Ultra-swelling pH-responsive hybrid hydrogel for oral heparin delivery

Oral delivery of heparin remains challenging because of poor stability and limited site-specific release within the gastrointestinal tract. Herein, an ultra-swelling pH-responsive hybrid hydrogel based on chitosan, acrylic acid, and 2-hydroxyethyl methacrylate (HEMA) was developed through low-temperature redox-initiated graft copolymerization and statistically optimized using a Box–Behnken design. The effects of the monomer-to-chitosan ratio, initiator concentration, and crosslinker content on hydrogel performance were systematically evaluated. Structural, morphological, and thermal characteristics were confirmed by FTIR, XRD, SEM, DSC, and TGA analyses. The optimized hydrogel exhibited a highly porous architecture and an exceptional swelling ratio exceeding 4000% under near-neutral conditions while maintaining limited swelling in acidic media. Heparin loading and in vitro release studies demonstrated minimal drug release at gastric pH and rapid, sustained release at neutral to mildly alkaline pH, reflecting the transition from stomach to intestinal environments. The combination of statistical optimization, pronounced pH responsiveness, and selective heparin release highlights the advantages of this hydrogel over conventional formulations. These findings establish the optimized chitosan-g-poly(AA-co-HEMA) hydrogel as a promising platform for oral delivery of heparin and other pH-sensitive therapeutics requiring controlled gastrointestinal release.