Rational design and in-vivo estimation of Ivabradine Hydrochloride loaded nanoparticles for management of stable angina

Abstract

Stable angina or angina pectoris is referred to as uneasiness/pain in the chest, resulting from coronary heart disease (CHD). Ivabradine Hydrochloride (IBH) is a recently approved drug to manage stable angina and heart failure symptoms. The approved IBH tablets exhibit some technical shortcomings i.e. short half-life (2 h), variable systemic absorption, and high first-pass metabolism (>50%). Therefore, utilizing a nanoformulation technique, we have designed a differentiated and innovative formulation of IBH. The IBH loaded polymeric nanoparticles (IBH-PNPs) are being developed for per-oral delivery by double emulsion method, using Poly lactic-co-glycolic acid (PLGA) as polymer, and D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) as a stabilizer. The pre-formulation studies performed are UV spectroscopy, FT-IR, and X-ray diffraction. The Box-Behnken design was exploited for formulation optimization. The optimized formulation was characterized for its particle size, zeta potential, morphology, entrapment efficiency, in-vitro release, stability studies, ex-vivo permeability, and in-vivo pharmacodynamics study. The optimized IBH-PNPs were found to be spherical (<200nm) and exhibited normal size distribution under transmission electron microscopy and atomic force microscopy respectively. The zeta potential and entrapment efficiency were found to be −43.75 mv and 60 ± 4.8% respectively. Developed IBH-PNPs analyzed for in-vitro drug release where they exhibited biphasic release. The ex-vivo drug permeation study showed 1.85 folds increment in intestinal permeability as compared to IBH tablets. The in-vivo anti-anginal efficacy studies were performed using vasopressin-induced angina model in Wistar rats. Developed formulation was found to have a therapeutic effect for three days.