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Jenny Bryan is a freelance writer based in London
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With a surface area of 100 square metres, it is not hard to see why the
alveoli of the lungs are such an inviting target for pharmaceutical companies
intent on developing fast acting peptide and other products which cannot
be administered orally. But it has taken 80 years for Exubera — the
first inhaled formulation of insulin — to come within sight of
the winning post. Currently under scrutiny at the European Medicines
Evaluation Agency, Exubera will also be the first inhaled product of
the modern era to reach the market for a condition that does not affect
the respiratory system.
Lining up behind are rival insulin inhalers, impotence treatments, hormones
and analgesics. But, for each, it is a long and arduous journey. For
asthma and chronic obstructive airways disease, it may be enough for
a metered dose inhaler to get as little as 20 per cent of the drug dose
into the deep lung. But to get enough drug into the alveoli for viable
systemic absorption has required a rethink of the characteristics needed
both for drug particles and for delivery devices.
Where it all began
Ironically, however, it was the need to replace chlorofluorocarbons
(CFCs) as propellants in respiratory inhalers which breathed new life
into
pulmonary delivery, and the research which followed is at last bringing
products for systemic diseases, such as diabetes, to market.
“In the 1980s, people were working on hydrofluoroalkanes (HFAs) as
replacements for CFCs, but there were concerns that, if HFAs did not work
well enough,
other systems would be needed. At the same time, biological products
were starting to make inroads, and everyone was looking for new ways
to deliver proteins,” says Andy Clark, chief scientist at Nektar
Therapeutics, the company which developed the inhalers and insulin formulation
for Exubera. The result is a new generation of dry powder devices, designed
to fulfil different requirements to inhalers for lung diseases.
Chris Blackwell, chief executive of UK-based pulmonary product development
company, Vectura, explains that the key requirement is to get small particles,
smaller than 5mm and preferably smaller than 3mm, into the deep lung.
Once there, it is equally important to ensure that active drug deaggregates
easily from its carriers, for fast absorption from the alveoli into the
circulation.
Devices like Vectura’s Aspirair get up to 70 per cent of the fine
particle dose into the alveoli, compared with the 35 to 40 per cent achieved
with conventional dry powder devices for respiratory diseases. Earlier
attempts at intranasal insulin delivery fell by the wayside because it
proved impossible to get enough drug through the nasal mucosa without
adding permeation enhancers that made patients’ noses sore. In
contrast, by getting 60 to 80 per cent of the insulin dose into the alveoli,
Nektar is achieving absorption levels into the circulation of about 15
per cent with Exubera — sufficient to keep blood glucose levels
within accepted parameters. Comparable with insulin by injection
Latest results with Exubera for treatment periods up to four years,
show that type 1 and type 2 diabetes patients maintain glycaemic control
comparable with that achieved with insulin injections. Equally important,
Exubera — which will be marketed by Pfizer and Aventis — does
not cause any clinically important changes in pulmonary function.
As Dr Clark points out: “When you take a drug to the regulators
that you’re putting into the lungs for systemic treatment, you’ve
got to be very sure that you aren’t doing any damage to the lungs.”
While Exubera is a dry powder formulation, delivered from an inhaler
about the size of a household torch, Novo Nordisk’s inhaled insulin,
NN1998, is a liquid formulation which uses the AERx inhaler developed
by the California-based company, Aradigm. Using a liquid makes it possible
to adjust the dose of insulin to the nearest unit — just as with
injections — something that does not appear to be possible with
powders.
However, NN1998 hit a setback earlier this year when Novo Nordisk ended
a 24-month phase III safety and efficacy study early because it became
clear that post-prandial glucose suppression was being delayed in the
type 1 diabetes patients in the trial. This meant that post-prandial
glucose levels were
higher and night-time levels lower than in a comparator group using subcutaneous
insulin. Previous phase II studies in type 2 diabetes had not shown the
same problem.
Both Exubera and NN1998 have been developed for mealtime glucose administration,
since companies have not yet found a way to prolong pulmonary insulin
absorption for baseline glucose control.
“The current formulations are fast acting but they come out quickly
too. So people with type 1 diabetes will still need to inject to control
their
baseline glucose,” explains Dr Clark. “We’re now trying
to formulate the insulin to slow things down, for example, by attaching
polyethylene glycols,” he adds. Analgesics
Pain control is another area where there has been considerable interest
in pulmonary delivery, and Nektar is looking at the potential for
novel migraine treatments. Aradigm is using its AERx system for morphine
inhalation in acute and breakthrough pain control. It recently reported
results of a placebo controlled trial of multiple doses of inhaled
morphine, intravenous morphine or placebo in 89 patients following
bunion removal. There was similar efficacy in onset of pain relief
between the inhaled and intravenous delivery methods and superior
efficacy
to placebo.
But, again, there is the challenge of controlled release from the
lungs so that analgesia is prolonged beyond acute relief. Erectile dysfunction
Although Vectura believes that Aspirair has the potential to deliver
peptides and other macromolecules, it is currently focusing its research
on pulmonary delivery of small molecules. In addition to respiratory
products, it is developing inhaled dry powder apomorphine hydrochloride
(VR004) for the treatment of erectile dysfunction (ED).
A recent small dose response study showed that VR004 was rapidly absorbed
from the lung, with maximum plasma concentrations one to three minutes
after dosing. Elimination of drug from plasma was relatively rapid, with
a terminal half-life of approximately 60 minutes.
In a previous study, an improvement in erectile performance was achieved
in 59 per cent of 35 patients with mild to moderate ED. The median onset
of response was eight minutes, with some subjects responding three minutes
after dosing. Further phase II studies are planned for the end of 2004/early
2005.
Another apomorphine-based inhaler product, VR400, is ready to go into
phase II studies for the treatment of female sexual dysfunction, but
Dr Blackwell explains that the company is likely to wait for a marketing
partner for VR004, before proceeding further with VR400. In contrast,
the company is eager to start phase I studies with its third systemic
product for pulmonary delivery. This is VR776, an as yet unidentified,
off-patent neuroactive drug for the treatment of premature ejaculation. “There
are three times as many men with premature ejaculation as with ED, and
there are no approved treatments on the market to help them. There is
a tablet version of the product we are developing, but it takes about
two hours to work. We are reformulating it to work much more quickly
by inhalation,” says Dr Blackwell. Time to see products benefit patients
Although inhalation products like VR776 will inevitably steal the headlines,
it is the income from refinements in delivery devices for asthma and
chronic obstructive pulmonary disease which will fund future developments
at companies like Vectura, Nektar and Aradigm into novel treatments
for non-respiratory conditions. Because, as Dr Clark points out: “The
90s were a pretty wild decade for new technologies and potential applications
for pulmonary delivery. It’s about time we got some of the products
onto the market where they can benefit patients.” |
The
Pharmaceutical Journal