HSPiP and Neuro-Fuzzy Model-Enabled Optimized Nanoemulsions for Nose-to-Brain Delivery of Valproic Acid

The present work is the extended findings of our previous study on valproic acid (VA)-loaded cationic nanoemulsions for HSPiP and Neuro-fuzzy model (ANFIS)-enabled optimized composition to attain targeted permeation flux, the influence of permeation enhancers, and characterizations of the optimized product. The binding efficiency of the formulations with nasal mucus was assessed. The pH dependent in-vitro drug release (dialysis membrane) study, ex-vivo permeation assessment using a goat nasal mucosa, and benchtop physically stable at room temperature, were investigated. The fluorescence microscopy (FM) study compared the penetration potential across the nasal mucosa. The cationic nanoemulsions exhibited low particle size range (29-373 nm), narrow distribution (0.12-0.37), and high zeta potential (22-35.7 mV). HSPiP-generated permeation flux (Y₁) and diffusion coefficients (Y₂) values across nasal mucosa. The trained ANFIS model considered X₁ (oil as SO), X₂ (S_mix), and X₃ (size) for achieving maximal Y₁ (681 µg/cm²/h) and Y₂ (2.74 cm²/s) with high correlation (r² ˃ 0.99) to actual values. The optimized V-PG exhibited desired formulation characteristics and pH-dependent (pH 6.8 ˃ pH 7.4) sustained drug release. V-PG (optimized gel containing polyethylenimine as permeation enhancer, PEI) revealed the highest binding capacity, prolonged mucoadhesion, maximum permeation flux (J_ss ~ 126 µg/cm²/h), enhancement ratio (~ 70), and the desired percent drug deposition (%DD) (22.9 ± 0.7%) than DS (VA suspension). The study revealed maximized cationic V-PG-mediated penetration across nasal mucosal membrane as compared to the suspension, emphasizing its potentiated nose-to-brain delivery to control convulsion in children and aged patients with high patient compliance.