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Biopharmaceutical Modeling of Drug Supersaturation During Lipid-Based Formulation Digestion Considering an Absorption Sink

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Abstract

Purpose

In vitro lipolysis is widely utilized for predicting in vivo performance of oral lipid-based formulations (LBFs). However, evaluation of LBFs in the absence of an absorption sink may have limited in vivo relevance. This study aimed at employing biopharmaceutical modeling to simulate LBF digestion and drug supersaturation in a continuous absorptive environment.

Methods

Three fenofibrate-loaded LBFs were characterized in vitro (dispersion and lipolysis) and drug precipitation was monitored using in-line Raman spectroscopy. In vitro data were combined with pharmacokinetic data derived from an in vivo study in pigs to simulate intestinal LBF transit. This biopharmaceutical model allowed calculation of lipolysis-triggered drug supersaturation while drug and lipolysis products are absorbed from the intestine.

Results

The biopharmaceutical model predicted that, in a continuous absorption environment, fenofibrate supersaturation was considerably lower compared to in vitro lipolysis (non-sink). Hence, the extensive drug precipitation observed in vitro was predicted to be unlikely in vivo. The absorption of lipolysis products increased drug supersaturation, but drug precipitation was unlikely for highly permeable drugs.

Conclusions

Biopharmaceutical modeling is a valuable approach for predicting LBFs performance in vivo. In the absence of in vitro tools simulating absorptive conditions, modeling strategies should be further considered.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland

    Cordula Stillhart & Georgios Imanidis

  2. Institute of Pharma Technology, School of Life Sciences, University of Applied Sciences and Arts Northwestern Switzerland, Gründenstrasse 40, 4132, Muttenz, Switzerland

    Cordula Stillhart, Georgios Imanidis & Martin Kuentz

  3. School of Pharmacy, University College Cork, Cork, Ireland

    Brendan T. Griffin

Authors
  1. Cordula Stillhart
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  2. Georgios Imanidis
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  3. Brendan T. Griffin
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  4. Martin Kuentz
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Correspondence to Martin Kuentz.

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Stillhart, C., Imanidis, G., Griffin, B.T. et al. Biopharmaceutical Modeling of Drug Supersaturation During Lipid-Based Formulation Digestion Considering an Absorption Sink. Pharm Res 31, 3426–3444 (2014). https://doi.org/10.1007/s11095-014-1432-1

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  • DOI: https://doi.org/10.1007/s11095-014-1432-1

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