Toxicity studies of cremophor-free paclitaxel solid dispersion formulated by a supercritical antisolvent process.

To evaluate the acute toxicity of a paclitaxel solid dispersion formulation, single dose studies in ICR mice were carried out for injectable excipients, paclitaxel solid dispersion powder, and Taxol. In the dose range of excipients used for preparing paclitaxel solid dispersion, each excipient was clinically safe, and the LD(50) for exicipients was higher than 2,000 mg/kg for both males and females. In this study, there were no remarkable clinical signs or deaths related to paclitaxel solid dispersion even at doses up to 160 mg/kg of paclitaxel. But Taxol resulted in clinical signs when it contained more than 30 mg/mL paclitaxel. The LD(50) for paclitaxel solid dispersion was above 160 mg/kg and the LD(50) for Taxol was 31.3 mg/kg, more than 5 times lower than that of paclitaxel solid dispersion. However, paclitaxel solid dispersion could not be administered i.v. at a dose exceeding 160 mg/kg, because of high viscosity. To evaluate the nephrotoxicity of paclitaxel solid dispersion, plasma level of creatinine and kidney weight were measured and compared to Taxol. At the doses administered, paclitaxel solid dispersion did not change creatinine clearance, while Taxol killed all animals at doses >15 mg/kg. To investigate membrane damage when paclitaxel formulations were injected, hemolytic activity was determined for different concentrations. Paclitaxel solid dispersion showed about 10% hemolytic activity, whereas Taxol showed about 40% hemolytic activity when it contained 2 mg of paclitaxel. Comparisons with the LD(50) value, nephrotoxicity, and hemolytic activity of Taxol suggested that Cremophor-free paclitaxel solid dispersion as an injectable formulation is a promising approach to increasing the safety and clinical efficacy of paclitaxel for treatment of cancer.

Development of novel ibuprofen-loaded solid dispersion with improved bioavailability using aqueous solution.

To develop a novel ibuprofen-loaded solid dispersion with enhanced bioavailability, various ibuprofen-loaded solid dispersions were prepared with water, HPMC and poloxamer. The effect of HPMC and poloxamer on aqueous solubility of ibuprofen was investigated. The dissolution and bioavailability of solid dispersion in rats were then evaluated compared to ibuprofen powder. When the amount of carrier increased with a decreased in HPMC/poloxamer ratio, the aqueous solubility of ibuprofen was elevated. The solid dispersion composed of ibuprofen/HPMC/poloxamer at the weight ratio of 10:3:2 improved the drug solubility approximately 4 fold. It gave significantly higher initial plasma concentration, AUC and Cmax of drug than did ibuprofen powder in rats. The solid dispersion improved the bioavailability of drug about 4-fold compared to ibuprofen powder. Thus, this ibuprofen-loaded solid dispersion with water, HPMC and poloxamer was a more effective oral dosage form for improving the bioavailability of poor water-soluble ibuprofen.