Development of thermosensitive mucoadhesive gel incorporated lipid microspheres of donepezil for enhanced nose-to-brain delivery.

Abstract

Alzheimer's disease (ALZ) is a chronic disease that affects the brain neurons leading to dementia. Donepezil (DPZ), a first-line treatment for ALZ is a potent symptomatic therapeutic agent. However, the oral and transdermal route represents non-targeted delivery, causing various adverse effects. This study presents the successful incorporation of a DPZ-loaded lipid microsphere (DPZ-LM) system into a thermosensitive-mucoadhesive gel (TMG), thereby enhancing the delivery of DPZ through the nose-to-brain route. To optimize the formulations, several evaluations were conducted, resulting in an optimized formulation of LM using Compritol^® exhibited particle size of 8.75 µm, 98.44% of DPZ entrapped, and 93.40% of DPZ loaded in the system with a sustained release manner in the in vitro studies. The TMG-DPZ-LM was prepared using Pluronic^® F127 and F68, as the gelling agents, with the addition of sodium alginate, as the mucoadhesive polymer. Following incorporation into TMG-DPZ-LM, the system exhibited excellent physicochemical properties and effective nasal delivery in ex vivo permeation has found that 88.58 ± 12.53 µg/cm² and retention studies with a mean concentration of 0.0077 mg of retention DPZ in porcine nasal mucosa. The in vivo pharmacokinetic studies demonstrated that the administration of TMG-DPZ-LM via the nose-to-brain route resulted in a significant (p < 0.05) increase in the C_max, with 207.24 ± 5.16 µg/cm³ of DPZ in the brain that exhibited a significantly different profile compared to the other route and formulation. The TMG-DPZ-LM system that was developed in this study was considered to have improved its efficacy in the treatment of ALZ.