Etherlipid-containing multiple lipid liposomes

• US RE39,042 E1
• Filed: 10/11/2001
• Issued: 03/28/2006
• Est. Priority Date: 02/16/1996
• Status: Expired due to Fees

• Current Assignee: Zeneus Pharma Ltd. (Teva Pharmaceutical Industries Limited)
• Original Assignee: The Liposome Co., Inc. (Perrigo Company PLC)
• Inventors: Ahmad, Imran, Janoff, Andrew S., Mayhew, Eric, Bhatia, Suresh K.
• Primary Examiner(s): Kishore, Gollamudi S.
• Application Number:
  US09/976,936
• Time in Patent Office: 1,629 Days
• Field of Search: 424/450, 424/1.21, 424/9.321, 424/9.51, 428/402.2
• US Class Current: 424/450
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: Y10T 428/2984 Microcapsule with fluid core [includes liposome]

Abstract

Described herein are liposomes containing etherlipids of the formula:
as well as a phosphatidylcholine, a sterol, and a headgroup-derivatized lipid. These liposomes are useful in a variety of therapeutic regimens, including the treatment of cancers and inflammatory disorders.

Claims

1. A liposome having a lipid bilayer which comprises:

(a) a phosphatidylcholine;

(b) a sterol;

(c) a headgroup-derivatized lipid comprising a phosphatidylethanolamine linked at the ethanolamine group to a dicarboxylic acid; and

, (d) an etherlipid having the formula;

wherein R₁ is Y₁ Y₂, Y₂ is CH₃ or CO₂H, Y₁ is (CH₂)_n1 (CH═

CH)_n2(CH₂)_n3(CH═

CH)_n4 (CH₂)_n5(CH═

CH)_n6 (CH₂)_n7(CH═

CH)_n8(CH₂)_n9, the sum of n1+2n2+n3+2n4+n5+2n6+n7+2n8+n9 is an integer of from 3 to 23, n1 is zero or an integer of from 1 to 23, n3 is zero or an integer of from 1 to 20, n5 is zero or an integer of from 1 to 17, n7 is zero or an integer of from 1 to 14, n9 is zero or an integer of from 1 to 11, and each of n2, n4, n6 and 8 n8 is independently zero or 1;

wherein Z is oxygen or sulfur and R₂ is CH₃;

wherein R₃ is —

O—

P(O)₂—

O—

CH₂CH₂N(CH₃)₃;

and wherein the phosphatidylethanolamine-dicarboxylic acid comprises from about 5 mole percent to about 20 mole percent of the lipid bilayer and the etherlipid comprises from greater than about 10 mole percent to less than about 30 mole percent of the lipid bilayer.

2. The liposome of claim 1 which is a unilamellar liposome having a diameter of from greater than about 50 nm to less than about 200 nm.

3. The liposome of claim 1, wherein the phosphatidylcholine is an unsaturated or partially unsaturated phosphatidylcholine.

4. The liposome of claim 3, wherein the phosphatidylcholine is dioleoyl phosphatidylcholine.

5. The liposome of claim 1, wherein the sterol is cholesterol.

6. The liposome of claim 1, wherein the headgroup derivatized lipid comprises a phosphatidylethanolamine selected from the group consisting of dipalmitoyl phosphatidylethanolamine, palmitoyloleoyl phosphatidylethanolamine and dioleoyl phosphatidylethanolamine.

7. The liposome of claim 6, wherein the headgroup derivatized lipid comprises dioleoyl phosphatidylethanolamine.

8. The liposome of claim 1, wherein the headgroup-derivatized lipid comprises a dicarboxylic acid selected from the group consisting of glutaric acid, sebacic acid, succinic acid and tartaric acid.

9. The liposome of claim 8, wherein the dicarboxylic acid is glutaric acid.

10. The liposome of claim 1, wherein the headgroup-derivatized lipid comprises dioleoyl phosphatidylethanolamine and glutaric acid.

11. The liposome of claim 1, wherein R₁ is (CH₂)_n1CH₃ and Z is O.

12. The liposome of claim 11, wherein the etherlipid is:

13. The liposome of claim 12, wherein the phosphatidylcholine is dioleoyl phosphatidylethanolamine, the sterol is cholesterol and the headgroup derivatized lipid comprises dioleoyl phosphatidylethanolamine and glutaric acid.

14. The liposome of claim 13, wherein the bilayer comprises about 20 mole percent of the etherlipid, about 10 mole percent of the headgroup-derivatized lipid, about 30 mole percent cholesterol and about 40 mole percent dioleoyl phosphatidylcholine.

15. The liposome of claim 1, comprising an additional bioactive agent.

16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the liposome of claim 1.

17. A liposome having a lipid bilayer which comprises:

(a) a phosphatidylcholine;

(b) a sterol;

(c) a headgroup-derivatized lipid comprising a phosphatidylethanolamine linked at the ethanolamine group to a dicarboxylic acid; and

, (d) an etherlipid having the formula;

wherein R₁ is Y₁ Y₂, Y₂ is CH₃ or CO₂H, Y₁ is (CH₂)_n1(CH═

CH)_n2(CH₂)_n3(CH═

CH)_n4(CH₂)_n5(CH═

CH)_n6(CH₂)_n7(CH═

CH)_n8(CH₂)_n9, the sum of n1+2n2+n3+2n4+n5+2n6+n7+2n8+n9 is an integer of from 3 to 23, n1 is zero or an integer of from 1 to 23, n3 is zero or an integer of from 1 to 20, n5 is zero or an integer of from 1 to 17, n7 is zero or an integer of from 1 to 14, n9 is zero or an integer of from 1 to 11, and each of n2, n4, n6 and n8 is independently zero or 1;

wherein Z is NH₂,C(O)O₂ or HNC(O);

R₂ is CH₃;

R₃ is —

O—

P(O)₂—

O—

CH₂CH₂N(CH₃)₃; and

wherein the phosphatidylethanolamine-dicarboxylic acid comprises from about 5 mole percent to about 20 mole percent of the lipid bilayer and the etherlipid comprises from greater than about 10 mole percent to less than about 30 mole percent of the lipid bilayer.

18. The liposomes of claim 17 which is a unilamellar liposome having a diameter of from greater than about 50 nm to less than about 200 nm.

19. The liposome of claim 17, wherein the phosphatidylcholine is an unsaturated or partially unsaturated phosphatidylcholine.

20. The liposome of claim 19, wherein the phosphatidylcholine is dioleoyl phosphatidylcholine.

21. The liposome of claim 17, wherein the sterol is cholesterol.

22. The liposome of claim 17, wherein the headgroup derivatized lipid comprises a phosphatidylethanolamine selected from the group consisting of dipalmitoyl phosphatidylethanolamine, palmitoyloleoyl phosphatidylethanolamine and dioleoyl phosphatidylethanolamine.

23. The liposome of claim 22, wherein the headgroup derivatized lipid comprises dioleoyl phosphatidylethanolamine.

24. The liposome of claim 17, wherein the headgroup-derivatized lipid comprises a dicarboxylic acid selected from the group consisting of glutaric acid, sebacic acid, succinic acid and tartaric acid.

25. The liposome of claim 24, wherein the dicarboxylic acid is glutaric acid.

26. The liposome of claim 17, wherein the headgroup-derivatized lipid comprises dioleoyl phosphatidylethanolamine and glutaric acid.

27. The liposome of claim 17, wherein R₁ is (CH₂)_n1CH₃ and Z is C(O)O.

28. The liposome of claim 17, wherein R₁ is (CH₂)_n1CH₃ and Z is NH.

29. The liposome of claim 17, wherein R₁ is (CH₂)_n1CH₃ and Z is HNC(O).

30. The liposome of claim 17, comprising an additional bioactive agent.

31. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the liposome of claim 17.