Intestinal absorption of penclomedine from lipid vehicles in the conscious rat:: contribution of emulsification versus digestibility

While the inclusion of highly lipophilic compounds in self-emulsifying drug delivery systems (SEDDS) is often reported to result in strongly enhanced oral absorption, it is still controversial whether further lipolysis of the dispersed lipidic material is required for final transfer to the enterocyte membranes. In order to assess the relative roles of lipid vehicle dispersion and vehicle digestibility in the oral absorption of penclomedine (Pcm), a series of formulations of Pcm in medium chain triglyceride (MCT)/tocophersolan (TPGS) was developed having three sizes (160 nm, 720 nm, and mm-sized ('crude' oil)); with or without the inclusion of tetrahydrolipstatin (THL), a known lipase-inhibitor. Oral absorption of Pcm was studied after administration of small volumes of these formulations in the conscious rat. Kinetic evaluation was performed using population analysis. Formulations with particle size 160 nm had the highest relative bioavailability (set at F = 1), whereas administration in particle size 720 run had slightly lower bioavailability (F = 0.79). Co-inclusion of THL yielded similar bioavailability for these two SEDDS. 'Crude' oil formulations had F = 0.62 (without THL) and 0.25 (with THL). The data in the current investigation emphasize the prominent role of increased vehicle dispersion relative to digestibility in the absorption of Pcm from MCT-TPGS in submicron emulsions. Only with Pcm administered as undispersed MCT, absorption was more dependent on the action of lipase as bioavailability was inhibited two-fold by the co-incorporation of THL. (C) 2003 Elsevier B.V. All rights reserved.