Claims for Patent: 6,994,847

Summary for Patent: 6,994,847

Title:	Stabilized interferon compositions
Abstract:	Stabilized pharmaceutical formulations comprising IFN-.beta. and highly purified mannitol are provided. The highly purified mannitol stabilizes the compositions by reducing the formation of IFN-.beta. adducts in comparison with IFN-.beta. formulated with mannitol that has not been highly purified. Methods for increasing the stability of IFN-.beta. or a variant thereof in a liquid or lyophilized composition and for increasing storage stability of such a composition are also provided.
Inventor(s):	Wolfe; Sidney N. (Lafayette, CA), Hora; Maninder S. (Danville, CA)
Assignee:	Chiron Corporation (Emeryville, CA)
Application Number:	10/010,448
Patent Claims:	1. A composition comprising biologically active interferon-.beta. (IFN-.beta.) and highly purified mannitol wherein said biologically active IFN-.beta. has the ability to bind to IFN-.beta. receptors and said highly purified mannitol has a reducing activity of less than 20 parts per million. 2. The composition of claim 1, wherein said composition is characterized by increased stability. 3. The composition of claim 1, wherein said composition is lyophilized. 4. The composition of claim 1, wherein said composition is a liquid. 5. The composition of claim 1, wherein said highly purified mannitol is present at a concentration of about 0.25% to about 5% by weight per volume. 6. The composition of claim 1, wherein said IFN-.beta. is present at a concentration of 0.01 mg/ml to 15 mg/ml. 7. The composition of claim 1, wherein said formulation has a pH within a range of about pH 3.0 to about pH 9.0. 8. The composition of claim 1, also comprising human albumin. 9. The composition of claim 8, wherein said human albumin is present at a concentration of about 0.01% to about 15% by weight per volume. 10. A composition comprising biologically active interferon-.beta. (IFN-.beta.) and highly purified mannitol, wherein said IFN-.beta. is recombinant human-IFN-.beta. and has the ability to bind to IFN-.beta. receptors, said recombinant human IFN-.beta. is present at a concentration of about 0.01 mg/ml to about 15 mg/ml, said highly purified mannitol has a reducing activity of less than 20 parts per million and is present at a concentration of about 0.25% to about 5% by weight per volume, the pH of the composition is about 3.0 to about 9.0, and the composition additionally comprises human albumin at a concentration of about 0.01% to about 15% by weight per volume. 11. The composition of claim 10, wherein said composition is lyophilized. 12. The composition of claim 10, wherein said composition is a liquid or is frozen. 13. The composition of claim 10, further comprising sufficient sodium chloride to render the composition isotonic. 14. The composition of claim 13, wherein said composition is lyophilized. 15. The composition of claim 13, wherein said composition is a liquid or frozen. 16. A composition comprising biologically active interferon-.beta. (IFN-.beta.) and highly purified mannitol, wherein the IFN-.beta. is recombinant human-IFN-.beta. and has the ability to bind to IFN-.beta. receptors, said recombinant human IFN-.beta. is present at a concentration of about 0.05 mg/ml to about 1 mg/ml, said highly purified mannitol has a reducing activity of less than 20 parts per million and is present at a concentration of about 0.25% to about 2.5% by weight per volume, the pH of the composition is about 6.8 to about 8.2, and the composition additionally comprises human albumin at a concentration of about 0.25% to about 2.5% by weight per volume. 17. The composition of claim 16, further comprising sufficient sodium chloride to render the composition isotonic. 18. The composition of claim 16, wherein said composition is a liquid, wherein said liquid is frozen or lyophilized. 19. The composition of claim 17, wherein said composition is a liquid, wherein said liquid is frozen or lyophilized. 20. A composition comprising biologically active interferon-.beta. (IFN-.beta.) and highly purified mannitol, wherein the IFN-.beta. is recombinant human-IFN-.beta. and has the ability to bind to IFN-.beta. receptors, said recombinant human IFN-.beta. is present at a concentration of about 0.25 mg/ml, said highly purified mannitol has a reducing activity of less than 20 parts per million and is present at a concentration of about 1.25% by weight per volume, the pH of the composition is about 7.3 to about 7.5, and the composition additionally comprises human albumin at a concentration of about 1.25% by weight per volume. 21. The composition of claim 20, further comprising sufficient sodium chloride to render the composition isotonic. 22. The composition of claim 20, wherein said composition is a liquid, wherein said liquid is frozen or lyophilized. 23. The composition of claim 21, wherein said composition is a liquid, wherein said liquid is frozen or lyophilized. 24. The composition of claim 1, wherein said biologically active IFN-.beta. has the amino acid sequence set forth in SEQ ID NO:1 or SEQ ID NO:2. 25. The composition of claim 24, wherein said IFN-.beta. is glycosylated or unglycosylated. 26. The composition of claim 1, wherein said IFN-.beta. is recombinantly produced. 27. A pre-filled syringe comprising the composition of claim 1. 28. The pre-filled syringe of claim 27, wherein said composition is frozen. 29. A composition comprising a pharmaceutical polypeptide and highly-purified mannitol wherein said highly-purified mannitol has a reducing activity of less than 20 parts per million. 30. The composition of claim 29, wherein said pharmaceutical polypeptide is selected from the group consisting of human growth hormone, interferon, interleukin, granulocyte-macrophage colony stimulating factor, granulocyte colony stimulating factor, macrophage colony stimulating factor, beta-glucocerebrosidase, thyrotropins, etanercept, monoclonal antibodies, factor VIIa, factor VIII, urokinase, asparginase, anistreplase, and alteplase. 31. A method of producing a formulation of biologically active interferon-.beta. (IFN-.beta.) characterized by improved stability, said method comprising producing a formulation comprising said IFN-.beta. and highly purified mannitol in an amount sufficient to stabilize said IFN-.beta. wherein said biologically active INF.beta. has the ability to bind to IFN-.beta. receptors and said highly purified mannitol has a reducing activity of less than 20 parts per million. 32. A formulation made according to the method of claim 31. 33. A method of producing a formulation of biologically active interferon-.beta. (IFN-.beta.) having the ability to bind to IFN-.beta. receptors, comprising the steps of: a) removing sodium dodecyl sulfate and salts from the IFN-.beta. by chromatography; b) combining said IFN-.beta. with a solution of human albumin at a pH of about 11.5 to about 12.0; c) adjusting the pH of the solution to 7.5 with HCl; and d) adding a solution of highly purified mannitol having a reducing activity of less than 20 parts per million. 34. A formulation produced according to the method of claim 33. 35. The method of claim 33, further comprising the step of lyophilizing the formulation. 36. A method for increasing the stability of biologically active interferon-.beta. (IFN-.beta.) in a pharmaceutical composition, said method comprising incorporating into said composition highly purified mannitol in an amount sufficient to stabilize said IFN-.beta., wherein said IFN-.beta. has the ability to bind to IFN-.beta. receptors and said highly purified mannitol has a reducing activity of less than 20 parts per million. 37. The method of claim 33, further comprising the step of adding sufficient sodium chloride to render the composition isotonic. 38. A formulation produced according to the method of claim 37. 39. The method of claim 37, further comprising the step of lyophilizing the formulation. 40. The composition of claim 1, wherein said biologically active IFN-.beta. has at least 80% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:1 as calculated using the ALIGN program with a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. 41. The composition of claim 1, wherein said highly purified mannitol has a reducing activity of less than 15 parts per million. 42. The composition of claim 1, wherein said highly purified mannitol has a reducing activity of at least 8.9 parts per million. 43. The composition of claim 2, wherein said composition contains less than 0.02 mg/ml of glucosylated IFN-.beta.. 44. The composition of claim 43, wherein said composition contains less than 0.02 mg/ml of glucosylated IFN-.beta. when stored at 25.degree. C. for a period of at least one month. 45. The composition of claim 44, wherein said composition contains less than 0.02 mg/ml of glucosylated IFN-.beta. when stored at 25.degree. C. for a period of at least three months. 46. The composition of claim 43, wherein said composition contains less than 0.02 mg/ml of glucosylated IFN-.beta. when stored at 30.degree. C. for a period of at least two months. 47. The composition of claim 46, wherein said composition contains less than 0.02 mg/ml of glucosylated IFN-.beta. when stored at 30.degree. C. for a period of at least six months. 48. The composition of claim 47, wherein said composition contains less than 0.02 mg/ml of glucosylated IFN-.beta. when stored at 30.degree. C. for a period of at least twelve months. 49. The composition of claim 48, wherein said composition contains less than 0.02 mg/ml of glucosylated IFN-.beta. when stored at 30.degree. C. for a period of at least two years. 50. The composition of claim 10, wherein said biologically active IFN-.beta. has at least 80% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:1 as calculated using the ALIGN program with a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. 51. The composition of claim 10, wherein said highly purified mannitol has a reducing activity of less than 15 parts per million. 52. The composition of claim 10, wherein said highly purified mannitol has a reducing activity of at least 8.9 parts per million. 53. The composition of claim 10, wherein said biologically active IFN-.beta. has the amino acid sequence set forth in SEQ ID NO:1 or SEQ ID NO:2. 54. The composition of claim 13, wherein said highly purified mannitol has a reducing activity of less than 15 parts per million. 55. The composition of claim 13, wherein said highly purified mannitol has a reducing activity of at least 8.9 parts per million. 56. The composition of claim 16, wherein said recombinantly produced IFN-.beta. has at least 80% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:1 as calculated using the ALIGN program with a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. 57. The composition of claim 16, wherein said highly purified mannitol has a reducing activity of less than 15 parts per million. 58. The composition of claim 16, wherein said highly purified mannitol has a reducing activity of at least 8.9 parts per million. 59. The composition of claim 20, wherein said recombinantly produced IFN-.beta. has at least 80% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:1 as calculated using the ALIGN program with a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. 60. The composition of claim 20, wherein said highly purified mannitol has a reducing activity of less than 15 parts per million. 61. The composition of claim 20, wherein said highly purified mannitol has a reducing activity of at least 8.9 parts per million. 62. The composition of claim 29, wherein said highly purified mannitol has a reducing activity of less than 15 parts per million. 63. The composition of claim 29, wherein said highly purified mannitol has a reducing activity of at least 8.9 parts per million. 64. The method of claim 31, wherein said formulation contains less than 0.02 mg/ml of glucosylated IFN-.beta.. 65. The method of claim 64, wherein said formulation contains less than 0.02 mg/ml of glucosylated IFN-.beta. when stored at 25.degree. C. for a period of at least one month. 66. The method of claim 64, wherein said formulation contains less than 0.02 mg/ml of glucosylated IFN-.beta. when stored at 30.degree. C. for a period of at least two months. 67. The method of claim 66, wherein said formulation contains less than 0.02 mg/ml of glucosylated IFN-.beta. when stored at 30.degree. C. for a period of at least six months. 68. The method of claim 31, wherein said biologically active IFN-.beta. has at least 80% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:1 as calculated using the ALIGN program with a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. 69. The method of claim 31, wherein said highly purified mannitol has a reducing activity of less than 15 parts per million. 70. The method of claim 31, wherein said highly purified mannitol has a reducing activity of at least 8.9 parts per million. 71. The method of claim 31, wherein said biologically active IFN-.beta. has the amino acid sequence set forth in SEQ ID NO:1 or SEQ ID NO:2. 72. The method of claim 33, wherein said biologically active IFN-.beta. has at least 80% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:1 as calculated using the ALIGN program with a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. 73. The method of claim 33, wherein said highly purified mannitol has a reducing activity of less than 15 parts per million. 74. The method of claim 33, wherein said highly purified mannitol has a reducing activity of at least 8.9 parts per million. 75. The method of claim 36, wherein said biologically active IFN-.beta. has at least 80% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:1 as calculated using the ALIGN program with a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. 76. The method of claim 36, wherein said highly purified mannitol has a reducing activity of less than 15 parts per million. 77. The method of claim 36, wherein said highly purified mannitol has a reducing activity of at least 8.9 parts per million.

Details for Patent 6,994,847

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Microbix Biosystems Inc.	KINLYTIC	urokinase	For Injection	021846	01/16/1978		2020-11-07
Genentech, Inc.	ACTIVASE	alteplase	For Injection	103172	11/13/1987		2020-11-07
Genentech, Inc.	CATHFLO ACTIVASE	alteplase	For Injection	103172	09/04/2001		2020-11-07
Immunex Corporation	ENBREL	etanercept	For Injection	103795	11/02/1998		2020-11-07
Immunex Corporation	ENBREL	etanercept	For Injection	103795	05/27/1999		2020-11-07
Immunex Corporation	ENBREL	etanercept	Injection	103795	09/27/2004		2020-11-07
Immunex Corporation	ENBREL	etanercept	Injection	103795	02/01/2007		2020-11-07