Relationship Between Gelation Rate of Controlled-release Acetaminophen Tablets Containing Polyethylene Oxide and Colonic Drug Release in Dogs

Abstract

Purpose. We hypothesized that sufficient gelation of orally administered hydrophilic matrix tablets before they reach the colon could, as a result of continuous erosion of the gelated matrix, prevent the decrease in colonic drug release which normally occurs here. The purpose of this study was to elucidate the effect of gelation of hydrophilic matrices containing polyethylene oxide on colonic drug release in dogs using controlled-release (CR) acetaminophen tablets. Methods. Two types of CR tablets were prepared, a slow gelling tablet (SG) and a rapid gelling tablet (RG) containing an extra highly water soluble filler. In vitro and in vivo performance were examined. Results. SG and RG showed similar drug release behavior in vitro. In oral administration to dogs, the two formulations showed similar gastrointestinal transit, reaching the colon within 2–4 h after oral dosing. Further, they showed similar maximum plasma levels (Cmax) and time to Cmax (Tmax). In contrast, however, the two tablets produced different plasma levels from 2 h post-dosing, with plasma levels of RG higher than those of SG and with smaller individual variation. Directly observed colonic drug release behavior of RG was similar to in vitro drug release, whereas that from SG was suppressed. Conclusions. Colonic drug release is closely related to the gelation of hydrophilic matrix, and rapid gelation provides continuous in vivo drug release.