GLUTARALDEHYDE CROSS-LINKED CHITOSAN MICROSPHERES AS A LONG-ACTING BIODEGRADABLE DRUG-DELIVERY VEHICLE - STUDIES ON THE IN-VITRO RELEASE OF MITOXANTRONE AND IN-VIVO DEGRADATION OF MICROSPHERES IN RAT MUSCLE

Chitosan microspheres were prepared from 74% deacetylated chitin by the glutaraldehyde crosslinking of an aqueous acetic acid dispersion of chitosan in a mixture of liquid paraffin and petroleum ether stabilized using sorbitan sesquioleate as the surfactant. Cross-linking and hardening of the spherical particles were achieved by the addition of glutaraldehyde-saturated toluene through the organic phase. A relatively novel antineoplastic agent, mitoxantrone, was incorporated into the microspheres and the drug release was studied in vitro into phosphate buffer for over 4 weeks at 27 degrees C. Drug release was found to be effectively controlled by the extent of cross-linking. Only about 25% of the incorporated drug was released over 36 days from microspheres of high cross-linking density. Implantation of placebo chitosan microspheres in the skeletal muscle of rats was carried out in order to assess the biocompatibility and biodegradability of the microspheres. Histological analysis showed that the microspheres were well tolerated by the living tissue. However, no significant biodegradation of the material was noticed over a period of 3 months in the skeletal muscle of rats. Data obtained indicate the possibility of using cross-linked chitosan microspheres as a drug carrier for sustained drug release for very long periods.