(M1430-11-75) Rizatriptan Nasal Spray with Effective Olfactory Deposition for Improving Migraine Treatment

Purpose: Specific attention is paid to the nose-to-brain delivery system (NBDDS) due to the unique physiological connection between the nasal cavity and the brain. Evidence suggested that NBDDS could bypass the blood brain barrier and directly enter the brain, offering an ample potential for treatment of central nervous system (CNS) diseases. Despite intensive attention has been paid to the establishment of efficient nasal spray based nose-to-brain delivery, its formulation design and optimization remain an empiricism-based process due to the ambiguity of the nasal delivery process. Herein, a rizatriptan nasal spray (RIZ-NS) with efficient nose-to-brain delivery was fabricated to elucidate the impact of viscosity on nose-to-brain delivery and clarify the nasal delivery process.

Methods: The RIZ-NS with different viscosity were prepared by adjusting chitosan-alginate ratios, and the viscosity, osmotic pressure, pH and pump delivery were characterized. Then, a modular 3D-printed nasal cast coupled with next generation impactor was employed to explore the in vitro nasal deposition distribution and olfactory deposition. The in vivo nose-to-brain delivery process and intracephalic distribution were evaluated by in vivo fluorescence imaging. Besides, the efficient nose-to-brain delivery of RIZ-NS was further validated by in vivo pharmacokinetics and pharmacodynamics.

Results: The viscosity of nasal spray formulations increased from 1.95±0.02 mP·s to 287.97±0.28 mP·s (Fig. 1A), and the osmotic pressure (Fig. 1B) and pH (Fig. 1C) were in the physiological range (except F1). There was no significant difference in pump delivery (Fig. 1D), suggesting good delivery dose uniformity. The deposition of nasal spray mainly occurred in nasal vestibule and nasal meatus, while the deposition in the oropharynx and lower respiratory tract was less than 1%. The olfactory deposition fraction of nasal spray increased first and then decreased, and F5 had the highest olfactory deposition fraction of 23.58% (Fig. 1E-G). The results of in vivo fluorescence imaging were consistent with those of in vitro olfactory deposition. Too low or too high viscosity was not conducive to nose-to-brain delivery, and the F5 has the most distribution in the brain (Fig. 2A-F). Finally, in vivo pharmacokinetic experiments elaborated that the enhanced bioavailability in plasma and brain (Fig. 3A-B). In vivo pharmacodynamic experiments showed that RIZ-NS improved the spontaneous activity behavior, exploratory behavior, sound/light fear behavior, pain threshold, and c-Fos expressions of migraine rats (Fig. 3C-I), which had obvious advantages compared with commercially available oral tablets.

Conclusion: This study elucidated the enhancement mechanism of viscosity on the nasal delivery process of nasal spray, which was of great significance for the design and optimization of novel nose-to-brain delivery formulations.

References: [1] C. Peng, et al., Nature, 2022, 606(7914):550-556.
[2] Y. Kim, et al., J Control Release, 2020, 317: 181-194.

Acknowledgements: This work was supported by National Science Foundation of China under Grant No. 82104072; Science and Technology Foundation Guangdong under Grant No. 2021A0505080011.

Figure 1. The characterization and in vitro nasal deposition of RIZ-NS: (A) Viscosity; (B) Osmotic pressure; (C) pH; (D) Pump delivery; (E) Schematic diagram of 3D-printed human nasal model; (F) Nasal deposition distribution; (G) Olfactory deposition of RIZ-NS.

Figure 2. (A) The nose-to-brain delivery process of RIZ-NS; (B) The fluorescence distribution in the brain; (C) Schematic diagram of different brain segment; (D) Semi-quantitative analysis of the whole brain; (E) Semi-quantitative analysis of different brain segment; (F) Semi-quantitative analysis of trigeminal nerve.

Figure 3. (A) Pharmacokinetic profile of RIZ in the plasma; (B) Pharmacokinetic profile of RIZ in the brain; (C) Total movement distance of migraine rats in open-field; (D) Non-moving behavior of migraine rats; (E) Central area residence time; (F) Central area entry times; (G) Immobility duration in sound/light stimulation; (H) Orbital pain threshold; (I) Immunofluorescence staining of c-Fos in brain and trigeminal nerve.