For decades, nose-to-brain (N2B) drug delivery has offered an attractive proposition as a non-invasive means of reaching the central nervous system (CNS) while reducing reliance on transport across the blood–brain barrier. The scientific rationale has been supported by extensive preclinical research yet one fundamental question has continued to limit clinical confidence: can a molecule administered through the nose be shown to reach relevant regions of the human brain?
Nasal administration is already established in several CNS-related conditions, including epilepsy, migraine, depression and opioid overdose. These products demonstrate many of the advantages that continue to drive interest in the nasal route, offering a non-invasive, easy-to-use alternative to injectable administration while providing a similarly rapid onset of action. Most, however, primarily depend on absorption through the nasal mucosa into the systemic circulation, with CNS exposure achieved after the active molecule crosses the blood–brain barrier.
Direct N2B delivery has a different objective. It seeks to use the anatomical connections of the olfactory and trigeminal pathways to transport therapeutics from the nasal cavity to the CNS. Interest in this approach is increasing as the development pipelines expand to include peptides, proteins and other molecules with limited blood–brain barrier permeability. It is also being driven by demand for patient-friendly treatments capable of achieving rapid and meaningful CNS targeting while reducing systemic exposure and the associated risk of peripheral effects.
Recent human imaging studies have now provided direct evidence of N2B transport in humans. As a result, the development question is no longer limited to whether this pathway exists.9 Attention is increasingly turning to how reliably it can be achieved, which factors influence delivery in different individuals and how the formulation and delivery system can be configured to improve performance.
The Challenge of Human Validation
Before this direct human imaging data became available, N2B delivery had long generated scientific interest but translation into clinical development was constrained by two related challenges: 1) demonstrating that a molecule reached the human brain and 2) achieving sufficiently consistent administration to interpret therapeutic outcomes.
Preclinical studies have provided substantial evidence that compounds can move from the nasal cavity into the CNS along pathways associated with the olfactory and trigeminal nerves.2 However, evidence of transport in an animal model does not necessarily establish how a formulation and delivery system will perform in humans.10 Differences in nasal anatomy, administration technique, formulation behaviour and disease-related physiology may all affect the amount, location and timing of brain exposure.
