Advanced modafinil-loaded transethosomes for brain targeting: development, ex-vivo permeation and radio-distribution evaluations.

Modafinil is a well-established wake-promoting agent with emerging applications as a cognitive enhancer; however, its clinical potential is constrained by poor aqueous solubility and suboptimal systemic absorption, limiting effective brain delivery. This study presents transethosomes as a hitherto unexplored nanocarrier for modafinil and combines design-driven formulation with nuclear imaging-based biodistribution. Transethosomal vesicles were prepared using the ethanol injection method and systematically optimized through a 23 factorial design employing Design-Expert® software. Key formulation variables were investigated for their impact on EE%, PS, PDI, and ZP. Additionally, an in-vivo biodistribution and pharmacokinetic studies were conducted after labeling MOD with Technetium-99 m using sodium dithionite as a reducing agent. The optimized formulation achieved a high desirability value (0.919), superior EE% (85.87%), nanoscale PS (180.30 nm), and a negative ZP (- 42.60 mV), indicative of excellent vesicular stability. Morphological and FTIR analyses confirmed spherical vesicles, drug-excipient compatibility, and preservation of Modafinil's structure. In-vitro studies demonstrated a controlled biphasic release, supporting sustained drug availability, while stability assessments revealed no significant changes in vesicular characteristics over time. Ex-vivo studies highlighted markedly enhanced permeability, due to improved membrane fluidity and vesicle deformability from ethanol and the edge activator. The radiolabeling efficiency was high (92.18%), and it was stable for two hours. Biodistribution and pharmacokinetic studies confirmed significantly higher brain drug accumulation, elevated brain Cmax (5.4%ID/g) and AUC, reduced Tmax (10 min) and high relative bioavailability (424.3 ± 4.5%). Importantly, histopathological examination of nasal mucosa revealed normal architecture. Collectively, these findings establish transethosomes as a promising and safe nano-platform for advanced brain targeting. HIGHLIGHTS: Modafinil-loaded transethosomes were designed as nanovesicles for brain targeting. The optimized formulation showed spherical morphology, uniform size distribution, and strong drug-carrier compatibility. Stability studies confirmed preserved physicochemical properties throughout storage. Ex-vivo permeation revealed significantly enhanced mucosal drug transport versus plain modafinil dispersion. In-vivo radio-distribution unambiguously confirmed superior uptake into the brain and improved targeting efficiency when contrasted with the reference preparation.