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

被引：11

作者：

Perkusic, Mirna ^{[1
]}

Nizic Nodilo, Laura ^{[1
]}

Ugrina, Ivo ^{[2
]}

Spoljaric, Drago ^{[3
]}

Jakobusic Brala, Cvijeta ^{[4
]}

Pepic, Ivan ^{[1
]}

Lovric, Jasmina ^{[1
]}

Safundzic Kucuk, Masa ^{[5
]}

Trenkel, Marie ^{[6
]}

Scherliess, Regina ^{[6
,7
]}

Zadravec, Dijana ^{[8
]}

Kalogjera, Livije ^{[9
]}

Hafner, Anita ^{[1
]}

机构：

[1] Univ Zagreb, Fac Pharm & Biochem, Dept Pharmaceut Technol, Zagreb 10000, Croatia

[2] Intellomics Ltd, Split 21000, Croatia

[3] Visage Technol doo, Zagreb 10000, Croatia

[4] Univ Zagreb, Fac Pharm & Biochem, Dept Phys Chem, Zagreb 10000, Croatia

[5] Jadran Galenski Lab d d, Rijeka 51000, Croatia

[6] Univ Kiel, Fac Math & Nat Sci, Dept Pharmaceut & Biopharmaceut, D-24118 Kiel, Germany

[7] Univ Kiel, Prior Res Area Kiel Nano Surface & Interface Sci K, D-24118 Kiel, Germany

[8] Univ Zagreb, Univ Hosp Ctr Sestre Milosrdnice, Sch Dent Med, Dept Diagnost & Intervent Radiol, Zagreb 10000, Croatia

[9] Univ Hosp Ctr Sestre Milosrdnice, Zagreb Sch Med, HNS Dept, ORL, Zagreb 10000, Croatia

来源：

PHARMACEUTICS | 2023年 / 15卷 / 06期

关键词：

donepezil; chitosan; nose-to-brain delivery; thermoresponsive in situ gelling system; 3D nasal cavity model; olfactory deposition; SITU GELLING SYSTEM; IN-VITRO; MOLECULAR-WEIGHT; PERMEABILITY; GEL; OPTIMIZATION; HYDROGELS; DESIGN; SPRAY; PHARMACOKINETICS;

D O I：

10.3390/pharmaceutics15061660

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 degrees C and olfactory deposition reaching a remarkably high 71.8% of the applied dose. The optimised formulation showed prolonged drug release (t(1/2) 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.

引用

页数：29