Sophie Geboers

Gastrointestinal behavior of itraconazole in humans – Part 1: Supersaturation from a solid dispersion and a cyclodextrin-based solution

This study evaluated the fasted state gastrointestinal behavior of the lipophilic drug itraconazole, orally administered to healthy volunteers as either a solid dispersion (Sporanox® capsules) or a cyclodextrin-based solution (Sporanox® solution). Following intake of the drug products, gastric and duodenal fluids were aspirated and analyzed for itraconazole concentration, total content and solubilizing capacity. Release of itraconazole from the solid dispersion generated high and metastable supersaturated levels in the stomach, but the dissolved fraction in the duodenum remained extremely low (median 2.5%). After intake of the itraconazole solution, precipitation was limited in the stomach but pronounced in the small intestine. Still, the dissolved fraction of itraconazole in the duodenum (median 38%) appeared much higher than after intake of the solid dispersion, possibly explaining the improved absorption of itraconazole from the solution. As for the solid dispersion, the absorption-enabling ability of the solution appeared mainly related to increased intraluminal concentrations by means of supersaturation. Cyclodextrin-based solubilization of itraconazole occurred only in the case of limited intraluminal dilution, but did not further enhance itraconazole absorption. The obtained data will help to understand critical aspects of supersaturating drug delivery systems and act as direct reference for the optimization of in vitro simulation tools for gastrointestinal drug behavior.

In vitro and in vivo investigation of the gastrointestinal behavior of simvastatin.

Simvastatin (SV) is marketed as a lactone ester prodrug which is hydrolyzed to the active simvastatin hydroxyacid (SVA). SV is characterized by a low solubility and undergoes extensive first-pass metabolism. In this study, the influence of the upper gastrointestinal environment on the intraluminal behavior of simvastatin was investigated by a series of in vitro experiments. Dissolution, stability and two-stage dissolution tests were performed using simulated and human gastrointestinal fluids. The dissolution studies revealed a relatively slow dissolution of SV as well as conversion of SV to SVA. The hydrolysis of SV was further examined and stability studies indicated a faster conversion in gastric fluids than in intestinal fluids. These isolated phenomena were then confirmed by the more integrative two-stage dissolution studies. To estimate the predictive value of the in vitro tests, an additional in vivo study was performed in which the gastrointestinal concentration-time profiles also revealed a slow dissolution of SV and faster degradation of SV to SVA in the stomach than in the intestinal tract. However, the plasma concentrations of SV and SVA did not directly correlate with the observed gastrointestinal concentrations, suggesting that gut wall and hepatic metabolism have a greater impact on systemic exposure of SV than the intraluminal interconversion between SV and SVA.