Temperature-sensitive liposomal formulation

• US 6,200,598 B1
• Filed: 06/18/1998
• Issued: 03/13/2001
• Est. Priority Date: 06/18/1998
• Status: Expired due to Term

• Current Assignee: Duke University
• Original Assignee: Duke University
• Inventors: Needham, David
• Primary Examiner(s): Kishore, Gollamudi S.
• Application Number:
  US09/099,668
• Time in Patent Office: 999 Days
• Field of Search: 424/450, 424/1.21, 424/9.321, 424/9.51, 424/94.3, 935/54, 436/829
• US Class Current: 424/450
• CPC Class Codes: A61K 9/127 Liposomes
• 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: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection

Abstract

Temperature sensitive liposomes containing active agents are described. The liposomes comprise phospholipids and a surface active agent, such as a lysolipid, that increases the amount of active agent released by the liposome at the phase transition temperature of the liposome. Such liposomes are useful in methods of administering active agents using mild hyperthermic conditions.

Claims

1. A liposome containing an active agent entrapped within the liposome interior space, said liposome having a gel-phase lipid bilayer membrane comprising phospholipid which is dipalmitoylphosphatidylcholine (DPPC) and lysolipid which is monopalmitoylphosphatidylcholine (MPPC), wherein phospholipid and lysolipid are contained in the bilayer membrane in a ratio of from 99:

10 to 80;

20 by molar weight and wherein phospholipids are the primary lipid source for the lipid bilayer membrane and wherein lysolipid is contained in the bilayer membrane in an amount sufficient to increase the percentage of active agent released at the phase transition temperature compared to that which would occur in the absence of said lysolipid.

2. A liposome according to claim 1 having a diameter of from about 50 nanometers to about 400 nanometers.

3. A liposome according to claim 1, wherein the liposome bilayer further comprises phospholipid derivatized with a hydrophilic polymer.

4. A liposome according to claim 3, 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 said active agent is a pharmacologically active agent, a flavor agent, a diagnostic agent, or a nutritional agent.

6. 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.

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

8. A liposome according to claim 1, wherein said active agent is paclitaxel.

9. A liposome according to claim 1, wherein said active agent is camptothecin.

10. A liposome containing an active agent entrapped within the liposome interior space and having a gel-phase lipid bilayer membrane comprising a phospholipid which is dipalmitoylphosphatidylcholine (DPPC) and lysolipid which is monopalmitoylphosphatidylcholine (MPPC), wherein phospholipids are the primary lipid source for the lipid bilayer membrane, and wherein phospholipid and lysolipid are contained in the bilayer membrane in a ratio of from 90:

10 to 80;

20 by molar weight.

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

12. A liposome according to claim 10, 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.

13. A liposome according to claim 10, wherein said active agent is selected from the group consisting of methotrexate, doxorubicin, epirubicin, daunorubicin, vincristine, vinblastine, etoposide, ellipticine, camptothecin, paclitaxel, docetaxol, cisplatin, prednisone, methyl-prednisone, and ibuprofen.

14. A liposome according to claim 10, wherein said active agent is paclitaxel.

15. A liposome according to claim 10, wherein said active agent is camptothecin.

16. A method of administering an active agent to a preselected hyperthermic target site in a subject, the improvement comprising:

entrapping said active agent in the aqueous interior of a liposome, said liposome having a gel-phase lipid bilayer membrane comprising phospholipid which is dipalmitoylphosphatidylcholine (DPPC) and lysolipid which is monopalmitoylphosphatidylcholine (MPPC), wherein phospholipids are the primary lipid source for the lipid bilayer membrane, and wherein the aqueous interior of the liposome further comprises lysolipid in an equilibrating amount to the lysolipid contained in the lipid bilayer, and wherein phospholipid and lysolipid are contained in the bilayer membrane in a ratio of from 90;

10 to 80;

20 by molar weight.

17. A method according to claim 16, wherein said active agent is also entrapped within the lipid bilayer membrane.

18. A method according to claim 16, wherein said liposome bilayer further comprises phospholipid derivatized with a hydrophilic polymer.

19. A method according to claim 18, 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.

20. A method according to claim 16, wherein said active agent is a pharmacologically active agent, a diagnostic agent, or a nutritional agent.

21. A method according to claim 16, 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.

22. A method according to claim 16, wherein said active agent is selected from the group consisting of methotrexate, doxorubicin, epirubicin, daunorubicin, vincristine, vinblastine, etoposide, ellipticine, camptothecin, paclitaxel, docetaxol, cisplatin, prednisone, methyl-prednisone, and ibuprofen.

23. A method according to claim 16, wherein said active agent is paclitaxel.

24. A liposome according to claim 16, wherein said active agent is camptothecin.