An in vivo comparison of intestinal pH and bacteria as physiological trigger mechanisms for colonic targeting in man

Abstract

Targeting the colon for site-specific oral delivery can exploit one of two main physiological triggers; the intestinal pH changes or the increase in bacterial numbers in the distal gut. This study aimed to assess how these triggers compared in vivo to determine which concept provides better colon-specific release. Pellets were prepared using theophylline (model drug) and coated with methacrylic acid/methylmethcrylate co-polymer (Eudragit S [a pH-responsive polymer which dissolves above pH 7]) or amylose/ethylcellulose (a polysaccharide/polymeric mixture which is partially digested by colonic bacteria). The immediate release (uncoated) and the two sets of modified release (coated) pellets were administered to eight healthy fasted volunteers in a three-way crossover study. Drug levels were measured in the plasma, and the transit of the modified release pellets was followed by gamma scintigraphy. The immediate release pellets had T(max) values ranging from 0.5-2 h and bioavailability (AUC) ranging from 24.8-50.7 mcg h/ml. The pH-responsive pellets released drug in seven out of eight subjects. In those subjects in whom drug release occurred, the pellets had variable in vivo performance (T(max) ranging from 5-9 h; AUC 8.8-55.0 mcg h/ml) and drug release started in the small intestine for these pellets. The bacterially-triggered pellets (T(max) 8-10 h; AUC 16.5-47.9 mcg h/ml) were colon-specific; drug was detected in the blood only when the pellets reached the colon and release was more sustained than the pH system. The use of the bacterially-triggered delivery concept provided improved colonic delivery over the pH approach.