Stabilized pharmaceutical composition

• US 5,977,164 A
• Filed: 11/26/1997
• Issued: 11/02/1999
• Est. Priority Date: 11/27/1992
• Status: Expired due to Term

• Current Assignee: Mayne Pharma (USA) Incorporated (Pfizer Inc.)
• Original Assignee: NAPRO BIOTHERAPEUTICS INC.
• Inventors: Carver, David, Ewald, Hernita, Prout, Timothy, Handreck, Paul, Elliott, Robyn
• Primary Examiner(s): VENKAT, JYOTHSNA A
• Application Number:
  US08/979,836
• Time in Patent Office: 706 Days
• Field of Search: 514/449
• US Class Current: 514/449
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• 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 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00

Abstract

A pharmaceutical formulation of taxol and polyethoxylated castor oil is disclosed to be relatively acidified to pH of less 8.1 and preferably within a pH range of 5 to 7, inclusively, by an acidifying agent. Ethanol is optionally included in the formulation which is adapted for use in a body for the treatment cancer. A formulation method is disclosed and includes the step of mixing an acid with a carrier material, such as polyethoxylated castor oil, to form a carrier solution after which taxol is added in an amount such that the resulting pH is less than 8.1 and preferably in a pH range of 5 to 7. Ethanol may optionally be slurried with the taxol before mixing with the carrier solution. A variety of acidifying agents, a preferred one being anhydrous citric acid, are described.

Claims

1. A method of formulating a taxol solution for injection in which the taxol does not readily degrade, comprising the following steps:

mixing acid with a carrier material to form a first carrier solution; and

mixing taxol with the first carrier solution to form a taxol solution having a pH of less than 8.1 whereby the taxol in the taxol solution does not readily degrade.

2. An improved pharmaceutical carrier composition useful for combining with taxol to yield a taxol formulation, the improvement comprising mixing an acid with said carrier composition.

3. The improved pharmaceutical carrier composition of claim 2, wherein said carrier composition comprises polyethoxylated castor oil.

4. The improved pharmaceutical carrier composition of claim 3, wherein said carrier composition further comprises ethanol.

5. The improved pharmaceutical carrier composition of claim 2, wherein said acid is a mineral acid.

6. The improved pharmaceutical carrier composition of claim 2, wherein said acid is an organic acid.

7. The improved pharmaceutical carrier composition of claim 6, wherein said organic acid is citric acid.

8. The improved pharmaceutical carrier composition of claim 7, wherein said citric acid is anhydrous.

9. The improved pharmaceutical carrier composition of claim 6, wherein said organic acid is acetic acid.

10. The improved pharmaceutical carrier composition of claim 2, having a resulting pH of less than about 7.

11. The improved pharmaceutical carrier composition of claim 10, having a resulting pH of from about 7 to about 5.

12. The improved pharmaceutical carrier composition of claim 3, wherein said acid is a mineral acid.

13. The improved pharmaceutical carrier composition of claim 3, wherein said acid is an organic acid.

14. The improved pharmaceutical carrier composition of claim 13, wherein said organic acid is citric acid.

15. The improved pharmaceutical carrier composition of claim 14, wherein said citric acid is anhydrous.

16. The improved pharmaceutical carrier composition of claim 13, wherein said organic acid is acetic acid.

17. The improved pharmaceutical carrier composition of claim 3, having a resulting pH of less than about 7.

18. The improved pharmaceutical carrier composition of claim 17, having a resulting pH of from about 7 to about 5.

19. The improved pharmaceutical carrier composition of claim 4, wherein said acid is a mineral acid.

20. The improved pharmaceutical carrier composition of claim 4, wherein said acid is an organic acid.

21. The improved pharmaceutical carrier composition of claim 20, wherein said organic acid is citric acid.

22. The improved pharmaceutical carrier composition of claim 21, wherein said citric acid is anhydrous.

23. The improved pharmaceutical carrier composition of claim 20, wherein said organic acid is acetic acid.

24. The improved pharmaceutical carrier composition of claim 4, having a resulting pH of less than about 7.

25. The improved pharmaceutical carrier composition of claim 24, having a resulting pH of from about 7 to about 5.

26. A pharmaceutical taxol composition comprising taxol and a pharmaceutically-acceptable carrier wherein said pharmaceutical taxol composition has a pH less than or equal to 7.0.

27. The pharmaceutical taxol composition of claim 26 having a pH between 5 and 7.

28. The pharmaceutical taxol composition of claim 26 further comprising ethanol as a constituent thereof.

29. The pharmaceutical taxol composition of claim 28 having a pH of between 5 and 7.

30. The pharmaceutical taxol composition of claim 26, wherein said pharmaceutically-acceptable carrier is polyethoxylated castor oil.

31. The pharmaceutical taxol composition of claim 26, wherein said composition is anhydrous.

32. An improved method of formulating a pharmaceutical taxol solution, such that the taxol does not readily degrade, comprising the following steps:

mixing taxol with a carrier material to form a taxol solution; and

reducing the pH of said taxol solution to a level whereby the taxol solution is stabilized such that at least 95% of the taxol potency is retained when the composition is stored at 40°

C. for seven (7) days.

33. The method of claim 32, wherein said carrier material is polyethoxylated castor oil.

34. The method of claim 32 further comprising the step of slurrying said taxol in alcohol before mixing said taxol with the carrier material.

35. An article of manufacture comprising a container and a pharmaceutical formulation contained therein, said pharmaceutical formulation comprising a pharmaceutically-acceptable carrier and taxol, wherein said pharmaceutical formulation has a pH of about 7 or less.

36. The article of claim 35, wherein said pharmaceutical-acceptable carrier is polyethoxylated castor oil.

37. The article of manufacture of claim 35, wherein said pharmaceutical formulation further comprises ethanol.

38. The article of manufacture of claim 35, wherein said pharmaceutical formulation has a pH between 5 and 7.

39. The article of manufacture of claim 35 further comprising instructions for administering said pharmaceutical formulation to a patient.

40. A pharmaceutical taxol composition comprising:

taxol;

polyethoxylated castor oil; and

ethanol, wherein said taxol composition has a pH sufficient to improve the stability of said taxol such that at least 95% of the taxol potency is retained when the composition is stored at 40°

C. for seven (7) days.

41. A pharmaceutical taxol composition comprising:

taxol;

polyethoxylated castor oil; and

an acid in sufficient amounts to improve the stability of the taxol such that at least 95% of the taxol potency is retained when the composition is stored at 40°

C. for 7 days.

42. The pharmaceutical taxol composition of claim 41, wherein said acid is an organic acid.

43. The pharmaceutical taxol composition of claim 41, wherein said acid is a mineral acid.

44. The pharmaceutical taxol composition of claim 41, wherein said acid is citric acid.

45. The pharmaceutical taxol composition of claim 44, wherein said citric acid is monohydrous.

46. The pharmaceutical taxol composition of claim 44, wherein the citric acid is hydrous.

47. The pharmaceutical taxol composition of claim 41, wherein said acid is formic acid.

48. The pharmaceutical taxol composition of claim 41, wherein said acid is ascorbic acid.

49. The pharmaceutical taxol composition of claim 41, wherein said acid is aspartic acid.

50. The pharmaceutical taxol composition of claim 41, wherein said acid is benzene sulphonic acid.

51. The pharmaceutical taxol composition of claim 41, wherein said acid is benzoic acid.

52. The pharmaceutical taxol composition of claim 41, wherein said acid is hydrochloric acid.

53. The pharmaceutical taxol composition of claim 41, wherein said acid is sulphuric acid.

54. The pharmaceutical taxol composition of claim 41, wherein said acid is phosphoric acid.

55. The pharmaceutical taxol composition of claim 41, wherein said acid is nitric acid.

56. The pharmaceutical taxol composition of claim 41, wherein said acid is tartaric acid.

57. The pharmaceutical taxol composition of claim 41, wherein said acid is diatrizoic acid.

58. The pharmaceutical taxol composition of claim 41, wherein said acid is glutamic acid.

59. The pharmaceutical taxol composition of claim 41, wherein said acid is lactic acid.

60. The pharmaceutical taxol composition of claim 41, wherein said acid is maleic acid.

61. The pharmaceutical taxol composition of claim 41, wherein said acid is succinic acid.