Development of a supersaturable SEDDS (S‐SEDDS) formulation of paclitaxel with improved oral bioavailability

Abstract

A new, supersaturable self‐emulsifying drug delivery system (S‐SEDDS) of paclitaxel was developed employing hydroxypropyl methylcellulose (HPMC) as a precipitation inhibitor with a conventional SEDDS formulation. In vitro dilution of the S‐SEDDS formulation results in formation of a microemulsion, followed by slow crystallization of paclitaxel on standing. This result indicates that the system is supersaturated with respect to crystalline paclitaxel, and the supersaturated state is prolonged by HPMC in the formulation. In the absence of HPMC the SEDDS formulation undergoes rapid precipitation, yielding a low paclitaxel solution concentration. A pharmacokinetic study was conducted in male Sprague‐Dawley rats to assess exposure after an oral paclitaxel dose of 10 mg/kg in the SEDDS formulations with (S‐SEDDS) and without HPMC. The paclitaxel S‐SEDDS formulation shows ∼10‐fold higher maximum concentration (Cmax) and five‐fold higher oral bioavailability (F ≈ 9.5%) compared with that of the orally dosed Taxol® formulation (F ≈ 2.0%) and the SEDDS formulation without HPMC (F ≈ 1%). Coadministration of cyclosporin A (CsA), an inhibitor of P‐glycoprotein and CYP 3A4 enzyme, at a dose of 5 mg/kg with the S‐SEDDS formulation further increased the oral bioavailability (F ≈ 22.6%). This assessment demonstrates that the systemic exposure of paclitaxel following oral administration can be substantially improved via the S‐SEDDS approach. © 2003 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2386–2398, 2003