In vivo nose-to-brain delivery of the hydrophilic antiviral ribavirin by microparticle agglomerates

Abstract

Nasal administration has been proposed as a potential approach for the delivery of drugs to the central nervous system. Ribavirin (RBV), an antiviral drug potentially useful to treat viral infections both in humans and animals, has been previously demonstrated to attain several brain compartments after nasal administration. Here, a powder formulation in the form of agglomerates comprising micronized RBV and spray-dried microparticles containing excipients with potential absorption enhancing properties, i.e. mannitol, chitosan, and α-cyclodextrin, was developed for nasal insufflation. The agglomerates were characterized for particle size, agglomeration yield, and ex vivo RBV permeation across rabbit nasal mucosa as well as delivery from an animal dry powder insufflator device. Interestingly, permeation enhancers such as chitosan and mannitol showed a lower amount of RBV permeating across the excised nasal tissue, whereas α-cyclodextrin proved to outperform the other formulations and to match the highly soluble micronized RBV powder taken as a reference. In vivo nasal administration to rats of the agglomerates containing α-cyclodextrin showed an overall higher accumulation of RBV in all the brain compartments analyzed as compared with the micronized RBV administered as such without excipient microparticles. Hence, powder agglomerates are a valuable approach to obtain a nasal formulation potentially attaining nose-to-brain delivery of drugs with minimal processing of the APIs and improvement of the technological and biopharmaceutical properties of micronized API and excipients, as they combine optimal flow properties for handling and dosing, suitable particle size for nasal deposition, high surface area for drug dissolution, and penetration enhancing properties from excipients such as cyclodextrins.

Engineering and Development of Chitosan-Based Nanocoatings for Ocular Contact Lenses

“…Chitosan has previously been utilised as a release modulator and PE for an array of biological membranes including buccal tissue (Duttagupta, Jadhav et al 2015, Kontogiannidou, Andreadis et al 2017, intestinal tissue (Chougule, Patel et al 2014, Maher, Mrsny et al 2016, Ates, Kaynak et al 2016, nasal cavity (Benediktsdottir, Baldursson et al 2014, Giuliani, Balducci et al 2018. Chitosan has also been scrutinised in the ocular drug delivery due to its permeation enhancement properties; with drugs such as ofloxacin (Di Colo, Burgalassi et al 2004), triamcinolone acetonide (Raval, Khunt et al 2018) and timolol maleate (Rodriguez, Antonio Vazquez et al 2017).…”

Intranasal Zotepine Nanosuspension: intended for improved brain distribution in rats

“…Nerve endings of CNS in nasal cavity can take-up the drug directly from nose by means of olfactory pathway and trigeminal nerves by circumventing BBB [15][16][17]. Different formulation approaches like nanosuspension based gels [18], polymeric nanoparticles [19], solid lipid nanoparticles [20], nanostructured lipid nanoparticles [21], microemulsions [22], cyclodextrin complexes [23] etc., are being experimented to carry drug directly to brain. However, the surface area of nasal cavity is 150 cm 2 with total volume of 15-20 mL nasal fluid and thus the volume of intranasal drug delivery is restricted to 25-200 μL [19,24,25].…”

How to characterize a nasal product. The state of the art of in vitro and ex vivo specific methods

“…They were initially intended to deliver powders into lungs of rats (DP-4R) or mice (DP-4 M) after inserting the tip into the trachea of the anaesthetized animal. However, the DP-4 device has also been used to deliver powder into the nasal cavity of rats (Giuliani et al, 2018) and to deposit powder onto Calu-3 monolayers under an air-liquid interface (ALI) (Meindl et al, 2015;Cingolani, 2017).…”