Liposome compositions

• US 7,829,113 B2
• Filed: 03/08/2006
• Issued: 11/09/2010
• Est. Priority Date: 03/10/2005
• Status: Expired due to Fees

• Current Assignee: Mebiopharm Co., Ltd.
• Original Assignee: Mebiopharm Co., Ltd.
• Inventors: Okada, Kazushi, Ibuki, Tadayuki, Fujisawa, Tadashi, Kim, Donghyun
• Primary Examiner(s): HILL, KEVIN KAI
• Application Number:
  US11/371,586
• Publication Number:
  US 20060222696A1
• Time in Patent Office: 1,707 Days
• Field of Search: 424/450
• US Class Current: 424/450
• CPC Class Codes: A61K 31/282 Platinum compounds
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present disclosure provides lipid-containing compositions, including targeted liposomes encapsulating drug, and pharmaceutical formulations thereof, as well as methods for the making and using the lipid-containing compositions, including the use of the targeted liposomes in the treatment of cancer and other diseases.

Claims

1. A targeted liposome comprising one or more phosphatidylcholines, an N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, a targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, an encapsulated drug, and at least one additional lipid, which is cholesterol,

wherein the mol % of the phosphatidylcholines is 40-60 mol %, the mol % of the cholesterol is 35-55 mol %, and the mol % of the total of the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine plus targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is 2-8 mol %, where the total mol % of the phosphatidylcholines, the cholesterol, and the derivatized phosphatidylethanolamines is 100%

wherein the targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine comprises transferrin linked to a second N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine; and

wherein

the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is represented by Formula 1,

2. The targeted liposome of claim 1, wherein the targeted liposome contains from about 10 μ

g transferrin/mg lipid to about 25 μ

g transferrin/mg lipid.

3. The targeted liposome of claim 1, wherein the total mol % of N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine and targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is 2-6 mol % of total lipid content.

4. The targeted liposome of claim 1, wherein the phosphatidylcholine includes a moiety of a saturated fatty acid.

5. The targeted liposome of claim 1, wherein the one or more phosphatidylcholines is DMPC, DSPC, POPC or DPPC.

6. The targeted liposome of claim 1, wherein the liposome comprises DMPC.

7. The targeted liposome according to claim 1, wherein the transferrin is in a holo-form but not in an apo-form.

8. The targeted liposome according to claim 1, wherein the mean diameter of the liposome is from about 9 nm to about 250 nm.

9. The targeted liposome of claim 1, wherein R¹, R², R⁵ and R⁶ are oleoyl or stearoyl, and m and p are 3.

10. The targeted liposome of claim 9, wherein the drug is an anticancer agent.

11. The targeted liposome of claim 9, wherein the one or more phosphatidylcholines is DMPC or DSPC.

12. The targeted liposome of claim 9, wherein R¹, R², R⁵ and R⁶ are oleoyl.

13. The targeted liposome of claim 1, wherein m and p are each, independently, an integer from 2 to 4.

14. The targeted liposome of claim 1, wherein m and p are equal and are an integer from 2 to 4.

15. The targeted liposome of claim 13, wherein m and p are equal and are 3.

16. The targeted liposome of claim 1, wherein R¹, R², R⁵ and R⁶ are oleoyl or stearoyl.

17. The targeted liposome of claim 1, wherein R¹, R², R⁵ and R⁶ are the same.

18. The targeted liposome of claim 1, wherein the drug is oxaliplatin.

19. The targeted liposome according to claim 1, wherein the drug is an anticancer agent.

20. The targeted liposome according to claim 1, wherein the drug is a cytotoxic drug.

21. The targeted liposome according to claim 1, wherein the drug is a topoisomerase I inhibitor.

22. The targeted liposome according to claim 21, wherein the topoisomerase I inhibitor is topotecan or irinotecan.

23. The targeted liposome according to claim 1, wherein the drug is a vinca alkaloid.

24. The targeted liposome according to claim 23, wherein the vinca alkaloid is vincristine, vinblastine, vinleurosine, vinrodisine, vinorelbine or vindesine.

25. The targeted liposome according to claim 1, wherein the drug is a nucleic acid.

26. The targeted liposome according to claim 25, wherein the nucleic acid is an antisense oligonucleotide or a ribozyme.

27. The targeted liposome according to claim 1, wherein the drug is a platinum compound.

28. The targeted liposome according to claim 17, wherein the platinum compound is biplatin, cisplatin, carboplatin, ormaplatin, oxaliplatin, zeniplatin, enloplatin, lobaplatin or spiroplatin.

29. The targeted liposome according to claim 28, wherein the platinum compound is oxaliplatin.

30. The targeted liposome according to claim 29, wherein R¹, R², R⁵ and R⁶ are oleoyl, m and p are 3, and the one or more phosphatidylcholines is DMPC.

31. The targeted liposome of claim 30, wherein the targeted liposome contains from about 10 μ

g transferrin/mg lipid to about 25 μ

g transferrin/mg lipid.

32. The targeted liposome of claim 30, wherein the total mol % of N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine and targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is 2-6 mol % of total lipid content.

33. The targeted liposome according to claim 1, wherein the drug is an alkylating agent.

34. The targeted liposome according to claim 1, wherein the drug is a taxane.

35. The targeted liposome according to claim 1, wherein the drug is a metabolic antagonist.

36. The targeted liposome according to claim 1, wherein the drug is an antitumour antibiotic.

37. The targeted liposome according to claim 1, wherein the drug is a hormone therapy drug.

38. The targeted liposome according to claim 1, wherein the drug is a molecular target drug.

39. The targeted liposome according to claim 29, wherein the oxaliplatin is dissolved in an aqueous solution of a sugar selected from the group consisting of trehalose, maltose, sucrose, mannose, lactose, mannitol, glycerol and dextrose.

40. The targeted liposome of claim 39, wherein the sugar is at a concentration of about 300 mM sugar.

41. The targeted liposome of claim 39, wherein the concentration of oxaliplatin is from about 0.1 mg/ml to about 25 mg/ml within the liposome.

42. The targeted liposome of claim 29, wherein the transferrin is in a holo-form.

43. The targeted liposome claim 1, wherein the liposome does not comprise a cationic lipid.

44. The targeted liposome of claim 1, wherein the liposome does not comprise an anionic lipid.

48. A pharmaceutical formulation comprising a targeted liposome according to claim 1 and one or more pharmaceutically acceptable carriers, excipients, diluents, stabilizers, or preservatives.

45. A targeted liposome comprising one or more phosphatidylcholines, an N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, a targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, an encapsulated drug, and, at least one additional lipid which is cholesterol,

wherein the mol % of the phosphatidylcholines is 40-60 mol %, the mol % of the cholesterol is 35-55 mol %, and the mol % of the total of the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine plus targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is 2-8 mol %, where the total mol % of the phosphatidylcholines, the cholesterol, and the derivatized phosphatidylethanolamines is 100%

wherein the targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine comprises a transferrin linked to a second N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine; and

wherein

the N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is represented by Formula 1,

46. The targeted liposome of claim 45, wherein the targeted liposome contains from about 10 μ

g transferrin/mg lipid to about 25 μ

g transferrin/mg lipid.

47. The targeted liposome of claim 45, wherein the total mol % of N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine and targeting factor-modified N-(ω

)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is from about 2 to about 6 mol % of total lipid content.