A multi-mechanistic drug release approach in a bead dosage form and in vitro/in vivo correlations

An in vitro/in vivo relationship of a combined multi-mechanistic dosage form has now been established in the literature. In our previous study, we successfully prepared a combination of immediate release, enteric coated, and controlled-release (CR) beads and mathematically modeled in vitro and in vivo drug release characteristics of the combination based on the release profiles of individual beads. The objective of the present study is to develop in vitro/in vivo correlations (IVIVC) for three individual beads and the combination using theophylline as a model drug and the beagle dog as an animal model. In the study, an IVIVC correlation is estimated by two-stage procedures: deconvolution followed by comparison of the fraction of drug absorbed to the fraction of drug dissolved. The Wagner-Nelson mass balance method was used to deconvolute plasma drug concentration-time curves. In vitro, a two-stage medium (0.1 N HCl and pH 6.5 phosphate buffer) was used for the dissolution test; a 2h first stage (acidic) was selected based on the average gastric emptying time in a fasted dog. In vivo, t(lag) was used for the gastric emptying process for enteric coated beads and the combination, which contains enteric coated beads. A time-scaling technique was used to consider the rate difference between in vitro dissolution and in vivo absorption in the process of IVIVC. As shown in the results, a point-to-point correlation was established for each formulation. The linear regression analysis of the correlation was r2>0.99 for all three individual beads and 0.97 for the combined bead dosage form. The results suggest level A IVIVCs indicating an appropriateness for the in vitro and in vivo models used in this study.