Claims for Patent: 5,935,566

Summary for Patent: 5,935,566

Title:	Stable aqueous alfa interferon solution formulations
Abstract:	Stable aqueous solution formulations containing alfa-interferon type interferon, e.g., interferon alfa-2a and interferon alfa-2b, a buffer to maintain the pH in the range of 4.5-7.1, polysorbate 80 as a stabilizer, edetate disodium as a chelating agent, sodium chloride as a tonicity agent, and m-cresol as an antimicrobial preservative and which maintain high chemical, physical and biological stability of the alfa-type interferon for an extended storage period of at least 24 months are disclosed.
Inventor(s):	Yuen; Pui-Ho C. (Princeton Junction, NJ), Kline; Douglas F. (Hoboken, NJ)
Assignee:	Schering Corporation (Kenilworth, NJ)
Application Number:	09/096,708
Patent Claims:	1. A stable, aqueous formulation having at least 75% of the initial biological activity for alfa interferon and free of human blood-derived products which consists essentially of: a. 0.1.times.10.sup.6 to 100.times.10.sup.6 IU/mL of alfa-interferon; b. a buffer system to maintain a pH in the range of 4.5 to 7.1. c. an effective amount of edetate disodium dihydrogen ethylenediamine tetraacetate as a chelating agent sufficient to avoid visible particulate matter; d. an amount of a sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl) derivative sufficient to stabilize the alfa-type interferon against loss of alfa-type interferon biological activity; e. an effective amount of a tonicity agent sufficient to render said formulation iso-osmotic with human serum; f. an effective amount of an antimicrobial preservative selected from m-cresol, phenol, methylparaben, propylparaben or mixtures thereof sufficient to provide appropriate antimicrobial protection for said formulation without causing undesirable hazing formation; and g. an amount of water for injection sufficient to prepare a solution of the above-listed ingredients. 2. The composition of claim 1 wherein the buffer system is sodium dibasic phosphate and sodium monobasic phosphate. 3. The composition of claim 1 wherein the chelating agent is edetate disodium or citric acid. 4. The composition of claim 1 wherein the tonicity agent is sodium chloride. 5. The composition of claim 1 wherein the alfa-interferon is interferon alfa-2. 6. The stable, aqueous formulation of claim 1 wherein the buffer system is sodium citrate/citric acid. 7. A stable, aqueous formulation having at least 75% of the initial alfa interferon biological activity and substantially free of human blood-derived products which consists essentially of: a. 0.1.times.10.sup.6 to 100.times.10.sup.6 IU/mL of alfa interferon. b. a buffer system sufficient to maintain the pH of the solution in the range of 4.5 to 7.1; c. about 0.01 to 1 mg/mL of edetate disodium dihydrogen ethylenediaminetetraacetate; d. about 0.01 to 1 mg/mL of a sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl) derivative; e. about 1 to 9 mg/mL of sodium chloride; f. an effective amount of an antimicrobial preservative selected from m-cresol, phenol, methylparaben, propylparaben or mixtures thereof sufficient to provide appropriate antimicrobial protection for said formulation without causing undesirable hazing formation; and g. a quantity of water for injection sufficient to make a 1 mL solution of the above-listed ingredients. 8. The composition of claim 7 wherein interferon alfa-2b is used. 9. The composition of claim 7 wherein interferon alfa-2a is used. 10. The composition of claim 7 wherein said preservative is m-cresol. 11. The composition of claim 7 wherein said preservative is a mixture of methylparaben and propylparaben. 12. The stable aqueous formulation of claim 7 wherein the buffer system is sodium citrate/citric acid. 13. A stable aqueous solution formulation having at least 75% of initial biological activity of interferon alfa-2 and free of human serum albumin, which consists essentially of: 14. The formulation of claim 13 wherein interferon alfa-2b is used. 15. A stabile, aqueous solution formulation having at least 75% of the initial biological activity for interferon alfa-2 and free of human serum albumin, which consisting essentially of: 16. The formulation of claim 15 wherein interferon alfa-2a is used. 17. The formulation of claim 15 wherein interferon alfa-2b is used. 18. A stable, aqueous formulation having at least 75% of initial alfa interferon biological activity and free of human blood-derived products and manitol as a bulking agent which comprises about 0.1.times.10.sup.6 to 100.times.10.sup.6 /U/mL of alfa interfferon and about 0.01. to 1 mg/mL of a chelating agent effective to avoid formation of visible particulate matter in the formulation. 19. The stable aqueous formulation of claim 18 wherein the chelating agent is edetate disodium. 20. A method of avoiding visible particulate matter formation in an aqueous alfa interferon formulation having at least 75% of the initial biological activity of the alfa interferon and free of human blood-derived products which comprises admixing an aqueous alfa interferon formulation with an amount of a chelating agent effective to avoid formation of visible particulate matter in the formulation. 21. The method of claim 20 wherein the amount of alfa interferon is about 0.1.times.10.sup.6 to 100.times.10.sup.6 IU/mL. 22. The method of claim 20 wherein the chelating agent is edetate disodium. 23. The method of claim 20 wherein the alfa interferon is inteferon alfa-2a. 24. The method of claim 20 wherein the alfa interferon is interferon alfa-2b.

Details for Patent 5,935,566

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132	06/04/1986		2014-10-11
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2014-10-11
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	Injection	103132			2014-10-11

International Patent Family for US Patent 5,935,566

Country	Patent Number	Estimated Expiration
Austria	194774
Austria	245033
Australia	3727995
Australia	708337
Brazil	9509313
Canada	2201749
China	1102408