Pharmaceutical developers seeking
their next opportunity need look no further than
their own medicine cabinets. Unlike many me-too
reformulations, controlled-release (CR) versions
of successful, marketed drugs provide value for
patients, insurers, and manufacturers alike.
Fuji-Keizai USA estimates the
2002 global market for drug-delivery systems at
$47 billion, predicting a 2006 figure of $67
billion based on a compound annual growth rate of
nearly 8%. With blockbuster drugs losing about $37
billion to generics between 2002 and 2006, the
argument for CR has never been better.
By controlling the amount of drug
delivered over time, CR optimizes dose while
generally consuming less active ingredient, thus
reducing side effects. This benefit, along with
less frequent dosing, improves compliance. And as
a new formulation, CR helps extend the brand name,
market exclusivity, and patent life. As
continuations of successful products, CR
formulations mitigate much of the risk associated
with drug discovery, development, clinical
testing, and regulatory approval, says George
Haley, PhD, in the Department of International
Business at the University of New Haven.
"Controlled release is both an offensive and
defensive strategy," he explains. "R&D-based
pharmaceutical firms depend on the flow of new
drugs out of their pipelines, a difficult, risky
enterprise made a lot less risky through new forms
of products already known to be safe and
effective."
Dr. Haley believes that from a
larger strategic view CR (and other dosage form
enhancements) can help U.S. firms compete with the
coming flood of generics, including biogenerics,
from overseas. "Controlled release can keep
innovator companies that embrace it on the cutting
edge of new pharmaceutical technology."
Despite the obvious appeal of CR,
most medications are not optimized for delivery,
observes James Howard-Tripp, CEO of specialty drug
maker Labopharm (Laval, Quebec). "Pharmaceutical
companies do a good job of launching products, but
they often fail to invest the extra two to four
years to optimize their products." Labopharm's
Contramid delivery vehicle uses a cross-linked,
high-amylase starch. Dry, the starch behaves like
any other dry excipient. When ingested, moisture
helps polymerize the starch into a semipermeable
matrix that regulates release of actives over a
precisely adjustable time period. "We can generate
umpteen release profiles," boasts Howard-Tripp,
"for example an initial burst followed by
sustained release, double pulse, or more
traditional sustained release."
Within the traditional
delivery-enhancement business model, delivery
companies approach large drug manufacturers and if
the deal goes through collect modest royalties
through a licensing or manufacturing/supply
relationship. "It's hard to build a robust company
on that model," notes Howard- Tripp. Labopharm
thought it could do better, and has been pursuing
its own products based on in-house delivery
technology and established, off-patent drugs.
For its first product, Labopharm
chose tramadol, a nonopioid, non-nonsteroidal
anti-inflammatory analgesic that has been
available in Europe for 20 years and in the United
States since 1995. Patients take immediate-release
tramadol six times per day; Labopharm's version is
taken just once daily. A Contramid-formulated
tramadol, Topalgique, was approved in France in
January 2005. Labopharm's European marketing
partners read like a Who's Who of Continental
Pharmaceuticals.
Long term, Howard-Tripp sees the
commercial opportunity for CR with drugs at the
far ends of the solubility spectrum: too soluble
and the material is released immediately;
insoluble and it never sees the bloodstream
(tramadol falls into the former category).
Labopharm developed its version of tramadol in
about four years. Next up: A once-daily version of
betahistine, for Mennier's disease, which is a
form of vertigo.
Depomed's (Menlo Park, Calif)
version of the "smart pill," gastric retention
(GR), is also based on a proprietary
drug-sequestering polymer. After swallowing, GR
swells and is retained where the stomach meets the
small intestine, from which point it delivers its
payload through release kinetics based on one of
four mechanisms (diffusion, erosion, bilayer, and
combinations of these).
GR's targeted, sustained delivery
spares the stomach and large intestine, where many
side effects originate, while exploiting the small
intestine's high surface area. In a head-to-head
comparison between Depomed's Proquin XR
(ciprofloxacin) antibiotic and a standard cipro
product from Bayer, Proquin provided steadier
pharmacokinetics and fewer gastrointestinal (GI)
side effects. According to Depomed CEO John Fara,
PhD, fear of GI problems is the number-one reason
cited by patients for poor drug regimen
compliance.
Dr. Fara claims Depomed can
create new CR, oral formulations in a few months
and complete preclinical and phase 1 trials in
about a year, at a cost of about $1 million.
During manufacture, GR adds about 1 cent to the
cost of a pill. The company's Glumetza GRmetformin
(for diabetes) spent just four years in the clinic
and review. GR-delivered furosemide (for heart
failure) and gabapentin (for pain) are under
development at Depomed, while Bristol-Myers Squibb
has licensed GR for its own metformin product.
Pegylation adds punch
Pegylation—the chemical
attachment of polyethylene glycol (PEG) residues
to drugs—works with almost any type of molecule
but shines with proteins and peptides. Several
pegylated cytokines have become blockbusters,
among them Amgen's Neulasta granulocyte
colony-stimulating factor white blood cell booster
and Roche's Pegasys pegylated interferon-alfa.
By providing steady plasma
concentrations versus the usual spikes and troughs
associated with injected protein treatments,
pegylation raises the interferon cure rate for
hepatitis C from about 10% (with very nasty side
effects) to 40% with only modest flu-like symptoms
limited to the day of the injection.
Early on, scientists had
difficulty sizing add-ons and attaching them at
the right locations. That didn't stop Roche with
Pegasys, which while retaining just 7% of native
interferon activity is still four times more
bioavailable (and many times more effective) per
dose than the original.
More than any CR technology,
pegylation has the best chance to rescue promising
peptides, which generally possess abysmal
pharmacokinetics. Pegylated peptides don't raise
undesirable immune activity and last far longer in
the bloodstream than naked drugs, provided the PEG
moiety is in the 30,000 to 40,000 molecular weight
range.
Steve Charles, PhD, vice
president of business development and licensing at
pegylation specialist Nektar Therapeutics,
believes pegylation has a "huge" future with small
molecule drugs as well, especially for insoluble
molecules.
Transdermal CR
Even though oral delivery is
king, depending on your application it may pay to
investigate alternatives to conventional oral
delivery. NexMed (Princeton, NJ) specializes in
out-of-the-ordinary delivery vehicles (eg, creams,
gels, nasal sprays, and lacquers, in addition to
patches) for delivering drugs through the skin.
The company's erectile dysfunction cream, in phase
3, uses the same prostaglandin vasodilator in Rx
penile suppositories, but NexMed found a way to
get the compound into the skin.
The company enhances absorption
of unlikely molecules through proprietary agents
that overcome the skin's natural barrier
properties. Think of this idea, which the company
calls NexACT, as an enabler for transdermal CR
formulations. According to Kenneth Anderson, vice
president, NexMed, NexACT works best with
low-molecular-weight molecules. No great benefit
there, but unlike traditional pills and tablets,
NexACT delivers many types of poorly soluble
compounds as well as hydrophilic drugs.
Anderson's advice to sponsors
looking for delivery partners is to start a lot
earlier than you think you need to. "Too often,
companies don't think about novel delivery systems
until the original drug is about to come off
patent, which is too late. ‘Evergreening' brands
must come early, ideally at the same time as
launch, because it's the brand that ultimately
matters. The longer you sustain it, the longer you
reap the rewards."
Erodable CR formulations, like
Leupron and Zoladex prostate cancer treatments or
the Norplant birth control product, usually rely
on biocompatible polymers. pSivida (Australia)
uses an entirely novel "biomaterial," porous
silicon, nanofabricated into a honeycomb structure
containing drugs. The payload is liberated as the
silicon dissolves to benign silica acid.
According to commercial director
Jill Ogden, PhD, the problem with sustained
delivery is not long-term release, but CR. "Most
drug firms solve the problem by using extra drug
to keep pharmacokinetics within the desired range.
In some cases, for delivery by patch, 10 times the
amount of active ingredient is used." Such high
ratios of effective to actual dose raise
additional concerns of dose dumping. "Together,
these shortcomings waste a lot of product and
money, but frequently there's no other option,"
says Dr. Ogden.
Since we last reported on
pSivida, its 32P-based brachytherapy product has
breezed through most of phase 2. The treatment,
based on BioSilicon microparticles, is indicated
for primary liver cancer but shows potential as an
implantable CR treatment for other cancer types.
