Peptide Nasal Sprays: What Intranasal Delivery Actually Does

Intranasal delivery is usually described as a direct route to the brain that bypasses the blood–brain barrier. The anatomy behind that claim is real. The numbers are a great deal less generous than the claim implies, and most of the difference comes down to a dull physical question: where in the nose does a spray actually land?

Why peptides are given intranasally at all

A peptide is a chain of amino acids. The digestive system is purpose-built to take chains of amino acids apart — gastric acid first, then pancreatic proteases, then peptidases in the intestinal wall, and finally first-pass metabolism in the liver for anything that survives. The result is that oral bioavailability for most peptides rounds to nothing.

Desmopressin makes the comparison concrete, because it is one of the few peptides available by both routes. As an oral tablet its bioavailability is roughly 0.1%. As a nasal spray it is 3–5%. That is a thirty- to fifty-fold improvement, which sounds impressive until you read it the other way round: even by the better route, about 95% of the dose never reaches circulation.

This is the honest framing for intranasal delivery. It is not chosen because it is efficient. It is chosen because the oral route is worse and because it avoids a needle.

The two nose-to-brain pathways

There are two anatomical routes from the nasal cavity to the central nervous system, and both are genuine.

The olfactory route runs through the olfactory epithelium at the roof of the nasal cavity. Olfactory sensory neurons there send axons up through the perforations in the cribriform plate and directly into the olfactory bulb. This is the only site in the body where central nervous system neurons are exposed to the outside environment, which is what makes the route interesting in the first place.

The trigeminal route runs through branches of the trigeminal nerve that innervate the nasal mucosa and enter the brainstem. It serves a much larger area of the nose than the olfactory region does, and it is probably underweighted in most popular accounts.

Both routes do bypass the blood–brain barrier. What they do not do is work quickly or completely. Transport along an axon runs at a maximum of around 130 mm per day, which in a mouse sets a floor of roughly 45 minutes for anything genuinely travelling inside a nerve fibre. When a study reports a substance appearing in cerebrospinal fluid within five minutes, it did not get there intra-axonally — it moved by bulk flow through the perineural and paravascular spaces around the nerves. "Direct to brain" is a statement about anatomy, not about speed or dose.

The deposition problem

This is where most of the optimism goes. The human nasal cavity has a total surface area of roughly 150 cm². The olfactory epithelium accounts for about 10 cm² of that — under 10% of the available surface — and it sits at the roof of the cavity, above the main path that air takes through the nose.

A conventional spray actuated into a nostril deposits most of its dose on respiratory epithelium in the front of the nose, nowhere near the olfactory region. Device geometry, spray angle, actuation force and head position all shift the distribution to some degree. Most of them do not shift it dramatically.

So the fraction of an intranasal dose that reaches the olfactory epithelium is small. More awkwardly for anyone trying to interpret results, it is also variable — between devices, between doses from the same device, and between people with differently shaped noses.

Why rodent results overstate the case

In rats and mice, the olfactory epithelium occupies something like 40–50% of total nasal surface area. In humans it is under 10%. That is a four- to five-fold difference in the proportion of the nose that constitutes the target, before accounting for the much shorter distance from nasal mucosa to olfactory bulb in a small animal and the different airflow pattern through a smaller cavity.

A rodent intranasal study is therefore testing the route under substantially more favourable anatomy than a human has. This is not a minor technicality. It is one of the main reasons nose-to-brain findings that look strong in preclinical work tend to thin out when the same approach is taken into human trials.

When reading any intranasal result, the species is one of the first things worth checking.

The clock: mucociliary clearance

The nasal mucosa is covered by a mucus layer that cilia move steadily backwards toward the nasopharynx, at a mean rate of about 12.7 mm per minute in healthy adults. Mean transit time is roughly 9.5 minutes. At the end of that journey, the mucus and anything still in it is swallowed.

That sets a hard window. Whatever has not crossed the epithelium within a few minutes is not going to, because it is no longer in the nose. Residence time, rather than the quantity loaded into the device, is often the binding constraint on how much of a dose is absorbed — which is why formulation work in this area leans heavily on mucoadhesive polymers, gels and thermoresponsive systems whose entire purpose is to slow that clock down.

Several ordinary things change it. Congestion and rhinitis alter both clearance rate and the airflow pattern that determines deposition. So does preservative exposure: benzalkonium chloride, which is widely used in aqueous nasal formulations, is ciliotoxic with repeated use. A preserved formulation can, over time, degrade the clearance mechanism its own absorption profile was characterised against.

Droplet size and volume are not packaging details

Nasal sprays typically produce droplets in the 20–200 micron range. The size distribution matters in both directions.

At the fine end, droplets below about 10 microns can pass through the nasal cavity and deposit in the lower respiratory tract, which is not where a nasal product is supposed to go. Regulators treat this as a safety parameter rather than a performance one: the FDA requires the sub-10-micron fraction of a nasal spray to be quantified, and in a well-behaved product it is typically under 5%.

At the coarse end, droplets that are too large, or volumes beyond what the cavity can hold, simply run back out of the nostril or straight down the throat. The usable volume is small — around 100 microlitres per actuation is a common design point, with both nostrils used when more is needed.

The consequence is that the device is part of the formulation. The same solution through two different actuators is, in any meaningful sense, two different products with two different deposition profiles. Any result reported without the device characterised is missing a variable that could account for the finding.

Reading the literature with this in mind

Pulling the above together gives a short checklist for assessing any intranasal claim.

What species was it? Rodent anatomy flatters the route considerably. What device, what volume, what head position? These determine deposition, and deposition determines everything downstream. Was central nervous system exposure actually measured, or inferred? Plasma concentration tells you about systemic absorption and almost nothing about brain exposure; cerebrospinal fluid sampling is invasive, so in human work it is rare, and its absence is usually filled with assumption. And how variable were the results between subjects, as opposed to on average?

None of this makes intranasal delivery uninteresting. The pathways are real and the route genuinely does circumvent both the gut and the blood–brain barrier. But the accurate description of it is a low-efficiency, high-variance route whose performance depends as much on hardware and anatomy as on the molecule — and that is a long way from the version that appears in most marketing copy.

The science here is interesting precisely because it is difficult. Any source that presents intranasal delivery as a straightforward shortcut to the brain is describing the diagram rather than the data.

References

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