Claims for Patent: 8,007,793

Summary for Patent: 8,007,793

Title:	Stabilized liquid anti-RSV antibody formulations
Abstract:	The present invention provides liquid formulations of SYNAGIS.RTM. or an antigen-binding fragment thereof that immunospecifically bind to a respiratory syncytial virus (RSV) antigen, which formulations exhibit stability, low to undetectable levels of aggregation, and very little to no loss of the biological activities of SYNAGIS.RTM. or an antigen-binding fragment thereof, even during long periods of storage. In particular, the present invention provides liquid formulations of SYNAGIS.RTM. or an antigen-binding fragment thereof which immunospecifically binds to a RSV antigen, which formulations are substantially free of surfactant, inorganic salts, and/or other common excipients. Furthermore, the invention provides method of preventing, treating or ameliorating symptoms associated with RSV infection utilizing liquid formulations of the present invention.
Inventor(s):	Oliver; Cynthia N. (North Potomac, MD), Shane; Erica (McLean, VA), Isaacs; Benjamin S. (Andover, MA), Allan; Christian B. (Brookeville, MD), Chang; Stephen T. (Frederick, MD)
Assignee:	MedImmune, LLC (Gaithersburg, MD)
Application Number:	12/817,097
Patent Claims:	1. A method for preventing a symptom of a respiratory syncytial virus (RSV) infection, comprising administering to a human subject an aqueous palivizumab formulation comprising, in an aqueous carrier: (a) at least 75 mg/ml of palivizumab or an antigen-binding fragment thereof; and (b) histidine, wherein said palivizumab or palivizumab antigen-binding fragment in the formulation is stable at 2.degree. C. to 8.degree. C. for at least 15 months as determined by high performance size exclusion chromatography (HPSEC). 2. A method for preventing a symptom of a RSV infection, comprising administering to a human subject an aqueous palivizumab formulation comprising, in an aqueous carrier: (a) at least 75 mg/ml of palivizumab or an antigen-binding fragment thereof; (b) histidine at a concentration of 23 mM to 27 mM; and (c) glycine at a concentration of less than 2 mM, wherein said formulation has a pH of between about 5.5 to 6.5, and wherein said palivizumab or palivizumab antigen-binding fragment in the formulation is stable at 2.degree. C. to 8.degree. C. for at least 15 months as determined by HPSEC. 3. A method for preventing a symptom of a RSV infection, comprising administering to a human subject an aqueous palivizumab formulation comprising, in an aqueous carrier: (a) at least 95 mg/ml of palivizumab or an antigen-binding fragment thereof; (b) histidine at a concentration of about 25 mM; and (c) glycine at a concentration of 1.6 mM, wherein said formulation has a pH of between about 5.5 to 6.5, and wherein said palivizumab or palivizumab antigen-binding fragment in the formulation is stable at 2.degree. C. to 8.degree. C. for at least 15 months as determined by HPSEC. 4. A method for preventing a symptom of a RSV infection, comprising administering to a human subject an aqueous palivizumab formulation comprising, in an aqueous carrier: (a) at least 95 mg/ml of palivizumab or an antigen-binding fragment thereof; (b) histidine at a concentration of about 25 mM; and (c) glycine at a concentration of 1.6 mM, wherein said formulation has a pH of between about 5.8 to 6.2 and does not contain mannitol, and wherein said palivizumab or palivizumab antigen-binding fragment in the formulation is stable at 2.degree. C. to 8.degree. C. for at least 15 months as determined by HPSEC. 5. The method of claim 1 or 2, wherein said palivizumab or palivizumab antigen-binding fragment is at a concentration of at least 80 mg/kg, at least 85 mg/ml, at least 90 mg/ml or at least 95 mg/ml. 6. The method of claim 3 or 4, wherein said palivizumab or palivizumab antigen-binding fragment is at a concentration of about 100 mg/kg. 7. The method of claim 1 or 2, wherein said palivizumab or antigen-binding fragment thereof is at a concentration of at least 100 mg/ml. 8. The method of claim 7, wherein said palivizumab or antigen-binding fragment thereof is at a concentration of 103.+-.3 mg/ml. 9. The method of claim 3 or 4, wherein said palivizumab or antigen-binding fragment thereof is at a concentration of at least 100 mg/ml. 10. The method of claim 9, wherein said palivizumab or antigen-binding fragment thereof is at a concentration of 103.+-.3 mg/ml. 11. The method of claim 1, wherein the histidine is at a concentration of 1 mM to 100 mM or 10 mM to 50 mM. 12. The method of claim 1, wherein the histidine is at a concentration of 20 mM to 30 mM. 13. The method of claim 1 or 2, wherein the histidine is at a concentration of 23 mM to 27 mM. 14. The method of claim 1, wherein the formulation comprises an excipient other than a surfactant. 15. The method of claim 14, wherein the excipient is glycine. 16. The method of claim 1 or 2, wherein the formulation is substantially free of surfactants and inorganic salts. 17. The method of claim 3 or 4, wherein the formulation is substantially free of surfactants and inorganic salts. 18. The method of claim 1 or 2, wherein the formulation is substantially free of surfactants, inorganic salts and other excipients. 19. The method of claim 3 or 4, wherein the formulation is substantially free of surfactants, inorganic salts and other excipients. 20. The method of claim 6, wherein the formulation is substantially free of surfactants, inorganic salts and other excipients. 21. The method of claim 9, wherein the formulation is substantially free of surfactants, inorganic salts and other excipients. 22. The method of claim 1 or 2, wherein the formulation does not contain mannitol. 23. The method of claim 1 or 2, wherein the formulation has a pH of between about 5.5 to about 7.0. 24. The method of claim 1 or 2, wherein the formulation has a pH of between about 5.5 to about 6.5. 25. The method of claim 3 or 4, wherein the formulation has a pH of about 6.0. 26. The method of claim 6, wherein the formulation has a pH of about 6.0. 27. The method of claim 9, wherein the formulation has a pH of about 6.0. 28. The method of claim 1 or 2, wherein said palivizumab or palivizumab antigen-binding fragment in the formulation is stable at 20.degree. C. to 24.degree. C. for at least 1 year as determined by HPSEC. 29. The method of claim 3 or 4, wherein said palivizumab or palivizumab antigen-binding fragment in the formulation is stable at 20.degree. C. to 24.degree. C. for at least 1 year as determined by HPSEC. 30. The method of claim 1 or 2, wherein said palivizumab or palivizumab antigen-binding fragment in the formulation is stable at 38.degree. C. to 42.degree. C. for at least 60 days as determined by HPSEC. 31. The method of claim 30, wherein said palivizumab or palivizumab antigen-binding fragment in the formulation is stable at 38.degree. C. to 42.degree. C. for no more than 120 days as determined by HPSEC. 32. The method of claim 3 or 4, wherein said palivizumab or palivizumab antigen-binding fragment in the formulation is stable at 38.degree. C. to 42.degree. C. for at least 60 days as determined by HPSEC. 33. The method of claim 32, wherein said palivizumab or palivizumab antigen-binding fragment in the formulation is stable at 38.degree. C. to 42.degree. C. for no more than 120 days as determined by HPSEC. 34. The method of claim 1 or 2, wherein the aqueous palivizumab formulation contains no more than 3% aggregation by weight protein as measured by HPSEC. 35. The method of claim 3 or 4, wherein the aqueous palivizumab formulation contains no more than 3% aggregation by weight protein as measured by HPSEC. 36. The method of claim 1 or 2, wherein the stable aqueous palivizumab formulation contains equal to or more than 98% of the total protein in a single peak as determined by HSPEC and contains no other single peaks having more than 2% of total protein each. 37. The method of claim 3 or 4, wherein the stable aqueous palivizumab formulation contains equal to or more than 98% of the total protein in a single peak as determined by HSPEC and contains no other single peaks having more than 2% of total protein each. 38. The method of claim 1 or 2, wherein the aqueous carrier is distilled water. 39. The method of claim 3 or 4, wherein the aqueous carrier is distilled water. 40. The method of claim 3 or 4, wherein the formulation has a pH of about 6.0, the aqueous carrier is distilled water, and said palivizumab or palivizumab antigen-binding fragment is at a concentration of 103.+-.3 mg/ml. 41. The method of claim 19, wherein the formulation has a pH of 6.0, the aqueous carrier is distilled water, and said palivizumab or palivizumab antigen-binding fragment is at a concentration of 103.+-.3 mg/ml. 42. The method of claim 40, wherein the human subject is an elderly human, a human with cystic fibrosis, a human with congenital immunodeficiency or acquired immunodeficiency, or a human who has had a bone marrow transplant. 43. The method of claim 40, wherein the human subject is a human infant. 44. The method of claim 40, wherein the human subject is a human infant born prematurely or a human infant at high risk for hospitalization for a RSV infection. 45. The method of claim 40, wherein the human subject is a human with bronchopulmonary dysplasia or congenital heart disease. 46. The method of claim 40, wherein the formulation is administered to the human subject intramuscularly. 47. A method for preventing serious lower respiratory tract disease caused by RSV in pediatric patients, comprising administering to a pediatric patient an aqueous palivizumab formulation comprising, in an aqueous carrier: (a) 103.+-.3 mg/ml of palivizumab or an antigen-binding fragment thereof; (b) histidine at a concentration of 25 mM; and (c) glycine at a concentration of 1.6 mM, wherein said formulation has a pH of 6.0 does not contain mannitol, and wherein said palivizumab or palivizumab antigen-binding fragment in the formulation is stable at 2.degree. C. to 8.degree. C. for at least 15 months as determined by HPSEC.

Details for Patent 8,007,793

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Swedish Orphan Biovitrum Ab (publ)	SYNAGIS	palivizumab	For Injection	103770	06/19/1998		2022-06-14
Swedish Orphan Biovitrum Ab (publ)	SYNAGIS	palivizumab	Injection	103770	07/23/2004		2022-06-14