The World of Drug Delivery

IT MAY SOUND FARFETCHED, even futuristic, but the world of drug delivery is evolving and there are a few companies jockeying for position with innovations that include a nasal spray that thinks for you, a microchip that controls how much drug you take, and an eye medication without those cold drops. Among the vying firms is Kurve Technology, Inc. �

(Bothell, Wash.), which has developed an "intelligent" drug delivery device that features lockout and drug authentication technologies. One of the reasons behind ViaNase ID, its creators say, is if an attempt is made to use an unapproved-or counterfeit-drug, the device can be rendered inoperable.

ViaNaseID Electronic Atomizer

PHOTO COURTESY OF KURVE TECHNOLOGY, INC.

Counterfeit drugs can include sugar pills, poorly manufactured substitutes, or mislabeled generic medicines that give the consumer the impression they are authentic, according to information obtained by the company from www. pacificresearch.org. and www.drugresearcher.com. pSivida, Inc., a Perth, Australia-based pharma firm, recently acquired drug device company Control Delivery Systems (Boston, Mass.)-now called pSivida America. With its own drug device arm, the company is now developing Medidur, a back-of-the-eye drug delivery system for diabetic patients, and Brachysil, a cancer-fighting isotope capable of shrinking small tumors.

"You need two components for truly intelligent drug delivery devices; drug release by command, and a control piece on the device that controls its intelligence," says John Santini, president of MicroCHIPS (Boston, Mass), a medical device research company. "Right now we are developing with Eli Lilly Co. an active microchip device that can be implanted in a patient long term, and dose controlled by a doctor via biosensors. When approved, our device will be a time-released device for patients with osteoporosis that will help them rebuild their bone anabolically."

MOVING AWAY FROM IV USE

The drug delivery sector has evolved from being just a pharmaceutical production process, to a driving force for innovation. As a result, developers of drug delivery products and technology are seeing significant attention from customers and investors alike, with notable merger and acquisition activity, as in the case of pSivida and Control Delivery Systems. RandD spending coupled with increasing competition, new technologies, and changing customer bases are leading to new kinds of drug delivery systems.

This can be a very complex marketplace, with many technologies combined to provide better delivery systems, giving rise to niche markets with very specialized applications, such as Kurve's ViaNase ID inhalation delivery device, says Christine Slocumb, a spokesperson for Kurve Technologies.

"The ViaNase ID has a radio frequency identification (RFID) reader with the drug having an RFID tag specific to that prescription drug," adds Marc Giroux, Kurve's president. "The device will only turn on if the reader sees the correct tag. If counterfeiters or generic producers want to operate in the device, they would have to have the correct RFID code, which is virtually impossible given all the available combinations."

Drug delivery is moving away from IVs to simpler and less expensive means of drug delivery. There is one trend that is working to reformulate drugs for oral, topical and inhalation use wherever possible. But on the flip side, there is now strong interest in biotech drugs that are highly targeted and may take the route of using bacteria carriers, direct injection into tumors, direct delivery using other body mechanisms. The most exciting developments researchers have seen are the fast acting therapies that use the lung/skin/ nasal routes-metered dose inhalers, transdermal patches, antibiotic bones cements and drug-eluting stents-which have inherently less risk and in many cases are more effective. Biotech and pharmaceuticals companies are increasingly interested in drug-device combinations. They offer a more effective means for transmitting drugs to a patient. The correct drug-device combination can target areas of the body for receipt of the drug. There is also a trend towards high viscosity products in bio-erodible device systems that deliver drug molecules, Santini said.

"There are different definitions as to what drug delivery encompasses," says Marion Robinson, vice preside of marketing at Baxa Corp. (Englewood, Colo.). "The term now encompasses all means by which a drug is given a patient. When I first worked in the industry years ago, you typically heard the term in relationship to IV pumps and other systems for direct delivery. Today it includes nasal sprays, needles, tables, patches. If you look at a table of contents for a drug delivery market research report, it has an overwhelming number of these delivery options."

BRAND NAME VERSUS GENERIC

Pharmaceutical companies are turning towards products that are diffusing the impact of generic competition and "revitalizing" already established brands. Drug companies-with few potential blockbusters on the horizon-are protecting their patented drugs in the markets they still control. There are concerns in the generic industry that they could one day be shut out of the marketplace entirely. For example, a court recently ruled that Pfizer Inc. (New York, N.Y.) could retain exclusive rights to its drug, Lipitor, until 2011, despite a challenge by Ranbaxy (New Delhi, India) a generic pharma company.

With this in mind, the worry among small generic companies is that big pharma companies will financially entice device firms to exclusively use brand name drugs, or buy the company out entirely, according to the Generic Pharmaceutical Association (Rockville, Md.). Also, Public Citizen (Washington, D.C.), a national non-profit consumer advocacy group, has become concerned as of late about the struggle between brand name and generic drug firms. For example, Biolyse, a small Ontario, Canada firm was forced to shut down production after Bristol-Myers Squibb succeeded in removing its rival's ovarian and breast cancer drug from the market. Biolyse's Paclitaxel drug would have offered Bristol Myers' Taxol some stiff competition, but a Canadian court decided in favor of the pharmaceutical giant. Here in the U.S., the Federal Trade Commission has launched a campaign to prevent companies from illegally blocking introduction of competing generic drugs through securing new and frivolous patents on older products, a tactic known as "evergreening."

GMP cleanroom manufacture of BrachySil

Here in the U.S., the Federal Trade Commission has launched a campaign to prevent companies from illegally blocking introduction of competing generic drugs through securing new and frivolous patents on older products, a tactic known as "evergreening."

"With the potential of losing millions of dollars to a generic company's product, brand name companies have contemplated either buying up smaller generic companies or creating their own," says Larry Salish, a pharmacist and consultant to Public Citizen. "What this means is that the generic drug you're taking could come from the same production facility as the brand name product-the only difference is the labeling, tablet or capsule design, and of course the price."

Consider what's at stake for both industries from these FDA findings. Officials say they have seen an approximate 10 percent increase in drug-device, drug-biologic, and device-biologic application submissions for fiscal year 2005.

Potential BioSilicon capsules

PHOTO COURTESY OF pSIVIDA

When asked by PFQ, the FDA refused to name which companies were submitting recent applications, saying the information is confidential and, therefore, privileged information. However, FDA Spokesperson Crystal Rice noted that an FDA Web site that can be accessed for applications already approved at www.fda.gov/oc/combination.approvals.html.

One example from the Web site is Stryker Biotech (Hopkinton, Mass.). Stryker was approved in 2004 for its OP-1 Putty, which is used to make a new posterolateral spinal fusion in patients who have had a failed posterolateral spinal fusion. OP-1 helps form new bone by imitating the body's own method of bone healing and growth. Another new device featured on the site is the Taxus Express 2 Paclitaxel-Eluting Coronary Stent System. The Express 2 is an expandable, slotted, stainless steel tube, with a drug contained within a thin polymer coating on its surface. It works by having a catheter with a deflated balloon at its tip inserted into a blood vessel in the arm or groin, and advanced to the narrowed section of the coronary artery.

Other FDA findings indicate that:

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The total market for drug-device combinations worldwide is valued at $5.4 billion in 2004, and is expected to rise at an annual growth rate of 14 percent to $11.5 billion in 2010.
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The medical device sector created its own blockbuster product with the dawn of drug-eluting stents. FDA stats show that drug-eluting stents will continue to show average annual growth of 12 percent. This will result in the market doubling to around $8 billion by 2010.
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America presently dominates the market for drug-device combination products, mainly because the largest selling drug eluting stents have been accepted in the market and are penetrating more quickly here than in Europe. For more information on the market, consult the FDA's Approval Website at www.fda.gov/oc/combination/approvals.html.

DRUG DEVICE INDUSTRY HOT

To emphasize how hot the industry is right now, the FDA has established the Office of Combination Products (OCP) to help streamline the processing of complex drug-devices. The spin-off was established in December 2002, as required by the Medical Device User Free and Modernization Act of 2002. The law gives the office broad responsibilities covering the regulatory life cycle of drug-device, drug-biologic and device-biologic combination products. However, the primary responsibilities for, and oversight of, specific combination products will remain one of three product centers: The Center For Drug Evaluation and Research, the Center For Biologics Evaluation and Research, or the Center For Devices and Radiological Health-to which they are assigned.

"Innovative drug delivery devices have the potential to make treatments safer and more effective," says Rice. "The OCP is increasingly incorporating cutting-edge novel technologies that hold great promise for advancing [medical] care."

Top: BioSilicon Particles; Center: BioSilicon cross section; Bottom: Retisert, a novel treatment for vision impairment.

PHOTO COURTESY OF pSIVIDA

"Despite challenges from the pharma giants, the generic drug business is one that will only grow over time. So, while there is concern on the generic side, there is still room for everybody, particularly when it comes to the relatively new frontier of the drug-device business."

-LARRY SALISH A PHARMACIST AND CONSULTANT FOR PUBLIC CITIZEN

Among the duties performed by the office include:

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Assigning a FDA center to have primary jurisdiction for review of a combination product.
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Ensuring timely and effective premarket review of combination products by overseeing reviews involving more than one agency center;
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Ensuring consistency and approprasiteness of postmarket regulation of combination products;
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Resolving disputes regarding the timeliness of premarket review of combination products.
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Updating agreements, guidance documents, or practices specific to the assignment of combination products;
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Submitting annual reports to congress of the office's activities and impact.
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Working with FDA centers to develop guidance or regulations to clarify the agency regulation of combination products;
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Serving as a focal point for combination products' issues for internal and external stakeholders.

"We are receiving significantly more combination product reviews from [companies] as device technologies continue to advance and merge therapeutic products," Rice indicated.

The Public Citizen's Salish says the market is still a long way away from being dominated by futuristic technologies so for the moment, drug delivery devices will continue to be applied mainly to sustain the development of existing products. Despite challenges from the pharma giants, the generic drug business is one that will only grow over time. So, while there is concern on the generic side, there is still room for everybody, particularly when it comes to the relatively new frontier of the drug-device business, he says.

"An immense amount of promising technology is available for the delivery of drugs, but its impact on the global market is still to be felt," Salish adds. "There is no doubt that drug delivery devices will play an increasingly important role in medicine, but the rapidity of their uptake by RandD will be decided by those companies that have the confidence to let them play a leading role in new drug development rather than a supporting role."