Chitosan-Coated Eudragit® Nanocomposite Hesperetin Nanoparticles: A Dual Mucoadhesive and pH-Responsive Strategy for Colon-Targeted Drug Delivery

Abstract

Hesperetin (HSP), a naturally occurring citrus flavanone with diverse antioxidant, anti-inflammatory, and pharmacological activities, has attracted considerable attention as a promising candidate for oral therapeutic delivery. However, its pharmaceutical applicability remains limited due to poor aqueous solubility, rapid metabolism, limited intestinal permeability, and low oral bioavailability. In the present study, chitosan-coated Eudragit® S100 nanoparticles were developed and optimized for colon-targeted delivery of HSP using a hybrid ionic gelation–solvent evaporation technique. Formulation optimization was performed using a 3² factorial response surface design by varying the Eudragit® S100:Chitosan ratio and Poloxamer-188 concentration. The developed nanoparticles were characterized for particle size, polydispersity index (PDI), zeta potential, entrapment efficiency, morphology, crystallinity, in vitro drug release, and Ex vivo intestinal permeation behavior. The optimized formulation (F4) exhibited nanosized particles (195.4 ± 6.2 nm), a narrow size distribution, a favorable zeta potential (− 31.0 ± 2.0 mV), and a high entrapment efficiency (86.7 ± 2.6%). FTIR, DSC, and XRD analyses confirmed successful incorporation and partial amorphization of HSP within the polymeric matrix without significant incompatibility, while SEM analysis demonstrated spherical nanoparticles with smooth surface morphology. In vitro release studies revealed minimal drug release under gastric conditions, followed by sustained and controlled release at colonic pH over 24 h. Drug release kinetics predominantly followed the Korsmeyer–Peppas model with anomalous non-Fickian diffusion behavior. Ex vivo permeation studies further demonstrated enhanced intestinal permeation and prolonged mucosal retention of the optimized nanoparticles. However, the study was limited to in vitro and ex vivo evaluations, warranting further in vivo validation. The developed chitosan-coated Eudragit® S100 nanoparticle system, therefore, represents a promising platform for sustained, colon-targeted oral delivery of HSP and other poorly bioavailable bioactive compounds.