Quercetin-Loaded Nanostructured Lipid Carrier In Situ Gel for Brain Targeting Through Intranasal Route: Formulation, In Vivo Pharmacokinetic and Pharmacodynamic Studies

Quercetin (QT) shows potential for protecting against neurodegenerative diseases like Alzheimer's. However, its limited bioavailability and instability in physiological pH hinder its clinical use. The purpose of this work is to construct QT-filled nanostructured lipid carriers (QT-NLC) intranasal in situ gel to enhance pharmacokinetic and pharmacodynamic performance. NLCs were developed using a melt emulsification-high-pressure homogenization and were optimized using design expert software with the Box-Behnken design. NLCs were then incorporated into an in situ gel based on Lutrol F127 and further characterized. The pharmacodynamics of the formulation was evaluated in neurodegeneration induced by trimethyl tin (TMT) Wistar rats. The optimized QT in situ gel had spherical shape, entrapment efficiency of 96.1 +/- 4.40%, and in vitro drug release of 83.74 +/- 1.40%. The mean particle size was 123.3 +/- 5.46 nm. After intranasal administration, in vivo single-dose pharmacokinetic studies demonstrated a significant therapeutic concentration of drug in CNS, having C-max 183.41 +/- 11.76 ng/mL and T-max of 2 h. The more brain targeting efficiency of NLCs was proved by the developed QT in situ gel, which had a higher drug targeting efficiency (DTE) of 117.47% and drug targeting potential (DTP) of 88.9%. As compared to the neurodegeneration control group, the QT in situ gel-treated group had significantly decreased escape latency and pathlength. Biochemical analysis and histological investigations demonstrated that QT in situ gel exhibited superior anti-Alzheimer's potential compared to standard drug, donepezil. The promising results of the developed and optimized intranasal QT in situ gel suggest its potential and can be used in Alzheimer's disease management.