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

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.