Source: http://www.google.com/patents/US5955448?dq=5,072,412
Timestamp: 2015-05-07 07:04:23
Document Index: 307218747

Matched Legal Cases: ['art 1', 'art 1', 'Application No. 0433679', 'Application No. 0433679', 'art 1', 'art 1']

Patent US5955448 - Method for stabilization of biological substances during drying and ... - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsThe present invention encompasses methods of increasing stability of biological substances during drying and the dried compositions derived therefrom. The compositions have improved storage stability....http://www.google.com/patents/US5955448?utm_source=gb-gplus-sharePatent US5955448 - Method for stabilization of biological substances during drying and subsequent storage and compositions thereofAdvanced Patent SearchPublication numberUS5955448 APublication typeGrantApplication numberUS 08/293,157Publication dateSep 21, 1999Filing dateAug 19, 1994Priority dateAug 19, 1994Fee statusPaidAlso published asCN1160345A, DE69532137D1, DE69532137T2, EP0804163A1, EP0804163B1, US6313102, WO1996005809A1Publication number08293157, 293157, US 5955448 A, US 5955448A, US-A-5955448, US5955448 A, US5955448AInventorsCamilo Colaco, Bruce J. Roser, Shevanti SenOriginal AssigneeQuadrant Holdings Cambridge LimitedExport CitationBiBTeX, EndNote, RefManPatent Citations (30), Non-Patent Citations (65), Referenced by (76), Classifications (39), Legal Events (8) External Links: USPTO, USPTO Assignment, EspacenetMethod for stabilization of biological substances during drying and subsequent storage and compositions thereof
US 5955448 AAbstract
The present invention encompasses methods of increasing stability of biological substances during drying and the dried compositions derived therefrom. The compositions have improved storage stability.
1. A method of increasing stability of a biological sample containing molecules that contain free amino, imino, or guanidino side chains during drying, said method comprising (a) adding to an aqueous solution or suspension of the sample a non-reducing carbohydrate excipient in an amount sufficient to stabilize the sample and an inhibitor of the Maillard reaction in an amount effective to prevent condensation of amino groups and reactive carbonyl groups and (b) drying the resulting composition.
The present invention relates generally to methods for increasing stabilization of biological substances during drying and storage of dry formulations. Compositions of stabilized biological substances are also provided.
Storage stability is the ultimate goal for dried formulations of biological substances. Dried formulations are preferred to aqueous formulations as the water, a nucleophile in hydrolysis reactions and a plasticizer, increases the molecular mobility of reactive chemical species, making aqueous formulations of biological substances inherently less stable than their dry counterparts. This increased stability of dry formulations has focused attention on techniques of drying and led to the development of freeze-drying as a popular method of water removal. Pikal (1990a) Biopharm. 3:18-27; Pikal (1990b) Biopharm. 3:26-30; and Franks (1990) Cryoletters 11:93-100. However, despite its widespread use, many freeze-dried products are still unstable at ambient temperatures. Carpenter and Crowe (1988) Cryobiol. 25:244-255; and Crowe et al. (1990) Cryobiol. 27:219-231. Detailed theoretical analyses of the physicochemical events during freeze-drying have led to a substantial literature on the use of lyoprotectants as stabilizing excipients. Pikal (1990b); Carpenter and Crowe (1988); Crowe et al. (1990); and Levine and Slade (1988) Pure Appl. Chem. 60:1841-1864. Various carbohydrates have been advocated as stabilizing excipients in freeze-drying, and these are proposed to act via the generation of an amorphous, glassy, solid state in the freezing step. Pikal (1990b); Franks (1990); Levine and Slade (1988); and Franks et al. (1992) U.S. Pat. No. 5,098,893. Nevertheless, the freezing step remains a major variable, as evidenced by the equivocal values for the experimentally measured glass transition temperature of the maximally freeze-concentrated unfrozen matrix (T'g) for various carbohydrate excipients. Franks (1990); Levine and Slade (1988); Ablett et al. (1992) J. Chem. Soc. Faraday Trans. 88:789-794; and Roos (1993) Carbo. Res. 238:39-48.
The present invention encompasses methods of increasing stability of biological substances during drying and the dried compositions derived therefrom. One method includes drying the biological substances in the presence of a carbohydrate excipient in an amount effective to stabilize the dried biological substance and an inhibitor of the Maillard reaction in an amount effective to substantially prevent condensation of amino groups and reactive carbonyl groups. Another method includes increasing storage stability of dried biological substances by storing the substances in the presence of a carbohydrate excipient in an amount sufficient to stabilize the biological substance and an inhibitor of the Maillard reaction in an amount sufficient to substantially prevent condensation of amino groups and reactive carbonyl groups. Compositions of biological substances, carbohydrates and inhibitors of the Maillard reaction are also included.
FIG. 1. Accelerated aging study on the restriction enzyme Pst I.
Previous work of the stabilization of dry protein formulations in the presence of carbohydrate excipients has emphasized the ability of stabilizing excipients to replace structural water and/or provide an amorphous or glassy solid matrix in the dry state. These studies have failed to realize the effect and nature of chemical reactions during drying and storage subsequent to drying. As shown in the examples presented herein, these reactions, which may begin during drying, are greatly enhanced during storage. These examples show that the Maillard reaction is the main chemical reaction occurring during drying and upon storage of dried biological substances in the presence of carbohydrate excipients. The methods and formulations described herein prevent the Maillard reaction during storage and thus increase shelf life of stored, dried biological substances.
Trehalose Stabilization of Biomolecules
It has previously been shown that antibodies, air-dried in the presence of trehalose, are undamaged, and full biological activity is recovered on rehydration, even after several years storage at room temperature or 37� C. Roser (1991); Blakely et al. (1990); and Colaco et al. (1990). Similar results were obtained with a variety of enzymes, hormones and blood coagulation factors, suggesting that this process may be generally applicable to biological substances. Roser (1991); Roser and Colaco (1993); Blakely et al. (1990); Colaco et al. (1990); and Colaco et al. (1992). As a stringent test of this technology to preserve labile biological substances, the enzymes used in molecular biology, which are notoriously fragile and thus usually transported and stored at or below -20� C., were studied in detail. It has previously been shown that both restriction endonucleases and DNA modifying enzymes can be dried from trehalose solutions at ambient temperatures without loss of activity. Furthermore, these dried enzymes show stability on storage for extended periods even at elevated temperatures. Colaco et al (1992).
Non-Enzymatic Browning of Dried Formulations during Storage
It appears that the relative chemical stability and non-reducing nature of trehalose may be significant features in its mechanism of action, especially with regard to the long term stability observed at high temperatures. This was first suggested by a surprising feature observed in the accelerated ageing trial described in FIG. 1 above. As shown in FIG. 2, non-enzymatic browning was observed in the samples used in the accelerated ageing study reported in FIG. 1 after two weeks storage at 37� C. (top panel), 55� C. (middle panel) and 70� C. (bottom panel). The carbohydrate excipients used were trehalose (row 1), sucrose (row 2), maltose (row 3), reduced iso-maltulose (row 4), glucopyranosyl-sorbitol (row 5) and glucopyranosyl-mannitol (row 6).
Evidence for Maillard Reactions in Dried Formulations
Studies were undertaken to correlate changes in biological activity with the development of brown pigments, as observed in the accelerated ageing studies on restriction enzymes (FIG. 2). These studies were carried out on samples of the enzyme alkaline phosphates which were dried, under the conditions described in Example 1 above, from solutions containing glucose, fructose, maltose or trehalose and stored for various periods at 55� C., before enzymatic activity was reassayed. Residual activity was determined in samples of alkaline phosphatase dried in the presence of various carbohydrate excipients and assayed calorimetrically after storage at 55� C.
Maillard-Related Modifications of Glucagon
To exemplify the generality of these chemical modifications of proteins by carbohydrate excipients, a relevant pharmaceutical model system was studied. The protein modifications of a therapeutic peptide, glucagon, dried from solution for 18 hr under a vacuum of 30 milliTorr, with a shelf-temperature rising from 25 to 42� C., were studied. Formulations containing various carbohydrate excipients were analyzed by reverse-phase HPLC analysis. The results obtained from a comparison of glucose and sucrose stored for varying times are presented in FIG. 5.
The Effect of Water on Storage Stability
To investigate directly the effect of residual moisture on chemical reactivity, a model system containing lysine with two non-reducing excipients trehalose and sorbitol, dried and stored at 3 different defined residual water contents, was used. Chemical reactivity was ensured by spiking the drying mixtures with a 5% trace of glucose, and its reaction with the lysine was measured by the quantitation of the glucose remaining after storage at 50� C.
The Effect of a Noncompetitive Inhibitor of the Maillard Reaction
Bovine serum albumin was dried from solutions containing reducing sugars and incubated at 55� C. for 3 weeks, in the presence or absence of various concentrations of the Maillard reaction inhibitor aminoguanidine. The extent of the Maillard reaction was quantified spectrophotometrically at 277-290 nm by the formation of brown color.
The Effect of Competitive Inhibitors of the Maillard Reaction
In order to determine the effect of competitive inhibitors on reducing the effects of the Maillard reaction upon storage of dried compositions, the following experiment was performed. The results are presented in FIG. 7.
Patent CitationsCited PatentFiling datePublication dateApplicantTitleUS3557717 *May 17, 1968Jan 26, 1971Gen Mills IncProcess for making candy flossUS3619294 *Jul 15, 1968Nov 9, 1971Penick & Ford LtdMethod of combining crystalline sugar with impregnating agents and products produced therebyUS3632357 *Jul 29, 1969Jan 4, 1972Standard Brands IncMethod of producing hard candyUS3655442 *Aug 27, 1969Apr 11, 1972California & Hawaiian SugarMethod of making sugar and sugar productsUS4127502 *Jun 10, 1977Nov 28, 1978Eastman Kodak CompanyStabilizers for reconstituted, lyophilized samplesUS4158544 *Jul 17, 1978Jun 19, 1979Beckman Instruments, Inc.Process for preparing a biological composition for use as a reference control in diagnostic analysisUS4327076 *Nov 17, 1980Apr 27, 1982Life Savers, Inc.Compressed chewable antacid tablet and method for forming sameUS4327077 *May 29, 1981Apr 27, 1982Life Savers, Inc.Compressed chewable antacid tablet and method for forming sameUS4588744 *Jan 27, 1981May 13, 1986Mchugh John EMethod of forming an aqueous solution of 3-3-Bis(p-hydroxyphenyl)-phthalideUS4701417 *Nov 21, 1985Oct 20, 1987Boehringer Mannheim GmbhControl or calibration serum for lipid diagnosisUS4758583 *Nov 14, 1985Jul 19, 1988The Rockefeller UniversityMethod and agents for inhibiting protein agingUS4812444 *Dec 16, 1986Mar 14, 1989Kabushiki Kaisha Hayashibara Seibutsu Kagaku KenkyujoDehydration of hydrous matter using anhydrous glycosylfructoseUS4865871 *Jul 11, 1988Sep 12, 1989Board Of Regents The University Of Texas SystemMethod for cryopreparing biological tissueUS4883762 *Jan 12, 1989Nov 28, 1989Ciba Corning Diagnostics Corp.Stabilized isoenzyme control productsUS4891319 *Jul 9, 1986Jan 2, 1990Quadrant Bioresources LimitedProtection of proteins and the likeUS5026772 *Aug 29, 1988Jun 25, 1991Yamanouchi Pharmaceutical Co., Ltd.Lyophilized pharmaceutical composition of neocarzinostatin derivativeUS5098893 *Feb 12, 1990Mar 24, 1992Pafra LimitedStorage of materialsUS5290765 *Feb 11, 1992Mar 1, 1994Boyce Thompson Institute For Plant Research, Inc.Method of protecting biological materials from destructive reactions in the dry stateUS5348852 *Apr 27, 1992Sep 20, 1994Analytical Control Systems Inc.Diagnostic and therapeutic compositionsUS5422384 *Nov 25, 1992Jun 6, 1995Battelle Memorial InstituteGlass/polymer composites and methods of makingEP0090356A1 *Mar 24, 1983Oct 5, 1983Takeda Chemical Industries, Ltd.Stabilized solid compositions and method of making themEP0222313A2 *Nov 5, 1986May 20, 1987The Rockefeller UniversityMethod and agents for inhibiting protein agingEP0415567A2 *Jul 31, 1990Mar 6, 1991Quadrant Bioresources LimitedComposition and method for stabilising organic compoundsEP0600730A1 *Dec 1, 1993Jun 8, 1994Kabushiki Kaisha Hayashibara Seibutsu Kagaku KenkyujoDesiccant, dehydration therewith, and dehydrated product obtainable therebyGB2206273A * Title not availableWO1987000196A1 *Jul 9, 1986Jan 15, 1987Quadrant Bioresources LtdProtection of proteins and the likeWO1989006542A1 *Jan 18, 1989Jul 27, 1989Quadrant Bioresources LtdPreservation of virusesWO1991018091A1 *May 14, 1991Nov 28, 1991Quadrant Holdings CambridgeStabilization of biological macromolecular substances and other organic compoundsWO1992002133A1 *Aug 7, 1991Feb 20, 1992Analytical Control Syst IncImproved diagnostic and therapeutic compositionsWO1995033488A1 *Jun 2, 1995Dec 14, 1995Quadrant Holdings CambridgeMethod of preventing aggregation of various substances upon rehydration or thawing and compositions obtained thereby* Cited by examinerNon-Patent CitationsReference1Ablett, S., et al., "Differential scanning calorimetric study of frozen sucrose and glycerol solutions" J. Chem. Soc. Faraday Trans. (1992) 88:789-794.2 *Ablett, S., et al., Differential scanning calorimetric study of frozen sucrose and glycerol solutions J. Chem. Soc. Faraday Trans. (1992) 88:789 794.3Akers, M.J., et al., "Top 10 current technical issues in parenteral science" Pharm. Tech. (1994) 18:26, 28, 30-33, 36.4 *Akers, M.J., et al., Top 10 current technical issues in parenteral science Pharm. Tech. (1994) 18:26, 28, 30 33, 36.5Blakeley, D., et al., "Dry instant blood typing plate for bedside use" The Lancet (1990) 336:854-855. A four page article reprint is enclosed herewith.6 *Blakeley, D., et al., Dry instant blood typing plate for bedside use The Lancet (1990) 336:854 855. A four page article reprint is enclosed herewith.7Burke, M.J., "The glassy state and survival of anhydrous biological systems" Membranes, Metabolism and Dry Organisms (1985) Leopold, ed., Cornell Univ. Press, Ithaca, New York, Appendix D, pp. 358-363.8 *Burke, M.J., The glassy state and survival of anhydrous biological systems Membranes, Metabolism and Dry Organisms (1985) Leopold, ed., Cornell Univ. Press, Ithaca, New York, Appendix D, pp. 358 363.9Carpenter, J.F., et al. "The mechanism of cryoprotection of proteins by solutes" Cryobiology (1988) 25:244-255.10 *Carpenter, J.F., et al. The mechanism of cryoprotection of proteins by solutes Cryobiology (1988) 25:244 255.11Carpenter, J.F., et al., "Modes of stabilization of a protein by organic solutes during desiccation" Cryobiology (1988) 25:459-470.12 *Carpenter, J.F., et al., Modes of stabilization of a protein by organic solutes during desiccation Cryobiology (1988) 25:459 470.13Clegg, J.S., "The physical properties and metabolic status of Artemia cysts at low water contents: The `water replacement hypothesis`" Membranes, Metabolism and Dry Organisms (1985) Leopold, ed., Cornell Univ. Press, Ithaca, New York, Chapter 10, pp. 169-187.14 *Clegg, J.S., The physical properties and metabolic status of Artemia cysts at low water contents: The water replacement hypothesis Membranes, Metabolism and Dry Organisms (1985) Leopold, ed., Cornell Univ. Press, Ithaca, New York, Chapter 10, pp. 169 187.15Colaco, C., et al., "Extraordinary stability of enzymes dried in trehalose: Simplified molecular biology" Bio/Technol. (1992) 10:1007-1011.16Colaco, C., et al., "Trehalose stabilisation of biological molecules" Biotechnol. Intl. (1992) Century Press, London, pp. 345, 347-350.17 *Colaco, C., et al., Extraordinary stability of enzymes dried in trehalose: Simplified molecular biology Bio/Technol. (1992) 10:1007 1011.18 *Colaco, C., et al., Trehalose stabilisation of biological molecules Biotechnol. Intl. (1992) Century Press, London, pp. 345, 347 350.19Crowe, J.H., "Are freezing and dehydration similar stress vectors? A comparsion of modes of interaction of stabilizing solutes with biomolecules" Cryobiology (1990) 27:219-231.20 *Crowe, J.H., Are freezing and dehydration similar stress vectors A comparsion of modes of interaction of stabilizing solutes with biomolecules Cryobiology (1990) 27:219 231.21Crowe, J.H., et al., "Preserving dry biomaterials: The water replacement hypothesis, part 1" BioPharm (1993) 6:28-29, 32-33, 37.22 *Crowe, J.H., et al., Preserving dry biomaterials: The water replacement hypothesis, part 1 BioPharm (1993) 6:28 29, 32 33, 37.23 *Dialog Abstract of European Patent Application No. 0433679 (Jun. 26, 1994).24Dialog� Abstract of European Patent Application No. 0433679 (Jun. 26, 1994).25 *Finot, P.A., et al., eds, The Maillard Reaction in Food Processing, Human Nutrition and Physiology , Birkh a user Verlag, Basel, (1990). The title page and table of contents are included herewith.26Finot, P.A., et al., eds, The Maillard Reaction in Food Processing, Human Nutrition and Physiology, Birkhauser Verlag, Basel, (1990). The title page and table of contents are included herewith.27Franks, F., "Freeze drying: From empiricism to predictability" Cryo-Letters (1990) 11:93-110.28Franks, F., "Long-term stabilization of biologicals" Bio/Tech. (1994) 12:253-256.29Franks, F., et al., "Materials science and the production of shelf-stable biologicals" BioPharm (1991) 14:38, 40-42, 55.30Franks, F., et al., "Stable enzymes by water removal" Stability and Stabilization of Enzymes (1993) van den Tweel, W.J.J., et al., eds., Elsevier, Amsterdam, pp. 45-54.31 *Franks, F., et al., Materials science and the production of shelf stable biologicals BioPharm (1991) 14:38, 40 42, 55.32 *Franks, F., et al., Stable enzymes by water removal Stability and Stabilization of Enzymes (1993) van den Tweel, W.J.J., et al., eds., Elsevier, Amsterdam, pp. 45 54.33 *Franks, F., Freeze drying: From empiricism to predictability Cryo Letters (1990) 11:93 110.34 *Franks, F., Long term stabilization of biologicals Bio/Tech. (1994) 12:253 256.35Green, J.L., et al., "Phase relations and vitrification in saccharide-water solutions and the trehalose anomaly" J. Phys. Chem. (1989) 93:2880-2882.36 *Green, J.L., et al., Phase relations and vitrification in saccharide water solutions and the trehalose anomaly J. Phys. Chem. (1989) 93:2880 2882.37Harrington, C.R., et al., "A glycation connection" Nature (1994) 370:247-248.38 *Harrington, C.R., et al., A glycation connection Nature (1994) 370:247 248.39Igaki et al. "The inhibition of the Maillard reaction by L lysine in-vitro" J. JPN. Diabetes Soc., vol. 34, No. 5, pp. 403-407, abstract only, 1991.40 *Igaki et al. The inhibition of the Maillard reaction by L lysine in vitro J. JPN. Diabetes Soc., vol. 34, No. 5, pp. 403 407, abstract only, 1991.41Ledl, F., et al., "New aspects of the Maillard reaction in foods and in the human body" Ang. Chem. (1990) 29:565-595.42 *Ledl, F., et al., New aspects of the Maillard reaction in foods and in the human body Ang. Chem. (1990) 29:565 595.43Levine, H., et al., "Another view of trehalose for drying and stabilizing biological materials" BioPharm (1992) 5:36-40.44 *Levine, H., et al., Another view of trehalose for drying and stabilizing biological materials BioPharm (1992) 5:36 40.45Mouradian et al. "Degradation of functional integrity during long-term storage of a freeze-dried biological membrane" Cryobiology, vol. 22, pp. 119-127, 1985.46 *Mouradian et al. Degradation of functional integrity during long term storage of a freeze dried biological membrane Cryobiology, vol. 22, pp. 119 127, 1985.47Nursten, H.E., "Maillard browning reactions in dried foods" Concentration and Drying of Foods (1986) McCarthy, D., ed., Elsevier Applied Science, London, pp. 53-68.48 *Nursten, H.E., Maillard browning reactions in dried foods Concentration and Drying of Foods (1986) McCarthy, D., ed., Elsevier Applied Science, London, pp. 53 68.49Pikal, M.J., "Freeze-drying of proteins. Part 1: Process design" BioPharm (1990) 3:18-20, 22-23, 26-27.50 *Pikal, M.J., Freeze drying of proteins. Part 1: Process design BioPharm (1990) 3:18 20, 22 23, 26 27.51Reynolds, T.M., "Chemistry of nonenzymic browning II" Adv. Food Res. (1965) 14:167-283.52 *Reynolds, T.M., Chemistry of nonenzymic browning II Adv. Food Res. (1965) 14:167 283.53Roos, Y., "Melting and glass transitions of low molecular weight carbohydrates" Carbohydrate Res. (1993) 238:39-48.54 *Roos, Y., Melting and glass transitions of low molecular weight carbohydrates Carbohydrate Res. (1993) 238:39 48.55Roser, B., "Trehalose drying: A novel replacement for freeze drying" BioPharm (1991) 4:47-53.56Roser, B., et al., "A sweeter way to fresher food" New Scientist (1993) 138:25-28.57 *Roser, B., et al., A sweeter way to fresher food New Scientist (1993) 138:25 28.58 *Roser, B., Trehalose drying: A novel replacement for freeze drying BioPharm (1991) 4:47 53.59Slade, L., et al., "Non-equilibrium behavior of small carbohydrate-water systems" Pure & Appl. Chem. (1988) 60:1841-1864.60 *Slade, L., et al., Non equilibrium behavior of small carbohydrate water systems Pure & Appl. Chem. (1988) 60:1841 1864.61Smith, M.A., et al., "Advanced Maillard reaction end products are associated with Alzheimer disease pathology" Proc. Natl. Acad. Sci. USA (1994) 91:5710-5714.62 *Smith, M.A., et al., Advanced Maillard reaction end products are associated with Alzheimer disease pathology Proc. Natl. Acad. Sci. USA (1994) 91:5710 5714.63Vitek, M.P., et al., "Advanced glycation end products contribute to amyloidosis in Alzheimer disease" Proc. Natl. Acad. Sci. USA (1994) 91:4766-4770.64 *Vitek, M.P., et al., Advanced glycation end products contribute to amyloidosis in Alzheimer disease Proc. Natl. Acad. Sci. USA (1994) 91:4766 4770.65 *Written Opinion from the International Preliminary Examining Authority (PCT) dated May 13, 1996 directed to the International Application No. PCT/GB95/01967.* Cited by examinerReferenced byCiting PatentFiling datePublication dateApplicantTitleUS6313102 *Sep 3, 1999Nov 6, 2001Quardrant Holdings Cambridge, Ltd.Method for stabilization of biological substances during drying and subsequent storage and compositions thereofUS6475979Mar 7, 2001Nov 5, 2002Grain Processing CorporationReduced malto-oligosaccharide cleansing compositionsUS6511699Mar 31, 2000Jan 28, 2003Cornell Research Foundation, Inc.Enzymes with improved phytase activityUS6551622Jul 12, 2000Apr 22, 2003Quadrant Holdings Cambridge, LtdDry powder compositionsUS6579688Dec 14, 2000Jun 17, 2003Biostar, Inc.Stabilizing diluent for polypeptides and antigensUS6593469Oct 20, 2000Jul 15, 2003Grain Processing CorporationCompositions including reduced malto-oligosaccharide preserving agentsUS6596702Jun 3, 2002Jul 22, 2003Elan Drug Delivery LimitedCompositions for use in rehydration and nutrition during athletic exercise and methods of making sameUS6610672Jan 9, 2002Aug 26, 2003Grain Processing CorporationCompositions including reduced malto-oligosaccharide preserving agents, and methods for preserving a materialUS6669963Mar 18, 1998Dec 30, 2003Elan Drug Delivery LimitedStable particle in liquid formulationsUS6689755 *Nov 3, 1998Feb 10, 2004Boehringer Mannheim GmbhMethod of stabilizing biologically active substancesUS6720418Dec 13, 2001Apr 13, 2004Grain Processing CorporationDerivatized reduced malto-oligosaccharidesUS6919446Jul 13, 2000Jul 19, 2005Grain Processing Corp.Reduced malto-oligosaccharidesUS6927062Nov 25, 2002Aug 9, 2005Agdia, Inc.Controls and standards for assays and method for manufacture thereofUS6946117Dec 22, 1998Sep 20, 2005Nektar TherapeuticsStabilized preparations for use in nebulizersUS6964771 *Sep 4, 1997Nov 15, 2005Elan Drug Delivery LimitedMethod for stably incorporating substances within dry, foamed glass matricesUS6974690Oct 7, 2002Dec 13, 2005Cornell Research Foundation, Inc.Phosphatases with improved phytase activityUS7026150Mar 8, 2002Apr 11, 2006Cornell Research Foundation, Inc.Overexpression of phytase genes in yeast systemsUS7078057 *Dec 19, 2000Jul 18, 2006Kerkhof Nicholas JProcess for producing nanometer particles by fluid bed spray-dryingUS7101693Jul 22, 2002Sep 5, 2006Brigham Young UniversityPlasticized hydrophilic glasses for improved stabilization of biological agentsUS7172999 *Oct 24, 1996Feb 6, 2007Roche Diagnostics GmbhMethod and preparations for stabilizing biological materials by drying methods without freezingUS7229645Jun 10, 2002Jun 12, 2007Powderject Research LimitedSpray freeze-dried compositionsUS7235253Nov 28, 2001Jun 26, 2007Jcr Pharmaceuticals Co., Ltd.Powder containing physiologically active peptideUS7270946Sep 26, 2003Sep 18, 2007Organ Recovery Systems, Inc.Method for treatment of cellular materials with sugars prior to preservationUS7285426May 5, 2005Oct 23, 2007Medtox Scientific, Inc.Bulking materials containing starch reagent for use in test devicesUS7300781Dec 20, 2004Nov 27, 2007Cornell Research Foundation, Inc.Site-directed mutagenesis of Escherichia coli phytaseUS7309505Sep 15, 2003Dec 18, 2007Cornell Research Foundation, Inc.Using mutations to improve Aspergillus phytasesUS7312063Mar 10, 2006Dec 25, 2007Cornell Research Foundation, Inc.Overexpression of phytase genes in yeast systemsUS7320876Oct 31, 2002Jan 22, 2008Phytex, LlcPhytase-containing animal food and methodUS7381796 *Mar 23, 2007Jun 3, 2008Quadrant Drug Delivery LimitedDried blood factor composition comprising trehaloseUS7405293Aug 29, 2003Jul 29, 2008Grain Processing CorporationReduced malto-oligosaccharidesUS7501493 *Aug 20, 2007Mar 10, 2009Quadrant Drug Delivery LimitedDried blood factor composition comprising trehaloseUS7589184May 24, 2005Sep 15, 2009Genvault CorporationStable protein storage and stable nucleic acid storage in recoverable formUS7595393Oct 13, 2004Sep 29, 2009Grain Processing CorporationReduced malto-oligosaccharidesUS7700722Jun 12, 2003Apr 20, 2010Amgen Inc.Compositions of pegylated soluble tumor necrosis factor receptors and methods of preparingUS7705132Oct 5, 2007Apr 27, 2010Amgen Inc.Stable polypeptide formulationsUS7736680Dec 7, 2007Jun 15, 2010Cornell Research Foundation, Inc.Using mutations to improve Aspergillus phytasesUS7803911Feb 13, 2009Sep 28, 2010Quandrant Drug Delivery LimitedDried blood factor composition comprising trehaloseUS7829318Dec 21, 2007Nov 9, 2010Cornell Research Foundation, Inc.Overexpression of phytase genes in yeast systemsUS7833743Dec 21, 2007Nov 16, 2010Phytex, LlcPhytase-containing animal food and methodUS7919294 *Nov 12, 2002Apr 5, 2011Biotools Biotechnological & Medical Laboratories, S.A.Process for preparing stabilized reaction mixtures which are partially dried, comprising at least one enzyme, reaction mixtures and kits containing said mixturesUS7919297Feb 21, 2007Apr 5, 2011Cornell Research Foundation, Inc.Mutants of Aspergillus niger PhyA phytase and Aspergillus fumigatus phytaseUS7947649Apr 8, 2009May 24, 2011Advanced Technologies And Regenerative Medicine, LlcLiquid buffered GDF-5 formulationsUS7956028Dec 4, 2007Jun 7, 2011Johnson & Johnson Regenerative Therapeutics, LlcProtein stabilization formulationsUS7964561Jan 28, 2010Jun 21, 2011Advanced Technologies And Regenerative Medicine, LlcProtein formulations for use at elevated temperaturesUS7972805Nov 15, 2010Jul 5, 2011Phytex, LlcPhytase-containing animal food and methodUS8017311Sep 17, 2007Sep 13, 2011Organ Recovery Systems, Inc.Method for treatment of cellular materials with sugars prior to preservationUS8058237Jul 16, 2008Nov 15, 2011Advanced Technologies & Regenerative Medicine, LLCStable composition of GDF-5 and method of storageUS8192734Jul 9, 2008Jun 5, 2012Cornell UniversityCompositions and methods for bone strengtheningUS8241632Mar 5, 2010Aug 14, 2012Amgen Inc.Stable polypeptide formulationsUS8283165Sep 14, 2009Oct 9, 2012Genvault CorporationMatrices and media for storage and stabilization of biomoleculesUS8431384Jul 7, 2009Apr 30, 2013Genvault CorporationStable protein storage and stable nucleic acid storage in recoverable formUS8435943Apr 19, 2011May 7, 2013Advanced Technogies And Regenerative Medicine, LlcProtein stabilization formulationsUS8440390Feb 23, 2010May 14, 2013Lifeline Scientific, Inc.Method for ice-free cryopreservation of tissueUS8455232Nov 8, 2010Jun 4, 2013Cornell Research Foundation, Inc.Overexpression of phytase genes in yeast systemsUS8540984Aug 3, 2007Sep 24, 2013Cornell Research Foundation, Inc.Phytases with improved thermal stabilityUS8551724Jun 7, 2011Oct 8, 2013Huvepharma AdPhytase-Containing Animal Food and MethodUS8771740May 21, 2006Jul 8, 2014Nicholas J. KerkhofProcess for producing nanoparticles by spray dryingUS8835146Dec 12, 2011Sep 16, 2014Micronics, Inc.Rehydratable matrices for dry storage of TAQ polymerase in a microfluidic deviceUS8895506Mar 7, 2013Nov 25, 2014DePuy Synthes Products, LLCProtein stabilization formulationsUS8900856Apr 8, 2005Dec 2, 2014Biomatrica, Inc.Integration of sample storage and sample management for life scienceUS8921085Dec 12, 2011Dec 30, 2014Micronics, Inc.Compositions and methods for dehydrated storage of on-board reagents in microfluidic devicesUS8951719Aug 20, 2012Feb 10, 2015Gentegra, LLC.Matrices and media for storage and stabilization of biomoleculesUS8993300May 17, 2013Mar 31, 2015Cornell Research Foundation, Inc.Overexpression of phytase genes in yeast systemsUS20080050737 *May 23, 2007Feb 28, 2008Boaz ArieliAmbient Temperature Stable Kits for Molecular DiagnosticsEP1430117A2 *Sep 6, 2002Jun 23, 2004Brigham Young UniversityPlasticized hydrophilic glasses for improved stabilization of biological agentsEP1430117A4 *Sep 6, 2002Jan 25, 2006Univ Brigham YoungPlasticized hydrophilic glasses for improved stabilization of biological agentsWO2001028325A2 *Oct 20, 2000Apr 26, 2001Richard L AntrimCompositions including reduced malto-oligosaccharide preserving agentsWO2002072002A2Mar 11, 2002Sep 19, 2002Biotools Biotechnological & MeMethod for preparing stabilised reaction mixtures, which are totally or partially dried, comprising at least one enzyme, reaction mixtures and kits containing said mixturesWO2002101412A2 *Jun 10, 2002Dec 19, 2002Powderject Res LtdSpray freeze-dried compositionsWO2003035827A2 *Sep 6, 2002May 1, 2003Univ Brigham YoungPlasticized hydrophilic glasses for improved stabilization of biological agentsWO2003041637A2 *Oct 18, 2002May 22, 2003Centocor IncLyophilized monoclonal antibody compositionsWO2010096821A2Feb 23, 2010Aug 26, 2010Cell & Tissue Systems, Inc.Method for ice-free cryopreservation of tissueWO2010144682A1Jun 10, 2010Dec 16, 2010Micronics, Inc.Rehydratable matrices for dry storage of taq polymerase in a microfluidic deviceWO2010144683A2Jun 10, 2010Dec 16, 2010Micronics, Inc.Compositions and methods for dehydrated storage of on-board reagents in microfluidic devicesWO2011048227A1Oct 22, 2009Apr 28, 2011Biotools Biotechnological & Medical Laboratories, S.A.Composition, method and kit for detecting bacteria by means of sequencingWO2013110956A1Jan 28, 2013Aug 1, 2013Stablepharma LtdImproved injections* Cited by examinerClassifications U.S. Classification514/53, 426/241, 514/400, 426/443, 514/399, 514/391, 426/242, 436/18International ClassificationA61K31/155, A61K31/00, A61K47/26, A61K47/22, C12N7/00, A61K38/46, C12N5/00, C07K1/00, A61K38/26, C12N1/00, F26B1/00, A61K9/14, A23L3/42, A61K9/19, A01N1/02Cooperative ClassificationY10T436/108331, A61K38/00, A61K47/22, A61K31/00, A61K9/19, A61K47/26, A61K31/155, A61K31/70European ClassificationA61K9/19, A61K31/155, A61K31/70, A61K31/00, A61K38/46, A61K47/22, A61K38/26, A61K47/26Legal EventsDateCodeEventDescriptionMar 16, 2011FPAYFee paymentYear of fee payment: 12Mar 19, 2007FPAYFee paymentYear of fee payment: 8Dec 26, 2006ASAssignmentOwner name: QUADRANT DRUG DELIVERY LIMITED, UNITED KINGDOMFree format text: CHANGE OF NAME;ASSIGNOR:ELAN DRUG DELIVERY LIMITED;REEL/FRAME:018668/0751Effective date: 20030728May 27, 2003ASAssignmentOwner name: QUADRANT HEALTHCARE (UK) LIMITED, UNITED KINGDOMFree format text: CHANGE OF NAME;ASSIGNOR:QUADRANT HOLDINGS CAMBRIDGE LIMITED;REEL/FRAME:014090/0668Effective date: 20030506Owner name: QUADRANT HEALTHCARE (UK) LIMITED 1 MERE WAY, RUDDIFree format text: CHANGE OF NAME;ASSIGNOR:QUADRANT HOLDINGS CAMBRIDGE LIMITED /AR;REEL/FRAME:014090/0668Owner name: QUADRANT HEALTHCARE (UK) LIMITED 1 MERE WAY, RUDDIOwner name: QUADRANT HEALTHCARE (UK) LIMITED 1 MERE WAY, RUDDIFree format text: CHANGE OF NAME;ASSIGNOR:QUADRANT HOLDINGS CAMBRIDGE LIMITED /AR;REEL/FRAME:014090/0668Effective date: 20030506Owner name: QUADRANT HEALTHCARE (UK) LIMITED 1 MERE WAY, RUDDIFree format text: CHANGE OF NAME;ASSIGNOR:QUADRANT HOLDINGS CAMBRIDGE LIMITED;REEL/FRAME:014090/0668Effective date: 20030506Apr 17, 2003ASAssignmentOwner name: ELAN DRUG DELIVERY LIMITED, UNITED KINGDOMFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:QUADRANT HEALTHCARE (UK) LIMITED;REEL/FRAME:013964/0452Effective date: 20020919Owner name: ELAN DRUG DELIVERY LIMITED 1 MERE WAY, RUDDINGTONNFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:QUADRANT HEALTHCARE (UK) LIMITED /AR;REEL/FRAME:013964/0452Owner name: ELAN DRUG DELIVERY LIMITED 1 MERE WAY, RUDDINGTONNOwner name: ELAN DRUG DELIVERY LIMITED 1 MERE WAY, RUDDINGTONNFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:QUADRANT HEALTHCARE (UK) LIMITED /AR;REEL/FRAME:013964/0452Effective date: 20020919Owner name: ELAN DRUG DELIVERY LIMITED 1 MERE WAY, RUDDINGTONNFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:QUADRANT HEALTHCARE (UK) LIMITED;REEL/FRAME:013964/0452Effective date: 20020919Dec 25, 2002FPAYFee paymentYear of fee payment: 4Oct 24, 1994ASAssignmentOwner name: QUADRANT HOLDINGS CAMBRIDGE LIMITED, ENGLANDFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:COLACO, CAMILO;ROSER, BRUCE J.;SEN, SHEVANTI;REEL/FRAME:007176/0612Effective date: 19941010Oct 24, 1994AS02Assignment of assignor's interestOwner name: QUADRANT HOLDINGS CAMBRIDGE LIMITED MARIS LANE, TREffective date: 19941010Owner name: SEN, SHEVANTIEffective date: 19941010Owner name: COLACO, CAMILOEffective date: 19941010Owner name: ROSER, BRUCE J.Effective date: 19941010RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services