Development of Lyophilised Eudragit<sup>®</sup> Retard Nanoparticles for the Sustained Release of Clozapine via Intranasal Administration
Rosamaria Lombardo,
Marika Ruponen,
Jarkko Rautio,
Carla Ghelardini,
Lorenzo Di Cesare Mannelli,
Laura Calosi,
Daniele Bani,
Riikka Lampinen,
Katja M. Kanninen,
Anne M. Koivisto,
Elina Penttilä,
Heikki Löppönen,
Rosario Pignatello
Affiliations
Rosamaria Lombardo
Laboratory of Drug Delivery Technology, Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
Marika Ruponen
School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland
Jarkko Rautio
School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland
Carla Ghelardini
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA)—Pharmacology and Toxicology Section, University of Florence, 50139 Florence, Italy
Lorenzo Di Cesare Mannelli
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA)—Pharmacology and Toxicology Section, University of Florence, 50139 Florence, Italy
Laura Calosi
Platform of Imaging, Department of Experimental & Clinical Medicine, University of Florence, 50139 Florence, Italy
Daniele Bani
Platform of Imaging, Department of Experimental & Clinical Medicine, University of Florence, 50139 Florence, Italy
Riikka Lampinen
A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70210 Kuopio, Finland
Katja M. Kanninen
A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70210 Kuopio, Finland
Anne M. Koivisto
Brain Research Unit, Department of Neurology, School of Medicine, University of Eastern Finland, 70200 Kuopio, Finland
Elina Penttilä
Department of Otorhinolaryngology, University of Eastern Finland, Kuopio University Hospital, 70210 Kuopio, Finland
Heikki Löppönen
Department of Otorhinolaryngology, University of Eastern Finland, Kuopio University Hospital, 70210 Kuopio, Finland
Rosario Pignatello
Laboratory of Drug Delivery Technology, Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
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® RS100 and RL100 copolymers. Slow-release polymeric NPs with dimensions around 400–500 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-β-CD as a cryoprotectant. It ensured the preservation of the NPs’ 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.
