Guiding a Diclofenac Sodium Dual-Release Sustained Formulation Development Through In Vitro-In Vivo Relationship...

Background: Dual-release sustained formulations enable rapid drug release for prompt therapeutic onset while retaining the characteristics of sustained-release dosage forms. However, due to the complexity of this dosage form, conventional trial-and-error approaches fail to mitigate development risks or improve the success rate of bioequivalence studies of the generic product. Accordingly, the present study aims to investigate the feasibility of guiding a dual-release generic formulation screening through establishing a quality-related media condition through construction of PBPK models and IVIVR for the reference product. Methods: Here, Difene^® was selected as the reference product, and GastroPlus^TM was employed as the simulation platform. Pharmacokinetic data obtained from the literature and in vitro dissolution test results were integrated to construct the PBPK model for the reference product and establish IVIVR in different media, respectively. A quality-related media condition was determined for formulation screening of the generic product. A pharmacokinetic study in beagle dogs was then conducted to evaluate the bioequivalence between the generic and the reference product. Results: In the PBPK modeling and IVIVR study, the PBPK model was successfully established. The IVIVR for the pH 4.0-pH 6.0-pH 6.8 media was optimal in all media conditions, with fold error ratios of 1.11, 0.86, and 1.11 for C_max, AUC, and T_max, respectively, all falling within the 0.80-1.25 range. Employing this medium as the quality-related media, the optimized generic product exhibited an f2 factor of 76 with the reference product in vitro. Pharmacokinetic studies in beagle dogs demonstrated that the geometric mean ratios and 90% confidence intervals for AUC and C_max of the generic product versus the reference product were within the 80.0-125.0% range. No statistically significant difference was observed for T_max, indicating bioequivalence between the two products. Conclusions: Overall, our study provides a strategic approach for generic development and a novel research framework for the generic development of other dual-release formulations.