A lipophilic paclitaxel derivative incorporated in a lipid emulsion for parenteral administration

Paclitaxel is one of the most effective and most widely-used anti-cancer agents. However, paclitaxel is difficult to formulate for parenteral administration because of its low aqueous solubility and Cremophor EL, the excipient used for its formulation, has been shown to cause serious side effects. This study reports an alternative administration vehicle involving a lipophilic paclitaxel derivative, paclitaxel oleate, incorporated in the core of a nano-size sterically stabilized oil-in-water (o/w) lipid emulsion. This lipid emulsion, with a particle size of 50 run, has many favourable properties such as drug-carrier like biocompatibility, physical stability and ease of preparation. When paclitaxel in Cremophor EL/ethanol and paclitaxel oleate in emulsion were incubated with plasma a greater proportion of paclitaxel was found in the lipoprotein pool when formulated as paclitaxel oleate in a lipid emulsion compared to unesterified paclitaxel. The paclitaxel prodrug, paclitaxel oleate, demonstrated cytotoxic activity against cultured HeLa cells and with a marked increase in activity with incubation time. The 50% inhibition (IC50) was calculated to be 5500, 500, 150, and 100 nM for 24, 48, 72, and 96 h, respectively. Pharmacokinetic data, obtained with rabbits, showed significantly greater AUC, higher C-max lower systemic clearance and lower V-SS when paclitaxel was formulated as an oleate prodrug in a lipid emulsion than when formulated in Cremophor EL/ethanol. The formulated emulsion may be clinically useful not only for eliminating toxic effects of Cremophor EL but also for improvement of the pharmacokinetic parameters of paclitaxel. (C) 2002 Elsevier Science B.V. All rights reserved.