pH-responsive agarose hydrogel for enhanced gastrointestinal ibuprofen delivery: A novel pressure-sensitive adhesive system

Recent advances in pH-responsive drug delivery systems have demonstrated their promising potential for targeted therapeutic delivery. However, challenges remain in developing platforms that combine precise spatiotemporal control with robust mechanical properties. Herein, we present a novel plant-derived (agarose-polyacrylic acid hybrid) hydrogel pressure-sensitive adhesive (PSA) system that combines the biocompatibility of agarose with the pH-responsiveness of polyacrylic acid for controlled ibuprofen delivery. Unlike conventional physical encapsulation methods, our covalently tethered design achieved 78.1 ± 3.4 % drug incorporation efficiency with minimal burst release (<15 %), representing a 3.5-fold improvement over traditional alginate systems (p < 0.01). The hybrid matrix demonstrated pH-dependent swelling ratios ranging from 1.58 ± 0.09 (pH 1.2) to 3.29 ± 0.12 (pH 7.4) and programmable mechanical properties, with the storage modulus decreasing from 2000 ± 150 Pa to 1000 ± 90 Pa across pH 1.2–9.0 (F = 28.4, p < 0.001). The hierarchically porous architecture (11.33 ± 6.27 μm) enables Fickian diffusion-controlled release (Korsmeyer-Peppas n = 0.30–0.41), while molecular dynamics simulations confirm stable drug-polymer interactions (ΔG = −25.3 kJ/mol). Thermal analysis revealed significant drug amorphization (87.8 % reduction in crystallinity), promoting enhanced solubility. In vitro studies demonstrated pH-triggered delivery, with 64.9 ± 1.7 % release at intestinal pH versus < 15 % at gastric pH, while maintaining PSA adhesive strength (>150 kPa). This scalable platform addresses the critical limitations of conventional NSAID delivery, including gastric toxicity (prevalent in 50–60 % of chronic users) and frequent dosing, by synergizing plant-derived biocompatibility with synthetic flexibility.