Lipid carrier compositions with protected surface reactive functions

• US 20030147944A1
• Filed: 11/04/2002
• Published: 08/07/2003
• Est. Priority Date: 12/10/1999
• Status: Abandoned Application

• Current Assignee: Celator Pharmaceuticals Inc.
• Original Assignee: Celator Pharmaceuticals Inc.
• Inventors: Mayer, Lawrence D, Bally, Marcel B, Chiu, Gigi
• Application Number:
  US10/149,559
• Publication Number:
  US 20030147944A1
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911

Abstract

The liposomes of the invention have a reactive surface that demonstrates reduced interaction with macromolecules and increased blood circulation time. The reactive surface may comprise phosphatidylserine. The liposomes are protected by the presence of high levels of a hydrophilic polymer conjugated to a lipid. The invention further provides means for adjusting the appropriate ratio of hydrophilic polymer to a reactive lipid by a) determining the reactivity of the lipid; b) determining the time required for the carrier to reach its desired target location; c) determining the affinity of desired interactions with the reactive surface; and d) incorporating in the liposome or lipid carrier the amount of polyethylene glycol required to protect the reactive surface.

Claims

1. A lipid carrier for administration to a warm blooded animal comprising one or more reactive phospholipids and, wherein the carrier has an outer leaflet comprising one or more hydrophilic polymer-lipid conjugates in an amount equivalent to that provided if the lipid carrier is formed in the presence of greater than 10 mol % of the hydrophilic polymer-lipid conjugates relative to total lipid content of the carrier.

2. The lipid carrier of claim 1 wherein the carrier is a liposome.

3. The lipid carrier of claim 1 or 2, comprising from about 0.1 to about 50 mol % relative to total lipid content of the carrier of one or more reactive phospholipids.

4. The lipid carrier of any one of claims 1-3, wherein a reactive phospholipid present in the carrier is a phosphatidylserine (PS).

5. The lipid carrier of claim 4 wherein the carrier comprises from about 10 to about 50 mol % PS.

6. The lipid carrier of claim 4 wherein the carrier comprises from about 10 to about 30 mol % PS.

7. The lipid carrier of any one of claims 1-6, wherein total concentration of the one or more hydrophilic polymer-lipid conjugates in the carrier relative to total lipid content of the carrier is greater than 10 mol %.

8. The lipid carrier of any one of claims 1-7, wherein a hydrophilic polymer-lipid conjugate present in the carrier is a lipid conjugated to a polyalkylether of from about 500 to about 5000 Daltons.

9. The lipid carrier of claim 8 wherein the polyalkylether is polyethylene glycol (PEG).

10. The lipid carrier of claim 9 wherein the PEG has a molecular weight of from about 500 to about 1500 Daltons and the carrier comprises greater than about 15 mol % PEG-lipid.

11. The lipid carrier of claim 10 wherein the PEG has a molecular weight of about 750 to about 1250 Daltons.

12. The lipid carrier of claim 10 wherein the PEG has a molecular weight of about 750 Daltons.

13. The lipid carrier of any one of claims 10-12, wherein the carrier comprises from about 15 to about 20 mol % PEG-lipid.

14. The lipid carrier of claim 13 wherein the PEG has a molecular weight of about 750 Daltons.

15. The lipid carrier of claim 9 wherein the PEG has a molecular weight of from about 1500 to about 5000 Daltons.

16. The lipid carrier of claim 15 wherein the molecular weight is from about 1500 to about 3000 Daltons.

17. The lipid carrier of claim 15 wherein the molecular weight is about 2000 Daltons.

18. The lipid carrier of any one of claims 15-17, wherein the carrier comprises at least about 12 mol % PEG-lipid.

19. The lipid carrier of any one of claims 15-17, wherein the carrier comprises at least about 15 mol % PEG-lipid.

20. The lipid carrier of claim 18 or 19, wherein the carrier comprises less than about 20 mol % PEG-lipid.

21. A lipid carrier according to any one of claims 1-20 wherein an amount of the carrier that would remain in a bloodstream of a warm blooded animal 4 hours after intravenous administration of the carrier is a value that is at least about 5 fold over the amount that would remain in the bloodstream of a reference.

22. The lipid carrier of claim 21 wherein the value is at least about 15 fold.

23. The lipid carrier of claim 21 wherein the value is at least about 25 fold.

24. The lipid carrier of claim 21 wherein the value is at least about 50 fold.

25. The lipid carrier of claim 21 wherein the value is at least about 75 fold.

26. The lipid carrier of claim 21 wherein the value is at least about 100 fold.

27. The lipid carrier of any one of claims 21-26 wherein the reference comprises 5 mol % or less of a hydrophilic polymer-lipid conjugate relative to total lipid content of the reference.

28. The lipid carrier of any one of claims 21-26 wherein the reference does not contain a hydrophilic polymer-lipid conjugate.

29. The lipid carrier of any one of claims 1-28 in which a non-lipid therapeutic agent is encapsulated.

30. The use of a lipid carrier comprising PS according to any one of claims 1-29 as a cytotoxic agent.

31. The use of a lipid carrier comprising PS according to of any one of claims 1-29 in the preparation of a medicament for treatment of cancer.

32. The use of a lipid carrier comprising PS according to any one of claims 1-29 in the preparation of a medicament for inducing thrombogenesis.