Sphingosomes for enhanced drug delivery

• US 5,543,152 A
• Filed: 06/20/1994
• Issued: 08/06/1996
• Est. Priority Date: 06/20/1994
• Status: Expired due to Term

• Current Assignee: Tekmira Pharmaceuticals Corporation
• Original Assignee: Inex Pharmaceuticals Corporation
• Inventors: Webb, Murray S., Mayer, Lawrence D., Bally, Marcel B.
• Primary Examiner(s): Nutter, Nathan M.
• Application Number:
  US08/263,603
• Time in Patent Office: 778 Days
• Field of Search: 424/450, 514/27, 514/283
• US Class Current: 424/450
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543

Abstract

Liposomal formulations having extended circulation time in vivo and increased drug retention are comprised of sphingomyelin and cholesterol and have an acidic intraliposomal pH. The formulations have enhanced stability and thus are used in methods which provide improved drug delivery and more effective treatment. The delivery of lipophilic drugs such as the vinca alkaloids, and particularly vincristine and vinblastine, to tumors is significantly improved.

Claims

1. A liposomal composition for delivery of a therapeutic compound to a mammalian host which comprises a liposome having one or more membranes which comprise sphingomyelin and cholesterol, a liposomal interior having an acidic pH which is less than that of the liposomal exterior, and a lipophilic therapeutic compound contained in said liposome for delivery to the host.

2. The liposomal composition of claim 1, wherein the sphingomyelin and cholesterol are present at a molar ratio from 75/25 mol %/mol % sphingomyelin/cholesterol to 30/50 mol %/mol % sphingomyelin/cholesterol.

3. The liposomal composition of claim 2, wherein the sphingomyelin and cholesterol are present at a molar ratio from 70/30 mol %/mol % sphingomyelin/cholesterol to 40/45 mol %/mol % sphingomyelin/cholesterol.

4. The liposomal composition of claim 3, wherein the sphingomyelin and cholesterol are present at a ratio of approximately 55/45 mol %/mol % sphingomyelin/cholesterol.

5. The liposomal composition of claim 1, wherein the lipophilic therapeutic compound is an alkaloid.

6. The liposomal composition of claim 5 wherein the alkaloid is selected from vincristine, vinblastine, or etoposide or prodrugs thereof.

7. The liposomal composition of claim 5, wherein the alkaloid is vincristine.

8. The liposomal composition of claim 7, wherein the vincristine is present at a drug to lipid ratio of approximately 0.01/1.0 to 0.2/1.0.

9. The liposomal composition of claim 1, further comprising at least one lipid selected from a phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidic acid, cardiolipin, phosphatidylinositol, ceramide, cerebroside and ganglioside.

10. The liposomal composition of claim 1, wherein the liposomes are unilamellar.

11. The liposomal composition of claim 1, wherein the liposomes have mean diameters of about 0.05 microns to 0.45 microns.

12. The liposomal composition of claim 1, wherein the liposomes have mean diameters of about 0.05 microns to 0.2 microns.

13. The liposomal composition of claim 1, wherein the interior comprises a citrate buffer at about pH 4.0.

14. A liposome for delivery of a lipophilic therapeutic compound, produced by the process of:

forming a liposome from a mixture which comprises sphingomyelin and cholesterol, in a first buffered aqueous solution having an acidic pH greater than pH 2; and

suspending the liposome in a second buffered solution having a pH which is greater than that of the first buffered aqueous solution, whereby a transmembrane pH gradient is formed which facilitates the transfer of the therapeutic compound to the liposome, wherein the interior of the liposome containing the therapeutic compound is from pH 2 to pH 6.

15. The liposome produced by the process of claim 14, wherein the process further comprises the step of separating the liposome containing the therapeutic compound from the second buffer containing therapeutic compound which has not been entrapped by the liposome.