Drug Supersaturation in Simulated and Human Intestinal Fluids Representing Different Nutritional States

It was the purpose of this study to explore supersaturation of poorly soluble drugs in human intestinal fluids (HIF), and to assess potential food effects on the creation and maintenance of supersaturation. Duodenal fluids were collected from healthy volunteers and pooled according to three nutritional states (fasted-, fed-, and fat-enriched fed state). Supersaturation was created at a fixed degree of supersaturation (DS=20) using the solvent-shift method. Fasted- and fed-state simulated intestinal fluids (FaSSIF and FeSSIF) were used as intestinal simulation media.
Supersaturation in HIF showed to be stable up to a certain degree for different poorly soluble drugs. In HIF as well as in FaSSIF and FeSSIF, supersaturation appeared to be compound and medium specific. Supersaturation stability was found to be inversely proportional to the solubility in the corresponding media. Food intake affected itraconazole supersaturation positively. On the contrary, etravirine and loviride supersaturation decreased upon food intake. Supersaturation experiments in FaSSIF and FeSSIF showed similar results as in HIF for etravirine and loviride, whereas itraconazole supersaturation behaved differently in HIF versus simulation media. The present study illustrates, for the first time, that supersaturation can be created and maintained in HIF, even in the absence of excipients.
Bevernage J, Brouwers J, Clarysse S, Vertzoni M, Tack J, Annaert P, Augustijins P. Drug Supersaturation in Simulated and Human Intestinal Fluids Representing Different Nutritional States. J Pharm Sci. 2010. 99:4525–4534. Correspondence to Patrick Augustijns, Laboratory for Pharmacotechnology and Biopharmacy, Katholieke Universiteit Leuven, at patrick.augustijns@pharm.kuleuven.b) or 0032-16-33-03-12.