SUSTAINED-RELEASE OF CISPLATIN IN DOGS FROM AN INJECTABLE IMPLANT DELIVERY SYSTEM

Cisplatin was incorporated into an in-situ forming biodegradable impla nt delivery system (ATRIGEL(R)) consisting of a biodegradable polymer dissolved in a pharmaceutically acceptable solvent. The polymer soluti on with the suspended cisplatin was injected subcutaneously into the f lank or shoulder of six healthy beagle dogs where the water-insoluble polymer precipitated upon contact with body fluids and formed a solid implant for the controlled release of the drug. Each dog received four injections, spaced thirty days apart, of a formulation containing eit her poly(DL-lactide-co-caprolactone) (PLC) or poly(DL-lactide-co-glyco lide) (PLGA) dissolved in dimethyl sulfoxide (DMSO) and loaded with 8% by weight cisplatin. Dosage levels of 70, 105, and 157.5 mg/m(2) were used to determine dosage escalation effects. Injections of the same f ormulations without the drug served as controls. Samples of blood were taken at appropriate times over the four months of treatment and anal yzed for platinum concentration by atomic absorption spectroscopy. Loc al tissue and systemic toxicities were also determined. Both formulati ons exhibited sustained release of cisplatin with peak serum concentra tions of platinum being attained in about two days followed by gradual ly decreasing platinum levels to day thirty. Consistent drug release p rofiles were observed for each of the four thirty-day treatment period s. The dosage escalation results exhibited an approximate 50% increase in peak platinum levels and area-under-the-curve (AUG) values for eac h 50% increase in drug dose. Local tissue toxicity to the cisplatin-co ntaining implants was variable and appeared to be unrelated to dose le vel or injection number. Tissue reaction to the implants without drug was minimal indicating a role of cisplatin in the tissue reactions. Sy stemic toxicity, as judged by clinical parameters and clinicopathologi c evaluation, was not noted at any dose level or injection time.