Optimizing Extended-release Formulation of l-tetrahydropalmatine Based on In Vivo Outcomes Using Integrated Modeling Approaches.

Abstract

l-Tetrahydropalmatine (l-THP) is a promising drug candidate for addiction treatment and needs to be delivered in extended-release dosage forms for safety and efficiency. This study aims to optimize extended-release formulations containing l-THP to achieve desired in vivo outcomes (C_max, onset of action, and duration of action) by integrating multiple computational tools including in vitro-in vivo correlation (IVIVC), physiologically based pharmacokinetic (PBPK), and design of experiments (DoE). The in vivo predictable dissolution method was chosen based on level A IVIVC. Then, PBPK model was developed and validated to explore the influences of physiological and formulation factors on the bioavailability of l-THP from hydrophilic matrix tablets. Finally, the PBPK model was incorporated with DoE to investigate the impact of formulation variables on in vivo outcomes and optimize the hydrophilic matrix tablet formulation for desired C_max, start time of action, and duration of action. USP Apparatus I, 450 ml HCl 0.1 N, 100 rpm demonstrated the highest level of correlation between in vitro dissolution and in vivo absorption, among the tested conditions. The PBPK model accurately predicted l-THP pharmacokinetics, meeting U.S.FDA requirements for prediction errors. The PBPK model identified dissolution parameters and gut first-pass extraction as key factors affecting l-THP bioavailability. The optimized formulation was estimated to exhibit an early onset of action (0.68 h), remain effective for more than 11.4 h, and be safe with C_max consistently falling within the therapeutic window. The present approach can be applied to design other drug delivery systems for flexible in vivo outcomes.