Intranasal co-delivery of riluzole and berberine via chitosan-coated PLGA nanoparticles for synergistic neuroprotection in Alzheimer's disease: formulation, characterization, and pharmacokinetics analysis.

This study presents an intranasal chitosan-coated PLGA nanoparticle system co-loaded with riluzole (RLZ) and berberine (BER) to achieve synergistic neuroprotection and enhanced brain targeting for Alzheimer's disease therapy. Chitosan-coated PLGA nanoparticles containing riluzole and berberine (RLZ-BER-CTS-PLGA) were prepared via a modified single emulsion-solvent evaporation method using 0.9% PLGA and 1% PVA, and 0.99% chitosan. The optimized formulation exhibited a size of 203.5 nm, zeta potential of + 34.7 mV, and high entrapment efficiencies of 73.9% (RLZ) and 71.4% (BER). In vitro release showed sustained delivery, with only 36.3% BER and 28.4% RLZ released after 2 h compared to 82.6% and 57.3% from suspensions. Ex vivo nasal permeation demonstrated 2.8-fold (BER) and 2.1-fold (RLZ) increases in permeability coefficients relative to drug suspensions. Pharmacokinetic evaluation confirmed superior brain delivery, with intranasal RLZ-BER-CTS-PLGA achieving Cmax levels of 596 ng/mL for BER and 1345 ng/mL for RLZ, versus only 213 ng/mL and 385 ng/mL from intranasal suspensions. Direct transport percentage (DTP) reached 81.4% for BER and 56.4% for RLZ, with corresponding drug targeting efficiencies (DTE) of 536.6% and 229.3%. Histopathology confirmed nasal safety with no mucosal irritation. These results establish chitosan-functionalized PLGA nanocarriers as a promising noninvasive co-delivery platform for multifunctional Alzheimer's therapeutics.