PHARMACEUTICAL AND PHYSICAL-PROPERTIES OF PACLITAXEL (TAXOL) COMPLEXES WITH CYCLODEXTRINS

Paclitaxel (as Taxol) is under clinical investigation for treatment of a variety of cancers. Because of its low aqueous solubility, paclitax el is administered in polyethoxylated castor oil (Cremophor EL) and et hanol, a Vehicle associated with severe hypersensitivity reactions. Cy clodextrins (CyDs) are molecular complexing agents that can increase t he solubility and stability of some poorly soluble drugs and were inve stigated here as a means to obviate the requirement for Cremophor. A v ariety of beta- and gamma-cyclodextrins were tested; (hydroxypropyl)-( HP beta CyD), (hydroxyethyl)-(HE beta CyD), and dimethyl-(DM beta CyD) beta CyD increased paclitaxel solubility 2 x 10(3)-fold or more and d id not alter the cytostatic properties of paclitaxel in vitro. The qua ntity of drug solubilized increased with the CyD concentration, but pr ecipitation upon dilution occurred with some CyDs of stoichiometries. Thermal and spectroscopic (fluorescence, IR, NMR, and circular dichroi sm) analyses provided evidence of complex formation that was stable in the solid state but weak in solution, suggesting an explanation for t he observed precipitation upon dilution. DM beta CyD solutions of less than or equal to 3.7 mol % (mole of drug:mole of CyD) showed no preci pitation upon dilution, nor did HP beta CyD solutions of less than or equal to 0.14 mol %. Maximum tolerated dose (MTD) experiments showed u ncomplexed DM beta CyD to be toxic in mice at doses of 2 g CyD/kg body weight, the quantity required to administer paclitaxel at 10 mg/kg. H P beta CyD allowed paclitaxel administration at higher doses and had a n MTD of 25 mg drug/kg. The CyDs tested are marginal in feasibility fo r paclitaxel administration, and their use in taxane formulation will require a reduction of the dose-limiting toxicity of the CyD itself.