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KMID : 0043320090320010139
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Archives of Pharmacal Research
2009 Volume.32 No. 1 p.139 ~ p.148
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Toxicity Studies of Cremophor-free Paclitaxel Solid Dispersion Formulated by a Supercritical Antisolvent Process
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Woo Jong-Soo
Choi Han-Gon
Yong Chul-Soon
Chi Sang-Cheol
Park Jae-Hyun
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Abstract
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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 LD50 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 LD50 for paclitaxel solid dispersion was above 160 mg/kg and the LD50 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 LD50 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.
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KEYWORD
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Paclitaxel, Solid dispersion, Toxicity, LD50, Taxol, Nephrotoxicity
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