Development of docetaxel-loaded intravenous formulation, Nanoxel-PM? using polymer-based delivery system

摘要

Nanoxel-PM?, docetaxel-loaded methoxy-poly(ethylene glycol)-block-poly(d,l-lactide) (mPEG-PDLLA) micellar formulation was prepared in an effort to develop alternative, less toxic and efficacious Tween 80-free docetaxel formulation, and its pharmacokinetics, efficacy, and toxicity were evaluated in comparison with Taxotere? in preclinical studies. The mean diameter of the Nanoxel-PM? was 10-50 nm and the polydispersity of samples exhibited a narrow size distribution and monodisperse unimodal pattern. Pharmacokinetic study in mice, rats and beagle dogs revealed that Nanoxel-PM? exhibited similar pharmacokinetic profiles (C_(max), AUC, t_(1/2), CL, V_(ss)) to Taxotere, and the relative mean AUC_t and C_(max) of Nanoxel-PM? to Taxotere? were within 80-120%. Furthermore, excretion study in rats demonstrated that there was no statistically significant difference in the amount excreted in feces or urine as an unmetabolized docetaxel between Nanoxel-PM? and Taxotere?. Its pharmacokinetic bioequivalence resulted in comparable anti-tumor efficacy to Taxotere? in human lung cancer xenografts H-460 in nude mice as well as in lung, ovary and breast cancer cell lines. Several animal toxicity studies on Nanoxel-PM? compared with Taxotere? were carried out. In single dose rat and dog model and repeated dose mouse model, both Nanoxel-PM? and Taxotere? exhibited similar toxic effects on hematology and body weight gain. On the other hand, vehicle related hypersensitivity reactions and fluid retentions were not observed when Nanoxel-PM? was administered, unlike Taxotere?, in the beagle dog study. Based on these results, it is expected that Nanoxel-PM? can reduce side effects of hypersensitivity reactions and fluid retention while retaining antitumor efficacy in cancer patients. Currently, Nanoxel-PM? is under evaluation for bioequivalence with Taxotere? in a multi-center, open-label, randomized, crossover study.