HSA- free formulations of interferon-beta

• US 20020172661A1
• Filed: 10/25/2001
• Published: 11/21/2002
• Est. Priority Date: 04/09/2001
• Status: Active Grant

• Current Assignee: Glaxosmithkline Biologicals SA (GlaxoSmithKline PLC)
• Original Assignee: Chiron Corporation (Bayer AG)
• Inventors: Babuka, Susan, Shirley, Bret A., Tellers, Melanie, Hora, Maninder, Chen, Bao-Lu, Choe, Minna
• Granted Patent: US 6,887,462 B2
• Time in Patent Office: Days
• US Class Current: 424/85.6
• CPC Class Codes: A61K 38/1816 Erythropoietin [EPO]
• CPC Class Codes: A61K 38/215 IFN-beta
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system

Abstract

Stabilized pharmaceutical compositions comprising substantially monomeric interferon-beta (IFN-β) and methods useful in their preparation are provided. The compositions comprise the IFN-β solubilized in a low-ionic-strength formulation that maintains the composition at a pH of about 3.0 to about 5.0. Methods for preparing these compositions, and for increasing solubility of IFN-β in pharmaceutical compositions, are provided.

Claims

1. A stabilized HSA-free pharmaceutical composition comprising substantially monomeric interferon-beta (IFN-β

) or biologically active variant thereof solubilized in a low-ionic-strength formulation, wherein said low-ionic-strength formulation is a solution that comprises a buffer in an amount sufficient to maintain the pH of said composition within plus or minus 0.5 units of a specified pH, where the specified pH is about 3.0 to about 5.0, said formulation having an ionic strength that is not greater than about 60 mM.

2. The composition of claim 1, wherein said buffer is present at a concentration of about 1 mM to about 30 mM.

3. The composition of claim 2, wherein said buffer is present at a concentration of about 1 mM to about 10 mM.

4. The composition of claim 3, wherein said buffer is present at a concentration of about 2 mM to about 7 mM.

5. The composition of claim 4, wherein said buffer is present at a concentration of about 2 to about 5 mM.

6. The composition of claim 5, wherein said buffer is present at a concentration of about 5 mM.

7. The composition of claim 1, wherein said specified pH is about 3.0 and wherein said buffer is glycine.

8. The composition of claim 1, wherein said specified pH is about 4.0 and wherein said buffer is aspartic acid.

9. The composition of claim 1, wherein said specified pH is about 5.0 and wherein said buffer is sodium succinate.

10. The composition of claim 6, wherein said specified pH is about 3.0 and wherein said buffer is glycine.

11. The composition of claim 6, wherein said specified pH is about 4.0 and wherein said buffer is aspartic acid.

12. The composition of claim 6, wherein said specified pH is about 5.0 and wherein said buffer is sodium succinate.

13. The composition of claim 1, wherein said composition is a liquid or a dried form, wherein said dried form is selected from the group consisting of a lyophilized form, an air-dried form, and a spray-dried form.

14. The composition of claim 1, wherein said composition is an aqueous or nonaqueous solution, an aqueous or nonaqueous suspension, or a dry powder form that is suitable for delivery to a subject by pulmonary inhalation.

15. The composition of claim 1, further comprising an amount of a non-ionic tonicifying agent sufficient to render said composition isotonic, wherein said non-ionic tonicifying agent is trehalose.

16. The composition of claim 15, wherein said trehalose is present at a concentration of about 9% by weight per volume.

17. The composition of claim 15, wherein said composition is a liquid or a dried form, wherein said dried form is selected from the group consisting of a lyophilized form, an air-dried form, and a spray-dried form.

18. The composition of claim 15, wherein said composition is an aqueous or nonaqueous solution, an aqueous or nonaqueous suspension, or a dry powder form that is suitable for delivery to a subject by pulmonary inhalation.

19. The composition of claim 10, further comprising an amount of a non-ionic tonicifying agent sufficient to render the composition isotonic, wherein said non-ionic tonicifying agent is trehalose.

20. The composition of claim 19, wherein said trehalose is present at a concentration of about 9% by weight per volume.

21. The composition of claim 19, wherein said composition is a liquid or a dried form, wherein said dried form is selected from the group consisting of a lyophilized form, an air-dried form, and a spray-dried form.

22. The composition of claim 19, wherein said composition is an aqueous or nonaqueous solution, an aqueous or nonaqueous suspension, or a dry powder form that is suitable for delivery to a subject by pulmonary inhalation.

23. The composition of claim 11, further comprising an amount of a non-ionic tonicifying agent sufficient to render the composition isotonic, wherein said non-ionic tonicifying agent is trehalose.

24. The composition of claim 23, wherein said trehalose is present at a concentration of about 9% by weight per volume.

25. The composition of claim 23, wherein said composition is a liquid or a dried form, wherein said dried form is selected from the group consisting of a lyophilized form, an air-dried form, and a spray-dried form.

26. The composition of claim 23, wherein said composition is an aqueous or nonaqueous solution, an aqueous or nonaqueous suspension, or a dry powder form that is suitable for delivery to a subject by pulmonary inhalation.

27. The composition of claim 12, further comprising an amount of a non-ionic tonicifying agent sufficient to render the composition isotonic, wherein said non-ionic tonicifying agent is trehalose.

28. The composition of claim 27, wherein said trehalose is present at a concentration of about 9% by weight per volume.

29. The composition of claim 27, wherein said composition is a liquid or a dried form, wherein said dried form is selected from the group consisting of a lyophilized form, an air-dried form, and a spray-dried form.

30. The composition of claim 27, wherein said composition is an aqueous or nonaqueous solution, an aqueous or nonaqueous suspension, or a dry powder form that is suitable for delivery to a subject by pulmonary inhalation.

31. The composition of claim 1, wherein said IFN-β

is the polypeptide with the amino acid sequence of mature native IFN-β

or biologically active variant thereof.

32. The composition of claim 31, wherein said IFN-β

is recombinantly produced.

33. The composition of claim 32, wherein said IFN-β

is glycosylated or unglycosylated.

34. The composition of claim 33, wherein said IFN-β

is unglycosylated human IFN-β

(hIFN-β

) or biologically active mutein thereof.

35. The composition of claim 34, wherein said mutein is hIFN-β

_ser17.

37. The composition of claim 36, wherein said IFN-β

is recombinant human IFN-β

(rhIFN-β

) or biologically active mutein thereof.

38. The composition of claim 37, wherein said rhIFN-β

or biologically active mutein thereof is unglycosylated.

39. The composition of claim 38, wherein said mutein is hIFN-β

_ser17.

40. The composition of claim 36, wherein said rhIFN-β

is present at a concentration of about 0.01 mg/ml to about 20.0 mg/ml.

41. The composition of claim 36, wherein said buffer is glycine, said glycine being present at a concentration of about 5 mM, and wherein said composition has a pH of about 3.0.

42. The composition of claim 41 further comprising about 9% trehalose by weight per volume.

43. The composition of claim 36, wherein said buffer is aspartic acid, said aspartic acid being present at a concentration of about 5 mM, and wherein said composition has a pH of about 4.0.

44. The composition of claim 43 further comprising about 9% trehalose by weight per volume.

45. The composition of claim 36, wherein said buffer is sodium succinate, said sodium succinate being present at a concentration of about 5 mM, and wherein said composition has a pH of about 5.0.

46. The composition of claim 45, further comprising about 9% trehalose by weight per volume.

47. The composition of claim 36, wherein said composition is a liquid or a dried form, wherein said dried form is selected from the group consisting of a lyophilized form, an air-dried form, and a spray-dried form.

48. The composition of claim 36, wherein said composition is an aqueous or nonaqueous solution, an aqueous or nonaqueous suspension, or a dry powder form that is suitable for delivery to a subject by pulmonary inhalation.

49. The composition of claim 41, wherein said composition is a liquid or a dried form, wherein said dried form is selected from the group consisting of a lyophilized form, an air-dried form, and a spray-dried form.

50. The composition of claim 41, wherein said composition is an aqueous or nonaqueous solution, an aqueous or nonaqueous suspension, or a dry powder form that is suitable for delivery to a subject by pulmonary inhalation.

51. The composition of claim 43, wherein said composition is a liquid or a dried form, wherein said dried form is selected from the group consisting of a lyophilized form, an air-dried form, and a spray-dried form.

52. The composition of claim 43, wherein said composition is an aqueous or nonaqueous solution, an aqueous or nonaqueous suspension, or a dry powder form that is suitable for delivery to a subject by pulmonary inhalation.

53. The composition of claim 45, wherein said composition is a liquid or a dried form, wherein said dried form is selected from the group consisting of a lyophilized form, an air-dried form, and a spray-dried form.

54. The composition of claim 45, wherein said composition is an aqueous or nonaqueous solution, an aqueous or nonaqueous suspension, or a dry powder form that is suitable for delivery to a subject by pulmonary inhalation.

55. The composition of claim 42, wherein said composition is a liquid or a dried form, wherein said dried form is selected from the group consisting of a lyophilized form, an air-dried form, and a spray-dried form.

56. The composition of claim 42, wherein said composition is an aqueous or nonaqueous solution, an aqueous or nonaqueous suspension, or a dry powder form that is suitable for delivery to a subject by pulmonary inhalation.

57. The composition of claim 44, wherein said composition is a liquid or a dried form, wherein said dried form is selected from the group consisting of a lyophilized form, an air-dried form, and a spray-dried form.

58. The composition of claim 44, wherein said composition is an aqueous or nonaqueous solution, an aqueous or nonaqueous suspension, or a dry powder form that is suitable for delivery to a subject by pulmonary inhalation.

59. The composition of claim 46, wherein said composition is a liquid or a dried form, wherein said dried form is selected from the group consisting of a lyophilized form, an air-dried form, and a spray-dried form.

60. The composition of claim 46, wherein said composition is an aqueous or nonaqueous solution, an aqueous or nonaqueous suspension, or a dry powder form that is suitable for delivery to a subject by pulmonary inhalation.

102. A formulation for the diagnosis, prevention, or treatment of diseases responsive to therapy with interferon-β

(IFN-β

), said formulation comprising the pharmaceutical composition according to claims 1, 36, 61, 68, or 75.

36. A stabilized HSA-free pharmaceutical composition comprising substantially monomeric interferon-beta (IFN-β

) or biologically active variant thereof solubilized in a low-ionic-strength formulation, wherein said low-ionic-strength formulation is a solution that comprises a buffer selected from the group consisting of glycine, aspartic acid, or sodium succinate present at a concentration of about 1 mM to about 10 mM, said composition having a pH of about 3.0 to about 5.0, and wherein said formulation has an ionic-strength that is not greater than about 60 mM.

61. A stabilized HSA-free pharmaceutical composition comprising substantially monomeric human interferon-beta (IFN-β

) or biologically active mutein thereof solubilized in a low-ionic-strength formulation, wherein said low-ionic-strength formulation is a solution that comprises glycine as a buffer, where said buffer is present at a concentration of about 2 mM to about 5 mM, said composition having a pH of about 3.0 to about 4.0, and wherein said formulation has an ionic-strength that is not greater than about 40 mM.

62. The composition of claim 61, wherein said rhIFN-β

or biologically active mutein thereof is unglycosylated.

63. The composition of claim 62, wherein said mutein is hIFN-β

_ser17.

64. The composition of claim 63, wherein said buffer is present at a concentration of about 5 mM, said pH is about 3.0, and said ionic-strength is not greater than about 20 mM.

65. The composition of claim 61, wherein said composition is a liquid or a dried form, wherein said dried form is selected from the group consisting of a lyophilized form, an air-dried form, and a spray-dried form.

66. The composition of claim 61, wherein said composition is an aqueous or nonaqueous solution, an aqueous or nonaqueous suspension, or a dry powder form that is suitable for delivery to a subject by pulmonary inhalation.

67. The composition of claim 61, further comprising about 9% trehalose by weight per volume.

69. The composition of claim 68, wherein said rhIFN-β

or biologically active mutein thereof is unglycosylated.

70. The composition of claim 69, wherein said mutein is hIFN-β

_ser17.

71. The composition of claim 68, wherein said buffer is present at a concentration of about 5 mM, said pH is about 4.0, and said ionic-strength is not greater than about 20 mM.

72. The composition of claim 68, wherein said composition is a liquid or a dried form, wherein said dried form is selected from the group consisting of a lyophilized form, an air-dried form, and a spray-dried form.

73. The composition of claim 68, wherein said composition is an aqueous or nonaqueous solution, an aqueous or nonaqueous suspension, or a dry powder form that is suitable for delivery to a subject by pulmonary inhalation.

74. The composition of claim 68, further comprising about 9% trehalose by weight per volume.

68. A stabilized HSA-free pharmaceutical composition comprising substantially monomeric human interferon-beta (IFN-β

) or biologically active mutein thereof solubilized in a low-ionic-strength formulation, wherein said low-ionic-strength formulation is a solution that comprises aspartic acid as a buffer, where said buffer is present at a concentration of about 2 mM to about 5 mM, said composition having a pH of about 3.5 to about 4.5, and wherein said formulation has an ionic-strength that is not greater than about 40 mM.

75. A stabilized HSA-free pharmaceutical composition comprising substantially monomeric human interferon-beta (IFN-β

) or biologically active mutein thereof solubilized in a low-ionic-strength formulation, wherein said low-ionic-strength formulation is a solution that comprises sodium succinate as a buffer, where said buffer is present at a concentration of about 2 mM to about 5 mM, said composition having a pH of about 4.5 to about 5.0, and wherein said formulation has an ionic-strength that is not greater than about 40 mM.

76. The composition of claim 75, wherein said rhIFN-β

or biologically active mutein thereof is unglycosylated.

77. The composition of claim 76, wherein said mutein is hIFN-β

_ser17.

78. The composition of claim 75, wherein said buffer is present at a concentration of about 5 mM, said pH is about 5.0, and said ionic-strength is not greater than about 20 mM.

79. The composition of claim 75, wherein said composition is a liquid or a dried form, wherein said dried form is selected from the group consisting of a lyophilized form, an air-dried form, and a spray-dried form.

80. The composition of claim 75, wherein said composition is an aqueous or nonaqueous solution, an aqueous or nonaqueous suspension, or a dry powder form that is suitable for delivery to a subject by pulmonary inhalation.

81. The composition of claim 75, further comprising about 9% trehalose by weight per volume.

82. A method for increasing solubility of interferon-beta (IFN-β

) or biologically active variant thereof in a pharmaceutical composition in the absence of human serum albumin, said method comprising preparing said composition with a low-ionic-strength formulation, wherein said low-ionic-strength formulation is a solution that comprises a buffer in an amount sufficient to maintain the pH of said composition within plus or minus 0.5 units of a specified pH, where the specified pH is about 3.0 to about 5.0, said formulation having an ionic strength that is not greater than about 60 mM, and incorporating said IFN-β

or biologically active variant thereof into said composition.

83. The method of claim 82, wherein said buffer is present at a concentration of about 1 mM to about 30 mM.

84. The method of claim 83, wherein said buffer is present at a concentration of about 2 mM to about 5 mM.

85. The method of claim 84, wherein said specified pH is about 3.0 and wherein said buffer is glycine.

86. The method of claim 84, wherein said specified pH is about 4.0 and wherein said buffer is aspartic acid.

87. The method of claim 84, wherein said specified pH is about 5.0 and wherein said buffer is sodium succinate.

88. The method of claim 82, wherein said composition further comprises a non-ionic tonicifying agent in an amount sufficient to render said composition isotonic, wherein said non-ionic tonicifying agent is trehalose.

89. The method of claim 82, further comprising the step of preparing a dried form of said composition, wherein said dried form is selected from the group consisting of a lyophilized form, an air-dried form, and a spray-dried form.

90. The method of claim 82, wherein said composition is an aqueous or nonaqueous solution, an aqueous or nonaqueous suspension, or a dry powder form that is suitable for delivery to a subject by pulmonary inhalation.

91. A pharmaceutical composition produced according to the method of claim 82.

92. A method for preparing an HSA-free pharmaceutical composition comprising substantially monomeric interferon-beta (IFN-β

), said method comprising preparing said composition with a low-ionic-strength formulation, wherein said low-ionic-strength formulation is a solution that comprises a buffer in an amount sufficient to maintain the pH of said composition within plus or minus 0.5 units of a specified pH, wherein the specified pH is about 3.0 to about 5.0, said formulation having an ionic strength not greater than about 60 mM, and incorporating said IFN-β

or biologically active variant thereof into said composition.

93. The method of claim 92, wherein said buffer is present at a concentration of about 1 mM to about 30 mM.

94. The method of claim 93, wherein said buffer is present at a concentration of about 2 mM to about 5 mM.

95. The method of claim 94, wherein said specified pH is about 3.0 and wherein said buffer is glycine.

96. The method of claim 94, wherein said specified pH is about 4.0 and wherein said buffer is aspartic acid.

97. The method of claim 94, wherein said specified pH is about 5.0 and wherein said buffer is sodium succinate.

98. The method of claim 92, wherein said composition further comprises a non-ionic tonicifying agent in an amount sufficient to render said composition isotonic, wherein said non-ionic tonicifying agent is trehalose.

99. The method of claim 92, further comprising the step of preparing a dried form of said composition, wherein said dried form is selected from the group consisting of a lyophilized form, an air-dried form, and a spray-dried form.

100. The method of claim 92, wherein said composition is an aqueous or nonaqueous solution, an aqueous or nonaqueous suspension, or a dry powder form that is suitable for delivery to a subject by pulmonary inhalation.

101. A pharmaceutical composition produced according to the method of claim 92.