Chitosan-Based Thermogelling System for Nose-to-Brain Donepezil Delivery: Optimising Formulation Properties and Nasal Deposition Profile

Abstract

Donepezil nasal delivery strategies are being continuously investigated for advancing therapy in Alzheimer’s disease. The aim of this study was to develop a chitosan-based, donepezil-loaded thermogelling formulation tailored to meet all the requirements for efficient nose-to-brain delivery. A statistical design of the experiments was implemented for the optimisation of the formulation and/or administration parameters, with regard to formulation viscosity, gelling and spray properties, as well as its targeted nasal deposition within the 3D-printed nasal cavity model. The optimised formulation was further characterised in terms of stability, in vitro release, in vitro biocompatibility and permeability (using Calu-3 cells), ex vivo mucoadhesion (using porcine nasal mucosa), and in vivo irritability (using slug mucosal irritation assay). The applied research design resulted in the development of a sprayable donepezil delivery platform characterised by instant gelation at 34 °C and olfactory deposition reaching a remarkably high 71.8% of the applied dose. The optimised formulation showed prolonged drug release (t1/2 about 90 min), mucoadhesive behaviour, and reversible permeation enhancement, with a 20-fold increase in adhesion and a 1.5-fold increase in the apparent permeability coefficient in relation to the corresponding donepezil solution. The slug mucosal irritation assay demonstrated an acceptable irritability profile, indicating its potential for safe nasal delivery. It can be concluded that the developed thermogelling formulation showed great promise as an efficient donepezil brain-targeted delivery system. Furthermore, the formulation is worth investigating in vivo for final feasibility confirmation.

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“…Animal implants using Schwann cell-seeded scaffolds showed significantly improved innervation compared with NSC scaffolds. 92 …”

“…The applications and effects of AM are being studied. 92 4D printing can be performed in two ways. One possibility is to include the transformation of information into the structural design.…”

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“…Conversely, Perkušić et al reported that drug deposition within the olfactory region was significantly influenced by administration parameters, rather than formulation parameters. 115 Enhanced drug deposition in the olfactory region was achieved with a higher administration angle, ranging from 45° to 75°, when intranasally delivering a chitosan-based temperature-sensitive ISG containing donepezil using the VP7 spray pump in an in-vitro 3D nasal model coated with Sar-Gel ® paste. In addition, olfactory deposition was diminished by an increase in inspiratory flow rate, as breathing and airflow directed the formulation towards the turbinate region.…”

“…111,112 To address these limitations, researchers have studied how to predict drug deposition in the nasal cavity using in-vitro 3D models that mimic human nasal conditions or in-vivo models. 101,[113][114][115] This section discusses drug deposition in the nasal cavity after intranasal administration of ISGs using a nasal device.…”

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