Most of us assume that when a drug works in the lab, the hard part is over. For brain diseases, the hard part is often just beginning.
A compound that performs beautifully in a dish may never reach the tissue it was designed to treat, because between the bloodstream and the brain sits one of the most effective security systems in biology: the blood-brain barrier.
The barrier is not a flaw. It is a tightly sealed layer of cells lining the brain’s blood vessels, and it exists to keep toxins, pathogens, and swings in blood chemistry away from the most sensitive organ we have. The trouble is that it does not distinguish between a threat and a therapy. William Pardridge, who spent decades studying the barrier at UCLA, estimated that it excludes essentially all large-molecule drugs and more than 98 percent of small-molecule drugs from the brain (1). That single figure explains a great deal about why neurology has so few effective treatments relative to the size of the problem.
And the problem is enormous. The Global Burden of Disease analysis published in The Lancet Neurology in 2024 found that disorders of the nervous system affected 3.4 billion people in 2021 – 43 percent of the world’s population – and had become the leading cause of overall disease burden worldwide (2). Stroke, dementia, migraine, epilepsy, Parkinson’s disease, depression, brain tumors: the list of conditions where we have promising biology and inadequate delivery is long, and growing as populations age.
The industry’s traditional answer has been to design molecules small and fat-soluble enough to slip through the barrier on their own. That works for some drugs – anesthetics, many antidepressants – but it rules out most of the interesting chemistry, and it tends to produce compounds that also slip into every other tissue in the body, which is where side effects come from. The alternatives are harsher: direct injection into the brain or spinal fluid, or deliberately opening the barrier with focused ultrasound or chemical agents. These have their place in extreme cases. They are not something a patient can do at home every morning.
There is, however, a route into the brain that does not require crossing the barrier at all. It sits at the top of the nasal cavity.
The olfactory region – the patch of tissue responsible for our sense of smell – is the one place in the body where the central nervous system is directly exposed to the outside world. Olfactory nerve fibers pass from the nasal lining through a thin, perforated bone and connect straight to the olfactory bulb at the front of the brain. Branches of the trigeminal nerve, which supplies sensation to the face, run a parallel path. Compounds deposited on that tissue can travel along these nerve pathways and the fluid-filled spaces around them, reaching the brain within minutes while bypassing the bloodstream and the barrier entirely. Jeffrey Lochhead and Robert Thorne mapped these pathways in a 2012 review that remains a reference point for the field (3).
This is not a theoretical idea. Nasal sprays for the brain are already on pharmacy shelves. Esketamine for treatment-resistant depression was approved in the United States in 2019. Nasal formulations of midazolam and diazepam for seizure clusters followed. Zavegepant for migraine was approved in 2023. Not all of these depend on the direct nose-to-brain pathway – the nose is also a fast route into the bloodstream – but together they have established that regulators, physicians, and patients accept the nasal route for serious neurological and psychiatric conditions. The route is no longer the obstacle.
The formulation is. Only a small fraction of what is sprayed into the nose lands on the olfactory region; most of it hits the respiratory lining lower down, drains toward the throat, or is swept away within minutes by the mucus layer that keeps the nose clean. Many of the compounds we would most like to deliver this way dissolve poorly in water, which makes a simple nasal solution impractical. And a liquid spray is only as stable as the molecule suspended in it. For nose-to-brain delivery to work across a wide range of drugs, the compound has to be carried in something that protects it, puts it on the right tissue, and holds it there long enough to be absorbed.
That is a delivery-technology problem, and it is the kind of problem my company, AGCP Farmacêuticos, exists to solve. We are a pharmaceutical nanotechnology company based at TecLabs at the University of Lisbon. Our core expertise is in nanoemulsions – oil-in-water systems in which a drug is carried inside droplets measured in nanometers – which dramatically improve the solubility and absorption of difficult compounds. Our model is to develop a delivery platform, validate it with rigorous data, and then license it to partners who take products through full clinical development and to market.
We are now applying that expertise to the nose-to-brain route, working with researchers at the University of Lisbon. Our test compound is berberine, a plant-derived alkaloid with a long history in traditional medicine and a growing body of research into its effects on metabolism, inflammation, and the nervous system. We chose it not because it is the final target, but because it is a well-characterized, poorly absorbed molecule that we have ready access to – a demanding and honest test case. If we can carry berberine into the brain efficiently and reproducibly, the same approach should extend to other compounds that share its delivery problem.
I want to be clear about where this stands. It is early-stage, preclinical work, and the distance between a promising formulation and an approved medicine is measured in years and in data. Anyone who tells you otherwise is selling something.
But I also believe the opportunity is underappreciated. The pharmaceutical industry has spent enormous sums searching for new molecules to treat brain disease, and comparatively little on the delivery problem that so often stops those molecules from reaching their target. There are compounds sitting on shelves – natural products, repurposed generics, candidates abandoned for poor bioavailability – that may never have had a fair hearing because they could not get past the gate. A delivery platform that gives them that hearing is worth building.
The shortest path to the brain, it turns out, has been in front of our faces all along. The work now is making it a path that medicines can reliably follow.
References
1. Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx. 2005;2(1):3–14. doi:10.1602/neurorx.2.1.3
2. GBD 2021 Nervous System Disorders Collaborators. Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Neurol. 2024;23(4):344–381. doi:10.1016/S1474-4422(24)00038-3
3. Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev. 2012;64(7):614–628. doi:10.1016/j.addr.2011.11.002
Author Biography
Lawrence Fine is CEO and Co-Founder of AGCP Farmacêuticos, a pharmaceutical nanotechnology company based at TecLabs, University of Lisbon, developing delivery platforms in nanoemulsion drug delivery, advanced materials, and pain and wound care. He holds a PhD in Engineering from Stanford University and an MBA from Emory University.
He spent 17 years at Microsoft in a range of leadership roles, has since advised and led companies through growth, turnaround, and sale, and is the author of five books on leadership. He has served on a number of boards and divides his time between Portugal and the United States.
