Nexstar Pharmaceuticals, Inc.

Gilead Sciences, Inc.

Vestar, Inc.

Vestar Research, Inc.

Richard T Proffitt

Su-Ming Chiang

Jill P Adler-Moore

Eskild A Petersen

Kevin R Bracken

Evan M Hersch

Cary A Presant

George W Tin

Raymond L Teplitz

Lawrence E Williams

Ronald C Gamble

A novel composition and method for solubilizing amphiphilic drugs in a small amount of organic solvent for use in improved liposomes is disclosed. A phosphatidylglycerol is acidified in a small amount of organic solvent. The amphiphilic drug, such as Amphotericin B, suspended in organic solvent is then added to the acidified phosphatidylycerol and a soluble complex is formed between the phosphatidylglycerol and the amphiphilic drug. When the liposome composition incorporating the soluble complex is hydrated, the final pH of the hydrating aqueous buffer is carefully controlled. The Amphotericin B liposomes formed have markedly reduced toxicity.

Amphotericin B liposome preparation

Micellular particles such as small unilamellar vesicles of less than 2000 A&deg; loaded with,In are administered to BALB/c mice in which EMT,tumors had been induced. Whole body scintographs of the mice to which either neutral or positively or negatively charged vesicles had been administered show a substantial quantity of the vesicle entrapped,In localized in the tumor. Blocking of macrophages in the liver and spleen by first administering unlabeled, aminomannose substituted vesicles before administration of the labeled vesicles increases uptake of the,In labeled vesicles in the tumor.

Method of targeting a specific location in a body using phospholipid and cholesterol liposomes which encapsulate an agent

A liposomal aminoglycoside formulation comprising a neutral lipid, a negatively charged lipids and a sterol. The formulation contains unilamellar vesicles having an average size below 100 nm. A process of making liposomes containing an aminoglycoside is also provided. A method is also provided for the treatment of drug susceptible and drug resistant bacteria.

Antibiotic formulation and use for bacterial infections

A liposomal aminoglycoside formulation comprising a neutral lipid, a negatively charged lipid and a sterol. The formulation contains unilamellar vesicles having an average size below 100 nm. A process of making liposomes containing an aminoglycoside is provided. A method is also provide for the treatment of drug susceptible and drug resistant bacteria.

Formulations consisting of phospholipid small unilamellar particles encapsulating polyene antifungal antibiotics and methods for using such compositions to treat systemic fungal infections are described. In a preferred embodiment, the particles are in the form of vesicles which comprise a polyene antifungal antibiotic, preferably amphotericin B and/or nystatin, egg phosphatidylcholine and cholesterol, preferably in the molar ratio of about 0.2 (AMB):2(PL):1(CHOL). These vesicles may also have an amine modified surface. The vesicles are suspended in a low isonic strength saccharide/tris solution at a pH of from about 6.0 to about 8.0 and may be administered to deliver the antifungal antibiotic to treat systemic fungal infections.

Treatment of systemic fungal infections with phospholipid particles

Antibiotic formulation and use for drug resistant infections

A liposomal aminoglycoside formulation comprising a neutral lipid, a negatively charged lipids and a sterol. The formulation contains unilamellar vesicles having an average size below 100 nm. A process of making liposomes containing an aminoglycoside is provided where the hydration temperature is significantly below the transition temperature of the formulation. A method for the treatment of drug susceptible and drug resistant bacteria.

A method is provided for delivering micellular particles containing chemotherapeutic agents and a marker to tumors within a body for the diagnosis and treatment of such tumors. The micellular particles are small, less than 2000 .ANG. and incorporate pure, neutral phospholipid molecules in their external surface. Enhanced delivery of the micellular particles containing marker and chemotherapeutic agents may be achieved by introducing an initial group of positively charged micellular particles to block the reticuloendothelial cells present in the body.

Method of delivering micellular particles encapsulating chemotherapeutic

Micellular particles such as small unilamellar vesicles of less than 2000 .ANG. loaded with .sup.111 In are administered to BALB/c mice in which EMT6 tumors had been induced. Whole body scintographs of the mice to which either neutral or positively or negatively charged vesicles had been administered show a substantial quantity of the vesicle entrapped .sup.111 In localized in the tumor. Blocking of macrophages in the liver and spleen by first administering unlabeled, aminomannose substituted vesicles before administration of the labeled vesicles increases uptake of the .sup.111 In labeled vesicles in the tumor.

Method of targeting a specific location in a body

Formulations consisting of phospholipid small unilamellar particles encapsulating polyene antifungal antibiotics and methods for using such compositions to treat systemic fungal infections are described. In a preferred embodiment, the particles are in the form of vesicles which comprise a polyene antifungal antibiotic, preferably amphotericin B and/or nystatin, egg phosphatidylcholine and cholesterol, preferably in the molar ratio of about 0.2 (AMB):2(PL):1(CHOL). These vesicles may also have an amine modified surface. The vesicles are suspended in a low ionic strength saccharide/tris solution at a pH of from about 6.0 to about 8.0 and may be administered to deliver the anti-fungal antibiotic to treat systemic fungal infections.

Preparation small unilamellar vesicles including polyene antifungal

A method is provided for delivering micellular particles containing a radiolabelled marker to tumors within humans. The micellular particles are less than approximately 2000.ANG. and incorporate essentially chemically pure phospholipid molecules in their external surface. Human patients given intravenous injections of such radiolabelled micellular particles showed tumors imaged by such method, without developing symptoms related to the micellular particles.

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Arcadia, CA, United States of America

Richard T Proffitt