{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T02:45:35Z","timestamp":1792118735842,"version":"4.4.0"},"reference-count":48,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,5,21]],"date-time":"2023-05-21T00:00:00Z","timestamp":1684627200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PhD program in Neurosciences, XXXVI cycle, University of Catania"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Clozapine (CZP) is the only effective drug in schizophrenia resistant to typical antipsychotics. However, existing dosage forms (oral or orodispersible tablets, suspensions or intramuscular injection) show challenging limitations. After oral administration, CZP has low bioavailability due to a large first-pass effect, while the i.m. route is often painful, with low patient compliance and requiring specialised personnel. Moreover, CZP has a very low aqueous solubility. This study proposes the intranasal route as an alternative route of administration for CZP, through its encapsulation in polymeric nanoparticles (NPs) based on Eudragit\u00ae RS100 and RL100 copolymers. Slow-release polymeric NPs with dimensions around 400\u2013500 nm were formulated to reside and release CZP in the nasal cavity, where it can be absorbed through the nasal mucosa and reach the systemic circulation. CZP-EUD-NPs showed a controlled release of CZP for up to 8 h. Furthermore, to reduce mucociliary clearance and increase the residence time of NPs in the nasal cavity to improve drug bioavailability, mucoadhesive NPs were formulated. This study shows that the NPs already exhibited strong electrostatic interactions with mucin at time zero due to the presence of the positive charge of the used copolymers. Furthermore, to improve the solubility, diffusion and adsorption of CZPs and the storage stability of the formulation, it was lyophilised using 5% (w\/v) HP-\u03b2-CD as a cryoprotectant. It ensured the preservation of the NPs\u2019 size, PDI and charge upon reconstitution. Moreover, physicochemical characterisation studies of solid-state NPs were performed. Finally, toxicity studies were performed in vitro on MDCKII cells and primary human olfactory mucosa cells and in vivo on the nasal mucosa of CD-1 mice. The latter showed non-toxicity of B-EUD-NPs and mild CZP-EUD-NP-induced tissue abnormalities.<\/jats:p>","DOI":"10.3390\/pharmaceutics15051554","type":"journal-article","created":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T01:31:46Z","timestamp":1684719106000},"page":"1554","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Development of Lyophilised Eudragit\u00ae Retard Nanoparticles for the Sustained Release of Clozapine via Intranasal Administration"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-8227-915X","authenticated-orcid":false,"given":"Rosamaria","family":"Lombardo","sequence":"first","affiliation":[{"name":"Laboratory of Drug Delivery Technology, Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marika","family":"Ruponen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2172-3980","authenticated-orcid":false,"given":"Jarkko","family":"Rautio","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Ghelardini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA)\u2014Pharmacology and Toxicology Section, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8374-4432","authenticated-orcid":false,"given":"Lorenzo","family":"Di Cesare Mannelli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA)\u2014Pharmacology and Toxicology Section, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Calosi","sequence":"additional","affiliation":[{"name":"Platform of Imaging, Department of Experimental & Clinical Medicine, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6302-901X","authenticated-orcid":false,"given":"Daniele","family":"Bani","sequence":"additional","affiliation":[{"name":"Platform of Imaging, Department of Experimental & Clinical Medicine, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1485-5179","authenticated-orcid":false,"given":"Riikka","family":"Lampinen","sequence":"additional","affiliation":[{"name":"A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70210 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6717-8589","authenticated-orcid":false,"given":"Katja M.","family":"Kanninen","sequence":"additional","affiliation":[{"name":"A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70210 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M.","family":"Koivisto","sequence":"additional","affiliation":[{"name":"Brain Research Unit, Department of Neurology, School of Medicine, University of Eastern Finland, 70200 Kuopio, Finland"},{"name":"Department of Neurology, Neuro Centre, Kuopio University Hospital, 70210 Kuopio, Finland"},{"name":"Department of Neurology and Geriatrics, Helsinki University Hospital and Neurosciences, Faculty of Medcine, University of Helsinki, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elina","family":"Penttil\u00e4","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, University of Eastern Finland, Kuopio University Hospital, 70210 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heikki","family":"L\u00f6pp\u00f6nen","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, University of Eastern Finland, Kuopio University Hospital, 70210 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5937-4192","authenticated-orcid":false,"given":"Rosario","family":"Pignatello","sequence":"additional","affiliation":[{"name":"Laboratory of Drug Delivery Technology, Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy"},{"name":"NANOMED\u2014Research Centre on Nanomedicine and Pharmaceutical Nanotechnology, University of Catania, Viale A. Doria 6, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,21]]},"reference":[{"key":"ref_1","unstructured":"Institute of Health Metrics and Evaluation (IHME) (2023, April 05). Global Health Data Exchange (GHDx). Available online: http:\/\/ghdx.healthdata.org\/gbd-results-tool?params=gbd-api-2019-permalink\/27a7644e8ad28e739382d31e77589dd7."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Pires, P.C., Paiva-Santos, A.C., and Veiga, F. (2022). Antipsychotics-Loaded Nanometric Emulsions for Brain Delivery. 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