Development of bicarbonate buffer flow-through cell dissolution test and its application in prediction of in vivo performance of colon targeting tablets.

The purpose of this study was to develop a bicarbonate buffer flow-through cell (FTC) dissolution test. Mesalazine colon targeting tablets of a generic development product (test formulation, TF; Mesalazine 400 mg tablet) and the original product (reference formulation, RF; Asacol® 400 mg tablet) were used as model formulations. A clinical bioequivalence (BE) study was conducted on 48 healthy male subjects under fasting conditions. The oral absorption time profiles were calculated by point-area deconvolution. The compendial paddle and FTC apparatus were used for dissolution tests. Bicarbonate or phosphate-citrate buffer solutions (McIlvaine buffer) were used as the dissolution media. A floating lid was used to maintain the pH value of the bicarbonate buffer solution in the vessel (paddle) or the reservoir (FTC). In the development of bicarbonate FTC method, the pH changes of bicarbonate buffer solution (pH 5.5-7.5; 5-50 mM bicarbonate) were evaluated. For the evaluation of colon targeting tablets, the dissolution profiles of TF and RF were measured at a pH of 7.5. The TF and RF formulations were exposed to 0.01 HCl (pH 2.0) for 2 h before pH 7.5. In the clinical BE study, drug dissolution started 4-8 h after oral administration and continued slowly more than 10 h. Both the area under the curve (AUC) and maximum plasma concentration (Cmax) of TF were approximately twice as high as those of RF. In the development of the bicarbonate FTC method, the pH change of the bicarbonate buffer solution was suppressed by the floating lid within ∆pH < 0.1 over 10 h. In the dissolution test of McIlvaine buffer solutions, TF and RF showed faster disintegration and higher dissolution than those observed in the clinical BE study. When using the paddle apparatus the dissolution profiles of TF and RF in both buffer solutions were not consistent with those of the clinical result. In bicarbonate FTC, the disintegration time, dissolution rate, and dissolution inequivalence between TF and RF were consistent with the results of the clinical BE study. In conclusion, the bicarbonate FTC method was constructed for the first time in this study. This method is simple and practically useful for predicting in vivo performance of colon targeting tablets during drug development.