Indomethacin-loaded methoxy poly(ethylene glycol)/poly(D,L-lactide) amphiphilic diblock copolymeric nanospheres: pharmacokinetic and toxicity studies in rodents.

Biodegradable methoxy poly(ethylene glycol)/poly(D,L-lactide) amphiphilic block copolymeric nanospheres were prepared for application as a particulate drug carrier. Drug-loaded nanospheres (ML50) showed a narrow size distribution with the average diameter of <200 nm. When the feed weight ratio of indomethacin (IMC) to polymer was 1:1, the ML50 nanosphere having a relatively high drug-loading efficiency of about 33.0% could be obtained. To investigate pharmacokinetic characteristics of IMC in rats, the IMC concentration in plasma was analyzed using a high-performance liquid chromatography system after intravenous bolus injection of free IMC and IMC-loaded ML50 nanospheres. ML50 nanosphere system exhibited a significant potential for sustained release of drug and showed slow clearance of IMC, but there was no significant effect on metabolism of IMC in the rats. Median lethal dose (LD50) and major organs (e.g., heart, lung, liver, and kidney) toxicities were determined using ICR mice to estimate the acute toxicity of ML50 nanospheres. The LD50 of ML50 nanospheres determined by Litchfield-Wilcoxon method was about 1.54 g/kg. After the mice were intraperitoneally administered with a half dose of LD50 for 7 days, no significant histopathologic changes were observed in ML50-treated mice compared with normal mice in the light and electron microscopic observations of major organs. This indicates that ML50 nanospheres might be a useful candidate as a novel sustained drug carrier for hydrophobic drugs.