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 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 did not alter the
cytostatic properties of
paclitaxel in 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.
DM beta CyD solutions of < or = 3.7 mol % (mole of
drug:mole of CyD) showed no precipitation upon dilution, nor did HP beta CyD solutions of < or = 0.14 mol %. Maximum tolerated dose (MTD) experiments showed uncomplexed
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. HP beta CyD 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.