Nasal Absorption Enhancement of Mometasone Furoate Nanocrystal Dispersions

Abstract

Shuya Masuda,1,* Saori Deguchi,1,* Fumihiko Ogata,1 Joji Yoshitomi,1 Hiroko Otake,1 Kazutaka Kanai,2 Naohito Kawasaki,1 Noriaki Nagai1 1Faculty of Pharmacy, Kindai University, Osaka, Japan; 2Department of Small Animal Internal Medicine, School of Veterinary Medicine, University of Kitasato, Aomori, Japan*These authors contributed equally to this workCorrespondence: Noriaki Nagai, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka, 577-8502, Japan, Tel [phone], Fax [phone], Email [email protected]: We designed a 0.05% mometasone furoate (MF) nanocrystal dispersion and investigated whether the application of MF nanocrystals in nasal formulations enhanced local absorption compared to traditional nasal MF formulations (CA-MF).Methods: MF nanocrystal dispersions (MF-NPs) were prepared by bead milling MF microcrystal dispersions (MF-MPs) consisting of MF, 2-hydroxypropyl-β-cyclodextrin, methylcellulose, and purified water. Pluronic F-127 combined with methylcellulose, Pluronic F-68, or carbopol was used as a base for in situ gelation (thickener). MF concentrations were measured using high-performance liquid chromatography, and nasal absorption of MF was evaluated in 6 week-old male Institute of Cancer Research (ICR) mice.Results: The particle size range of MF prepared with the bead mill treatment was 80– 200 nm, and the nanoparticles increased the local absorption of MF, which was higher than that of CA-MF and MF-MPs. In addition, unlike the results obtained in the small intestine and corneal tissue, the high absorption of nanocrystalline MF in the nasal mucosa was related to a pathway that was not derived from energy-dependent endocytosis. Moreover, the application of the in situ gelling system attenuated the local absorption of MF-NPs, owing to a decrease in drug diffusion in the dispersions.Conclusion: We found that nanoparticulation of MF enhances local intranasal absorption, and nasal bioavailability is higher than that of CA-MF. In addition, we demonstrate that viscosity regulation is an important factor in the design of nasal formulations based on MF nanocrystals. These findings provide insights for the design of novel nanomedicines with enhanced nasal bioavailability.Plain Language Summary: Mometasone furoate (MF) is administered nasally to treat nasal inflammatory diseases. In this study, we designed MF nanocrystal dispersions (MF-NPs) and investigated whether the application of MF nanocrystals in nasal MF formulations enhanced local absorption compared to traditional nasal MF formulations. MF-NPs were obtained via bead-milling of dispersions, consisting of MF, 2-hydroxypropyl-β-cyclodextrin, methylcellulose, and purified water, and the MF-NPs with in situ gelation were prepared by the addition of a gel base consisting of Pluronic F-127 combined with methylcellulose, Pluronic F-68, or carbopol. The nasal absorption of MF was evaluated in 6 week-old ICR mice. The bead-milled MF particles in the dispersions were crystalline with sizes of 80– 200 nm. Moreover, MF-NPs exhibited lower viscosity and higher local absorption than commercially available nasal formulations and dispersions containing microcrystalline MF. However, the application of in situ gelling systems attenuated the local absorption of the MF-NPs. This is the first study to investigate the nasal absorption of dispersions containing nanocrystalline MF and the basis of in situ gelation, providing important information for the design of nanomedicines with enhanced nasal bioavailability.Graphical Abstract: Keywords: mometasone furoate, nanocrystal, nasal absorption, drug delivery, in situ gel

Keywords

• mometasone furoate
• nanocrystal
• nasal absorption
• drug delivery
• in situ gel