In situ hydrogel containing diazepam-loaded nanostructured lipid carriers (DZP-NLC) for nose-to-brain delivery: development, characterization and deposition studies in a 3D-printed human nasal cavity model

Abstract

The nasal route has been investigated as a promising alternative for drug delivery to the central nervous system, avoiding passage through the blood-brain barrier and improving bioavailability. In this sense, it is necessary to develop and test the effectiveness of new formulations proposed for the management of neurological disorders. Thereby, the aim of this work was to develop and characterize an ion sensitive in situ hydrogel containing diazepam-loaded nanostructured lipid carriers (DZP-NLC) for nasal delivery in the treatment of epilepsy. Physical characterization of the developed formulations was performed and included the evaluation of rheological features, particle size, polydispersity index (PDI) and zeta potential (ZP) of an in situ hydrogel containing DZP-NLC. Afterwards, in vitro drug release, in vitro mucoadhesion and biocompatibility studies with RPMI 2650 nasal cells were performed. The in situ hydrogel containing DZP-NLC was aerosolized with a nasal spray device specifically designed for nose-to-brain delivery (VP7 multidose spray pump with a 232 N2B actuator) and characterized for droplet size distribution and spray cone angle. Finally, the deposition pattern of this hydrogel was evaluated in a 3D-printed human nasal cavity model. The developed in situ hydrogel containing DZP-NLC presented adequate characteristics for nasal administration, including good gelling ability, mucoadhesiveness and prolonged drug release. In addition, after inclusion in the hydrogel net, the particle size (81.79 ± 0.53 nm), PDI (0.21 ± 0.10) and ZP (-30.90 ± 0.10 mV), of the DZP-NLC remained appropriate for nose-to-brain delivery. Upon aerosolization in a nasal spray device, a suitable spray cone angle (22.5 ± 0.2°) and adequate droplet size distribution (Dv (90) of 317.77 ± 44.12 µm) were observed. Biocompatibility studies have shown that the developed formulation is safe towards RPMI 2650 cells in concentrations up to 100 μg/mL. Deposition studies on a 3D-printed human nasal cavity model revealed that the best nasal deposition profile was obtained upon formulation administration without airflow and at an angle from horizontal plane of 75°, resulting in 47% of administered dose deposited in the olfactory region and 89% recovery. The results of this study suggested that the intranasal administration of the developed in situ hydrogel containing DZP-NLC could be a promising alternative to the conventional treatments for epilepsy.

Keywords: 3D-printed human nasal cavity model; Diazepam; In situ hydrogel; Nanostructured lipid carriers (NLC); RPMI 2650 cells.