Stimuli-Responsive Carbamazepine-Loaded Chitosan Nanogel Systems for Targeted Nose-to-Brain Transport in Drug-Resistant Temporal Lobe Epilepsy: Mechanistic Insights and Ex Vivo Evaluation

Abstract

Drug-resistant temporal lobe epilepsy (TLE) remains a major clinical challenge due to limited drug penetration across the blood–brain barrier (BBB) and systemic side effects associated with conventional therapy. The present study focuses on the development of stimuli-responsive carbamazepine (CBZ)-loaded chitosan nanogels for targeted nose-to-brain delivery as an alternative therapeutic strategy. Chitosan-based nanogels were prepared using ionic gelation and optimized to achieve nanoscale particle size, high encapsulation efficiency, and favorable surface charge for enhanced mucoadhesion and permeation. Physicochemical characterization confirmed uniform morphology, stability, and stimuli-responsive gelation behavior under physiological conditions. In vitro drug release studies demonstrated a sustained and controlled release profile following non-Fickian diffusion kinetics, ensuring prolonged therapeutic action. Ex vivo permeation studies using nasal mucosa revealed significantly enhanced drug transport compared to pure CBZ, attributed to chitosan-mediated opening of tight junctions and increased residence time. Mucoadhesion studies further supported prolonged nasal retention, reducing mucociliary clearance and improving absorption efficiency. Histopathological evaluation confirmed the safety and biocompatibility of the formulation, showing no significant tissue damage or irritation. The findings suggest that CBZ-loaded chitosan nanogels effectively enhance drug delivery to the brain via the intranasal route, overcoming limitations of conventional formulations. This approach provides improved bioavailability, sustained release, and targeted delivery, making it a promising strategy for managing drug-resistant epilepsy. Further in vivo and clinical investigations are warranted to establish its therapeutic potential and translational applicability.