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  • Title: The conflict between in vitro release studies in human biorelevant media and the in vivo exposure in rats of the lipophilic compound fenofibrate.
    Author: Do TT, Van Speybroeck M, Mols R, Annaert P, Martens J, Van Humbeeck J, Vermant J, Augustijns P, Van den Mooter G.
    Journal: Int J Pharm; 2011 Jul 29; 414(1-2):118-24. PubMed ID: 21596119.
    Abstract:
    The performance of four different lipid-based (Tween 80-Captex 200P, Tween 80-Capmul MCM, Tween 80-Caprol 3GO and Tween 80-soybean oil) and one commercially available micronized formulation (Lipanthyl Micronized(®)) of the lipophilic compound fenofibrate was compared in vitro in various biorelevant media and in vivo in rats. In simulated gastric fluid without pepsin (SGF(sp)) and fasted state simulated intestinal fluid (FaSSIF), only Tween 80-Captex 200P system resulted in a stable fenofibrate concentration, but no supersaturation was obtained. The other three lipid based systems created fenofibrate supersaturation; however they did not maintain it. In fed state simulated intestinal fluid (FeSSIF), all lipid-based formulations resulted in complete dissolution of fenofibrate during the experiment, which represented a supersaturated state for Tween 80-Capmul MCM and Tween 80-Caprol 3GO systems. In both FaSSIF and FeSSIF, all lipid-based formulations yielded a higher fenofibrate concentration than the micronized formulation. Contrary to the in vitro results, no significant difference in the in vivo performance was observed among the four tested lipid-based formulations both in the fasted and the fed states. The in vivo performance of all lipid-based formulations was better than that of Lipanthyl Micronized(®), in the fasted as well as in the fed state. The fact that for the lipid based systems the in vitro differences in pharmaceutical performance were not translated into in vivo differences can be attributed to the continuous excretion of bile in the gastrointestinal tract of rats, causing enhanced solubilizing capacity for lipophilic drugs. This study clearly points to the conflicting situation that might arise during the preclinical phase of the development of lipid based formulations of lipophilic drugs as the performance of such systems is very often evaluated by both in vitro release studies in human biorelevant media as well as in vivo studies in rats. Care must be taken to select a relevant animal model.
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