Enhancement of Oral Bioavailability of Nimodipine using Quercetin Dihydrate: A Natural Cytochrome P450 Inhibitor

Background: Cytochrome P450 enzymes are responsible for the low bioavailability of many drugs. Nimodipine is a Biopharmaceutical Classification System class II dihydropyridine calcium channel blocker. Nimodipine’s oral bioavailability is limited to 3-13% due to poor water solubility and cytochrome P450 enzymes. Aim: The main aim of this study is to develop a bilayer tablet to improve the oral bioavailability of nimodipine using a cytochrome P3A4 inhibitor. Methods: Solid dispersion of quercetin dihydrate was prepared by the solvent evaporation technique, and the direct compression method was used to prepare a bilayer tablet. Solid dispersion of quercetin dihydrate and Polyvinylpyrrolidone K30 was prepared in a 1:3 ratio. Results: Various post-compression parameters were evaluated for the developed bilayer tablet and optimised by Design of Experiments. The effect of experimental factors such as polymer concentration, super disintegration concentration, and main compression force on % quercetin dihydrate release, % drug release, friability, and hardness remains to be investigated to get an optimised formulation. The NQ4 formulation was optimised batch to give 97.80% quercetin dihydrate release in 2 h and 98.74% nimodipine drug release in 12 h with 8.5 kg/cm2 hardness and 0.22 % W/W friability. The in vivo pharmacokinetic study data proved that the developed bilayer tablet enhances the oral bioavailability of nimodipine when compared to the nimodipine sustained release tablet. The physicochemical stability of optimised bilayer tablets during storage under accelerated conditions was also validated. Conclusion: The present research proved the development of a nimodipine bilayer tablet formulation with quercetin dihydrate as a CYP3A4 inhibitor in the immediate release form to increase nimodipine oral bioavailability. Major Findings: The oral bioavailability of nimodipine was increased with quercetin dihydrate as a CYP3A4 inhibitor in bilayer tablet formulation compared to the nimodipine sustained release tablet.