Liposomes containing active agents aggregated with lipid surfactants

• US 5,882,679 A
• Filed: 08/05/1998
• Issued: 03/16/1999
• Est. Priority Date: 02/06/1997
• Status: Expired due to Term

• Current Assignee: Duke University
• Original Assignee: Duke University
• Inventors: Needham, David
• Primary Examiner(s): Kishore, Gollamudi S.
• Application Number:
  US09/129,654
• Time in Patent Office: 223 Days
• Field of Search: 424/450, 428/402.2, 428/1.21, 428/9.321, 428/9.51, 935/54, 436/829
• US Class Current: 424/450
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911

Abstract

Liposomes contain active agents which are aggregated with a lipid surfactant. The composition of the liposome membrane stabilizes the membrane against the disruptive effects of the active agent-surfactant aggregate contained therein.

Claims

1. A liposome containing an active agent,

said liposome having a lipid bilayer membrane comprising vesicle-forming lipid and from about 1 mole percent to about 22 mole percent vesicle-forming lipid derivatized with hydrophilic polymer,

said active agent aggregated with lipid surfactant to form micelles, said micelles entrapped within the interior space of said liposome,

wherein said polymer-derivatized lipid inhibits fusion of the liposome membrane with said micelles, compared to fusion that would occur in the absence of polymer-derivatized lipid.

2. A liposome according to claim 1, wherein said lipid surfactant aggregated with said active agent is a lysolipid.

3. A liposome according to claim 1, wherein said lipid surfactant aggregated with said active agent is lysophosphatidylcholine.

4. A liposome according to claim 1, wherein said hydrophilic polymer is selected from the group consisting of polyethylene glycol, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, and polyvinyl alcohol.

5. A liposome according to claim 1, wherein the liposome membrane contains said polymer-derivatized lipid in a saturating amount.

6. A liposome according to claim 1, wherein said hydrophilic polymer is polyethylene glycol having a molecular weight of between about 300 daltons and about 10,000 daltons.

7. A liposome according to claim 1, wherein said hydrophilic polymer is polyethylene glycol having a molecular weight of between about 300 daltons and about 1,000 daltons.

8. A liposome according to claim 1, wherein said hydrophilic polymer is polyethylene glycol having a molecular weight of about 750 daltons.

9. A liposome according to claim 1, wherein said hydrophilic polymer has a cloud temperature within physiologic range.

10. A liposome according to claim 1, wherein said active agent is a pharmacologically active agent, a diagnostic agent, or a nutritional agent.

11. A liposome according to claim 1, wherein said active agent is a pharmacologically active agent selected from the group consisting of antineoplastic agents, anti-inflammatory agents, immunosuppressive agents, antibiotic agents, and anti-infective agents.

12. A liposome according to claim 1, wherein said active agent is selected from the group consisting of doxorubicin, epirubicin, daunorubicin, vincristine, vinblastine, etoposide, ellipticine, camptothecin, paclitaxel, docetaxol, cisplatin, prednisone, methyl-prednisolone, and ibuprofen.

13. A composition containing a plurality of liposomes according to claim 1.

14. A liposome containing an active agent,

said liposome having a lipid bilayer membrane comprising vesicle-forming lipid and from about 1 mole percent to about 22 mole percent vesicle-forming lipid derivatized with polyethylene glycol,

said active agent aggregated with lipid surfactant to form micelles, said micelles entrapped within the interior space of said liposome,

wherein said polyethyleneglycol-derivatized lipid inhibits fusion of the liposome membrane with said micelles, compared to fusion that would occur in the absence of polyethyleneglycol-derivatized lipid.

15. A liposome according to claim 14, wherein said polyethylene glycol has a molecular weight of between about 300 daltons and about 10,000 daltons.

16. A liposome according to claim 14, wherein said polyethylene glycol has a molecular weight of about 750 daltons.

17. A liposome according to claim 14 wherein said active agent is a pharmacologically active agent, a diagnostic agent, or a nutritional agent.

18. A liposome according to claim 14, wherein said active agent is a pharmacologically active agent selected from the group consisting of antineoplastic agents, anti-inflammatory agents, immunosuppressive agents, antibiotic agents, and anti-infective agents.

19. A liposome according to claim 14, wherein said active agent is selected from the group consisting of doxorubicin, epirubicin, daunorubicin, vincristine, vinblastine, etoposide, ellipticine, camptothecin, paclitaxel, docetaxol, cisplatin, prednisone, methyl-prednisolone, camptothecin and ibuprofen.

20. A composition containing a plurality of liposomes according to claim 14.

21. A liposome having a lipid bilayer membrane comprising a vesicle-forming lipid and from 1 mole percent to 22 mole percent vesicle-forming lipid derivatized with polyethylene glycol, said polyethylene glycol having a molecular weight of about 750 daltons, and containing a micellar preparation of paclitaxel entrapped within the interior liposomal space.

22. A method for preparing a liposome comprising:

(a) preparing a lipid film containing vesicle-forming lipid and vesicle-forming lipid derivatized with hydrophilic polymer;

b) obtaining a micellar preparation of an active agent aggregated with lipid surfactant; and

c) hydrating said lipid film with said micellar preparation of active agent, to produce a liposome having a lipid bilayer membrane comprising vesicle-forming lipids and from about 1 mole percent to about 22 mole percent vesicle-forming lipids derivatized with a hydrophilic polymer.

23. A method according to claim 22, wherein said hydrophilic polymer is selected from the group consisting of polyethylene glycol, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, and polyvinyl alcohol.

24. A method according to claim 22, wherein the liposome membrane contains said polymer-derivatized lipid in a saturating amount.

25. A method according to claim 22, wherein said hydrophilic polymer is polyethylene glycol having a molecular weight of between about 300 daltons and about 10,000 daltons.

26. A method according to claim 22, wherein said hydrophilic polymer is polyethylene glycol having a molecular weight of between about 300 daltons and about 1,000 daltons.

27. A method according to claim 22, wherein said hydrophilic polymer is polyethylene glycol having a molecular weight of about 750 daltons.

28. A method according to claim 22, wherein said hydrophilic polymer has a cloud temperature within physiologic range.

29. A method according to claim 22, wherein said active agent is a pharmacologically active agent, a diagnostic agent, or a nutritional agent.

30. A method according to claim 22, wherein said active agent is a pharmacologically active agent selected from the group consisting of antineoplastic agents, anti-inflammatory agents, immunosuppressive agents, antibiotic agents, and anti-infective agents.

31. A method according to claim 22, wherein said active agent is selected from the group consisting of doxorubicin, epirubicin, daunorubicin, vincristine, vinblastine, etoposide, ellipticine, camptothecin, paclitaxel, docetaxol, cisplatin, prednisone, methyl-prednisolone, and ibuprofen.