Studies On Docetaxel-Loaded Oral Micelles

Docetaxel (DTX) is a potent anticancer drug used to treat various cancers including prostate cancer, breast cancer, and advanced non-small cell lung cancer. DTX inhibits cell growth by binding to microtubules, stabilizing them, and preventing their depolymerization. However, the clinical application of DTX is limited by the poor aqueous solubility, low bioavailability and high toxicity. The currently marketed form of DTX (Taxotere(?)) for intravenous infusion is formulated utilizing Tween80and ethanol. Due to hemolysis caused by Tween80, patients were often subjected to hypersensitivity after administration. Moreover, it needs to be administered by injection or intravenous drip, which is painful to patients, restricting clinical application of DTX. Oral administration can decrease adverse reactions and increase compliance of patients. However, the poor adqueous solubility and efflux of gastrointestinal tract decrease the oral bioavailability of DTX.In order to overcome defects described above, mixed micelles composed of CSO-SA, D-a-tocopheryl polyethylene glycol1000succinate (TPGS) and mPEG-PLA were prepared. In this study, the thin-film hydration method was used to prepare mPEG-PLA/TPGS/CSO-SA/DTX mixed micelles with mPEG-PLA/TPGS/DTX mixed micelles as contrast. Taking the drug-loading content, encapsulation efficiency, precipitated drug, size and Zeta potential as indexes, weight of CSO-SA, weight ratio of TPGS and mPEG-PLA, feeding of DTX (mg), temperature of rotary evaporation (℃) and the way to hydration were investigated, and then the prescription was further optimized via the orthogonal design test. Stability study in gastric fluid without pepsin and simulated intestinal fluid without trypsin and critical micelle concentration determination were carried. Release behaviour of micelles were studied i, gastric fluid without pepsin, simulated intestinal fluid and PBS (pH=7.4). The pharmacokinetic experiments of DTX solution and DTX micelles were carried in rats.The optimization formulation was mPEG-PLA:TPGS=2:1(total weight of30mg),10mg of CSO-SA,10mg of DTX,40℃of rotary evaporation, and the film was vortex with60℃hydration fluid at room temperature. The drug loading content and encapsulation efficiency of the optimal formulation was19.42%and96.0%, and the mPEG-PLA/TPGS/CSO-SA/DTX mixed micelles exhibited spherical shape without conglutination. The mean particles size and Zeta potential of mPEG-PLA/TPGS/CSO-SA/DTX mixed micelles was34.9nm and+29.8mV, respectively. The results of stability study and critical micelle concentration determination indicates that the mPEG-PLA/TPGS/CSO-SA/DTX mixed micelles were stable in gastrointestinal tract and with the ability to maintain integrity even upon extreme dilution in gastrointestinal tract, with critical micelle concentration of2.11x10-5M. Results of release study indicates that mPEG-PLA/TPGS/CSO-SA/DTX mixed micelles manifested a certain delayed release, which can protect from degradation in gastrointestinal tract. And the relative bioavailability of mPEG-PLA/TPGS/CSO-SA/DTX mixed micelle was9.86%,2.52folds of that of DTX solution. Results indicated that mPEG-PLA/TPGS/CSO-SA/DTX mixed micelles could markedly improve the oral absorption of DTX.