First In Vivo Demonstration of Nose-to-Brain Drug Delivery of Memantine Using NosaPlugs Nasal Inserts

Abstract

Treatment of neurological disorders such as Alzheimers disease remains a challenge due to ineffective drug delivery to the brain. In recent years, intranasal administration has emerged as a promising non-invasive approach for nose-to-brain delivery. Compared to other routes of administration, nose-to-brain delivery provides a possibility of bypassing both the blood-brain-barrier and the first-pass metabolism in the liver, allowing for a decrease in the delivered dose and thereby a reduced risk of systemic side-effects. While the most common nasal devices, spray pumps, ensure a wide distribution in the nasal cavity and a fast onset of action, a slower release and increased retention time is desired for treatment of many neurological disorders. In this study, we tested the feasibility of a novel nasal insert, NosaPlugs, for prolonged release and delivery of memantine. Using an in vitro anatomically realistic nasal model, we demonstrated cumulative release of memantine from the nasal inserts up to eight hours. Additionally, the therapeutic substance was distributed to all parts of the nasal cavity, with higher amounts accumulating in the middle part. In vivo, an acute dose of memantine in the gas phase released from the nasal device reached pharmacologically relevant levels in both plasma and the brains of the mice. Future research should investigate the release and delivery of alternative substances interesting for brain diseases, and larger animal models are required to determine the efficacy of nose-to-brain delivery using NosaPlugs nasal inserts. Importantly, our study provides the first proof-of-concept that NosaPlugs can serve as an effective intranasal device for targeted drug delivery to the brain.