The Liposome Company, Inc.

The Lipsome Company, Inc.

Janoff, Andrew S.

Schieren, Hugh P.

Ginsberg, Richard S.

Jablonski, Regina L.

Fountain, Michael W.

Hope, Michael J.

Cullis, Pieter R.

Madden, Thomas D.

Bally, Marcel B.

Richard S Ginsberg

Pieter Rutter Cullis

Marcel B Bally

Michael W Fountain

Andrew S Janoff

Michael J Hope

Lawrence D Mayer

Thomas D Madden

Hugh P Schieren

George N Mitilenes

Regina L Jablonski

Mircea C Popescu

Robert P Lenk

Steven J Weiss

Marc J Ostro

Sol M Gruner

Huge P Schieren

Fountain Michael W

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.

High drug:lipid formulations of liposomal-antineoplastic agents

Dehydrated liposomes are prepared by drying liposome preparations under reduced pressure in the presence of one or more protective sugars, e.g., the disaccharides trehalose and sucrose. Preferably, the protective sugars are present at both the inside and outside surfaces of the liposome membranes. Freezing of the liposome preparation prior to dehydration is optional. Alternatively, the protective sugar can be omitted if: (1) the liposomes are of the type which have multiple lipid layers; (2) the dehydration is done without prior freezing; and (3) the dehydration is performed to an end point which results in sufficient water being left in the preparation (e.g., at least 12 moles water/mole lipid) so that the integrity of a substantial portion of the multiple lipid layers is retained upon rehydration. Concentration gradients capable of generating transmembrane potentials can be created across the liposome membranes either before or after dehydration, and the transmembrane potentials resulting from these gradients can be used to load charged materials, e.g., drugs, into the liposomes.

Methods of dehydrating, storing and rehydrating liposomes

Encapsulation of ionizable agents in liposomes

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 tranamembrane pH gradient. Using this technique, trapping efficiencies approach 100%, and liposomes may be loaded with drug immediately prior to use, eliminating stability problem 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.

Liposomal antineoplastic agent compositions

Methods of treatment using high drug-lipid formulations of

High drug:lipid formulations of liposomal antineoplastic agents

Method of dehydrating liposomes using protective sugars

A new and substantially improved type of lipid vesicle, called stable plurilamellar vesicles (SPLVs), are described, as well as the process for making the same and X-ray diffraction methods for identifying the same. SPLVs are characterized by lipid bilayers enclosing aqueous compartments containing one or more entrapped solutes, the concentration of such solutes in each aqueous compartment being substantially equal to the emunization of solutes used to prepare the SPLVs. The bilayers of SPLVs are substantially non-compressed. SPLVs are stable during storage and can be used in vivo for the sustained release of compounds and in the treatment of disease.

Stable plurilamellar vesicles

A new and substantially improved type of lipid vesicle, called stable plurilamellar vesicles (SPLVs), are described, as well as the process for making the same and X-ray diffraction methods for identifying the same. SPLVs are characterized by lipid bilayers enclosing aqueous compartments containing one or more entrapped solutes, the concentration of such solutes in each aqueous compartment being substantially equal to the concentration of solutes used to prepare the SPLVs. The bilayers of SPLVs are substantially non-compressed. SPLVs are stable during storage and can be used in vivo for the sustained release of compounds and in the treatment of disease.

The invention encompasses mixtures of antimicrobial agents coencapsulated in liposomes which when administered in vivo exert an enhanced therapeutic effect. The therapeutic effectiveness of the coencapsulated antimocrobial agents is greater than that of the same combination administered either in solution or as a mixture of liposome populations each containing one of the antimicrobial agents.

Enhancement of pharmaceutical activity

Dehydrated liposomes

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Jamesburg, NJ, United States of America

Richard S Ginsberg