Two-Stage Single-Compartment Models to Evaluate Dissolution in the Lower Intestine

ABSTRACT:The purpose was to propose two-stage single-compartment models for evaluating dissolution characteristics in distal ileum and ascending colon, under conditions simulating the bioavailability and bioequivalence studies in fasted and fed state by using the mini-paddle and the compendial flow-through apparatus (closed-loop mode). Immediate release products of two highly dosed active pharmaceutical ingredients (APIs), sulfasalazine and L-870,810, and one mesalamine colon targeting product were used for evaluating their usefulness. Change of medium composition simulating the conditions in distal ileum (SIFileum) to a medium simulating the conditions in ascending colon in fasted state and in fed state was achieved by adding an appropriate solution in SIFileum. Data with immediate release products suggest that dissolution in lower intestine is substantially different than in upper intestine and is affected by regional pH differences > type/intensity of fluid convection > differences in concentration of other luminal components. Asacol ® (400 mg/tab) was more sensitive to type/intensity of fluid convection. In all the cases, data were in line with available human data. Two-stage single-compartment models may be useful for the evaluation of dissolution in lower intestine. The impact of type/intensity of fluid convection and viscosity of media on luminal performance of other APIs and drug products requires further exploration.