Design, Formulation, and Optimization of Nano Emulsion-Based Nasal Delivery System of Quercetin for Alzheimer’s Therapy

Abstract

Alzheimer’s disease is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and neuronal dysfunction, with oxidative stress and neuroinflammation playing central roles in its pathogenesis. Conventional therapies offer only symptomatic relief and are limited by poor penetration across the blood–brain barrier (BBB). Quercetin, a dietary flavonoid with potent antioxidant and anti-inflammatory properties, has shown significant neuroprotective potential but suffers from poor solubility, rapid metabolism, and limited bioavailability. This study was designed to develop, optimize, and evaluate a nanoemulsion-based nasal delivery system for quercetin to enhance brain targeting and therapeutic efficacy in Alzheimer’s disease. Solubility studies identified Capmul MCM, Tween 80, and Transcutol P as optimal excipients for nanoemulsion formulation. Response surface methodology (RSM) guided optimization, with formulation F3 exhibiting superior properties including minimal droplet size, low polydispersity, high zeta potential, and >90% entrapment efficiency. In vitro release demonstrated sustained drug release with Korsmeyer–Peppas kinetics, while ex vivo studies confirmed enhanced nasal permeation without mucosal toxicity. In vivo pharmacokinetic and biodistribution studies revealed significantly improved Cmax, AUC, and brain/plasma ratio for the optimized nanoemulsion compared to oral suspension, alongside enhanced cognitive performance in Alzheimer’s animal models. These findings highlight intranasal quercetin nanoemulsion as a promising strategy to overcome bioavailability limitations, achieve direct brain delivery, and improve therapeutic outcomes in Alzheimer’s disease.