The Liposome Company, Inc.

Ortho Pharmaceutical Corporation

Interferon Sciences, Inc.

Robert J Klimchak

Robert P Lenk

Michelle L Tomsho

Robert L Suddith

Andrew S Janoff

Joel B Portnoff

Anthony G Durning

Joel Portnoff

Pieter Rutter Cullis

Thomas D Madden

Lawrence T Boni

Sharma R Minchey

Marc J Ostro

John J Kearns

Peter G Glavinos, Jr, Deceased

A method for preparing liposomal suspensions which comprises preparing a solution of a poorly soluble protein or other poorly soluble compound and an encapsulating amount of a suitable lipid in an alcoholic solvent, injecting the resulting solution into an aqueous solution of appropriate ionic strength, and removing the alcoholic solvent by thin-film evaporation at the transition temperature of the liposomal suspension. This process is suitable for continuous production on an industrial manufacturing scale. It is of particular application in the preparation of KL4 pulmonary surfactant composition, wherein the thin film evaporation is conducted within the transition temperature range of the surfactant (approximately 35-50.degree. C.), thereby enhancing the KL4 peptide insertion into the lipid bilayer and leading to a product with reduced viscosity and enhanced surface tension lowering properties.

Manufacture of liposomes and lipid-protein complexes by ethanolic

Tangential flow filtration is used in the size separation of particles, such as liposomes and lipid particles. These particles may be passed through a tangential flow filtration device of any pore size desired. Tangential flow filter systems of various pore sizes may be used sequentially to obtain particles such as lipid particles or liposomes having a defined size range.

Method for size separation of particles

This invention provides a multilamellar liposome containing an arachidonic acid metabolite, two or more lipid-containing bilayers and two or more aqueous compartments containing a release-inhibiting buffer. Preferred arachidonic acid metabolites are the prostaglandins, particularly PGE.sub.1. The liposomal formulations can be used to treat animals, particularly humans, for diseases, disorders or conditions which can be ameliorated by prostaglandins, e.g., disorders characterized by cellular activation and adhesion, inflammation and/or toxemia.

Therapeutic use of multilamellar liposomal prostaglandin formulations

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.

Low toxicity drug-lipid systems

A liposome composition and methods for making same are disclosed, such compositions comprise an arachidonic acid metabolite such as a prostaglandin, preferably prostaglandin E.sub.1, a lipid, and a drying protectant such as a saccharide. The liposomes may be loaded with prostaglandin passively, or using a transmembrane concentration gradient, preferably using a transmembrane pH gradient. Using this transmembrane loading technique, trapping efficiencies of 50% to 100% are achieved, and the release rate of the prostaglandin from the liposomes is reduced. The liposome size is maintained after lyophilization and reconstitution.

Prostaglandin-lipid formulations

Hydroxyalkyl celluloses are useful as sedimenting agents in the non-destructive separation of red and white blood cells. Intact WBC recovery is higher than with conventional methods. The white blood cells may be used in interferon production.

Blood cell separation

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Flemington, NJ, United States of America

Robert J Klimchak