Abstract 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 2 3 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 C max (5.4%ID/g) and AUC, reduced T max (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. Graphical Abstract
Sayyed et al. (Fri,) studied this question.