Source: https://patents.google.com/patent/US5955448A/en
Timestamp: 2018-06-25 01:17:04
Document Index: 557695814

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

US5955448A - Method for stabilization of biological substances during drying and subsequent storage and compositions thereof - Google Patents
Method for stabilization of biological substances during drying and subsequent storage and compositions thereof Download PDF
US5955448A
US5955448A US08293157 US29315794A US5955448A US 5955448 A US5955448 A US 5955448A US 08293157 US08293157 US 08293157 US 29315794 A US29315794 A US 29315794A US 5955448 A US5955448 A US 5955448A
Shevanti Sen
Similarly, the glassy state theory alone cannot explain the stability conferred by trehalose. In high temperature storage stability data reported in FIG. 1 above, the glass transition temperatures of the samples dried in trehalose to a water content of 2.6-3.6% were all below 37° C. as measured by differential scanning calorimetry. Thus, their stability persists at well above their glass transition temperatures, and although the glassy state may be important in other systems, contrary to accepted belief (Franks et al. (1992); and Franks (1994)), it appears not to be a factor in the long-term high temperature stability of biomolecules dried in trehalose.
The method of drying may be any known in the art and includes, but is not limited to, freeze drying, spray drying, fluidized-bed drying, drum drying, drying at ambient temperature and atmosphere pressure, drying at ambient temperature and decreased pressure, drying at elevated temperatures and atmospheric pressure and drying at elevated temperatures and decreased pressure. In the case of freeze drying, the samples are typically frozen at -70 to -30° C. and dried at a condenser temperature of -50 to -80° C., although any suitable temperature may be used. Freezing can be performed by any method known in the art including, but not limited to, immersing in liquid nitrogen, placing in a freezer which may be at -4° C. to -80° C., dry ice and alcohol freezing bath. In the case of ambient or elevated temperature drying, any temperature above freezing may be used, provided it is not so high that the biological substance becomes denatured; preferably the temperatures are less than 80° C., more preferably less than 65° C. and most preferably 20-50° C. Preferably the temperature is above ambient to 50° C. In the case of spray drying, the temperature range is less than 250° C., more preferably in the range of 150-220° C., and most preferably, 180-200° C.
As used herein, with respect to storage or drying, ambient, or "room temperature" is generally about 20° C. and elevated temperatures are all those above freezing. Temperatures "above ambient" are those greater than 20° C.
The invention also encompasses methods of increasing the "shelf-life" or storage stability of dried biological substances stored at elevated temperatures. Increased storage stability is determined by recovery of biological activity in accelerated aging trials. The methods include drying, or otherwise incorporating, at least one biological substance in the presence of at least one carbohydrate excipient in an amount sufficient to stabilize the biological substance, and at least one inhibitor of the Maillard reaction. Other suitable buffers, salts, cofactors, etc., may be added to the composition. The composition may be stored at any suitable temperature. Preferably, the compositions are stored at 0° C. to 80° C. More preferably, the compositions are stored at 20° C.-60° C. Most preferably, the compositions are stored at above ambient temperatures.
EXAMPLE 1 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).
TABLE 1__________________________________________________________________________STABILITY OF PST I DRIED IN VARIOUS CARBOHYDRATE EXCIPIENTS                           RED TEMP                                   TIMECARBOHYDRATE      CHEMICAL NAME        SUGAR                               ° C.                                   days                                       ACTIVITY__________________________________________________________________________MONOSACCHARIDESAND ALCOHOLSGlucose    α-D-glucopyranose                           +   37° C.                                    1  +                               "   14  -Sorbitol   sugar alcohol of glucose                           -   "   14  +                               "   35  +                               "   70  -Galactose  α-D-galactopyranose                           +   "    1  -Galactitol sugar alcohol of galactose                           -   "    1  -Mannose    α-D-mannopyranose                           +   "    1  -Mannitol   sugar alcohol of mannose                           -   "    1  -DISACCHARIDESTrehalose  α-D-glucopyranosyl-α-D-glucopyranoside                           -   "   98  +++                               55° C.                                   70  +++                               70° C.                                   35  +++Maltose    4-O-α-D-glucopyranosyl-D-glucose                           +   "   14  ++                               "    7  -Maltotriose      O-α-D-glucopyranosyl(1 → 4)-O-α-D-                           +   "   14  -      glucopyranosyl-(1 → 4)-D-glucoseLactose    4-O-β-D-galactopyranosyl-D-glucopyranose                           +   "   14  -Lactulose  4-O-β-D-galactopyranosyl-D-fructose                           +   "   14  +                                   35  -Sucrose    β-D-fructofuranosyl-α-D-glucopyranoside                           -   37° C.                                   14  ++                               "   35  -POLYMERSInulin     Polymer of 1-O-β-D-fructofuranosyl-D-                           -   "    7  -      fructoseDextran    Polymer of α-(1 → 6)-D-glucopyranose (1 →      3,                   +   "    7  -      1 → 4 branch)Ficoll     Polymer of β-D-fructofuranosyl-α-D-                           -   "    7  +      glucopyranose__________________________________________________________________________ Quantitation of activity - no detectable activity + some activity (10-20% of titre) ++ partial activity (25-40% of titre) +++ full activity Reducing properties + reducing sugar - nonreducing sugar
Development of brown coloration assayed by absorbance between 277-290 nm was compared with loss of enzymic activity in samples of alkaline phosphatase dried in fructose and glucose after storage at 55° C. FIG. 5 shows the results obtained where color development was measured at O.D. 277-290; (•) glucose, (+) fructose. Enzymic activity (O.D. 405); and depicted as follows: (*) glucose, (□) fructose. The production of melanoid pigments occurred later than the loss of enzymatic activity assayed calorimetrically (FIG. 4). This is consistent with the fact that the generation of brown melanoid pigments occurs in the terminal stages of the Maillard reaction and thus cannot be used to predict enzyme inactivation due to the early reactions of the cascade (FIG. 3). Similarly, analysis of the samples by SDS-PAGE showed a complex pattern of protein breakdown and cross-linking in all samples, except those dried in trehalose, and the complexity of these patterns precludes the use of this technique in determining the extent of protein modification by the Maillard reaction.
FIG. 6 shows the results obtained where solutions of 10% w/v lysine and 5% glucose in 85% trehalose (a) or 85% sorbitol (b) in water were freeze-dried with primary drying at -50° C. for 48 hr and secondary drying for a further 24 hr at 20° C. The desired water content was achieved by storage at 20° C. over anhydrous P2 O5 followed by exposure to a saturated water vapor atmosphere for either 0 hr, 8 hr or 25 hr. The actual final water content of the samples was determined by thermogravimetry using a Kahn microbalance. FIG. 7 depicts the results as follows:
Alkaline phosphatase (0.25 mg/ml) was dried under vacuum (80 microns) at ambient temperature for 16 hours from a formulation containing 15% glucose as the carbohydrate excipient with either 0, 7.5, 15 and 25% lysine added as a competitive Maillard reaction inhibitor. The samples were stored for four days at 55° C. and assayed by running on a 10% polyacrylamide gel and stained for enzymatic activity using α-napthyl acid phosphate and Fast Blue BB (1 mg/ml and 1.33 mg/ml, respectively, in 0.38 M Tris-HCl (pH 10.3) containing 0.5 mM MgCl2) (FIG. 7, tracks 1-4, respectively). Controls run were enzyme in aqueous buffer and enzyme dried in trehalose (FIG. 7, lanes 8-9, respectively). Although only partial activity was recovered in the glucose plus lysine samples, these showed increased activity recovered with increasing concentration of added lysine. In the sample with glucose but with no added lysine, no enzymatic activity was recovered.
4. The method according to claim 1 wherein the method of drying is selected from the group consisting of freeze drying, spray drying, fluidized bed drying, drum drying, drying at about 20° C. and atmospheric pressure, drying at about 20° C. and decreased pressure, drying at elevated temperatures and atmospheric pressure and drying at elevated temperatures and decreased pressure.
21. The method according to claim 18 wherein the method of drying is selected from the group consisting of freeze drying, spray drying, fluidized bed drying, drum drying, drying at about 20° C. and atmospheric pressure, drying at about 20° C. and decreased pressure, drying at elevated temperatures and atmospheric pressure and drying at elevated temperatures and decreased pressure.
32. The method according to claim 18 wherein storage is at 0° C.-80° C.
33. The method according to claim 18 wherein storage is at 0°-65° C.
34. The method according to claim 18 wherein storage is at 10° C.-60° C.
35. The method according to claim 18 wherein storage is at 20°-50° C.
39. The method according to claim 36 wherein the method of drying is selected from the group consisting of freeze drying, spray drying, fluidized bed drying, drum drying, drying at about 20° C. and atmospheric pressure, drying at about 20° C. and decreased pressure, drying at elevated temperatures and atmospheric pressure and drying at elevated temperatures and decreased pressure.
50. The method according to claim 36 wherein storage is at 0° C.-80° C.
51. The method according to claim 36 wherein storage is at 0°-65° C.
52. The method according to claim 36 wherein storage is at 10° C.-60° C.
53. The method according to claim 36 wherein storage is at 20°-50° C.
US08293157 1994-08-19 1994-08-19 Method for stabilization of biological substances during drying and subsequent storage and compositions thereof Expired - Lifetime US5955448A (en)
US08293157 US5955448A (en) 1994-08-19 1994-08-19 Method for stabilization of biological substances during drying and subsequent storage and compositions thereof
DE1995632137 DE69532137T2 (en) 1994-08-19 1995-08-18 An improved process for the stabilization of biological substances during drying and subsequent storage as well as the corresponding compositions
DE1995632137 DE69532137D1 (en) 1994-08-19 1995-08-18 An improved process for the stabilization of biological substances during drying and subsequent storage as well as the corresponding compositions
CN 95195602 CN1160345A (en) 1994-08-19 1995-08-18 Improved method for stabilization of biological substances during drying and subsequent storage and compositions thereof
PCT/GB1995/001967 WO1996005809A1 (en) 1994-08-19 1995-08-18 Improved method for stabilization of biological substances during drying and subsequent storage and compositions thereof
DK95929935T DK0804163T3 (en) 1994-08-19 1995-08-18 Improved method for stabilization of biological substances during drying and subsequent storage and compositions thereof
JP50786896A JP3815793B2 (en) 1994-08-19 1995-08-18 Improved methods and compositions thereof for the stabilization of biological substances during and subsequent storage dried
EP19950929935 EP0804163B1 (en) 1994-08-19 1995-08-18 Improved method for stabilization of biological substances during drying and subsequent storage and compositions thereof
ES95929935T ES2208693T3 (en) 1994-08-19 1995-08-18 Improved process for stabilization of biological substances during drying and subsequent storage and compositions of these substances.
US09389949 US6313102B1 (en) 1994-04-13 1999-09-03 Method for stabilization of biological substances during drying and subsequent storage and compositions thereof
US09389949 Continuation US6313102B1 (en) 1994-04-13 1999-09-03 Method for stabilization of biological substances during drying and subsequent storage and compositions thereof
US5955448A true US5955448A (en) 1999-09-21
ID=23127893
US08293157 Expired - Lifetime US5955448A (en) 1994-08-19 1994-08-19 Method for stabilization of biological substances during drying and subsequent storage and compositions thereof
US09389949 Expired - Lifetime US6313102B1 (en) 1994-04-13 1999-09-03 Method for stabilization of biological substances during drying and subsequent storage and compositions thereof
US (2) US5955448A (en)
EP (1) EP0804163B1 (en)
JP (1) JP3815793B2 (en)
CN (1) CN1160345A (en)
DE (2) DE69532137T2 (en)
DK (1) DK0804163T3 (en)
ES (1) ES2208693T3 (en)
WO (1) WO1996005809A1 (en)
WO2001028325A2 (en) * 1999-10-20 2001-04-26 Grain Processing Corporation Compositions including reduced malto-oligosaccharide preserving agents
WO2002101412A2 (en) * 2001-06-08 2002-12-19 Powderject Vaccines, Inc. Spray freeze-dried compositions
WO2003035827A2 (en) 2001-09-07 2003-05-01 Brigham Young University Plasticized hydrophilic glasses for improved stabilization of biological agents
US6689755B1 (en) * 1997-11-03 2004-02-10 Boehringer Mannheim Gmbh Method of stabilizing biologically active substances
US20080050737A1 (en) * 2006-05-23 2008-02-28 Boaz Arieli Ambient Temperature Stable Kits for Molecular Diagnostics
WO2013110956A1 (en) 2012-01-27 2013-08-01 Stablepharma Ltd Improved injections
CN101210353A (en) * 2006-12-28 2008-07-02 山东海龙股份有限公司 Anti-flame fusion-resisting cellulose viscose and producing method thereof
CA2712170C (en) * 2008-01-18 2014-04-22 Asahi Kasei Pharma Corporation Stable pharmaceutical composition
WO2011069529A1 (en) * 2009-12-09 2011-06-16 Curevac Gmbh Mannose-containing solution for lyophilization, transfection and/or injection of nucleic acids
EP0090356A1 (en) * 1982-03-25 1983-10-05 Takeda Chemical Industries, Ltd. Stabilized solid compositions and method of making them
EP0600730A1 (en) * 1992-12-02 1994-06-08 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Desiccant, dehydration therewith, and dehydrated product obtainable thereby
Ablett, S., et al., "Differential scanning calorimetric study of frozen sucrose and glycerol solutions" J. Chem. Soc. Faraday Trans. (1992) 88:789-794.
Ablett, S., et al., Differential scanning calorimetric study of frozen sucrose and glycerol solutions J. Chem. Soc. Faraday Trans. (1992) 88:789 794. *
Akers, M.J., et al., "Top 10 current technical issues in parenteral science" Pharm. Tech. (1994) 18:26, 28, 30-33, 36.
Akers, M.J., et al., Top 10 current technical issues in parenteral science Pharm. Tech. (1994) 18:26, 28, 30 33, 36. *
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.
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. *
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.
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. *
Carpenter, J.F., et al. "The mechanism of cryoprotection of proteins by solutes" Cryobiology (1988) 25:244-255.
Carpenter, J.F., et al. The mechanism of cryoprotection of proteins by solutes Cryobiology (1988) 25:244 255. *
Carpenter, J.F., et al., "Modes of stabilization of a protein by organic solutes during desiccation" Cryobiology (1988) 25:459-470.
Carpenter, J.F., et al., Modes of stabilization of a protein by organic solutes during desiccation Cryobiology (1988) 25:459 470. *
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.
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. *
Colaco, C., et al., "Extraordinary stability of enzymes dried in trehalose: Simplified molecular biology" Bio/Technol. (1992) 10:1007-1011.
Colaco, C., et al., "Trehalose stabilisation of biological molecules" Biotechnol. Intl. (1992) Century Press, London, pp. 345, 347-350.
Colaco, C., et al., Extraordinary stability of enzymes dried in trehalose: Simplified molecular biology Bio/Technol. (1992) 10:1007 1011. *
Colaco, C., et al., Trehalose stabilisation of biological molecules Biotechnol. Intl. (1992) Century Press, London, pp. 345, 347 350. *
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.
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. *
Crowe, J.H., et al., "Preserving dry biomaterials: The water replacement hypothesis, part 1" BioPharm (1993) 6:28-29, 32-33, 37.
Crowe, J.H., et al., Preserving dry biomaterials: The water replacement hypothesis, part 1 BioPharm (1993) 6:28 29, 32 33, 37. *
Dialog Abstract of European Patent Application No. 0433679 (Jun. 26, 1994). *
Dialog™ Abstract of European Patent Application No. 0433679 (Jun. 26, 1994).
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. *
Finot, 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.
Franks, F., "Freeze drying: From empiricism to predictability" Cryo-Letters (1990) 11:93-110.
Franks, F., "Long-term stabilization of biologicals" Bio/Tech. (1994) 12:253-256.
Franks, F., et al., "Materials science and the production of shelf-stable biologicals" BioPharm (1991) 14:38, 40-42, 55.
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.
Franks, F., et al., Materials science and the production of shelf stable biologicals BioPharm (1991) 14:38, 40 42, 55. *
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. *
Franks, F., Freeze drying: From empiricism to predictability Cryo Letters (1990) 11:93 110. *
Franks, F., Long term stabilization of biologicals Bio/Tech. (1994) 12:253 256. *
Green, J.L., et al., "Phase relations and vitrification in saccharide-water solutions and the trehalose anomaly" J. Phys. Chem. (1989) 93:2880-2882.
Green, J.L., et al., Phase relations and vitrification in saccharide water solutions and the trehalose anomaly J. Phys. Chem. (1989) 93:2880 2882. *
Harrington, C.R., et al., "A glycation connection" Nature (1994) 370:247-248.
Harrington, C.R., et al., A glycation connection Nature (1994) 370:247 248. *
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.
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. *
Ledl, F., et al., "New aspects of the Maillard reaction in foods and in the human body" Ang. Chem. (1990) 29:565-595.
Ledl, F., et al., New aspects of the Maillard reaction in foods and in the human body Ang. Chem. (1990) 29:565 595. *
Levine, H., et al., "Another view of trehalose for drying and stabilizing biological materials" BioPharm (1992) 5:36-40.
Levine, H., et al., Another view of trehalose for drying and stabilizing biological materials BioPharm (1992) 5:36 40. *
Mouradian et al. "Degradation of functional integrity during long-term storage of a freeze-dried biological membrane" Cryobiology, vol. 22, pp. 119-127, 1985.
Mouradian et al. Degradation of functional integrity during long term storage of a freeze dried biological membrane Cryobiology, vol. 22, pp. 119 127, 1985. *
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.
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. *
Pikal, M.J., "Freeze-drying of proteins. Part 1: Process design" BioPharm (1990) 3:18-20, 22-23, 26-27.
Pikal, M.J., Freeze drying of proteins. Part 1: Process design BioPharm (1990) 3:18 20, 22 23, 26 27. *
Reynolds, T.M., "Chemistry of nonenzymic browning II" Adv. Food Res. (1965) 14:167-283.
Reynolds, T.M., Chemistry of nonenzymic browning II Adv. Food Res. (1965) 14:167 283. *
Roos, Y., "Melting and glass transitions of low molecular weight carbohydrates" Carbohydrate Res. (1993) 238:39-48.
Roos, Y., Melting and glass transitions of low molecular weight carbohydrates Carbohydrate Res. (1993) 238:39 48. *
Roser, B., "Trehalose drying: A novel replacement for freeze drying" BioPharm (1991) 4:47-53.
Roser, B., et al., "A sweeter way to fresher food" New Scientist (1993) 138:25-28.
Roser, B., et al., A sweeter way to fresher food New Scientist (1993) 138:25 28. *
Roser, B., Trehalose drying: A novel replacement for freeze drying BioPharm (1991) 4:47 53. *
Slade, L., et al., "Non-equilibrium behavior of small carbohydrate-water systems" Pure & Appl. Chem. (1988) 60:1841-1864.
Slade, L., et al., Non equilibrium behavior of small carbohydrate water systems Pure & Appl. Chem. (1988) 60:1841 1864. *
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.
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. *
Vitek, M.P., et al., "Advanced glycation end products contribute to amyloidosis in Alzheimer disease" Proc. Natl. Acad. Sci. USA (1994) 91:4766-4770.
Vitek, M.P., et al., Advanced glycation end products contribute to amyloidosis in Alzheimer disease Proc. Natl. Acad. Sci. USA (1994) 91:4766 4770. *
Written Opinion from the International Preliminary Examining Authority (PCT) dated May 13, 1996 directed to the International Application No. PCT/GB95/01967. *
US6593469B1 (en) 1999-10-20 2003-07-15 Grain Processing Corporation Compositions including reduced malto-oligosaccharide preserving agents
WO2001028325A3 (en) * 1999-10-20 2001-11-08 Richard L Antrim Compositions including reduced malto-oligosaccharide preserving agents
WO2002101412A3 (en) * 2001-06-08 2003-03-20 Powderject Res Ltd Spray freeze-dried compositions
EP1430117A4 (en) * 2001-09-07 2006-01-25 Univ Brigham Young Plasticized hydrophilic glasses for improved stabilization of biological agents
EP1430117A2 (en) * 2001-09-07 2004-06-23 Brigham Young University Plasticized hydrophilic glasses for improved stabilization of biological agents
WO2003035827A3 (en) * 2001-09-07 2003-12-11 Univ Brigham Young Plasticized hydrophilic glasses for improved stabilization of biological agents
US20100196904A1 (en) * 2006-05-23 2010-08-05 Molecular Detection, Inc. Ambient temperature stable kits for molecular diagnostics
JP3815793B2 (en) 2006-08-30 grant
EP0804163B1 (en) 2003-11-12 grant
DK0804163T3 (en) 2004-03-29 grant
EP0804163A1 (en) 1997-11-05 application
US6313102B1 (en) 2001-11-06 grant
CN1160345A (en) 1997-09-24 application
WO1996005809A1 (en) 1996-02-29 application
DE69532137T2 (en) 2004-04-22 grant
ES2208693T3 (en) 2004-06-16 grant
JPH10505591A (en) 1998-06-02 application
DK804163T3 (en) grant
DE69532137D1 (en) 2003-12-18 grant
US6210683B1 (en) 2001-04-03 Stabilizers containing recombinant human serum albumin for live virus vaccines
Sun et al. 1998 Protein stability in the amorphous carbohydrate matrix: relevance to anhydrobiosis
Park 1988 Reaction of S-nitrosoglutathione with sulfhydryl groups in protein
EP0383569B1 (en) 1994-05-18 Storage of materials
Raiha et al. 1962 Effect of ethanol oxidation on levels of pyridine nucleotides in liver and yeast.
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:COLACO, CAMILO;ROSER, BRUCE J.;SEN, SHEVANTI;REEL/FRAME:007176/0612