Nose-to-brain delivery of donepezil within a small dose improves bioavailability and efficacy for Alzheimer's disease treatment.

Oral administration of donepezil (Don) is the first-line medication for Alzheimer's disease (AD); however, the dysphagia of elderly patients and severe gastrointestinal side effects substantially restrict administration compliance. Herein, we exploit a nose-to-brain pathway for Don administration to obtain smaller dosage but higher intracerebral bioavailability (BA), thereby achieving inhibition of acetylcholinesterase (AChE) activity and avoiding side effects. With respect to the intranasal administration design, a patient-friendly Don nasal spray without preservatives was developed. The administration of Don nasal spray demonstrated good nasal deposition and mucosa permeation ability comparable to that of the model drug propranolol. The mice intranasally administered Don at an equivalent oral dose (0.65 mg/kg) demonstrated rapid brain distribution (∼5 min) and long-lasting AChE inhibition effects (72 h). To obtain the optimal intranasal dose, a dose-descending study was conducted by cascading the oral dosage at a 1:3 ratio. The results demonstrated that intranasal administration of Don at 0.07 mg/kg resulted in intracerebral BA and AChE inhibition comparable to oral administration at 0.65 mg/kg, suggesting an 89% dose reduction. Compared with oral administration, anti-AD effectiveness was evaluated in AD model mice after 34-d- intranasal administration of Don, resulting in a shorter onset time, higher intracerebral drug concentration, and a longer duration of AChE inhibition (0.07 mg/kg). The nasal and systemic safety of intranasal administration of Don was confirmed in an allergic rhinitis mouse model after 4 weeks of intranasal administration. Thus, a small dose of Don exhibits improved intracerebral BA and AChE inhibition via intranasal administration, thereby offering better compliance and reducing side effects in AD treatment.