Design and Optimization of Pulsatile and Extended-Release Bilayer Tablets for Chronomodulated Delivery of Antidiabetic Drugs Using Box-Behnken Model
Abstract
Objective: To develop and optimize a chronotherapeutic bilayer tablet containing Metformin as an extended-release (ER) layer and Empagliflozin and Gliclazide as a pulsatile-release (PR) layer, with the aim of synchronizing drug release with the circadian rhythm of glucose metabolism to improve the management of type 2 diabetes mellitus.
Methods: A 3-factor, 3-level box–behnken design (BBD) was employed to optimize the formulation by investigating the effects of polymer ratio, coating concentration, and compression force on tablet hardness, lag time, and drug release. The optimized bilayer tablets were evaluated for physical characteristics, in vitro dissolution, and release kinetics using zero-order, first-order, Higuchi, and Korsmeyer–peppas models. Accelerated stability studies were performed according to ICH Q1A(R2) guidelines at 40±2 °C/75±5% RH for 3 mo.
Results: The optimized bilayer tablet exhibited satisfactory physical properties and a programmable pulsatile lag time of approximately 8 h. The ER layer provided sustained release of Metformin for up to 18 h, whereas the PR layer released Empagliflozin and Gliclazide following the predetermined lag period. Drug release kinetics revealed that Metformin followed the Higuchi diffusion model (R² = 0.992), while Empagliflozin and Gliclazide exhibited anomalous (erosion–diffusion) transport, best described by the Korsmeyer–Peppas model (R²>0.98). Stability testing demonstrated no significant changes in tablet appearance,…
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