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.
Highlights
Viral diseases are considered a major global threat to human and veterinary public health (Howard & Fletcher, 2012)
The first part of the work attempted to formulate RBV as a powder for nasal insufflation focusing on the production of microparticles containing the antiviral drug along with the excipients selected
RBV was successfully formulated for nose-to-brain administration in the form of agglomerates with spray-dried excipient microparticles suitable for efficient nasal deposition and able to provide mucoadhesion and permeation enhancing properties
Summary
Viral diseases are considered a major global threat to human and veterinary public health (Howard & Fletcher, 2012). The nasal route has been extensively studied for the administration of drugs directly to the CNS (Landis et al, 2012) This route exploits the olfactory region and the trigeminal nerve pathway to enable drugs’ entry into the CNS bypassing the BBB (Hanson & Frey, 2008). This delivery approach was explored for the administration of ribavirin (RBV), in view of an innovative treatment of the encephalitis associated with canine distemper virus, a major veterinary infection that could serve as a proof of concept of the approach. This virus belongs to the Morbillivirus genus as the Supplemental data for this article can be accessed here
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