High drug:lipid formulations of liposomal-antineoplastic agents
First Claim
1. A composition comprising:
- (i) liposomes which comprise an ionizable basic antineoplastic agent, an aqueous release inhibiting buffer and a bilayer comprising a lipid; and
(ii) an aqueous solution external to the liposomes which is basic with respect to the buffer.
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Abstract
A method for encapsulation of antineoplastic agents in liposomes is provided, having preferably a high drug:lipid ratio. Liposomes may be made by a process that loads the drug by an active mechanism using a transmembrane ion gradient, preferably a transmembrane pH gradient. Using this technique, trapping efficiencies approach 100%, and liposomes may be loaded with drug immediately prior to use, eliminating stability problems related to drug retention in the liposomes. Drug:lipid ratios employed are about 3-80 fold higher than for traditional liposome preparations, and the release rate of the drug from the liposomes is reduced. An assay method to determine free antineoplastic agents in a liposome preparation is also disclosed.
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Citations
12 Claims
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1. A composition comprising:
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(i) liposomes which comprise an ionizable basic antineoplastic agent, an aqueous release inhibiting buffer and a bilayer comprising a lipid; and (ii) an aqueous solution external to the liposomes which is basic with respect to the buffer. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8)
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9. A composition comprising:
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(i) liposomes which comprise an ionizable basic antineoplastic agent, an aqueous release inhibiting buffer and a bilayer comprising a lipid; (a) wherein the liposomes are large unilamellar liposomes; (b) wherein the basic antineoplastic agent is an anthracycline or a vinca alkaloid; (c) wherein the anthracycline is selected from the group consisting of doxorubicin and daunorubicin; (d) wherein the vinca alkaloid is selected from the group consisting of vincristine and vinblastine, and wherein the preferred vinca alkaloid is vincristine; (e) wherein the release-inhibiting buffer is a polyanionic buffer selected from the group consisting of citrate, oxalate and succinate buffers; and (f) wherein the lipid comprises at least one phospholipid selected from the group consisting of egg phosphatidylcholine (EPC);
distearoyl phosphatidylcholine (DSPC);
hydrogenated soy phosphatidylcholine (HSPC);
dipalmitoyl phosphatidylcholine (DPPC);
dimyristoyl phosphatidylcholine (DMPC); and
diarachidonoyl phosphatidylcholine (DAPC); and(ii) an aqueous solution external to the liposomes which is basic with respect to the buffer. - View Dependent Claims (10, 11, 12)
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Specification