Claims for Patent: 4,447,355

Summary for Patent: 4,447,355

Title:	Method for stabilizing a tumor necrosis factor and a stable aqueous solution or powder containing the same
Abstract:	A method for stabilizing a Tumor Necrosis Factor (TNF), which comprises adding at least one member selected from the group consisting of an albumin, a gelatin, a globulin, a protamine and a salt of protamine to an aqueous solution or powder containing TNF, and a stable aqueous solution or powder which contains TNF and an effective amount of such a protein. The aqueous solution or powder containing TNF can be stored for a prolonged period of time without losing its activity, and is stable on freezing, thawing, lyophilization or the like.
Inventor(s):	Sakamoto; Hajimu (Fuji, JP), Kiyota; Takao (Fuji, JP), Hayashi; Hiroshi (Fuji, JP)
Assignee:	Asahi Kasei Kogyo Kabushiki Kaisha (Osaka, JP) Dainippon Pharmaceutical Co., Ltd. (Osaka, JP)
Application Number:	06/477,866
Patent Claims:	1. A method for stabilizing Tumor Necrosis Factor, which comprises adding to an aqueous solution or powder containing Tumor Necrosis Factor an effective amount of at least one stabilizing agent selected from the group consisting of an albumin, a gelatin, a globulin, a protamine and a salt of protamine. 2. A method according to claim 1, which further comprises subjecting to lyophilization the resulting aqueous solution having said stabilizing agent added thereto. 3. A method according to claim 1, wherein said stabilizing agent is added in an amount of about 10 .mu.g to 50 mg per ml of the aqueous solution containing Tumor Necrosis Factor, said aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml. 4. A method according to claim 3, which further comprises subjecting to lyophilization the resulting aqueous solution having said stabilizing agent added thereto. 5. A method according to claim 3, wherein said stabilizing agent is added in an amount of about 100 .mu.g to 10 mg per ml of the aqueous solution containing Tumor Necrosis Factor, said aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml. 6. A method according to claim 5, which further comprises subjecting to lyophilization the resulting aqueous solution having said stabilizing agent added thereto. 7. A method according to claim 1, wherein said stabilizing agent is an albumin. 8. A method according to claim 7, wherein said albumin is human serum albumin. 9. A method according to claim 8, wherein said human serum albumin is added in an amount of about 10 .mu.g to 50 mg per ml of the aqueous solution containing Tumor Necrosis Factor, said aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml. 10. A method according to claim 9, which further comprises subjecting to lyophilization the resulting aqueous solution having the human serum albumin added thereto. 11. A method according to claim 9, wherein said human serum albumin is added in an amount of about 100 .mu.g to 10 mg per ml of the aqueous solution containing Tumor Necrosis Factor, said aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml. 12. A method according to claim 11, which further comprises subjecting to lyophilization the resulting aqueous solution having the human serum albumin added thereto. 13. A method according to claim 1, wherein said stabilizing agent is a gelatin. 14. A method according to claim 13, wherein said gelatin is a water-soluble partially hydrolyzed gelatin. 15. A method according to claim 14, wherein said water-soluble partially hydrolyzed gelatin is added in an amount of about 10 .mu.g to 50 mg per ml of the aqueous solution containing Tumor Necrosis Factor, said aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml. 16. A method according to claim 15, which further comprises subjecting to lyophilization the resulting aqueous solution having the water-soluble partially hydrolyzed gelatin added thereto. 17. A method according to claim 15, wherein said water-soluble partially hydrolyzed gelatin is added in an amount of about 100 .mu.g to 10 mg per ml of the aqueous solution containing Tumor Necrosis Factor, said aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml. 18. A method according to claim 17, which further comprises subjecting to lyophilization the resulting aqueous solution having the water-soluble partially hydrolyzed gelatin added thereto. 19. A method according to claim 1, wherein said stabilizing agent is a globulin. 20. A method according to claim 19, wherein said globulin is human gamma globulin or a derivative thereof. 21. A method according to claim 20, wherein said human gamma globulin or derivative thereof is added in an amount of about 10 .mu.g to 50 mg per ml of the aqueous solution containing Tumor Necrosis Factor, said aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml. 22. A method according to claim 21, which further comprises subjecting to lyophilization the resulting aqueous solution having the human gamma globulin or derivative thereof added thereto. 23. A method according to claim 21, wherein said human gamma globulin or derivative thereof is added in an amount of about 100 .mu.g to 10 mg per ml of the aqueous solution containing Tumor Necrosis Factor, said aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml. 24. A method according to claim 23, which further comprises subjecting to lyophilization the resulting aqueous solution having the human gamma globulin or derivative thereof added thereto. 25. A method according to claim 1, wherein said stabilizing agent is a protamine or a salt of protamine. 26. A method according to claim 25, wherein said protamine or salt of protamine is added in an amount of about 10 .mu.g to 50 mg per ml of the aqueous solution containing Tumor Necrosis Factor, said aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml. 27. A method according to claim 26, which further comprises subjecting to lyophilization the resulting aqueous solution having the protamine or salt of protamine added thereto. 28. A method according to claim 26, wherein said protamine or salt of protamine is added in an amount of about 100 .mu.g to 10 mg per ml of the aqueous solution containing Tumor Necrosis Factor, said aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml. 29. A method according to claim 28, which further comprises subjecting to lyophilization the resulting aqueous solution having the protamine or salt of protamine added thereto. 30. A stable aqueous solution or powder which contains Tumor Necrosis Factor and an effective amount of at least one stabilizing agent selected from the group consisting of an albumin, a gelatin, a globulin, a protamine and a salt of protamine. 31. A stable aqueous solution or powder according to claim 30, wherein said stabilizing agent is contained in an amount of about 10 .mu.g to 50 mg per ml of the aqueous solution containing Tumor Necrosis Factor, said aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml, or is contained in an amount of about 10 .mu.g to 50 mg per ml of an aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml which solution is one obtained by dissolving the powder containing Tumor Necrosis Factor. 32. A stable aqueous solution or powder according to claim 31, wherein said stabilizing agent is contained in an amount of about 100 .mu.g to 10 mg per ml of the aqueous solution containing Tumor Necrosis Factor, said aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml, or is contained in an amount of about 100 .mu.g to 10 mg per ml of an aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml which solution is one obtained by dissolving the powder containing Tumor Necrosis Factor. 33. A stable aqueous solution or powder according to claim 30, wherein said stabilizing agent is an albumin. 34. A stable aqueous solution or powder according to claim 33, wherein said albumin is human serum albumin. 35. A stable aqueous solution or powder according to claim 34, wherein said human serum albumin is contained in an amount of about 10 .mu.g to 50 mg per ml of the aqueous solution containing Tumor Necrosis Factor, said aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml, or is contained in an amount of about 10 .mu.g to 50 mg per ml of an aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml which solution is one obtained by dissolving the powder containing Tumor Necrosis Factor. 36. A stable aqueous solution or powder according to claim 35, wherein said human serum albumin is contained in an amount of about 100 .mu.g to 10 mg per ml of the aqueous solution containing Tumor Necrosis Factor, said aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml, or is contained in an amount of about 100 .mu.g to 10 mg per ml of an aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml which solution is one obtained by dissolving the powder containing Tumor Necrosis Factor. 37. A stable aqueous solution or powder according to claim 30, wherein said stabilizing agent is a gelatin. 38. A stable aqueous solution or powder according to claim 37, wherein said gelatin is a water-soluble partially hydrolyzed gelatin. 39. A stable aqueous solution or powder according to claim 38, wherein said water-soluble partially hydrolyzed gelatin is contained in an amount of about 10 .mu.g to 50 mg per ml of the aqueous solution containing Tumor Necrosis Factor, said aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml, or is contained in an amount of about 10 .mu.g to 50 mg per ml of an aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml which solution is one obtained by dissolving the powder containing Tumor Necrosis Factor. 40. A stable aqueous solution or powder according to claim 39, wherein said water-soluble partially hydrolyzed gelatin is contained in an amount of about 100 .mu.g to 10 mg per ml of the aqueous solution containing Tumor Necrosis Factor, said aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml, or is contained in an amount of about 100 .mu.g to 10 mg per ml of an aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml which solution is one obtained by dissolving the powder containing Tumor Necrosis Factor. 41. A stable aqueous solution or powder according to claim 30, wherein said stabilizing agent is a globulin. 42. A stable aqueous solution or powder according to claim 41, wherein said globulin is human gamma globulin or a derivative thereof. 43. A stable aqueous solution or powder according to claim 42, wherein said human gamma globulin or derivative thereof is contained in an amount of about 10 .mu.g to 50 mg per ml of the aqueous solution containing Tumor Necrosis Factor, said aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml, or is contained in an amount of about 10 .mu.g to 50 mg per ml of an aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml which solution is one obtained by dissolving the powder containing Tumor Necrosis Factor. 44. A stable aqueous solution or powder according to claim 43, wherein said human gamma globulin or derivative thereof is contained in an amount of about 100 .mu.g to 10 mg per ml of the aqueous solution containing Tumor Necrosis Factor, said aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml, or is contained in an amount of about 100 .mu.g to 10 mg per ml of an aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml which solution is one obtained by dissolving the powder containing Tumor Necrosis Factor. 45. A stable aqueous solution or powder according to claim 30, wherein said stabilizing agent is a protamine or a salt of protamine. 46. A stable aqueous solution or powder according to claim 45, wherein said protamine or salt of protamine is contained in an amount of about 10 .mu.g to 50 mg per ml of the aqueous solution containing Tumor Necrosis Factor, said aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml, or is contained in an amount of about 10 .mu.g to 50 mg per ml of an aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml which solution is one obtained by dissolving the powder containing Tumor Necrosis Factor. 47. A stable aqueous solution or powder according to claim 46, wherein said protamine or salt of protamine is contained in an amount of about 100 .mu.g to 10 mg per ml of the aqueous solution containing Tumor Necrosis Factor, said aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml, or is contained in an amount of about 100 .mu.g to 10 mg per ml of an aqueous solution having a TNF activity of 10.sup.2 to 10.sup.9 units/ml which solution is one obtained by dissolving the powder containing Tumor Necrosis Factor.

Details for Patent 4,447,355

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Grifols Therapeutics Llc	ALBUKED, PLASBUMIN-20, PLASBUMIN-25, PLASBUMIN-5	albumin (human)	For Injection	101138	10/21/1942		2002-04-07
Baxalta Us Inc.	BUMINATE, FLEXBUMIN	albumin (human)	Injection	101452	03/03/1954		2002-04-07
Csl Behring Ag	ALBURX	albumin (human)	Injection	102366	07/23/1976		2002-04-07
Grifols Biologicals Llc	ALBUTEIN	albumin (human)	Injection	102478	08/15/1978		2002-04-07