Pharmaceutical compositions containing interdigitation-fusion liposomes and gels

• US 6,086,851 A
• Filed: 06/24/1997
• Issued: 07/11/2000
• Est. Priority Date: 01/12/1990
• Status: Expired due to Term

• Current Assignee: Transave Inc. (Insmed Incorporated)
• Original Assignee: The Liposome Co., Inc. (Perrigo Company PLC)
• Inventors: Perkins, Walter R., Davis, Thomas S., Minchey, Sharma R., Boni, Lawrence T., Ahl, Patrick L., Janoff, Andrew S., Swenson, Christine E.
• Primary Examiner(s): Dees, Jose' G.
• Assistant Examiner(s): Hartley, Michael G.
• Application Number:
  US08/881,651
• Time in Patent Office: 1,113 Days
• Field of Search: 424/9.4, 424/9.45, 424/450, 424/812, 428/402.2, 428/402.24, 264/4, 264/4.1, 264/4.3, 264/4.6, 264/4.32, 427/2.14, 427/213.3, 427/213.31, 427/213.32, 427/213.33, 436/829
• US Class Current: 424/9.4
• CPC Class Codes: A61K 9/1277 Processes for preparing; Proliposomes
• CPC Class Codes: A61L 2/0011 using physical methods
• CPC Class Codes: Y10S 436/829 Liposomes, e.g. encapsulation
• CPC Class Codes: Y10T 428/2984 Microcapsule with fluid core [includes liposome]
• CPC Class Codes: Y10T 428/2989 Microcapsule with solid core [includes liposome]

Abstract

This invention provides a composition containing a sized liposome comprising a lipid and an inducer; the sized liposome has a diameter of at most about 1 micron and the inducer is present in an amount effective to induce interdigitation-fusion of the sized liposome. Also provided herein are interdigitation-fusion liposomes and gels, and methods of making the same.

Claims

1. An interdigitation-fusion liposome prepared by a method which comprises the steps of:

(a) preparing sized liposomes having an average diameter of less than about 0.40 microns and comprising a symmetrical saturated phospholipid;

(b) combining the sized liposomes with an amount of an inducer effective to induce fusion of the sized liposomes and interdigitation of the saturated phospholipid at a temperature and for a period of time effective to induce fusion of the sized liposomes and interdigitation of the saturated phospholipid, so as to form an interdigitation-fusion gel from the sized liposomes; and

,

(c) incubating the interdigitation-fusion gel at a temperature above the transition temperature of the saturated phospholipid in the gel for a period of time effective to form an interdigitation-fusion liposome from the gel.

2. The interdigitation-fusion liposome of claim 1, wherein the sized liposomes have an average diameter of no greater than about 0.05 microns.

3. The interdigitation-fusion liposome of claim 2, wherein the sized liposomes have an average diameter of about 0.025 microns.

4. The interdigitation-fusion liposome of claim 1, wherein the symmetrical saturated phospholipid is selected from the group consisting of dimyristoyl phosphatidylcholine, distearoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, dimyristoyl phosphatidylserine, dipalmitoyl phosphatidylserine, distearoyl phosphatidylserine, dimyristoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, distearoyl phosphatidylethanolamine, dimyristoyl phosphatidic acid, distearoyl phosphatidic acid, dipalmitoyl phosphatidic acid, dimyristoyl phosphatidylinositol, distearoyl phosphatidylinositol, dipalmitoyl phosphatidylinositol, hydrogenated soy phosphatidylcholine, dipalmitoyl phosphatidylglycerol, distearoyl phosphatidylglycerol and dimyristoyl phosphatidylglycerol.

5. The interdigitation-fusion liposome of claim 1, further comprising a bioactive agent.

6. The interdigitation-fusion liposome of claim 5, wherein the bioactive agent is an iodinated radiocontrast agent.

7. The interdigitation-fusion liposome of claim 6, wherein the weight ratio of iodine in the iodinated radiocontrast agent to the saturated phospholipid in the interdigitation-fusion liposome is at least about 4:

1 (g/g).

8. The interdigitation-fusion liposome of claim 7, wherein the weight ratio of iodine in the iodinated radiocontrast agent to the saturated phospholipid in the interdigitation-fusion liposome is at least about 8:

1 (g/g).

9. The interdigitation-fusion liposome of claim 1, wherein the incubation is for a period of time of from about 1 minute to about 1 hour.

10. The interdigitation-fusion liposome of claim 1, wherein the inducer is selected from the group consisting of short-chain alcohols, polyols, chaotropic salts and aqueous buffers.

11. The interdigitation-fusion liposome of claim 10, wherein the inducer is the short-chain alcohol ethanol.

12. The interdigitation-fusion liposome of claim 11, wherein the amount of ethanol is an amount equal to about 5% of the weight of the saturated phospholipid in the sized liposomes to about 20% of the weight of the saturated phospholipid.

13. The interdigitation-fusion liposome of claim 12, wherein the amount of ethanol is equal to about 14% of the weight of the saturated phospholipid in the sized liposomes.

14. A pharmaceutical composition comprising the interdigitation-fusion liposome of claim 1, and a pharmaceutically acceptable carrier.