LIPOSOMES

• US 20030152618A1
• Filed: 03/21/2003
• Published: 08/14/2003
• Est. Priority Date: 10/20/1988
• Status: Abandoned Application

• Current Assignee: PolyMASC Pharmaceuticals PLC (Vaneltix Pharma, Inc.)
• Original Assignee: PolyMASC Pharmaceuticals PLC (Vaneltix Pharma, Inc.)
• Inventors: Fisher, Derek
• Application Number:
  US10/394,317
• Publication Number:
  US 20030152618A1
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 49/1812 liposomes, polymersomes, e.g. immunoliposomes
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911

Abstract

Abstract of Disclosure

Liposomes with covalently bound PEG moieties on the external surface which demonstrate improved serum half-life following intravenous administration are provided.

Claims

1. Liposomes having PEG moieties covalently bound to phospholipids on the external surface, wherein said liposomes are selected from large unilamellar vesicles (LUV'"'"'s), small unilamellar vesicles (SUV'"'"'s) and multilamellar vesicles (MLV'"'"'s).

2. Liposomes according to claim 1, wherein said liposomes comprise a mixture of lipids.

3. Liposomes according to claim 2 wherein the lipid bilayers comprise a 7:

3 to 5;

5 molar ratio of DOPC to DOPE.

4. Liposomes according to claim 2 wherein the lipid bilayers comprise a mixture of dioleylphosphatidylcholine (DOPC) and dioleylphosphatidylethanolamine (DOPE).

5. A pharmaceutical composition comprising an aqueous suspension of liposomes according to claim 1 and a pharmaceutically acceptable carrier or diluent.

6. A process for producing a liposome according to claim 1 comprising treating liposomes with a polyethylene glycol having at least one activating group capable of coupling said polyethylene glycol to said liposome.

7. A process according to claim 6 wherein the reactive derivatave is 2,2,2-trifluoroethane sulphonyl-monomethoxy-polyethylene glycol.

8. Liposomes according to claim 1, obtained by reacting 2,2,2-trifluoroethane sulfonyl-monomethoxy PEG derivatives with liposomes.

9. Liposomes according to claim 1, wherein essentially all said PEG moieties are bound on the external surface of the liposome.

10. Liposomes according to claim 1, wherein said liposomes display an enhanced partition to the PEG-rich (upper) phase of a PEG:

dextran aqueous two phase system in which liposomes not having PEG moieties covalently bound to phospholipids on the external surface separate predominantly to the interface or bottom phase.

11. Liposomes according to claim 1, wherein said liposomes display a decreased adsorption of serum proteins than liposomes not having PEG moieties covalently bound to phospholipids on the external surface.

12. Modified liposomes having a reduced rate of removal from in vivo circulation, characterized in that said liposomes comprise an aqueous interior compartment enclosed by a lipid bilayer comprising phospholipid species having covalently linked PEG moieties, wherein those PEG moieties that are on an exterior surface of the liposomes reduce the rate of removal of the liposomes from in vivo circulation.

13. Liposomes according to claim 12, wherein said liposomes comprise a mixture of lipids.

14. Liposomes according to claim 12, wherein said liposomes display an enhanced partition to the PEG-rich (upper) phase of a PEG:

dextran aqueous two phase system in which liposomes not having covalently linked PEG moieties separate predominately to the interface or bottom phase.

15. Liposomes according to claim 13 wherein the lipid bilayers comprise a mixture of dioleylphosphatidylcholine (DOPC) and dioleylphosphatidylethanolamine (DOPE).

30. The liposomes of claim 12, wherein the phospholipid species having covalently linked PEG moieties comprise phosphatidylethanolamine or phosphatidyl serine.

31. The liposomes of claim 30, wherein PEG moieties are covalently linked to phosphatidylethanolamine.

32. The liposomes of claim 31, wherein PEG moieties covalently linked to phosphatidylethanolamine are asymmetrically disposed to the outer surface of the liposomes.

33. The liposomes of claim 32, wherein essentially all the PEG moieties covalently linked to phosphatidylethanolamine are on the outer surface of the liposomes.

16. A plurality of liposomes each comprising an aqueous compartment contained by a lipid bilayer, the lipid bilayer comprising:

a) phosphatidylcholine; and

b) phosphatidylethanolamine, wherein at least a portion of the phosphatidylethanolamine is covalently linked to PEG moieties, and wherein those PEG moieties that are on an exterior surface of the liposome provide a decreased rate of removal of the liposomes from in vivo circulation.

18. The liposomes of claims 16 or 17, wherein the liposomes show partitioning primarily to the PEG-rich phase of a PEG:

dextran aqueous two phase system.

19. The liposomes of claims 16 or 17, wherein the aqueous compartment further comprises a therapeutic or diagnostic agent.

20. The liposomes of claims 16 or 17, wherein the PEG moieties covalently linked to phosphatidylethanolamine are asymmetrically disposed to the outer surface of the liposomes.

21. The liposomes of claim 20, wherein essentially all the PEG moieties covalently linked to phosphatidylethanolamine are on the outer surface of the liposomes.

22. A method of increasing the circulation half-life of a therapeutic or diagnostic agent comprising encapsulating the therapeutic or diagnostic agent in the aqueous compartment of the liposomes of claims 16 or 17.

23. The liposomes of claims 16 or 17, wherein the covalent linkage of PEG moieties does not affect the permeability barrier of the lipid bilayer.

17. A plurality of liposomes each comprising an aqueous compartment contained by a lipid bilayer, the lipid bilayer comprising:

a) phosphatidylcholine; and

b) phosphatidylethanolamine, wherein at least a portion of the phosphatidylethanolamine is covalently linked to PEG moieties, and wherein those PEG moieties that are on an exterior surface of the liposome are present in an amount sufficient to extend the in vivo circulation life-time of the liposomes.

24. A method of increasing the circulation half-life of a therapeutic or diagnostic agent comprising encapsulating the therapeutic or diagnostic agent in an aqueous compartment of a PEG-bearing liposome, wherein said liposome comprises two or more phospholipids, at least one of which is a phosphatidylethanolamine or phosphatidyl serine covalently attached to PEG.

27. The method of claim 24, wherein the PEG is covalently linked to phosphatidylethanolamine.

28. The method of claim 27, wherein the PEG covalently linked to phosphatidylethanolamine is asymmetrically disposed to the outer surface of the liposome.

29. The method of claim 28, wherein essentially all the PEG covalently linked to phosphatidylethanolamine is on the outer surface of the liposome.

25. A method of increasing the circulation half-life of a therapeutic or diagnostic agent comprising encapsulating the therapeutic or diagnostic agent in an aqueous compartment of a PEG modified liposome, said PEG-modified liposome comprising a PEG moiety covalently linked to an amino group in a head group of at least one phospholipid species forming the liposome.

26. The method of claim 25, wherein the PEG-modified liposome comprises two or more phospholipids, at least one of which is a phosphatidylethanolamine or phosphatidyl serine covalently linked to PEG.