Innovative Approaches in Mirtazapine Delivery: Pharmacokinetic Simulations, Immediate Release to Controlled-Release Tablets, Formulation Optimization via D-optimal Mixture Design

Abstract

This research study describes the formulation and evaluation of Mirtazapine Controlled-Release (CR) Tablets, intended to improve therapeutic efficacy and patient compliance. Utilizing pharmacokinetic data from the USFDA-approved Remeron Immediate-Release (IR) Tablets, we constructed a plasma profile curve and calculated the following pharmacokinetic parameters Cmax, T max, AUC, Vd, and Ke. The principle of superposition method was employed to simulate steady-state plasma concentrations (Css), establishing target Css max and Css min values. These targets guided the development of our controlled-release formulation, which was designed to achieve a zero-order release mechanism. The dose and release rate of the proposed controlled-release tablets were precisely adjusted to meet the targeted Css max and Css min concentrations. Our formulation strategy utilized different hydrophilic polymers such as HPMC, Carbopol, and Polyethylene oxide to create a robust ER matrix, we employed D Optimal Mixture Design to optimize the concentration of these three critical formulation variables. Dissolution studies were conducted in different media such as 0.01 N HCl, pH 4.5 Acetate buffer, and pH 6.8 Phosphate buffer for 14 hours to evaluate the rate, extent, and drug release kinetics. The successful simulation of plasma concentrations, followed by adjustments of dose, release rate, and subsequent optimization of formulation variables using the Design of experiments yielded a CR tablet that meets the pharmacokinetic endpoints set by the IR reference. This innovative approach to Mirtazapine CR tablet formulation could significantly enhance patient compliance by providing a more consistent and controlled drug delivery system.