Stable pharmaceutical compositions of 2-aza-bicyclo(3.3.0)-octane-3-carboxylic acid derivatives

• US 20080015188A1
• Filed: 04/19/2007
• Published: 01/17/2008
• Est. Priority Date: 04/19/2006
• Status: Abandoned Application

• Current Assignee: Teva Pharmaceuticals USA, Inc. (Teva Pharmaceutical Industries Limited)
• Original Assignee: Teva Pharmaceuticals USA, Inc. (Teva Pharmaceutical Industries Limited)
• Inventors: Sebban, Hagit, Hrakovsky, Julia
• Application Number:
  US11/788,771
• Publication Number:
  US 20080015188A1
• Time in Patent Office: Days
• US Class Current: 514/223.5
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

Provided are stable pharmaceutical compositions comprising from about 2.5% to about 20% of a 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivative by weight of the composition and at least one pharmaceutically acceptable excipient, wherein the composition preferably has a total weight of less than 100 mg. Also provided are stable pharmaceutical compositions comprising a 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivative in a stabilizing-effective concentration and at least one pharmaceutically acceptable excipient. Further provided are methods for improving the stability of a pharmaceutical composition and methods for treating hypertension by administering a therapeutically effective amount of the stable pharmaceutical compositions of the invention.

Claims

1. A stable pharmaceutical composition comprising from about 2.5% to about 20% of a 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivative by weight of the composition and at least one pharmaceutically acceptable excipient, wherein the composition has a total weight of less than 100 mg.

2. The stable pharmaceutical composition of claim 1, wherein the composition has a total weight of from about 50 mg to about 75 mg.

3. The stable pharmaceutical composition of claim 1, wherein the composition has a total weight of about 50 mg.

4. The stable pharmaceutical composition of claim 1 comprising about 2.5% of a 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivative by weight of the composition.

5. The stable pharmaceutical composition of claim 1 comprising about 5% of a 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivative by weight of the composition.

6. The stable pharmaceutical composition of claim 1 comprising about 10% of a 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivative by weight of the composition.

7. The stable pharmaceutical composition of claim 1, wherein the composition comprises about 1.25 mg, 2.5 mg, 5 mg, or 10 mg of the derivative.

8. The stable pharmaceutical composition of claim 1, wherein the composition exhibits at least one of the following characteristics:

(a) less than about 2% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for one month;

(b) less than about 3% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for two months;

or

(c) less than about 3.5% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for three months.

9. The stable pharmaceutical composition of claim 1, wherein the composition exhibits at least one of the following characteristics:

(a) less than about 1% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for one month;

(b) less than about 2% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for two months;

or

(c) less than about 3% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for three months.

10. The stable pharmaceutical composition of claim 1, wherein:

(a) less than about 2% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for one month;

(b) less than about 3% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for two months; and

(c) less than about 3.5% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for three months.

11. The stable pharmaceutical composition of claim 1, wherein the composition exhibits at least one of the following characteristics:

(a) less than about 2% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for one month;

(b) less than about 3% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for two months;

or

(c) less than about 3.5% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for three months.

12. The stable pharmaceutical composition of claim 1, wherein the composition exhibits at least one of the following characteristics:

(a) less than about 1% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for one month;

or

(b) less than about 2% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for two months;

or

(c) less than about 3% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for three months.

13. The stable pharmaceutical composition of claim 1, wherein:

(a) less than about 2% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for one month;

(b) less than about 3% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for two months; and

(c) less than about 3.5% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for three months.

14. The stable pharmaceutical composition of claim 1, wherein the 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivative includes at least one of ramipril, quinapril, moexipril, enalapril, perindopril, or trandolapril.

15. The stable pharmaceutical composition of claim 1, wherein the 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivative includes ramipril.

16. The stable pharmaceutical composition of claim 1, wherein the composition is in tablet, capsule, or powder form.

17. The stable pharmaceutical composition of claim 1, wherein the composition is in capsule form.

18. The stable pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipient is at least one of pregelatinized starch, lactose anhydrous, povidone, or sodium stearyl fumarate.

19. The stable pharmaceutical composition of claim 1, wherein the composition comprises pregelatinized starch, lactose anhydrous, and sodium stearyl fumarate.

20. The stable pharmaceutical composition of claim 1, wherein the composition further comprises at least one diuretic agent.

21. The stable pharmaceutical composition of claim 1, wherein the composition further comprises hydrochlorothiazide.

22. The stable pharmaceutical composition of claim 1, wherein:

(a) less than about 1% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for one month;

(b) less than about 2% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for two months; and

(c) less than about 3% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for three months.

23. The stable pharmaceutical composition of claim 1, wherein:

(a) less than about 1% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for one month;

(b) less than about 2% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for two months; and

(c) less than about 3% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for three months.

45. A method of treating hypertension in a mammal in need thereof comprising administering a therapeutically effective amount of the composition of claim 1.

24. A method for improving the stability of a pharmaceutical composition comprising combining a stabilizing-effective concentration of a 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivative with at least one pharmaceutically acceptable excipient, wherein the composition has a total weight of less than 100 mg.

25. The method of claim 24, wherein the composition comprises about 2.5% of a 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivative by weight of the composition.

26. The method of claim 24, wherein the composition comprises about 1.25 mg, 2.5 mg, 5 mg, or 10 mg of the derivative.

27. The method of claim 24, wherein the composition exhibits at least one of the following characteristics:

(a) less than about 2% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for one month;

(b) less than about 3% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for two months;

or

(c) less than about 3.5% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for three months.

28. The method of claim 24, wherein the composition exhibits at least one of the following characteristics:

(a) less than about 1% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for one month;

(b) less than about 2% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for two months;

or

(c) less than about 3% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for three months.

29. The method of claim 24, wherein:

(a) less than about 2% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for one month;

(b) less than about 3% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for two months; and

(c) less than about 3.5% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for three months.

30. The method of claim 24, wherein:

(a) less than about 1% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for one month;

(b) less than about 2% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for two months; and

(c) less than 3% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for three months.

31. The method of claim 24, wherein the composition exhibits at least one of the following characteristics:

(a) less than about 2% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for one month;

(b) less than about 3% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for two months;

or

(c) less than about 3.5% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for three months.

32. The method of claim 24, wherein the composition exhibits at least one of the following characteristics:

(a) less than about 1% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for one month;

(b) less than about 2% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for two months;

or

(c) less than about 3% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for three months.

33. The method of claim 24, wherein:

(a) less than about 2% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for one month;

(b) less than about 3% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for two months; and

(c) less than about 3.5% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for three months.

34. The method of claim 24, wherein:

(a) less than about 1% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for one month;

(b) less than about 2% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for two months; and

(c) less than about 3% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for three months.

35. The method of claim 24, wherein the method comprises at least one of dry mixing, dry granulation or wet granulation.

36. A stable pharmaceutical composition prepared by the method of claim 24.

37. A stable pharmaceutical composition comprising a 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivative in a stabilizing-effective concentration and at least one pharmaceutically acceptable excipient, wherein:

(a) less than about 2% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for one month;

(b) less than about 3% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for two months; and

(c) less than about 3.5% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for three months.

38. The stable pharmaceutical composition of claim 37, wherein:

(a) less than about 2% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for one month;

(b) less than about 3% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for two months; and

(c) less than about 3.5% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for three months.

39. The stable pharmaceutical composition of claim 37, wherein:

(a) less than about 1% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for one month;

(b) less than about 2% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for two months; and

(c) less than about 3% of a diketopiperazine by weight of the derivative before degradation is present after storage at 40°

C. under 75% relative humidity for three months.

40. The stable pharmaceutical composition of claim 37, wherein:

(a) less than about 1% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for one month;

(b) less than about 2% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for two months; and

(c) less than about 3% by weight of the derivative is converted to diketopiperazine after storage at 40°

C. under 75% relative humidity for three months.

41. A stable pharmaceutical composition comprising about 1.25 mg of ramipril, wherein the composition has a total weight of about 50 mg.

42. A stable pharmaceutical composition comprising about 2.5 mg of ramipril, wherein the composition has a total weight of about 50 mg.

43. A stable pharmaceutical composition comprising about 5 mg of ramipril, wherein the composition has a total weight of about 50 mg.

44. A stable pharmaceutical composition comprising about 10 mg of ramipril, wherein the composition has a total weight of about 50 mg.