Atsushi Kajiyama

Influence of physical factors in gastrointestinal tract on acetaminophen release from controlled-release tablets in fasted dogs

Abstract Four types of controlled-release (CR) acetaminophen (AAP) tablets, namely A, B, C and D, were prepared to investigate the influence of physical factors in the gastrointestinal (GI) tract on AAP release in fasted dogs. CR-A was designed as a completely resistant formulation to mechanical destructive force but to show an agitation speed-dependent dissolution rate. CR-B, CR-C and CR-D were designed to have different wet strengths but to show similar dissolution rates. The absorption profiles of the four CR forms in dogs showed biphasic patterns, with phase change about 2 h after oral dosing. The first phase of the absorption profile of CR-A and in vivo release directly observed were close to its in vitro profiles at a speed of 25–50 revs./min, indicating that agitation intensity in the dog GI tract may be relatively low. The first phase of the absorption profiles of the CR-B, CR-C and CR-D differed from each other, despite the fact that dissolution rates in vitro were similar. The tablet with low wet strength showed a faster absorption rate, indicating that it would be destructed by GI mechanical forces. Furthermore, absorption during the second phase was extremely low for all CR tablets. We confirmed on necroscopy that the suppression of drug absorption in the second phase was caused by the termination of AAP release from the tablets in the colon. These results will be useful in evaluating the in vivo performance of CR tablets in fasted dogs.