Chitosan-Based Thermogelling System for Nose-to-Brain Donepezil Delivery: Optimising Formulation Properties and Nasal Deposition Profile
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 statis...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-06-01
|
| Series: | Pharmaceutics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4923/15/6/1660 |
| _version_ | 1827736020114735104 |
|---|---|
| author | Mirna Perkušić Laura Nižić Nodilo Ivo Ugrina Drago Špoljarić Cvijeta Jakobušić Brala Ivan Pepić Jasmina Lovrić Maša Safundžić Kučuk Marie Trenkel Regina Scherließ Dijana Zadravec Livije Kalogjera Anita Hafner |
| author_facet | Mirna Perkušić Laura Nižić Nodilo Ivo Ugrina Drago Špoljarić Cvijeta Jakobušić Brala Ivan Pepić Jasmina Lovrić Maša Safundžić Kučuk Marie Trenkel Regina Scherließ Dijana Zadravec Livije Kalogjera Anita Hafner |
| author_sort | Mirna Perkušić |
| collection | DOAJ |
| description | 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 (<i>t</i><sub>1/2</sub> 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. |
| first_indexed | 2024-03-11T02:03:04Z |
| format | Article |
| id | doaj.art-4795cd6ed44c40d882c5cbb56926b50f |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T02:03:04Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-4795cd6ed44c40d882c5cbb56926b50f2023-11-18T12:04:40ZengMDPI AGPharmaceutics1999-49232023-06-01156166010.3390/pharmaceutics15061660Chitosan-Based Thermogelling System for Nose-to-Brain Donepezil Delivery: Optimising Formulation Properties and Nasal Deposition ProfileMirna Perkušić0Laura Nižić Nodilo1Ivo Ugrina2Drago Špoljarić3Cvijeta Jakobušić Brala4Ivan Pepić5Jasmina Lovrić6Maša Safundžić Kučuk7Marie Trenkel8Regina Scherließ9Dijana Zadravec10Livije Kalogjera11Anita Hafner12Department of Pharmaceutical Technology, University of Zagreb Faculty of Pharmacy and Biochemistry, 10000 Zagreb, CroatiaDepartment of Pharmaceutical Technology, University of Zagreb Faculty of Pharmacy and Biochemistry, 10000 Zagreb, CroatiaIntellomics Ltd., 21000 Split, CroatiaVisage Technologies d.o.o., 10000 Zagreb, CroatiaDepartment of Physical Chemistry, University of Zagreb Faculty of Pharmacy and Biochemistry, 10000 Zagreb, CroatiaDepartment of Pharmaceutical Technology, University of Zagreb Faculty of Pharmacy and Biochemistry, 10000 Zagreb, CroatiaDepartment of Pharmaceutical Technology, University of Zagreb Faculty of Pharmacy and Biochemistry, 10000 Zagreb, CroatiaJadran-Galenski Laboratorij d.d., 51000 Rijeka, CroatiaDepartment of Pharmaceutics and Biopharmaceutics, Faculty of Mathematics and Natural Sciences, Kiel University, 24118 Kiel, GermanyDepartment of Pharmaceutics and Biopharmaceutics, Faculty of Mathematics and Natural Sciences, Kiel University, 24118 Kiel, GermanyDepartment of Diagnostic and Interventional Radiology, University Hospital Center Sestre Milosrdnice, University of Zagreb School of Dental Medicine, 10000 Zagreb, CroatiaORL/HNS Department, University Hospital Center Sestre Milosrdnice, Zagreb School of Medicine, 10000 Zagreb, CroatiaDepartment of Pharmaceutical Technology, University of Zagreb Faculty of Pharmacy and Biochemistry, 10000 Zagreb, CroatiaDonepezil 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 (<i>t</i><sub>1/2</sub> 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.https://www.mdpi.com/1999-4923/15/6/1660donepezilchitosannose-to-brain deliverythermoresponsive in situ gelling system3D nasal cavity modelolfactory deposition |
| spellingShingle | Mirna Perkušić Laura Nižić Nodilo Ivo Ugrina Drago Špoljarić Cvijeta Jakobušić Brala Ivan Pepić Jasmina Lovrić Maša Safundžić Kučuk Marie Trenkel Regina Scherließ Dijana Zadravec Livije Kalogjera Anita Hafner Chitosan-Based Thermogelling System for Nose-to-Brain Donepezil Delivery: Optimising Formulation Properties and Nasal Deposition Profile Pharmaceutics donepezil chitosan nose-to-brain delivery thermoresponsive in situ gelling system 3D nasal cavity model olfactory deposition |
| title | Chitosan-Based Thermogelling System for Nose-to-Brain Donepezil Delivery: Optimising Formulation Properties and Nasal Deposition Profile |
| title_full | Chitosan-Based Thermogelling System for Nose-to-Brain Donepezil Delivery: Optimising Formulation Properties and Nasal Deposition Profile |
| title_fullStr | Chitosan-Based Thermogelling System for Nose-to-Brain Donepezil Delivery: Optimising Formulation Properties and Nasal Deposition Profile |
| title_full_unstemmed | Chitosan-Based Thermogelling System for Nose-to-Brain Donepezil Delivery: Optimising Formulation Properties and Nasal Deposition Profile |
| title_short | Chitosan-Based Thermogelling System for Nose-to-Brain Donepezil Delivery: Optimising Formulation Properties and Nasal Deposition Profile |
| title_sort | chitosan based thermogelling system for nose to brain donepezil delivery optimising formulation properties and nasal deposition profile |
| topic | donepezil chitosan nose-to-brain delivery thermoresponsive in situ gelling system 3D nasal cavity model olfactory deposition |
| url | https://www.mdpi.com/1999-4923/15/6/1660 |
| work_keys_str_mv | AT mirnaperkusic chitosanbasedthermogellingsystemfornosetobraindonepezildeliveryoptimisingformulationpropertiesandnasaldepositionprofile AT lauranizicnodilo chitosanbasedthermogellingsystemfornosetobraindonepezildeliveryoptimisingformulationpropertiesandnasaldepositionprofile AT ivougrina chitosanbasedthermogellingsystemfornosetobraindonepezildeliveryoptimisingformulationpropertiesandnasaldepositionprofile AT dragospoljaric chitosanbasedthermogellingsystemfornosetobraindonepezildeliveryoptimisingformulationpropertiesandnasaldepositionprofile AT cvijetajakobusicbrala chitosanbasedthermogellingsystemfornosetobraindonepezildeliveryoptimisingformulationpropertiesandnasaldepositionprofile AT ivanpepic chitosanbasedthermogellingsystemfornosetobraindonepezildeliveryoptimisingformulationpropertiesandnasaldepositionprofile AT jasminalovric chitosanbasedthermogellingsystemfornosetobraindonepezildeliveryoptimisingformulationpropertiesandnasaldepositionprofile AT masasafundzickucuk chitosanbasedthermogellingsystemfornosetobraindonepezildeliveryoptimisingformulationpropertiesandnasaldepositionprofile AT marietrenkel chitosanbasedthermogellingsystemfornosetobraindonepezildeliveryoptimisingformulationpropertiesandnasaldepositionprofile AT reginascherließ chitosanbasedthermogellingsystemfornosetobraindonepezildeliveryoptimisingformulationpropertiesandnasaldepositionprofile AT dijanazadravec chitosanbasedthermogellingsystemfornosetobraindonepezildeliveryoptimisingformulationpropertiesandnasaldepositionprofile AT livijekalogjera chitosanbasedthermogellingsystemfornosetobraindonepezildeliveryoptimisingformulationpropertiesandnasaldepositionprofile AT anitahafner chitosanbasedthermogellingsystemfornosetobraindonepezildeliveryoptimisingformulationpropertiesandnasaldepositionprofile |