Novel Taxol Formulations: Preparation and Characterization of Taxol-Containing Liposomes

Abstract

Taxol is a promising anticancer agent under investigation for therapy of ovarian, breast, colon, and head and neck cancer. One problem associated with the administration of taxol is its low solubility in most pharmaceutically-acceptable solvents; the formulation used clinically contains Cremophor EL^® (polyethoxylated castor oil) and ethanol as excipients, which cause serious adverse effects. To eliminate this vehicle and possibly improve the antitumor efficacy of taxol, we have formulated taxol in liposomes of various compositions. Liposome formulations containing taxol and phospholipid in the molar ratio 1:33 were prepared from phosphatidylglycerol (PG) and phosphatidylcholine (PC) (1:9 molar ratio), and were physically and chemically stable for more than 2 months at 4°C, or for 1 month at 20°C. A method of producing taxol-liposomes by lyophilization has been developed, by which large batches can be prepared reproducibly in a ‘pharmaceutically rational’ manner. Taxol-liposomes retained the growth-inhibitory activity of the free drug in vitro against a variety of tumor cell lines. In mice, taxol-liposomes were well-tolerated when given in bolus doses by both iv and ip routes. The Maximum Tolerated Dose (MTD) was >200 mg/kg; it exceeded that of free taxol, which had a MTD of 30 mg/kg by iv or 50 mg/kg by ip administration. Free taxol administered in the Cremophor vehicle was toxic at doses >30 mg/kg, as was the equivalent volume of vehicle without drug. Taxol-liposomes may prove to be useful not only for eliminating the toxic effects attributed to the Cremophor vehicle, but also for providing opportunities to widen the taxol therapeutic index through alterations in route and schedule of administration.