Alternative strategies to improve intranasal and nose-to-brain drug delivery

The nasal route is an appealing option for drug administration due to features like increased patient compliance, avoidance of the first-pass effect, fast onset of action, and direct access to the central nervous system. Despite advantages, challenges include limited nasal tissue surface, mucus and epithelial barriers, as well as mucociliary clearance. This Ph.D. project aimed to overcome these shortcomings by investigating strategies capable of enhancing drug permeation through the nasal mucosa. Two main approaches were considered. One method involved adding molecular enhancers to increase membrane apparent permeability, specifically highlighting postbiotics as potential natural and eco-friendly excipients for nasal drug delivery. The other approach intended to counter mucociliary clearance using mucoadhesive agents and “smart” polymers, thus extending the residence time and favoring complete drug absorption. Parallel to this, the usefulness and applicability of different in vitro tools in the pre-clinical assessment of drug permeability were considered. Great attention was paid to the ready-to-use PermeaPad® biomimetic membrane, which was implemented with a layer of reconstituted mucin to mimic the composition of the nasal mucosa. This membrane was employed, together with tissue-based models and a primary cell-based system, to establish the ability and the mechanism of diffusion improvement by liquid and semisolid formulations.