Simulation of gut motility effect in the USP dissolution apparatus to study drug release in the large intestine.

Abstract

An apparatus was designed and constructed to simulate the effect of large intestinal motility on drug release measurement in vitro, the purpose being to evaluate the influence of implementing gut motility on release rate from matrix tablets intended for controlled colonic delivery. The USP 1 dissolution apparatus was modified by replacing the basket with a bag holder and a mesh bag that contained the dosage form and adding polymer beads inside and outside of the bag in the dissolution vessel (Bag-Beads model). The motility index resulting from contractions of the gut wall was calculated from intraluminal pressure data measured in the large intestine of healthy volunteers with the SmartPill® ingestible telemetric capsule. It was possible to reproduce this motility index in the in vitro Bag-Beads model utilizing the SmartPill® by adjusting the number of beads of appropriate size and density and the rotation rate of the shaft holding the bag. Reproducibility of motility index and drug release measurement was established and a correlation between in vitro motility index and drug release rate was found for matrix tablets consisting of xyloglycan. This is a plant polysaccharide used as matrix former that was demonstrated previously to provide controlled colonic release by the action of bacterial enzymes. Drug release rate in the Bag-Beads model replicating the in vivo motility index was higher than release rate measured in the compendial USP 2 apparatus. This was true for different levels of bacterial xyloglucanase activity. It is concluded that this simulation of motility provides an indication of the effect of large intestinal dynamics on drug release. A comparison of the measured release rate with preclinical in vivo results is discussed, additional data is required, however, for an in vitro - in vivo correlation. The study highlights the potential to simulate the effect of contractile large intestinal activity for better in vitro prediction of drug release and the possibility to develop and optimize colonic targeting formulations under improved biorelevant testing conditions.