Nanonized carbamazepine for nose-to-brain delivery: pharmaceutical formulation development

Abstract

Epilepsy is one of the most common neurological disorders in the world. The therapeutic treatment is challenging since conventional drugs have limited efficacy and several side effects that impair patient management. Efforts are being made to find innovative strategies to control epileptic seizures. Intranasal administration provides a convenient route to deliver the drug to the brain. Carbamazepine (CBZ) is an anticonvulsant characterized by poor water solubility, nanonization can improve its bioavailability. Therefore, the design of CBZ nanocrystals (NCs) was assessed to obtain a formulation suitable for nose-to-brain delivery. CBZ NCs were prepared by sonoprecipitation following the Quality by Design approach identifying the impact of process and formulation variables on the critical quality attributes of the final product. The formulation was characterized by a technological point of view (thermotropic behavior, crystallinity, morphology, mucoadhesive strength). Response surface methodology was a reliable tool (error % 2.6) to optimize CBZ NCs with size ≤300 nm. Incubation of CBZ NCs in artificial cerebrospinal fluid at 37 °C did not promote aggregation and degradation phenomena. Preliminary biological studies revealed the biocompatibility of CBZ NCs towards Olfactory Ensheating Cells. The suspension was successfully converted into a powder. The highly concentrated formulation can be obtained, providing the possibility to administer the maximum dose of the drug in the lowest volume.

Graphical Abstract

Keywords:

• Nanocrystals
• design of experiment
• nose-to-brain
• stability
• biocompatibility

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Acknowledgements

A.B. is a Researcher at the University of Catania within the EU-funded PON REACT project (Azione IV.4 – ‘Dottorati e contratti di ricerca su tematiche dell’innovazione’, nuovo Asse IV del PON Ricerca e Innovazione 2014–2020 ‘Istruzione e ricerca per il recupero – REACT – EU’; Progetto ‘Approcci terapeutici innovativi per il targeting cerebrale di farmaci e materiale genico’, CUP E65F21002640005).

Author contributions

A.B. conceptualization, investigation, methodology, validation, data curation, software, writing—original draft; writing—review and editing; M.R.G. methodology, data curation, writing—original draft; R.L. investigation, methodology; R.P. methodology, data curation, writing—original draft; P.D.M. formal analysis, writing—review and editing, A.M. writing—review and editing; T.M. conceptualization, formal analysis, project administration, writing—original draft; funding acquisition. All authors have read and agreed to the published version of the manuscript.

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Funding

This research was funded by Ricerca di Ateneo 2020–2022, Piano di incentivi per la ricerca (PIA.CE.RI.), Linea di intervento 2; Naso, Nanomedicina e Neuroterapie: Le 3 N per il target cerebrale di molecole bioattive (3 N-ORACLE). PI: Teresa Musumeci, Progetto interdipartimentale, CUP 57722172124.