March 2005
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    PBS - March 2005

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Controlled release adds to drug longevity

(from the March 2005 edition of PBS)

Angelo DePalma

Drug makers are turning to CR to "evergreen" their branded products

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.

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