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Jenny Bryan is a freelance writer based in London
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Matching drug release to the body’s circadian rhythms has been
the elusive goal of a select band of drug delivery companies for at least
two decades. But the hazards of the gastrointestinal tract have meant
that only a handful of truly chronopharmaceutical products have reached
the market, and few are in development. Researchers such as Howard Stevens,
head of exploratory drug delivery at the University of Strathclyde, recognise
the value of a chronopharmaceutical approach, but differ in their level
of optimism about what can be achieved.
“The idea of targeting release to the specific time of day when
there is maximal clinical manifestation of a disease has obvious advantages,
and there is no shortage of ingenuity in designing formulations for time-delayed
drug release. But the difficulty lies in designing products that are
resistant to breakdown by the fluids in the GI tract,” explains
Professor Stevens.
In 2000, his group reported the successful pulsatile release over a two-
to 12-hour period of propranolol sealed inside an insoluble capsule by
an erodible tablet, the release time being controlled by the amounts
of insoluble and gel-forming excipients in the tablet.1 But Professor
Stevens remains pessimistic about the large-scale development of timed-release
formulations of commonly used drugs, not least because of the need to
show practical, and not just theoretical, advantages of a chronopharmaceutical
approach.
However, in a recent major review of chronopharmaceutical applications,
Bi-Botti Youan, from the department of pharmaceutical sciences, at the
Texas Tech University Health Sciences Centre School of Pharmacy, Amarillo,
Texas, argues that, in addition to their scientific advantages, such
approaches have commercial benefits for pharmaceutical companies seeking
to prolong the patent life of expiring products.2 “Until now, the
emphasis has been on formulations that maintain constant drug levels
throughout the day. But we now need to develop more biologically appropriate
formulations that take account of variations in bodily functions, such
as blood pressure, during the day,” says Dr Youan.
As well as in hypertension and other cardiovascular disease, Dr Youan
offers good theoretical reasons for carefully timed drug delivery in
the treatment of asthma, arthritis, duodenal ulcer, cancer, diabetes,
hypercholesterolaemia and some neurological disorders. In cancer, for
example, he argues that chemotherapy could be more effective and less
toxic if drugs could be administered at times that take more advantage
of tumour cell cycles. In asthma, a drug that could address the progressive
increase in airway resistance during the night could offer better symptom
control in the early morning hours.
A number of systems have been developed for timed release of commonly
used medicines. Most established is probably the OROS technology marketed
by Alza and used, among other products, for a controlled onset extended
release formulation of verapamil.
The drug is released overnight, four to five hours after the tablet is
ingested, to provide optimal blood pressure control in the early hours
of the day, with the aim of addressing the peak morning risk of cardiac
events.
OROS uses osmosis to release the drug contained within a semi-permeable
membrane. As water from the GI tract enters the tablet, a layer of osmotically
active agents expands and pushes on the drug core, so that the drug is
released through laser-drilled holes in the outer membrane. An additional
layer between the active drug core and the semi-permeable membrane enables
release to be delayed.
An alternative approach, used by Elan in its chronotherapeutic oral drug
absorption system (CODAS), relies on a combination of water soluble and
water insoluble polymers, coated on to drug-loaded beads to delay release
by four to five hours after ingestion. The polymer coat is gradually
dissolved by water from the GI tract, and the drug diffuses through the
resulting pores in the coating.
The Italian drug delivery company, Eurand, also uses a polymer layer
for timed release from drug-containing particles in its Diffucaps technology.
By incorporating beads with differing drug release profiles, the company
offers capsules with both immediate and delayed release components.
In contrast, US-based drug delivery company, Penwest, uses a gum matrix
for its TIMERx controlled release technology. On exposure to GI fluids,
the combination of xanthan and locus bean gels becomes hydrated and the
drug core is gradually released. The TIMERx system is being adapted for
chronopharmaceutical applications, with lagtime controlled by variations
in the gum matrix.
Demonstrating that chronopharmaceutical technologies can deliver active
drug, when and where they say they will, is difficult enough. But before
cost-conscious purchasers are prepared to pay for what will inevitably
be premium-priced brands, they will want clear evidence of beneficial
effects on clinical outcomes and, as Professor Stevens points out, such
data are sadly lacking.
One aim of the controlled onset verapamil investigation of cardiovascular
endpoints (CONVINCE) trial was to find out if the OROS-based system of
verapamil delivery could reduce morning cardiac events, compared with
a standard beta blocker or diuretic. But the study was halted two years
early, and there were too few events to show whether there was any real
value of the chronopharmaceutical approach to blood pressure control.3
Both Professor Stevens and Dr Youan agree that outcomes trials like CONVINCE
are needed if chronopharmaceutical products are to compete with conventional
formulations. But the cost of such large studies may be prohibitive.
Dr Youan believes that future chronopharmaceuticals will also have to
be “smarter” than current systems.
“Most people are using polymers to control release, but they are
not smart enough to think about when a drug should be released. Nanomedicine
and
microchips may improve control, but we will need to balance that against
the invasiveness of the system,” he says.
As Dr Youan points out, external and internal infusion pumps have been
delivering timed doses of insulin and analgesics for many years. But
their invasive nature continues to limit their wider use for common chronic
conditions. Even so, he remains optimistic: “We have focused on
the physics and chemistry of drug delivery for long enough, now it is
really is time for us to think more about what the body needs. Chronopharmaceutics
is not just a gimmick, it has clinical relevance, but we need doctors,
pharmacists, chemists and others to work together to assess its real
benefits.”
References
1. Ross AC, MacRae RJ, Walther M, Stevens HN. Chronopharmaceutical
drug delivery from a pulsatile capsule device based on programmable erosion.
Journal of Pharmacy and Pharmacology 2000;52:903–9.
2. Youan B-B C. Chronopharmaceutics: gimmick or clinically relevant approach
to drug delivery. Journal of Controlled Release 2004;98:337–53.
3. Black HR, Elliott WJ, Grandits G, Grambsch P, Lucente T, White WB
et al. Principal results of the Controlled Onset Verapamil Investigation
of Cardiovascular Endpoints (CONVINCE) trial. JAMA 2003;
289:2073–82 |
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