Sustained Release of Cisplatin in Dogs from an Injectable Implant Delivery System

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Abstract
Cisplatin was incorporated into an in-situ forming biodegradable implant delivery system (ATRIGELO) consisting of a biodegradable polymer dissolved in a pharmaceutically acceptable solvent. The polymer solution with the suspended cisplatin was injected subcutaneously into the flank 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 either poly(DL-lactide-co-caprolactone) (PLC) or pely(DL-lactide-co-glycolide) (PLGA) dissolved in dimethyl sulfoxide (DM8O) and loaded with 8% by weight cisplatin. Dosage levels of 70, 105, and 157.5 mg/m2 were used to determine dosage escalation effects. Injections of the same formulations without the drug served as controls. Samples of blood were taken at appropriate times over the four months of treatment and analyzed for platinum concentration by atomic absorption spectroscopy. Local tissue and systemic toxicities were also determined. Both formulations exhibited sustained release of cisplatin with peak serum concentrations of platinum being attained in about two days followed by gradually decreasing platinum levels to day thirty. Consistent drug release profiles were observed for each of the four thirty-day treatment periods. The dosage escalation results exhibited an approximate 50% increase in peak platinum levels and area-under-the-curve (AUC) values for each 50% increase in drug dose. Local tissue toxicity to the cisplatin-containing implants was variable and appeared to be unrelated to dose level or direction number. Tissue reaction to the implants without drug was minimal indicating a role of cisplatin in the tissue reactions. Systemic toxicity, as judged by clinical parameters and clinicopathologic evaluation, was not noted at any dose level or injection time.