Rivastigmine nasal spray for the treatment of Alzheimer's Disease: Olfactory deposition and brain delivery.

Alzheimer's disease (AD) is characterized by a gradual decline in cognitive function and memory impairment, significantly impacting the daily lives of patients. Rivastigmine (RHT), a cholinesterase inhibitor, is used to treat mild to moderate AD via oral administration. However, oral administration is associated with slow absorption rate and severe systemic side effects. RHT nasal spray (RHT-ns), as a nose-to-brain delivery system, is more promising for AD management due to its efficient brain delivery and reduced peripheral exposure. This study constructed RHT-ns for enhancing AD treatment efficacy, and meanwhile the correlation between drug olfactory deposition and drug entering into the brain was explored. A 3D-printed nasal cast was employed to quantify the drug olfactory deposition. Brain delivery of RHT-ns was quantified using fluorescence tracking and Desorption Electrospray Ionization Mass Spectrometry (DESI-MS) analysis, which showed a good correlation to the olfactory deposition. F2 (containing 1% (w/v) viscosity modifier Avicel® RC-591) with high olfactory deposition and drug brain delivery was further investigated for pharmacodynamics study. F2 exhibited superiority in AD treatment over the commercially available oral formulation. In summary, the present study showed the successful development of RHT-ns with improved olfactory deposition and enhanced brain delivery. It might provide new insight into the design and development of nose-to-brain systems for the treatment of AD.