Oral Solid Controlled Release Dosage Forms: Role of GI-Mechanical Destructive Forces and Colonic Release in Drug Absorption Under Fasted and Fed Conditions in Humans

Purpose. This study was undertaken to examine the effects of mechanical destructive forces on drug release from controlled release (CR) dosage forms in vitro and in vivo and their colonic release, using two CR tablets of acetaminophen A and B, showing slower and faster erosion rates, respectively.Methods. In vitro release rates were determined by several official methods. Tablets were administered to healthy volunteers under fasting and fed conditions.Results. Both tablets showed similar release rates under mild destructive conditions (e.g., paddle method at 10 rpm) but CR-B showed faster release under highly destructive conditions (e.g., rotating basket method at 150 rpm), where the tablet was eroded. The in vivo release from CR-B was faster than from CR-A, possibly because of enhanced erosion. The variable in vivo release from CR-B indicated large inter-subject differences in destructive GI forces. The fastest in vivo release from CR-B among individuals was approximated by the in vitro dissolution determined by destructive methods such as the rotating basket at 150 rpm. The slowest in vivo release from tablets A and B was lower than the dissolution by the paddle method at 10 rpm. The release from both tablets was markedly reduced at 3–4 hrs after dosing irrespective of feeding conditions which can be attributed to release inhibition in the colon.Conclusions. Effects of GI destructive forces on the tablet erosion and the release inhibition in the colon must be considered in the development of CR dosage forms.