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Int J Pharm. 2018 Aug 25;547(1-2):158-168. doi: 10.1016/j.ijpharm.2018.05.029. Epub 2018 May 11.

The effects of three absorption-modifying critical excipients on the in vivo intestinal absorption of six model compounds in rats and dogs.

Author information

1
Department of Pharmacy, Uppsala University, Uppsala, Sweden.
2
AstraZeneca R&D, Gothenburg, Sweden.
3
School of Pharmacy, Johannes Gutenberg-University, Mainz, Germany.
4
Department of Neuroscience, Division of Physiology, Uppsala University, Uppsala, Sweden.
5
Department of Pharmacy, Uppsala University, Uppsala, Sweden. Electronic address: hans.lennernas@farmaci.uu.se.

Abstract

Pharmaceutical excipients that may affect gastrointestinal (GI) drug absorption are called critical pharmaceutical excipients, or absorption-modifying excipients (AMEs) if they act by altering the integrity of the intestinal epithelial cell membrane. Some of these excipients increase intestinal permeability, and subsequently the absorption and bioavailability of the drug. This could have implications for both the assessment of bioequivalence and the efficacy of the absorption-enhancing drug delivery system. The absorption-enhancing effects of AMEs with different mechanisms (chitosan, sodium caprate, sodium dodecyl sulfate (SDS)) have previously been evaluated in the rat single-pass intestinal perfusion (SPIP) model. However, it remains unclear whether these SPIP data are predictive in a more in vivo like model. The same excipients were in this study evaluated in rat and dog intraintestinal bolus models. SDS and chitosan did exert an absorption-enhancing effect in both bolus models, but the effect was substantially lower than those observed in the rat SPIP model. This illustrates the complexity of the AME effects, and indicates that additional GI physiological factors need to be considered in their evaluation. We therefore recommend that AME evaluations obtained in transit-independent, preclinical permeability models (e.g. Ussing, SPIP) should be verified in animal models better able to predict in vivo relevant GI effects, at multiple excipient concentrations.

KEYWORDS:

Absorption modifiers; Bioequivalence; Intraintestinal administration; Permeation enhancers; Pharmaceutical development

PMID:
29758344
DOI:
10.1016/j.ijpharm.2018.05.029
[Indexed for MEDLINE]

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