold distance; and wherein the theta atom type is identified uniquely in b) such that there is no intersection between the data of a theta contact set extracted in c) for a given theta atom type and the data of any other theta contact set extracted in c) for any other theta atom type, apart from data concerning contacts involving the given theta atom as the iota atom. 2. The method according to claim 1, wherein for each non-bonding intra-molecular contact extracted from the structural database of protein members in c) the following condition is also satisfied: the theta atom and the iota atom of the contact are on different residues separated by at least four residues along the linear polypeptide or are on separate polypeptide chains. 3. The method according to claim 1, wherein the theta atom type is identified as being one and only one of: the 167 non-hydrogen atoms present in the 20 natural amino acids of proteins; the 82 non-hydrogen atoms present in the 4 nucleotides of the deoxyribonucleic acid polymer (DNA); the 42 non-hydrogen atoms present in the methylated DNA nucleotides, cytidine phosphate and adenosine phosphate; the 85 non-hydrogen atoms present in the 4 nucleotide phosphates of the ribonucleic acid polymer (RNA); the 89 non-hydrogen atoms present in 2-O′-methylated ribose nucleotide phosphates of RNA; the over 400 non-hydrogen atoms present in the commonest post-transcription base modified RNA. 4. The method according to claim 1, wherein the information extracted in c) is collected in a secondary database comprising one and only one theta contact set for each of the theta atom types. 5. The method according to claim 4, wherein each of said secondary database theta contact sets is sub-divided into a plurality of non-overlapping iota atom types or non-overlapping groups of related iota atom types. 6. The method according to claim 1, wherein the iota atom type is identified as being one and only one of: the 167 non-hydrogen atoms present in the 20 natural amino acids of proteins; the oxygen atom present in protein bound, structurally relevant, water molecules; the 82 non-hydrogen atoms present in the 4 nucleotides of the deoxyribonucleic acid polymer (DNA); the 42 non-hydrogen atoms present in the methylated DNA nucleotides, cytidine phosphate and adenosine phosphate; the 85 non-hydrogen atoms present in the 4 nucleotide phosphates of the ribonucleic acid polymer (RNA); the 89 non-hydrogen atoms present in 2-O′-methylated ribose nucleotide phosphates of RNA; and/or the over 400 non-hydrogen atoms present in the commonest post-transcription modified bases of RNA. 7. The method according to claim 1, wherein said predetermined group of related iota atom types is one of a plurality of non-overlapping groups obtained by sorting the 167 non-hydrogen atoms present in the 20 natural amino acids of proteins into groups of similar chemical type. 8. The method according to claim 7, wherein the iota atom types are sorted into the plurality of non-overlapping groups according to one or more of the following factors: elemental nature of the atom type, hybridisation state of the atom type. 9. The method according to claim 7, wherein the iota atom types are sorted into a plurality of non-overlapping groups comprising the following: C sp3, C sp2(aromatic), C sp2(non-aromatic), N sp3, N sp2, O sp3, O sp2, S. 10. The method according to claim 1, wherein: said spatial data extracted in c) defines the position of each iota atom specified in the theta contact set by geometrical reference to the position of the theta atom and to the positions of third and fourth atoms; the third atom is covalently bonded to the theta atom; and the fourth atom is covalently bonded to the third atom. 11. The method according to claim 10, wherein: for each iota atom specified in the theta contact set, said spatial data extracted in c) defines the position of fifth and sixth atoms by geometrical reference to the position of the theta atom and to the positions of the third and fourth atoms; the fifth atom is covalently bonded to the iota atom; and the sixth atom is covalently bonded to either the fifth atom or the iota atom. 12. The method according to claim 11, wherein the superimposition in or around the target site of (d) comprises: parsing the theta contact set to extract spatial data for contacts comprising the given iota atom type or one or more of the predetermined group of related iota atom types; and plotting this spatial data to determine theoretical locations representing where each iota atom type, or each of the one or more of the predetermined group of related iota atom types, would be located if: i) the theta atom of the contact were located at the position of the corresponding theta atom in the target binding site; and ii) the third and fourth atoms of the contact were located at the positions of the third and fourth atoms of the corresponding theta atom in the target binding site. 13. The method according to claim 12, wherein: the extracted spatial data is parsed against said contextual data before said plotting step. 14. The method according to claim 12, wherein a region in which a density of theoretical locations for the given iota atom type, or for the one or more of the predetermined group of related iota atom types, is above a predetermined threshold is identified as one of the favoured regions. 15. The method according to claim 12, wherein theoretical locations for the given iota atom type, or for one or more of the predetermined group of related iota atom types, are determined for a plurality of theta atoms on the target list and a region in which a density of the cumulative theoretical locations is above the predetermined threshold is identified as one of the favoured regions. 16. The method according to claim 12, wherein: if the theoretical location of an individual iota atom intersects with the location of an atom of the target macromolecule closer than Rw−0.2 angstroms then the said iota atom is excluded from subsequent analysis. 17. The method according to claim 11, wherein: the third and fourth atoms are chosen uniquely for each specified theta atom type. 18. The method according to claim 11, wherein: the fifth and sixth atoms are chosen uniquely for each specified iota atom type. 19. The method according to claim 11, wherein: for each favoured region, vectors are derived to describe the position of the fifth atom relative to its respective iota atom and analysis is carried out on said vectors in order to identify a favoured bond vector representing a prediction of the covalent attachment of a theoretical consensus iota atom in the said region, said identified favoured bond vector being used to refine the design of the candidate ligand or modification of the candidate ligand. 20. The method according to claim 1, wherein: said contextual data extracted in (c), contains contextual information concerning the local environment of each contact pair in the theta contact set, including one or more of the following in any combination: secondary structure, amino acid types or other monomer types comprising the contact pair, adjacent monomer units and/or local geometry thereof in a polymer chain either side of the contact, adjacent amino acids in a polypeptide chain on either side of the contact, local geometry of the said adjacent monomer units or amino acids, temperature factor of the theta atom, temperature factor of the iota atom, accessible surface area of the theta atom, accessible surface area of the iota atom, the number of different iota atom contacts for the particular theta atom and the number of other theta atoms on the same monomer unit as the theta atom. 21. The method according to claim 1, wherein (f) comprises: identifying a modification of the candidate ligand that increases a degree of overlap between one or more atoms of the candidate ligand and a predicted favoured region or regions for an iota atom type or predetermined group of related iota atom types in the binding site. 22. The method according to claim 1, wherein a plurality of modifications to the candidate ligand are identified in (f) and the method further comprises selecting a subset of the identified modifications based on one or both of the following: 1) the extent to which the intersection between the alternate and/or additional candidate ligand atoms and the respective iota atom type favoured regions is greater compared to the unmodified candidate ligand; and 2) the extent to which one or more factors contributing to the total energy of the complex formed by the binding of the modified candidate ligand to the binding site is/are reduced compared to the case where the unmodified candidate ligand is bound. 23. The method according to claim 1, wherein t=2.5 angstroms 24. The method according to claim 1, wherein t=0.8 angstroms 25. The method according to claim 1, further comprising: out-putting data representing the modification identified in (f). 26. The method according to claim 1, wherein the ligand is a protein. 27. The method according to claim 26, wherein the ligand is an antibody. 28. The method according to claim 26, wherein (f) comprises replacing each of one or more of the amino acid residues of the ligand that is/are in direct contact with the target binding site, or in close proximity to the target binding site, with each of one or more alternative residues chosen from the other 19 natural amino acids, each replacement being referred to as a residue replacement, wherein for each residue replacement that does not cause conflict between the replacement residue and adjacent atoms of the ligand or target, the type and position of each atom of the replacement residue is compared with the respective iota atom type favoured regions to identify whether they will produce a greater intersection than the atoms of the original residue. 29. The method according to claim 28, further comprising: outputting a list of the residue replacements that are identified as producing a greater intersection than atoms of the original residue; for each listed residue replacement, using mutation of the candidate ligand to produce a modified ligand that incorporates the residue replacement; testing the affinity of each of the modified ligands to the target binding site in order to determine which residue replacements result in an affinity improvement that is above a predetermined threshold. 30. The method according to claim 29, further comprising: modifying the candidate ligand to incorporate a plurality of the residue replacements that have been determined to result in an affinity improvement that is above the predetermined threshold. 31. A computer readable medium or signal comprising computer readable instructions for causing a computer to carry out the method of claim 1. 32. The medium or signal according to claim 31, wherein the computer is caused to carry out at least (c)-(e). 33. The medium or signal according to claim 31, wherein the computer is caused to carry to carry out at least (f). 34. A method of manufacturing a therapeutic ligand, comprising: designing a therapeutic ligand according to the method of claim 1; and manufacturing the therapeutic ligand thus designed. 35. A therapeutic ligand manufactured according to the method of claim 34. 36. The method or ligand according to claim 34, wherein the ligand is a protein. 37. The method or ligand according to claim 36, wherein the protein is an antibody. 38. A method of generating a database for use in a method for designing a ligand ab initio that will bind to a binding site of a macromolecular target, or of identifying a modification to a ligand for improving the affinity of the ligand to a binding site of a macromolecular target, comprising: analysing the relative positions of atoms in each of a plurality of proteins or other biological macromolecules in order to identify instances of a non-bonding intra-molecular contact between a first atom, referred to as a theta atom, and a second atom, referred to as an iota atom, of the protein or macromolecule; and generating a database that for each identified contact specifies: the type of the theta atom, the type of the iota atom, and the position of the iota atom relative to the theta atom; wherein a non-bonding intra-molecular contact is defined as an instance where the following conditions are satisfied: s−Rw≦t, where s is the separation between the theta and iota atoms, Rw is the sum of the van de Waals radii of the theta and iota atoms, and t is a predetermined threshold distance of typically 2.5 angstroms and preferably 0.8 angstroms; and wherein in the case of proteins, the theta and iota atoms are on amino acid residues separated from each other by at least four residues on a linear polypeptide or are on separate polypeptide chains. 39. The method according to claim 38, wherein the method comprises sub-dividing the database to form groups of identified contacts in which the theta atom is one and only one of the 167 non-hydrogen atoms present in the 20 natural amino acids of proteins and the iota atom is in one and only one of a plurality of non-overlapping groups obtained by sorting the 167 non-hydrogen atoms present in the 20 natural amino acids of proteins into groups based on chemical similarity. 40. A method of generating a database for use in a method for designing a ligand ab initio that will bind to a binding site of a macromolecular target, or of identifying a modification to a ligand for improving the affinity of the ligand to a binding site of a macromolecular target, comprising: analysing the relative positions of atoms in each of a plurality of proteins or other biological macromolecules in order to identify instances of a non-bonding intra-molecular contact between a first atom referred to as a theta atom, and a second atom, referred to as an iota atom, of the protein or macromolecule; and generating a database that for each identified contact specifies: the type of the theta atom, the type of the iota atom, and the position of the iota atom relative to the theta atom; wherein a non-bonding intra-molecular contact is defined as an instance where the following condition is satisfied: s−Rw≦t, where s is the separation between the theta and iota atoms, Rw is the sum of the van de Waals radii of the theta and iota atoms, and t is a predetermined threshold distance of typically 2.5 angstroms and preferably 0.8 angstroms; and wherein the method comprises sub-dividing the database to form groups of identified contacts in which the theta atom is one and only one of the 167 non-hydrogen atoms present in the 20 natural amino acids of proteins and the iota atom is in one and only one of a plurality of non-overlapping groups obtained by sorting the 167 non-hydrogen atoms present in the 20 natural amino acids of proteins into groups based on chemical similarity. 41. The method according to claim 39, wherein: for each contact, the position of the iota atom is defined by geometrical reference to the position of the theta atom and to the positions of third and fourth atoms, the third atom being covalently bonded to the theta atom and the fourth atom being covalently bonded to the third atom, the method further comprising: normalizing the coordinates of the iota atom, theta atom, third atom, and fourth atom of each contact as a group to generate a normalized coordinate group; for each of one or more of the theta atom types, using the normalized coordinate groups for a plurality of contacts involving the theta atom type and a given iota atom type to generate a two-dimensional polar plot that represents a distribution of directions of the given iota atom, in terms of latitude and longitude, relative to the theta atom; repeating the above for different iota atom types; comparing the resultant two-dimensional polar plots to identify groups of iota atom types that yield similar distributions of directions and using those groups as the groups based on chemical similarity to sort the 167 non-hydrogen atoms present in the 20 natural amino acids of proteins into the plurality of non-overlapping groups. 42. The method of generating a database according to claim 38, comprising: extracting contact information from at least 2000 proteins or other biological macromolecules, the extracted information containing information about at least two million contact atom pairs. 43. The method of generating a database according to claim 38, comprising: extracting contact information from at least 10000 proteins or other biological macromolecules, the extracted contact information containing information about at least ten million contact atom pairs. 44. The computer readable medium storing a database generated according to claim 1. 45. The method according to claim 1, wherein for a given antibody-antigen complex, specific mutations to amino acid residues in or around the antibody binding site are predicted to produce higher binding affinity of the antibody to the antigen.

Methods and associated apparatus involving designing a ligand ab initio that will bind to a binding site of a macromolecular target, or of identifying a modification to a ligand for improving the affinity of the ligand to a binding site of a macromolecular target, comprising using information about non-bonding, intra-molecular or inter-molecular atom to atom contacts extracted from a database of biological macromolecules to identify favoured regions adjacent to the binding site for particular atom types and modifying a candidate ligand to increase the intersection between atoms of the candidate ligand and the favoured regions. One or more steps of the methods may be performed by a computer.1. A method for designing a ligand ab initio that will bind to a binding site of a macromolecular target, or of identifying a modification to a ligand for improving the affinity of the ligand to a binding site of a macromolecular target, comprising: a) identifying a target list of atoms forming the surface of the target binding site; b) identifying each atom, hereinafter referred to as a theta atom, in the target list, as a particular theta atom type; c) extracting from a structural database of biological macromolecules, information about non-bonding, intra-molecular or inter-molecular atom to atom contacts, where the first atom in a contacting pair of atoms is of a particular theta atom type and the opposing, second atom of the pair, hereinafter referred to as an iota atom, is of a particular iota atom type, said information comprising spatial and/or contextual data about the iota atom relative to the theta atom, and said data collected for a plurality of contacts of the given theta atom type from the said database is hereinafter referred to as a theta contact set; d) for each theta atom identified in the target list in b), superimposing in or around the target binding site data relating to a given iota atom type, or a predetermined group of related iota atom types, from the corresponding theta contact set extracted in c); e) combining and/or parsing the superimposed data in such a way as to predict one or more favoured regions of the binding site where the given iota atom type, or the predetermined group of related iota atom types, has high theoretical propensity; and f) with a candidate ligand notionally docked into the binding site, comparing the type and position of one or more of the atoms of the candidate ligand with the predicted favoured regions for the respective iota atom types, to identify a modification to the candidate ligand, in terms of alternate and/or additional candidate ligand atoms, that will produce a greater intersection between the alternate and/or additional candidate ligand atoms and the respective iota atom type favoured regions, leading to an improvement in the affinity of the modified candidate ligand to the binding site compared to the unmodified candidate ligand; wherein each non-bonding intra-molecular or inter-molecular contact in the database is defined as a contact between opposing residues of a protein fold or between opposing monomer units of a macromolecular fold or between two interacting macromolecular partners and is specifically between a theta atom on one side of the fold or first interacting partner and an iota atom on the opposing side or second interacting partner; in an instance where the following condition is satisfied: s−Rw≦t, where s is the separation between the two atoms of the contact, Rw is the sum of the van de Waals radii of the two atoms of the contact, and t is a predetermined threshold distance; and wherein the theta atom type is identified uniquely in b) such that there is no intersection between the data of a theta contact set extracted in c) for a given theta atom type and the data of any other theta contact set extracted in c) for any other theta atom type, apart from data concerning contacts involving the given theta atom as the iota atom. 2. The method according to claim 1, wherein for each non-bonding intra-molecular contact extracted from the structural database of protein members in c) the following condition is also satisfied: the theta atom and the iota atom of the contact are on different residues separated by at least four residues along the linear polypeptide or are on separate polypeptide chains. 3. The method according to claim 1, wherein the theta atom type is identified as being one and only one of: the 167 non-hydrogen atoms present in the 20 natural amino acids of proteins; the 82 non-hydrogen atoms present in the 4 nucleotides of the deoxyribonucleic acid polymer (DNA); the 42 non-hydrogen atoms present in the methylated DNA nucleotides, cytidine phosphate and adenosine phosphate; the 85 non-hydrogen atoms present in the 4 nucleotide phosphates of the ribonucleic acid polymer (RNA); the 89 non-hydrogen atoms present in 2-O′-methylated ribose nucleotide phosphates of RNA; the over 400 non-hydrogen atoms present in the commonest post-transcription base modified RNA. 4. The method according to claim 1, wherein the information extracted in c) is collected in a secondary database comprising one and only one theta contact set for each of the theta atom types. 5. The method according to claim 4, wherein each of said secondary database theta contact sets is sub-divided into a plurality of non-overlapping iota atom types or non-overlapping groups of related iota atom types. 6. The method according to claim 1, wherein the iota atom type is identified as being one and only one of: the 167 non-hydrogen atoms present in the 20 natural amino acids of proteins; the oxygen atom present in protein bound, structurally relevant, water molecules; the 82 non-hydrogen atoms present in the 4 nucleotides of the deoxyribonucleic acid polymer (DNA); the 42 non-hydrogen atoms present in the methylated DNA nucleotides, cytidine phosphate and adenosine phosphate; the 85 non-hydrogen atoms present in the 4 nucleotide phosphates of the ribonucleic acid polymer (RNA); the 89 non-hydrogen atoms present in 2-O′-methylated ribose nucleotide phosphates of RNA; and/or the over 400 non-hydrogen atoms present in the commonest post-transcription modified bases of RNA. 7. The method according to claim 1, wherein said predetermined group of related iota atom types is one of a plurality of non-overlapping groups obtained by sorting the 167 non-hydrogen atoms present in the 20 natural amino acids of proteins into groups of similar chemical type. 8. The method according to claim 7, wherein the iota atom types are sorted into the plurality of non-overlapping groups according to one or more of the following factors: elemental nature of the atom type, hybridisation state of the atom type. 9. The method according to claim 7, wherein the iota atom types are sorted into a plurality of non-overlapping groups comprising the following: C sp3, C sp2(aromatic), C sp2(non-aromatic), N sp3, N sp2, O sp3, O sp2, S. 10. The method according to claim 1, wherein: said spatial data extracted in c) defines the position of each iota atom specified in the theta contact set by geometrical reference to the position of the theta atom and to the positions of third and fourth atoms; the third atom is covalently bonded to the theta atom; and the fourth atom is covalently bonded to the third atom. 11. The method according to claim 10, wherein: for each iota atom specified in the theta contact set, said spatial data extracted in c) defines the position of fifth and sixth atoms by geometrical reference to the position of the theta atom and to the positions of the third and fourth atoms; the fifth atom is covalently bonded to the iota atom; and the sixth atom is covalently bonded to either the fifth atom or the iota atom. 12. The method according to claim 11, wherein the superimposition in or around the target site of (d) comprises: parsing the theta contact set to extract spatial data for contacts comprising the given iota atom type or one or more of the predetermined group of related iota atom types; and plotting this spatial data to determine theoretical locations representing where each iota atom type, or each of the one or more of the predetermined group of related iota atom types, would be located if: i) the theta atom of the contact were located at the position of the corresponding theta atom in the target binding site; and ii) the third and fourth atoms of the contact were located at the positions of the third and fourth atoms of the corresponding theta atom in the target binding site. 13. The method according to claim 12, wherein: the extracted spatial data is parsed against said contextual data before said plotting step. 14. The method according to claim 12, wherein a region in which a density of theoretical locations for the given iota atom type, or for the one or more of the predetermined group of related iota atom types, is above a predetermined threshold is identified as one of the favoured regions. 15. The method according to claim 12, wherein theoretical locations for the given iota atom type, or for one or more of the predetermined group of related iota atom types, are determined for a plurality of theta atoms on the target list and a region in which a density of the cumulative theoretical locations is above the predetermined threshold is identified as one of the favoured regions. 16. The method according to claim 12, wherein: if the theoretical location of an individual iota atom intersects with the location of an atom of the target macromolecule closer than Rw−0.2 angstroms then the said iota atom is excluded from subsequent analysis. 17. The method according to claim 11, wherein: the third and fourth atoms are chosen uniquely for each specified theta atom type. 18. The method according to claim 11, wherein: the fifth and sixth atoms are chosen uniquely for each specified iota atom type. 19. The method according to claim 11, wherein: for each favoured region, vectors are derived to describe the position of the fifth atom relative to its respective iota atom and analysis is carried out on said vectors in order to identify a favoured bond vector representing a prediction of the covalent attachment of a theoretical consensus iota atom in the said region, said identified favoured bond vector being used to refine the design of the candidate ligand or modification of the candidate ligand. 20. The method according to claim 1, wherein: said contextual data extracted in (c), contains contextual information concerning the local environment of each contact pair in the theta contact set, including one or more of the following in any combination: secondary structure, amino acid types or other monomer types comprising the contact pair, adjacent monomer units and/or local geometry thereof in a polymer chain either side of the contact, adjacent amino acids in a polypeptide chain on either side of the contact, local geometry of the said adjacent monomer units or amino acids, temperature factor of the theta atom, temperature factor of the iota atom, accessible surface area of the theta atom, accessible surface area of the iota atom, the number of different iota atom contacts for the particular theta atom and the number of other theta atoms on the same monomer unit as the theta atom. 21. The method according to claim 1, wherein (f) comprises: identifying a modification of the candidate ligand that increases a degree of overlap between one or more atoms of the candidate ligand and a predicted favoured region or regions for an iota atom type or predetermined group of related iota atom types in the binding site. 22. The method according to claim 1, wherein a plurality of modifications to the candidate ligand are identified in (f) and the method further comprises selecting a subset of the identified modifications based on one or both of the following: 1) the extent to which the intersection between the alternate and/or additional candidate ligand atoms and the respective iota atom type favoured regions is greater compared to the unmodified candidate ligand; and 2) the extent to which one or more factors contributing to the total energy of the complex formed by the binding of the modified candidate ligand to the binding site is/are reduced compared to the case where the unmodified candidate ligand is bound. 23. The method according to claim 1, wherein t=2.5 angstroms 24. The method according to claim 1, wherein t=0.8 angstroms 25. The method according to claim 1, further comprising: out-putting data representing the modification identified in (f). 26. The method according to claim 1, wherein the ligand is a protein. 27. The method according to claim 26, wherein the ligand is an antibody. 28. The method according to claim 26, wherein (f) comprises replacing each of one or more of the amino acid residues of the ligand that is/are in direct contact with the target binding site, or in close proximity to the target binding site, with each of one or more alternative residues chosen from the other 19 natural amino acids, each replacement being referred to as a residue replacement, wherein for each residue replacement that does not cause conflict between the replacement residue and adjacent atoms of the ligand or target, the type and position of each atom of the replacement residue is compared with the respective iota atom type favoured regions to identify whether they will produce a greater intersection than the atoms of the original residue. 29. The method according to claim 28, further comprising: outputting a list of the residue replacements that are identified as producing a greater intersection than atoms of the original residue; for each listed residue replacement, using mutation of the candidate ligand to produce a modified ligand that incorporates the residue replacement; testing the affinity of each of the modified ligands to the target binding site in order to determine which residue replacements result in an affinity improvement that is above a predetermined threshold. 30. The method according to claim 29, further comprising: modifying the candidate ligand to incorporate a plurality of the residue replacements that have been determined to result in an affinity improvement that is above the predetermined threshold. 31. A computer readable medium or signal comprising computer readable instructions for causing a computer to carry out the method of claim 1. 32. The medium or signal according to claim 31, wherein the computer is caused to carry out at least (c)-(e). 33. The medium or signal according to claim 31, wherein the computer is caused to carry to carry out at least (f). 34. A method of manufacturing a therapeutic ligand, comprising: designing a therapeutic ligand according to the method of claim 1; and manufacturing the therapeutic ligand thus designed. 35. A therapeutic ligand manufactured according to the method of claim 34. 36. The method or ligand according to claim 34, wherein the ligand is a protein. 37. The method or ligand according to claim 36, wherein the protein is an antibody. 38. A method of generating a database for use in a method for designing a ligand ab initio that will bind to a binding site of a macromolecular target, or of identifying a modification to a ligand for improving the affinity of the ligand to a binding site of a macromolecular target, comprising: analysing the relative positions of atoms in each of a plurality of proteins or other biological macromolecules in order to identify instances of a non-bonding intra-molecular contact between a first atom, referred to as a theta atom, and a second atom, referred to as an iota atom, of the protein or macromolecule; and generating a database that for each identified contact specifies: the type of the theta atom, the type of the iota atom, and the position of the iota atom relative to the theta atom; wherein a non-bonding intra-molecular contact is defined as an instance where the following conditions are satisfied: s−Rw≦t, where s is the separation between the theta and iota atoms, Rw is the sum of the van de Waals radii of the theta and iota atoms, and t is a predetermined threshold distance of typically 2.5 angstroms and preferably 0.8 angstroms; and wherein in the case of proteins, the theta and iota atoms are on amino acid residues separated from each other by at least four residues on a linear polypeptide or are on separate polypeptide chains. 39. The method according to claim 38, wherein the method comprises sub-dividing the database to form groups of identified contacts in which the theta atom is one and only one of the 167 non-hydrogen atoms present in the 20 natural amino acids of proteins and the iota atom is in one and only one of a plurality of non-overlapping groups obtained by sorting the 167 non-hydrogen atoms present in the 20 natural amino acids of proteins into groups based on chemical similarity. 40. A method of generating a database for use in a method for designing a ligand ab initio that will bind to a binding site of a macromolecular target, or of identifying a modification to a ligand for improving the affinity of the ligand to a binding site of a macromolecular target, comprising: analysing the relative positions of atoms in each of a plurality of proteins or other biological macromolecules in order to identify instances of a non-bonding intra-molecular contact between a first atom referred to as a theta atom, and a second atom, referred to as an iota atom, of the protein or macromolecule; and generating a database that for each identified contact specifies: the type of the theta atom, the type of the iota atom, and the position of the iota atom relative to the theta atom; wherein a non-bonding intra-molecular contact is defined as an instance where the following condition is satisfied: s−Rw≦t, where s is the separation between the theta and iota atoms, Rw is the sum of the van de Waals radii of the theta and iota atoms, and t is a predetermined threshold distance of typically 2.5 angstroms and preferably 0.8 angstroms; and wherein the method comprises sub-dividing the database to form groups of identified contacts in which the theta atom is one and only one of the 167 non-hydrogen atoms present in the 20 natural amino acids of proteins and the iota atom is in one and only one of a plurality of non-overlapping groups obtained by sorting the 167 non-hydrogen atoms present in the 20 natural amino acids of proteins into groups based on chemical similarity. 41. The method according to claim 39, wherein: for each contact, the position of the iota atom is defined by geometrical reference to the position of the theta atom and to the positions of third and fourth atoms, the third atom being covalently bonded to the theta atom and the fourth atom being covalently bonded to the third atom, the method further comprising: normalizing the coordinates of the iota atom, theta atom, third atom, and fourth atom of each contact as a group to generate a normalized coordinate group; for each of one or more of the theta atom types, using the normalized coordinate groups for a plurality of contacts involving the theta atom type and a given iota atom type to generate a two-dimensional polar plot that represents a distribution of directions of the given iota atom, in terms of latitude and longitude, relative to the theta atom; repeating the above for different iota atom types; comparing the resultant two-dimensional polar plots to identify groups of iota atom types that yield similar distributions of directions and using those groups as the groups based on chemical similarity to sort the 167 non-hydrogen atoms present in the 20 natural amino acids of proteins into the plurality of non-overlapping groups. 42. The method of generating a database according to claim 38, comprising: extracting contact information from at least 2000 proteins or other biological macromolecules, the extracted information containing information about at least two million contact atom pairs. 43. The method of generating a database according to claim 38, comprising: extracting contact information from at least 10000 proteins or other biological macromolecules, the extracted contact information containing information about at least ten million contact atom pairs. 44. The computer readable medium storing a database generated according to claim 1. 45. The method according to claim 1, wherein for a given antibody-antigen complex, specific mutations to amino acid residues in or around the antibody binding site are predicted to produce higher binding affinity of the antibody to the antigen.

The present invention provides a method for the isolation of sperm DNA from swabs taken from rape victims without having to perform a change in buffers. Non-sperm cells from the victim are digested with an enzyme and solubilized, and then in the same buffer an enzyme capable of digesting soluble DNA is added and the victim's DNA is degraded, leaving only the rapist's DNA intact. Since no change of buffer is needed, no centrifugation or filtration steps are needed. The inventive method has utility particularly in the forensic science field.

1. A method for purifying sperm DNA from sexual assault samples comprising: a) obtaining a sample containing sperm cells and non-sperm cells, and placing these cells in a buffer compatible with enzymes that can digest non-sperm cells and soluble DNA, b) selectively degrading the non-sperm cells with an enzyme to obtain soluble non-sperm DNA and intact sperm, c) digesting the soluble DNA with an enzyme, and d) purifying the intact sperm DNA for further analysis. 2. The method according to claim 1, wherein the buffer does not contain Sodium Dodecyl Sulfate. 3. The method according to claim 1, wherein the buffer contains Triton X-100. 4. The method according to claim 1, wherein the non-sperm cell degrading agent is Proteinase K. 5. The method according to claim 1, wherein the DNA degrading agent is DNase-I. 6. The method according to claim 1, wherein the sample is obtained from a victim of sexual assault. 7. An identification method, comprising: obtaining sperm DNA according to the method of claim 1; and determining an identity for the sperm donor, based, at least in part, on the isolated sperm DNA. 8. The method of claim 8, wherein the identity determined is that of a perpetrator of a sexual assault.

The present invention provides a method for the isolation of sperm DNA from swabs taken from rape victims without having to perform a change in buffers. Non-sperm cells from the victim are digested with an enzyme and solubilized, and then in the same buffer an enzyme capable of digesting soluble DNA is added and the victim's DNA is degraded, leaving only the rapist's DNA intact. Since no change of buffer is needed, no centrifugation or filtration steps are needed. The inventive method has utility particularly in the forensic science field.1. A method for purifying sperm DNA from sexual assault samples comprising: a) obtaining a sample containing sperm cells and non-sperm cells, and placing these cells in a buffer compatible with enzymes that can digest non-sperm cells and soluble DNA, b) selectively degrading the non-sperm cells with an enzyme to obtain soluble non-sperm DNA and intact sperm, c) digesting the soluble DNA with an enzyme, and d) purifying the intact sperm DNA for further analysis. 2. The method according to claim 1, wherein the buffer does not contain Sodium Dodecyl Sulfate. 3. The method according to claim 1, wherein the buffer contains Triton X-100. 4. The method according to claim 1, wherein the non-sperm cell degrading agent is Proteinase K. 5. The method according to claim 1, wherein the DNA degrading agent is DNase-I. 6. The method according to claim 1, wherein the sample is obtained from a victim of sexual assault. 7. An identification method, comprising: obtaining sperm DNA according to the method of claim 1; and determining an identity for the sperm donor, based, at least in part, on the isolated sperm DNA. 8. The method of claim 8, wherein the identity determined is that of a perpetrator of a sexual assault.

The present invention provides 2,4-pyrimidinediamine compounds that inhibit the IgE and/or IgG receptor signaling cascades that lead to the release of chemical mediators, intermediates and methods of synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and prevention of diseases characterized by, caused by or associated with the release of chemical mediators via degranulation and other processes effected by activation of the IgE and/or IgG receptor signaling cascades.

1-71. (canceled) 72. A compound according to formula (I): or a salt or N-oxide thereof, wherein: Q is selected from the group consisting of nitro and amino; and two R35 bonded to the same carbon atom are taken together to form an oxo (═O) group and the other two R35 are each, independently of one another, selected from the group consisting of halo and (C1-C6) alkyl. 73. The compound of claim 72 in which the other two R35 are each independently methyl or fluoro. 74. A compound of the formula: where Q is —NH2 or —NO2 or a salt or N-oxide thereof. 75. A compound of the formula: where Q is —NH2 or —NO2 or a salt or N-oxide thereof.

The present invention provides 2,4-pyrimidinediamine compounds that inhibit the IgE and/or IgG receptor signaling cascades that lead to the release of chemical mediators, intermediates and methods of synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and prevention of diseases characterized by, caused by or associated with the release of chemical mediators via degranulation and other processes effected by activation of the IgE and/or IgG receptor signaling cascades.1-71. (canceled) 72. A compound according to formula (I): or a salt or N-oxide thereof, wherein: Q is selected from the group consisting of nitro and amino; and two R35 bonded to the same carbon atom are taken together to form an oxo (═O) group and the other two R35 are each, independently of one another, selected from the group consisting of halo and (C1-C6) alkyl. 73. The compound of claim 72 in which the other two R35 are each independently methyl or fluoro. 74. A compound of the formula: where Q is —NH2 or —NO2 or a salt or N-oxide thereof. 75. A compound of the formula: where Q is —NH2 or —NO2 or a salt or N-oxide thereof.

The present invention relates generally to agents and devices for promoting hemostasis and tissue sealing and, more particularly, to hemostatic pads comprising bioabsorbable scaffolds that can deliver lyophilized hemostasis promoting proteins, such as fibrinogen and thrombin, to a wound site or injured organ or tissue.

1. A hemostatic wound treatment device comprising: a bioabsorbable scaffold having a wound facing surface and an opposing surface; said scaffold wetted with a biocompatible liquid that is not blood or plasma; and a hemostatic powder that adheres by moisture to at least the wound facing surface of said bioabsorbable scaffold. 2. The hemostatic wound treatment device of claim 1 wherein the hemostatic powder comprises a mixture of dry fibrinogen and dry thrombin. 3. The hemostatic wound treatment device of claim 1 wherein the hemostatic powder comprises dry fibrinogen. 4. The hemostatic wound treatment device of claim 1 wherein the hemostatic powder comprises dry thrombin. 5. The hemostatic wound treatment device according to claim 1 wherein the biocompatible liquid is selected from the group consisting of an aqueous solution, normal saline, ethanol, and ethanol-water mixture. 6. The hemostatic wound treatment device according to claim 5 wherein the biocompatible liquid comprises a hemostatic agent. 7. The hemostatic wound treatment device according to claim 6 wherein the biocompatible liquid comprises thrombin, fibrinogen, hemostasis promoting agents, growth factors, calcium salts, absorbable disaggregation aids, bulking agents, gelatin, collagen, and combinations thereof. 8. The hemostatic wound treatment device according to claim 7 wherein the biocompatible liquid comprises proteins, prothrombin, fibrin, fibronectin, heparinase, Factor X/Xa, Factor VII/VIIa, Factor IX/IXa, Factor XI/XIa, Factor XII/XIIa, tissue factor, batroxobin, ancrod, ecarin, von Willebrand Factor, collagen, elastin, albumin, gelatin, platelet surface glycoproteins, vasopressin, vasopressin analogs, epinephrine, selectin, procoagulant venom, plasminogen activator inhibitor, platelet activating agents, synthetic peptides having hemostatic activity, and/or combinations thereof. 9. The hemostatic wound treatment device according to claim 1 wherein the scaffold comprises an oxidized polysaccharide or bioabsorbable synthetic polymer. 10. The hemostatic wound treatment device according to claim 9 wherein the scaffold is a multi-layered structured composite material comprising a lactide-glycolide polymer layer and a cellulosic layer comprising oxidized regenerated cellulose. 11. The hemostatic wound treatment pad of claim 10 wherein the hemostatic powder adheres to the lactide-glycolide polymer layer and the opposing surface layer comprises the oxidized regenerated cellulose. 12. A method of making and using the hemostatic wound treatment pad of claim 1, comprising: a) wetting the scaffold with the biocompatible liquid; b) contacting the scaffold with the hemostatic powder and adhering at least a portion of the hemostatic powder to at least the wound facing surface of the scaffold; and c) applying the wound facing surface of the hemostatic wound treatment pad onto a wound. 13. The method of claim 12 wherein the time period between initial contact of the scaffold with the hemostatic powder and the subsequent application of the hemostatic wound treatment pad onto the wound is less than two minutes. 14. A prep kit for a hemostatic wound treatment pad comprising: a) at least one powdered hemostatic material; b) a bioabsorbable scaffold; c) a biocompatible liquid; and d) an application tray; wherein components a) to d) are combined into a unitary packaging unit. 15. The kit of claim 14 wherein said at least one powdered hemostatic material comprises a protein selected from the group consisting of a fibrinogen, a thrombin, and mixtures thereof. 16. The kit of claim 14 wherein said biocompatible liquid is selected from the group consisting of water, an aqueous solution, a normal saline, a thrombin solution, a fibrinogen solution, an alcohol, and a glycerol. 17. The kit of claim 14 wherein the at least one powdered hemostatic material comprises a mixture of a dry fibrinogen and a dry thrombin and said biocompatible liquid comprises normal saline. 18. The kit of claim 17 wherein the powdered hemostatic material comprises a dry fibrinogen and said biocompatible liquid comprises a thrombin solution. 19. The kit of claim 14 further comprising a means for wetting said bioabsorbable scaffold with said liquid. 20. The kit of claim 19 wherein said means for wetting are: (1) a liquid transfer pad; (2) a spray bottle; (3) a transfer pen; or (4) a liquid tray having size accommodating immersion of said bioabsorbable scaffold with the wound facing side facing into said liquid tray. 21. The kit of claim 20 wherein said liquid transfer pad comprises a bundle of surgical gauze. 22. The kit of claim 14 wherein said powdered hemostatic material is packaged into said powder tray. 23. The kit of claim 14 wherein said bioabsorbable scaffold is a bioabsorbable polysaccharide, a bioabsorbable synthetic polymer, a bioabsorbable protein, or combinations thereof. 24. The kit of claim 14, wherein said bioabsorbable scaffold is a fabric, a woven material, a non-woven material, a mesh, or combinations thereof. 25. The kit of claim 14 wherein said bioabsorbable scaffold is a multilayer composite structure having a cellulosic layer comprising oxidized regenerated cellulose and a polymer layer comprising Polyglactin 910.

The present invention relates generally to agents and devices for promoting hemostasis and tissue sealing and, more particularly, to hemostatic pads comprising bioabsorbable scaffolds that can deliver lyophilized hemostasis promoting proteins, such as fibrinogen and thrombin, to a wound site or injured organ or tissue.1. A hemostatic wound treatment device comprising: a bioabsorbable scaffold having a wound facing surface and an opposing surface; said scaffold wetted with a biocompatible liquid that is not blood or plasma; and a hemostatic powder that adheres by moisture to at least the wound facing surface of said bioabsorbable scaffold. 2. The hemostatic wound treatment device of claim 1 wherein the hemostatic powder comprises a mixture of dry fibrinogen and dry thrombin. 3. The hemostatic wound treatment device of claim 1 wherein the hemostatic powder comprises dry fibrinogen. 4. The hemostatic wound treatment device of claim 1 wherein the hemostatic powder comprises dry thrombin. 5. The hemostatic wound treatment device according to claim 1 wherein the biocompatible liquid is selected from the group consisting of an aqueous solution, normal saline, ethanol, and ethanol-water mixture. 6. The hemostatic wound treatment device according to claim 5 wherein the biocompatible liquid comprises a hemostatic agent. 7. The hemostatic wound treatment device according to claim 6 wherein the biocompatible liquid comprises thrombin, fibrinogen, hemostasis promoting agents, growth factors, calcium salts, absorbable disaggregation aids, bulking agents, gelatin, collagen, and combinations thereof. 8. The hemostatic wound treatment device according to claim 7 wherein the biocompatible liquid comprises proteins, prothrombin, fibrin, fibronectin, heparinase, Factor X/Xa, Factor VII/VIIa, Factor IX/IXa, Factor XI/XIa, Factor XII/XIIa, tissue factor, batroxobin, ancrod, ecarin, von Willebrand Factor, collagen, elastin, albumin, gelatin, platelet surface glycoproteins, vasopressin, vasopressin analogs, epinephrine, selectin, procoagulant venom, plasminogen activator inhibitor, platelet activating agents, synthetic peptides having hemostatic activity, and/or combinations thereof. 9. The hemostatic wound treatment device according to claim 1 wherein the scaffold comprises an oxidized polysaccharide or bioabsorbable synthetic polymer. 10. The hemostatic wound treatment device according to claim 9 wherein the scaffold is a multi-layered structured composite material comprising a lactide-glycolide polymer layer and a cellulosic layer comprising oxidized regenerated cellulose. 11. The hemostatic wound treatment pad of claim 10 wherein the hemostatic powder adheres to the lactide-glycolide polymer layer and the opposing surface layer comprises the oxidized regenerated cellulose. 12. A method of making and using the hemostatic wound treatment pad of claim 1, comprising: a) wetting the scaffold with the biocompatible liquid; b) contacting the scaffold with the hemostatic powder and adhering at least a portion of the hemostatic powder to at least the wound facing surface of the scaffold; and c) applying the wound facing surface of the hemostatic wound treatment pad onto a wound. 13. The method of claim 12 wherein the time period between initial contact of the scaffold with the hemostatic powder and the subsequent application of the hemostatic wound treatment pad onto the wound is less than two minutes. 14. A prep kit for a hemostatic wound treatment pad comprising: a) at least one powdered hemostatic material; b) a bioabsorbable scaffold; c) a biocompatible liquid; and d) an application tray; wherein components a) to d) are combined into a unitary packaging unit. 15. The kit of claim 14 wherein said at least one powdered hemostatic material comprises a protein selected from the group consisting of a fibrinogen, a thrombin, and mixtures thereof. 16. The kit of claim 14 wherein said biocompatible liquid is selected from the group consisting of water, an aqueous solution, a normal saline, a thrombin solution, a fibrinogen solution, an alcohol, and a glycerol. 17. The kit of claim 14 wherein the at least one powdered hemostatic material comprises a mixture of a dry fibrinogen and a dry thrombin and said biocompatible liquid comprises normal saline. 18. The kit of claim 17 wherein the powdered hemostatic material comprises a dry fibrinogen and said biocompatible liquid comprises a thrombin solution. 19. The kit of claim 14 further comprising a means for wetting said bioabsorbable scaffold with said liquid. 20. The kit of claim 19 wherein said means for wetting are: (1) a liquid transfer pad; (2) a spray bottle; (3) a transfer pen; or (4) a liquid tray having size accommodating immersion of said bioabsorbable scaffold with the wound facing side facing into said liquid tray. 21. The kit of claim 20 wherein said liquid transfer pad comprises a bundle of surgical gauze. 22. The kit of claim 14 wherein said powdered hemostatic material is packaged into said powder tray. 23. The kit of claim 14 wherein said bioabsorbable scaffold is a bioabsorbable polysaccharide, a bioabsorbable synthetic polymer, a bioabsorbable protein, or combinations thereof. 24. The kit of claim 14, wherein said bioabsorbable scaffold is a fabric, a woven material, a non-woven material, a mesh, or combinations thereof. 25. The kit of claim 14 wherein said bioabsorbable scaffold is a multilayer composite structure having a cellulosic layer comprising oxidized regenerated cellulose and a polymer layer comprising Polyglactin 910.

A microbe-specific medium, containing specific chromogenic substrates, for the detection of vancomycin-resistant enterococci in a biological sample, whereby both the detection and identification of vancomycin-resistant enterococci at the species level is achieved utilizing one sample and one test.

1. A medium for identifying and distinguishing species of a microorganism placed in the medium comprising: a first substrate conjugated to a first imaging moiety, wherein the first substrate is selected to interact preferentially with a first enzyme that is produced by a first species of microorganism compared to a second enzyme that is produced by a second species of microorganism; and a second substrate conjugated to a second imaging moiety, wherein the second substrate is selected to interact preferentially with the second enzyme that is produced by the second species of microorganism compared to the first enzyme that is produced by the first species of microorganism; wherein the first imaging moiety images a first indicator when the first substrate interacts with the first enzyme and the second imaging moiety images a second indicator when the second substrate interacts with the second enzyme and wherein the first indicator is perceptually different from the second indicator. 2. The medium of claim 1, wherein the first imaging moiety is a first chromophore and the second imaging moiety is a second chromophore. 3. The medium of claim 2 further comprising a third substrate that interacts with at least a third microorganism to image a third indicator that is perceptually different from either the first indicator or the second indicator. 4. The medium of claim 3, wherein the third microorganism produces a normally repressed enzyme in response to the interaction with the third substrate wherein the normally repressed enzyme interacts preferentially with the first substrate to image the first indicator. 5. The medium of claim 4 wherein the third microorganism produces an enzyme that is the same or different from the second enzyme and that interacts preferentially with the second substrate to image the second indicator and wherein the first indicator and the second indicator together are the third indicator. 6. The medium of claim 1 further comprising inhibitors of non-vancomycin resistant enterococci. 7. The medium of claim 6 wherein the inhibitors comprise vancomycin. 8. The medium of claim 7 wherein the vancomycin is present in an amount effective to inhibit the growth of at least some non-vancomycin resistant enterococci and not significantly inhibit the growth of vancomycin resistant enterococci. 9. The medium of claim 7 further comprising an inhibitor of vanC-containing enterococci wherein the inhibitor of vanC-containing enterococci comprises a cephalosporin. 10. The medium of claim 9 wherein the cephalosporin is cefoxitin. 11. The medium of claim 10 wherein the cefoxitin is present in an amount effective to suppress the growth of the vanC-containing enterococci. 12. The medium of claim 11 wherein the amount of cefoxitin does not significantly suppress the growth of a vancomycin resistant enterococci selected from the group consisting of vancomycin resistant enterococci containing a vanA gene and vancomycin resistant enterococci containing a vanB gene. 13. The medium of claim 7 wherein the inhibitors further comprise erythromycin. 14. The medium of claim 13, wherein the inhibitors further comprise at least one inhibitor selected from the group consisting of colistin, nalidixic acid, aztreonam, and amphotericin B and combinations thereof. 15. The medium of claim 9 wherein the inhibitors further comprise erythromycin. 16. The medium of claim 1, wherein the first substrate is alpha-D-glucopyranoside and the first enzyme is alpha-D-glucopyranosidase. 17. The medium of claim 16, wherein the first microorganism is a first species of vancomycin resistant enterococci. 18. The medium of claim 17 wherein the first species of vancomycin resistant enterococci is E. faecalis. 19. The medium of claim 9, wherein the second substrate is beta-D-galactopyranoside and the second enzyme is beta-D-galactopyranosidase. 20. The medium of claim 19, wherein the second microorganism is as a second species of vancomycin resistant enterococci. 21. The medium of claim 20 wherein the second species of vancomycin resistant enterococci is E. faecium. 22. The medium of claim 4, wherein the third substrate is methyl-alpha-D-glucopyranoside. 23. The medium of claim 22 wherein the third substrate induces the first enzyme, wherein the first enzyme is alpha-D-glucopyranosidase. 24. The medium of claim 23, wherein the at least third microorganism is selected from the group consisting of E. casseliflavus and E. gallinarum. 25. A medium for detecting and differentiating species of a microorganisms comprising: a first substrate conjugated to a first imaging moiety, wherein the first substrate preferentially interacts with a first enzyme that is produced by a first species of the microorganism compared to a second enzyme that is produced by a second species of the microorganism; and a second substrate conjugated to a second imaging moiety, wherein the second substrate preferentially interacts with the second enzyme that is produced by the second species of a microorganism compared to the first enzyme that is produced by the first species of the microorganism; an inhibitor of non-vancomycin resistant enterococci comprising vancomycin; and at least one of a third substrate or a cephalosporin, wherein the third substrate induces the production of the first enzyme by at least a third species of the microorganism wherein the first imaging moiety images a first indicator when the first substrate interacts with the first enzyme and the second imaging moiety images a second indicator when the second substrate interacts with the second enzyme, and the combined presence of the first imaging moiety and second imaging moiety image a third indicator in the combined presence of the first enzyme and the second enzyme produced by the at least third species of the microorganism, wherein the first, second and third indicators are perceptually different from each other. 26. The medium of claim 25 wherein the first and second imaging moieties are selected from the group consisting of chromophores and fluorophores. 27. The medium of claim 26 wherein the first imaging moiety conjugated to the first substrate is a first chromogen and the second imaging moiety conjugated to the second substrate is a second chromogen. 28. The medium of claim 25, wherein the first substrate is alpha-D-glucopyranoside and the first enzyme is alpha-D-glucopyranosidase. 29. The medium of claim 25, wherein the second substrate is beta-D-galactopyranoside and the second enzyme is beta-D-galactopyranosidase. 30. The medium of claim 25, wherein the third substrate is methyl-alpha-D-glucopyranoside. 31. The medium of claim 25 wherein the first species of microorganism is a first species of vancomycin resistant enterococci. 32. The medium of claim 31 wherein the first species of vancomycin resistant enterococci is E. faecalis. 33. The medium of claim 25 wherein the second species of microorganism is a second species of vancomycin resistant enterococci. 34. The medium of claim 33 wherein the second species of vancomycin resistant enterococci is E. faecium. 35. The medium of claim 25 wherein the at least third species of microorganism is a third species of vancomycin resistant enterococci selected from the group consisting of E. casseliflavus, E. gallinarum and combinations thereof. 36. The medium of claim 25 wherein the inhibitor of non-vancomycin resistant enterococci further comprises an inhibitor selected from the group consisting of colistin, nalidixic acid, aztreonam, amphotericin B, and combinations thereof. 37. The medium of claim 36 wherein the cephalosporin is cefoxitin. 38. The medium of claim 37 wherein the inhibitor of non-vancomycin resistant enterococci further comprise erythromycin. 39. A method of detecting the presence of a species of vancomycin resistant enterococci comprising: combining a biological sample with a medium, the medium comprising a first substrate conjugated to a first imaging moiety, wherein the first substrate is selected to preferentially interact with a first enzyme that is produced by a first species of vancomycin resistant enterococci compared to a second enzyme that is produced by a second species of vancomycin resistant enterococci; and a second substrate conjugated to a second imaging moiety, wherein the second substrate preferentially interacts with the second enzyme that is produced by the second species of vancomycin resistant enterococci compared to the first enzyme that is produced by the first species of vancomycin resistant enterococci; at least one inhibitor of non-vancomycin resistant enterococci the at least one inhibitor comprising vancomycin; and at least one of a third substrate or a cephalosporin, wherein the third substrate induces the production of the first enzyme by at least a third species of the vancomycin resistant enterococci wherein the first imaging moiety images a first indicator when the first substrate interacts with the first enzyme and the second imaging moiety images a second indicator when the second substrate interacts with the second enzyme, and the combined presence of the first imaging moiety and second imaging moiety image a third indicator in the combined presence of the first enzyme and the second enzyme produced by the at least third species of the vancomycin resistant enterococci, wherein the first, second and third indicators are perceptually different from each other; and detecting the presence or absence of at least the first and second species of the vancomycin resistant enterococci directly from the medium. 40. The medium of claim 39 wherein the first and second imaging moieties are selected from the group consisting of chromophores and fluorophores. 41. The method of claim 39 wherein the first imaging moiety conjugated to the first substrate is a first chromogen and the second imaging moiety conjugated to the second substrate is a second chromogen. 42. The method of claim 39, wherein the first substrate is alpha-D-glucopyranoside and the first enzyme is alpha-D-glucopyranosidase. 43. The method of claim 39, wherein the second substrate is beta-D-galactopyranoside and the second enzyme is beta-D-galactopyranosidase. 44. The method of claim 39, wherein the third substrate is methyl-alpha-D-glucopyranoside. 45. The method of claim 39 wherein the first species of vancomycin resistant enterococci is E. faecalis. 46. The method of claim 39 wherein the second species of vancomycin resistant enterococci is E. faecium. 47. The method of claim 39 wherein the third species of vancomycin resistant enterococci is selected from the group consisting of E. casseliflavus, E. gallinarum and combinations thereof. 48. The method of claim 39 wherein the inhibitor of non-vancomycin resistant enterococci further comprises an inhibitor selected from the group consisting of colistin, nalidixic acid, aztreonam, erythromycin, amphotericin B, and combinations thereof. 49. The method of claim 48 wherein the cephalosporin is cefoxitin. 50. The medium of claim 39 wherein the inhibitor of non-vancomycin resistant enterococci further comprises erythromycin.

A microbe-specific medium, containing specific chromogenic substrates, for the detection of vancomycin-resistant enterococci in a biological sample, whereby both the detection and identification of vancomycin-resistant enterococci at the species level is achieved utilizing one sample and one test.1. A medium for identifying and distinguishing species of a microorganism placed in the medium comprising: a first substrate conjugated to a first imaging moiety, wherein the first substrate is selected to interact preferentially with a first enzyme that is produced by a first species of microorganism compared to a second enzyme that is produced by a second species of microorganism; and a second substrate conjugated to a second imaging moiety, wherein the second substrate is selected to interact preferentially with the second enzyme that is produced by the second species of microorganism compared to the first enzyme that is produced by the first species of microorganism; wherein the first imaging moiety images a first indicator when the first substrate interacts with the first enzyme and the second imaging moiety images a second indicator when the second substrate interacts with the second enzyme and wherein the first indicator is perceptually different from the second indicator. 2. The medium of claim 1, wherein the first imaging moiety is a first chromophore and the second imaging moiety is a second chromophore. 3. The medium of claim 2 further comprising a third substrate that interacts with at least a third microorganism to image a third indicator that is perceptually different from either the first indicator or the second indicator. 4. The medium of claim 3, wherein the third microorganism produces a normally repressed enzyme in response to the interaction with the third substrate wherein the normally repressed enzyme interacts preferentially with the first substrate to image the first indicator. 5. The medium of claim 4 wherein the third microorganism produces an enzyme that is the same or different from the second enzyme and that interacts preferentially with the second substrate to image the second indicator and wherein the first indicator and the second indicator together are the third indicator. 6. The medium of claim 1 further comprising inhibitors of non-vancomycin resistant enterococci. 7. The medium of claim 6 wherein the inhibitors comprise vancomycin. 8. The medium of claim 7 wherein the vancomycin is present in an amount effective to inhibit the growth of at least some non-vancomycin resistant enterococci and not significantly inhibit the growth of vancomycin resistant enterococci. 9. The medium of claim 7 further comprising an inhibitor of vanC-containing enterococci wherein the inhibitor of vanC-containing enterococci comprises a cephalosporin. 10. The medium of claim 9 wherein the cephalosporin is cefoxitin. 11. The medium of claim 10 wherein the cefoxitin is present in an amount effective to suppress the growth of the vanC-containing enterococci. 12. The medium of claim 11 wherein the amount of cefoxitin does not significantly suppress the growth of a vancomycin resistant enterococci selected from the group consisting of vancomycin resistant enterococci containing a vanA gene and vancomycin resistant enterococci containing a vanB gene. 13. The medium of claim 7 wherein the inhibitors further comprise erythromycin. 14. The medium of claim 13, wherein the inhibitors further comprise at least one inhibitor selected from the group consisting of colistin, nalidixic acid, aztreonam, and amphotericin B and combinations thereof. 15. The medium of claim 9 wherein the inhibitors further comprise erythromycin. 16. The medium of claim 1, wherein the first substrate is alpha-D-glucopyranoside and the first enzyme is alpha-D-glucopyranosidase. 17. The medium of claim 16, wherein the first microorganism is a first species of vancomycin resistant enterococci. 18. The medium of claim 17 wherein the first species of vancomycin resistant enterococci is E. faecalis. 19. The medium of claim 9, wherein the second substrate is beta-D-galactopyranoside and the second enzyme is beta-D-galactopyranosidase. 20. The medium of claim 19, wherein the second microorganism is as a second species of vancomycin resistant enterococci. 21. The medium of claim 20 wherein the second species of vancomycin resistant enterococci is E. faecium. 22. The medium of claim 4, wherein the third substrate is methyl-alpha-D-glucopyranoside. 23. The medium of claim 22 wherein the third substrate induces the first enzyme, wherein the first enzyme is alpha-D-glucopyranosidase. 24. The medium of claim 23, wherein the at least third microorganism is selected from the group consisting of E. casseliflavus and E. gallinarum. 25. A medium for detecting and differentiating species of a microorganisms comprising: a first substrate conjugated to a first imaging moiety, wherein the first substrate preferentially interacts with a first enzyme that is produced by a first species of the microorganism compared to a second enzyme that is produced by a second species of the microorganism; and a second substrate conjugated to a second imaging moiety, wherein the second substrate preferentially interacts with the second enzyme that is produced by the second species of a microorganism compared to the first enzyme that is produced by the first species of the microorganism; an inhibitor of non-vancomycin resistant enterococci comprising vancomycin; and at least one of a third substrate or a cephalosporin, wherein the third substrate induces the production of the first enzyme by at least a third species of the microorganism wherein the first imaging moiety images a first indicator when the first substrate interacts with the first enzyme and the second imaging moiety images a second indicator when the second substrate interacts with the second enzyme, and the combined presence of the first imaging moiety and second imaging moiety image a third indicator in the combined presence of the first enzyme and the second enzyme produced by the at least third species of the microorganism, wherein the first, second and third indicators are perceptually different from each other. 26. The medium of claim 25 wherein the first and second imaging moieties are selected from the group consisting of chromophores and fluorophores. 27. The medium of claim 26 wherein the first imaging moiety conjugated to the first substrate is a first chromogen and the second imaging moiety conjugated to the second substrate is a second chromogen. 28. The medium of claim 25, wherein the first substrate is alpha-D-glucopyranoside and the first enzyme is alpha-D-glucopyranosidase. 29. The medium of claim 25, wherein the second substrate is beta-D-galactopyranoside and the second enzyme is beta-D-galactopyranosidase. 30. The medium of claim 25, wherein the third substrate is methyl-alpha-D-glucopyranoside. 31. The medium of claim 25 wherein the first species of microorganism is a first species of vancomycin resistant enterococci. 32. The medium of claim 31 wherein the first species of vancomycin resistant enterococci is E. faecalis. 33. The medium of claim 25 wherein the second species of microorganism is a second species of vancomycin resistant enterococci. 34. The medium of claim 33 wherein the second species of vancomycin resistant enterococci is E. faecium. 35. The medium of claim 25 wherein the at least third species of microorganism is a third species of vancomycin resistant enterococci selected from the group consisting of E. casseliflavus, E. gallinarum and combinations thereof. 36. The medium of claim 25 wherein the inhibitor of non-vancomycin resistant enterococci further comprises an inhibitor selected from the group consisting of colistin, nalidixic acid, aztreonam, amphotericin B, and combinations thereof. 37. The medium of claim 36 wherein the cephalosporin is cefoxitin. 38. The medium of claim 37 wherein the inhibitor of non-vancomycin resistant enterococci further comprise erythromycin. 39. A method of detecting the presence of a species of vancomycin resistant enterococci comprising: combining a biological sample with a medium, the medium comprising a first substrate conjugated to a first imaging moiety, wherein the first substrate is selected to preferentially interact with a first enzyme that is produced by a first species of vancomycin resistant enterococci compared to a second enzyme that is produced by a second species of vancomycin resistant enterococci; and a second substrate conjugated to a second imaging moiety, wherein the second substrate preferentially interacts with the second enzyme that is produced by the second species of vancomycin resistant enterococci compared to the first enzyme that is produced by the first species of vancomycin resistant enterococci; at least one inhibitor of non-vancomycin resistant enterococci the at least one inhibitor comprising vancomycin; and at least one of a third substrate or a cephalosporin, wherein the third substrate induces the production of the first enzyme by at least a third species of the vancomycin resistant enterococci wherein the first imaging moiety images a first indicator when the first substrate interacts with the first enzyme and the second imaging moiety images a second indicator when the second substrate interacts with the second enzyme, and the combined presence of the first imaging moiety and second imaging moiety image a third indicator in the combined presence of the first enzyme and the second enzyme produced by the at least third species of the vancomycin resistant enterococci, wherein the first, second and third indicators are perceptually different from each other; and detecting the presence or absence of at least the first and second species of the vancomycin resistant enterococci directly from the medium. 40. The medium of claim 39 wherein the first and second imaging moieties are selected from the group consisting of chromophores and fluorophores. 41. The method of claim 39 wherein the first imaging moiety conjugated to the first substrate is a first chromogen and the second imaging moiety conjugated to the second substrate is a second chromogen. 42. The method of claim 39, wherein the first substrate is alpha-D-glucopyranoside and the first enzyme is alpha-D-glucopyranosidase. 43. The method of claim 39, wherein the second substrate is beta-D-galactopyranoside and the second enzyme is beta-D-galactopyranosidase. 44. The method of claim 39, wherein the third substrate is methyl-alpha-D-glucopyranoside. 45. The method of claim 39 wherein the first species of vancomycin resistant enterococci is E. faecalis. 46. The method of claim 39 wherein the second species of vancomycin resistant enterococci is E. faecium. 47. The method of claim 39 wherein the third species of vancomycin resistant enterococci is selected from the group consisting of E. casseliflavus, E. gallinarum and combinations thereof. 48. The method of claim 39 wherein the inhibitor of non-vancomycin resistant enterococci further comprises an inhibitor selected from the group consisting of colistin, nalidixic acid, aztreonam, erythromycin, amphotericin B, and combinations thereof. 49. The method of claim 48 wherein the cephalosporin is cefoxitin. 50. The medium of claim 39 wherein the inhibitor of non-vancomycin resistant enterococci further comprises erythromycin.

Administration of a salt of bi-cyclo [2.2.2] octane-2-carbonic acid reduces dysphoria in dysphoric subjects, ameliorates ethanol craving in alcoholics, reduces the erythrocyte sedimentation rate and the level of liver function markers (AST, ALT, and bilirubin) in human subjects, and reduces the number or strength of seizures in epileptics.

1. A method for reducing the number or strength of seizures in a human subject suffering from epilepsy, the method comprising the step of orally administering to the subject 50-1200 mg of the bicyclo-[2.2.2]-octane-2-carboxylate salt per day at least until the number or strength of seizures in a human subject is reduced. 2. The method of claim 1, wherein the human subject is administered the 50-1200 mg of the bicyclo-[2.2.2]-octane-2-carboxylate salt per day for at least 60 days. 3. The method of claim 1, wherein the epilepsy is partial epilepsy. 4. The method of claim 1, wherein the bicyclo-[2.2.2]-octane-2-carboxylate salt is formulated for sustained or delayed release. 5. The method of claim 1, wherein the human subject also suffers from dysphoria and the bicyclo-[2.2.2]-octane-2-carboxylate salt is administered at least until the dysphoria and the number or strength of seizures in the subject is reduced. 6. The method of claim 1, wherein the human subject also suffers from ethanol addiction and the bicyclo-[2.2.2]-octane-2-carboxylate salt is administered at least until ethanol craving and the number or strength of seizures in the subject is reduced. 7. The method of claim 1, wherein the human subject has an elevated liver function marker selected from the group consisting of AST, ALT, and bilirubin, and the bicyclo-[2.2.2]-octane-2-carboxylate salt is administered at least until the liver function marker and the number or strength of seizures in the subject is reduced. 8. The method of claim 1, wherein the human subject has an elevated erythrocyte sedimentation rate, and the bicyclo-[2.2.2]-octane-2-carboxylate salt is administered at least until the erythrocyte sedimentation rate and the number or strength of seizures in the subject is reduced.

Administration of a salt of bi-cyclo [2.2.2] octane-2-carbonic acid reduces dysphoria in dysphoric subjects, ameliorates ethanol craving in alcoholics, reduces the erythrocyte sedimentation rate and the level of liver function markers (AST, ALT, and bilirubin) in human subjects, and reduces the number or strength of seizures in epileptics.1. A method for reducing the number or strength of seizures in a human subject suffering from epilepsy, the method comprising the step of orally administering to the subject 50-1200 mg of the bicyclo-[2.2.2]-octane-2-carboxylate salt per day at least until the number or strength of seizures in a human subject is reduced. 2. The method of claim 1, wherein the human subject is administered the 50-1200 mg of the bicyclo-[2.2.2]-octane-2-carboxylate salt per day for at least 60 days. 3. The method of claim 1, wherein the epilepsy is partial epilepsy. 4. The method of claim 1, wherein the bicyclo-[2.2.2]-octane-2-carboxylate salt is formulated for sustained or delayed release. 5. The method of claim 1, wherein the human subject also suffers from dysphoria and the bicyclo-[2.2.2]-octane-2-carboxylate salt is administered at least until the dysphoria and the number or strength of seizures in the subject is reduced. 6. The method of claim 1, wherein the human subject also suffers from ethanol addiction and the bicyclo-[2.2.2]-octane-2-carboxylate salt is administered at least until ethanol craving and the number or strength of seizures in the subject is reduced. 7. The method of claim 1, wherein the human subject has an elevated liver function marker selected from the group consisting of AST, ALT, and bilirubin, and the bicyclo-[2.2.2]-octane-2-carboxylate salt is administered at least until the liver function marker and the number or strength of seizures in the subject is reduced. 8. The method of claim 1, wherein the human subject has an elevated erythrocyte sedimentation rate, and the bicyclo-[2.2.2]-octane-2-carboxylate salt is administered at least until the erythrocyte sedimentation rate and the number or strength of seizures in the subject is reduced.

Orally administerable deferasirox formulations are disclosed having reduced release under gastric conditions and fast release at near neutral pH or at neutral pH.

1-36. (canceled) 37. A method of treatment of chronic iron overload in a patient comprising directly orally administering 90 mg deferasirox or a pharmaceutically acceptable salt thereof in a solid swallowable dosage form wherein the dosage form is a whole and intact tablet. 38. A method of treatment of chronic iron overload in a patient comprising directly orally administering 180 mg deferasirox or a pharmaceutically acceptable salt thereof in a solid swallowable dosage form wherein the dosage form is a whole and intact tablet. 39.-46. (canceled) 47. A method of treatment of chronic iron overload in a patient comprising directly orally administering an amount of deferasirox selected from the group consisting of 90, 180, and 360 mg in a solid swallowable dosage form, wherein the dosage form is a whole and intact tablet, and wherein the tablet comprises (i) at least one filler selected from the group consisting of microcrystalline cellulose, and ethylcellulose in an amount of 10% to 40% by weight based on total weight of the tablet, (ii) at least one disintegrant selected from the group consisting of polyvinylpyrrolidone (crospovidone), starch, CMC-Ca, CMC-Na, microcrystalline cellulose, alginic acid, sodium alginate, and guar gum in an amount of 1% to 10% by weight based on the total weight of the tablet; and, (iii) at least one binder selected from the group consisting of polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, microcrystalline cellulose, hypromellose, and starch in an amount of 1% to 5% by weight based on the total weight of the tablet. 48. A method according to claim 47 wherein the tablet comprises about 1-55% microcrystalline cellulose. 49. A method according to claim 37 wherein the tablet comprises about 1-55% microcrystalline cellulose. 50. A method according to claim 38 wherein the tablet comprises about 1-55% microcrystalline cellulose. 51. A method of treatment of chronic iron overload in a patient comprising directly orally administering an amount of deferasirox selected from the group consisting of 90, 180, and 360 mg in a solid swallowable dosage form, wherein the dosage form is a whole and intact tablet, and wherein the tablet comprises at least one binder selected from the group consisting of polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, microcrystalline cellulose, hypromellose, and starch in an amount of 1% to 5% by weight based on the total weight of the tablet. 52. A method according to claim 51 wherein the tablet comprises about 32-33% Microcrystalline Cellulose and about 8-10% polyvinylpyrrolidone.

Orally administerable deferasirox formulations are disclosed having reduced release under gastric conditions and fast release at near neutral pH or at neutral pH.1-36. (canceled) 37. A method of treatment of chronic iron overload in a patient comprising directly orally administering 90 mg deferasirox or a pharmaceutically acceptable salt thereof in a solid swallowable dosage form wherein the dosage form is a whole and intact tablet. 38. A method of treatment of chronic iron overload in a patient comprising directly orally administering 180 mg deferasirox or a pharmaceutically acceptable salt thereof in a solid swallowable dosage form wherein the dosage form is a whole and intact tablet. 39.-46. (canceled) 47. A method of treatment of chronic iron overload in a patient comprising directly orally administering an amount of deferasirox selected from the group consisting of 90, 180, and 360 mg in a solid swallowable dosage form, wherein the dosage form is a whole and intact tablet, and wherein the tablet comprises (i) at least one filler selected from the group consisting of microcrystalline cellulose, and ethylcellulose in an amount of 10% to 40% by weight based on total weight of the tablet, (ii) at least one disintegrant selected from the group consisting of polyvinylpyrrolidone (crospovidone), starch, CMC-Ca, CMC-Na, microcrystalline cellulose, alginic acid, sodium alginate, and guar gum in an amount of 1% to 10% by weight based on the total weight of the tablet; and, (iii) at least one binder selected from the group consisting of polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, microcrystalline cellulose, hypromellose, and starch in an amount of 1% to 5% by weight based on the total weight of the tablet. 48. A method according to claim 47 wherein the tablet comprises about 1-55% microcrystalline cellulose. 49. A method according to claim 37 wherein the tablet comprises about 1-55% microcrystalline cellulose. 50. A method according to claim 38 wherein the tablet comprises about 1-55% microcrystalline cellulose. 51. A method of treatment of chronic iron overload in a patient comprising directly orally administering an amount of deferasirox selected from the group consisting of 90, 180, and 360 mg in a solid swallowable dosage form, wherein the dosage form is a whole and intact tablet, and wherein the tablet comprises at least one binder selected from the group consisting of polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, microcrystalline cellulose, hypromellose, and starch in an amount of 1% to 5% by weight based on the total weight of the tablet. 52. A method according to claim 51 wherein the tablet comprises about 32-33% Microcrystalline Cellulose and about 8-10% polyvinylpyrrolidone.

The present disclosure provides a rapidly disintegrating orally administrable powder. The powder may include an active ingredient such as a dietary supplement. Methods of using the same are also provided herein.

1. A composition comprising a powder including: at least one bulking agent; at least one sweetening ingredient; and at least one active ingredient selected from the group consisting of Vitamin A, Vitamin C, Vitamin D, Vitamin E, Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Selenium, Zinc, Boron, omega-3 fatty acids, coenzyme Q10, calcium, probiotics, and combinations thereof, wherein the powder dissolves in the mouth upon contact with saliva. 2. The composition of claim 1, the powder further comprising a flow agent selected from the group consisting of sodium bicarbonate, sodium ferrocyanide, postassium ferrocyanide, calcium ferrocyanide, bone phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminum silicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, polydimethylsiloxane, and combinations thereof. 3. The composition of claim 1, wherein the at least one bulking agent is selected from the group consisting of polyols, sucrose, maltodextrin, and combinations thereof. 4. The composition of claim 3, wherein the polyol is selected from the group consisting of mannitol, xylitol, sorbitol, maltitol, erythritol, isomalt, lactitol, polyglycitol, and combinations thereof. 5. The composition of claim 1, wherein the sweetening ingredient is selected from the group consisting of stevia, sucralose, aspartame, saccharin, acesulfame K, sucrose, fructose, maltose, dextrose, thaumatin, and combinations thereof. 6. The composition of claim 1, wherein the bulking agent is present in an amount from about 40 percent by weight to about 80 percent by weight of the powder. 7. The composition of claim 1, further comprising an organic acid selected from the group consisting of malic acid, citric acid, fumaric acid, adipic acid, tartaric acid, acetic acid, lactic acid, phosphoric acid, sodium acid sulfate, and combinations thereof. 8. The composition of claim 1, wherein the at least one active ingredient comprises calcium in an amount from about 8% to about 23% by weight of the powder. 9. The composition of claim 1, wherein the active ingredient further comprises magnesium oxide. 10. The composition of claim 1, wherein the powder dissolves within a period of time from about 2 seconds to about 30 seconds after placement in the mouth. 11. A composition comprising a powder including: at least one bulking agent in an amount of from about 40% to about 80% by weight of the powder; at least one active ingredient in an amount of from about 10% to about 50% by weight of the powder; calcium in an amount from about 12% to about 18% by weight of the powder; at least one flow agent in an amount of from about 0% to about 2% by weight of the powder; at least one sweetening ingredient in an amount of from about 0.5% to about 25% by weight of the powder; at least one organic acid in an amount of from about 0.5% to about 5% by weight of the powder; and at least one soluble fiber in an amount of from about 1% to about 25% by weight of the powder, wherein the powder dissolves in the mouth upon contact with saliva. 12. The composition of claim 11, wherein the powder dissolves within a period of time from about 2 seconds to about 30 seconds after placement in the mouth. 13. A method comprising: preparing a dietary supplement by dry blending a mixture comprising at least one bulking agent, at least one sweetening ingredient, and an active ingredient selected from the group consisting of Vitamin A, Vitamin C, Vitamin D, Vitamin E, Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Selenium, Zinc, Boron, omega-3 fatty acids, coenzyme Q10, calcium, probiotics, and combinations thereof, to form a rapidly dissolving orally administrable palatable powder; introducing the orally administrable powder into a mouth of a consumer; and allowing the orally administrable powder to dissolve in the mouth. 14. The method of claim 13, wherein the orally administrable palatable powder dissolves in saliva. 15. The method of claim 13, further comprising packeting the rapidly dissolving orally administrable powder. 16. The method of claim 13, wherein the orally administrable powder dissolves over a period of time from about 2 seconds to about 30 seconds after placement in the mouth.

The present disclosure provides a rapidly disintegrating orally administrable powder. The powder may include an active ingredient such as a dietary supplement. Methods of using the same are also provided herein.1. A composition comprising a powder including: at least one bulking agent; at least one sweetening ingredient; and at least one active ingredient selected from the group consisting of Vitamin A, Vitamin C, Vitamin D, Vitamin E, Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Selenium, Zinc, Boron, omega-3 fatty acids, coenzyme Q10, calcium, probiotics, and combinations thereof, wherein the powder dissolves in the mouth upon contact with saliva. 2. The composition of claim 1, the powder further comprising a flow agent selected from the group consisting of sodium bicarbonate, sodium ferrocyanide, postassium ferrocyanide, calcium ferrocyanide, bone phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminum silicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, polydimethylsiloxane, and combinations thereof. 3. The composition of claim 1, wherein the at least one bulking agent is selected from the group consisting of polyols, sucrose, maltodextrin, and combinations thereof. 4. The composition of claim 3, wherein the polyol is selected from the group consisting of mannitol, xylitol, sorbitol, maltitol, erythritol, isomalt, lactitol, polyglycitol, and combinations thereof. 5. The composition of claim 1, wherein the sweetening ingredient is selected from the group consisting of stevia, sucralose, aspartame, saccharin, acesulfame K, sucrose, fructose, maltose, dextrose, thaumatin, and combinations thereof. 6. The composition of claim 1, wherein the bulking agent is present in an amount from about 40 percent by weight to about 80 percent by weight of the powder. 7. The composition of claim 1, further comprising an organic acid selected from the group consisting of malic acid, citric acid, fumaric acid, adipic acid, tartaric acid, acetic acid, lactic acid, phosphoric acid, sodium acid sulfate, and combinations thereof. 8. The composition of claim 1, wherein the at least one active ingredient comprises calcium in an amount from about 8% to about 23% by weight of the powder. 9. The composition of claim 1, wherein the active ingredient further comprises magnesium oxide. 10. The composition of claim 1, wherein the powder dissolves within a period of time from about 2 seconds to about 30 seconds after placement in the mouth. 11. A composition comprising a powder including: at least one bulking agent in an amount of from about 40% to about 80% by weight of the powder; at least one active ingredient in an amount of from about 10% to about 50% by weight of the powder; calcium in an amount from about 12% to about 18% by weight of the powder; at least one flow agent in an amount of from about 0% to about 2% by weight of the powder; at least one sweetening ingredient in an amount of from about 0.5% to about 25% by weight of the powder; at least one organic acid in an amount of from about 0.5% to about 5% by weight of the powder; and at least one soluble fiber in an amount of from about 1% to about 25% by weight of the powder, wherein the powder dissolves in the mouth upon contact with saliva. 12. The composition of claim 11, wherein the powder dissolves within a period of time from about 2 seconds to about 30 seconds after placement in the mouth. 13. A method comprising: preparing a dietary supplement by dry blending a mixture comprising at least one bulking agent, at least one sweetening ingredient, and an active ingredient selected from the group consisting of Vitamin A, Vitamin C, Vitamin D, Vitamin E, Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Selenium, Zinc, Boron, omega-3 fatty acids, coenzyme Q10, calcium, probiotics, and combinations thereof, to form a rapidly dissolving orally administrable palatable powder; introducing the orally administrable powder into a mouth of a consumer; and allowing the orally administrable powder to dissolve in the mouth. 14. The method of claim 13, wherein the orally administrable palatable powder dissolves in saliva. 15. The method of claim 13, further comprising packeting the rapidly dissolving orally administrable powder. 16. The method of claim 13, wherein the orally administrable powder dissolves over a period of time from about 2 seconds to about 30 seconds after placement in the mouth.

The present invention relates to methods for increasing the accuracy of sample classification characterized by the detection of the protein YKL-40 and the protein MASP2 in the samples and methods for determining the efficacy of a drug in treating a cancer in an individual, as well as reagent kits for the same uses.

1. A method for increasing the accuracy of sample classification, characterized by the detection of the protein YKL-40 and the protein MASP2 in the samples. 2. The method according to claim 1, characterized in that the detection comprises: (1) measuring the concentrations of YKL-40 and MASP2 in the samples; (2) algorithmic analysis of the concentrations of YKL-40 and MASP2, and (3) classification of the samples according to the results of the algorithmic analysis. 3. The method according to claim 2, characterized in that the concentrations of YKL-40 and MASP2 are measured separately. 4. The method according to claim 2, characterized in that the algorithmic analysis is to draw ROC curves that reflects sensitivity and specificity of the measurements, wherein the ratios of the YKL-40 and MASP2 concentrations are used as variables to draw ROC curves, the area under curve is calculated; then the samples are classified according to the desired sensitivity and specificity according to different threshold values. 5. The method according to claim 2, characterized in that the concentration of at least one of YKL-40 and MASP2 is measured by ELISA. 6. The method according to claim 2, characterized in that the concentration of at least one of YKL-40 and MASP2 is measured by the Lowery assay, the Bradford assay, the BCA assay, UV absorbance, or any modification based thereon. 7. The method according to claim 2, characterized in that the samples are selected from a group consisting of whole blood, blood plasma, blood serum, urine, cerebrospinal fluid, saliva, and tear. 8. The method according to claim 1, characterized in that the method is used for the diagnosis, prognosis evaluation, and monitoring of treatment effect and disease course of cancer. 9. The method according to claim 8, characterized in that the cancer is hepatocarcinoma. 10. A reagent kit comprising: (1) binding antibodies capable of binding YKL-40 and MASP2, and (2) marking antibodies capable of binding YKL-40 and MASP2 when YKL-40 and/or MASP2 is bound by the binding antibodies stated in (1). 11. The reagent kit according to claim 10, characterized in that it further comprises: (3) standard samples composed of solutions containing known concentrations of YKL-40 and MASP2, and (4) antibody markers for detection, which can bind antibodies to form conjugates. 12. The reagent kit according to claim 10, wherein the antibodies in (1) or (2) are capable of binding hepatitis virus. 13. A method for the diagnosis, prognosis evaluation, and monitoring of treatment effect or disease state of a cancer or disease of a specific tissue or organ of an individual, comprising: (1) assay of high-level expression of one or more than one proteins or genes of the cancer or disease in the individual's blood sample; (2) assay of low-level expression of one or more than one tissue-specific or organ-specific proteins or genes in the blood sample; (3) algorithmic analysis of the measured protein content or gene expression results, and (4) classification of the measured sample of the individual according to the algorithmic analysis results in order to obtain diagnosis results of the cancer or disease. 14. The method of claim 13, wherein the protein of high-level expression is YKL-40. 15. The method of claim 13, wherein the protein of low-level expression is MASP2. 16. The method of claim 13, wherein the protein of high-level expression is YKL-40 and the protein of low-level expression is MASP2. 17. A method for the diagnosis, prognosis evaluation, and monitoring of treatment effect or disease course of hepatocarcinoma in an individual, comprising: (1) detection of the expression of hepatitis virus in the blood sample of the individual; (2) detection of the expression of YKL-40 and MASP2 in the blood sample of the individual; (3) algorithmic analysis of the measured expression levels of hepatitis virus, YKL-40, and MASP2, and (4) classification of the measured blood sample according to the algorithmic analysis results and making judgment related to hepatocarcinoma. 18. A method for detecting the occurrence of a cancer in an individual, comprising: taking a test sample of the individual to be detected and a control sample of another individual free of the cancer, and measuring the concentrations of a first set of disease specific and a second set of tissue or organ specific proteins in the test sample and comparing their concentrations to those in the control sample, wherein the higher concentrations of the first set of disease specific protein and the lower concentrations of the second set of tissue or organ specific proteins in the test sample than the concentrations of the same proteins in the control sample are an indication of the occurrence of the cancer. 19. The method of claim 18, wherein the cancer is hepatocarcinoma. 20. The method of claim 18, wherein the first set of disease specific proteins are cancer over expression proteins. 21. The method of claim 20, wherein the first set of proteins contains YKL-40. 22. The method of claim 18, wherein the second set of proteins is a set of tissue or organ specific or enriched expression proteins. 23. The method of claim 22, wherein the second set of proteins contains MASP2. 24. The method of claim 18, wherein the tissue or organ is liver, breast, ovary, lung, prostate, bladder, mouth, nose, kidney, stomach, throat, pancreas, heart, ovary, colon, brain, skin, or bone. 25. The method of claim 18, wherein the test sample and control sample are whole blood, blood plasma, blood serum, urine, cerebrospinal fluid, saliva, or tear. 26. The method of claim 18, wherein the presence of the cancer results in higher expression of the first set of disease specific proteins and the lower expression of the second set of tissue or organ specific proteins. 27. The method of claim 26, wherein the cancer is hepatocarcinoma. 28. The method of claim 25, wherein the test sample and control sample are whole blood, blood plasma, blood serum, urine, cerebrospinal fluid, saliva, or tear. 29. The method of claim 26, wherein the first set of proteins contains YKL-40. 30. The method of claim 26, wherein the second set of proteins contains MASP2. 31. The method of claim 26, wherein the first set of proteins contains YKL-40 and the second set of proteins contains MASP2. 32. The method of claim 26, wherein the cancer is hepatocarcinoma, and the test sample and control sample are whole blood, blood plasma, blood serum, urine, cerebrospinal fluid, saliva, or tear. 33. A method for determining the efficacy of a drug in treating a cancer in an individual, comprising measuring the concentrations of a first set of disease specific proteins and a second set of tissue or organ specific proteins in the samples of the subject at different times of the treatment, wherein the presence of the cancer is indicated by the higher expression of the first set of disease specific proteins and lower expression of the second set of tissue or organ specific proteins than those in an individual free of the cancer, and the decrease of the concentrations of the first set of disease specific proteins and the increase of concentrations of the second set of tissue or organ specific proteins in the samples of the cancerous subject during the treatment indicates that the severity of the cancer has decreased. 34. The method of claim 33, wherein the cancer is hepatocarcinoma. 35. The method of claim 33, wherein the samples are whole blood, blood plasma, blood serum, urine, cerebrospinal fluid, saliva, or tear. 36. The method of claim 33, wherein the first set of proteins contains YKL-40. 37. The method of claim 33, wherein the second set of proteins contains MASP2. 38. The method of claim 33, wherein the first set of proteins comprise YKL-40 and the second set of proteins comprise MASP2. 39. The method of claim 38, wherein the cancer is hepatocarcinoma, and the samples are whole blood, blood plasma, blood serum, urine, cerebrospinal fluid, saliva, or tear of the subject.

The present invention relates to methods for increasing the accuracy of sample classification characterized by the detection of the protein YKL-40 and the protein MASP2 in the samples and methods for determining the efficacy of a drug in treating a cancer in an individual, as well as reagent kits for the same uses.1. A method for increasing the accuracy of sample classification, characterized by the detection of the protein YKL-40 and the protein MASP2 in the samples. 2. The method according to claim 1, characterized in that the detection comprises: (1) measuring the concentrations of YKL-40 and MASP2 in the samples; (2) algorithmic analysis of the concentrations of YKL-40 and MASP2, and (3) classification of the samples according to the results of the algorithmic analysis. 3. The method according to claim 2, characterized in that the concentrations of YKL-40 and MASP2 are measured separately. 4. The method according to claim 2, characterized in that the algorithmic analysis is to draw ROC curves that reflects sensitivity and specificity of the measurements, wherein the ratios of the YKL-40 and MASP2 concentrations are used as variables to draw ROC curves, the area under curve is calculated; then the samples are classified according to the desired sensitivity and specificity according to different threshold values. 5. The method according to claim 2, characterized in that the concentration of at least one of YKL-40 and MASP2 is measured by ELISA. 6. The method according to claim 2, characterized in that the concentration of at least one of YKL-40 and MASP2 is measured by the Lowery assay, the Bradford assay, the BCA assay, UV absorbance, or any modification based thereon. 7. The method according to claim 2, characterized in that the samples are selected from a group consisting of whole blood, blood plasma, blood serum, urine, cerebrospinal fluid, saliva, and tear. 8. The method according to claim 1, characterized in that the method is used for the diagnosis, prognosis evaluation, and monitoring of treatment effect and disease course of cancer. 9. The method according to claim 8, characterized in that the cancer is hepatocarcinoma. 10. A reagent kit comprising: (1) binding antibodies capable of binding YKL-40 and MASP2, and (2) marking antibodies capable of binding YKL-40 and MASP2 when YKL-40 and/or MASP2 is bound by the binding antibodies stated in (1). 11. The reagent kit according to claim 10, characterized in that it further comprises: (3) standard samples composed of solutions containing known concentrations of YKL-40 and MASP2, and (4) antibody markers for detection, which can bind antibodies to form conjugates. 12. The reagent kit according to claim 10, wherein the antibodies in (1) or (2) are capable of binding hepatitis virus. 13. A method for the diagnosis, prognosis evaluation, and monitoring of treatment effect or disease state of a cancer or disease of a specific tissue or organ of an individual, comprising: (1) assay of high-level expression of one or more than one proteins or genes of the cancer or disease in the individual's blood sample; (2) assay of low-level expression of one or more than one tissue-specific or organ-specific proteins or genes in the blood sample; (3) algorithmic analysis of the measured protein content or gene expression results, and (4) classification of the measured sample of the individual according to the algorithmic analysis results in order to obtain diagnosis results of the cancer or disease. 14. The method of claim 13, wherein the protein of high-level expression is YKL-40. 15. The method of claim 13, wherein the protein of low-level expression is MASP2. 16. The method of claim 13, wherein the protein of high-level expression is YKL-40 and the protein of low-level expression is MASP2. 17. A method for the diagnosis, prognosis evaluation, and monitoring of treatment effect or disease course of hepatocarcinoma in an individual, comprising: (1) detection of the expression of hepatitis virus in the blood sample of the individual; (2) detection of the expression of YKL-40 and MASP2 in the blood sample of the individual; (3) algorithmic analysis of the measured expression levels of hepatitis virus, YKL-40, and MASP2, and (4) classification of the measured blood sample according to the algorithmic analysis results and making judgment related to hepatocarcinoma. 18. A method for detecting the occurrence of a cancer in an individual, comprising: taking a test sample of the individual to be detected and a control sample of another individual free of the cancer, and measuring the concentrations of a first set of disease specific and a second set of tissue or organ specific proteins in the test sample and comparing their concentrations to those in the control sample, wherein the higher concentrations of the first set of disease specific protein and the lower concentrations of the second set of tissue or organ specific proteins in the test sample than the concentrations of the same proteins in the control sample are an indication of the occurrence of the cancer. 19. The method of claim 18, wherein the cancer is hepatocarcinoma. 20. The method of claim 18, wherein the first set of disease specific proteins are cancer over expression proteins. 21. The method of claim 20, wherein the first set of proteins contains YKL-40. 22. The method of claim 18, wherein the second set of proteins is a set of tissue or organ specific or enriched expression proteins. 23. The method of claim 22, wherein the second set of proteins contains MASP2. 24. The method of claim 18, wherein the tissue or organ is liver, breast, ovary, lung, prostate, bladder, mouth, nose, kidney, stomach, throat, pancreas, heart, ovary, colon, brain, skin, or bone. 25. The method of claim 18, wherein the test sample and control sample are whole blood, blood plasma, blood serum, urine, cerebrospinal fluid, saliva, or tear. 26. The method of claim 18, wherein the presence of the cancer results in higher expression of the first set of disease specific proteins and the lower expression of the second set of tissue or organ specific proteins. 27. The method of claim 26, wherein the cancer is hepatocarcinoma. 28. The method of claim 25, wherein the test sample and control sample are whole blood, blood plasma, blood serum, urine, cerebrospinal fluid, saliva, or tear. 29. The method of claim 26, wherein the first set of proteins contains YKL-40. 30. The method of claim 26, wherein the second set of proteins contains MASP2. 31. The method of claim 26, wherein the first set of proteins contains YKL-40 and the second set of proteins contains MASP2. 32. The method of claim 26, wherein the cancer is hepatocarcinoma, and the test sample and control sample are whole blood, blood plasma, blood serum, urine, cerebrospinal fluid, saliva, or tear. 33. A method for determining the efficacy of a drug in treating a cancer in an individual, comprising measuring the concentrations of a first set of disease specific proteins and a second set of tissue or organ specific proteins in the samples of the subject at different times of the treatment, wherein the presence of the cancer is indicated by the higher expression of the first set of disease specific proteins and lower expression of the second set of tissue or organ specific proteins than those in an individual free of the cancer, and the decrease of the concentrations of the first set of disease specific proteins and the increase of concentrations of the second set of tissue or organ specific proteins in the samples of the cancerous subject during the treatment indicates that the severity of the cancer has decreased. 34. The method of claim 33, wherein the cancer is hepatocarcinoma. 35. The method of claim 33, wherein the samples are whole blood, blood plasma, blood serum, urine, cerebrospinal fluid, saliva, or tear. 36. The method of claim 33, wherein the first set of proteins contains YKL-40. 37. The method of claim 33, wherein the second set of proteins contains MASP2. 38. The method of claim 33, wherein the first set of proteins comprise YKL-40 and the second set of proteins comprise MASP2. 39. The method of claim 38, wherein the cancer is hepatocarcinoma, and the samples are whole blood, blood plasma, blood serum, urine, cerebrospinal fluid, saliva, or tear of the subject.

Provided herein, among other things, is a computer-implemented method for assigning a sequence read to a genomic location, the method including: a) accessing a file containing a sequence read, wherein the sequence read is obtained from a nucleic acid sample that has been enriched by hybridization to a plurality of capture sequences; and b) assigning the sequence read to a genomic location by: i) identifying a capture sequence as being a match with the sequence read if the sequence read contains one or more subsequences of the capture sequence; ii) calculating, using a computer, a score indicating the degree of sequence similarity between each of the matched capture sequences and the sequence read; and iii) assigning the sequence read to the genomic location if the calculated score for a matched capture sequence is above a threshold.

1. A computer-implemented method for assigning a sequence read to a genomic location, comprising: a) accessing a file comprising a sequence read, wherein the sequence read is obtained from a nucleic acid sample that has been enriched by hybridization to a plurality of capture sequences; and b) assigning the sequence read to a genomic location by: i) identifying a capture sequence as being a match with the sequence read if the sequence read comprises one or more subsequences of the capture sequence; ii) calculating, using a computer, a score indicating the degree of sequence similarity between each of the matched capture sequences and the sequence read; and iii) assigning the sequence read to the genomic location if the calculated score for a matched capture sequence is above a threshold. 2. The method according to claim 1, wherein the identifying step i) comprises identifying one or more of the capture sequences as being a match with the sequence read if a terminal region of the sequence read comprises one or more subsequences of the capture sequences. 3. The method according to claim 2, wherein the terminal region is in the range of 10 bp (base pairs) to 50 bp from an end of the sequence read. 4. The method according to claim 1, wherein the one or more subsequences are in the range of 5 bp to 15 bp in length. 5. The method according to claim 1, wherein the one or more subsequences of the capture sequence is selected from between 4 to 20 subsequences of the capture sequence. 6. The method according to claim 1, wherein the subsequences are tiled across the entire capture sequence. 7. The method according to claim 1, wherein the calculated score is calculated based on the length of sequence identity between the matched capture sequence and the sequence read, the string edit distance between the matched capture sequence and the sequence read, the position within the sequence read of each of the mismatches, or a combination thereof. 8. The method according to claim 1, wherein step i) further comprises generating a data structure, wherein the capture sequences are stored in the data structure as values mapped by sequence keys comprising subsequences of the capture sequences, and the identifying step comprises identifying one or more of the capture sequences as being a match with the sequence read if the sequence read comprises one or more sequence keys. 9. The method according to claim 1, wherein the sequence read is a paired-end sequence read. 10. The method according to claim 1, wherein the enriched sample comprises amplified copies of fragmented genomic nucleic acids, wherein the fragmented genomic nucleic acids are enriched by hybridization to the plurality of capture sequences. 11. The method according to claim 10, wherein the fragmented genomic nucleic acids are fragmented by enzymatically cleaving genomic nucleic acids at predetermined sites. 12. The method according to claim 1, wherein the nucleic acid sample is enriched by a plurality of capture sequences that hybridize to an end of the nucleic acids. 13. The method according to claim 1, wherein the assigning step b) further comprises discarding a sequence read if the sequence read does not comprise any subsequences of the capture sequences. 14. The method according to claim 1, wherein the method is performed on a plurality of sequence reads, thereby assigning a plurality of sequence reads to genomic locations. 15. The method according to claim 1, wherein the assigning step b) further comprises: iv) identifying a matched capture sequence having the highest calculated score among all of the matched capture sequences as being the best match; and v) assigning the sequence read to the genomic location by adding the sequence read to a set of unique sequence reads matching the best matched capture sequence, wherein each unique sequence read in the set comprises a subsequence identical to a subsequence of all the other sequence reads in the set. 16. The method according to claim 15, wherein the subsequence identical to a subsequence of all the other sequence reads in the set is a barcode sequence. 17. The method according to claim 15, wherein the method further comprises counting the number of sets of unique sequence reads assigned to a capture sequence. 18. The method according to claim 1, wherein the capture sequences comprises from 102 to 108 distinct sequences. 19. A method for assigning a sequence read to a genomic location, comprising: a) inputting a set of capture sequences used to enrich a nucleic acid sample by hybridization to a plurality of capture sequences in the set into a computer system comprising a sequence read assignment program, wherein the sequence read assignment program comprises instructions for: i) accessing a file comprising a sequence read, wherein the sequence read is obtained from the enriched nucleic acid sample; and ii) assigning the sequence read to a genomic location by: identifying a capture sequence as being a match with the sequence read if the sequence read comprises one or more subsequences of the capture sequence; calculating, using a computer, a score indicating the degree of sequence similarity between each of the matched capture sequences and the sequence read; and assigning the sequence read to the genomic location if the calculated score for a matched capture sequence is above a threshold; b) inputting a file comprising the sequence read into the sequence read assignment program; and c) executing the sequence read assignment program. 20. A computer readable storage medium comprising a sequence read assignment program comprising instructions for: a) accessing a file comprising a sequence read, wherein the sequence read is obtained from a nucleic acid sample that has been enriched by hybridization to a plurality of capture sequences; and b) assigning the sequence read to a genomic location by: i) identifying a capture sequence as being a match with the sequence read if the sequence read comprises one or more subsequences of the capture sequence; ii) calculating, using a computer, a score indicating the degree of sequence similarity between each of the matched capture sequences and the sequence read; and iii) assigning the sequence read to the genomic location if the calculated score for a matched capture sequence is above a threshold.

Provided herein, among other things, is a computer-implemented method for assigning a sequence read to a genomic location, the method including: a) accessing a file containing a sequence read, wherein the sequence read is obtained from a nucleic acid sample that has been enriched by hybridization to a plurality of capture sequences; and b) assigning the sequence read to a genomic location by: i) identifying a capture sequence as being a match with the sequence read if the sequence read contains one or more subsequences of the capture sequence; ii) calculating, using a computer, a score indicating the degree of sequence similarity between each of the matched capture sequences and the sequence read; and iii) assigning the sequence read to the genomic location if the calculated score for a matched capture sequence is above a threshold.1. A computer-implemented method for assigning a sequence read to a genomic location, comprising: a) accessing a file comprising a sequence read, wherein the sequence read is obtained from a nucleic acid sample that has been enriched by hybridization to a plurality of capture sequences; and b) assigning the sequence read to a genomic location by: i) identifying a capture sequence as being a match with the sequence read if the sequence read comprises one or more subsequences of the capture sequence; ii) calculating, using a computer, a score indicating the degree of sequence similarity between each of the matched capture sequences and the sequence read; and iii) assigning the sequence read to the genomic location if the calculated score for a matched capture sequence is above a threshold. 2. The method according to claim 1, wherein the identifying step i) comprises identifying one or more of the capture sequences as being a match with the sequence read if a terminal region of the sequence read comprises one or more subsequences of the capture sequences. 3. The method according to claim 2, wherein the terminal region is in the range of 10 bp (base pairs) to 50 bp from an end of the sequence read. 4. The method according to claim 1, wherein the one or more subsequences are in the range of 5 bp to 15 bp in length. 5. The method according to claim 1, wherein the one or more subsequences of the capture sequence is selected from between 4 to 20 subsequences of the capture sequence. 6. The method according to claim 1, wherein the subsequences are tiled across the entire capture sequence. 7. The method according to claim 1, wherein the calculated score is calculated based on the length of sequence identity between the matched capture sequence and the sequence read, the string edit distance between the matched capture sequence and the sequence read, the position within the sequence read of each of the mismatches, or a combination thereof. 8. The method according to claim 1, wherein step i) further comprises generating a data structure, wherein the capture sequences are stored in the data structure as values mapped by sequence keys comprising subsequences of the capture sequences, and the identifying step comprises identifying one or more of the capture sequences as being a match with the sequence read if the sequence read comprises one or more sequence keys. 9. The method according to claim 1, wherein the sequence read is a paired-end sequence read. 10. The method according to claim 1, wherein the enriched sample comprises amplified copies of fragmented genomic nucleic acids, wherein the fragmented genomic nucleic acids are enriched by hybridization to the plurality of capture sequences. 11. The method according to claim 10, wherein the fragmented genomic nucleic acids are fragmented by enzymatically cleaving genomic nucleic acids at predetermined sites. 12. The method according to claim 1, wherein the nucleic acid sample is enriched by a plurality of capture sequences that hybridize to an end of the nucleic acids. 13. The method according to claim 1, wherein the assigning step b) further comprises discarding a sequence read if the sequence read does not comprise any subsequences of the capture sequences. 14. The method according to claim 1, wherein the method is performed on a plurality of sequence reads, thereby assigning a plurality of sequence reads to genomic locations. 15. The method according to claim 1, wherein the assigning step b) further comprises: iv) identifying a matched capture sequence having the highest calculated score among all of the matched capture sequences as being the best match; and v) assigning the sequence read to the genomic location by adding the sequence read to a set of unique sequence reads matching the best matched capture sequence, wherein each unique sequence read in the set comprises a subsequence identical to a subsequence of all the other sequence reads in the set. 16. The method according to claim 15, wherein the subsequence identical to a subsequence of all the other sequence reads in the set is a barcode sequence. 17. The method according to claim 15, wherein the method further comprises counting the number of sets of unique sequence reads assigned to a capture sequence. 18. The method according to claim 1, wherein the capture sequences comprises from 102 to 108 distinct sequences. 19. A method for assigning a sequence read to a genomic location, comprising: a) inputting a set of capture sequences used to enrich a nucleic acid sample by hybridization to a plurality of capture sequences in the set into a computer system comprising a sequence read assignment program, wherein the sequence read assignment program comprises instructions for: i) accessing a file comprising a sequence read, wherein the sequence read is obtained from the enriched nucleic acid sample; and ii) assigning the sequence read to a genomic location by: identifying a capture sequence as being a match with the sequence read if the sequence read comprises one or more subsequences of the capture sequence; calculating, using a computer, a score indicating the degree of sequence similarity between each of the matched capture sequences and the sequence read; and assigning the sequence read to the genomic location if the calculated score for a matched capture sequence is above a threshold; b) inputting a file comprising the sequence read into the sequence read assignment program; and c) executing the sequence read assignment program. 20. A computer readable storage medium comprising a sequence read assignment program comprising instructions for: a) accessing a file comprising a sequence read, wherein the sequence read is obtained from a nucleic acid sample that has been enriched by hybridization to a plurality of capture sequences; and b) assigning the sequence read to a genomic location by: i) identifying a capture sequence as being a match with the sequence read if the sequence read comprises one or more subsequences of the capture sequence; ii) calculating, using a computer, a score indicating the degree of sequence similarity between each of the matched capture sequences and the sequence read; and iii) assigning the sequence read to the genomic location if the calculated score for a matched capture sequence is above a threshold.

The present invention relates to pluripotent stem cells, particularly to pluripotent embryonic-like stem cells. The invention further relates to methods of purifying pluripotent embryonic-like stem cells and to compositions, cultures and clones thereof. The present invention also relates to a method of transplanting the pluripotent stem cells of the present invention in a mammalian host, such as human, comprising introducing the stem cells, into the host. The invention further relates to methods of in vivo administration of a protein or gene of interest comprising transfecting a pluripotent stem cell with a construct comprising DNA which encodes a protein of interest and then introducing the stem cell into the host where the protein or gene of interest is expressed. The present also relates to methods of producing mesodermal, endodermal or ectodermal lineage-committed cells by culturing or transplantation of the pluripotent stem cells of the present invention.

1. A pluripotent embryonic-like stem cell, derived from non-embryonic or postnatal animal cells or tissue, capable of self-renewal and capable of differentiation to cells of endodermal, ectodermal and mesodermal lineages. 2. The stem cell of claim 1 which is a human cell. 3. (canceled) 4. (canceled) 5. (canceled) 6. (canceled) 7. (canceled) 8. A culture comprising: (a) Pluripotent embryonic-like stem cells of claim 1, derived from postnatal animal cells or tissue, capable of self-renewal and capable of differentiation to cells of endodermal, ectodermal and mesodermal lineages; and (b) a medium capable of supporting the proliferation of said stem cells. 9. (canceled) 10. (canceled) 11. A method of isolating a an pluripotent embryonic-like stem cell of claim 1, comprising the steps of: (a) obtaining cells from a postnatal animal source; (b) slow freezing said cells in medium containing 7.5% (v/v) dimethyl sulfoxide until a final temperature of −80° C. is reached; and (c) culturing the cells. 12. (canceled) 13. (canceled) 14. The stem cell of claim 1 genetically engineered to express a gene or protein of interest. 15. A method of producing a genetically engineered pluripotent embryonic-like stem cell comprising the steps of: (a) transfecting the pluripotent embryonic-like stem cells of claim 1 with a DNA construct comprising at least one of a marker gene or a gene of interest; (b) selecting for expression of the marker gene or gene of interest in the pluripotent embryonic-like stem cells; (c) culturing the stem cells selected in (b). 16. (canceled) 17. (canceled) 18. (canceled) 19. A method of testing the ability of an agent, compound or factor to modulate the lineage-commitment of a lineage uncommitted cell which comprises A. culturing the stem cells of claim 1 in a growth medium which maintains the stem cells as lineage uncommited cells; B. adding the agent, compound or factor under test; and C. determining the lineage of the so contacted cells by mRNA expression, antigen expression or other means. 20. (canceled) 21. (canceled) 22. A method of testing the ability of an agent, compound or factor to modulate the proliferation of a lineage uncommitted cell which comprises A. culturing the stem cells of claim 1 in a growth medium which maintains the stem cells as lineage uncommited cells; B. adding the agent, compound or factor under test; and C. determining the proliferation and lineage of the so contacted cells by mRNA expression, antigen expression or other means. 23. (canceled) 24. A method of transplanting pluripotent embryonic-like stem cells in a host comprising the step of introducing into the host the stem cells of claim 1. 25. (canceled) 26. (canceled) 27. A method of preventing and/or treating cellular debilitations, derangements and/or dysfunctions and/or other disease states in mammals, comprising administering to a mammal a therapeutically effective amount of pluripotent embryonic-like stem cells, or cells or tissues derived therefrom. 28. (canceled) 29. (canceled) 30. A method of tissue repair or transplantation in mammals, comprising administering to a mammal a therapeutically effective amount of a endodermal, ectodermal or mesodermal lineage-committed cell derived from the stem cell of claim 1. 31. A pharmaceutical composition for the treatment of cellular debilitation, derangement and/or dysfunction in mammals, comprising: A. a therapeutically effective amount of pluripotent embryonic-like stem cells, or cells or tissues derived therefrom; and B. a pharmaceutically acceptable medium or carrier. 32. (canceled)

The present invention relates to pluripotent stem cells, particularly to pluripotent embryonic-like stem cells. The invention further relates to methods of purifying pluripotent embryonic-like stem cells and to compositions, cultures and clones thereof. The present invention also relates to a method of transplanting the pluripotent stem cells of the present invention in a mammalian host, such as human, comprising introducing the stem cells, into the host. The invention further relates to methods of in vivo administration of a protein or gene of interest comprising transfecting a pluripotent stem cell with a construct comprising DNA which encodes a protein of interest and then introducing the stem cell into the host where the protein or gene of interest is expressed. The present also relates to methods of producing mesodermal, endodermal or ectodermal lineage-committed cells by culturing or transplantation of the pluripotent stem cells of the present invention.1. A pluripotent embryonic-like stem cell, derived from non-embryonic or postnatal animal cells or tissue, capable of self-renewal and capable of differentiation to cells of endodermal, ectodermal and mesodermal lineages. 2. The stem cell of claim 1 which is a human cell. 3. (canceled) 4. (canceled) 5. (canceled) 6. (canceled) 7. (canceled) 8. A culture comprising: (a) Pluripotent embryonic-like stem cells of claim 1, derived from postnatal animal cells or tissue, capable of self-renewal and capable of differentiation to cells of endodermal, ectodermal and mesodermal lineages; and (b) a medium capable of supporting the proliferation of said stem cells. 9. (canceled) 10. (canceled) 11. A method of isolating a an pluripotent embryonic-like stem cell of claim 1, comprising the steps of: (a) obtaining cells from a postnatal animal source; (b) slow freezing said cells in medium containing 7.5% (v/v) dimethyl sulfoxide until a final temperature of −80° C. is reached; and (c) culturing the cells. 12. (canceled) 13. (canceled) 14. The stem cell of claim 1 genetically engineered to express a gene or protein of interest. 15. A method of producing a genetically engineered pluripotent embryonic-like stem cell comprising the steps of: (a) transfecting the pluripotent embryonic-like stem cells of claim 1 with a DNA construct comprising at least one of a marker gene or a gene of interest; (b) selecting for expression of the marker gene or gene of interest in the pluripotent embryonic-like stem cells; (c) culturing the stem cells selected in (b). 16. (canceled) 17. (canceled) 18. (canceled) 19. A method of testing the ability of an agent, compound or factor to modulate the lineage-commitment of a lineage uncommitted cell which comprises A. culturing the stem cells of claim 1 in a growth medium which maintains the stem cells as lineage uncommited cells; B. adding the agent, compound or factor under test; and C. determining the lineage of the so contacted cells by mRNA expression, antigen expression or other means. 20. (canceled) 21. (canceled) 22. A method of testing the ability of an agent, compound or factor to modulate the proliferation of a lineage uncommitted cell which comprises A. culturing the stem cells of claim 1 in a growth medium which maintains the stem cells as lineage uncommited cells; B. adding the agent, compound or factor under test; and C. determining the proliferation and lineage of the so contacted cells by mRNA expression, antigen expression or other means. 23. (canceled) 24. A method of transplanting pluripotent embryonic-like stem cells in a host comprising the step of introducing into the host the stem cells of claim 1. 25. (canceled) 26. (canceled) 27. A method of preventing and/or treating cellular debilitations, derangements and/or dysfunctions and/or other disease states in mammals, comprising administering to a mammal a therapeutically effective amount of pluripotent embryonic-like stem cells, or cells or tissues derived therefrom. 28. (canceled) 29. (canceled) 30. A method of tissue repair or transplantation in mammals, comprising administering to a mammal a therapeutically effective amount of a endodermal, ectodermal or mesodermal lineage-committed cell derived from the stem cell of claim 1. 31. A pharmaceutical composition for the treatment of cellular debilitation, derangement and/or dysfunction in mammals, comprising: A. a therapeutically effective amount of pluripotent embryonic-like stem cells, or cells or tissues derived therefrom; and B. a pharmaceutically acceptable medium or carrier. 32. (canceled)

The present invention discloses positive control material for nucleic acid amplification based detection of microorganisms in biological samples. The control material comprises purified microorganism that is rendered non-infectious but is amenable to nucleic acid amplification. Also disclosed is a process for making and using the control material.

1. A method for making a full process positive control material for detection of virus in biological samples comprising: a) purifying an intact virus from a source; b) exposing the purified intact virus to an aldehyde at a temperature and for a time such that one or more surface proteins are irreversibly modified while leaving the nuclear components substantially intact thereby rendering the purified intact virus non-pathogenic and wherein nucleic acids of the purified intact virus are amenable to amplification; and c) identifying that the purified intact virus can be used as a full process positive control by confirming absence of active virus and an ability of viral nucleic acids in the purified intact virus to be amplified. 2. The method of claim 1, wherein the aldehyde is selected from the group consisting of paraformaldehyde, formaldehyde, acetaldehyde, propionaldehyde, n-butyraldehyde, benzaldehyde, p-nitrobenzaldehyde, p-tolualdehyde, salicylaldehyde, phenylacetaldehyde, 2-methylpentanal, 3-methylpentanal, and 4-methylpentanal. 3. The method of claim 1, wherein the time is controlled by quenching the aldehyde to provide the exposing for the time such that one or more surface proteins are irreversibly modified while leaving the nuclear components substantially intact. 4. The method of claim 3, wherein the quenching is carried out by glycine. 5. The method of claim 1, further comprising storing the purified intact virus at a refrigeration temperature. 6. The method of claim 1, further comprising suspending the purified intact virus in a liquid matrix comprising a buffer, a biological fluid, or a synthetic biological fluid. 7. A non-pathogenic intact virus prepared by the method of claim 1, wherein the nucleic acids in the non-pathogenic intact virus are amenable to amplification. 8. A non-pathogenic intact virus prepared by the method of claim 1, wherein the nucleic acids in the non-pathogenic intact virus are amenable to amplification after storage at a refrigeration temperature.

The present invention discloses positive control material for nucleic acid amplification based detection of microorganisms in biological samples. The control material comprises purified microorganism that is rendered non-infectious but is amenable to nucleic acid amplification. Also disclosed is a process for making and using the control material.1. A method for making a full process positive control material for detection of virus in biological samples comprising: a) purifying an intact virus from a source; b) exposing the purified intact virus to an aldehyde at a temperature and for a time such that one or more surface proteins are irreversibly modified while leaving the nuclear components substantially intact thereby rendering the purified intact virus non-pathogenic and wherein nucleic acids of the purified intact virus are amenable to amplification; and c) identifying that the purified intact virus can be used as a full process positive control by confirming absence of active virus and an ability of viral nucleic acids in the purified intact virus to be amplified. 2. The method of claim 1, wherein the aldehyde is selected from the group consisting of paraformaldehyde, formaldehyde, acetaldehyde, propionaldehyde, n-butyraldehyde, benzaldehyde, p-nitrobenzaldehyde, p-tolualdehyde, salicylaldehyde, phenylacetaldehyde, 2-methylpentanal, 3-methylpentanal, and 4-methylpentanal. 3. The method of claim 1, wherein the time is controlled by quenching the aldehyde to provide the exposing for the time such that one or more surface proteins are irreversibly modified while leaving the nuclear components substantially intact. 4. The method of claim 3, wherein the quenching is carried out by glycine. 5. The method of claim 1, further comprising storing the purified intact virus at a refrigeration temperature. 6. The method of claim 1, further comprising suspending the purified intact virus in a liquid matrix comprising a buffer, a biological fluid, or a synthetic biological fluid. 7. A non-pathogenic intact virus prepared by the method of claim 1, wherein the nucleic acids in the non-pathogenic intact virus are amenable to amplification. 8. A non-pathogenic intact virus prepared by the method of claim 1, wherein the nucleic acids in the non-pathogenic intact virus are amenable to amplification after storage at a refrigeration temperature.

Methods for reducing the occurrence or preventing formation of bladder calculi associated with bladder augmentation or bladder reconstruction.

1. A method for reducing the occurrence of bladder calculi in a patient in need of a bladder augmentation or bladder reconstruction surgical procedure, the method comprising locally administering a composition comprising a therapeutically effective amount of a clostridial derivative to the patient. 2. The method of claim 1, whether the administering is to a non-bladder tissue to be grafted to the bladder of the patient. 3. The method of claim 1, wherein the administering is to the bladder neck of the patient. 4. The method of claim 1, wherein the administering is before the bladder augmentation or bladder reconstruction surgical procedure. 5. The method of claim 1, wherein the administering is during the bladder augmentation or bladder reconstruction surgical procedure. 6. The method of claim 1, wherein the administering is after the bladder augmentation or bladder reconstruction surgical procedure. 7. The method of claim 1, wherein the clostridial derivative is a botulinum toxin. 8. The method of claim 7, wherein the botulinum toxin is selected from the group consisting of botulinuin toxin types A, B, C, D, E, F and G. 9. The method of claim 8, wherein the botulinum neurotoxin is type A. 10. The method of claim 9, wherein the therapeutically effective amount is between about 10 Units to about 500 U. 11. The method of claim 1, wherein the administering is by injection. 12. The method of claim 1, wherein the administering is by instillation.

Methods for reducing the occurrence or preventing formation of bladder calculi associated with bladder augmentation or bladder reconstruction.1. A method for reducing the occurrence of bladder calculi in a patient in need of a bladder augmentation or bladder reconstruction surgical procedure, the method comprising locally administering a composition comprising a therapeutically effective amount of a clostridial derivative to the patient. 2. The method of claim 1, whether the administering is to a non-bladder tissue to be grafted to the bladder of the patient. 3. The method of claim 1, wherein the administering is to the bladder neck of the patient. 4. The method of claim 1, wherein the administering is before the bladder augmentation or bladder reconstruction surgical procedure. 5. The method of claim 1, wherein the administering is during the bladder augmentation or bladder reconstruction surgical procedure. 6. The method of claim 1, wherein the administering is after the bladder augmentation or bladder reconstruction surgical procedure. 7. The method of claim 1, wherein the clostridial derivative is a botulinum toxin. 8. The method of claim 7, wherein the botulinum toxin is selected from the group consisting of botulinuin toxin types A, B, C, D, E, F and G. 9. The method of claim 8, wherein the botulinum neurotoxin is type A. 10. The method of claim 9, wherein the therapeutically effective amount is between about 10 Units to about 500 U. 11. The method of claim 1, wherein the administering is by injection. 12. The method of claim 1, wherein the administering is by instillation.

Described herein are oral care compositions comprising a crosslinked polyvinylpyrrolidone complexed with hydrogen peroxide, together with a fatty amphiphile; including some embodiments which further comprise a calcium abrasive.

1. A dentifrice composition comprising (i) a whitening complex comprising crosslinked polyvinylpyrrolidone complexed with hydrogen peroxide, (ii) a fatty amphiphile. 2. The composition of claim 1 wherein the fatty amphiphile is selected from fatty C12 to C28 alcohols or mixtures thereof. 3. The composition of claim 1 wherein the fatty amphiphile is stearyl alcohol. 4. The composition of claim 1 wherein the fatty amphiphilie is stearyl alcohol, cetyl alcohol or a combination thereof in an amount of about 0.1 to about 20% by weight of the composition. 5. The composition of claim 1 comprising an ethylene oxide, propylene oxide co-polymer of average molecular weight greater than 1000 Da, being substantially free of an ethylene oxide, propylene oxide block co-polymer of average molecular weight less than 1000 Da. 6. The composition of claim 5 wherein the ethylene oxide, propylene oxide co-polymer has an average molecular weight of between 5000 and 13000 Da. 7. The composition of claim 1 wherein the whitening complex contains about 10-30% hydrogen peroxide, by weight, and about 5-15% total nitrogen by weight. 8. The composition of claim 1 wherein the total amount of hydrogen peroxide by weight of the composition is 0.5-5%. 9. The composition of claim 1 additionally comprising polyethylene glycol of average molecular weight 400 to 800 Da. 10. The composition of claim 1 which contains less than 3% water. 11. The composition of claim 1 which is a gel non-abrasive dentifrice. 12. The composition of claim 1 which is a toothpaste comprising a calcium abrasive selected from a calcium phosphate salt and calcium carbonate. 13. The composition of claim 12 wherein the calcium abrasive comprises calcium pyrophosphate. 14. The composition of claim 1 additionally comprising a tartar control agent such as tetrasodium pyrophosphate. 15. The composition of claim 14 comprising the following ingredients by weight: a. Glycerin 0-7% b. Propylene glycol 50-65% c. Ethylene oxide, propylene oxide 5-15% co-polymer, avg. MW >1 kDa d. Sodium lauryl sulfate 1-3% e. Crosslinked polyvinylpyrrolidone 5-12% complexed with 15-25% H2O2 f. Calcium pyrophosphate 5-35% g. tetrasodium pyrophosphate 0.3-5-%% 16. The composition of claim 1 comprising 0.5-1% by weight of a fluoride ion source, for example sodium monofluorophosphate. 17. The composition of claim 1 comprising a flavorant, a sweetener, an antioxidant, an antimicrobial or a combination of two or more thereof. 18. A composition of claim 1, wherein the top diameter of the tube in which the composition is packaged, expands less than 0.1 cm, after 1 week of aging at 60° C. 19. A composition of claim 1, wherein the top diameter of the tube in which the composition is packaged, expands less than 1% of the top diameter of the tube, after 1 week of aging at 60° C. 20. A composition of claim 1, wherein the composition does not exhibit an unacceptable level of phase separation after storage for 24 hours.

Described herein are oral care compositions comprising a crosslinked polyvinylpyrrolidone complexed with hydrogen peroxide, together with a fatty amphiphile; including some embodiments which further comprise a calcium abrasive.1. A dentifrice composition comprising (i) a whitening complex comprising crosslinked polyvinylpyrrolidone complexed with hydrogen peroxide, (ii) a fatty amphiphile. 2. The composition of claim 1 wherein the fatty amphiphile is selected from fatty C12 to C28 alcohols or mixtures thereof. 3. The composition of claim 1 wherein the fatty amphiphile is stearyl alcohol. 4. The composition of claim 1 wherein the fatty amphiphilie is stearyl alcohol, cetyl alcohol or a combination thereof in an amount of about 0.1 to about 20% by weight of the composition. 5. The composition of claim 1 comprising an ethylene oxide, propylene oxide co-polymer of average molecular weight greater than 1000 Da, being substantially free of an ethylene oxide, propylene oxide block co-polymer of average molecular weight less than 1000 Da. 6. The composition of claim 5 wherein the ethylene oxide, propylene oxide co-polymer has an average molecular weight of between 5000 and 13000 Da. 7. The composition of claim 1 wherein the whitening complex contains about 10-30% hydrogen peroxide, by weight, and about 5-15% total nitrogen by weight. 8. The composition of claim 1 wherein the total amount of hydrogen peroxide by weight of the composition is 0.5-5%. 9. The composition of claim 1 additionally comprising polyethylene glycol of average molecular weight 400 to 800 Da. 10. The composition of claim 1 which contains less than 3% water. 11. The composition of claim 1 which is a gel non-abrasive dentifrice. 12. The composition of claim 1 which is a toothpaste comprising a calcium abrasive selected from a calcium phosphate salt and calcium carbonate. 13. The composition of claim 12 wherein the calcium abrasive comprises calcium pyrophosphate. 14. The composition of claim 1 additionally comprising a tartar control agent such as tetrasodium pyrophosphate. 15. The composition of claim 14 comprising the following ingredients by weight: a. Glycerin 0-7% b. Propylene glycol 50-65% c. Ethylene oxide, propylene oxide 5-15% co-polymer, avg. MW >1 kDa d. Sodium lauryl sulfate 1-3% e. Crosslinked polyvinylpyrrolidone 5-12% complexed with 15-25% H2O2 f. Calcium pyrophosphate 5-35% g. tetrasodium pyrophosphate 0.3-5-%% 16. The composition of claim 1 comprising 0.5-1% by weight of a fluoride ion source, for example sodium monofluorophosphate. 17. The composition of claim 1 comprising a flavorant, a sweetener, an antioxidant, an antimicrobial or a combination of two or more thereof. 18. A composition of claim 1, wherein the top diameter of the tube in which the composition is packaged, expands less than 0.1 cm, after 1 week of aging at 60° C. 19. A composition of claim 1, wherein the top diameter of the tube in which the composition is packaged, expands less than 1% of the top diameter of the tube, after 1 week of aging at 60° C. 20. A composition of claim 1, wherein the composition does not exhibit an unacceptable level of phase separation after storage for 24 hours.

The present invention provides, in part, cochleate compositions and methods for making and using same.

1. A cochleate composition comprising a population of cochleates, wherein the cochleates comprise: a) a negatively charged first lipid; b) a cation, wherein the cation is a divalent cation or a higher valency cation selected from the group consisting of calcium, zinc, barium, and magnesium cations; c) a second lipid; and d) a biologically relevant molecule; wherein the second lipid is a neutral or cationic lipid or sterol and the second lipid comprises up to 50% of the total lipid component of the cochleates. 2-3. (canceled) 4. The cochleate composition of claim 1, wherein the second lipid is selected from the group consisting of phosphatidylcholine and sphingomyelin. 5. The cochleate composition of claim 1, wherein the second lipid comprises lipid capable of forming hydrogen bonds to the biologically relevant molecule. 6. The cochleate composition of claim 1, wherein the second lipid is embedded among the negatively charged first lipid. 7-9. (canceled) 10. The cochleate composition of claim 1, wherein the negatively charged lipid comprises phosphatidylserine, dioleoyl PS (DOPS), and soybean-derived phosphatidyl serine (soy PS). 11. The cochleate composition of claim 1, wherein the cochleates further comprise a minor amount of a third lipid. 12. The cochleate composition of claim 11, wherein the third lipid is selected from the group consisting of a zwitterionic lipid, a PEGylated lipid, a cationic lipid, or a polycationic lipid. 13-14. (canceled) 15. The cochleate composition of claim 1, wherein the biologically relevant molecule is hydrophilic. 16-18. (canceled) 19. The cochleate composition of claim 1, wherein the biologically relevant molecule is at least one member selected from the group consisting of a drug, a vitamin, a mineral, a fatty acid, an amino acid, a saccharide, a polynucleotide, a polypeptide, an antigen, a nutrient and a flavor substance, wherein the drug is an antifungal agent; a non-steroidal anti-inflammatory agent; an anticancer agent; an antiviral, an anesthetic, or an anti-infectious agent, an immunosuppressant, a steroidal anti-inflammatory, a tranquilizer, and a vasodilatory agent. 20. (canceled) 21. The cochleate composition of claim 19, wherein the drug is selected from the group consisting of amphotericin B and gentamicin. 22. The cochleate composition of claim 19, wherein the drug is an aminoglycoside. 23. The cochleate composition of claim 22, wherein the aminoglycoside is amikacin. 24-29. (canceled) 30. The cochleate composition of claim 1, further comprising an aggregation inhibitor. 31. The cochleate composition of claim 1, wherein the cochleate composition contains sodium chloride. 32. A pharmaceutical composition comprising an effective amount of the cochleate composition of claim 1 and a pharmaceutically acceptable carrier. 33. A method of making the cochleate composition of claim 1 comprising: a) mixing a biologically relevant molecule with a liposome comprising a negatively charged first lipid and a second lipid wherein the second lipid is a neutral or cationic lipid or sterol; and b) adding a cation, wherein the cation is a divalent cation or a higher valency cation selected from the group consisting of calcium, zinc, barium, and magnesium cations, to make the cochleate composition, wherein the second lipid comprises up to 50% of the total lipid component of the cochleates. 34. The method of claim 33, wherein the ratio of the total lipid to biologically relevant molecule is at least 4:1. 35-38. (canceled) 39. The method of claim 33, wherein the calcium cation is provided from calcium chloride, wherein the calcium chloride concentration of the mixture is 2 mM to 10 mM. 40-41. (canceled) 42. The method of claim 33, further comprising a step c), wherein an aggregation inhibitor is mixed with the cochleate compositions. 43. (canceled) 44. The method of claim 33, wherein sodium chloride is mixed with the cochleate compositions, wherein the sodium chloride concentration of the mixture is 1 mM to 1 M. 45-46. (canceled) 47. A method of treatment comprising administering to a host in need thereof a pharmaceutically effective amount of the composition of claim 1, wherein the host is selected from the group consisting of a cell, a cell culture, an organ, tissue, or an animal. 48. (canceled) 49. The method of treatment of claim 47, wherein the administration is a mucosal route selected from the group consisting of oral, intranasal, intraocular, intraanal, intravaginal, and intrapulmonary. 50-79. (canceled)

The present invention provides, in part, cochleate compositions and methods for making and using same.1. A cochleate composition comprising a population of cochleates, wherein the cochleates comprise: a) a negatively charged first lipid; b) a cation, wherein the cation is a divalent cation or a higher valency cation selected from the group consisting of calcium, zinc, barium, and magnesium cations; c) a second lipid; and d) a biologically relevant molecule; wherein the second lipid is a neutral or cationic lipid or sterol and the second lipid comprises up to 50% of the total lipid component of the cochleates. 2-3. (canceled) 4. The cochleate composition of claim 1, wherein the second lipid is selected from the group consisting of phosphatidylcholine and sphingomyelin. 5. The cochleate composition of claim 1, wherein the second lipid comprises lipid capable of forming hydrogen bonds to the biologically relevant molecule. 6. The cochleate composition of claim 1, wherein the second lipid is embedded among the negatively charged first lipid. 7-9. (canceled) 10. The cochleate composition of claim 1, wherein the negatively charged lipid comprises phosphatidylserine, dioleoyl PS (DOPS), and soybean-derived phosphatidyl serine (soy PS). 11. The cochleate composition of claim 1, wherein the cochleates further comprise a minor amount of a third lipid. 12. The cochleate composition of claim 11, wherein the third lipid is selected from the group consisting of a zwitterionic lipid, a PEGylated lipid, a cationic lipid, or a polycationic lipid. 13-14. (canceled) 15. The cochleate composition of claim 1, wherein the biologically relevant molecule is hydrophilic. 16-18. (canceled) 19. The cochleate composition of claim 1, wherein the biologically relevant molecule is at least one member selected from the group consisting of a drug, a vitamin, a mineral, a fatty acid, an amino acid, a saccharide, a polynucleotide, a polypeptide, an antigen, a nutrient and a flavor substance, wherein the drug is an antifungal agent; a non-steroidal anti-inflammatory agent; an anticancer agent; an antiviral, an anesthetic, or an anti-infectious agent, an immunosuppressant, a steroidal anti-inflammatory, a tranquilizer, and a vasodilatory agent. 20. (canceled) 21. The cochleate composition of claim 19, wherein the drug is selected from the group consisting of amphotericin B and gentamicin. 22. The cochleate composition of claim 19, wherein the drug is an aminoglycoside. 23. The cochleate composition of claim 22, wherein the aminoglycoside is amikacin. 24-29. (canceled) 30. The cochleate composition of claim 1, further comprising an aggregation inhibitor. 31. The cochleate composition of claim 1, wherein the cochleate composition contains sodium chloride. 32. A pharmaceutical composition comprising an effective amount of the cochleate composition of claim 1 and a pharmaceutically acceptable carrier. 33. A method of making the cochleate composition of claim 1 comprising: a) mixing a biologically relevant molecule with a liposome comprising a negatively charged first lipid and a second lipid wherein the second lipid is a neutral or cationic lipid or sterol; and b) adding a cation, wherein the cation is a divalent cation or a higher valency cation selected from the group consisting of calcium, zinc, barium, and magnesium cations, to make the cochleate composition, wherein the second lipid comprises up to 50% of the total lipid component of the cochleates. 34. The method of claim 33, wherein the ratio of the total lipid to biologically relevant molecule is at least 4:1. 35-38. (canceled) 39. The method of claim 33, wherein the calcium cation is provided from calcium chloride, wherein the calcium chloride concentration of the mixture is 2 mM to 10 mM. 40-41. (canceled) 42. The method of claim 33, further comprising a step c), wherein an aggregation inhibitor is mixed with the cochleate compositions. 43. (canceled) 44. The method of claim 33, wherein sodium chloride is mixed with the cochleate compositions, wherein the sodium chloride concentration of the mixture is 1 mM to 1 M. 45-46. (canceled) 47. A method of treatment comprising administering to a host in need thereof a pharmaceutically effective amount of the composition of claim 1, wherein the host is selected from the group consisting of a cell, a cell culture, an organ, tissue, or an animal. 48. (canceled) 49. The method of treatment of claim 47, wherein the administration is a mucosal route selected from the group consisting of oral, intranasal, intraocular, intraanal, intravaginal, and intrapulmonary. 50-79. (canceled)

Disclosed is a cosmetic or dermatological formulation comprising a) at least one polyol in a concentration of from 0.1 to 20% by weight, based on the total weight of the formulation, and b) at least one diol selected from 2-methyl-1,3-propanediol, pentanediol, and hexanediol, in a concentration of from 0.1 to 25% by weight, based on the total weight of the formulation.

1. A cosmetic or dermatological formulation, wherein the formulation comprises (a) one or more of glycerol, propylene glycol, and butylene glycol in a total concentration of from 0.1% to 20% by weight, based on a total weight of the formulation, (b) 2-methyl-1,3-propanediol and, optionally, one or both of pentanediol and hexanediol in a total concentration of from 1% to 25% by weight, based on the total weight of the formulation, 2-methyl-1,3-propanediol being present in a concentration of from 1% to 15% by weight, and (c) at least one substance selected from antioxidants, alpha-lipoic acid, phytoene, D-biotin, coenzyme Q10, α-glucosylrutin, carnitine, carnosine, isoflavonoids, creatine, taurine, and β-alanine, and wherein a ratio of (a) to (b) is from 5:1 to 1:1. 2. The formulation of claim 1, wherein the formulation is present as an ointment, a cream, a milk, a lotion or a spray. 3. The formulation of claim 1, wherein glycerol, propylene glycol, butylene glycol and 2-methyl-1,3-propanediol are present in a total concentration of at least 7.5% by weight. 4. The formulation of claim 1, wherein (a) comprises glycerol. 5. The formulation of claim 1, wherein (b) comprises pentanediol. 6. The formulation of claim 1, wherein (b) comprises hexanediol. 7. The formulation of claim 1, wherein (c) comprises at least one substance selected from alpha-lipoic acid, phytoene, D-biotin, coenzyme Q10, α-glucosylrutin, carnitine, carnosine, isoflavonoids, creatine, taurine, and β-alanine. 8. The formulation of claim 1, wherein (b) is present in a total concentration of from 3% to 8% by weight. 9. The formulation of claim 8, wherein (a) is present in a total concentration of from 1% to 15% by weight. 10. The formulation of claim 9, wherein the ratio of (a) to (b) is from 2:1 to 1:1. 11. The formulation of claim 1, wherein (a) comprises at least one of propylene glycol and butylene glycol. 12. A cosmetic or dermatological formulation, wherein the formulation is present as an ointment, a cream, a milk, a lotion or a spray and comprises (a) one or both of propylene glycol and butylene glycol and, optionally, glycerol in a total concentration of from 0.1% to 20% by weight, based on a total weight of the formulation, and (b) 2-methyl-1,3-propanediol and, optionally, one or both of pentanediol and hexanediol in a total concentration of from 1 to 25% by weight, based on the total weight of the formulation, 2-methyl-1,3-propanediol being present in a concentration of from 1% to 15% by weight, and wherein a ratio of (a) to (b) is from 1:3 to 3:1. 13. The formulation of claim 12, wherein the formulation is present as an ointment, a cream, a milk, a lotion or a spray. 14. The formulation of claim 13, wherein glycerol, propylene glycol, butylene glycol and 2-methyl-1,3-propanediol are present in a total concentration of at least 7.5% by weight. 15. The formulation of claim 13, wherein (b) is present in a total concentration of from 3% to 8% by weight. 16. The formulation of claim 12, wherein the ratio of (a) to (b) is from 2:1 to 1:1. 17. A cosmetic or dermatological formulation, wherein the formulation comprises (a) one or more of glycerol, propylene glycol, and butylene glycol in a total concentration of from 0.1% to 20% by weight, based on a total weight of the formulation, and (b) 2-methyl-1,3-propanediol and one or both of pentanediol and hexanediol in a total concentration of from 1% to 25% by weight, based on the total weight of the formulation, 2-methyl-1,3-propanediol being present in a concentration of from 1% to 15% by weight, and wherein a ratio of (a) to (b) is from 1:3 to 3:1. 18. The formulation of claim 17, wherein the formulation is present as an ointment, a cream, a milk, a lotion or a spray. 19. The formulation of claim 18, wherein (b) is present in a total concentration of from 3% to 8% by weight. 20. The formulation of claim 19, wherein the ratio of (a) to (b) is from 2:1 to 1:1.

Disclosed is a cosmetic or dermatological formulation comprising a) at least one polyol in a concentration of from 0.1 to 20% by weight, based on the total weight of the formulation, and b) at least one diol selected from 2-methyl-1,3-propanediol, pentanediol, and hexanediol, in a concentration of from 0.1 to 25% by weight, based on the total weight of the formulation.1. A cosmetic or dermatological formulation, wherein the formulation comprises (a) one or more of glycerol, propylene glycol, and butylene glycol in a total concentration of from 0.1% to 20% by weight, based on a total weight of the formulation, (b) 2-methyl-1,3-propanediol and, optionally, one or both of pentanediol and hexanediol in a total concentration of from 1% to 25% by weight, based on the total weight of the formulation, 2-methyl-1,3-propanediol being present in a concentration of from 1% to 15% by weight, and (c) at least one substance selected from antioxidants, alpha-lipoic acid, phytoene, D-biotin, coenzyme Q10, α-glucosylrutin, carnitine, carnosine, isoflavonoids, creatine, taurine, and β-alanine, and wherein a ratio of (a) to (b) is from 5:1 to 1:1. 2. The formulation of claim 1, wherein the formulation is present as an ointment, a cream, a milk, a lotion or a spray. 3. The formulation of claim 1, wherein glycerol, propylene glycol, butylene glycol and 2-methyl-1,3-propanediol are present in a total concentration of at least 7.5% by weight. 4. The formulation of claim 1, wherein (a) comprises glycerol. 5. The formulation of claim 1, wherein (b) comprises pentanediol. 6. The formulation of claim 1, wherein (b) comprises hexanediol. 7. The formulation of claim 1, wherein (c) comprises at least one substance selected from alpha-lipoic acid, phytoene, D-biotin, coenzyme Q10, α-glucosylrutin, carnitine, carnosine, isoflavonoids, creatine, taurine, and β-alanine. 8. The formulation of claim 1, wherein (b) is present in a total concentration of from 3% to 8% by weight. 9. The formulation of claim 8, wherein (a) is present in a total concentration of from 1% to 15% by weight. 10. The formulation of claim 9, wherein the ratio of (a) to (b) is from 2:1 to 1:1. 11. The formulation of claim 1, wherein (a) comprises at least one of propylene glycol and butylene glycol. 12. A cosmetic or dermatological formulation, wherein the formulation is present as an ointment, a cream, a milk, a lotion or a spray and comprises (a) one or both of propylene glycol and butylene glycol and, optionally, glycerol in a total concentration of from 0.1% to 20% by weight, based on a total weight of the formulation, and (b) 2-methyl-1,3-propanediol and, optionally, one or both of pentanediol and hexanediol in a total concentration of from 1 to 25% by weight, based on the total weight of the formulation, 2-methyl-1,3-propanediol being present in a concentration of from 1% to 15% by weight, and wherein a ratio of (a) to (b) is from 1:3 to 3:1. 13. The formulation of claim 12, wherein the formulation is present as an ointment, a cream, a milk, a lotion or a spray. 14. The formulation of claim 13, wherein glycerol, propylene glycol, butylene glycol and 2-methyl-1,3-propanediol are present in a total concentration of at least 7.5% by weight. 15. The formulation of claim 13, wherein (b) is present in a total concentration of from 3% to 8% by weight. 16. The formulation of claim 12, wherein the ratio of (a) to (b) is from 2:1 to 1:1. 17. A cosmetic or dermatological formulation, wherein the formulation comprises (a) one or more of glycerol, propylene glycol, and butylene glycol in a total concentration of from 0.1% to 20% by weight, based on a total weight of the formulation, and (b) 2-methyl-1,3-propanediol and one or both of pentanediol and hexanediol in a total concentration of from 1% to 25% by weight, based on the total weight of the formulation, 2-methyl-1,3-propanediol being present in a concentration of from 1% to 15% by weight, and wherein a ratio of (a) to (b) is from 1:3 to 3:1. 18. The formulation of claim 17, wherein the formulation is present as an ointment, a cream, a milk, a lotion or a spray. 19. The formulation of claim 18, wherein (b) is present in a total concentration of from 3% to 8% by weight. 20. The formulation of claim 19, wherein the ratio of (a) to (b) is from 2:1 to 1:1.

A non-aqueous topical solution composition of pharmaceutically acceptable salt of diclofenac is disclosed. The non-aqueous topical solution composition comprises therapeutically effective amount of pharmaceutically acceptable salt of diclofenac, solublizer, penetration enhancer and solvent, and optionally a humectant, counter irritant, additional penetration enhancer and anti-oxidants and a process for preparing the same.

1. A novel composition of non-aqueous topical solution comprising: an effective amount of pharmaceutically acceptable salt of diclofenac; about 10 to 30% v/v of lower chain alcohol as penetration enhancer and solublizer; a solvent selected from propylene glycol, glycofurol or their mixture thereof; and optionally a humectant, and an additional penetration enhancer. 2. The composition according to claim 1, wherein the effective amount of pharmaceutically acceptable salt of diclofenac is in the range of about 1.16% to about 5% w/v, preferably about 1.16% to about 2.32% w/v. 3. The composition according to claim 1, wherein the pharmaceutically acceptable salt of diclofenac is preferably diethylamine salt of diclofenac. 4. The composition according to claim 1, wherein said lower chain alcohol is having carbon chain length of C2 to C5, preferably selected from ethanol, propanol, isopropanol and more preferably ethanol. 5. The composition according to claim 1, wherein said lower chain alcohol is preferably is in the range of about 10% to 20% v/v. 6. The composition according to claim 1, wherein the solvent is used in an amount to make up the volume of the composition up to 100%. 7. The composition according to claim 1, wherein said composition optionally comprises an anti-oxidant, preferably selected from monothioglycerol and tocopherol. 8. The composition according to claim 1, wherein said additional penetration enhancer is selected from saturated and unsaturated long chain fatty acids, esters thereof, alkyl substituted nitrogen containing heterocyclic compounds, alone or in combination thereof and more preferably selected from ethanol, propanol, isopropanol, oleic acid, isopropyl myristate, isopropyl palmitate, N-methyl-pyrollidone (NMP), 2-methyl-pyrrolidone or 1-methyl-pyrrolidone, alone or in combination thereof. 9. The composition according to claim 8, wherein said additional penetration enhancer is used in amount of about 1 to 5% w/v. 10. The composition according to claim 1, wherein said humectant is selected from the group comprising glycerine, propylene glycol, glyceryl triacetate, polyols, polymeric polyols, lactic acid, urea, alone or in combination thereof and most preferably selected from glycerol and/or urea, alone or in combination thereof. 11. The composition according to claim 1, wherein said humectant is used in an amount of about 2% to 5% w/v. 12. The composition according to claim 1, wherein said composition is characterized by having effective penetration of diclofenac into the affected parts of the body without irritating, without dehydrating or without leaving a greasy film on the skin of a mammal when the solution is applied topically. 13. The composition according to claim 1, wherein said composition is having viscosity in the range of about 10 to 50 cps. 14. The composition according to claim 1, wherein said composition is prepared by a process comprising the steps of: a) preparing a solution of pharmaceutically acceptable salt of diclofenac in the solvent; b) preparing a solution of penetration enhancer and solublizer; c) optionally adding an additional penetration enhancer in the resulting solution of step (b); d) adding, under constant stirring, the solution obtained in step (c), to the solution of step (a); e) optionally adding a humectant to the resulting solution of step (d); and f) adding a sufficient quantity of solvent to make up the volume of the composition up to 100%. 15. The composition according to claim 1, wherein said composition is further comprising one or more counter irritant. 16. The composition according to claim 15, wherein said counter irritant is selected from the group comprising methyl salicylate, capsaicin, menthol, oil of wintergreen, camphor, eucalyptus, mustard plasters and turpentine oil and most preferably selected from methyl salicylate, menthol, capsaicin and camphor, alone or in combination thereof. 17. The composition according to claim 15, wherein said composition is prepared by a process comprising the steps of: a) preparing a solution of therapeutically effective amount of pharmaceutically acceptable salt of diclofenac in the solvent; b) preparing a solution of counter-irritant in the penetration enhancer and solublizer; c) optionally dissolving the additional penetration enhancer and antioxidant in the solution obtained in step (b); d) adding under constant stirring, the solution obtained in step (c), to the solution of diclofenac in solvent to obtain clear transparent homogenous solution; and e) adding a sufficient quantity of solvent to make up the volume of the composition up to 100%.

A non-aqueous topical solution composition of pharmaceutically acceptable salt of diclofenac is disclosed. The non-aqueous topical solution composition comprises therapeutically effective amount of pharmaceutically acceptable salt of diclofenac, solublizer, penetration enhancer and solvent, and optionally a humectant, counter irritant, additional penetration enhancer and anti-oxidants and a process for preparing the same.1. A novel composition of non-aqueous topical solution comprising: an effective amount of pharmaceutically acceptable salt of diclofenac; about 10 to 30% v/v of lower chain alcohol as penetration enhancer and solublizer; a solvent selected from propylene glycol, glycofurol or their mixture thereof; and optionally a humectant, and an additional penetration enhancer. 2. The composition according to claim 1, wherein the effective amount of pharmaceutically acceptable salt of diclofenac is in the range of about 1.16% to about 5% w/v, preferably about 1.16% to about 2.32% w/v. 3. The composition according to claim 1, wherein the pharmaceutically acceptable salt of diclofenac is preferably diethylamine salt of diclofenac. 4. The composition according to claim 1, wherein said lower chain alcohol is having carbon chain length of C2 to C5, preferably selected from ethanol, propanol, isopropanol and more preferably ethanol. 5. The composition according to claim 1, wherein said lower chain alcohol is preferably is in the range of about 10% to 20% v/v. 6. The composition according to claim 1, wherein the solvent is used in an amount to make up the volume of the composition up to 100%. 7. The composition according to claim 1, wherein said composition optionally comprises an anti-oxidant, preferably selected from monothioglycerol and tocopherol. 8. The composition according to claim 1, wherein said additional penetration enhancer is selected from saturated and unsaturated long chain fatty acids, esters thereof, alkyl substituted nitrogen containing heterocyclic compounds, alone or in combination thereof and more preferably selected from ethanol, propanol, isopropanol, oleic acid, isopropyl myristate, isopropyl palmitate, N-methyl-pyrollidone (NMP), 2-methyl-pyrrolidone or 1-methyl-pyrrolidone, alone or in combination thereof. 9. The composition according to claim 8, wherein said additional penetration enhancer is used in amount of about 1 to 5% w/v. 10. The composition according to claim 1, wherein said humectant is selected from the group comprising glycerine, propylene glycol, glyceryl triacetate, polyols, polymeric polyols, lactic acid, urea, alone or in combination thereof and most preferably selected from glycerol and/or urea, alone or in combination thereof. 11. The composition according to claim 1, wherein said humectant is used in an amount of about 2% to 5% w/v. 12. The composition according to claim 1, wherein said composition is characterized by having effective penetration of diclofenac into the affected parts of the body without irritating, without dehydrating or without leaving a greasy film on the skin of a mammal when the solution is applied topically. 13. The composition according to claim 1, wherein said composition is having viscosity in the range of about 10 to 50 cps. 14. The composition according to claim 1, wherein said composition is prepared by a process comprising the steps of: a) preparing a solution of pharmaceutically acceptable salt of diclofenac in the solvent; b) preparing a solution of penetration enhancer and solublizer; c) optionally adding an additional penetration enhancer in the resulting solution of step (b); d) adding, under constant stirring, the solution obtained in step (c), to the solution of step (a); e) optionally adding a humectant to the resulting solution of step (d); and f) adding a sufficient quantity of solvent to make up the volume of the composition up to 100%. 15. The composition according to claim 1, wherein said composition is further comprising one or more counter irritant. 16. The composition according to claim 15, wherein said counter irritant is selected from the group comprising methyl salicylate, capsaicin, menthol, oil of wintergreen, camphor, eucalyptus, mustard plasters and turpentine oil and most preferably selected from methyl salicylate, menthol, capsaicin and camphor, alone or in combination thereof. 17. The composition according to claim 15, wherein said composition is prepared by a process comprising the steps of: a) preparing a solution of therapeutically effective amount of pharmaceutically acceptable salt of diclofenac in the solvent; b) preparing a solution of counter-irritant in the penetration enhancer and solublizer; c) optionally dissolving the additional penetration enhancer and antioxidant in the solution obtained in step (b); d) adding under constant stirring, the solution obtained in step (c), to the solution of diclofenac in solvent to obtain clear transparent homogenous solution; and e) adding a sufficient quantity of solvent to make up the volume of the composition up to 100%.

The invention pertains to dispersible tablets comprising as active ingredient 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid or pharmaceutically acceptable salt thereof in an amount of from 5 to 40% in weight by weight of the total tablet.

1-15. (canceled) 16. A dispersible tablet comprising deferasirox or a pharmaceutically acceptable salt thereof in an amount selected from the group consisting of about 125 mg, about 250 mg, and about 500 mg, wherein the tablet exhibits a disintegration time of less than 5 minutes when measured by a standard USP disintegration test; and, wherein the tablet further comprises, (i) at least one filler in a total amount of about 35 to 55% by weight based on total weight of the tablet; (ii) at least one disintegrant in a total amount of about 5 to 40% by weight based on the total weight of the tablet; (iii) at least one binder in a total amount of about 1 to 10% by weight based on the total weight of the tablet; (iv) at least one surfactant in a total amount of about 0.1 to 2% by weight based on the total weight of the tablet; (v) at least one glidant in a total amount of about 0.1 to 5% by weight based on the total weight of the tablet; and, (vi) at least one lubricant in a total amount of less than about 1% by weight based on the total weight of the tablet. 17. A tablet according to claim 16 wherein, (i) filler is selected from the group consisting essentially of lactose, ethylcellulose, and microcrystalline cellulose; (ii) disintegrant is selected from the group consisting essentially of cross-linked polyvinylpyrrolidone, starch, CMC-Ca, CMC-Na, microcrystalline cellulose, alginic acid, sodium alginate, and guar gum; (iii) binder is selected from the group consisting essentially of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, microcrystalline cellulose, and starch; (iv) surfactant is selected from the group consisting essentially of sodium laurylsulfate, betain, quaternary ammonium salt, polysorbate, sorbitan erter, and poloxamer; (v) glidant is selected from the group consisting essentially of silica, colloidal silica, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, and talc; and, (vi) lubricant is selected from the group consisting essentially of magnesium stearate, aluminum stearate, calcium stearate, polyoxyethylene glycol, talc, sodium benzoate, glyceryl mono fatty acid, glyceryl monostearate, glyceryl dibehenate, glyceryl palmito-stearic ester, hydrogenated cotton seed oil, and castor seed oil. 18. A tablet according to claim 17 wherein the tablet comprises, (i) about 125 mg deferasirox or a pharmaceutically acceptable salt thereof; (ii) at least one filler in a total amount of about 40 to 50%; (iii) at least one disintegrant in a total amount of about 10 to 35%; (iv) at least one binder in a total amount of about 1.5 to 5%; (v) at least one surfactant in a total amount of about 0.2 to 1%; (vi) at least one glidant in a total amount of about 0.1 to 2.5%; and, (vii) at least one lubricant in a total amount of less than about 0.5%. 19. A tablet according to claim 17 wherein the tablet comprises, (i) about 250 mg deferasirox or a pharmaceutically acceptable salt thereof; (ii) at least one filler in a total amount of about 40 to 50%; (iii) at least one disintegrant in a total amount of about 10 to 35%; (iv) at least one binder in a total amount of about 1.5 to 5%; (v) at least one surfactant in a total amount of about 0.2 to 1%; (vi) at least one glidant in a total amount of about 0.1 to 2.5%; and, (vii) at least one lubricant in a total amount of less than about 0.5%. 20. A tablet according to claim 17 wherein the tablet comprises, (i) about 500 mg deferasirox or a pharmaceutically acceptable salt thereof; (ii) at least one filler in a total amount of about 40 to 50%; (iii) at least one disintegrant in a total amount of about 10 to 35%; (iv) at least one binder in a total amount of about 1.5 to 5%; (v) at least one surfactant in a total amount of about 0.2 to 1%; (vi) at least one glidant in a total amount of about 0.1 to 2.5%; and, (vii) at least one lubricant in a total amount of less than about 0.5%. 21. A tablet according to claim 18 wherein the tablet comprises, (i) about 17% lactose; (ii) about 15% cross-linked polyvinylpyrrolidone; (iii) about 3% polyvinylpyrrolidone; (iv) about 0.5% sodium laurylsulfate; (v) about 5% further cross-linked polyvinylpyrrolidone; (vi) about 14.9% microcrystalline cellulose; (vii) about 14.9% further lactose; (viii) about 0.2% fumed silica; and, (ix) less than about 0.2% magnesium stearate. 22. A tablet according to claim 19 wherein the tablet comprises, (i) about 17% lactose; (ii) about 15% cross-linked polyvinylpyrrolidone; (iii) about 3% polyvinylpyrrolidone; (iv) about 0.5% sodium laurylsulfate; (v) about 5% further cross-linked polyvinylpyrrolidone; (vi) about 14.9% microcrystalline cellulose; (vii) about 14.9% further lactose; (viii) about 0.2% fumed silica; and, (ix) less than about 0.2% magnesium stearate. 23. A tablet according to claim 20 wherein the tablet comprises, (i) about 17% lactose; (ii) about 15% cross-linked polyvinylpyrrolidone; (iii) about 3% polyvinylpyrrolidone; (iv) about 0.5% sodium laurylsulfate; (v) about 5% further cross-linked polyvinylpyrrolidone; (vi) about 14.9% microcrystalline cellulose; (vii) about 14.9% further lactose; (viii) about 0.2% fumed silica; and, (ix) less than about 0.2% magnesium stearate. 24. A tablet according to claim 21 wherein the tablet comprises, (i) about 31.9% lactose; (ii) about 20% cross-linked polyvinylpyrrolidone; (iii) about 3% polyvinylpyrrolidone; (iv) about 0.5% sodium laurylsulfate; (v) about 14.9% microcrystalline cellulose; (vi) about 0.2% fumed silica; and, (vii) less than about 0.2% magnesium stearate. 25. A tablet according to claim 22 wherein the tablet comprises, (i) about 31.9% lactose; (ii) about 20% cross-linked polyvinylpyrrolidone; (iii) about 3% polyvinylpyrrolidone; (iv) about 0.5% sodium laurylsulfate; (v) about 14.9% microcrystalline cellulose; (vi) about 0.2% fumed silica; and, (vii) less than about 0.2% magnesium stearate. 26. A tablet according to claim 23 wherein the tablet comprises, (i) about 31.9% lactose; (ii) about 20% cross-linked polyvinylpyrrolidone; (iii) about 3% polyvinylpyrrolidone; (iv) about 0.5% sodium laurylsulfate; (v) about 14.9% microcrystalline cellulose; (vi) about 0.2% fumed silica; and, (vii) less than about 0.2% magnesium stearate.

The invention pertains to dispersible tablets comprising as active ingredient 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid or pharmaceutically acceptable salt thereof in an amount of from 5 to 40% in weight by weight of the total tablet.1-15. (canceled) 16. A dispersible tablet comprising deferasirox or a pharmaceutically acceptable salt thereof in an amount selected from the group consisting of about 125 mg, about 250 mg, and about 500 mg, wherein the tablet exhibits a disintegration time of less than 5 minutes when measured by a standard USP disintegration test; and, wherein the tablet further comprises, (i) at least one filler in a total amount of about 35 to 55% by weight based on total weight of the tablet; (ii) at least one disintegrant in a total amount of about 5 to 40% by weight based on the total weight of the tablet; (iii) at least one binder in a total amount of about 1 to 10% by weight based on the total weight of the tablet; (iv) at least one surfactant in a total amount of about 0.1 to 2% by weight based on the total weight of the tablet; (v) at least one glidant in a total amount of about 0.1 to 5% by weight based on the total weight of the tablet; and, (vi) at least one lubricant in a total amount of less than about 1% by weight based on the total weight of the tablet. 17. A tablet according to claim 16 wherein, (i) filler is selected from the group consisting essentially of lactose, ethylcellulose, and microcrystalline cellulose; (ii) disintegrant is selected from the group consisting essentially of cross-linked polyvinylpyrrolidone, starch, CMC-Ca, CMC-Na, microcrystalline cellulose, alginic acid, sodium alginate, and guar gum; (iii) binder is selected from the group consisting essentially of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, microcrystalline cellulose, and starch; (iv) surfactant is selected from the group consisting essentially of sodium laurylsulfate, betain, quaternary ammonium salt, polysorbate, sorbitan erter, and poloxamer; (v) glidant is selected from the group consisting essentially of silica, colloidal silica, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, and talc; and, (vi) lubricant is selected from the group consisting essentially of magnesium stearate, aluminum stearate, calcium stearate, polyoxyethylene glycol, talc, sodium benzoate, glyceryl mono fatty acid, glyceryl monostearate, glyceryl dibehenate, glyceryl palmito-stearic ester, hydrogenated cotton seed oil, and castor seed oil. 18. A tablet according to claim 17 wherein the tablet comprises, (i) about 125 mg deferasirox or a pharmaceutically acceptable salt thereof; (ii) at least one filler in a total amount of about 40 to 50%; (iii) at least one disintegrant in a total amount of about 10 to 35%; (iv) at least one binder in a total amount of about 1.5 to 5%; (v) at least one surfactant in a total amount of about 0.2 to 1%; (vi) at least one glidant in a total amount of about 0.1 to 2.5%; and, (vii) at least one lubricant in a total amount of less than about 0.5%. 19. A tablet according to claim 17 wherein the tablet comprises, (i) about 250 mg deferasirox or a pharmaceutically acceptable salt thereof; (ii) at least one filler in a total amount of about 40 to 50%; (iii) at least one disintegrant in a total amount of about 10 to 35%; (iv) at least one binder in a total amount of about 1.5 to 5%; (v) at least one surfactant in a total amount of about 0.2 to 1%; (vi) at least one glidant in a total amount of about 0.1 to 2.5%; and, (vii) at least one lubricant in a total amount of less than about 0.5%. 20. A tablet according to claim 17 wherein the tablet comprises, (i) about 500 mg deferasirox or a pharmaceutically acceptable salt thereof; (ii) at least one filler in a total amount of about 40 to 50%; (iii) at least one disintegrant in a total amount of about 10 to 35%; (iv) at least one binder in a total amount of about 1.5 to 5%; (v) at least one surfactant in a total amount of about 0.2 to 1%; (vi) at least one glidant in a total amount of about 0.1 to 2.5%; and, (vii) at least one lubricant in a total amount of less than about 0.5%. 21. A tablet according to claim 18 wherein the tablet comprises, (i) about 17% lactose; (ii) about 15% cross-linked polyvinylpyrrolidone; (iii) about 3% polyvinylpyrrolidone; (iv) about 0.5% sodium laurylsulfate; (v) about 5% further cross-linked polyvinylpyrrolidone; (vi) about 14.9% microcrystalline cellulose; (vii) about 14.9% further lactose; (viii) about 0.2% fumed silica; and, (ix) less than about 0.2% magnesium stearate. 22. A tablet according to claim 19 wherein the tablet comprises, (i) about 17% lactose; (ii) about 15% cross-linked polyvinylpyrrolidone; (iii) about 3% polyvinylpyrrolidone; (iv) about 0.5% sodium laurylsulfate; (v) about 5% further cross-linked polyvinylpyrrolidone; (vi) about 14.9% microcrystalline cellulose; (vii) about 14.9% further lactose; (viii) about 0.2% fumed silica; and, (ix) less than about 0.2% magnesium stearate. 23. A tablet according to claim 20 wherein the tablet comprises, (i) about 17% lactose; (ii) about 15% cross-linked polyvinylpyrrolidone; (iii) about 3% polyvinylpyrrolidone; (iv) about 0.5% sodium laurylsulfate; (v) about 5% further cross-linked polyvinylpyrrolidone; (vi) about 14.9% microcrystalline cellulose; (vii) about 14.9% further lactose; (viii) about 0.2% fumed silica; and, (ix) less than about 0.2% magnesium stearate. 24. A tablet according to claim 21 wherein the tablet comprises, (i) about 31.9% lactose; (ii) about 20% cross-linked polyvinylpyrrolidone; (iii) about 3% polyvinylpyrrolidone; (iv) about 0.5% sodium laurylsulfate; (v) about 14.9% microcrystalline cellulose; (vi) about 0.2% fumed silica; and, (vii) less than about 0.2% magnesium stearate. 25. A tablet according to claim 22 wherein the tablet comprises, (i) about 31.9% lactose; (ii) about 20% cross-linked polyvinylpyrrolidone; (iii) about 3% polyvinylpyrrolidone; (iv) about 0.5% sodium laurylsulfate; (v) about 14.9% microcrystalline cellulose; (vi) about 0.2% fumed silica; and, (vii) less than about 0.2% magnesium stearate. 26. A tablet according to claim 23 wherein the tablet comprises, (i) about 31.9% lactose; (ii) about 20% cross-linked polyvinylpyrrolidone; (iii) about 3% polyvinylpyrrolidone; (iv) about 0.5% sodium laurylsulfate; (v) about 14.9% microcrystalline cellulose; (vi) about 0.2% fumed silica; and, (vii) less than about 0.2% magnesium stearate.

We describe a particle secreted by a mesenchymal stem cell and comprising at least one biological property of a mesenchymal stem cell. The biological property may comprise a biological activity of a mesenchymal stem cell conditioned medium (MSC-CM) such as cardioprotection or reduction of infarct size. The particle may comprise a vesicle or an exosome.

1. A method of promoting wound healing, the method comprising administering to an individual in need thereof a pharmaceutical composition comprising an exosome derived from a mesenchymal stem cell (MSC). 2. The method of claim 1, in which the pharmaceutical composition comprises a pharmaceutically acceptable carrier. 3. The method of claim 1, in which the pharmaceutical composition is injected. 4. The method of claim 1, in which the exosome: (a) has a size of between 50 nm and 100 nm as determined by electron microscopy; (b) comprises a complex of molecular weight >100 kDa, comprising proteins of <100 kDa; (c) comprises a complex of molecular weight >300 kDa, comprising proteins of <300 kDa; (d) comprises a complex of molecular weight >1000 kDa; (e) has a size of between 2 nm and 200 nm, as determined by filtration against a 0.2 pM filter and concentration against a membrane with a molecular weight cut-off of 10 kDa; or (f) a hydrodynamic radius of below 100 nm, as determined by laser diffraction or dynamic light scattering.

We describe a particle secreted by a mesenchymal stem cell and comprising at least one biological property of a mesenchymal stem cell. The biological property may comprise a biological activity of a mesenchymal stem cell conditioned medium (MSC-CM) such as cardioprotection or reduction of infarct size. The particle may comprise a vesicle or an exosome.1. A method of promoting wound healing, the method comprising administering to an individual in need thereof a pharmaceutical composition comprising an exosome derived from a mesenchymal stem cell (MSC). 2. The method of claim 1, in which the pharmaceutical composition comprises a pharmaceutically acceptable carrier. 3. The method of claim 1, in which the pharmaceutical composition is injected. 4. The method of claim 1, in which the exosome: (a) has a size of between 50 nm and 100 nm as determined by electron microscopy; (b) comprises a complex of molecular weight >100 kDa, comprising proteins of <100 kDa; (c) comprises a complex of molecular weight >300 kDa, comprising proteins of <300 kDa; (d) comprises a complex of molecular weight >1000 kDa; (e) has a size of between 2 nm and 200 nm, as determined by filtration against a 0.2 pM filter and concentration against a membrane with a molecular weight cut-off of 10 kDa; or (f) a hydrodynamic radius of below 100 nm, as determined by laser diffraction or dynamic light scattering.

New combined therapeutic regimens for treatment of B-cell lymphomas are disclosed which comprise, in particular, administration of anti-CD20 antibodies to patients having low-, intermediate- or high-grade non-Hodgkin's lymphomas.

1. A method of extending median time to progression for responders by at least 13 months in patients with relapsed or refractory, low grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma, comprising administering four doses of 375 mg/m2 of rituximab to the patients. 2. A method according to claim 1, wherein the patients exhibit an overall response rate to the administration of about 48%. 3. A method of treating relapsed or refractory, low-grade or follicular non-Hodgkin's lymphoma in a human patient comprising administering to the patient four weekly infusions of rituximab, each at a dose of 375 mg/m2, wherein the initial infusion rate for the first dose is 50 mg/h, with a subsequent infusion rate increase if no toxicity is seen in the patient, and wherein the second, third, and fourth doses are administered at an infusion rate of more than 50 mg/h. 4. The method of claim 3, wherein the infusion is interrupted if an infusion-related toxicity reaction is seen in the patient. 5. The method of claim 4, wherein the infusion is resumed once the infusion-related toxicity reaction subsides.

New combined therapeutic regimens for treatment of B-cell lymphomas are disclosed which comprise, in particular, administration of anti-CD20 antibodies to patients having low-, intermediate- or high-grade non-Hodgkin's lymphomas.1. A method of extending median time to progression for responders by at least 13 months in patients with relapsed or refractory, low grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma, comprising administering four doses of 375 mg/m2 of rituximab to the patients. 2. A method according to claim 1, wherein the patients exhibit an overall response rate to the administration of about 48%. 3. A method of treating relapsed or refractory, low-grade or follicular non-Hodgkin's lymphoma in a human patient comprising administering to the patient four weekly infusions of rituximab, each at a dose of 375 mg/m2, wherein the initial infusion rate for the first dose is 50 mg/h, with a subsequent infusion rate increase if no toxicity is seen in the patient, and wherein the second, third, and fourth doses are administered at an infusion rate of more than 50 mg/h. 4. The method of claim 3, wherein the infusion is interrupted if an infusion-related toxicity reaction is seen in the patient. 5. The method of claim 4, wherein the infusion is resumed once the infusion-related toxicity reaction subsides.

The present disclosure provides a liposome for delivering an extracellular matrix, a method for promoting cell growth, and a method for preparing a liposome for delivering an extracellular matrix. According to the present disclosure, the liposome for delivering an extracellular matrix promotes cell attachment and growth, and through this matter, the liposome for delivering an extracellular matrix can be applied to cell or tissue regeneration.

1. A liposome for delivering an extracellular matrix, the liposome comprising: (a) a phospholipid membrane having an anionic lipid and a neutral lipid, which are self-assembled; and (b) an extracellular matrix bound to the anionic lipid by ionic boding to be disposed on a surface of the anionic lipid. 2. The liposome of claim 1, wherein the anionic lipid is at least one selected from the group consisting of dioleoyl phosphatidylserine (DOPS), dimyristoyl-phosphatidyl glycerol (DMPG), dipalmitoyl-phosphatidyl glycerol (DPPG), diethylenetriamine pentaacetic acid (DPTA), 1,4-dipalmitoyl-tartarate-2,3-diglutaric acid (DPTGA), 1,4-disteroyl-tartarate-2,3-disuccinic acid (DSTSA), 2-carboxyheptadecanoyl heptadecylamide (CHHDA), dimyristoylphosphatidylserin (DMPS), dipalmitoylphosphatidylserin (DPPS), palmitoyl-oleoylphosphatidylserin (POPS), dioleoylphosphatidylglycerol (DOPG), palmitoyl-oleoylphosphatidylglycerol (POPG), dimyristoylphosphatidic acid (DMPA), dipalmitoylphosphatidic acid (DPPA), dioleoylphosphatidic acid (DOPA), palmitoyl-oleoylphosphatidic acid (POPA), cetyl phosphate (CetylP), and cholesterol hemisuccinate (CHEMS). 3. The liposome of claim 1, wherein the neutral lipid is at least one selected from the group consisting of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), cholesterol, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), N-palmitoyl-D-erythro-sphingosylphosphorylcholine (SM), 1,2-dilauroyl-sn-glycero-3-phosphoethanolamine (DLPE), 2-diphytanoyl-sn-glycero-3-phosphoethanolamine (DiPPE), cholesterol, phosphatidyl choline, phosphatidyl ethanolamine, tetraether lipid, ceramide, sphigolipid, diacryl glycerol, and glyceride. 4. The liposome of claim 1, wherein the liposome comprises 1-30 mole % of the anionic lipid. 5. The liposome of claim 1, wherein the extracellular matrix is at least one selected from the group consisting of fibronectin, collagen, laminin, elastin, integrin, and glycosaminoglycan. 6. The liposome of claim 1, wherein the liposome is composed of DOPC: POPE: DOPS: cholesterol. 7. The liposome of claim 1, wherein the liposome has a size of 10 nm to 500 nm. 8. The liposome of claim 1, wherein the extracellular matrix is at least one selected from the group consisting of fibronectin, collagen, laminin, elastin, integrin, and glycosaminoglycan, wherein the liposome is composed of DOPC: POPE: DOPS: cholesterol, and wherein the liposome has a size of 10 nm to 500 nm. 9. A pharmaceutical composition comprising a pharmaceutically effective amount of the liposome for delivering an extracellular matrix of claim 1, and a pharmaceutically acceptable carrier. 10. The pharmaceutical composition of claim 9, wherein the extracellular matrix is at least one selected from the group consisting of fibronectin, collagen, laminin, elastin, integrin, and glycosaminoglycan, wherein the liposome is composed of DOPC: POPE: DOPS: cholesterol, and wherein the liposome has a size of 10 nm to 500 nm. 11. A cosmetic composition comprising a cosmetically effective amount of the liposome for delivering an extracellular matrix of claim 1, and a cosmetically acceptable carrier. 12. A method for promoting cell growth, the method comprising: bringing the liposome for delivering an extracellular matrix of claim 1 into contact with animal cells. 13. A method for preparing a liposome for delivering an extracellular matrix, the method comprising: (a) preparing an anionic liposome by dissolving an anionic lipid and a neutral lipid in an organic solvent; and (b) binding an extracellular matrix to a surface of the anionic liposome.

The present disclosure provides a liposome for delivering an extracellular matrix, a method for promoting cell growth, and a method for preparing a liposome for delivering an extracellular matrix. According to the present disclosure, the liposome for delivering an extracellular matrix promotes cell attachment and growth, and through this matter, the liposome for delivering an extracellular matrix can be applied to cell or tissue regeneration.1. A liposome for delivering an extracellular matrix, the liposome comprising: (a) a phospholipid membrane having an anionic lipid and a neutral lipid, which are self-assembled; and (b) an extracellular matrix bound to the anionic lipid by ionic boding to be disposed on a surface of the anionic lipid. 2. The liposome of claim 1, wherein the anionic lipid is at least one selected from the group consisting of dioleoyl phosphatidylserine (DOPS), dimyristoyl-phosphatidyl glycerol (DMPG), dipalmitoyl-phosphatidyl glycerol (DPPG), diethylenetriamine pentaacetic acid (DPTA), 1,4-dipalmitoyl-tartarate-2,3-diglutaric acid (DPTGA), 1,4-disteroyl-tartarate-2,3-disuccinic acid (DSTSA), 2-carboxyheptadecanoyl heptadecylamide (CHHDA), dimyristoylphosphatidylserin (DMPS), dipalmitoylphosphatidylserin (DPPS), palmitoyl-oleoylphosphatidylserin (POPS), dioleoylphosphatidylglycerol (DOPG), palmitoyl-oleoylphosphatidylglycerol (POPG), dimyristoylphosphatidic acid (DMPA), dipalmitoylphosphatidic acid (DPPA), dioleoylphosphatidic acid (DOPA), palmitoyl-oleoylphosphatidic acid (POPA), cetyl phosphate (CetylP), and cholesterol hemisuccinate (CHEMS). 3. The liposome of claim 1, wherein the neutral lipid is at least one selected from the group consisting of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), cholesterol, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), N-palmitoyl-D-erythro-sphingosylphosphorylcholine (SM), 1,2-dilauroyl-sn-glycero-3-phosphoethanolamine (DLPE), 2-diphytanoyl-sn-glycero-3-phosphoethanolamine (DiPPE), cholesterol, phosphatidyl choline, phosphatidyl ethanolamine, tetraether lipid, ceramide, sphigolipid, diacryl glycerol, and glyceride. 4. The liposome of claim 1, wherein the liposome comprises 1-30 mole % of the anionic lipid. 5. The liposome of claim 1, wherein the extracellular matrix is at least one selected from the group consisting of fibronectin, collagen, laminin, elastin, integrin, and glycosaminoglycan. 6. The liposome of claim 1, wherein the liposome is composed of DOPC: POPE: DOPS: cholesterol. 7. The liposome of claim 1, wherein the liposome has a size of 10 nm to 500 nm. 8. The liposome of claim 1, wherein the extracellular matrix is at least one selected from the group consisting of fibronectin, collagen, laminin, elastin, integrin, and glycosaminoglycan, wherein the liposome is composed of DOPC: POPE: DOPS: cholesterol, and wherein the liposome has a size of 10 nm to 500 nm. 9. A pharmaceutical composition comprising a pharmaceutically effective amount of the liposome for delivering an extracellular matrix of claim 1, and a pharmaceutically acceptable carrier. 10. The pharmaceutical composition of claim 9, wherein the extracellular matrix is at least one selected from the group consisting of fibronectin, collagen, laminin, elastin, integrin, and glycosaminoglycan, wherein the liposome is composed of DOPC: POPE: DOPS: cholesterol, and wherein the liposome has a size of 10 nm to 500 nm. 11. A cosmetic composition comprising a cosmetically effective amount of the liposome for delivering an extracellular matrix of claim 1, and a cosmetically acceptable carrier. 12. A method for promoting cell growth, the method comprising: bringing the liposome for delivering an extracellular matrix of claim 1 into contact with animal cells. 13. A method for preparing a liposome for delivering an extracellular matrix, the method comprising: (a) preparing an anionic liposome by dissolving an anionic lipid and a neutral lipid in an organic solvent; and (b) binding an extracellular matrix to a surface of the anionic liposome.

A method is provided for treating a subject in need of therapy for depression, anxiety, impaired cognition and/or pain comprising administering to said subject an amount of a ketogenic material sufficient to produce a ketosis in the subject sufficient to provide anti-depressant effect, cognition enhancing and/or analgesic effect. Preferred materials produce a ketosis is such that the total concentration of acetoacetate and (R)-3-hydroxybutyrate in the blood of the subject is raised to between 0.1 and 30 mM.

1-8. (canceled) 9. A method of treating a subject in need of therapy for depression and/or anxiety, comprising orally administering to said subject 5 to 5000 mg/kg body weight per day of a material selected from the group consisting of (R)-3-hydroxybutyrate, its salts, oligomers of (R)-3-hydroxybutyrate and esters of (R)-3-hydroxybutyrate with glycerol or (R)-1,3-butandiol sufficient to produce a ketosis in the subject sufficient to provide an anti-depressant effect and/or an anxiolytic effect, wherein the total concentration of acetoacetate and (R)-3-hydroxybutyrate in the blood is raised to between 1 and 10 mM.) 10. A method as claimed in claim 9 wherein the total concentration of acetoacetate and (R)-3-hydroxybutyrate in the blood is raised to between 3 and 8 mM. 11. Use of a ketogenic material for the manufacture of a medicament for the treatment of depression, anxiety, cognitive impairment and/or pain.) 12. A method as claimed in claim 9 wherein the ketogenic material is selected from the group consisting of triglycerides, free fatty acids, alcohols, acetoacetate and (R)-3-hydroxybutyrate and their conjugates with each other and further moieties. 13. A pharmaceutical composition for treating depression, anxiety, impaired cognition and/or pain comprising as active ingredient a ketogenic material. 14. A method as claimed in claim 12 wherein the alcohol is butan-1,3-diol and the further moieties are esters and polymers. 15. A method as claimed in claim 9 wherein the treatment is for a disorder selected from the group consisting of schizoaffective disorder, obsessive-compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder and post-traumatic stress disorder.

A method is provided for treating a subject in need of therapy for depression, anxiety, impaired cognition and/or pain comprising administering to said subject an amount of a ketogenic material sufficient to produce a ketosis in the subject sufficient to provide anti-depressant effect, cognition enhancing and/or analgesic effect. Preferred materials produce a ketosis is such that the total concentration of acetoacetate and (R)-3-hydroxybutyrate in the blood of the subject is raised to between 0.1 and 30 mM.1-8. (canceled) 9. A method of treating a subject in need of therapy for depression and/or anxiety, comprising orally administering to said subject 5 to 5000 mg/kg body weight per day of a material selected from the group consisting of (R)-3-hydroxybutyrate, its salts, oligomers of (R)-3-hydroxybutyrate and esters of (R)-3-hydroxybutyrate with glycerol or (R)-1,3-butandiol sufficient to produce a ketosis in the subject sufficient to provide an anti-depressant effect and/or an anxiolytic effect, wherein the total concentration of acetoacetate and (R)-3-hydroxybutyrate in the blood is raised to between 1 and 10 mM.) 10. A method as claimed in claim 9 wherein the total concentration of acetoacetate and (R)-3-hydroxybutyrate in the blood is raised to between 3 and 8 mM. 11. Use of a ketogenic material for the manufacture of a medicament for the treatment of depression, anxiety, cognitive impairment and/or pain.) 12. A method as claimed in claim 9 wherein the ketogenic material is selected from the group consisting of triglycerides, free fatty acids, alcohols, acetoacetate and (R)-3-hydroxybutyrate and their conjugates with each other and further moieties. 13. A pharmaceutical composition for treating depression, anxiety, impaired cognition and/or pain comprising as active ingredient a ketogenic material. 14. A method as claimed in claim 12 wherein the alcohol is butan-1,3-diol and the further moieties are esters and polymers. 15. A method as claimed in claim 9 wherein the treatment is for a disorder selected from the group consisting of schizoaffective disorder, obsessive-compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder and post-traumatic stress disorder.

Model systems and methods for exploring mechanisms of carcinogenesis and the acquisition of metastatic ability, and to provide insights into potential therapeutic targets. The systems include and methods involve fusion of a stem cell and a genetically altered cell to evaluate carcinogenesis and metastasis and for the discovery and evaluation of new therapeutic targets to inhibit metastasis and other markers of carcinogenesis.

1. A composition comprising, an antibody against ubiquitin in a pharmaceutically acceptable carrier and one or more tumor cells. 2. The composition of claim 1, wherein said antibody against ubiquitin is present in an amount of between approximately 5 μg/ml/million tumor cells to 180 μg/ml/million tumor cells. 3. The composition of claim 1, wherein said tumor cells are from a carcinoma or carcinoma cell line. 4. The composition of claim 3, wherein said carcinoma cell is selected from the group consisting of breast, prostate, and skin cells. 5. A composition comprising about 4 mg of an antibody against ubiquitin in a pharmaceutically acceptable carrier per kilogram of body weight. 6. In a syringe, a dosage of an antibody against ubiquitin in a pharmaceutically acceptable carrier for intravenous administration, wherein said dosage comprises about 4 mg of antibody per kilogram of body weight of a mammal.

Model systems and methods for exploring mechanisms of carcinogenesis and the acquisition of metastatic ability, and to provide insights into potential therapeutic targets. The systems include and methods involve fusion of a stem cell and a genetically altered cell to evaluate carcinogenesis and metastasis and for the discovery and evaluation of new therapeutic targets to inhibit metastasis and other markers of carcinogenesis.1. A composition comprising, an antibody against ubiquitin in a pharmaceutically acceptable carrier and one or more tumor cells. 2. The composition of claim 1, wherein said antibody against ubiquitin is present in an amount of between approximately 5 μg/ml/million tumor cells to 180 μg/ml/million tumor cells. 3. The composition of claim 1, wherein said tumor cells are from a carcinoma or carcinoma cell line. 4. The composition of claim 3, wherein said carcinoma cell is selected from the group consisting of breast, prostate, and skin cells. 5. A composition comprising about 4 mg of an antibody against ubiquitin in a pharmaceutically acceptable carrier per kilogram of body weight. 6. In a syringe, a dosage of an antibody against ubiquitin in a pharmaceutically acceptable carrier for intravenous administration, wherein said dosage comprises about 4 mg of antibody per kilogram of body weight of a mammal.

A high-volume gene therapy vector manufacturing process which produces a recombinant gene therapy vector which is able to transform host cells even when they are not dividing.

1. A method comprising: a. Transducing a mammalian cell with a baculovirus to make a transduced mammalian producer cell; and then b. Culturing said transduced mammalian producer cell in culture media, and harvesting from said transduced mammalian producer cell and/or culture media a second virus having a therapeutic transgene. 2. The method of claim 1, wherein said harvesting comprises harvesting at about 144 hours after said transduction. 3. The method of claim 1, wherein said second virus is derived from a virus which in its wild state has a single-stranded genome. 4. The method of claim 1, wherein said second virus is able to transduce a human cell which is not actively dividing. 5. The method of claim 1, wherein said second virus is replication deficient. 6. The method of claim 1, wherein said second virus can integrate in host genome at specific site and can produce stable long-term expression. 7. The method of claim 1, wherein said second virus is non-immunogenic. 8. A recombinant baculovirus having at least one nucleic acid sequence coding for a second virus derived from a virus which in its wild state has a single stranded genome, said second virus being replication-deficient and having a therapeutic transgene. 9. The recombinant baculovirus of claim 8, wherein said second virus is able to transduce a human cell which is not actively dividing. 10. The recombinant baculovirus of claim 8, wherein said second virus can integrate in the human genome and can produce stable long-term expression in a transduced human cell. 11. A method comprising: a. Obtaining the recombinant baculovirus of claim 8; and then b. Transducing a mammalian producer cell with said recombinant baculovirus to make a transduced mammalian producer cell; and then c. Culturing said transduced mammalian producer cell in culture media, and harvesting said second virus from said transduced mammalian producer cell and/or culture media. 12. A viral vector able to transfect a human cell which is not actively dividing, said viral vector produced by a mammalian producer cell transduced with a recombinant baculovirus. 13. The viral vector of claim 12, wherein said viral vector has a therapeutic transgene. 14. The viral vector of claim 12, said viral vector comprises virus derived from a virus which in its wild state has a single stranded genome. 15. A method comprising: a. Obtaining the viral vector of claim 12; and b. Transducing a human patient's cells with said viral vector. 16. A method comprising: a. Obtaining the viral vector of claim 13; and b. Transducing a human patient's cells with said viral vector. 17. A method comprising: a. Obtaining the viral vector of claim 14; and b. Transducing a human patient's cells with said viral vector.

A high-volume gene therapy vector manufacturing process which produces a recombinant gene therapy vector which is able to transform host cells even when they are not dividing.1. A method comprising: a. Transducing a mammalian cell with a baculovirus to make a transduced mammalian producer cell; and then b. Culturing said transduced mammalian producer cell in culture media, and harvesting from said transduced mammalian producer cell and/or culture media a second virus having a therapeutic transgene. 2. The method of claim 1, wherein said harvesting comprises harvesting at about 144 hours after said transduction. 3. The method of claim 1, wherein said second virus is derived from a virus which in its wild state has a single-stranded genome. 4. The method of claim 1, wherein said second virus is able to transduce a human cell which is not actively dividing. 5. The method of claim 1, wherein said second virus is replication deficient. 6. The method of claim 1, wherein said second virus can integrate in host genome at specific site and can produce stable long-term expression. 7. The method of claim 1, wherein said second virus is non-immunogenic. 8. A recombinant baculovirus having at least one nucleic acid sequence coding for a second virus derived from a virus which in its wild state has a single stranded genome, said second virus being replication-deficient and having a therapeutic transgene. 9. The recombinant baculovirus of claim 8, wherein said second virus is able to transduce a human cell which is not actively dividing. 10. The recombinant baculovirus of claim 8, wherein said second virus can integrate in the human genome and can produce stable long-term expression in a transduced human cell. 11. A method comprising: a. Obtaining the recombinant baculovirus of claim 8; and then b. Transducing a mammalian producer cell with said recombinant baculovirus to make a transduced mammalian producer cell; and then c. Culturing said transduced mammalian producer cell in culture media, and harvesting said second virus from said transduced mammalian producer cell and/or culture media. 12. A viral vector able to transfect a human cell which is not actively dividing, said viral vector produced by a mammalian producer cell transduced with a recombinant baculovirus. 13. The viral vector of claim 12, wherein said viral vector has a therapeutic transgene. 14. The viral vector of claim 12, said viral vector comprises virus derived from a virus which in its wild state has a single stranded genome. 15. A method comprising: a. Obtaining the viral vector of claim 12; and b. Transducing a human patient's cells with said viral vector. 16. A method comprising: a. Obtaining the viral vector of claim 13; and b. Transducing a human patient's cells with said viral vector. 17. A method comprising: a. Obtaining the viral vector of claim 14; and b. Transducing a human patient's cells with said viral vector.

The present invention refers to a novel combination of nucleotide and cellular vaccine composition and pharmaceutical composition and use thereof for treating and/or preventing diseases, including infectious diseases, cancer, autoimmune diseases, allergy, diabetes and blood disorders. The vaccine composition comprises a nucleotide sequence encoding an antigenic molecule and gene-modified antigen-presenting cells (APCs), preferably provided as an intermixture. The APCs are modified to express immune modulating molecules. Immunization with the vaccine composition of present invention into a subject, induces the host immune system to respond and generate efficient immunity against either pre-existing disease or protect the host against the disease.

1.-43. (canceled) 44. A nucleotide vaccine composition comprising a mixture of: nucleotide sequence encoding an antigen; and antigen-presenting cells modified for expression of at least one of an immune response modulating molecule and a cell-survival modulating molecule. 45. The vaccine composition according to claim 44, wherein said vaccine composition is provided as pre-incubated mixture of said nucleotide sequence and said modified antigen-presenting cells. 46. The vaccine composition according to claim 44 wherein said antigen-presenting cells are professional antigen-presenting cells. 47. The vaccine composition according to claim 44, wherein said professional antigen-presenting cells are a subclass of dendritic cells. 48. The vaccine composition according to claim 47, wherein said subclass of dendritic cells are plasmacytoid dendritic cells. 49. The vaccine composition according to claim 47, wherein said subclass of dendritic cells are human equivalents to a subclass of dendritic cells that express CD8α, B220, CD11C and B7 molecules in mice. 50. The vaccine composition according to claim 44, wherein said antigen-presenting cells express Toll-like receptor and P2 receptor. 51. The vaccine composition according to claim 44, wherein said antigen-presenting cells can be induced to produce type I interferon-alpha and/or interferon-beta. 52. The vaccine composition according to claim 51, wherein said antigen-presenting cells produce said type I interferon-alpha and/or interferon-beta when interacting with microbes and said nucleotide sequence. 53. The vaccine composition according to claim 44, wherein said antigen-presenting cells are selected from at least one of: natural-interferon producing cells; monocytes; macrophages; bone marrow derived cells; cells differentiated from stem cells B cells; T cells; and Mast cells. 54. The vaccine composition according to claim 44, wherein said immune response modulating molecule is encoded by a nucleotide sequence engineered into said antigen-presenting cells, and said gene sequence is selected from at least one of: cytokine gene; Interleukin gene; adhesion molecule gene; interferon gene; and chemokine and chemokine receptor gene. 55. The vaccine composition according to claim 54, wherein said immune response modulating molecule is selected from at least one of CD40 ligand and GM-CSF. 56. The vaccine composition according to claim 44, wherein said cell-survival modulating molecule is encoded by a nucleotide sequence engineered into said antigen-presenting cells, said gene sequence is selected from at least one of: anti-apoptosis gene; and apoptosis inducing gene; 57. The vaccine composition according to claim 44, wherein said nucleotide sequence is provided in a vector selected from at least one of: virus vector; non-viral vector; plasmid; microbe-derived vector liposome; and small molecule carrier. 58. The vaccine composition according to claim 57, wherein said vector comprises an immune response modulating nucleotide sequence. 59. The vaccine composition according to claim 58, wherein said immune response modulating nucleotide sequence is an unmethylated cytidine phosphate guanosine (CpG) sequence. 60. The vaccine composition according to claim 44, further comprising an immune response modulating nucleotide sequence. 61. The vaccine composition according to claim 60, wherein said immune response modulating nucleotide sequence is an unmethylated cytidine phosphate guanosine (CpG) sequence. 62. The vaccine composition according to claim 44, wherein said antigen comprises at least one of the mini-e1a2 fusion protein of SEQ ID NO: 4, the e1a2 fusion peptide of SEQ ID NO: 5, and an amino acid sequence encoded by the mini-e1a2 fusion gene of SEQ ID NO: 3. 63. A method of producing a nucleotide and cellular vaccine composition comprising the steps of: providing nucleotide sequence encoding an antigen; providing antigen-presenting cells modified for expression of at least one of an immune response modulating molecule and a cell-survival modulating molecule; and mixing said nucleotide sequence encoding said antigen and said modified antigen-presenting cells. 64. The method according to claim 63, further comprising the step of pre-incubating said nucleotide sequence with said modified antigen-presenting cells for enhancing their binding and interaction. 65. The method according to claim 63, wherein said nucleotide sequence providing step comprises the steps of: providing a MHC-binding antigenic protein or peptide; cloning said nucleotide sequence encoding said antigenic protein or said antigenic peptide into a said vector; and propagating said vector in a propagation system. 66. The method according to claim 63, wherein said antigen-presenting cells providing step comprises the steps of: isolating said antigen presenting cells from a subject; and engineering said antigen-presenting cells to express at least one of said immune response modulating molecule and said cell-survival modulating molecule. 67. The method according to claim 66, wherein said isolating step comprises the step of isolating a subclass of dendritic cells that expresses Toll-like receptor and has the ability to produce Interferon alpha and/or Interferon beta. 68. The method according to claim 67, wherein said subclass of dendritic cells are plasmocytoid dendritic cells. 69. A method of producing an immune response comprising the step of administering the vaccine composition according to claim 44. 70. A method of treating or preventing a disease in a subject comprising the step of administering to said subject a vaccine composition according to claim 44, said antigen being associated with an agent involved in said disease. 71. The method according to claim 70, wherein said subject is a mammalian subject. 72. The method according to claim 70, wherein said disease is selected from at least one of: infectious disease; cancer; leukemia; lymphoma; autoimmune disease/disorder; inflammation; blood disease; allergy; inherited disease; transplantation required disease; and diabetes. 73. A kit comprising nucleotide sequence encoding an antigen and antigen-presenting cells modified for expression of an immune response modulating molecule, provided or used as an inter-mixture. 74. The kit according to claim 73, further comprising an immune response modulating sequence.

The present invention refers to a novel combination of nucleotide and cellular vaccine composition and pharmaceutical composition and use thereof for treating and/or preventing diseases, including infectious diseases, cancer, autoimmune diseases, allergy, diabetes and blood disorders. The vaccine composition comprises a nucleotide sequence encoding an antigenic molecule and gene-modified antigen-presenting cells (APCs), preferably provided as an intermixture. The APCs are modified to express immune modulating molecules. Immunization with the vaccine composition of present invention into a subject, induces the host immune system to respond and generate efficient immunity against either pre-existing disease or protect the host against the disease.1.-43. (canceled) 44. A nucleotide vaccine composition comprising a mixture of: nucleotide sequence encoding an antigen; and antigen-presenting cells modified for expression of at least one of an immune response modulating molecule and a cell-survival modulating molecule. 45. The vaccine composition according to claim 44, wherein said vaccine composition is provided as pre-incubated mixture of said nucleotide sequence and said modified antigen-presenting cells. 46. The vaccine composition according to claim 44 wherein said antigen-presenting cells are professional antigen-presenting cells. 47. The vaccine composition according to claim 44, wherein said professional antigen-presenting cells are a subclass of dendritic cells. 48. The vaccine composition according to claim 47, wherein said subclass of dendritic cells are plasmacytoid dendritic cells. 49. The vaccine composition according to claim 47, wherein said subclass of dendritic cells are human equivalents to a subclass of dendritic cells that express CD8α, B220, CD11C and B7 molecules in mice. 50. The vaccine composition according to claim 44, wherein said antigen-presenting cells express Toll-like receptor and P2 receptor. 51. The vaccine composition according to claim 44, wherein said antigen-presenting cells can be induced to produce type I interferon-alpha and/or interferon-beta. 52. The vaccine composition according to claim 51, wherein said antigen-presenting cells produce said type I interferon-alpha and/or interferon-beta when interacting with microbes and said nucleotide sequence. 53. The vaccine composition according to claim 44, wherein said antigen-presenting cells are selected from at least one of: natural-interferon producing cells; monocytes; macrophages; bone marrow derived cells; cells differentiated from stem cells B cells; T cells; and Mast cells. 54. The vaccine composition according to claim 44, wherein said immune response modulating molecule is encoded by a nucleotide sequence engineered into said antigen-presenting cells, and said gene sequence is selected from at least one of: cytokine gene; Interleukin gene; adhesion molecule gene; interferon gene; and chemokine and chemokine receptor gene. 55. The vaccine composition according to claim 54, wherein said immune response modulating molecule is selected from at least one of CD40 ligand and GM-CSF. 56. The vaccine composition according to claim 44, wherein said cell-survival modulating molecule is encoded by a nucleotide sequence engineered into said antigen-presenting cells, said gene sequence is selected from at least one of: anti-apoptosis gene; and apoptosis inducing gene; 57. The vaccine composition according to claim 44, wherein said nucleotide sequence is provided in a vector selected from at least one of: virus vector; non-viral vector; plasmid; microbe-derived vector liposome; and small molecule carrier. 58. The vaccine composition according to claim 57, wherein said vector comprises an immune response modulating nucleotide sequence. 59. The vaccine composition according to claim 58, wherein said immune response modulating nucleotide sequence is an unmethylated cytidine phosphate guanosine (CpG) sequence. 60. The vaccine composition according to claim 44, further comprising an immune response modulating nucleotide sequence. 61. The vaccine composition according to claim 60, wherein said immune response modulating nucleotide sequence is an unmethylated cytidine phosphate guanosine (CpG) sequence. 62. The vaccine composition according to claim 44, wherein said antigen comprises at least one of the mini-e1a2 fusion protein of SEQ ID NO: 4, the e1a2 fusion peptide of SEQ ID NO: 5, and an amino acid sequence encoded by the mini-e1a2 fusion gene of SEQ ID NO: 3. 63. A method of producing a nucleotide and cellular vaccine composition comprising the steps of: providing nucleotide sequence encoding an antigen; providing antigen-presenting cells modified for expression of at least one of an immune response modulating molecule and a cell-survival modulating molecule; and mixing said nucleotide sequence encoding said antigen and said modified antigen-presenting cells. 64. The method according to claim 63, further comprising the step of pre-incubating said nucleotide sequence with said modified antigen-presenting cells for enhancing their binding and interaction. 65. The method according to claim 63, wherein said nucleotide sequence providing step comprises the steps of: providing a MHC-binding antigenic protein or peptide; cloning said nucleotide sequence encoding said antigenic protein or said antigenic peptide into a said vector; and propagating said vector in a propagation system. 66. The method according to claim 63, wherein said antigen-presenting cells providing step comprises the steps of: isolating said antigen presenting cells from a subject; and engineering said antigen-presenting cells to express at least one of said immune response modulating molecule and said cell-survival modulating molecule. 67. The method according to claim 66, wherein said isolating step comprises the step of isolating a subclass of dendritic cells that expresses Toll-like receptor and has the ability to produce Interferon alpha and/or Interferon beta. 68. The method according to claim 67, wherein said subclass of dendritic cells are plasmocytoid dendritic cells. 69. A method of producing an immune response comprising the step of administering the vaccine composition according to claim 44. 70. A method of treating or preventing a disease in a subject comprising the step of administering to said subject a vaccine composition according to claim 44, said antigen being associated with an agent involved in said disease. 71. The method according to claim 70, wherein said subject is a mammalian subject. 72. The method according to claim 70, wherein said disease is selected from at least one of: infectious disease; cancer; leukemia; lymphoma; autoimmune disease/disorder; inflammation; blood disease; allergy; inherited disease; transplantation required disease; and diabetes. 73. A kit comprising nucleotide sequence encoding an antigen and antigen-presenting cells modified for expression of an immune response modulating molecule, provided or used as an inter-mixture. 74. The kit according to claim 73, further comprising an immune response modulating sequence.

The invention relates to an implant having a base body, consisting completely or partially of a biocorrodible metallic material, such that it decomposes in an aqueous environment to form an alkaline product, and the base body has a coating or a cavity filling, comprising a polymer matrix and at least one drug embedded in the polymer matrix, characterized in that at least one polymer of the matrix and the at least one drug are coordinated so that the drug elution rate from the matrix is increased with an increase in pH.

1. An implant with a base body at least partially comprised of a biocorrodible metallic material, whereby the material is such that it decomposes in an aqueous environment to form an alkaline product and whereby the base body has one or more of a coating and a cavity filling comprising a polymer matrix and at least one drug embedded in the polymer matrix, characterized in that at least one polymer of the polymer matrix and the at least one drug are coordinated so that the drug elution rate from the polymer matrix is increased at an elevated pH. 2. The implant according to claim 1, wherein the implant is a stent. 3. The implant according to claim 1, wherein the biocorrodible metallic material is a magnesium alloy. 4. The implant according to claim 1, wherein the drug elution rate from the polymer matrix is increased at a pH above 8. 5. Implant according to claim 1, wherein the drug elution rate from the polymer matrix is at least twice as high when the pH is greater than 8 as compared to the rate when the pH is at the physiological pH. 6. The implant according to claim 1, wherein the polymer has at least one functional group which shows a transition between an ionic charge state and a neutral charge state when there is an increase in pH. 7. The implant according to claim 6, wherein the functional group is selected from the group comprising a carboxylic acid function, an amine function and an amide function. 8. The implant according to claim 1, wherein the polymer matrix comprises a hydrogel. 9. The implant according to claim 8, wherein the hydrogel is selected from the group comprising a polymer based on acrylic acid, methacrylic acid, a derivative of acrylic acids, and methacrylic acid. 10. The implant according to claim 1, wherein the implant has an additional outer coating containing a degradable polymer. 11. The implant according to claim 1, wherein the drug is a prodrug embedded in the polymer matrix. 12. The implant according to claim 11, wherein the drug is affixed in the polymer matrix by chemical bonds cleaved by base catalysis. 13. The implant according to claim 1, wherein the drug is selected from the group comprising vasodilators, anti-inflammatories and pH regulating drugs. 14. The implant according to claim 1, wherein the drug is selected from the group comprising NO-eluting substances and bosentan, dipyridamol, dODN, endothelin receptor antagonists, calcium channel blockers, amlodipine, nifidipine and verapamil. 15. A stent comprising: a base body at least partially comprised of a biocorrodible magnesium alloy that decomposes in an aqueous environment to form an alkaline product; the base body having one or more of a coating and a cavity filling comprising a hydrogel; at least one drug embedded in the hydrogel, the at least one drug and the hydrogel selected to result in the drug elution rate from the hydrogel being increased at an elevated pH; and, an outer coating containing a degradable polymer. 16. A stent comprising: a base body at least partially comprised of a biocorrodible magnesium alloy that decomposes in an aqueous environment to form an alkaline product; the base body having one or more of a coating and a cavity filling comprising a hydrogel, the hydrogel selected from the group comprising a polymer based on acrylic acid, methacrylic acid, a derivative of acrylic acid, and methacrylic acid; at least one drug embedded in the hydrogel, the at least one drug and the hydrogel selected to result in the drug elution rate from the hydrogel being increased at an elevated pH, the drug selected from the group comprising NO-eluting substances and bosentan, dipyridamol, dODN, endothelin receptor antagonists, calcium channel blockers, amlodipine, nifidipine and verapamil; and, an outer coating containing a degradable polymer.

The invention relates to an implant having a base body, consisting completely or partially of a biocorrodible metallic material, such that it decomposes in an aqueous environment to form an alkaline product, and the base body has a coating or a cavity filling, comprising a polymer matrix and at least one drug embedded in the polymer matrix, characterized in that at least one polymer of the matrix and the at least one drug are coordinated so that the drug elution rate from the matrix is increased with an increase in pH.1. An implant with a base body at least partially comprised of a biocorrodible metallic material, whereby the material is such that it decomposes in an aqueous environment to form an alkaline product and whereby the base body has one or more of a coating and a cavity filling comprising a polymer matrix and at least one drug embedded in the polymer matrix, characterized in that at least one polymer of the polymer matrix and the at least one drug are coordinated so that the drug elution rate from the polymer matrix is increased at an elevated pH. 2. The implant according to claim 1, wherein the implant is a stent. 3. The implant according to claim 1, wherein the biocorrodible metallic material is a magnesium alloy. 4. The implant according to claim 1, wherein the drug elution rate from the polymer matrix is increased at a pH above 8. 5. Implant according to claim 1, wherein the drug elution rate from the polymer matrix is at least twice as high when the pH is greater than 8 as compared to the rate when the pH is at the physiological pH. 6. The implant according to claim 1, wherein the polymer has at least one functional group which shows a transition between an ionic charge state and a neutral charge state when there is an increase in pH. 7. The implant according to claim 6, wherein the functional group is selected from the group comprising a carboxylic acid function, an amine function and an amide function. 8. The implant according to claim 1, wherein the polymer matrix comprises a hydrogel. 9. The implant according to claim 8, wherein the hydrogel is selected from the group comprising a polymer based on acrylic acid, methacrylic acid, a derivative of acrylic acids, and methacrylic acid. 10. The implant according to claim 1, wherein the implant has an additional outer coating containing a degradable polymer. 11. The implant according to claim 1, wherein the drug is a prodrug embedded in the polymer matrix. 12. The implant according to claim 11, wherein the drug is affixed in the polymer matrix by chemical bonds cleaved by base catalysis. 13. The implant according to claim 1, wherein the drug is selected from the group comprising vasodilators, anti-inflammatories and pH regulating drugs. 14. The implant according to claim 1, wherein the drug is selected from the group comprising NO-eluting substances and bosentan, dipyridamol, dODN, endothelin receptor antagonists, calcium channel blockers, amlodipine, nifidipine and verapamil. 15. A stent comprising: a base body at least partially comprised of a biocorrodible magnesium alloy that decomposes in an aqueous environment to form an alkaline product; the base body having one or more of a coating and a cavity filling comprising a hydrogel; at least one drug embedded in the hydrogel, the at least one drug and the hydrogel selected to result in the drug elution rate from the hydrogel being increased at an elevated pH; and, an outer coating containing a degradable polymer. 16. A stent comprising: a base body at least partially comprised of a biocorrodible magnesium alloy that decomposes in an aqueous environment to form an alkaline product; the base body having one or more of a coating and a cavity filling comprising a hydrogel, the hydrogel selected from the group comprising a polymer based on acrylic acid, methacrylic acid, a derivative of acrylic acid, and methacrylic acid; at least one drug embedded in the hydrogel, the at least one drug and the hydrogel selected to result in the drug elution rate from the hydrogel being increased at an elevated pH, the drug selected from the group comprising NO-eluting substances and bosentan, dipyridamol, dODN, endothelin receptor antagonists, calcium channel blockers, amlodipine, nifidipine and verapamil; and, an outer coating containing a degradable polymer.

Described herein are methods, devices, and compositions for providing personalized medicine tests for hematological neoplasms. In some embodiments, the methods comprise measuring the efficacy of inducing apoptosis selectively in malignant cells using any number of potential alternative combination drug treatments. In some embodiments, the ex vivo testing is measured using a recently extracted patient hematological samples. In other embodiments, the efficacy is measured ex vivo using an automated flow cytometry platform. For example, by using an automated flow cytometry platform, the evaluation of hundreds, or even thousands of drugs and compositions, can be made ex vivo. Thus, alternative polytherapy treatments can be explored. Non-cytotoxic drugs surprisingly induce apoptosis selectively in malignant cells ex vivo. In some embodiments, the methods described herein comprise evaluating non-cytotoxic drugs.

1.-55. (canceled) 56. A method for analyzing cellular responsiveness to drugs, comprising: a. obtaining a sample of whole blood, whole peripheral blood or whole bone marrow that has been withdrawn from a patient with a hematological neoplasm; b. dividing the whole sample into at least 35 aliquots; c. combining each of the at least 35 aliquots with a drug composition; and d. measuring apoptosis or cell depletion in each of the at least 35 aliquots by flow cytometry. 57. The method of claim 56, wherein at least two of the drug compositions comprise the same drug at different concentrations. 58. The method of claim 56, wherein at least one of the drug compositions comprises a plurality of drugs. 59. The method of claim 56, wherein at least one of the drug compositions comprises a plurality of drugs that are non-cytotoxic. 60. The method of claim 56, wherein at least one of the drug compositions comprises a non-cytotoxic drug that is the same as or in the same therapeutic category as a drug already being administered to the patient. 61. The method of claim 60, wherein at least one of the drug compositions combines a non-cytotoxic drug and a cytotoxic drug. 62. The method of claim 56, wherein the analysis is completed within 72 hours of combining the aliquots with a drug composition. 63. The method of claim 56, wherein the number of aliquots combined with a drug composition is at least 96. 64. The method of claim 56, wherein the whole sample comprises cells from a hematological neoplasm selected from the group consisting of chronic lymphocytic leukemia, adult acute lymphoblastic leukemia, pediatric acute lymphoblastic leukemia, multiple myeloma, myelodysplastic syndrome, non-M3 acute myeloblastic leukemia, acute myeloblastic leukemia M3, non-Hodgkin's lymphoma, Hodgkin's lymphoma, and chronic myeloid leukemia. 65. The method of claim 56, wherein the drug composition comprises a compound selected from the group consisting of 5-Azacitidine, alemtuzumab, aminopterin, Amonafide, Amsacrine, CAT-8015, Bevacizumab, ARR Y520, arsenic trioxide, AS1413, Atra, AZD 6244, AZD1152, Banoxantrone, Behenoylara-C, Bendamustine, Bleomycin, Blinatumomab, Bortezomib, Busulfan, carboplatin, CEP-701, Chlorambucil, Chloro Deoxiadenosine, Cladribine, clofarabine, CPX-351, Cyclophosphamide, Cyclosporine, Cytarabine, Cytosine Arabinoside, Dasatinib, Daunorubicin, decitabine, Deglycosylated-ricin-A chain-conjugated anti-CD19/anti-CD22 immunotoxins, Dexamethasone, Doxorubicine, Elacytarabine, entinostat, epratuzumab, Erwinase, Etoposide, everolimus, Exatecan mesilate, flavopiridol, fludarabine, forodesine, Gemcitabine, Gemtuzumab-ozogamicin, Homoharringtonine, Hydrocortisone, Hydroxycarbamide, Idarubicin, Ifosfamide, Imatinib, interferon alpha 2a, iodine 1131 monoclonal antibody BC8, Iphosphamide, isotretinoin, Laromustine, L-Asparaginase, Lenalidomide, Lestaurtinib, Maphosphamide, Melphalan, Mercaptopurine, Methotrexate, Methylprednisolone, Methylprednisone, Midostaurin, Mitoxantrone, Nelarabine, Nilotinib, Oblimersen, Paclitaxel, panobinostat, Pegaspargase, Pentostatin, Pirarubicin, PKC412, Prednisolone, Prednisone, PSC-833, Rapamycin, Rituximab, Rivabirin, Sapacitabine, Dinaciclib, Sorafenib, STA-9090, tacrolimus, tanespimycin, temsirolimus, Teniposide, Terameprocol, Thalidomide, Thioguanine, Thiotepa, Tipifarnib, Topotecan, Treosulfan, Troxacitabine, Vinblastine, Vincristine, Vindesine, Vinorelbine, Voreloxin, Vorinostat, Etoposide, Zosuquidar, and combinations thereof. 66. The method of claim 56, wherein the drug composition comprises a compound selected from the group consisting of Aluminum Oxide Hydrate, Lorazepam, Amikacine, Meropenem, Cefepime, Vancomycin, Teicoplanin, Ondansetron, Dexamethasone, Amphotericin B (liposomal), Caspofugin, Itraconazole, Fluconazole, Voriconazole, Trimetoprime, sulfamethoxazole, G-CSF, Ranitidine, Rasburicase, Paracetamol, Metamizole, Morphine chloride, Omeprazole, Paroxetine, Fluoxetine, Sertraline and combinations thereof. 67. The method of claim 56, wherein each of the at least 35 aliquots contains 500 or more diseased or neoplastic cells per well. 68. The method of claim 56, wherein each of the at least 35 aliquots contains 5,000 or more diseased or neoplastic cells per well. 69. The method of any of claims 1 to 11, wherein each of the at least 35 aliquots contains 10,000 or more diseased or neoplastic cells per well. 70. The method of any of claims 1 to 11, wherein each of the at least 35 aliquots contains 20,000 or more diseased or neoplastic cells per well. 71. The method of any of claims 1 to 11, wherein each of the at least 35 aliquots contains 40,000 or more diseased or neoplastic cells per well.

Described herein are methods, devices, and compositions for providing personalized medicine tests for hematological neoplasms. In some embodiments, the methods comprise measuring the efficacy of inducing apoptosis selectively in malignant cells using any number of potential alternative combination drug treatments. In some embodiments, the ex vivo testing is measured using a recently extracted patient hematological samples. In other embodiments, the efficacy is measured ex vivo using an automated flow cytometry platform. For example, by using an automated flow cytometry platform, the evaluation of hundreds, or even thousands of drugs and compositions, can be made ex vivo. Thus, alternative polytherapy treatments can be explored. Non-cytotoxic drugs surprisingly induce apoptosis selectively in malignant cells ex vivo. In some embodiments, the methods described herein comprise evaluating non-cytotoxic drugs.1.-55. (canceled) 56. A method for analyzing cellular responsiveness to drugs, comprising: a. obtaining a sample of whole blood, whole peripheral blood or whole bone marrow that has been withdrawn from a patient with a hematological neoplasm; b. dividing the whole sample into at least 35 aliquots; c. combining each of the at least 35 aliquots with a drug composition; and d. measuring apoptosis or cell depletion in each of the at least 35 aliquots by flow cytometry. 57. The method of claim 56, wherein at least two of the drug compositions comprise the same drug at different concentrations. 58. The method of claim 56, wherein at least one of the drug compositions comprises a plurality of drugs. 59. The method of claim 56, wherein at least one of the drug compositions comprises a plurality of drugs that are non-cytotoxic. 60. The method of claim 56, wherein at least one of the drug compositions comprises a non-cytotoxic drug that is the same as or in the same therapeutic category as a drug already being administered to the patient. 61. The method of claim 60, wherein at least one of the drug compositions combines a non-cytotoxic drug and a cytotoxic drug. 62. The method of claim 56, wherein the analysis is completed within 72 hours of combining the aliquots with a drug composition. 63. The method of claim 56, wherein the number of aliquots combined with a drug composition is at least 96. 64. The method of claim 56, wherein the whole sample comprises cells from a hematological neoplasm selected from the group consisting of chronic lymphocytic leukemia, adult acute lymphoblastic leukemia, pediatric acute lymphoblastic leukemia, multiple myeloma, myelodysplastic syndrome, non-M3 acute myeloblastic leukemia, acute myeloblastic leukemia M3, non-Hodgkin's lymphoma, Hodgkin's lymphoma, and chronic myeloid leukemia. 65. The method of claim 56, wherein the drug composition comprises a compound selected from the group consisting of 5-Azacitidine, alemtuzumab, aminopterin, Amonafide, Amsacrine, CAT-8015, Bevacizumab, ARR Y520, arsenic trioxide, AS1413, Atra, AZD 6244, AZD1152, Banoxantrone, Behenoylara-C, Bendamustine, Bleomycin, Blinatumomab, Bortezomib, Busulfan, carboplatin, CEP-701, Chlorambucil, Chloro Deoxiadenosine, Cladribine, clofarabine, CPX-351, Cyclophosphamide, Cyclosporine, Cytarabine, Cytosine Arabinoside, Dasatinib, Daunorubicin, decitabine, Deglycosylated-ricin-A chain-conjugated anti-CD19/anti-CD22 immunotoxins, Dexamethasone, Doxorubicine, Elacytarabine, entinostat, epratuzumab, Erwinase, Etoposide, everolimus, Exatecan mesilate, flavopiridol, fludarabine, forodesine, Gemcitabine, Gemtuzumab-ozogamicin, Homoharringtonine, Hydrocortisone, Hydroxycarbamide, Idarubicin, Ifosfamide, Imatinib, interferon alpha 2a, iodine 1131 monoclonal antibody BC8, Iphosphamide, isotretinoin, Laromustine, L-Asparaginase, Lenalidomide, Lestaurtinib, Maphosphamide, Melphalan, Mercaptopurine, Methotrexate, Methylprednisolone, Methylprednisone, Midostaurin, Mitoxantrone, Nelarabine, Nilotinib, Oblimersen, Paclitaxel, panobinostat, Pegaspargase, Pentostatin, Pirarubicin, PKC412, Prednisolone, Prednisone, PSC-833, Rapamycin, Rituximab, Rivabirin, Sapacitabine, Dinaciclib, Sorafenib, STA-9090, tacrolimus, tanespimycin, temsirolimus, Teniposide, Terameprocol, Thalidomide, Thioguanine, Thiotepa, Tipifarnib, Topotecan, Treosulfan, Troxacitabine, Vinblastine, Vincristine, Vindesine, Vinorelbine, Voreloxin, Vorinostat, Etoposide, Zosuquidar, and combinations thereof. 66. The method of claim 56, wherein the drug composition comprises a compound selected from the group consisting of Aluminum Oxide Hydrate, Lorazepam, Amikacine, Meropenem, Cefepime, Vancomycin, Teicoplanin, Ondansetron, Dexamethasone, Amphotericin B (liposomal), Caspofugin, Itraconazole, Fluconazole, Voriconazole, Trimetoprime, sulfamethoxazole, G-CSF, Ranitidine, Rasburicase, Paracetamol, Metamizole, Morphine chloride, Omeprazole, Paroxetine, Fluoxetine, Sertraline and combinations thereof. 67. The method of claim 56, wherein each of the at least 35 aliquots contains 500 or more diseased or neoplastic cells per well. 68. The method of claim 56, wherein each of the at least 35 aliquots contains 5,000 or more diseased or neoplastic cells per well. 69. The method of any of claims 1 to 11, wherein each of the at least 35 aliquots contains 10,000 or more diseased or neoplastic cells per well. 70. The method of any of claims 1 to 11, wherein each of the at least 35 aliquots contains 20,000 or more diseased or neoplastic cells per well. 71. The method of any of claims 1 to 11, wherein each of the at least 35 aliquots contains 40,000 or more diseased or neoplastic cells per well.

The present disclosure describes a pharmaceutical combination of an anti-CD19 antibody and a purine analog for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or acute lymphoblastic leukemia.

1. A synergistic combination of an antibody specific for CD19 comprising an antibody that cross-competes with an antibody comprising an HCDR1 region of sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of sequence MQHLEYPIT (SEQ ID NO: 6) and fludarabine for use in the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or acute lymphoblastic leukemia. 2. A combination according to claim 1, wherein the antibody comprises an antibody that binds to the same epitope as an antibody comprising an HCDR1 region of sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of sequence MQHLEYPIT (SEQ ID NO: 6). 3. A combination according to claim 2, wherein the antibody comprises an HCDR1 region of sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of sequence MQHLEYPIT (SEQ ID NO: 6). 4. A combination according to claim 3, wherein the antibody comprises a variable heavy chain of the sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPY NDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFD YWG QGTLVTVSS (SEQ ID NO: 10) and a variable light chain of the sequence (SEQ ID NO: 11) DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYR MSNLNSGVPDRFSGSGSGTEFILTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK. 5. A combination according to claim 4, wherein the antibody comprises a heavy chain constant domain of the sequence (SEQ ID NO: 12) ASTKGPSVFPLAPSSKSTSGGTAALGGINKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC PAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEV HNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKT KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK. 6. A combination according to claim 1, wherein said antibody specific for CD19 and fludarabine are administered separately. 7. A combination according to claim 6, wherein fludarabine is administered prior to administration of the antibody specific for CD19. 8. A combination according to claim 1, which is able to mediate killing of MEC-1 cells by ADCC in the presence of isolated human PBMCs with an at least two-fold better efficacy than fludarabine alone. 9. A combination according to claim 1 for use in the treatment of non-Hodgkin's lymphoma, wherein the non-Hodgkin's lymphoma is selected from the group consisting of follicular lymphoma, small lymphocytic lymphoma, mucosa-associated lymphoid tissue, marginal zone, diffuse large B cell, Burkitt's, and mantle cell.

The present disclosure describes a pharmaceutical combination of an anti-CD19 antibody and a purine analog for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or acute lymphoblastic leukemia.1. A synergistic combination of an antibody specific for CD19 comprising an antibody that cross-competes with an antibody comprising an HCDR1 region of sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of sequence MQHLEYPIT (SEQ ID NO: 6) and fludarabine for use in the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or acute lymphoblastic leukemia. 2. A combination according to claim 1, wherein the antibody comprises an antibody that binds to the same epitope as an antibody comprising an HCDR1 region of sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of sequence MQHLEYPIT (SEQ ID NO: 6). 3. A combination according to claim 2, wherein the antibody comprises an HCDR1 region of sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of sequence MQHLEYPIT (SEQ ID NO: 6). 4. A combination according to claim 3, wherein the antibody comprises a variable heavy chain of the sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPY NDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFD YWG QGTLVTVSS (SEQ ID NO: 10) and a variable light chain of the sequence (SEQ ID NO: 11) DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYR MSNLNSGVPDRFSGSGSGTEFILTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK. 5. A combination according to claim 4, wherein the antibody comprises a heavy chain constant domain of the sequence (SEQ ID NO: 12) ASTKGPSVFPLAPSSKSTSGGTAALGGINKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC PAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEV HNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKT KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK. 6. A combination according to claim 1, wherein said antibody specific for CD19 and fludarabine are administered separately. 7. A combination according to claim 6, wherein fludarabine is administered prior to administration of the antibody specific for CD19. 8. A combination according to claim 1, which is able to mediate killing of MEC-1 cells by ADCC in the presence of isolated human PBMCs with an at least two-fold better efficacy than fludarabine alone. 9. A combination according to claim 1 for use in the treatment of non-Hodgkin's lymphoma, wherein the non-Hodgkin's lymphoma is selected from the group consisting of follicular lymphoma, small lymphocytic lymphoma, mucosa-associated lymphoid tissue, marginal zone, diffuse large B cell, Burkitt's, and mantle cell.

Compositions of matter that have antimicrobial properties and adhesion properties and are highly dispersible in aqueous solutions. The presence of a large number of silanols on the molecules of this invention creates a solubility or disperseability of these molecules in aqueous solutions that is not obtainable from prior art antimicrobial monomers.

1-10. (canceled) 11. A method of reducing the number of bacteria, viruses, algae, mildew or mold, said method comprising: i. providing bacteria, a virus, algae, mildew, or mold to be reduced in numbers; ii. treating said bacteria, virus, algae, mildew or mold using a composition of matter having the average general formula: wherein the average molar ratio of x:y:z is 0.25-3:4:0.25-3, with the proviso that there is present at least one RSi-unit and at least one R′Si unit and W is independently selected from the group consisting essentially of Si, Ti, and Zr, and Al, wherein R is a cure functionality based on the chemistry selected from the group consisting of glycidoxy, amino, acrylamide, methacrylamide, acrylate, methacrylate, C2-C8 alkenyl, mercapto, ester, isocyanato, epoxycyclohexyl, carboxylic acid, and wherein p has a value of from 1 to 6 and R3 is selected from the group consisting of hydroxyl and alkoxy groups having 1 to 4 carbon atoms; R2 is independently selected from the group consisting of hydroxyl groups, s has a value of about 1 to 5; y has a value of 4; R1 is selected from the group consisting of: i. a sulfonium salt of the formula Si(R5)2CdH2dS+(R4)2X− in which R4 is independently an alkyl group or aralkyl group wherein there is a total of less than 60 carbon atoms in the molecule, R5 is independently selected from the group consisting of hydroxyl groups, d is an integer of 1 or greater and X− is a water soluble monovalent anion; ii. an isothiuronium salt of the formula Si(R5)2CdH2dS+C(NH2)2X−, R5 is independently selected from the group consisting of hydroxyl groups, d is an integer of 1 or greater and X− is a water soluble monovalent anion; iii. a phosphonium salt of the formula Si(R5)2CdH2dP+(R6)3X− in which R6 is independently selected from an alkyl group or aralkyl group wherein there is a total of less than 60 carbon atoms in the molecule, R5 is independently selected from the group consisting of hydroxyl groups, d is an integer of 1 or greater and X− is a water soluble monovalent anion and, iv. an amine of the formula Si(R5)2CdH2dN(H)(CdH2d)NH2 wherein R5 is independently selected from the group consisting of hydroxyl groups, in which d is an integer of 1 or greater, wherein (WOy) is derived from W(OR7)4 wherein (OR7) is independently selected from the group consisting of i. —OCH3, ii. —OCH2CH3, iii. —OCH(CH3)2, iv. —O(CH2)3CH3, v. —OCH2CH(CH3)2, vi. —O(2-ethylhexyl), vii. acetoxy, and, viii. oximo.

Compositions of matter that have antimicrobial properties and adhesion properties and are highly dispersible in aqueous solutions. The presence of a large number of silanols on the molecules of this invention creates a solubility or disperseability of these molecules in aqueous solutions that is not obtainable from prior art antimicrobial monomers.1-10. (canceled) 11. A method of reducing the number of bacteria, viruses, algae, mildew or mold, said method comprising: i. providing bacteria, a virus, algae, mildew, or mold to be reduced in numbers; ii. treating said bacteria, virus, algae, mildew or mold using a composition of matter having the average general formula: wherein the average molar ratio of x:y:z is 0.25-3:4:0.25-3, with the proviso that there is present at least one RSi-unit and at least one R′Si unit and W is independently selected from the group consisting essentially of Si, Ti, and Zr, and Al, wherein R is a cure functionality based on the chemistry selected from the group consisting of glycidoxy, amino, acrylamide, methacrylamide, acrylate, methacrylate, C2-C8 alkenyl, mercapto, ester, isocyanato, epoxycyclohexyl, carboxylic acid, and wherein p has a value of from 1 to 6 and R3 is selected from the group consisting of hydroxyl and alkoxy groups having 1 to 4 carbon atoms; R2 is independently selected from the group consisting of hydroxyl groups, s has a value of about 1 to 5; y has a value of 4; R1 is selected from the group consisting of: i. a sulfonium salt of the formula Si(R5)2CdH2dS+(R4)2X− in which R4 is independently an alkyl group or aralkyl group wherein there is a total of less than 60 carbon atoms in the molecule, R5 is independently selected from the group consisting of hydroxyl groups, d is an integer of 1 or greater and X− is a water soluble monovalent anion; ii. an isothiuronium salt of the formula Si(R5)2CdH2dS+C(NH2)2X−, R5 is independently selected from the group consisting of hydroxyl groups, d is an integer of 1 or greater and X− is a water soluble monovalent anion; iii. a phosphonium salt of the formula Si(R5)2CdH2dP+(R6)3X− in which R6 is independently selected from an alkyl group or aralkyl group wherein there is a total of less than 60 carbon atoms in the molecule, R5 is independently selected from the group consisting of hydroxyl groups, d is an integer of 1 or greater and X− is a water soluble monovalent anion and, iv. an amine of the formula Si(R5)2CdH2dN(H)(CdH2d)NH2 wherein R5 is independently selected from the group consisting of hydroxyl groups, in which d is an integer of 1 or greater, wherein (WOy) is derived from W(OR7)4 wherein (OR7) is independently selected from the group consisting of i. —OCH3, ii. —OCH2CH3, iii. —OCH(CH3)2, iv. —O(CH2)3CH3, v. —OCH2CH(CH3)2, vi. —O(2-ethylhexyl), vii. acetoxy, and, viii. oximo.

The present disclosure describes a pharmaceutical combination of an anti-CD19 antibody and a nitrogen mustard for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or acute lymphoblastic leukemia.

1. A synergistic combination of an antibody specific for CD19 comprising an antibody that cross-competes with an antibody comprising an HCDR1 region of sequence SYVMH (SEQ ID NO:1), an HCDR2 region of sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of sequence RSSKSLONVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of sequence MQHLEYPIT (SEQ ID NO: 6) and bendamustine for use in the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or acute lymphoblastic leukemia. 2. A combination according to claim 1, wherein the antibody comprises an antibody that binds to the same epitope as an antibody comprising an HCDR1 region of sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of sequence RSSKSLONVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of sequence MQHLEYPIT (SEQ ID NO: 6). 3. A combination according to claim 2, wherein the antibody comprises an HCDR1 region of sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of sequence RSSKSLONVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of sequence MQHLEYPIT (SEQ ID NO: 6). 4. A combination according to claim 3, wherein the antibody comprises a variable heavy chain of the sequence (SEQ ID NO: 10) EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGY INPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGT YYYGTRVFDYWG QGTLVTVSS and a variable light chain of the sequence (SEQ ID NO: 11) DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQL LIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPIT FGAGTKLEIK. 5. A combination according to claim 4, wherein the antibody comprises a heavy chain constant domain of the sequence (SEQ ID NO: 12) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGV HTPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC DKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCK VSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGK. 6. A combination according to claim 1, wherein said antibody specific for CD19 and bendamustine are administered separately. 7. A combination according to claim 6, wherein bendamustine is administered prior to administration of the antibody specific for CD19. 8. A combination according to claim 1, which is able to mediate killing of MEC-1 cells by ADCC in the presence of isolated human PBMCs with an at least two-fold better efficacy than bendamustine alone. 9. A combination according to claim 1 for use in the treatment of non-Hodgkin's lymphoma, wherein the non-Hodgkin's lymphoma is selected from the group consisting of follicular lymphoma, small lymphocytic lymphoma, mucosa-associated lymphoid tissue, marginal zone, diffuse large B cell, Burkitt's, and mantle cell.

The present disclosure describes a pharmaceutical combination of an anti-CD19 antibody and a nitrogen mustard for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or acute lymphoblastic leukemia.1. A synergistic combination of an antibody specific for CD19 comprising an antibody that cross-competes with an antibody comprising an HCDR1 region of sequence SYVMH (SEQ ID NO:1), an HCDR2 region of sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of sequence RSSKSLONVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of sequence MQHLEYPIT (SEQ ID NO: 6) and bendamustine for use in the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or acute lymphoblastic leukemia. 2. A combination according to claim 1, wherein the antibody comprises an antibody that binds to the same epitope as an antibody comprising an HCDR1 region of sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of sequence RSSKSLONVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of sequence MQHLEYPIT (SEQ ID NO: 6). 3. A combination according to claim 2, wherein the antibody comprises an HCDR1 region of sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of sequence RSSKSLONVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of sequence MQHLEYPIT (SEQ ID NO: 6). 4. A combination according to claim 3, wherein the antibody comprises a variable heavy chain of the sequence (SEQ ID NO: 10) EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGY INPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGT YYYGTRVFDYWG QGTLVTVSS and a variable light chain of the sequence (SEQ ID NO: 11) DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQL LIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPIT FGAGTKLEIK. 5. A combination according to claim 4, wherein the antibody comprises a heavy chain constant domain of the sequence (SEQ ID NO: 12) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGV HTPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC DKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCK VSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGK. 6. A combination according to claim 1, wherein said antibody specific for CD19 and bendamustine are administered separately. 7. A combination according to claim 6, wherein bendamustine is administered prior to administration of the antibody specific for CD19. 8. A combination according to claim 1, which is able to mediate killing of MEC-1 cells by ADCC in the presence of isolated human PBMCs with an at least two-fold better efficacy than bendamustine alone. 9. A combination according to claim 1 for use in the treatment of non-Hodgkin's lymphoma, wherein the non-Hodgkin's lymphoma is selected from the group consisting of follicular lymphoma, small lymphocytic lymphoma, mucosa-associated lymphoid tissue, marginal zone, diffuse large B cell, Burkitt's, and mantle cell.

The invention relates to cosmetic and dermatological photoprotective preparations comprising, in addition to UV filter substances, polyglyceryl-10 stearate as emulsifier. Said preparations have improved water resistance.

1.-13. (canceled) 14. A water-resistant cosmetic or dermatological photoprotective preparation, wherein the preparation comprises one or more UV filter substances, less than 6% by weight of polyglyceryl-10 stearate, based on a total weight of the preparation, and comprises no lecithins, O/W emulsion preparations of the following compositions I to IV being excluded: Composition I II Panthenol 0.7 0 Butylene glycol 5 10 Propylene glycol 5 — Benzethonium chloride 0.5 0.9 Lauroyl ethyl arginate 1.0 0.5 Caprylic/capric triglyceride 0 1.00 Cetearyl alcohol 2.5 4.00 Linear silicone oil 0 0.50 C12-15 Alkyl benzoate 0 2.00 Dicaprylyl ether 10 0 Glyceryl stearate 2.4 2.4 Glycerol 8 8 Butylene glycol 1 0 Sodium hydroxide solution 45% 0.25 1 Polyglyceryl-10 stearate 1 1 Acrylic acid/VP crosspolymer 0.5 0.75 Trisodium EDTA 1 Ethylhexyl methoxycinnamate 2 0 Butylmethoxy dibenzoylmethane 0 2 Phenylbenzimidazole sulfonic acid, sodium salt 0 2 Ethylhexyl salicylate 0 2 Titanium dioxide, silicone-coated 0.3600 0 Octocrylene 0 2 Perfume 0 0.20 Water ad 100 ad 100 Composition III IV Panthenol 0.7 0 Butylene glycol 5 10 Propylene glycol 5 — Methylisothiazolinones 0.06 — Benzethonium chloride 0.15 — Piroctone olamine 0.15 — Lauroyl ethyl arginate 0.15 1.75 Caprylic/capric triglyceride 0 1.00 Cetearyl alcohol 2.5 4.00 Linear silicone oil 0 0.50 C12-15 Alkyl benzoate 0 2.00 Dicaprylyl ether 10 0 Glyceryl stearate 2.4 2.4 Glycerol 8 8 Sodium hydroxide solution 45% strength 0.25 1 Polyglyceryl-10 stearate 1 1 Acrylic acid/VP crosspolymer 0.5 0.75 Trisodium EDTA 1 Ethylhexyl methoxycinnamate 2 0 Butylmethoxy dibenzoylmethane 0 2 Phenylbenzimidazole sulfonic acid 0 2 Ethylhexyl salicylate 0 2 Titanium dioxide + trimethoxycaprylylsilane 0.3600 0 Octocrylene 0 2 Perfume 0 0.20 Water ad 100 ad 100 numerical values representing fractions by weight, based on a total mass of the preparation. 15. The preparation of claim 14, wherein the preparation further comprises one or more film formers. 16. The preparation of claim 14, wherein the preparation comprises from 0.1% to 2.8% by weight of polyglyceryl-10 stearate 17. The preparation of claim 14, wherein apart from polyglycerol-10 stearate, the preparation comprises no further emulsifiers. 18. The preparation of claim 16, wherein apart from polyglycerol-10 stearate, the preparation comprises no further emulsifiers. 19. The preparation of claim 18, wherein the preparation further comprises one or more film formers. 20. The preparation of claim 14, wherein in addition to polyglycerol-10 stearate, the preparation further comprises one or more non-ethoxylated emulsifiers which are solid, pasty or liquid at 25° C. 21. The preparation of claim 20, wherein the one or more non-ethoxylated emulsifiers comprise glyceryl stearate. 22. The preparation of claim 16, wherein in addition to polyglycerol-10 stearate, the preparation further comprises one or more non-ethoxylated emulsifiers which are solid, pasty or liquid at 25° C. 23. The preparation of claim 22, wherein the one or more non-ethoxylated emulsifiers comprise glyceryl stearate. 24. The preparation of claim 14, wherein the preparation is present as an O/W emulsion. 25. The preparation of claim 14, wherein the preparation is present as a hydrodispersion. 26. The preparation of claim 14, wherein the one or more UV filter substances comprise one or more of octocrylene, homosalate, ethylhexyl salicylate (octyl salicylate), butylmethoxy dibenzoylmethane, titanium dioxide, phenylbenzimidazole sulfonic acid, bisethylhexyloxyphenol methoxyphenyltriazine, polysilicone-15, diethylamino-hydroxybenzoyl hexylbenzoate, disodium phenyldibenzimidazole tetrasulfonate, terephthalidene camphorsulfonic acid, ethylhexyltriazone, diethylhexylbutamidotriazone, 2-ethylhexyl methoxycinnamate, isoamyl p-methoxycinnamate, benzophenone-4, methylenebisbenzotriazolyltetramethylbutylphenol, titanium dioxide (with and without coating), zinc oxide (with and without coating), 2,4,6-tris(biphenyl)-1,3,5-triazine, and benzophenone-3. 27. The preparation of claim 14, wherein the preparation further comprises one or more skin moisturizers. 28. The preparation of claim 14, wherein the preparation is free of parabens, formaldehyde donors, organohalic substances, benzoic acid and salts thereof, formats, and tea tree oil. 29. The preparation of claim 16, wherein the preparation is free of parabens, formaldehyde donors, organohalic substances, benzoic acid and salts thereof, formats, and tea tree oil. 30. The preparation of claim 18, wherein the preparation is free of parabens, formaldehyde donors, organohalic substances, benzoic acid and salts thereof, formats, and tea tree oil. 31. The preparation of claim 20, wherein the preparation is free of parabens, formaldehyde donors, organohalic substances, benzoic acid and salts thereof, formats, and tea tree oil. 32. A method of improving the water resistance of a photoprotective preparation comprising one or more UV filter substances, wherein the method comprises incorporating in the preparation polyglyceryl-10 stearate. 33. A method of improving the stickiness of a photoprotective preparation comprising one or more UV filter substances and one or more film formers and/or one or more skin moisturizers, wherein the method comprises incorporating in the preparation polyglyceryl-10 stearate.

The invention relates to cosmetic and dermatological photoprotective preparations comprising, in addition to UV filter substances, polyglyceryl-10 stearate as emulsifier. Said preparations have improved water resistance.1.-13. (canceled) 14. A water-resistant cosmetic or dermatological photoprotective preparation, wherein the preparation comprises one or more UV filter substances, less than 6% by weight of polyglyceryl-10 stearate, based on a total weight of the preparation, and comprises no lecithins, O/W emulsion preparations of the following compositions I to IV being excluded: Composition I II Panthenol 0.7 0 Butylene glycol 5 10 Propylene glycol 5 — Benzethonium chloride 0.5 0.9 Lauroyl ethyl arginate 1.0 0.5 Caprylic/capric triglyceride 0 1.00 Cetearyl alcohol 2.5 4.00 Linear silicone oil 0 0.50 C12-15 Alkyl benzoate 0 2.00 Dicaprylyl ether 10 0 Glyceryl stearate 2.4 2.4 Glycerol 8 8 Butylene glycol 1 0 Sodium hydroxide solution 45% 0.25 1 Polyglyceryl-10 stearate 1 1 Acrylic acid/VP crosspolymer 0.5 0.75 Trisodium EDTA 1 Ethylhexyl methoxycinnamate 2 0 Butylmethoxy dibenzoylmethane 0 2 Phenylbenzimidazole sulfonic acid, sodium salt 0 2 Ethylhexyl salicylate 0 2 Titanium dioxide, silicone-coated 0.3600 0 Octocrylene 0 2 Perfume 0 0.20 Water ad 100 ad 100 Composition III IV Panthenol 0.7 0 Butylene glycol 5 10 Propylene glycol 5 — Methylisothiazolinones 0.06 — Benzethonium chloride 0.15 — Piroctone olamine 0.15 — Lauroyl ethyl arginate 0.15 1.75 Caprylic/capric triglyceride 0 1.00 Cetearyl alcohol 2.5 4.00 Linear silicone oil 0 0.50 C12-15 Alkyl benzoate 0 2.00 Dicaprylyl ether 10 0 Glyceryl stearate 2.4 2.4 Glycerol 8 8 Sodium hydroxide solution 45% strength 0.25 1 Polyglyceryl-10 stearate 1 1 Acrylic acid/VP crosspolymer 0.5 0.75 Trisodium EDTA 1 Ethylhexyl methoxycinnamate 2 0 Butylmethoxy dibenzoylmethane 0 2 Phenylbenzimidazole sulfonic acid 0 2 Ethylhexyl salicylate 0 2 Titanium dioxide + trimethoxycaprylylsilane 0.3600 0 Octocrylene 0 2 Perfume 0 0.20 Water ad 100 ad 100 numerical values representing fractions by weight, based on a total mass of the preparation. 15. The preparation of claim 14, wherein the preparation further comprises one or more film formers. 16. The preparation of claim 14, wherein the preparation comprises from 0.1% to 2.8% by weight of polyglyceryl-10 stearate 17. The preparation of claim 14, wherein apart from polyglycerol-10 stearate, the preparation comprises no further emulsifiers. 18. The preparation of claim 16, wherein apart from polyglycerol-10 stearate, the preparation comprises no further emulsifiers. 19. The preparation of claim 18, wherein the preparation further comprises one or more film formers. 20. The preparation of claim 14, wherein in addition to polyglycerol-10 stearate, the preparation further comprises one or more non-ethoxylated emulsifiers which are solid, pasty or liquid at 25° C. 21. The preparation of claim 20, wherein the one or more non-ethoxylated emulsifiers comprise glyceryl stearate. 22. The preparation of claim 16, wherein in addition to polyglycerol-10 stearate, the preparation further comprises one or more non-ethoxylated emulsifiers which are solid, pasty or liquid at 25° C. 23. The preparation of claim 22, wherein the one or more non-ethoxylated emulsifiers comprise glyceryl stearate. 24. The preparation of claim 14, wherein the preparation is present as an O/W emulsion. 25. The preparation of claim 14, wherein the preparation is present as a hydrodispersion. 26. The preparation of claim 14, wherein the one or more UV filter substances comprise one or more of octocrylene, homosalate, ethylhexyl salicylate (octyl salicylate), butylmethoxy dibenzoylmethane, titanium dioxide, phenylbenzimidazole sulfonic acid, bisethylhexyloxyphenol methoxyphenyltriazine, polysilicone-15, diethylamino-hydroxybenzoyl hexylbenzoate, disodium phenyldibenzimidazole tetrasulfonate, terephthalidene camphorsulfonic acid, ethylhexyltriazone, diethylhexylbutamidotriazone, 2-ethylhexyl methoxycinnamate, isoamyl p-methoxycinnamate, benzophenone-4, methylenebisbenzotriazolyltetramethylbutylphenol, titanium dioxide (with and without coating), zinc oxide (with and without coating), 2,4,6-tris(biphenyl)-1,3,5-triazine, and benzophenone-3. 27. The preparation of claim 14, wherein the preparation further comprises one or more skin moisturizers. 28. The preparation of claim 14, wherein the preparation is free of parabens, formaldehyde donors, organohalic substances, benzoic acid and salts thereof, formats, and tea tree oil. 29. The preparation of claim 16, wherein the preparation is free of parabens, formaldehyde donors, organohalic substances, benzoic acid and salts thereof, formats, and tea tree oil. 30. The preparation of claim 18, wherein the preparation is free of parabens, formaldehyde donors, organohalic substances, benzoic acid and salts thereof, formats, and tea tree oil. 31. The preparation of claim 20, wherein the preparation is free of parabens, formaldehyde donors, organohalic substances, benzoic acid and salts thereof, formats, and tea tree oil. 32. A method of improving the water resistance of a photoprotective preparation comprising one or more UV filter substances, wherein the method comprises incorporating in the preparation polyglyceryl-10 stearate. 33. A method of improving the stickiness of a photoprotective preparation comprising one or more UV filter substances and one or more film formers and/or one or more skin moisturizers, wherein the method comprises incorporating in the preparation polyglyceryl-10 stearate.

Liquid lipstick compositions capable of forming a multilayer structure after application to lips are provided, as well as methods of applying such compositions to lips.

1. A liquid lipstick composition capable of forming a multilayer structure after application to lips, wherein the liquid lipstick composition comprises at east two immiscible components prior to application, wherein the at least two immiscible components are: Component A which comprises 15% to 60% by weight with respect to the total weight of the composition of at least one film forming agent having at least one glass transition temperature which is lower than normal human body temperature; and Component B which comprises 0.01% to about 80% by weight with respect to the total weight of the composition of one or more silicone compounds in amounts sufficient to achieve a viscosity of 1000 cSt to 900,000 cSt, wherein the weight ratio of film forming agents) in Component A to silicone compound(s) in Component B is from 50:1 to 1:2. 2. The liquid lipstick composition of claim 1, wherein the liquid lipstick composition is anhydrous. 3. The liquid lipstick composition of claim 1, wherein Component B is self-leveling such that it imparts shine to the liquid lipstick composition after application to lips. 4. The liquid lipstick composition of claim 1, wherein Component A and Component B have a density difference of 0.001-1 kg/m3. 5. The liquid lipstick composition of claim 1, wherein Component A and Component B have a density difference of 0.01-0.6 kg/m3. 6. A kit comprising: (a) the liquid lipstick composition according to claim 1; (b) at least one container which contains the liquid lipstick composition according to claim 1; and (c) at least one applicator. 7. A method of applying the liquid lipstick composition of claim 1 to lips comprising mixing the liquid lipstick composition to form a mixed composition in which Component A and Component B are temporarily miscible, and applying the mixed composition to lips. 8. The liquid lipstick composition of claim 1, wherein Component B comprises at least one silicone compound selected from the group consisting of a silicone gum, a silicone fluid, and mixtures thereof. 9. The liquid lipstick composition of claim 1, wherein Component A comprises at least one film forming agent selected from the group consisting of a silicone resin, a silicone acrylate copolymer, and mixtures thereof. 10. The liquid lipstick composition of claim 1, wherein Component A comprises at least one polymer having a critical molecular weight of entanglement (Mc) such that Mc<wMw, where w=weight fraction and Mw=molecular weight of the polymer. 11. The liquid lipstick composition of claim 1, wherein Component B comprises at least one polymer having a critical molecular weight of entanglement (Mc) such that Mc≦wMw≦108 g/mol, where w=weight fraction and Mw=molecular eight of the polymer. 12. The liquid lipstick composition of claim 1, where Component A further comprises 0.001% to 30% by weight with respect to the total weight of the composition of at least one colorant

Liquid lipstick compositions capable of forming a multilayer structure after application to lips are provided, as well as methods of applying such compositions to lips.1. A liquid lipstick composition capable of forming a multilayer structure after application to lips, wherein the liquid lipstick composition comprises at east two immiscible components prior to application, wherein the at least two immiscible components are: Component A which comprises 15% to 60% by weight with respect to the total weight of the composition of at least one film forming agent having at least one glass transition temperature which is lower than normal human body temperature; and Component B which comprises 0.01% to about 80% by weight with respect to the total weight of the composition of one or more silicone compounds in amounts sufficient to achieve a viscosity of 1000 cSt to 900,000 cSt, wherein the weight ratio of film forming agents) in Component A to silicone compound(s) in Component B is from 50:1 to 1:2. 2. The liquid lipstick composition of claim 1, wherein the liquid lipstick composition is anhydrous. 3. The liquid lipstick composition of claim 1, wherein Component B is self-leveling such that it imparts shine to the liquid lipstick composition after application to lips. 4. The liquid lipstick composition of claim 1, wherein Component A and Component B have a density difference of 0.001-1 kg/m3. 5. The liquid lipstick composition of claim 1, wherein Component A and Component B have a density difference of 0.01-0.6 kg/m3. 6. A kit comprising: (a) the liquid lipstick composition according to claim 1; (b) at least one container which contains the liquid lipstick composition according to claim 1; and (c) at least one applicator. 7. A method of applying the liquid lipstick composition of claim 1 to lips comprising mixing the liquid lipstick composition to form a mixed composition in which Component A and Component B are temporarily miscible, and applying the mixed composition to lips. 8. The liquid lipstick composition of claim 1, wherein Component B comprises at least one silicone compound selected from the group consisting of a silicone gum, a silicone fluid, and mixtures thereof. 9. The liquid lipstick composition of claim 1, wherein Component A comprises at least one film forming agent selected from the group consisting of a silicone resin, a silicone acrylate copolymer, and mixtures thereof. 10. The liquid lipstick composition of claim 1, wherein Component A comprises at least one polymer having a critical molecular weight of entanglement (Mc) such that Mc<wMw, where w=weight fraction and Mw=molecular weight of the polymer. 11. The liquid lipstick composition of claim 1, wherein Component B comprises at least one polymer having a critical molecular weight of entanglement (Mc) such that Mc≦wMw≦108 g/mol, where w=weight fraction and Mw=molecular eight of the polymer. 12. The liquid lipstick composition of claim 1, where Component A further comprises 0.001% to 30% by weight with respect to the total weight of the composition of at least one colorant

Compositions and methods for treating ear infections are disclosed. More specifically, these methods may refer to treatment of internal otitis using an otic composition, such as otic gel for animals and humans. Poloxamer otic gel may be in liquid state at room temperature and may change to gel at about temperature (64° F.) as poloxamer otic gel reaches body temperature, because of the thermo-reversible properties. Consequently, poloxamer otic gel may be an effective treatment in animals and humans, where poloxamer otic gel may reach otitis affected site and remain there for a longer period of time. Additionally, poloxamer otic gel may include APIs such as antifungals, antibiotics and corticosteroids, among others. Furthermore, poloxamer otic gel may be instilled inside the ear, employing calibrated delivery device into the vertical ear canal in order to reach the horizontal ear canal, without puncturing the tympanic membrane.

1. An otic pharmaceutical composition, comprising: a) an active pharmaceutical ingredient (API); and b) a vehicle, wherein the vehicle is poloxamer 407; wherein the composition is a gel. 2. The otic pharmaceutical composition of claim 1, wherein the composition comprises 20% to 30% poloxamer 407. 3. The otic pharmaceutical composition of claim 1, wherein the vehicle further comprises poloxamer L-64. 4. The otic pharmaceutical composition of claim 1, wherein the composition is liquid at room temperature and a gel at 64° F. to 85° F. 5. The otic pharmaceutical composition of claim 1, wherein the API is selected from the group consisting of an antibacterial, antifungal, corticosteroid, antiparasitic, antiviral, anaesthetic, and non-steroidal anti-inflammatory agent. 6. The otic pharmaceutical composition of claim 5, wherein the antibacterial is an antibiotic. 7. The otic pharmaceutical composition of claim 6, wherein the antibacterial is selected from the group consisting of enrofloxacin, amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, paromomycin, geldanamycin, herbimycin, loracarbef, ertapenem, doripenem, imipenem, cilastatin, meropenem, cefadroxil, cefazolin, cefalotin, cefalexin, cefaclor, cefamandole, cefoxitin, defprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftobiprole, teicoplanin, vancomycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spectinomycin, aztreonam, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, meticillin, nafcillin, oxacillin, penicillin, piperacillin, ticarcillan, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trovfloxacin, mafenide, prontosil, sulfacetamide, sulfamethizole, sulfanimilimde, sulfasalazine, sulfisoxazole, trimetoprim, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, arsphenamine, chloramphenicol, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, metronidazole, mupirocin, nitrofurantoin, platensimycin, pyrazinamide, quinuspristin/dalfopristin, rifampin, tinidazole, and combinations thereof. 8. The otic pharmaceutical composition of claim 7, wherein the enrofloxacin is about 1% to about 5% by weight of the composition. 9. The otic pharmaceutical composition of claim 5, wherein the antifungal is selected from the group consisting of amrolfine, utenafine, naftifine, terbinafine, flucytosine, fluconazole, itraconazole, ketoconazole, posaconazole, ravuconazole, voriconazole, clotrimazole, econazole, miconazole, oxiconazole, sulconazole, terconazole, tioconazole, nikkomycin Z, caspofungin, micafungin, anidulafungin, amphotericin B, liposomal nystastin, pimaricin, griseofulvin, ciclopirox olamine, haloprogin, tolnaftate, undecylenate, clioquinol, and combinations thereof. 10. The otic pharmaceutical composition of claim 9, wherein the ketoconazole is about 1% to about 5% by weight of the composition. 11. The otic pharmaceutical composition of claim 5, wherein the corticosteroid is selected from the group consisting of hydrocortisone, prednisone, fluprednisolone, triamcinolone, dexamethasone, betamethasone, cortisone, prednilosone, methylprednisolone, fluocinolone acetonide, flurandrenolone acetonide, and fluorometholone. 12. The otic pharmaceutical composition of claim 11, wherein the triamcinolone is about 1% by weight of the composition. 13. The otic pharmaceutical composition of claim 5, wherein the antiviral is selected from the group consisting of acyclovir, famciclovir and valacyclovir. Other antiviral agents include abacavir, aciclovir, adefovir, amantadine, amprenavir, arbidol., atazanavir, artipla, brivudine, cidofovir, combivir, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, fomvirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, gardasil, ibacitabine, immunovir, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitors, interferons, including interferon type III, interferon type II, interferon type I, lamivudine, lopinavir, loviride, MK-0518, maraviroc, moroxydine, nelfinavir, nevirapine, nexavir, nucleoside analogues, oseltamivir, penciclovir, peramivir, pleconaril, podophyllotoxin, protease inhibitors, reverse transcriptase inhibitors, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, and combinations thereof. 14. The otic pharmaceutical composition of claim 5, wherein the antiparasitic is selected from the group consisting of amitraz, amoscanate, avermectin, carbadox, diethylcarbamizine, dimetridazole, diminazene, ivermectin, macrofilaricide, malathion, mitaban, oxamniquine, permethrin, praziquantel, prantel pamoate, selamectin, sodium stibogluconate, thiabendazole, and combinations thereof. 15. The otic pharmaceutical composition of claim 5, wherein the anaesthetic is selected from the group consisting of benzocaine, butamben picrate, tetracaine, dibucaine, prilocalne, etidocaine, mepivacaine, bupivicaine, lidocaine, and combinations thereof. 16. The otic pharmaceutical composition of claim 5, wherein the non-steroidal anti-inflammatory agent is selected from the group consisting of detoprofen, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, indomethacin, ketoprofen, mechlofenameate, mefenamic acid, meloxicam, nabumeone, naproxen sodium, oxaprozin, piroxicam, sulindac, tolmeting, celecoxib, rofecoxib, choline salicylate, salsate, sodium salicylate, magnesium salicylate, aspirin, ibuprofen, paracetamol, acetaminophen, pseudoephedrine, and combinations thereof. 17. A method of treating otitis media or otitis interna, comprising administering an otic pharmaceutical composition to internal ear of an animal or human, wherein the composition is a gel and comprises a) an active pharmaceutical ingredient (API); and b) a vehicle, wherein the vehicle is poloxamer 407. 18. The method of claim 17, wherein the composition comprises 20% to 30% poloxamer 407. 19. The method of claim 17, wherein the vehicle further comprises poloxamer L-64. 20. The method of claim 17, wherein the composition is liquid at room temperature and a gel at 64° F. to 85° F. 21. The method of claim 17, wherein the API is selected from the group consisting of an antibacterial, antifungal, corticosteroid, antiparasitic, antiviral, anaesthetic, and non-steroidal anti-inflammatory agent. 22. The method of claim 21, wherein the antibacterial comprises enrofloxacin, the antifungal comprises ketoconazole, the corticosteroid comprises triamcinolone, the antiparasitic comprises amitraz, the anaesthetic comprises benzocaine, and the non-steroidal anti-inflammatory agent comprises detoprofen.

Compositions and methods for treating ear infections are disclosed. More specifically, these methods may refer to treatment of internal otitis using an otic composition, such as otic gel for animals and humans. Poloxamer otic gel may be in liquid state at room temperature and may change to gel at about temperature (64° F.) as poloxamer otic gel reaches body temperature, because of the thermo-reversible properties. Consequently, poloxamer otic gel may be an effective treatment in animals and humans, where poloxamer otic gel may reach otitis affected site and remain there for a longer period of time. Additionally, poloxamer otic gel may include APIs such as antifungals, antibiotics and corticosteroids, among others. Furthermore, poloxamer otic gel may be instilled inside the ear, employing calibrated delivery device into the vertical ear canal in order to reach the horizontal ear canal, without puncturing the tympanic membrane.1. An otic pharmaceutical composition, comprising: a) an active pharmaceutical ingredient (API); and b) a vehicle, wherein the vehicle is poloxamer 407; wherein the composition is a gel. 2. The otic pharmaceutical composition of claim 1, wherein the composition comprises 20% to 30% poloxamer 407. 3. The otic pharmaceutical composition of claim 1, wherein the vehicle further comprises poloxamer L-64. 4. The otic pharmaceutical composition of claim 1, wherein the composition is liquid at room temperature and a gel at 64° F. to 85° F. 5. The otic pharmaceutical composition of claim 1, wherein the API is selected from the group consisting of an antibacterial, antifungal, corticosteroid, antiparasitic, antiviral, anaesthetic, and non-steroidal anti-inflammatory agent. 6. The otic pharmaceutical composition of claim 5, wherein the antibacterial is an antibiotic. 7. The otic pharmaceutical composition of claim 6, wherein the antibacterial is selected from the group consisting of enrofloxacin, amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, paromomycin, geldanamycin, herbimycin, loracarbef, ertapenem, doripenem, imipenem, cilastatin, meropenem, cefadroxil, cefazolin, cefalotin, cefalexin, cefaclor, cefamandole, cefoxitin, defprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftobiprole, teicoplanin, vancomycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spectinomycin, aztreonam, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, meticillin, nafcillin, oxacillin, penicillin, piperacillin, ticarcillan, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trovfloxacin, mafenide, prontosil, sulfacetamide, sulfamethizole, sulfanimilimde, sulfasalazine, sulfisoxazole, trimetoprim, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, arsphenamine, chloramphenicol, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, metronidazole, mupirocin, nitrofurantoin, platensimycin, pyrazinamide, quinuspristin/dalfopristin, rifampin, tinidazole, and combinations thereof. 8. The otic pharmaceutical composition of claim 7, wherein the enrofloxacin is about 1% to about 5% by weight of the composition. 9. The otic pharmaceutical composition of claim 5, wherein the antifungal is selected from the group consisting of amrolfine, utenafine, naftifine, terbinafine, flucytosine, fluconazole, itraconazole, ketoconazole, posaconazole, ravuconazole, voriconazole, clotrimazole, econazole, miconazole, oxiconazole, sulconazole, terconazole, tioconazole, nikkomycin Z, caspofungin, micafungin, anidulafungin, amphotericin B, liposomal nystastin, pimaricin, griseofulvin, ciclopirox olamine, haloprogin, tolnaftate, undecylenate, clioquinol, and combinations thereof. 10. The otic pharmaceutical composition of claim 9, wherein the ketoconazole is about 1% to about 5% by weight of the composition. 11. The otic pharmaceutical composition of claim 5, wherein the corticosteroid is selected from the group consisting of hydrocortisone, prednisone, fluprednisolone, triamcinolone, dexamethasone, betamethasone, cortisone, prednilosone, methylprednisolone, fluocinolone acetonide, flurandrenolone acetonide, and fluorometholone. 12. The otic pharmaceutical composition of claim 11, wherein the triamcinolone is about 1% by weight of the composition. 13. The otic pharmaceutical composition of claim 5, wherein the antiviral is selected from the group consisting of acyclovir, famciclovir and valacyclovir. Other antiviral agents include abacavir, aciclovir, adefovir, amantadine, amprenavir, arbidol., atazanavir, artipla, brivudine, cidofovir, combivir, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, fomvirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, gardasil, ibacitabine, immunovir, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitors, interferons, including interferon type III, interferon type II, interferon type I, lamivudine, lopinavir, loviride, MK-0518, maraviroc, moroxydine, nelfinavir, nevirapine, nexavir, nucleoside analogues, oseltamivir, penciclovir, peramivir, pleconaril, podophyllotoxin, protease inhibitors, reverse transcriptase inhibitors, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, and combinations thereof. 14. The otic pharmaceutical composition of claim 5, wherein the antiparasitic is selected from the group consisting of amitraz, amoscanate, avermectin, carbadox, diethylcarbamizine, dimetridazole, diminazene, ivermectin, macrofilaricide, malathion, mitaban, oxamniquine, permethrin, praziquantel, prantel pamoate, selamectin, sodium stibogluconate, thiabendazole, and combinations thereof. 15. The otic pharmaceutical composition of claim 5, wherein the anaesthetic is selected from the group consisting of benzocaine, butamben picrate, tetracaine, dibucaine, prilocalne, etidocaine, mepivacaine, bupivicaine, lidocaine, and combinations thereof. 16. The otic pharmaceutical composition of claim 5, wherein the non-steroidal anti-inflammatory agent is selected from the group consisting of detoprofen, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, indomethacin, ketoprofen, mechlofenameate, mefenamic acid, meloxicam, nabumeone, naproxen sodium, oxaprozin, piroxicam, sulindac, tolmeting, celecoxib, rofecoxib, choline salicylate, salsate, sodium salicylate, magnesium salicylate, aspirin, ibuprofen, paracetamol, acetaminophen, pseudoephedrine, and combinations thereof. 17. A method of treating otitis media or otitis interna, comprising administering an otic pharmaceutical composition to internal ear of an animal or human, wherein the composition is a gel and comprises a) an active pharmaceutical ingredient (API); and b) a vehicle, wherein the vehicle is poloxamer 407. 18. The method of claim 17, wherein the composition comprises 20% to 30% poloxamer 407. 19. The method of claim 17, wherein the vehicle further comprises poloxamer L-64. 20. The method of claim 17, wherein the composition is liquid at room temperature and a gel at 64° F. to 85° F. 21. The method of claim 17, wherein the API is selected from the group consisting of an antibacterial, antifungal, corticosteroid, antiparasitic, antiviral, anaesthetic, and non-steroidal anti-inflammatory agent. 22. The method of claim 21, wherein the antibacterial comprises enrofloxacin, the antifungal comprises ketoconazole, the corticosteroid comprises triamcinolone, the antiparasitic comprises amitraz, the anaesthetic comprises benzocaine, and the non-steroidal anti-inflammatory agent comprises detoprofen.

A galenical form for the administration transmucously of at least one active ingredient, characterized in that the active ingredient is in a stable and complete dissolved state in a hydroalcoholic solution that includes at least 20% by mass of alcohol so as to allow rapid absorption of the active ingredient through the mucous membranes of the buccal cavity and/or the oropharynx. Uses of the galenical form are also disclosed.

1. Galenical form for the administration by transmucous means of at least one active ingredient, characterized in that said active ingredient is in a stable and complete dissolved state in a hydroalcoholic solution that comprises at least 20% by mass of alcohol so as to allow rapid absorption of said active ingredient through the mucous membranes of the buccal cavity and/or the oropharynx. 2. Galenical form according to claim 1, wherein at least one active ingredient has a molecular weight that is less than 10,000 Da. 3. Galenical form according to claim 1, wherein the degree of alcohol of the hydroalcoholic solution is between 20 and 95°. 4. Galenical form according to claim 1, wherein the hydroalcoholic solution comprises between 20 and 95% alcohol and between 5 and 80% by mass of water. 5. Galenical form according to claim 1, wherein the hydroalcoholic solution comprises at least ethanol. 6. Galenical form according to claim 1, wherein the hydroalcoholic solution comprises at least isopropyl alcohol. 7. Galenical form according to claim 1, wherein the hydroalcoholic solution comprises one or more dissolution adjuvants. 8. Galenical form according to claim 6, wherein the dissolution adjuvants are selected from among the polyethylene glycol-type polymers of low molecular weight, the surfactants, isopropyl alcohol and/or alcohol-oil mixtures. 9. Galenical form according to claim 1, wherein the hydroalcoholic solution comprises an aroma and/or a sweetener to sweeten the taste sensation. 10. Galenical form according to claim 1, wherein the active ingredient contains a carbonyl acid group and wherein the hydroalcoholic solution comprises a pH-correcting agent and/or a sequestering agent. 11. Galenical form according to claim 1, wherein it allows active ingredient(s) to passively pass through the mucous membranes of the oropharynx in a time period of less than 20 seconds after administration. 12. Galenical form according to claim 1, wherein the volume for administration is less than 5 ml. 13. Galenical form according to claim 1, wherein it is packaged by means of a flexible container, ensuring the stability of the active ingredient(s) in its/their dissolving over time. 14. Galenical form according to claim 13, wherein the container comes in the form of a single-dose or multi-dose airtight case with a maximum capacity of 5 ml. 15. Galenical form according to claim 1, wherein the active ingredient(s) is/are selected from among the hormones, the anti-hormones, and any active agents on the endocrine glands, cholesterol-lowering agents, anti-infective agents, anti-viral agents, anti-parasitic agents, vascular platelet inhibitors, molecules that treat menopause, andropause or sterility, instant contraceptives, analgesic agents, anti-inflammatory agents, anti-cancer agents, immunosuppressors, anti-migraine agents, anti-emetic agents, anti-diarrhea agents, anti-spasmodic agents, anti-allergy agents, anti-arrythmic agents, erectogenic agents, anxiolytic agents, anti-diabetic agents, anti-hypertensive agents, anti-asthmatic agents, anti-parkinsonian agents and/or antihistamine agents. 16. (canceled)

A galenical form for the administration transmucously of at least one active ingredient, characterized in that the active ingredient is in a stable and complete dissolved state in a hydroalcoholic solution that includes at least 20% by mass of alcohol so as to allow rapid absorption of the active ingredient through the mucous membranes of the buccal cavity and/or the oropharynx. Uses of the galenical form are also disclosed.1. Galenical form for the administration by transmucous means of at least one active ingredient, characterized in that said active ingredient is in a stable and complete dissolved state in a hydroalcoholic solution that comprises at least 20% by mass of alcohol so as to allow rapid absorption of said active ingredient through the mucous membranes of the buccal cavity and/or the oropharynx. 2. Galenical form according to claim 1, wherein at least one active ingredient has a molecular weight that is less than 10,000 Da. 3. Galenical form according to claim 1, wherein the degree of alcohol of the hydroalcoholic solution is between 20 and 95°. 4. Galenical form according to claim 1, wherein the hydroalcoholic solution comprises between 20 and 95% alcohol and between 5 and 80% by mass of water. 5. Galenical form according to claim 1, wherein the hydroalcoholic solution comprises at least ethanol. 6. Galenical form according to claim 1, wherein the hydroalcoholic solution comprises at least isopropyl alcohol. 7. Galenical form according to claim 1, wherein the hydroalcoholic solution comprises one or more dissolution adjuvants. 8. Galenical form according to claim 6, wherein the dissolution adjuvants are selected from among the polyethylene glycol-type polymers of low molecular weight, the surfactants, isopropyl alcohol and/or alcohol-oil mixtures. 9. Galenical form according to claim 1, wherein the hydroalcoholic solution comprises an aroma and/or a sweetener to sweeten the taste sensation. 10. Galenical form according to claim 1, wherein the active ingredient contains a carbonyl acid group and wherein the hydroalcoholic solution comprises a pH-correcting agent and/or a sequestering agent. 11. Galenical form according to claim 1, wherein it allows active ingredient(s) to passively pass through the mucous membranes of the oropharynx in a time period of less than 20 seconds after administration. 12. Galenical form according to claim 1, wherein the volume for administration is less than 5 ml. 13. Galenical form according to claim 1, wherein it is packaged by means of a flexible container, ensuring the stability of the active ingredient(s) in its/their dissolving over time. 14. Galenical form according to claim 13, wherein the container comes in the form of a single-dose or multi-dose airtight case with a maximum capacity of 5 ml. 15. Galenical form according to claim 1, wherein the active ingredient(s) is/are selected from among the hormones, the anti-hormones, and any active agents on the endocrine glands, cholesterol-lowering agents, anti-infective agents, anti-viral agents, anti-parasitic agents, vascular platelet inhibitors, molecules that treat menopause, andropause or sterility, instant contraceptives, analgesic agents, anti-inflammatory agents, anti-cancer agents, immunosuppressors, anti-migraine agents, anti-emetic agents, anti-diarrhea agents, anti-spasmodic agents, anti-allergy agents, anti-arrythmic agents, erectogenic agents, anxiolytic agents, anti-diabetic agents, anti-hypertensive agents, anti-asthmatic agents, anti-parkinsonian agents and/or antihistamine agents. 16. (canceled)

A pharmaceutical composition for treatment of a pathological condition in a patient comprises, as a first component, a manganese complex of Formula I( ), and, as a second component, a non-manganese complex compound of Formula (I), optionally together with one or more physiologically acceptable carriers and/or excipients, wherein X, R, R, R, and R are as defined herein. Methods for treatment of a pathological condition in a patient, for example, a pathological condition caused by the presence of oxygen-derived free radicals, comprises administering to said patient the first component and the second component.

1. A pharmaceutical composition for treatment of a pathological condition in a patient, comprising, as a first component, a manganese complex of Formula I, and, as a second component, a non-manganese complex compound of Formula I, optionally together with one or more physiologically acceptable carriers and/or excipients, wherein X represents CH or N, each R1 independently represents hydrogen or —CH2COR5; R5 represents hydroxy, optionally hydroxylated alkoxy, amino or alkylamido; each R2 independently represents ZYR6 wherein Z represents a bond or a C1-3 alkylene or oxoalkylene group optionally substituted by R7; Y represents a bond, an oxygen atom or NR6; R6 is a hydrogen atom, COOR8, alkyl, alkenyl, cycloalkyl, aryl or aralkyl group optionally substituted by one or more groups selected from COOR8, CONR8 2, NR8 2, OR8, ═NR8, ═O, OP(O)(OR8)R7 and OSO3M; R7 is hydroxy, optionally hydroxylated, optionally alkoxylated alkyl or aminoalkyl group; R8 is a hydrogen atom or an optionally hydroxylated, optionally alkoxylated alkyl group; M is a hydrogen atom or one equivalent of a physiologically tolerable cation; R3 represents a C1-8 alkylene, a 1,2-cykloalkylene, or a 1,2-arylene group, optionally substituted with R7; and each R4 independently represents hydrogen or C1-3 alkyl. 2. A pharmaceutical composition according to claim 1, wherein R5 is hydroxy, C1-8 alkoxy, ethylene glycol, glycerol, amino or C1-8 alkylamido; Z is a bond or a group selected from CH2, (CH2)2, CO, CH2CO, CH2CH2CO and CH2COCH2; Y is a bond; R6 is a mono- or poly(hydroxy or alkoxylated)alkyl group or of the formula OP(O)(OR8)R7; and R7 is hydroxy, or an unsubstituted alkyl or aminoalkyl group. 3. A pharmaceutical composition according to claim 1, wherein R3 is ethylene and each group R1 represents —CH2COR5 in which R5 is hydroxy. 4. A pharmaceutical composition according to claim 1, wherein the first component has a Ka value in the range of from 108 to 1024. 5. A pharmaceutical composition according to claim 1, wherein the second component has a lower Ka value for Mn2+ than the corresponding Ka value for zinc (Zn2+)—, by a factor of at least 10. 6. A pharmaceutical composition according to claim 1, wherein the second component is included in an equimolar or greater amount relative to the first component. 7. A pharmaceutical composition according to claim 1, wherein the first component and the second component are included in a first component:second component molar ratio in the range of about 1:1 to 1:20. 8. A pharmaceutical composition according to claim 1, wherein the first component and the second component are included in a first component:second component molar ratio in the range of about 1:2 to 3:4. 9. A pharmaceutical composition according to claim 1, wherein the first component is manganese N,N′-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N′-diacetic acid or a salt thereof (MnDPDP) and the second component is N,N′-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N′-diacetic acid (DPDP) or a salt or non-manganese complex thereof. 10. A pharmaceutical composition according to claim 9, wherein the second component is DPDP, calcium DPDP or magnesium DPDP, or a combination of two or more thereof. 11. A method of treatment of a pathological condition in a patient, comprising administering to said patient as a first component, a manganese complex of Formula I, and, as a second component, a non-manganese complex compound of Formula I, optionally together with one or more physiologically acceptable carriers and/or excipients, wherein X represents CH or N, each R1 independently represents hydrogen or —CH2COR5; R5 represents hydroxy, optionally hydroxylated alkoxy, amino or alkylamido; each R2 independently represents ZYR6 wherein Z represents a bond or a C1-3 alkylene or oxoalkylene group optionally substituted by R7; Y represents a bond, an oxygen atom or NR6; R6 is a hydrogen atom, COOR8, alkyl, alkenyl, cycloalkyl, aryl or aralkyl group optionally substituted by one or more groups selected from COOR8, CONR8 2, NR8 2, OR8, ═NR8, ═O, OP(O)(OR8)R7 and OSO3M; R7 is hydroxy, optionally hydroxylated, optionally alkoxylated alkyl or aminoalkyl group; R8 is a hydrogen atom or an optionally hydroxylated, optionally alkoxylated alkyl group; M is a hydrogen atom or one equivalent of a physiologically tolerable cation; R3 represents a C1-8 alkylene, a 1,2-cykloalkylene, or a 1,2-arylene group, optionally substituted with R7; and each R4 independently represents hydrogen or C1-3 alkyl. 12. A method for treatment of a pathological condition in a patient, comprising administering to said patient a pharmaceutical composition according to claim 1. 13. A method according to claim 11, wherein the pathological condition is caused by the presence of oxygen-derived free radicals. 14. A method according to claim 11, wherein said condition is a cytotoxic or cytostatic drug injury. 15. A method according to claim 14, wherein the cytotoxic or cytostatic drug is a cancer treatment drug. 16. A method according to claim 14, wherein the cytotoxic or cytostatic drug comprises at least one of doxorubicin, oxaliplatin, 5-fluorouracil or paclitaxel. 17. A method according to claim 11, wherein said condition is an ischemia-reperfusion-induced injury. 18. A method according to claim 11, wherein said condition is a result of myocardial ischemia-reperfusion-induced injury. 19. A method according to claim 11, wherein said condition is associated with a thrombolytic treatment, a cardiopulmonary bypass, or percutaneous transluminal angioplasty, or is a result of cardiac or organ transplantation surgery. 20. A method according to claim 11, wherein said condition is acetaminophen-induced acute liver failure. 21. A method according to claim 11, wherein said condition is a pathological condition of iron. 22. A method according to claim 11, wherein said condition is thalassemia, sickle cell anemia, or transfusional hemosiderosis. 23. A method according to claim 11, wherein said condition is hepatitis-induced liver cirrhosis. 24. A method according to claim 11, wherein said condition is a radiation-induced injury. 25. A method according to claim 11, wherein the first component and the second component are administered simultaneously. 26. A method according to claim 11, wherein the first component and the second component are administered sequentially. 27. A method according to claim 11, comprising administering about 0.01 to 10 μmol/kg body weight of the first component and about 1 to 100 μmol/kg body weight of the second component and wherein the second component is administered in an equimolar or greater amount relative to the first component. 28. A pharmaceutical composition according to claim 1, wherein the first component and the second component are included in a first component:second component molar ratio in the range of about 1:1 to 1:10. 29. A pharmaceutical composition according to claim 1, wherein the first component and the second component are included in a first component:second component molar ratio in the range of about 1:1 to 1:5.

A pharmaceutical composition for treatment of a pathological condition in a patient comprises, as a first component, a manganese complex of Formula I( ), and, as a second component, a non-manganese complex compound of Formula (I), optionally together with one or more physiologically acceptable carriers and/or excipients, wherein X, R, R, R, and R are as defined herein. Methods for treatment of a pathological condition in a patient, for example, a pathological condition caused by the presence of oxygen-derived free radicals, comprises administering to said patient the first component and the second component.1. A pharmaceutical composition for treatment of a pathological condition in a patient, comprising, as a first component, a manganese complex of Formula I, and, as a second component, a non-manganese complex compound of Formula I, optionally together with one or more physiologically acceptable carriers and/or excipients, wherein X represents CH or N, each R1 independently represents hydrogen or —CH2COR5; R5 represents hydroxy, optionally hydroxylated alkoxy, amino or alkylamido; each R2 independently represents ZYR6 wherein Z represents a bond or a C1-3 alkylene or oxoalkylene group optionally substituted by R7; Y represents a bond, an oxygen atom or NR6; R6 is a hydrogen atom, COOR8, alkyl, alkenyl, cycloalkyl, aryl or aralkyl group optionally substituted by one or more groups selected from COOR8, CONR8 2, NR8 2, OR8, ═NR8, ═O, OP(O)(OR8)R7 and OSO3M; R7 is hydroxy, optionally hydroxylated, optionally alkoxylated alkyl or aminoalkyl group; R8 is a hydrogen atom or an optionally hydroxylated, optionally alkoxylated alkyl group; M is a hydrogen atom or one equivalent of a physiologically tolerable cation; R3 represents a C1-8 alkylene, a 1,2-cykloalkylene, or a 1,2-arylene group, optionally substituted with R7; and each R4 independently represents hydrogen or C1-3 alkyl. 2. A pharmaceutical composition according to claim 1, wherein R5 is hydroxy, C1-8 alkoxy, ethylene glycol, glycerol, amino or C1-8 alkylamido; Z is a bond or a group selected from CH2, (CH2)2, CO, CH2CO, CH2CH2CO and CH2COCH2; Y is a bond; R6 is a mono- or poly(hydroxy or alkoxylated)alkyl group or of the formula OP(O)(OR8)R7; and R7 is hydroxy, or an unsubstituted alkyl or aminoalkyl group. 3. A pharmaceutical composition according to claim 1, wherein R3 is ethylene and each group R1 represents —CH2COR5 in which R5 is hydroxy. 4. A pharmaceutical composition according to claim 1, wherein the first component has a Ka value in the range of from 108 to 1024. 5. A pharmaceutical composition according to claim 1, wherein the second component has a lower Ka value for Mn2+ than the corresponding Ka value for zinc (Zn2+)—, by a factor of at least 10. 6. A pharmaceutical composition according to claim 1, wherein the second component is included in an equimolar or greater amount relative to the first component. 7. A pharmaceutical composition according to claim 1, wherein the first component and the second component are included in a first component:second component molar ratio in the range of about 1:1 to 1:20. 8. A pharmaceutical composition according to claim 1, wherein the first component and the second component are included in a first component:second component molar ratio in the range of about 1:2 to 3:4. 9. A pharmaceutical composition according to claim 1, wherein the first component is manganese N,N′-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N′-diacetic acid or a salt thereof (MnDPDP) and the second component is N,N′-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N′-diacetic acid (DPDP) or a salt or non-manganese complex thereof. 10. A pharmaceutical composition according to claim 9, wherein the second component is DPDP, calcium DPDP or magnesium DPDP, or a combination of two or more thereof. 11. A method of treatment of a pathological condition in a patient, comprising administering to said patient as a first component, a manganese complex of Formula I, and, as a second component, a non-manganese complex compound of Formula I, optionally together with one or more physiologically acceptable carriers and/or excipients, wherein X represents CH or N, each R1 independently represents hydrogen or —CH2COR5; R5 represents hydroxy, optionally hydroxylated alkoxy, amino or alkylamido; each R2 independently represents ZYR6 wherein Z represents a bond or a C1-3 alkylene or oxoalkylene group optionally substituted by R7; Y represents a bond, an oxygen atom or NR6; R6 is a hydrogen atom, COOR8, alkyl, alkenyl, cycloalkyl, aryl or aralkyl group optionally substituted by one or more groups selected from COOR8, CONR8 2, NR8 2, OR8, ═NR8, ═O, OP(O)(OR8)R7 and OSO3M; R7 is hydroxy, optionally hydroxylated, optionally alkoxylated alkyl or aminoalkyl group; R8 is a hydrogen atom or an optionally hydroxylated, optionally alkoxylated alkyl group; M is a hydrogen atom or one equivalent of a physiologically tolerable cation; R3 represents a C1-8 alkylene, a 1,2-cykloalkylene, or a 1,2-arylene group, optionally substituted with R7; and each R4 independently represents hydrogen or C1-3 alkyl. 12. A method for treatment of a pathological condition in a patient, comprising administering to said patient a pharmaceutical composition according to claim 1. 13. A method according to claim 11, wherein the pathological condition is caused by the presence of oxygen-derived free radicals. 14. A method according to claim 11, wherein said condition is a cytotoxic or cytostatic drug injury. 15. A method according to claim 14, wherein the cytotoxic or cytostatic drug is a cancer treatment drug. 16. A method according to claim 14, wherein the cytotoxic or cytostatic drug comprises at least one of doxorubicin, oxaliplatin, 5-fluorouracil or paclitaxel. 17. A method according to claim 11, wherein said condition is an ischemia-reperfusion-induced injury. 18. A method according to claim 11, wherein said condition is a result of myocardial ischemia-reperfusion-induced injury. 19. A method according to claim 11, wherein said condition is associated with a thrombolytic treatment, a cardiopulmonary bypass, or percutaneous transluminal angioplasty, or is a result of cardiac or organ transplantation surgery. 20. A method according to claim 11, wherein said condition is acetaminophen-induced acute liver failure. 21. A method according to claim 11, wherein said condition is a pathological condition of iron. 22. A method according to claim 11, wherein said condition is thalassemia, sickle cell anemia, or transfusional hemosiderosis. 23. A method according to claim 11, wherein said condition is hepatitis-induced liver cirrhosis. 24. A method according to claim 11, wherein said condition is a radiation-induced injury. 25. A method according to claim 11, wherein the first component and the second component are administered simultaneously. 26. A method according to claim 11, wherein the first component and the second component are administered sequentially. 27. A method according to claim 11, comprising administering about 0.01 to 10 μmol/kg body weight of the first component and about 1 to 100 μmol/kg body weight of the second component and wherein the second component is administered in an equimolar or greater amount relative to the first component. 28. A pharmaceutical composition according to claim 1, wherein the first component and the second component are included in a first component:second component molar ratio in the range of about 1:1 to 1:10. 29. A pharmaceutical composition according to claim 1, wherein the first component and the second component are included in a first component:second component molar ratio in the range of about 1:1 to 1:5.

The invention provides compositions of novel high penetration compositions (HPC) or high penetration prodrugs (HPP) for treatment of pulmonary conditions (e.g. asthma). The HPCs/HPPs are capable of being converted to parent active drugs or drug metabolites after crossing the biological barrier and thus can render treatments for the conditions that the parent drugs or metabolites can. Additionally, the HPPs are capable of reaching areas that parent drugs may not be able to access or to render a sufficient concentration at the target areas and therefore render novel treatments. The HPCs/HPPs can be administered to a subject through various administration routes, e.g., locally delivered to an action site of a condition with a high concentration or systematically administered to a biological subject and enter the general circulation with a faster rate.

1. A high penetration prodrug for treatment of a pulmonary condition comprising a) a functional unit; b) a linker c) a transportational unit; the functional unit being covalently linked to the transportational unit via the linker; the functional unit comprising a moiety of a parent drug or of a related compound of the parent drug, the parent drug selected from the group consisting of antihistamines, β2-adrenergic receptor agonists, 5-lipoxygenase-activating protein (FLAP) inhibitors, 5-lipoxygenase inhibitors, leukotriene receptor antagonists, cough suppressants, and decongestants; the transportational unit comprising a protonatable amine group; and the linker comprising a chemical bond that is capable of being cleaved after the high penetration prodrug penetrates across a biological barrier. 2. The high penetration prodrug according to claim 1, wherein the chemical bond is selected from the group consisting of a covalent chemical bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a carbonate bond, a carbamate bond, a phosphate bond, and an oxime bond. 3. The high penetration prodrug according to claim 1, the functional unit further comprising a lipophilic derivative of a moiety of the first parent drug or the related compound of the first parent drug. 4. The high penetration prodrug according to claim 3, wherein the lipophilic derivative is selected from the group consisting of carbonate, ester, amide, carbamate, N-mannich base, ether, thioether, thioester, phosphate, oxime and imine. 5. The high penetration prodrug according to claim 1, wherein the antihistamines is selected from the group consisting of fexofenadine (RS)-2-[4-[1-Hydroxy-4-[4-(hydroxy-diphenyl-methyl)-1-piperidyl]butyl]phenyl]-2-methyl-propanoic acid, clemastine ((2R)-2-{2-[(1R)-1-(4-chlorophenyl)-1-phenylethoxy]ethyl}-1-methylpyrrolidine), diphenhydramine[2-(diphenylmethoxy)-N,N-dimethylethanamine], doxylamine [(RS)—N,N-dimethyl-2-(1-phenyl-1-pyridine-2-yl-ethoxy)-ethanamine], desloratadine [8-chloro-6,11-dihydro-11-(4-piperdinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine], brompheniramine (3-(4-bromophenyl)-N,N-dimethyl-3-pyridin-2-yl-propan-1-amine), chlorophenamine [3-(4-chlorophenyl)-N,N-dimethyl-3-pyridin-2-yl-propan-1-amine, pheniramine, fluorpheniramine, chlorpheniramine, dexchlorpheniramine (Polaramine), deschlorpheniramine, dipheniramine, iodopheniramine, cromoglicic acid (5,5′-(2-hydroxypropane-1,3-diyl)bis(oxy)bis(4-oxo-4H-chromene-2-carboxylic acid), loratadine [ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidine)-1-piperidinecarboxylate, acrivastine [(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoic acid], ebastine [4-(4-benzhydryloxy-1-piperidyl)-1-(4-tert-butylphenyl)butan-1-one], carebastine, promethazine [(RS)—N,N-dimethyl-1-(10H-phenothiazin-10-yl)propan-2-amine], and olopatadine[{(11Z)-11-[3-(dimethylamino)-propylidene]-6,11-dihydrodibenzo[b,e]oxepin-2-yl}acetic acid]. 6. The high penetration prodrug according to claim 1, wherein the β2-adrenergic receptor agonists is selected from the group consisting of albuterol [(RS)-4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol], levosalbuterol [4-[(1R)-2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol], terbutaline [(RS)-5-[2-(tert-butylamino)-1-hydroxyethyl]benzene-1,3-diol], pirbuterol [(RS)-6-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)pyridin-3-ol], procaterol [(±)-(1R,2S)-rel-8-Hydroxy-5-[1-hydroxy-2-(isopropylamino)butyl]-quinolin-2(1H)-one], metaproterenol [(RS)-5-[1-hydroxy-2-(isopropylamino)ethyl]benzene-1,3-diol], fenoterol [(RR,SS)-5-(1-hydroxy-2-{[2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)benzene-1,3-diol], bitolterol mesylate [(RS)-[4-(1-Hydroxy-2-tert-butylamino-ethyl)-2-(4-methylbenzoyl)oxy-phenyl]4-methylbenzoate], ritodrine [4-((1R,2S)-1-hydroxy-2-{[2-(4-hydroxyphenyl)ethyl]amino}propyl)phenol], salmeterol [(RS)-2-(hydroxymethyl)-4-{1-hydroxy-2-[6-(4-phenylbutoxyl)hexylamino]ethyl}phenol], formoterol [(RS,SR)—N-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide], bambuterol [(RS)-5-[2-(tert-butylamino)-1-hydroxyethyl]benzene-1,3-diyl bis(dimethylcarbamate)], clenbuterol [(RS)-1-(4-amino-3,5-dichlorophenyl)-2-(tert-butylamino)ethanol], and indacaterol [(R)-5-[2-[(5,6-Diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-hydroxyethyl]-8-hydroxyquinolin-2(1H)-one]. 7. The high penetration prodrug according to claim 1, wherein the 5-lipoxygenase-activating protein (FLAP) inhibitors are selected from the group consisting of MK-886 [3-(1-(4-Chlorobenzyl)-3-t-butylthio-5-isopropylindol-2-yl)-2,2-dimethylpropanoic acid], MK-0591 [3-(1-(4-chlorobenzyl-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl))-2,2-dimethyl propanoic acid], 2-cyclopentyl-2-[4-(quinolin-2-ylmethoxy)phenyl]acetic acid, and 3-[[1-(4-chlorobenzyl)-4-methyl-6-(5-phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]-2,2-dimethylpropanoic acid. 8. The high penetration prodrug according to claim 1, wherein the 5-lipoxygenase inhibitors are selected from the group consisting of zileuton [(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-hydroxyurea], theophylline (1,3-dimethyl-7H-purine-2,6-dione), 2,6-dimethyl-4-[2-(4-fluorophenyl)ethenyl]phenol, 2,6-dimethyl-4-[2-(3-pyridyl)ethenyl]phenol, and 2,6-dimethyl-4-[2-(2-thienyl)ethenyl]phenol. 9. The high penetration prodrug according to claim 1, wherein the leukotriene receptor antagonists are selected from the group consisting of montelukast {R-(E)-1-[[[-1-[3-[2-(7-chloro2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid}, 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid, (E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl][[3-dimethylamino]-3-oxopropyl]thio]methyl]thio]propanoic acid sodium salt, 2(S)-hydroxyl-3(R)-carboxyethylthio)-3-[2-(8-phenyloctyl)phenyl]propanoic acid, 4-[4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl]phenyl]-4-oxo-butanoic acid, and 3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)((3-dimethylamino-3-oxopropyl)thio)methyl)thiopropanoic acid. 10. The high penetration prodrug according to claim 1, wherein the cough suppressants are selected from the group consisting of dextromethorphan ((+)-3-methoxy-17-methyl-(9α,13α,14α)-morphinan), tipepidine (3-(di-2-thienylmethylene)-1-methylpiperidine), cloperastine (1-[2-[(4-chlorophenyl)-phenyl-methoxy]ethyl]piperidine), benproperine (1-[2-(2-benzylphenoxy)-1-methylethyl]piperidine), dioxopromethazine (9,9-dioxopromethazine), promolate (2-morpholinoethyl-2-phenoxy-2-methylpropionate), fominoben (N-2-chloro-6-benzoyl-aminobenzyl-methylaminoacetyl-morpholine), and pentoxyverine (2-[2-(diethylamino)ethoxy]ethyl 1-phenylcyclopentanecarboxylate). 11. The high penetration prodrug according to claim 1, wherein the decongestants are selected from the group consisting of ephedrine [(R,S)-2-(methylamino)-1-phenylpropan-1-ol], levomethamphetamine [(R)—N-methyl-1-phenyl-propan-2-amine], phenylephrine [(R)-3-[-1-hydroxy-2-(methylamino)ethyl]phenol], propylhexedrine [(RS)—N,α-dimethyl-cyclohexylethylamine], pseudoephedrine [(R*,R*)-2-methylamino-1-phenylpropan-1-ol], synephrine [4-[1-hydroxy-2-(methylamino)ethyl]phenol], and tetrahydrozoline [(RS)-2-(1,2,3,4-tetrahydronaphthalen-1-yl)-4,5-dihydro-1H-imidazole]. 12. The high penetration prodrug according to claim 1, further comprising an HPP having a structure selected from the group consisting of. Structure FLAP-1, Structure FLAP-2, Structure FLAP-3, Structure FLAP-4, Structure FLAP-5, Structure FLAP-6, Structure 5-LI-1-, Structure 5-LI-2, Structure 5-LI-3, Structure 5-LI-4, Structure 5-LI-5, Structure 5-LI-6, Structure 5-LI-7, Structure 5-LI-8, Structure LRA-1, Structure LRA-2, Structure LRA-3, Structure LRA-4, Structure LRA-5, Structure LRA-6, Structure ARA-1, Structure ARA-2, Structure ARA-3, Structure ARA-4, Structure ARA-5, Structure ARA-6, Structure ARA-7, Structure ARA-8, Structure ARA-9, Structure ARA-10, Structure ARA-11, Structure ARA-12, Structure ARA-13, and Structure ARA-14, including stereoisomers and pharmaceutically acceptable salts thereof. 13. The high penetration prodrug according to claim 1, wherein the protonatable amine group is selected from the group consisting of a substituted and unsubstituted primary amine group, a substituted and unsubstituted secondary amine group, and a substituted and unsubstituted tertiary amine group. 14. The high penetration prodrug according to claim 13, wherein the protonatable amine group is selected from the group consisting of Structure W-1, Structure W-2, Structure W-3, Structure W-4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11, Structure W-12, Structure W-13, Structure W-14, Structure W-15, Structure W-16, Structure W-17 and Structure W-18, including stereoisomers and pharmaceutically acceptable salts thereof. 15. A pharmaceutical composition for treatment of a pulmonary condition comprising a first group of high penetration prodrug(s) and a pharmaceutically acceptable carrier, wherein one or more HPPs of the first group of high penetration prodrugs are a compound according to claim 1, 16. A pharmaceutical composition comprising a second group of HPP and a pharmaceutically acceptable carrier, wherein the second group of HPP comprises one or more HPPs selected from the group consisting of Structures NSAID-1-NSAID-13, and Structure AB-1. 17. The pharmaceutical composition according to claim 15 further comprising a second group of HPP and a pharmaceutically acceptable carrier, wherein the second group of HPP comprises one or more HPPs selected from the group consisting of Structures NSAID-1-NSAID-13, and Structure AB-1. 18. The pharmaceutical composition according to claim 15, the pharmaceutically acceptable carrier being selected from the group of alcohol, acetone, ester, water, and aqueous solution. 19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and more than one high penetration prodrug for the treatment of a pulmonary condition, the high penetration prodrug comprising a functional unit covalently linked to a transportational unit via a linker; the functional unit comprising a moiety of a parent drug or a related compound of the parent drug; the parent drug selected from the group consisting of antihistamines, β2-adrenergic receptor agonists, 5-lipoxygenase-activating protein (FLAP) inhibitors, 5-lipoxygenase inhibitors, leukotriene receptor antagonists, cough suppressants, antibiotics, anti-inflammatory drugs, and decongestants; the transportational unit comprising a protonatable amine group; and the linker comprising a chemical bond that is capable of being cleaved after the high penetration prodrug penetrates across a biological barrier. 20. The pharmaceutical composition according to claim 17, wherein the more than one high penetration prodrug comprise functional units of a first parent drug and a second parent drug, and the first and the second parent drugs can be the same or different. 21. The pharmaceutical composition according to claim 17, wherein the anti-inflammatory drugs are selected from the group consisting of non-steroid anti-inflammatory agents, aspirin, ibuprofen, diflunisal, diclofenac, leukotriene antagonists, montelukast and zileuton. 22. The pharmaceutical composition according to claim 17, wherein the antibiotics are selected from the group consisting of beta-lactam antibiotics, sulfonamides and quinolones. 23. The pharmaceutical composition according to claim 20, wherein the beta-lactam antibiotics are selected from the group consisting of penicillin derivatives, cephalosporins, penems, monobactams, carbapenems, beta-lactamase inhibitors, aminopenicillins, amoxicillin, ampicillin, epicillin, carboxypenicillins, carbenicillin, ticarcillin, temocillin, ureidopenicillins, azlocillin, piperacillin, mezlocillin, mecillinam, sulbenicillin, benzathine penicillin, penicillin G, penicillin V, penicillin O, procaine penicillin, oxacillin, methicillin, nafcillin, cloxacillin, dicloxacillin, flucloxacillin, pivampicillin, hetacillin, becampicillin, metampicillin, talampicillin, co-amoxiclav, piperacillion, cephalexin, cephalothin, cefazolin, cefaclor, cefuroxime, cefamandole, cefotetan, cefoxitin, ceforanide, ceftriaxone, cefotaxime, cefpodoxime proxetil, ceftazidime, cefepime, cefoperazone, ceftizoxime, cefixime, cefpirome, faropenem, aztreonam, tigemonam, biapenem, •doripenem, ertapenem, •imipenem, •meropenem, •panipenem, tazobactam, sulbactam, clavulanic acid, [(N-benzyloxycarbonylamino)methyl]-phosphonic acid mono-(4-nitrophenyl) ester sodium salt, [(N-benzyloxycarbonylamino)methyl]-phosphonic acid mono-(3-pyridinyl) ester sodium salt, sulfanilamide (4-aminobenzenesulfonamide), sulfasalazine (6-oxo-3-(2-[4-(N-pyridin-2-ylsulfamoyl)phenyl]hydrazono)cyclohexa-1,4-dienecarboxylic acid), 1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-quinoline-3-carboxylic acid, and nalidixic acid (1-ethyl-7-methyl-4-oxo-[1,8]naphthyridine-3-carboxylic acid). 24. The pharmaceutical composition according to claim 20, wherein the sulfonamides are selected from the group consisting of sulfaisodimidine, sulfanilamide, sulfadiazine, sulfisoxazole, sulfamethoxazole, sulfadimethoxine, sulfamethoxypyridazine, sulfacetamide, sulfadoxine, acetazolamide, bumetanide, chlorthalidone, clopamide, furosemide, hydrochlorothiazide, indapamide, mefruside, metolazone, xipamide, dichlorphenamide, dorzolamide, acetazolamide, ethoxzolamide, sultiame, zonisamide, mafenide, celecoxib, darunavir, probenecid, sulfasalazine, and sumatriptan. 25. The pharmaceutical composition according to claim 20, wherein the quinolones are selected from the group consisting of cinoxacin, flumequine, nalidixic acid, oxolinic acid, piromidic acid, pipemidic acid, rosoxacin, ciprofloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, clinafloxacin, gemifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, garenoxacin, ecinofloxacin, delafloxacin and nalidixic acid. 26. The pharmaceutical composition according to claim 18, wherein the parent drugs comprise penicillin V, aspirin, zileuton, metaproterenol, and fexofenadine. 27. The pharmaceutical composition according to claim 18, wherein the parent drugs comprise aspirin, and zileuton. 28. The pharmaceutical composition according to claim 18, wherein the parent drugs comprise cefoxitin, aspirin, zileuton, albuterol, and clemastine. 29. The pharmaceutical composition according to claim 18, wherein the parent drugs comprise cefoxitin, aspirin, montelukast, albuterol, and acrivastine. 30. The pharmaceutical composition according to claim 18, wherein the parent drugs comprise cefoxitin, ibuprofen, montelukast, albuterol, and clemastine. 31. The pharmaceutical composition according to claim 18, wherein the second parent drug is acrivastine and the first parent drugs comprise cefoxitin, ibuprofen, montelukast, and albuterol. 32. The pharmaceutical composition according to claim 18, wherein the first parent drugs comprise ibuprofen, montelukast, and acrivastine. 33. The pharmaceutical composition according to claim 18, wherein the second parent drug is selected from the group consisting of dextromethorphan, pentoxyverine, acrivastine, diphenhydramine, doxylamine, desloratadine, chlorophenamine, ephedrine, and levomethamphetamin. 34. The pharmaceutical composition according to claim 18, wherein the second parent drug is acrivastine and the first parent drugs comprise cefoxitin, ibuprofen, and montelukast. 35. The pharmaceutical composition according to claim 18, wherein the first parent drugs comprise diclofenac, montelukast, pirbuterol, and acrivastine. 36. The pharmaceutical composition according to claim 18, wherein the second parent drug is acrivastine and the first parent drugs comprise diclofenac, montelukast, and pirbuterol. 37. The pharmaceutical composition according to claim 18, wherein the first parent drugs comprise diflunisal, zileuton, terbutaline, and acrivastine. 38. The pharmaceutical composition according to claim 18, wherein the second parent drug is acrivastine and the first parent drugs comprise diflunisal, zileuton, and terbutaline. 39. The pharmaceutical composition according to claim 18, wherein the first parent drugs comprise azlocillin, diflunisal, montelukast, and acrivastine. 40. The pharmaceutical composition according to claim 18, wherein the second parent drug is acrivastine and the first parent drugs comprise azlocillin, diflunisal, and montelukast. 41. The pharmaceutical composition according to claim 18, wherein the first parent drugs comprise piperacillin, diclofenac, zileuton, metaproterenol, and acrivastine. 42. The pharmaceutical composition according to claim 18, wherein the second parent drug is acrivastine and the first parent drugs comprise piperacillin, aspirin, zileuton, and metaproterenol. 43. A pharmaceutical composition for the treatment of a pulmonary condition comprising a pharmaceutically acceptable carrier, at least one high penetration prodrug, and at least a second compound selected from the group consisting of sildenafil, vardenafil, tadalafil, acetildenafil, avanafil, lodenafil, mirodenafil, clemastine, metaproterenol, udenafil, and salts thereof; the high penetration prodrug comprising a functional unit covalently linked to a transportational unit via a linker; the functional unit comprising a moiety of a parent drug or a related compound of the parent drug; the parent drug selected from the group consisting of antihistamines, β2-adrenergic receptor agonists, 5-lipoxygenase-activating protein (FLAP) inhibitors, 5-lipoxygenase inhibitors, leukotriene receptor antagonists, cough suppressants, antibiotics, anti-inflammatory drugs, and decongestants; the transportational unit comprising a protonatable amine group; and the linker comprising a chemical bond that is capable of being cleaved after the high penetration prodrug penetrates across a biological barrier. 44. The pharmaceutical composition according to claim 41, wherein the second compounds are sildenafil and metaproterenol, and the parent drugs are 6-phenoxyacetacetamidopenicillanic acid, aspirin, zileuton, and fexofenadine. 45. The pharmaceutical composition according to claim 41, wherein the second compounds are vardenafil and metaproterenol, and the parent drugs are 6-phenoxyacetacetamidopenicillanic acid, aspirin, zileuton, and fexofenadine. 46. The pharmaceutical composition according to claim 41, wherein the second compounds are tadalafil and clemastine, and the parent drugs are 3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, aspirin, and montelukast. 47. The pharmaceutical composition according to claim 41, wherein the second compounds are udenafil and clemastine, and the parent drugs are 3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, ibuprofen, and montelukast. 48. The pharmaceutical composition according to claim 41, wherein the second compounds are udenafil and clemastine, and the parent drugs are 3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, ibuprofen, and zileuton. 49. A method for treating a pulmonary condition in a biological subject, comprising administrating to the biological subject a high penetration drug according to claim 1 or the pharmaceutical composition according to claim 15, claim 17 or claim 41. 50. The method according to claim 47, the pulmonary condition being selected from the group consisting of asthma, lower, and upper respiratory tract infections, chronic bronchitis, chronic obstructive pulmonary disease, emphysema, cystic fibrosis, pneumonia, sarcoidosis, pulmonary fibrosis, allergic rhinitis, allergic conjunctivitis, itchiness, and runny nose.

The invention provides compositions of novel high penetration compositions (HPC) or high penetration prodrugs (HPP) for treatment of pulmonary conditions (e.g. asthma). The HPCs/HPPs are capable of being converted to parent active drugs or drug metabolites after crossing the biological barrier and thus can render treatments for the conditions that the parent drugs or metabolites can. Additionally, the HPPs are capable of reaching areas that parent drugs may not be able to access or to render a sufficient concentration at the target areas and therefore render novel treatments. The HPCs/HPPs can be administered to a subject through various administration routes, e.g., locally delivered to an action site of a condition with a high concentration or systematically administered to a biological subject and enter the general circulation with a faster rate.1. A high penetration prodrug for treatment of a pulmonary condition comprising a) a functional unit; b) a linker c) a transportational unit; the functional unit being covalently linked to the transportational unit via the linker; the functional unit comprising a moiety of a parent drug or of a related compound of the parent drug, the parent drug selected from the group consisting of antihistamines, β2-adrenergic receptor agonists, 5-lipoxygenase-activating protein (FLAP) inhibitors, 5-lipoxygenase inhibitors, leukotriene receptor antagonists, cough suppressants, and decongestants; the transportational unit comprising a protonatable amine group; and the linker comprising a chemical bond that is capable of being cleaved after the high penetration prodrug penetrates across a biological barrier. 2. The high penetration prodrug according to claim 1, wherein the chemical bond is selected from the group consisting of a covalent chemical bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a carbonate bond, a carbamate bond, a phosphate bond, and an oxime bond. 3. The high penetration prodrug according to claim 1, the functional unit further comprising a lipophilic derivative of a moiety of the first parent drug or the related compound of the first parent drug. 4. The high penetration prodrug according to claim 3, wherein the lipophilic derivative is selected from the group consisting of carbonate, ester, amide, carbamate, N-mannich base, ether, thioether, thioester, phosphate, oxime and imine. 5. The high penetration prodrug according to claim 1, wherein the antihistamines is selected from the group consisting of fexofenadine (RS)-2-[4-[1-Hydroxy-4-[4-(hydroxy-diphenyl-methyl)-1-piperidyl]butyl]phenyl]-2-methyl-propanoic acid, clemastine ((2R)-2-{2-[(1R)-1-(4-chlorophenyl)-1-phenylethoxy]ethyl}-1-methylpyrrolidine), diphenhydramine[2-(diphenylmethoxy)-N,N-dimethylethanamine], doxylamine [(RS)—N,N-dimethyl-2-(1-phenyl-1-pyridine-2-yl-ethoxy)-ethanamine], desloratadine [8-chloro-6,11-dihydro-11-(4-piperdinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine], brompheniramine (3-(4-bromophenyl)-N,N-dimethyl-3-pyridin-2-yl-propan-1-amine), chlorophenamine [3-(4-chlorophenyl)-N,N-dimethyl-3-pyridin-2-yl-propan-1-amine, pheniramine, fluorpheniramine, chlorpheniramine, dexchlorpheniramine (Polaramine), deschlorpheniramine, dipheniramine, iodopheniramine, cromoglicic acid (5,5′-(2-hydroxypropane-1,3-diyl)bis(oxy)bis(4-oxo-4H-chromene-2-carboxylic acid), loratadine [ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidine)-1-piperidinecarboxylate, acrivastine [(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoic acid], ebastine [4-(4-benzhydryloxy-1-piperidyl)-1-(4-tert-butylphenyl)butan-1-one], carebastine, promethazine [(RS)—N,N-dimethyl-1-(10H-phenothiazin-10-yl)propan-2-amine], and olopatadine[{(11Z)-11-[3-(dimethylamino)-propylidene]-6,11-dihydrodibenzo[b,e]oxepin-2-yl}acetic acid]. 6. The high penetration prodrug according to claim 1, wherein the β2-adrenergic receptor agonists is selected from the group consisting of albuterol [(RS)-4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol], levosalbuterol [4-[(1R)-2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol], terbutaline [(RS)-5-[2-(tert-butylamino)-1-hydroxyethyl]benzene-1,3-diol], pirbuterol [(RS)-6-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)pyridin-3-ol], procaterol [(±)-(1R,2S)-rel-8-Hydroxy-5-[1-hydroxy-2-(isopropylamino)butyl]-quinolin-2(1H)-one], metaproterenol [(RS)-5-[1-hydroxy-2-(isopropylamino)ethyl]benzene-1,3-diol], fenoterol [(RR,SS)-5-(1-hydroxy-2-{[2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)benzene-1,3-diol], bitolterol mesylate [(RS)-[4-(1-Hydroxy-2-tert-butylamino-ethyl)-2-(4-methylbenzoyl)oxy-phenyl]4-methylbenzoate], ritodrine [4-((1R,2S)-1-hydroxy-2-{[2-(4-hydroxyphenyl)ethyl]amino}propyl)phenol], salmeterol [(RS)-2-(hydroxymethyl)-4-{1-hydroxy-2-[6-(4-phenylbutoxyl)hexylamino]ethyl}phenol], formoterol [(RS,SR)—N-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide], bambuterol [(RS)-5-[2-(tert-butylamino)-1-hydroxyethyl]benzene-1,3-diyl bis(dimethylcarbamate)], clenbuterol [(RS)-1-(4-amino-3,5-dichlorophenyl)-2-(tert-butylamino)ethanol], and indacaterol [(R)-5-[2-[(5,6-Diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-hydroxyethyl]-8-hydroxyquinolin-2(1H)-one]. 7. The high penetration prodrug according to claim 1, wherein the 5-lipoxygenase-activating protein (FLAP) inhibitors are selected from the group consisting of MK-886 [3-(1-(4-Chlorobenzyl)-3-t-butylthio-5-isopropylindol-2-yl)-2,2-dimethylpropanoic acid], MK-0591 [3-(1-(4-chlorobenzyl-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl))-2,2-dimethyl propanoic acid], 2-cyclopentyl-2-[4-(quinolin-2-ylmethoxy)phenyl]acetic acid, and 3-[[1-(4-chlorobenzyl)-4-methyl-6-(5-phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]-2,2-dimethylpropanoic acid. 8. The high penetration prodrug according to claim 1, wherein the 5-lipoxygenase inhibitors are selected from the group consisting of zileuton [(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-hydroxyurea], theophylline (1,3-dimethyl-7H-purine-2,6-dione), 2,6-dimethyl-4-[2-(4-fluorophenyl)ethenyl]phenol, 2,6-dimethyl-4-[2-(3-pyridyl)ethenyl]phenol, and 2,6-dimethyl-4-[2-(2-thienyl)ethenyl]phenol. 9. The high penetration prodrug according to claim 1, wherein the leukotriene receptor antagonists are selected from the group consisting of montelukast {R-(E)-1-[[[-1-[3-[2-(7-chloro2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid}, 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid, (E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl][[3-dimethylamino]-3-oxopropyl]thio]methyl]thio]propanoic acid sodium salt, 2(S)-hydroxyl-3(R)-carboxyethylthio)-3-[2-(8-phenyloctyl)phenyl]propanoic acid, 4-[4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl]phenyl]-4-oxo-butanoic acid, and 3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)((3-dimethylamino-3-oxopropyl)thio)methyl)thiopropanoic acid. 10. The high penetration prodrug according to claim 1, wherein the cough suppressants are selected from the group consisting of dextromethorphan ((+)-3-methoxy-17-methyl-(9α,13α,14α)-morphinan), tipepidine (3-(di-2-thienylmethylene)-1-methylpiperidine), cloperastine (1-[2-[(4-chlorophenyl)-phenyl-methoxy]ethyl]piperidine), benproperine (1-[2-(2-benzylphenoxy)-1-methylethyl]piperidine), dioxopromethazine (9,9-dioxopromethazine), promolate (2-morpholinoethyl-2-phenoxy-2-methylpropionate), fominoben (N-2-chloro-6-benzoyl-aminobenzyl-methylaminoacetyl-morpholine), and pentoxyverine (2-[2-(diethylamino)ethoxy]ethyl 1-phenylcyclopentanecarboxylate). 11. The high penetration prodrug according to claim 1, wherein the decongestants are selected from the group consisting of ephedrine [(R,S)-2-(methylamino)-1-phenylpropan-1-ol], levomethamphetamine [(R)—N-methyl-1-phenyl-propan-2-amine], phenylephrine [(R)-3-[-1-hydroxy-2-(methylamino)ethyl]phenol], propylhexedrine [(RS)—N,α-dimethyl-cyclohexylethylamine], pseudoephedrine [(R*,R*)-2-methylamino-1-phenylpropan-1-ol], synephrine [4-[1-hydroxy-2-(methylamino)ethyl]phenol], and tetrahydrozoline [(RS)-2-(1,2,3,4-tetrahydronaphthalen-1-yl)-4,5-dihydro-1H-imidazole]. 12. The high penetration prodrug according to claim 1, further comprising an HPP having a structure selected from the group consisting of. Structure FLAP-1, Structure FLAP-2, Structure FLAP-3, Structure FLAP-4, Structure FLAP-5, Structure FLAP-6, Structure 5-LI-1-, Structure 5-LI-2, Structure 5-LI-3, Structure 5-LI-4, Structure 5-LI-5, Structure 5-LI-6, Structure 5-LI-7, Structure 5-LI-8, Structure LRA-1, Structure LRA-2, Structure LRA-3, Structure LRA-4, Structure LRA-5, Structure LRA-6, Structure ARA-1, Structure ARA-2, Structure ARA-3, Structure ARA-4, Structure ARA-5, Structure ARA-6, Structure ARA-7, Structure ARA-8, Structure ARA-9, Structure ARA-10, Structure ARA-11, Structure ARA-12, Structure ARA-13, and Structure ARA-14, including stereoisomers and pharmaceutically acceptable salts thereof. 13. The high penetration prodrug according to claim 1, wherein the protonatable amine group is selected from the group consisting of a substituted and unsubstituted primary amine group, a substituted and unsubstituted secondary amine group, and a substituted and unsubstituted tertiary amine group. 14. The high penetration prodrug according to claim 13, wherein the protonatable amine group is selected from the group consisting of Structure W-1, Structure W-2, Structure W-3, Structure W-4, Structure W-5, Structure W-6, Structure W-7, Structure W-8, Structure W-9, Structure W-10, Structure W-11, Structure W-12, Structure W-13, Structure W-14, Structure W-15, Structure W-16, Structure W-17 and Structure W-18, including stereoisomers and pharmaceutically acceptable salts thereof. 15. A pharmaceutical composition for treatment of a pulmonary condition comprising a first group of high penetration prodrug(s) and a pharmaceutically acceptable carrier, wherein one or more HPPs of the first group of high penetration prodrugs are a compound according to claim 1, 16. A pharmaceutical composition comprising a second group of HPP and a pharmaceutically acceptable carrier, wherein the second group of HPP comprises one or more HPPs selected from the group consisting of Structures NSAID-1-NSAID-13, and Structure AB-1. 17. The pharmaceutical composition according to claim 15 further comprising a second group of HPP and a pharmaceutically acceptable carrier, wherein the second group of HPP comprises one or more HPPs selected from the group consisting of Structures NSAID-1-NSAID-13, and Structure AB-1. 18. The pharmaceutical composition according to claim 15, the pharmaceutically acceptable carrier being selected from the group of alcohol, acetone, ester, water, and aqueous solution. 19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and more than one high penetration prodrug for the treatment of a pulmonary condition, the high penetration prodrug comprising a functional unit covalently linked to a transportational unit via a linker; the functional unit comprising a moiety of a parent drug or a related compound of the parent drug; the parent drug selected from the group consisting of antihistamines, β2-adrenergic receptor agonists, 5-lipoxygenase-activating protein (FLAP) inhibitors, 5-lipoxygenase inhibitors, leukotriene receptor antagonists, cough suppressants, antibiotics, anti-inflammatory drugs, and decongestants; the transportational unit comprising a protonatable amine group; and the linker comprising a chemical bond that is capable of being cleaved after the high penetration prodrug penetrates across a biological barrier. 20. The pharmaceutical composition according to claim 17, wherein the more than one high penetration prodrug comprise functional units of a first parent drug and a second parent drug, and the first and the second parent drugs can be the same or different. 21. The pharmaceutical composition according to claim 17, wherein the anti-inflammatory drugs are selected from the group consisting of non-steroid anti-inflammatory agents, aspirin, ibuprofen, diflunisal, diclofenac, leukotriene antagonists, montelukast and zileuton. 22. The pharmaceutical composition according to claim 17, wherein the antibiotics are selected from the group consisting of beta-lactam antibiotics, sulfonamides and quinolones. 23. The pharmaceutical composition according to claim 20, wherein the beta-lactam antibiotics are selected from the group consisting of penicillin derivatives, cephalosporins, penems, monobactams, carbapenems, beta-lactamase inhibitors, aminopenicillins, amoxicillin, ampicillin, epicillin, carboxypenicillins, carbenicillin, ticarcillin, temocillin, ureidopenicillins, azlocillin, piperacillin, mezlocillin, mecillinam, sulbenicillin, benzathine penicillin, penicillin G, penicillin V, penicillin O, procaine penicillin, oxacillin, methicillin, nafcillin, cloxacillin, dicloxacillin, flucloxacillin, pivampicillin, hetacillin, becampicillin, metampicillin, talampicillin, co-amoxiclav, piperacillion, cephalexin, cephalothin, cefazolin, cefaclor, cefuroxime, cefamandole, cefotetan, cefoxitin, ceforanide, ceftriaxone, cefotaxime, cefpodoxime proxetil, ceftazidime, cefepime, cefoperazone, ceftizoxime, cefixime, cefpirome, faropenem, aztreonam, tigemonam, biapenem, •doripenem, ertapenem, •imipenem, •meropenem, •panipenem, tazobactam, sulbactam, clavulanic acid, [(N-benzyloxycarbonylamino)methyl]-phosphonic acid mono-(4-nitrophenyl) ester sodium salt, [(N-benzyloxycarbonylamino)methyl]-phosphonic acid mono-(3-pyridinyl) ester sodium salt, sulfanilamide (4-aminobenzenesulfonamide), sulfasalazine (6-oxo-3-(2-[4-(N-pyridin-2-ylsulfamoyl)phenyl]hydrazono)cyclohexa-1,4-dienecarboxylic acid), 1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-quinoline-3-carboxylic acid, and nalidixic acid (1-ethyl-7-methyl-4-oxo-[1,8]naphthyridine-3-carboxylic acid). 24. The pharmaceutical composition according to claim 20, wherein the sulfonamides are selected from the group consisting of sulfaisodimidine, sulfanilamide, sulfadiazine, sulfisoxazole, sulfamethoxazole, sulfadimethoxine, sulfamethoxypyridazine, sulfacetamide, sulfadoxine, acetazolamide, bumetanide, chlorthalidone, clopamide, furosemide, hydrochlorothiazide, indapamide, mefruside, metolazone, xipamide, dichlorphenamide, dorzolamide, acetazolamide, ethoxzolamide, sultiame, zonisamide, mafenide, celecoxib, darunavir, probenecid, sulfasalazine, and sumatriptan. 25. The pharmaceutical composition according to claim 20, wherein the quinolones are selected from the group consisting of cinoxacin, flumequine, nalidixic acid, oxolinic acid, piromidic acid, pipemidic acid, rosoxacin, ciprofloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, clinafloxacin, gemifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, garenoxacin, ecinofloxacin, delafloxacin and nalidixic acid. 26. The pharmaceutical composition according to claim 18, wherein the parent drugs comprise penicillin V, aspirin, zileuton, metaproterenol, and fexofenadine. 27. The pharmaceutical composition according to claim 18, wherein the parent drugs comprise aspirin, and zileuton. 28. The pharmaceutical composition according to claim 18, wherein the parent drugs comprise cefoxitin, aspirin, zileuton, albuterol, and clemastine. 29. The pharmaceutical composition according to claim 18, wherein the parent drugs comprise cefoxitin, aspirin, montelukast, albuterol, and acrivastine. 30. The pharmaceutical composition according to claim 18, wherein the parent drugs comprise cefoxitin, ibuprofen, montelukast, albuterol, and clemastine. 31. The pharmaceutical composition according to claim 18, wherein the second parent drug is acrivastine and the first parent drugs comprise cefoxitin, ibuprofen, montelukast, and albuterol. 32. The pharmaceutical composition according to claim 18, wherein the first parent drugs comprise ibuprofen, montelukast, and acrivastine. 33. The pharmaceutical composition according to claim 18, wherein the second parent drug is selected from the group consisting of dextromethorphan, pentoxyverine, acrivastine, diphenhydramine, doxylamine, desloratadine, chlorophenamine, ephedrine, and levomethamphetamin. 34. The pharmaceutical composition according to claim 18, wherein the second parent drug is acrivastine and the first parent drugs comprise cefoxitin, ibuprofen, and montelukast. 35. The pharmaceutical composition according to claim 18, wherein the first parent drugs comprise diclofenac, montelukast, pirbuterol, and acrivastine. 36. The pharmaceutical composition according to claim 18, wherein the second parent drug is acrivastine and the first parent drugs comprise diclofenac, montelukast, and pirbuterol. 37. The pharmaceutical composition according to claim 18, wherein the first parent drugs comprise diflunisal, zileuton, terbutaline, and acrivastine. 38. The pharmaceutical composition according to claim 18, wherein the second parent drug is acrivastine and the first parent drugs comprise diflunisal, zileuton, and terbutaline. 39. The pharmaceutical composition according to claim 18, wherein the first parent drugs comprise azlocillin, diflunisal, montelukast, and acrivastine. 40. The pharmaceutical composition according to claim 18, wherein the second parent drug is acrivastine and the first parent drugs comprise azlocillin, diflunisal, and montelukast. 41. The pharmaceutical composition according to claim 18, wherein the first parent drugs comprise piperacillin, diclofenac, zileuton, metaproterenol, and acrivastine. 42. The pharmaceutical composition according to claim 18, wherein the second parent drug is acrivastine and the first parent drugs comprise piperacillin, aspirin, zileuton, and metaproterenol. 43. A pharmaceutical composition for the treatment of a pulmonary condition comprising a pharmaceutically acceptable carrier, at least one high penetration prodrug, and at least a second compound selected from the group consisting of sildenafil, vardenafil, tadalafil, acetildenafil, avanafil, lodenafil, mirodenafil, clemastine, metaproterenol, udenafil, and salts thereof; the high penetration prodrug comprising a functional unit covalently linked to a transportational unit via a linker; the functional unit comprising a moiety of a parent drug or a related compound of the parent drug; the parent drug selected from the group consisting of antihistamines, β2-adrenergic receptor agonists, 5-lipoxygenase-activating protein (FLAP) inhibitors, 5-lipoxygenase inhibitors, leukotriene receptor antagonists, cough suppressants, antibiotics, anti-inflammatory drugs, and decongestants; the transportational unit comprising a protonatable amine group; and the linker comprising a chemical bond that is capable of being cleaved after the high penetration prodrug penetrates across a biological barrier. 44. The pharmaceutical composition according to claim 41, wherein the second compounds are sildenafil and metaproterenol, and the parent drugs are 6-phenoxyacetacetamidopenicillanic acid, aspirin, zileuton, and fexofenadine. 45. The pharmaceutical composition according to claim 41, wherein the second compounds are vardenafil and metaproterenol, and the parent drugs are 6-phenoxyacetacetamidopenicillanic acid, aspirin, zileuton, and fexofenadine. 46. The pharmaceutical composition according to claim 41, wherein the second compounds are tadalafil and clemastine, and the parent drugs are 3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, aspirin, and montelukast. 47. The pharmaceutical composition according to claim 41, wherein the second compounds are udenafil and clemastine, and the parent drugs are 3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, ibuprofen, and montelukast. 48. The pharmaceutical composition according to claim 41, wherein the second compounds are udenafil and clemastine, and the parent drugs are 3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, ibuprofen, and zileuton. 49. A method for treating a pulmonary condition in a biological subject, comprising administrating to the biological subject a high penetration drug according to claim 1 or the pharmaceutical composition according to claim 15, claim 17 or claim 41. 50. The method according to claim 47, the pulmonary condition being selected from the group consisting of asthma, lower, and upper respiratory tract infections, chronic bronchitis, chronic obstructive pulmonary disease, emphysema, cystic fibrosis, pneumonia, sarcoidosis, pulmonary fibrosis, allergic rhinitis, allergic conjunctivitis, itchiness, and runny nose.

Cosmetic oil-in-water emulsions that can provide a hydrophobic film to protect from excessive hydration are disclosed. In some aspects, a cosmetic oil-in-water emulsion can include water at a concentration of at least about 70% by total weight of the cosmetic oil-in-water emulsion, a plurality of water-in-oil emulsifiers, a base oil, an oil-in-water emulsifier, and a film-forming polymer. The base oil can have a wVTR of about 1.0 to 30 g/m 2 /hr and can be at a concentration of no more than about 15% by weight of the cosmetic oil-in water emulsion.

1. A cosmetic oil-in-water emulsion comprising: water at a concentration of at least about 70% by total weight of the cosmetic oil-in-water emulsion; a plurality of water-in-oil emulsifiers; a base oil; the base oil having a wVTR of about 1.0 to 30 g/m2/hr and being at a concentration of no more than about 15% by total weight of the cosmetic oil-in water emulsion; an oil-in-water emulsifier; and a film-forming polymer. 2. The cosmetic oil-in-water emulsion of claim 1, wherein the cosmetic oil-in-water emulsion has a post-immersion wVTR value of between about 1.0 to about 40 g/m2/hr and an Oxygen Permeability of at least about 1.0 cc/100 in2 per day. 3. The cosmetic oil-in-water emulsion of claim 1, wherein the base oil is selected from the group consisting of: Petrolatum, Mineral Oil, Hydrogenated Didecene, Hydrogenated Polydecene, Lanolin, and combinations thereof. 4. The cosmetic oil-in-water emulsion of claim 1, wherein the cosmetic oil-in-water emulsion has a pre-immersion wVTR value of less than about 30 g/m2/hr. 5. The cosmetic oil-in-water emulsion of claim 1, wherein the cosmetic oil-in-water emulsion has a contact angle greater than about 60°. 6. The cosmetic oil-in-water emulsion of claim 1, wherein the plurality of water-in-oil emulsifiers provide a total concentration of about 0.05% to about 5.0% by total weight of the cosmetic oil-in-water emulsion. 7. The cosmetic oil-in-water emulsion of claim 1, wherein the plurality of water-in-oil emulsifiers provide a total concentration of about 0.05% to about 2.0% by total weight of the cosmetic oil-in-water emulsion. 8. The cosmetic oil-in-water emulsion of claim 1, wherein the plurality of water-in-oil emulsifiers are selected from the group consisting of: Diisostearoyl Polyglyceryl-3 Dimer Dilinoleate, Polyglyceryl-4 Diisostearate/Polyhydroxystearate/Sebacate, Polyglyceryl-2 Diisostearate, Polyglyceryl-2 Dipolyhydroxystearate, PEG-30 Dipolyhydroxystearate, Glyceryl Stearate, and combinations thereof. 9. The cosmetic oil-in-water emulsion of claim 1, wherein the film-forming polymer is selected from the group consisting of Acrylates/C12-22 Alkyl Methacrylate Copolymer, Acrylates Copolymer, and combinations thereof; and wherein the film-forming polymer is at a concentration of about 0.05% to about 5.0% by total weight of the cosmetic oil-in-water emulsion. 10. The cosmetic oil-in-water emulsion of claim 9, wherein the film-forming polymer is at a concentration of about 0.5% to about 2.0% by total weight of the cosmetic oil-in-water emulsion. 11. The cosmetic oil-in-water emulsion of claim 1, wherein the oil-in water-emulsifier is selected from the group consisting of: Laureth-4, Steareth-21, PEG-100 Stearate, PEG-40 Stearate, and combinations thereof. 12. The cosmetic oil-in-water emulsion of claim 11, wherein the oil-in water-emulsifier is at concentration of about 0.1% to about 10.0% by total weight of the cosmetic oil-in-water emulsion. 13. The cosmetic oil-in-water emulsion of claim 11, wherein the oil-in water-emulsifier is at a concentration of about 1.0% to about 5.0% by total weight of the cosmetic oil-in-water emulsion. 14. The cosmetic oil-in-water emulsion of claim 1, further comprising a skin protectant, the skin protectant being selected from the group consisting of: Allantoin, Dimethicone, and Zinc Oxide. 15. A cosmetic oil-in-water emulsion comprising: water at a concentration of about 70% to about 95% by total weight of the cosmetic oil-in-water emulsion; a base oil; an oil-in-water emulsifier; at least two water-in-oil emulsifiers that are selected from the group consisting of: Diisostearoyl Polyglyceryl-3 Dimer Dilinoleate, Polyglyceryl-4 Diisostearate/Polyhydroxystearate/Sebacate, Polyglyceryl-2 Diisostearate, Polyglyceryl-2 Dipolyhydroxystearate, PEG-30 Dipolyhydroxystearate, Glyceryl Stearate, and combinations thereof; and a film forming polymer. 16. The cosmetic oil-in-water emulsion of claim 15, wherein the film forming polymer is selected from the group consisting of: Acrylates/C12-22 Alkyl Methacrylate Copolymer, Acrylates Copolymer, and combinations thereof, and wherein the film forming polymer is at a concentration of about 0.05% to about 5.0% by total weight of the cosmetic oil-in-water emulsion. 17. The cosmetic oil-in-water emulsion of claim 15, wherein the oil-in water-emulsifier is selected from the group consisting of: Laureth-4, Steareth-21, PEG-100 Stearate, PEG-40 Stearate, and a combination thereof. 18. The cosmetic oil-in-water emulsion of claim 15, wherein the base oil has a wVTR of about 5 to 30 g/m2/hr and is at a concentration of no more than about 15% by total weight of the cosmetic oil-in-water emulsion. 19. The cosmetic oil-in-water emulsion of claim 15, wherein the cosmetic oil-in-water emulsion has a post-immersion wVTR value of between 0 to about 40 g/m2/hr and an Oxygen Permeability of at least about 1.0 (cc/100 in2 per day). 20. The emulsion of claim 15, wherein the cosmetic oil-in-water emulsion has a pre-immersion wVTR value of less than 30 g/m2/hr.

Cosmetic oil-in-water emulsions that can provide a hydrophobic film to protect from excessive hydration are disclosed. In some aspects, a cosmetic oil-in-water emulsion can include water at a concentration of at least about 70% by total weight of the cosmetic oil-in-water emulsion, a plurality of water-in-oil emulsifiers, a base oil, an oil-in-water emulsifier, and a film-forming polymer. The base oil can have a wVTR of about 1.0 to 30 g/m 2 /hr and can be at a concentration of no more than about 15% by weight of the cosmetic oil-in water emulsion.1. A cosmetic oil-in-water emulsion comprising: water at a concentration of at least about 70% by total weight of the cosmetic oil-in-water emulsion; a plurality of water-in-oil emulsifiers; a base oil; the base oil having a wVTR of about 1.0 to 30 g/m2/hr and being at a concentration of no more than about 15% by total weight of the cosmetic oil-in water emulsion; an oil-in-water emulsifier; and a film-forming polymer. 2. The cosmetic oil-in-water emulsion of claim 1, wherein the cosmetic oil-in-water emulsion has a post-immersion wVTR value of between about 1.0 to about 40 g/m2/hr and an Oxygen Permeability of at least about 1.0 cc/100 in2 per day. 3. The cosmetic oil-in-water emulsion of claim 1, wherein the base oil is selected from the group consisting of: Petrolatum, Mineral Oil, Hydrogenated Didecene, Hydrogenated Polydecene, Lanolin, and combinations thereof. 4. The cosmetic oil-in-water emulsion of claim 1, wherein the cosmetic oil-in-water emulsion has a pre-immersion wVTR value of less than about 30 g/m2/hr. 5. The cosmetic oil-in-water emulsion of claim 1, wherein the cosmetic oil-in-water emulsion has a contact angle greater than about 60°. 6. The cosmetic oil-in-water emulsion of claim 1, wherein the plurality of water-in-oil emulsifiers provide a total concentration of about 0.05% to about 5.0% by total weight of the cosmetic oil-in-water emulsion. 7. The cosmetic oil-in-water emulsion of claim 1, wherein the plurality of water-in-oil emulsifiers provide a total concentration of about 0.05% to about 2.0% by total weight of the cosmetic oil-in-water emulsion. 8. The cosmetic oil-in-water emulsion of claim 1, wherein the plurality of water-in-oil emulsifiers are selected from the group consisting of: Diisostearoyl Polyglyceryl-3 Dimer Dilinoleate, Polyglyceryl-4 Diisostearate/Polyhydroxystearate/Sebacate, Polyglyceryl-2 Diisostearate, Polyglyceryl-2 Dipolyhydroxystearate, PEG-30 Dipolyhydroxystearate, Glyceryl Stearate, and combinations thereof. 9. The cosmetic oil-in-water emulsion of claim 1, wherein the film-forming polymer is selected from the group consisting of Acrylates/C12-22 Alkyl Methacrylate Copolymer, Acrylates Copolymer, and combinations thereof; and wherein the film-forming polymer is at a concentration of about 0.05% to about 5.0% by total weight of the cosmetic oil-in-water emulsion. 10. The cosmetic oil-in-water emulsion of claim 9, wherein the film-forming polymer is at a concentration of about 0.5% to about 2.0% by total weight of the cosmetic oil-in-water emulsion. 11. The cosmetic oil-in-water emulsion of claim 1, wherein the oil-in water-emulsifier is selected from the group consisting of: Laureth-4, Steareth-21, PEG-100 Stearate, PEG-40 Stearate, and combinations thereof. 12. The cosmetic oil-in-water emulsion of claim 11, wherein the oil-in water-emulsifier is at concentration of about 0.1% to about 10.0% by total weight of the cosmetic oil-in-water emulsion. 13. The cosmetic oil-in-water emulsion of claim 11, wherein the oil-in water-emulsifier is at a concentration of about 1.0% to about 5.0% by total weight of the cosmetic oil-in-water emulsion. 14. The cosmetic oil-in-water emulsion of claim 1, further comprising a skin protectant, the skin protectant being selected from the group consisting of: Allantoin, Dimethicone, and Zinc Oxide. 15. A cosmetic oil-in-water emulsion comprising: water at a concentration of about 70% to about 95% by total weight of the cosmetic oil-in-water emulsion; a base oil; an oil-in-water emulsifier; at least two water-in-oil emulsifiers that are selected from the group consisting of: Diisostearoyl Polyglyceryl-3 Dimer Dilinoleate, Polyglyceryl-4 Diisostearate/Polyhydroxystearate/Sebacate, Polyglyceryl-2 Diisostearate, Polyglyceryl-2 Dipolyhydroxystearate, PEG-30 Dipolyhydroxystearate, Glyceryl Stearate, and combinations thereof; and a film forming polymer. 16. The cosmetic oil-in-water emulsion of claim 15, wherein the film forming polymer is selected from the group consisting of: Acrylates/C12-22 Alkyl Methacrylate Copolymer, Acrylates Copolymer, and combinations thereof, and wherein the film forming polymer is at a concentration of about 0.05% to about 5.0% by total weight of the cosmetic oil-in-water emulsion. 17. The cosmetic oil-in-water emulsion of claim 15, wherein the oil-in water-emulsifier is selected from the group consisting of: Laureth-4, Steareth-21, PEG-100 Stearate, PEG-40 Stearate, and a combination thereof. 18. The cosmetic oil-in-water emulsion of claim 15, wherein the base oil has a wVTR of about 5 to 30 g/m2/hr and is at a concentration of no more than about 15% by total weight of the cosmetic oil-in-water emulsion. 19. The cosmetic oil-in-water emulsion of claim 15, wherein the cosmetic oil-in-water emulsion has a post-immersion wVTR value of between 0 to about 40 g/m2/hr and an Oxygen Permeability of at least about 1.0 (cc/100 in2 per day). 20. The emulsion of claim 15, wherein the cosmetic oil-in-water emulsion has a pre-immersion wVTR value of less than 30 g/m2/hr.

Methods for treatment of cancer selected from lung cancer, ovarian cancer, squamous cell carcinoma, pancreas exocrine cancer, malignant melanoma, gastric cancer, esophageal cancer, a metastases thereof, and leukemia, in a human or non-human body, comprise administrating to the body a cancer-inhibiting amount of a first compound of Formula (I): or a physiologically acceptable salt thereof, wherein X, R 1 , R 2 , R 3 and R 4 are as defined herein.

1. A method for treatment of cancer selected from lung cancer, ovarian cancer, squamous cell carcinoma, pancreas exocrine cancer, malignant melanoma, gastric cancer, esophageal cancer, a metastases thereof, and leukemia, in a human or non-human body, said method comprising administrating to said body a cancer-inhibiting amount of a first compound of Formula I: or a physiologically acceptable salt thereof, wherein X is CH or N, each R1 independently is hydrogen or —CH2COR5; R5 is hydroxy, ethylene glycol, glycerol, optionally hydroxylated alkoxy, amino or alkylamido; each R2 independently is a group ZYR6; Z is a bond, CO, or a C1-3 alkylene or oxoalkylene group optionally substituted by a group R7; Y is a bond, an oxygen atom or a group NR6; R6 is a hydrogen atom, COOR8, an alkyl, alkenyl, cycloalkyl, aryl or aralkyl group optionally substituted by one or more groups selected from COOR8, CONR8 2, NR8 2, OR8, ═NR8, ═O, OP(O)(OR8)R7 and OSO3M; R7 is hydroxy, an optionally hydroxylated, optionally alkoxylated alkyl or aminoalkyl group; R8 is a hydrogen atom or an optionally hydroxylated, optionally alkoxylated alkyl group; M is a hydrogen atom or one equivalent of a physiologically tolerable cation; R3 is a C1-8 alkylene group, a 1,2-cykloalkylene group, or a 1,2-arylene group, optionally substituted with R7; and each R4 independently is hydrogen or C1-3 alkyl. 2. The method of claim 1, wherein: R5 is hydroxy, C1-8 alkoxy, ethylene glycol, glycerol, amino or C1-8 alkylamido; Z is a bond or a group selected from CH2, (CH2)2, CO, CH2CO, CH2CH2CO and CH2COCH2; Y is a bond; R6 is a mono- or poly(hydroxy or alkoxylated) alkyl group or a group of the formula OP(O) (OR8)R7; and R7 is hydroxy, or an unsubstituted alkyl or aminoalkyl group. 3. The method of claim 1, wherein R3 is ethylene and each group R1 represents —CH2COR8 in which R5 is hydroxy. 4. The method of claim 1, wherein the first compound is N,N′-dipyridoxyl ethylenediamine-N,N′-diacetic acid. 5. The method of claim 1, wherein the first compound is N,N′-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N′-diacetic acid. 6. The method of claim 1, wherein the cancer is lung cancer and/or metastases thereof. 7. The method of claim 1, wherein the cancer is non-small cell lung cancer and/or metastases thereof. 8. The method of claim 1, wherein the cancer is ovarian cancer and/or metastases thereof. 9. The method of claim 1, wherein the cancer is pancreas exocrine cancer and/or metastases thereof. 10. The method of claim 1, wherein the cancer is malignant melanoma cancer and/or metastases thereof. 11. The method of claim 1, wherein the cancer is gastric cancer and/or metastases thereof. 12. The method of claim 1, wherein the cancer is esophagael cancer and/or metastases thereof. 13. The method of claim 1, wherein the cancer is leukemia. 14. The method of claim 1, wherein the first compound is administered with a cyto-protective amount of a metal chelate of a compound of Formula I. 15. The method of claim 14, wherein said metal chelate has a Ka value in the range of from 108 to 1024. 16. The method of claim 14, wherein said metal chelate has a lower Ka value than the Ka value of an iron (Fe3+) chelate of a compound of Formula I, by a factor of at least 103. 17. The method of claim 14, wherein the metal chelate is a manganese (Mn2+ or Mn3+) or copper (Cu+ or Cu2+) chelate. 18. The method of claim 14, wherein the first compound is N, N′-dipyridoxyl ethylenediamine-N,N′-diacetic acid and metal chelate is a metal chelate of N, N′-dipyridoxyl ethylenediamine-N,N′-diacetic acid. 19. The method of claim 14, wherein the first compound is N,N-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N′-diacetic acid and the metal chelate is a metal chelate of N,N′-dipyridoxyl ethylenediamine-N,N′-diacetic acid. 20. The method of claim 1, wherein the first compound is administered together with one or more other anti-cancer drugs selected from the group consisting of doxorubicin, epirubicin, oxaliplatin, cisplatin, carboplatin, paclitaxel, docetaxel, 5-fluorouracil, cyclophosphamide, gemcitabine, irinotecan, and methotrexate. 21. The method of claim 20, wherein the first compound and the one or more other anti-cancer drug(s) are administered simultaneously, separately or sequentially to said patient. 22. The method of claim 1, wherein the first compound is administered in combination with radiation therapy. 23. The method of claim 5, wherein the cancer is lung cancer and/or metastases thereof. 24. The method of claim 5, wherein the cancer is non-small cell lung cancer and/or metastases thereof. 25. The method of claim 5, wherein the cancer is ovarian cancer and/or metastases thereof. 26. The method of claim 5, wherein the cancer is pancreas exocrine cancer and/or metastases thereof. 27. The method of claim 5, wherein the cancer is malignant melanoma cancer and/or metastases thereof. 28. The method of claim 5, wherein the cancer is gastric cancer and/or metastases thereof. 29. The method of claim 5, wherein the cancer is esophagael cancer and/or metastases thereof. 30. The method of claim 5, wherein the cancer is leukemia.

Methods for treatment of cancer selected from lung cancer, ovarian cancer, squamous cell carcinoma, pancreas exocrine cancer, malignant melanoma, gastric cancer, esophageal cancer, a metastases thereof, and leukemia, in a human or non-human body, comprise administrating to the body a cancer-inhibiting amount of a first compound of Formula (I): or a physiologically acceptable salt thereof, wherein X, R 1 , R 2 , R 3 and R 4 are as defined herein.1. A method for treatment of cancer selected from lung cancer, ovarian cancer, squamous cell carcinoma, pancreas exocrine cancer, malignant melanoma, gastric cancer, esophageal cancer, a metastases thereof, and leukemia, in a human or non-human body, said method comprising administrating to said body a cancer-inhibiting amount of a first compound of Formula I: or a physiologically acceptable salt thereof, wherein X is CH or N, each R1 independently is hydrogen or —CH2COR5; R5 is hydroxy, ethylene glycol, glycerol, optionally hydroxylated alkoxy, amino or alkylamido; each R2 independently is a group ZYR6; Z is a bond, CO, or a C1-3 alkylene or oxoalkylene group optionally substituted by a group R7; Y is a bond, an oxygen atom or a group NR6; R6 is a hydrogen atom, COOR8, an alkyl, alkenyl, cycloalkyl, aryl or aralkyl group optionally substituted by one or more groups selected from COOR8, CONR8 2, NR8 2, OR8, ═NR8, ═O, OP(O)(OR8)R7 and OSO3M; R7 is hydroxy, an optionally hydroxylated, optionally alkoxylated alkyl or aminoalkyl group; R8 is a hydrogen atom or an optionally hydroxylated, optionally alkoxylated alkyl group; M is a hydrogen atom or one equivalent of a physiologically tolerable cation; R3 is a C1-8 alkylene group, a 1,2-cykloalkylene group, or a 1,2-arylene group, optionally substituted with R7; and each R4 independently is hydrogen or C1-3 alkyl. 2. The method of claim 1, wherein: R5 is hydroxy, C1-8 alkoxy, ethylene glycol, glycerol, amino or C1-8 alkylamido; Z is a bond or a group selected from CH2, (CH2)2, CO, CH2CO, CH2CH2CO and CH2COCH2; Y is a bond; R6 is a mono- or poly(hydroxy or alkoxylated) alkyl group or a group of the formula OP(O) (OR8)R7; and R7 is hydroxy, or an unsubstituted alkyl or aminoalkyl group. 3. The method of claim 1, wherein R3 is ethylene and each group R1 represents —CH2COR8 in which R5 is hydroxy. 4. The method of claim 1, wherein the first compound is N,N′-dipyridoxyl ethylenediamine-N,N′-diacetic acid. 5. The method of claim 1, wherein the first compound is N,N′-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N′-diacetic acid. 6. The method of claim 1, wherein the cancer is lung cancer and/or metastases thereof. 7. The method of claim 1, wherein the cancer is non-small cell lung cancer and/or metastases thereof. 8. The method of claim 1, wherein the cancer is ovarian cancer and/or metastases thereof. 9. The method of claim 1, wherein the cancer is pancreas exocrine cancer and/or metastases thereof. 10. The method of claim 1, wherein the cancer is malignant melanoma cancer and/or metastases thereof. 11. The method of claim 1, wherein the cancer is gastric cancer and/or metastases thereof. 12. The method of claim 1, wherein the cancer is esophagael cancer and/or metastases thereof. 13. The method of claim 1, wherein the cancer is leukemia. 14. The method of claim 1, wherein the first compound is administered with a cyto-protective amount of a metal chelate of a compound of Formula I. 15. The method of claim 14, wherein said metal chelate has a Ka value in the range of from 108 to 1024. 16. The method of claim 14, wherein said metal chelate has a lower Ka value than the Ka value of an iron (Fe3+) chelate of a compound of Formula I, by a factor of at least 103. 17. The method of claim 14, wherein the metal chelate is a manganese (Mn2+ or Mn3+) or copper (Cu+ or Cu2+) chelate. 18. The method of claim 14, wherein the first compound is N, N′-dipyridoxyl ethylenediamine-N,N′-diacetic acid and metal chelate is a metal chelate of N, N′-dipyridoxyl ethylenediamine-N,N′-diacetic acid. 19. The method of claim 14, wherein the first compound is N,N-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N′-diacetic acid and the metal chelate is a metal chelate of N,N′-dipyridoxyl ethylenediamine-N,N′-diacetic acid. 20. The method of claim 1, wherein the first compound is administered together with one or more other anti-cancer drugs selected from the group consisting of doxorubicin, epirubicin, oxaliplatin, cisplatin, carboplatin, paclitaxel, docetaxel, 5-fluorouracil, cyclophosphamide, gemcitabine, irinotecan, and methotrexate. 21. The method of claim 20, wherein the first compound and the one or more other anti-cancer drug(s) are administered simultaneously, separately or sequentially to said patient. 22. The method of claim 1, wherein the first compound is administered in combination with radiation therapy. 23. The method of claim 5, wherein the cancer is lung cancer and/or metastases thereof. 24. The method of claim 5, wherein the cancer is non-small cell lung cancer and/or metastases thereof. 25. The method of claim 5, wherein the cancer is ovarian cancer and/or metastases thereof. 26. The method of claim 5, wherein the cancer is pancreas exocrine cancer and/or metastases thereof. 27. The method of claim 5, wherein the cancer is malignant melanoma cancer and/or metastases thereof. 28. The method of claim 5, wherein the cancer is gastric cancer and/or metastases thereof. 29. The method of claim 5, wherein the cancer is esophagael cancer and/or metastases thereof. 30. The method of claim 5, wherein the cancer is leukemia.

The invention disclosed herein includes nanocomplexes that are designed include enzymes that have complementary functional attributes and methods for using these nanocomplexes. Illustrative examples include nanocomplexes that comprise both an alcohol oxidase enzyme as well as a catalase enzyme. These nanocomplexes can be used in methods designed to lower blood alcohol levels in vivo, and/or to break down the toxic byproducts of alcohol metabolism. Consequently these nanocomplexes can be used to treat a variety of conditions resulting from the consumption of alcohol, including for example, acute alcohol intoxication.

1. A method of decreasing the concentration of ethanol in an individual comprising the steps of: (a) administering a multiple-enzyme nanocomplex system to the individual, wherein the multiple-enzyme nanocomplex system comprises: an alcohol oxidase enzyme that generates hydrogen peroxide in a first enzymatic reaction with ethanol; a catalase enzyme that converts the hydrogen peroxide into water in a second enzymatic reaction; and a polymeric network configured to form a shell that encapsulates the alcohol oxidase and the catalase, wherein: the polymeric network exhibits a permeability sufficient to allow the ethanol to diffuse from an external environment outside of the shell to the alcohol oxidase so that the hydrogen is peroxide is generated; the polymeric network exhibits a permeability sufficient to allow the hydrogen peroxide to diffuse away from the alcohol oxidase and to the catalase so that the water is generated; and the alcohol oxidase is coupled to the catalase; or the polymeric network is coupled to the alcohol oxidase or the catalase; and (b) allowing the alcohol oxidase and the catalase in the multiple-enzyme nanocomplex system to react with ethanol in the individual and generate hydrogen peroxide and water; so that the concentration of ethanol in the individual is decreased. 2. The method of claim 1, wherein the multiple-enzyme nanocomplex system is administered prior to the consumption of ethanol so as to avoid ethanol intoxication. 3. The method of claim 1, wherein the multiple-enzyme nanocomplex system is administered orally. 4. The method of claim 1, wherein the individual suffers from acute ethanol intoxication. 5. The method of claim 1, wherein the multiple-enzyme nanocomplex system is administered parenterally. 6. The method of claim 1, wherein the multiple-enzyme nanocomplex system reduces blood ethanol concentrations in the individual by at least 25, 50, 75 or 100 mg/dL within 90 minutes following administration to the individual. 7. The method of claim 1, further comprising a third enzyme encapsulated within the polymeric network, wherein the third enzyme is an alcohol dehydrogenase, an aldehyde dehydrogenase or an acetaldehyde oxidase. 8. The method of claim 1, wherein the first enzyme and the second enzyme are coupled together by strands of complimentary polynucleotides. 9. The method of claim 1, wherein the polymeric network encapsulates the alcohol oxidase and the catalase in a manner that inhibits degradation of the alcohol oxidase and the catalase when the multiple-enzyme nanocomplex is disposed in an in vivo environment. 10. A multiple-enzyme nanocomplex system for use in a patient for the treatment of a condition resulting from the consumption of alcohol, wherein the multiple-enzyme nanocomplex system comprises: an alcohol oxidase enzyme that generates hydrogen peroxide in a first enzymatic reaction with alcohol; a catalase enzyme that converts the hydrogen peroxide into water in a second enzymatic reaction; and a polymeric network configured to form a shell that encapsulates the alcohol oxidase and the catalase, wherein: the polymeric network exhibits a permeability sufficient to allow the alcohol to diffuse from an external environment outside of the shell to the alcohol oxidase so that the hydrogen peroxide is generated; the polymeric network exhibits a permeability sufficient to allow the hydrogen peroxide to diffuse away from the alcohol oxidase and to the catalase so that the water is generated; and the alcohol oxidase is coupled to the catalase; or the polymeric network is coupled to the alcohol oxidase or the catalase. 11. The multiple-enzyme nanocomplex system for use according to claim 1, wherein the multiple-enzyme nanocomplex system is administered in an amount sufficient to reduce the blood alcohol concentration of the patient by at least 10%, 20% or 30% within 90 minutes following administration. 12. The multiple-enzyme nanocomplex system for use according to claim 1, wherein the condition in the patient resulting from the consumption of alcohol is acute alcohol intoxication. 13. The multiple-enzyme nanocomplex system for use according to claim 1, wherein the multiple-enzyme nanocomplex system is administered orally. 14. The multiple-enzyme nanocomplex system for use according to claim 1, wherein the alcohol oxidase enzyme and catalase enzyme are disposed within the polymeric network at a distance from each other of less than 50, 40, 30, 20 or 10 nm. 15. A method of decreasing a concentration of hydrogen peroxide in an aqueous environment comprising the steps of: (a) introducing a multiple-enzyme nanocomplex system into the aqueous environment, wherein the multiple-enzyme nanocomplex system comprises: a first enzyme that generates hydrogen peroxide in a first enzymatic reaction with a first substrate present in the aqueous environment; a second enzyme that converts the hydrogen peroxide into water in a second enzymatic reaction; and a polymeric network configured to form a shell that encapsulates the first enzyme and the second enzyme, wherein: the polymeric network encapsulates the first enzyme and the second enzyme in a manner that inhibits degradation of the first enzyme and the second enzyme when the multiple-enzyme nanocomplex is disposed in an in vivo environment; the polymeric network exhibits a permeability sufficient to allow the substrate to diffuse from an external environment outside of the shell to the first enzyme so that the hydrogen peroxide is generated; the polymeric network exhibits a permeability sufficient to allow the hydrogen peroxide to diffuse away from the first enzyme and to the second enzyme so that the water is generated; and the first enzyme is coupled to the second enzyme; or the polymeric network is coupled to the first enzyme or the second enzyme; and (b) allowing the first enzyme and the second enzyme in the multiple-enzyme nanocomplex system to react with the substrate and generate hydrogen peroxide and water; so that the concentration of hydrogen peroxide in the aqueous environment is decreased. 16. The method of claim 15, wherein at least one enzyme encapsulated within the polymeric network is selected from the group consisting of an alcohol oxidase, a catalase, a peroxidase, an alcohol dehydrogenase, an aldehyde dehydrogenase or an acetaldehyde oxidase. 17. The method of claim 15, wherein: the first enzyme is an alcohol oxidase; and the second enzyme is a catalase. 18. The method of claim 17, wherein the aqueous environment comprises an in vivo environment. 19. The method of claim 15, wherein: the first enzyme is a glucose oxidase; and the second enzyme is a horseradish peroxidase. 20. The method of claim 19, wherein the aqueous environment comprises an in vitro environment.

The invention disclosed herein includes nanocomplexes that are designed include enzymes that have complementary functional attributes and methods for using these nanocomplexes. Illustrative examples include nanocomplexes that comprise both an alcohol oxidase enzyme as well as a catalase enzyme. These nanocomplexes can be used in methods designed to lower blood alcohol levels in vivo, and/or to break down the toxic byproducts of alcohol metabolism. Consequently these nanocomplexes can be used to treat a variety of conditions resulting from the consumption of alcohol, including for example, acute alcohol intoxication.1. A method of decreasing the concentration of ethanol in an individual comprising the steps of: (a) administering a multiple-enzyme nanocomplex system to the individual, wherein the multiple-enzyme nanocomplex system comprises: an alcohol oxidase enzyme that generates hydrogen peroxide in a first enzymatic reaction with ethanol; a catalase enzyme that converts the hydrogen peroxide into water in a second enzymatic reaction; and a polymeric network configured to form a shell that encapsulates the alcohol oxidase and the catalase, wherein: the polymeric network exhibits a permeability sufficient to allow the ethanol to diffuse from an external environment outside of the shell to the alcohol oxidase so that the hydrogen is peroxide is generated; the polymeric network exhibits a permeability sufficient to allow the hydrogen peroxide to diffuse away from the alcohol oxidase and to the catalase so that the water is generated; and the alcohol oxidase is coupled to the catalase; or the polymeric network is coupled to the alcohol oxidase or the catalase; and (b) allowing the alcohol oxidase and the catalase in the multiple-enzyme nanocomplex system to react with ethanol in the individual and generate hydrogen peroxide and water; so that the concentration of ethanol in the individual is decreased. 2. The method of claim 1, wherein the multiple-enzyme nanocomplex system is administered prior to the consumption of ethanol so as to avoid ethanol intoxication. 3. The method of claim 1, wherein the multiple-enzyme nanocomplex system is administered orally. 4. The method of claim 1, wherein the individual suffers from acute ethanol intoxication. 5. The method of claim 1, wherein the multiple-enzyme nanocomplex system is administered parenterally. 6. The method of claim 1, wherein the multiple-enzyme nanocomplex system reduces blood ethanol concentrations in the individual by at least 25, 50, 75 or 100 mg/dL within 90 minutes following administration to the individual. 7. The method of claim 1, further comprising a third enzyme encapsulated within the polymeric network, wherein the third enzyme is an alcohol dehydrogenase, an aldehyde dehydrogenase or an acetaldehyde oxidase. 8. The method of claim 1, wherein the first enzyme and the second enzyme are coupled together by strands of complimentary polynucleotides. 9. The method of claim 1, wherein the polymeric network encapsulates the alcohol oxidase and the catalase in a manner that inhibits degradation of the alcohol oxidase and the catalase when the multiple-enzyme nanocomplex is disposed in an in vivo environment. 10. A multiple-enzyme nanocomplex system for use in a patient for the treatment of a condition resulting from the consumption of alcohol, wherein the multiple-enzyme nanocomplex system comprises: an alcohol oxidase enzyme that generates hydrogen peroxide in a first enzymatic reaction with alcohol; a catalase enzyme that converts the hydrogen peroxide into water in a second enzymatic reaction; and a polymeric network configured to form a shell that encapsulates the alcohol oxidase and the catalase, wherein: the polymeric network exhibits a permeability sufficient to allow the alcohol to diffuse from an external environment outside of the shell to the alcohol oxidase so that the hydrogen peroxide is generated; the polymeric network exhibits a permeability sufficient to allow the hydrogen peroxide to diffuse away from the alcohol oxidase and to the catalase so that the water is generated; and the alcohol oxidase is coupled to the catalase; or the polymeric network is coupled to the alcohol oxidase or the catalase. 11. The multiple-enzyme nanocomplex system for use according to claim 1, wherein the multiple-enzyme nanocomplex system is administered in an amount sufficient to reduce the blood alcohol concentration of the patient by at least 10%, 20% or 30% within 90 minutes following administration. 12. The multiple-enzyme nanocomplex system for use according to claim 1, wherein the condition in the patient resulting from the consumption of alcohol is acute alcohol intoxication. 13. The multiple-enzyme nanocomplex system for use according to claim 1, wherein the multiple-enzyme nanocomplex system is administered orally. 14. The multiple-enzyme nanocomplex system for use according to claim 1, wherein the alcohol oxidase enzyme and catalase enzyme are disposed within the polymeric network at a distance from each other of less than 50, 40, 30, 20 or 10 nm. 15. A method of decreasing a concentration of hydrogen peroxide in an aqueous environment comprising the steps of: (a) introducing a multiple-enzyme nanocomplex system into the aqueous environment, wherein the multiple-enzyme nanocomplex system comprises: a first enzyme that generates hydrogen peroxide in a first enzymatic reaction with a first substrate present in the aqueous environment; a second enzyme that converts the hydrogen peroxide into water in a second enzymatic reaction; and a polymeric network configured to form a shell that encapsulates the first enzyme and the second enzyme, wherein: the polymeric network encapsulates the first enzyme and the second enzyme in a manner that inhibits degradation of the first enzyme and the second enzyme when the multiple-enzyme nanocomplex is disposed in an in vivo environment; the polymeric network exhibits a permeability sufficient to allow the substrate to diffuse from an external environment outside of the shell to the first enzyme so that the hydrogen peroxide is generated; the polymeric network exhibits a permeability sufficient to allow the hydrogen peroxide to diffuse away from the first enzyme and to the second enzyme so that the water is generated; and the first enzyme is coupled to the second enzyme; or the polymeric network is coupled to the first enzyme or the second enzyme; and (b) allowing the first enzyme and the second enzyme in the multiple-enzyme nanocomplex system to react with the substrate and generate hydrogen peroxide and water; so that the concentration of hydrogen peroxide in the aqueous environment is decreased. 16. The method of claim 15, wherein at least one enzyme encapsulated within the polymeric network is selected from the group consisting of an alcohol oxidase, a catalase, a peroxidase, an alcohol dehydrogenase, an aldehyde dehydrogenase or an acetaldehyde oxidase. 17. The method of claim 15, wherein: the first enzyme is an alcohol oxidase; and the second enzyme is a catalase. 18. The method of claim 17, wherein the aqueous environment comprises an in vivo environment. 19. The method of claim 15, wherein: the first enzyme is a glucose oxidase; and the second enzyme is a horseradish peroxidase. 20. The method of claim 19, wherein the aqueous environment comprises an in vitro environment.

The present invention is directed to pharmaceutical compositions and dosage forms comprising TPR beads, wherein said TPR beads comprise a solid dispersion of at least one active pharmaceutical ingredient in at least one solubility-enhancing polymer, and a TPR coating comprising a water insoluble polymer and an enteric polymer, wherein the active pharmaceutical ingredient comprises a weakly basic active pharmaceutical ingredient having a solubility of not more than 100 μg/mL at pH 6.8.

1. A pharmaceutical composition comprising TPR beads, wherein said TPR beads comprise: a solid dispersion of at least one active pharmaceutical ingredient in at least one solubility-enhancing polymer; and a TPR coating comprising a water insoluble polymer and an enteric polymer; wherein the active pharmaceutical ingredient comprises a weakly basic active pharmaceutical ingredient having a solubility of not more than 100 μg/mL at pH 6.8. 2. The pharmaceutical composition of claim 1, wherein the composition provides a therapeutically effective plasma concentration of the active pharmaceutical ingredient over a period of at least about 18 hours. 3. The pharmaceutical composition of claim 1, wherein the ratio of water-insoluble polymer to enteric polymer in the TPR coating ranges from about 9:1 to about 1:9. 4. The pharmaceutical dosage form of claim 3, wherein the TPR coating further comprises about 3% to about 30% by weight of a plasticizer (compared to the total weight of the TPR coating). 5. The pharmaceutical composition of claim 1, wherein the solid dispersion of the active pharmaceutical ingredient and solubility-enhancing polymer is deposited on an inert core. 6. The pharmaceutical composition of claim 5, wherein the solubility-enhancing polymer is selected from the group consisting of polyvinylpyrrolidone, vinyl acetate/vinyl pyrrolidone copolymers, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene oxide, polyethylene glycol, and cyclodextrins. 7. The pharmaceutical composition of claim 5, wherein the solid dispersion further comprises a pharmaceutically acceptable organic acid. 8. The pharmaceutical composition of claim 7, wherein the ratio of organic acid to active pharmaceutical ingredient ranges from about 4/1 to about 1/9 by weight. 9. The pharmaceutical composition of claim 5, wherein the water-insoluble polymer is selected from the group consisting of polymers or copolymers of methacrylic acid esters having quaternary ammonium groups, polyvinyl acetate polymers or copolymers, cellulose acetate, cellulose acetate butyrate, ethylcellulose, and mixtures thereof. 10. The pharmaceutical composition of claim 5, wherein the TPR beads comprise IR beads coated with the TPR coating; and the IR beads comprise inert cores coated with the solid dispersion. 11. The pharmaceutical composition of claim 10, wherein the ratio of active pharmaceutical ingredient to solubility-enhancing polymer ranges of from about 6:1 to about 1:9. 12. The pharmaceutical composition of claim 10, wherein the TPR beads further comprise an enteric coating applied over the solid dispersion; the enteric coating is up to about 40% of the total weight of the TPR beads; and the TPR beads provide a lag time of about 1-4 hours. 13. The pharmaceutical composition of claim 10, wherein the TPR beads further comprise an enteric coating applied over the TPR coating; the enteric coating is up to about 40% of the total weight of the TPR beads; and the TPR beads provide a lag time of up to about 4 hours. 14. The pharmaceutical composition of claim 10, wherein the TPR beads further comprise a first enteric coating applied over the solid dispersion; a second enteric coating applied over the TPR coating; the first and second enteric coatings are each up to about 40% of the total weight of the TPR beads; and the TPR beads provide a lag time of up to about 4 hours. 15. The pharmaceutical composition of claim 11, comprising a combination of IR and TPR beads, wherein the ratio of IR to TPR beads is 1:9 to 5:5. 16. The pharmaceutical composition of claim 1, wherein said composition is an orally disintegrating tablet comprising TPR beads and rapidly-dissolving microgranules; wherein the average particle size of the TPR beads and rapidly-dissolving microgranules is not more than 400 μm; the rapidly-dissolving microgranules comprise particles of at least one disintegrant, and a sugar alcohol and/or saccharide, said particles having an average particle size of not more than 30 μm. 17. The pharmaceutical composition of claim 10, comprising TPR beads, rapidly-dissolving microgranules, and IR beads, wherein the ratio of IR beads to TPR beads ranges from about 10:90 to about 50:50. 18. The pharmaceutical composition of claim 17, wherein the IR beads further comprise a taste-masking layer coated over the solid dispersion; and wherein the taste-masking layer comprises a water-insoluble polymer or a water-insoluble polymer in combination with a water-soluble or gastrosoluble pore former. 19. The pharmaceutical composition of claim 1, wherein the one or more active pharmaceutical ingredients are selected from the group consisting of analgesics, anticonvulsants, anti-diabetic agents, anti-infective agents, anti-neoplastic agents, anti-Parkinsonian agents, anti-rheumatic agents, cardiovascular agents, CNS (central nervous system) stimulants, dopamine receptor agonists, anti-emetics, gastrointestinal agents, psychotherapeutic agents, opioid agonists, opioid antagonists, anti-epileptic drugs, histamine H2 antagonists, anti-asthmatic agents, and skeletal muscle relaxants. 20. The pharmaceutical composition of claim 23, wherein the active pharmaceutical ingredient is lercanidipine, or pharmaceutically acceptable salts, solvates, and/or esters thereof. 21. The pharmaceutical composition of claim 17, wherein: the IR beads further comprise a seal coating comprising hypromellose applied over the solid dispersion; the solubility-enhancing polymer comprises a vinylpyrrolidone-vinyl acetate copolymer or polyvinyl pyrrolidone; the TPR coating comprises a pharmaceutically acceptable methacrylate ester/methylmethacrylate ester copolymer and a pH-sensitive methacrylic acid-methylmethacrylate copolymer at a ratio of 9:1 to 1:9; the weight of the TPR coating is up to about 50% of the weight of the TPR beads; and the active pharmaceutical ingredient is selected from the group consisting of nifedipine, nicorandil, lercanidipine, iloperidone, clonazepam, and pharmaceutically acceptable salts, solvates and/or esters thereof. 22. A method of preparing the pharmaceutical composition of claim 1, comprising: dissolving the active pharmaceutical ingredient and sufficient solubility-enhancing polymer in a pharmaceutically acceptable solvent; removing the pharmaceutically acceptable solvent from the solution of active pharmaceutical ingredient and solubility-enhancing polymer, whereby particles of a solid dispersion comprising molecularly dispersed active pharmaceutical ingredient and solubility-enhancing polymer are formed; dissolving a water insoluble polymer and an enteric polymer in a pharmaceutically acceptable coating solvent, thereby forming a TPR coating solution; coating the particles of solid dispersion with the TPR coating solution; removing the coating solvent, thereby forming TPR beads comprising a TPR coating formed on the particles of solid dispersion. 23. The method of claim 22, wherein the solution of active pharmaceutical ingredient and solubility-enhancing polymer is coated onto inert cores prior to forming the solid dispersion particles by removing the pharmaceutically acceptable solvent, whereby IR beads are formed; coating the IR beads with the TPR coating solution, whereby TPR beads are formed. 24. The method of claim 23, further comprising: granulating at least one disintegrant with at least one sugar alcohol and/or at least one saccharide, thereby forming rapidly-dissolving microgranules; mixing the TPR beads with the rapidly-dissolving microgranules; compressing the mixture, whereby an orally disintegrating tablet is formed. 25. The method of claim 23, further comprising: granulating at least one disintegrant with at least one sugar alcohol and/or at least one saccharide, thereby forming rapidly-dissolving microgranules; mixing the TPR beads, IR beads, and the rapidly-dissolving microgranules; compressing the mixture, whereby an orally disintegrating tablet is formed.

The present invention is directed to pharmaceutical compositions and dosage forms comprising TPR beads, wherein said TPR beads comprise a solid dispersion of at least one active pharmaceutical ingredient in at least one solubility-enhancing polymer, and a TPR coating comprising a water insoluble polymer and an enteric polymer, wherein the active pharmaceutical ingredient comprises a weakly basic active pharmaceutical ingredient having a solubility of not more than 100 μg/mL at pH 6.8.1. A pharmaceutical composition comprising TPR beads, wherein said TPR beads comprise: a solid dispersion of at least one active pharmaceutical ingredient in at least one solubility-enhancing polymer; and a TPR coating comprising a water insoluble polymer and an enteric polymer; wherein the active pharmaceutical ingredient comprises a weakly basic active pharmaceutical ingredient having a solubility of not more than 100 μg/mL at pH 6.8. 2. The pharmaceutical composition of claim 1, wherein the composition provides a therapeutically effective plasma concentration of the active pharmaceutical ingredient over a period of at least about 18 hours. 3. The pharmaceutical composition of claim 1, wherein the ratio of water-insoluble polymer to enteric polymer in the TPR coating ranges from about 9:1 to about 1:9. 4. The pharmaceutical dosage form of claim 3, wherein the TPR coating further comprises about 3% to about 30% by weight of a plasticizer (compared to the total weight of the TPR coating). 5. The pharmaceutical composition of claim 1, wherein the solid dispersion of the active pharmaceutical ingredient and solubility-enhancing polymer is deposited on an inert core. 6. The pharmaceutical composition of claim 5, wherein the solubility-enhancing polymer is selected from the group consisting of polyvinylpyrrolidone, vinyl acetate/vinyl pyrrolidone copolymers, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene oxide, polyethylene glycol, and cyclodextrins. 7. The pharmaceutical composition of claim 5, wherein the solid dispersion further comprises a pharmaceutically acceptable organic acid. 8. The pharmaceutical composition of claim 7, wherein the ratio of organic acid to active pharmaceutical ingredient ranges from about 4/1 to about 1/9 by weight. 9. The pharmaceutical composition of claim 5, wherein the water-insoluble polymer is selected from the group consisting of polymers or copolymers of methacrylic acid esters having quaternary ammonium groups, polyvinyl acetate polymers or copolymers, cellulose acetate, cellulose acetate butyrate, ethylcellulose, and mixtures thereof. 10. The pharmaceutical composition of claim 5, wherein the TPR beads comprise IR beads coated with the TPR coating; and the IR beads comprise inert cores coated with the solid dispersion. 11. The pharmaceutical composition of claim 10, wherein the ratio of active pharmaceutical ingredient to solubility-enhancing polymer ranges of from about 6:1 to about 1:9. 12. The pharmaceutical composition of claim 10, wherein the TPR beads further comprise an enteric coating applied over the solid dispersion; the enteric coating is up to about 40% of the total weight of the TPR beads; and the TPR beads provide a lag time of about 1-4 hours. 13. The pharmaceutical composition of claim 10, wherein the TPR beads further comprise an enteric coating applied over the TPR coating; the enteric coating is up to about 40% of the total weight of the TPR beads; and the TPR beads provide a lag time of up to about 4 hours. 14. The pharmaceutical composition of claim 10, wherein the TPR beads further comprise a first enteric coating applied over the solid dispersion; a second enteric coating applied over the TPR coating; the first and second enteric coatings are each up to about 40% of the total weight of the TPR beads; and the TPR beads provide a lag time of up to about 4 hours. 15. The pharmaceutical composition of claim 11, comprising a combination of IR and TPR beads, wherein the ratio of IR to TPR beads is 1:9 to 5:5. 16. The pharmaceutical composition of claim 1, wherein said composition is an orally disintegrating tablet comprising TPR beads and rapidly-dissolving microgranules; wherein the average particle size of the TPR beads and rapidly-dissolving microgranules is not more than 400 μm; the rapidly-dissolving microgranules comprise particles of at least one disintegrant, and a sugar alcohol and/or saccharide, said particles having an average particle size of not more than 30 μm. 17. The pharmaceutical composition of claim 10, comprising TPR beads, rapidly-dissolving microgranules, and IR beads, wherein the ratio of IR beads to TPR beads ranges from about 10:90 to about 50:50. 18. The pharmaceutical composition of claim 17, wherein the IR beads further comprise a taste-masking layer coated over the solid dispersion; and wherein the taste-masking layer comprises a water-insoluble polymer or a water-insoluble polymer in combination with a water-soluble or gastrosoluble pore former. 19. The pharmaceutical composition of claim 1, wherein the one or more active pharmaceutical ingredients are selected from the group consisting of analgesics, anticonvulsants, anti-diabetic agents, anti-infective agents, anti-neoplastic agents, anti-Parkinsonian agents, anti-rheumatic agents, cardiovascular agents, CNS (central nervous system) stimulants, dopamine receptor agonists, anti-emetics, gastrointestinal agents, psychotherapeutic agents, opioid agonists, opioid antagonists, anti-epileptic drugs, histamine H2 antagonists, anti-asthmatic agents, and skeletal muscle relaxants. 20. The pharmaceutical composition of claim 23, wherein the active pharmaceutical ingredient is lercanidipine, or pharmaceutically acceptable salts, solvates, and/or esters thereof. 21. The pharmaceutical composition of claim 17, wherein: the IR beads further comprise a seal coating comprising hypromellose applied over the solid dispersion; the solubility-enhancing polymer comprises a vinylpyrrolidone-vinyl acetate copolymer or polyvinyl pyrrolidone; the TPR coating comprises a pharmaceutically acceptable methacrylate ester/methylmethacrylate ester copolymer and a pH-sensitive methacrylic acid-methylmethacrylate copolymer at a ratio of 9:1 to 1:9; the weight of the TPR coating is up to about 50% of the weight of the TPR beads; and the active pharmaceutical ingredient is selected from the group consisting of nifedipine, nicorandil, lercanidipine, iloperidone, clonazepam, and pharmaceutically acceptable salts, solvates and/or esters thereof. 22. A method of preparing the pharmaceutical composition of claim 1, comprising: dissolving the active pharmaceutical ingredient and sufficient solubility-enhancing polymer in a pharmaceutically acceptable solvent; removing the pharmaceutically acceptable solvent from the solution of active pharmaceutical ingredient and solubility-enhancing polymer, whereby particles of a solid dispersion comprising molecularly dispersed active pharmaceutical ingredient and solubility-enhancing polymer are formed; dissolving a water insoluble polymer and an enteric polymer in a pharmaceutically acceptable coating solvent, thereby forming a TPR coating solution; coating the particles of solid dispersion with the TPR coating solution; removing the coating solvent, thereby forming TPR beads comprising a TPR coating formed on the particles of solid dispersion. 23. The method of claim 22, wherein the solution of active pharmaceutical ingredient and solubility-enhancing polymer is coated onto inert cores prior to forming the solid dispersion particles by removing the pharmaceutically acceptable solvent, whereby IR beads are formed; coating the IR beads with the TPR coating solution, whereby TPR beads are formed. 24. The method of claim 23, further comprising: granulating at least one disintegrant with at least one sugar alcohol and/or at least one saccharide, thereby forming rapidly-dissolving microgranules; mixing the TPR beads with the rapidly-dissolving microgranules; compressing the mixture, whereby an orally disintegrating tablet is formed. 25. The method of claim 23, further comprising: granulating at least one disintegrant with at least one sugar alcohol and/or at least one saccharide, thereby forming rapidly-dissolving microgranules; mixing the TPR beads, IR beads, and the rapidly-dissolving microgranules; compressing the mixture, whereby an orally disintegrating tablet is formed.

A method of preventing degeneration of photoreceptor cells in an eye of a mammalian subject includes the step of administering pharmaceutical composition comprising a sulindac agent to the eye of the subject.

1. A method of preventing degeneration of photoreceptor cells and retinal pigment epithelial cells in an eye of a mammalian subject having or at high risk of developing retinal disease, the method comprising the step of administering an ophthalmically-acceptable pharmaceutical composition comprising a sulindac agent to the eye of the subject. 2. The method of claim 1, wherein the subject has been diagnosed with age-related macular degeneration. 3. The method of claim 2, wherein the age-related macular degeneration is dry age-related macular degeneration. 4. The method of claim 1, wherein the sulindac agent is sulindac. 5. The method of claim 1, wherein the sulindac agent is sulindac sulfone. 6. The method of claim 1, wherein the sulindac agent is sulindac sulfide. 7. The method of claim 1, wherein the pharmaceutical composition is formulated in eye drops and administered topically to the eye. 8. The method of claim 1, wherein the pharmaceutical composition is formulated for injection and administered by intravitreal injection. 9. The method of claim 1, wherein the pharmaceutical composition comprises the sulindac agent at between 0.001 to 3% by weight. 10. The method of claim 1, wherein the pharmaceutical composition comprises the sulindac agent at between 0.005 to 2% by weight. 11. The method of claim 1, wherein the pharmaceutical composition has a pH of between 6.5 and 8.0. 12. The method of claim 1, wherein the pharmaceutical composition has a pH of between 6.8 and 7.8. 13. The method of claim 1, wherein the pharmaceutical composition comprises a sterile aqueous buffer and dimethylsulfoxide.

A method of preventing degeneration of photoreceptor cells in an eye of a mammalian subject includes the step of administering pharmaceutical composition comprising a sulindac agent to the eye of the subject.1. A method of preventing degeneration of photoreceptor cells and retinal pigment epithelial cells in an eye of a mammalian subject having or at high risk of developing retinal disease, the method comprising the step of administering an ophthalmically-acceptable pharmaceutical composition comprising a sulindac agent to the eye of the subject. 2. The method of claim 1, wherein the subject has been diagnosed with age-related macular degeneration. 3. The method of claim 2, wherein the age-related macular degeneration is dry age-related macular degeneration. 4. The method of claim 1, wherein the sulindac agent is sulindac. 5. The method of claim 1, wherein the sulindac agent is sulindac sulfone. 6. The method of claim 1, wherein the sulindac agent is sulindac sulfide. 7. The method of claim 1, wherein the pharmaceutical composition is formulated in eye drops and administered topically to the eye. 8. The method of claim 1, wherein the pharmaceutical composition is formulated for injection and administered by intravitreal injection. 9. The method of claim 1, wherein the pharmaceutical composition comprises the sulindac agent at between 0.001 to 3% by weight. 10. The method of claim 1, wherein the pharmaceutical composition comprises the sulindac agent at between 0.005 to 2% by weight. 11. The method of claim 1, wherein the pharmaceutical composition has a pH of between 6.5 and 8.0. 12. The method of claim 1, wherein the pharmaceutical composition has a pH of between 6.8 and 7.8. 13. The method of claim 1, wherein the pharmaceutical composition comprises a sterile aqueous buffer and dimethylsulfoxide.

A topically applicable chemical peel composition for home use having from about 4% to about 13%, by weight, of alpha hydroxy acid, from about 0.1% to about 2.0%, by weight, of salicylic acid, from about 0.1% to about 2.0%, by weight, of phenylethyl resorcinol and balance essentially dermatologically acceptable liquid solvent. In addition, a chemical skin peel regime or regimen including topical application onto the skin is also disclosed.

1. A topically applicable chemical peel composition comprising: from about 8% to about 12%, by weight, of alpha hydroxy acid; from about 0.1% to about 2.0%, by weight, of salicylic acid; from about 0.1% to about 2.0%, by weight, of phenylethyl resorcinol; balance essentially dermatologically acceptable liquid solvent. 2. The chemical peel composition of claim 1, wherein the dermatologically acceptable liquid solvent includes ethanol. 3. The chemical peel composition of claim 1, wherein the composition includes from about 0.2% to about 1.5%, by weight, of phenylethyl resorcinol. 4. The chemical peel composition of claim 1, wherein the composition includes from about 0.6% to about 0.9%, by weight, of phenylethyl resorcinol. 5. The chemical peel composition of claim 1, wherein the composition includes about 0.75%, by weight, of phenylethyl resorcinol. 6. The chemical peel composition of claim 1, wherein the alpha hydroxy acid is selected from the group consisting of lactic acid, glycolic acid, tartaric acid, mandelic acid, citric acid, ester derivatives thereof and combinations thereof. 7. The chemical peel composition of claim 1, wherein the alpha hydroxy acid is lactic acid. 8. (canceled) 9. The chemical peel composition of claim 1, wherein the composition includes from about 9% to about 11%, by weight, of alpha hydroxy acid. 10. The chemical peel composition of claim 1, wherein the composition includes about 10.0%, by weight, of alpha hydroxy acid. 11. The chemical peel composition of claim 1, wherein the composition includes from about 0.3% to about 1.0%, by weight, of salicylic acid. 12. The chemical peel composition of claim 1, wherein the composition includes from about 0.4% to about 0.5%, by weight, of salicylic acid. 13. The chemical peel composition of claim 1, wherein the composition includes about 0.45%, by weight, of salicylic acid. 14. The chemical peel composition of claim 1, further comprising an additive selected from the group consisting of preservatives, stabilizers, antioxidants, thickening agents, surfactants, pigments, colorants, fragrances and combinations thereof. 15. A chemical skin peel regime or regimen including topical application onto the skin of the chemical peel composition of claim 1. 16. The chemical skin peel regime or regimen of claim 15 comprising treating photodamaged skin, hyperpigmentation, acne vulgaris, rosacea, wrinkles, fine lines or superficial scars. 17. A topically applicable chemical peel composition comprising: from about 8% to about 12%, by weight, of alpha hydroxy acid; from about 0.4% to about 1.0%, by weight, of salicylic acid; from about 0.1% to about 2.0%, by weight, of phenylethyl resorcinol; balance essentially dermatologically acceptable liquid solvent. 18. The chemical peel composition of claim 17, wherein the alpha hydroxy acid is selected from the group consisting of lactic acid, glycolic acid, tartaric acid, mandelic acid, citric acid, ester derivatives thereof and combinations thereof, and further comprising an additive selected from the group consisting of preservatives, stabilizers, antioxidants, thickening agents, surfactants, pigments, colorants, fragrances and combinations thereof. 19. A topically applicable chemical peel composition comprising: about 10%, by weight, of alpha hydroxy acid; about 0.45%, by weight, of salicylic acid; about 00.75%, by weight, of phenylethyl resorcinol; an additive selected from the group consisting of preservatives, stabilizers, antioxidants, thickening agents, surfactants, pigments, colorants, fragrances and combinations thereof, balance essentially dermatologically acceptable liquid solvent. 20. The chemical peel composition of claim 19, wherein the alpha hydroxy acid is selected from the group consisting of lactic acid, glycolic acid, tartaric acid, mandelic acid, citric acid, ester derivatives thereof and combinations thereof, and wherein the additive includes a solvent selected from denatured alcohol. 21. The chemical peel composition of claim 20, wherein the alpha hydroxy acid is lactic acid and the alcohol is ethanol.

A topically applicable chemical peel composition for home use having from about 4% to about 13%, by weight, of alpha hydroxy acid, from about 0.1% to about 2.0%, by weight, of salicylic acid, from about 0.1% to about 2.0%, by weight, of phenylethyl resorcinol and balance essentially dermatologically acceptable liquid solvent. In addition, a chemical skin peel regime or regimen including topical application onto the skin is also disclosed.1. A topically applicable chemical peel composition comprising: from about 8% to about 12%, by weight, of alpha hydroxy acid; from about 0.1% to about 2.0%, by weight, of salicylic acid; from about 0.1% to about 2.0%, by weight, of phenylethyl resorcinol; balance essentially dermatologically acceptable liquid solvent. 2. The chemical peel composition of claim 1, wherein the dermatologically acceptable liquid solvent includes ethanol. 3. The chemical peel composition of claim 1, wherein the composition includes from about 0.2% to about 1.5%, by weight, of phenylethyl resorcinol. 4. The chemical peel composition of claim 1, wherein the composition includes from about 0.6% to about 0.9%, by weight, of phenylethyl resorcinol. 5. The chemical peel composition of claim 1, wherein the composition includes about 0.75%, by weight, of phenylethyl resorcinol. 6. The chemical peel composition of claim 1, wherein the alpha hydroxy acid is selected from the group consisting of lactic acid, glycolic acid, tartaric acid, mandelic acid, citric acid, ester derivatives thereof and combinations thereof. 7. The chemical peel composition of claim 1, wherein the alpha hydroxy acid is lactic acid. 8. (canceled) 9. The chemical peel composition of claim 1, wherein the composition includes from about 9% to about 11%, by weight, of alpha hydroxy acid. 10. The chemical peel composition of claim 1, wherein the composition includes about 10.0%, by weight, of alpha hydroxy acid. 11. The chemical peel composition of claim 1, wherein the composition includes from about 0.3% to about 1.0%, by weight, of salicylic acid. 12. The chemical peel composition of claim 1, wherein the composition includes from about 0.4% to about 0.5%, by weight, of salicylic acid. 13. The chemical peel composition of claim 1, wherein the composition includes about 0.45%, by weight, of salicylic acid. 14. The chemical peel composition of claim 1, further comprising an additive selected from the group consisting of preservatives, stabilizers, antioxidants, thickening agents, surfactants, pigments, colorants, fragrances and combinations thereof. 15. A chemical skin peel regime or regimen including topical application onto the skin of the chemical peel composition of claim 1. 16. The chemical skin peel regime or regimen of claim 15 comprising treating photodamaged skin, hyperpigmentation, acne vulgaris, rosacea, wrinkles, fine lines or superficial scars. 17. A topically applicable chemical peel composition comprising: from about 8% to about 12%, by weight, of alpha hydroxy acid; from about 0.4% to about 1.0%, by weight, of salicylic acid; from about 0.1% to about 2.0%, by weight, of phenylethyl resorcinol; balance essentially dermatologically acceptable liquid solvent. 18. The chemical peel composition of claim 17, wherein the alpha hydroxy acid is selected from the group consisting of lactic acid, glycolic acid, tartaric acid, mandelic acid, citric acid, ester derivatives thereof and combinations thereof, and further comprising an additive selected from the group consisting of preservatives, stabilizers, antioxidants, thickening agents, surfactants, pigments, colorants, fragrances and combinations thereof. 19. A topically applicable chemical peel composition comprising: about 10%, by weight, of alpha hydroxy acid; about 0.45%, by weight, of salicylic acid; about 00.75%, by weight, of phenylethyl resorcinol; an additive selected from the group consisting of preservatives, stabilizers, antioxidants, thickening agents, surfactants, pigments, colorants, fragrances and combinations thereof, balance essentially dermatologically acceptable liquid solvent. 20. The chemical peel composition of claim 19, wherein the alpha hydroxy acid is selected from the group consisting of lactic acid, glycolic acid, tartaric acid, mandelic acid, citric acid, ester derivatives thereof and combinations thereof, and wherein the additive includes a solvent selected from denatured alcohol. 21. The chemical peel composition of claim 20, wherein the alpha hydroxy acid is lactic acid and the alcohol is ethanol.

In many situations, particularly in forensic science, there is a need to consider one piece of evidence against one or more other pieces of evidence. For instance, it may be desirable to compare a sample collected from a crime scene with a sample collected from a person, with a view to linking the two by comparing the characteristics of their DNA, particularly by expressing the strength or likelihood of the comparison made, a so called likelihood ratio. The method provides a more accurate or robust method for establishing likelihood ratios through the definitions of the likelihood ratios used and the manner in which the probability distribution functions for use in establishing likelihood ratios are obtained. The methods provide due consideration of stutter and/or dropout of alleles in DNA analysis, as well as taking into consideration one or more peak imbalance effects, such as degradation, amplification efficiency, sampling effects and the like.

1. A method of comparing a first sample result set with a second sample result set, the method comprising: a) providing information for the first result set on the one or more identities detected for a variable characteristic of DNA; b) providing information for the second result set on the one or more identities detected for a variable characteristic of DNA; and c) considering the relative likelihoods of one hypothesis to another hypothesis as a likelihood ratio; wherein the method uses in the definition of the likelihood ratio the factor: ƒ(Cl(i)|gl(i),χl(i),δ) where gl(i) is the genotype of the donor of sample Cl(i), δ is an effect parameter and χl(i) denotes the quantitative measure, for instance peak-height sum or peak area sum, for the locus i; or wherein the method uses as the definition of the likelihood ratio the factor: ƒ(cl(i)|gU,1,l(i),gU,2,l(i),χl(i),δ) where gU,1,l(i) is one of the genotypes of the donor of sample cl(i), gU,1,l(i), is another of the genotypes of the donor of the sample cl(i)), δ is an effect parameter and χl(i) denotes the quantitative measure, for instance peak-height sum or peak area sum, for the locus i; or wherein the method uses in the definition of the likelihood ratio the factor: ƒ(cl(i)|g1,l(i),g2,l(i),ω, χl(i),δ) where gU,1,l(i) is one of the genotypes of the donor of sample cl(i), gU,l(i) is another of the genotypes of the donor of the sample cl(i), δ is an effect parameter and χl(i) denotes the quantitative measure, for instance peak-height sum or peak area sum, for the locus i and ω is the mixing proportion. 2. A method according to claim 1 wherein the method of comparing considers the relative likelihoods of one hypothesis to another hypothesis as a likelihood ratio, the likelihood ratio being of the form: L   R =  p  ( c , gs  V p ) p  ( c , gs  V d ) =  f  ( c , gs  V p ) f   c , gs  V d ) where c is the first or test result set from a test sample, gs is the second or another result set, Vp is one hypothesis and Vd is an alternative hypothesis. 3. A method according to claim 1 wherein the likelihood includes a factor accounting for stutter and/or a factor accounting for allele dropout and/or a factor accounting for one of more effects which impact upon the amount of an allele. 4. A method according to claim 3 wherein the one or more effects may be and/or include degradation effects and/or variations in amplification efficiency and/or variations in amount of allele in a sub-sample of a sample. 5. A method according to claim 1 wherein: a) the method is computer implemented method; and/or b) the first sample is a test sample and the test sample is analysed to establish the identities present in respect of one or more variable parts of the DNA of the test sample, the analysis comprising one or more of: a sampling step; a dilution step; a purification step; a pooling of samples step; a division of samples step; an amplification step, such as PCR; a detection step; an electrophoresis step; an interpretation step; a peak identification step; a peak height and/or area determination step; and/or c) the first sample and/or control samples are analysed to determine the peak height or heights present for one or more peaks indicative of one or more identities and/or to determine the peak area or areas present for one or more peaks indicative of one or more identities and/or to determine the peak weight or weights present for one or more peaks indicative of one or more identities and/or to determine a level indicator for one or more identities.

In many situations, particularly in forensic science, there is a need to consider one piece of evidence against one or more other pieces of evidence. For instance, it may be desirable to compare a sample collected from a crime scene with a sample collected from a person, with a view to linking the two by comparing the characteristics of their DNA, particularly by expressing the strength or likelihood of the comparison made, a so called likelihood ratio. The method provides a more accurate or robust method for establishing likelihood ratios through the definitions of the likelihood ratios used and the manner in which the probability distribution functions for use in establishing likelihood ratios are obtained. The methods provide due consideration of stutter and/or dropout of alleles in DNA analysis, as well as taking into consideration one or more peak imbalance effects, such as degradation, amplification efficiency, sampling effects and the like.1. A method of comparing a first sample result set with a second sample result set, the method comprising: a) providing information for the first result set on the one or more identities detected for a variable characteristic of DNA; b) providing information for the second result set on the one or more identities detected for a variable characteristic of DNA; and c) considering the relative likelihoods of one hypothesis to another hypothesis as a likelihood ratio; wherein the method uses in the definition of the likelihood ratio the factor: ƒ(Cl(i)|gl(i),χl(i),δ) where gl(i) is the genotype of the donor of sample Cl(i), δ is an effect parameter and χl(i) denotes the quantitative measure, for instance peak-height sum or peak area sum, for the locus i; or wherein the method uses as the definition of the likelihood ratio the factor: ƒ(cl(i)|gU,1,l(i),gU,2,l(i),χl(i),δ) where gU,1,l(i) is one of the genotypes of the donor of sample cl(i), gU,1,l(i), is another of the genotypes of the donor of the sample cl(i)), δ is an effect parameter and χl(i) denotes the quantitative measure, for instance peak-height sum or peak area sum, for the locus i; or wherein the method uses in the definition of the likelihood ratio the factor: ƒ(cl(i)|g1,l(i),g2,l(i),ω, χl(i),δ) where gU,1,l(i) is one of the genotypes of the donor of sample cl(i), gU,l(i) is another of the genotypes of the donor of the sample cl(i), δ is an effect parameter and χl(i) denotes the quantitative measure, for instance peak-height sum or peak area sum, for the locus i and ω is the mixing proportion. 2. A method according to claim 1 wherein the method of comparing considers the relative likelihoods of one hypothesis to another hypothesis as a likelihood ratio, the likelihood ratio being of the form: L   R =  p  ( c , gs  V p ) p  ( c , gs  V d ) =  f  ( c , gs  V p ) f   c , gs  V d ) where c is the first or test result set from a test sample, gs is the second or another result set, Vp is one hypothesis and Vd is an alternative hypothesis. 3. A method according to claim 1 wherein the likelihood includes a factor accounting for stutter and/or a factor accounting for allele dropout and/or a factor accounting for one of more effects which impact upon the amount of an allele. 4. A method according to claim 3 wherein the one or more effects may be and/or include degradation effects and/or variations in amplification efficiency and/or variations in amount of allele in a sub-sample of a sample. 5. A method according to claim 1 wherein: a) the method is computer implemented method; and/or b) the first sample is a test sample and the test sample is analysed to establish the identities present in respect of one or more variable parts of the DNA of the test sample, the analysis comprising one or more of: a sampling step; a dilution step; a purification step; a pooling of samples step; a division of samples step; an amplification step, such as PCR; a detection step; an electrophoresis step; an interpretation step; a peak identification step; a peak height and/or area determination step; and/or c) the first sample and/or control samples are analysed to determine the peak height or heights present for one or more peaks indicative of one or more identities and/or to determine the peak area or areas present for one or more peaks indicative of one or more identities and/or to determine the peak weight or weights present for one or more peaks indicative of one or more identities and/or to determine a level indicator for one or more identities.

The present invention provides methods and devices for isolating cells from a subject by circulating the subject's body fluid over an affinity moeity coupled matrix to isolate isolate cells from a subject either ex vivo or in vivo. One aspect of the invention is directed to connecting a subject to a system capable of circulating the subject's body fluid through an affinity moiety coupled matrix, such that the affinity moiety coupled matrix is capable of binding to and extracting target cells from the body fluid, and then eluting the target cells from the affinity moiety. Another aspect of the invention is directed to the apparatus for isolating cells from a subject, comprising a blood circulation system with an arterial side blood circuit for extracting blood and flowing the blood over an affinity moiety coupled matrix that binds to and extracts target cells and a venous side blood circuit for returning the blood to the patient. The invention is also directed to in vivo seeding of biomatrials by implanting the affinity moiety coupled matrix in a subject to attract and bind the target cells in vivo.

1. A method of isolating cells from a subject, comprising: connecting a subject to a system capable of circulating body fluid therethrough, wherein the system comprises an affinity moiety coupled matrix; passing the body fluid through the affinity moiety coupled matrix, such that the body fluid is returned to the subject following passage through said matrix; wherein the affinity moiety coupled matrix is capable of binding to and extracting target cells from the body fluid; and eluting the target cells from the affinity moiety. 2. The method of claim 1, wherein the affinity moiety is selected from the group consisting of antibodies, protein ligands, nucleic acids and peptides. 3. The method of claim 1, wherein the body fluid is selected from the group consisting of peripheral blood, cord blood, spinal fluid, bone marrow, amniotic fluid, cerebrospinal fluid (CSF), follicular fluid, interstitial fluid, intracellular fluid, prostatic fluid, Scarpa's fluid, seminal fluid, and synovial fluid. 4. The method of claim 1, wherein the affinity moiety has substantial affinity for stem cells. 5. The method of claim 1, wherein the affinity moiety has substantial affinity for one or more of the stem cell markers selected from the group consisting of CD133, CD34, sca-1, c-kit and CD33. 6. The method of claim 1, wherein the affinity moiety has substantial affinity for cancer cells. 7. The method of claim 1, wherein the affinity moiety has substantial affinity for cells selected from the group consisting of stem cells, hematopoietic stem cells, embryonic stem cells, embryonic-like stem cells, mesenchymal stem cells, myeloid stem cell, neuronal stem cells, and adult stem cells. 8. An apparatus for isolating cells from a subject comprising: a blood circulation system comprising an arterial side blood circuit for extracting blood from a subject and flowing it into an affinity moiety coupled matrix; and a venous side blood circuit for returning blood from the matrix to the patient, wherein the affinity moiety coupled matrix is capable of binding to and extracting target cells from the blood. 9. An apparatus for ex vivo filtering of cells from a subject comprising: a body fluid circulation system comprising an inlet side for extracting body fluid from a subject and flowing it into an affinity moiety coupled matrix; and an outlet side for returning body fluid from the matrix to the patient, wherein the affinity moiety coupled matrix is capable of binding to and extracting target cells from the body fluid. 10. A method of in vivo seeding of biomaterials comprising: selecting a target population of cells; covalently coupling an affinity moiety to a matrix, wherein the affinity moiety is capable of binding to said target cells; and implanting said affinity moiety coupled matrix in a subject at a target site; such that the target population of cells bind to said matrix at the target site. 11. The method of claim 10, wherein said matrix is biodegradable. 12. The method of claim 10, wherein said matrix is selected from the group consisting of a stent and a prosthetic. 13. A self-seeding scaffold for in vivo seeding of target cells comprising: a biomatrix; and an affinity moiety with substantial specificity for binding to a target cell population, wherein the affinity moiety is capable of attracting and binding to said target cells. 14. The self-seeding scaffold of claim 13, wherein said affinity moiety is covalently coupled to a biomatrix. 15. The self-seeding scaffold of claim 13, wherein the biomatrix is selected from the group consisting of a synthetic matrix and a decellularized matrix. 16. The self-seeding scaffold of claim 13, wherein the biomatrix is selected from the group consisting of stents and prosthetics. 17. The self-seeding scaffold of claim 13, wherein the biomatrix is covalently coupled to the affinity moiety using a linker. 18. The self-seeding scaffold of claim 17, wherein the linker is SPDP (N-succinimidyi-3-(2-pyridyldithio)propionate). 19. The self-seeding scaffold of claim 13, wherein said biomatrix comprises a recombinant protein comprising the affinity moiety. 20. The self-seeding scaffold of claim 19, wherein the recombinant protein is selected from the group consisting of an antibody, a protein and a peptide. 21. The self-seeding scaffold of claim 19, wherein the recombinant protein is a chimeric protein further comprising a biomatrix polymer. 22. The self-seeding scaffold of claim 19, wherein the recombinant protein is incorporated in the biomatrix.

The present invention provides methods and devices for isolating cells from a subject by circulating the subject's body fluid over an affinity moeity coupled matrix to isolate isolate cells from a subject either ex vivo or in vivo. One aspect of the invention is directed to connecting a subject to a system capable of circulating the subject's body fluid through an affinity moiety coupled matrix, such that the affinity moiety coupled matrix is capable of binding to and extracting target cells from the body fluid, and then eluting the target cells from the affinity moiety. Another aspect of the invention is directed to the apparatus for isolating cells from a subject, comprising a blood circulation system with an arterial side blood circuit for extracting blood and flowing the blood over an affinity moiety coupled matrix that binds to and extracts target cells and a venous side blood circuit for returning the blood to the patient. The invention is also directed to in vivo seeding of biomatrials by implanting the affinity moiety coupled matrix in a subject to attract and bind the target cells in vivo.1. A method of isolating cells from a subject, comprising: connecting a subject to a system capable of circulating body fluid therethrough, wherein the system comprises an affinity moiety coupled matrix; passing the body fluid through the affinity moiety coupled matrix, such that the body fluid is returned to the subject following passage through said matrix; wherein the affinity moiety coupled matrix is capable of binding to and extracting target cells from the body fluid; and eluting the target cells from the affinity moiety. 2. The method of claim 1, wherein the affinity moiety is selected from the group consisting of antibodies, protein ligands, nucleic acids and peptides. 3. The method of claim 1, wherein the body fluid is selected from the group consisting of peripheral blood, cord blood, spinal fluid, bone marrow, amniotic fluid, cerebrospinal fluid (CSF), follicular fluid, interstitial fluid, intracellular fluid, prostatic fluid, Scarpa's fluid, seminal fluid, and synovial fluid. 4. The method of claim 1, wherein the affinity moiety has substantial affinity for stem cells. 5. The method of claim 1, wherein the affinity moiety has substantial affinity for one or more of the stem cell markers selected from the group consisting of CD133, CD34, sca-1, c-kit and CD33. 6. The method of claim 1, wherein the affinity moiety has substantial affinity for cancer cells. 7. The method of claim 1, wherein the affinity moiety has substantial affinity for cells selected from the group consisting of stem cells, hematopoietic stem cells, embryonic stem cells, embryonic-like stem cells, mesenchymal stem cells, myeloid stem cell, neuronal stem cells, and adult stem cells. 8. An apparatus for isolating cells from a subject comprising: a blood circulation system comprising an arterial side blood circuit for extracting blood from a subject and flowing it into an affinity moiety coupled matrix; and a venous side blood circuit for returning blood from the matrix to the patient, wherein the affinity moiety coupled matrix is capable of binding to and extracting target cells from the blood. 9. An apparatus for ex vivo filtering of cells from a subject comprising: a body fluid circulation system comprising an inlet side for extracting body fluid from a subject and flowing it into an affinity moiety coupled matrix; and an outlet side for returning body fluid from the matrix to the patient, wherein the affinity moiety coupled matrix is capable of binding to and extracting target cells from the body fluid. 10. A method of in vivo seeding of biomaterials comprising: selecting a target population of cells; covalently coupling an affinity moiety to a matrix, wherein the affinity moiety is capable of binding to said target cells; and implanting said affinity moiety coupled matrix in a subject at a target site; such that the target population of cells bind to said matrix at the target site. 11. The method of claim 10, wherein said matrix is biodegradable. 12. The method of claim 10, wherein said matrix is selected from the group consisting of a stent and a prosthetic. 13. A self-seeding scaffold for in vivo seeding of target cells comprising: a biomatrix; and an affinity moiety with substantial specificity for binding to a target cell population, wherein the affinity moiety is capable of attracting and binding to said target cells. 14. The self-seeding scaffold of claim 13, wherein said affinity moiety is covalently coupled to a biomatrix. 15. The self-seeding scaffold of claim 13, wherein the biomatrix is selected from the group consisting of a synthetic matrix and a decellularized matrix. 16. The self-seeding scaffold of claim 13, wherein the biomatrix is selected from the group consisting of stents and prosthetics. 17. The self-seeding scaffold of claim 13, wherein the biomatrix is covalently coupled to the affinity moiety using a linker. 18. The self-seeding scaffold of claim 17, wherein the linker is SPDP (N-succinimidyi-3-(2-pyridyldithio)propionate). 19. The self-seeding scaffold of claim 13, wherein said biomatrix comprises a recombinant protein comprising the affinity moiety. 20. The self-seeding scaffold of claim 19, wherein the recombinant protein is selected from the group consisting of an antibody, a protein and a peptide. 21. The self-seeding scaffold of claim 19, wherein the recombinant protein is a chimeric protein further comprising a biomatrix polymer. 22. The self-seeding scaffold of claim 19, wherein the recombinant protein is incorporated in the biomatrix.

Surprisingly, it has been found in accordance with the invention that, by adding guanidinoacetic acid, creatine and/or their salts to the feed of parent animals, the hatching rate of eggs can be increased, the embryo mortality can be reduced and the chicks' growth and feed conversion can be increased.

1-15. (canceled) 16. A method for increasing the hatching rate in eggs, and/or for reducing embryo mortality, and/or for improving chick growth, and/or for improving the chicks' feed conversion, comprising feeding parent animals a feed which comprises guanidinoacetic acid; creatine; salts of these compounds; and mixtures of the compounds and/or their salts. 17. The method of claim 16, wherein said parent animals are selected from the group consisting of: poultry; broilers; geese; ducks; turkeys; quails; peacocks; pheasants; pigeons; guinea fowl; partridges; grouse; and ostriches. 18. The method of claim 17, wherein said parent animals are selected from the group consisting of: chickens; broilers and quails. 19. The method of claim 16, wherein said guanidinoacetic acid, and/or creatine, and/or salts of these compounds are present in the feed in an amount of from 0.04 to 0.20% by weight. 20. The method of claim 19, wherein guanidinoacetic acid and/or creatine and/or salts of these compounds are present in the feed in an amount of from 0.08 to 0.16% by weight. 21. The method of claim 16, wherein said feed further comprises at least one of the following components: a) maize or maize meal, in an amount of from 20 to 70% by weight; b) extracted soybean meal, in an amount of from 10 to 50% by weight; c) an oil or fat, in an amount of from 1 to 10% by weight; d) calcium carbonate, in an amount of from 4 to 14% by weight; e) dicalcium phosphate, in an amount of from 0.2 to 2.5% by weight; f) wheat or wheat flour, in an amount of up to 60% by weight; g) barley or barley flour, in an amount of up to 40% by weight; h) one or more amino acids selected from the group consisting of: lysine; methionine; threonine; valine; arginine; and mixtures thereof; i) vitamins. 22. The method of claim 21, wherein said feed further comprises at least three of components a)-i). 23. The method of claim 16, wherein said parent animals are wild fowl, and said feed comprises guanidinoacetic acid, and/or creatine, and/or salts of these compounds in an amount of from 0.06 to 0.2% by weight. 24. The method of claim 23, wherein said feed further comprises at least one of the following components: a) maize or maize meal, in an amount of from 20 to 70% by weight; b) extracted soybean meal, in an amount of from 10 to 50% by weight; c) an oil or fat, in an amount of from 1 to 10% by weight; d) calcium carbonate, in an amount of from 4 to 14% by weight; e) dicalcium phosphate, in an amount of from 0.2 to 2.5% by weight; f) wheat or wheat flour, in an amount of up to 60% by weight; g) barley or barley flour, in an amount of up to 40% by weight; h) one or more amino acids selected from the group consisting of: lysine; methionine; threonine; valine; arginine; and mixtures of thereof; i) vitamins. 25. The method of claim 16, wherein said parent animals are quail, and said feed comprises guanidinoacetic acid, and/or creatine, and/or salts of these compounds in an amount of from 0.06 to 0.2% by weight. 26. The method of claim 25, wherein said feed further comprises at least one of the following components: a) maize or maize meal, in an amount of from 20 to 70% by weight; b) extracted soybean meal, in an amount of from 10 to 50% by weight; c) an oil or fat component, in an amount of from 1 to 10% by weight; d) calcium carbonate, in an amount of from 4 to 14% by weight; e) dicalcium phosphate, in an amount of from 0.2 to 2.5% by weight; f) wheat or wheat flour, in an amount of up to 60% by weight; g) barley or barley flour, in an amount of up to 40% by weight; h) one or more amino acids selected from the group consisting of: lysine; methionine; threonine; valine; arginine; and mixtures of thereof; i) vitamins. 27. An animal feed, comprising guanidinoacetic acid, and/or creatine, and/or a salt of these compounds in an amount of from 0.02 to 0.2% by weight. 28. The animal feed of claim 27, further comprising one or more of the following components: a) maize or maize meal, in an amount of from 20 to 70%; b) extracted soybean meal, in an amount of from 10 to 50%; c) an oil or fat component, in an amount of from 1 to 10% by weight; d) calcium carbonate, in an amount of from 4 to 14% by weight; e) dicalcium phosphate, in an amount of from 0.2 to 2.5% by weight; f) wheat or wheat flour, in an amount of up to 40% by weight; g) barley or barley flour, in an amount of up to 40% by weight; h) one or more amino acids, selected from the group consisting of: lysine, methionine, threonine, valine and arginine, and mixtures of these; i) vitamins. 29. The animal feed of claim 28, wherein said feed comprises maize or maize meal in an amount of from 20 to 70% by weight. 30. The animal feed of claim 29, wherein said feed comprises extracted soybean meal in an amount of from 10 to 50% 31. The animal feed of claim 30, wherein said feed comprises at least 3 of components c)-i). 32. The animal feed of claim 27, wherein said guanidinoacetic acid, and/or creatine, and/or salt of these compounds is present in an amount of from 0.07 to 0.16% by weight, and further comprising: a) maize or maize meal, in an amount of from 30 to 60% by weight; b) extracted soybean meal, in an amount of from 15 to 45% by weight and at least three further components, selected from the group consisting of; c) soya oil, in an amount of from 1 to 10% by weight; d) calcium carbonate, in an amount of from 6 to 12% by weight; e) dicalcium phosphate, in an amount of from 0.5 to 1.5% by weight; f) wheat or wheat flour, in an amount of up to 10% by weight; g) barley or barley flour, in an amount of up to 10% by weight; h) one or more amino acids selected from the group consisting of: lysine; methionine; threonine; valine; arginine; and mixtures thereof; and i) vitamins. 33. The animal feed of claim 27, further comprising one or more of the following: a) crude protein, in an amount of from 10 to 30% by weight; b) calcium, in an amount of from 1 to 5% by weight; c) phosphorus, in an amount of from 0.2 to 0.6% by weight; d) methionine and/or cysteine, in an amount of from 0.25 to 1.0% by weight; e) lysine, in an amount of from 0.5 to 1.5% by weight. 34. The animal feed of claim 33, further comprising at least 4 of components a)-e). 35. The animal feed of claim 27, further comprising: a) crude protein in an amount of from 12 to 25% by weight; b) calcium in an amount of from 1 to 5% by weight; c) phosphorus in an amount of from 0.2 to 0.6% by weight; d) methionine and/or cysteine in an amount of from 0.25 to 1.0% by weight; and e) lysine in an amount of from 0.5 to 1.5% by weight.

Surprisingly, it has been found in accordance with the invention that, by adding guanidinoacetic acid, creatine and/or their salts to the feed of parent animals, the hatching rate of eggs can be increased, the embryo mortality can be reduced and the chicks' growth and feed conversion can be increased.1-15. (canceled) 16. A method for increasing the hatching rate in eggs, and/or for reducing embryo mortality, and/or for improving chick growth, and/or for improving the chicks' feed conversion, comprising feeding parent animals a feed which comprises guanidinoacetic acid; creatine; salts of these compounds; and mixtures of the compounds and/or their salts. 17. The method of claim 16, wherein said parent animals are selected from the group consisting of: poultry; broilers; geese; ducks; turkeys; quails; peacocks; pheasants; pigeons; guinea fowl; partridges; grouse; and ostriches. 18. The method of claim 17, wherein said parent animals are selected from the group consisting of: chickens; broilers and quails. 19. The method of claim 16, wherein said guanidinoacetic acid, and/or creatine, and/or salts of these compounds are present in the feed in an amount of from 0.04 to 0.20% by weight. 20. The method of claim 19, wherein guanidinoacetic acid and/or creatine and/or salts of these compounds are present in the feed in an amount of from 0.08 to 0.16% by weight. 21. The method of claim 16, wherein said feed further comprises at least one of the following components: a) maize or maize meal, in an amount of from 20 to 70% by weight; b) extracted soybean meal, in an amount of from 10 to 50% by weight; c) an oil or fat, in an amount of from 1 to 10% by weight; d) calcium carbonate, in an amount of from 4 to 14% by weight; e) dicalcium phosphate, in an amount of from 0.2 to 2.5% by weight; f) wheat or wheat flour, in an amount of up to 60% by weight; g) barley or barley flour, in an amount of up to 40% by weight; h) one or more amino acids selected from the group consisting of: lysine; methionine; threonine; valine; arginine; and mixtures thereof; i) vitamins. 22. The method of claim 21, wherein said feed further comprises at least three of components a)-i). 23. The method of claim 16, wherein said parent animals are wild fowl, and said feed comprises guanidinoacetic acid, and/or creatine, and/or salts of these compounds in an amount of from 0.06 to 0.2% by weight. 24. The method of claim 23, wherein said feed further comprises at least one of the following components: a) maize or maize meal, in an amount of from 20 to 70% by weight; b) extracted soybean meal, in an amount of from 10 to 50% by weight; c) an oil or fat, in an amount of from 1 to 10% by weight; d) calcium carbonate, in an amount of from 4 to 14% by weight; e) dicalcium phosphate, in an amount of from 0.2 to 2.5% by weight; f) wheat or wheat flour, in an amount of up to 60% by weight; g) barley or barley flour, in an amount of up to 40% by weight; h) one or more amino acids selected from the group consisting of: lysine; methionine; threonine; valine; arginine; and mixtures of thereof; i) vitamins. 25. The method of claim 16, wherein said parent animals are quail, and said feed comprises guanidinoacetic acid, and/or creatine, and/or salts of these compounds in an amount of from 0.06 to 0.2% by weight. 26. The method of claim 25, wherein said feed further comprises at least one of the following components: a) maize or maize meal, in an amount of from 20 to 70% by weight; b) extracted soybean meal, in an amount of from 10 to 50% by weight; c) an oil or fat component, in an amount of from 1 to 10% by weight; d) calcium carbonate, in an amount of from 4 to 14% by weight; e) dicalcium phosphate, in an amount of from 0.2 to 2.5% by weight; f) wheat or wheat flour, in an amount of up to 60% by weight; g) barley or barley flour, in an amount of up to 40% by weight; h) one or more amino acids selected from the group consisting of: lysine; methionine; threonine; valine; arginine; and mixtures of thereof; i) vitamins. 27. An animal feed, comprising guanidinoacetic acid, and/or creatine, and/or a salt of these compounds in an amount of from 0.02 to 0.2% by weight. 28. The animal feed of claim 27, further comprising one or more of the following components: a) maize or maize meal, in an amount of from 20 to 70%; b) extracted soybean meal, in an amount of from 10 to 50%; c) an oil or fat component, in an amount of from 1 to 10% by weight; d) calcium carbonate, in an amount of from 4 to 14% by weight; e) dicalcium phosphate, in an amount of from 0.2 to 2.5% by weight; f) wheat or wheat flour, in an amount of up to 40% by weight; g) barley or barley flour, in an amount of up to 40% by weight; h) one or more amino acids, selected from the group consisting of: lysine, methionine, threonine, valine and arginine, and mixtures of these; i) vitamins. 29. The animal feed of claim 28, wherein said feed comprises maize or maize meal in an amount of from 20 to 70% by weight. 30. The animal feed of claim 29, wherein said feed comprises extracted soybean meal in an amount of from 10 to 50% 31. The animal feed of claim 30, wherein said feed comprises at least 3 of components c)-i). 32. The animal feed of claim 27, wherein said guanidinoacetic acid, and/or creatine, and/or salt of these compounds is present in an amount of from 0.07 to 0.16% by weight, and further comprising: a) maize or maize meal, in an amount of from 30 to 60% by weight; b) extracted soybean meal, in an amount of from 15 to 45% by weight and at least three further components, selected from the group consisting of; c) soya oil, in an amount of from 1 to 10% by weight; d) calcium carbonate, in an amount of from 6 to 12% by weight; e) dicalcium phosphate, in an amount of from 0.5 to 1.5% by weight; f) wheat or wheat flour, in an amount of up to 10% by weight; g) barley or barley flour, in an amount of up to 10% by weight; h) one or more amino acids selected from the group consisting of: lysine; methionine; threonine; valine; arginine; and mixtures thereof; and i) vitamins. 33. The animal feed of claim 27, further comprising one or more of the following: a) crude protein, in an amount of from 10 to 30% by weight; b) calcium, in an amount of from 1 to 5% by weight; c) phosphorus, in an amount of from 0.2 to 0.6% by weight; d) methionine and/or cysteine, in an amount of from 0.25 to 1.0% by weight; e) lysine, in an amount of from 0.5 to 1.5% by weight. 34. The animal feed of claim 33, further comprising at least 4 of components a)-e). 35. The animal feed of claim 27, further comprising: a) crude protein in an amount of from 12 to 25% by weight; b) calcium in an amount of from 1 to 5% by weight; c) phosphorus in an amount of from 0.2 to 0.6% by weight; d) methionine and/or cysteine in an amount of from 0.25 to 1.0% by weight; and e) lysine in an amount of from 0.5 to 1.5% by weight.

The invention relates to a composition for dip treatment of plant roots comprising a substance of interest and a branched polysaccharide, in particular xanthan gum.

1. A composition intended for dip treatment of a plant, comprising a branched polysaccharide and also a substance of interest. 2. The composition as claimed in claim 1, characterized in that said substance of interest is an endomycorrhizal fungus. 3. The composition as claimed in claim 2, characterized in that said endomycorrhizal fungus is a glomeromycete. 4. The composition as claimed in claim 1, characterized in that said substance of interest is an antifungal microorganism. 5. The composition as claimed in claim 4, characterized in that said antifungal microorganism is a Trichoderma. 6. The composition as claimed in claim 2, characterized in that it also comprises an antifungal microorganism. 7. The composition as claimed in claim 6, characterized in that said antifungal microorganism is a Trichoderma. 8. The composition as claimed in claim 1, characterized in that said branched polysaccharide consists of a combination of glucose, mannose, glucuronic acid and pyruvic acid. 9. The composition as claimed in claim 1, characterized in that said branched polysaccharide is xanthan gum. 10. The composition as claimed in claim 9, characterized in that said xanthan gum is in a pulverulent form of particles having a size of less than 177 microns. 11. The composition as claimed in claim 1, characterized in that it comprises only said substance of interest, said branched polysaccharide and also water. 12. The composition as claimed in claim 2, characterized in that it comprises between 3000 and 4000 propagules of said endomycorrhizal fungus for 1 liter of water. 13. The composition as claimed in claim 9, characterized in that it comprises between 6 and 15 g of said xanthan gum, for 1 liter of water. 14. The composition as claimed in claim 1, characterized in that it is in the form of a gel. 15. A particulate composition which comprises: a) particles of branched polysaccharide, having a diameter of greater than 70 microns, and less than 250 microns; b) an active ingredient of interest which is in “dry” form; c) optionally, a neutral matrix stabilizing the active ingredient. 16. The composition as claimed in claim 15, characterized in that said branched polysaccharide is xanthan gum. 17. The composition as claimed in claim 15, characterized in that said active ingredient of interest is an endomycorrhizal fungus, in the form of propagules, which is optionally stabilized with clay. 18. The composition as claimed in claim 15, characterized in that said active ingredient of interest is a Trichoderma, in the form of spores. 19. The composition as claimed in claim 15, characterized in that said active ingredient of interest is a mixture of Trichoderma, in the form of spores, and of an endomycorrhizal fungus, in the form of propagules. 20. A method for preparing a composition, comprising a step of adding water to a composition as claimed in claim 15. 21. (canceled) 22. (canceled) 23. A method for providing a substance of interest to the roots of a plant, comprising the steps of (i) preparing a dip-treatment composition containing said substance of interest and a branched polysaccharide and (ii) applying this dip-treatment composition to the roots of said plant. 24. The method as claimed in claim 23, characterized in that said composition was prepared a few days before application to the plant. 25. A method for planting a plant, comprising the step of planting a plant in a substrate which allows growth of the plant, characterized in that the plant roots are coated with a composition as claimed in claim 1. 26. The method as claimed in claim 24, characterized in that the coating of the roots of the plant was carried out more than 12 hours before the step of planting the plant.

The invention relates to a composition for dip treatment of plant roots comprising a substance of interest and a branched polysaccharide, in particular xanthan gum.1. A composition intended for dip treatment of a plant, comprising a branched polysaccharide and also a substance of interest. 2. The composition as claimed in claim 1, characterized in that said substance of interest is an endomycorrhizal fungus. 3. The composition as claimed in claim 2, characterized in that said endomycorrhizal fungus is a glomeromycete. 4. The composition as claimed in claim 1, characterized in that said substance of interest is an antifungal microorganism. 5. The composition as claimed in claim 4, characterized in that said antifungal microorganism is a Trichoderma. 6. The composition as claimed in claim 2, characterized in that it also comprises an antifungal microorganism. 7. The composition as claimed in claim 6, characterized in that said antifungal microorganism is a Trichoderma. 8. The composition as claimed in claim 1, characterized in that said branched polysaccharide consists of a combination of glucose, mannose, glucuronic acid and pyruvic acid. 9. The composition as claimed in claim 1, characterized in that said branched polysaccharide is xanthan gum. 10. The composition as claimed in claim 9, characterized in that said xanthan gum is in a pulverulent form of particles having a size of less than 177 microns. 11. The composition as claimed in claim 1, characterized in that it comprises only said substance of interest, said branched polysaccharide and also water. 12. The composition as claimed in claim 2, characterized in that it comprises between 3000 and 4000 propagules of said endomycorrhizal fungus for 1 liter of water. 13. The composition as claimed in claim 9, characterized in that it comprises between 6 and 15 g of said xanthan gum, for 1 liter of water. 14. The composition as claimed in claim 1, characterized in that it is in the form of a gel. 15. A particulate composition which comprises: a) particles of branched polysaccharide, having a diameter of greater than 70 microns, and less than 250 microns; b) an active ingredient of interest which is in “dry” form; c) optionally, a neutral matrix stabilizing the active ingredient. 16. The composition as claimed in claim 15, characterized in that said branched polysaccharide is xanthan gum. 17. The composition as claimed in claim 15, characterized in that said active ingredient of interest is an endomycorrhizal fungus, in the form of propagules, which is optionally stabilized with clay. 18. The composition as claimed in claim 15, characterized in that said active ingredient of interest is a Trichoderma, in the form of spores. 19. The composition as claimed in claim 15, characterized in that said active ingredient of interest is a mixture of Trichoderma, in the form of spores, and of an endomycorrhizal fungus, in the form of propagules. 20. A method for preparing a composition, comprising a step of adding water to a composition as claimed in claim 15. 21. (canceled) 22. (canceled) 23. A method for providing a substance of interest to the roots of a plant, comprising the steps of (i) preparing a dip-treatment composition containing said substance of interest and a branched polysaccharide and (ii) applying this dip-treatment composition to the roots of said plant. 24. The method as claimed in claim 23, characterized in that said composition was prepared a few days before application to the plant. 25. A method for planting a plant, comprising the step of planting a plant in a substrate which allows growth of the plant, characterized in that the plant roots are coated with a composition as claimed in claim 1. 26. The method as claimed in claim 24, characterized in that the coating of the roots of the plant was carried out more than 12 hours before the step of planting the plant.

Novel methods of synthesis of chelator-targeting ligand conjugates, compositions comprising such conjugates, and therapeutic and diagnostic applications of such conjugates are disclosed. The compositions include chelator-targeting ligand conjugates optionally chelated to one or more metal ions. Methods of synthesizing these compositions in high purity are also presented. Also disclosed are methods of imaging, treating and diagnosing disease in a subject using these novel compositions, such as methods of imaging a tumor within a subject and methods of diagnosing myocardial ischemia.

1.-80. (canceled) 81. A method of imaging a site, diagnosing a disease, or treating a disease within a subject comprising: (a) obtaining an ethylenedicysteine-glucosamine (EC-DG) metal ion-labeled-chelator targeting ligand conjugate, the conjugate being between about 90% and about 99.9% pure; and (b) administering to the subject a pharmaceutically or diagnostically effective amount of conjugate, wherein the metal ion labeled-chelator-targeting ligand conjugate is prepared by a method comprising the method set forth in claim 12, wherein the site is imaged, the disease is diagnosed, or the disease is treated. 82.-85. (canceled) 86. The method of claim 81, wherein the metal ion is a radionuclide. 87. The method of claim 81, wherein the subject is a human. 88. The method of claim 81, wherein the method is further defined as a method of treating a subject with cancer. 89. The method of claim 88, wherein the cancer is breast cancer, lung cancer, prostate cancer, ovarian cancer, brain cancer, liver cancer, cervical cancer, colon cancer, renal cancer, skin cancer, head and neck cancer, bone cancer, a esophageal cancer, bladder cancer, uterine cancer, lymphatic cancer, stomach cancer, pancreatic cancer, testicular cancer, lymphoma, or leukemia. 90. The method of claim 81, wherein the method is further defined as a method for performing dual radio/chemotherapy. 91. The method of claim 90, further comprising administering one or more secondary forms of therapy of a hyperproliferative disease. 92. The method of claim 81, further defined as a method of imaging a site within a subject comprising detecting a signal from the metal ion labeled-chelator-targeting ligand conjugate that is localized at the site. 93. The method of claim 92, wherein the signal is detected using a technique selected from the group consisting of PET, PET/CT, CT, SPECT, SPECT/CT, MRI, optical imaging and ultrasound. 94. The method of claim 81, wherein the site to be imaged is a tumor or the heart. 95. The method of claim 81, further defined as a method of imaging, diagnosing, or treating a subject with a cardiovascular disease. 96. The method of claim 95, further comprising performing one or more additional diagnostic or imaging procedures to evaluate the subject for a cardiovascular disease. 97. The method of claim 95, wherein the cardiovascular disease is a myocardial infarction, congestive heart failure, cardiomyopathy, valvular heart disease, an arrhythmia, congenital heart disease, angina pectoris, noncardiac circulatory congestion, systolic heart failure, heart failure with normal systolic function, or right-sided heart failure. 98. The method of claim 97, wherein the cardiovascular disease is a myocardial infarction, myocardial ischemia, or angina pectoris and the method further comprises imaging the heart of the subject. 99. The method of claim 81, wherein the metal ion labeled-chelator-targeting ligand conjugate is 99mTc-EC-glucosamine, 188Re-EC-glucosamine, or 187Re-EC-glucosamine. 100.-112. (canceled)

Novel methods of synthesis of chelator-targeting ligand conjugates, compositions comprising such conjugates, and therapeutic and diagnostic applications of such conjugates are disclosed. The compositions include chelator-targeting ligand conjugates optionally chelated to one or more metal ions. Methods of synthesizing these compositions in high purity are also presented. Also disclosed are methods of imaging, treating and diagnosing disease in a subject using these novel compositions, such as methods of imaging a tumor within a subject and methods of diagnosing myocardial ischemia.1.-80. (canceled) 81. A method of imaging a site, diagnosing a disease, or treating a disease within a subject comprising: (a) obtaining an ethylenedicysteine-glucosamine (EC-DG) metal ion-labeled-chelator targeting ligand conjugate, the conjugate being between about 90% and about 99.9% pure; and (b) administering to the subject a pharmaceutically or diagnostically effective amount of conjugate, wherein the metal ion labeled-chelator-targeting ligand conjugate is prepared by a method comprising the method set forth in claim 12, wherein the site is imaged, the disease is diagnosed, or the disease is treated. 82.-85. (canceled) 86. The method of claim 81, wherein the metal ion is a radionuclide. 87. The method of claim 81, wherein the subject is a human. 88. The method of claim 81, wherein the method is further defined as a method of treating a subject with cancer. 89. The method of claim 88, wherein the cancer is breast cancer, lung cancer, prostate cancer, ovarian cancer, brain cancer, liver cancer, cervical cancer, colon cancer, renal cancer, skin cancer, head and neck cancer, bone cancer, a esophageal cancer, bladder cancer, uterine cancer, lymphatic cancer, stomach cancer, pancreatic cancer, testicular cancer, lymphoma, or leukemia. 90. The method of claim 81, wherein the method is further defined as a method for performing dual radio/chemotherapy. 91. The method of claim 90, further comprising administering one or more secondary forms of therapy of a hyperproliferative disease. 92. The method of claim 81, further defined as a method of imaging a site within a subject comprising detecting a signal from the metal ion labeled-chelator-targeting ligand conjugate that is localized at the site. 93. The method of claim 92, wherein the signal is detected using a technique selected from the group consisting of PET, PET/CT, CT, SPECT, SPECT/CT, MRI, optical imaging and ultrasound. 94. The method of claim 81, wherein the site to be imaged is a tumor or the heart. 95. The method of claim 81, further defined as a method of imaging, diagnosing, or treating a subject with a cardiovascular disease. 96. The method of claim 95, further comprising performing one or more additional diagnostic or imaging procedures to evaluate the subject for a cardiovascular disease. 97. The method of claim 95, wherein the cardiovascular disease is a myocardial infarction, congestive heart failure, cardiomyopathy, valvular heart disease, an arrhythmia, congenital heart disease, angina pectoris, noncardiac circulatory congestion, systolic heart failure, heart failure with normal systolic function, or right-sided heart failure. 98. The method of claim 97, wherein the cardiovascular disease is a myocardial infarction, myocardial ischemia, or angina pectoris and the method further comprises imaging the heart of the subject. 99. The method of claim 81, wherein the metal ion labeled-chelator-targeting ligand conjugate is 99mTc-EC-glucosamine, 188Re-EC-glucosamine, or 187Re-EC-glucosamine. 100.-112. (canceled)

The present invention relates to compositions comprising substances of natural origin for use in the treatment or preventing the onset or the aggravation of diabetic foot ulcers.

1. A composition comprising beeswax, an extract of Hypericum, an extract of red grape vine, an extract of horse chestnut, an extract of Centella, an extract of butcher's broom, and an extract of Aloe for use in treating or preventing onset or aggravation of diabetic foot ulcers. 2. The composition according to claim 1, wherein said diabetic foot ulcers are diabetic foot ulcers of the first grade. 3. The composition according to claim 1, further comprising jojoba oil. 4. The composition according to claim 1, further comprising one or more perfuming and/or colouring agents. 5. The composition according to claim 4, wherein said one or more perfuming agents are essential oils selected from the group consisting of: lavender essential oil, melaleuca essential oil, and peppermint essential oil. 6. The composition according to claim 1, wherein said extract of Centella asiatica is an oily extract of leaves. 7. The composition according to claim 1, wherein said extract of Hypericum is an oily extract of flowers and/or leaves and/or stems. 8. The composition according to claim 3, wherein said jojoba oil is seed oil. 9. The composition according to claim 1, wherein said beeswax is yellow wax from Apis mellifera honeycomb. 10. The composition according to claim 1 in the form of gel, ointment, cream, pomade, foam, powder, spray, emulsion oil in water, emulsion water in oil, emulsion oil in gel, emulsion gel in oil, or suspension. 11. The composition according to claim 1, wherein said extract of Hypericum is comprised at a concentration by weight of the composition from 3% to 10%. 12. The composition according to claim 1, wherein said extract of Centella asiatica is comprised at a concentration by weight of the composition from 0.01% to 2%. 13. The composition according to claim 3, wherein said jojoba oil is comprised at a concentration by weight of the composition from 2% to 12%. 14. The composition according to claim 1, wherein said beeswax is comprised at a concentration by weight of the composition from 0.1% to 3%. 15. A medical device comprising the composition according to claim 1. 16. The medical device according to claim 15 in the form of medicated patch, medicated gauze, or medicated bandage. 17. A method for treating or preventing onset or aggravation of diabetic foot ulcers; comprising topically applying a composition comprising beeswax, an extract of Hypericum, an extract of red grape vine, an extract of horse chestnut, an extract of Centella, an extract of butcher's broom, and an extract of Aloe to a patient in need thereof. 18. The method according to claim 17, wherein said diabetic foot ulcers are diabetic foot ulcers of the first grade. 19. The method according to claim 17, wherein said composition is administered once or more per day. 20. The method according to claim 19, wherein said composition is locally applied for a time period from three weeks to six weeks.

The present invention relates to compositions comprising substances of natural origin for use in the treatment or preventing the onset or the aggravation of diabetic foot ulcers.1. A composition comprising beeswax, an extract of Hypericum, an extract of red grape vine, an extract of horse chestnut, an extract of Centella, an extract of butcher's broom, and an extract of Aloe for use in treating or preventing onset or aggravation of diabetic foot ulcers. 2. The composition according to claim 1, wherein said diabetic foot ulcers are diabetic foot ulcers of the first grade. 3. The composition according to claim 1, further comprising jojoba oil. 4. The composition according to claim 1, further comprising one or more perfuming and/or colouring agents. 5. The composition according to claim 4, wherein said one or more perfuming agents are essential oils selected from the group consisting of: lavender essential oil, melaleuca essential oil, and peppermint essential oil. 6. The composition according to claim 1, wherein said extract of Centella asiatica is an oily extract of leaves. 7. The composition according to claim 1, wherein said extract of Hypericum is an oily extract of flowers and/or leaves and/or stems. 8. The composition according to claim 3, wherein said jojoba oil is seed oil. 9. The composition according to claim 1, wherein said beeswax is yellow wax from Apis mellifera honeycomb. 10. The composition according to claim 1 in the form of gel, ointment, cream, pomade, foam, powder, spray, emulsion oil in water, emulsion water in oil, emulsion oil in gel, emulsion gel in oil, or suspension. 11. The composition according to claim 1, wherein said extract of Hypericum is comprised at a concentration by weight of the composition from 3% to 10%. 12. The composition according to claim 1, wherein said extract of Centella asiatica is comprised at a concentration by weight of the composition from 0.01% to 2%. 13. The composition according to claim 3, wherein said jojoba oil is comprised at a concentration by weight of the composition from 2% to 12%. 14. The composition according to claim 1, wherein said beeswax is comprised at a concentration by weight of the composition from 0.1% to 3%. 15. A medical device comprising the composition according to claim 1. 16. The medical device according to claim 15 in the form of medicated patch, medicated gauze, or medicated bandage. 17. A method for treating or preventing onset or aggravation of diabetic foot ulcers; comprising topically applying a composition comprising beeswax, an extract of Hypericum, an extract of red grape vine, an extract of horse chestnut, an extract of Centella, an extract of butcher's broom, and an extract of Aloe to a patient in need thereof. 18. The method according to claim 17, wherein said diabetic foot ulcers are diabetic foot ulcers of the first grade. 19. The method according to claim 17, wherein said composition is administered once or more per day. 20. The method according to claim 19, wherein said composition is locally applied for a time period from three weeks to six weeks.

The present invention relates to systems and methods for the characterization of biological material within a sample or isolate. The characterization may utilize probabilistic methods that compare sequencing information from fragment reads to sequencing information of reference genomic databases and/or trait-specific database catalogs. The characterization may be of the identities and/or relative concentrations or abundance of one or more organisms contained in the sample or isolate. The identification of the organisms may be to the species and/or sub-species and/or strain level with their relative concentrations or abundance. The characterization may additionally or alternatively be of one or more traits (i.e., characteristics) of the biological material contained in the sample or isolate. The characterization of the one or more traits may be with the relative abundance of the traits.

1. A method of characterizing organisms based on sequence information derived from a sample containing genetic material from the organisms, the method comprising: (a) receiving, by a processing unit including a processor and memory, the sequence information derived from the sample, wherein the sequence information includes unassembled nucleotide fragment reads; (b) performing, by the processing unit, probabilistic methods that compare the unassembled nucleotide fragment reads with trait-specific reference sequence information contained in a trait-specific database catalog and produce probabilistic trait results; and (c) determining, by the processing unit, one or more traits associated with the organisms using the probabilistic trait results. 2. The method of claim 1, further comprising: (d) performing, by the processing unit, probabilistic methods that compare the unassembled nucleotide fragment reads with reference sequence information contained in a reference database containing genomic identities of organisms and produce probabilistic identity results; and (e) determining, by the processing unit, the identities of the organisms contained in the sample at least at the species level using the probabilistic identity results. 3. The method of claim 2, wherein the reference sequence information contained in the reference database is assembled or partially assembled sequence information. 4. The method of claim 2, wherein the organisms are microorganisms, and the reference database comprises a microbial whole genome database. 5. The method of claim 2, further comprising determining, by the processing unit, the identities of the organisms contained in the sample at the sub-species level using the probabilistic identity results. 6. The method of claim 2, further comprising determining, by the processing unit, the identities of the organisms contained in the sample at the strain level using the probabilistic identity results. 7. The method of claim 2, wherein steps (d) and (e) are performed while steps (b) and (c) are performed. 8. The method of claim 2, wherein steps (b) and (c) are performed after steps (d) and (e) have been performed. 9. The method of claim 2, further comprising characterizing the relative populations or abundance of species and/or sub-species and/or strains of the identified organisms. 10. The method of claim 2, wherein the probabilistic methods of steps (b) and (d) comprise probabilistic matching. 11. The method of claim 2, wherein the trait-specific reference sequence information contained in the trait-specific database catalog is a subset of the reference sequence information contained in the reference database. 12. The method of claim 2, further comprising: creating a sample sequence library with words or n-mers derived from the unassembled nucleotide fragment reads; and creating a reference sequence library with words or n-mers derived from the reference sequence information; wherein the probabilistic methods compare the unassembled nucleotide fragment reads with the reference sequence information by comparing words or n-mers from the sample sequence library with words or n-mers from the reference sequence library. 13. The method of claim 1, further comprising: creating a sample sequence library with words or n-mers derived from the unassembled nucleotide fragment reads; and creating a trait-specific sequence library with words or n-mers from the trait-specific reference sequence information; wherein the probabilistic methods compare the unassembled nucleotide fragment reads with trait-specific reference sequence information contained in the trait-specific database catalog by comparing words or n-mers from the sample sequence library with words or n-mers from the trait-specific sequence library. 14. The method of claim 13, wherein trait-specific sequence library is a library of dictionaries of words from the trait-specific reference sequence information, each dictionary containing words for a particular trait. 15. The method of claim 13, wherein the sample sequence library is a sample sequence hash table, and the trait-specific sequence library is a trait-specific hash table. 16. The method of claim 1, wherein the trait-specific reference sequence information contained in the trait-specific database catalog are closed-genomes, draft genomes, contigs, and/or short reads associated with a particular organism trait. 17. The method of claim 16, wherein the particular organism trait is an antibiotic resistance trait, a pathogenicity trait, a bioterror agent marker, or a biochemical trait. 18. The method of claim 1, wherein step (c) comprises scoring and ranking of organism traits likely to be found in the sample. 19. The method of claim 1, wherein the trait-specific reference sequence information contained in the trait-specific database catalog consists of sequence information of one or more mobile genetic elements. 20. The method of claim 19, wherein the one or more mobile genetic elements comprise phages or pathogenicity islands associated with a particular microbial genus or species. 21. The method of claim 19, wherein step (c) determines the probability and relative abundance of the one or more mobile genetic elements. 22. The method of claim 1, wherein the trait-specific reference sequence information contained in the trait-specific database catalog consists of sequence information associated with a particular phenotypical characteristic. 23. The method of claim 22, wherein step (e) comprise scoring and ranking of particular phenotypical characteristics likely to be found in the sample. 24. The method of claim 1, wherein the trait-specific reference sequence information contained in the trait-specific database catalog consists of signature sequences or genome sequences that confirm the presence of particular traits or phenotypes of interest. 25. The method of claim 1, further comprising: (f) performing, by the processing unit, probabilistic matching that compares the unassembled nucleotide fragment reads with second trait-specific reference sequence information contained in a second trait-specific database catalog and produces second probabilistic trait results; and (g) determining, by the processing unit, one or more second traits associated with the organisms using the second probabilistic trait results, wherein the one or more traits are different than the one or more second traits. 26. The method of claim 25, wherein steps (f) and (g) are performed while steps (b) and (c) are performed. 27. The method of claim 1, wherein the probabilistic methods of step (b) comprise probabilistic matching. 28. The method of claim 1, wherein the sample is a metagenomic sample. 29. The method of claim 1, further comprising: (d) performing, by the processing unit, probabilistic methods that compare the unassembled nucleotide fragment reads with reference sequence information contained in a reference database containing genomic identities of organisms and produce probabilistic identity results; (e1) for organisms contained in the sample that are contained in the reference database, determining, by the processing unit, the identities of the organisms contained in the sample that are contained in the reference database at least at the species level using the probabilistic identity results; and (e2) for organisms contained in the sample that are not contained in the reference database, determining, by the processing unit, the identities of organisms contained in the reference database that are nearest neighbors to organisms contained in the sample. 30. An apparatus for characterizing organisms based on sequence information derived from a sample containing genetic material from the organisms, the apparatus comprising: a processing unit including a processor and memory, wherein the processing unit is configured to: (a) receive the sequence information derived from the sample, wherein the sequence information includes unassembled nucleotide fragment reads; (b) perform probabilistic matching that compares the unassembled nucleotide fragment reads with trait-specific reference sequence information contained in a trait-specific database catalog and produces probabilistic trait results; and (c) determine one or more traits associated with the organisms using the probabilistic trait results. 31. The apparatus of claim 26, wherein the processing unit is further configured to: (d) perform probabilistic methods that compare the unassembled nucleotide fragment reads with reference sequence information contained in a reference database containing genomic identities of organisms and produce probabilistic identity results; and (e) determine the identities of the organisms at least at the species level using the probabilistic identity results. 32. The apparatus of claim 31, wherein the processing unit is further configured to: create a sample sequence library with words or n-mers derived from the unassembled nucleotide fragment reads; and create a reference sequence library with words or n-mers derived from the reference sequence information; wherein the probabilistic methods compare the unassembled nucleotide fragment reads with the reference sequence information by comparing words or n-mers from the sample sequence library with words or n-mers from the reference sequence library. 33. The apparatus of claim 31, wherein the processing unit is further configured to: create a sample sequence library with words or n-mers derived from the unassembled nucleotide fragment reads; and create a trait-specific sequence library with words or n-mers derived from the trait-specific reference sequence information; wherein the probabilistic methods compare the unassembled nucleotide fragment reads with trait-specific reference sequence information contained in the trait-specific database catalog by comparing words or n-mers from the sample sequence library with words or n-mers from the trait-specific sequence library. 34. The apparatus of claim 33, wherein trait-specific sequence library is a library of dictionaries of words from the trait-specific reference sequence information, each dictionary containing words for a particular trait. 35. The apparatus of claim 33, wherein the sample sequence library is a sample sequence hash table, and the trait-specific sequence library is a trait-specific hash table. 36. The apparatus of claim 30, wherein the processing unit is further configured to: (f) perform, by the processing unit, probabilistic matching that compares the unassembled nucleotide fragment reads with second trait-specific reference sequence information contained in a second trait-specific database catalog and produces second probabilistic trait results; and (g) determine, by the processing unit, one or more second traits associated with the organisms using the second probabilistic trait results, wherein the one or more traits are different than the one or more second traits. 37. The apparatus of claim 30, wherein the processing unit is further configured to: (d) perform probabilistic methods that compare the unassembled nucleotide fragment reads with reference sequence information contained in a reference database containing genomic identities of organisms and produce probabilistic identity results; (e1) for organisms contained in the sample that are contained in the reference database, determine the identities of the organisms contained in the sample that are contained in the reference database at least at the species level using the probabilistic identity results; and (e2) for organisms contained in the sample that are not contained in the reference database, determine the identities of organisms contained in the reference database that are nearest neighbors to organisms contained in the sample. 38. A method of characterizing an organism based on sequence information derived from an isolate containing genetic material from the organism, the method comprising: (a) receiving, by a processing unit including a processor and memory, the sequence information derived from the isolate, wherein the sequence information includes unassembled nucleotide fragment reads; (b) performing, by the processing unit, probabilistic matching that compares the unassembled nucleotide fragment reads with trait-specific reference sequence information contained in a trait-specific database catalog and produces probabilistic trait results; and (c) determining, by the processing unit, one or more traits associated with the organism using the probabilistic trait results. 39. The method of claim 38, further comprising: (d) performing, by the processing unit, probabilistic methods that compare the unassembled nucleotide fragment reads with reference sequence information contained in a reference database containing genomic identities of organisms and produce probabilistic identity results; and (e) determining, by the processing unit, the identities of the organism contained in the isolate at least at the species level using the probabilistic identity results. 40. The method of claim 39, wherein the reference sequence information contained in the reference database is assembled or partially assembled sequence information. 41. The method of claim 39, wherein the organism is a microorganism, and the reference database comprises a microbial whole genome databases. 42. The method of claim 39, further comprising determining, by the processing unit, the identity of the organism at the sub-species level using the probabilistic identity results. 43. The method of claim 39, further comprising determining, by the processing unit, the identity of the organism at the strain level using the probabilistic identity results. 44. The method of claim 39, wherein steps (d) and (e) are performed while steps (b) and (c) are performed. 45. The method of claim 39, wherein steps (b) and (c) are performed after steps (d) and (e) have been performed. 46. The method of claim 39, wherein the probabilistic methods of steps (b) and (d) comprise probabilistic matching. 47. The method of claim 39, wherein the trait-specific reference sequence information contained in the trait-specific database catalog is a subset of the reference sequence information contained in the reference database. 48. The method of claim 39, further comprising: creating a sample sequence library with words or n-mers derived from the unassembled nucleotide fragment reads; and creating a reference sequence library with words or n-mers derived from the reference sequence information; wherein the probabilistic methods compare the unassembled nucleotide fragment reads with the reference sequence information by comparing words or n-mers from the sample sequence library with words or n-mers from the reference sequence library. 49. The method of claim 38, further comprising: creating a sample sequence library with words or n-mers derived from the unassembled nucleotide fragment reads; and creating a trait-specific sequence library with words or n-mers derived from the trait-specific reference sequence information; wherein the probabilistic methods compare the unassembled nucleotide fragment reads with trait-specific reference sequence information contained in the trait-specific database catalog by comparing words or n-mers from the sample sequence library with words or n-mers from the trait-specific sequence library. 50. The method of claim 49, wherein trait-specific sequence library is a library of dictionaries of words from the trait-specific reference sequence information, each dictionary containing words for a particular trait. 51. The method of claim 49, wherein the sample sequence library is a sample sequence hash table, and the trait-specific sequence library is a trait-specific hash table. 52. The method of claim 38, wherein the trait-specific reference sequence information contained in the trait-specific database catalog are closed-genomes, draft genomes, contigs, and/or short reads associated with a particular organism trait and/or one or more metagenomics samples. 53. The method of claim 48, wherein the particular organism trait is an antibiotic resistance trait, a pathogenicity trait, a bioterror agent marker, or a biochemical trait. 54. The method of claim 48, wherein the particular organism trait is a human identity trait, a cancer susceptibility trait, or a disease trait. 55. The method of claim 38, wherein the trait-specific reference sequence information contained in the trait-specific database catalog consists of sequence information of one or more mobile genetic elements. 56. The method of claim 51, wherein the one or more mobile genetic elements comprise phages or pathogenicity islands associated with a particular microbial genus or species. 57. The method of claim 38, wherein step (c) determines the probability and relative abundance of the one or more mobile genetic elements. 58. The method of claim 38, wherein the trait-specific reference sequence information contained in the trait-specific database catalog consists of sequence information associated with a particular phenotypical characteristic. 59. The method of claim 54, wherein step (e) comprise scoring and ranking of particular phenotypical characteristics likely to be found in the organism. 60. The method of claim 38, wherein the trait-specific reference sequence information contained in the trait-specific database catalog consists of signature sequences or genome sequences that confirm the presence of particular traits or phenotypes of interest. 61. The method of claim 38, further comprising: (f) performing, by the processing unit, probabilistic matching that compares the unassembled nucleotide fragment reads with second trait-specific reference sequence information contained in a second trait-specific database catalog and produces second probabilistic trait results; and (g) determining, by the processing unit, one or more second traits associated with the organism using the second probabilistic trait results, wherein the one or more traits are different than the one or more second traits. 62. The method of claim 61, wherein steps (f) and (g) are performed while steps (b) and (c) are performed. 63. The method of claim 38, wherein the probabilistic methods of step (b) comprise probabilistic matching. 64. The method of claim 38, wherein the sample is a metagenomic sample. 65. The method of claim 38, further comprising: (d) performing, by the processing unit, probabilistic methods that compare the unassembled nucleotide fragment reads with reference sequence information contained in a reference database containing genomic identities of organisms and produce probabilistic identity results; (e1) if the organism is contained in the reference database, determining, by the processing unit, the identity of the organism at least at the species level using the probabilistic identity results; and (e2) if the organism is not contained in the reference database, determining, by the processing unit, the identity of an organism contained in the reference database that is the nearest neighbor to the organism whose genetic material is contained in the isolate. 66. An apparatus for characterizing an organism based on sequence information derived from an isolate containing genetic material from the organism, the apparatus comprising: a processing unit including a processor and memory, wherein the processing unit is configured to: (a) receive the sequence information derived from the isolate, wherein the sequence information includes unassembled nucleotide fragment reads; (b) perform probabilistic matching that compares the unassembled nucleotide fragment reads with trait-specific reference sequence information contained in a trait-specific database catalog and produces probabilistic trait results; and (c) determine one or more traits associated with the organism using the probabilistic trait results. 67. The apparatus of claim 66, wherein the processing unit is further configured to: (d) perform probabilistic methods that compare the unassembled nucleotide fragment reads with reference sequence information contained in a reference database containing genomic identities of organisms and produce probabilistic identity results; and (e) determine the identity of the organism at least at the species level using the probabilistic identity results. 68. The apparatus of claim 66, wherein the processing unit is further configured to: (f) perform, by the processing unit, probabilistic matching that compares the unassembled nucleotide fragment reads with second trait-specific reference sequence information contained in a second trait-specific database catalog and produces second probabilistic trait results; and (g) determine, by the processing unit, one or more second traits associated with the organisms using the second probabilistic trait results, wherein the one or more traits are different than the one or more second traits. 69. The apparatus of claim 66, wherein the processing unit is further configured to: (d) perform probabilistic methods that compare the unassembled nucleotide fragment reads with reference sequence information contained in a reference database containing genomic identities of organisms and produce probabilistic identity results; (e1) if the organism is contained in the reference database, determine the identity of the organism at least at the species level using the probabilistic identity results; and (e2) if the organism is not contained in the reference database, determine the identity of an organism contained in the reference database that is the nearest neighbor to the organism whose genetic material is contained in the isolate. 70. The apparatus of claim 66, wherein the processing unit is further configured to: create a sample sequence library with words or n-mers derived from the unassembled nucleotide fragment reads; and create a trait-specific sequence library with words or n-mers derived from the trait-specific reference sequence information; wherein the probabilistic methods compare the unassembled nucleotide fragment reads with trait-specific reference sequence information contained in the trait-specific database catalog by comparing words or n-mers from the sample sequence library with words or n-mers from the trait-specific sequence library. 71. The apparatus of claim 70, wherein trait-specific sequence library is a library of dictionaries of words from the trait-specific reference sequence information, each dictionary containing words for a particular trait. 72. The apparatus of claim 70, wherein the sample sequence library is a sample sequence hash table, and the trait-specific sequence library is a trait-specific hash table. 73. The method of claim 1, wherein the processing unit may be further configured to: (d) perform probabilistic methods that compare the unassembled nucleotide fragment reads with reference sequence information contained in a reference database to identify unique sequences along with the occurrence and distribution of non-unique sequences generated from neighboring sequences conserved among other bacteria at different taxonomic levels. 74. The method of claim 73, wherein the unique sequences identified by probabilistic methods are flanked by conserved sequences found in other bacteria to further differentiate one bacterium from another at least at the species level. 75. The method of claim 74, wherein the unique sequences identified by probabilistic methods are capable of being used to design macro or microarrays for identification of microbes at least at the species level.

The present invention relates to systems and methods for the characterization of biological material within a sample or isolate. The characterization may utilize probabilistic methods that compare sequencing information from fragment reads to sequencing information of reference genomic databases and/or trait-specific database catalogs. The characterization may be of the identities and/or relative concentrations or abundance of one or more organisms contained in the sample or isolate. The identification of the organisms may be to the species and/or sub-species and/or strain level with their relative concentrations or abundance. The characterization may additionally or alternatively be of one or more traits (i.e., characteristics) of the biological material contained in the sample or isolate. The characterization of the one or more traits may be with the relative abundance of the traits.1. A method of characterizing organisms based on sequence information derived from a sample containing genetic material from the organisms, the method comprising: (a) receiving, by a processing unit including a processor and memory, the sequence information derived from the sample, wherein the sequence information includes unassembled nucleotide fragment reads; (b) performing, by the processing unit, probabilistic methods that compare the unassembled nucleotide fragment reads with trait-specific reference sequence information contained in a trait-specific database catalog and produce probabilistic trait results; and (c) determining, by the processing unit, one or more traits associated with the organisms using the probabilistic trait results. 2. The method of claim 1, further comprising: (d) performing, by the processing unit, probabilistic methods that compare the unassembled nucleotide fragment reads with reference sequence information contained in a reference database containing genomic identities of organisms and produce probabilistic identity results; and (e) determining, by the processing unit, the identities of the organisms contained in the sample at least at the species level using the probabilistic identity results. 3. The method of claim 2, wherein the reference sequence information contained in the reference database is assembled or partially assembled sequence information. 4. The method of claim 2, wherein the organisms are microorganisms, and the reference database comprises a microbial whole genome database. 5. The method of claim 2, further comprising determining, by the processing unit, the identities of the organisms contained in the sample at the sub-species level using the probabilistic identity results. 6. The method of claim 2, further comprising determining, by the processing unit, the identities of the organisms contained in the sample at the strain level using the probabilistic identity results. 7. The method of claim 2, wherein steps (d) and (e) are performed while steps (b) and (c) are performed. 8. The method of claim 2, wherein steps (b) and (c) are performed after steps (d) and (e) have been performed. 9. The method of claim 2, further comprising characterizing the relative populations or abundance of species and/or sub-species and/or strains of the identified organisms. 10. The method of claim 2, wherein the probabilistic methods of steps (b) and (d) comprise probabilistic matching. 11. The method of claim 2, wherein the trait-specific reference sequence information contained in the trait-specific database catalog is a subset of the reference sequence information contained in the reference database. 12. The method of claim 2, further comprising: creating a sample sequence library with words or n-mers derived from the unassembled nucleotide fragment reads; and creating a reference sequence library with words or n-mers derived from the reference sequence information; wherein the probabilistic methods compare the unassembled nucleotide fragment reads with the reference sequence information by comparing words or n-mers from the sample sequence library with words or n-mers from the reference sequence library. 13. The method of claim 1, further comprising: creating a sample sequence library with words or n-mers derived from the unassembled nucleotide fragment reads; and creating a trait-specific sequence library with words or n-mers from the trait-specific reference sequence information; wherein the probabilistic methods compare the unassembled nucleotide fragment reads with trait-specific reference sequence information contained in the trait-specific database catalog by comparing words or n-mers from the sample sequence library with words or n-mers from the trait-specific sequence library. 14. The method of claim 13, wherein trait-specific sequence library is a library of dictionaries of words from the trait-specific reference sequence information, each dictionary containing words for a particular trait. 15. The method of claim 13, wherein the sample sequence library is a sample sequence hash table, and the trait-specific sequence library is a trait-specific hash table. 16. The method of claim 1, wherein the trait-specific reference sequence information contained in the trait-specific database catalog are closed-genomes, draft genomes, contigs, and/or short reads associated with a particular organism trait. 17. The method of claim 16, wherein the particular organism trait is an antibiotic resistance trait, a pathogenicity trait, a bioterror agent marker, or a biochemical trait. 18. The method of claim 1, wherein step (c) comprises scoring and ranking of organism traits likely to be found in the sample. 19. The method of claim 1, wherein the trait-specific reference sequence information contained in the trait-specific database catalog consists of sequence information of one or more mobile genetic elements. 20. The method of claim 19, wherein the one or more mobile genetic elements comprise phages or pathogenicity islands associated with a particular microbial genus or species. 21. The method of claim 19, wherein step (c) determines the probability and relative abundance of the one or more mobile genetic elements. 22. The method of claim 1, wherein the trait-specific reference sequence information contained in the trait-specific database catalog consists of sequence information associated with a particular phenotypical characteristic. 23. The method of claim 22, wherein step (e) comprise scoring and ranking of particular phenotypical characteristics likely to be found in the sample. 24. The method of claim 1, wherein the trait-specific reference sequence information contained in the trait-specific database catalog consists of signature sequences or genome sequences that confirm the presence of particular traits or phenotypes of interest. 25. The method of claim 1, further comprising: (f) performing, by the processing unit, probabilistic matching that compares the unassembled nucleotide fragment reads with second trait-specific reference sequence information contained in a second trait-specific database catalog and produces second probabilistic trait results; and (g) determining, by the processing unit, one or more second traits associated with the organisms using the second probabilistic trait results, wherein the one or more traits are different than the one or more second traits. 26. The method of claim 25, wherein steps (f) and (g) are performed while steps (b) and (c) are performed. 27. The method of claim 1, wherein the probabilistic methods of step (b) comprise probabilistic matching. 28. The method of claim 1, wherein the sample is a metagenomic sample. 29. The method of claim 1, further comprising: (d) performing, by the processing unit, probabilistic methods that compare the unassembled nucleotide fragment reads with reference sequence information contained in a reference database containing genomic identities of organisms and produce probabilistic identity results; (e1) for organisms contained in the sample that are contained in the reference database, determining, by the processing unit, the identities of the organisms contained in the sample that are contained in the reference database at least at the species level using the probabilistic identity results; and (e2) for organisms contained in the sample that are not contained in the reference database, determining, by the processing unit, the identities of organisms contained in the reference database that are nearest neighbors to organisms contained in the sample. 30. An apparatus for characterizing organisms based on sequence information derived from a sample containing genetic material from the organisms, the apparatus comprising: a processing unit including a processor and memory, wherein the processing unit is configured to: (a) receive the sequence information derived from the sample, wherein the sequence information includes unassembled nucleotide fragment reads; (b) perform probabilistic matching that compares the unassembled nucleotide fragment reads with trait-specific reference sequence information contained in a trait-specific database catalog and produces probabilistic trait results; and (c) determine one or more traits associated with the organisms using the probabilistic trait results. 31. The apparatus of claim 26, wherein the processing unit is further configured to: (d) perform probabilistic methods that compare the unassembled nucleotide fragment reads with reference sequence information contained in a reference database containing genomic identities of organisms and produce probabilistic identity results; and (e) determine the identities of the organisms at least at the species level using the probabilistic identity results. 32. The apparatus of claim 31, wherein the processing unit is further configured to: create a sample sequence library with words or n-mers derived from the unassembled nucleotide fragment reads; and create a reference sequence library with words or n-mers derived from the reference sequence information; wherein the probabilistic methods compare the unassembled nucleotide fragment reads with the reference sequence information by comparing words or n-mers from the sample sequence library with words or n-mers from the reference sequence library. 33. The apparatus of claim 31, wherein the processing unit is further configured to: create a sample sequence library with words or n-mers derived from the unassembled nucleotide fragment reads; and create a trait-specific sequence library with words or n-mers derived from the trait-specific reference sequence information; wherein the probabilistic methods compare the unassembled nucleotide fragment reads with trait-specific reference sequence information contained in the trait-specific database catalog by comparing words or n-mers from the sample sequence library with words or n-mers from the trait-specific sequence library. 34. The apparatus of claim 33, wherein trait-specific sequence library is a library of dictionaries of words from the trait-specific reference sequence information, each dictionary containing words for a particular trait. 35. The apparatus of claim 33, wherein the sample sequence library is a sample sequence hash table, and the trait-specific sequence library is a trait-specific hash table. 36. The apparatus of claim 30, wherein the processing unit is further configured to: (f) perform, by the processing unit, probabilistic matching that compares the unassembled nucleotide fragment reads with second trait-specific reference sequence information contained in a second trait-specific database catalog and produces second probabilistic trait results; and (g) determine, by the processing unit, one or more second traits associated with the organisms using the second probabilistic trait results, wherein the one or more traits are different than the one or more second traits. 37. The apparatus of claim 30, wherein the processing unit is further configured to: (d) perform probabilistic methods that compare the unassembled nucleotide fragment reads with reference sequence information contained in a reference database containing genomic identities of organisms and produce probabilistic identity results; (e1) for organisms contained in the sample that are contained in the reference database, determine the identities of the organisms contained in the sample that are contained in the reference database at least at the species level using the probabilistic identity results; and (e2) for organisms contained in the sample that are not contained in the reference database, determine the identities of organisms contained in the reference database that are nearest neighbors to organisms contained in the sample. 38. A method of characterizing an organism based on sequence information derived from an isolate containing genetic material from the organism, the method comprising: (a) receiving, by a processing unit including a processor and memory, the sequence information derived from the isolate, wherein the sequence information includes unassembled nucleotide fragment reads; (b) performing, by the processing unit, probabilistic matching that compares the unassembled nucleotide fragment reads with trait-specific reference sequence information contained in a trait-specific database catalog and produces probabilistic trait results; and (c) determining, by the processing unit, one or more traits associated with the organism using the probabilistic trait results. 39. The method of claim 38, further comprising: (d) performing, by the processing unit, probabilistic methods that compare the unassembled nucleotide fragment reads with reference sequence information contained in a reference database containing genomic identities of organisms and produce probabilistic identity results; and (e) determining, by the processing unit, the identities of the organism contained in the isolate at least at the species level using the probabilistic identity results. 40. The method of claim 39, wherein the reference sequence information contained in the reference database is assembled or partially assembled sequence information. 41. The method of claim 39, wherein the organism is a microorganism, and the reference database comprises a microbial whole genome databases. 42. The method of claim 39, further comprising determining, by the processing unit, the identity of the organism at the sub-species level using the probabilistic identity results. 43. The method of claim 39, further comprising determining, by the processing unit, the identity of the organism at the strain level using the probabilistic identity results. 44. The method of claim 39, wherein steps (d) and (e) are performed while steps (b) and (c) are performed. 45. The method of claim 39, wherein steps (b) and (c) are performed after steps (d) and (e) have been performed. 46. The method of claim 39, wherein the probabilistic methods of steps (b) and (d) comprise probabilistic matching. 47. The method of claim 39, wherein the trait-specific reference sequence information contained in the trait-specific database catalog is a subset of the reference sequence information contained in the reference database. 48. The method of claim 39, further comprising: creating a sample sequence library with words or n-mers derived from the unassembled nucleotide fragment reads; and creating a reference sequence library with words or n-mers derived from the reference sequence information; wherein the probabilistic methods compare the unassembled nucleotide fragment reads with the reference sequence information by comparing words or n-mers from the sample sequence library with words or n-mers from the reference sequence library. 49. The method of claim 38, further comprising: creating a sample sequence library with words or n-mers derived from the unassembled nucleotide fragment reads; and creating a trait-specific sequence library with words or n-mers derived from the trait-specific reference sequence information; wherein the probabilistic methods compare the unassembled nucleotide fragment reads with trait-specific reference sequence information contained in the trait-specific database catalog by comparing words or n-mers from the sample sequence library with words or n-mers from the trait-specific sequence library. 50. The method of claim 49, wherein trait-specific sequence library is a library of dictionaries of words from the trait-specific reference sequence information, each dictionary containing words for a particular trait. 51. The method of claim 49, wherein the sample sequence library is a sample sequence hash table, and the trait-specific sequence library is a trait-specific hash table. 52. The method of claim 38, wherein the trait-specific reference sequence information contained in the trait-specific database catalog are closed-genomes, draft genomes, contigs, and/or short reads associated with a particular organism trait and/or one or more metagenomics samples. 53. The method of claim 48, wherein the particular organism trait is an antibiotic resistance trait, a pathogenicity trait, a bioterror agent marker, or a biochemical trait. 54. The method of claim 48, wherein the particular organism trait is a human identity trait, a cancer susceptibility trait, or a disease trait. 55. The method of claim 38, wherein the trait-specific reference sequence information contained in the trait-specific database catalog consists of sequence information of one or more mobile genetic elements. 56. The method of claim 51, wherein the one or more mobile genetic elements comprise phages or pathogenicity islands associated with a particular microbial genus or species. 57. The method of claim 38, wherein step (c) determines the probability and relative abundance of the one or more mobile genetic elements. 58. The method of claim 38, wherein the trait-specific reference sequence information contained in the trait-specific database catalog consists of sequence information associated with a particular phenotypical characteristic. 59. The method of claim 54, wherein step (e) comprise scoring and ranking of particular phenotypical characteristics likely to be found in the organism. 60. The method of claim 38, wherein the trait-specific reference sequence information contained in the trait-specific database catalog consists of signature sequences or genome sequences that confirm the presence of particular traits or phenotypes of interest. 61. The method of claim 38, further comprising: (f) performing, by the processing unit, probabilistic matching that compares the unassembled nucleotide fragment reads with second trait-specific reference sequence information contained in a second trait-specific database catalog and produces second probabilistic trait results; and (g) determining, by the processing unit, one or more second traits associated with the organism using the second probabilistic trait results, wherein the one or more traits are different than the one or more second traits. 62. The method of claim 61, wherein steps (f) and (g) are performed while steps (b) and (c) are performed. 63. The method of claim 38, wherein the probabilistic methods of step (b) comprise probabilistic matching. 64. The method of claim 38, wherein the sample is a metagenomic sample. 65. The method of claim 38, further comprising: (d) performing, by the processing unit, probabilistic methods that compare the unassembled nucleotide fragment reads with reference sequence information contained in a reference database containing genomic identities of organisms and produce probabilistic identity results; (e1) if the organism is contained in the reference database, determining, by the processing unit, the identity of the organism at least at the species level using the probabilistic identity results; and (e2) if the organism is not contained in the reference database, determining, by the processing unit, the identity of an organism contained in the reference database that is the nearest neighbor to the organism whose genetic material is contained in the isolate. 66. An apparatus for characterizing an organism based on sequence information derived from an isolate containing genetic material from the organism, the apparatus comprising: a processing unit including a processor and memory, wherein the processing unit is configured to: (a) receive the sequence information derived from the isolate, wherein the sequence information includes unassembled nucleotide fragment reads; (b) perform probabilistic matching that compares the unassembled nucleotide fragment reads with trait-specific reference sequence information contained in a trait-specific database catalog and produces probabilistic trait results; and (c) determine one or more traits associated with the organism using the probabilistic trait results. 67. The apparatus of claim 66, wherein the processing unit is further configured to: (d) perform probabilistic methods that compare the unassembled nucleotide fragment reads with reference sequence information contained in a reference database containing genomic identities of organisms and produce probabilistic identity results; and (e) determine the identity of the organism at least at the species level using the probabilistic identity results. 68. The apparatus of claim 66, wherein the processing unit is further configured to: (f) perform, by the processing unit, probabilistic matching that compares the unassembled nucleotide fragment reads with second trait-specific reference sequence information contained in a second trait-specific database catalog and produces second probabilistic trait results; and (g) determine, by the processing unit, one or more second traits associated with the organisms using the second probabilistic trait results, wherein the one or more traits are different than the one or more second traits. 69. The apparatus of claim 66, wherein the processing unit is further configured to: (d) perform probabilistic methods that compare the unassembled nucleotide fragment reads with reference sequence information contained in a reference database containing genomic identities of organisms and produce probabilistic identity results; (e1) if the organism is contained in the reference database, determine the identity of the organism at least at the species level using the probabilistic identity results; and (e2) if the organism is not contained in the reference database, determine the identity of an organism contained in the reference database that is the nearest neighbor to the organism whose genetic material is contained in the isolate. 70. The apparatus of claim 66, wherein the processing unit is further configured to: create a sample sequence library with words or n-mers derived from the unassembled nucleotide fragment reads; and create a trait-specific sequence library with words or n-mers derived from the trait-specific reference sequence information; wherein the probabilistic methods compare the unassembled nucleotide fragment reads with trait-specific reference sequence information contained in the trait-specific database catalog by comparing words or n-mers from the sample sequence library with words or n-mers from the trait-specific sequence library. 71. The apparatus of claim 70, wherein trait-specific sequence library is a library of dictionaries of words from the trait-specific reference sequence information, each dictionary containing words for a particular trait. 72. The apparatus of claim 70, wherein the sample sequence library is a sample sequence hash table, and the trait-specific sequence library is a trait-specific hash table. 73. The method of claim 1, wherein the processing unit may be further configured to: (d) perform probabilistic methods that compare the unassembled nucleotide fragment reads with reference sequence information contained in a reference database to identify unique sequences along with the occurrence and distribution of non-unique sequences generated from neighboring sequences conserved among other bacteria at different taxonomic levels. 74. The method of claim 73, wherein the unique sequences identified by probabilistic methods are flanked by conserved sequences found in other bacteria to further differentiate one bacterium from another at least at the species level. 75. The method of claim 74, wherein the unique sequences identified by probabilistic methods are capable of being used to design macro or microarrays for identification of microbes at least at the species level.

An antimicrobial agent to kill microorganisms by enhancing the concentration of metal ions through use of compound containing a hydantoin ring in the presence of a liquid. The method includes the step of to enhancing the effectiveness of the biocidal component to lessen the need for a supplemental biocide wherein the antimicrobial agent may be in an active state i.e. liquid or an inactive state i.e. solid, tablet, powder, granular form or combinations thereof. The apparatus includes a dispenser containing an antimicrobial agent in either an active state or an inactive state with the antimicrobial agent comprising a compound containing a hydantoin ring and a source of biocidal metals ions for delivery of the antimicrobial agent to a site of microorganisms.

1. An antimicrobial agent for use in killing microorganisms comprising: a microorganism killing material comprising a source of biocidal metal ions wherein the level of available biocidal metal ions to kill microorganisms is limited by the presence of a liquid; and a compound containing a hydantoin ring, wherein the compound containing a hydantoin ring may lack antimicrobial properties but the presence of the liquid with the combination of the compound containing a hydantoin ring and the source of biocidal metal ions generates a higher level of available biocidal metal ions to killing microorganisms than the source of biocidal metal ions without the compound containing the hydantoin ring. 2. The antimicrobial agent of claim 1 wherein the source of biocidal metal ions comprises a metallic silver, silver chloride or a metallic silver alloy. 3. The antimicrobial agent of claim 1 wherein the source of biocidal metal ions and the compound containing a hydantoin ring are in a dry state in either powder, pellet or granular form and the compound containing the hydantoin ring lacks antimicrobial properties. 4. The antimicrobial agent of claim 1 wherein the compound containing a hydantoin ring comprises 5,5-dimethylhydantoin (DMH) and the liquid is water. 5. The antimicrobial agent of claim 1 including: a carrier having an exterior surface; a water penetrable matrix on the exterior surface of said carrier wherein the microorganism killing material comprising a source of biocidal metal is dispersed within said water penetrable matrix. 6. The antimicrobial agent of claim 1 wherein the compound containing a hydantoin ring comprises either bromochlorodimethylhydantoin (BCDMH) dichlorodimethylhydatoin (DCDMH) or silverdimethylhydantoin (AgDMH) 7. The antimicrobial agent of claim 1 wherein the antimicrobial agent is in a dry state and is carried by either a stick having a handle or a puck containing the antimicrobial agent, 8. A method for antimicrobial treating to kill microorganisms in the presence of water comprising the steps of: in the presence of water supplying a microorganism killing material comprising a source of biocidal metal ions; in the presence of water adding a compound containing a hydantoin ring, which may not have antimicrobial properties, to the source of biocidal metal ions to thereby increase an availability of biocidal metal ions to kill microorganisms; and applying the source of biocidal metal ions and the compound containing a hydantoin ring to a source of harmful microorganisms to thereby kill the harmful microorganisms. 9. The method of antimicrobial treating in the presence of water of claim 8 including the step of adding a biocidal metal includes adding a transition metal, a transition metal oxide, a transition metal salt, silver, silver oxide, silver salt, or a combination thereof to in the presence of water 10. The method of antimicrobial treating in presence of water of claim 9 wherein the step of adding the compound containing a hydantoin ring comprises adding a halogenated hydantoin selected from the group consisting of Bromochlorodimethylhydantoin (BCDMH), Dichlorodimethylhydatoin (DCDMH), Dibromodimethylhydantoin (DBDMH) or an unhalogeneated hydantoin comprising 5,5-dimethylhydantoin (DMH). 11. The method of treating in presence of water of claim 8 wherein the step of adding a compound containing a hydantoin ring includes dispensing sufficient 5,5-dimethylhydantoin into bring the level of 5,5-dimethylhydantoin to at least 5 ppm. 12. An antimicrobial dispenser comprising: a housing having a compartment therein; a source of biocidal metal ions for generating a first level of biocidal metal ions in a liquid and a compound containing a hydantoin ring located in the housing, wherein the compound containing a hydantoin ring may lack antimicrobial properties but the presence of the compound containing the hydantoin ring together with the source of biocidal metal ions generates a second level of available of biocidal metal ions which the second level of available biocidal metal ions greater than the first level of biocidal metal ions when the source of biocidal metal ions and the compound containing the hydantoin ring are in the presence of the liquid. 13. The antimicrobial dispenser of claim 12 wherein the source of biocidal metal ions comprises silver chloride. 14. The antimicrobial dispenser of claim 13 wherein the compound containing the hydantoin ring is either 5,5-dimethylhydantoin comprises a 5,5-dimethylhydantoin (DMH), bromochlorodimethylhydantoin (BCDMH) or dichlorodimethylhydatoin (DCDMH) in either powder, pellet, tablet or granular form. 15. The antimicrobial dispenser of claim 12 wherein the source of biocidal metal ions comprises a silver chloride, metallic silver alloy, pure silver or a substrate coated or impregnated with metallic silver or combinations thereof. 16. The antimicrobial dispenser of claim 12 wherein the compound containing the hydantoin ring comprises 5,5-dimethylhydantoin. 17. The method of claim 11 wherein the method of treatment in the presence of water comprises dispensing the antimicrobial agent into a footbath container. 18. The method of antimicrobial treating of an object to kill microorganisms that may come in contact with the object by: applying an antimicrobial agent including a source of biocidal metal ions in a dry state to the object; applying a compound containing a hydantoin ring in a dry state to the object; and bringing a liquid into contact with the source of biocidal metal ions in a dry state and the compound containing a hydantoin ring in a dry state to thereby generate a level of biocidal metal ions in the liquid that is greater than if the liquid came into contact with only the source of biocidal metal ions 19. The method of claim 18 wherein the antimicrobial treating of an object comprises applying the antimicrobial agent to medical devices and agricultural products. 20. The method of claim 18 wherein the step of bringing the liquid into contact with the source of biocidal metal ions in a dry state and the compound containing a hydantoin ring in a dry state comprises bringing water into the contact with the source of biocidal metal ions and the source of biocidal metal ions comprises silver chloride and the compound containing a hydantoin ring comprises 5,5-dimethylhydantoin.

An antimicrobial agent to kill microorganisms by enhancing the concentration of metal ions through use of compound containing a hydantoin ring in the presence of a liquid. The method includes the step of to enhancing the effectiveness of the biocidal component to lessen the need for a supplemental biocide wherein the antimicrobial agent may be in an active state i.e. liquid or an inactive state i.e. solid, tablet, powder, granular form or combinations thereof. The apparatus includes a dispenser containing an antimicrobial agent in either an active state or an inactive state with the antimicrobial agent comprising a compound containing a hydantoin ring and a source of biocidal metals ions for delivery of the antimicrobial agent to a site of microorganisms.1. An antimicrobial agent for use in killing microorganisms comprising: a microorganism killing material comprising a source of biocidal metal ions wherein the level of available biocidal metal ions to kill microorganisms is limited by the presence of a liquid; and a compound containing a hydantoin ring, wherein the compound containing a hydantoin ring may lack antimicrobial properties but the presence of the liquid with the combination of the compound containing a hydantoin ring and the source of biocidal metal ions generates a higher level of available biocidal metal ions to killing microorganisms than the source of biocidal metal ions without the compound containing the hydantoin ring. 2. The antimicrobial agent of claim 1 wherein the source of biocidal metal ions comprises a metallic silver, silver chloride or a metallic silver alloy. 3. The antimicrobial agent of claim 1 wherein the source of biocidal metal ions and the compound containing a hydantoin ring are in a dry state in either powder, pellet or granular form and the compound containing the hydantoin ring lacks antimicrobial properties. 4. The antimicrobial agent of claim 1 wherein the compound containing a hydantoin ring comprises 5,5-dimethylhydantoin (DMH) and the liquid is water. 5. The antimicrobial agent of claim 1 including: a carrier having an exterior surface; a water penetrable matrix on the exterior surface of said carrier wherein the microorganism killing material comprising a source of biocidal metal is dispersed within said water penetrable matrix. 6. The antimicrobial agent of claim 1 wherein the compound containing a hydantoin ring comprises either bromochlorodimethylhydantoin (BCDMH) dichlorodimethylhydatoin (DCDMH) or silverdimethylhydantoin (AgDMH) 7. The antimicrobial agent of claim 1 wherein the antimicrobial agent is in a dry state and is carried by either a stick having a handle or a puck containing the antimicrobial agent, 8. A method for antimicrobial treating to kill microorganisms in the presence of water comprising the steps of: in the presence of water supplying a microorganism killing material comprising a source of biocidal metal ions; in the presence of water adding a compound containing a hydantoin ring, which may not have antimicrobial properties, to the source of biocidal metal ions to thereby increase an availability of biocidal metal ions to kill microorganisms; and applying the source of biocidal metal ions and the compound containing a hydantoin ring to a source of harmful microorganisms to thereby kill the harmful microorganisms. 9. The method of antimicrobial treating in the presence of water of claim 8 including the step of adding a biocidal metal includes adding a transition metal, a transition metal oxide, a transition metal salt, silver, silver oxide, silver salt, or a combination thereof to in the presence of water 10. The method of antimicrobial treating in presence of water of claim 9 wherein the step of adding the compound containing a hydantoin ring comprises adding a halogenated hydantoin selected from the group consisting of Bromochlorodimethylhydantoin (BCDMH), Dichlorodimethylhydatoin (DCDMH), Dibromodimethylhydantoin (DBDMH) or an unhalogeneated hydantoin comprising 5,5-dimethylhydantoin (DMH). 11. The method of treating in presence of water of claim 8 wherein the step of adding a compound containing a hydantoin ring includes dispensing sufficient 5,5-dimethylhydantoin into bring the level of 5,5-dimethylhydantoin to at least 5 ppm. 12. An antimicrobial dispenser comprising: a housing having a compartment therein; a source of biocidal metal ions for generating a first level of biocidal metal ions in a liquid and a compound containing a hydantoin ring located in the housing, wherein the compound containing a hydantoin ring may lack antimicrobial properties but the presence of the compound containing the hydantoin ring together with the source of biocidal metal ions generates a second level of available of biocidal metal ions which the second level of available biocidal metal ions greater than the first level of biocidal metal ions when the source of biocidal metal ions and the compound containing the hydantoin ring are in the presence of the liquid. 13. The antimicrobial dispenser of claim 12 wherein the source of biocidal metal ions comprises silver chloride. 14. The antimicrobial dispenser of claim 13 wherein the compound containing the hydantoin ring is either 5,5-dimethylhydantoin comprises a 5,5-dimethylhydantoin (DMH), bromochlorodimethylhydantoin (BCDMH) or dichlorodimethylhydatoin (DCDMH) in either powder, pellet, tablet or granular form. 15. The antimicrobial dispenser of claim 12 wherein the source of biocidal metal ions comprises a silver chloride, metallic silver alloy, pure silver or a substrate coated or impregnated with metallic silver or combinations thereof. 16. The antimicrobial dispenser of claim 12 wherein the compound containing the hydantoin ring comprises 5,5-dimethylhydantoin. 17. The method of claim 11 wherein the method of treatment in the presence of water comprises dispensing the antimicrobial agent into a footbath container. 18. The method of antimicrobial treating of an object to kill microorganisms that may come in contact with the object by: applying an antimicrobial agent including a source of biocidal metal ions in a dry state to the object; applying a compound containing a hydantoin ring in a dry state to the object; and bringing a liquid into contact with the source of biocidal metal ions in a dry state and the compound containing a hydantoin ring in a dry state to thereby generate a level of biocidal metal ions in the liquid that is greater than if the liquid came into contact with only the source of biocidal metal ions 19. The method of claim 18 wherein the antimicrobial treating of an object comprises applying the antimicrobial agent to medical devices and agricultural products. 20. The method of claim 18 wherein the step of bringing the liquid into contact with the source of biocidal metal ions in a dry state and the compound containing a hydantoin ring in a dry state comprises bringing water into the contact with the source of biocidal metal ions and the source of biocidal metal ions comprises silver chloride and the compound containing a hydantoin ring comprises 5,5-dimethylhydantoin.

Stable aerosol solution formulations comprising glycopyrronium bromide are useful for administration to patients with COPD and other respiratory conditions.

1. A pharmaceutical composition, comprising glycopyrronium bromide dissolved in an HFA propellant and a co-solvent, wherein said composition comprises an amount of hydrochloric acid equivalent to 0.005 to 1.0 μg/μl of 1M hydrochloric acid. 2. A composition according to claim 1, wherein said composition comprises an amount of hydrochloric acid equivalent to 0.18 to 0.32 μg/μl of 1M hydrochloric acid. 3. A composition according to claim 1, wherein the co-solvent is ethanol. 4. A composition according to claim 1, comprising glycopyrronium bromide in an amount in the range of 0.005 to 0.14% w/w of the composition. 5. A composition according to claim 1, further comprising one or more pharmaceutically active ingredients selected from the group consisting of beta-2-agonists, corticosteroids, antimuscarinic agents, and phosphodiesterase (IV) inhibitors. 6. A composition according to claim 5, comprising formoterol fumarate. 7. A composition according to claim 5, further comprising beclometasone dipropionate. 8. A metered dose inhaler, comprising a pharmaceutical composition according to claim 1. 9. A kit-of-parts, comprising a pharmaceutical composition according to claim 1 and further comprising one or more pharmaceutically active ingredients for separate, sequential or simultaneous administration, wherein said pharmaceutically active ingredients are selected from the group consisting of beta-2-agonists, corticosteroids, antimuscarinic agents, and phosphodiesterase (IV) inhibitors. 10. A method of filling an aerosol canister with a pharmaceutical composition according to claim 1, comprising: a) preparing a solution comprising glycopyrronium bromide, a co-solvent, a mineral acid and optionally a low volatility component; b) filling an open canister with the solution; c) placing a valve onto the canister and crimping; and d) pressure-filling the canister with HFA propellant through the valve. 11. A method for the prevention and/or treatment of a respiratory disorder, comprising administering an effective amount of a composition according to claim 1 to a subject in need thereof. 12. A method for the prevention and/or treatment of a respiratory disorder, comprising administering an effective amount of a composition according to claim 2 to a subject in need thereof. 13. A method for the prevention and/or treatment of a respiratory disorder, comprising administering an effective amount of a composition according to claim 3 to a subject in need thereof. 14. A method for the prevention and/or treatment of a respiratory disorder, comprising administering an effective amount of a composition according to claim 4 to a subject in need thereof. 15. A method for the prevention and/or treatment of a respiratory disorder, comprising administering an effective amount of a composition according to claim 5 to a subject in need thereof. 16. A method for the prevention and/or treatment of a respiratory disorder, comprising administering an effective amount of a composition according to claim 6 to a subject in need thereof. 17. A method for the prevention and/or treatment of a respiratory disorder, comprising administering an effective amount of a composition according to claim 7 to a subject in need thereof.

Stable aerosol solution formulations comprising glycopyrronium bromide are useful for administration to patients with COPD and other respiratory conditions.1. A pharmaceutical composition, comprising glycopyrronium bromide dissolved in an HFA propellant and a co-solvent, wherein said composition comprises an amount of hydrochloric acid equivalent to 0.005 to 1.0 μg/μl of 1M hydrochloric acid. 2. A composition according to claim 1, wherein said composition comprises an amount of hydrochloric acid equivalent to 0.18 to 0.32 μg/μl of 1M hydrochloric acid. 3. A composition according to claim 1, wherein the co-solvent is ethanol. 4. A composition according to claim 1, comprising glycopyrronium bromide in an amount in the range of 0.005 to 0.14% w/w of the composition. 5. A composition according to claim 1, further comprising one or more pharmaceutically active ingredients selected from the group consisting of beta-2-agonists, corticosteroids, antimuscarinic agents, and phosphodiesterase (IV) inhibitors. 6. A composition according to claim 5, comprising formoterol fumarate. 7. A composition according to claim 5, further comprising beclometasone dipropionate. 8. A metered dose inhaler, comprising a pharmaceutical composition according to claim 1. 9. A kit-of-parts, comprising a pharmaceutical composition according to claim 1 and further comprising one or more pharmaceutically active ingredients for separate, sequential or simultaneous administration, wherein said pharmaceutically active ingredients are selected from the group consisting of beta-2-agonists, corticosteroids, antimuscarinic agents, and phosphodiesterase (IV) inhibitors. 10. A method of filling an aerosol canister with a pharmaceutical composition according to claim 1, comprising: a) preparing a solution comprising glycopyrronium bromide, a co-solvent, a mineral acid and optionally a low volatility component; b) filling an open canister with the solution; c) placing a valve onto the canister and crimping; and d) pressure-filling the canister with HFA propellant through the valve. 11. A method for the prevention and/or treatment of a respiratory disorder, comprising administering an effective amount of a composition according to claim 1 to a subject in need thereof. 12. A method for the prevention and/or treatment of a respiratory disorder, comprising administering an effective amount of a composition according to claim 2 to a subject in need thereof. 13. A method for the prevention and/or treatment of a respiratory disorder, comprising administering an effective amount of a composition according to claim 3 to a subject in need thereof. 14. A method for the prevention and/or treatment of a respiratory disorder, comprising administering an effective amount of a composition according to claim 4 to a subject in need thereof. 15. A method for the prevention and/or treatment of a respiratory disorder, comprising administering an effective amount of a composition according to claim 5 to a subject in need thereof. 16. A method for the prevention and/or treatment of a respiratory disorder, comprising administering an effective amount of a composition according to claim 6 to a subject in need thereof. 17. A method for the prevention and/or treatment of a respiratory disorder, comprising administering an effective amount of a composition according to claim 7 to a subject in need thereof.

Compositions that include at least one isolated, class I HLA trimolecular complex that includes a peptide ligand unique to M. tuberculosis -infected cells are disclosed. Isolated compositions that include the three components of the trimolecular complex and/or a polynucleotide encoding one or more of the three components are also disclosed.

1. A composition, comprising at least one of: (a) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:1, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (b) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:2 and/or 3, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (c) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:4, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (d) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:5, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (e) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising at least one of SEQ ID NOS:6-9, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (f) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:10 and/or 11, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (g) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:12 and/or 13, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (h) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:14, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (i) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:15, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (j) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:16, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (k) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising at least one of SEQ ID NOS:17-20, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (l) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:21, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (m) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:22, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (n) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:23 and/or 24, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (o) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:25 and/or 26, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (p) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:27, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (q) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:28, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; and (r) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:29, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain. 2. The composition of claim 1, wherein the HLA-E of (a)-(r) is HLA-E*01:01 or HLA-E*01:03. 3. The composition of claim 1, wherein the HLA-E heavy chain of at least one of (a)-(r) is further defined as a soluble, recombinantly produced HLA-E heavy chain. 4. The composition of claim 3, wherein the class I HLA trimolecular complex of at least one of (a)-(r) is produced in a host cell made recombinant by a construct encoding the soluble, truncated HLA-E heavy chain, and wherein the construct does not encode the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain, and wherein the peptide is further defined as an endogenous peptide that is produced by the host cell and loaded in the trimolecular complex by the host cell. 5. The composition of claim 1, wherein the peptide of at least one of (a)-(r) is a synthetic peptide. 6. The composition of claim 1, wherein the peptide of at least one of (a)-(r) is further defined as a peptide having a length of from 8 to 20 amino acids. 7. The composition of claim 1, further defined as comprising at least two of (a)-(r). 8. The composition of claim 1, further defined as comprising at least three of (a)-(r). 9. The composition of claim 1, further defined as comprising at least four of (a)-(r). 10. The composition of claim 1, further defined as comprising at least five of (a)-(r). 11. A composition, comprising at least one of: (a) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:30 and comprising SEQ ID NO:1, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (b) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:31 and comprising SEQ ID NO:2 and/or 3, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (c) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:31 and comprising SEQ ID NO:4, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (d) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:31 and comprising SEQ ID NO:5, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (e) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:32 and comprising at least one of SEQ ID NOS:6-9, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (f) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:32 and comprising SEQ ID NO:10 and/or 11, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (g) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:33 and comprising SEQ ID NO:12 and/or 13, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (h) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:34 and comprising SEQ ID NO:14, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (i) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:35 and comprising SEQ ID NO:15, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (j) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:36 and comprising SEQ ID NO:16, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (k) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:37 and comprising at least one of SEQ ID NOS:17-20, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (l) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:38 and comprising SEQ ID NO:21, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (m) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:39 and comprising SEQ ID NO:22, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (n) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:40 and comprising SEQ ID NO:23 and/or 24, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (o) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:41 and comprising SEQ ID NO:25 and/or 26, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (p) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:42 and comprising SEQ ID NO:27, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (q) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:43 and comprising SEQ ID NO:28, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; and (r) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:44 and comprising SEQ ID NO:29, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain. 12. The composition of claim 11, wherein the HLA-E of (a)-(r) is HLA-E*01:01 or HLA-E*01:03. 13. The composition of claim 11, wherein the HLA-E heavy chain of at least one of (a)-(r) is further defined as a soluble, recombinantly produced HLA-E heavy chain. 14. The composition of claim 13, wherein the class I HLA trimolecular complex of at least one of (a)-(r) is produced in a host cell made recombinant by a construct encoding the soluble, truncated HLA-E heavy chain, and wherein the construct does not encode the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain, and wherein the peptide is further defined as an endogenous peptide that is produced by the host cell and loaded in the trimolecular complex by the host cell. 15. The composition of claim 11, wherein the peptide of at least one of (a)-(r) is a synthetic peptide. 16. The composition of claim 11, wherein the peptide of at least one of (a)-(r) is further defined as a peptide having a length of from 8 to 20 amino acids. 17. The composition of claim 11, further defined as comprising at least two of (a)-(r). 18. The composition of claim 11, further defined as comprising at least three of (a)-(r). 19. The composition of claim 11, further defined as comprising at least four of (a)-(r). 20. The composition of claim 11, further defined as comprising at least five of (a)-(r). 21. An isolated composition, comprising: a soluble, truncated class I HLA-E heavy chain or DNA encoding a soluble, truncated HLA-E heavy chain, wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; beta-2-microglobulin or DNA encoding beta-2-microglobulin; and at least one peptide comprising at least one of SEQ ID NOS:1-29, or DNA encoding the at least one peptide.

Compositions that include at least one isolated, class I HLA trimolecular complex that includes a peptide ligand unique to M. tuberculosis -infected cells are disclosed. Isolated compositions that include the three components of the trimolecular complex and/or a polynucleotide encoding one or more of the three components are also disclosed.1. A composition, comprising at least one of: (a) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:1, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (b) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:2 and/or 3, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (c) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:4, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (d) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:5, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (e) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising at least one of SEQ ID NOS:6-9, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (f) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:10 and/or 11, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (g) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:12 and/or 13, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (h) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:14, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (i) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:15, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (j) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:16, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (k) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising at least one of SEQ ID NOS:17-20, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (l) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:21, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (m) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:22, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (n) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:23 and/or 24, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (o) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:25 and/or 26, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (p) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:27, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (q) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:28, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; and (r) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide comprising SEQ ID NO:29, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain. 2. The composition of claim 1, wherein the HLA-E of (a)-(r) is HLA-E*01:01 or HLA-E*01:03. 3. The composition of claim 1, wherein the HLA-E heavy chain of at least one of (a)-(r) is further defined as a soluble, recombinantly produced HLA-E heavy chain. 4. The composition of claim 3, wherein the class I HLA trimolecular complex of at least one of (a)-(r) is produced in a host cell made recombinant by a construct encoding the soluble, truncated HLA-E heavy chain, and wherein the construct does not encode the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain, and wherein the peptide is further defined as an endogenous peptide that is produced by the host cell and loaded in the trimolecular complex by the host cell. 5. The composition of claim 1, wherein the peptide of at least one of (a)-(r) is a synthetic peptide. 6. The composition of claim 1, wherein the peptide of at least one of (a)-(r) is further defined as a peptide having a length of from 8 to 20 amino acids. 7. The composition of claim 1, further defined as comprising at least two of (a)-(r). 8. The composition of claim 1, further defined as comprising at least three of (a)-(r). 9. The composition of claim 1, further defined as comprising at least four of (a)-(r). 10. The composition of claim 1, further defined as comprising at least five of (a)-(r). 11. A composition, comprising at least one of: (a) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:30 and comprising SEQ ID NO:1, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (b) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:31 and comprising SEQ ID NO:2 and/or 3, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (c) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:31 and comprising SEQ ID NO:4, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (d) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:31 and comprising SEQ ID NO:5, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (e) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:32 and comprising at least one of SEQ ID NOS:6-9, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (f) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:32 and comprising SEQ ID NO:10 and/or 11, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (g) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:33 and comprising SEQ ID NO:12 and/or 13, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (h) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:34 and comprising SEQ ID NO:14, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (i) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:35 and comprising SEQ ID NO:15, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (j) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:36 and comprising SEQ ID NO:16, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (k) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:37 and comprising at least one of SEQ ID NOS:17-20, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (l) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:38 and comprising SEQ ID NO:21, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (m) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:39 and comprising SEQ ID NO:22, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (n) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:40 and comprising SEQ ID NO:23 and/or 24, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (o) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:41 and comprising SEQ ID NO:25 and/or 26, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (p) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:42 and comprising SEQ ID NO:27, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; (q) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:43 and comprising SEQ ID NO:28, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; and (r) an isolated class I HLA trimolecular complex formed in vitro, the trimolecular complex comprising a soluble, truncated HLA-E heavy chain, beta-2-microglobulin, and a peptide consisting essentially of a fragment of SEQ ID NO:44 and comprising SEQ ID NO:29, and wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain. 12. The composition of claim 11, wherein the HLA-E of (a)-(r) is HLA-E*01:01 or HLA-E*01:03. 13. The composition of claim 11, wherein the HLA-E heavy chain of at least one of (a)-(r) is further defined as a soluble, recombinantly produced HLA-E heavy chain. 14. The composition of claim 13, wherein the class I HLA trimolecular complex of at least one of (a)-(r) is produced in a host cell made recombinant by a construct encoding the soluble, truncated HLA-E heavy chain, and wherein the construct does not encode the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain, and wherein the peptide is further defined as an endogenous peptide that is produced by the host cell and loaded in the trimolecular complex by the host cell. 15. The composition of claim 11, wherein the peptide of at least one of (a)-(r) is a synthetic peptide. 16. The composition of claim 11, wherein the peptide of at least one of (a)-(r) is further defined as a peptide having a length of from 8 to 20 amino acids. 17. The composition of claim 11, further defined as comprising at least two of (a)-(r). 18. The composition of claim 11, further defined as comprising at least three of (a)-(r). 19. The composition of claim 11, further defined as comprising at least four of (a)-(r). 20. The composition of claim 11, further defined as comprising at least five of (a)-(r). 21. An isolated composition, comprising: a soluble, truncated class I HLA-E heavy chain or DNA encoding a soluble, truncated HLA-E heavy chain, wherein the soluble, truncated HLA-E heavy chain does not contain the transmembrane and cytoplasmic domains of the native, full length HLA-E heavy chain; beta-2-microglobulin or DNA encoding beta-2-microglobulin; and at least one peptide comprising at least one of SEQ ID NOS:1-29, or DNA encoding the at least one peptide.

Disclosed herein are controlled-release oral pharmaceutical dosage forms comprising MGBG, and their application for the improved treatment of diseases with reduced side effects and/or longer time at maximum concentration.

1-24. (canceled) 25. A method of treating inflammation or a related disorder, comprising the administration, to a patient in need thereof, a delayed-release oral pharmaceutical dosage form comprising MGBG. 26. The method as recited in claim 25, wherein said delayed release oral pharmaceutical dosage form is an enterically-coated capsule comprising MGBG. 27. The method as recited in claim 26, wherein the administration of the enterically-coated capsule comprising MGBG results in a reduction of one or more gastrointestinal side effects when compared to a reference standard that is not enterically coated. 28. The method as recited in claim 27, wherein said one or more gastrointestinal side effects is chosen from nausea, emesis, diarrhea, abdominal pain, oral mucositis, oral ulceration, pharyngitis, stomatitis, irritation of the gastric mucosa, and gastrointestinal ulceration. 29. The method as recited in claim 28, wherein said gastrointestinal side effect is emesis. 30. The method as recited in claim 27, wherein MGBG is administered at a dosage level which would result in dose-limiting side effects if administered as a non-enteric coated dosage form.

Disclosed herein are controlled-release oral pharmaceutical dosage forms comprising MGBG, and their application for the improved treatment of diseases with reduced side effects and/or longer time at maximum concentration.1-24. (canceled) 25. A method of treating inflammation or a related disorder, comprising the administration, to a patient in need thereof, a delayed-release oral pharmaceutical dosage form comprising MGBG. 26. The method as recited in claim 25, wherein said delayed release oral pharmaceutical dosage form is an enterically-coated capsule comprising MGBG. 27. The method as recited in claim 26, wherein the administration of the enterically-coated capsule comprising MGBG results in a reduction of one or more gastrointestinal side effects when compared to a reference standard that is not enterically coated. 28. The method as recited in claim 27, wherein said one or more gastrointestinal side effects is chosen from nausea, emesis, diarrhea, abdominal pain, oral mucositis, oral ulceration, pharyngitis, stomatitis, irritation of the gastric mucosa, and gastrointestinal ulceration. 29. The method as recited in claim 28, wherein said gastrointestinal side effect is emesis. 30. The method as recited in claim 27, wherein MGBG is administered at a dosage level which would result in dose-limiting side effects if administered as a non-enteric coated dosage form.

Light protecting compositions contain at least one polysiloxane-based UV filter. The composition has an increased ratio of the sunprotecting factor to the total UV filter amount. This is achieved by the combination with at least one UV filter which chromophore contains appropriate bulky (sterically demanding) substituents as steric protection groups.

1. A light protecting composition comprising: a) polysilicone-15 (Parsol SLX), b) at least one additional UV filter selected from the group consisting of 2-(4-diethylamino-2-hydroxy-benzoyl)-benzoic acid hexylester, 4-methyl benzylidene camphor, and methylene bis-benzotriazol bis-benzotriazo tetramethylbutylphenol, c) a carrier for the components a), b) and d), and optionally d) additional UV filter(s), wherein the UV filter(s) in the light protecting composition consist(s) of one or more compounds selected from the group consisting of polysilicone-15 (Parsol SLX); 2-(4-diethylamino-2-hydroxy-benzoyl)-benzoic acid hexylester, 4-methyl benzylidene camphor, or methylene bis-benzotriazol tetramethylbutylphenol; an acrylate selected from the group consisting of 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (octocrylene, PARSOL® 340), ethyl 2-cyano-3,3-diphenylacrylate, and combinations thereof; a cinnamate derivative selected from the group consisting of octyl methoxycinnamate (PARSOL® MCX), ethoxyethyl methoxycinnamate, diethanolamine methoxycinnamate (PARSOL® Hydro), isoamyl methoxycinnamate, and combinations thereof; a p-aminobenzoic acid derivative selected from the group consisting of p-aminobenzoic acid, 2-ethylhexyl pdimethylaminobenzoate, N-oxypropylenated ethyl p-aminobenzoate, or glyceryl p-aminobenzoate, and combinations thereof; a benzophenone selected from the group consisting of benzophenone-3, benzophenone-4, 2,2′,4,4′-tetrahydroxy-benzophenone, 2,2′-dihydroxy-4,4′-dimethoxybenzophenone, and combinations thereof; di-(2-ethylhexyl) 4-methoxybenzalmalonate; 2-(4-ethoxy anilinomethylene)propandioic acid diethyl ester; a pigment selected from the group consisting of microparticulated TiO2, ZnO, and combinations thereof; a salicylate derivative selected from the group consisting of isopropylbenzyl salicylate, benzyl salicylate, butyl salicylate, octyl salicylate (NEO HELIOPAN OS), isooctyl salicylate, and combinations thereof; a UVA screening agent; salts of the UV filters listed above thereof; and combinations thereof; and with the proviso that 4,4′,4″-(1,3,5-triazine-2,4,6-triyltriimino)-tris-benzoic-acid-tris(2-ethylhexylester) is not present in the composition. 2. A light protecting composition according to claim 1, wherein the additional UV filter(s) of d) are selected from the group consisting of disodium phenyl dibenzimidazole tetrasulfonate, benzophenone-3, benzophenone-4, TiO2 and ZnO. 3. A light protecting composition according to claim 1, wherein the sum-amount of all UV filters a) is lower or equal to the sum-amount of all UV filters b) and d). 4. The composition according to claim 1, wherein the microparticulated TiO2 or ZnO is coated by a metal oxide. 5. The composition according to claim 1, wherein the microparticulated TiO2 or ZnO is coated by aluminum oxide, zirconium oxide, polyols, methicone, aluminum stearate, or alkyl silane. 6. The composition according to claim 1, wherein the UVA screening agent is selected from the group consisting of phenylene-1,4-bisbenzimidazolsulfonic acid, salts thereof, a pigment, and combinations thereof. 7. The composition according to claim 6, wherein the salt of phenylene-1,4-bis-benzimidazolsulfonic acids is 2,2-(1,4-phenylene)bis-(1H-benzimidazol-4,6-disulfonic acid) (Neoheliopan AP). 8. A light protecting composition consisting essentially of: a) polysilicone-15 (Parsol SLX), b) at least one additional UV filter selected from the group consisting of 2-(4-diethylamino-2-hydroxy-benzoyl)-benzoic acid hexylester, 4-methyl benzylidene camphor, and methylene bis-benzotriazol tetramethylbutylphenol, c) a carrier for the components a), b) and d), and optionally d) additional UV filter(s), wherein the UV filter(s) in the light protecting composition consist(s) of one or more compounds selected from the group consisting of polysilicone-15 (Parsol SLX); 2-(4-diethylamino-2-hydroxy-benzoyl)-benzoic acid hexylester, 4-methyl benzylidene camphor, or methylene bis-benzotriazol tetramethylbutylphenol; an acrylate selected from the group consisting of 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (octocrylene, PARSOL® 340), ethyl 2-cyano-3,3-diphenylacrylate, and combinations thereof; a cinnamate derivative selected from the group consisting of octyl methoxycinnamate (PARSOL® MCX), ethoxyethyl methoxycinnamate, diethanolamine methoxycinnamate (PARSOL® Hydro), isoamyl methoxycinnamate, and combinations thereof; a p-aminobenzoic acid derivative selected from the group consisting of p-aminobenzoic acid, 2-ethylhexyl pdimethylaminobenzoate, N-oxypropylenated ethyl p-aminobenzoate, or glyceryl paminobenzoate, and combinations thereof; a benzophenone selected from the group consisting of benzophenone-3, benzophenone-4, 2,2′,4,4′-tetrahydroxy-benzophenone, 2,2′-dihydroxy-4,4′-dimethoxybenzophenone, and combinations thereof; di-(2-ethylhexyl) 4-methoxybenzalmalonate; 2-(4-ethoxy anilinomethylene)propandioic acid diethyl ester; a pigment selected from the group consisting of microparticulated TiO2, ZnO, and combinations thereof; a salicylate derivative selected from the group consisting of isopropylbenzyl salicylate, benzyl salicylate, butyl salicylate, octyl salicylate (NEO HELIOPAN OS), isooctyl salicylate, and combinations thereof; a UVA screening agent; salts of the UV filters listed above; and combinations thereof; and with the proviso that 4,4′,4″-(1,3,5-triazine-2,4,6-triyltriimino)-tris-benzoic-acid-tris(2-ethylhexylester) is not present in the composition. 9. A light protecting composition consisting of: a) polysilicone-15 (Parsol SLX), b) at least one additional UV filter selected from the group consisting of 2-(4-diethylamino-2-hydroxy-benzoyl)-benzoic acid hexylester, 4-methyl benzylidene camphor, and bis-benzotriazol tetramethylbutylphenol, c) a carrier for the components a), b) and d), and optionally d) additional UV filter(s), wherein the UV filter(s) in the light protecting composition consist(s) of one or more compounds selected from the group consisting of polysilicone-15 (Parsol SLX); 2-(4-diethylamino-2-hydroxy-benzoyl)-benzoic acid hexylester, 4-methyl benzylidene camphor, or methylene bis-benzotriazol tetramethylbutylphenol; an acrylate selected from the group consisting of 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (octocrylene, PARSOL® 340), ethyl 2-cyano-3,3-diphenylacrylate, and combinations thereof; a cinnamate derivative selected from the group consisting of octyl methoxycinnamate (PARSOL® MCX), ethoxyethyl methoxycinnamate, diethanolamine methoxycinnamate (PARSOL® Hydro), isoamyl methoxycinnamate, and combinations thereof; a p-aminobenzoic acid derivative selected from the group consisting of p-aminobenzoic acid, 2-ethylhexyl p-dimethylaminobenzoate, N-oxypropylenated ethyl p-aminobenzoate, or glyceryl paminobenzoate, and combinations thereof; a benzophenone selected from the group consisting of benzophenone-3, benzophenone-4, 2,2′,4,4′-tetrahydroxy-benzophenone, 2,2′-dihydroxy-4,4′-dimethoxybenzophenone, and combinations thereof; di-(2-ethylhexyl) 4-methoxybenzalmalonate; 2-(4-ethoxy anilinomethylene)propandioic acid diethyl ester; a pigment selected from the group consisting of microparticulated TiO2, ZnO, and combinations thereof; a salicylate derivative selected from the group consisting of isopropylbenzyl salicylate, benzyl salicylate, butyl salicylate, octyl salicylate (NEO HELIOPAN OS), isooctyl salicylate, and combinations thereof; a UVA screening agent; salts of the UV filters listed above; and combinations thereof; and with the proviso that 4,4′,4″-(1,3,5-triazine-2,4,6-triyltriimino)-tris-benzoic-acid-tris(2-ethylhexylester) is not present in the composition. 10. A method to increase the ratio of the sun-protecting factor to the total UV filter amount in a light protecting composition, the method comprising: a) the addition of a polysiloxane-based UV filter in order to reduce the amount of a UV filter which is liquid at room temperature by which the total UV filter amount will be reduced, and b) the addition of UV filter(s) containing bulky groups and, and optionally c) the addition of UV filter(s) which are not liquid at room temperature in order to increase the sunprotecting factor of the light protecting composition. 11. A method according to claim 10, wherein the UV filter which is liquid at room temperature is selected from the group consisting of octocrylene, ethylhexyl methoxycinnamate, PEG-25 PABA, isoamyl p-methoxycinnamate and octyl dimethyl PABA. 12. A method according to claim 10, wherein the UV filter(s) containing bulky substituents are selected from the group consisting of 2-(4-Diethylamino-2-hydroxybenzoyl)-benzoic acid hexylester, 4-methyl benzylidene champhor, 3-benzylidenecamphor, butyl methoxydibenzoylmethane, homosalate, benzylidenecamphor sulfonic acid, methylene bis-benzotriazol tetramethylbutylphenol and drometrizole trisiloxane. 13. A method according to claim 10, wherein the UV filter(s) which is not liquid at room temperature is selected from the group consisting of phenylbenzimidazole sulfonic acid, disodium phenyl dibenzimidazole, tetrasulfonate ethylhexy triazone, diethylhexyl butamido triazone, bis-ethylhexyloxyphenolmethoxyphenyl triazine, benzophenone-3, benzophenone-4, TiO2 and ZnO.

Light protecting compositions contain at least one polysiloxane-based UV filter. The composition has an increased ratio of the sunprotecting factor to the total UV filter amount. This is achieved by the combination with at least one UV filter which chromophore contains appropriate bulky (sterically demanding) substituents as steric protection groups.1. A light protecting composition comprising: a) polysilicone-15 (Parsol SLX), b) at least one additional UV filter selected from the group consisting of 2-(4-diethylamino-2-hydroxy-benzoyl)-benzoic acid hexylester, 4-methyl benzylidene camphor, and methylene bis-benzotriazol bis-benzotriazo tetramethylbutylphenol, c) a carrier for the components a), b) and d), and optionally d) additional UV filter(s), wherein the UV filter(s) in the light protecting composition consist(s) of one or more compounds selected from the group consisting of polysilicone-15 (Parsol SLX); 2-(4-diethylamino-2-hydroxy-benzoyl)-benzoic acid hexylester, 4-methyl benzylidene camphor, or methylene bis-benzotriazol tetramethylbutylphenol; an acrylate selected from the group consisting of 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (octocrylene, PARSOL® 340), ethyl 2-cyano-3,3-diphenylacrylate, and combinations thereof; a cinnamate derivative selected from the group consisting of octyl methoxycinnamate (PARSOL® MCX), ethoxyethyl methoxycinnamate, diethanolamine methoxycinnamate (PARSOL® Hydro), isoamyl methoxycinnamate, and combinations thereof; a p-aminobenzoic acid derivative selected from the group consisting of p-aminobenzoic acid, 2-ethylhexyl pdimethylaminobenzoate, N-oxypropylenated ethyl p-aminobenzoate, or glyceryl p-aminobenzoate, and combinations thereof; a benzophenone selected from the group consisting of benzophenone-3, benzophenone-4, 2,2′,4,4′-tetrahydroxy-benzophenone, 2,2′-dihydroxy-4,4′-dimethoxybenzophenone, and combinations thereof; di-(2-ethylhexyl) 4-methoxybenzalmalonate; 2-(4-ethoxy anilinomethylene)propandioic acid diethyl ester; a pigment selected from the group consisting of microparticulated TiO2, ZnO, and combinations thereof; a salicylate derivative selected from the group consisting of isopropylbenzyl salicylate, benzyl salicylate, butyl salicylate, octyl salicylate (NEO HELIOPAN OS), isooctyl salicylate, and combinations thereof; a UVA screening agent; salts of the UV filters listed above thereof; and combinations thereof; and with the proviso that 4,4′,4″-(1,3,5-triazine-2,4,6-triyltriimino)-tris-benzoic-acid-tris(2-ethylhexylester) is not present in the composition. 2. A light protecting composition according to claim 1, wherein the additional UV filter(s) of d) are selected from the group consisting of disodium phenyl dibenzimidazole tetrasulfonate, benzophenone-3, benzophenone-4, TiO2 and ZnO. 3. A light protecting composition according to claim 1, wherein the sum-amount of all UV filters a) is lower or equal to the sum-amount of all UV filters b) and d). 4. The composition according to claim 1, wherein the microparticulated TiO2 or ZnO is coated by a metal oxide. 5. The composition according to claim 1, wherein the microparticulated TiO2 or ZnO is coated by aluminum oxide, zirconium oxide, polyols, methicone, aluminum stearate, or alkyl silane. 6. The composition according to claim 1, wherein the UVA screening agent is selected from the group consisting of phenylene-1,4-bisbenzimidazolsulfonic acid, salts thereof, a pigment, and combinations thereof. 7. The composition according to claim 6, wherein the salt of phenylene-1,4-bis-benzimidazolsulfonic acids is 2,2-(1,4-phenylene)bis-(1H-benzimidazol-4,6-disulfonic acid) (Neoheliopan AP). 8. A light protecting composition consisting essentially of: a) polysilicone-15 (Parsol SLX), b) at least one additional UV filter selected from the group consisting of 2-(4-diethylamino-2-hydroxy-benzoyl)-benzoic acid hexylester, 4-methyl benzylidene camphor, and methylene bis-benzotriazol tetramethylbutylphenol, c) a carrier for the components a), b) and d), and optionally d) additional UV filter(s), wherein the UV filter(s) in the light protecting composition consist(s) of one or more compounds selected from the group consisting of polysilicone-15 (Parsol SLX); 2-(4-diethylamino-2-hydroxy-benzoyl)-benzoic acid hexylester, 4-methyl benzylidene camphor, or methylene bis-benzotriazol tetramethylbutylphenol; an acrylate selected from the group consisting of 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (octocrylene, PARSOL® 340), ethyl 2-cyano-3,3-diphenylacrylate, and combinations thereof; a cinnamate derivative selected from the group consisting of octyl methoxycinnamate (PARSOL® MCX), ethoxyethyl methoxycinnamate, diethanolamine methoxycinnamate (PARSOL® Hydro), isoamyl methoxycinnamate, and combinations thereof; a p-aminobenzoic acid derivative selected from the group consisting of p-aminobenzoic acid, 2-ethylhexyl pdimethylaminobenzoate, N-oxypropylenated ethyl p-aminobenzoate, or glyceryl paminobenzoate, and combinations thereof; a benzophenone selected from the group consisting of benzophenone-3, benzophenone-4, 2,2′,4,4′-tetrahydroxy-benzophenone, 2,2′-dihydroxy-4,4′-dimethoxybenzophenone, and combinations thereof; di-(2-ethylhexyl) 4-methoxybenzalmalonate; 2-(4-ethoxy anilinomethylene)propandioic acid diethyl ester; a pigment selected from the group consisting of microparticulated TiO2, ZnO, and combinations thereof; a salicylate derivative selected from the group consisting of isopropylbenzyl salicylate, benzyl salicylate, butyl salicylate, octyl salicylate (NEO HELIOPAN OS), isooctyl salicylate, and combinations thereof; a UVA screening agent; salts of the UV filters listed above; and combinations thereof; and with the proviso that 4,4′,4″-(1,3,5-triazine-2,4,6-triyltriimino)-tris-benzoic-acid-tris(2-ethylhexylester) is not present in the composition. 9. A light protecting composition consisting of: a) polysilicone-15 (Parsol SLX), b) at least one additional UV filter selected from the group consisting of 2-(4-diethylamino-2-hydroxy-benzoyl)-benzoic acid hexylester, 4-methyl benzylidene camphor, and bis-benzotriazol tetramethylbutylphenol, c) a carrier for the components a), b) and d), and optionally d) additional UV filter(s), wherein the UV filter(s) in the light protecting composition consist(s) of one or more compounds selected from the group consisting of polysilicone-15 (Parsol SLX); 2-(4-diethylamino-2-hydroxy-benzoyl)-benzoic acid hexylester, 4-methyl benzylidene camphor, or methylene bis-benzotriazol tetramethylbutylphenol; an acrylate selected from the group consisting of 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (octocrylene, PARSOL® 340), ethyl 2-cyano-3,3-diphenylacrylate, and combinations thereof; a cinnamate derivative selected from the group consisting of octyl methoxycinnamate (PARSOL® MCX), ethoxyethyl methoxycinnamate, diethanolamine methoxycinnamate (PARSOL® Hydro), isoamyl methoxycinnamate, and combinations thereof; a p-aminobenzoic acid derivative selected from the group consisting of p-aminobenzoic acid, 2-ethylhexyl p-dimethylaminobenzoate, N-oxypropylenated ethyl p-aminobenzoate, or glyceryl paminobenzoate, and combinations thereof; a benzophenone selected from the group consisting of benzophenone-3, benzophenone-4, 2,2′,4,4′-tetrahydroxy-benzophenone, 2,2′-dihydroxy-4,4′-dimethoxybenzophenone, and combinations thereof; di-(2-ethylhexyl) 4-methoxybenzalmalonate; 2-(4-ethoxy anilinomethylene)propandioic acid diethyl ester; a pigment selected from the group consisting of microparticulated TiO2, ZnO, and combinations thereof; a salicylate derivative selected from the group consisting of isopropylbenzyl salicylate, benzyl salicylate, butyl salicylate, octyl salicylate (NEO HELIOPAN OS), isooctyl salicylate, and combinations thereof; a UVA screening agent; salts of the UV filters listed above; and combinations thereof; and with the proviso that 4,4′,4″-(1,3,5-triazine-2,4,6-triyltriimino)-tris-benzoic-acid-tris(2-ethylhexylester) is not present in the composition. 10. A method to increase the ratio of the sun-protecting factor to the total UV filter amount in a light protecting composition, the method comprising: a) the addition of a polysiloxane-based UV filter in order to reduce the amount of a UV filter which is liquid at room temperature by which the total UV filter amount will be reduced, and b) the addition of UV filter(s) containing bulky groups and, and optionally c) the addition of UV filter(s) which are not liquid at room temperature in order to increase the sunprotecting factor of the light protecting composition. 11. A method according to claim 10, wherein the UV filter which is liquid at room temperature is selected from the group consisting of octocrylene, ethylhexyl methoxycinnamate, PEG-25 PABA, isoamyl p-methoxycinnamate and octyl dimethyl PABA. 12. A method according to claim 10, wherein the UV filter(s) containing bulky substituents are selected from the group consisting of 2-(4-Diethylamino-2-hydroxybenzoyl)-benzoic acid hexylester, 4-methyl benzylidene champhor, 3-benzylidenecamphor, butyl methoxydibenzoylmethane, homosalate, benzylidenecamphor sulfonic acid, methylene bis-benzotriazol tetramethylbutylphenol and drometrizole trisiloxane. 13. A method according to claim 10, wherein the UV filter(s) which is not liquid at room temperature is selected from the group consisting of phenylbenzimidazole sulfonic acid, disodium phenyl dibenzimidazole, tetrasulfonate ethylhexy triazone, diethylhexyl butamido triazone, bis-ethylhexyloxyphenolmethoxyphenyl triazine, benzophenone-3, benzophenone-4, TiO2 and ZnO.

The present disclosure provides a method for the treatment of Parkinson's disease comprising simultaneously or sequentially administering to a patient in need of treatment of Parkinson's disease a dosage form comprising (i) levodopa in an amount ranging from 50 mg to 300 mg, (ii) carbidopa in an amount ranging from 25 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor, and (iii) entacapone in an amount ranging from 50 mg to 300 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.3:1.0 to 3.2:1.0 by weight, a moderately potent COMT inhibitor in an amount ranging from 25 mg to 200 mg, wherein the proportion of said COMT inhibitor to carbidopa in said dosage form ranges from 0.16:1.0 to 3.08:1.0 by weight, or a highly potent COMT Inhibitor in an amount ranging from 1 mg to 100 mg, wherein the proportion of said COMT inhibitor to carbidopa in said dosage form ranges from 0.006:1.0 to 1.54:1.0 by weight. Pharmaceutical dosage forms used in said methods are also disclosed.

1. A method for the treatment of Parkinson's disease comprising simultaneously or sequentially orally administering to a patient in need of treatment of Parkinson's disease (i) levodopa in an amount ranging from 75 mg to 175 mg, (ii) carbidopa in an amount ranging from 65 mg to 105 mg, and (iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa ranges from 0.95:1.0 to 3.08:1.0 by weight, and wherein the total number of doses administered per day of each of levodopa, carbidopa, and entacapone ranges from 3 to 10. 2-4. (canceled) 5. The method according to claim 1, wherein said treatment comprises administering orally an oral solid dosage form. 6. (canceled) 7. The method according to claim 1, wherein the proportion of entacapone to carbidopa ranges from 1.90:1.0 to 3.08:1.0 by weight. 8. The method according to claim 1, wherein entacapone is present in an amount of 100 mg, 150 mg, or 200 mg. 9. The method according to claim 8, wherein entacapone is present in an amount of 200 mg. 10. The method according to claim 1, wherein carbidopa is present in an amount of 65 mg, 80 mg, 85 mg, or 105 mg. 11. The method according to claim 10, wherein carbidopa is present in an amount of 65 mg. 12. The method according to claim 10, wherein carbidopa is present in an amount of 85 mg. 13. The method according to claim 10, wherein carbidopa is present in an amount of 105 mg. 14. The method according to claim 1, wherein the proportion of entacapone to carbidopa is 0.95:1.0, 1.18:1.0, 1.33:1.0, 1.54:1.0, 1.6:1.0, 1.9:1.0, 2.35:1.0, 2.5:1.0, or 3.08:1.0 by weight. 15. The method according to claim 1, wherein the proportion of entacapone and carbidopa is 100 mg:105 mg, 100 mg:85 mg, 100 mg:80 mg, 100 mg:65 mg, 200 mg:105 mg, 200 mg:85 mg, 200 mg:80 mg, or 200 mg:65 mg. 16. (canceled) 17. The method according to claim 1, wherein levodopa is present in an amount of 75 mg, 100 mg, 125 mg or 150 mg. 18. (canceled) 19. The method according to claim 1, wherein the proportion of levodopa to carbidopa ranges from 0.71:1.0 to 2.31:1.0 by weight. 20-21. (canceled) 22. The method according to claim 1, wherein the proportions of levodopa, carbidopa and entacapone are 75 mg:65 mg:200 mg, 75 mg:85 mg:200 mg, 75 mg:105 mg:200 mg, 100 mg:65 mg:200 mg, 100 mg:85 mg:200 mg, 100 mg:105 mg:200 mg, 125 mg:65 mg:200 mg, 125 mg:85 mg:200 mg, 125 mg:105 mg:200 mg, 150 mg:65 mg:200 mg, 150 mg:85 mg:200 mg, or 150 mg:105 mg:200 mg. 23. The method of claim 1, wherein the patient to be treated is an adult patient with Parkinson's disease experiencing symptoms of end-of-dose wearing off. 24. (canceled) 25. The method of claim 1, wherein the total number of doses administered per day ranges from 3 to 7. 26. An oral dosage form comprising (i) levodopa in an amount ranging from 75 mg to 175 mg, (ii) carbidopa in an amount ranging from 65 mg to 105 mg, and (iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa ranges from 0.95:1.0 to 3.08:1.0 by weight, and wherein the total number of doses administered per day of each of levodopa, carbidopa, and entacapone ranges from 3 to 10. 27-28. (canceled) 29. (canceled) 30. The dosage form according to claim 26, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 1.6:1.0 to 1.9:1.0 by weight. 31. The dosage form according to claim 26, wherein entacapone is present in an amount of 200 mg, 150 mg, or 100 mg. 32. The dosage form according to claim 31, wherein entacapone is present in an amount of 200 mg. 33. The dosage form according to claim 26, wherein carbidopa is present in an amount of 65 mg, 80 mg, 85 mg, or 105 mg. 34-36. (canceled) 37. The dosage form according to claim 26, wherein the proportion of entacapone to carbidopa in said dosage form is 1.3:1.0, 1.6:1.0, 1.9:1.0, 2.4:1.0, 2.5:1.0, 2.4:1.0, or 2.5:1.0 by weight. 38. The dosage form according to claim 26, wherein the proportion of entacapone and carbidopa in said dosage form is 100 mg:105 mg, 100 mg:85 mg, 100 mg:80 mg, 100 mg:65 mg, 200 mg:105 mg, 200 mg:85 mg, 200 mg:80 mg, or 200 mg:65 mg. 39. (canceled) 40. The dosage form according to claim 26, wherein levodopa is present in an amount of 75 mg, 100 mg, 125 mg or 150 mg. 41. (canceled) 42. The dosage form according to claim 1, wherein the proportion of levodopa to carbidopa in said dosage form ranges from 1.4:1.0 to 2.3:1.0 by weight. 43-44. (canceled) 45. The dosage form according to claim 26, wherein the proportions of levodopa, carbidopa and entacapone in said dosage form are 75 mg:65 mg:200 mg, 75 mg:85 mg:200 mg, 75 mg:105 mg:200 mg, 100 mg:65 mg:200 mg, 100 mg:85 mg:200 mg, 100 mg:105 mg:200 mg, 125 mg:65 mg:200 mg, 125 mg:85 mg:200 mg, 125 mg:105 mg:200 mg, 150 mg:65 mg:200 mg, 150 mg:85 mg:200 mg, or 150 mg:105 mg:200 mg. 46-55. (canceled)

The present disclosure provides a method for the treatment of Parkinson's disease comprising simultaneously or sequentially administering to a patient in need of treatment of Parkinson's disease a dosage form comprising (i) levodopa in an amount ranging from 50 mg to 300 mg, (ii) carbidopa in an amount ranging from 25 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor, and (iii) entacapone in an amount ranging from 50 mg to 300 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.3:1.0 to 3.2:1.0 by weight, a moderately potent COMT inhibitor in an amount ranging from 25 mg to 200 mg, wherein the proportion of said COMT inhibitor to carbidopa in said dosage form ranges from 0.16:1.0 to 3.08:1.0 by weight, or a highly potent COMT Inhibitor in an amount ranging from 1 mg to 100 mg, wherein the proportion of said COMT inhibitor to carbidopa in said dosage form ranges from 0.006:1.0 to 1.54:1.0 by weight. Pharmaceutical dosage forms used in said methods are also disclosed.1. A method for the treatment of Parkinson's disease comprising simultaneously or sequentially orally administering to a patient in need of treatment of Parkinson's disease (i) levodopa in an amount ranging from 75 mg to 175 mg, (ii) carbidopa in an amount ranging from 65 mg to 105 mg, and (iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa ranges from 0.95:1.0 to 3.08:1.0 by weight, and wherein the total number of doses administered per day of each of levodopa, carbidopa, and entacapone ranges from 3 to 10. 2-4. (canceled) 5. The method according to claim 1, wherein said treatment comprises administering orally an oral solid dosage form. 6. (canceled) 7. The method according to claim 1, wherein the proportion of entacapone to carbidopa ranges from 1.90:1.0 to 3.08:1.0 by weight. 8. The method according to claim 1, wherein entacapone is present in an amount of 100 mg, 150 mg, or 200 mg. 9. The method according to claim 8, wherein entacapone is present in an amount of 200 mg. 10. The method according to claim 1, wherein carbidopa is present in an amount of 65 mg, 80 mg, 85 mg, or 105 mg. 11. The method according to claim 10, wherein carbidopa is present in an amount of 65 mg. 12. The method according to claim 10, wherein carbidopa is present in an amount of 85 mg. 13. The method according to claim 10, wherein carbidopa is present in an amount of 105 mg. 14. The method according to claim 1, wherein the proportion of entacapone to carbidopa is 0.95:1.0, 1.18:1.0, 1.33:1.0, 1.54:1.0, 1.6:1.0, 1.9:1.0, 2.35:1.0, 2.5:1.0, or 3.08:1.0 by weight. 15. The method according to claim 1, wherein the proportion of entacapone and carbidopa is 100 mg:105 mg, 100 mg:85 mg, 100 mg:80 mg, 100 mg:65 mg, 200 mg:105 mg, 200 mg:85 mg, 200 mg:80 mg, or 200 mg:65 mg. 16. (canceled) 17. The method according to claim 1, wherein levodopa is present in an amount of 75 mg, 100 mg, 125 mg or 150 mg. 18. (canceled) 19. The method according to claim 1, wherein the proportion of levodopa to carbidopa ranges from 0.71:1.0 to 2.31:1.0 by weight. 20-21. (canceled) 22. The method according to claim 1, wherein the proportions of levodopa, carbidopa and entacapone are 75 mg:65 mg:200 mg, 75 mg:85 mg:200 mg, 75 mg:105 mg:200 mg, 100 mg:65 mg:200 mg, 100 mg:85 mg:200 mg, 100 mg:105 mg:200 mg, 125 mg:65 mg:200 mg, 125 mg:85 mg:200 mg, 125 mg:105 mg:200 mg, 150 mg:65 mg:200 mg, 150 mg:85 mg:200 mg, or 150 mg:105 mg:200 mg. 23. The method of claim 1, wherein the patient to be treated is an adult patient with Parkinson's disease experiencing symptoms of end-of-dose wearing off. 24. (canceled) 25. The method of claim 1, wherein the total number of doses administered per day ranges from 3 to 7. 26. An oral dosage form comprising (i) levodopa in an amount ranging from 75 mg to 175 mg, (ii) carbidopa in an amount ranging from 65 mg to 105 mg, and (iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa ranges from 0.95:1.0 to 3.08:1.0 by weight, and wherein the total number of doses administered per day of each of levodopa, carbidopa, and entacapone ranges from 3 to 10. 27-28. (canceled) 29. (canceled) 30. The dosage form according to claim 26, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 1.6:1.0 to 1.9:1.0 by weight. 31. The dosage form according to claim 26, wherein entacapone is present in an amount of 200 mg, 150 mg, or 100 mg. 32. The dosage form according to claim 31, wherein entacapone is present in an amount of 200 mg. 33. The dosage form according to claim 26, wherein carbidopa is present in an amount of 65 mg, 80 mg, 85 mg, or 105 mg. 34-36. (canceled) 37. The dosage form according to claim 26, wherein the proportion of entacapone to carbidopa in said dosage form is 1.3:1.0, 1.6:1.0, 1.9:1.0, 2.4:1.0, 2.5:1.0, 2.4:1.0, or 2.5:1.0 by weight. 38. The dosage form according to claim 26, wherein the proportion of entacapone and carbidopa in said dosage form is 100 mg:105 mg, 100 mg:85 mg, 100 mg:80 mg, 100 mg:65 mg, 200 mg:105 mg, 200 mg:85 mg, 200 mg:80 mg, or 200 mg:65 mg. 39. (canceled) 40. The dosage form according to claim 26, wherein levodopa is present in an amount of 75 mg, 100 mg, 125 mg or 150 mg. 41. (canceled) 42. The dosage form according to claim 1, wherein the proportion of levodopa to carbidopa in said dosage form ranges from 1.4:1.0 to 2.3:1.0 by weight. 43-44. (canceled) 45. The dosage form according to claim 26, wherein the proportions of levodopa, carbidopa and entacapone in said dosage form are 75 mg:65 mg:200 mg, 75 mg:85 mg:200 mg, 75 mg:105 mg:200 mg, 100 mg:65 mg:200 mg, 100 mg:85 mg:200 mg, 100 mg:105 mg:200 mg, 125 mg:65 mg:200 mg, 125 mg:85 mg:200 mg, 125 mg:105 mg:200 mg, 150 mg:65 mg:200 mg, 150 mg:85 mg:200 mg, or 150 mg:105 mg:200 mg. 46-55. (canceled)

As a simple and convenient method for promoting the proliferation of algae, a method for cultivating the algae while conducting a procedure S 1 for irradiating a red illuminative light to the algae and a procedure S 2 for irradiating a blue illuminative light to the algae separately and independently of each other within a certain time period is provided.

1. An algae cultivation method for promoting the proliferation of algae by conducting a procedure for irradiating a red illuminative light to the algae and a procedure for irradiating a blue illuminative light to the algae separately and independently of each other within a certain time period. 2. The algae cultivation method according to claim 1 wherein the procedure for irradiating the red illuminative light and the procedure for irradiating the blue illuminative light are conducted alternately and successively. 3. The algae cultivation method according to claim 1 wherein the procedure for irradiating the red illuminative light and the procedure for irradiating the blue illuminative light are conducted while being switched to each other at a time interval suited to the cell division cycle of the algae. 4. The algae cultivation method according to claim 1 wherein the algae are green algae of Botryococcus genus or Chlorella genus. 5. The algae cultivation method according to claim 1 wherein the algae are green algae of Hematococcus genus. 6. An algae cultivation equipment comprising: a light irradiation part for irradiating a red illuminative light and a blue illuminative light to the algae; and a controlling part for controlling the light irradiation part to conduct a step for irradiating the red illuminative light to the algae and a step for irradiating the blue illuminative light to the algae separately and independently of each other within a certain time period. 7. The algae cultivation equipment according to claim 6 wherein the controlling part allows the light quantity, wavelength, and/or irradiation time of the red illuminative light and the blue illuminative light irradiated from the light irradiation part to be kept at certain values or to be varied in certain patterns. 8. The algae cultivation equipment according to claim 6 wherein the light irradiation part comprises light emitting diodes which emit a red light or a blue light.

As a simple and convenient method for promoting the proliferation of algae, a method for cultivating the algae while conducting a procedure S 1 for irradiating a red illuminative light to the algae and a procedure S 2 for irradiating a blue illuminative light to the algae separately and independently of each other within a certain time period is provided.1. An algae cultivation method for promoting the proliferation of algae by conducting a procedure for irradiating a red illuminative light to the algae and a procedure for irradiating a blue illuminative light to the algae separately and independently of each other within a certain time period. 2. The algae cultivation method according to claim 1 wherein the procedure for irradiating the red illuminative light and the procedure for irradiating the blue illuminative light are conducted alternately and successively. 3. The algae cultivation method according to claim 1 wherein the procedure for irradiating the red illuminative light and the procedure for irradiating the blue illuminative light are conducted while being switched to each other at a time interval suited to the cell division cycle of the algae. 4. The algae cultivation method according to claim 1 wherein the algae are green algae of Botryococcus genus or Chlorella genus. 5. The algae cultivation method according to claim 1 wherein the algae are green algae of Hematococcus genus. 6. An algae cultivation equipment comprising: a light irradiation part for irradiating a red illuminative light and a blue illuminative light to the algae; and a controlling part for controlling the light irradiation part to conduct a step for irradiating the red illuminative light to the algae and a step for irradiating the blue illuminative light to the algae separately and independently of each other within a certain time period. 7. The algae cultivation equipment according to claim 6 wherein the controlling part allows the light quantity, wavelength, and/or irradiation time of the red illuminative light and the blue illuminative light irradiated from the light irradiation part to be kept at certain values or to be varied in certain patterns. 8. The algae cultivation equipment according to claim 6 wherein the light irradiation part comprises light emitting diodes which emit a red light or a blue light.

The present invention provides a hydroxyalkyl cellulose having a viscosity of 1.10 mPa·s to 1.95 mPa·s in a 2%-concentration aqueous solution at 20° C., and a solid formulation containing the hydroxyalkyl cellulose.

1-4. (canceled) 5. Coated particles comprising: core particles; and a coating layer that covers the core particles, wherein the coating layer contains a hydroxyalkyl cellulose that has a viscosity of 1.10 mPa·s to 1.95 mPa·s in a 2%-concentration aqueous solution at 20° C. 6. The coated particles according to claim 5, wherein a volume average primary particle size of the core particles 5 μm to 1000 μm. 7. The coated particles according to claim 5, wherein the content of the hydroxyalkyl cellulose in the coating layer is 1% by weight to 50% by weight. 8. The coated particles according to claim 5, wherein the coating layer further contains drug particles. 9. The coated particles according to claim 8, wherein a volume average primary particle size of the drug particles is smaller than a volume average primary particle size of the core particles.

The present invention provides a hydroxyalkyl cellulose having a viscosity of 1.10 mPa·s to 1.95 mPa·s in a 2%-concentration aqueous solution at 20° C., and a solid formulation containing the hydroxyalkyl cellulose.1-4. (canceled) 5. Coated particles comprising: core particles; and a coating layer that covers the core particles, wherein the coating layer contains a hydroxyalkyl cellulose that has a viscosity of 1.10 mPa·s to 1.95 mPa·s in a 2%-concentration aqueous solution at 20° C. 6. The coated particles according to claim 5, wherein a volume average primary particle size of the core particles 5 μm to 1000 μm. 7. The coated particles according to claim 5, wherein the content of the hydroxyalkyl cellulose in the coating layer is 1% by weight to 50% by weight. 8. The coated particles according to claim 5, wherein the coating layer further contains drug particles. 9. The coated particles according to claim 8, wherein a volume average primary particle size of the drug particles is smaller than a volume average primary particle size of the core particles.

What is proposed is aqueous surfactant compositions comprising one or more alpha-sulfo fatty acid disalts (A) of the general formula (I), R 1 CH(SO 3 M 1 )COOM 2   (I) in which the radical R 1 is a linear or branched alkyl or alkenyl radical with 6 to 16 carbon atoms and the radicals M 1 and M 2 —independently of one another—are selected from the group H, Li, Na, K, Ca/2, Mg/2, ammonium and alkanolamine, one or more alkyl glycosides (B) of the general formula (II), R 2 O—[G] p   (I) in which R 2 is an alkyl and/or alkenyl radical with 8 to 18 carbon atoms, G is a sugar radical with 5 or 6 carbon atoms and p is numbers between 1 and 10, and water, where specific limiting conditions are to be observed. These compositions have excellent foaming ability and are suitable for use in cosmetic products.

1. An aqueous surfactant composition comprising one or more alpha-sulfo fatty acid disalt (A) of general formula (I), R1CH(SO3M1)COOM2   (I) in which radical R1 is a linear or branched alkyl or alkenyl radical with 6 to 16 carbon atoms and the radicals M1 and M2, independently of one another, are selected from the group consisting of H, Li, Na, K, Ca/2, Mg/2, ammonium, and alkanolamine, one or more alkyl glycosides (B) of general formula (II), R2O—[G]p   (II), in which R2 is an alkyl and/or alkenyl radical with 8 to 18 carbon atoms, G is a sugar radical with 5 or 6 carbon atoms and p is numbers between 1 and 10, water, where the following provisos apply: with regard to the compound (A), it is the case that a fraction of the compound (A) in which the radical R1 is an alkyl or alkenyl radical with 14 or more carbon atoms, based on the total amount of the compound (A) in the aqueous surfactant composition, is 20% by weight or less; with regard to the compound (B), it is the case that a fraction of the compound (B) in which the radical R2 is an alkyl or alkenyl radical with 15 or more carbon atoms, based on the total amount of the compound (B) in the aqueous surfactant composition, is 5% by weight or less; if the aqueous surfactant composition comprises one or more ester sulfonate (E) of general formula (V), R5CH(SO3M5)COOR6   (V) in which radical R5 is a linear or branched alkyl or alkenyl radical with 6 to 18 carbon atoms and radical R6 is a linear or branched alkyl or alkenyl radical with 1 to 20 carbon atoms, and the radical M5 is selected from the group consisting of Li, Na, K, Ca/2, Mg/2, ammonium and alkanolamine, it is the case that the compound (A), based on the totality of the compounds (A) and (E), is present to 50% by weight or more; a weight ratio of the compounds (A):(B) in the aqueous surfactant composition is in the range from 0.6:1 to 1:0.6. 2. The composition according to claim 1, where the radicals M1 and M2 are Na. 3. The composition according to claim 1, wherein the composition additionally comprises one or more compound (C) of general formula (III), R4COOM3   (III), in which the radical R4 is a linear or branched alkyl or alkenyl radical with 7 to 19 carbon atoms and the radical M3 is selected from the group consisting of H, Li, Na, K, Ca/2, Mg/2, ammonium, and alkanolamine. 4. The composition according to claim 1, wherein the composition additionally comprises one or more inorganic salt of sulfuric acid (D) of general formula (IV), (M4)2SO4   (IV) wherein M4 is selected from the group consisting of Li, Na, K, Ca/2, Mg/2, ammonium, and alkanolamine. 5. The composition according to claim 1, wherein a pH of the composition is in the range from 4.3 to 5.8. 6. A cosmetic product comprising a composition according claim 1. 7. The cosmetic product according to claim 6 in the form of hair shampoos, shower gels, soaps, syndets, washing pastes, washing lotions, scrub preparations, foam baths, oil baths, shower baths, shaving foams, shaving lotions, and shaving creams. 8. The composition according to claim 1 wherein the radical R6 is an alkenyl radical or is branched above 3 carbon atoms.

What is proposed is aqueous surfactant compositions comprising one or more alpha-sulfo fatty acid disalts (A) of the general formula (I), R 1 CH(SO 3 M 1 )COOM 2   (I) in which the radical R 1 is a linear or branched alkyl or alkenyl radical with 6 to 16 carbon atoms and the radicals M 1 and M 2 —independently of one another—are selected from the group H, Li, Na, K, Ca/2, Mg/2, ammonium and alkanolamine, one or more alkyl glycosides (B) of the general formula (II), R 2 O—[G] p   (I) in which R 2 is an alkyl and/or alkenyl radical with 8 to 18 carbon atoms, G is a sugar radical with 5 or 6 carbon atoms and p is numbers between 1 and 10, and water, where specific limiting conditions are to be observed. These compositions have excellent foaming ability and are suitable for use in cosmetic products.1. An aqueous surfactant composition comprising one or more alpha-sulfo fatty acid disalt (A) of general formula (I), R1CH(SO3M1)COOM2   (I) in which radical R1 is a linear or branched alkyl or alkenyl radical with 6 to 16 carbon atoms and the radicals M1 and M2, independently of one another, are selected from the group consisting of H, Li, Na, K, Ca/2, Mg/2, ammonium, and alkanolamine, one or more alkyl glycosides (B) of general formula (II), R2O—[G]p   (II), in which R2 is an alkyl and/or alkenyl radical with 8 to 18 carbon atoms, G is a sugar radical with 5 or 6 carbon atoms and p is numbers between 1 and 10, water, where the following provisos apply: with regard to the compound (A), it is the case that a fraction of the compound (A) in which the radical R1 is an alkyl or alkenyl radical with 14 or more carbon atoms, based on the total amount of the compound (A) in the aqueous surfactant composition, is 20% by weight or less; with regard to the compound (B), it is the case that a fraction of the compound (B) in which the radical R2 is an alkyl or alkenyl radical with 15 or more carbon atoms, based on the total amount of the compound (B) in the aqueous surfactant composition, is 5% by weight or less; if the aqueous surfactant composition comprises one or more ester sulfonate (E) of general formula (V), R5CH(SO3M5)COOR6   (V) in which radical R5 is a linear or branched alkyl or alkenyl radical with 6 to 18 carbon atoms and radical R6 is a linear or branched alkyl or alkenyl radical with 1 to 20 carbon atoms, and the radical M5 is selected from the group consisting of Li, Na, K, Ca/2, Mg/2, ammonium and alkanolamine, it is the case that the compound (A), based on the totality of the compounds (A) and (E), is present to 50% by weight or more; a weight ratio of the compounds (A):(B) in the aqueous surfactant composition is in the range from 0.6:1 to 1:0.6. 2. The composition according to claim 1, where the radicals M1 and M2 are Na. 3. The composition according to claim 1, wherein the composition additionally comprises one or more compound (C) of general formula (III), R4COOM3   (III), in which the radical R4 is a linear or branched alkyl or alkenyl radical with 7 to 19 carbon atoms and the radical M3 is selected from the group consisting of H, Li, Na, K, Ca/2, Mg/2, ammonium, and alkanolamine. 4. The composition according to claim 1, wherein the composition additionally comprises one or more inorganic salt of sulfuric acid (D) of general formula (IV), (M4)2SO4   (IV) wherein M4 is selected from the group consisting of Li, Na, K, Ca/2, Mg/2, ammonium, and alkanolamine. 5. The composition according to claim 1, wherein a pH of the composition is in the range from 4.3 to 5.8. 6. A cosmetic product comprising a composition according claim 1. 7. The cosmetic product according to claim 6 in the form of hair shampoos, shower gels, soaps, syndets, washing pastes, washing lotions, scrub preparations, foam baths, oil baths, shower baths, shaving foams, shaving lotions, and shaving creams. 8. The composition according to claim 1 wherein the radical R6 is an alkenyl radical or is branched above 3 carbon atoms.

The invention is generally directed to reducing inflammation by means of cells that secrete factors that reduce leukocyte extravasation. Specifically, the invention is directed to methods using cells that secrete factors that downregulate the expression of cellular adhesion molecules in leukocytes. Downregulating expression of cellular adhesion molecules reduces leukocyte adhesion to endothelial cells such that extravasation is reduced. The end result is a reduction of inflammation. The cells are non-embryonic non-germ cells that have pluripotent characteristics. These may include expression of pluripotential markers and broad differentiation potential.

1. (canceled) 2. A method to treat inflammation in a subject, said method comprising assessing cells in a preparation of cells for a desired potency for one or more of the following: (1) reduce leukocyte extravasation, (2) reduce leukocyte adhesion to vascular endothelium or to isolated endothelial cells, (3) reduce Fut-7 expression, (4) reduce expression of CD15s on a leukocyte, and, where the assessed cells are found to have the desired potency, administering cells from that preparation to the subject in a therapeutically effective amount and for a time sufficient to achieve a therapeutic result, the assessed and administered cells being non-embryonic, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1, and/or can differentiate into cell types of at least two of endodermal, ectodermal, and mesodermal germ layers. 3. A method to construct a cell bank, said the method comprising assessing cells in a preparation of cells for a desired potency for one or more of the following: (1) reduce leukocyte extravasation, (2) reduce leukocyte adhesion to vascular endothelium or to isolated endothelial cells, (3) reduce cytokine-mediated activation of endothelial cells, (4) reduce expression of one or more cell adhesion molecules on an endothelial cell, and, where the assessed cells are found to have the desired potency, expanding and storing cells from that preparation for future administration to a subject, the assessed, expanded, and stored cells being non-embryonic, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1, and/or can differentiate into cell types of at least two of endodermal, ectodermal, and mesodermal germ layers. 4. A method for drug discovery, said method comprising assessing cells in a preparation of cells for a desired potency for one or more of the following: (1) reduce leukocyte extravasation, (2) reduce leukocyte adhesion to vascular endothelium or to isolated endothelial cells, (3) reduce cytokine-mediated activation of endothelial cells, (4) reduce expression of one or more cell adhesion molecules on an endothelial cell, and, where the assessed cells are found to have the desired potency, contacting cells from that preparation with an agent to assess the effect of the agent on the ability of the cells to effect any of (1)-(4), the assessed and contacted cells being non-embryonic, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1, and/or can differentiate into cell types of at least two of endodermal, ectodermal, and mesodermal germ layers. 5. (canceled) 6. The method of claim 1 wherein adhesion is of E-selectin and/or P-selectin to CD15s. 7. The method of claim 1 wherein the leukocyte is a lymphocyte. 8. The method of claim 7 wherein the lymphocyte is a CD4+ of CD8+ lymphocyte. 9. The method of claim 6 wherein the leukocyte is a lymphocyte. 10. The method of claim 9 wherein the lymphocyte is a CD4+ of CD8+ lymphocyte. 11. The method of claim 1 wherein the leukocyte is a neutrophil. 12. The method of claim 6 wherein the leukocyte is a neutrophil. 13. The method of any of claims 2-4 wherein the non-embryonic, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1, can differentiate into cell types of each of endodermal, ectodermal, and mesodermal germ layers.

The invention is generally directed to reducing inflammation by means of cells that secrete factors that reduce leukocyte extravasation. Specifically, the invention is directed to methods using cells that secrete factors that downregulate the expression of cellular adhesion molecules in leukocytes. Downregulating expression of cellular adhesion molecules reduces leukocyte adhesion to endothelial cells such that extravasation is reduced. The end result is a reduction of inflammation. The cells are non-embryonic non-germ cells that have pluripotent characteristics. These may include expression of pluripotential markers and broad differentiation potential.1. (canceled) 2. A method to treat inflammation in a subject, said method comprising assessing cells in a preparation of cells for a desired potency for one or more of the following: (1) reduce leukocyte extravasation, (2) reduce leukocyte adhesion to vascular endothelium or to isolated endothelial cells, (3) reduce Fut-7 expression, (4) reduce expression of CD15s on a leukocyte, and, where the assessed cells are found to have the desired potency, administering cells from that preparation to the subject in a therapeutically effective amount and for a time sufficient to achieve a therapeutic result, the assessed and administered cells being non-embryonic, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1, and/or can differentiate into cell types of at least two of endodermal, ectodermal, and mesodermal germ layers. 3. A method to construct a cell bank, said the method comprising assessing cells in a preparation of cells for a desired potency for one or more of the following: (1) reduce leukocyte extravasation, (2) reduce leukocyte adhesion to vascular endothelium or to isolated endothelial cells, (3) reduce cytokine-mediated activation of endothelial cells, (4) reduce expression of one or more cell adhesion molecules on an endothelial cell, and, where the assessed cells are found to have the desired potency, expanding and storing cells from that preparation for future administration to a subject, the assessed, expanded, and stored cells being non-embryonic, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1, and/or can differentiate into cell types of at least two of endodermal, ectodermal, and mesodermal germ layers. 4. A method for drug discovery, said method comprising assessing cells in a preparation of cells for a desired potency for one or more of the following: (1) reduce leukocyte extravasation, (2) reduce leukocyte adhesion to vascular endothelium or to isolated endothelial cells, (3) reduce cytokine-mediated activation of endothelial cells, (4) reduce expression of one or more cell adhesion molecules on an endothelial cell, and, where the assessed cells are found to have the desired potency, contacting cells from that preparation with an agent to assess the effect of the agent on the ability of the cells to effect any of (1)-(4), the assessed and contacted cells being non-embryonic, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1, and/or can differentiate into cell types of at least two of endodermal, ectodermal, and mesodermal germ layers. 5. (canceled) 6. The method of claim 1 wherein adhesion is of E-selectin and/or P-selectin to CD15s. 7. The method of claim 1 wherein the leukocyte is a lymphocyte. 8. The method of claim 7 wherein the lymphocyte is a CD4+ of CD8+ lymphocyte. 9. The method of claim 6 wherein the leukocyte is a lymphocyte. 10. The method of claim 9 wherein the lymphocyte is a CD4+ of CD8+ lymphocyte. 11. The method of claim 1 wherein the leukocyte is a neutrophil. 12. The method of claim 6 wherein the leukocyte is a neutrophil. 13. The method of any of claims 2-4 wherein the non-embryonic, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1, can differentiate into cell types of each of endodermal, ectodermal, and mesodermal germ layers.

Twenty-one PSGR-derived peptides predicted by an immuno-informatics approach based on the HLA-A2 binding motif were examined for their ability to induce peptide-specific T cell responses in peripheral blood mononuclear cells (PBMCs) obtained from either HLA-A2+ healthy donors or HLA-A2+ prostate cancer patients. The recognition of HLA-A2 positive and PSGR expressing LNCaP cells was also tested. Three peptides, PSGR3, PSGR4 and PSGR14 frequently induced peptide-specific T cell responses in PBMCs from both healthy donors and prostate cancer patients, and are recognized by CD8+ T cells in an HLA-A2 dependent manner. These peptide-specific T cells recognize HLA-A2+ and PSGR+ tumor cells, and killed LNCaP prostate cancer cells in an HLA class I-restricted manner. These PSGR-derived peptides identified are useful as diagnostic markers as well as immune targets for anticancer vaccines.

1. A method of treating prostate cancer comprising administering to a patient in need thereof an effective amount of a peptide selected from the group consisting of PSGR3, PSGR4 and PSGR4, or combinations of two or more of the three peptides. 2. The method of claim 1 wherein the peptides are co-administered. 3. The method of claim 1 wherein the peptides are administered concurrently. 4. The method of claim 1 wherein the peptides are administered sequentially. 5. The method of claim 1 wherein the administration route is intradermal. 6. The method of claim 1 further comprising administering to the patient granulocyte macrophage colony stimulating factor (GM-CSF). 7. The method of claim 6 wherein the peptides and. GM-CSF are co-administered in multiple injections. 8. The method of claim 6 wherein the peptides and GM-CSF are administered concurrently. 9. The method of claim 6 wherein the peptides and GM-CSF are administered sequentially. 10. The method of claim 1 or claim 6 further comprising administering to a patient in an amount effective to increase a T cell immune response: a TLR9 agonist, an inhibitor of CTLA4 or an inhibitor of PD-1. 11. The method of claim 10 wherein the TLR9 agonist is a CpG-oligodeoxynucleotide (CpG-ODN). 12. The method of claim 10 wherein the inhibitor of CTLA4 is a monoclonal antibody. 13. The method of claim 10 wherein the inhibitor of PD-1 is a monoclonal antibody. 14. The method of claim 11 wherein the peptides are administered in weeks 1, 4 and 10, and then every six months up to four years. 15. The method of claim 10 wherein the peptides are administered in weeks 1, 4 and 10, and then every six months up to four years, and wherein an inhibitor of CTLA4 is administered in weeks 1, 4 and 10, and then every eight weeks up until week 52. 16. The method of claim 10 wherein the peptides are administered in weeks 1, 4 and 10, and then every six months up to four years, and wherein an inhibitor of PD-1 is administered in weeks 1, 4 and 10, and then every eight weeks up until week 52. 17. A composition comprising: (i) a pharmaceutically acceptable carrier, (ii) one or more PSGR peptides selected from the group consisting of PSGR3, PSGR4, and pSGR14. 18. The composition of claim 17, wherein the composition if formulated as a vaccine. 19. A kit comprising a composition of claim 17, instructions for administration of the composition and a device for administering the composition to a patient. 20. A method for preventing prostate cancer in a human subject in need thereof, the method comprising administering to the human subject a composition of claim 18.

Twenty-one PSGR-derived peptides predicted by an immuno-informatics approach based on the HLA-A2 binding motif were examined for their ability to induce peptide-specific T cell responses in peripheral blood mononuclear cells (PBMCs) obtained from either HLA-A2+ healthy donors or HLA-A2+ prostate cancer patients. The recognition of HLA-A2 positive and PSGR expressing LNCaP cells was also tested. Three peptides, PSGR3, PSGR4 and PSGR14 frequently induced peptide-specific T cell responses in PBMCs from both healthy donors and prostate cancer patients, and are recognized by CD8+ T cells in an HLA-A2 dependent manner. These peptide-specific T cells recognize HLA-A2+ and PSGR+ tumor cells, and killed LNCaP prostate cancer cells in an HLA class I-restricted manner. These PSGR-derived peptides identified are useful as diagnostic markers as well as immune targets for anticancer vaccines.1. A method of treating prostate cancer comprising administering to a patient in need thereof an effective amount of a peptide selected from the group consisting of PSGR3, PSGR4 and PSGR4, or combinations of two or more of the three peptides. 2. The method of claim 1 wherein the peptides are co-administered. 3. The method of claim 1 wherein the peptides are administered concurrently. 4. The method of claim 1 wherein the peptides are administered sequentially. 5. The method of claim 1 wherein the administration route is intradermal. 6. The method of claim 1 further comprising administering to the patient granulocyte macrophage colony stimulating factor (GM-CSF). 7. The method of claim 6 wherein the peptides and. GM-CSF are co-administered in multiple injections. 8. The method of claim 6 wherein the peptides and GM-CSF are administered concurrently. 9. The method of claim 6 wherein the peptides and GM-CSF are administered sequentially. 10. The method of claim 1 or claim 6 further comprising administering to a patient in an amount effective to increase a T cell immune response: a TLR9 agonist, an inhibitor of CTLA4 or an inhibitor of PD-1. 11. The method of claim 10 wherein the TLR9 agonist is a CpG-oligodeoxynucleotide (CpG-ODN). 12. The method of claim 10 wherein the inhibitor of CTLA4 is a monoclonal antibody. 13. The method of claim 10 wherein the inhibitor of PD-1 is a monoclonal antibody. 14. The method of claim 11 wherein the peptides are administered in weeks 1, 4 and 10, and then every six months up to four years. 15. The method of claim 10 wherein the peptides are administered in weeks 1, 4 and 10, and then every six months up to four years, and wherein an inhibitor of CTLA4 is administered in weeks 1, 4 and 10, and then every eight weeks up until week 52. 16. The method of claim 10 wherein the peptides are administered in weeks 1, 4 and 10, and then every six months up to four years, and wherein an inhibitor of PD-1 is administered in weeks 1, 4 and 10, and then every eight weeks up until week 52. 17. A composition comprising: (i) a pharmaceutically acceptable carrier, (ii) one or more PSGR peptides selected from the group consisting of PSGR3, PSGR4, and pSGR14. 18. The composition of claim 17, wherein the composition if formulated as a vaccine. 19. A kit comprising a composition of claim 17, instructions for administration of the composition and a device for administering the composition to a patient. 20. A method for preventing prostate cancer in a human subject in need thereof, the method comprising administering to the human subject a composition of claim 18.

The present invention relates to a method for detecting the presence of expanded-spectrum β-lactamase (β-lactamase hydrolyzing expanded-spectrum cephalosporin)-producing bacteria in a sample, said method comprising the steps of: a) performing cell lysis on a test sample in order to obtain an enzymatic suspension; b) reacting a fraction of the enzymatic suspension obtained in step a) with a reagent kit, said reagent kit comprising—expanded-spectrum β-lactamase substrate selected from the group consisting of cephalosporins, aztreonam, and cephamycins, —a pH color indicator which will change color when the pH of the reaction mixture is comprised between 6.4 and 8.4, wherein a color change after step b) indicates the presence of expanded-spectrum β-lactamase-producing bacteria in the test sample. The invention also relates to a reagent kit, to a microtiter plate and to their uses in detecting the presence of expanded-spectrum β-lactamase producers in a test sample.

1. A method for detecting the presence of expanded-spectrum β-lactamase-producing bacteria in a sample, said method comprising the steps of: a) performing cell lysis on a test sample in order to obtain an enzymatic suspension; b) reacting a fraction of the enzymatic suspension obtained in step a) with a reagent kit, said reagent kit comprising an expanded-spectrum β-lactamase substrate selected from the group consisting of cephalosporins, aztreonam and cephamycins, a pH color indicator which will change color when the pH of the reaction mixture is comprised between 6.4 and 8.4, wherein a color change after step b) indicates the presence of expanded-spectrum β-lactamase-producing bacteria in the test sample. 2. The method according to claim 1, wherein the test sample is a biological sample selected from the group consisting of a blood sample and a urine sample. 3. The method according to claim 1, wherein the carbapenemase-producing bacteria are selected from the genera consisting of Acinetobacter, Aeromonas, Bacillus, Bacteroides, Citrobacter, Enterobacter, Escherichia, Klebsiella, Morganella, Pandoraea, Proteus, Providencia, Pseudomonas, Ralstonia, Raoultella, Salmonella, Serratia, Shewanella, Shigella and Strenotrophomonas. 4. The method according to claim 1, wherein reaction in step b) is carried out at a temperature comprised between 15° C. and 40° C. 5. The method according to claim 1, wherein the reaction in step b) is carried out over a period of time comprised between 5 minutes and 120 minutes. 6. A method according to claim 1, said method comprising the steps of: a) performing cell lysis on a biological sample in order to obtain an enzymatic suspension; b) reacting a fraction of the enzymatic suspension obtained in step a) with a reagent kit, said reagent kit comprising cefotaxime as the expanded-spectrum β-lactamase substrate, phenol red as the pH color indicator, and wherein a color change from red to yellow after step b) indicates the presence of expanded-spectrum β-lactamase-producing bacteria in the biological sample. 7. A reagent kit comprising expanded-spectrum β-lactamase substrate selected from the group consisting of cephalosporins, aztreonam and cephamycins and a pH color indicator. 8. The reagent kit according to claim 7, further comprising a β-lactamase inhibitor. 9. (canceled) 10. A microtiter plate comprising a well or a series of wells comprising an expanded-spectrum β-lactamase substrate selected from the group consisting of cephalosporins, aztreonam, and cephamycins. 11. The microliter plate according to claim 10 further comprising: a well or a series of wells which comprise a expanded-spectrum β-lactamase selected from the group consisting of cephalosporins, aztreonam and cephamycins and a β-lactamase inhibitor of Ambler class A; a well or a series of wells which comprise a expanded-spectrum β-lactamase selected from the group consisting of cephalosporins, aztreonam and cephamycins and a β-lactamase inhibitor of Ambler class B; a well or a series of wells which comprise an expanded-spectrum β-lactamase substrate selected from the group consisting of cephalosporins aztreonam, and cephamycins and a β-lactamase inhibitor of Ambler class C; and a well or a series of wells which comprise expanded-spectrum β-lactamase substrate selected from the group consisting of cephalosporins, aztreonam and cephamycins and a β-lactamase inhibitor of Ambler class D. 12-13. (canceled) 14. The microtiter plate according to claim 11, wherein the cephalosporin is selected from the group consisting of cefotaxime, ceftriaxone, ceftazidime, cefepime, cefpirome, and the aztreonam is cefotaxime, and the cephamycin is selected from the group consisting of moxalactam and cefoxitin 15. The method according to claim 1, wherein reaction in step b) is carried out at a temperature comprised between 20° C. and 37° C. 16. The method according to claim 1, wherein the reaction in step b) is carried out over a period of time sufficient to observe a color change. 17. The method according to claim 1, wherein the reaction in step b) is carried out over a period of time comprised between 20 minutes and 40 minutes. 18. The method according to claim 1, wherein the cephalosporin is selected from the group consisting of cefotaxime, ceftriaxone, ceftazidime, cefepime, cefpirome, and the aztreonam is cefotaxime, and the cephamycin is selected from the group consisting of moxalactam and cefoxitin. 19. The reagent kit according to claim 6, wherein the cephalosporin is selected from the group consisting of cefotaxime, ceftriaxone, ceftazidime, cefepime, cefpirome, and the aztreonam is cefotaxime, and the cephamycin is selected from the group consisting of moxalactam and cefoxitin.

The present invention relates to a method for detecting the presence of expanded-spectrum β-lactamase (β-lactamase hydrolyzing expanded-spectrum cephalosporin)-producing bacteria in a sample, said method comprising the steps of: a) performing cell lysis on a test sample in order to obtain an enzymatic suspension; b) reacting a fraction of the enzymatic suspension obtained in step a) with a reagent kit, said reagent kit comprising—expanded-spectrum β-lactamase substrate selected from the group consisting of cephalosporins, aztreonam, and cephamycins, —a pH color indicator which will change color when the pH of the reaction mixture is comprised between 6.4 and 8.4, wherein a color change after step b) indicates the presence of expanded-spectrum β-lactamase-producing bacteria in the test sample. The invention also relates to a reagent kit, to a microtiter plate and to their uses in detecting the presence of expanded-spectrum β-lactamase producers in a test sample.1. A method for detecting the presence of expanded-spectrum β-lactamase-producing bacteria in a sample, said method comprising the steps of: a) performing cell lysis on a test sample in order to obtain an enzymatic suspension; b) reacting a fraction of the enzymatic suspension obtained in step a) with a reagent kit, said reagent kit comprising an expanded-spectrum β-lactamase substrate selected from the group consisting of cephalosporins, aztreonam and cephamycins, a pH color indicator which will change color when the pH of the reaction mixture is comprised between 6.4 and 8.4, wherein a color change after step b) indicates the presence of expanded-spectrum β-lactamase-producing bacteria in the test sample. 2. The method according to claim 1, wherein the test sample is a biological sample selected from the group consisting of a blood sample and a urine sample. 3. The method according to claim 1, wherein the carbapenemase-producing bacteria are selected from the genera consisting of Acinetobacter, Aeromonas, Bacillus, Bacteroides, Citrobacter, Enterobacter, Escherichia, Klebsiella, Morganella, Pandoraea, Proteus, Providencia, Pseudomonas, Ralstonia, Raoultella, Salmonella, Serratia, Shewanella, Shigella and Strenotrophomonas. 4. The method according to claim 1, wherein reaction in step b) is carried out at a temperature comprised between 15° C. and 40° C. 5. The method according to claim 1, wherein the reaction in step b) is carried out over a period of time comprised between 5 minutes and 120 minutes. 6. A method according to claim 1, said method comprising the steps of: a) performing cell lysis on a biological sample in order to obtain an enzymatic suspension; b) reacting a fraction of the enzymatic suspension obtained in step a) with a reagent kit, said reagent kit comprising cefotaxime as the expanded-spectrum β-lactamase substrate, phenol red as the pH color indicator, and wherein a color change from red to yellow after step b) indicates the presence of expanded-spectrum β-lactamase-producing bacteria in the biological sample. 7. A reagent kit comprising expanded-spectrum β-lactamase substrate selected from the group consisting of cephalosporins, aztreonam and cephamycins and a pH color indicator. 8. The reagent kit according to claim 7, further comprising a β-lactamase inhibitor. 9. (canceled) 10. A microtiter plate comprising a well or a series of wells comprising an expanded-spectrum β-lactamase substrate selected from the group consisting of cephalosporins, aztreonam, and cephamycins. 11. The microliter plate according to claim 10 further comprising: a well or a series of wells which comprise a expanded-spectrum β-lactamase selected from the group consisting of cephalosporins, aztreonam and cephamycins and a β-lactamase inhibitor of Ambler class A; a well or a series of wells which comprise a expanded-spectrum β-lactamase selected from the group consisting of cephalosporins, aztreonam and cephamycins and a β-lactamase inhibitor of Ambler class B; a well or a series of wells which comprise an expanded-spectrum β-lactamase substrate selected from the group consisting of cephalosporins aztreonam, and cephamycins and a β-lactamase inhibitor of Ambler class C; and a well or a series of wells which comprise expanded-spectrum β-lactamase substrate selected from the group consisting of cephalosporins, aztreonam and cephamycins and a β-lactamase inhibitor of Ambler class D. 12-13. (canceled) 14. The microtiter plate according to claim 11, wherein the cephalosporin is selected from the group consisting of cefotaxime, ceftriaxone, ceftazidime, cefepime, cefpirome, and the aztreonam is cefotaxime, and the cephamycin is selected from the group consisting of moxalactam and cefoxitin 15. The method according to claim 1, wherein reaction in step b) is carried out at a temperature comprised between 20° C. and 37° C. 16. The method according to claim 1, wherein the reaction in step b) is carried out over a period of time sufficient to observe a color change. 17. The method according to claim 1, wherein the reaction in step b) is carried out over a period of time comprised between 20 minutes and 40 minutes. 18. The method according to claim 1, wherein the cephalosporin is selected from the group consisting of cefotaxime, ceftriaxone, ceftazidime, cefepime, cefpirome, and the aztreonam is cefotaxime, and the cephamycin is selected from the group consisting of moxalactam and cefoxitin. 19. The reagent kit according to claim 6, wherein the cephalosporin is selected from the group consisting of cefotaxime, ceftriaxone, ceftazidime, cefepime, cefpirome, and the aztreonam is cefotaxime, and the cephamycin is selected from the group consisting of moxalactam and cefoxitin.

An effervescent composition is provided which contains a phase-stable oil-in-water emulsion comprising a discontinuous oil phase homogenously distributed within continuous water phase, wherein the discontinuous oil phase comprises a UV-absorbing compound; and from about 20% to about 30% by weight of the composition of a combination of at least two propellants selected from the group consisting of dimethyl ether, a hydrocarbon, or mixtures thereof, and 1, 1-difluoroethane, where the composition includes from about 8% to about 15% by weight of each propellant in the propellant combination, and where the composition provides a phase-stable, effervescent foam when discharged from a pressurized aerosol container.

1. A composition, comprising: a phase-stable oil-in-water emulsion comprising a discontinuous oil phase homogenously distributed within continuous a water phase, wherein said discontinuous oil phase comprises a UV-absorbing compound; and from about 20% to about 30% by weight of said composition of a combination of at least two propellants, said combination comprising at least two propellants selected from the group consisting of dimethyl ether, a hydrocarbon, and 1, 1-difluoroethane, wherein said composition comprises from about 8% to about 15% by weight of each of said propellants comprising said combination, and wherein said composition provides a phase-stable, effervescent foam when discharged from a pressurized container. 2. The composition of claim 1 wherein said hydrocarbon is selected from the group consisting of isobutane and a mixture of 80% butane and 20% propane, based on total weight of said mixture of butane and propane. 3. The composition of claim 2 wherein said propellant combination comprises said dimethyl ether and said mixture of butane and propane. 4. The composition of claim 2 wherein said propellant combination comprises said dimethyl ether and said isobutane. 5. The composition of claim 1 wherein said propellant combination comprises said dimethyl ether and said 1,1-difluoroethane. 6. The composition of claim 2 wherein said propellant combination comprises said 1,1-difluoroethane and said mixture of butane and propane. 7. The composition of claim 1 wherein said UV-absorbing compound comprises a UV-absorbing moiety selected from the group consisting of a UV-absorbing triazole and UV-absorbing benzoylmethane. 8. The composition of claim 1 wherein said UV-absorbing compound comprises UV-absorbing particles. 9. The composition of claim 1 wherein said UV-absorbing compound is an organic UV-absorber. 10. The composition of claim 1 wherein said discontinuous oil phase is substantially free of an oil soluble polymer. 11. The composition of claim 1 comprising an emulsifier selected from the group consisting of an anionic emulsifier and a non-ionic emulsifier. 12. The composition of claim 1 wherein said composition is essentially free of monomeric surfactants. 13. The composition of claim 1 wherein said continuous water phase comprises from about 0.75% to about 6% by weight of a superhydrophilic amphiphilic copolymer and from about 1% to about 5% by weight of a non-UV-absorbing light-scattering particle, each based on total weight of the composition.

An effervescent composition is provided which contains a phase-stable oil-in-water emulsion comprising a discontinuous oil phase homogenously distributed within continuous water phase, wherein the discontinuous oil phase comprises a UV-absorbing compound; and from about 20% to about 30% by weight of the composition of a combination of at least two propellants selected from the group consisting of dimethyl ether, a hydrocarbon, or mixtures thereof, and 1, 1-difluoroethane, where the composition includes from about 8% to about 15% by weight of each propellant in the propellant combination, and where the composition provides a phase-stable, effervescent foam when discharged from a pressurized aerosol container.1. A composition, comprising: a phase-stable oil-in-water emulsion comprising a discontinuous oil phase homogenously distributed within continuous a water phase, wherein said discontinuous oil phase comprises a UV-absorbing compound; and from about 20% to about 30% by weight of said composition of a combination of at least two propellants, said combination comprising at least two propellants selected from the group consisting of dimethyl ether, a hydrocarbon, and 1, 1-difluoroethane, wherein said composition comprises from about 8% to about 15% by weight of each of said propellants comprising said combination, and wherein said composition provides a phase-stable, effervescent foam when discharged from a pressurized container. 2. The composition of claim 1 wherein said hydrocarbon is selected from the group consisting of isobutane and a mixture of 80% butane and 20% propane, based on total weight of said mixture of butane and propane. 3. The composition of claim 2 wherein said propellant combination comprises said dimethyl ether and said mixture of butane and propane. 4. The composition of claim 2 wherein said propellant combination comprises said dimethyl ether and said isobutane. 5. The composition of claim 1 wherein said propellant combination comprises said dimethyl ether and said 1,1-difluoroethane. 6. The composition of claim 2 wherein said propellant combination comprises said 1,1-difluoroethane and said mixture of butane and propane. 7. The composition of claim 1 wherein said UV-absorbing compound comprises a UV-absorbing moiety selected from the group consisting of a UV-absorbing triazole and UV-absorbing benzoylmethane. 8. The composition of claim 1 wherein said UV-absorbing compound comprises UV-absorbing particles. 9. The composition of claim 1 wherein said UV-absorbing compound is an organic UV-absorber. 10. The composition of claim 1 wherein said discontinuous oil phase is substantially free of an oil soluble polymer. 11. The composition of claim 1 comprising an emulsifier selected from the group consisting of an anionic emulsifier and a non-ionic emulsifier. 12. The composition of claim 1 wherein said composition is essentially free of monomeric surfactants. 13. The composition of claim 1 wherein said continuous water phase comprises from about 0.75% to about 6% by weight of a superhydrophilic amphiphilic copolymer and from about 1% to about 5% by weight of a non-UV-absorbing light-scattering particle, each based on total weight of the composition.

This disclosure is directed to, inter alia, methods and compositions for hybridizing at least one molecule to a target. The invention may, for example, eliminate the use of, or reduce the dependence on formamide in hybridization. Compositions for use in the invention include an aqueous composition comprising at least one nucleic acid sequence and at least one polar aprotic solvent in an amount effective to denature double-stranded nucleotide sequences.

1. A method of hybridizing nucleic acid sequences without a denaturation step, or using a low-temperature denaturation step comprising: providing a first nucleic acid sequence, providing a second nucleic acid sequence, providing a hybridization composition comprising an effective amount of at least one polar aprotic solvent, and combining the first and the second nucleic acid sequence and the hybridization composition for at least a time period sufficient to hybridize the first and second nucleic acid sequences, wherein the polar aprotic solvent is not dimethyl sulfoxide (DMSO). 2. A method of hybridizing nucleic acid sequences without a denaturation step, or using a low-temperature denaturation step comprising: providing a first nucleic acid sequence, and applying a hybridization composition comprising a second nucleic acid sequence and an effective amount of at least one polar aprotic solvent for at least a time period sufficient to hybridize the first and second nucleic acid sequences, wherein the polar aprotic solvent is not dimethyl sulfoxide (DMSO). 3. The method according to claim 1, wherein the first nucleic acid sequence is in a biological sample. 4. The method according to claim 3, wherein the biological sample is a cytology or histology sample. 5. The method according to claim 1, wherein the first nucleic acid sequence is a single stranded sequence and the second nucleic acid sequence is a double stranded sequence. 6. The method according to claim 1, wherein the first nucleic acid sequence is a double stranded sequence in a biological sample and the second nucleic acid sequence is a single stranded sequence. 7. The method according to claim 1, wherein the first and second nucleic acid sequences are double stranded sequences. 8. The method according to claim 1, wherein the first and second nucleic acid sequences are single stranded sequences. 9. The method according to claim 1, wherein a sufficient amount of energy to hybridize the first and second nucleic acids is provided. 10. The method according to claim 1, wherein a sufficient amount of energy to denature the first and second nucleic acids is provided. 11. The method according to claim 10, wherein the denaturation energy is provided to the first and second nucleic acid sequences in separate steps. 12. The method according to claim 10, wherein the denaturation energy is provided to the first and second nucleic acid sequences in a single step. 13. The method according to claim 9, wherein the energy is provided by heating the hybridization composition and nucleic acid sequence. 14. The method according to claim 13, wherein the heating step is performed by the use of microwaves, hot baths, hot plates, heat wire, peltier element, induction heating or heat lamps. 15. The method according to claim 1, wherein the denaturation temperature is 70° C. to 85° C. 16. The method according to claim 15, wherein the denaturation temperature is 60° C. to 75° C. 17. The method according to claim 15, wherein the denaturation temperature is 62° C., 67° C., 72° C., or 82° C. 18. The method according to claim 1, wherein the step of hybridizing includes the steps of heating and cooling the hybridization composition and nucleic acid sequences. 19. The method according to claim 1, wherein the step of hybridization takes less than 8 hours. 20. The method according to claim 19, wherein the step of hybridization takes less than 1 hour. 21. The method according to claim 20, wherein the step of hybridization takes less than 30 minutes. 22. The method according to claim 21, wherein the step of hybridization takes less than 15 minutes. 23. The method according to claim 22, wherein the step of hybridization takes less than 5 minutes. 24. The method according to claim 1, further comprising a blocking step. 25. The method according to claim 1, wherein the concentration of polar aprotic solvent in the hybridization composition is about 1% to 95% (v/v). 26. The method according to claim 25, wherein the concentration of polar aprotic solvent is 5% to 10% (v/v). 27. The method according to claim 25, wherein the concentration of polar aprotic solvent is 10% to 20% (v/v). 28. The method according to claim 25, wherein the concentration of polar aprotic solvent is 20% to 30% (v/v). 29. The method according to claim 1, wherein the polar aprotic solvent in the hybridization composition is non-toxic. 30. The method according to claim 1, with the proviso that the hybridization composition does not contain formamide. 31. The method according to claim 1, with the proviso that the hybridization composition contains less than 10% formamide. 32. The method according to claim 31, with the proviso that the hybridization composition contains less than 2% formamide. 33. The method according to claim 32, with the proviso that the hybridization composition contains less than 1% formamide. 34. The method according to claim 1, wherein the polar aprotic solvent in the hybridization composition has lactone, sulfone, nitrile, sulfite, and/or carbonate functionality. 35. The method according to claim 1, wherein the polar aprotic solvent in the hybridization composition has a dispersion solubility parameter between 17.7 to 22.0 MPa1/2, a polar solubility parameter between 13 to 23 MPa1 2, and a hydrogen bonding solubility parameter between 3 to 13 MPa. 36. The method according to claim 1, wherein the polar aprotic solvent in the hybridization composition has a cyclic base structure. 37. The method according to claim 1, wherein the polar aprotic solvent in the hybridization composition is selected from the group consisting of: wherein X is O and R1 is alkyldiyl, and wherein X is optional and if present, is chosen from O or S, wherein Z is optional and if present, is chosen from O or S, wherein A and B are independently O, N, S, part of the alkyldiyl, or a primary amine, wherein R is alkyldiyl, and wherein Y is O, S or C. 38. The method according to claim 1, wherein the polar aprotic solvent in the hybridization composition is acetanilide, acetonitrile, N-acetyl pyrrolidone, 4-amino pyridine, benzamide, benzimidazole, 1,2,3-benzotriazole, butadienedioxide, 2,3-butylene carbonate, γ-butyrolactone, caprolactone (epsilon), chloro maleic anhydride, 2-chlorocyclohexanone, chloroethylene carbonate, chloronitromethane, citraconic anhydride, crotonlactone, 5-cyano-2-thiouracil, cyclopropylnitrile, dimethyl sulfate, dimethyl sulfone, 1,3-dimethyl-5-tetrazole, 1,5-dimethyl tetrazole, 1,2-dinitrobenzene, 2,4-dinitrotoluene, dipheynyl sulfone, 1,2-dinitrobenzene, 2,4-dinitrotoluene, dipheynyl sulfone, epsilon-caprolactam, ethanesulfonylchloride, ethyl ethyl phosphinate, N-ethyl tetrazole, ethylene carbonate, ethylene trithiocarbonate, ethylene glycol sulfate, glycol sulfite, furfural, 2-furonitrile, 2-imidazole, isatin, isoxazole, malononitrile, 4-methoxy benzonitrile, 1-methoxy-2-nitrobenzene, methyl alpha bromo tetronate, 1-methyl imidazole, N-methyl imidazole, 3-methyl isoxazole, N-methyl morpholine-N-oxide, methyl phenyl sulfone, N-methylpyrrolidinone, methyl sulfolane, methyl-4-toluenesulfonate, 3-nitroaniline, nitrobenzimidazole, 2-nitrofuran, 1-nitroso-2-pyrrolidinone, 2-nitrothiophene, 2-oxazolidinone, 9,10-phenanthrenequinone, N-phenyl sydnone, phthalic anhydride, picolinonitrile (2-cyanopyridine), 1,3-propane sultone, β-propiolactone, propylene carbonate, 4H-pyran-4-thione, 4H-pyran-4-one (γ-pyrone), pyridazine, 2-pyrrolidone, saccharin, succinonitrile, sulfanilamide, sulfolane, 2,2,6,6-tetrachlorocyclohexanone, tetrahydrothiapyran oxide, tetramethylene sulfone (sulfolane), thiazole, 2-thiouracil, 3,3,3-trichloro propene, 1,1,2-trichloro propene, 1,2,3-trichloro propene, trimethylene sulfide-dioxide, trimethylene sulfite, N-formyl piperidine, N-ethyl-2-pyrrolidone, N-methyl-2-pyrrolidone, delta-valerolactam (2-piperidone), gamma valerolactone, vinylene carbonate, tetrahydrothiophene 1-oxide (tetramethylene sulfoxide), butadiene sulfone (sulfolene), or cyclopentanone. 39. The method according to claims claim 1, wherein the polar aprotic solvent in the hybridization composition is: 40. The method according to claim 1, wherein the polar aprotic solvent in the hybridization composition is: 41. The method according to claim 1, wherein the polar aprotic solvent in the hybridization composition is: 42. The method according to claim 1, wherein the polar aprotic solvent in the hybridization composition is ethylene carbonate, sulfolane, gamma-butyrolactone, or propylene carbonate. 43. The method according to claim 1, wherein the polar aprotic solvent in the hybridization composition is selected from the group consisting of ethylene carbonate, sulfolane, gamma-butyrolactone, propylene carbonate, ethylene trithiocarbonate, glycol sulfite/ethylene sulfite, delta-valerolactam (2-piperidone), and tetrahydrothiophene 1-oxide. 44. The method according to claim 1, wherein the hybridization composition further comprises at least one additional component selected from the group consisting of: buffering agents, salts, accelerating agents, chelating agents, detergents, and blocking agents. 45. The method according to claim 44, wherein the accelerating agent is dextran sulfate and the salts are NaCl and/or phosphate buffer. 46. The method according to claim 45, wherein the dextran sulfate is present at a concentration of 5% to 40%, the NaCl is present at a concentration of 0 mM to 1200 mM, and/or the phosphate buffer is present at a concentration of 0 mM to 50 mM. 47. The method according to claim 46, wherein the dextran sulfate is present at a concentration of 10% to 30%, the NaCl is present at a concentration of 300 mM to 600 mM, and/or the phosphate buffer is present at a concentration of 5 mM to 20 mM. 48. The method according to claim 44, wherein the accelerating agent is formamide, DMSO, glycerol, propylene glycol, 1,2-propanediol, diethylene glycol, ethylene glycol, glycol, or 1,3 propanediol, and wherein the buffering agent is citric acid buffer. 49. The method according to claim 48, wherein the accelerating agent is formamide and the formamide is present at a concentration of 0.1-5%, or wherein the accelerating agent is DMSO and the DMSO is present at a concentration of 0.01% to 10%, or wherein the accelerating agent is glycerol, propylene glycol, 1,2-propanediol, diethylene glycol, ethylene glycol, glycol, or 1,3 propanediol-ace present at a concentration of 0.1% to 10%, and wherein the citric acid buffer is present at a concentration of 1 mM to 50 mM. 50. The method according to claim 44, wherein the blocking agent is total human DNA, herring sperm DNA, salmon sperm DNA, or calf thymus DNA. 51. The method according to claim 50, wherein the total human DNA, herring sperm DNA, salmon sperm DNA, or calf thymus DNA is present at a concentration of 0.01 to 10 μg/μL. 52. The method according to claim 44, wherein the hybridization composition comprises 40% of at least one polar aprotic solvent, 10% dextran sulfate, 300 mM NaCl, and 5 mM phosphate buffer. 53. The method according to claim 44, wherein the hybridization composition comprises 15% of at least one polar aprotic solvent, 20% dextran sulfate, 600 mM NaCl, and 10 mM phosphate buffer. 54. The method according to claim 44, wherein the hybridization composition comprises 15% of at least one polar aprotic solvent, 20% dextran sulfate, 600 mM NaCl, and 10 mM citric acid buffer pH 6.2. 55. The method according to claim 1, wherein the hybridization composition comprises one phase at room temperature. 56. The method according to claim 1, wherein the hybridization composition comprises multiple phases at room temperature. 57. The method according to claim 56, wherein the hybridization composition comprises two phases at room temperature. 58. The method according to claim 56, wherein the phases of the hybridization composition are mixed. 59. (canceled) 60. (canceled) 61. A hybridization composition comprising: at least one polar aprotic solvent in the range of 1% to 95% (v/v) selected from the group consisting of: wherein X is O and R1 is alkyldiyl, and wherein X is optional and if present, is chosen from O or S, wherein Z is optional and if present, is chosen from O or S, wherein A and B are independently O, N, S, part of the alkyldiyl, or a primary amine, wherein R is alkyldiyl, wherein Y is O, S or C; or at least one polar aprotic solvent selected from the group consisting of ethylene carbonate, propylene carbonate, formamide, sulfolane, and butyrolactone; and further comprising at least one component selected from the group consisting of buffering agents, salts, accelerating agents, chelating agents, detergents and blocking agents, wherein if an accelerating agent is present and if dextran sulfate is chosen as an accelerating agent, it is present at a concentration in the range 5% to 40% (v/v), and if a buffering agent is present, then the buffering agent is phosphate or citric acid buffer. 62. A method of using the composition of claim 61 in a hybridization assay without a denaturation step, or in a hybridization assay having a low temperature denaturation step, comprising combining the composition with a first and second nucleic acid sequence and heating and cooling the composition and nucleic acid sequences together.

This disclosure is directed to, inter alia, methods and compositions for hybridizing at least one molecule to a target. The invention may, for example, eliminate the use of, or reduce the dependence on formamide in hybridization. Compositions for use in the invention include an aqueous composition comprising at least one nucleic acid sequence and at least one polar aprotic solvent in an amount effective to denature double-stranded nucleotide sequences.1. A method of hybridizing nucleic acid sequences without a denaturation step, or using a low-temperature denaturation step comprising: providing a first nucleic acid sequence, providing a second nucleic acid sequence, providing a hybridization composition comprising an effective amount of at least one polar aprotic solvent, and combining the first and the second nucleic acid sequence and the hybridization composition for at least a time period sufficient to hybridize the first and second nucleic acid sequences, wherein the polar aprotic solvent is not dimethyl sulfoxide (DMSO). 2. A method of hybridizing nucleic acid sequences without a denaturation step, or using a low-temperature denaturation step comprising: providing a first nucleic acid sequence, and applying a hybridization composition comprising a second nucleic acid sequence and an effective amount of at least one polar aprotic solvent for at least a time period sufficient to hybridize the first and second nucleic acid sequences, wherein the polar aprotic solvent is not dimethyl sulfoxide (DMSO). 3. The method according to claim 1, wherein the first nucleic acid sequence is in a biological sample. 4. The method according to claim 3, wherein the biological sample is a cytology or histology sample. 5. The method according to claim 1, wherein the first nucleic acid sequence is a single stranded sequence and the second nucleic acid sequence is a double stranded sequence. 6. The method according to claim 1, wherein the first nucleic acid sequence is a double stranded sequence in a biological sample and the second nucleic acid sequence is a single stranded sequence. 7. The method according to claim 1, wherein the first and second nucleic acid sequences are double stranded sequences. 8. The method according to claim 1, wherein the first and second nucleic acid sequences are single stranded sequences. 9. The method according to claim 1, wherein a sufficient amount of energy to hybridize the first and second nucleic acids is provided. 10. The method according to claim 1, wherein a sufficient amount of energy to denature the first and second nucleic acids is provided. 11. The method according to claim 10, wherein the denaturation energy is provided to the first and second nucleic acid sequences in separate steps. 12. The method according to claim 10, wherein the denaturation energy is provided to the first and second nucleic acid sequences in a single step. 13. The method according to claim 9, wherein the energy is provided by heating the hybridization composition and nucleic acid sequence. 14. The method according to claim 13, wherein the heating step is performed by the use of microwaves, hot baths, hot plates, heat wire, peltier element, induction heating or heat lamps. 15. The method according to claim 1, wherein the denaturation temperature is 70° C. to 85° C. 16. The method according to claim 15, wherein the denaturation temperature is 60° C. to 75° C. 17. The method according to claim 15, wherein the denaturation temperature is 62° C., 67° C., 72° C., or 82° C. 18. The method according to claim 1, wherein the step of hybridizing includes the steps of heating and cooling the hybridization composition and nucleic acid sequences. 19. The method according to claim 1, wherein the step of hybridization takes less than 8 hours. 20. The method according to claim 19, wherein the step of hybridization takes less than 1 hour. 21. The method according to claim 20, wherein the step of hybridization takes less than 30 minutes. 22. The method according to claim 21, wherein the step of hybridization takes less than 15 minutes. 23. The method according to claim 22, wherein the step of hybridization takes less than 5 minutes. 24. The method according to claim 1, further comprising a blocking step. 25. The method according to claim 1, wherein the concentration of polar aprotic solvent in the hybridization composition is about 1% to 95% (v/v). 26. The method according to claim 25, wherein the concentration of polar aprotic solvent is 5% to 10% (v/v). 27. The method according to claim 25, wherein the concentration of polar aprotic solvent is 10% to 20% (v/v). 28. The method according to claim 25, wherein the concentration of polar aprotic solvent is 20% to 30% (v/v). 29. The method according to claim 1, wherein the polar aprotic solvent in the hybridization composition is non-toxic. 30. The method according to claim 1, with the proviso that the hybridization composition does not contain formamide. 31. The method according to claim 1, with the proviso that the hybridization composition contains less than 10% formamide. 32. The method according to claim 31, with the proviso that the hybridization composition contains less than 2% formamide. 33. The method according to claim 32, with the proviso that the hybridization composition contains less than 1% formamide. 34. The method according to claim 1, wherein the polar aprotic solvent in the hybridization composition has lactone, sulfone, nitrile, sulfite, and/or carbonate functionality. 35. The method according to claim 1, wherein the polar aprotic solvent in the hybridization composition has a dispersion solubility parameter between 17.7 to 22.0 MPa1/2, a polar solubility parameter between 13 to 23 MPa1 2, and a hydrogen bonding solubility parameter between 3 to 13 MPa. 36. The method according to claim 1, wherein the polar aprotic solvent in the hybridization composition has a cyclic base structure. 37. The method according to claim 1, wherein the polar aprotic solvent in the hybridization composition is selected from the group consisting of: wherein X is O and R1 is alkyldiyl, and wherein X is optional and if present, is chosen from O or S, wherein Z is optional and if present, is chosen from O or S, wherein A and B are independently O, N, S, part of the alkyldiyl, or a primary amine, wherein R is alkyldiyl, and wherein Y is O, S or C. 38. The method according to claim 1, wherein the polar aprotic solvent in the hybridization composition is acetanilide, acetonitrile, N-acetyl pyrrolidone, 4-amino pyridine, benzamide, benzimidazole, 1,2,3-benzotriazole, butadienedioxide, 2,3-butylene carbonate, γ-butyrolactone, caprolactone (epsilon), chloro maleic anhydride, 2-chlorocyclohexanone, chloroethylene carbonate, chloronitromethane, citraconic anhydride, crotonlactone, 5-cyano-2-thiouracil, cyclopropylnitrile, dimethyl sulfate, dimethyl sulfone, 1,3-dimethyl-5-tetrazole, 1,5-dimethyl tetrazole, 1,2-dinitrobenzene, 2,4-dinitrotoluene, dipheynyl sulfone, 1,2-dinitrobenzene, 2,4-dinitrotoluene, dipheynyl sulfone, epsilon-caprolactam, ethanesulfonylchloride, ethyl ethyl phosphinate, N-ethyl tetrazole, ethylene carbonate, ethylene trithiocarbonate, ethylene glycol sulfate, glycol sulfite, furfural, 2-furonitrile, 2-imidazole, isatin, isoxazole, malononitrile, 4-methoxy benzonitrile, 1-methoxy-2-nitrobenzene, methyl alpha bromo tetronate, 1-methyl imidazole, N-methyl imidazole, 3-methyl isoxazole, N-methyl morpholine-N-oxide, methyl phenyl sulfone, N-methylpyrrolidinone, methyl sulfolane, methyl-4-toluenesulfonate, 3-nitroaniline, nitrobenzimidazole, 2-nitrofuran, 1-nitroso-2-pyrrolidinone, 2-nitrothiophene, 2-oxazolidinone, 9,10-phenanthrenequinone, N-phenyl sydnone, phthalic anhydride, picolinonitrile (2-cyanopyridine), 1,3-propane sultone, β-propiolactone, propylene carbonate, 4H-pyran-4-thione, 4H-pyran-4-one (γ-pyrone), pyridazine, 2-pyrrolidone, saccharin, succinonitrile, sulfanilamide, sulfolane, 2,2,6,6-tetrachlorocyclohexanone, tetrahydrothiapyran oxide, tetramethylene sulfone (sulfolane), thiazole, 2-thiouracil, 3,3,3-trichloro propene, 1,1,2-trichloro propene, 1,2,3-trichloro propene, trimethylene sulfide-dioxide, trimethylene sulfite, N-formyl piperidine, N-ethyl-2-pyrrolidone, N-methyl-2-pyrrolidone, delta-valerolactam (2-piperidone), gamma valerolactone, vinylene carbonate, tetrahydrothiophene 1-oxide (tetramethylene sulfoxide), butadiene sulfone (sulfolene), or cyclopentanone. 39. The method according to claims claim 1, wherein the polar aprotic solvent in the hybridization composition is: 40. The method according to claim 1, wherein the polar aprotic solvent in the hybridization composition is: 41. The method according to claim 1, wherein the polar aprotic solvent in the hybridization composition is: 42. The method according to claim 1, wherein the polar aprotic solvent in the hybridization composition is ethylene carbonate, sulfolane, gamma-butyrolactone, or propylene carbonate. 43. The method according to claim 1, wherein the polar aprotic solvent in the hybridization composition is selected from the group consisting of ethylene carbonate, sulfolane, gamma-butyrolactone, propylene carbonate, ethylene trithiocarbonate, glycol sulfite/ethylene sulfite, delta-valerolactam (2-piperidone), and tetrahydrothiophene 1-oxide. 44. The method according to claim 1, wherein the hybridization composition further comprises at least one additional component selected from the group consisting of: buffering agents, salts, accelerating agents, chelating agents, detergents, and blocking agents. 45. The method according to claim 44, wherein the accelerating agent is dextran sulfate and the salts are NaCl and/or phosphate buffer. 46. The method according to claim 45, wherein the dextran sulfate is present at a concentration of 5% to 40%, the NaCl is present at a concentration of 0 mM to 1200 mM, and/or the phosphate buffer is present at a concentration of 0 mM to 50 mM. 47. The method according to claim 46, wherein the dextran sulfate is present at a concentration of 10% to 30%, the NaCl is present at a concentration of 300 mM to 600 mM, and/or the phosphate buffer is present at a concentration of 5 mM to 20 mM. 48. The method according to claim 44, wherein the accelerating agent is formamide, DMSO, glycerol, propylene glycol, 1,2-propanediol, diethylene glycol, ethylene glycol, glycol, or 1,3 propanediol, and wherein the buffering agent is citric acid buffer. 49. The method according to claim 48, wherein the accelerating agent is formamide and the formamide is present at a concentration of 0.1-5%, or wherein the accelerating agent is DMSO and the DMSO is present at a concentration of 0.01% to 10%, or wherein the accelerating agent is glycerol, propylene glycol, 1,2-propanediol, diethylene glycol, ethylene glycol, glycol, or 1,3 propanediol-ace present at a concentration of 0.1% to 10%, and wherein the citric acid buffer is present at a concentration of 1 mM to 50 mM. 50. The method according to claim 44, wherein the blocking agent is total human DNA, herring sperm DNA, salmon sperm DNA, or calf thymus DNA. 51. The method according to claim 50, wherein the total human DNA, herring sperm DNA, salmon sperm DNA, or calf thymus DNA is present at a concentration of 0.01 to 10 μg/μL. 52. The method according to claim 44, wherein the hybridization composition comprises 40% of at least one polar aprotic solvent, 10% dextran sulfate, 300 mM NaCl, and 5 mM phosphate buffer. 53. The method according to claim 44, wherein the hybridization composition comprises 15% of at least one polar aprotic solvent, 20% dextran sulfate, 600 mM NaCl, and 10 mM phosphate buffer. 54. The method according to claim 44, wherein the hybridization composition comprises 15% of at least one polar aprotic solvent, 20% dextran sulfate, 600 mM NaCl, and 10 mM citric acid buffer pH 6.2. 55. The method according to claim 1, wherein the hybridization composition comprises one phase at room temperature. 56. The method according to claim 1, wherein the hybridization composition comprises multiple phases at room temperature. 57. The method according to claim 56, wherein the hybridization composition comprises two phases at room temperature. 58. The method according to claim 56, wherein the phases of the hybridization composition are mixed. 59. (canceled) 60. (canceled) 61. A hybridization composition comprising: at least one polar aprotic solvent in the range of 1% to 95% (v/v) selected from the group consisting of: wherein X is O and R1 is alkyldiyl, and wherein X is optional and if present, is chosen from O or S, wherein Z is optional and if present, is chosen from O or S, wherein A and B are independently O, N, S, part of the alkyldiyl, or a primary amine, wherein R is alkyldiyl, wherein Y is O, S or C; or at least one polar aprotic solvent selected from the group consisting of ethylene carbonate, propylene carbonate, formamide, sulfolane, and butyrolactone; and further comprising at least one component selected from the group consisting of buffering agents, salts, accelerating agents, chelating agents, detergents and blocking agents, wherein if an accelerating agent is present and if dextran sulfate is chosen as an accelerating agent, it is present at a concentration in the range 5% to 40% (v/v), and if a buffering agent is present, then the buffering agent is phosphate or citric acid buffer. 62. A method of using the composition of claim 61 in a hybridization assay without a denaturation step, or in a hybridization assay having a low temperature denaturation step, comprising combining the composition with a first and second nucleic acid sequence and heating and cooling the composition and nucleic acid sequences together.

In a process for preparing an esterified cellulose ether a cellulose ether is esterified with (i) an aliphatic monocarboxylic acid anhydride or (ii) a dicarboxylic acid anhydride or (iii) a combination of an aliphatic monocarboxylic acid anhydride and a dicarboxylic acid anhydride in the presence of an alkali metal carboxylate and an aliphatic carboxylic acid, wherein the molar ratio [alkali metal carboxylate/anhydroglucose units of cellulose ether] is not more than [1.20/1] and the molar ratio [aliphatic carboxylic acid/anhydroglucose units of cellulose ether] is from [3.55/1] to [9.0/1].

1. A process for preparing an esterified cellulose ether wherein a cellulose ether is esterified with (i) an aliphatic monocarboxylic acid anhydride or (ii) a dicarboxylic acid anhydride or (iii) a combination of an aliphatic monocarboxylic acid anhydride and a dicarboxylic acid anhydride in the presence of an alkali metal carboxylate and an aliphatic carboxylic acid, wherein the molar ratio [alkali metal carboxylate/anhydroglucose units of cellulose ether] is from [0.30/1] to [1.00/1], the molar ratio [aliphatic carboxylic acid/anhydroglucose units of cellulose ether] is from [3.55/1] to [9.0/1] and the cellulose ether is a hydroxyalkyl alkylcellulose. 2. The process of claim 1 wherein the molar ratio [aliphatic carboxylic acid/anhydroglucose units of cellulose ether] is from [3.8/1] to [8.0/1]. 3. The process of claim 2 wherein the molar ratio [aliphatic carboxylic acid/anhydroglucose units of cellulose ether] is from [4.5/1] to [ 6.0/1]. 4. The process of claim 1 wherein the molar ratio [alkali metal carboxylate/anhydroglucose units of cellulose ether] is from [0.35/1] to [0.90/1]. 5. The process of claim 4 wherein the molar ratio [alkali metal carboxylate/anhydroglucose units of cellulose ether] is from [0.50/1] to [0.80/1]. 6. The process of claim 1 wherein the cellulose ether has a viscosity of from 2.4 to 200 mPa·s, measured as a 2 weight-% solution in water at 20° C. according to ASTM D2363-79 (Reapproved 2006). 7. The process of claim 1 wherein the cellulose ether is hydroxypropyl methylcellulose. 8. The process of claim 1 wherein the cellulose ether is esterified with a combination of an aliphatic monocarboxylic acid anhydride and a dicarboxylic acid anhydride. 9. The process of claim 1 wherein the cellulose ether is esterified with (ii) succinic anhydride or phthalic anhydride or with (iii) succinic anhydride or phthalic anhydride in combination with an aliphatic monocarboxylic acid anhydride selected from the group consisting of acetic anhydride, butyric anhydride and propionic anhydride. 10. The process of claim 9 wherein hydroxypropyl methylcellulose is esterified with succinic anhydride and acetic anhydride to produce hydroxypropyl methyl cellulose acetate succinate. 11. The process of claim 1 wherein the produced esterified cellulose a weight average molecular weight Mw of from 40,000 to 700,000 Dalton. 12. The process of claim 1 wherein the weight average molecular weight Mw of the esterified cellulose ether is varied by varying the molar ratio [aliphatic carboxylic acid/anhydroglucose units of cellulose ether]. 13. The process of claim 1 wherein the weight average molecular weight Mw of the esterified cellulose ether is varied by varying the molar ratio [alkali metal carboxylate/anhydroglucose units of cellulose ether]. 14. The process of claim 2 wherein the molar ratio [alkali metal carboxylate/anhydroglucose units of cellulose ether] is from [0.50/1] to [0.80/1]. 15. The process of claim 14 wherein hydroxypropyl methylcellulose is esterified with succinic anhydride and acetic anhydride to produce hydroxypropyl methyl cellulose acetate succinate. 16. The process of claim 15 wherein the produced hydroxypropyl methyl cellulose acetate succinate has a weight average molecular weight Mw of from 40,000 to 700,000 Dalton.

In a process for preparing an esterified cellulose ether a cellulose ether is esterified with (i) an aliphatic monocarboxylic acid anhydride or (ii) a dicarboxylic acid anhydride or (iii) a combination of an aliphatic monocarboxylic acid anhydride and a dicarboxylic acid anhydride in the presence of an alkali metal carboxylate and an aliphatic carboxylic acid, wherein the molar ratio [alkali metal carboxylate/anhydroglucose units of cellulose ether] is not more than [1.20/1] and the molar ratio [aliphatic carboxylic acid/anhydroglucose units of cellulose ether] is from [3.55/1] to [9.0/1].1. A process for preparing an esterified cellulose ether wherein a cellulose ether is esterified with (i) an aliphatic monocarboxylic acid anhydride or (ii) a dicarboxylic acid anhydride or (iii) a combination of an aliphatic monocarboxylic acid anhydride and a dicarboxylic acid anhydride in the presence of an alkali metal carboxylate and an aliphatic carboxylic acid, wherein the molar ratio [alkali metal carboxylate/anhydroglucose units of cellulose ether] is from [0.30/1] to [1.00/1], the molar ratio [aliphatic carboxylic acid/anhydroglucose units of cellulose ether] is from [3.55/1] to [9.0/1] and the cellulose ether is a hydroxyalkyl alkylcellulose. 2. The process of claim 1 wherein the molar ratio [aliphatic carboxylic acid/anhydroglucose units of cellulose ether] is from [3.8/1] to [8.0/1]. 3. The process of claim 2 wherein the molar ratio [aliphatic carboxylic acid/anhydroglucose units of cellulose ether] is from [4.5/1] to [ 6.0/1]. 4. The process of claim 1 wherein the molar ratio [alkali metal carboxylate/anhydroglucose units of cellulose ether] is from [0.35/1] to [0.90/1]. 5. The process of claim 4 wherein the molar ratio [alkali metal carboxylate/anhydroglucose units of cellulose ether] is from [0.50/1] to [0.80/1]. 6. The process of claim 1 wherein the cellulose ether has a viscosity of from 2.4 to 200 mPa·s, measured as a 2 weight-% solution in water at 20° C. according to ASTM D2363-79 (Reapproved 2006). 7. The process of claim 1 wherein the cellulose ether is hydroxypropyl methylcellulose. 8. The process of claim 1 wherein the cellulose ether is esterified with a combination of an aliphatic monocarboxylic acid anhydride and a dicarboxylic acid anhydride. 9. The process of claim 1 wherein the cellulose ether is esterified with (ii) succinic anhydride or phthalic anhydride or with (iii) succinic anhydride or phthalic anhydride in combination with an aliphatic monocarboxylic acid anhydride selected from the group consisting of acetic anhydride, butyric anhydride and propionic anhydride. 10. The process of claim 9 wherein hydroxypropyl methylcellulose is esterified with succinic anhydride and acetic anhydride to produce hydroxypropyl methyl cellulose acetate succinate. 11. The process of claim 1 wherein the produced esterified cellulose a weight average molecular weight Mw of from 40,000 to 700,000 Dalton. 12. The process of claim 1 wherein the weight average molecular weight Mw of the esterified cellulose ether is varied by varying the molar ratio [aliphatic carboxylic acid/anhydroglucose units of cellulose ether]. 13. The process of claim 1 wherein the weight average molecular weight Mw of the esterified cellulose ether is varied by varying the molar ratio [alkali metal carboxylate/anhydroglucose units of cellulose ether]. 14. The process of claim 2 wherein the molar ratio [alkali metal carboxylate/anhydroglucose units of cellulose ether] is from [0.50/1] to [0.80/1]. 15. The process of claim 14 wherein hydroxypropyl methylcellulose is esterified with succinic anhydride and acetic anhydride to produce hydroxypropyl methyl cellulose acetate succinate. 16. The process of claim 15 wherein the produced hydroxypropyl methyl cellulose acetate succinate has a weight average molecular weight Mw of from 40,000 to 700,000 Dalton.

The presently disclosed subject matter relates to nitric oxide-releasing particles for delivering nitric oxide, and their use in biomedical and pharmaceutical applications.

1. A nitric oxide-releasing particle, the nitric oxide-releasing particle comprising a nitric oxide donor and having a total releasable nitric oxide storage of at least 1.2 μmol of NO per milligram of the nitric oxide releasing particle. 2. The nitric oxide releasing particle of claim 1, wherein the nitric oxide-releasing particle has a total releasable nitric oxide storage in a range of 1.2 μmol to 36 μmol of NO per milligram of the nitric oxide releasing particle. 3. The nitric oxide-releasing particle of claim 1, wherein the nitric oxide-releasing particle has a total releasable nitric oxide storage in a range of 1.2 μmol to 10 μmol of NO per milligram of the nitric oxide releasing particle. 4. The nitric oxide-releasing particle of claim 1, wherein the nitric oxide-releasing particle comprises a co-condensed silica network. 5. The nitric oxide-releasing particle of claim 1, wherein the nitric oxide-releasing particle comprises a dendritic network. 6. The nitric oxide-releasing particle of claim 4, wherein the dendritic network is hyperbranched. 7. The nitric oxide-releasing particle of claim 1, further comprising one or more chemical moieties selected from the group consisting of: (a) a moiety that modulates nitric oxide release kinetics; (b) a moiety that affects biocompatibility of the particle; (c) a moiety that affects biodistribution of the particle; (d) a moiety that provides for targeted delivery of the particle; (e) a moiety that imparts an ability to image or track the particle; (f) a moiety that affects solubility of the particle, (g) a therapeutic agent; and (h) a combination thereof. 8. The nitric oxide-releasing particle of claim 1, wherein the nitric releasing particle comprises an organic linker selected from the group consisting of: (a) a labile linker responsive to changes in pH; (b) a labile linker sensitive to electromagnetic radiation; (c) a labile linker susceptible to degradation by enzymatic action; (d) a hydrophobic linker; (e) an amphiphilic linker; and (f) a combination thereof. 9. The nitric oxide-releasing particle of claim 8, wherein the linker comprises a functional group capable of conferring an on/off state of nitric oxide release to the nitric oxide-releasing particle, further wherein the functional group is selected from the group consisting of an ester, a hydrazone, an acetal, a thiopropionate, a photolabile moiety, and an amino acid sequence subject to enzymatic degradation. 10. The nitric oxide-releasing particle of claim 1, comprising a moiety capable of delivering the nitric oxide-releasing particle to a target. 11. The nitric oxide-releasing particle of claim 10, wherein the target is selected from the group consisting of a cell, a tissue, and an organ. 12. The nitric oxide-releasing particle of claim 11, wherein the cell is a cancer cell. 13. The nitric oxide-releasing particle of claim 10, wherein the moiety capable of delivering the nitric oxide-releasing particle to a target is selected from the group consisting of a protein responsible for antibody/antigen interaction, folic acid, guanidine, transferrin, a hormone, a carbohydrate, a peptide containing the amino acid sequence RGD, and a TAT peptide. 14. The nitric oxide-releasing particle of claim 10, comprising a moiety selected from the group consisting of a (poly)ethyleneoxide, a (poly)urethane, an N-(2-hydroxypropyl), methacrylamide copolymer, lactide/glycolide copolymers (e.g., PLGA), a sugar, a fluorescent moiety, an organic dye, an MR1 contrast agent, a thiol, a methyl-terminated alkyl chain, an antibiotic, an anti-cancer therapeutic, a sulfonate, a carboxylate, a phosphate, a cationic amine, a quaternary amine, and combinations thereof 15. The nitric oxide-releasing particle of claim 1, wherein the particle is a nanoparticle or a microparticle. 16. The nitric oxide-releasing particle of claim 15, wherein the particle is a nanoparticle. 17. The nitric oxide-releasing particle of claim 1, wherein the nitric oxide donor is selected from the group consisting of a diazeniumdiolate, a nitrosamine, a hydroxyl nitrosamine, a nitrosothiol, a hydroxyl amine, a hydroxyurea, and combination thereof. 18. The nitric oxide-releasing particle of claim 1, wherein the nitric oxide donor is covalently bound to the nitric oxide-releasing particle. 19. The nitric oxide-releasing particle of claim 1, wherein the nitric oxide donor is encapsulated in the nitric oxide-releasing particle. 20. The nitric oxide-releasing particle of claim 1, wherein the nitric oxide donor is associated with the nitric oxide-releasing particle via non-covalent interactions selected from the group consisting of Van der Waals interactions, electrostatic interactions, hydrogen bonding, and combinations thereof. 21. A method of delivering nitric oxide to a subject, the method comprising: (a) providing a nitric oxide-releasing particle comprising a nitric oxide donor and having a total nitric oxide release in a range of 1.2 μmol to 36 μmol of NO per milligram of the nitric oxide releasing particle; and (b) administering an effective amount of the nitric oxide-releasing particle to the subject. 22. The method of claim 21, wherein the nitric oxide-releasing particle comprises a co-condensed silica network. 23. The method of claim 21, wherein the nitric oxide-releasing particle comprises a dendritic network. 24. The method of claim 23, wherein the dendritic network is hyperbranched. 25. The method of claim 21, wherein the nitric-oxide releasing particle further comprises one or more chemical moieties selected from the group consisting of: (a) a moiety that modulates nitric oxide release kinetics; (b) a moiety that affects biocompatibility of the particle; (c) a moiety that affects biodistribution of the particle; (d) a moiety that provides for targeted delivery of the particle; (e) a moiety that imparts an ability to image or track the particle; (f) a moiety that affects solubility of the particle, (g) a therapeutic agent; and (h) a combination thereof. 26. The method of claim 21, wherein the nitric oxide releasing particle comprises an organic linker selected from the group consisting of: (a) a labile linker responsive to changes in pH; (b) a labile linker sensitive to electromagnetic radiation; (c) a labile linker susceptible to degradation by enzymatic action; (d) a hydrophobic linker; (e) an amphiphilic linker; and (f) a combination thereof. 27. The method of claim 26, wherein the linker comprises a functional group capable of conferring an on/off state of nitric oxide release to the nitric oxide-releasing particle, further wherein the functional group is selected from the group consisting of an ester, a hydrazone, an acetal, a thiopropionate, a photolabile moiety, and an amino acid sequence subject to enzymatic degradation. 28. The method of claim 21, wherein the nitric oxide-releasing particle comprises a moiety capable of delivering the nitric oxide-releasing particle to a target. 29. The method of claim 28, wherein the target is selected from the group consisting of a cell, a tissue, and an organ. 30. The method of claim 29, wherein the cell is a cancer cell. 31. The method of claim 28, wherein the moiety capable of delivering the nitric oxide-releasing particle to a target is selected from the group consisting of a protein responsible for antibody/antigen interaction, folic acid, guanidine, transferrin, a hormone, a carbohydrate, a peptide containing the amino acid sequence RGD, and a TAT peptide. 32. The method of claim 28, wherein the nitric oxide-releasing particle comprises a moiety selected from the group consisting of a (poly)ethyleneoxide, a (poly)urethane, an N-(2-hydroxypropyl), methacrylamide copolymer, lactide/glycolide copolymers (e.g. PLGA), a sugar, a fluorescent moiety, an organic dye, an MR1 contrast agent, a thiol, a methyl-terminated alkyl chain, an antibiotic, an anti-cancer therapeutic, a sulfonate, a carboxylate, a phosphate, a cationic amine, a quaternary amine, and combinations thereof. 33. The method of claim 21, wherein the nitric oxide-releasing particle is a nanoparticle or a microparticle. 34. The method of claim 33, wherein the nitric oxide-releasing particle is a nanoparticle. 35. The nitric oxide-releasing particle of claim 21, wherein the nitric oxide donor is selected from the group consisting of a diazeniumdiolate, a nitrosamine, a hydroxyl nitrosamine, a nitrosothiol, a hydroxyl amine, a hydroxyurea, and combination thereof. 36. The method of claim 21, wherein the nitric oxide donor is covalently bound to the nitric oxide-releasing particle. 37. The method of claim 21, wherein the nitric oxide donor is encapsulated in the nitric oxide-releasing particle. 38. The method of claim 21, wherein the nitric oxide donor is associated with the nitric oxide-releasing particle via non-covalent interactions selected from the group consisting of Van der Waals interactions, electrostatic interactions, hydrogen bonding, and combinations thereof. 39. A method of treating a disease state in a subject in need of treatment thereof, the method comprising: (a) providing a nitric oxide-releasing particle comprising a nitric oxide donor and having a total nitric oxide release in a range of 1.2 μmol to 36 μmol of NO per milligram of the nitric oxide releasing particle; and (b) administering an effective amount of the nitric oxide-releasing particle to the subject. 40. The method of claim 39, wherein the disease state is selected from the group consisting of a cancer, a cardiovascular disease, a microbial infection; platelet aggregation and platelet adhesion caused by the exposure of blood to a medical device; pathological conditions resulting from abnormal cell proliferation; transplantation rejections, autoimmune diseases, inflammation, vascular diseases; scar tissue; wound contraction, restenosis, pain, fever, gastrointestinal disorders, respiratory disorders, sexual dysfunctions, and sexually transmitted diseases. 41. The method of claim 39, further wherein the nitric oxide-releasing particle comprises a targeting moiety capable of directing the delivery of the particle to a target in the subject, said target comprising a cell, a tissue or an organ. 42. A pharmaceutical formulation comprising: (a) a nitric oxide-releasing particle comprising a nitric oxide donor and having a total releasable nitric oxide storage in a range of 1.2 μmol to 36 μmol of NO per milligram of the nitric oxide releasing particle; and (b) a pharmacuetically acceptable carrier. 43. The formulation of claim 42, wherein the formulation is selected from the group consisting of an oral formulation, an intraveneous formulation, and a topical formulation. 44. A nitric oxide-releasing polymeric film comprising an organic polymer and a nitric oxide-releasing particle, said nitric oxide-releasing particle comprising a nitric oxide donor and having a total releasable nitric oxide storage in a range of 1.2 μmol to 36 μmol of NO per milligram of the nitric oxide releasing particle. 45. The nitric oxide-releasing polymeric film of claim 44, wherein the organic polymer is a polyurethane. 46. A medical device comprising a nitric oxide-releasing polymeric film, wherein the nitric oxide-releasing film comprises an organic polymer and a nitric oxide-releasing particle, the nitric oxide-releasing particle comprising a nitric oxide donor and having a total releasable nitric oxide storage in a range of 1.2 μmol to 36 μmol of NO per milligram of the nitric oxide releasing particle. 47. The medical device of claim 46, wherein one or more surface of the medical device is coated with the nitric oxide-releasing film. 48. The medical device of claim 46, wherein the medical device is selected from the group comprising arterial stents, guide wires, catheters, trocar needles, bone anchors, bone screws, protective platings, hip and joint replacements, electrical leads, biosensors, probes, sutures, surgical drapes, wound dressings and bandages. 49. A nitric oxide-releasing particle that releases at least 1.2 μmol of NO per milligram of the nitric oxide releasing particle. 50. The nitric oxide-releasing particle of claim 49, wherein the particle releases nitric oxide in a range of from 1.2 μmol to 36 μmol of NO per milligram of the nitric oxide-releasing particle. 51. The nitric oxide-releasing particle of claim 49, wherein the particle is a nanoparticle or a microparticle. 52. A particle comprising means for releasably storing at least 1.2 μmol of NO per milligram of the particle. 53. The particle of claim 52, wherein the means for releasably storing comprises an NO donor. 54. The particle of claim 53, wherein the means for releasably storing further comprises one or more of a dendritic network or a co-condensed silica network. 55. The particle of claim 52, wherein the means for releasably storing comprises means for releasably storing nitric oxide in a range from 1.2 μmol to 36 μmol of NO per milligram of the particle. 56. The particle of claim 52, wherein the particle comprises a nanoparticle or a microparticle.

The presently disclosed subject matter relates to nitric oxide-releasing particles for delivering nitric oxide, and their use in biomedical and pharmaceutical applications.1. A nitric oxide-releasing particle, the nitric oxide-releasing particle comprising a nitric oxide donor and having a total releasable nitric oxide storage of at least 1.2 μmol of NO per milligram of the nitric oxide releasing particle. 2. The nitric oxide releasing particle of claim 1, wherein the nitric oxide-releasing particle has a total releasable nitric oxide storage in a range of 1.2 μmol to 36 μmol of NO per milligram of the nitric oxide releasing particle. 3. The nitric oxide-releasing particle of claim 1, wherein the nitric oxide-releasing particle has a total releasable nitric oxide storage in a range of 1.2 μmol to 10 μmol of NO per milligram of the nitric oxide releasing particle. 4. The nitric oxide-releasing particle of claim 1, wherein the nitric oxide-releasing particle comprises a co-condensed silica network. 5. The nitric oxide-releasing particle of claim 1, wherein the nitric oxide-releasing particle comprises a dendritic network. 6. The nitric oxide-releasing particle of claim 4, wherein the dendritic network is hyperbranched. 7. The nitric oxide-releasing particle of claim 1, further comprising one or more chemical moieties selected from the group consisting of: (a) a moiety that modulates nitric oxide release kinetics; (b) a moiety that affects biocompatibility of the particle; (c) a moiety that affects biodistribution of the particle; (d) a moiety that provides for targeted delivery of the particle; (e) a moiety that imparts an ability to image or track the particle; (f) a moiety that affects solubility of the particle, (g) a therapeutic agent; and (h) a combination thereof. 8. The nitric oxide-releasing particle of claim 1, wherein the nitric releasing particle comprises an organic linker selected from the group consisting of: (a) a labile linker responsive to changes in pH; (b) a labile linker sensitive to electromagnetic radiation; (c) a labile linker susceptible to degradation by enzymatic action; (d) a hydrophobic linker; (e) an amphiphilic linker; and (f) a combination thereof. 9. The nitric oxide-releasing particle of claim 8, wherein the linker comprises a functional group capable of conferring an on/off state of nitric oxide release to the nitric oxide-releasing particle, further wherein the functional group is selected from the group consisting of an ester, a hydrazone, an acetal, a thiopropionate, a photolabile moiety, and an amino acid sequence subject to enzymatic degradation. 10. The nitric oxide-releasing particle of claim 1, comprising a moiety capable of delivering the nitric oxide-releasing particle to a target. 11. The nitric oxide-releasing particle of claim 10, wherein the target is selected from the group consisting of a cell, a tissue, and an organ. 12. The nitric oxide-releasing particle of claim 11, wherein the cell is a cancer cell. 13. The nitric oxide-releasing particle of claim 10, wherein the moiety capable of delivering the nitric oxide-releasing particle to a target is selected from the group consisting of a protein responsible for antibody/antigen interaction, folic acid, guanidine, transferrin, a hormone, a carbohydrate, a peptide containing the amino acid sequence RGD, and a TAT peptide. 14. The nitric oxide-releasing particle of claim 10, comprising a moiety selected from the group consisting of a (poly)ethyleneoxide, a (poly)urethane, an N-(2-hydroxypropyl), methacrylamide copolymer, lactide/glycolide copolymers (e.g., PLGA), a sugar, a fluorescent moiety, an organic dye, an MR1 contrast agent, a thiol, a methyl-terminated alkyl chain, an antibiotic, an anti-cancer therapeutic, a sulfonate, a carboxylate, a phosphate, a cationic amine, a quaternary amine, and combinations thereof 15. The nitric oxide-releasing particle of claim 1, wherein the particle is a nanoparticle or a microparticle. 16. The nitric oxide-releasing particle of claim 15, wherein the particle is a nanoparticle. 17. The nitric oxide-releasing particle of claim 1, wherein the nitric oxide donor is selected from the group consisting of a diazeniumdiolate, a nitrosamine, a hydroxyl nitrosamine, a nitrosothiol, a hydroxyl amine, a hydroxyurea, and combination thereof. 18. The nitric oxide-releasing particle of claim 1, wherein the nitric oxide donor is covalently bound to the nitric oxide-releasing particle. 19. The nitric oxide-releasing particle of claim 1, wherein the nitric oxide donor is encapsulated in the nitric oxide-releasing particle. 20. The nitric oxide-releasing particle of claim 1, wherein the nitric oxide donor is associated with the nitric oxide-releasing particle via non-covalent interactions selected from the group consisting of Van der Waals interactions, electrostatic interactions, hydrogen bonding, and combinations thereof. 21. A method of delivering nitric oxide to a subject, the method comprising: (a) providing a nitric oxide-releasing particle comprising a nitric oxide donor and having a total nitric oxide release in a range of 1.2 μmol to 36 μmol of NO per milligram of the nitric oxide releasing particle; and (b) administering an effective amount of the nitric oxide-releasing particle to the subject. 22. The method of claim 21, wherein the nitric oxide-releasing particle comprises a co-condensed silica network. 23. The method of claim 21, wherein the nitric oxide-releasing particle comprises a dendritic network. 24. The method of claim 23, wherein the dendritic network is hyperbranched. 25. The method of claim 21, wherein the nitric-oxide releasing particle further comprises one or more chemical moieties selected from the group consisting of: (a) a moiety that modulates nitric oxide release kinetics; (b) a moiety that affects biocompatibility of the particle; (c) a moiety that affects biodistribution of the particle; (d) a moiety that provides for targeted delivery of the particle; (e) a moiety that imparts an ability to image or track the particle; (f) a moiety that affects solubility of the particle, (g) a therapeutic agent; and (h) a combination thereof. 26. The method of claim 21, wherein the nitric oxide releasing particle comprises an organic linker selected from the group consisting of: (a) a labile linker responsive to changes in pH; (b) a labile linker sensitive to electromagnetic radiation; (c) a labile linker susceptible to degradation by enzymatic action; (d) a hydrophobic linker; (e) an amphiphilic linker; and (f) a combination thereof. 27. The method of claim 26, wherein the linker comprises a functional group capable of conferring an on/off state of nitric oxide release to the nitric oxide-releasing particle, further wherein the functional group is selected from the group consisting of an ester, a hydrazone, an acetal, a thiopropionate, a photolabile moiety, and an amino acid sequence subject to enzymatic degradation. 28. The method of claim 21, wherein the nitric oxide-releasing particle comprises a moiety capable of delivering the nitric oxide-releasing particle to a target. 29. The method of claim 28, wherein the target is selected from the group consisting of a cell, a tissue, and an organ. 30. The method of claim 29, wherein the cell is a cancer cell. 31. The method of claim 28, wherein the moiety capable of delivering the nitric oxide-releasing particle to a target is selected from the group consisting of a protein responsible for antibody/antigen interaction, folic acid, guanidine, transferrin, a hormone, a carbohydrate, a peptide containing the amino acid sequence RGD, and a TAT peptide. 32. The method of claim 28, wherein the nitric oxide-releasing particle comprises a moiety selected from the group consisting of a (poly)ethyleneoxide, a (poly)urethane, an N-(2-hydroxypropyl), methacrylamide copolymer, lactide/glycolide copolymers (e.g. PLGA), a sugar, a fluorescent moiety, an organic dye, an MR1 contrast agent, a thiol, a methyl-terminated alkyl chain, an antibiotic, an anti-cancer therapeutic, a sulfonate, a carboxylate, a phosphate, a cationic amine, a quaternary amine, and combinations thereof. 33. The method of claim 21, wherein the nitric oxide-releasing particle is a nanoparticle or a microparticle. 34. The method of claim 33, wherein the nitric oxide-releasing particle is a nanoparticle. 35. The nitric oxide-releasing particle of claim 21, wherein the nitric oxide donor is selected from the group consisting of a diazeniumdiolate, a nitrosamine, a hydroxyl nitrosamine, a nitrosothiol, a hydroxyl amine, a hydroxyurea, and combination thereof. 36. The method of claim 21, wherein the nitric oxide donor is covalently bound to the nitric oxide-releasing particle. 37. The method of claim 21, wherein the nitric oxide donor is encapsulated in the nitric oxide-releasing particle. 38. The method of claim 21, wherein the nitric oxide donor is associated with the nitric oxide-releasing particle via non-covalent interactions selected from the group consisting of Van der Waals interactions, electrostatic interactions, hydrogen bonding, and combinations thereof. 39. A method of treating a disease state in a subject in need of treatment thereof, the method comprising: (a) providing a nitric oxide-releasing particle comprising a nitric oxide donor and having a total nitric oxide release in a range of 1.2 μmol to 36 μmol of NO per milligram of the nitric oxide releasing particle; and (b) administering an effective amount of the nitric oxide-releasing particle to the subject. 40. The method of claim 39, wherein the disease state is selected from the group consisting of a cancer, a cardiovascular disease, a microbial infection; platelet aggregation and platelet adhesion caused by the exposure of blood to a medical device; pathological conditions resulting from abnormal cell proliferation; transplantation rejections, autoimmune diseases, inflammation, vascular diseases; scar tissue; wound contraction, restenosis, pain, fever, gastrointestinal disorders, respiratory disorders, sexual dysfunctions, and sexually transmitted diseases. 41. The method of claim 39, further wherein the nitric oxide-releasing particle comprises a targeting moiety capable of directing the delivery of the particle to a target in the subject, said target comprising a cell, a tissue or an organ. 42. A pharmaceutical formulation comprising: (a) a nitric oxide-releasing particle comprising a nitric oxide donor and having a total releasable nitric oxide storage in a range of 1.2 μmol to 36 μmol of NO per milligram of the nitric oxide releasing particle; and (b) a pharmacuetically acceptable carrier. 43. The formulation of claim 42, wherein the formulation is selected from the group consisting of an oral formulation, an intraveneous formulation, and a topical formulation. 44. A nitric oxide-releasing polymeric film comprising an organic polymer and a nitric oxide-releasing particle, said nitric oxide-releasing particle comprising a nitric oxide donor and having a total releasable nitric oxide storage in a range of 1.2 μmol to 36 μmol of NO per milligram of the nitric oxide releasing particle. 45. The nitric oxide-releasing polymeric film of claim 44, wherein the organic polymer is a polyurethane. 46. A medical device comprising a nitric oxide-releasing polymeric film, wherein the nitric oxide-releasing film comprises an organic polymer and a nitric oxide-releasing particle, the nitric oxide-releasing particle comprising a nitric oxide donor and having a total releasable nitric oxide storage in a range of 1.2 μmol to 36 μmol of NO per milligram of the nitric oxide releasing particle. 47. The medical device of claim 46, wherein one or more surface of the medical device is coated with the nitric oxide-releasing film. 48. The medical device of claim 46, wherein the medical device is selected from the group comprising arterial stents, guide wires, catheters, trocar needles, bone anchors, bone screws, protective platings, hip and joint replacements, electrical leads, biosensors, probes, sutures, surgical drapes, wound dressings and bandages. 49. A nitric oxide-releasing particle that releases at least 1.2 μmol of NO per milligram of the nitric oxide releasing particle. 50. The nitric oxide-releasing particle of claim 49, wherein the particle releases nitric oxide in a range of from 1.2 μmol to 36 μmol of NO per milligram of the nitric oxide-releasing particle. 51. The nitric oxide-releasing particle of claim 49, wherein the particle is a nanoparticle or a microparticle. 52. A particle comprising means for releasably storing at least 1.2 μmol of NO per milligram of the particle. 53. The particle of claim 52, wherein the means for releasably storing comprises an NO donor. 54. The particle of claim 53, wherein the means for releasably storing further comprises one or more of a dendritic network or a co-condensed silica network. 55. The particle of claim 52, wherein the means for releasably storing comprises means for releasably storing nitric oxide in a range from 1.2 μmol to 36 μmol of NO per milligram of the particle. 56. The particle of claim 52, wherein the particle comprises a nanoparticle or a microparticle.

The invention provides a compound of formula (I): or a salt thereof, wherein R 1 -R 5 have any of the values described in the specification, as well as compositions comprising a compound of formula (I). The compounds are useful as RNA polymerase inhibitors and antibacterial agents.

1. A compound of formula I: wherein: R1 is one of aryl and heteroaryl, and optionally is substituted with one or more groups independently selected from halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NaRb; R2 is one of H, halo, hydroxy, carboxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, or —NRcRd, wherein any (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, and heteroaryl, and is optionally substituted with one or more halo, hydroxy, carboxy, cyano, nitro, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy or —NRcRd; R3 is (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NReRf; R4 is H, (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRgRh; R5 is H, (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRjRk; Ra and Rb are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl or heteroaryl(C1-C6)alkyl; or Ra and Rb together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Rc and Rd are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rc and Rd together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Re and Rf are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Re and Rf together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Rg and Rh are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rg and Rh together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; and Rj and Rk are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rj and Rk together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; or a salt thereof; provided that when R1 is phenyl, then at least one of R3, R4, and R5 is other than methyl or CH2CH═C(CH3)2; and provided that when R1 is phenyl, or when R1 is phenyl substituted with at least one of hydroxy, methoxy, or carboxy, then R4 is other than H. 2. The compound of claim 1, wherein R1 is one of aryl and heteroaryl, and optionally is substituted with one or more groups independently selected from halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRaRb. 3. The compound of claim 1 wherein R1 is phenyl substituted at the ortho, meta, or para position with halo, (C1-C6)alkoxy, (C1-C6)alkyl or (C1-C6)alkenyl. 4. The compound of claim 1, wherein R2 is H or methyl. 5. The compound of claim 1, wherein R3 and R4 are each independently one of (C1-C7)alkyl, (C2-C7)alkenyl, substituted (C1-C7)alkyl or substituted (C2-C7)alkenyl. 6. The compound of claim 1, wherein R5 is one of H, (C1-C7)alkyl, (C2-C7)alkenyl, substituted (C1-C7)alkyl or substituted (C2-C7)alkenyl. 7. The compound of claim 1, wherein R3 is (C3-C6)alkyl, which is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NReRf. 8. The compound of claim 1, wherein R4 is (C3-C6)alkyl, which is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRgRh. 9. The compound of claim 1, wherein R5 is H or (C3-C6)alkyl, which is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRjRk. 10. The compound of claim 1, wherein R1 is substituted with halo. 11. The compound of claim 1, wherein R1 is substituted with fluorine, chlorine, or bromine. 12. The compound of claim 1, wherein R1 is substituted with chlorine. 13. The compound of claim 1, wherein R1 is phenyl, which is optionally substituted with one or more groups independently selected from halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRaRb. 14. The compound of claim 1, wherein R1 is phenyl, which optionally is substituted in one or more of para or ortho positions with one or more groups independently selected from halo, methyl, trifluoromethyl, or methoxy. 15. The compound of claim 1, wherein R3 is propyl, butyl, pentyl, or isopentyl. 16. The compound of claim 1, wherein R4 is propyl, butyl, pentyl, or isopentyl. 17. The compound of claim 1, wherein R5 is H. 18. The compound of claim 1, wherein R5 is propyl, butyl, pentyl, or isopentyl. 19. The compound of claim 1 which is: or a salt thereof. 20. The compound of claim 1 which is: or a salt thereof. 21. A composition comprising a compound of formula I as described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 22. A method for inhibiting the growth of a bacterium comprising contacting the bacterium with a compound of formula I as described in claim 1, or a salt thereof. 23. A method for inhibiting a bacterial RNA polymerase comprising contacting the bacterial RNA polymerase with a compound of formula I as described in claim 1 or a salt thereof. 24. A method for treating a bacterial infection in a mammal comprising administering to the mammal an effective amount of a compound of formula I as described in claim 1, or a pharmaceutically acceptable salt thereof. 25-26. (canceled) 27. The method of claim 24, wherein the bacteria is selected from Mycobacterium tuberculosis, Staphylococcus aureus MSSA and MRSA, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Streptococcus pyogenes, Bacillus anthracis, Escherichia coli, Moraxella catarrhalis, and Francisella tularensis. 28-29. (canceled) 30. A composition comprising a compound of formula I: wherein: R1 is one of aryl and heteroaryl, and optionally is substituted with one or more groups independently selected from halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRaRb; R2 is one of H, halo, hydroxy, carboxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, or —NRcRd, wherein any (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, and heteroaryl, and is optionally substituted with one or more halo, hydroxy, carboxy, cyano, nitro, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy or —NRcRd; R3 is (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NReRf; R4 is H, (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRgRh; R5 is H, (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRjRk; Ra and Rb are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl or heteroaryl(C1-C6)alkyl; or Ra and Rb together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Rc and Rd are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rc and Rd together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Re and Rf are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Re and Rf together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Rg and Rh are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rg and Rh together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; and Rj and Rk are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rj and Rk together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 31. A method for inhibiting the growth of a bacterium comprising contacting the bacterium with a compound of formula I: wherein: R1 is one of aryl and heteroaryl, and optionally is substituted with one or more groups independently selected from halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRaRb; R2 is one of H, halo, hydroxy, carboxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, or —NRcRd, wherein any (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, and heteroaryl, and is optionally substituted with one or more halo, hydroxy, carboxy, cyano, nitro, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy or —NRcRd; R3 is (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NReRf; R4 is H, (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRgRh; R5 is H, (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRjRk; Ra and Rb are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl or heteroaryl(C1-C6)alkyl; or Ra and Rb together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Rc and Rd are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rc and Rd together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Re and Rf are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Re and Rf together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Rg and Rh are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rg and Rh together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; and Rj and Rk are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rj and Rk together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; or a salt thereof. 32. A method for inhibiting a bacterial RNA polymerase comprising contacting the bacterial RNA polymerase with a compound of formula I: wherein: R1 is one of aryl and heteroaryl, and optionally is substituted with one or more groups independently selected from halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRaRb; R2 is one of H, halo, hydroxy, carboxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, or —NRcRd, wherein any (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, and heteroaryl, and is optionally substituted with one or more halo, hydroxy, carboxy, cyano, nitro, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy or —NRcRd; R3 is (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NReRf; R4 is H, (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRgRh; R5 is H, (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRjRk; Ra and Rb are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl or heteroaryl(C1-C6)alkyl; or Ra and Rb together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Rc and Rd are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rc and Rd together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Re and Rf are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Re and Rf together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Rg and Rh are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rg and Rh together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; and Rj and Rk are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rj and Rk together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; or a salt thereof. 33. A method for treating a bacterial infection in a mammal comprising administering to the mammal an effective amount of a compound of formula I: wherein: R1 is one of aryl and heteroaryl, and optionally is substituted with one or more groups independently selected from halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRaRb; R2 is one of H, halo, hydroxy, carboxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, or —NRcRd, wherein any (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, and heteroaryl, and is optionally substituted with one or more halo, hydroxy, carboxy, cyano, nitro, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy or —NRcRd; R3 is (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NReRf; R4 is H, (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRgRh; R5 is H, (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRjRk; Ra and Rb are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl or heteroaryl(C1-C6)alkyl; or Ra and Rb together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Rc and Rd are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Re and Rd together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Re and Rf are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Re and Rf together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Rg and Rh are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rg and Rh together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; and Rj and Rk are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rj and Rk together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; or a pharmaceutically acceptable salt thereof. 34-35. (canceled) 36. The method of claim 33, wherein the bacteria is selected from Mycobacterium tuberculosis, Staphylococcus aureus MSSA and MRSA, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Streptococcus pyogenes, Bacillus anthracis, Escherichia coli, Moraxella catarrhalis, and Francisella tularensis. 37-38. (canceled)

The invention provides a compound of formula (I): or a salt thereof, wherein R 1 -R 5 have any of the values described in the specification, as well as compositions comprising a compound of formula (I). The compounds are useful as RNA polymerase inhibitors and antibacterial agents.1. A compound of formula I: wherein: R1 is one of aryl and heteroaryl, and optionally is substituted with one or more groups independently selected from halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NaRb; R2 is one of H, halo, hydroxy, carboxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, or —NRcRd, wherein any (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, and heteroaryl, and is optionally substituted with one or more halo, hydroxy, carboxy, cyano, nitro, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy or —NRcRd; R3 is (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NReRf; R4 is H, (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRgRh; R5 is H, (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRjRk; Ra and Rb are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl or heteroaryl(C1-C6)alkyl; or Ra and Rb together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Rc and Rd are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rc and Rd together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Re and Rf are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Re and Rf together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Rg and Rh are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rg and Rh together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; and Rj and Rk are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rj and Rk together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; or a salt thereof; provided that when R1 is phenyl, then at least one of R3, R4, and R5 is other than methyl or CH2CH═C(CH3)2; and provided that when R1 is phenyl, or when R1 is phenyl substituted with at least one of hydroxy, methoxy, or carboxy, then R4 is other than H. 2. The compound of claim 1, wherein R1 is one of aryl and heteroaryl, and optionally is substituted with one or more groups independently selected from halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRaRb. 3. The compound of claim 1 wherein R1 is phenyl substituted at the ortho, meta, or para position with halo, (C1-C6)alkoxy, (C1-C6)alkyl or (C1-C6)alkenyl. 4. The compound of claim 1, wherein R2 is H or methyl. 5. The compound of claim 1, wherein R3 and R4 are each independently one of (C1-C7)alkyl, (C2-C7)alkenyl, substituted (C1-C7)alkyl or substituted (C2-C7)alkenyl. 6. The compound of claim 1, wherein R5 is one of H, (C1-C7)alkyl, (C2-C7)alkenyl, substituted (C1-C7)alkyl or substituted (C2-C7)alkenyl. 7. The compound of claim 1, wherein R3 is (C3-C6)alkyl, which is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NReRf. 8. The compound of claim 1, wherein R4 is (C3-C6)alkyl, which is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRgRh. 9. The compound of claim 1, wherein R5 is H or (C3-C6)alkyl, which is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRjRk. 10. The compound of claim 1, wherein R1 is substituted with halo. 11. The compound of claim 1, wherein R1 is substituted with fluorine, chlorine, or bromine. 12. The compound of claim 1, wherein R1 is substituted with chlorine. 13. The compound of claim 1, wherein R1 is phenyl, which is optionally substituted with one or more groups independently selected from halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRaRb. 14. The compound of claim 1, wherein R1 is phenyl, which optionally is substituted in one or more of para or ortho positions with one or more groups independently selected from halo, methyl, trifluoromethyl, or methoxy. 15. The compound of claim 1, wherein R3 is propyl, butyl, pentyl, or isopentyl. 16. The compound of claim 1, wherein R4 is propyl, butyl, pentyl, or isopentyl. 17. The compound of claim 1, wherein R5 is H. 18. The compound of claim 1, wherein R5 is propyl, butyl, pentyl, or isopentyl. 19. The compound of claim 1 which is: or a salt thereof. 20. The compound of claim 1 which is: or a salt thereof. 21. A composition comprising a compound of formula I as described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 22. A method for inhibiting the growth of a bacterium comprising contacting the bacterium with a compound of formula I as described in claim 1, or a salt thereof. 23. A method for inhibiting a bacterial RNA polymerase comprising contacting the bacterial RNA polymerase with a compound of formula I as described in claim 1 or a salt thereof. 24. A method for treating a bacterial infection in a mammal comprising administering to the mammal an effective amount of a compound of formula I as described in claim 1, or a pharmaceutically acceptable salt thereof. 25-26. (canceled) 27. The method of claim 24, wherein the bacteria is selected from Mycobacterium tuberculosis, Staphylococcus aureus MSSA and MRSA, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Streptococcus pyogenes, Bacillus anthracis, Escherichia coli, Moraxella catarrhalis, and Francisella tularensis. 28-29. (canceled) 30. A composition comprising a compound of formula I: wherein: R1 is one of aryl and heteroaryl, and optionally is substituted with one or more groups independently selected from halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRaRb; R2 is one of H, halo, hydroxy, carboxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, or —NRcRd, wherein any (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, and heteroaryl, and is optionally substituted with one or more halo, hydroxy, carboxy, cyano, nitro, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy or —NRcRd; R3 is (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NReRf; R4 is H, (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRgRh; R5 is H, (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRjRk; Ra and Rb are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl or heteroaryl(C1-C6)alkyl; or Ra and Rb together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Rc and Rd are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rc and Rd together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Re and Rf are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Re and Rf together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Rg and Rh are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rg and Rh together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; and Rj and Rk are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rj and Rk together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. 31. A method for inhibiting the growth of a bacterium comprising contacting the bacterium with a compound of formula I: wherein: R1 is one of aryl and heteroaryl, and optionally is substituted with one or more groups independently selected from halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRaRb; R2 is one of H, halo, hydroxy, carboxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, or —NRcRd, wherein any (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, and heteroaryl, and is optionally substituted with one or more halo, hydroxy, carboxy, cyano, nitro, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy or —NRcRd; R3 is (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NReRf; R4 is H, (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRgRh; R5 is H, (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRjRk; Ra and Rb are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl or heteroaryl(C1-C6)alkyl; or Ra and Rb together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Rc and Rd are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rc and Rd together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Re and Rf are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Re and Rf together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Rg and Rh are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rg and Rh together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; and Rj and Rk are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rj and Rk together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; or a salt thereof. 32. A method for inhibiting a bacterial RNA polymerase comprising contacting the bacterial RNA polymerase with a compound of formula I: wherein: R1 is one of aryl and heteroaryl, and optionally is substituted with one or more groups independently selected from halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRaRb; R2 is one of H, halo, hydroxy, carboxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, or —NRcRd, wherein any (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, and heteroaryl, and is optionally substituted with one or more halo, hydroxy, carboxy, cyano, nitro, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy or —NRcRd; R3 is (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NReRf; R4 is H, (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRgRh; R5 is H, (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRjRk; Ra and Rb are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl or heteroaryl(C1-C6)alkyl; or Ra and Rb together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Rc and Rd are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rc and Rd together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Re and Rf are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Re and Rf together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Rg and Rh are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rg and Rh together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; and Rj and Rk are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rj and Rk together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; or a salt thereof. 33. A method for treating a bacterial infection in a mammal comprising administering to the mammal an effective amount of a compound of formula I: wherein: R1 is one of aryl and heteroaryl, and optionally is substituted with one or more groups independently selected from halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRaRb; R2 is one of H, halo, hydroxy, carboxy, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, or —NRcRd, wherein any (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, and heteroaryl, and is optionally substituted with one or more halo, hydroxy, carboxy, cyano, nitro, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy or —NRcRd; R3 is (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NReRf; R4 is H, (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRgRh; R5 is H, (C1-C7)alkyl or (C2-C7)alkenyl, which (C1-C7)alkyl or (C2-C7)alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NRjRk; Ra and Rb are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl or heteroaryl(C1-C6)alkyl; or Ra and Rb together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Rc and Rd are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Re and Rd together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Re and Rf are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Re and Rf together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; Rg and Rh are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rg and Rh together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; and Rj and Rk are each independently H, (C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; or Rj and Rk together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; or a pharmaceutically acceptable salt thereof. 34-35. (canceled) 36. The method of claim 33, wherein the bacteria is selected from Mycobacterium tuberculosis, Staphylococcus aureus MSSA and MRSA, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Streptococcus pyogenes, Bacillus anthracis, Escherichia coli, Moraxella catarrhalis, and Francisella tularensis. 37-38. (canceled)

Described herein are abuse deterrent controlled release oral pharmaceutical compositions comprising and methods for making the same. In particular, an abuse deterrent controlled release oral pharmaceutical composition comprising a soft capsule and an abuse deterrent controlled release matrix comprising an active pharmaceutical ingredient are described.

1. An abuse deterrent oral pharmaceutical composition comprising a tamper resistant controlled release matrix comprising: (a) at least one lipid or lipophilic vehicle; (b) at least one organogelator; (c) at least one hydrophilic polymer; (d) at least one hydrophilic vehicle; and (e) at least one active pharmaceutical ingredient; wherein the matrix is resistant to tampering and is encapsulated in a soft capsule shell. 2. The composition of claim 1, wherein the tamper resistant controlled release matrix further comprises at least one antioxidant. 3. (canceled) 4. The composition of claim 1, wherein the lipid or lipophilic vehicle comprises about 30% to about 85% of the total matrix mass. 5. The composition of claim 1, wherein the at least one organogelator comprises from about 0.5% to about 25% of the total matrix mass. 6. The composition of claim 1, wherein the at least one hydrophilic polymer comprises about 1% to about 30% of the total matrix mass. 7. The composition of claim 1, wherein the at least one hydrophilic vehicle comprises about 2% to about 40% of the total matrix mass. 8. The composition of claim 1, wherein the at least one active pharmaceutical ingredient comprises about 1% to about 35% of the total matrix mass. 9. The composition of claim 2, wherein the at least one anti-oxidant comprises about 0.05% to about 0.5% of the total matrix mass. 10. (canceled) 11. The composition of claim 1, wherein the ratio of the active pharmaceutical ingredient percent mass to the matrix percent mass is about 1:100 to about 1:3. 12-13. (canceled) 14. The composition of claim 1, wherein the liquid lipid or lipophilic vehicle comprises: olive oil, sunflower oil, canola oil, palmitoleic acid, oleic acid, myristoleic acid, linoleic acid, arachidonic acid, paraffin oil, or mineral oil. 15-18. (canceled) 19. The composition of claim 1, wherein the organogelator forms a gel at a temperature of about 90° C. to about 120° C. 20. (canceled) 21. The composition of claim 1, wherein the organogelator comprises ethyl cellulose having a viscosity value of about 3 cP to about 20 cP. 22-24. (canceled) 25. The composition of claim 1, wherein the hydrophilic polymer comprises methylcellulose, hydroxypropylmethyl cellulose, a mixture of hydroxypropylmethyl cellulose and methylcellulose, polymethylmethacrylate, polyvinyl pyrrolidone, or a combination thereof. 26. The composition of claim 1, wherein the hydrophilic polymer comprises methylcellulose or hydroxypropylmethyl cellulose. 27. (canceled) 28. The composition of claim 26, wherein methylcellulose has a viscosity value of about 50 to about 4,000 cP and hydroxypropylmethyl cellulose has a viscosity value of about 50 to about 100,000 cP. 29. (canceled) 30. The composition of claim 2, wherein the anti-oxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), or a combination thereof. 31. (canceled) 32. The composition of claim 1, wherein the active pharmaceutical ingredient comprises at least one of: hydrocodone, morphine, morphine analogues, or morphine antagonists, tapentadol, codeine, morphine, methadone, fentanyl and analogs, hydrocodone hydrochloride, hydrocodone bitartrate, hydromorphone, oxymorphone, oxycodone, meperidine, propoxyphene, flunitrazepam, barbiturates, amytal, nembutal, seconal, phenobarbital; benzodiazepines, zolpidem, zaleplon, eszopiclone, amphetamines, methylphenidate, or a combination thereof. 33. The composition of claim 1, wherein the active pharmaceutical ingredient comprises hydrocodone or oxycodone. 34-41. (canceled) 42. The composition of claim 1, wherein the tamper resistant controlled release matrix comprises: (a) soybean oil; (b) ethyl cellulose; (e) hydroxypropylmethyl cellulose; (f) polyethylene glycol; (g) hydrocodone or oxycodone; and optionally (h) BHT; and (i) BHA. 43. The composition of claim 42, wherein the tamper resistant controlled release matrix comprises: (a) about 30% to about 70% soybean oil; (b) about 1% to about 7% Ethocel™ 20 cP; (c) about 1% to about 30% Methocel™ K100M; (d) about 2% to about 40% polyethylene glycol 400; (e) about 10.5% of hydrocodone or oxycodone; and optionally (f) about 0.25% BHT; and (g) about 0.1% BHA. 44-47. (canceled) 48. The composition of claim 1, wherein the soft capsule shell comprises: (a) about 25% to about 50% of at least one film-forming polymer; (b) about 15% to about 25% of at least one plasticizer; and (c) about 20% to about 40% of a solvent, wherein the at least one film-forming polymer comprises gelatin, the at least one plasticizer comprises glycerol, and the solvent comprises water. 49. The composition of claim 47, wherein the soft capsule shell comprises: (a) about 42% of at least one film-forming polymer; (b) about 20% of at least one plasticizer; and (c) about 38% of a solvent. 50. (canceled) 51. A method for making a tamper resistant controlled release matrix dosage form comprising: (i) heating one or more liquid lipophilic vehicles to about 60° C. and adding one or more organogelators until completely dissolved to form a first clear gel mixture; (ii) hydrating one or more hydrophilic polymers with one or more hydrophilic vehicles; (iii) mixing one or more active pharmaceutical ingredients with the mixture of step (b) to form a second uniform mixture; and (iv) adding the second uniform mixture of step (c) to the first clear gel mixture of (i) to form a final uniform matrix composition, wherein the tamper resistant controlled release matrix dosage form comprises (a) soybean oil; (b) ethyl cellulose; (e) hydroxypropylmethyl cellulose; (f) polyethylene glycol; and (g) hydrocodone or oxycodone. 52-57. (canceled) 58. A tamper resistant oral pharmaceutical composition comprising a tamper resistant controlled release matrix comprising: (a) about 30% to about 70% soybean oil; (b) about 1% to about 7% Ethocel™ 20 cP; (c) about 1% to about 30% Methocel™ K100M; (d) about 2% to about 40% polyethylene glycol 400; (e) about 10.5% of hydrocodone or oxycodone; and optionally (f) about 0.25% BHT; and (g) about 0.1% BHA. wherein the matrix is resistant to tampering and has controlled release properties; the matrix being encapsulated in a soft capsule shell comprising: (h) about 25% to about 50% gelatin; (i) about 15% to about 25% glycerol; and (j) about 20% to about 40% water. 59-63. (canceled) 64. A method for treating, reducing the symptoms or onset of, or prophylaxis of pain stemming from diabetic neuropathy, chronic arthritis, osteoarthritis, rheumatoid arthritis, acute tendonitis, bursitis, headaches, migraines, chronic neuropathies, shingles, premenstrual symptoms, sports injuries, malignancy, radiculopathy, sciatica/sciatic pain, sarcoidosis, necrobiosis, lipoidica or granuloma annulare comprising administering to a subject in need thereof the pharmaceutical composition of claim 1. 65-79. (canceled)

Described herein are abuse deterrent controlled release oral pharmaceutical compositions comprising and methods for making the same. In particular, an abuse deterrent controlled release oral pharmaceutical composition comprising a soft capsule and an abuse deterrent controlled release matrix comprising an active pharmaceutical ingredient are described.1. An abuse deterrent oral pharmaceutical composition comprising a tamper resistant controlled release matrix comprising: (a) at least one lipid or lipophilic vehicle; (b) at least one organogelator; (c) at least one hydrophilic polymer; (d) at least one hydrophilic vehicle; and (e) at least one active pharmaceutical ingredient; wherein the matrix is resistant to tampering and is encapsulated in a soft capsule shell. 2. The composition of claim 1, wherein the tamper resistant controlled release matrix further comprises at least one antioxidant. 3. (canceled) 4. The composition of claim 1, wherein the lipid or lipophilic vehicle comprises about 30% to about 85% of the total matrix mass. 5. The composition of claim 1, wherein the at least one organogelator comprises from about 0.5% to about 25% of the total matrix mass. 6. The composition of claim 1, wherein the at least one hydrophilic polymer comprises about 1% to about 30% of the total matrix mass. 7. The composition of claim 1, wherein the at least one hydrophilic vehicle comprises about 2% to about 40% of the total matrix mass. 8. The composition of claim 1, wherein the at least one active pharmaceutical ingredient comprises about 1% to about 35% of the total matrix mass. 9. The composition of claim 2, wherein the at least one anti-oxidant comprises about 0.05% to about 0.5% of the total matrix mass. 10. (canceled) 11. The composition of claim 1, wherein the ratio of the active pharmaceutical ingredient percent mass to the matrix percent mass is about 1:100 to about 1:3. 12-13. (canceled) 14. The composition of claim 1, wherein the liquid lipid or lipophilic vehicle comprises: olive oil, sunflower oil, canola oil, palmitoleic acid, oleic acid, myristoleic acid, linoleic acid, arachidonic acid, paraffin oil, or mineral oil. 15-18. (canceled) 19. The composition of claim 1, wherein the organogelator forms a gel at a temperature of about 90° C. to about 120° C. 20. (canceled) 21. The composition of claim 1, wherein the organogelator comprises ethyl cellulose having a viscosity value of about 3 cP to about 20 cP. 22-24. (canceled) 25. The composition of claim 1, wherein the hydrophilic polymer comprises methylcellulose, hydroxypropylmethyl cellulose, a mixture of hydroxypropylmethyl cellulose and methylcellulose, polymethylmethacrylate, polyvinyl pyrrolidone, or a combination thereof. 26. The composition of claim 1, wherein the hydrophilic polymer comprises methylcellulose or hydroxypropylmethyl cellulose. 27. (canceled) 28. The composition of claim 26, wherein methylcellulose has a viscosity value of about 50 to about 4,000 cP and hydroxypropylmethyl cellulose has a viscosity value of about 50 to about 100,000 cP. 29. (canceled) 30. The composition of claim 2, wherein the anti-oxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), or a combination thereof. 31. (canceled) 32. The composition of claim 1, wherein the active pharmaceutical ingredient comprises at least one of: hydrocodone, morphine, morphine analogues, or morphine antagonists, tapentadol, codeine, morphine, methadone, fentanyl and analogs, hydrocodone hydrochloride, hydrocodone bitartrate, hydromorphone, oxymorphone, oxycodone, meperidine, propoxyphene, flunitrazepam, barbiturates, amytal, nembutal, seconal, phenobarbital; benzodiazepines, zolpidem, zaleplon, eszopiclone, amphetamines, methylphenidate, or a combination thereof. 33. The composition of claim 1, wherein the active pharmaceutical ingredient comprises hydrocodone or oxycodone. 34-41. (canceled) 42. The composition of claim 1, wherein the tamper resistant controlled release matrix comprises: (a) soybean oil; (b) ethyl cellulose; (e) hydroxypropylmethyl cellulose; (f) polyethylene glycol; (g) hydrocodone or oxycodone; and optionally (h) BHT; and (i) BHA. 43. The composition of claim 42, wherein the tamper resistant controlled release matrix comprises: (a) about 30% to about 70% soybean oil; (b) about 1% to about 7% Ethocel™ 20 cP; (c) about 1% to about 30% Methocel™ K100M; (d) about 2% to about 40% polyethylene glycol 400; (e) about 10.5% of hydrocodone or oxycodone; and optionally (f) about 0.25% BHT; and (g) about 0.1% BHA. 44-47. (canceled) 48. The composition of claim 1, wherein the soft capsule shell comprises: (a) about 25% to about 50% of at least one film-forming polymer; (b) about 15% to about 25% of at least one plasticizer; and (c) about 20% to about 40% of a solvent, wherein the at least one film-forming polymer comprises gelatin, the at least one plasticizer comprises glycerol, and the solvent comprises water. 49. The composition of claim 47, wherein the soft capsule shell comprises: (a) about 42% of at least one film-forming polymer; (b) about 20% of at least one plasticizer; and (c) about 38% of a solvent. 50. (canceled) 51. A method for making a tamper resistant controlled release matrix dosage form comprising: (i) heating one or more liquid lipophilic vehicles to about 60° C. and adding one or more organogelators until completely dissolved to form a first clear gel mixture; (ii) hydrating one or more hydrophilic polymers with one or more hydrophilic vehicles; (iii) mixing one or more active pharmaceutical ingredients with the mixture of step (b) to form a second uniform mixture; and (iv) adding the second uniform mixture of step (c) to the first clear gel mixture of (i) to form a final uniform matrix composition, wherein the tamper resistant controlled release matrix dosage form comprises (a) soybean oil; (b) ethyl cellulose; (e) hydroxypropylmethyl cellulose; (f) polyethylene glycol; and (g) hydrocodone or oxycodone. 52-57. (canceled) 58. A tamper resistant oral pharmaceutical composition comprising a tamper resistant controlled release matrix comprising: (a) about 30% to about 70% soybean oil; (b) about 1% to about 7% Ethocel™ 20 cP; (c) about 1% to about 30% Methocel™ K100M; (d) about 2% to about 40% polyethylene glycol 400; (e) about 10.5% of hydrocodone or oxycodone; and optionally (f) about 0.25% BHT; and (g) about 0.1% BHA. wherein the matrix is resistant to tampering and has controlled release properties; the matrix being encapsulated in a soft capsule shell comprising: (h) about 25% to about 50% gelatin; (i) about 15% to about 25% glycerol; and (j) about 20% to about 40% water. 59-63. (canceled) 64. A method for treating, reducing the symptoms or onset of, or prophylaxis of pain stemming from diabetic neuropathy, chronic arthritis, osteoarthritis, rheumatoid arthritis, acute tendonitis, bursitis, headaches, migraines, chronic neuropathies, shingles, premenstrual symptoms, sports injuries, malignancy, radiculopathy, sciatica/sciatic pain, sarcoidosis, necrobiosis, lipoidica or granuloma annulare comprising administering to a subject in need thereof the pharmaceutical composition of claim 1. 65-79. (canceled)

Described herein are abuse deterrent controlled release oral pharmaceutical compositions comprising and methods for making the same. In particular, an abuse deterrent controlled release oral pharmaceutical composition comprising a soft capsule and an abuse deterrent controlled release matrix comprising an active pharmaceutical ingredient are described.

1. An abuse deterrent oral pharmaceutical composition comprising a tamper resistant controlled release matrix comprising: (a) at least one lipid or lipophilic vehicle; (b) at least one organogelator; (c) at least one hydrophilic polymer; (d) at least one hydrophilic vehicle; and (e) at least one active pharmaceutical ingredient; wherein the matrix is resistant to tampering and is encapsulated in a soft capsule shell. 2. The composition of claim 1, wherein the tamper resistant controlled release matrix further comprises at least one antioxidant. 3. (canceled) 4. The composition of claim 1, wherein the lipid or lipophilic vehicle comprises about 30% to about 85% of the total matrix mass. 5. The composition of claim 1, wherein the at least one organogelator comprises from about 2% to about 25% of the total matrix mass. 6. The composition of claim 1, wherein the at least one hydrophilic polymer comprises about 2% to about 25% of the total matrix mass. 7. The composition of claim 1, wherein the at least one hydrophilic vehicle comprises about 2% to about 20% of the total matrix mass. 8. The composition of claim 1, wherein the at least one active pharmaceutical ingredient comprises about 1% to about 35% of the total matrix mass. 9. The composition of claim 2, wherein the at least one anti-oxidant comprises about 0.05% to about 0.5% of the total matrix mass. 10. (canceled) 11. The composition of claim 1, wherein the ratio of the active pharmaceutical ingredient percent mass to the matrix percent mass is about 1:100 to about 1:3. 12. The composition of claim 1, wherein the lipid or lipophilic vehicle comprises at least one liquid lipid or lipophilic vehicle and at least one semisolid lipid or lipophilic vehicle. 13. The composition of claim 12, wherein the liquid lipid or lipophilic vehicle comprises: olive oil, sunflower oil, canola oil, palmitoleic acid, oleic acid, myristoleic acid, linoleic acid, arachidonic acid, paraffin oil, or mineral oil. 14. The composition of claim 13, wherein the lipid or lipophilic vehicle comprises olive oil or soybean oil. 15. The composition of claim 12, wherein the semisolid lipid or lipophilic vehicle comprises one or more of: polyethylene glycol glyceride ester, paraffin wax, carnauba wax, or bee's wax. 16. The composition of claim 12, wherein the semisolid lipid or lipophilic vehicle comprises a combination of carnauba wax and bee's wax. 17. The composition of claim 12, wherein the lipid or lipophilic vehicle comprises soybean oil and carnauba wax, soybean oil and bee's wax, or soybean oil and a combination of carnauba wax and bee's wax. 18. The composition of claim 1, wherein the organogelator forms a gel at a temperature of about 90° C. to about 120° C. 19. (canceled) 20. The composition of claim 19, wherein the organogelator comprises ethyl cellulose. 21-22. (canceled) 23. The composition of claim 20, wherein the ethyl cellulose comprises a centipoise viscosity value of about 3 cP to about 20 cP. 24. The composition of claim 1, wherein the hydrophilic polymer comprises methylcellulose, hydroxypropylmethyl cellulose, a mixture of hydroxypropylmethyl cellulose and methylcellulose, polymethylmethacrylate, polyvinyl pyrrolidone, or a combination thereof. 25. The composition of claim 24, wherein the hydrophilic polymer comprises methylcellulose. 26. The composition of claim 25, wherein methylcellulose has a centipoise viscosity value of about 500 to about 10,000. 27. The composition of claim 2, wherein the anti-oxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), or a combination thereof. 28. (canceled) 29. The composition of claim 1, wherein the active pharmaceutical ingredient comprises at least one of: hydrocodone, morphine, morphine analogues, or morphine antagonists, tapentadol, codeine, morphine, methadone, fentanyl and analogs,: hydrocodone hydrochloride, hydrocodone bitartrate, hydromorphone, oxymorphone, oxycodone, meperidine, propoxyphene, flunitrazepam, barbiturates, amytal, nembutal, seconal, phenobarbital; benzodiazepines, zolpidem, zaleplon, eszopiclone, amphetamines, methylphenidate, or a combination thereof. 30. The composition of claim 1, wherein the active pharmaceutical ingredient comprises hydrocodone or oxycodone. 31-36. (canceled) 37. The composition of claim 1, wherein the tamper resistant controlled release matrix comprises: (a) soybean oil; (b) ethyl cellulose; (c) carnauba wax; (d) bee's wax; (e) methylcellulose; (f) polyethylene glycol; (g) hydrocodone or oxycodone; (h) BHT; and (i) BHA. 38. The composition of claim 37, wherein the tamper resistant controlled release matrix comprises: (a) about 50% to about 70% soybean oil; (b) about 1% to about 7% Ethocel™ 20 cP; (c) about 1% to about 7% bee's wax; (d) about 1% to about 7% carnauba wax; (e) about 2% to about 15% Methocel™ A4M; (f) about 4% to 11% polyethylene glycol 400; (g) about 10.5% of hydrocodone or oxycodone; (h) about 0.25% BHT; and (i) about 0.1% BHA. 39-41. (canceled) 42. The composition of claim 1, wherein the soft capsule shell comprises a film forming polymer, a plasticizer, a solvent, optionally, an opacifying agent, a coloring agent, or a pharmaceutical excipient. 43. The composition of claim 42, wherein the soft capsule shell comprises: (a) about 25% to about 50% of at least one film-forming polymer; (b) about 15% to about 25% of at least one plasticizer; and (c) about 20% to about 40% of a solvent. 44. The composition of claim 43, wherein the soft capsule shell comprises: (a) about 42% of at least one film-forming polymer; (b) about 20% of at least one plasticizer; and (c) about 38% of a solvent. 45. The composition of claim 44, wherein the soft capsule shell comprises gelatin, glycerol, and water. 46-48. (canceled) 49. A tamper resistent oral pharmaceutical composition comprising a tamper resistant controlled release matrix comprising: (a) about 50% to about 70% soybean oil; (b) about 1% to about 7% Ethocel™ 20 cP; (c) about 1% to about 7% bee's wax; (d) about 1% to about 7% carnauba wax; (e) about 2% to about 15% Methocel™ A4M; (f) about 4% to about 11% of polyethylene glycol 400; (g) about 10.5% of hydrocodone or oxycodone; (h) about 0.25% BHT; and (i) about 0.1% BHA; wherein the matrix is resistant to tampering and has controlled release properties; the matrix being encapsulated in a soft capsule shell comprising: (g) about 25% to about 50% gelatin; (h) about 15% to about 25% glycerol; and (i) about 20% to about 40% water. 50-68. (canceled) 69. The composition of claim 1, wherein the at least one hydrophilic vehicle comprises propylene glycol, or polyethylene glycols of a molecular weight ranging from about 200 to about 8000, or a combination thereof. 70. The composition of claim 69, wherein the at least one hydrophilic vehicle comprises polyethylene glycol 400.

Described herein are abuse deterrent controlled release oral pharmaceutical compositions comprising and methods for making the same. In particular, an abuse deterrent controlled release oral pharmaceutical composition comprising a soft capsule and an abuse deterrent controlled release matrix comprising an active pharmaceutical ingredient are described.1. An abuse deterrent oral pharmaceutical composition comprising a tamper resistant controlled release matrix comprising: (a) at least one lipid or lipophilic vehicle; (b) at least one organogelator; (c) at least one hydrophilic polymer; (d) at least one hydrophilic vehicle; and (e) at least one active pharmaceutical ingredient; wherein the matrix is resistant to tampering and is encapsulated in a soft capsule shell. 2. The composition of claim 1, wherein the tamper resistant controlled release matrix further comprises at least one antioxidant. 3. (canceled) 4. The composition of claim 1, wherein the lipid or lipophilic vehicle comprises about 30% to about 85% of the total matrix mass. 5. The composition of claim 1, wherein the at least one organogelator comprises from about 2% to about 25% of the total matrix mass. 6. The composition of claim 1, wherein the at least one hydrophilic polymer comprises about 2% to about 25% of the total matrix mass. 7. The composition of claim 1, wherein the at least one hydrophilic vehicle comprises about 2% to about 20% of the total matrix mass. 8. The composition of claim 1, wherein the at least one active pharmaceutical ingredient comprises about 1% to about 35% of the total matrix mass. 9. The composition of claim 2, wherein the at least one anti-oxidant comprises about 0.05% to about 0.5% of the total matrix mass. 10. (canceled) 11. The composition of claim 1, wherein the ratio of the active pharmaceutical ingredient percent mass to the matrix percent mass is about 1:100 to about 1:3. 12. The composition of claim 1, wherein the lipid or lipophilic vehicle comprises at least one liquid lipid or lipophilic vehicle and at least one semisolid lipid or lipophilic vehicle. 13. The composition of claim 12, wherein the liquid lipid or lipophilic vehicle comprises: olive oil, sunflower oil, canola oil, palmitoleic acid, oleic acid, myristoleic acid, linoleic acid, arachidonic acid, paraffin oil, or mineral oil. 14. The composition of claim 13, wherein the lipid or lipophilic vehicle comprises olive oil or soybean oil. 15. The composition of claim 12, wherein the semisolid lipid or lipophilic vehicle comprises one or more of: polyethylene glycol glyceride ester, paraffin wax, carnauba wax, or bee's wax. 16. The composition of claim 12, wherein the semisolid lipid or lipophilic vehicle comprises a combination of carnauba wax and bee's wax. 17. The composition of claim 12, wherein the lipid or lipophilic vehicle comprises soybean oil and carnauba wax, soybean oil and bee's wax, or soybean oil and a combination of carnauba wax and bee's wax. 18. The composition of claim 1, wherein the organogelator forms a gel at a temperature of about 90° C. to about 120° C. 19. (canceled) 20. The composition of claim 19, wherein the organogelator comprises ethyl cellulose. 21-22. (canceled) 23. The composition of claim 20, wherein the ethyl cellulose comprises a centipoise viscosity value of about 3 cP to about 20 cP. 24. The composition of claim 1, wherein the hydrophilic polymer comprises methylcellulose, hydroxypropylmethyl cellulose, a mixture of hydroxypropylmethyl cellulose and methylcellulose, polymethylmethacrylate, polyvinyl pyrrolidone, or a combination thereof. 25. The composition of claim 24, wherein the hydrophilic polymer comprises methylcellulose. 26. The composition of claim 25, wherein methylcellulose has a centipoise viscosity value of about 500 to about 10,000. 27. The composition of claim 2, wherein the anti-oxidant comprises butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), or a combination thereof. 28. (canceled) 29. The composition of claim 1, wherein the active pharmaceutical ingredient comprises at least one of: hydrocodone, morphine, morphine analogues, or morphine antagonists, tapentadol, codeine, morphine, methadone, fentanyl and analogs,: hydrocodone hydrochloride, hydrocodone bitartrate, hydromorphone, oxymorphone, oxycodone, meperidine, propoxyphene, flunitrazepam, barbiturates, amytal, nembutal, seconal, phenobarbital; benzodiazepines, zolpidem, zaleplon, eszopiclone, amphetamines, methylphenidate, or a combination thereof. 30. The composition of claim 1, wherein the active pharmaceutical ingredient comprises hydrocodone or oxycodone. 31-36. (canceled) 37. The composition of claim 1, wherein the tamper resistant controlled release matrix comprises: (a) soybean oil; (b) ethyl cellulose; (c) carnauba wax; (d) bee's wax; (e) methylcellulose; (f) polyethylene glycol; (g) hydrocodone or oxycodone; (h) BHT; and (i) BHA. 38. The composition of claim 37, wherein the tamper resistant controlled release matrix comprises: (a) about 50% to about 70% soybean oil; (b) about 1% to about 7% Ethocel™ 20 cP; (c) about 1% to about 7% bee's wax; (d) about 1% to about 7% carnauba wax; (e) about 2% to about 15% Methocel™ A4M; (f) about 4% to 11% polyethylene glycol 400; (g) about 10.5% of hydrocodone or oxycodone; (h) about 0.25% BHT; and (i) about 0.1% BHA. 39-41. (canceled) 42. The composition of claim 1, wherein the soft capsule shell comprises a film forming polymer, a plasticizer, a solvent, optionally, an opacifying agent, a coloring agent, or a pharmaceutical excipient. 43. The composition of claim 42, wherein the soft capsule shell comprises: (a) about 25% to about 50% of at least one film-forming polymer; (b) about 15% to about 25% of at least one plasticizer; and (c) about 20% to about 40% of a solvent. 44. The composition of claim 43, wherein the soft capsule shell comprises: (a) about 42% of at least one film-forming polymer; (b) about 20% of at least one plasticizer; and (c) about 38% of a solvent. 45. The composition of claim 44, wherein the soft capsule shell comprises gelatin, glycerol, and water. 46-48. (canceled) 49. A tamper resistent oral pharmaceutical composition comprising a tamper resistant controlled release matrix comprising: (a) about 50% to about 70% soybean oil; (b) about 1% to about 7% Ethocel™ 20 cP; (c) about 1% to about 7% bee's wax; (d) about 1% to about 7% carnauba wax; (e) about 2% to about 15% Methocel™ A4M; (f) about 4% to about 11% of polyethylene glycol 400; (g) about 10.5% of hydrocodone or oxycodone; (h) about 0.25% BHT; and (i) about 0.1% BHA; wherein the matrix is resistant to tampering and has controlled release properties; the matrix being encapsulated in a soft capsule shell comprising: (g) about 25% to about 50% gelatin; (h) about 15% to about 25% glycerol; and (i) about 20% to about 40% water. 50-68. (canceled) 69. The composition of claim 1, wherein the at least one hydrophilic vehicle comprises propylene glycol, or polyethylene glycols of a molecular weight ranging from about 200 to about 8000, or a combination thereof. 70. The composition of claim 69, wherein the at least one hydrophilic vehicle comprises polyethylene glycol 400.

Methods and systems for filtering variants in data sets comprising genomic information are provided herein.

1. A biological context filter wherein the biological context filter: (a) is configured to receive a data set comprising variants wherein the data set comprises variant data from one or more samples from one or more individuals, (b) is in communication with a database of biological information, and (c) is capable of transforming the data set by filtering the data set by variants associated with biological information, wherein the filtering comprises establishing associations between the data set and some or all of the biological information. 2. The biological context filter of claim 1, wherein the database of biological information is a knowledge base of curated biomedical content, wherein the knowledge base is structured with an ontology. 3. The biological context filter of claim 2, wherein the associations between the variants and the biological information comprises a relationship defined by one or more hops. 4. The biological context filter of claim 2 wherein a user selects the biological information for filtering. 5. The biological context filter of claim 2 wherein the filtering unmasks variants associated with the biological information. 6. The biological context filter of claim 2 wherein the filtering masks variants not associated with the biological information. 7. The biological context filter of claim 2 wherein the filtering masks variants associated with biological information. 8. The biological context filter of claim 2 wherein the filtering unmasks variants not associated with the biological information. 9. The biological context filter of claim 2 wherein biological information for filtering is inferred from the data set. 10. The biological context filter of claim 2 wherein biological information for filtering is inferred from study design information previously inputted by a user. 11. The biological context filter of claim 2 wherein the biological context filter is combined with other filters in a filter cascade to generate a final variant list. 12. The biological context filter of claim 11 wherein the biological context filter is combined with one or more of the following filters in a filter cascade to reach a final variant list of less than 200 variants: common variant filter, predicted deleterious filter, cancer driver variants filter, physical location filter, genetic analysis filter, expression filter, user-defined variants filter, pharmacogenetics filter, or custom annotation filter. 13. The biological context filter of claim 2 wherein the biological context filter is combined with one or more of the following filters in a filter cascade to reach a final variant list of less than 50 variants: common variant filter, predicted deleterious filter, cancer driver variants filter, physical location filter, genetic analysis filter, expression filter, user-defined variants filter, pharmacogenetics filter, or custom annotation filter. 14. The biological context filter of claim 3 wherein the stringency of the biological context filter can be adjusted by a user, and wherein the stringency adjustment from the user alters one or more of the following: (a) the number of hops in an association used for filtering; (b) the strength of hops in an association used for filtering; (c) the net effect of the hops in an association used for filtering; and/or (d) the upstream or downstream nature of hops in an association used for filtering. 15. The biological context filter of claim 3 wherein the stringency of the biological context filter is adjusted automatically based upon the desired number of variants in the final filtered data set, wherein the stringency adjustment alters one or more of the following: (a) the number of hops in an association used for filtering; (b) the strength of hops in an association used for filtering; (c) the net effect of the hops in an association used for filtering; and/or (d) the upstream or downstream nature of hops in an association used for filtering. 16. The biological context filter of claims 2-15 wherein only upstream hops are used. 17. The biological context filter of claims 2-15 wherein only downstream hops are used. 18. The biological context filter of claims 2-15 wherein the net effects of hops are used. 19. The biological context filter of claim 2 wherein the biological information for filtering is biological function. 20. The biological context filter of claim 19 wherein the biological function is a gene, a transcript, a protein, a molecular complex, a molecular family or enzymatic activity, a therapeutic or therapeutic molecular target, a pathway, a process, a phenotype, a disease, a functional domain, a behavior, an anatomical characteristic, a physiological trait or state, a biomarker or a combination thereof. 21. The biological context filter of claim 2 where the stringency of the biological context filter is adjusted by selection of the biological information for filtering. 22. The biological context filter of claim 2 wherein the biological context filter is configured to accept a mask from another filter previously performed on the same data set. 23. The biological context filter of claim 2 wherein the biological context filter is in communication with hardware for outputting the filtered data set to a user. 24. A computer program product bearing machine readable instructions to enact the biological context filter of any of claims 1-23. 25. A cancer driver variants filter wherein the cancer driver variants filter: (a) is configured to receive a data set comprising variants wherein said data set comprises variant data from one or more samples from one or more individuals, and (b) is capable of transforming the data set by filtering the data set by variants associated with one or more proliferative disorders. 26. The cancer driver variants filter of claim 25 wherein the cancer driver variants filter is in communication with hardware for outputting the filtered data set to a user. 27. The cancer driver variant filter of claim 25 wherein the data set is suspected to contain variants associated with one or more proliferative disorders. 28. The cancer driver variant filter of claim 27 wherein the data set includes one or more samples derived from a patient with a proliferative disorder. 29. The cancer driver variants filter of claim 25 wherein the proliferative disorder is cancer. 30. The cancer driver variants filter of claim 25 wherein a user specifies one or more proliferative disorders of interest for filtering. 31. The cancer driver variants filter of claim 25 wherein the filtering unmasks variants associated with the one or more proliferative disorders. 32. The cancer driver variants filter of claim 25 wherein the filtering masks variants not associated with the one or more proliferative disorders. 33. The cancer driver variants filter of claim 25 wherein the filtering masks variants associated with the one or more proliferative disorders. 34. The cancer driver variants filter of claim 25 wherein the filtering unmasks variants not associated with the one or more proliferative disorders. 35. The cancer driver variants filter of claim 25 wherein the one or more proliferative disorders for filtering is inferred from the data set. 36. The cancer driver variants filter of claim 25 wherein the one or more proliferative disorders for filtering is inferred from study design information previously inputted by a user. 37. The cancer driver variants filter of claim 25 wherein cancer driver variants filter is combined with other filters in a filter cascade to generate a final variant list. 38. The cancer driver variants filter of claim 37 wherein the cancer driver variants filter is combined with one or more of the following filters in a filter cascade to reach a final variant list of less than 200 variants: common variant filter, predicted deleterious filter, biological context filter, physical location filter, genetic analysis filter, expression filter, user-defined variants filter, pharmacogenetics filter, or custom annotation filter. 39. The cancer driver variants filter of claim 37 wherein the cancer driver variants filter is combined with one or more of the following filters in a filter cascade to reach a final variant list of less than 50 variants: common variant filter, predicted deleterious filter, biological context filter, physical location filter, genetic analysis filter, expression filter, user-defined variants filter, pharmacogenetics filter, or custom annotation filter. 40. The cancer driver variants filter of claim 25 wherein the filtered variants are variants observed or predicted to meet one or more of the following criteria: a) are located in human genes having animal model orthologs with cancer-associated gene disruption phenotypes, b) impact known or predicted cancer subnetwork regulatory sites, c) impact cancer-associated cellular processes with or without enforcement of appropriate directionality, d) are associated with published cancer literature findings in a knowledge base at the variant- and/or gene-level, e) impact cancer-associated pathways with or without enforcement of appropriate directionality, and/or f) are associated with cancer therapeutic targets and/or upstream/causal subnetworks. 41. The cancer driver variants filter of claim 40 wherein the criteria are restricted to one or more specific cancer disease models. 42. The cancer driver variants filter of claim 25 wherein the cancer driver variants filter is in communication with a database of biological information, wherein the database of biological information is a knowledge base of curated biomedical content, wherein the knowledge base is structured with an ontology. 43. The cancer driver variants filter of claim 42 wherein the stringency of the cancer driver variants filter is user adjustable, wherein the stringency adjustment from the user alters the number of hops and/or the strength of hops in a relationship and/or whether or not the variants are observed or predicted to have one or more of the following characteristics: a) are located in human genes having animal model orthologs with cancer-associated gene disruption phenotypes, b) impact known or predicted cancer subnetwork regulatory sites, c) impact cancer-associated cellular processes with or without enforcement of appropriate directionality, d) are associated with published cancer literature findings in a knowledge base at the variant- and/or gene-level, e) impact cancer-associated pathways with or without enforcement of appropriate directionality, and/or f) are associated with cancer therapeutic targets and/or upstream/causal subnetworks. 44. The cancer driver variants filter of claim 42 wherein the stringency of the cancer driver variants filter is adjusted automatically based upon the desired number of variants in the final filtered data set, wherein the stringency adjustment alters the number of hops and/or the strength of hops in a relationship and/or whether or not the variants are observed or predicted to have one or more of the following characteristics: a) are located in human genes having animal model orthologs with cancer-associated gene disruption phenotypes, b) impact known or predicted cancer subnetwork regulatory sites, c) impact cancer-associated cellular processes with or without enforcement of appropriate directionality, d) are associated with published cancer literature findings in a knowledge base at the variant- and/or gene-level, e) impact cancer-associated pathways with or without enforcement of appropriate directionality, and/or f) are associated with cancer therapeutic targets and/or upstream/causal subnetworks. 45. The cancer driver variants filter of claim 42 wherein the variants associated with one or more proliferative disorders are variants which are one or more hops from variants that are predicted or observed to have one or more of the following characteristics: a) are located in human genes having animal model orthologs with cancer-associated gene disruption phenotypes, b) impact known or predicted cancer subnetwork regulatory sites, c) impact cancer-associated cellular processes with or without enforcement of appropriate directionality, d) are associated with published cancer literature findings in a knowledge base at the variant- and/or gene-level, e) impact cancer-associated pathways with or without enforcement of appropriate directionality, and/or f) are associated with cancer therapeutic targets and/or upstream/causal subnetworks. 46. The cancer driver variants filter of claims 42-45 wherein the stringency of the cancer driver variants filter is adjusted by weighting the strength of the hops. 47. The cancer driver variants filter of claims 42-45 wherein the stringency of the cancer driver variants filter is adjusted by altering the number of hops. 48. The cancer driver variants filter of claims 42-45 wherein the hops are upstream hops. 49. The cancer driver variants filter of claims 42-45 wherein the hops are downstream hops. 50. The cancer driver variants filter of claims 42-45 wherein the net effects of the hops are determined and only variants associated with cancer driving net effects are filtered. 51. The cancer driver variants filter of claim 25 wherein the cancer driver variants filter is configured to accept a mask from another filter previously performed on the same data set. 52. A computer program product bearing machine readable instructions to enact the cancer driver variants filter of claims 25-51. 53. A genetic analysis filter wherein the genetic analysis filter: (a) is configured to receive a data set comprising variants wherein said data set comprises variant data from one or more samples from one or more individuals, (b) is capable of transforming the data set by filtering the data set according to genetic logic. 54. The genetic analysis filter of claim 53 wherein the genetic analysis filter is in communication with hardware for outputting the filtered data set to a user. 55. The genetic analysis filter of claim 53 further configured to receive information optionally identifying samples from the same individual or hereditary relationships among individuals with samples in the data set. 56. The genetic analysis filter of claim 53 wherein the filtering comprises a) filtering variants that are present with a given zygosity in greater than or equal to a specified fraction of case samples but less than or equal to a specified fraction of control samples, and/or b) filtering variants that are present with a given zygosity in less than or equal to a specified fraction of case samples but greater than or equal to a specified fraction of control samples. 57. The genetic analysis filter of claim 53 wherein the filtering comprises a) filtering variants that are present at a given quality level in greater than or equal to a specified fraction of case samples but less than or equal to a specified fraction of control samples, and/or b) filtering variants that are present at a given quality level in less than or equal to a specified fraction of case samples but greater than or equal to a specified fraction of control samples. 58. The genetic analysis filter of claim 55 wherein at least one sample in the data set is a disease case sample and another sample in the data set is a normal control sample from the same individual, wherein the filtering comprises filtering variants either observed in both the disease and normal samples or observed uniquely in either the disease sample or the normal sample. 59. The genetic analysis filter of claim 53 wherein the genetic logic is configured based on presets from a user for recessive hereditary disease, dominant hereditary disease, de novo mutation, or cancer somatic variants. 60. The genetic analysis filter of claim 53 wherein variants are filtered that are inferred to contribute to a gain or loss of function of a gene in either (a) greater than or equal to a specified fraction of case samples but less than or equal to a specified fraction of control samples, or (b) less than or equal to a specified fraction of case samples but greater than or equal to a specified fraction of control samples. 61. The genetic analysis filter of claim 55 wherein the one or more samples in the data set are genetic parents of another sample in the data set. 62. The genetic analysis filter of claim 61 wherein the filtering comprises filtering variants from the data set that are incompatible with Mendelian genetics. 63. The genetic analysis filter of claim 61 wherein the filtering comprises filtering variants that are (a) absent in the child when at least one parent is homozygous, and/or (b) heterozygous in the child if both parents are homozygous. 64. The genetic analysis filter of claim 61 wherein the filtering comprises filtering variants absent in at least one of the parents of a homozygous child. 65. The genetic analysis filter of claim 61 wherein the filtering comprises filtering variants absent in both of the parents of a child with the variant. 66. The genetic analysis filter of claim 61 wherein filtered variants are single copy variants located in a hemizygous region of the genome. 67. The genetic analysis filter of claim 53-66 wherein the genetic analysis filter is further in communication with a database of biological information, wherein the database of biological information is a knowledge base of curated biomedical content, wherein the knowledge base is structured with an ontology, and wherein the variants from the data set can be associated with the biological information by hops. 68. The genetic analysis filter of claim 67 wherein the biological information comprises information regarding haploinsufficiency of genes. 69. The genetic analysis filter of claim 68 wherein heterozygous variants associated with haploinsuffucient genes are filtered. 70. The genetic analysis filter of claim 67 wherein variants are filtered that occur with zygosity and/or quality settings specified by the user in either (a) at least a specified number or minimal fraction of case samples and at most a specified number or maximum fraction of control samples, or (b) at most a specified number or maximum fraction of case samples and at least a specified number or minimum fraction of control samples. 71. The genetic analysis filter of claim 68 wherein variants are filtered that affect the same gene in either (a) at least a specified number or minimal fraction of case samples and at most a specified number or maximum fraction of control samples, or (b) at most a specified number or maximum fraction of case samples and at least a specified number or minimum fraction of control samples. 72. The genetic analysis filter of claim 68 wherein variants are filtered that affect the same network within 1 or more hops in either: (a) at least a specified number or minimal fraction of case samples and at least a specified number or maximum fraction of control samples, or (b) at most a specified number or maximum fraction of case samples and at least a specified number or minimum fraction of control samples. 73. The genetic analysis filter of claim 67 wherein the stringency of the genetic analysis filter is adjusted by weighting the strength of the hops. 74. The genetic analysis filter of claim 67 wherein the stringency of the genetic analysis filter is adjusted altering the number of hops. 75. The genetic analysis filter of claim 67 wherein the hops are upstream hops. 76. The genetic analysis filter of claim 67 wherein the hops are downstream hops. 77. The genetic analysis filter of claim 53 wherein the data set has been previously filtered and wherein a subset of the data points in the data set have been masked by the previous filter. 78. The genetic analysis filter of claim 53 wherein the stringency is adjusted by a user. 79. The genetic analysis filter of claim 53 wherein the filter stringency is adjusted automatically based on the desired number of variants in the final filtered data set. 80. The genetic analysis filter of claim 53 wherein the genetic analysis filter is combined with other filters in a filter cascade to yield a final filtered data set of interest to a user. 81. The genetic analysis filter of claim 80 combined with one or more of the following filters in a filter cascade to reach a final variant list of less than 50 variants: common variant filter, predicted deleterious filter, biological context filter, physical location filter, cancer driver variants filter, expression filter, user-defined variants filter, pharmacogenetics filter, or custom annotation filter. 82. The genetic analysis filter of claim 80 combined with one or more of the following filters in a filter cascade to reach a final variant list of less than 200 variants: common variant filter, predicted deleterious filter, biological context filter, physical location filter, cancer driver variants filter, expression filter, user-defined variants filter, pharmacogenetics filter, or custom annotation filter. 83. The genetic analysis filter of claims 78-79 wherein the stringency adjustment alters a zygosity requirement of the filter. 84. The genetic analysis filter of claims 78-79 wherein the stringency adjustment alters a variant quality requirement of the filter. 85. The genetic analysis filter of claims 78-79 wherein the stringency adjustment alters the required number or fraction of case samples for filtering. 86. The genetic analysis filter of claims 78-79 wherein the stringency adjustment alters whether the genetic analysis filter is filtering variants based on whether they (a) occur with zygosity and/or quality settings specified by the user, or (b) affect the same gene, or (c) affect the same network within 1 or more hops. 87. The genetic analysis filter of claims 78-79 wherein the stringency of the genetic analysis filter is adjusted by weighting the strength of the hops. 88. The genetic analysis filter of claims 78-79 wherein the stringency of the genetic analysis filter is adjusted by altering the number of hops. 89. The genetic analysis filter of claim 67 wherein the net effects of the hops are determined and only variants associated with user selected net effects are filtered. 90. The genetic analysis filter of claims 53-89 wherein the genetic analysis filter is configured to accept a mask from another filter previously performed on the same data set. 91. A computer program product bearing machine readable instructions to enact the genetic analysis filter of claims 53-90. 92. A pharmacogenetics filter wherein the pharmacogenetics filter (a) is configured to receive a data set comprising variants, wherein the data set comprises variant data from one or more samples from one or more individuals, (b) is in communication with a database of biological information, wherein the database of biological information is a knowledge base of curated biomedical content, wherein the knowledge base is structured with an ontology, wherein the biological information is information related to one or more drugs, and (c) is capable of transforming the data set by filtering the data set by variants associated with biological information, wherein the filtering comprises establishing associations between the data set and some or all of the biological information. 93. The pharmacogenetics filter of claim 92 wherein the pharmacogenetics filter is in communication with hardware for outputting the filtered data set to a user. 94. The pharmacogenetics filter of claim 92 wherein information related to one or more drugs comprises drug targets, drug responses, drug metabolism, or drug toxicity. 95. The pharmacogenetics filter of claim 92 wherein the associations between the variants and the biological information comprises a relationship defined by one or more hops. 96. The pharmacogenetics filter of claim 92 wherein a user selects the biological information for filtering. 97. The pharmacogenetics filter of claim 92 wherein the filtering unmasks variants associated with the biological information. 98. The pharmacogenetics filter of claim 92 wherein the filtering masks variants not associated with the biological information. 99. The pharmacogenetics filter of claim 92 wherein the filtering masks variants associated with biological information. 100. The pharmacogenetics filter of claim 92 wherein the filtering unmasks variants not associated with the biological information. 101. The pharmacogenetics filter of claim 92 wherein biological information for filtering is inferred from the data set. 102. The pharmacogenetics filter of claim 92 wherein biological information for filtering is inferred from study design information previously inputted by a user. 103. The pharmacogenetics filter of claim 92 wherein the pharmacogenetics filter is combined with other filters in a filter cascade to generate a final variant list. 104. The pharmacogenetics filter of claim 92 wherein the pharmacogenetics filter is combined with one or more of the following filters in a filter cascade to reach a final variant list of less than 200 variants: common variant filter, predicted deleterious filter, cancer driver variants filter, physical location filter, genetic analysis filter, expression filter, user-defined variants filter, biological context filter, or custom annotation filter. 105. The pharmacogenetics filter of claim 92 wherein the pharmacogenetics filter is combined with one or more of the following filters in a filter cascade to reach a final variant list of less than 50 variants: common variant filter, predicted deleterious filter, cancer driver variants filter, physical location filter, genetic analysis filter, expression filter, user-defined variants filter, biological context filter, or custom annotation filter. 106. The pharmacogenetics filter of claim 92 wherein the stringency of the pharmacogenetics filter can be adjusted by a user, and wherein the stringency adjustment from the user alters one or more of the following: (a) the number of hops in an association used for filtering; (b) the strength of hops in an association used for filtering; (c) whether or not predicted drug response information is used for filtering; (d) whether or not predicted drug metabolism or toxicity information is used for filtering; (e) whether or not established drug target(s) are used for filtering; (f) the net effect of the hops in an association used for filtering; and/or (g) the upstream or downstream nature of hops in an association used for filtering. 107. The pharmacogenetics filter of claim 92 wherein the stringency of the pharmacogenetics filter is adjusted automatically based upon the desired number of variants in the final filtered data set, wherein the stringency adjustment alters one or more of the following: (a) the number of hops in an association used for filtering (b) the strength of hops in an association used for filtering (c) whether or not predicted drug response information is used for filtering (d) whether or not predicted drug metabolism or toxicity information is used for filtering (e) whether or not established drug target(s) are used for filtering (f) the net effect of the hops in an association used for filtering and/or (g) the upstream or downstream nature of hops in an association used for filtering. 108. The pharmacogenetics filter of claim 92-107 wherein only upstream hops are used. 109. The pharmacogenetics filter of claim 92-107 wherein only downstream hops are used. 110. The pharmacogenetics filter of claim 92-109 wherein the net effects of hops are used. 111. The pharmacogenetics filter of claims 92-110 wherein a stringency of the pharmacogenetic filter is adjustable by the user. 112. The pharmacogenetics filter of claim 92 wherein the pharmacogenetics filter is configured to accept a mask from another filter previously performed on the same data set. 113. A computer program product bearing machine readable instructions to enact the pharmacogenetic filter variants filter of claims 92-112. 114. A predicted deleterious filter wherein the predicted deleterious filter: a) is configured to receive a data set comprising variants, wherein the data set comprises variant data from one or more samples from one or more individuals, and b) is capable of transforming the data set by filtering the data by variants predicted to be deleterious or non-deleterious. 115. The predicted deleterious filter of claim 114 wherein the predicted deleterious filter is in communication with hardware for outputting the filtered data set to a user. 116. The predicted deleterious filter of claim 114 wherein the filtering comprises utilizing at least one algorithm for predicting deleterious or non-deleterious variants in the data set and then filtering the predicted deleterious or non-deleterious variants. 117. The predicted deleterious filter of claim 116 wherein the at least one algorithm is SIFT, BSIFT, PolyPhen, PolyPhen2, PANTHER, SNPs3D, FastSNP, SNAP, LS-SNP, PMUT, PupaSuite, SNPeffect, SNPeffectV2.0, F-SNP, MAPP, PhD-SNP, MutDB, SNP Function Portal, PolyDoms, SNP@Promoter, Auto-Mute, MutPred, SNP@Ethnos, nsSNPanalyzer, SNP@Domain, StSNP, MtSNPscore, or Genome Variation Server. 118. The predicted deleterious filter of claim 114 wherein highly evolutionarily conserved variants are filtered. 119. The predicted deleterious filter of claim 116 wherein the predicted deleterious variants are filtered based on a gene fusion prediction algorithm. 120. The predicted deleterious filter of claim 114 wherein the predicted deleterious variants are filtered based on variants creating or disrupting a predicted or experimentally validated microRNA binding site. 121. The predicted deleterious filter of claim 116 wherein the predicted deleterious variants are filtered based on a predicted copy number gain algorithm. 122. The predicted deleterious filter of claim 116 wherein the predicted deleterious variants are filtered based on a predicted copy number loss algorithm. 123. The predicted deleterious filter of claim 116 wherein the predicted deleterious variants are filtered based on a predicted splice site loss or splice site gain. 124. The predicted deleterious filter of claim 114 wherein the predicted deleterious variants are filtered based on disruption of a known or predicted microRNA or ncRNA. 125. The predicted deleterious filter of claim 114 wherein the predicted deleterious variants are filtered based on disruption of or creation of a known or predicted transcription factor binding site. 126. The predicted deleterious filter of claim 114 wherein the predicted deleterious variants are filtered based on disruption of or creation of a known or predicted enhancer site. 127. The predicted deleterious filter of claim 114 wherein the predicted deleterious variants are filtered based on disruption of an untranslated region (UTR). 128. The predicted deleterious filter of claims 114-127 wherein the predicted deleterious filter is further in communication with a database of biological information, wherein the database of biological information is a knowledge base of curated biomedical content, wherein the knowledge base is structured with an ontology, and wherein the variants from the data set can be associated with the biological information either (a) directly based on one or more variant findings in the knowledge base, or (b) by a combination of gene findings and a functional prediction algorithm. 129. The predicted deleterious filter of claim 128 wherein the biological information comprises a deleterious phenotype, wherein the variants associated with the deleterious phenotypes are filtered. 130. The predicted deleterious filter of claim 129 wherein the deleterious phenotype is a disease. 131. The predicted deleterious filter of claim 114 wherein predicted deleterious variants comprise variants which are a) directly associated with a variant finding in the knowledge base, b) predicted deleterious (or non-innocuous) single nucleotide variants; c) predicted to create or disrupt a RNA splice site, d) predicted to create or disrupt a transcription factor binding site, e) predicted to disrupt non-coding RNAs, f) predicted to create or disrupt a microRNA target, or g) predicted to disrupt known enhancers. 132. The predicted deleterious filter of claim 114, combined with other filters in a filter cascade to yield a final filtered data set of interest to the user. 133. The predicted deleterious filter of claim 114 combined with one or more of the following filters in a filter cascade to reach a final variant list of less than 50 variants: common variant filter, biological context filter, physical location filter, genetic analysis filter, cancer driver variants filter, expression filter, user-defined variants filter, pharmacogenetics filter, or custom annotation filter. 134. The predicted deleterious filter of claim 114 combined with one or more of the following filters in a filter cascade to reach a final variant list of less than 200 variants: common variant filter, biological context filter, physical location filter, genetic analysis filter, cancer driver variants filter, expression filter, user-defined variants filter, pharmacogenetics filter, or custom annotation filter. 135. The predicted deleterious filter of claims 114-134 wherein a stringency of the predicted deleterious filter is adjustable by the user. 136. The predicted deleterious filter of 114-135 wherein the stringency is adjusted automatically based on the desired number of variants in the final filtered data set. 137. The predicted deleterious filter of claims 114-136 wherein the predicted deleterious variants are filtered based on a pathogenicity annotator. 138. The predicted deleterious filter of claims 114-137 wherein the predicted deleterious filter is configured to accept a mask from another filter previously performed on the same data set. 139. A computer program product bearing machine readable instructions to enact predicted deleterious filter of claims 114-138. 140. A pathogenicity annotator wherein the pathogenicity annotator categorizes variants using a predicted deleterious filter and a database of biological information, wherein the database of biological information is a knowledge base of curated biomedical content, and wherein the knowledge base is structured with an ontology. 141. The pathogenicity annotator of claim 140 wherein the pathogenicity annotator is in communication with hardware for outputting the categorization to a user. 142. The pathogenicity annotator of claim 140 wherein the variants outputted into the following categories: Pathogenic, Presumed Pathogenic or Likely Pathogenic, Unknown or Uncertain, Presumed Benign or Likely Benign, or Benign based upon a combination of the results of the predicted deleterious filter and the weight of evidence in the knowledge base supporting or refuting each variant's association with a deleterious phenotype. 143. The method of claim 142 wherein a) “Pathogenic” means <0.07% frequency of the variant in a database of genomes of individuals free from known genetic disease, and 2 or more findings drawing a causal or associative link between the variant and a deleterious phenotype from multiple different articles in the biomedical literature; b) “Presumed Pathogenic” or “Likely Pathogenic” means <0.07% frequency of the variant in a database of genomes of individuals free from known genetic disease, and 1 finding drawing a causal or associative link between the variant and a deleterious phenotype; c) “Unknown” or “Uncertain” means between 0.07% and 0.1% frequency of the variant in a database of genomes of individuals free from known genetic disease; d) “Presumed Benign” or “Likely Benign” means between 0.1% and 1% frequency of the variant in a database of genomes of individuals free from known genetic disease; and e) “Benign” means >=1% frequency of the variant in a database of genomes of individuals free from known genetic disease. 144. A preconfigurator wherein the preconfigurator is a) configured to receive information provided by a user related to a data set comprising variants wherein said data set comprises variant data from one or more samples from one or more individuals, b) in communication with one or more filters, c) in communication with the data set comprising variants, and d) capable of controlling the filters at least in part according to the information provided by the user; wherein the preconfigurator selects filters and filter stringency related to the information provided by the user to yield a final filtered data set. 145. The preconfigurator of claim 144 wherein the preconfigurator controls the addition, removal, and stringency settings of one or more of the following filters: common variants filter, predicted deleterious filter, genetic analysis filter, biological context filter, pharmacogenetics filter, physical location filter, or cancer driver variants filter. 146. The preconfigurator of claim 144 wherein the preconfigurator optimizes the addition or removal of filters and filter stringency settings to achieve a final filtered data set of no more than 200 variants 147. The preconfigurator of claim 144 wherein the preconfigurator optimizes the addition or removal of filters and filter stringency settings to achieve a final filtered data set of no more than 50 variants. 148. The preconfigurator of claim 144 wherein the information provided by the user includes the mode of inheritance of a disease of interest. 149. The preconfigurator of claim 144 wherein the information provided by the user includes a user input which can be recognized by the preconfigurator as an instruction for selecting filtering which: a) identifies causal disease variants, b) identifies cancer driver variants, c) identifies variants that stratify or differentiate one set of samples from another, or d) analyzes a genome to identify variants of interest for health management, treatment, personalized medicine and/or individualized medicine. 150. The preconfigurator of claim 144, wherein the preconfigurator is in communication with a knowledge base of curated biomedical content, wherein the knowledge base is structured with an ontology. 151. The preconfigurator of claim 144 wherein the information from a user includes biological information including one or more genes, transcripts, proteins, drugs, pathways, processes, phenotypes, diseases, functional domains, behaviors, anatomical characteristics, physiological traits or states, biomarkers or a combination thereof. 152. A computer program product bearing machine readable instructions to enact claims 144-151. 153. A method for identifying prospective causal variants comprising: (a) receiving a list of variants, (b) filtering the list of variants with one or more common variants filters, (c) filtering the list of variants with one or more predicted deleterious filters, (d) filtering the list of variants with one or more genetic analysis filters, (e) filtering the list of variants with one or more biological context filters, and (f) outputting the filtered list of variants as a list of prospective causal variants. 154. The method of claim 153 wherein the causal outputting step occurs less than 1 day following the receiving step. 155. The method of claim 153 wherein the causal outputting step occurs less than 1 week following the receiving step. 156. The method of claim 153 wherein the list of variants comprises more than 1 million variants and the outputted filtered list of variants comprises less than 50 variants. 157. A graphical user interface for displaying the output of a filter cascade, wherein the filter cascade comprises one or more of the following: a) a common variants filter, b) a predicted deleterious filter, c) a genetic analysis filter, d) a biological context filter, e) a pharmacogenetics filter, f) a statistical association filter, or g) a frequent hitter filter. 158. A method for the delivery of an interactive report method comprising the steps of: (a) receiving a request for a quotation, wherein the quotation request comprises a disclosure of a number by a customer, wherein the number is the number of samples the costumer would like a price quotation on for genomic analysis services; (b) transmitting a price quotation based at least in part upon the number of samples, wherein the price quotation comprises the cost of an interactive report for the biological interpretation of variants in the samples using a database of biological information, wherein the database of biological information is a knowledge base of curated biomedical content, and wherein the knowledge base is structured with an ontology; (c) receiving an order from a customer, wherein the order comprises ordering the interactive report for the biological interpretation of variants using a database of biological information; and (d) providing a hyperlink to the customer, wherein the hyperlink directs the customer to the interactive report for the biological interpretation of variants using a database of biological information. 159. A method for the delivery of an interactive report method comprising the steps of: (a) receiving a request for a quotation, wherein the quotation request comprises a disclosure of a number by a customer, wherein the number is the number of samples the costumer would like a price quotation on for genomic analysis services; (b) transmitting a price quotation at least in part based upon the number of samples, wherein the price quotation comprises the cost of an interactive report for the biological interpretation of variants using a database of biological information; (c) receiving an order from a customer, wherein the order does not include ordering the interactive report for the biological interpretation of variants using a database of biological information; and (d) providing a hyperlink to the customer, wherein the hyperlink directs the customer to the interactive report for the biological interpretation of variants using a database of biological information which provides the customer with the ability to transact for said interactive report online. 160. The method of claim 159 wherein the interactive report for the biological interpretation of variants using a database of biological information has been generated prior to providing the second price quotation. 161. A method for providing an interactive report to a customer for the biological interpretation of variants using a database of biological information comprising: (a) receiving a data set comprising genomic information from a partner company, wherein the partner company received the sample from a customer and generated the data set from the sample, and (b) loading the data set into a software system for biological interpretation of variants for future access by the user. 162. The method of claim 161 further comprising: (a) receiving a confirmation of an order from the customer after generation of an interactive report; and (b) providing the interactive report to the customer. 163. The method of claims 158-162 wherein the database of biological information is a knowledge base of curated biomedical content, and wherein the knowledge base is structured with an ontology. 164. The method of claims 158-162 wherein customer is a healthcare provider. 165. The method of claims 158-162 wherein customer is an individual. 166. The method of claims 158-162 wherein customer is a healthcare consumer. 167. The method of claims 158-162 wherein customer is an organization. 168. The method of claims 158-167 wherein the data set delivered by the provider of genomic analysis services and the interactive report for said data set are delivered to the customer on the same day. 169. The method of claims 158-167 wherein the data set delivered by the provider of genomic analysis services and the interactive report for said data set are delivered to the customer in the same week. 170. The method of claims 158-167 wherein genomic analysis services and the interactive report for the data set to be produced by said genomic analysis services are quoted to the customer on the same day. 171. The method of claims 158-170 wherein interactive report is generated using a filter cascade, wherein the filter cascade comprises one or more of: a pharmacogenetics, a common variant filter, a predicted deleterious filter, a cancer driver variants filter, a physical location filter, a genetic analysis filter, a expression filter, a user-defined variants filter, a biological context filter, or a custom annotation filter. 172. A method for displaying genetic information to a user comprising: (a) displaying to a user a two dimensional grid with samples on one axis and variants occurring in one or more samples on the other axis, wherein each cell of the grid represents a distinct instance of a variant (or lack thereof) in each sample, (b) displaying, in each cell one or more colored icons, wherein the color of the one or more icons in each cell of the grid varies depending upon whether the variant represented by that cell is predicted to cause a gain-of-function, loss-of-function, or result in normal function of a gene or gene network in the sample represented by that cell. 173. The method of claim 172, wherein a number of visually distinct shapes within a cell representing a particular variant and a particular sample correlates linearly with zygosity and/or copy number at the position of said particular variant in said particular sample. 174. The method of claim 172, wherein the icon in a cell is distinct in shape and/or color if the sample represented by that cell has a genotype that is identical to the reference genome. 175. The method of claim 172-174 wherein the color intensity is varied according to genotype quality, wherein higher color intensity indicates a higher quality measurement 176. The method of claim 172-174 wherein one or more of the icons in a cell change shape and/or color if the variant represented by that cell is predicted to create a gene fusion in the sample represented by that cell. 177. The method of claim 172-174 wherein the icon in a cell is distinct in shape and/or color if the location of the variant represented by that cell has no data or there is an inability to make an accurate genotype call at the position of that variant in the sample represented by that cell. 178. A computer program product bearing machine readable instructions to enact claims 158-177. 179. A computer-implemented pedigree builder wherein the pedigree builder is configured to: (a) utilize input from the user to identify the sample most likely derived from the mother of the individual from which a given sample was derived; (b) utilize input from the user to identify the sample most likely derived from the father of the individual from which a given sample was derived; 180. A computer-implemented pedigree builder of claim 179 wherein the pedigree builder is configured to construct pedigree information and make information available to a genetic analysis filter of claim 62 for further filtering of variants. 181. The pedigree builder of claim 180, wherein the pedigree builder infers trios and family relationships within a given study. 182. The pedigree builder of claim 180, wherein the pedigree builder identifies potential pedigree inconsistencies. 183. The pedigree builder of claim 182, wherein the pedigree builder identifies inconsistencies between relationships derived from user input and those derived from computational analysis. 184. The pedigree builder of claim 182, wherein pedigree inconsistencies may comprise non-paternity, sample mislabeling or sample mix-up errors or identification of related individuals in an association study designed to be comprised of unrelated individuals. 185. The pedigree builder of claim 180, wherein the pedigree builder assigns the same individual identifier to multiple samples derived from the same individual. 186. The pedigree builder of claim 185, wherein the pedigree builder is able to infer a patient's normal genome and the matched tumor genome(s) from the same patient. 187. A computer-implemented statistical association filter wherein the statistical association filter is configured to: (a) utilize inputs of a previous filter in a filter cascade as input; (b) filter variants using a basic allelic, dominant, or recessive model that are statistically significantly different between two or more sample groups; 188. The computer-implemented statistical association filter of claim 187, wherein the statistical association filter is configured to filter variants that perturb a gene differently between two or more sample groups with statistical significance using a burden test. 189. The computer-implemented statistical association filter of claim 187, wherein the statistical association filter is configured to filter variants that perturb a pathway/gene set differently between two or more sample groups using a pathway or gene set burden test. 190. The statistical association filter of claim 188 wherein the statistical significance distinguishes between phenotype-affected and unaffected states using a burden test selected from the following: a case-burden, control-burden, and 2-sided burden test. 191. The statistical association filter of claim 188 wherein the statistical significance of step (c) distinguishes between phenotype-affected and unaffected states using a burden test that utilizes only variants that pass the previous filter in the filter cascade of step (a) in computing statistically significant variants. 192. The statistical association filter of claim 188, wherein the statistical association filter is able to identify variants that are deleterious and contribute to inferred gene-level loss of function or inferred gene-level gain-of-function by utilizing the predicted deleterious filter of claim 114 and the genetic analysis filter of claim 53. 193. The statistical association filter of claim 189 wherein the pathway/geneset burden test distinguishes between phenotype-affected and unaffected states by utilizing a knowledge base of findings from the literature is able to identify genes that together form a collective interrelated set based upon one or more shared elements selected from one or more of the following: pathway biology, domain, expression, biological process, disease relevance, group and complex annotation; 194. The statistical association filter of claim 189 wherein the pathway or gene set burden test distinguishes between phenotype-affected and unaffected states by identifying variants that perturb said pathway or gene set significantly more or significantly less between two or more sample groups. 195. The statistical association filter of claim 189 wherein the pathway or gene set burden test is performed across a library of pathways/gene sets or a user-specified subset thereof. 196. A computer-implemented Publish Feature wherein the Publish Feature is configured to: (a) enable the user to specify an analysis of interest; (b) enable the user to enter a brief name and/or description of said analysis; (c) provide the user with a URL internet link that can be embedded by the user in a publication; (d) provide the user with the ability to release the published analysis for broad access; and (e) upon said release by the user, provide access to the user's published analysis to other users who access the URL of step (c) or who browse a list of available published analyses. 197. A computer-implemented Druggable Pathway Feature wherein, given one or more variants that are causal or driver variants for disease in one or more patient samples, the Druggable Pathway Feature is configured to: (a) identify drugs that are known to target, activate and/or repress a gene, gene product, or gene set that co-occurs in the same pathway or genetic network as said one or more variants; (b) identify the predicted net effect of said one or more variants in the patient sample on the pathway or genetic network above through causal network analysis; and (c) further identify drugs identified in step (a) that have a net effect on the pathway or genetic network that is directly opposite of the predicted impact of the said one or more variants on the said pathway or genetic network. 198. The Druggable Pathway Feature of claim 197 wherein the method is utilized to identify patient samples representing patients likely to respond to one or more specific drugs of interest based on their sequence variant profiles. 199. The pathogenicity annotator of claim 140 wherein said pathogenicity annotator is in communication with a knowledge base of disease models that define variants, genes, and pathways that are associated with that disease, wherein pathogenicity annotator utilizes the disease models to provide a pathogenicity assessment for a particular combination of a specific variant and a specific disease. 200. A computer-implemented Trinucleotide Repeat Annotator wherein the Trinucleotide Repeat Annotator is configured to: (a) interact with a knowledge base of known trinucleotide repeat regions that contain information on the number of repeats that are benign and the number of repeats that are associated with one or more human phenotypes or severities thereof; (b) assess the number of trinucleotide repeats at one or more genomic regions defined in the knowledge base in one or more patient whole genome or exome sequencing samples; (c) assess whether the trinucleotide repeat length calculated in (b) is sufficient to cause a phenotype based on the knowledge base, for each trinucleotide repeat; (d) communicate phenotype information to the user associated with the trinucleotide repeat length calculated in step (b) based on the knowledge base; and (e) communicate with a predicted deleterious filter to enable filtering of variants that cause a phenotype based on the results of the trinucleotide repeat annotator. 201. A Frequent Hitters Filter wherein the Frequent Hitters Filter is configured to: (a) access a knowledge base of hypervariable genes and genomic regions that are mutated among a collection of samples derived from individuals unaffected by the disease or phenotype of interest; (b) filter variants that occur within hypervariable genes and/or genomic regions.

Methods and systems for filtering variants in data sets comprising genomic information are provided herein.1. A biological context filter wherein the biological context filter: (a) is configured to receive a data set comprising variants wherein the data set comprises variant data from one or more samples from one or more individuals, (b) is in communication with a database of biological information, and (c) is capable of transforming the data set by filtering the data set by variants associated with biological information, wherein the filtering comprises establishing associations between the data set and some or all of the biological information. 2. The biological context filter of claim 1, wherein the database of biological information is a knowledge base of curated biomedical content, wherein the knowledge base is structured with an ontology. 3. The biological context filter of claim 2, wherein the associations between the variants and the biological information comprises a relationship defined by one or more hops. 4. The biological context filter of claim 2 wherein a user selects the biological information for filtering. 5. The biological context filter of claim 2 wherein the filtering unmasks variants associated with the biological information. 6. The biological context filter of claim 2 wherein the filtering masks variants not associated with the biological information. 7. The biological context filter of claim 2 wherein the filtering masks variants associated with biological information. 8. The biological context filter of claim 2 wherein the filtering unmasks variants not associated with the biological information. 9. The biological context filter of claim 2 wherein biological information for filtering is inferred from the data set. 10. The biological context filter of claim 2 wherein biological information for filtering is inferred from study design information previously inputted by a user. 11. The biological context filter of claim 2 wherein the biological context filter is combined with other filters in a filter cascade to generate a final variant list. 12. The biological context filter of claim 11 wherein the biological context filter is combined with one or more of the following filters in a filter cascade to reach a final variant list of less than 200 variants: common variant filter, predicted deleterious filter, cancer driver variants filter, physical location filter, genetic analysis filter, expression filter, user-defined variants filter, pharmacogenetics filter, or custom annotation filter. 13. The biological context filter of claim 2 wherein the biological context filter is combined with one or more of the following filters in a filter cascade to reach a final variant list of less than 50 variants: common variant filter, predicted deleterious filter, cancer driver variants filter, physical location filter, genetic analysis filter, expression filter, user-defined variants filter, pharmacogenetics filter, or custom annotation filter. 14. The biological context filter of claim 3 wherein the stringency of the biological context filter can be adjusted by a user, and wherein the stringency adjustment from the user alters one or more of the following: (a) the number of hops in an association used for filtering; (b) the strength of hops in an association used for filtering; (c) the net effect of the hops in an association used for filtering; and/or (d) the upstream or downstream nature of hops in an association used for filtering. 15. The biological context filter of claim 3 wherein the stringency of the biological context filter is adjusted automatically based upon the desired number of variants in the final filtered data set, wherein the stringency adjustment alters one or more of the following: (a) the number of hops in an association used for filtering; (b) the strength of hops in an association used for filtering; (c) the net effect of the hops in an association used for filtering; and/or (d) the upstream or downstream nature of hops in an association used for filtering. 16. The biological context filter of claims 2-15 wherein only upstream hops are used. 17. The biological context filter of claims 2-15 wherein only downstream hops are used. 18. The biological context filter of claims 2-15 wherein the net effects of hops are used. 19. The biological context filter of claim 2 wherein the biological information for filtering is biological function. 20. The biological context filter of claim 19 wherein the biological function is a gene, a transcript, a protein, a molecular complex, a molecular family or enzymatic activity, a therapeutic or therapeutic molecular target, a pathway, a process, a phenotype, a disease, a functional domain, a behavior, an anatomical characteristic, a physiological trait or state, a biomarker or a combination thereof. 21. The biological context filter of claim 2 where the stringency of the biological context filter is adjusted by selection of the biological information for filtering. 22. The biological context filter of claim 2 wherein the biological context filter is configured to accept a mask from another filter previously performed on the same data set. 23. The biological context filter of claim 2 wherein the biological context filter is in communication with hardware for outputting the filtered data set to a user. 24. A computer program product bearing machine readable instructions to enact the biological context filter of any of claims 1-23. 25. A cancer driver variants filter wherein the cancer driver variants filter: (a) is configured to receive a data set comprising variants wherein said data set comprises variant data from one or more samples from one or more individuals, and (b) is capable of transforming the data set by filtering the data set by variants associated with one or more proliferative disorders. 26. The cancer driver variants filter of claim 25 wherein the cancer driver variants filter is in communication with hardware for outputting the filtered data set to a user. 27. The cancer driver variant filter of claim 25 wherein the data set is suspected to contain variants associated with one or more proliferative disorders. 28. The cancer driver variant filter of claim 27 wherein the data set includes one or more samples derived from a patient with a proliferative disorder. 29. The cancer driver variants filter of claim 25 wherein the proliferative disorder is cancer. 30. The cancer driver variants filter of claim 25 wherein a user specifies one or more proliferative disorders of interest for filtering. 31. The cancer driver variants filter of claim 25 wherein the filtering unmasks variants associated with the one or more proliferative disorders. 32. The cancer driver variants filter of claim 25 wherein the filtering masks variants not associated with the one or more proliferative disorders. 33. The cancer driver variants filter of claim 25 wherein the filtering masks variants associated with the one or more proliferative disorders. 34. The cancer driver variants filter of claim 25 wherein the filtering unmasks variants not associated with the one or more proliferative disorders. 35. The cancer driver variants filter of claim 25 wherein the one or more proliferative disorders for filtering is inferred from the data set. 36. The cancer driver variants filter of claim 25 wherein the one or more proliferative disorders for filtering is inferred from study design information previously inputted by a user. 37. The cancer driver variants filter of claim 25 wherein cancer driver variants filter is combined with other filters in a filter cascade to generate a final variant list. 38. The cancer driver variants filter of claim 37 wherein the cancer driver variants filter is combined with one or more of the following filters in a filter cascade to reach a final variant list of less than 200 variants: common variant filter, predicted deleterious filter, biological context filter, physical location filter, genetic analysis filter, expression filter, user-defined variants filter, pharmacogenetics filter, or custom annotation filter. 39. The cancer driver variants filter of claim 37 wherein the cancer driver variants filter is combined with one or more of the following filters in a filter cascade to reach a final variant list of less than 50 variants: common variant filter, predicted deleterious filter, biological context filter, physical location filter, genetic analysis filter, expression filter, user-defined variants filter, pharmacogenetics filter, or custom annotation filter. 40. The cancer driver variants filter of claim 25 wherein the filtered variants are variants observed or predicted to meet one or more of the following criteria: a) are located in human genes having animal model orthologs with cancer-associated gene disruption phenotypes, b) impact known or predicted cancer subnetwork regulatory sites, c) impact cancer-associated cellular processes with or without enforcement of appropriate directionality, d) are associated with published cancer literature findings in a knowledge base at the variant- and/or gene-level, e) impact cancer-associated pathways with or without enforcement of appropriate directionality, and/or f) are associated with cancer therapeutic targets and/or upstream/causal subnetworks. 41. The cancer driver variants filter of claim 40 wherein the criteria are restricted to one or more specific cancer disease models. 42. The cancer driver variants filter of claim 25 wherein the cancer driver variants filter is in communication with a database of biological information, wherein the database of biological information is a knowledge base of curated biomedical content, wherein the knowledge base is structured with an ontology. 43. The cancer driver variants filter of claim 42 wherein the stringency of the cancer driver variants filter is user adjustable, wherein the stringency adjustment from the user alters the number of hops and/or the strength of hops in a relationship and/or whether or not the variants are observed or predicted to have one or more of the following characteristics: a) are located in human genes having animal model orthologs with cancer-associated gene disruption phenotypes, b) impact known or predicted cancer subnetwork regulatory sites, c) impact cancer-associated cellular processes with or without enforcement of appropriate directionality, d) are associated with published cancer literature findings in a knowledge base at the variant- and/or gene-level, e) impact cancer-associated pathways with or without enforcement of appropriate directionality, and/or f) are associated with cancer therapeutic targets and/or upstream/causal subnetworks. 44. The cancer driver variants filter of claim 42 wherein the stringency of the cancer driver variants filter is adjusted automatically based upon the desired number of variants in the final filtered data set, wherein the stringency adjustment alters the number of hops and/or the strength of hops in a relationship and/or whether or not the variants are observed or predicted to have one or more of the following characteristics: a) are located in human genes having animal model orthologs with cancer-associated gene disruption phenotypes, b) impact known or predicted cancer subnetwork regulatory sites, c) impact cancer-associated cellular processes with or without enforcement of appropriate directionality, d) are associated with published cancer literature findings in a knowledge base at the variant- and/or gene-level, e) impact cancer-associated pathways with or without enforcement of appropriate directionality, and/or f) are associated with cancer therapeutic targets and/or upstream/causal subnetworks. 45. The cancer driver variants filter of claim 42 wherein the variants associated with one or more proliferative disorders are variants which are one or more hops from variants that are predicted or observed to have one or more of the following characteristics: a) are located in human genes having animal model orthologs with cancer-associated gene disruption phenotypes, b) impact known or predicted cancer subnetwork regulatory sites, c) impact cancer-associated cellular processes with or without enforcement of appropriate directionality, d) are associated with published cancer literature findings in a knowledge base at the variant- and/or gene-level, e) impact cancer-associated pathways with or without enforcement of appropriate directionality, and/or f) are associated with cancer therapeutic targets and/or upstream/causal subnetworks. 46. The cancer driver variants filter of claims 42-45 wherein the stringency of the cancer driver variants filter is adjusted by weighting the strength of the hops. 47. The cancer driver variants filter of claims 42-45 wherein the stringency of the cancer driver variants filter is adjusted by altering the number of hops. 48. The cancer driver variants filter of claims 42-45 wherein the hops are upstream hops. 49. The cancer driver variants filter of claims 42-45 wherein the hops are downstream hops. 50. The cancer driver variants filter of claims 42-45 wherein the net effects of the hops are determined and only variants associated with cancer driving net effects are filtered. 51. The cancer driver variants filter of claim 25 wherein the cancer driver variants filter is configured to accept a mask from another filter previously performed on the same data set. 52. A computer program product bearing machine readable instructions to enact the cancer driver variants filter of claims 25-51. 53. A genetic analysis filter wherein the genetic analysis filter: (a) is configured to receive a data set comprising variants wherein said data set comprises variant data from one or more samples from one or more individuals, (b) is capable of transforming the data set by filtering the data set according to genetic logic. 54. The genetic analysis filter of claim 53 wherein the genetic analysis filter is in communication with hardware for outputting the filtered data set to a user. 55. The genetic analysis filter of claim 53 further configured to receive information optionally identifying samples from the same individual or hereditary relationships among individuals with samples in the data set. 56. The genetic analysis filter of claim 53 wherein the filtering comprises a) filtering variants that are present with a given zygosity in greater than or equal to a specified fraction of case samples but less than or equal to a specified fraction of control samples, and/or b) filtering variants that are present with a given zygosity in less than or equal to a specified fraction of case samples but greater than or equal to a specified fraction of control samples. 57. The genetic analysis filter of claim 53 wherein the filtering comprises a) filtering variants that are present at a given quality level in greater than or equal to a specified fraction of case samples but less than or equal to a specified fraction of control samples, and/or b) filtering variants that are present at a given quality level in less than or equal to a specified fraction of case samples but greater than or equal to a specified fraction of control samples. 58. The genetic analysis filter of claim 55 wherein at least one sample in the data set is a disease case sample and another sample in the data set is a normal control sample from the same individual, wherein the filtering comprises filtering variants either observed in both the disease and normal samples or observed uniquely in either the disease sample or the normal sample. 59. The genetic analysis filter of claim 53 wherein the genetic logic is configured based on presets from a user for recessive hereditary disease, dominant hereditary disease, de novo mutation, or cancer somatic variants. 60. The genetic analysis filter of claim 53 wherein variants are filtered that are inferred to contribute to a gain or loss of function of a gene in either (a) greater than or equal to a specified fraction of case samples but less than or equal to a specified fraction of control samples, or (b) less than or equal to a specified fraction of case samples but greater than or equal to a specified fraction of control samples. 61. The genetic analysis filter of claim 55 wherein the one or more samples in the data set are genetic parents of another sample in the data set. 62. The genetic analysis filter of claim 61 wherein the filtering comprises filtering variants from the data set that are incompatible with Mendelian genetics. 63. The genetic analysis filter of claim 61 wherein the filtering comprises filtering variants that are (a) absent in the child when at least one parent is homozygous, and/or (b) heterozygous in the child if both parents are homozygous. 64. The genetic analysis filter of claim 61 wherein the filtering comprises filtering variants absent in at least one of the parents of a homozygous child. 65. The genetic analysis filter of claim 61 wherein the filtering comprises filtering variants absent in both of the parents of a child with the variant. 66. The genetic analysis filter of claim 61 wherein filtered variants are single copy variants located in a hemizygous region of the genome. 67. The genetic analysis filter of claim 53-66 wherein the genetic analysis filter is further in communication with a database of biological information, wherein the database of biological information is a knowledge base of curated biomedical content, wherein the knowledge base is structured with an ontology, and wherein the variants from the data set can be associated with the biological information by hops. 68. The genetic analysis filter of claim 67 wherein the biological information comprises information regarding haploinsufficiency of genes. 69. The genetic analysis filter of claim 68 wherein heterozygous variants associated with haploinsuffucient genes are filtered. 70. The genetic analysis filter of claim 67 wherein variants are filtered that occur with zygosity and/or quality settings specified by the user in either (a) at least a specified number or minimal fraction of case samples and at most a specified number or maximum fraction of control samples, or (b) at most a specified number or maximum fraction of case samples and at least a specified number or minimum fraction of control samples. 71. The genetic analysis filter of claim 68 wherein variants are filtered that affect the same gene in either (a) at least a specified number or minimal fraction of case samples and at most a specified number or maximum fraction of control samples, or (b) at most a specified number or maximum fraction of case samples and at least a specified number or minimum fraction of control samples. 72. The genetic analysis filter of claim 68 wherein variants are filtered that affect the same network within 1 or more hops in either: (a) at least a specified number or minimal fraction of case samples and at least a specified number or maximum fraction of control samples, or (b) at most a specified number or maximum fraction of case samples and at least a specified number or minimum fraction of control samples. 73. The genetic analysis filter of claim 67 wherein the stringency of the genetic analysis filter is adjusted by weighting the strength of the hops. 74. The genetic analysis filter of claim 67 wherein the stringency of the genetic analysis filter is adjusted altering the number of hops. 75. The genetic analysis filter of claim 67 wherein the hops are upstream hops. 76. The genetic analysis filter of claim 67 wherein the hops are downstream hops. 77. The genetic analysis filter of claim 53 wherein the data set has been previously filtered and wherein a subset of the data points in the data set have been masked by the previous filter. 78. The genetic analysis filter of claim 53 wherein the stringency is adjusted by a user. 79. The genetic analysis filter of claim 53 wherein the filter stringency is adjusted automatically based on the desired number of variants in the final filtered data set. 80. The genetic analysis filter of claim 53 wherein the genetic analysis filter is combined with other filters in a filter cascade to yield a final filtered data set of interest to a user. 81. The genetic analysis filter of claim 80 combined with one or more of the following filters in a filter cascade to reach a final variant list of less than 50 variants: common variant filter, predicted deleterious filter, biological context filter, physical location filter, cancer driver variants filter, expression filter, user-defined variants filter, pharmacogenetics filter, or custom annotation filter. 82. The genetic analysis filter of claim 80 combined with one or more of the following filters in a filter cascade to reach a final variant list of less than 200 variants: common variant filter, predicted deleterious filter, biological context filter, physical location filter, cancer driver variants filter, expression filter, user-defined variants filter, pharmacogenetics filter, or custom annotation filter. 83. The genetic analysis filter of claims 78-79 wherein the stringency adjustment alters a zygosity requirement of the filter. 84. The genetic analysis filter of claims 78-79 wherein the stringency adjustment alters a variant quality requirement of the filter. 85. The genetic analysis filter of claims 78-79 wherein the stringency adjustment alters the required number or fraction of case samples for filtering. 86. The genetic analysis filter of claims 78-79 wherein the stringency adjustment alters whether the genetic analysis filter is filtering variants based on whether they (a) occur with zygosity and/or quality settings specified by the user, or (b) affect the same gene, or (c) affect the same network within 1 or more hops. 87. The genetic analysis filter of claims 78-79 wherein the stringency of the genetic analysis filter is adjusted by weighting the strength of the hops. 88. The genetic analysis filter of claims 78-79 wherein the stringency of the genetic analysis filter is adjusted by altering the number of hops. 89. The genetic analysis filter of claim 67 wherein the net effects of the hops are determined and only variants associated with user selected net effects are filtered. 90. The genetic analysis filter of claims 53-89 wherein the genetic analysis filter is configured to accept a mask from another filter previously performed on the same data set. 91. A computer program product bearing machine readable instructions to enact the genetic analysis filter of claims 53-90. 92. A pharmacogenetics filter wherein the pharmacogenetics filter (a) is configured to receive a data set comprising variants, wherein the data set comprises variant data from one or more samples from one or more individuals, (b) is in communication with a database of biological information, wherein the database of biological information is a knowledge base of curated biomedical content, wherein the knowledge base is structured with an ontology, wherein the biological information is information related to one or more drugs, and (c) is capable of transforming the data set by filtering the data set by variants associated with biological information, wherein the filtering comprises establishing associations between the data set and some or all of the biological information. 93. The pharmacogenetics filter of claim 92 wherein the pharmacogenetics filter is in communication with hardware for outputting the filtered data set to a user. 94. The pharmacogenetics filter of claim 92 wherein information related to one or more drugs comprises drug targets, drug responses, drug metabolism, or drug toxicity. 95. The pharmacogenetics filter of claim 92 wherein the associations between the variants and the biological information comprises a relationship defined by one or more hops. 96. The pharmacogenetics filter of claim 92 wherein a user selects the biological information for filtering. 97. The pharmacogenetics filter of claim 92 wherein the filtering unmasks variants associated with the biological information. 98. The pharmacogenetics filter of claim 92 wherein the filtering masks variants not associated with the biological information. 99. The pharmacogenetics filter of claim 92 wherein the filtering masks variants associated with biological information. 100. The pharmacogenetics filter of claim 92 wherein the filtering unmasks variants not associated with the biological information. 101. The pharmacogenetics filter of claim 92 wherein biological information for filtering is inferred from the data set. 102. The pharmacogenetics filter of claim 92 wherein biological information for filtering is inferred from study design information previously inputted by a user. 103. The pharmacogenetics filter of claim 92 wherein the pharmacogenetics filter is combined with other filters in a filter cascade to generate a final variant list. 104. The pharmacogenetics filter of claim 92 wherein the pharmacogenetics filter is combined with one or more of the following filters in a filter cascade to reach a final variant list of less than 200 variants: common variant filter, predicted deleterious filter, cancer driver variants filter, physical location filter, genetic analysis filter, expression filter, user-defined variants filter, biological context filter, or custom annotation filter. 105. The pharmacogenetics filter of claim 92 wherein the pharmacogenetics filter is combined with one or more of the following filters in a filter cascade to reach a final variant list of less than 50 variants: common variant filter, predicted deleterious filter, cancer driver variants filter, physical location filter, genetic analysis filter, expression filter, user-defined variants filter, biological context filter, or custom annotation filter. 106. The pharmacogenetics filter of claim 92 wherein the stringency of the pharmacogenetics filter can be adjusted by a user, and wherein the stringency adjustment from the user alters one or more of the following: (a) the number of hops in an association used for filtering; (b) the strength of hops in an association used for filtering; (c) whether or not predicted drug response information is used for filtering; (d) whether or not predicted drug metabolism or toxicity information is used for filtering; (e) whether or not established drug target(s) are used for filtering; (f) the net effect of the hops in an association used for filtering; and/or (g) the upstream or downstream nature of hops in an association used for filtering. 107. The pharmacogenetics filter of claim 92 wherein the stringency of the pharmacogenetics filter is adjusted automatically based upon the desired number of variants in the final filtered data set, wherein the stringency adjustment alters one or more of the following: (a) the number of hops in an association used for filtering (b) the strength of hops in an association used for filtering (c) whether or not predicted drug response information is used for filtering (d) whether or not predicted drug metabolism or toxicity information is used for filtering (e) whether or not established drug target(s) are used for filtering (f) the net effect of the hops in an association used for filtering and/or (g) the upstream or downstream nature of hops in an association used for filtering. 108. The pharmacogenetics filter of claim 92-107 wherein only upstream hops are used. 109. The pharmacogenetics filter of claim 92-107 wherein only downstream hops are used. 110. The pharmacogenetics filter of claim 92-109 wherein the net effects of hops are used. 111. The pharmacogenetics filter of claims 92-110 wherein a stringency of the pharmacogenetic filter is adjustable by the user. 112. The pharmacogenetics filter of claim 92 wherein the pharmacogenetics filter is configured to accept a mask from another filter previously performed on the same data set. 113. A computer program product bearing machine readable instructions to enact the pharmacogenetic filter variants filter of claims 92-112. 114. A predicted deleterious filter wherein the predicted deleterious filter: a) is configured to receive a data set comprising variants, wherein the data set comprises variant data from one or more samples from one or more individuals, and b) is capable of transforming the data set by filtering the data by variants predicted to be deleterious or non-deleterious. 115. The predicted deleterious filter of claim 114 wherein the predicted deleterious filter is in communication with hardware for outputting the filtered data set to a user. 116. The predicted deleterious filter of claim 114 wherein the filtering comprises utilizing at least one algorithm for predicting deleterious or non-deleterious variants in the data set and then filtering the predicted deleterious or non-deleterious variants. 117. The predicted deleterious filter of claim 116 wherein the at least one algorithm is SIFT, BSIFT, PolyPhen, PolyPhen2, PANTHER, SNPs3D, FastSNP, SNAP, LS-SNP, PMUT, PupaSuite, SNPeffect, SNPeffectV2.0, F-SNP, MAPP, PhD-SNP, MutDB, SNP Function Portal, PolyDoms, SNP@Promoter, Auto-Mute, MutPred, SNP@Ethnos, nsSNPanalyzer, SNP@Domain, StSNP, MtSNPscore, or Genome Variation Server. 118. The predicted deleterious filter of claim 114 wherein highly evolutionarily conserved variants are filtered. 119. The predicted deleterious filter of claim 116 wherein the predicted deleterious variants are filtered based on a gene fusion prediction algorithm. 120. The predicted deleterious filter of claim 114 wherein the predicted deleterious variants are filtered based on variants creating or disrupting a predicted or experimentally validated microRNA binding site. 121. The predicted deleterious filter of claim 116 wherein the predicted deleterious variants are filtered based on a predicted copy number gain algorithm. 122. The predicted deleterious filter of claim 116 wherein the predicted deleterious variants are filtered based on a predicted copy number loss algorithm. 123. The predicted deleterious filter of claim 116 wherein the predicted deleterious variants are filtered based on a predicted splice site loss or splice site gain. 124. The predicted deleterious filter of claim 114 wherein the predicted deleterious variants are filtered based on disruption of a known or predicted microRNA or ncRNA. 125. The predicted deleterious filter of claim 114 wherein the predicted deleterious variants are filtered based on disruption of or creation of a known or predicted transcription factor binding site. 126. The predicted deleterious filter of claim 114 wherein the predicted deleterious variants are filtered based on disruption of or creation of a known or predicted enhancer site. 127. The predicted deleterious filter of claim 114 wherein the predicted deleterious variants are filtered based on disruption of an untranslated region (UTR). 128. The predicted deleterious filter of claims 114-127 wherein the predicted deleterious filter is further in communication with a database of biological information, wherein the database of biological information is a knowledge base of curated biomedical content, wherein the knowledge base is structured with an ontology, and wherein the variants from the data set can be associated with the biological information either (a) directly based on one or more variant findings in the knowledge base, or (b) by a combination of gene findings and a functional prediction algorithm. 129. The predicted deleterious filter of claim 128 wherein the biological information comprises a deleterious phenotype, wherein the variants associated with the deleterious phenotypes are filtered. 130. The predicted deleterious filter of claim 129 wherein the deleterious phenotype is a disease. 131. The predicted deleterious filter of claim 114 wherein predicted deleterious variants comprise variants which are a) directly associated with a variant finding in the knowledge base, b) predicted deleterious (or non-innocuous) single nucleotide variants; c) predicted to create or disrupt a RNA splice site, d) predicted to create or disrupt a transcription factor binding site, e) predicted to disrupt non-coding RNAs, f) predicted to create or disrupt a microRNA target, or g) predicted to disrupt known enhancers. 132. The predicted deleterious filter of claim 114, combined with other filters in a filter cascade to yield a final filtered data set of interest to the user. 133. The predicted deleterious filter of claim 114 combined with one or more of the following filters in a filter cascade to reach a final variant list of less than 50 variants: common variant filter, biological context filter, physical location filter, genetic analysis filter, cancer driver variants filter, expression filter, user-defined variants filter, pharmacogenetics filter, or custom annotation filter. 134. The predicted deleterious filter of claim 114 combined with one or more of the following filters in a filter cascade to reach a final variant list of less than 200 variants: common variant filter, biological context filter, physical location filter, genetic analysis filter, cancer driver variants filter, expression filter, user-defined variants filter, pharmacogenetics filter, or custom annotation filter. 135. The predicted deleterious filter of claims 114-134 wherein a stringency of the predicted deleterious filter is adjustable by the user. 136. The predicted deleterious filter of 114-135 wherein the stringency is adjusted automatically based on the desired number of variants in the final filtered data set. 137. The predicted deleterious filter of claims 114-136 wherein the predicted deleterious variants are filtered based on a pathogenicity annotator. 138. The predicted deleterious filter of claims 114-137 wherein the predicted deleterious filter is configured to accept a mask from another filter previously performed on the same data set. 139. A computer program product bearing machine readable instructions to enact predicted deleterious filter of claims 114-138. 140. A pathogenicity annotator wherein the pathogenicity annotator categorizes variants using a predicted deleterious filter and a database of biological information, wherein the database of biological information is a knowledge base of curated biomedical content, and wherein the knowledge base is structured with an ontology. 141. The pathogenicity annotator of claim 140 wherein the pathogenicity annotator is in communication with hardware for outputting the categorization to a user. 142. The pathogenicity annotator of claim 140 wherein the variants outputted into the following categories: Pathogenic, Presumed Pathogenic or Likely Pathogenic, Unknown or Uncertain, Presumed Benign or Likely Benign, or Benign based upon a combination of the results of the predicted deleterious filter and the weight of evidence in the knowledge base supporting or refuting each variant's association with a deleterious phenotype. 143. The method of claim 142 wherein a) “Pathogenic” means <0.07% frequency of the variant in a database of genomes of individuals free from known genetic disease, and 2 or more findings drawing a causal or associative link between the variant and a deleterious phenotype from multiple different articles in the biomedical literature; b) “Presumed Pathogenic” or “Likely Pathogenic” means <0.07% frequency of the variant in a database of genomes of individuals free from known genetic disease, and 1 finding drawing a causal or associative link between the variant and a deleterious phenotype; c) “Unknown” or “Uncertain” means between 0.07% and 0.1% frequency of the variant in a database of genomes of individuals free from known genetic disease; d) “Presumed Benign” or “Likely Benign” means between 0.1% and 1% frequency of the variant in a database of genomes of individuals free from known genetic disease; and e) “Benign” means >=1% frequency of the variant in a database of genomes of individuals free from known genetic disease. 144. A preconfigurator wherein the preconfigurator is a) configured to receive information provided by a user related to a data set comprising variants wherein said data set comprises variant data from one or more samples from one or more individuals, b) in communication with one or more filters, c) in communication with the data set comprising variants, and d) capable of controlling the filters at least in part according to the information provided by the user; wherein the preconfigurator selects filters and filter stringency related to the information provided by the user to yield a final filtered data set. 145. The preconfigurator of claim 144 wherein the preconfigurator controls the addition, removal, and stringency settings of one or more of the following filters: common variants filter, predicted deleterious filter, genetic analysis filter, biological context filter, pharmacogenetics filter, physical location filter, or cancer driver variants filter. 146. The preconfigurator of claim 144 wherein the preconfigurator optimizes the addition or removal of filters and filter stringency settings to achieve a final filtered data set of no more than 200 variants 147. The preconfigurator of claim 144 wherein the preconfigurator optimizes the addition or removal of filters and filter stringency settings to achieve a final filtered data set of no more than 50 variants. 148. The preconfigurator of claim 144 wherein the information provided by the user includes the mode of inheritance of a disease of interest. 149. The preconfigurator of claim 144 wherein the information provided by the user includes a user input which can be recognized by the preconfigurator as an instruction for selecting filtering which: a) identifies causal disease variants, b) identifies cancer driver variants, c) identifies variants that stratify or differentiate one set of samples from another, or d) analyzes a genome to identify variants of interest for health management, treatment, personalized medicine and/or individualized medicine. 150. The preconfigurator of claim 144, wherein the preconfigurator is in communication with a knowledge base of curated biomedical content, wherein the knowledge base is structured with an ontology. 151. The preconfigurator of claim 144 wherein the information from a user includes biological information including one or more genes, transcripts, proteins, drugs, pathways, processes, phenotypes, diseases, functional domains, behaviors, anatomical characteristics, physiological traits or states, biomarkers or a combination thereof. 152. A computer program product bearing machine readable instructions to enact claims 144-151. 153. A method for identifying prospective causal variants comprising: (a) receiving a list of variants, (b) filtering the list of variants with one or more common variants filters, (c) filtering the list of variants with one or more predicted deleterious filters, (d) filtering the list of variants with one or more genetic analysis filters, (e) filtering the list of variants with one or more biological context filters, and (f) outputting the filtered list of variants as a list of prospective causal variants. 154. The method of claim 153 wherein the causal outputting step occurs less than 1 day following the receiving step. 155. The method of claim 153 wherein the causal outputting step occurs less than 1 week following the receiving step. 156. The method of claim 153 wherein the list of variants comprises more than 1 million variants and the outputted filtered list of variants comprises less than 50 variants. 157. A graphical user interface for displaying the output of a filter cascade, wherein the filter cascade comprises one or more of the following: a) a common variants filter, b) a predicted deleterious filter, c) a genetic analysis filter, d) a biological context filter, e) a pharmacogenetics filter, f) a statistical association filter, or g) a frequent hitter filter. 158. A method for the delivery of an interactive report method comprising the steps of: (a) receiving a request for a quotation, wherein the quotation request comprises a disclosure of a number by a customer, wherein the number is the number of samples the costumer would like a price quotation on for genomic analysis services; (b) transmitting a price quotation based at least in part upon the number of samples, wherein the price quotation comprises the cost of an interactive report for the biological interpretation of variants in the samples using a database of biological information, wherein the database of biological information is a knowledge base of curated biomedical content, and wherein the knowledge base is structured with an ontology; (c) receiving an order from a customer, wherein the order comprises ordering the interactive report for the biological interpretation of variants using a database of biological information; and (d) providing a hyperlink to the customer, wherein the hyperlink directs the customer to the interactive report for the biological interpretation of variants using a database of biological information. 159. A method for the delivery of an interactive report method comprising the steps of: (a) receiving a request for a quotation, wherein the quotation request comprises a disclosure of a number by a customer, wherein the number is the number of samples the costumer would like a price quotation on for genomic analysis services; (b) transmitting a price quotation at least in part based upon the number of samples, wherein the price quotation comprises the cost of an interactive report for the biological interpretation of variants using a database of biological information; (c) receiving an order from a customer, wherein the order does not include ordering the interactive report for the biological interpretation of variants using a database of biological information; and (d) providing a hyperlink to the customer, wherein the hyperlink directs the customer to the interactive report for the biological interpretation of variants using a database of biological information which provides the customer with the ability to transact for said interactive report online. 160. The method of claim 159 wherein the interactive report for the biological interpretation of variants using a database of biological information has been generated prior to providing the second price quotation. 161. A method for providing an interactive report to a customer for the biological interpretation of variants using a database of biological information comprising: (a) receiving a data set comprising genomic information from a partner company, wherein the partner company received the sample from a customer and generated the data set from the sample, and (b) loading the data set into a software system for biological interpretation of variants for future access by the user. 162. The method of claim 161 further comprising: (a) receiving a confirmation of an order from the customer after generation of an interactive report; and (b) providing the interactive report to the customer. 163. The method of claims 158-162 wherein the database of biological information is a knowledge base of curated biomedical content, and wherein the knowledge base is structured with an ontology. 164. The method of claims 158-162 wherein customer is a healthcare provider. 165. The method of claims 158-162 wherein customer is an individual. 166. The method of claims 158-162 wherein customer is a healthcare consumer. 167. The method of claims 158-162 wherein customer is an organization. 168. The method of claims 158-167 wherein the data set delivered by the provider of genomic analysis services and the interactive report for said data set are delivered to the customer on the same day. 169. The method of claims 158-167 wherein the data set delivered by the provider of genomic analysis services and the interactive report for said data set are delivered to the customer in the same week. 170. The method of claims 158-167 wherein genomic analysis services and the interactive report for the data set to be produced by said genomic analysis services are quoted to the customer on the same day. 171. The method of claims 158-170 wherein interactive report is generated using a filter cascade, wherein the filter cascade comprises one or more of: a pharmacogenetics, a common variant filter, a predicted deleterious filter, a cancer driver variants filter, a physical location filter, a genetic analysis filter, a expression filter, a user-defined variants filter, a biological context filter, or a custom annotation filter. 172. A method for displaying genetic information to a user comprising: (a) displaying to a user a two dimensional grid with samples on one axis and variants occurring in one or more samples on the other axis, wherein each cell of the grid represents a distinct instance of a variant (or lack thereof) in each sample, (b) displaying, in each cell one or more colored icons, wherein the color of the one or more icons in each cell of the grid varies depending upon whether the variant represented by that cell is predicted to cause a gain-of-function, loss-of-function, or result in normal function of a gene or gene network in the sample represented by that cell. 173. The method of claim 172, wherein a number of visually distinct shapes within a cell representing a particular variant and a particular sample correlates linearly with zygosity and/or copy number at the position of said particular variant in said particular sample. 174. The method of claim 172, wherein the icon in a cell is distinct in shape and/or color if the sample represented by that cell has a genotype that is identical to the reference genome. 175. The method of claim 172-174 wherein the color intensity is varied according to genotype quality, wherein higher color intensity indicates a higher quality measurement 176. The method of claim 172-174 wherein one or more of the icons in a cell change shape and/or color if the variant represented by that cell is predicted to create a gene fusion in the sample represented by that cell. 177. The method of claim 172-174 wherein the icon in a cell is distinct in shape and/or color if the location of the variant represented by that cell has no data or there is an inability to make an accurate genotype call at the position of that variant in the sample represented by that cell. 178. A computer program product bearing machine readable instructions to enact claims 158-177. 179. A computer-implemented pedigree builder wherein the pedigree builder is configured to: (a) utilize input from the user to identify the sample most likely derived from the mother of the individual from which a given sample was derived; (b) utilize input from the user to identify the sample most likely derived from the father of the individual from which a given sample was derived; 180. A computer-implemented pedigree builder of claim 179 wherein the pedigree builder is configured to construct pedigree information and make information available to a genetic analysis filter of claim 62 for further filtering of variants. 181. The pedigree builder of claim 180, wherein the pedigree builder infers trios and family relationships within a given study. 182. The pedigree builder of claim 180, wherein the pedigree builder identifies potential pedigree inconsistencies. 183. The pedigree builder of claim 182, wherein the pedigree builder identifies inconsistencies between relationships derived from user input and those derived from computational analysis. 184. The pedigree builder of claim 182, wherein pedigree inconsistencies may comprise non-paternity, sample mislabeling or sample mix-up errors or identification of related individuals in an association study designed to be comprised of unrelated individuals. 185. The pedigree builder of claim 180, wherein the pedigree builder assigns the same individual identifier to multiple samples derived from the same individual. 186. The pedigree builder of claim 185, wherein the pedigree builder is able to infer a patient's normal genome and the matched tumor genome(s) from the same patient. 187. A computer-implemented statistical association filter wherein the statistical association filter is configured to: (a) utilize inputs of a previous filter in a filter cascade as input; (b) filter variants using a basic allelic, dominant, or recessive model that are statistically significantly different between two or more sample groups; 188. The computer-implemented statistical association filter of claim 187, wherein the statistical association filter is configured to filter variants that perturb a gene differently between two or more sample groups with statistical significance using a burden test. 189. The computer-implemented statistical association filter of claim 187, wherein the statistical association filter is configured to filter variants that perturb a pathway/gene set differently between two or more sample groups using a pathway or gene set burden test. 190. The statistical association filter of claim 188 wherein the statistical significance distinguishes between phenotype-affected and unaffected states using a burden test selected from the following: a case-burden, control-burden, and 2-sided burden test. 191. The statistical association filter of claim 188 wherein the statistical significance of step (c) distinguishes between phenotype-affected and unaffected states using a burden test that utilizes only variants that pass the previous filter in the filter cascade of step (a) in computing statistically significant variants. 192. The statistical association filter of claim 188, wherein the statistical association filter is able to identify variants that are deleterious and contribute to inferred gene-level loss of function or inferred gene-level gain-of-function by utilizing the predicted deleterious filter of claim 114 and the genetic analysis filter of claim 53. 193. The statistical association filter of claim 189 wherein the pathway/geneset burden test distinguishes between phenotype-affected and unaffected states by utilizing a knowledge base of findings from the literature is able to identify genes that together form a collective interrelated set based upon one or more shared elements selected from one or more of the following: pathway biology, domain, expression, biological process, disease relevance, group and complex annotation; 194. The statistical association filter of claim 189 wherein the pathway or gene set burden test distinguishes between phenotype-affected and unaffected states by identifying variants that perturb said pathway or gene set significantly more or significantly less between two or more sample groups. 195. The statistical association filter of claim 189 wherein the pathway or gene set burden test is performed across a library of pathways/gene sets or a user-specified subset thereof. 196. A computer-implemented Publish Feature wherein the Publish Feature is configured to: (a) enable the user to specify an analysis of interest; (b) enable the user to enter a brief name and/or description of said analysis; (c) provide the user with a URL internet link that can be embedded by the user in a publication; (d) provide the user with the ability to release the published analysis for broad access; and (e) upon said release by the user, provide access to the user's published analysis to other users who access the URL of step (c) or who browse a list of available published analyses. 197. A computer-implemented Druggable Pathway Feature wherein, given one or more variants that are causal or driver variants for disease in one or more patient samples, the Druggable Pathway Feature is configured to: (a) identify drugs that are known to target, activate and/or repress a gene, gene product, or gene set that co-occurs in the same pathway or genetic network as said one or more variants; (b) identify the predicted net effect of said one or more variants in the patient sample on the pathway or genetic network above through causal network analysis; and (c) further identify drugs identified in step (a) that have a net effect on the pathway or genetic network that is directly opposite of the predicted impact of the said one or more variants on the said pathway or genetic network. 198. The Druggable Pathway Feature of claim 197 wherein the method is utilized to identify patient samples representing patients likely to respond to one or more specific drugs of interest based on their sequence variant profiles. 199. The pathogenicity annotator of claim 140 wherein said pathogenicity annotator is in communication with a knowledge base of disease models that define variants, genes, and pathways that are associated with that disease, wherein pathogenicity annotator utilizes the disease models to provide a pathogenicity assessment for a particular combination of a specific variant and a specific disease. 200. A computer-implemented Trinucleotide Repeat Annotator wherein the Trinucleotide Repeat Annotator is configured to: (a) interact with a knowledge base of known trinucleotide repeat regions that contain information on the number of repeats that are benign and the number of repeats that are associated with one or more human phenotypes or severities thereof; (b) assess the number of trinucleotide repeats at one or more genomic regions defined in the knowledge base in one or more patient whole genome or exome sequencing samples; (c) assess whether the trinucleotide repeat length calculated in (b) is sufficient to cause a phenotype based on the knowledge base, for each trinucleotide repeat; (d) communicate phenotype information to the user associated with the trinucleotide repeat length calculated in step (b) based on the knowledge base; and (e) communicate with a predicted deleterious filter to enable filtering of variants that cause a phenotype based on the results of the trinucleotide repeat annotator. 201. A Frequent Hitters Filter wherein the Frequent Hitters Filter is configured to: (a) access a knowledge base of hypervariable genes and genomic regions that are mutated among a collection of samples derived from individuals unaffected by the disease or phenotype of interest; (b) filter variants that occur within hypervariable genes and/or genomic regions.

This invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.

1. Method for the treatment of cancerous cell growth mediated by raf kinase comprising administering a compound of Formula I: A-D-B  (I) or a pharmaceutically acceptable salt thereof, wherein D is —NH—C(O)—NH—, A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L1)q, where L is a 5 or 6 membered cyclic structure bound directly to D, L1 comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L1 contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein L1 is substituted by at least one substituent selected from the group consisting of —SO2Rx, —C(O)Rx and —C(NRy)Rz, Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo, Rz is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; Rx is Rz or NRaRb where Ra and Rb are a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or —OSi(Rf)3 where Rf is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or c) one of Ra or Rb is —C(O)—, a C1-C5 divalent alkylene group or a substituted C1-C5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C1-C5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; where B is substituted, L is substituted or L1 is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3; wherein each W is independently selected from the group consisting of —CN, —CO2R7, —C(O)NR7R7, —C(O)—R7, —NO2, —OR7, —SR7, —NR7R7, —NR7C(O)OR7, —NR7C(O)R7, -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —CN, —CO2R7, —C(O)R7, —C(O)NR7R7, —OR7, —SR7, —NR7R7, —NO2, —NR7C(O)R7, —NR7C(O)OR7 and halogen up to per-halo; with each R7 independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, wherein Q is —O—, —S—, —N(R7)—, —(CH2)m—, —C(O)—, —CH(OH)—, —(CH2)mO—, —(CH2)mS—, —(CH2)mN(R7)—, —O(CH2)m—CHXa—, —CXa 2—, —S—(CH2)m— and —N(R7)(CH2)m—, where m=1-3, and Xa is halogen; and Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Zn1, wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —CN, —CO2R7, —C(O)R7, —C(O)NR7R7, —NO2, —OR7, —SR7—NR7R7, —NR7C(O)OR7, —NR7C(O)R7, and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of —CN, —CO2R7, —COR7, —C(O)NR7R7, —OR7, —SR7, —NO2, —NR7R7, —NR7C(O)R7, and —NR7C(O)OR7, with R7 as defined above. 2. A method as in claim 1 wherein: Ry is hydrogen, C1-10 alkyl, C1-10 alkoxy, C3-10 cycloalkyl having 0-3 heteroatoms, C2-10 alkenyl, C1-10 alkenoyl, C6-12 aryl, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C7-24 aralkyl, C7-24 alkaryl, substituted C1-10 alkyl, substituted C1-10 alkoxy, substituted C3-10 cycloalkyl having 0-3 heteroatoms selected from N, S and O, substituted C6-C14 aryl, substituted C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, substituted C7-24 alkaryl or substituted C7-C24 aralkyl, where Ry is a substituted group, it is substituted by halogen up to per halo, Rz is hydrogen, C1-10 alkyl, C1-10 alkoxy, C3-10 cycloalkyl having 0-3 heteroatom, C2-10 alkenyl, C1-10 alkenoyl, C6-12 aryl, C3-C12 hetaryl having 1-3 heteroatoms selected from, S, N and O, C7-24 alkaryl, C7-24 aralkyl, substituted C1-10 alkyl, substituted C1-10 alkoxy, substituted C6-C14 aryl, substituted C3-C10 cycloalkyl having 0-3 heteroatoms selected from S, N and O, substituted C3-12 hetaryl having 1-3 heteroatoms selected from S, N and O, substituted C7-24 alkaryl or substituted C7-C24 aralkyl where Rz is a substituted group, it is substituted by halogen up to per halo, hydroxy, C1-10 alkyl, C3-12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C1-10 alkoxy, C6-12 aryl, C1-6 halo substituted alkyl up to per halo alkyl, C6-C12 halo substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl up to per halo cycloalkyl having 0-3 heteroatoms selected from N, S and O, halo substituted C3-C12 hetaryl up to per halo hetaryl having 1-3 heteroatoms selected from O, N and S, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per halo alkaryl, and —C(O)Rg, Ra and Rb are, a) independently hydrogen, a carbon based moiety selected from to group consisting of C1-C10 alkyl, C1-C10 alkoxy, C3-10 cycloalkyl, C2-10 alkenyl, C1-10 alkenoyl, C6-12 aryl, C3-12 hetaryl having 1-3 heteroatoms selected from O, N and S, C3-12 cycloalkyl having 0-3 heteroatoms selected from N, S and O, C7-24 aralkyl, C7-C24 alkaryl, substituted C1-10 alkyl, substituted C1-10 alkoxy, substituted C3-10 cycloalkyl, having 0-3 heteroatoms selected from N, S and O, substituted C6-12 aryl, substituted C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, substituted C7-24 aralkyl, substituted C7-24 alkaryl, where Ra and Rb are a substituted group, they are substituted by halogen up to per halo, hydroxy, C1-10 alkyl, C3-12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C1-10 alkoxy, C6-12 aryl, C1-6 halo substituted alkyl up to per halo alkyl, C6-C12 halo substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3-C12 hetaryl up to per halo heteroaryl, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per halo alkaryl, and —C(O)Rg; or —OSi(Rf)3 where Rf is hydrogen, C1-10 alkyl, C1-10 alkoxy, C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C6-12 aryl, C3-C12 hetaryl having 1-3 heteroatoms selected from O, S and N, C7-24 aralkyl, substituted C1-10 alkyl, substituted C1-C10 alkoxy, substituted C3-C12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, substituted C3-C12 heteroaryl having 1-3 heteroatoms selected from O, S, and N, substituted C6-12 aryl, and substituted C7-24 alkaryl, where Rf is a substituted group it is substituted halogen up to per halo, hydroxy, C1-10 alkyl, C3-12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C1-10 alkoxy, C6-12 aryl, C7-C24 alkaryl, C7-C24 aralkyl, C1-6 halo substituted alkyl up to per halo alkyl, C6-C12 halo substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3-C12 hetaryl up to per halo heteroaryl, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per halo alkaryl, and —C(O)Rg, or b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O with substituents selected from the group consisting of halogen up to per halo, hydroxy, C1-10 alkyl, C3-12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C1-10 alkoxy, C6-12 aryl, C7-C24 alkaryl, C7-C24 aralkyl, halo substituted C1-6 alkyl up to per halo alkyl, halo substituted C6-C12 aryl up to per halo aryl, halo substituted C3-C12 cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3-C12 hetaryl up to per halo heteroaryl, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per halo alkaryl, and —C(O)Rg, or c) one of Ra or Rb is —C(O)—, a C1-C5 divalent alkylene group or a substituted C1-C5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C1-C5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, C1-10 alkyl, C3-12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C1-10 alkoxy, C6-12 aryl, C7-C24 alkaryl, C7-C24 aralkyl, C1-6 halo substituted alkyl up to per halo alkyl, C6-C12 halo substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3-C12 hetaryl up to per halo heteroaryl, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per halo alkaryl, and —C(O)Rg, where Rg is C1-10 alkyl; —CN, —CO2Rd, —ORd, —SRd, —NO2, —C(O)Re, —NRdRe, —NRdC(O)ORe and —NRdC(O)Re, and Rd and Re are independently selected from the group consisting of hydrogen, C1-10, alkyl, C1-10 alkoxy, C3-10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, C6-12 aryl, C3-C12 hetaryl with 1-3 heteroatoms selected from O, N and S and C7-C24 aralkyl, C7-C24 alkaryl, up to per halo substituted C1-C10 alkyl, up to per halo substituted C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, up to per halo substituted C6-C14 aryl, up to per halo substituted C3-C12 hetaryl having 1-3 heteroatoms selected from O, N, and S, halo substituted C7-C24 alkaryl up to per halo alkaryl, and up to per halo substituted C7-C24 aralkyl, W is independently selected from the group consisting of —CN, —CO2R7, —C(O)NR7R7, —C(O)—R7, —NO2, —OR7, —SR7, —NR7R7, —NR7C(O)OR7, —NR7C(O)R7, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C1-C10 alkenoyl, C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C6-C14 aryl, C7-C24 alkaryl, C7-C24 aralkyl, C3-C12 heteroaryl having 1-3 heteroatoms selected from O, N and S, C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N and S, substituted C1-C10 alkyl, substituted C1-C10 alkoxy, substituted C2-C10 alkenyl, substituted C1-C10 alkenoyl, substituted C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, substituted C6-C12 aryl, substituted C3-C12 hetaryl having 1-3 heteroatoms selected from O, N and S, substituted C7-C24 aralkyl, substituted C7-C24 alkaryl, substituted C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N and S, and -Q-Ar; R7 is independently selected from H, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C1-C10 alkenoyl, C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C6-C14 aryl, C3-C13 hetaryl having 1-3 heteroatoms selected from O, N and S, C7-C14 alkaryl, C7-C24 aralkyl, C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N and S, up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, up to per-halosubstituted C6-C14 aryl, up to per-halosubstituted C3-C13 hetaryl having 1-3 heteroatoms selected from O, N and S, up to per-halosubstituted C7-C24 aralkyl, up to per-halosubstituted C7-C24 alkaryl, and up to per-halosubstituted C4-C23 alkheteroaryl; and each Z is independently selected from the group consisting of —CN, —CO2R7, —C(O)R7, —C(O)NR7R7, —NO2, —OR7, —SR7—NR7R7, —NR7C(O)OR7, —NR7C(O)R7, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C1-C10 alkenoyl, C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, C6-C14 aryl, C3-C13 hetaryl having 1-3 heteroatoms selected from O, N and S, C7-C24 alkaryl, C7-C24 aralkyl, C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N and S, substituted C1-C10 alkyl, substituted C1-C10 alkoxy, substituted C2-C10 alkenyl, substituted C1-C10 alkenoyl, substituted C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, substituted C6-C12 aryl, substituted C7-C24 alkaryl, substituted C7-C24 aralkyl and substituted C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N and S; wherein if Z is a substituted group, the one or more substituents are selected from the group consisting of —CN, —CO2R7, —COR7, —C(O)NR7R7, —OR7, —SR7, —NO2, —NR7R7, —NR7C(O)R7, and —NR7C(O)OR7. 3-28. (canceled) 29-38. (canceled) 39. Method for the treatment of cancerous cell growth mediated by raf kinase comprising administering a urea of Formula I: A-D-B  (I) or a pharmaceutically acceptable salt thereof, wherein D is —NH—C(O)—NH—, A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L1)q, where L is a substituted or unsubstituted phenyl or peritoneal moiety bound directly to D, L1 comprises a substituted phenyl, peritoneal or pyrimidinyl moiety, M is a bridging group having at least one atom, q is an integer of from 1-3; and B is a substituted or unsubstituted phenyl or pyridine group bound directly to D, wherein L1 is substituted by at least one substituent selected from the group consisting of —SO2Rx, —C(O)Rx and —C(NRy)Rz, Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo, and; Rz is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; Rx is Rz or NRaRb where Ra and Rb are a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or —OSi(Rf)3 where Rf is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or c) one of Ra or Rb is —C(O)—, a C1-C5 divalent alkylene group or a substituted C1-C5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C1-C5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; where B is substituted, L is substituted or L1 is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3; wherein each W is independently selected from the group consisting of —CN, —CO2R7, —C(O)NR7R7, —C(O)—R7, —NO2, —OR7, —SR7, —NR7R7, —NR7C(O)OR7, —NR7C(O)R7, -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —CN, —CO2R7, —C(O)R7, —C(O)NR7R7, —OR7, —SR7, —NR7R7, —NO2, —NR7C(O)R7, —NR7C(O)OR7 and halogen up to per-halo; with each R7 independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, wherein Q is —O—, —S—, —N(R7)—, —(CH2)m—, —C(O)—, —CH(OH)—, —(CH2)mO—, —(CH2)mS—, —(CH2)mN(R7)—, —O(CH2)m—CHXa—, —CXa 2—, —S—(CH2)m— and —N(R7)(CH2)m—, where m=1-3, and Xa is halogen; Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Zn1, wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —CN, —CO2R7, —C(O)R7, —C(O)NR7R7, —NO2, —OR7, —SR7—NR7R7, —NR7C(O)OR7, —NR7C(O)R7, and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of —CN, —CO2R7, —COR7, —C(O)NR7R7, —OR7, —SR7, —NO2, —NR7R7, —NR7C(O)R7, and —NR7C(O)OR7; and wherein M is one or more bridging groups selected from the group consisting of —O—, —S—, —N(R7)—, —(CH2)m—, —C(O)—, —CH(OH)—, —(CH2)mO—, —(CH2)mS—, —(CH2)mN(R7)—, —O(CH2)m—CHXa—, —CXa 2—, —S—(CH2)m— and —N(R7)(CH2)m—, where m=1-3, Xa is halogen. 40-46. (canceled) 47. A method of claim 39 wherein L1 is substituted by C(O)Rx. 48. (canceled) 49. A method of claim 47 wherein Rx is NRaRb and Ra and Rb are independently hydrogen and a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen. 50. A method of claim 1 wherein the compound of formula I is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations. 51-53. (canceled) 54. A method of claim 39 wherein the urea of formula I is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations. 55-66. (canceled) 67. A method for the treatment of a cancerous cell growth mediated by raf kinase, comprising administrating a compound selected from the group consisting of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea.

This invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.1. Method for the treatment of cancerous cell growth mediated by raf kinase comprising administering a compound of Formula I: A-D-B  (I) or a pharmaceutically acceptable salt thereof, wherein D is —NH—C(O)—NH—, A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L1)q, where L is a 5 or 6 membered cyclic structure bound directly to D, L1 comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L1 contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein L1 is substituted by at least one substituent selected from the group consisting of —SO2Rx, —C(O)Rx and —C(NRy)Rz, Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo, Rz is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; Rx is Rz or NRaRb where Ra and Rb are a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or —OSi(Rf)3 where Rf is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or c) one of Ra or Rb is —C(O)—, a C1-C5 divalent alkylene group or a substituted C1-C5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C1-C5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; where B is substituted, L is substituted or L1 is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3; wherein each W is independently selected from the group consisting of —CN, —CO2R7, —C(O)NR7R7, —C(O)—R7, —NO2, —OR7, —SR7, —NR7R7, —NR7C(O)OR7, —NR7C(O)R7, -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —CN, —CO2R7, —C(O)R7, —C(O)NR7R7, —OR7, —SR7, —NR7R7, —NO2, —NR7C(O)R7, —NR7C(O)OR7 and halogen up to per-halo; with each R7 independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, wherein Q is —O—, —S—, —N(R7)—, —(CH2)m—, —C(O)—, —CH(OH)—, —(CH2)mO—, —(CH2)mS—, —(CH2)mN(R7)—, —O(CH2)m—CHXa—, —CXa 2—, —S—(CH2)m— and —N(R7)(CH2)m—, where m=1-3, and Xa is halogen; and Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Zn1, wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —CN, —CO2R7, —C(O)R7, —C(O)NR7R7, —NO2, —OR7, —SR7—NR7R7, —NR7C(O)OR7, —NR7C(O)R7, and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of —CN, —CO2R7, —COR7, —C(O)NR7R7, —OR7, —SR7, —NO2, —NR7R7, —NR7C(O)R7, and —NR7C(O)OR7, with R7 as defined above. 2. A method as in claim 1 wherein: Ry is hydrogen, C1-10 alkyl, C1-10 alkoxy, C3-10 cycloalkyl having 0-3 heteroatoms, C2-10 alkenyl, C1-10 alkenoyl, C6-12 aryl, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C7-24 aralkyl, C7-24 alkaryl, substituted C1-10 alkyl, substituted C1-10 alkoxy, substituted C3-10 cycloalkyl having 0-3 heteroatoms selected from N, S and O, substituted C6-C14 aryl, substituted C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, substituted C7-24 alkaryl or substituted C7-C24 aralkyl, where Ry is a substituted group, it is substituted by halogen up to per halo, Rz is hydrogen, C1-10 alkyl, C1-10 alkoxy, C3-10 cycloalkyl having 0-3 heteroatom, C2-10 alkenyl, C1-10 alkenoyl, C6-12 aryl, C3-C12 hetaryl having 1-3 heteroatoms selected from, S, N and O, C7-24 alkaryl, C7-24 aralkyl, substituted C1-10 alkyl, substituted C1-10 alkoxy, substituted C6-C14 aryl, substituted C3-C10 cycloalkyl having 0-3 heteroatoms selected from S, N and O, substituted C3-12 hetaryl having 1-3 heteroatoms selected from S, N and O, substituted C7-24 alkaryl or substituted C7-C24 aralkyl where Rz is a substituted group, it is substituted by halogen up to per halo, hydroxy, C1-10 alkyl, C3-12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C1-10 alkoxy, C6-12 aryl, C1-6 halo substituted alkyl up to per halo alkyl, C6-C12 halo substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl up to per halo cycloalkyl having 0-3 heteroatoms selected from N, S and O, halo substituted C3-C12 hetaryl up to per halo hetaryl having 1-3 heteroatoms selected from O, N and S, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per halo alkaryl, and —C(O)Rg, Ra and Rb are, a) independently hydrogen, a carbon based moiety selected from to group consisting of C1-C10 alkyl, C1-C10 alkoxy, C3-10 cycloalkyl, C2-10 alkenyl, C1-10 alkenoyl, C6-12 aryl, C3-12 hetaryl having 1-3 heteroatoms selected from O, N and S, C3-12 cycloalkyl having 0-3 heteroatoms selected from N, S and O, C7-24 aralkyl, C7-C24 alkaryl, substituted C1-10 alkyl, substituted C1-10 alkoxy, substituted C3-10 cycloalkyl, having 0-3 heteroatoms selected from N, S and O, substituted C6-12 aryl, substituted C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, substituted C7-24 aralkyl, substituted C7-24 alkaryl, where Ra and Rb are a substituted group, they are substituted by halogen up to per halo, hydroxy, C1-10 alkyl, C3-12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C1-10 alkoxy, C6-12 aryl, C1-6 halo substituted alkyl up to per halo alkyl, C6-C12 halo substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3-C12 hetaryl up to per halo heteroaryl, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per halo alkaryl, and —C(O)Rg; or —OSi(Rf)3 where Rf is hydrogen, C1-10 alkyl, C1-10 alkoxy, C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C6-12 aryl, C3-C12 hetaryl having 1-3 heteroatoms selected from O, S and N, C7-24 aralkyl, substituted C1-10 alkyl, substituted C1-C10 alkoxy, substituted C3-C12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, substituted C3-C12 heteroaryl having 1-3 heteroatoms selected from O, S, and N, substituted C6-12 aryl, and substituted C7-24 alkaryl, where Rf is a substituted group it is substituted halogen up to per halo, hydroxy, C1-10 alkyl, C3-12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C1-10 alkoxy, C6-12 aryl, C7-C24 alkaryl, C7-C24 aralkyl, C1-6 halo substituted alkyl up to per halo alkyl, C6-C12 halo substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3-C12 hetaryl up to per halo heteroaryl, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per halo alkaryl, and —C(O)Rg, or b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O with substituents selected from the group consisting of halogen up to per halo, hydroxy, C1-10 alkyl, C3-12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C1-10 alkoxy, C6-12 aryl, C7-C24 alkaryl, C7-C24 aralkyl, halo substituted C1-6 alkyl up to per halo alkyl, halo substituted C6-C12 aryl up to per halo aryl, halo substituted C3-C12 cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3-C12 hetaryl up to per halo heteroaryl, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per halo alkaryl, and —C(O)Rg, or c) one of Ra or Rb is —C(O)—, a C1-C5 divalent alkylene group or a substituted C1-C5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C1-C5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, C1-10 alkyl, C3-12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C1-10 alkoxy, C6-12 aryl, C7-C24 alkaryl, C7-C24 aralkyl, C1-6 halo substituted alkyl up to per halo alkyl, C6-C12 halo substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3-C12 hetaryl up to per halo heteroaryl, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per halo alkaryl, and —C(O)Rg, where Rg is C1-10 alkyl; —CN, —CO2Rd, —ORd, —SRd, —NO2, —C(O)Re, —NRdRe, —NRdC(O)ORe and —NRdC(O)Re, and Rd and Re are independently selected from the group consisting of hydrogen, C1-10, alkyl, C1-10 alkoxy, C3-10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, C6-12 aryl, C3-C12 hetaryl with 1-3 heteroatoms selected from O, N and S and C7-C24 aralkyl, C7-C24 alkaryl, up to per halo substituted C1-C10 alkyl, up to per halo substituted C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, up to per halo substituted C6-C14 aryl, up to per halo substituted C3-C12 hetaryl having 1-3 heteroatoms selected from O, N, and S, halo substituted C7-C24 alkaryl up to per halo alkaryl, and up to per halo substituted C7-C24 aralkyl, W is independently selected from the group consisting of —CN, —CO2R7, —C(O)NR7R7, —C(O)—R7, —NO2, —OR7, —SR7, —NR7R7, —NR7C(O)OR7, —NR7C(O)R7, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C1-C10 alkenoyl, C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C6-C14 aryl, C7-C24 alkaryl, C7-C24 aralkyl, C3-C12 heteroaryl having 1-3 heteroatoms selected from O, N and S, C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N and S, substituted C1-C10 alkyl, substituted C1-C10 alkoxy, substituted C2-C10 alkenyl, substituted C1-C10 alkenoyl, substituted C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, substituted C6-C12 aryl, substituted C3-C12 hetaryl having 1-3 heteroatoms selected from O, N and S, substituted C7-C24 aralkyl, substituted C7-C24 alkaryl, substituted C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N and S, and -Q-Ar; R7 is independently selected from H, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C1-C10 alkenoyl, C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C6-C14 aryl, C3-C13 hetaryl having 1-3 heteroatoms selected from O, N and S, C7-C14 alkaryl, C7-C24 aralkyl, C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N and S, up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, up to per-halosubstituted C6-C14 aryl, up to per-halosubstituted C3-C13 hetaryl having 1-3 heteroatoms selected from O, N and S, up to per-halosubstituted C7-C24 aralkyl, up to per-halosubstituted C7-C24 alkaryl, and up to per-halosubstituted C4-C23 alkheteroaryl; and each Z is independently selected from the group consisting of —CN, —CO2R7, —C(O)R7, —C(O)NR7R7, —NO2, —OR7, —SR7—NR7R7, —NR7C(O)OR7, —NR7C(O)R7, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C1-C10 alkenoyl, C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, C6-C14 aryl, C3-C13 hetaryl having 1-3 heteroatoms selected from O, N and S, C7-C24 alkaryl, C7-C24 aralkyl, C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N and S, substituted C1-C10 alkyl, substituted C1-C10 alkoxy, substituted C2-C10 alkenyl, substituted C1-C10 alkenoyl, substituted C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, substituted C6-C12 aryl, substituted C7-C24 alkaryl, substituted C7-C24 aralkyl and substituted C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N and S; wherein if Z is a substituted group, the one or more substituents are selected from the group consisting of —CN, —CO2R7, —COR7, —C(O)NR7R7, —OR7, —SR7, —NO2, —NR7R7, —NR7C(O)R7, and —NR7C(O)OR7. 3-28. (canceled) 29-38. (canceled) 39. Method for the treatment of cancerous cell growth mediated by raf kinase comprising administering a urea of Formula I: A-D-B  (I) or a pharmaceutically acceptable salt thereof, wherein D is —NH—C(O)—NH—, A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L1)q, where L is a substituted or unsubstituted phenyl or peritoneal moiety bound directly to D, L1 comprises a substituted phenyl, peritoneal or pyrimidinyl moiety, M is a bridging group having at least one atom, q is an integer of from 1-3; and B is a substituted or unsubstituted phenyl or pyridine group bound directly to D, wherein L1 is substituted by at least one substituent selected from the group consisting of —SO2Rx, —C(O)Rx and —C(NRy)Rz, Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo, and; Rz is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; Rx is Rz or NRaRb where Ra and Rb are a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or —OSi(Rf)3 where Rf is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or c) one of Ra or Rb is —C(O)—, a C1-C5 divalent alkylene group or a substituted C1-C5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C1-C5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; where B is substituted, L is substituted or L1 is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3; wherein each W is independently selected from the group consisting of —CN, —CO2R7, —C(O)NR7R7, —C(O)—R7, —NO2, —OR7, —SR7, —NR7R7, —NR7C(O)OR7, —NR7C(O)R7, -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —CN, —CO2R7, —C(O)R7, —C(O)NR7R7, —OR7, —SR7, —NR7R7, —NO2, —NR7C(O)R7, —NR7C(O)OR7 and halogen up to per-halo; with each R7 independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, wherein Q is —O—, —S—, —N(R7)—, —(CH2)m—, —C(O)—, —CH(OH)—, —(CH2)mO—, —(CH2)mS—, —(CH2)mN(R7)—, —O(CH2)m—CHXa—, —CXa 2—, —S—(CH2)m— and —N(R7)(CH2)m—, where m=1-3, and Xa is halogen; Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Zn1, wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —CN, —CO2R7, —C(O)R7, —C(O)NR7R7, —NO2, —OR7, —SR7—NR7R7, —NR7C(O)OR7, —NR7C(O)R7, and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of —CN, —CO2R7, —COR7, —C(O)NR7R7, —OR7, —SR7, —NO2, —NR7R7, —NR7C(O)R7, and —NR7C(O)OR7; and wherein M is one or more bridging groups selected from the group consisting of —O—, —S—, —N(R7)—, —(CH2)m—, —C(O)—, —CH(OH)—, —(CH2)mO—, —(CH2)mS—, —(CH2)mN(R7)—, —O(CH2)m—CHXa—, —CXa 2—, —S—(CH2)m— and —N(R7)(CH2)m—, where m=1-3, Xa is halogen. 40-46. (canceled) 47. A method of claim 39 wherein L1 is substituted by C(O)Rx. 48. (canceled) 49. A method of claim 47 wherein Rx is NRaRb and Ra and Rb are independently hydrogen and a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen. 50. A method of claim 1 wherein the compound of formula I is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations. 51-53. (canceled) 54. A method of claim 39 wherein the urea of formula I is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations. 55-66. (canceled) 67. A method for the treatment of a cancerous cell growth mediated by raf kinase, comprising administrating a compound selected from the group consisting of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea.

An oral care composition comprising (a) a silica abrasive having an average particle size of no greater than the diameter of a dentin tubule, or, alternatively 8 microns or less; (b) zinc citrate, (c) a bioadhesive agent, and (d) an anticalculus agent. The oral care composition can reduce or inhibit biofilm formation and/or dentinal hypersensitivity in an oral cavity.

1. An oral care composition comprising (a) a silica abrasive having an average particle size of 8 microns or less, 1.5-6 microns, 2.7-4 microns or 3.5 microns; (b) zinc citrate, (c) a bioadhesive agent, and (d) an anticalculus agent. 2. The oral care composition of claim 1, in the form of a dentifrice wherein the silica having an average particle size of no greater than the diameter of a dentin tubule is in an amount of 1% to 20% by weight, 2% to 10% by weight or 4%-6% by weight based on the total weight of the composition, and the zinc citrate is present in an amount of 0.01 to 5%, or 0.1 to 5%, or 0.2 to 5%, or 0.2 to 3%, or 1% to 3% to 5% by weight based on the total weight of the composition, and further comprising an orally acceptable carrier that is a dentifrice base. 3. The oral care composition of claim 1, wherein the bioadhesive agent is in an amount of from 0.1 weight % to 10 weight %; 0.5 weight % to 4 weight %; 1 weight % to 2 weight %; or 1.5 weight %, based on the total weight of the composition. 4. The oral care composition of claim 1, wherein the total amount of anticalculus agent is in an amount of from 0.5 weight % to 5 weight %; 1.0 weight % to 3 weight %; or 2.4 to 2.5 weight %, based on the total weight of the composition. 5. The oral care composition of claim 1, wherein the total amount of abrasives is 5 to 60% by weight, 5 to 45% by weight, 5 to 35% by weight, 5 to 30% by weight, 5 to 25% by weight, 10 to 20% by weight, or 20% by weight based on the total weight of the composition. 6. The oral care composition of claim 1, wherein the total amount of bioadhesive agent is a polyvinyl methyl ether/maleic anhydride copolymer in amount of 0.1 weight % to 10 weight %; 0.5 weight % to 4 weight %; 1 weight % to 2 weight %; or 1.5 weight %, based on the total weight of the composition, and the antialculus agent is tetrapotassium pyrophosphate or tetrasodium pyrophosphate in an amount from in an amount of from 0.5 weight % to 5 weight %; 1.0 weight % to 3 weight %; or 2.4 to 2.5 weight %, based on the total weight of the composition. 7. The oral care composition of claim 1 further comprising an effective amount of fluoride wherein the fluoride is a salt selected from stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride (e.g., N′-octadecyltrimethylendiamine-N,N,N′-tris(2-ethanol)-dihydrofluoride), ammonium fluoride, titanium fluoride, hexafluorosulfate, and combinations thereof. 8. The oral care composition of claim 1 further comprising one or more surfactants selected from anionic, cationic, zwitterionic, and nonionic surfactants, and mixtures thereof. 9. The oral care composition of claim 1 further comprising a humectant selected from glycerin, sorbitol, propylene glycol, polyethylene glycol, xylitol, and mixtures thereof. 10. The oral care composition of claim 1 further comprising a viscosity modifying amount of one or more polymers selected from polyethylene glycols, polysaccharides, cellulose derivatives, carboxymethyl cellulose, polysaccharide gums, xanthan gum, carrageenan gum, and combinations thereof. 11. The oral care composition of claim 1 further comprising a buffering agent, a flavorant, a colorant, a fragrance, a whitening agent or a combination thereof. 12. The oral care composition of claim 1 further comprising an effective amount of one or more antibacterial agents selected from the group consisting of halogenated diphenyl ether, triclosan, herbal extracts, essential oils, rosemary extract, tea extract, magnolia extract, thymol, menthol, eucalyptol, geraniol, carvacrol, citral, hinokitol, catechol, methyl salicylate, epigallocatechin gallate, epigallocatechin, gallic acid, miswak extract, sea-buckthorn extract, bisguanide antiseptics, chlorhexidine, alexidine or octenidine, quaternary ammonium compounds, cetylpyridinium chloride (CPC), benzalkonium chloride, tetradecylpyridinium chloride (TPC), N-tetradecyl-4-ethylpyridinium chloride (TDEPC), phenolic antiseptics, hexetidine, octenidine, sanguinarine, povidone iodine, delmopinol, salifluor, stannous salts, copper salts, iron salts, sanguinarine, propolis and oxygenating agents, hydrogen peroxide, buffered sodium peroxyborate or peroxycarbonate, phthalic acid and its salts, monoperthalic acid and its salts and esters, ascorbyl stearate, oleoyl sarcosine, alkyl sulfate, dioctyl sulfosuccinate, salicylanilide, domiphen bromide, delmopinol, octapinol and other piperidino derivatives, nicin preparations, chlorite salts, and mixtures of any of the foregoing. 13. The oral care composition of claim 1 comprising: 10-60 wt. % sorbitol; 1-3 wt. % polyvinyl methyl ether/maleic anhydride copolymer; 0.5-3 wt. % zinc citrate; 0.1-1 wt. % carboxymethyl cellulose; 0.01-1 wt. % flavoring and/or sweetener; 1-5% wt. % propylene glycol; 1-15 wt. % silica, average diameter 8 microns or less; 0.5-3 wt. % tetrapotassium pyrophosphate; 0.5-3 wt. % sodium monofluorophosphate; 5-25 wt % glycerin; and 0.5-5 wt. % sodium lauryl sulfate, based on the total weight of the composition. 14. An oral care composition according to claim 1, for use in reducing or inhibiting biofilm formation in an oral cavity. 15. An oral care composition according to claim 1, for use in reducing or inhibiting dentinal hypersensitivity. 16. A method of reducing or inhibiting biofilm formation and/or dentinal hypersensitivity in an oral cavity, the method comprising contacting the oral cavity with an oral care composition according to claim 1. 17. Use of a combination of (a) a silica abrasive having an average particle size of 8 microns or less, 1.5-6 microns, 2.7-4 microns or 3.5 microns; (b) zinc citrate, (c) a bioadhesive agent, and (d) an anticalculus agent, to prepare an oral care composition for the reduction or inhibition of biofilm formation or dentinal hypersensitivity in an oral cavity.

An oral care composition comprising (a) a silica abrasive having an average particle size of no greater than the diameter of a dentin tubule, or, alternatively 8 microns or less; (b) zinc citrate, (c) a bioadhesive agent, and (d) an anticalculus agent. The oral care composition can reduce or inhibit biofilm formation and/or dentinal hypersensitivity in an oral cavity.1. An oral care composition comprising (a) a silica abrasive having an average particle size of 8 microns or less, 1.5-6 microns, 2.7-4 microns or 3.5 microns; (b) zinc citrate, (c) a bioadhesive agent, and (d) an anticalculus agent. 2. The oral care composition of claim 1, in the form of a dentifrice wherein the silica having an average particle size of no greater than the diameter of a dentin tubule is in an amount of 1% to 20% by weight, 2% to 10% by weight or 4%-6% by weight based on the total weight of the composition, and the zinc citrate is present in an amount of 0.01 to 5%, or 0.1 to 5%, or 0.2 to 5%, or 0.2 to 3%, or 1% to 3% to 5% by weight based on the total weight of the composition, and further comprising an orally acceptable carrier that is a dentifrice base. 3. The oral care composition of claim 1, wherein the bioadhesive agent is in an amount of from 0.1 weight % to 10 weight %; 0.5 weight % to 4 weight %; 1 weight % to 2 weight %; or 1.5 weight %, based on the total weight of the composition. 4. The oral care composition of claim 1, wherein the total amount of anticalculus agent is in an amount of from 0.5 weight % to 5 weight %; 1.0 weight % to 3 weight %; or 2.4 to 2.5 weight %, based on the total weight of the composition. 5. The oral care composition of claim 1, wherein the total amount of abrasives is 5 to 60% by weight, 5 to 45% by weight, 5 to 35% by weight, 5 to 30% by weight, 5 to 25% by weight, 10 to 20% by weight, or 20% by weight based on the total weight of the composition. 6. The oral care composition of claim 1, wherein the total amount of bioadhesive agent is a polyvinyl methyl ether/maleic anhydride copolymer in amount of 0.1 weight % to 10 weight %; 0.5 weight % to 4 weight %; 1 weight % to 2 weight %; or 1.5 weight %, based on the total weight of the composition, and the antialculus agent is tetrapotassium pyrophosphate or tetrasodium pyrophosphate in an amount from in an amount of from 0.5 weight % to 5 weight %; 1.0 weight % to 3 weight %; or 2.4 to 2.5 weight %, based on the total weight of the composition. 7. The oral care composition of claim 1 further comprising an effective amount of fluoride wherein the fluoride is a salt selected from stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride (e.g., N′-octadecyltrimethylendiamine-N,N,N′-tris(2-ethanol)-dihydrofluoride), ammonium fluoride, titanium fluoride, hexafluorosulfate, and combinations thereof. 8. The oral care composition of claim 1 further comprising one or more surfactants selected from anionic, cationic, zwitterionic, and nonionic surfactants, and mixtures thereof. 9. The oral care composition of claim 1 further comprising a humectant selected from glycerin, sorbitol, propylene glycol, polyethylene glycol, xylitol, and mixtures thereof. 10. The oral care composition of claim 1 further comprising a viscosity modifying amount of one or more polymers selected from polyethylene glycols, polysaccharides, cellulose derivatives, carboxymethyl cellulose, polysaccharide gums, xanthan gum, carrageenan gum, and combinations thereof. 11. The oral care composition of claim 1 further comprising a buffering agent, a flavorant, a colorant, a fragrance, a whitening agent or a combination thereof. 12. The oral care composition of claim 1 further comprising an effective amount of one or more antibacterial agents selected from the group consisting of halogenated diphenyl ether, triclosan, herbal extracts, essential oils, rosemary extract, tea extract, magnolia extract, thymol, menthol, eucalyptol, geraniol, carvacrol, citral, hinokitol, catechol, methyl salicylate, epigallocatechin gallate, epigallocatechin, gallic acid, miswak extract, sea-buckthorn extract, bisguanide antiseptics, chlorhexidine, alexidine or octenidine, quaternary ammonium compounds, cetylpyridinium chloride (CPC), benzalkonium chloride, tetradecylpyridinium chloride (TPC), N-tetradecyl-4-ethylpyridinium chloride (TDEPC), phenolic antiseptics, hexetidine, octenidine, sanguinarine, povidone iodine, delmopinol, salifluor, stannous salts, copper salts, iron salts, sanguinarine, propolis and oxygenating agents, hydrogen peroxide, buffered sodium peroxyborate or peroxycarbonate, phthalic acid and its salts, monoperthalic acid and its salts and esters, ascorbyl stearate, oleoyl sarcosine, alkyl sulfate, dioctyl sulfosuccinate, salicylanilide, domiphen bromide, delmopinol, octapinol and other piperidino derivatives, nicin preparations, chlorite salts, and mixtures of any of the foregoing. 13. The oral care composition of claim 1 comprising: 10-60 wt. % sorbitol; 1-3 wt. % polyvinyl methyl ether/maleic anhydride copolymer; 0.5-3 wt. % zinc citrate; 0.1-1 wt. % carboxymethyl cellulose; 0.01-1 wt. % flavoring and/or sweetener; 1-5% wt. % propylene glycol; 1-15 wt. % silica, average diameter 8 microns or less; 0.5-3 wt. % tetrapotassium pyrophosphate; 0.5-3 wt. % sodium monofluorophosphate; 5-25 wt % glycerin; and 0.5-5 wt. % sodium lauryl sulfate, based on the total weight of the composition. 14. An oral care composition according to claim 1, for use in reducing or inhibiting biofilm formation in an oral cavity. 15. An oral care composition according to claim 1, for use in reducing or inhibiting dentinal hypersensitivity. 16. A method of reducing or inhibiting biofilm formation and/or dentinal hypersensitivity in an oral cavity, the method comprising contacting the oral cavity with an oral care composition according to claim 1. 17. Use of a combination of (a) a silica abrasive having an average particle size of 8 microns or less, 1.5-6 microns, 2.7-4 microns or 3.5 microns; (b) zinc citrate, (c) a bioadhesive agent, and (d) an anticalculus agent, to prepare an oral care composition for the reduction or inhibition of biofilm formation or dentinal hypersensitivity in an oral cavity.

Photoprotective cosmetic compositions having at least reduced shine, stickiness, whitening and/or fluffiness and/or enhanced SPF contain an effective amount of at least one UV radiation filtering agent, at least one aqueous phase and at least one apolar wax having a melting point greater than or equal to 30° C. and a fusion enthalpy of less than 250 J/g, formulated into a topically applicable, cosmetically acceptable carrier therefor.

1. A topically applicable photoprotective cosmetic composition comprising an effective amount of at least one UV radiation filtering agent, at least one aqueous phase and at least one apolar wax having a melting point greater than or equal to 30° C. and a fusion enthalpy of less than 250 J/g, formulated into a topically applicable, cosmetically acceptable carrier therefor. 2. The photoprotective cosmetic composition as defined by claim 1, said at least one apolar wax having a melting point ranging from 30° C. to 80° C. 3. The photoprotective cosmetic composition as defined by claim 2, said at least one apolar wax having a melting point greater than 40° C. 4. The photoprotective cosmetic composition as defined by claim 3, said at least one apolar wax having a melting point of up to 70° C. 5. The photoprotective cosmetic composition as defined by claim 1, said at least one apolar wax having a fusion enthalpy of up to 240 J/g. 6. The photoprotective cosmetic composition as defined by claim 1, said at least one apolar wax having a fusion enthalpy of up to 220 J/g. 7. The photoprotective cosmetic composition as defined by claim 1, said at least one apolar wax comprising a polyolefin wax polymerizate of an α-olefin having the formula R—CH2═CH2 in which R is an alkyl radical having from 10 to 50 carbon atoms. 8. The photoprotective cosmetic composition as defined by claim 7, said polyolefin wax having a number-average molecular weight ranging from 400 to 3,000 daltons 9. The photoprotective cosmetic composition as defined by claim 7, said polyolefin wax having a number-average molecular weight ranging from 1,800 to 2,700 daltons 10. The photoprotective cosmetic composition as defined by claim 1, said at least one apolar wax comprising a paraffin wax having a number-average molecular weight ranging from 350 to 600 daltons. 11. The photoprotective cosmetic composition as defined by claim 1, said at least one apolar wax comprising a polymethylene wax prepared via the Fischer-Tropsch process. 12. The photoprotective cosmetic composition as defined by claim 11, said polymethylene wax having a number-average molecular weight ranging from 350 to 600 daltons. 13. The photoprotective cosmetic composition as defined by claim 1, said at least one apolar wax comprising from 0.1% to 5% by weight thereof. 14. The photoprotective cosmetic composition as defined by claim 1, said at least one apolar wax comprising from 0.5% to 3% by weight thereof. 15. The photoprotective cosmetic composition as defined by claim 1, said at least one apolar wax comprising from 0.5% to 1.5% by weight thereof. 16. The photoprotective cosmetic composition as defined by claim 1, said at least one UV radiation filtering agent comprising an organic and/or inorganic UV filter active in the UV-A and/or UV-B range and which is hydrophilic and/or lipophilic and/or insoluble in conventional cosmetic solvents. 17. The photoprotective cosmetic composition as defined by claim 16, comprising at least one organic UV filter selected from the group consisting of anthranilates; dibenzoylmethane derivatives; cinnamic derivatives; salicylic derivatives, camphor derivatives; benzophenone derivatives; derivatives of β,β-diphenylacrylate; triazine derivatives; benzotriazole derivatives; benzalmalonate derivatives; benzimidazole derivatives; imidazolines; bis-benzoazolyl derivatives; derivatives of p-aminobenzoic acid (PABA); derivatives of methylene bis-(hydroxyphenyl benzotriazole); benzoxazole derivatives; polymer filters and silicone filters; dimers derived from α-alkylstyrene; the 4,4-diarylbutadienes and mixtures thereof. 18. The photoprotective cosmetic composition as defined by claim 17, comprising at least one organic UV filter selected from the group consisting of: Ethylhexyl methoxycinnamate, Homosalate, Ethylhexyl salicylate, Butyl methoxydibenzoylmethane, Octocrylene, Phenylbenzimidazole sulfonic acid, Benzophenone-3, Benzophenone-4, Benzophenone-5, n-Hexyl 2-(4-diethylamino-2-hydroxybenzoyl)-benzoate, 4-Methyl benzylidene camphor, Terephthalylidene dicamphor sulfonic acid, Camphor benzalkonium methosulfate, Disodium phenyl dibenzimidazole tetrasulfonate, Ethylhexyl triazone, Bis-Ethylhexyloxyphenol methoxyphenyl triazine, Diethylhexyl butamido triazone, 2,4,6-Tris-(dineopentyl 4′-amino benzalmalonate)-s-triazine, 2,4,6-Tris-(diisobutyl 4′-amino benzalmalonate)-s-triazine, 2,4,6-Tris-(biphenyl)-1,3,5-triazine, 2,4,6-Tris-(terphenyl)-1,3,5-triazine, Methylene bis-benzotriazolyl tetramethylbutylphenol, Drometrizole trisiloxane, Polysilicone-15, Di-neopentyl-4′-methoxybenzalmalonate, 1,1-Dicarboxy-(2,2′-dimethylpropyl)-4,4-diphenylbutadiene, 2,4-bis-[5-1(dimethylpropyl)benzoxazol-2-yl-(4-phenyl)-imino]-6-(2-ethylhexyl)-imino-1,3,5-triazine, and mixtures thereof. 19. The photoprotective cosmetic composition as defined by claim 16, comprising at least one inorganic UV filter selected from the group consisting of pigments and nanopigments of metal oxides, whether treated or untreated. 20. The photoprotective cosmetic composition as defined by claim 19, comprising at least one inorganic UV filter selected from the group consisting of the oxides of titanium, zinc, iron, zirconium, cerium and mixtures thereof, treated or untreated. 21. The photoprotective cosmetic composition as defined by claim 1, further comprising at least one agent for artificial bronzing and/or tanning of the skin. 22. The photoprotective cosmetic composition as defined by claim 1, further comprising at least one cosmetic additive selected from the group consisting of fats, organic solvents, ionic or non-ionic, hydrophilic or lipophilic thickeners, softeners, moisturizers, opacifiers, stabilizers, emollients, silicones, anti-foaming agents, perfumes, preservatives, anionic, cationic, non-ionic, zwitterionic or amphoteric surfactants, active ingredients, fillers, polymers, propellants, alkalizing or acidifying agents, and mixtures thereof. 23. The photoprotective cosmetic composition as defined by claim 1, formulated as an emulsion or dispersion. 24. The photoprotective cosmetic composition as defined by claim 1, formulated as a product for the cosmetic treatment of the skin, lips, nails, hair, eyelashes, eyebrows and/or scalp. 25. The photoprotective cosmetic composition as defined by claim 1, formulated as a product for the care of the skin, lips, nails, hair and/or scalp. 26. The photoprotective cosmetic composition as defined by claim 1, formulated as a makeup. 27. The photoprotective cosmetic composition as defined by claim 1, formulated as a sunscreen. 28. A regime or regimen for the UV photoprotection of the skin, lips, nails, hair, eyelashes, eyebrows and/or scalp, comprising topically applying thereon a thus effective amount of the photoprotective cosmetic composition as defined by claim 1. 29. A method for reducing or eliminating the shine and/or reducing or eliminating the stickiness and/or replacing or eliminating the whitening and/or reducing or eliminating fluffiness and/or increasing the sun protection factor (SPF) of a photoprotective cosmetic composition comprising, in a cosmetically acceptable carrier, at least one aqueous phase and at least one UV filtering agent, which comprises formulating therein at least one apolar wax having a melting point greater than or equal to 30° C. and a fusion enthalpy of less than 250 J/g.

Photoprotective cosmetic compositions having at least reduced shine, stickiness, whitening and/or fluffiness and/or enhanced SPF contain an effective amount of at least one UV radiation filtering agent, at least one aqueous phase and at least one apolar wax having a melting point greater than or equal to 30° C. and a fusion enthalpy of less than 250 J/g, formulated into a topically applicable, cosmetically acceptable carrier therefor.1. A topically applicable photoprotective cosmetic composition comprising an effective amount of at least one UV radiation filtering agent, at least one aqueous phase and at least one apolar wax having a melting point greater than or equal to 30° C. and a fusion enthalpy of less than 250 J/g, formulated into a topically applicable, cosmetically acceptable carrier therefor. 2. The photoprotective cosmetic composition as defined by claim 1, said at least one apolar wax having a melting point ranging from 30° C. to 80° C. 3. The photoprotective cosmetic composition as defined by claim 2, said at least one apolar wax having a melting point greater than 40° C. 4. The photoprotective cosmetic composition as defined by claim 3, said at least one apolar wax having a melting point of up to 70° C. 5. The photoprotective cosmetic composition as defined by claim 1, said at least one apolar wax having a fusion enthalpy of up to 240 J/g. 6. The photoprotective cosmetic composition as defined by claim 1, said at least one apolar wax having a fusion enthalpy of up to 220 J/g. 7. The photoprotective cosmetic composition as defined by claim 1, said at least one apolar wax comprising a polyolefin wax polymerizate of an α-olefin having the formula R—CH2═CH2 in which R is an alkyl radical having from 10 to 50 carbon atoms. 8. The photoprotective cosmetic composition as defined by claim 7, said polyolefin wax having a number-average molecular weight ranging from 400 to 3,000 daltons 9. The photoprotective cosmetic composition as defined by claim 7, said polyolefin wax having a number-average molecular weight ranging from 1,800 to 2,700 daltons 10. The photoprotective cosmetic composition as defined by claim 1, said at least one apolar wax comprising a paraffin wax having a number-average molecular weight ranging from 350 to 600 daltons. 11. The photoprotective cosmetic composition as defined by claim 1, said at least one apolar wax comprising a polymethylene wax prepared via the Fischer-Tropsch process. 12. The photoprotective cosmetic composition as defined by claim 11, said polymethylene wax having a number-average molecular weight ranging from 350 to 600 daltons. 13. The photoprotective cosmetic composition as defined by claim 1, said at least one apolar wax comprising from 0.1% to 5% by weight thereof. 14. The photoprotective cosmetic composition as defined by claim 1, said at least one apolar wax comprising from 0.5% to 3% by weight thereof. 15. The photoprotective cosmetic composition as defined by claim 1, said at least one apolar wax comprising from 0.5% to 1.5% by weight thereof. 16. The photoprotective cosmetic composition as defined by claim 1, said at least one UV radiation filtering agent comprising an organic and/or inorganic UV filter active in the UV-A and/or UV-B range and which is hydrophilic and/or lipophilic and/or insoluble in conventional cosmetic solvents. 17. The photoprotective cosmetic composition as defined by claim 16, comprising at least one organic UV filter selected from the group consisting of anthranilates; dibenzoylmethane derivatives; cinnamic derivatives; salicylic derivatives, camphor derivatives; benzophenone derivatives; derivatives of β,β-diphenylacrylate; triazine derivatives; benzotriazole derivatives; benzalmalonate derivatives; benzimidazole derivatives; imidazolines; bis-benzoazolyl derivatives; derivatives of p-aminobenzoic acid (PABA); derivatives of methylene bis-(hydroxyphenyl benzotriazole); benzoxazole derivatives; polymer filters and silicone filters; dimers derived from α-alkylstyrene; the 4,4-diarylbutadienes and mixtures thereof. 18. The photoprotective cosmetic composition as defined by claim 17, comprising at least one organic UV filter selected from the group consisting of: Ethylhexyl methoxycinnamate, Homosalate, Ethylhexyl salicylate, Butyl methoxydibenzoylmethane, Octocrylene, Phenylbenzimidazole sulfonic acid, Benzophenone-3, Benzophenone-4, Benzophenone-5, n-Hexyl 2-(4-diethylamino-2-hydroxybenzoyl)-benzoate, 4-Methyl benzylidene camphor, Terephthalylidene dicamphor sulfonic acid, Camphor benzalkonium methosulfate, Disodium phenyl dibenzimidazole tetrasulfonate, Ethylhexyl triazone, Bis-Ethylhexyloxyphenol methoxyphenyl triazine, Diethylhexyl butamido triazone, 2,4,6-Tris-(dineopentyl 4′-amino benzalmalonate)-s-triazine, 2,4,6-Tris-(diisobutyl 4′-amino benzalmalonate)-s-triazine, 2,4,6-Tris-(biphenyl)-1,3,5-triazine, 2,4,6-Tris-(terphenyl)-1,3,5-triazine, Methylene bis-benzotriazolyl tetramethylbutylphenol, Drometrizole trisiloxane, Polysilicone-15, Di-neopentyl-4′-methoxybenzalmalonate, 1,1-Dicarboxy-(2,2′-dimethylpropyl)-4,4-diphenylbutadiene, 2,4-bis-[5-1(dimethylpropyl)benzoxazol-2-yl-(4-phenyl)-imino]-6-(2-ethylhexyl)-imino-1,3,5-triazine, and mixtures thereof. 19. The photoprotective cosmetic composition as defined by claim 16, comprising at least one inorganic UV filter selected from the group consisting of pigments and nanopigments of metal oxides, whether treated or untreated. 20. The photoprotective cosmetic composition as defined by claim 19, comprising at least one inorganic UV filter selected from the group consisting of the oxides of titanium, zinc, iron, zirconium, cerium and mixtures thereof, treated or untreated. 21. The photoprotective cosmetic composition as defined by claim 1, further comprising at least one agent for artificial bronzing and/or tanning of the skin. 22. The photoprotective cosmetic composition as defined by claim 1, further comprising at least one cosmetic additive selected from the group consisting of fats, organic solvents, ionic or non-ionic, hydrophilic or lipophilic thickeners, softeners, moisturizers, opacifiers, stabilizers, emollients, silicones, anti-foaming agents, perfumes, preservatives, anionic, cationic, non-ionic, zwitterionic or amphoteric surfactants, active ingredients, fillers, polymers, propellants, alkalizing or acidifying agents, and mixtures thereof. 23. The photoprotective cosmetic composition as defined by claim 1, formulated as an emulsion or dispersion. 24. The photoprotective cosmetic composition as defined by claim 1, formulated as a product for the cosmetic treatment of the skin, lips, nails, hair, eyelashes, eyebrows and/or scalp. 25. The photoprotective cosmetic composition as defined by claim 1, formulated as a product for the care of the skin, lips, nails, hair and/or scalp. 26. The photoprotective cosmetic composition as defined by claim 1, formulated as a makeup. 27. The photoprotective cosmetic composition as defined by claim 1, formulated as a sunscreen. 28. A regime or regimen for the UV photoprotection of the skin, lips, nails, hair, eyelashes, eyebrows and/or scalp, comprising topically applying thereon a thus effective amount of the photoprotective cosmetic composition as defined by claim 1. 29. A method for reducing or eliminating the shine and/or reducing or eliminating the stickiness and/or replacing or eliminating the whitening and/or reducing or eliminating fluffiness and/or increasing the sun protection factor (SPF) of a photoprotective cosmetic composition comprising, in a cosmetically acceptable carrier, at least one aqueous phase and at least one UV filtering agent, which comprises formulating therein at least one apolar wax having a melting point greater than or equal to 30° C. and a fusion enthalpy of less than 250 J/g.