Claims for Patent: 4,237,229

Summary for Patent: 4,237,229

Title:	Immobilization of biological material with polyurethane polymers
Abstract:	A process for immobilizing a biological material which can be a protein, a coenzyme having at least one primary or secondary amino group per molecule, an admixture of said coenzyme and an enzyme which is mediated by said coenzyme, or an antibiotic having at least one primary or secondary amino group per molecule, wherein the biological material is contacted with an excess of an isocyanate-capped liquid polyurethane prepolymer in the absence of water, and the resulting mixture is cured by contacting it with a curing agent to cure the prepolymer and to immobilize the biological material. The resulting mixture can be cured under foam-forming conditions or under nonfoam-forming conditions. The resulting mixture can be formed into a predetermined shape before or during curing or coated onto a surface before or during curing.
Inventor(s):	Hartdegen; Frank J. (Columbia, MD), Swann; Wayne E. (Pasadena, MD)
Assignee:	W. R. Grace & Co. (New York, NY)
Application Number:	05/849,990
Patent Claims:	1. A process for immobilizing a biological material selected from the group consisting of: (a) a protein; (b) a coenzyme having at least one primary or secondary amino group per molecule; (c) an admixture of said coenzyme and an enzyme; and (d) an antibiotic having at least one primary or secondary amino group per molecule, the process comprising: A. contacting the group member and an excess of an isocyanate-capped liquid polyurethane prepolymer in the absence of water to form a resulting mixture where said prepolymer is the reaction product of a polyether polyol with sufficient polyisocyanate to provide at least two free NCO groups per molecule of the prepolymer; B. shaping the resulting mixture; and C. curing the shaped resulting mixture by contacting it with a curing agent to form a cured shaped article comprising the immobilized biological material. 2. The product prepared by the process of claim 1. 3. The process of claim 1 in which the isocyanate-capped liquid polyurethane prepolymer is prepared by reacting toluene diisocyanate and a polyethylene glycol. 4. The process of claim 1 in which the isocyanate-capped liquid polyurethane prepolymer is prepared by reacting toluene diisocyanate and a polyethylene glycol having a molecular weight of about 800-1,200. 5. The process of claim 1 in which the isocyanate-capped liquid polyurethane prepolymer is prepared by reacting toluene diisocyanate and a member selected from the group consisting of a polyoxybutylene polyol polymer, a polyoxyethylene polyol polymer, a polyoxypropylene polyol polymer, and propylene oxide/ethylene oxide copolymers. 6. The process of claim 1 in which the isocyanate-capped liquid polyurethane prepolymer is prepared by reacting toluene diisocyanate with an admixture of a polyethylene glycol having a molecular weight of about 800-1,200 and trimethylolpropane, the trimethylolpropane and the polyethylene glycol being provided in a mole ratio of about 1:1-4 and the toluene diisocyanate being provided at a rate of about 1-1.25 mole per equivalent of --OH provided by the polyethylene glycol plus the trimethylolpropane. 7. The process of claim 1 in which the cured product is washed to remove unbound nonimmobilized group member and to hydrolyze any unreacted isocyanate groups. 8. The process of claim 1 in which the curing agent is in vapor form. 9. The process of claim 8 in which the curing agent in vapor form is contained in an inert gas. 10. The process of claim 9 in which the inert gas is air, nitrogen, oxygen, carbon dioxide, hydrogen, argon, helium, xenon, or a mixture of at least 2 of said inert gases. 11. The process of claim 1 in which the curing agent is water. 12. The process of claim 1 in which the curing agent is an amine having zero to about 10 carbon atoms per molecule and at least one primary or secondary amino group per molecule. 13. The process of claim 12 in which the curing agent is ammonia, hydroxylamine, hydrazine, diethylenetriamine propylamine, butylamine, ethylenediamine, or aniline. 14. The process of claim 1 in which the group member is the protein. 15. The process of claim 14 in which the protein is an enzyme, an antibody, or an antigen. 16. The process of claim 15 in which the enzyme is urease, trypsin, lactase, glucose oxidase, chymotrypsin, ribonuclease, peroxidase, pepsin, rennin, invertase, papain, asparaginase, pectinase, pectin esterase, penicillin amidase, glucose isomerase, lysozyme, amino acid acylase, pronase, alcohol dehydrogenase, .alpha.-amylase, .beta.-amylase, subtilisin, amino acid oxidase, catalase, tannase, phenol oxidase, glucoamylase, pullulanase, cellulase, ficin, bromelain, pancreatin, isoamylase, lipase, malic dehydrogenase, hexokinase, lactate dehydrogenase, adenosine deaminase, uricase, galactose oxidase, diaphorase, cholinesterase, aldolase, pyruvate carboxylase, phospharylase, cephalosporin amidase, isocitric dehydrogenase, .alpha.-glycerolphosphate dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase, malic enzyme, glucose-6-phosphate dehydrogenase, 5-dehydroshikimic reductase, glutathione reductase, glycolic acid oxidase, yeast cytochrome c reductase, luciferase, nitrite reductase, glutamyl transferase, glutathione synthetase, glycocyamine phosphokinase, hippuric acid synthetase, aldehyde oxidase, succinic dehydrogenase, nitrate reductase, xanthine oxidase, lipoyl dehydrogenase, flavin peroxidase, glycine oxidase, carboxylase, .alpha.-keto acid dehydrogenase, or transketolase. 17. The process of claim 15 in which the antibody is human immunoglobulin G or hepatitis antibody. 18. The process of claim 15 in which the antigen is rheumatoid arthritis factor. 19. The process of claim 1 in which the group member is the coenzyme having at least one primary or secondary amino group per molecule. 20. The process of claim 19 in which the coenzyme is nicotinamide-adenine dinucleotide, nicotinamide-adenine dinucleotide phosphate, flavin mononucleotide, adenosine triphosphate, flavin adenine dinucleotide, or thiamin pyrophosphate. 21. The process of claim 1 in which the group member is an admixture of the coenzyme having at least one primary or secondary amino group per molecule. 22. The process of claim 21 in which: (a) the coenzyme is nicotinamide-adenine dinucleotide and the enzyme is alcohol dehydrogenase, isocitric dehydrogenase, .alpha.-glycerolphosphate dehydrogenase, lactic dehydrogenase, or glyceraldehyde-3-phosphate dehydrogenase; (b) the coenzyme is nicotinamide-adenine dinucleotide phosphate and the enzyme is malic enzyme, glucose-6-phosphate dehydrogenase, 5-dehydroshikimic reductase, or glutathione reductase; (c) the coenzyme is flavin mononucleotide and the enzyme is glycolic acid oxidase, yeast cytochrome c reductase, luciferase, or nitro reductase; (d) the coenzyme is adenosine triphosphate and the enzyme is glutamyl transferase, glutathione synthetase, glycocyamine phosphokinase, hippuric acid synthetase, or luciferase; (e) the coenzyme is flavin adenine dinucleotide and the enzyme is D-amino acid oxidase, aldehyde oxidase, succinic dehydrogenase, nitrate reductase, xanthine oxidase, lipoyl dehydrogenase, diaphorase, flavin peroxidase, or glycine oxidase; or (f) the coenzyme is thiamin pyrophosphate and the enzyme is carboxylase, .alpha.-keto acid dehydrogenase, or transketolase. 23. The process of claim 1 in which the group member is the antibiotic having at least one primary or secondary amino group per molecule. 24. The process of claim 23 in which the antibiotic is ampicillin, bacitracin, colistin, or neomycin. 25. The process of claim 1 in which the cured shaped article is a self supporting cured film. 26. The process of claim 25 in which: (a) the resulting mixture is applied to an inert solid surface and spread thereon to form a film of the resulting mixture supported on the inert solid surface; and (b) the film of resulting mixture is cured by exposing it to an amount of the curing agent effective for curing the resulting mixture and immobilizing the group member. 27. The cured film prepared by the process of claim 26. 28. The process of claim 26 in which the cured film is stripped from the inert solid surface. 29. The process of claim 28 in which the cured film is cut into discs after being stripped from the inert solid surface. 30. The discs prepared by the process of claim 29. 31. The process of claim 26 in which a second film of the resulting mixture is applied to the cured film and cured thereon and bonded thereto by exposing the second film to an amount of the curing agent effective for curing the resulting mixture and immobilizing the group member to increase the thickness and strength of the cured film. 32. The process of claim 26 in which a film of isocyanate-capped liquid polyurethane prepolymer is applied to the cured film and cured thereon and bonded thereto by exposing the film of isocyanate-capped liquid polyurethane prepolymer to an amount of the curing agent effective for curing the film of isocyanate-capped liquid polyurethane prepolymer to strengthen the film of immobilized group member. 33. The process of claim 32 in which the: (a) isocyanate-capped liquid polyurethane prepolymer is diluted with an inert volatile solvent before being applied to the cured film; and (b) the solvent is vaporized during curing. 34. The process of claim 26 in which: (a) the resulting mixture is admixed with an inert volatile solvent to form a solution which is applied to the inert surface; and (b) the volatile solvent is vaporized during curing. 35. The process of claim 1 in which the cured shaped article is a cured tube. 36. The process of claim 35 in which: (a) the resulting mixture is applied to the inner surface of a pattern tube having an inner surface and an outer surface to form a film of the resulting mixture on the inner surface of the pattern tube; and (b) the film of resulting mixture is cured by exposing it to an amount of the curing agent effective for curing the resulting mixture and immobilizing the group member to form the cured tube comprising the immobilized group member, the cured tube having an inner surface and an outer surface. 37. The process of claim 36 in which the cured tube is separated from the pattern tube. 38. The process of claim 36 in which the pattern tube is made of glass, metal, rubber, or polymer. 39. The process of claim 36 in which: (a) the resulting mixture is admixed with an inert volatile solvent to form a solution which is applied to the inner surface of the pattern tube; and (b) the volatile solvent is vaporized during curing. 40. The process of claim 36 in which a second film of resulting mixture is applied to the inner surface of the cured tube comprising the immobilized group member and cured thereon and bonded thereto by exposing the second film to an amount of the curing agent effective for curing the resulting mixture and immobilizing the group member to increase the thickness and strength of the tube comprising the immobilized group member. 41. The process of claim 36 in which a film of isocyanate-capped liquid polyurethane prepolymer is applied to the inner surface of cured tube comprising the immobilized group member and cured thereon and bonded thereto by exposing the film of isocyanate-capped liquid polyurethane prepolymer to an amount of the agent effective for curing the prepolymer to increase the strength of the tube comprising the immobilized group member. 42. The process of claim 41 in which the: isocyanate-capped liquid polyurethane prepolymer is diluted with an inert volatile solvent before being applied to the inner surface of the tube comprising the immobilized group member; and (b) the solvent is vaporized during curing. 43. The process of claim 35 in which: (a) the isocyanate-capped liquid polyurethane is applied to the inner surface of a first tube which is a pattern tube having an inner surface and an outer surface to form a film of the isocyanate-capped liquid polyurethane prepolymer on the inner surface of the first tube; (b) the film of isocyanate-capped liquid polyurethane prepolymer is cured by exposing it to an amount of the curing agent effective for curing the prepolymer to form a second tube comprising cured prepolymer, the second tube having an inner surface and an outer surface; (c) the resulting mixture is applied to the inner surface of the second tube to form a film of the resulting mixture on the inner surface of the second tube; and (d) the film of resulting mixture is cured and bonded to the inner surface of the second tube by exposing the film of resulting mixture to an amount of the curing agent effective for curing the resulting mixture and immobilizing the group member to form a third tube comprising the immobilized group member bonded to the inner surface of the second tube. 44. The process of claim 43 in which the third tube is separated from the first tube. 45. The process of claim 43 in which the first tube is made of glass, metal, rubber, or plastic. 46. The process of claim 43 in which the isocyanate-capped liquid polyurethane prepolymer is diluted with an inert volatile solvent before being applied to the inner surface of the first tube. 47. The process of claim 46 in which the inert volatile solvent is vaporized during the curing step. 48. The process of claim 1 in which the cured shaped article is a rod comprising the immobilized group member. 49. The process of claim 48 in which: (a) the resulting mixture is applied to the longitudinal surface of a pattern rod having a longitudinal surface and two end surfaces to form a film of the resulting mixture on the longitudinal surface; and (b) the film of resulting mixture is cured by exposing it to an amount of the curing agent effective for curing the resulting mixture and immobilizing the group member to form a product rod comprising the pattern rod having on its longitudinal surface a coating comprising the immobilized group member. 50. The product rod prepared by the process of claim 49. 51. The process of claim 49 in which the coating comprising the immobilized group member is separated from the pattern rod to form a tube comprising the immobilized group member. 52. The tube formed by the process of claim 51. 53. The process of claim 49 in which: (a) the resulting mixture is admixed with an inert volatile solvent to form a solution which is applied to the longitudinal surface of the pattern rod; and (b) the volatile solvent is vaporized during curing. 54. The process of claim 49 in which a second film of the resulting mixture is applied to the coating comprising the immobilized group member and cured thereon and bonded thereto by exposing the second film to an amount of curing agent effective for curing the resulting mixture and immobilizing the group member to strengthen and increase the thickness of the coating comprising the immobilized group member. 55. The process of claim 49 in which a film of the isocyanate-capped liquid polyurethane prepolymer is applied to the coating comprising the immobilized group member and cured thereon and bonded thereto by exposing the film of isocyanate-capped liquid polyurethane prepolymer to an amount of curing agent effective for curing the isocyanate-capped liquid polyurethane prepolymer to strengthen the coating comprising the immobilized group member. 56. The process of claim 55 in which the coating comprising the immobilized group member with the cured prepolymer bound thereto is separated from the pattern rod to form a tube having an inner surface comprising the immobilized group member and an outer surface comprising the cured prepolymer. 57. The tube prepared by the process of claim 56. 58. The process of claim 55 in which the: (a) isocyanate-capped liquid polyurethane prepolymer is diluted with an inert volatile solvent before being applied to the coating comprising the immobilized group member; and (b) the solvent is vaporized during curing. 59. The process of claim 48 in which: (a) the isocyanate-capped liquid polyurethane prepolymer is applied to a pattern rod having a longitudinal surface and two end surfaces to form a film of isocyanate-capped liquid polyurethane prepolymer on the longitudinal surface; (b) the film of isocyanate-capped liquid polyurethane prepolymer is cured by exposing it to an amount of the curing agent effective for curing the isocyanate-capped liquid polyurethane prepolymer to form an intermediate rod comprising the pattern rod having on its longitudinal surface a first coating of cured prepolymer, the first coating having an inner surface adjacent to the longitudinal surface of the pattern rod and an outer surface; and (c) a film of resulting mixture is applied to the outer surface of the first coating and cured thereon and bonded thereto by exposing the film of resulting mixture to an amount of the curing agent effective for curing the resulting mixture and immobilizing the group member to form a product rod comprising the pattern rod with a final coating thereon, the final coating comprising the first coating with the second coating bound thereto. 60. The product rod formed by the process of claim 59. 61. The process of claim 59 in which the final coating is separated from the pattern rod to form a tube. 62. The tube formed by the process of claim 61. 63. The process of claim 1 in which the shaped article is a cured sphere. 64. The process of claim 63 in which the sphere is formed and cured by feeding the resulting mixture dropwise into a fluid comprising the curing agent and permitting the resulting spherical drop to fall freely through the fluid. 65. The process of claim 64 in which the fluid is a liquid. 66. The process of claim 65 in which the liquid consists of the curing agent. 67. The process of claim 65 in which the liquid consists essentially of the curing agent dissolved in a solvent. 68. The process of claim 64 in which the fluid is a vapor. 69. The process of claim 68 in which the vapor consists of the curing agent. 70. The process of claim 68 in which the vapor consists essentially of a mixture of curing agent and inert gas. 71. The process of claim 64 in which: (a) the resulting mixture is admixed with an inert volatile solvent to form a solution which is fed dropwise into the fluid comprising the curing agent. 72. The process of claim 71 in which the volatile solvent is vaporized while curing the resulting mixture. 73. The process of claim 71 in which the volatile solvent is acetone, methyl ethyl ketone, methyl alcohol, ethyl alcohol, a propyl alcohol, a butyl alcohol, dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, methylchloroform, benzene, toluene, xylene, carbon tetrachloride, chloroform, hexane, or petroleum ether.

Details for Patent 4,237,229

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		1995-12-24
Csl Behring Ag	CARIMUNE, CARIMUNE NF, PANGLOBULIN, SANDOGLOBULIN	immune globulin intravenous (human)	For Injection	102367	07/27/2000		1995-12-24
Csl Behring Ag	PRIVIGEN	immune globulin intravenous (human), 10% liquid	Injection	125201	07/26/2007		1995-12-24
Csl Behring Ag	PRIVIGEN	immune globulin intravenous (human), 10% liquid	Injection	125201	10/02/2009		1995-12-24
Csl Behring Ag	PRIVIGEN	immune globulin intravenous (human), 10% liquid	Injection	125201	02/07/2013		1995-12-24