DEVELOPMENT OF A LIPOSOME BASED INTRAMUSCULAR SUSTAINED RELE

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 2.575 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