Acetylcholinesterase Inhibitor-Based Nose‑to‑Brain Delivery of Donepezil‑Loaded Lipid Nanoemulsion for Alzheimer’s Therapy

Intranasal delivery offers a promising route for direct drug transport to the central nervous system, bypassing the blood-brain barrier and improving therapeutic outcomes in neurodegenerative diseases like Alzheimer’s disease. Donepezil, a widely prescribed drug for Alzheimer’s, suffers from poor oral bioavailability, delayed onset, and limited nootropic activity due to extensive systemic metabolism. To address these limitations, this study aimed to develop and optimize a Donepezil-loaded lipid-based nanoemulsion for enhanced nose-to-brain delivery. A Box–Behnken Design (BBD) was employed to optimize three formulation variables: drug-to-lipid ratio (1:2 to 1:6), surfactant concentration (1–2% w/v), and stirring speed (1500–2500 rpm), with their effects assessed on particle size, drug entrapment efficiency, and drug loading. Based on solubility and hydrophilic-lipophilic balance, Glyceryl Monostearate and Tween 80 were selected as excipients. Seventeen formulations were prepared and analyzed using Response Surface Methodology. The optimized formulation (Batch 18) exhibited a particle size of 160.12 nm, entrapment efficiency of 80.75%, and drug loading of 19.98%, with a desirability score of 0.977. Predicted and observed values were within ±5% variation, confirming model reliability with high Adjusted R² (>0.95), Predicted R² (>0.90), and a non-significant lack of fit (p > 0.05) by ANOVA. The optimized nanoemulsion showed enhanced brain-targeting efficiency and improved nootropic potential of Donepezil via the intranasal route, presenting a promising strategy for Alzheimer’s therapy. However, the study was limited to in vitro assessments, and further in vivo pharmacokinetic, pharmacodynamic, and long-term safety evaluations are warranted to comprehensively establish its therapeutic potential.