Development of a Supersaturable SEDDS (S-SEDDS) Formulation of Paclitaxel with Improved Oral Bioavailability PING GAO, 1 BOBBY D. RUSH, 2 WILLIAM P. PFUND, 1 TIEHUA HUANG, 1 JULIANE M. BAUER, 1 WALTER MOROZOWICH, 1 MING-SHANG KUO AND, 3 MICHAEL J. HAGEMAN 1 1 Global Pharmaceutical Sciences, Pfizer Inc., 301 Henrietta Street, Kalamazoo, Michigan 49007 2 Global Drug Metabolism, Pfizer Inc., 301 Henrietta Street, Kalamazoo, Michigan 49007 3 Drug Discovery, Pfizer Inc., 301 Henrietta Street, Kalamazoo, Michigan 49007 Received 28 April 2003; revised 7 July 2003; accepted 14 July 2003 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 (C max ) and five-fold higher oral bioavailability (F & 9.5%) compared with that of the orally dosed Taxol 1 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 sub- stantially improved via the S-SEDDS approach. ß 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2386– 2398, 2003 Keywords: bioavailability; hydroxypropyl methylcellulose; emulsion/microemulsion; oral absorption; solubility; supersaturation; paclitaxel; precipitation INTRODUCTION Conventional self-emulsifying drug delivery for- mulations (SEDDS) are widely used in enhancing the oral absorption of poorly soluble drugs. 1–5 The high surfactant level typically present in SEDDS formulations can lead to gastrointestinal (GI) side-effects as well as a reduction in the free drug concentration and thus a reduced rate of intest- inal absorption. 6 In an attempt to reduce the surfactant side-effects and achieve rapid absorp- tion of poorly soluble drugs, we recently designed and developed a new class of supersaturable formulations including supersaturable SEDDS (S-SEDDS) formulations. 7 The S-SEDDS ap- proach is to generate a protracted supersaturated solution of the drug when the formulation is released from an appropriate dosage form (i.e., capsule) into an aqueous medium. The S- SEDDS formulations contain a reduced surfac- tant level and a polymeric precipitation inhibitor 2386 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 12, DECEMBER 2003 Correspondence to: Ping Gao (Telephone: 269-833-6474; Fax: 269-833-2325; E-mail: ping.gao@pfizer.com) Journal of Pharmaceutical Sciences, Vol. 92, 2386–2398 (2003) ß 2003 Wiley-Liss, Inc. and the American Pharmacists Association