Stable pharmaceutical compositions of 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivatives

• US 20050069586A1
• Filed: 06/24/2004
• Published: 03/31/2005
• Est. Priority Date: 06/26/2003
• Status: Abandoned Application

• Current Assignee: Teva Pharmaceutical Industries Limited
• Original Assignee: Teva Pharmaceutical Industries Limited
• Inventors: Hrakovsky, Julia, Tenengauzer, Ruth
• Application Number:
  US10/877,027
• Publication Number:
  US 20050069586A1
• Time in Patent Office: Days
• US Class Current: 424/464
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A stable composition of a 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivative and a method for its preparation are described. The stable composition includes an intimate admixture of the derivative and a stabilizing effective amount of a lubricant. The stable composition further includes an external excipient. A method of preparing the stable composition includes forming an intimate admixture of the derivative and a lubricant and then blending the intimate admixture with at least one excipient. Preferably the final blend is transformed into solid unit dosage form.

Claims

1. A stable pharmaceutical composition comprising:

an intimate admixture including a 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivative and an effective amount of a lubricant to stabilize the composition; and

an external excipient.

2. The composition according to claim 1, wherein the intimate admixture is in granular form.

3. The composition according to claim 1, wherein the effective amount of the lubricant ranges from about 0.3% to about 60% by weight of the intimate admixture.

4. The composition according to claim 1, wherein the effective amount of the lubricant ranges from about 0.8% to about 50% by weight of the intimate admixture.

5. The composition according to claim 1, wherein the effective amount of the lubricant ranges from about 1% to about 40% by weight of the intimate admixture.

6. The composition according to claim 1, wherein the effective amount of the lubricant ranges from about 2% to about 10% by weight of the intimate admixture.

7. The composition according to claim 1, wherein the lubricant is selected from the group consisting of magnesium stearate, talc, stearic acid, glycerylbehenate, polyethylene glycol, ethylene oxide polymers, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, DL-leucine, and sodium stearyl fumarate.

8. The composition according to claim 7, wherein the lubricant is sodium stearyl fumarate.

9. The composition according to claim 1, wherein the intimate admixture further comprises one non-lubricant excipient.

10. The composition according to claim 9, wherein the non-lubricant excipient is microcrystalline cellulose.

11. The composition according to claim 9, wherein the non-lubricant excipient is in the amount of about 95% or less by weight of the intimate admixture.

12. The composition according to claim 1, further comprising a diuretic agent.

13. The composition according to claim 12, wherein the diuretic agent is hydrochlorothiazide.

14. The composition according to claim 1, wherein the derivative is selected from the group consisting of ramipril, quinapril, moexipril, fosinopril, enalapril, perindopril, and trandolapril.

15. The composition according to claim 14, wherein the derivative is ramipril.

16. The composition according to claim 1, wherein the derivative is present in an amount of from about 0.3% to about 6% by weight of the total composition.

17. The composition according to claim 1, wherein the derivative is present in an amount of from about 0.8% to about 5% by weight of the total composition.

18. The composition according to claim 1, wherein the derivative is present in an amount of from about 0.8% to about 4.2% by weight of the total composition.

19. The composition according to claim 1, wherein the composition is in solid unit dosage form.

20. The composition according to claim 19, wherein the composition is in tablet form.

21. The composition according to claim 19, wherein the composition is in capsule form.

22. The composition according to claim 1, wherein the amount of a principal degradant present in the composition after 48 hours at 55°

C. is less than 3% by weight of the derivative.

23. The composition according to claim 1, wherein the amount of a principal degradant present in the composition after 48 hours at 55°

C. is less than 1% by weight of the derivative.

24. The composition according to claim 22, wherein the principal degradant is diketopiperazine and the derivative is rampiril.

25. The composition according to claim 23, wherein the principal degradant is diketopiperazine and the derivative is rampiril.

26. The composition according to claim 1, wherein the amount of an active form degradant present in the composition after 48 hours at 55°

C. is less than 0.3% by weight of the derivative.

27. The composition according to claim 1, wherein the amount of an active form degradant present in the composition after 48 hours at 55°

C. is less than 0.2% by weight of the derivative.

28. The composition according to claim 1, wherein the total amount of an active form degradant and a principal degradant present in the composition after 48 hours at 55°

C. is less than 3.3% by weight of the derivative.

29. The composition according to claim 1, wherein the total amount of an active form degradant and a principal degradant present in the composition after 48 hours at 55°

C. is less than 1% by weight of the derivative.

30. The composition according to claim 28, wherein the active form degradant is ramprilat, the principal degradant is diketopiperazine, and the derivative is rampiril.

31. The composition according to claim 29, wherein the active form degradant is ramprilat, the principal degradant is diketopiperazine, and the derivative is rampiril.

32. A method for preparing a stable pharmaceutical composition comprising:

forming an intimate admixture including a 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivative and a lubricant; and

blending the intimate admixture with an external excipient.

33. The method of claim 32, further comprising transforming the final blend into solid unit dosage form.

34. The method of claim 33, wherein the composition is in tablet form.

35. The method of claim 33, wherein the composition is in capsule form.

36. The method of claim 32, wherein the intimate admixture is in granular form.

37. The method of claim 32, wherein the intimate admixture is formed by dry granulation or wet granulation.

38. A 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivative composition made by the process of claim 32.