Relation between dissolution profiles and toxicity of cisplatin-loaded microspheres.

The aim of this study is to evaluate and compare the dissolution profiles of cisplatin-loaded microspheres (CDDP-MS) in vitro and in vivo, and to determine the relationship between the dissolution profiles in vitro and systemic toxicity. For this purpose, three types of CDDP-MS that release the CDDP for 1, 2 and 5 weeks without a large amount of initial release in phosphate buffered saline (pH 7.4) were prepared. The dissolution profiles of these formulations in vivo were well correlated with in vitro studies, and resulted in well-controlled plasma platinum concentration. The systemic toxicity of the CDDP-MS and CDDP dissolved in saline (CDDP-SOL) were assessed by intraperitoneal administration in mice. The maximal tolerable dose (MTD) of CDDP-SOL was 13.4 mg/kg, whereas the CDDP-MS of 1, 2 and 5-week types were 34.6, 44.2, 62.6 mg/kg, respectively. The MTD of CDDP increased proportionally when 50% of CDDP had been released from MS in vitro (MTD (mg/kg)=5.22 x T(50(day)) + 13.2, R(2)=0.9935). We demonstrate that the systemic toxicity of CDDP-MS can be predicted by evaluation of the dissolution rate in vitro since in vivo dissolution was correlated with the in vitro.