Preparation and evaluation of paclitaxel-containing liposomes

Paclitaxel, an antitumoral drug, is poorly soluble in aqueous media. Therefore, in a commercialised formulation (Taxol), paclitaxel (30 mg active compound) is dissolved in polyethoxylated castor oil (Cremophor EL) and ethanol. After dilution of Taxol in aqueous media paclitaxel tends to precipitate. Several side effects, attributed to the surfactant Cremophor EL, occur, e.g. bronchospasm, hypotension, neuro- and nephrotoxicity, and anaphylactic reactions. To eliminate these side effects, the solubility of paclitaxel was enhanced using liposomes instead of Cremophor EL. The amount of entrapped paclitaxel in crystal-free liposomes was 0.5 mg/ml liposome suspension, i.e. almost 85 times the native solubility. Thus, 30 mg paclitaxel had to be dissolved in 60 ml liposome suspension, of either multi-lamellar vesicles (MLV's) or of small unilamellar vesicles (SUV's) with 5% sucrose as cryoprotector. No precipitation was observed after dilution of the MLV-formulation with (physiological) water or with 5% aqueous dextrose solution, which proves their suitability for administration with perfusions. The chemical stability of paclitaxel in the prepared MLV's stored at 4 degrees C was demonstrated during a period of 5 months. The chemical degradation to conjugated dienes and hydroperoxides, two oxidative degradation products of EPC, was negligible (less than 1%).