Dual carboxylic ionization driven MCC/MAA/IA hydrogels for enhanced oral insulin delivery

Oral delivery of insulin is hindered by enzymatic degradation and poor intestinal permeability. In this study, pH-responsive semi-interpenetrating network (semi-IPN) hydrogels based on microcrystalline cellulose (MCC), methacrylic acid (MAA), and itaconic acid (IA) were developed to enable site-specific intestinal release. The system leverages the differential ionization of MAA and IA to induce sequential network expansion through carboxyl group deprotonation. Hydrogels were synthesized via free radical polymerization using N, N'-methylene bisacrylamide as a crosslinker. The optimized formulation exhibited a high swelling ratio (2853%) and strong pH sensitivity, with minimal swelling at pH 1.2 and enhanced swelling at pH levels between 6.8 and 7.4. Structural characterization by FTIR confirmed the formation of a network, while TGA showed improved thermal stability. Insulin encapsulation efficiency was 52.00 ± 0.06%. In vitro release studies showed limited insulin release under simulated gastric conditions (∼10% in 2 h) and sustained release in simulated intestinal fluid (∼91% over 8 h), attributed to ionization-induced electrostatic repulsion and polymer relaxation. Release kinetics followed a first-order model (R² = 0.9877), showing concentration-dependent diffusion. In streptozotocin (STZ)-induced diabetic rats, the oral administration of insulin-loaded hydrogels (40 IU/Kg) resulted in a maximal reduction of blood glucose by 27.06%, accompanied by sustained hypoglycemic activity over 24 h. The relative pharmacological availability was ∼ 6.8% compared to subcutaneous insulin. These findings highlight the potential of dual-ionizable MCC-based semi-IPN hydrogels for effective oral insulin delivery.