Dissolution and dissolution/permeation experiments for predicting systemic exposure following oral administration of the BCS class II drug clarithromycin.
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.
Department of Pharmaceutical Technology and Biopharmaceutics, Johannes Gutenberg University, Mainz, Germany. Electronic address: krmeinha@uni-mainz.de.
Forner
F
Kristin
Drug Product Development, Janssen Research and Development, Johnson & Johnson, Beerse, Belgium. Electronic address: rholm@ITS.JNJ.com.
Holm
H
René
Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Thailand.
Morakul
M
Boontida
Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Thailand. Electronic address: varaporn.jun@mahidol.ac.th.
Junyaprasert Varaporn
JV
Buraphacheep
Institute of Clinical and Functional Anatomy, University Medical Center Johannes Gutenberg University, Mainz, Germany. Electronic address: maximilian.ackermann@uni-mainz.de.
Ackermann
A
Maximilian
Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center Johannes Gutenberg University, Mainz, Germany. Electronic address: mazur@uni-mainz.de.
Mazur
M
Johanna
Department of Pharmaceutical Technology and Biopharmaceutics, Johannes Gutenberg University, Mainz, Germany. Electronic address: langguth@uni-mainz.de.
Langguth
L
Peter
D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000502:physiology*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D017291:Clarithromycin / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism*; D005079:Excipients / Q000737:chemistry; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D009093:Mucus / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility
D005079:Excipients; D017291:Clarithromycin
Caco-2 cells; Excised rat intestinal sheets; Nanoparticles; Poloxamer 407; SLS; Ussing Chamber