An Artificial Gut/Absorption Simulator: Simultaneous Evaluation of Desupersaturation and Absorption from Ketoconazole Supersaturated Solutions.

Autor:	Jain KMH; Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455., Hou HH; Small Molecule Pharmaceutical Sciences, Genentech Inc., South San Francisco, CA 94080. Electronic address: hou.hao@gene.com., Siegel RA; Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455; Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota 55455. Electronic address: siege017@umn.edu.
Jazyk:	angličtina
Zdroj:	Journal of pharmaceutical sciences [J Pharm Sci] 2023 Aug; Vol. 112 (8), pp. 2212-2222. Date of Electronic Publication: 2022 Sep 24.
DOI:	10.1016/j.xphs.2022.09.017
Abstrakt:	For supersaturating formulations of BCS-II compounds, which by definition have high intestinal permeability, a closed USP apparatus does not provide the necessary absorptive conditions during dissolution. To address this, an artificial gut simulator (AGS) has been constructed consisting of a 2.5 mL donor compartment in which a hollow fiber-based absorption module is suspended. Drug from donor diffuses across the hollow fiber membrane to be absorbed by the continuously flowing intraluminal receiver fluid. The membrane surface area and intraluminal fluid flow rate are tuned to obtain the physiologically observed absorption rate constant for a weakly basic, poorly water-soluble model compound, ketoconazole (KTZ). Supersaturated solutions of KTZ were generated in the donor in pH 6.5 phosphate buffer by the pH-shift method in the absence (closed system, control) and presence (open system, biorelevant) of an optimally or suboptimally tuned absorption module. Drug concentrations in the donor and intraluminal fluids were determined by in-line UV spectroscopy. The presence of an absorptive sink reduced the supersaturated solution's crystallization propensity, more so in the case of the optimally tuned AGS. This study demonstrates the significance of simulating absorption of drug at a physiological rate during dissolution studies, especially to predict the performance of formulations of BCS-II drugs. Competing Interests: Declaration of Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2022. Published by Elsevier Inc.)
Databáze:	MEDLINE
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