The Liposome Company, Inc.

Air Products and Chemicals, Inc.

John J Kearns

Paul A Tremblay

Andrew S Janoff

Pieter Rutter Cullis

Thomas D Madden

Robert L Suddith

Anthony G Durning

Alan L Weiner

Swaminathan Sunder

Mircea C Popescu

Lawrence T Boni

Robert P Lenk

Michael W Fountain

Joel B Portnoff

Steven J Weiss

Robert J Klimchak

Raymond J Robey

Joel Portnoff

Methods and compositions are described for nonliposomal lipid complexes in association with toxic hydrophobic drugs such as the polyene antibiotic amphotericin B. Lipid compositions are preferably a combination of the phospholipids dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) in about a 7:3 mole ratio. The lipid complexes contain a bioactive agent, and may be made by a number of procedures, at high drug:lipid ratios. These compositions of high drug:lipid complexes (HDLCs) may be administered to mammals such as humans for the treatment of infections, with substantially equivalent or greater efficacy and reduced drug toxicities as compared to the drugs in their free form. Also disclosed is a novel liposome-loading procedure, which may also be used in the formation of the HDLCs.

Methods of preparing low-toxicity drug-lipid complexes

A composition having equal to or greater than about 97 percent by weight phosphatidylcholine and about equal to or less than about 3 percent by weight to about 0.5% sphingomylin and equal to or less than about 0.5% lysophosphatidylcholine (undetectable by UV at 205 nm) has been found to result in liposomes having improved stability. Methods for preparing the composition are disclosed whereby the phospholipids are extracted and then purified using silica chromatography.

Phospholipid composition

Low toxicity drug-lipid systems

Phospholipid composition and liposomes made therefrom

A process for the separation and purification of individual phospholipids, especially phosphatidylcholine or lecithin and phosphatidylethanolaine, from mixtures containing members of the sub-class of phosphatides, incorporating methods of solvent extraction appropriate to the scale of the sample and utilizing an acetonitrile, acetonitrile-hydrocarbon, or acetonitrile-fluorocarbon solvent, which exhibit differential solubility properties towards the individual phospholipids.

Process for purification of phospholipids

A process for the separation and purification of individual phospholipids, especially phosphatidylcholine or lecithin and phosphatidylethanolamine, from mixtures containing members of the sub-class of phosphatides, incorporating methods of solvent extraction appropriate to the scale of the sample and utilizing an acetonitrile, acetonitrile-hydrocarbon, or acetonitrile-fluorocarbon solvent, which exhibit differential solubility properties towards the individual phospholipids.

Lipid matrix carriers are described which provide for the sustained release of bioactive agents in vivo or in vitro. The properties of the lipid matrix carriers of the present invention include high entrapment efficiencies; release of entrapped compounds in their active form; biodegradability and avoidance of vascular occlusion in vivo; and avoidance of sequestration of the bioactive agent in the liver and spleen.

Lipid matrix carriers for use in drug delivery systems

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Princeton, NJ, United States of America

John J Kearns