Nose to brain targeting of the donepezil nanostructured lipid carrier in situ gel: formulation, in vitro, ex vivo, in vivo pharmacokinetic and pharmacodynamic characterization†

Abstract

Donepezil (DPZ) is a reversible, noncompetitive inhibitor of acetylcholinesterase commonly prescribed against Alzheimer's disease (AD). Its dose-dependent side effects limit its therapeutic benefits. The current study endeavors to design an in situ gel for intranasal delivery of a DPZ nanostructured lipid carrier (DPZ-NLC) to boost pharmacokinetic and pharmacodynamic outcomes. The Box–Behnken design was employed to optimize the NLCs that were produced utilizing a melt emulsification high-pressure homogenization process. Afterward, NLCs were embedded in an in situ gel based on Lutrol F127 and analyzed further. The effects of formulation pharmacodynamics were evaluated in a Wistar rat model with trimethyl tin (TMT) induced neurodegeneration. The batch of the optimized DPZ in situ gel had a spherical shape, with a mean particle size of 112.5 ± 2.44 nm. It showed a high drug entrapment of 98.7 ± 4.01% and an in vitro drug release of 89.51 ± 2.94%. With a C_max value of 193.41 ± 26.4 ng mL⁻¹ and a T_max value of 2 hours, the drug's significant therapeutic concentration in the CNS following intranasal (IN) administration was demonstrated by in vivo single-dose pharmacokinetic investigation. The Drug Targeting Efficiency (DTE) of 213.123% and the Drug Targeting Potential (DTP) of 66.27% were greater for the constructed DPZ in situ gel, indicating superior brain targeting efficiency through NLCs. The outcomes showed that as compared to the neurodegeneration control group, the DPZ in situ gel treatment group dramatically reduced the escape latency and path length. The DPZ in situ gel demonstrated superior anti-AD potency to DPZ-sol, as revealed by biochemical and histological investigations. Its potential for managing AD is suggested by the favorable outcomes of the developed and enhanced intranasal DPZ in situ gel.