Source: http://www.google.com/patents/US8114883?dq=6,757,682
Timestamp: 2014-12-21 00:14:01
Document Index: 294523995

Matched Legal Cases: ['Application No. 61', 'Application No. 61', 'Application No. 61', 'Application No. 60', 'Application No. 60', 'Application No. 60']

Patent US8114883 - Polymer formulations for delivery of bioactive materials - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsDelivery of drugs in association with PLGA polymers which have crystallinity resulting from the presence of long chain alkyl groups in terminal units....http://www.google.com/patents/US8114883?utm_source=gb-gplus-sharePatent US8114883 - Polymer formulations for delivery of bioactive materialsAdvanced Patent SearchPublication numberUS8114883 B2Publication typeGrantApplication numberUS 12/287,520Publication dateFeb 14, 2012Filing dateOct 10, 2008Priority dateDec 4, 2007Also published asCA2707666A1, EP2229150A2, EP2229150B1, EP2502619A2, EP2502619A3, US8529922, US20090209558, US20120142581, WO2009073192A2, WO2009073192A3Publication number12287520, 287520, US 8114883 B2, US 8114883B2, US-B2-8114883, US8114883 B2, US8114883B2InventorsDavid Taft, Stelios Tzannis, Wei-Guo Dai, Sandra Ottensmann, Steven Bitler, Qiang Zheng, Adam BellOriginal AssigneeLandec CorporationExport CitationBiBTeX, EndNote, RefManPatent Citations (102), Non-Patent Citations (53), Classifications (18), Legal Events (1) External Links: USPTO, USPTO Assignment, EspacenetPolymer formulations for delivery of bioactive materialsUS 8114883 B2Abstract Delivery of drugs in association with PLGA polymers which have crystallinity resulting from the presence of long chain alkyl groups in terminal units.
We claim: 1. A pharmaceutical formulation comprising a drug and a polymer, wherein
�CF1F2�CO�O� (1)
-b�Cy (2)
(2A) moieties (i) in which b is a bond, (ii) which have the formula �Cy and (iii) which are directly linked to the terminal �CO�O� moiety of one of the repeating units having formula (1),
(2B) moieties (i) in which b is a moiety having the formula �O�CO�, (ii) which have the formula
�O�CO�Cy
and (iii) which are directly linked to the terminal �CF1F2�moiety of one of the repeating units having formula (1), and
-Rpbalc�CO�, (ii) which have the formula
-Rpbalc�CO�Cy, where Rpbalc is the residue of a polyol, and (iii) which are directly linked to the terminal �CO�O� moiety of one of the repeating units having formula (1);
-Rpubic�CO�Cy, where Rpbalc is the residue of a polyol, and (iii) which are directly linked to the terminal �CO�O� moiety of one of the repeating units having formula (1);
�CH2�CO�O� (1A)
�CH(CH3)�CO�O� (1B)
(2A) moieties (i) in which b is a bond, (ii) which have the formula �Cy and (iii) which are directly linked to the terminal �CO��O� moiety of one of the repeating units having formula (1),
and (iii) which are directly linked to the terminal �CF1F2� moiety of one of the repeating units having formula (1), and
(2C) moieties (i) in which b is a moiety having the formula -Rpbalc�CO�, (ii) which have the formula -Rpbalc�CO�Cy, where Rpbalc is the residue of a polyol, and (iii) which are directly linked to the terminal -0CO�O� moiety of one of the repeating units having formula (1);
�CH2�CH(OH)�CH2�O�CO-Cy
�CH2�CH(O�CO�Cy)�CH2�O�CO�Cy
�CF1F2�CO�O�
HO�(�CF1F2�CO�O�)n�H
�CF1�F2�CO�O� (1)
CROSS-REFERENCE TO RELATED APPLICATION This application claims priority from and the benefit of (1) U.S. provisional Application No. 61/005,400, filed Dec. 4, 2007 (2) U.S. provisional Application No. 61/131,123, filed Jun. 4, 2008 and (3) U.S. provisional Application No. 61/131,716, filed Jun. 10, 2008. This application is related to (1) U.S. application Ser. No. 11/999,415, filed Dec. 4, 2007, which claims priority from and the benefit of U.S. provisional Application No. 60/873,234, filed Dec. 5, 2006 (2) International Application No. PCT/U.S. 2007/024909, filed Dec. 4, 2007, claiming priority from U.S. provisional Application No. 60/873,234, filed Dec. 5, 2006, and (3) International Application No. PCT/US 2007/025032, filed Dec. 5, 2007, claiming priority from U.S. provisional Application No. 60/873,234, filed Dec. 5, 2006. This application is also related to copending, commonly assigned application Ser. No. 12/284,755, filed Sep. 25, 2008. The entire disclosure of each of those applications is incorporated herein by reference for all purposes.
FIELD OF THE INVENTION This invention relates to polymeric systems for the delivery of drugs.
BACKGROUND There are many known polymeric systems for the delivery of drugs. A continuing problem is obtaining a desired loading and delivery profile at a desired location and at a desired time.
SUMMARY OF THE INVENTION We have discovered, in accordance with the present invention, that useful delivery of drugs can be obtained through the association of drugs with certain polymers which are referred to herein as �ECC polymers� (ECC being an abbreviation for end cap crystalline).
The term �ECC polymer� is used in this specification to mean a polymer which
�CF1F2�CO�O� (1) wherein F1 is hydrogen and F2 is hydrogen or methyl, the repeating units being the same or different, and (ii) at least one terminal unit which has the formula
-b�Cy (2) wherein Cy is an n-alkyl moiety containing 18-24 carbon atoms, and b is a bond or a moiety which has a valence of at least 2 and which links the Cy moiety to the polymer backbone, and which optionally contains one or more additional Cy moieties; (B) has a crystalline melting temperature, Tp, of at least 35� C., optionally at least 40� C., an onset of melting temperature, To, such that the value of (Tp−To) is less than Tp0.7, and a heat of fusion of at least 5 J/g, Tp, To and the heat of fusion being measured on a differential scanning calorimeter (DSC) as hereinafter described; (C) has a number average molecular weight, Mn, measured as hereinafter described, of less than 10,000. In ECC polymers containing more than one terminal unit of formula (2), and/or a terminal unit containing two or more Cy moieties, for example a total of 2, 3, 4 or 5 Cy moieties in one or more terminal units of formula (2), one or both of b and Cy can be the same or different in the different terminal units, and in a terminal unit containing more than one Cy moiety, the Cy moieties can be the same or different. A wide variety of such moieties are described below. The ECC polymer can optionally contain, in addition to the repeating units of formula (1) and one or more terminal units of formula (2), repeating units and/or terminal units having a different formula. Purely by way of example, the repeating units can be derived from a mixture of lactic acid and glycolic acid, and the polymer can contain two terminal units of formula (2), each containing at least one n-alkyl moiety containing 18 carbon atoms.
BRIEF DESCRIPTION OF THE DRAWINGS The invention is illustrated in the accompanying drawings, in which the Figures are graphs showing the total release of a drug (risperidone or diclofenac sodium) over time from a pharmaceutical formulation of the invention or, for comparison purposes, a similar formulation in which the polymer does not contain a Cy moiety.
DETAILED DESCRIPTION OF THE INVENTION The term �pharmaceutical formulation� is used herein to mean a composition which (i) is suitable for administration to a human being or other mammal or which can be treated, e.g. sterilized, to make it suitable for such administration, and (ii) comprises at least one drug and at least one ECC polymer. The formulation can be part or all of any device that can deliver a drug, including pills, capsules, gels, depots, medical implantable devices (e.g., stents, including self-expanding stents, balloon-expandable stents, drug-eluting stents and stent-grafts, grafts (e.g., aortic grafts), artificial heart valves, cerebrospinal fluid shunts, pacemaker electrodes, endocardial leads, bioerodable implants and the like, and externally manipulated devices (e.g. drug devices and catheters, including catheters which can release a drug, e.g. as a result of heating the tip of the catheter). The pharmaceutical formulation may also include one or more other additives, for example pharmaceutically acceptable excipients, carriers, penetration enhancers, stabilizers, buffers or other materials physically associated with the drug and/or the CYSC polymer to enhance the deliverability of the dosage form and/or the effectiveness of the drug. The formulation may be, for example, a liquid, a suspension, a solid such as a tablet, pill, capsule (including a microcapsule), emulsion, micelle, ointment, gel, emulsion, depot (including a subcutaneously implanted depot), or coating on an implanted device, e.g. a stent or the like. The formulation can for example be applied externally, e.g. as a patch, or a device applied partly externally and partly implanted, or completely implanted or injected subcutaneously.
The term �drug� means a material which is biologically active in a human being or other mammal, locally and/or systemically. Examples of drugs are disclosed in the Merck Index, the Physicians Desk Reference, and in column 11, line 16, to column 12, line 58, of U.S. Pat. No. 6,297,337, and in paragraph 0045 of U.S. 2003/0224974, the entire disclosures of which are incorporated by reference herein for all purposes. Drugs can for example be substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness, including vitamins and mineral supplements; substances which affect the structure or the function of a mammal; pro-drugs, which are substances which become biologically active or more active after they have been placed in a physiological environment; and metabolites of drugs. Examples of drugs are proteins, peptides, small molecule drugs, and antipsychotic drugs. Examples of diagnostic agents are imaging agents containing radioisotopes, contrasting agents containing for example iodine, enzymes, fluorescent substances and the like.
The term �therapeutically effective amount� means an amount of a drug effective to facilitate a desired therapeutic effect.
As an indicator of the rate at which a drug will be released from a pharmaceutical formulation in vivo, it is possible to make use of in vitro tests which are designed to mimic the expected physiological conditions in the delivery site or organ of interest (e.g. gastrointestinally for a pill or subcutaneously for an implant). The Examples below make use of such an in vitro test. The results of a suitable in vitro test are no more than an indicator of in vivo results, but are useful for making comparative measurements. The terms �association�, �associated� and the like mean any type of interaction, including chemical bonds (including, for example, covalent, ionic and hydrogen bonds) and/or Van der Waals forces, and/or polar and non-polar interaction through other physical constraints provided by molecular structure, and interactions through physical mixing.
In this specification, parts, ratios and percentages are by weight, except where otherwise noted. Temperatures are in degrees Centigrade (� C.). Molecular weights of polymers are in Daltons, are number average molecular weights (Mn) unless stated to be weight average molecular weights (Mw), and are measured by gel permeation chromatography (GPC) with a light scattering detection method, for example using a DAWN DSP laser photometer from Wyatt Technology. In defining the polymers, this specification uses the terms �melting point� (often abbreviated to Tp), �onset of melting temperature� (often abbreviated to To) and �heat of fusion� (which is a measure of crystallinity of the polymer, is expressed in J/g and is often abbreviated to ΔH). Tp, To and ΔH are determined using a differential scanning calorimeter (hereinafter DSC), e.g. a Q 100 DSC from TA Instruments at a rate of temperature change of 10� C./min, e.g. from −10 to 150� C. Tp is the peak melting temperature, and To is the temperature at the intersection of the baseline of the DSC peak and the onset line, the onset line being defined as the tangent to the steepest part of the DSC curve below Tp. Unless otherwise stated, the values of Tp, To and ΔH are measured on the second heat cycle.
As used in this specification, the singular forms �a�, �an�, and �the� include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to �a part� includes a plurality of such parts.
The term �comprises� and grammatical equivalents thereof are used in this specification to mean that, in addition to the features specifically identified, other features are optionally present. For example a formulation which comprises an ECC polymer and a drug can contain a single ECC polymer and a single drug, or two or more ECC polymers and/or two or more drugs, and optionally contains one or more other ingredients which are not ECC polymers, for example other ingredients as disclosed herein. The term �consisting essentially of� and grammatical equivalents thereof is used herein to mean that, in addition to the features specifically identified, other features may be present which do not materially alter the claimed invention. The term �at least� followed by a number is used herein to denote the start of a range beginning with that number (which may be a range having an upper limit or no upper limit, depending on the variable being defined). For example �at least 1� means 1 or more than 1, and �at least 80%� means 80% or more than 80%. The term �at most� followed by a number is used herein to denote the end of a range ending with that number (which may be a range having 1 or 0 as its lower limit, or a range having no lower limit, depending upon the variable being defined). For example, �at most 4� means 4 or less than 4, and �at most 40%� means 40% or less than 40%. When, in this specification, a range is given as �(a first number) to (a second number)� or �(a first number)-(a second number)�, this means a range whose lower limit is the first number and whose upper limit is the second number. For example, �from 8 to 20 carbon atoms� or �8-20 carbon atoms� means a range whose lower limit is 8 carbon atoms, and whose upper limit is 20 carbon atoms. The terms �plural�, �multiple�, �plurality� and �multiplicity� are used herein to denote two or more than two features.
Where reference is made in this specification to a method comprising two or more defined steps, the defined steps can be carried out in any order or simultaneously (except where the context excludes that possibility), and the method can optionally include one or more other steps which are carried out before any of the defined steps, between two of the defined steps, or after all the defined steps (except where the context excludes that possibility). Where reference is made herein to �first� and �second� features, this is generally done for identification purposes; unless the context requires otherwise, the first and second features can be the same or different, and reference to a first feature does not mean that a second feature is necessarily present (though it may be present). Where reference is made herein to �a� or �an� feature, this includes the possibility that there are two or more such features (except where the context excludes that possibility). Where reference is made herein to two or more features, this includes the possibility that the two or more features are replaced by a lesser number or greater number of features providing the same function (except where the context excludes that possibility). The numbers given herein should be construed with the latitude appropriate to their context and expression; for example, each number is subject to variation which depends on the accuracy with which it can be measured by methods conventionally used by those skilled in the art.
When the ECC polymer contains more than one b�Cy moiety, all the Cy moieties can be the same, or there can be a plurality of (i.e. two or more) different types of moiety which differ from each other in one or both of b and Cy. Some useful Cy moieties optionally include polyoxyalkylene, e.g. polyoxyethylene, units. Such a polyoxyalkylene unit can be a homopolymer, random copolymer, or block copolymer containing 2 to 100, e.g. 5 to 100, preferably 5 to 60, oxyalkylene units, preferably 2-20, e.g. 2-4, oxyalkylene units.
�Cy (2A)�O�CO-Cy (2B)-Rpbalc�CO-Cy (2C) where Rpbalc is the residue of a polyol, for example a polyethylene glycol, 1,3-propanediol, glycerin or sorbitol, and optionally contains one or more Cy moieties, the terminal and other Cy moieties, if any, being introduced for example by esterification, transesterification or alkylation of one or more of the hydroxyl groups, e.g. by reaction with an acid or acid chloride containing a Cy moiety; and has for example the formula
�CH2�CH(OH)�CH2�O�CO-Cyor�CH2�CH(O�CO-Cy)-CH2�O�CO-Cy; (A7) the polymer contains less than 170 repeating units of formula
�CF1F2�CO�;
EXAMPLES The invention is illustrated by the following Examples. The Examples illustrating the preparation of the ECC polymers are summarized in Table EC1 below. Table EC1 identifies the ingredients used, and the amounts thereof in grams, and the molecular weight and DSC values of various products. In the PLGA polymers used in the Examples, the molar ratio of (units derived from) glycolic acid to lactic acid was 1:1. After the Table, there is a detailed account of the procedures used in each of the Examples. The heading of each detailed example includes an abbreviation indicating the polymer produced in the example, in the form PLGA, indicating that the polymer is an unmodified PLGA [in comparative Example EC1(C)], or nECC-PLGA, where n is 1, 2, 3 or 4, indicating that the polymer is an end-capped PLGA containing 1, 2, 3 or 4 Cy moieties.
Example EC1 1ECC-PLGA Glycolic acid (51.925 g), lactic acid solution (70.291 g) and behenyl alcohol (11.15 g) were weighed into a 1000 ml reaction vessel equipped with a mechanical stirrer and heated to 140� C. After stirring for 15 to 25 min, vacuum was applied to remove water. The reaction was continued under reduced pressure at 140� C. for at least 16 hrs. A clear pale yellow viscous liquid was removed from the vessel while it was still hot. After cooling to room temperature, 85 gram of opaque solid (341-1-3) was obtained.
Example EC1(C) PLGA The procedure of Example EC1 was followed, but using glycolic acid (57.011 g) and lactic acid solution (77.175 g) as the starting materials. 84 g of clear solid (341-1-0) was obtained.
Example EC2 1ECC-PLGA PLGA (16.055 g of polymer 341-1-3, the product of Example EC1), succinic anhydride (2.002 g) and a catalytic amount of p-toluenesulfonic acid were combined with 200 mL toluene in a 250 mL round bottom flask fitted with a condenser and Dean-Stark trap. The reaction was stirred under reflux with a magnetic stir bar under nitrogen in a 135� C. oil bath overnight. The temperature was increased to 150� C. and stirring continued for 2 days, after which toluene was removed by distillation over 4.5 hours. Reaction progress was monitored by FTIR through loss of anhydride peaks at 1864 cm-1 and 1782 cm-1, loss of broad PLGA alcohol peak from 3600-3400 cm-1, and increase in broad acid OH peak from 3300-2400 cm-1. The product was purified by first dissolving in 50 mL warm dichloromethane and adding 50 mL water. The layers were separated in a separatory funnel and the water layer was extracted 1� with 25 mL dichloromethane. The organic layers were combined and washed 3� with 25 mL water. The dicholomethane layer was dried over anhydrous magnesium sulfate which was removed by gravity filtration. The resulting filtrate was condensed under reduced pressure to give 16.3 g product (338-80).
Example EC3 1ECC-PLGA Glycolic acid (55.53 g), lactic acid solution (75.18 g) and behenic acid (5.53 g) were weighed into a 1000 ml reaction vessel equipped with a mechanical stirrer and heated to 140� C. After stirring for 15 to 25 min, vacuum was applied to remove water. The reaction was continued under reduced pressure at 140� C. for at least 16 hrs. A clear pale yellow viscous liquid was removed from the vessel while still hot. After cooling to room temperature, 90 gram of opaque solid (341-41-5R) was obtained.
Example EC4 2ECC-PLGA PLGA (5.034 g of polymer Mn 3127 from Durect, Pelham, Ala.), behenic acid (1.145 g) and a catalytic amount of p-toluenesulfonic acid were combined in a 100 mL round bottom flask with 30 mL toluene. The reaction was stirred with a magnetic stir bar under nitrogen and heated for 1 hour until all solids dissolved and the toluene was refluxing. Toluene was removed under reduced pressure over 4 hours followed by continued heating under nitrogen at 140� C. for 3.5 days until completely reacted. Reaction progress was monitored by FTIR through loss of the 1708 cm-1 carboxylic acid carbonyl peak and conversion to an ester carbonyl peak at about 1757 cm-1 (overlap with PLGA ester carbonyl at same shift), and loss of the broad acid OH peak from 3300-2400 cm-1. The product was purified by first dissolving in 35 mL of warm dichloromethane followed by cooling for 5-10 minutes on dry ice until visibly cloudy with a white precipitate. Gravity filtration over fluted filter paper was performed to remove a white solid. Solvent was removed from the solution under reduced pressure yielding 4.3 grams of product (338-55).
Example EC5 2ECC-PLGA The product of Example EC1 (341-1-3) (5.033 g), behenic acid (2.071 g) and a catalytic amount of p-toluenesulfonic acid were placed in a 250 mL round bottom flask with 50 mL toluene. The reaction was stirred with a magnetic stir bar under nitrogen in a 140� C. oil bath for a quarter hour until all solids dissolved. Toluene was removed under reduced pressure over 2.5 hours followed by continued heating under nitrogen at 140� C. for 3.5 days until completely reacted. Reaction progress was monitored by FTIR as in Example EC4. Any residual toluene was removed under reduced pressure for 1 hour. The product was purified by first dissolving in 40 mL of warm dichloromethane followed by cooling for 5-10 minutes on dry ice until cloudy with white precipitate. Gravity filtration over fluted filter paper was performed to remove a white solid. Solvent was removed from the solution under reduced pressure yielding 3.5 grams of product (338-56).
Example EC6 3ECC-PLGA (a) A carboxy-terminated and C22 terminated PLGA polymer made by the same process as Example EC2 (6.73 g) and 60 mL glycerol were combined in a 250 mL round bottom flask. The reaction was stirred with a magnetic stir bar under nitrogen in a 130� C. oil bath overnight, until reacted. Reaction progress was monitored by taking small samples of the reaction mixture and extracting with dichloromethane, and monitoring by FTIR through the loss of the broad acid OH peak between 3200-2400 cm-1 and the appearance of the glycerol alcohol peak from 3600-3100 cm-1. The product was purified by addition of 100 mL dichloromethane and 100 mL water, stirred and shaken vigorously, and added to a separatory funnel. The resulting layers were separated, and the water layer extracted 3� with 50 mL dichloromethane. The organic layers were combined and washed 3� with 20 mL water, and then dried over anhydrous magnesium sulfate, which was subsequently removed by gravity filtration through fluted filter paper. This extraction and washing process was repeated on the water layers a second time to remove any remaining product, with all resulting organic layers combined and solvent removed under reduced pressure to yield 1.27 grams of intermediate product (338-75).
Example EC7 3ECC-PLGA (a) Acid capped C22 PLGA (15.077 g, the product of Example EC3, 341-41-5R), 35 mL glycerol and a catalytic amount of p-toluenesulfonic acid were combined in a 100 mL round bottom flask. The reaction was stirred by magnetic stir bar under nitrogen and heated in a 130� C. oil bath overnight until reaction was complete. Reaction progress was monitored by taking small samples of reaction mixture and performing a mini-extraction with dichloromethane, with progress monitored through FTIR through the loss of broad acid OH peak from 3300-2300 cm-1 and appearance of broad glycerol OH peak from 3700-3100 cm-1 in product. For purification 50 mL water and 20 mL dichloromethane was added to the reaction flask, warmed, and stirred vigorously until all was dissolved. Using a separatory funnel, the organic layer was isolated and the water layer extracted 2� with 30 mL dichloromethane. The organic layers were then combined and washed 3� with 20 mL water, then dried over anhydrous magnesium sulfate which was then removed by gravity filtration through fluted filter paper. Solvent was removed under reduced pressure to give 3.42 g reaction intermediate (338-91).
Example EC8 3ECC-PLGA C22 acid capped PLGA (8.133 g, the product of Example EC3, 341-41-5R), glycerol (0.282 g) and a catalytic amount of p-toluenesulfonic acid were combined in a 3 neck 250 ml round bottom flask. The reaction was stirred by magnetic stir bar and heated under nitrogen in a 135� C. oil bath. The reaction was stirred for 1.5 days until reaction was complete and removed from heat to produce the final product (338-92). Reaction progress was monitored by FTIR through the loss of the broad acid OH peak especially from 2800-2400 cm-1, the loss of the glycerol OH peak from 3700-3100 cm-1, and the slight shift of acid carbonyl peak from 1749 cm-1 to 1753 cm-1 due to ester formation (overlap with PLGA ester carbonyl peaks).
Example EC9 4ECC-PLGA (a) PLGA (15.027 g, the product of Example EC1(C), 341-1-0) and succinic anhydride (1.465 g) were combined with 150 mL toluene in a 250 mL round bottom flask fitted with a condenser and Dean-Stark trap. The reaction was stirred by magnetic stir bar under nitrogen in a 135� C. oil bath while refluxing. The reaction was stirred for 3 days until fully reacted. Reaction progress was monitored by FTIR through the loss of succinic anhydride peaks at 1864 cm-1 and 1782 cm-1 and loss of PLGA OH peaks from 3700-3300 cm-1. For purification about 50 mL warm dichloromethane and about 50 mL water were added to the reaction flask and stirred vigorously. The layers were then separated by separatory funnel, with the water layer extracted 2 times each with 30 mL with dichloromethane. The dichloromethane layers were combined and then washed with about 30 mL of water once only. The resulting organic layers were dried over anhydrous magnesium sulfate that was subsequently removed by gravity filtration through fluted filter paper. Solvent was removed under reduced pressure to yield 15.08 g of Intermediate 1 (338-85).
(b) 9.85 g of Intermediate 1 and 25 mL glycerol (large excess) were combined in a 250 mL round bottom flask. The reaction was stirred by magnetic stir bar under nitrogen in a 130� C. oil bath for 20 hours until complete. Reaction progress was monitored by FTIR through loss of the broad acid OH peak between 3200-2500 cm-1 and the appearance of the glycerol alcohol peak from 3700-3200 cm-1. The reaction was purified by adding �50 mL warm dichloromethane and �50 mL water to the flask and stirring vigorously. The layers were then separated in a separatory funnel, and the water layer extracted 2 times each with 50 mL dichloromethane. All organic layers were combined and washed 3 times each with �40 mL of water. The organic layer was then dried over anhydrous magnesium sulfate, which was then removed from gravity filtration through fluted filter paper. Solvent was removed under reduced pressure to give 2.41 g of Intermediate 2 (338-87).
Example EC10 3ECC-PLGA The procedure of Example EC6 was followed, but using the product from Example EC2 (338-80, 7.049 g) and 30 mL of glycerol to obtain intermediate 338-83. The intermediate 338-83 (1.86 g) was reacted with behenic acid (1.583 g) as in Example EC6 until the reaction was complete. After purification, 2.84 g of product (338-84) was obtained.
FIGURES The results of the testing are shown in the accompanying drawings in which FIGS. 1 a, 2, 3, 4 a, 5 a, 6, 7 and 8 show the cumulative release of risperidone from (i) a risperidone-containing mixture based on the unmodified PLGA polymer prepared in Example EC1(C), or, in FIG. 4 a, based on a commercially available unmodified PLGA polymer, and from (ii) one or more risperidone-containing mixtures based on one of the ECC polymer prepared in the Examples, namely based on Example EC1 in FIG. 1 a, based on Examples EC1 and EC2 in FIG. 2, based on Example EC3 in FIG. 3, based on Example EC4 in FIG. 4 a, based on Examples EC1 and EC5 in FIG. 5 a, based on Examples EC1, EC5 and EC10 in FIG. 6, based on Examples EC3 and EC7b in FIG. 7, and based on Examples EC3 and EC8 in FIG. 8.
Patent CitationsCited PatentFiling datePublication dateApplicantTitleUS3608549Jan 15, 1970Sep 28, 1971Merrill Edward WilsonMethod of administering drugs and capsule thereforUS4558690Jan 26, 1982Dec 17, 1985University Of ScrantonMethod of administration of chemotherapy to tumorsUS4830855Nov 13, 1987May 16, 1989Landec Labs, Inc.Temperature-controlled active agent dispenserUS5120349Dec 7, 1990Jun 9, 1992Landec Labs, Inc.Encapsulating active materialUS5129180Dec 7, 1990Jul 14, 1992Landec Labs, Inc.Temperature sensitive seed germination controlUS5143730Jul 25, 1989Sep 1, 1992Henkel Kommanditgesellschaft Auf AktienPolyglycolate and/or Polylactate OligomersUS5156911May 11, 1989Oct 20, 1992Landec Labs Inc.Skin-activated temperature-sensitive adhesive assembliesUS5213808Apr 6, 1990May 25, 1993Buhk Meditec A/AControlled release article with pulsatile releaseUS5308623Feb 27, 1992May 3, 1994Henkel Kommanditgesellschaft Auf AktienMixtures of lactic and glycolic acid oligomers, organic and inorganic acids, improved handlingUS5384333Mar 17, 1992Jan 24, 1995University Of MiamiTime release agentsUS5387450Feb 27, 1992Feb 7, 1995Landec CorporationFormulated with crystallizable polymers; medical applicationsUS5412035Aug 12, 1992May 2, 1995Landec CorporationPressure-sensitive adhesivesUS5429654Apr 30, 1992Jul 4, 1995Exxon Research & Engineering Co.Fertilizer having a coating of neutralized, sulfonated ethylene-propylene-diene monomer terpolymer for controlled releaseUS5469867Sep 2, 1992Nov 28, 1995Landec CorporationCast-in place thermoplastic channel occluderUS5662711Jun 7, 1995Sep 2, 1997Douglas; WilliamFlow adjustable artery shuntUS5665822Apr 14, 1993Sep 9, 1997Landec CorporationCopolymer with crystalline and amorphous blocksUS5687718Jun 14, 1995Nov 18, 1997Hewlett-Packard CompanyDevice for continuously detecting blood parametersUS5725881Oct 26, 1994Mar 10, 1998Boehringer Ingelheim KgBiocompatible, bioabsorbable material suitable for implantationUS5783302May 22, 1995Jul 21, 1998Landec CorporationThermoplastic elastomersUS5826584Oct 4, 1995Oct 27, 1998Schmitt; Edward E.Devices for occluding channels in living mammalsUS5852117Aug 26, 1997Dec 22, 1998National Starch And Chemical Investment Holding CorporationProcess for making lactide graft copolymersUS5895404Sep 29, 1997Apr 20, 1999Ruiz; Carlos E.Apparatus and methods for percutaneously forming a passageway between adjacent vessels or portions of a vesselUS5945457Oct 1, 1997Aug 31, 1999A.V. Topchiev Institute Of Petrochemical Synthesis, Russian Academy Of ScienceProcess for preparing biologically compatible polymers and their use in medical devicesUS6001395Jul 15, 1996Dec 14, 1999Danbiosyst Uk LimitedPolymeric lamellar substrate particles for drug deliveryUS6004549Dec 14, 1994Dec 21, 1999Schering CorporationCrystalline protein controlled release compositionsUS6199318Sep 15, 1997Mar 13, 2001Landec CorporationAqueous emulsions of crystalline polymers for coating seedsUS6214901Apr 15, 1999Apr 10, 2001Surmodics, Inc.Bioactive agent release coatingUS6224793 *Apr 27, 1999May 1, 2001The Dow Chemical CompanyEncapsulated active materialsUS6255367Dec 16, 1998Jul 3, 2001Landec CorporationCrosslinkable thermosetting polyester resin matrix in which is dispersed a solid particle modifying agent comprising a crystalline polymer bearing ionically bound polymerization catalyst moietiesUS6297337May 19, 1999Oct 2, 2001Pmd Holdings Corp.Bioadhesive polymer compositionsUS6319521Feb 9, 2000Nov 20, 2001University Technology CorporationExposing to a compressed antisolvent(carbon dioxide); controlled releaseUS6344035Oct 20, 2000Feb 5, 2002Surmodics, Inc.Bioactive agent in combination with a mixture of a first polymer component such as poly(butyl methacrylate) and a second polymer component such as poly(ethylene-co-vinyl acetate); especially for stents and catheters.US6352667Aug 24, 1999Mar 5, 2002Absorbable Polymer Technologies, Inc.Method of making biodegradable polymeric implantsUS6423345Feb 22, 1999Jul 23, 2002Acusphere, Inc.Matrices formed of polymer and hydrophobic compounds for use in drug deliveryUS6469133Dec 13, 2000Oct 22, 2002Board Of Trustees Of Michigan State UniversityProcess for the preparation of polymers of dimeric cyclic estersUS6524274Jun 7, 1995Feb 25, 2003Scimed Life Systems, Inc.Triggered release hydrogel drug delivery systemUS6528080Jan 14, 2002Mar 4, 2003Atrix Laboratories, Inc.Flowable, biocompatible, branched thermoplastic polymer used to form solid matrices such as implants and controlled-release, drug-formulations in a bodyUS6540984Jan 18, 2001Apr 1, 2003Landec CorporationAqueous dispersions of crystalline polymers and usesUS6569128Sep 22, 1999May 27, 2003Advanced Infusion CorporationCatheter with adjustable flow restrictorUS6576254May 24, 1999Jun 10, 2003University Of StrathclydeDrug delivery, gene therapyUS6653395Jun 5, 1997Nov 25, 2003Akzo Nobel NvOrthoester-based polymer as well as preparation and use thereofUS6656385Jan 25, 2002Dec 2, 2003The Procter & Gamble CompanyFunctionalized cubic liquid crystalline phase materials and methods for their preparation and useUS6657042Mar 19, 2002Dec 2, 2003Fraunhofer-Gesellschaft zur F�rderung der angewandten Forschung e.V.Ring scission polymerization of its cyclic monomers in molten phase in presence of an an initiator system containing a compound of tin and compounds of metals of the fourth subgroup to produce homo and copolymers of lactic acidUS6699952Jun 2, 2003Mar 2, 2004Emory UniversityModular cytomimetic biomaterials, transport studies, preparation and utilization thereofUS6730322Mar 6, 2003May 4, 2004Acusphere, Inc.Delaying release of encapsulated active material; using lipid or other hydrophobic or amphiphilic compoundUS6780930Nov 15, 2001Aug 24, 2004Biocompatibles Uk LimitedDispersing mixture of ethylenically unsaturated monomers including water insoluble monomer into aqueous liquid; adding ammonium phosphate ester zwitterionic monomer and a water-soluble radical initiator; emulsion polymerizationUS6831116Dec 8, 2000Dec 14, 2004Landec CorporationPolymeric modifying agentsUS6858634Sep 10, 2001Feb 22, 2005Monsanto Technology LlcControlled release formulations and methods for their production and useUS6866860Dec 19, 2002Mar 15, 2005Ethicon, Inc.Cationic alkyd polyesters for medical applicationsUS6887960Feb 5, 2001May 3, 2005Rohm And Haas CompanyGraft copolymer of ethylenically unsaturated nonionic monomers and terminally unsaturated acrylic acid oligomers or polymers; drug deliveryUS6890583Nov 21, 2001May 10, 2005Surmodics, Inc.Bioactive agent release coatingUS6951642Sep 28, 2001Oct 4, 20053M Innovative Properties CompanyWater-in-oil emulsions with anionic groups, compositions, and methodsUS6964778Sep 6, 2002Nov 15, 2005Health Research, Inc.Temperature controlled content release from liposomesUS6967234 *Dec 18, 2002Nov 22, 2005Ethicon, Inc.synthetic/biodegradable/biocompatible; comprises polybasic acid, monoglyceride, and lactone monomersUS6989417Mar 16, 2001Jan 24, 2006Landec CorporationUniform dispersion of crystalline polymerUS7008667Oct 10, 2002Mar 7, 2006Surmodics, Inc.Comprises polybutylmethacrylate and ethylene-vinyl acetate copolymer; for flexible catheters and stents; drug deliveryUS7030084Feb 10, 2004Apr 18, 2006Nobex CorporationDrug-oligomer conjugates with polyethylene glycol componentsUS7083572Mar 26, 2002Aug 1, 2006Bristol-Myers Squibb Medical Imaging, Inc.Therapeutic delivery systemsUS7220430Jan 26, 2001May 22, 2007Tanabe Seiyaku Co., Ltd.Sustained-release preparation and process for producing the sameUS20020106406Dec 8, 2000Aug 8, 2002Mchugh Anthony J.Crystallizable/non-crystallizable polymer compositesUS20020114827Sep 18, 2001Aug 22, 2002Jie ZhangMethods and apparatus for improved administration of analgesicsUS20020161437Feb 28, 2001Oct 31, 2002Medennium, Inc.Crystalline polymeric compositions for ophthalmic devicesUS20030082217Oct 25, 2001May 1, 2003Isabelle AfriatHeat resistant impregnated wipeUS20030224974Feb 27, 2003Dec 4, 2003Bolotin Elijah M.Compositions for delivery of therapeutics and other materials, and methods of making and using the sameUS20040009229 *Jun 5, 2003Jan 15, 2004Unger Evan CharlesStabilized nanoparticle formulations of camptotheca derivativesUS20040052746Aug 22, 2003Mar 18, 2004Krishnan TamareselvyCosmetic, cleaning compounds; crosslinked addition polymerUS20040117006Jan 11, 2002Jun 17, 2004Lewis Andrew L.Drug delivery from stentsUS20040208844Jul 31, 2002Oct 21, 2004Francis IgnatiousProducts and drug delivery vehiclesUS20040236013Jun 22, 2004Nov 25, 2004Biocompatibles Uk LimitedEmulsion polymerisation processes for forming high solids emulsions without the incorporation of non-polymerisable emulsifier, and to the use of these emulsions to biocompatibilise substrates.US20040254419Jun 14, 2004Dec 16, 2004Xingwu WangTherapeutic assemblyUS20050019923Oct 17, 2002Jan 27, 2005Ijeoma UchegbuNucleotide sequences comprising cationic polypropylenimine dendrimer and diaminobutane core for use as tool in delivery of drug agents and tissue targeted therapyUS20050169977Oct 28, 2004Aug 4, 2005Noven Pharmaceuticals, Inc.Compositions and methods for controlling drug loss and delivery in transdermal drug delivery systemsUS20050197251Apr 19, 2005Sep 8, 2005Monsanto Technology, L.L.C.Method of controlling the release of agricultural active ingredients from treated plant seedsUS20050249697Sep 24, 2004Nov 10, 2005Uhrich Kathryn ECompositions and methods for the inhibition of bone growth and resorptionUS20050249799Mar 3, 2005Nov 10, 2005Spherics, Inc.Polymeric drug delivery system for hydrophobic drugsUS20060018948Jun 24, 2005Jan 26, 2006Guire Patrick EBiodegradable implantable medical devices, methods and systemsUS20060024361Jul 28, 2004Feb 2, 2006Isa OdidiDisintegrant assisted controlled release technologyUS20060034891Jul 5, 2005Feb 16, 2006Laurie LawinBiodegradable controlled release bioactive agent delivery deviceUS20060148982Sep 22, 2003Jul 6, 2006Ijeoma UchegbuDrug deliveryUS20060167116Sep 22, 2003Jul 27, 2006Ijeoma UchegbuSolubilising polysaccharides substituted with dydrophilic and hydrophobic groupsUS20060286064Jun 2, 2006Dec 21, 2006Medivas, LlcBased on biodegradable polymers containing polyester amide (PEA), polyester urethane (PEUR), and polyester urea (PEU) and immunostimulatory adjuvants; for delivery of compositions that bind to major histocompatibility complexes (MHC) allelesUS20060292222Jun 21, 2006Dec 28, 2006Matthew JonasseDrug delivery device having zero or near zero-order release kineticsUS20070016284Sep 22, 2006Jan 18, 2007Advanced Cardiovascular Systems, Inc.Polymeric coating for reducing the rate of release of a therapeutic substance from a stentUS20070023226Jul 26, 2005Feb 1, 2007Hawash Suheal NSpecialized, tapered bolts for rear axle shaftsUS20070134310Sep 22, 2006Jun 14, 2007Nedberge Diane ETransdermal risperidone delivery systemUS20070142461Dec 15, 2006Jun 21, 2007Board Of Trustees Of Michigan State UniversityCyclic alkyl substituted glycolides and polylactides therefromUS20070259584May 4, 2007Nov 8, 2007Ronald WhitehouseBiodegradable polymer composites and related methodsUS20090124996May 2, 2008May 14, 2009Scott HeneveldApparatus and methods for injecting high viscosity dermal fillersUS20090177158Dec 22, 2008Jul 9, 2009Krumme John FSelf-contained pressurized injection deviceUS20090198183Aug 7, 2008Aug 6, 2009Krumme John FApparatus and methods for injecting dermal fillersUS20090240200Jun 3, 2009Sep 24, 2009Scott HeneveldApparatus and methods for injecting high viscosity dermal fillersEP0064379A1Apr 27, 1982Nov 10, 1982Uniroyal, Inc.Pesticidal composition and methods for controlling pestsEP0568345A1Apr 28, 1993Nov 3, 1993Exxon Research And Engineering CompanyCoated agricultural productsEP0778304A2Oct 28, 1996Jun 11, 1997Fraunhofer-Gesellschaft Zur F�rderung Der Angewandten Forschung E.V.Hydrophobic resorbable polyesters and their useEP1348451A1Mar 28, 2003Oct 1, 2003Ethicon Inc.Compositions and medical devices utilizing bioabsorbable liquid polymersEP1430916A1Dec 19, 2003Jun 23, 2004Ethicon, Inc.Crosslinked alkyd polyesters for medical applicationsEP1629835A2May 21, 2004Mar 1, 2006Osmotica Corp.Breakable, controlled release device comprising a preformed passageGB2160100A Title not availableGB2161819A Title not availableJP2002138033A Title not availableJPH03123730A Title not availableJPS6242918A Title not available* Cited by examinerNon-Patent CitationsReference1Abayashinghe, N., et al., "Oligoethylene-End-Capped-Polylactides", Journal of Polymer Science: Part A: Polymer Chemistry, vol. 43, 5257-5266 (2005).2Amsden, "Development of Biodegradable Injectable Thermoplastic Oligomers" Biomacromolecules 2004, vol. 5, pp. 637-642.3Anon. "Biodegradable Polymers: A Review" Environment and Plastics Industry Council (EPIC) Technical Report pp. 1-11; Nov. 24, 2000.4Anon. "What Are the Latest Drug Delivery Systems Made of?" Online Publication Science Scotland; The Royal Society of Edinburgh; Issue 2, pp. 9-10; Spring 2004.5Baker, G., et al., "New Polylactides from Hydroxyacids Derived from Renewable Sources". Polymer Preprints 2007, 48(2), 826.6Bendix, Dieter, "Chemical Synthesis of Polyactide and its Copolymers for Medical Applications" 1998, Polymer Degradation and Stability, vol. 59, pp. 129-135; Elsevier Science Limited.7Birnbaum, D., et al., "Microparticle Drug Delivery Systems" Drug Delivery Systems in Cancer Therapy, Chapter 6, pp. 117-135; Sep. 2003.8Boudreaux, C.J., et al., "Controlled Activity Polymers. XI Hydrolytic Release Studies of Hydrophilic Copolymers With Labile Esters of Model Allelopathic Phenols", Journal of Controlled Release, vol. 44, #2-3, pp. 185-194, Feb. 1997.9Brannon-Peppas, L., "Polymers in Controlled Drug Delivery", Medical Plastics and Biomaterials, p. 34, Nov. 1997.10Bulmus, V.; Woodward, M.; Lin, L.; Murthy, N.; Stayton, P.; and Hoffman, A.; A New pH Responsive and Glutathione-Reactive, Endosomal Membrane Disruptive Polymeric Carrier for Intracellular Delivery of Biomolecular Drugs; Dec. 2003; Journal of Controlled Release, vol. 93, #2, pp. 105-120; Elsevier, Netherlands.11Davaran, S., et al., "Release of 5-Aminosalicylic Acid from Acrylic Type Polymeric Prodrugs Designed for Colon Drug Delivery", 1999; Journal of Controlled Release, 58, #3, pp. 279-287.12Du, J., et al., "pH Sensitive Vesicles Based on a Biocompatible Zwitterionic Diblock Copolymer", Journal of American Chemistry Society, vol. 127, #51, pp. 17982-17983; 2005.13Emmanuel Roux et al. "Polymer based pH-sensitivecarriers as a means to improve the cytoplasmic delivery of drugs". Int. J. Pharmaceutics vol. 242, No. 1-2, 2002, pp. 25-36.14Greene, L., "Side-Chain Crystallizable Polymers for Temperature-Activated Controlled Release", Polymeric Delivery Systems: Properties and Applications (ACS Symposium Series, No. 520), pp. 244-256, 1993.15Hadlington, S. "Special Delivery", "Chemistry World" (online edition, previously "Chemistry in Britain"), Royal Society of Chemistry, UK; No. 5, pp. 1-3; May 2003.16Henry, C., "Cooking Cancer-Carbon Nanotubes and Near-Infrared Radiation Kill Cancer Cells by Heating" Chemical & Engineering News, vol. 83, #32, p. 16; 2005.17Henry, C., "Cooking Cancer�Carbon Nanotubes and Near-Infrared Radiation Kill Cancer Cells by Heating" Chemical & Engineering News, vol. 83, #32, p. 16; 2005.18Ivan, B., et al., "New Nanophase Separated Intelligent Amphiphilic Conetworks and Gels", Macromolecular Symposia, Jul. 2005 vol. 227 (1), pp. 265-274, Wiley-VCH GmbH & Co. KgaA, Weinheim.19Jiang, X., et al., ""Clickable" Polyglycolides: Tunable Synthons for Thermoresponsive, Degradable Polymers", Department of Chemistry, Michigan State University, East Lansing, MI, pp. 1-34.20K.M. Scholsky and R.M. Fitch; Controlled Release of Pendant Bioactive Materials from Acrylic Polymer Colloids; 1986; Journal of Controlled Release, vol. 3, #1-4, pp. 87-102; Elsevier, Netherlands.21Kaneko, T.; Miyazaki, T.; Yamaoka, K.; Katayama, Y.; Matsuda, A.; Gong, J.; and Osada, Y.; "Shape-Memory Gels with Multi-Stimuli Responses"; Proceedings of SPIE, vol. 3669, pp. 199-208, Smart Structures and Materials; May 1999: Electroactive Polymer Actuators and Devices.22LaVan, D.A.; McGuire, T.; and Langer, R.; Small Scale Systems for in Vivo Drug Delivery; Oct. 2003; Nature Biotechnology, vol. 21, #10, pp. 1184-1191; Nature Publishing Group., U.K.23Lee, J. et al, "Thermosenstive Permeation From Side-Chain Crystalline Ionomers", Journal of Polymer Science: Part B: Polymer Physics, vol. 38, pp. 823-830; 2000.24Loth, H., et al. "Methoxy-Polyethoxy Side-Chain Silastomers as Materials Controlling Drug Delivery by Diffusion Flux", Journal of Controlled Release, vol. 54, #3, pp. 273-282 Aug. 1998.25Luppi, B.; Cerchiara, T.; Bigucci, F.; Orienti, I.; and Zecchi, V.; pH-Sensitive Polymeric Physical-Mixture for Possible Site-Specific Delivery of Ibuprofen; Mar. 2003; European Journal of Pharmaceutics and Biopharmaceutics, 55, #2, pp. 199-202; Elsevier, Netherlands.26M. Dufresne et al.-Abstract-Preparation and characterization of water-soluble pH-sensitive nanocarriers for drug delivery Int. J. Pharmaceutics vol. 277, No. 1-2, 2004, pp. 81-90.27M. Dufresne et al.�Abstract�Preparation and characterization of water-soluble pH-sensitive nanocarriers for drug delivery Int. J. Pharmaceutics vol. 277, No. 1-2, 2004, pp. 81-90.28Maruyama, S., et al., "A Synthetic Polymer, Poly(2-methacryloyloxyethyl phosphorylcholine-co-n-stearyl methacrylate), Stimulates Insulin Release form RINm5F Insulinoma Cells", Biosci. Biotechnol. Biochem., 68 (10), 2197-2200, 2004.29Mehta, Nozer M., "Oral Delivery and Recombinant Production of Peptide Hormones. Part I: Making Oral Delivery Possible" Jun. 2004 BIOPHARM International pp. 1-6.30Mehta, Nozer M., "Oral Delivery and Recombinant Production of Peptide Hormones. Part II: Recombinant Production of Therapeutic Peptides" Jul. 2004 BIOPHARM International pp. 7-9.31Mehvar, R., "Modulation of the Pharmacokinetics and Pharmacodynamics of Proteins by Polyethylene Glycol Conjugation", J. Pharm. Pharmaceut. Sci. 3(1):125-136, 2000.32Mohr, J.M., et al, "Pulsatile Transdermal Drug Delivery", 1992; Proceedings of the 19th International Symposium on Controlled Release of Bioactive Materials, pp. 377-378; Controlled Release Society, U.S.A.33Mohr, J.M., et al., "Drug Delivery with Side Chain Crystallizable Polymer Blends", 1991; Proceedings of the 18th International Symposium on Controlled Release of Bioactive Materials, pp. 409-410; Controlled Release Society, U.S.A.34Morgan, V., "NOBEX: No Barriers" Overview. No date. File created Jun. 14, 2006; Nobex Corporation, Research Triangle Park, NC; 2 pp.35Ng, C.C.; Cheng, Y-L.; Saville, B.A.; Thermoresponsive Polymer Membrane for the Local Delivery of Drugs; Summer 2001; Journal of Sexual and Reproductive Medicine, vol. 1 #1, pp. 21-27; Pulses Group Inc., Canada.36Nishino, S., et al. "Preparation and Interfacial Properties of a Novel Biodegradable Polymer Surfactant: Poly(ethylene oxide monooleate-block-DL-lactide)", Macromolecular Bioscience; vol. 5, pp. 1066-1073; 2005.37Pollino, J., et al., "Non-Covalent Side-Chain Polymers: Design Principles, Functionalization Strategies and Perspectives", Chem. Soc. Rev., 2005, 34, 193-207.38Quintana, A., et al., "Design and Function of a Dendrimer-Based Therapeutic Nanodevice Targeted to Tumor Cells Through the Folate Receptor" Pharmaceutical Research, vol. 19, #9, pp. 1310-1316; Sep. 2002.39Roberts, M., et al., "Molecule Engineering Including Advanced PEGylation: Understanding the Full Potential", The Drug Delivery Companies Report Spring/Summer 2003, PharmaVentures, Ltd, 2003.40Schmidt, E.E.; Mohr, J.; and Stewart, R.F.; Side Chain Crystallizable Polymer Based Drug Delivery Phenomenon; 1991; in Proceedings of the 18th International Symposium on Controlled Release of Bioactive Materials, p. 134-135; Controlled Release Society, U.S.A.41Shang, S., et al., "Comb-Like Ionomeric Copolymer: Itaconic Anhydride-co-Stearyl Methacrylate", ACS Polymer Preprints, 2007, vol. 48(2), pp. 871-872.42Torchilin, V., "Structure and Design of Polymeric Surfactant-Based Drug Delivery Systems",Journal of Controlled Release, vol. 73, #2-3, pp. 137-172; Jun. 2001.43 *Tuncay, IntJPharm, 195, 2000.44U.S. Appl. No. 60/856,430, filed May 3, 2008, Schmitt.45U.S. Appl. No. 60/857,546, filed May 8, 2008, Schmitt.46U.S. Appl. No. 60/857,755, filed May 8, 2008, Krumme.47U.S. Appl. No. 60/964,066, filed Feb. 8, 2009, Krumme.48U.S. Appl. No. 60/993,541, filed Mar. 12, 2009, Krumme.49U.S. Appl. No. 61/016,223, filed Jun. 21, 2009, Krumme.50Wei, J-S.; Zeng, H-B.; Liu, S-Q.; Wang, X-G.; Tay, E.H.; and Yang, Y-Y.; Temperature and pH Sensitive Core-Shell Nanoparticles Self-Assembled From Poly(N-Isopropylacrylamide-Co-Acrylic Acid-CO-Cholesteryl Acrylate) for Intracellular Delivery of Anticancer Drugs; Sep. 2005; Frontiers in Bioscience 10, pp. 3058-3067; Frontier in Bioscience, U.S.A.51Yadav, S.K., et al., "Release Rates From Semi-Crystalline Polymer Microcapsules Formed by Interfacial Polycondensation", Journal of Membrane Science, vol. 125, #2, pp. 213-218; Mar. 1997.52Yan, X., et al., "Cisplatin Delivery from Poly(acrylic acid-co-methyl methacrylate) Microparticles", Journal of Controlled Release, vol. 106, #12, pp. 198-208; Aug. 2005.53Yu, L., et al., "A Subtle End-Group Effect on Macroscopic Physical Gelation of Triblock Copolymer Aqueous Solutions", Angew. Chem.Int. Ed. 2006, 45, 2232-2235.* Cited by examinerClassifications U.S. Classification514/259.41, 514/567International ClassificationA61K31/196, A61K31/519Cooperative ClassificationA61K31/5513, A61K31/519, A61K31/136, A61K9/146, A61K47/34, A61K9/1647, A61K31/196European ClassificationA61K9/16H6D4, A61K31/519, A61K31/5513, A61K9/14H6, A61K47/34, A61K31/196, A61K31/136Legal EventsDateCodeEventDescriptionJul 8, 2010ASAssignmentOwner name: LANDEC CORPORATION,CALIFORNIAFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:TAFT, DAVID, DR.;TZANNIS, STELIOS, DR.;BELL, ADAM, DR. AND OTHERS;SIGNED BETWEEN 20100603 AND 20100608;REEL/FRAME:24648/695Owner name: LANDEC CORPORATION, CALIFORNIAFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:TAFT, DAVID, DR.;TZANNIS, STELIOS, DR.;BELL, ADAM, DR.;AND OTHERS;SIGNING DATES FROM 20100603 TO 20100608;REEL/FRAME:024648/0695RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services©2012 Google