Degradation-resistant glucocorticosteroid formulations

• US 20030113268A1
• Filed: 01/24/2002
• Published: 06/19/2003
• Est. Priority Date: 11/10/2000
• Status: Abandoned Application

• Current Assignee: Michael Brucato, Mina Buenafae, Zhang Kai
• Original Assignee: Michael Brucato, Mina Buenafae, Zhang Kai
• Inventors: Zhang, Kai, Brucato, Michael, Buenafae, Mina
• Application Number:
  US10/056,962
• Publication Number:
  US 20030113268A1
• Time in Patent Office: Days
• US Class Current: 424/45
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/375 Ascorbic acid, i.e. vitamin C; Salts thereof
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/568 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 9/008 comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]

Abstract

The present invention thus provides chemically and physically stable formulations of glucocorticosteroids obtained by formulating the glucocorticosteroid with a cosolvent, a propellant and a radical quencher where the glucocorticosteroid remains chemically and physically stable under standard conditions.

Claims

1. A pharmaceutical composition comprising a glucocorticosteroid, a propellant, a cosolvent, and a radical quencher.

2. The pharmaceutical composition of claim 1, wherein the radical quencher is Vitamin E.

3. The pharmaceutical composition of claim 1, wherein the radical quencher is Vitamin E acetate.

4. The pharmaceutical composition of claim 1, wherein the radical quencher is ascorbyl palmitate.

5. The pharmaceutical composition of claim 1, wherein the radical quencher is butylated hydroxyanisole (BHA).

6. The pharmaceutical composition of claim 1, wherein the radical quencher is selected from the group consisting of ascorbic acid, ascorbyl palmitate, sodium bisulfite, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), glutathione, ubiquinone, carotenoids, Vitamin E, and functional equivalents and/or derivatives thereof.

7. The pharmaceutical composition of claim 1, wherein the glucocorticosteroid is selected from the group consisting of budesonide, testosterone, progesterone, estrogen, flunisolide, triamcinolone, beclomethasone, betamethasone, dexamethasone, fluticasone, methylprednisolone, prednisone, hydrocortisone, ciclesonide, mometasone, desonide, and rofleponide.

8. The pharmaceutical composition of claim 1, wherein the glucocorticosteroid is budesonide.

9. The pharmaceutical composition of claim 1, wherein the propellant is 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane, or a mixture thereof.

10. The pharmaceutical composition of claim 1, wherein the cosolvent is a polyol.

11. The pharmaceutical composition of claim 10, wherein the polyol is a C₂-C₆ alcohol.

12. The pharmaceutical composition of claim 10, wherein the polyol is selected from the group consisting of ethanol, isopropanol, and propylene glycol.

13. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is stored in a container coated with a polymer.

14. A pressurized metered dose inhaler comprising a container equipped with a metering valve and containing a pressurized aerosol formulation comprising a glucocorticosteroid, a propellant, a cosolvent, and a radical quencher.

15. The pressurized metered dose inhaler according to claim 14, wherein the glucocorticosteroid is selected from the group consisting of budesonide, testosterone, progesterone, estrogen, flunisolide, triamcinolone, beclomethasone, betamethasone, dexamethasone, fluticasone, methylprednisolone, prednisone, hydrocortisone, ciclesonide, mometasone, desonide, and rofleponide.

16. The pressurized metered dose inhaler according to claim 14, wherein the glucocorticosteroid is budesonide.

17. The pressurized metered dose inhaler according to claim 14, wherein the propellant is 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane, or a mixture thereof.

18. The pressurized metered dose inhaler according to claim 14, wherein the cosolvent is a polyol.

19. The pressurized metered dose inhaler according to claim 18, wherein the polyol is a C₂-C₆ alcohol.

20. The pressurized metered dose inhaler according to claim 18, wherein the polyol is selected from the group consisting of ethanol, isopropanol, and propylene glycol.

21. The pressurized metered dose inhaler according to claim 14, wherein the radical quencher is Vitamin E.

22. The pressurized metered dose inhaler according to claim 14, wherein the radical quencher is Vitamin E acetate.

23. The pressurized metered dose inhaler according to claim 14, wherein the radical quencher is ascorbyl palmitate.

24. The pressurized metered dose inhaler according to claim 14, wherein the radical quencher is butylated hydroxyanisole (BHA).

25. The pressurized metered dose inhaler according to claim 14, wherein the radical quencher is selected from the group consisting of ascorbic acid, ascorbyl palmitate, sodium bisulfite, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), glutathione, ubiquinone, carotenoids, Vitamin E, and functional equivalents and/or derivatives thereof.

26. The pressurized metered dose inhaler according to claim 14, wherein the interior of the container is coated with a polymer.

27. A method for the treatment of a bronchial disorder in a mammal by administering a pharmaceutical formulation comprising a glucocorticosteroid, a propellant, a cosolvent, and a radical quencher.

28. The method according to claim 27, wherein the glucocorticosteroid is selected from the group consisting of budesonide, testosterone, progesterone, estrogen, flunisolide, triamcinolone, beclomethasone, betamethasone, dexamethasone, fluticasone, methylprednisolone, prednisone, hydrocortisone, ciclesonide, mometasone, desonide, and rofleponide.

29. The method according to claim 27, wherein the glucocorticosteroid is budesonide.

30. The method according to claim 27, wherein the propellant is 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane, or a mixture thereof.

31. The method according to claim 27, wherein the cosolvent is a polyol.

32. The method according to claim 31, wherein the polyol is a C₂-C₆ alcohol.

33. The method according to claim 31, wherein the polyol is selected from the group consisting of ethanol, isopropanol, and propylene glycol.

34. The method according to claim 27, wherein the radical quencher is Vitamin E.

35. The method according to claim 27, wherein the radical quencher is Vitamin E acetate.

36. The method according to claim 27, wherein the radical quencher is ascorbyl palmitate.

37. The method according to claim 27, wherein the radical quencher is butylated hydroxyanisole (BHA).

38. The method according to claim 27, wherein the radical quencher is selected from the group consisting of ascorbic acid, ascorbyl palmitate, sodium bisulfite, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), glutathione, ubiquinone, carotenoids, Vitamin E, and functional equivalents and/or derivatives thereof.

39. The method according to claim 27, wherein the pharmaceutical formulation is stored in a container coated with a polymer.

40. A method for preventing oxidative degradation of an aerosol formulation including a glucocorticosteroid, a propellant, and a cosolvent, the method comprising introducing a radical quencher to the formulation.

41. The method according to claim 40, wherein the glucocorticosteroid is selected from the group consisting of budesonide, testosterone, progesterone, estrogen, flunisolide, triamcinolone, beclomethasone, betamethasone, dexamethasone, fluticasone, methylprednisolone, prednisone, hydrocortisone, ciclesonide, mometasone, desonide, and rofleponide.

42. The method according to claim 40, wherein the glucocorticosteroid is budesonide.

43. The method according to claim 40, wherein the propellant is 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane, or a mixture thereof.

44. The method according to claim 40, wherein the cosolvent is a polyol.

45. The method according to claim 44, wherein the polyol is a C₂-C₆ alcohol.

46. The method according to claim 44, wherein the polyol is selected from the group consisting of ethanol, isopropanol, and propylene glycol.

47. The method according to claim 40, wherein the radical quencher is Vitamin E.

48. The method according to claim 40, wherein the radical quencher is Vitamin E acetate.

49. The method according to claim 40, wherein the radical quencher is ascorbyl palmitate.

50. The method according to claim 40, wherein the radical quencher is butylated hydroxyanisole (BHA).

51. The method according to claim 40, wherein the radical quencher is selected from the group consisting of ascorbic acid, ascorbyl palmitate, sodium bisulfite, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), glutathione, ubiquinone, carotenoids, Vitamin E, and functional equivalents and/or derivatives thereof.

52. The method according to claim 40, further comprising storing the aerosol formulation in a container coated with a polymer.