STABLE CORTICOSTEROID MIXTURES

Abstract

A corticosteroid mixture, such as a budesonide solution, is prepared by the active and inactive ingredients of the mixture under oxygen-depleted conditions. The resulting mixture demonstrates superior stability of the active pharmaceutical ingredient corticosteroid. The invention provides novel methods of manufacturing corticosteroid mixtures, wherein the resulting mixtures possess superior stability as compared to known methods.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of certain embodiments of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

FIG. 1 is a flow diagram illustrating an embodiment of a budesonide solution manufacturing process according to the present invention.

Claims

1. A process of preparing a corticosteroid mixture, comprising mixing ingredients of the corticosteroid mixture in a mixing vessel under oxygen-depleted conditions to produce the corticosteroid mixture, wherein the ingredients include as starting materials corticosteroid and water.

2. The process of claim 1, further comprising storing the corticosteroid mixture in a holding tank.

3. The process of claim 2, wherein the corticosteroid is stored in the holding tank under oxygen depleted conditions.

4. The process of claim 3, further comprising dispensing the corticosteroid mixture into pharmaceutically acceptable containers.

5. The process of claim 4, wherein the corticosteroid mixture is dispensed into pharmaceutically acceptable containers under oxygen-depleted conditions.

6. The process of claim 1, further comprising dispensing the corticosteroid mixture into pharmaceutically acceptable containers.

7. The process of claim 6, wherein the corticosteroid mixture is dispensed into pharmaceutically acceptable containers under oxygen-depleted conditions.

8. The process of claim 6, further comprising packaging the pharmaceutically acceptable containers in one or more pouches.

9. The process of claim 8, wherein packaging the pharmaceutically acceptable containers in one or more pouches is carried out under oxygen-depleted conditions.

10. The process of claim 8, wherein the dispensing and pouching conditions are selected from one of the following: the corticosteroid is dispensed into pharmaceutically acceptable containers under oxygen-depleted conditions and the pharmaceutically acceptable containers are packaged in one or more pouches under oxygen-depleted conditions; the corticosteroid is dispensed into pharmaceutically acceptable containers under air and the pharmaceutically acceptable containers are packaged in one or more pouches under oxygen-depleted conditions; the corticosteroid is dispensed into pharmaceutically acceptable containers under oxygen-depleted conditions and the pharmaceutically acceptable containers are packaged in one or more pouches under air; and the corticosteroid is dispensed into pharmaceutically acceptable containers under air and the pharmaceutically acceptable containers are packaged in one or more pouches under air.

11. The process of claim 10, wherein the corticosteroid mixture contains less than about 0.5% impurities when one or more pouches are opened and the pharmaceutically acceptable containers are exposed to normal atmosphere for two weeks or less.

12. The process of claim 10, wherein the corticosteroid mixture contains less than about 1.0% impurities when one or more pouches are opened and the pharmaceutically acceptable containers are exposed to normal atmosphere for four weeks or less.

13. The process of claim 1, wherein the corticosteroid mixture is a solution.

14. The process of claim 1, wherein the corticosteroid mixture further comprises a solubility enhancer.

15. The process of claim 14, wherein the solubility enhancer is a sulfoalkyl ether cyclodextrin (SAE-CD).

16. The process of claim 15, wherein the solubility enhancer is SBE7-β-CD.

17. The process of claim 1, wherein the corticosteroid is budesonide.

18. The process of claim 1, wherein the cortitosteroid solution farther comprises an additional active pharmaceutical ingredient.

19. The process of claim 18, wherein the additional active pharmaceutical ingredient is a short acting β2 agonist.

20. The process of claim 19, wherein the short acting β2 agonist is albuterol.

21. The process of claim 1, wherein the oxygen-depleted conditions include one or more of: sparging the water, the mixture or both with inert gas; applying inert gas over the water, the mixture or both; or applying a vacuum to the water, the mixture or both.

22. A stable corticosteroid composition prepared by the process of claim 21.

23. The process of claim 21, wherein the inert gas is selected from nitrogen gas (N2), argon gas (Ar) and mixtures thereof.

24. A stable corticosteroid composition prepared by the process of claim 23.

25. A corticosteroid mixture which loses no more than about 2% of corticosteroid potency after exposing the corticosteroid mixture to accelerated conditions of 40° C. and 75% relative humidity for a stability testing period of at least about 3 months.

26. The corticosteroid mixture of claim 25, wherein the stability testing period is at least about 6 months.

27. The corticosteroid mixture of claim 25, wherein the stability testing period is at least about 9 months.

28. The corticosteroid mixture of claim 25, wherein the stability testing period is about 12 months.

29. The mixture of claim 25 in the form of a solution.

30. The mixture of claim 25, wherein the corticosteroid mixture loses no more than 10% corticosteroid potency after 24 months at 25° C. and 60% relative humidity.

31. The mixture of claim 25, wherein the corticosteroid mixture further comprises a solubility enhancer.

32. The mixture of claim 31, wherein the solubility enhancer is a sulfoalkyl ether cyclodextrin (SAE-CD).

33. The mixture of claim 32, wherein the solubility enhancer is SBE7-β-CD.

34. The mixture of claim 25, wherein the corticosteroid is budesonide.

35. The mixture of claim 25, wherein the corticosteroid mixture further comprises an additional active pharmaceutical ingredient.

36. The mixture of claim 35, wherein the additional active pharmaceutical ingredient is a short acting β2 agonist.

37. The mixture of claim 36, wherein the short acting β2 agonist is albuterol.

38. The mixture of claim 25, wherein the mixture is produced by a process comprising mixing ingredients of the corticosteroid mixture in a mixing vessel under oxygen-depleted conditions to produce the corticosteroid mixture, wherein the ingredients include as starting materials corticosteroid and water.

39. The mixture of claim 38, wherein the process further comprises storing the corticosteroid mixture in a holding tank.

40. The mixture of claim 39, wherein the process further comprises storing the mixture in the holding tank under oxygen-depleted conditions

41. The mixture of claim 38, wherein the process further comprises dispensing the corticosteroid mixture into pharmaceutically acceptable containers.

42. The mixture of claim 41, wherein the corticosteroid mixture is dispensed into pharmaceutically acceptable containers under oxygen-depleted conditions.

43. The mixture of claim 42, wherein the pharmaceutically acceptable container are further packaged in pharmaceutically acceptable pouches.

44. The mixture of claim 43, wherein packaging the pharmaceutically acceptable containers in pouches is carried out under oxygen-depleted conditions.

45. A corticosteroid mixture which contains no more than 1.0% of impurities after exposing the corticosteroid mixture to accelerated conditions of 40° C. and 75% relative humidity for a stability testing period of at least about 3 months.

46. The corticosteroid mixture of claim 45, wherein the stability testing period is at least about 6 months.

47. The corticosteroid mixture of claim 45, wherein the mixture contains less than about 1.5% impurities after a stability testing period of at least about 9 months.

48. The corticosteroid mixture of claim 45, wherein the mixture contains less than about 2.5% impurities after a stability testing period of about 12 months.

49. The mixture of claim 45 in the form of a solution.

50. The mixture of claim 45, wherein the corticosteroid mixture further comprises a solubility enhancer.

51. The mixture of claim 50, wherein the solubility enhancer is a sulfoalkyl ether cyclodextrin (SAE-CD).

52. The mixture of claim 51, wherein the solubility enhancer is SBE7-β-CD.

53. The mixture of claim 45, wherein the corticosteroid is budesonide.

54. The mixture of claim 45, wherein the corticosteroid mixture further comprises an additional active pharmaceutical ingredient.

55. The mixture of claim 54, wherein the additional active pharmaceutical ingredient is a short acting β2 agonist.

56. The mixture of claim 55, wherein the short acting β2 agonist is albuterol.

57. The mixture of claim 45, wherein the mixture is produced by a process comprising mixing ingredients of the corticosteroid mixture in a mixing vessel under oxygen-depleted conditions to produce the corticosteroid mixture, wherein the ingredients include as starting materials corticosteroid and water.

58. The mixture of claim 57, wherein the process further comprises storing the corticosteroid mixture in a holding tank.

59. The mixture of claim 58, wherein the process further comprises storing the mixture in the holding tank under oxygen-depleted conditions

60. The mixture of claim 58, wherein the process further comprises dispensing the corticosteroid mixture into pharmaceutically acceptable containers.

61. The mixture of claim 60, wherein the corticosteroid mixture is dispensed into pharmaceutically acceptable containers under oxygen-depleted conditions.

62. The mixture of claim 61, wherein the pharmaceutically acceptable container are further packaged in pharmaceutically acceptable pouches.

63. The mixture of claim 62, wherein packaging the pharmaceutically acceptable containers in pouches is carried out under oxygen-depleted conditions.

64. The mixture of claim 25, wherein the budesonide solution demonstrates stable aerosol performance for at least 3 months after it is manufactured.

65. The process of claim 64, wherein the budesonide solution demonstrates stable aerosol performance for at least 6 months after it is manufactured.

66. The process of claim 65, wherein the budesonide solution demonstrates stable aerosol performance for at least 9 months after it is manufacture.

67. The process of claim 1, wherein the budesonide solution demonstrates stable aerosol performance for at least 3 months after it is manufactured.

68. The process of claim 67, wherein the budesonide solution demonstrates stable aerosol performance for at least 6 months after it is manufactured.

69. The process of claim 64, wherein the budesonide solution demonstrates stable aerosol performance for at least 9 months after it is manufacture.

70. The mixture of claim 25, wherein the corticosteroid solution loses no more than about 10% of corticosteroid potency after 24 hours of exposure to conditions of 25° C. and 60% relative humidity.