Enhanced Systemic Exposure and Efficacy of Diltiazem from Novel Microemulsion Formulation: Characterization, In vitro Release, In vivo Pharmacokinetic and Efficacy Evaluation

Purpose: Diltiazem, a calcium ion cellular influx inhibitor is known for its limited and variable bioavailability. This study is intended to explore the benefits of microemulsion formulation as oral drug delivery system for immediate release to improve the bioavailability and efficacy of Diltiazem. Methods: Oil in water microemulsion was prepared using the simple water titration method. The optimized formulation was evaluated for physicochemical parameters like viscosity, pH, conductivity and accelerated stability studies. In vitro release, in vivo pharmacokinetics and in vivo efficacy of the optimized diltiazem microemulsion was investigated. Results: The optimized diltiazem microemulsion consisted of 60% water, 5% Almond oil, 35% mixture of surfactant (Tween 80) and cosurfactant (Polyethyne glycol 400) (1:8). The existence of microemulsion region was investigated using pseudoternary phase diagrams. The average particle size by dynamic light scattering technique was found to be 13.8 nm with polydispersity index of 0.474. The optimized microemulsion was found to be thermodynamically stable with in vitro release of 91.82% compared with that of suspension at 55.2%. The peak exposure of diltiazem was 1.23 fold higher and the extent of exposure was found to be 1.24 to 1.29 fold greater for microemulsion compared to the reference tablet formulation when tested in rabbits. The novel formulation was found to have greater efficacy compared to conventional tablet formulation in reducing systolic blood pressure in rats. Conclusion: The diltiazem microemulsion greatly improves the pharmacokinetic parameters and thus improves therapeutic efficacy of diltiazem and could be a potential alternative oral dosage form in therapeutic management of hypertension.