Claims for Patent: 9,309,316

Summary for Patent: 9,309,316

Title:	Stable subcutaneous protein formulations and uses thereof
Abstract:	The present invention relates generally to stable formulations comprising CTLA4Ig molecules, including lyophilized, and liquid formulations for administration via various routes including, for example, routes such as intravenous (IV) and subcutaneous (SC) for treating immune system diseases and tolerance induction.
Inventor(s):	Dali; Manisha D. (Bridgewater, NJ), Dahlheim; Charles E. (Lawrenceville, NJ), Borsadia; Sunita (Plainsboro, NJ), Naringrekar; Vijay H. (Princeton, NJ), Gandhi; Rajesh Babulal (Plainsboro, NJ), Nerurkar; Manoj (Kalyani Nagar, IN)
Assignee:	Bristol-Myers Squibb Company (Princeton, NJ)
Application Number:	13/796,586
Patent Claims:	1. A method for treating autoimmune disease comprising administering to a subject in need thereof an effective amount of a stable formulation suitable for subcutaneous administration comprising at least 100 mg/ml CTLA4Ig molecules, a sugar selected from the group consisting of sucrose, lactose, maltose, mannitol and trehalose and mixtures thereof and a pharmaceutically acceptable aqueous carrier wherein the formulation has a pH range of from 6 to 8 and a viscosity of from 9 to 20 centipoise, and the weight ratio of sugar:protein is 1.1:1 or higher. 2. The method of claim 1 wherein the autoimmune disease being treated is selected from the group consisting of lupus erythematosus, lupus nephritis Hashimoto's thyroiditis, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, type I diabetes mellitus, Goodpasture's syndrome, myasthenia gravis, pemphigus, Crohn's disease, sympathetic ophthalmia, autoimmune uveitis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulcerative colitis, Sjogren's syndrome, rheumatic disease rheumatoid arthritis polymyositis, scleroderma, and mixed connective tissue disease. 3. The method of claim 2 wherein the autoimmune disease being treated is rheumatoid arthritis, scleroderma, autoimmune uveitis, Sjogren's syndrome, type I diabetes mellitus or lupus nephritis. 4. A method for treating rheumatoid arthritis comprising administering to a subject in need thereof an effective amount of a stable formulation suitable for subcutaneous administration comprising the CTLA4Ig molecule having the amino acid sequence shown in SEQ ID NO:2 starting at methionine at position 27 or alanine at position 26 and ending at lysine at position 383 or glycine at position 382 in an amount of about 125 mg/ml, sucrose in an amount of about 170 mg/ml, at least one buffering agent, sterile water for injection and a surfactant, wherein the formulation has a pH range of from 6.8 to 7.4. 5. The method of claim 4 wherein the stable formulation suitable for subcutaneous formulation is administered in about 1 ml volume in a pre-filled syringe. 6. A method for treating autoimmune disease comprising administering to a subject in need thereof an effective amount of a stable formulation suitable for subcutaneous administration comprising at least 125 mg/m1 CTLA4Ig molecules, a sugar selected from the group consisting of sucrose, lactose, maltose, mannitol and trehalose and mixtures thereof and a pharmaceutically acceptable aqueous carrier, wherein the formulation has a pH range of from 6 to 8 and a viscosity of from 9 to 20 centipoise, and the weight ratio of sugar:protein is 1.1:1 or higher. 7. The method of claim 1 or 6 wherein the sugar is selected from the group connsisting of sucrose, mannitol or trehalose. 8. The method of claim 7 wherein the sugar is sucrose. 9. The method of claim 8 wherein the weight ratio of sucrose:protein is 1.3:1 to 5:1. 10. The method of claim 9 wherein the weight ratio of sucrose:protein is about 1.4:1. 11. The method of claim 8 wherein the pH range is from 6 to 7.8. 12. The method of claim 1 or 6 wherein the CTLA4Ig molecules have the amino acid sequence shown in SEQ ID NO:2 starting at methionine at position 27 or alanine at position 26 and ending at lysine at position 383 or glycine at position 382. 13. The method of claim 1 or 6 wherein the stable formulation suitable for subcutaneous administration comprises the CTLA4Ig molecules in an amount of about 125 mg/ml, sucrose in an amount of about 170 mg/ml, at least one buffering agent, sterile water for injection and optionally a surfactant, wherein the CTLA4Ig molecule has the amino acid sequence shown in SEQ ID NO:2 starting at methionine at position 27 or alanine at position 26 and ending at lysine at position 383 or glycine at position 382. 14. The method of any one of claim 1, 4 or 6 wherein the stable formulation suitable for subcutaneous administration is stable when stored at 2 to 8.degree. C. for at least 12 months. 15. The method of any one of claim 1, 4 or 6 wherein the stable formulation suitable for subcutaneous administration has an osmolality of from 700 mOsm/kgH.sub.2O to 800 mOsm/kgH.sub.2O. 16. The method of claim 1 or 6, wherein the stable formulation suitable for subcutaneous administration further comprises a surfactant. 17. The method of claim 16, wherein the surfactant is selected from the group consisting of polysorbates, polysorbate 20, polysorbate 80, poloxamers, poloxamer 188, sorbitan esters, sorbitan derivatives, Triton, sodium laurel sulfate, sodium octyl glycoside, lauryl- sulfobetadine, myristyl-sulfobetadine, linoleyl-sulfobetadine, stearyl-sulfobetadine, lauryl-sarcosine, myristyl-sarcosine, linoleyl-sarcosine, stearyl-sarcosine, linoleyl-betaine, myristyl-betaine, cetyl-betaine, lauramidopropyl-betaine, cocamidopropyl-betaine, linoleamidopropyl-betaine, myristamidopropyl-betaine, palmidopropyl-betaine, isostearamidopropyl-betaine, lauroamidopropyl-dimethylamine, myristamidopropyl-dimethylamine, palmidopropyl-dimethylamine, isostearamidopropyl-dimethylamine, sodium methyl cocoyl-taurate, and disodium methyl oleyl-tauratem, polyethylene glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol. 18. The method of claim 17, wherein the surfactant is poloxamer 188. 19. The method of claim 1 or 6, wherein the stable formulation suitable for subcutaneous administration further comprises a buffering agent. 20. The method of claim 19, wherein the buffering agent is selected from the group consisting of dibasic sodium phosphate anhydrous, monobasic sodium phosphate monohydrate, glycinate buffers, carbonate buffers, citrate buffers and combinations thereof. 21. The method of any one of claim 1, 4 or 6, wherein the stable formulation suitable for subcutaneous administration further comprises a preservative. 22. The method of claim 21, wherein the preservative is selected from the group consisting of octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl alcolhol, benzyl alcohol, alkyl parabens, methyl paraben, propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol. 23. The method of any one of claim 1, 4 or 6, wherein the percentage of CTLA4Ig high molecular weight species in the stable formulation suitable for subcutaneous administration is less than about 25%. 24. The method of any one of claim 1, 4 or 6, wherein the percentage of CTLA4Ig high molecular weight species in the stable formulation suitable for subcutaneous administration is less than about 15%. 25. The method of any one of claim 1, 4 or 6, wherein the percentage of CTLA4Ig high molecular weight species in the stable formulation suitable for subcutaneous administration is less than about 10%. 26. The method of any one of claim 1, 4 or 6, wherein the percentage of CTLA4Ig high molecular weight species in the stable formulation suitable for subcutaneous administration is less than about 5%. 27. The method of any one of claim 1, 4 or 6, wherein the percentage of CTLA4Ig high molecular weight species in the stable formulation suitable for subcutaneous administration is less than about 3%. 28. The method of any one of claim 1, 4 or 6, wherein the stable formulation suitable for subcutaneous administration is administered to a subject in single or multiple times per day. 29. The method of any one of claim 1, 4 or 6, wherein the stable formulation suitable for subcutaneous administration is administered to a subject weekly. 30. The method of any one of claim 1, 4 or 6, wherein the stable formulation suitable for subcutaneous administration is administered to a subject monthly. 31. The method of any one of claim 1, 4 or 6, wherein the stable formulation suitable for subcutaneous administration is administered to a subject yearly. 32. The method of claim 1 or 6, wherein the autoimmune disease is rheumatoid arthritis. 33. The method of claim 4 or 32, wherein the stable formulation suitable for subcutaneous administration is administered to a subject who is also being treated with an antirheumatic drug. 34. The method of claim 33, wherein the antirheumatic drug is methotrexate. 35. The method of claim 8, wherein the autoimmune disease is rheumatoid arthritis, the stable formulation suitable for subcutaneous administration further comprises a surfactant, and the percentage of CTLA4Ig high molecular weight species in the formulation is less than about 25%. 36. The method of claim 8, wherein the autoimmune disease is rheumatoid arthritis, the stable formulation suitable for subcutaneous administration further comprises poloxamer 188, and the percentage of CTLA4Ig high molecular weight species in the formulation is less than about 25%. 37. The method of claim 8, wherein the autoimmune disease is rheumatoid arthritis, the stable formulation suitable for subcutaneous administration further comprises a surfactant, and the percentage of CTLA4Ig high molecular weight species in the formulation is less than about 15%. 38. The method of claim 8, wherein the autoimmune disease is rheumatoid arthritis, the stable formulation suitable for subcutaneous administration further comprises poloxamer 188, and the percentage of CTLA4Ig high molecular weight species in the formulation is less than about 15%. 39. The method of claim 8, wherein the autoimmune disease is rheumatoid arthritis, the stable formulation suitable for subcutaneous administration further comprises a surfactant, and the percentage of CTLA4Ig high molecular weight species in the formulation is less than about 10%. 40. The method of claim 8, wherein the autoimmune disease is rheumatoid arthritis, the stable formulation suitable for subcutaneous administration further comprises poloxamer 188, and the percentage of CTLA4Ig high molecular weight species in the formulation is less than about 10%. 41. The method of claim 8, wherein the autoimmune disease is rheumatoid arthritis, the stable formulation suitable for subcutaneous administration further comprises a surfactant, and the percentage of CTLA4Ig high molecular weight species in the formulation is less than about 5%. 42. The method of claim 8, wherein the autoimmune disease is rheumatoid arthritis, the stable formulation suitable for subcutaneous administration further comprises poloxamer 188, and the percentage of CTLA4Ig high molecular weight species in the formulation is less than about 5%. 43. The method of claim 8, wherein the autoimmune disease is rheumatoid arthritis, the stable formulation suitable for subcutaneous administration further comprises a surfactant, and the percentage of CTLA4Ig high molecular weight species in the formulation is less than about 3%. 44. The method of claim 8, wherein the autoimmune disease is rheumatoid arthritis, the stable formulation suitable for subcutaneous administration further comprises poloxamer 188, and the percentage of CTLA4Ig high molecular weight species in the formulation is less than about 3%.

Details for Patent 9,309,316

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	ZOSTAVAX	zoster vaccine live	For Injection	125123	05/25/2006		2025-12-20