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Eur J Pharm Sci. 2017 Apr 1;101:211-219. doi: 10.1016/j.ejps.2017.02.003. Epub 2017 Feb 4.

Dissolution and dissolution/permeation experiments for predicting systemic exposure following oral administration of the BCS class II drug clarithromycin.

Author information

1
Department of Pharmaceutical Technology and Biopharmaceutics, Johannes Gutenberg University, Mainz, Germany. Electronic address: krmeinha@uni-mainz.de.
2
Drug Product Development, Janssen Research and Development, Johnson & Johnson, Beerse, Belgium. Electronic address: rholm@ITS.JNJ.com.
3
Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Thailand.
4
Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Thailand. Electronic address: varaporn.jun@mahidol.ac.th.
5
Institute of Clinical and Functional Anatomy, University Medical Center Johannes Gutenberg University, Mainz, Germany. Electronic address: maximilian.ackermann@uni-mainz.de.
6
Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center Johannes Gutenberg University, Mainz, Germany. Electronic address: mazur@uni-mainz.de.
7
Department of Pharmaceutical Technology and Biopharmaceutics, Johannes Gutenberg University, Mainz, Germany. Electronic address: langguth@uni-mainz.de.

Abstract

In order to save time and resources in early drug development, in vitro methods that correctly predict the formulation effect on oral drug absorption are necessary. The aim of this study was to 1) evaluate various BCS class II drug formulations with in vitro methods and in vivo in order to 2) determine which in vitro method best correlates with the in vivo results. Clarithromycin served as model compound in formulations with different particle sizes and content of excipients. The performed in vitro experiments were dissolution and dissolution/permeation experiments across two types of membrane, Caco-2 cells and excised rat intestinal sheets. The in vivo study was performed in rats. The oral absorption was enhanced by downsizing drug particles and by increasing the excipient concentration. This correlated strongly with the flux across Caco-2 cells but not with the other in vitro experiments. The insufficient correlation with the dissolution experiments can be partly explained by excipient caused problems during the filtration step. The very poor correlation of the in vivo data with the flux across excised rat intestinal sheets might be due to an artificially enlarged mucus layer ex vivo. In conclusion, downsizing BCS class II drug particles and the addition of surfactants enhanced the in vivo absorption, which was best depicted by dissolution/permeation experiments across Caco-2 cells. This setup is proposed as best model to predict the in vivo formulation effect. Also, this is the first study to evaluate the impact of the nature of the permeation membrane in dissolution/permeation experiments.

KEYWORDS:

Caco-2 cells; Excised rat intestinal sheets; Nanoparticles; Poloxamer 407; SLS; Ussing Chamber

PMID:
28179133
DOI:
10.1016/j.ejps.2017.02.003
[Indexed for MEDLINE]

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