The design and optimization of a chitosan-based lamotrigine-loaded intranasal mucoadhesive nanomicelle solution using response surface methodology and artificial neural networks

Abstract

The study aimed to develop and optimize chitosan-based mucoadhesive nanomicelles for intranasal delivery of lamotrigine (LTG), to enhance epilepsy treatment, bypass the blood-brain barrier, and potentially improve brain targeting. LTG-loaded nanomicelles were prepared using thin-film hydration and optimized using a central composite design, response surface methodology, and artificial neural networks. The formulation included D-ɑ-tocopheryl polyethylene glycol succinate, Poloxamer 407, chitosan, and glycerol. Critical quality attributes assessed were micelle size (MS), polydispersity index (PDI), Zeta potential (ZP), pH, LTG content, transmittance, in vitro mucoadhesion, LTG release, and 28-day stability. The MS, PDI, ZP, pH, and LTG content of the optimized mucoadhesive nanomicelles was 31.28 ± 0.34 nm, 0.487 ± 0.00, +31.37 ± 1.97 mV, 4.61 ± 0.01, and 2.89 ± 0.01 mg/mL, respectively. The transmittance was 98.50 ± 0.10%, and significant in vitro mucoadhesion, with reduced migration, was observed for mucin-containing gels. LTG release (96.94% at 6 hours) followed the Higuchi diffusion model, with sufficient LTG released at 40 minutes to potentially reach the minimum effective concentration, based on in vitro release data alone. The formulation remained stable for 28 days at 4 °C and 25 °C. Chitosan-based mucoadhesive nanomicelles are a promising intranasal delivery system for LTG, with the potential for brain targeting, controlled LTG release, and improved epilepsy management.