Etherlipid containing multiple lipid liposomes

• US 5,942,246 A
• Filed: 02/02/1998
• Issued: 08/24/1999
• Est. Priority Date: 02/16/1996
• Status: Expired due to Fees

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• 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:
  US09/017,366
• Time in Patent Office: 568 Days
• Field of Search: 424/450, 424/1.21, 424/9.321, 424/9.51, 424/417, 428/402.2, 436/829
• US Class Current: 424/450
• CPC Class Codes: A61K 31/685 one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
• 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: 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

Liposomes are provided which contain etherlipids having the formula: ##STR1## as well as an unsaturated or partially unsaturated phospholipid, a sterol, and a phosphatidylethanolamine-based 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) an unsaturated or partially unsaturated phospholipid;

(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;

##STR5## wherein;

R1 is Y₁ Y₂ ;

Y₂ is CH₃ or CO₂ H;

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 is independently zero or 1;

Z is oxygen or sulfur;

R₂ is an alkyl group or a halogen-substituted alkyl group having the formula (C(X₁)_n10 (X₂)_n11)_n12 CX₃ X₄ X₅ ;

each of X₁, X₂, X₃, X₄ and X₅ is independently H or a halogen atom;

each of n10 and n11 is independently equal to zero, 1 or 2;

n12 is zero or an integer of from 1 to 23;

when n12 is not equal to zero, the sum of n10+n11 is equal to 2; and

,

the headgroup-derivatized lipid 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 phospholipid is a phosphatidylethanolamine or a phosphatidylcholine.

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

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

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

7. 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.

8. The liposome of claim 7, wherein the phosphatidylethanolamine is dioleoyl phosphatidylethanolamine.

9. 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.

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

11. The liposome of claim 1, wherein the headgroup-derivatized lipid comprises dioleoyl phosphatidylethanolamine linked to glutaric acid.

12. The liposome of claim 1, wherein Y₂ is CH₃.

13. The liposome of claim 1, wherein Y₁ is (CH₂)_n1.

14. The liposome of claim 13, wherein Y₁ is (CH₂)₁₇.

15. The liposome of claim 1, wherein Z is O.

16. The liposome of claim 1, wherein R₂ is selected from the group consisting of CH₃, CH₂ F, CHF₂, CF₃, CH₂ CH₃, CH₂ CF₃ and CF₂ CF₃.

17. The liposome of claim 16, wherein R₂ is CH₃.

18. The liposome of claim 1, wherein Y₁ is (CH₂)₁₇, Y₂ is CH₃, Z is O, R₂ is CH₃ and the etherlipid has the formula:

##STR6##

19. The liposome of claim 18, wherein the phosphatidylcholine is dioleoyl phosphatidylcholine, the sterol is cholesterol, and the headgroup-derivatized lipid comprises dioleoyl phosphatidylethanolamine linked to glutaric acid.

20. The liposome of claim 19, wherein the dioleoyl phosphatidylcholine comprises about 40 mole %, cholesterol comprises about 30 mole %, dioleoyl phosphatidylcholine comprises about 10 mole % and the etherlipid comprises about 20 mole % of the bilayer'"'"'s lipid component.

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

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