Preparation and evaluation of Cremophor-free paclitaxel solid dispersion by a supercritical antisolvent process

• Published in: Journal of pharmacy and pharmacology 2011-04, Vol.63 (4), p.491-499
• Main Authors: Park, Jae-Hyun, Yan, Yi-Dong, Chi, Sang-Cheol, Hwang, Doo Hyung, Shanmugam, Srinivasan, Lyoo, Won Seok, Woo, Jong Soo, Yong, Chul Soon, Choi, Han-Gon
• Format: Article
• Language: English
• Subjects: Animals; Chemistry, Pharmaceutical - methods; Cremophor EL; Drug Stability; Glycerol - adverse effects; Glycerol - analogs & derivatives; Injections, Intravenous; Male; Nanotechnology - methods; paclitaxel; Paclitaxel - administration & dosage; Paclitaxel - chemistry; Paclitaxel - pharmacokinetics; Rats; Rats, Sprague-Dawley; solid dispersion; Solubility; supercritical fluid; Tissue Distribution
• ISSN: 0022-3573; 2042-7158
• DOI: 10.1111/j.2042-7158.2010.01218.x

Objectives  To avoid the major adverse effects induced by Cremophor EL formulated in the commercial paclitaxel products of Taxol. Methods  An injectable paclitaxel solid dispersion free of Cremophor was prepared by a supercritical antisolvent process and then was fully characterized and investigated with regard to its short‐term and long‐term stability. Pharmacokinetics in rats was also evaluated compared with the commercial product. Key findings  The solid dispersion system at a 1/20/40 weight ratio of paclitaxel/HP‐β‐CD/HCO‐40 had a paclitaxel solubility of about 10 mg/ml, an almost 10 000‐fold increase over its aqueous solubility. This system was physically stable for at least six months or four weeks in accelerated conditions (40 ± 2°C; RH: 75 ± 5%) and stress conditions (60°C), respectively. The precipitation time of paclitaxel solid dispersion in 0.9% sodium chloride injection at a concentration of 1000 µg/ml was above 70 h at room temperature. Intravenous administration of paclitaxel solid dispersion at a dose of 6 mg/kg revealed no significant differences when compared with the commercial product. However, our results obtained at a dose of 12 mg/kg showed a striking non‐linear increase in the plasma Cmax and AUCall with increased dose. In addition, the concentrations of paclitaxel in various organs in the solid dispersion group were found to be higher than those of Taxol at 6 mg/kg, and the paclitaxel levels in these organs increased proportionately with increasing dose. Conclusions  Nano‐scale paclitaxel solid dispersion without Cremophor EL provided advantageous results over Taxol with respect to the physicochemical properties, safety, clinic convenience and pharmacokinetic behaviour in rats.