Preparation, physicochemical characterization, ex vivo, and in vivo evaluations of asiatic acid-loaded solid lipid nanoparticles formulated with natural waxes for nose-to-brain delivery

Abstract

Asiatic acid (AA) has neuroprotective potential for prevention and treatment of Alzheimer's disease. Natural waxes with various ratios of Tween 80 and Span 80 or soybean lecithin were formulated to obtain AA-loaded solid lipid nanoparticles (AA-SLN) to improve direct nose to brain transport. Optimal AA-SLN had particle size below 200 nm with uniform size distribution and zeta potential of nearly -30 mV indicating a low risk of particle aggregation. Formulation with rice bran wax, Tween 80, and soybean lecithin (AA-RwS₁₀₀) showed the highest entrapment efficiency and yield of >98 % while in vitro AA release of AA-SLN was linearly up to 48 h For ex vivo permeation, confocal laser scanning microscopy (CLSM) and histopathological studies on porcine olfactory mucosa (OM) and respiratory mucosa (RM), AA-SLN showed significantly higher permeation across OM than RM (p < 0.05) up to 6 h and AA-RwS100 also showed the highest amount of drug permeated as confirmed by CLSM results. Although AA-SLN showed non-significantly lower permeation than AA solution (AA-SOL) (p > 0.05), no epithelial and mucosal structure damages were observed in OM treated with AA-RwS₁₀₀ and RM treated with all AA-SLNs indicating safety for nasal administration while AA-SOL showed significant damage to both OM and RM. In addition, in vivo brain distribution study by fluorescence imaging using Rhodamine (R6g) showed higher brain distribution after intranasal administration of R6g-loaded solid lipid nanoparticles (R6g-SLN) than R6g solution (R6g-SOL) and intravenous administration of R6g-SLN, and R6g-RwS₁₀₀ also showed the highest brain accumulation at 8 h post administration.