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, paclitaxel is administered in polyethoxylated castor oil (Cremophor EL) and ethanol, a vehicle associated with severe hypersensitivity reactions. Cyclodextrins (CyDs) are molecular complexing agents that can increase the solubility and stability of some poorly soluble drugs and were investigated here as a means to obviate the requirement for Cremophor. A variety of β‐ and γ‐cyclodextrins were tested; (hydroxypropyl)‐ (HPβCyD), (hydroxyethyl)‐(HEβCyD), and dimethyl‐ (DMβCyD) βCyD increased paclitaxel solubility 2 × 103‐fold or more and did not alter the cytostatic properties of paclitaxelin vitro.The quantity of drug solubilized increased with the CyD concentration, but precipitation upon dilution occurred with some CyDs or stoichiometries. Thermal and spectroscopic (fluorescence, IR, NMR, and circular dichroism) analyses provided evidence of complex formation that was stable in the solid state but weak in solution, suggesting an explanation for the observed precipitation upon dilution. DMβCyD solutions of ≤3.7 mol % (mole of drug:mole of CyD) showed no precipitation upon dilution, nor did HPβCyD solutions of ≤0.14 mol %. Maximum tolerated dose (MTD) experiments showed uncomplexed DMβCyD to be toxic in mice at doses of 2 g CyD/kg body weight, the quantity required to administer paclitaxel at 10 mg/kg. HPβCyD allowed paclitaxel administration at higher doses and had an MTD of 25 mg drug/kg. The CyDs tested are marginal in feasibility for paclitaxel administration, and their use in taxane formulation will require a reduction of the dose‐limiting toxicity of the CyD itself.