INTRODUCTION

As interest in non-invasive drug delivery grows, nasal sprays are being reconsidered not only as a route for systemic absorp­tion but also as a viable gateway to the brain. The prospect of bypassing the blood-brain barrier (BBB) through olfactory and trigeminal nerve pathways presents a compelling opportunity for treating central nervous system (CNS) disorders. In this article, Justin Lygrisse, Associate Director, Research & Development at Kindeva, explores the rationale behind nose-to-brain delivery and the early clinical and preclinical efforts now underway to assess its potential.

Targeting drug deposition within the nasal cavity is becoming more achievable through improvements in formulation science, device performance and in vitro modeling. However, several chal­lenges remain, including variability in human anatomy, limited predictability of absorption and evolving regulatory expectations. As development progresses, careful coordination between formu­lation, engineering and pharmacokinetics will be essential. With more companies advancing CNS pipelines that seek to avoid sys­temic or injectable routes, nasal delivery offers a promising yet complex alternative. Success will depend on partners who can in­tegrate drug delivery considerations from the outset.

The pursuit of effective therapies for CNS disorders is signif­icantly hindered by the body’s highly efficient defense mecha­nism: the BBB.¹ This highly selective physiological barrier, though crucial for protecting the brain from circulating harmful sub­stances, presents a formidable obstacle for pharmaceutical agents, thus limiting the efficacy of many promising medications.² The inability of numerous molecules to traverse the BBB has driven a significant and growing interest in exploring non-inva­sive, innovative drug delivery methods that can directly circumvent this biological fortification. Among the alternatives, nasal sprays, harnessing the potential of direct nose-to-brain pathways, have emerged as a particularly attractive and viable option.

 THE RISE OF INTRANASAL DELIVERY FOR BRAIN TARGETING

Nasal drug delivery, commonly referred to as “nose-to-brain” delivery, offers a unique and advantageous mechanism for directly transporting therapeutic agents to the brain.³ This di­rect route is primarily facilitated by the unique anatomical con­nections within the nasal cavity, specifically utilizing the olfactory and trigeminal nerve pathways. These neural routes represent a potential bypass of the systemic circulation and, most critically, the restrictive BBB, allowing for more direct, rapid, and potent delivery of therapeutics to the CNS.⁴ This direct access holds im­mense promise for revolutionizing the treatment landscape for an extensive array of neurological and psychiatric conditions, from neurodegenerative diseases to acute conditions like stroke and even localized brain tumors.

The therapeutic potential of this approach is reflected in its commercial momentum. The nasal drug delivery technology mar­ket is projected for robust growth, with its value expected to in­crease from $82.68 billion in 2024 to an impressive $168.58 billion globally by 2034. This expansion is forecasted to occur at a compound annual growth rate (CAGR) of 7.38% over the pe­riod, underscoring the potential of this delivery route.⁵

Despite the clear potential for direct brain targeting, the path to widespread clinical application for nasal drug delivery faces considerable challenges related to efficacy, consistency and formulation complexity. Successfully translating this potential into viable therapies necessitates a highly fo­cused development approach and seam­less collaboration across diverse disciplines, from molecule design through to commercial manufacturing.

UNDERSTANDING THE NASAL CAVITY’S DIRECT ROUTES

The functional efficacy of nose-to-brain drug delivery is fundamentally de­pendent on the intricate anatomy of the nasal cavity. The nasal cavity is a highly vascularized and richly innervated struc­ture that presents distinct regional oppor­tunities for drug absorption and direct transport to the CNS. The inner lining is broadly divided into two primary regions: the olfactory region and the respiratory re­gion.

The olfactory region, situated in the superior part of the nasal cavity, is the paramount area of interest for direct path­ways. It contains the specialized olfactory epithelium with receptor neurons whose axons project directly through the cribri­form plate to the olfactory bulb in the brain. This tissue is rich in nerves, creating a direct neural highway ideal for nose-to-brain transport.

In contrast, the larger respiratory re­gion is lined with highly vascularized ep­ithelium. While efficient for systemic absorption due to its profuse blood supply, drugs absorbed here enter the systemic bloodstream and must then confront the BBB, making it less ideal for direct brain targeting.

Nasal delivery’s main therapeutic po­tential lies in its capacity to utilize direct neural pathways, which effectively bypass both the systemic circulation and the BBB. The two primary direct neural routes are:

The olfactory nerve route: Drugs applied strategically to the olfactory region can travel along the olfactory nerves (per­ineural or intraneural transport), pass through the cribriform plate, and gain ac­cess to the cerebrospinal fluid (CSF) and the brain parenchyma. This route mini­mizes undesirable systemic exposure.

The trigeminal nerve route: The trigemi­nal nerve branches extensively to innervate the nasal cavity. Drug uptake by these nerve endings can facilitate transport along the nerve branches to the brainstem and other deeper CNS areas.

The third, less desirable pathway for direct brain targeting is the vascular route:

Systemic vascular absorption: Drugs ab­sorbed through the nasal mucosa’s rich blood supply, especially in the respiratory region, rapidly enter the systemic circula­tion. From there, they must cross the BBB to reach the brain.

At the cellular level, drugs must cross the nasal epithelial barriers using several distinct mechanisms: paracellular trans­port (between cells through tight junc­tions); transcellular transport (directly through cells via passive diffusion or active transport); and receptor-mediated transcy­tosis (RMT). Understanding these mecha­nisms is critical for designing effective nasal drug formulations.

APPLICATIONS ACROSS NEUROLOGICAL & PSYCHIATRIC DISORDERS

Nose-to-brain strategies offer im­mense promise for numerous neurological conditions. For neurodegenerative dis­eases such as Alzheimer’s, Parkinson’s, and Huntington’s disease, specific target­ing of brain regions is essential. Similarly, psychiatric disorders like major depression and anxiety could benefit from targeted delivery, allowing for more precise action on neural circuits and minimizing systemic side effects associated with orally admin­istered psychotropics.⁶

Beyond chronic conditions, nose-to-brain delivery is being vigorously explored for acute neurological emergencies. It rep­resents a viable option for the rapid deliv­ery of critical therapeutics in cases of stroke and traumatic brain injury (TBI), where immediate, high brain-specific drug concentrations are vital. Direct nasal de­livery also holds the potential to transform the treatment of brain tumors by delivering chemotherapeutic or immunotherapeutic agents directly to the tumor site, bypassing the BBB and enhancing drug concentra­tions while minimizing systemic toxicity. Fi­nally, pain management relying on central mechanisms could also see profound ad­vancements, offering a non-invasive route for analgesics to act directly within the brain.⁷

COMPLIANCE, CONVENIENCE & EMERGENCY USE

In addition to the powerful clinical benefits, the non-invasive nature of nasal drug delivery offers substantial advantages in terms of patient compliance and ease of administration. Unlike injections or in­fusions, nasal sprays are non-invasive, vir­tually painless and can be easily administered by patients themselves in a home setting. This crucial “at-home use” capability is a significant differentiator.

A compelling example is the develop­ment of rapidly acting agitation medica­tion for conditions such as bipolar disorder and schizophrenia.⁸ Currently, managing acute agitation often requires emergency medical intervention, but an effective in­tranasal therapy could empower a pa­tient’s family or friends to administer medication during a crisis, potentially pre­venting escalation and avoiding a trau­matic emergency room visit.

Similarly, the widespread availability and highly successful use of naloxone nasal sprays for reversing opioid overdose dramatically underscores the life-saving potential of easily administered, at-home and non-invasive therapies.⁹ The conven­ience and portability of modern nasal spray devices significantly enhance patient adherence, making these vital therapies more accessible. This ease of self-admin­istration is also a strong driver for enabling the development and adoption of self-ad­ministered nasal vaccines.

OVERCOMING DEVELOPMENT, MANUFACTURING & REGULATORY CHALLENGES

Despite the compelling rationale, the path to widespread clinical application for nose-to-brain drug delivery is not without significant hurdles. These challenges in­clude physiological barriers, intricate for­mulation requirements and an evolving regulatory landscape.

One of the foremost challenges lies in the formulation science itself. Enzymatic degradation of sensitive compounds and the limited surface area of the olfactory re­gion pose physicochemical constraints. Formulators must meticulously optimize drug solubility and stability, control viscos­ity and osmolarity, ensure mucoadhesion and carefully select permeation en­hancers.

Beyond the formulation, device engi­neering and the consistency of drug deliv­ery are equally crucial. Ensuring accurate, targeted and reproducible dosing, espe­cially to the small olfactory region, requires sophisticated device engineering that pre­cisely controls the spray pattern and droplet size distribution, while accounting for patient anatomical variability.

The journey to commercialization in­troduces further complexity. Reproducibility and variability remain major scientific and manufacturing challenges, often resulting in inconsistent drug targeting. Accurately and reliably quantifying true brain uptake in humans is extremely challenging, re­quiring sophisticated methods to differen­tiate direct nose-to-brain transport from systemically absorbed drug.

The regulatory landscape for novel nose-to-brain products is still developing and evolving, particularly concerning spe­cific standards for product sterility and par­ticulate matter. These ambiguities necessitate the implementation of robust development strategies to successfully meet future regulatory demands.

INTEGRATING TECHNOLOGY FOR CLINICAL & COMMERCIAL SUCCESS

Effectively overcoming these multifac­eted challenges demands a deep, end-to-end understanding of nose-to-brain science and the integrated infrastructure necessary to support development. This means possessing complete end-to-end capabilities, spanning from the initial mol­ecule concept through to full commercial manufacturing, and extensive internal ex­pertise across formulation, device engi­neering and analytical testing. This integrated approach can dramatically ac­celerate development timelines by stream­lining quality control and communication.

A core principle for success is inte­grated combination product thinking, where the drug and the delivery device are conceived and treated as a single, interde­pendent entity from the very outset. This is supported by advanced analytical and testing methodologies. For example, anatomically correct nasal casts allow for precise in vitro deposition studies. Unique skin transmission studies analyze drug passage across various cell types, and rig­orous reliability testing ensures product functionality. Comprehensive spray testing precisely characterizes pump delivery, plume geometry and droplet size distribu­tion, while hand studies provide vital in­sights into user interaction.

Additionally, access to a rapid proto­typing lab with 3D printing expertise facil­itates agile design iterations. All these efforts must be underpinned by a robust Quality by Design (QbD) approach, which involves defining clear quality targets early in development. Scaling from clinical trial material production to full commercial production involves meticulously address­ing chemistry and engineering considera­tions, with safety concerns integrated into every stage. By embodying this integrated, expert-driven approach, manufacturers help to significantly de-risk and accelerate the development of groundbreaking nose-to-brain therapies.

SHAPING THE FUTURE OF CNS THERAPEUTICS

The nose-to-brain drug delivery landscape is rich with fu­ture opportunities, driven primarily by advances in nanotech­nology and molecular science. A major growth area lies in the delivery of biologics, including therapeutic oligonucleotides and mRNA compounds. New generations of penetration en­hancers and mucoadhesives are enabling the successful trans­mission of these larger molecules, unlocking a new class of CNS medicines. Sophisticated nanocarriers like micelles, lipo­somes and polymeric nanoparticles are designed to enhance drug solubility, improve permeation across the nasal and neu­ral barriers and increase therapeutic stability.¹⁰ Crucially, tar­geted strategies using ligand-modified nanoparticles promise selective binding to neuronal receptors, while the integration of advanced imaging techniques offers the potential for real-time monitoring of drug distribution in the brain.

The evolution of nasal drug delivery points to a future of expanded therapeutic reach and precise targeting of specific neural circuits. As these critical innovations emerge, sustained collaboration across industry, academia and regulatory bodies will be paramount, particularly in addressing evolving guid­ance on sterility and particulate standards. The ongoing push for non-invasive, convenient and highly targeted treatments ensures that nasal drug delivery, including its immense poten­tial in nose-to-brain applications, will remain a vibrant and es­sential area of pharmaceutical innovation, poised to enhance patient care for decades to come.

REFERENCES

1. https://pmc.ncbi.nlm.nih.gov/articles/PMC7219022/
2. https://www.mdpi.com/2227-9059/12/10/2302
3. https://pmc.ncbi.nlm.nih.gov/articles/PMC10818989
4. https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2023.1341295/full
5. https://www.precedenceresearch.com/nasal-drug-delivery-technology-market
6. https://www.mdpi.com/1999-4923/14/9/1870
7. https://www.mdpi.com/1999-4923/16/4/481
8. https://pmc.ncbi.nlm.nih.gov/articles/PMC12027268/
9. https://nida.nih.gov/publications/drugfacts/naloxone
10. https://pubmed.ncbi.nlm.nih.gov/40430435/

Justin Lygrisse is the Director of Research & Development (R&D) for the Nasal Spray business unit at Kindeva. He received a Bachelors and Masters of Chemistry from Wichita State University in 2005 and 2009, respectively. He has been a researcher in the fields of analytical chemistry and drug development for over 20 years. In his current capacity as Director of R&D, he directs nasal spray drug product development for Kindeva.