Intranasal Drug Delivery to the Brain

The barriers that separate the blood from brain interstitial and cerebrospinal fluids present a significant challenge to efficient and practical drug delivery into the central nervous system (CNS). New strategies to circumvent the blood-brain barrier (BBB) have long been needed to utilize polar pharmaceuticals and large biotherapeutics for CNS disease treatment because the BBB is typically impermeable to such compounds. The increasing application of biologics as therapeutics over the past several decades has brought much new interest in routes of drug delivery that may be more easily utilized for chronic dosing of large molecules, e.g., oral, subcutaneous, transdermal, pulmonary, and intranasal administration. The intranasal route in particular offers a number of advantages for chronic dosing including its noninvasiveness, efficient uptake and absorption into a highly vascular submucosa, avoidance of hepatic first-pass elimination, rapid pharmacokinetic profiles, and ease of administration. Importantly, the intranasal route has also been demonstrated to potentially allow a variety of drugs direct access to the brain and/or cerebrospinal fluid. Studies over the past few decades have shown that even large biotherapeutics may have access to the CNS along extracellular pathways associated with the olfactory and trigeminal nerves. This chapter provides an overview of the unique anatomic and physiologic attributes of the nasal mucosa and its associated cranial nerves that allow small but significant fractions of certain intranasally applied drugs to transfer across the nasal epithelia and subsequently be transported directly into the CNS. We also review some of the preclinical and clinical literature related to intranasal targeting of biologics to the CNS and comment on future directions for the further clinical translation of this route of administration.