Laboratory for Pharmacotechnology and Biopharmacy, Katholieke Universiteit Leuven, O&N 2, Herestraat 49, Box 921, 3000 Leuven.
J Pharm Sci. 2010 Nov;99(11):4525-34. doi: 10.1002/jps.22154.
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.
本研究旨在探索人类肠液（HIF）中难溶性药物的过饱和度，并评估食物对过饱和度的产生和维持的潜在影响。从健康志愿者中收集十二指肠液，并根据三种营养状态（空腹、进食和高脂肪进食状态）进行分组。使用溶剂转移法在固定过饱和度程度（DS=20）下创建过饱和度。使用模拟肠液（FaSSIF 和 FeSSIF）作为肠模拟介质。结果显示，HIF 中的过饱和度对于不同的难溶性药物在一定程度上是稳定的。在 HIF 以及 FaSSIF 和 FeSSIF 中，过饱和度似乎与化合物和介质特异性有关。过饱和度稳定性与相应介质中的溶解度成反比。食物摄入对依曲康唑的过饱和度有积极影响。相反，依曲韦林和洛匹那韦的过饱和度在进食后会降低。FaSSIF 和 FeSSIF 中的过饱和度实验结果与 HIF 中依曲韦林和洛匹那韦的结果相似，而 HIF 中依曲康唑的过饱和度行为与模拟介质不同。本研究首次表明，即使没有赋形剂，过饱和度也可以在 HIF 中产生和维持。
