Methods and apparatus for making liposomes containing hydrophobic drugs

• US 5,776,486 A
• Filed: 04/12/1996
• Issued: 07/07/1998
• Est. Priority Date: 05/28/1993
• Status: Expired due to Term

• Current Assignee: Aphios Corporation
• Original Assignee: Aphios Corporation
• Inventors: Chu, Ling, Castor, Trevor P.
• Primary Examiner(s): Kishore, Gollamudi S.
• Application Number:
  US08/631,808
• Time in Patent Office: 816 Days
• Field of Search: 424/450, 264/4.1, 264/4.3, 264/4.6, 436/829
• US Class Current: 424/450
• CPC Class Codes: A61K 9/1277 Processes for preparing; Proliposomes

Abstract

The present application features methods and apparatus for making liposomes containing hydrophobic drugs, with critical, supercritical or near critical fluids. The methods and apparatus combine a phospholipid, a drug, and an aqueous phase, or multilamellar vesicles, with a critical, supercritical or near critical fluid. Upon a reduction in pressure, liposomes are formed.

Claims

1. A method of making liposomes comprising:

a) forming a solution or mixture of a phospholipid, one or more hydrophobic drugs and an aqueous phase in a fluid selected from the group consisting of critical, supercritical and near critical fluids; and

,

b) reducing the pressure of the solution or mixture to separate the selected fluid from the phospholipid and the aqueous phase, said phospholipid and aqueous phase forming liposomes containing said drug.

2. The method of claim 1 wherein said drug is selected from the group consisting of taxoids, camptothecins, doxorubicin, michellamine B, vincristine, bryostatin-1, halomon and cisplatin.

3. The method of claim 1 wherein said fluid is selected from the group of compositions capable of forming critical fluids consisting of carbon dioxide, nitrous oxide, halocarbons, propane, ethylene and ethane.

4. The method of claim 1 wherein said mixture or solution is decompressed as the mixture or solution exits a nozzle.

5. The method of claim 4 wherein said nozzle has one or more openings which opening has a diameter ranging from approximately 0.5 to 0.06 millimeters.

6. The method of claim 1 wherein said fluid further contains entrainers.

7. The method of claim 6 wherein said entrainers are selected from the group of compositions consisting of methanol, ethanol and acetone.

8. The method of claim 1 wherein said phospholipids are selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and sphingomyelin.

9. The method of claim 1 wherein said phospholipids are synthetic phospholipids selected from the group consisting of dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, distearoyl phosphatidylglycerol, dipalmitoyl phosphatidylglycerol, dimyristoyl phosphatidylserine, distearoyl phosphatidylserine and dipalmitoyl phosphatidylserine.

10. The method of claim 1 wherein said phospholipids contain cholesterol.

11. The method of claim 1 wherein said liposome has a hydrophobic drug incorporated in its lipid bilayer.

12. The method of claim 2 wherein said taxoid is paclitaxel.

13. The method of claim 2 wherein said camptothecin is camptothecin.

14. A method of making liposomes comprising:

a) forming a solution or mixture of a phospholipid, a drug and a fluid, said fluid selected from the group consisting of critical, supercritical and near critical fluid; and

b) injecting said solution or mixture into an aqueous phase to form liposomes.

15. The method of claim 14 wherein said drug is selected from the group of hydrophobic drugs consisting of taxoids, camptothecins, doxorubicin, michellamine B, vincristine, bryostatin-1, halomon, and cisplatin.

16. The method of claim 14 further comprising the step of decompressing the solution or mixture as said solution or mixture is injected.

17. The method of claim 14 wherein said solution or mixture is injected into said aqueous phase through a nozzle.

18. The method of claim 17 wherein said nozzle has at least one opening having a diameter in the range of approximately 0.5 to 0.06 millimeters.

19. The method of claim 14 wherein said fluid is selected from the group of compositions capable of forming critical fluids consisting of carbon dioxide, nitrous oxide, halocarbons, propane, ethylene and ethane.

20. The method of claim 14 wherein said critical, supercritical or near critical fluid further comprises entrainers.

21. The method of claim 20 wherein said entrainer is selected from the group consisting of methanol, ethanol, and acetone.

22. The method of claim 14 wherein said phospholipids are selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and sphingomyelin.

23. The method of claim 14 wherein said phospholipids are synthetic phospholipids selected from the group consisting of dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, distearoyl phosphatidylglycerol, dipalmitoyl phosphatidylglycerol, dimyristoyl phosphatidylserine, distearoyl phosphatidylserine and dipalmitoyl phosphatidylserine.

24. The method of claim 14 wherein said phospholipids contain cholesterol.

25. The method of claim 14 wherein said liposome has a hydrophobic drug incorporated in its lipid bilayer.

26. The method of claim 15 wherein said taxoid is paclitaxel or cephalomannine.

27. The method of claim 15 wherein said camptothecin is camptothecin.

28. A method of making liposomes comprising:

a) forming a mixture of multiple bilayer liposomes and a fluid selected from the group consisting of critical, supercritical and near critical fluids, said multiple bilayer liposomes containing a hydrophobic drug; and

b) reducing the pressure of the mixture to separate the fluid to form liposomes of a uniform size containing said drug.

29. The method of claim 28 wherein said drug is selected from the group consisting of taxoids, camptothecins, doxorubicin, michellamine B, vincristine, bryostatin-1, halomon, and cisplatin.

30. A method of making liposomes comprising:

a) forming a solution or mixture of a phospholipid, one or more hydrophobic drugs and a near critical fluid, wherein said near critical fluid is at a temperature between the critical temperature and 75% of the critical temperature of the composition of such fluid and at a pressure which is at least 75% of the critical pressure of the composition of such fluid, said fluid selected from the group of carbon dioxide, nitrous oxide, halocarbons, propane, ethylene and ethane; and

,

b) injecting said solution or mixture into an aqueous phase to form liposomes.

31. A method of making liposomes comprising:

a) forming a solution or mixture of a phospholipid, one or more hydrophobic drugs and a near critical fluid, wherein said near critical fluid is at a pressure between the critical pressure and 75% of the critical pressure of the composition of such fluid and at a temperature which is at least 75% of the critical temperature of the composition of such fluid, said fluid selected from the group of carbon dioxide, nitrous oxide, halocarbons, propane, ethylene and ethane; and

,

b) injecting said solution or mixture into an aqueous phase to form liposomes.