Platinum Aggregates and Process for Producing the Same

• US 20080187578A1
• Filed: 02/07/2008
• Published: 08/07/2008
• Est. Priority Date: 08/02/2002
• Status: Active Grant

• Current Assignee: Insmed Incorporated
• Original Assignee: Transave Inc. (Insmed Incorporated)
• Inventors: Malinin, Vladimir, Boni, Lawrence T., Miller, Brian S., Wu, Fangjun, Lee, Jin K.
• Granted Patent: US 9,186,322 B2
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 31/28 Compounds containing heavy metals
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 47/544 Phospholipids
• CPC Class Codes: A61K 47/554 the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/1277 Processes for preparing; Proliposomes
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

One aspect of the disclosure relates to a new form of lipid-complexed active platinum compound, which allows for high concentrations of platinum compound in the composition. For example, the concentration of cisplatin in the composition is higher at room temperature, e.g., about greater than 1.2 mg/mL, compared to 1 mg/mL in aqueous solution. In one embodiment, the present invention is directed to a composition comprising a lipid-complexed active platinum compound, wherein the complex has a lipid to drug (L/D) ratio of less than about 1 by weight, e.g. about 0.10 to 1, wherein the lipid-complexed active platinum compound comprises at least one lipid and at least one active platinum compound. In other embodiments, wherein lipid-complexed active platinum compound has an average volume-weighted diameter of about 0.5 to about 20 microns. In still other embodiments, the composition further comprises a liposome. The liposome may comprise at least one lipid, and may further comprise at least one active platinum compound. The disclosure also relates to a pharmaceutical formulation comprising a lipid complexed active platinum compound and a pharmaceutically acceptable carrier or diluent. The pharmaceutical formulation may be formulated for inhalation or injection.

Claims

1. A composition comprising a lipid-complexed active platinum compound, wherein the complex has a lipid to drug ratio less than about 1 by weight, wherein the lipid-complexed active platinum compound comprises at least one lipid and at least one active platinum compound.

2. The composition of claim 1, wherein the lipid to drug ratio is about 0.10 to about 1 by weight.

3. The composition of claim 2, wherein the lipid to drug ratio is about 0.10 to about 0.50 by weight.

4. The composition of claim 3, wherein the lipid to drug ratio is about 0.15 to about 0.45 by weight.

5. The composition of claim 4, wherein the lipid to drug ratio is about 0.20 to about 0.40 by weight.

6. The composition of claim 5, wherein the lipid to drug ratio is about 0.2 by weight.

7. The composition of claim 1, wherein lipid-complexed active platinum compound has an average volume-weighted diameter of about 0.5 to about 20 microns.

8. The composition of claim 7, wherein the average volume-weighted diameter is about 1 to about 15 microns.

9. The composition of claim 8, wherein the average volume-weighted diameter is about 2 to 10 microns.

10. The composition of claim 1, wherein the concentration of the active platinum compound is greater than about 1.2 mg/mL.

11. The composition of claim 10, wherein the active platinum compound has a concentration of about 1.2 to about 20 mg/mL.

12. The composition of claim 11, wherein the platinum compound has a concentration of about 1.5 to about 5 mg/mL.

13. The composition of claim 1, further comprising a liposome.

14. The composition of claim 13, wherein the liposome comprises an active platinum compound.

15. The composition of claim 14, wherein the lipid-complexed active platinum compound contains about 70 to about 100% of the total active platinum compound in the composition.

16. The composition of claim 15, wherein in the lipid-complexed active platinum compound contains about 75 to about 99% of the total active platinum compound.

17. The composition of claim 16, wherein the lipid-complexed active platinum compound contains about 80 to about 90% of the total active platinum compound.

18. The composition of claim 14, wherein the liposome contains about 0 to about 30% of the total active platinum compound in the composition.

19. The composition of claim 18, wherein the liposome contains about 0.5 to about 25% of the total active platinum compound.

20. The composition of claim 19, wherein the liposome contains about 1 to about 20% of the total platinum compound.

21. The composition of claim 13, wherein the lipid-complexed active platinum compound contains about 0.1 to about 5% of the total lipid in the composition,

22. The composition of claim 21, wherein the lipid-complexed active platinum compound contains about 0.25 to about 3% of the total lipid.

23. The composition of claim 13, wherein the liposome contains about 75 to about 99.5% of the total lipid in the composition.

24. The composition of claim 23, wherein the liposome contains about 80 to about 95% of the total lipid

25. The composition of claim 13, wherein the lipid-complexed active platinum compound has a lipid to platinum compound ratio of about 0.10 to about 0.50.

26. The composition of claim 14, wherein the liposome has a lipid to active platinum compound ratio of about 100:

1 to about 400;

1 by weight.

27. The composition of claim 26, wherein the lipid to active platinum compound ratio is about 200:

1 to 400;

1 by weight.

28. The composition of claim 13, wherein the active platinum compound has a concentration of greater than about 1.2 mg/mL.

29. The composition of claim 28, wherein the active platinum compound has a concentration of about 1.2 to about 20 mg/mL.

30. The composition of claim 24, wherein the platinum compound has a concentration of about 1.2 to about 10 mg/mL.

31. The composition of claim 1, wherein the active platinum compound is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, iproplatin, tetraplatin, transplatin, JM118 (cis-amminedichloro(cyclohexylamine)platinum(II)), JM149 (cis-amminedichloro(cyclohexylamine)-trans-dihydroxoplatinum(IV)), JM216 (bis-acetato-cis-amminedichloro(cyclohexylamine)platinum(IV)) and JM335 (trans-amminedichloro(cyclohexylamine)dihydroxoplatinum(IV)).

32. The composition of claim 31, wherein the active platinum compound is selected from the group consisting of cisplatin, transplatin, oxaliplatin or carboplatin.

33. The composition of claim 32, wherein the active platinum compound is cisplatin.

34. The composition of claim 1, wherein the lipid-complexed active platinum compound comprises a phosphatidyl choline.

35. The composition of claim 34, wherein the phosphatidyl choline is DPPC.

36. The composition of claim 35, wherein the lipid-complexed active platinum compound further comprises a sterol.

37. The composition of claim 30, wherein the sterol is cholesterol.

38. The composition of claim 1, wherein the lipid-complexed active platinum compound does not comprise a negatively charged phospholipid.

39. The composition of claim 1, wherein the lipid complexed active platinum compound comprises DPPC and cholesterol in a ratio of about 1:

1 to about 5;

1 by weight.

40. The composition of claim 39, wherein the lipid complexed active platinum compound comprises DPPC and cholesterol in a ratio of about 2:

1 to about 4;

1 by weight.

41. The composition of claim 34, the lipid complexed active platinum compound comprises DPPC and cholesterol in a ratio of about 2.25:

1 by weight.

42. A pharmaceutical formulation comprising the composition of claim 1 and a pharmaceutically acceptable carrier or diluent.

43. The pharmaceutical formulation of claim 42, adapted for inhalation by a patient.

44. A pharmaceutical formulation of claim 43, adapted for injection into a patient.