Nose to brain delivery of donepezil through surface modified NLCs: Formulation development, optimization, and brain targeting study

Abstract

The research was aimed to formulate the Donepezil (DPZ)-loaded nanostructured lipid carriers (NLCs) and coated with chitosan (CH) for brain targeting through the intranasal route. NLCs were prepared by homogenization & sonication technique and optimized by three factors-three levels Box-Behnken design (BBD). The composition of DPZ-loaded CH-NLCs was established by using a mixture of Compritol & Capryol 90 as lipid, poloxamer 188 as a surfactant, and CH as a coating agent. The effect of formulation factors was evaluated on particle size, entrapment efficiency, and polydispersity index (PDI). Finally, ex-vivo permeation, in-situ perfusion as well as in-vivo study was conducted on albino Wistar rats for the detection of pharmacokinetic and neuropharmacokinetic parameters like drug targeting efficiency (% DTE), nose to brain drug transport percentage (DTP), etc of the optimized formulation. Optimized formulation (DPZ-CH-NLCs-OPT2) exhibited an acceptable particle size (192.5 ± 7.3 nm) with 89.85 ± 2.17% entrapment efficiency, 0.298 ± 0.021 PDI, and 38.9 mV zeta potential and particles were spherical shape as shown by TEM. DSC thermogram displayed that the drug existed in amorphous form within the NLCs matrix. Permeability coefficient (Papp) of DPZ-CH-NLCs-OPT2 formulation (10.14 ± 1.73 × 10−3 cm h−1) was two folds than DPZ-Sol (4.55 ± 1.18 × 10−3 cm h−1). The nasal absorption rate constant for DPZ-CH-NLCs-OPT2 (1.4 × 10−3 h−1) was found to be significantly higher than DPZ-Sol (0.5 × 10−3 h−1). The bioavailability of DPZ-CH-NLCs was 2.02 fold than that of DPZ-Sol administered intranasally and 2.41 fold than DPZ-CH-NLCs administered via the intravenous route. Efficient brain targeting and targeting potential was observed as showed by DTE (321.21%) and DTP (74.55%) after intranasal administration of DPZ-CH-NLCs as compared to DPZ-Sol (DTE 158.52% and DTP 36.92%). From the findings, it could be concluded that DPZ-CH-NLCs might be an effective strategy for the brain targeting of DPZ through the intranasal route for the treatment of Alzheimer's disease.