SBIR-STTR Award

A liposome based sustained release delivery system for i.m. injection of water soluble drugs was developed using gentamicin (I) as a model drug. The pharmacokinetic profile of (I) in mice, biodegradation of the carrier at the site of injection, and histological effects were investigated. Three types of liposomal carriers with different release characteristics were tested. Peak plasma concentrations of comparable doses of (I), in liposomes or as solution, were reduced 2.5-5 times when given encapsulated. Prolonged plasma levels over at least 4 hours were achieved with encapsulated (I), whereas a comparable dose of (I) in solution was eliminated from plasma within 2 hours. The carrier was slowly degraded in muscle over several days. Both drug input and degradation rate were a function of liposome composition. The carrier was found no more irritating to muscle tissue than saline. No adverse histological reaction was found over 14 days. Pharmacokinetic modeling indicated that drug input can be tailored over a wide range. Clinically, dosage frequency may be reduced to one daily injection and less fluctuation of plasma levels, reduction of side effects, and improved patient compliance may be expected. In Phase II, efficacy and toxicity studies in animals and production of pilot batches to support preclinical and clinical studies are planned.National Institute of Allergy and Infectious Diseases (NIAID)

A liposome-based sustained delivery system for IM injection of water-soluble antibiotics (gentamicin sulphate) is proposed. Technical feasibility, improved pharmacokinetics, biodegradation of the carrier, and absence of local irritation were demonstrated in Phase I. To provide a basis for product development and clinical trials in Phase III, the objectives of this Phase I project include:(1) formulation of a pharmaceutically acceptable dosage form;(2) preclinical efficacy and safety evaluation;(3) in vitro-in vivo correlation;(4) pilot batch production; and(5) stability testing.Expansion of these aims is as follows: Three dosage forms covering a wide range of drug input rates will be formulated. The relative nephrotoxicity of liposomal versus free gentamicin will be assessed in rats. Efficacy will be tested in salmonella infected mice. A lyophilized dosage form will be formulated to improve the product shelf-life. A new homogenization technique, microfluidization, will be employed for batch production. In vitro release profiles will be established with a How-through dialysis device. Three pilot batches will be prepared and undergo extensive stability testing. Preliminary product specifications, standard operating procedures, and documentation will be provided.Following Phase II, product development of a nontoxic, biodegradable depot carrier for gentamicin or other aminoglycoside derivatives and extension of the program to other injectable, water-soluble drugs is planned.National Institute of Allergy and Infectious Diseases (NIAID)