Chitosan microspheres in PLG films as devices for cytarabine release

Cytarabine was included in chitosan microspheres and several of these microspheres were embedded in a poly(lactide-co-glycolide) (PLG) film to constitute a comatrix system, to develop a prolonged release form. Chitosan microspheres, in the range of 92 +/- 65 mu m, having good spherical geometry and a smooth surface incorporating cytarabine, were prepared. The cytarabine amount included in chitosan microspheres was 43.7 mu g of ara-C per milligram microsphere. The incorporation efficiency of the cytarabine in microspheres was 70.6%. Total cytarabine release from microspheres in vitro was detected at 48 h. Inclusion of cytarabine-loaded microspheres in poly(lactide-co-glycolide) film initiated a slower release of the drug and, in this way, the maximum of cytarabine released (80%) took place in vitro at 94.5 h. Comatrices, with 8.7 mg of cytarabine, signifying a dose of 34.5 mu g/kg, were subcutaneously implanted in the back of rats. Maximum plasma cytarabine concentration was 18.5 +/- 1.5 mu g/ml, 48 h after the device implantation and the drug was detected in plasma for 13 days. The histological studies show a slow degradative process. After 6 months of implantation, most of the microspheres of the matrix seemed to be intact, the comatrix appeared surrounded by conjunctiva tissue and small blood vessels and nerve packets were detected in the periphery of the implant. (C) 2000 Elsevier Science B.V. All rights reserved.