Transient Supersaturation Supports Drug Absorption from Lipid-Based Formulations for Short Periods of Time, but Ongoing Solubilization Is Required for Longer Absorption Periods

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• 作者：Matthew F. Crum ; Natalie L. Trevaskis ; Colin W. Pouton ; Christopher J. H. Porter
• 刊名：Molecular Pharmaceutics
• 出版年：2017
• 出版时间：February 6, 2017
• 年：2017
• 卷：14
• 期：2
• 页码：394-405
• 全文大小：492K
• ISSN：1543-8392

文摘

The current studies sought to explore the impact of drug supersaturation and precipitation during the dispersion and digestion of lipid-based formulations (LBFs), on in vivo absorption using a coupled in vitro digestion–in vivo perfusion absorption model. Fenofibrate absorption was evaluated from a number of LBFs with different solubilization and supersaturation capacities, and conditions at the absorptive membrane manipulated by changing perfusion conditions, intestine segment lengths, and by the conduct of experiments in the presence or absence of suspended/precipitated drug. LBF dispersion and digestion resulted in varying periods of supersaturation across the different formulations. Even fleeting (5–10 min) periods of supersaturation were able to drive flux across a perfused 10 cm intestinal segment for up to 60 min, although over longer infusion periods (60–80 min) flux dropped in the absence of ongoing drug solubilization and supersaturation. In contrast, the presence or absence of precipitated/suspended drug, had little impact on drug flux. When perfused intestinal segment lengths were extended, the role of initial supersaturation was attenuated and ongoing solubilization conditions became the primary driver of absorptive flux. The data suggest that for highly permeable drugs such as fenofibrate, a short period of supersaturation at the absorptive membrane may be sufficient to drive absorptive drug flux in spite of significant drug precipitation on formulation dispersion or digestion in vitro. In contrast, where longer periods of absorption are required, for example, at higher doses, the requirement for ongoing solubilization and supersaturation becomes more apparent.