Design and development of a chitosan-based nasal powder of dimethyl fumarate-cyclodextrin binary systems aimed at nose-to-brain administration. A stability study

The nasal administration route has been studied for the delivery of active molecules directed to the Central Nervous System, thanks to the anatomical connection between the nasal cavity and the brain.

Dimethyl fumarate is used to treat relapsing-remitting multiple sclerosis, with a role as an immunomodulator towards T- T-cells and a cytoprotector towards neurons and glial cells. Its use in therapy is hindered by its low aqueous solubility, and low stability, due to hydrolysis and sublimation at room temperature. To overcome this limitation, in this study we evaluated the feasibility of using two amorphous β-cyclodextrin derivatives, namely hydroxypropyl β-cyclodextrin and methyl β-cyclodextrin, to obtain a nasally administrable powder with a view to nose-to-brain administration.

Initially, the interaction product was studied using different analytical methods (differential scanning calorimetry, Fourier transform infrared spectroscopy and powder X-ray diffraction) to detect the occurrence of binary product formation, while phase solubility analysis was used to probe the complexation in solution.

The dimethyl fumarate-cyclodextrin binary product showing best solubility and stability properties was subsequently used in the development of a chitosan-based mucoadhesive nasally administrable powder comparing different preparative methods. The best performance in terms of both hydrolytic stability and DMF recovery was achieved by the powder obtained via freeze-drying.

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Materials

Dimethyl fumarate (DMF, 99 %) was purchased from AK Scientific Inc. (Union City, USA). Monomethyl fumarate (MMF, 97 %) and fumaric acid (FA, 99 %) were purchased from Sigma Aldrich, Co (St Louis, MO, USA). Hydroxypropyl-β-cyclodextrin (HPβCD, Mw: 1,400 g/mol) was a gift from Cyclolab Ltd. (Budapest, Hungary). Randomly methylated β-cyclodextrin (RAMEB, Cavasol® W7 M Pharma, Mw: 1,302 g/mol) was purchased from Wacker-Chemie Italia (Peschiera Borromeo, Milan, IT). Mannitol was purchased from Roquette Italia (Cassano Spinola, Alessandria, IT). Chitosan-HCl (CS⋅HCl), Tripolyphosphate sodium, Agar and Gastrin mucin porcine type III were purchased from Sigma Aldrich (Milan, IT). Ultrapure water was obtained from a MilliQ® apparatus (Millipore, USA). Methanol of chromatographic grade was acquired from PanReac® AppliChem® (ITW Reagents®, Darmstadt, Germany).

Eleonora Sofia Cama, Laura Catenacci, Sara Perteghella, Milena Sorrenti, Mino R. Caira, Giovanna Rassu, Elisabetta Gavini, Paolo Giunchedi, Maria Cristina Bonferoni, Design and development of a chitosan-based nasal powder of dimethyl fumarate-cyclodextrin binary systems aimed at nose-to-brain administration. A stability study, International Journal of Pharmaceutics, 2024, 124216, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124216.

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