Thermosensitive Hydrogels Based on Chitosan and Carboxymethyl Cellulose for Potential Nasal Insulin Delivery System

Abstract

Managing diabetes, especially for insulin-dependent patients remains a major challenge which often requires multiple subcutaneous injections daily, that can lead to risks like hypoglycemia and lipohypertrophy associated with pain and inconvenience. This study explores a non-invasive alternative insulin delivery system by nasal administration using a thermosensitive hydrogel formulated by chitosan and carboxymethyl cellulose (CMC), with sodium bicarbonate (NaHCO₃) used as initiator. In this study, hydrogels with varying concentrations of chitosan, CMC, and NaHCO₃ were characterized to determine their gelling temperature, mechanical strength, and insulin release profiles. The optimized formulation showed a favorable gelling temperature of 37°C, sufficient mechanical stability for nasal application, a sustained release of insulin over time. Rheological analysis confirmed the thermosensitive behavior, with the hydrogel gelling within 10 minutes at the target temperature. The three optimized hydrogel formulations, Ch/CMC1-NaHCO3 (0.025M), Ch/CMC2-NaHCO3 (0.05M) and Ch/CMC3-NaHCO3 (0.025M) showed gelling temperature of 31°C, 27.5°C and 37°C respectively. (Ch/CMCx denotes that the hydrogel was formlulated using chitosan and CMC at 1:x mass ratio; the number in the bracket denotes the NaHCO3 concentration in M). SEM imaging showed a porous structure favourable to insulin encapsulation and controlled release. FTIR analysis confirmed the integration of chitosan and CMC within the hydrogel matrix, enhancing its biocompatibility and stability. The swelling ratio for the chosen three formulations were between 600% to 800%. The insulin release kinetics showed an initial burst phase, followed by a controlled, slower release, which could allow for more consistent glucose regulation and reduced dosing frequency. Formulations with higher CMC and NaHCO₃ content, Ch/CMC3-NaHCO3 (0.025M) displayed slower release rates, achieving up to 80% insulin release within 5 hours. This release profile matched the Higuchi's model for drug release from an insoluble matrix as a square root of a time-dependent process based on Fickian diffusion. In terms of mechanical properties, increased CMC concentration enhanced the gel’s structural integrity, making it suitable for nasal application, while NaHCO₃ played a vital role in adjusting gelling temperature and pH balance. Considering the cumulative release of insulin, mechanical strength and ease of storage and administration, Ch/CMC3-NaHCO3 (0.025M) would be the best hydrogel for insulin delivery via nasal administration.