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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 \u00b0C 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.<\/jats:p>","DOI":"10.3390\/pharmaceutics15061660","type":"journal-article","created":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T01:38:26Z","timestamp":1686015506000},"page":"1660","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Chitosan-Based Thermogelling System for Nose-to-Brain Donepezil Delivery: Optimising Formulation Properties and Nasal Deposition Profile"],"prefix":"10.3390","volume":"15","author":[{"given":"Mirna","family":"Perku\u0161i\u0107","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Technology, University of Zagreb Faculty of Pharmacy and Biochemistry, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8139-5803","authenticated-orcid":false,"given":"Laura","family":"Ni\u017ei\u0107 Nodilo","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology, University of Zagreb Faculty of Pharmacy and Biochemistry, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9882-2250","authenticated-orcid":false,"given":"Ivo","family":"Ugrina","sequence":"additional","affiliation":[{"name":"Intellomics Ltd., 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Drago","family":"\u0160poljari\u0107","sequence":"additional","affiliation":[{"name":"Visage Technologies d.o.o., 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5738-9809","authenticated-orcid":false,"given":"Cvijeta","family":"Jakobu\u0161i\u0107 Brala","sequence":"additional","affiliation":[{"name":"Department of Physical Chemistry, University of Zagreb Faculty of Pharmacy and Biochemistry, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Pepi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology, University of Zagreb Faculty of Pharmacy and Biochemistry, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmina","family":"Lovri\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology, University of Zagreb Faculty of Pharmacy and Biochemistry, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u0161a","family":"Safund\u017ei\u0107 Ku\u010duk","sequence":"additional","affiliation":[{"name":"Jadran-Galenski Laboratorij d.d., 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Trenkel","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Biopharmaceutics, Faculty of Mathematics and Natural Sciences, Kiel University, 24118 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8685-5672","authenticated-orcid":false,"given":"Regina","family":"Scherlie\u00df","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Biopharmaceutics, Faculty of Mathematics and Natural Sciences, Kiel University, 24118 Kiel, Germany"},{"name":"Priority Research Area Kiel Nano, Surface and Interface Sciences (KiNSIS), Kiel University, 24118 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dijana","family":"Zadravec","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Interventional Radiology, University Hospital Center Sestre Milosrdnice, University of Zagreb School of Dental Medicine, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livije","family":"Kalogjera","sequence":"additional","affiliation":[{"name":"ORL\/HNS Department, University Hospital Center Sestre Milosrdnice, Zagreb School of Medicine, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Hafner","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology, University of Zagreb Faculty of Pharmacy and Biochemistry, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Giunchedi, P., Gavini, E., and Bonferoni, M.C. 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