Optimized Lamotrigine-Loaded Polymeric Nanoparticles for Enhanced Drug Delivery: A Box-Behnken Design Approach with Integrated In Vivo Evaluation

Abstract

The clinical utility of lamotrigine in epilepsy is limited by poor aqueous solubility, variable oral absorption, short half-life, and P-glycoprotein-mediated efflux at the blood-brain barrier. This study aimed to develop an optimized chitosan-sodium alginate polymeric nanoparticle system for Lamotrigine with desired physicochemical characteristics and enhanced in vivo performance. Nanoparticles were prepared by the emulsification-solvent evaporation method. A Box-Behnken design guided the optimization of polymer concentration and sonication time. Formulations were characterized for particle size, polydispersity index, zeta potential, drug content, entrapment efficiency, and in vitro release behavior. Release kinetics were evaluated using standard mathematical models. Pharmacodynamic studies (MES, PTZ, and GABA estimation) were performed in mice, whereas pharmacokinetic studies were carried out in rats The optimized batch LP7 exhibited a particle size of 168.7 nm, entrapment efficiency of 85.91%, and smooth spherical morphology. LP7 released 89.11% of drug within 24 hours via non-Fickian diffusion. In vivo pharmacokinetic studies showed significantly higher Cmax, AUC, and half-life with enhanced brain drug levels compared to pure drug. MES and PTZ models demonstrated reduced seizure duration and prominent anticonvulsant protection. GABA levels were significantly elevated in treated groups. The nanoparticle system achieved controlled drug release, improved stability, and enhanced brain transport. Pharmacokinetic and pharmacodynamic data confirmed sustained systemic exposure and superior seizure control at reduced doses. Lamotrigine-loaded chitosan-sodium alginate nanoparticles optimized by BoxBehnken Design demonstrated improved release control, enhanced pharmacokinetic parameters, and superior anticonvulsant activity in vivo, supporting their potential as a sustained-release system for epilepsy management.