Novel approach for direct drug delivery to the central nervous system via intratympanic administration

Therapeutic drugs for central nervous system (CNS) diseases need to reach CNS tissues. However, the blood-brain barrier often limits their therapeutic effects. To address this issue, highly invasive drug administration routes, such as intracerebroventricular or intrathecal administration, can be used. In addition, intranasal (i.n.) administration is increasingly being recognized as a non-invasive route, although its application in humans is limited. Hence, we explored intratympanic (i.t.) administration as a novel, minimally invasive route for direct drug delivery to the CNS. The aim of this study was to develop a new administration route that enables efficient and comprehensive evaluation of CNS drug transport by employing cassette dosing. Using this approach, we assessed multiple low- and high-permeability drugs concurrently in rodents and non-human primates. Pharmacokinetics were evaluated in cerebrospinal fluid (CSF) and brain tissues to investigate the potential for enhanced CNS penetration. Furthermore, the effects of cetirizine, a second-generation histamine receptor antagonist, on spontaneous locomotor activity were examined following i.t. and intravenous (i.v.) administration. I.t. of low-permeable drugs such as cetirizine markedly increased their penetration into CSF and brain in both rats and monkeys. Pharmacologically, i.t. of cetirizine significantly decreased spontaneous locomotor activity in rats, whereas such effects were not observed following i.v.. This study demonstrates that i.t. may serve as a promising route (Ear-to-Brain) for treating neurodegenerative diseases that currently lack effective treatment options.