June 19, 2023 – Noses are like caverns — twisting, turning, no two exactly the same. But if you nose past anyone’s nostrils, you’ll discover a surprisingly sprawling space.
“The size of the nasal cavity is about the same as a large handkerchief,” said Hugh Smyth, PhD, a professor of molecular pharmaceutics and drug delivery at the University of Texas at Austin.
Thoroughly coating that cavity with medication can result in rapid, efficient absorption, making the nose’s inner chamber an attractive target for drug delivery.
“It’s very accessible tissue, and it has a lot of blood flow,” said Smyth. “The speed of onset can often be as fast as injections, sometimes even faster.”
It’s nothing new to get medicines via your nose. For decades, we’ve squirted various sprays into our nostrils to treat local maladies like allergies or infections. Even the ancients saw wisdom in the nasal route.
But recently, the nose has gained scientific attention as a gateway to the rest of the body – even the brain, a notoriously difficult target.
The upshot: Someday, inhaling therapies could be as routine as swallowing pills.
The nasal route is quick, needle-free, and user-friendly, and it often requires a smaller dose than other methods, since the drug doesn’t have to pass through the digestive tract, losing potency during digestion.
But there are challenges.
How Hard Can It Be?
Old-school nasal sprayers, mostly unchanged since the 1800s, aren’t cut out for deep-nose delivery. “The technology is relatively limited because you’ve just got a single spray nozzle,” said Michael Hindle, PhD, a professor of pharmaceutics at Virginia Commonwealth University.
These traditional devices (similar to perfume sprayers) don’t consistently push meds past the lower to middle sections inside the nose, called the nasal valve – if they do so at all: In a 2020 Rhinology study, conventional nasal sprays only reached this first segment of the nose, a less-than-ideal spot to land.
Inside the nasal valve, the surface is skin-like and doesn’t absorb very well. Its narrow design slows airflow, preventing particles from moving to deeper regions, where tissue is vascular and porous like the lungs.
Even if you surpass this structural roadblock, other hurdles remain.
Your nose is designed to keep stuff out. Nose hair, cilia, mucus, sneezing, coughing – all make “distributing drugs evenly across the nasal cavity difficult,” said Smyth. “The spray gets filtered out before it reaches those deeper zones,” potentially dripping out of the nostrils instead of being absorbed.
Complicating matters is how every person’s nose is different. In a 2018 study, Smyth and a research team created 3D-printed models of people’s nasal cavities. They varied widely. “Nasal cavities are very different in size, length, and internal geometry,” he said. “This makes it challenging to target specific areas.”
Although carefully positioning the spray nozzle can help, even something as minor as sniffing too hard (constricting the nostrils) can keep sprays from reaching the absorptive deeper regions.
Still, the benefits are enough to compel researchers to find a way in.
“This really is a drug delivery challenge we’ve been wrestling with,” said Hindle. “It’s not new formulations we hear about. It’s new devices and delivery methods trying to target the different nasal regions.”
Delivering the Goods
In the late aughts, John Hoekman was a graduate student in the University of Washington’s pharmaceutics program, studying nasal drug delivery. In his experiments, he noticed that drugs distributed differently, depending on the region targeted – aiming for the upper nasal cavity led to a spike in absorption.
The results convinced Hoekman to stake his future on nasal drug delivery.
In 2008, while still in graduate school, he started his own company, now known as Impel Pharmaceuticals. In 2021, Impel released its first product: Trudhesa, a nasal spray for migraines. Although the drug itself – dihydroergotamine mesylate – was hardly novel, used for migraine relief since 1946, it was usually delivered through an IV, often in the emergency room.
But with Hoekman’s POD device – short for precision olfactory delivery – the drug can be given by the patient, via the nose. This generally means faster, more reliable relief, with fewer side effects. “We were able to lower the dose and improve the overall absorption,” said Hoekman.
The POD’s nozzle is engineered to spray a soft, narrow plume. It’s gas-propelled, so patients don’t have to breathe in any special way to ensure delivery. The drug can zip right through the nasal valve into the upper nasal cavity.
Another company – OptiNose – has a “bidirectional” delivery method that propels drugs, either liquid or dry powder, deep into the nose.
“You insert the nozzle into your nose, and as you blow through the mouthpiece, your soft palate closes,” said Hindle. With the throat sealed off, “the only place for the drug to go is into one nostril and out the other, coating both sides of the nasal passageways.”
The device is only available for Onzetra Xsail, a powder for migraines. But another application is on its way.
In May, OptiNose announced that the FDA is reviewing Xhance, which uses the system to direct a steroid to the sinuses. In a clinical trial, patients with chronic sinusitis who tried the drug-device combo saw a decline in congestion, facial pain, and inflammation.
Targeting the Brain
Both of those migraine drugs — Trudhesa and Onzetra Xsail – are thought to penetrate the upper nasal cavity. That’s where you’ll find the olfactory zone, a sheet of neurons that connects to the olfactory bulb. Located behind the eyes, these two nerve bundles detect odors.
“The olfactory region is almost like a backdoor to the brain,” said Hoekman.
By bypassing the “blood-brain barrier” (a sort of TSA checkpoint for that most vital of organs), it offers a direct pathway – the only direct pathway, actually – between an exposed area of the body and the brain. Meaning it can ferry drugs straight from the nasal cavity to the central nervous system.
Nose-to-brain treatments could be game-changing for central nervous system disorders, such as Parkinson’s disease, Alzheimer’s, or anxiety.
But reaching the olfactory zone is notoriously hard. “The vasculature in your nose is like a big freeway, and the olfactory tract is like a side alley,” explained Hoekman. “It’s very limiting in what it will allow through.” The region is also small, occupying only 3% to 10% of the nasal cavity’s surface area.
Again, POD means “precision olfactory delivery.” But the device isn’t quite as laser-focused on the region as its name implies. “We’re not at the stage where we’re able to exclusively deliver to one target site in the nose,” said Hindle.
While wending its way toward the olfactory zone, some of the drug will be absorbed by other regions, then circulate throughout the body.
“About 59% of the drug that we put into the upper nasal space gets absorbed into the bloodstream,” said Hoekman.
Janssen Pharmaceuticals’ Spravato – a nasal spray for treatment-resistant depression – is thought to work similarly: Some goes straight to the brain via the olfactory nerves, while the rest takes a more roundabout route, passing through the blood vessels to circulate in your system.
A Needle-Free Option
Sometimes, the bloodstream is the main target. Because the nose’s middle and upper stretches are so vascular, drugs can be rapidly absorbed.
This is especially valuable for time-sensitive conditions. “If you give something nasally, you can have peak uptake in 15 to 30 minutes,” said Hoekman.
Take Narcan nasal spray, which delivers a burst of naloxone to quickly reverse the effects of opioid an overdose. Or Noctiva nasal spray. Taken just half an hour before bed, it can prevent frequent nighttime urination.
There’s also a group of seizure-stopping sprays, known as “rescue treatments.” One works by temporarily loosening the space between nasal cells, allowing the seizure drug to be quickly absorbed through the vessels.
This systemic access also has potential for drugs that would otherwise have to be injected, such as biologics.
The same goes for vaccines. Mucosal tissue inside the nasal cavity offers direct access to the infection-fighting lymphatic system, making the nose a prime target for inoculation against certain viruses.
Inhaling Protection Against Viruses
Despite the recent surge of interest, nasal vaccines faced a rocky start. After the first nasal flu vaccine hit the market in 2001, it was pulled due to potential toxicity and reports of Bell’s palsy, a type of facial paralysis.
FluMist came in 2003 and has been plagued by problems ever since. Because it contains a weakened live virus, flu-like side effects can occur. And it doesn’t always work. During the 2016-2017 flu season, FluMist protected only 3% of kids, prompting the CDC to advise against the nasal route that year.
Why FluMist can be so hit-or-miss is poorly understood. But generally, the nose can pose an effectiveness challenge. “The nose is highly cycling,” said Hindle. “Anything we deposit usually gets transported out within 15 to 20 minutes.”
For kids – big fans of not using needles – chronically runny noses can be an issue. “You squirt it in the nose, and it will probably just come back out in their snot,” said Jay Kolls, MD, a professor of medicine and pediatrics at Tulane University, who is developing an intranasal pneumonia vaccine.
Even so, nasal vaccines became a hot topic among researchers after the world was shut down by a virus that invades through the nose.
“We realized that intramuscular vaccines were effective at preventing severe disease, but they weren’t that effective at preventing transmission,” said Michael Diamond, MD, PhD, an immunologist at Washington University School of Medicine in St. Louis.
Nasal vaccines could solve that problem by putting an immune barrier at the point of entry, denying access to the rest of the body. “You squash the infection early enough that it not only prevents disease,” said Kolls, “but potentially prevents transmission.”
And Yes, a Nasal COVID Vaccine Is On the Way
In March 2020, Diamond’s team began exploring a nasal COVID vaccine. Promising results in animals prompted a vaccine development company to license the technology. The resulting nasal vaccine – the first for COVID – has been approved in India, both as a primary vaccine and a booster.
It works by stimulating an influx of IgA, a type of antibody found in the nasal passages, and production of resident memory T cells, immune cells on standby just beneath the surface tissue in the nose.
By contrast, injected vaccines generate mostly IgG antibodies, which struggle to enter the respiratory tract. Only a tiny fraction – an estimated 1% – typically reach the nose.
Nasal vaccines could also be used along with shots. The latter could prime the whole body to fight back, while a nasal spritz could pull that immune protection to the mucosal surfaces.
Nasal technology could yield more effective vaccines for infections like tuberculosis or malaria, or even safeguard against new – sometimes surprising – conditions.
In a 2021 Nature study, an intranasal vaccine derived from fentanyl was better at preventing overdose than an injected vaccine. “Through some clever chemistry, the drug [in the vaccine] isn’t fentanyl anymore,” said study author Elizabeth Norton, PhD, an assistant professor of microbiology and immunology at Tulane University School of Medicine. “But the immune system still has an antibody response to it.”
Novel applications like this represent the future of nasal drug delivery.
“We’re not going to innovate in asthma or COPD. We’re not going to innovate in local delivery to the nose,” said Hindle. “Innovation will only come if we look to treat new conditions.”
