Compositions and methods for stabilizing liposomal drug formulations

• US 20090285878A1
• Filed: 11/04/2005
• Published: 11/19/2009
• Est. Priority Date: 11/05/2004
• Status: Abandoned Application

• Current Assignee: Tekmira Pharmaceuticals Corporation
• Original Assignee: Tekmira Pharmaceuticals Corporation
• Inventors: Mui, Barbara, Madden, Thomas D., Hope, Michael J.
• Application Number:
  US11/667,138
• Publication Number:
  US 20090285878A1
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The present invention is directed to liposomal compositions comprising a camptothecin, which are optimized to reduce camptothecin degradation and/or precipitation of camptothecin degradation products in the external medium. The invention further provides improved methods of formulating liposomal camptothecins, kits comprising liposome-encapsulated camptothecins, and methods of using the same to treat a variety of diseases and disorders, including cancer.

Claims

1. A liposomal camptothecin formulation adapted for increased camptothecin stability, comprising:

(a) a camptothecin encapsulated in a liposome;

(b) a first solution exterior of said liposome wherein said first solution has a pH less than or equal to 4.5; and

(c) a second solution interior of said liposome.

2. The formulation of claim 1, wherein said second solution comprises MnSO₄.

3. The formulation of claim 1, wherein said liposome comprises dihydrosphingomyelin and cholesterol.

4. The formulation of claim 1, wherein said formulation further comprises an anti-oxidant or free radical scavenger.

5. The formulation of claim 1 wherein said formulation further comprises empty liposomes.

6. The formulation of claim 1, wherein said first solution comprises a citrate or tartrate buffer.

7. The formulation of claim 1, wherein said liposome comprises dihydrosphingomyelin and cholesterol, wherein said formulation further comprises an anti-oxidant or free radical scavenger, and wherein said second solution comprises MnSO₄.

16. The formulation of claim 4 or 8, wherein said anti-oxidant or free radical scavenger is ascorbic acid.

17. The formulation of claim 16, wherein the ascorbic acid is present at a concentration in the range of 1 mM to 100 mM.

18. The formulation of claim 17, wherein the concentration of the ascorbic acid is approximately 10 mM.

19. The formulation of claim 4 or 8, wherein said anti-oxidant or free radical scavenger is alpha-tocopherol.

20. The formulation of claim 19, wherein said alpha-tocopherol is present at a concentration in the range of 0.1 to 10 mole percent.

21. The formulation of claim 20, wherein said alpha-tocopherol is present at a concentration in the range of 0.4 to 3 mole percent.

22. The formulation of claim 21, wherein said alpha-tocopherol is present at a concentration of approximately 2 mole percent.

23. The formulation of claim 1 or 8, wherein said camptothecin is topotecan.

24. The formulation of claim 23, wherein said formulation is a unit dosage form of topotecan.

25. The formulation of claim 24, wherein said topotecan is present at a unit dosage form of about 0.01 mg/M²/dose to about 7.5 mg/M²/dose.

33. A pharmaceutical composition adapted for intravenous administration of a liposome-encapsulated camptothecin, wherein said pharmaceutical composition comprises a formulation of claim 1 or 8.

35. The formulation or pharmaceutical composition of claim 1 or 8, wherein the first solution has a reduced oxygen content, as compared to the oxygen content under atmospheric conditions.

63. A method of treating a cancer, comprising administering the pharmaceutical composition of claim 33 to a patient in need thereof, such that said cancer is treated.

8. A liposomal camptothecin formulation adapted for increased camptothecin stability, comprising:

(a) a camptothecin encapsulated in a liposome;

(b) a first solution exterior of said liposome;

(c) a second solution interior of said liposome; and

(d) an anti-oxidant or free radical scavenger.

9. The formulation of claim 8, wherein said first solution has a pH less than or equal to 4.5.

10. The formulation of claim 8, wherein said second solution comprises MnSO₄.

11. The formulation of claim 8, wherein said liposome comprises dihydrosphingomyelin and cholesterol.

14. The formulation of claim 8, wherein said formulation further comprises empty liposomes.

15. The formulation of claim 8, wherein said first solution comprises a citrate or tartrate buffer.

12. (canceled)

13. (canceled)

26-32. -32. (canceled)

34. (canceled)

36. A method for reducing the accumulation of camptothecin degradation products in a solution containing a camptothecin encapsulated in a liposome, comprising

formulating a camptothecin encapsulated in a liposome with a solution exterior of the liposome with a pH less than or equal to 4.5, and a solution interior of said liposome having the pH of the solution exterior of said liposomes at or below 4.5.

37. The method of claim 36, wherein said interior solution comprises MnSO₄.

38. The method of claim 36, wherein said liposome comprises dihydrosphingomyelin and cholesterol.

39. The method of claim 36, wherein said solution or liposome further comprises an anti-oxidant.

40. The method of claim 36, further comprising empty liposomes in the solution.

41-47. -47. (canceled)

48. A kit comprising a liposome-encapsulated camptothecin for administration to a patient in need thereof, comprising:

(a) a vial comprising a solution containing a camptothecin encapsulated in a liposome, wherein said solution exterior of said liposome has a pH less than or equal to 4.5; and

(b) instructions for preparing and/or administering the liposome encapsulated camptothecin to a patient.

49. The kit of claim 48, wherein the interior of said liposome comprises MnSO₄.

50. The kit of claim 48, wherein said solution or liposome comprises an antioxidant.

51. The kit of claim 48, wherein the solution containing a camptothecin encapsulated in a liposome further contains empty liposomes.

52-62. -62. (canceled)