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Jenny Bryan is a freelance writer based in London
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For an emerging pharmaceutical company, Seattle-based Nastech hit the
jackpot last month. It will be paid $5m by Merck for rights to its novel
obesity nasal spray — a formulation containing PYY3-36 — and,
if clinical trials go well, the company stands to make hundreds of millions
more in sales and royalties. All this is happening on the basis of three
small phase I clinical trials involving PYY3-36, a gut-derived hormone
that is released postprandially in proportion to the calories ingested.
The trials show that intranasal delivery of PYY3-36 increases plasma
levels of the peptide, makes healthy volunteers feel less hungry, and
does not make them feel sick, unless they inhale too much.
Industry goal
Getting systemic treatments into the bloodstream via the nasal mucosa
has been a goal of many pharmaceutical companies for at least a decade.
In principle, nasal delivery should provide fast onset of activity,
comparable to intravenous delivery, and avoid gastric breakdown of
peptide-based treatments. But only a handful of products, including
nicotine, sumatriptan, nafarelin and calcitonin nasal sprays, have
made it to the market.
Lisbeth Illum, chief scientific officer at Phaeton Research, and associate
to the School of Pharmacy at Nottingham University, explains that, although
lipid soluble molecules cross the nasal membrane into the bloodstream
with a bioavailability of up to 100 per cent, the figure falls to 10
per cent for small, polar molecules and to less than 1 per cent for large
peptide molecules.1
A major barrier is the tight junctions between the epithelial cells of
the nasal mucosa which need to be prised apart to gain access to the
systemic circulation. Early attempts at opening the junctions with permeation
enhancers, for example, for intranasal insulin products ran in to toxicity
problems (see PJ, 31 July, p161).
However, recent developments in permeation enhancers are proving more
promising.
Chitosan is a linear polysaccharide, produced by alkaline hydrolysis
(deacetylation) of chitin from crustacean shells. It is bioadhesive and
interacts strongly with the nasal mucus and with nasal epithelial cells.
It prolongs the period of time that a drug stays on the nasal membrane
and in vitro studies suggest that it opens tight junctions so that hydrophilic
drugs can pass through. Most importantly, explains Professor Illum, who
developed the substance, chitosan is non-toxic and non-irritant.
“
We started looking for positively charged materials that were abundant
and cheap, and came across chitosan,” she says. “We then
used it for nasal delivery of insulin in rat studies and found that it
was very effective. For nasal drug delivery, chitosan is really the only
enhancer that has been fully developed so far.”
The chitosan system has been shown to increase bioavailability of morphine
from less than 10 per cent without permeation enhancers to over 60 per
cent with chitosan. In Nottingham, West Pharmaceuticals will soon start
a clinical study of nasal leuprolide with chitosan as permeation enhancer
for the treatment of endometriosis. Nasal formulations of calcitonin
and parathyroid hormone are expected to follow, when the company finds
pharmaceutical partners to complete development and market its products.
Nasal vaccines are another area of interest for West’s chitosan
delivery system. Alan Smith, vice-president for research and development,
explains that, although conventional injected vaccines stimulate production
of systemic antibodies, the aim of nasal vaccines is to stimulate immunoglobulin
A antibodies in the nasal mucosa.
“
A nasal vaccine against influenza is very attractive because it provides
local immunity at the site where the virus gains access to the body,” he
says.
Less is known about how Nastech is optimising the bioavailability of
its new nasal anti-obesity treatment. Peptide YY is a naturally occurring
hormone produced by L-cells in the gut after a meal to trigger feelings
of satiety. L-cells are distributed throughout the intestine facing the
gut lumen, which suggests that they sense the luminal concentration of
lipids and carbohydrates directly. Nastech has used the 34 amino acid
C-terminal fraction, PYY3-36, in its phase I studies. At a US congress
in June, the company reported bioavailability of approximately 16 per
cent in healthy volunteer studies. The elimination half life of 35–49
minutes with the three highest doses of PYY3-36 (100µg, 150µg
and 200µg) compared favourably with the nine minutes seen with
intravenous dosing, and is thought to reflect prolonged wash-in from
the nasal mucosa.
Also focusing on improved bioavailability from the nasal route is Icelandic
drug delivery company Lyfjathroun Biopharmaceuticals, which last month
announced promising phase I results from an intranasal formulation of
sumatriptan to rival that of GlaxoSmithKline. The company is claiming
17-fold greater bioavailability for its formulation compared with the
GSK product during the first 20 minutes after administration. Maximal
blood levels were 75 per cent of those achieved with an injectable sumatriptan
product.
Further away — but with significant potential for the treatment
of neurological disorders — is the prospect of nasal drug delivery,
not for systemic absorption through the nasal mucosa in the front and
middle parts of the nose, but as a means of bypassing the blood-brain
barrier.
In the roof of the nasal cavity, some 7cm back from the nostrils, lies
the olfactory region from which nerve pathways, including the trigeminal
pathway, have the potential to carry drugs to distant parts of the brain,
with no need to cross the blood-brain barrier.
Another option for nose-to-brain drug transport is to improve absorption
of drugs through the olfactory epithelia into the cerebral circulation
and cerebrospinal fluid — also providing faster and potentially
more efficient access to brain tissues.
A key problem for enthusiasts of nose-to-brain transport is the difficulty
of getting drugs as far as the olfactory region. Conventional nasal sprays
do not attempt to get drugs beyond the areas of the nose affected by
rhinitis. Reducing particle size improves deposition to the further recesses
of the nose, but increases the likelihood that large amounts of each
dose will go down the throat. New device
Norwegian company OptiNose has recently unveiled a unique bidirectional
nasal drug delivery device which, it believes, propels drugs to parts
of the nasal cavity that other products have never reached — and
avoids the problem of drug being lost down the throat.
Users blow into a mouthpiece to release drug which is then delivered
through a sealing nozzle into their nose. Blowing into the device automatically
closes the soft palate, so that drug will not be lost down the throat,
and a combination of particle size and device design ensures that drug
passes up one nostril, reaches the olfactory area, does a U-turn and
exits the nose through the other nostril. Gamma-scintigraphy images confirm
the coverage at the back of the nose that can be achieved with OptiNose,
and further adaptations to the device are planned to target
specific parts of the olfactory area more
precisely.
Rod Hafner, operations director at the newly established OptiNose UK,
explains that the company will start by showing that the bidirectional
device is superior to conventional nasal sprays for delivering nasal
steroids for the treatment of rhinosinusitis. It then hopes to acquire
business partners to test the device for nose-to-brain delivery of drugs
for neurological disorders.
As Mr Hafner points out: “Previous nasal delivery technology has
only considered parts of the nose that people can see. But there is a
much larger volume of interest which is buried behind the nose. With
different nozzles, airflows and spray plumes, we can go much further
and higher than before.” Reference
1. Illum L. Is nose-to-brain transport of drugs in man a reality? Journal
of Pharmacy and Pharmacology 2004;56:3–17/
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