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Int J Pharm. 2017 Jun 15;525(1):211-217. doi: 10.1016/j.ijpharm.2017.04.029. Epub 2017 Apr 13.

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

Author information

1
Drug Delivery and Disposition, KU Leuven, Gasthuisberg O&N II, Herestraat 49 - Box 921, 3000 Leuven, Belgium.
2
Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
3
Drug Delivery and Disposition, KU Leuven, Gasthuisberg O&N II, Herestraat 49 - Box 921, 3000 Leuven, Belgium. Electronic address: patrick.augustijns@kuleuven.be.

Abstract

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.

KEYWORDS:

Cyclodextrin-based oral solution; Intestinal absorption; Itraconazole; Precipitation; Solid dispersion; Supersaturation

PMID:
28414135
DOI:
10.1016/j.ijpharm.2017.04.029
[Indexed for MEDLINE]

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