QbD-based optimization and evaluation of chitosan-adorned nanostructured lipid carriers for nose-to-brain delivery of 17 β-Estradiol in rat model of Alzheimer 's disease

Alzheimer ' s disease, a prevalent form of dementia affecting millions worldwide, poses a significant challenge, especially in elderly females after postmenopausal. The delivery of 17 beta -estradiol (EST), a potential therapeutic agent, is hindered by low water solubility and bioavailability. This study aimed to develop, optimize, and characterize nanostructured lipid carriers (NLCs) coated with chitosan (CS) for intranasal administration to enhance EST delivery to the brain for AD management. The NLCs were formulated through a solvent -free meltemulsification and sonication method and optimized via a Box-Behnken design. The EST-NLCs that were optimized showed favorable colloidal properties. They had a particle size (PS) of 115.64 +/- 2.44 nm, a polydispersity index (PDI) of 24 +/- 1.66 %, a zeta potential (ZP) of -26.5 +/- 0.72 mV, and an entrapment efficiency (EE) of 81.99 +/- 1.43 %. When CS was introduced to form CS-EST-NLCs, it led to changes in the PS (126.76 +/- 3.04 nm), % PDI (22.7 +/- 1.78), a shift in ZP from negative to positive (34.07 +/- 1.10 mV), and an increase in % EE of 84.39 +/- 1.07. Differential scanning calorimetry and powder X-ray diffraction confirmed the amorphous dispersion of EST in the nanocarriers. Surface characterization confirmed the nanoscale size, spherical shape, and smooth exterior. In vitro drug release studies demonstrated a biphasic release pattern, with a burst followed by sustained release, fitting the Korsmeyer-Peppas model. The stability study results confirmed that formulations are stable for three months under ambient room temperature and refrigerated condition. Ex vivo studies supported the safety of EST using NLCs. Behavioral testing revealed the superior efficacy of intranasally administered CS-EST-NLCs compared to plain EST dispersion. The findings suggest that the biodegradable and mucoadhesive CS-ESTNLCs hold promise as a viable drug carrier for intranasal delivery to the brain, demonstrating both good safety and high tolerability.