Stereoselective Disposition of Ibuprofen Enantiomer Sustained Release Microspheres in Rats: I. Bioavailability Considerations

Abstract

The purpose of this study was to examine the gastrointestinal tract (GIT) disposition of sustained release microspheres of ibuprofen enantiomers. Male Wistar rats were dosed with three formulations of ibuprofen enantiomers (R and S): intravenous solution (IV), conventional suspensions, and suspensions of the sustained release wax matrix microspheres. Blood samples were withdrawn at predetermined time intervals and analyzed by a stereospecific HPLC assay. The Cmax was reduced, the Tmax delayed, and the (AUC) increased for sustained release (SR) as compared with conventional suspensions (CS) of the enantiomers. In all cases, the AUC for Sibuprofen was greater than that for R-ibuprofen. The bioavailability of the SR formulation of both the enantiomers was much higher than that of the CS. Plasma concentration-time profiles of the intravenous, conventional, and sustained release suspension showed inversion of R- to S-ibuprofen indicating that inversion was both systemic and presystemic. The concentration-time profiles of the microspheres showed bimodal absorption with the second peak appearing after 8 hr. Greater S/R (AUC0 48) values were observed for conventional suspension compared with the sustained release microsphere suspension. The S/R (AUC) ratios calculated for the two different time segments of (0-8) and (0-48) hours showed that most of the inversion took place within 8 hr for the conventional suspension, whereas for the microspheres, more inversion took place beyond 8 hr. This finding indicated that greater inversion took place in the upper GIT for CS and lower GIT for SR. The amount absorbed was also site-specific. Significant (p < .05) Level A in vitro-in vivo correlations (IVIVC) were developed for different formulations of the enantiomers of ibuprofen. Ibuprofen microspheres made with the enantiomers showed higher bioavailability than the conventional suspension. Inversion was observed both systemically and presystemically. Bimodal plasma concentration time profiles indicating colonic absorption were observed with the sustained release suspension. On the basis of the IVIVC, a reliable prediction of the plasma concentrations obtained following a single dose was found.