news

PSTT Vol. 3, No. 8 August 2000

update

New technology for pulmonary

drug delivery
Kathryn Senior, tel: 144 118 9421639, e-mail: ksenior@dircon.co.uk

In April this year, the Aradigm Corporation

(Hayward, CA, USA) announced a new development agreement with the University of
California at San Francisco (San Francisco, CA,
USA), to evaluate the pulmonary drug delivery
system known as AERx. Already in Phase II and
III trials for breakthrough pain and diabetes, the
intention is now to develop the system to deliver non-viral gene vectors by inhalation.
The AERx system is a microprocessor-controlled inhalation system that converts, at a
pre-programmed moment during inspiration, a
unit dose of liquid drug into fine aerosol
droplets. The aqueous drug solutions are extruded through a single-use nozzle system,
deep into the lungs of the user. Whereas conventional pressurized metered dose inhalers deliver only a small fraction of each emitted dose
of drug beyond the oropharynx, the AERx system is capable of delivering reproducible levels
of the drug into the bloodstream. In an earlier
trial of a prototype device, 10 healthy human
volunteers were dosed with an aqueous solution containing 99mTc-DTPA and then assessed
for the distribution of this radioactive marker
by gamma scintigraphic imaging. Analysis
showed that 53.3% of the dose of drug loaded
into the AERx device reached the lungs, whilst
only 6.9% remained at the oropharynx. This
compared favourably with the performance of
an MDI device, which deposited only 21.7% of
the dose in the lungs, with 42% detectable in
the oropharynx and stomach1.
Aerosolizing DNA for gene transfection
Numerous published studies indicate that
more than 50% of people using inhalers do so
incorrectly, says Igor Gonda, Vice President of
Research and Development at Aradigm. The
key difference between the AERx system and
conventional inhalers is that the device guides

the patients breathing as they use it, he explains. The collaborative studies will be carried
out in the laboratory of Jeanine WienerKronish (Professor of Anaesthesia and
Medicine, UCSF, San Francisco, CA, USA) and
will investigate the potency of the gene
therapy formulation in in vitro and in vivo
models following administration through the
AERx system. Their research will build on earlier work that has shown that DNA packaged in
artificial viral envelopes can be aerosolized
effectively with the AERx system, leading
to transfection in an in vitro system (I. Gonda,
pers. commun.). The gene vectors were
not damaged during the production of
the aerosol.
Assessing inflammatory effects of non-viral
gene products
In a related study, researchers led by Joseph
Brain, Professor of Environmental Physiology at
Harvard University School of Public Health
(Boston, MA, USA) will look at the inflammatory
responses of lung cells in vitro and in vivo to
the non-viral gene products.
One of the primary objectives of developing
a non-viral gene vector is to ensure maximum
efficacy with minimum side effects. While
the other research groups will focus on transfection efficiency, we shall be looking at the
aqueous formulations in small animal models
to assess their inflammatory effects said Brain.
His team has extensive experience of the lung
lavage model in which a small amount of saline
containing a test substance is introduced into
the lung of a mouse, and then removed so that
the aspirated fluid can be tested for the presence of inflammatory cells and factors. The response to environmental substances, such as
fumes produced by welding metals and urban
pollution particles, is well documented2. We

are in a very good position to compare the

response to non-viral gene vectors with various
environmental particulate preparations, and
this should help to provide a perspective to any
risk that we find, says Brain. Experiments using
Aradigms formulations for gene therapy are
due to begin later this year.
Pulmonary delivery to become a standard
delivery route?
The importance of pulmonary drug and gene
vector delivery is likely to continue to grow exponentially for the treatment of lung disease
and systemic diseases. The large surface area of
the lungs gives them the potential to be an effective systemic delivery system, says Brain.
Gonda predicts that the approval of inhaled insulin for diabetes will be a turning point that
will see pulmonary delivery become accepted
as a standard drug delivery route. The pulmonary route is definitely the most promising
non-invasive route of administration for proteins and peptides, he says. Aradigm is already
in Phase II studies with Novo Nordisk
(Bagsvaerd, Denmark) for inhaled insulin for
type I and II diabetes and for inhaled morphine
for breakthrough pain management with
SmithKline Beecham (Philadelphia, PA, USA).
We also have two other Phase II studies in
progress. One is inhaled rhDNase for cystic fibrosis with Genentech (San Francisco, CA, USA),
the other is a program with a protein for inflammatory disease of the lung, confirms
Gonda. Other studies are at earlier stages of development, such as the INS365 compound for
chronic obstructive pulmonary disease from
Inspire (Durham, NC, USA), currently partnered
with Genentech and Kissei (Matsumoto, Japan).
However, there are still technical hurdles.
Our focus for the next few years will be on
scaling up our manufacturing process, confirms

1461-5347/00/$ see front matter 2000 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(00)00284-4

261

update

news

PSTT Vol. 3, No. 8 August 2000

Gonda. Aradigm is also keen to accelerate the

development of second-generation technology,
so that we can meet user demand to reduce the
size of the AERx device. Currently, we are
building a balanced pipeline, pushing several
products into Phase III and towards commercialization, while, at the same time, getting
several new compounds into earlier development, says Gonda. In addition to researching

new compounds for pulmonary delivery, the

company intends to explore new options for
device technology and we plan further development of new formulations that will enhance
the liquid-delivery approach. The genomics
revolution is likely to yield many valuable medicines including proteins and therapeutic genes,
all of which could be administered via the AERx
system, predicts Gonda.

References
1

Farr, S.J. et al. (2000) Comparison of in vitro

and in vivo efficiencies of a novel unit-dose
liquid aerosol generator and a pressurised
metered dose inhaler. Int. J. Pharm. 198,
6370

Brain, J.D. (1996) Environmental lung disease:

exposures and mechanisms. Chest 109(3),
74S78S

Niaspan: managing hyperlipidaemia with

extended-release niacin
David Bradley, tel/fax: 144 1954 202218, Web: http://www.sciencebase.com

Niaspan, a new extended-release niacin, has

been demonstrated to have superior efficacy in
raising the serum concentration of high-density lipoprotein1 (HDL). It also rapidly improves
other lipid components, and demonstrates a
consistent safety profile, according to research
commissioned by its manufacturer, Kos
Pharmaceuticals1 (Miami, FL, USA). Numerous
epidemiological studies have demonstrated
that both low HDL-cholesterol and high LDL(low density lipoprotein) cholesterol are independent risk factors for coronary heart disease,
and therefore the need for potent drugs to rebalance serum lipids has become increasingly
important.
Comparative studies of Niaspan
The comparative study of Niaspan [2000 mg
daily of niacin (nicotinic acid) extended-release
tablets] and gemfibrozil, originally developed
by Park-Davis in the 1970s, was conducted as a
multicentre, randomized, double-blind trial in
173 male and female patients (aged 2175
years) with low levels of HDL cholesterol2.
Gemfibrozil is one of a group of prescription
drugs known as fibrates, which are lipid-regulating agents that decrease serum triglycerides
and very low density lipoprotein (VLDL) cholesterol, and increase HDL cholesterol. However,

262

although it induces modest decreases in total

and LDL cholesterol, gemfibrozil can also result
in a rise in LDL cholesterol in patients with elevated triglycerides caused by type IV hyperlipoproteinaemia.
The comparative trial conducted by John
Guyton (Associate Professor of Endocrinology)
and colleagues at the Duke University Medical
Center (Durham, NC, USA) found that patients
with a low baseline HDL-cholesterol serum
level, who were given Niaspan at higher doses
over a 19-week therapeutic period, demonstrated a two-fold greater HDL-cholesterol increase (~26%), a decrease in lipoprotein(a)
(~20%), an improvement in lipoprotein cholesterol ratios and lower fibrinogen levels
compared with patients administered gemfirozil. The average HDL-cholesterol increase
was only 13% for patients administered with
gemfibrozil.
Adverse effects seen in some of the patients
in the comparative trial led to their discontinuation from the study. In the Niaspan group, 10
patients developed side effects such as gastrointestinal tract problems and skin irritation.
Modifying the HDL and LDL balance
Guyton pointed out that although gemfibrozil
gave a greater triglyceride reduction it also

increased the LDL cholesterol level, which did

not occur with Niaspan. Niaspan, with its
strong efficacy on HDL and other lipoprotein
parameters, can offer unique benefits in treating high-risk patients with low levels of HDL
cholesterol, says Guyton. The main goal of
lipid treatment with such drugs is to prevent
atherosclerotic disease. These results not only
demonstrate the potential efficacy and the
safety of Niaspan in this regard but also add to
the growing record of beneficial effects of
niacin and gemfibrozil.
Gemfibrozil has also been studied independently in the US Veterans Administration HDL
Intervention Trial3 (Washington, DC, USA) for its
benefits in treating lipid problems. The trial
confirmed the importance of treating HDL as
an independent risk factor in coronary heart
disease. When compared against placebo in
2531 male patients, gemfibrozil demonstrated
a 22% reduction in coronary events over five
years.
Demonstrating safety and efficacy
A second study also demonstrated the safety
and efficacy of Niaspan, and investigated escalating doses of this drug4. Increasing doses of
500 mg daily to 3000 mg daily were given to
patients. The study revealed that Niaspan, at

1461-5347/00/$ see front matter 2000 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(00)00285-6