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Jenny Bryan is a freelance writer based in London
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At first glance, using a small electric current to push medicines through
their skin may not appeal to many patients. But specialist transdermal
drug delivery companies in the US, Israel and Australia are confident
that, within five to 10 years, electricity, ultrasound, radiofrequencies
and microneedles will be widely used to get many commonly used products
into the bloodstream quickly and efficiently, through the skin.
Iontophoresis
This autumn, New Jersey-based Vyteris Inc will launch Lidosite, an
iontophoretic formulation of lidocaine and noradrenaline, in the US.
Recently licensed
by the Food and Drug Administration for local analgesia prior to superficial
dermatological procedures, Lidosite is likely to be targeted at the
paediatric market. It will numb a child’s skin in just a few
minutes instead of the one to two hours it takes for an anaesthetic
cream to work.
Lidosite is a patch with two reservoirs. One contains lidocaine and
noradrenaline, the other saline. The patch is wired to a device containing
a battery
and a preprogrammed microcomputer which controls the electric charge
that is administered.
Although no licence application has been submitted yet in the European
Union for Lidosite, Jonathan Hadgraft, professor of biophysical chemistry
in the department of pharmaceutics at the School of Pharmacy, University
of London, believes that the Food and Drug Administration decision will
encourage manufacturers to press on with their research.
“Previously, there were concerns about how the licensing authorities
would deal with products that use these novel delivery devices, but this
decision
opens the window for active transdermal preparations,” he says.
Companies have been putting drugs into patches since the late 1970s.
But the lipid-rich matrix of the stratum corneum means that only small,
lipophilic molecules that are required in low doses are suitable for
the passive diffusion-based transdermal products marketed to date.
Adding chemical penetration enhancers, including surfactants, fatty acids/esters,
terpenes or solvents, can increase skin permeability by enhancing solubility
or by dissolving the crystalline or lipid areas of
the stratum corneum. But success has been limited and the more powerful
chemical enhancers can irritate the skin, hence the current interest
in active physical methods of enhancing transdermal drug delivery.
Iontophoresis can enhance delivery by driving charged compounds across
the skin by a direct interaction with the electric field. Those with
the greatest charge, and smaller molecules, get across quickest. Alternatively,
molecules can be dragged across by electronically induced solvent flow.
Next on Vyteris’s list for transdermal development are tryptans
for migraine treatment and dopamine agonists for Parkinson’s disease.
Richard Guy, newly appointed professor of pharmaceutical sciences in
the department of pharmacy and pharmacology at the University of Bath,
explains that iontophoresis has been around for years, but it is only
in the past few years that researchers have been matching the right drugs
to the technique.
“In the 1980s, people tried to use iontophoresis with insulin, but
the molecule is too large and it is hard to get it across the negatively
charged skin because it, too, is negatively charged,” he says.
Professor Guy points out that the real attraction of iontophoresis is
that it does not rely on a concentration gradient and it is not affected
by individual differences in skin permeability. When the electric current
is switched on, an electric circuit is established. Positively charged
ions and drug molecules move from the positively charged electrode chamber
(anode) through the stratum corneum and are then attracted back out to
the negatively charged cathode. (Similarly, negatively charged molecules
move from the cation into the skin and are attracted back to the anode.)
At the same time, electrons travel externally between the electrodes,
and the number of electrons flowing in this “exterior” part
of the circuit determines the number of ions moving through the skin.
This means that the same amount of drug will always be delivered for
the same amount of charge.
The technique also has the potential to deliver pulses of drugs, for
example, hormonal treatments, such as luteinising hormone releasing hormone,
simply by switching the current on and off. Electrical patch
Hot on Vyteris’s heels is the Alza Corporation, part of Johnson & Johnson,
with its credit card-sized, electrical patch delivery system, called
E-TRANS, for delivering fentanyl. Having submitted a licence application
in the US last September, the company is currently addressing issues
raised by the FDA.
In addition to its iontophoretic patches, Alza is also developing a microprojection
system for transdermal drug delivery. Called Macroflux, it consists of
a thin titanium screen with 200µm projections attached to the underside.
When this is applied to the skin, it creates superficial pathways through
the stratum corneum.
Drug can be coated onto the microprojections for bolus delivery, or it
can be attached to a drug reservoir for continuous or iontophoretic application.
Alza considers that the system could be particularly useful for delivering
vaccines, small molecules and biopharmaceuticals.
In preclinical studies, peak plasma levels of bolus doses of peptides
were achieved within one hour of administration. Macroflux has also been
successfully combined with E-TRANS for pulse and continuous delivery
of recombinant human growth hormone.
Professor Hadgraft predicts that microprojection systems (and the related
hollow microneedle approach) will be slower to market than iontophoretic
products.
“They appear to be painless but, by making holes in the skin, they do
open up the potential for other compounds to go through that are not
wanted. Research is therefore looking at how quickly the holes are regenerated,” he
explains.
Using low frequency ultrasound to improve penetration may have fewer
safety issues than microneedles. In vitro studies have shown that it
can be used successfully to enhance transport of high molecular mass
drugs, including insulin, erythropoietin and interferon, and low molecule
weight heparin.
The most likely mechanism appears to be cavitation — development
of bubbles in the skin that expand and contract to disorganise the lipid
bilayer of the stratum corneum. This leads to formation of reversible
microchannels in the skin through which drugs can be delivered. Ultrasound
SonoPrep is an ultrasound device which has been developed by Sontra,
a Massachusetts-based company set up in 1996 initially to develop the
ultrasound system from research carried out at the Massachusetts Institute
of Technology. The company claims that its SonoPrep topical anaesthesia
can significantly reduce the time to achieve analgesia compared with
conventional devices.
Professor Guy believes that the technology may be more useful for biochemical
monitoring than for drug delivery.
“You can render the skin permeable with a fairly short burst of ultrasound,
but the channels stay open for about 12 hours, making it useful for glucose
monitoring,” he explains. Radiofrequencies
In Israel, TransPharma has used radiofrequencies as the energy source
to create highly localised microchannels in the skin. In healthy volunteer
studies, patches containing the anti-emetic agent, granisetron, were
applied to treated areas of skin, and consistent plasma levels achieved
for at least 24 hours before the patches were removed.
Like Professor Hadgraft, Professor Guy questions the feasibility of
long-term transdermal drug treatments that rely on making holes, however
small,
in the skin.
He sees significant potential in the field of immunisation but, realistically,
he considers it unlikely that someone with diabetes, for example, will
apply ultrasound to his or her skin three times a day for life.
“The field is littered with cute ideas for controlling drug delivery,
but the bottom line for [the pharmaceutical industry] is to create billion
dollar drugs and there are not too many cases where the method of delivery
has converted a drug into a blockbuster,” Professor Guy points
out. “For the time being, I think that [the industry] will be happy
to watch and wait, and maybe invest in what the small companies are doing
later on.” |
The
Pharmaceutical Journal