{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T05:23:32Z","timestamp":1787203412093,"version":"build-2736575974"},"reference-count":81,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["KK.01.1.1.02.0021"],"award-info":[{"award-number":["KK.01.1.1.02.0021"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: The aim of this study was to develop and apply a novel integrated approach for predicting local mucosal tolerability of spray-dried chitosan\/mannitol microspheres previously developed for nose-to-brain donepezil delivery. Methods: Microspheres were prepared by ultrasonic spray-drying, and process reproducibility was evaluated based on particle size distribution, entrapment efficiency, and process yield across independent batches. A lactose-based formulation served as a comparative control. A novel biomimetic model was developed to investigate water evaporation under simulated nasal conditions, enabling prediction of formulation dehydration and crust-like layer formation on the nasal mucosa during nasal residence time. Donepezil-loaded chitosan microspheres and their physical mixture with mannitol were used as controls. Analyses were complemented by solid-state and rheological characterization to elucidate the effects of formulation composition and processing on the observed behavior. Irritation potential was further assessed using the established slug mucosal irritation (SMI) assay. Results: Reproducible microsphere size distribution (Dv10 11.5 \u00b1 1.1 \u00b5m, RSD 9.6%; Dv50 28.4 \u00b1 3.9 \u00b5m, RSD 13.7; Dv90 61.3 \u00b1 8.4 \u00b5m, RSD 8.4%), entrapment efficiency (99.6 \u00b1 1.8%, RSD 1.8%) and process yield (40.9 \u00b1 5.5%, RSD 13.3%) confirmed the robustness of the ultrasonic spray-drying. Replacing mannitol with lactose failed to achieve the desired particle size distribution, highlighting the key role of mannitol under the investigated processing conditions. The biomimetic model coupled with rheological studies demonstrated that chitosan-based gels formed by microsphere swelling in simulated nasal fluid, maintain viscosity, resist dehydration, and undergo rehydration. Additionally, mannitol enhanced water retention and reduced evaporation without increasing occlusivity or the risk of mucosal dehydration. Furthermore, powders containing mannitol exhibited a lower irritation potential in the SMI assay compared to chitosan microspheres alone. Conclusions: Mannitol is a critical determinant of the performance of donepezil-loaded chitosan-based microspheres, contributing to the desired particle size distribution, process reproducibility, favorable hydration and improved mucosal tolerability, thereby supporting the suitability of this platform for nasal donepezil delivery.<\/jats:p>","DOI":"10.3390\/pharmaceutics18081023","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T08:08:41Z","timestamp":1787040521000},"page":"1023","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mannitol as a Critical Excipient in Spray-Dried Chitosan Microspheres for Nasal Donepezil Delivery: Insights from Integrated Biomimetic Models"],"prefix":"10.3390","volume":"18","author":[{"given":"Mirna","family":"Perku\u0161i\u0107","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Ni\u017ei\u0107 Nodilo","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7473-9807","authenticated-orcid":false,"given":"Mario","family":"Jug","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cvijeta","family":"Jakobu\u0161i\u0107 Brala","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia"}],"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, 24143 Kiel, Germany"},{"name":"Priority Research Area Kiel Nano, Surface and Interface Sciences (KiNSIS), Kiel University, 24143 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Hafner","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"120994","DOI":"10.1016\/j.ijpharm.2021.120994","article-title":"Progress in Nasal Drug Delivery Systems","volume":"607","author":"Laffleur","year":"2021","journal-title":"Int. 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