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-βser17.
- 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.
- 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-βser17.
- 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.
- 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-βser17.
- 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.
- 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.
- 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-βser17.
- 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.
- 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-βser17.
- 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.
- 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.
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional Application Serial No. ______, filed Oct. 18, 2001, entitled “HSA-Free Formulations of Interferon-Beta,” and U.S. Provisional Application Serial No. 60/282,614, filed Apr. 9, 2001, each of which is herein incorporated by reference in its entirety.
Provisional Applications (2)
|
Number |
Date |
Country |
|
60282614 |
Apr 2001 |
US |
|
60330404 |
Oct 2001 |
US |