At a sprawling office park in Redwood City, Calif., four converted printing presses, each the size of a minivan, punch out 3 million nicotine patches a week at Cygnus Therapeutic Systems. Cygnus, which launched its Nicotrol patch with Warner-Lambert Co. in August, says it has since doubled its capacity to meet demand. Rival patch producers, who suffered shortages earlier this year, are scrambling to catch up. To everyone's surprise, the nicotine patch has become one of the hottest pharmaceuticals in history. First-year sales could top $800 million--double the most upbeat predictions.
The popularity of patches that help people quit smoking is just one sign that finding superior ways of delivering drugs to the body can offer a huge payoff to drugmakers. After years of research and of lobbying large pharmaceutical houses to use their technologies, companies such as Alza Corp. in Palo Alto, Calif., and Elan Corp. in Westmeath, Ireland, have produced goldmines from such products as the transdermal patch and once-a-day pills that dispense drugs more precisely. "Major milestones have been reached," in drug-delivery technology, says Robert Langer, a professor of biochemical engineering at Massachusetts Institute of Technology.
NEW LIFE. These advances are, foremost, a boon to patients. They boost effectiveness and limit side effects by precisely controlling how quickly drugs are released in the body, by keeping drugs at a constant level, and by delivering them exactly where they're needed. They also promise to greatly expand the usefulness of large, fragile proteins such as insulin and of many biotech drugs, which currently can be administered only by injection.
For drugmakers, meanwhile, a new delivery system garners up to 17 years of patent protection. And that can greatly extend the life of an aging compound. "Historically, the major breakthroughs have come because people invented drugs," says Martin S. Gerstel, co-chairman of Alza, the best-known drug-delivery research company. "Now, there's a new pathway to important products."
Most of the cutting-edge research is taking place at Alza and several dozen startups, which are drawing investors. In February, Zynaxis Inc., a Malvern (Pa.) company that is developing ways to attach drugs for vascular ailments, arthritis, and cancer to diseased cells, raised $23 million in an initial public offering. Enzon, based in South Plainfield, N.J., has raised $91.7 million since its founding in 1983. Big drugmakers can't wait to forge alliances with such companies. Last November, Ciba-Geigy Co. struck a deal to license an estrogen patch from Miami-based Noven Pharmaceuticals Inc. and invested in the startup. In April, Eli Lilly & Co. invested $3 million in Zynaxis. And Alza counts such big-name companies as Pfizer, Merck, and Marion Merrell Dow as clients. Cygnus CEO Gregory B. Lawless boasts that he has fielded calls from executives across the industry inquiring about his company's research: "You can hear 'em drool on the phone."
Who can blame them? Developing a new drug costs $230 million-plus, and winning marketing approval can take up to 12 years. Extending patents with a new method of administering drugs is cheap by comparison. Take the case of Procardia, Pfizer's top-selling anti-angina drug. A key patent for it was set to expire in early 1991, and generics makers were starting to circle when Alza reformulated the drug from a three-times-a-day to a once-daily version called Procardia XL. Launched in 1989, the drug employs a controlled-release technology that Alza President Jane E. Shaw calls "the world's smallest pump." The medicine sits in one chamber of the pill, a polymer sponge in another. As the sponge absorbs body liquids, it swells, pushing out the drug through a laser-drilled hole over a period of time.
This year, sales of Procardia XL may hit $1 billion, up from a one-year peak of $420 million for the earlier version. One reason: The new controlled-release pill is approved for treating high blood pressure, a much larger market. "Procardia was a pretty good drug," says Ira Loss, an analyst with Washington Analysis Co., a research and investment analysis firm. "But when they put it in controlled-release form, it became a spectacular drug."
Alza hopes to apply the same technology--with a new wrinkle--to verapamil, a $500 million antihypertensive that G.D. Searle & Co. sells as Calan SR. Most heart attacks occur in the morning, when changes in blood pressure exert considerable stress on the organ, but antihypertensives taken before bedtime usually wear off by sunrise. So Alza is developing a Calan formulation that packs its punch in the early hours. It works like the Procardia system, except that the drug chamber is layered with a placebo that takes four to six hours to diffuse. The medication then kicks in just an hour or two before the patient's normal wake-up time. Reformulated Calan could reach market by the mid-1990s.
THICK SKIN. Patches are also evolving. Their next target is a second-generation hormone treatment for contraception and such problems as postmenopausal syndrome. Cygnus and Noven Pharmaceuticals have both licensed patches containing a mixture of female hormones to Warner-Lambert Co. and Rhone-Poulenc Rorer. And TheraTech, a Salt Lake City startup, has begun advanced clinical trials with a testosterone patch for men who are deficient in that hormone.
Because the skin is such a dense barrier, current patches have a big limitation: They can deliver just a few, small-molecule drugs. That's why a number of companies are pursuing the transport of drugs across the skin using electricity. Elan, for one, is in the early stages of human trials to test a watch-size device. Strapped to the wrist, the mechanism houses a disposable drug cartridge and microelectronics that control the amount and timing of drugs entering the bloodstream. Elan has teamed up with the Swiss maker of Swatch watches to develop the system.
Electrotransport's main advantage is its ability to move a wide variety of large-size molecules through the skin. Delivering protein-based drugs, such as insulin, as well as the rapidly expanding list of biotech products, is one of the drug industry's thorniest problems. Now, the only way to give such drugs is through injections. That bypasses the stomach and gastrointenstinal tract, which digest protein-based compounds, rendering them useless. But injections limit the usefulness of these drugs to severe or life-threatening diseases. Shots may be a good way to administer IL-1 receptor antagonist, a drug that Synergen Inc. in Boulder, Colo., is working on to treat septic shock, a sometimes fatal malady. But sufferers of rheumatoid arthritis, which the drug may also control, "are just not going to inject themselves for 20 years," says David M. Steinberg, an analyst with Volpe, Welty & Co., a San Francisco investment bank.
Indeed, researchers will have to find new ways of administering most gene-spliced drugs if they are to be useful in treating chronic diseases--the biggest potential markets. That's especially true of drugs to treat such neurological disorders as Alzheimer's and Parkinson's diseases, where penetrating the so-called blood-brain barrier has proved vexing. "The oral delivery of peptides protein fragments is the equivalent of the holy grail in the drug industry," says Aleksandar Erdeljan, president of R. P. Scherer Corp. in Troy, Mich. "It is a huge, huge opportunity."
FATTY DRUGS. There are several promising approaches. For example, Enzytech in Cambridge, Mass., is trying to encapsulate protein-based drugs in biodegradable polymers to prevent them from being broken down in the gastrointestinal tract before they can reach the bloodstream. This technology is being tested with insulin and erythropoietin (EPO), a biotech drug that boosts red blood cells. Emisphere, located in Hawthorne, N.Y., is attempting to shield drugs from the harsh workings of the gut by surrounding them with hollow microscopic spheres, made of amino acids, that remain solid in the stomach's acidic environment. In late July, the company announced that it had successfully administered an oral form of heparin, an anticoagulant, to animals.
The stomach isn't the only enemy of protein-based drugs. The body's immune system--which hunts down foreign invaders--can also hinder their activity. To get around that obstacle, Emisphere in July began a research collaboration with Enzon to combine the two companies' approaches. Enzon is pursuing what it calls "pegnology"--an approach in which polymers are attached to protein-based drugs. The polymer forms a shell around the protein, shielding it from immune-system cells. A drug called Adagen that employs the technology is already on the market to treat so-called "bubble boy" disease, a genetic disorder that causes partial or total disfunction of the immune system.
REDUCING DOSES. A primary goal of drug-delivery research is to make therapies more effective with fewer side effects. Using liposomes--microscopic, fatty-based particles--is one promising approach. By injecting or implanting liposome-surrounded drugs at disease sites, researchers at Liposome Co. in Princeton, N.J., and at Liposome Technology in Menlo Park, Calif., hope to reduce the dose--and toxicity--of such compounds as cancer drugs and powerful antibiotics. So far, just one liposome product is on the market, available only in Europe: It's a powerful antifungal agent from Vestar Inc. in San Dimas, Calif., that is used fight systemic fungal infections in AIDS patients.
Other encapsulating compounds are under study. DepoTech Corp., a startup in La Jolla, Calif., is in clinical trials with a foam-like product that contains powerful drugs to treat malignant meningitis--an aggressive variety of brain cancer. The conventional therapy involves repeated, painful spinal taps, whereas the long-lasting foam is injected into cerebral spinal fluid far less frequently. Similarly, various kinds of polymer implants, including the contraceptive Norplant, are being tried to slowly release drugs in the body over time. Scios Nova Inc. in Mountain View, Calif., has completed trials on its dime-size polymer wafers, which can be implanted in the brain to treat recurrent malignant cancer. The company hopes to file for a new drug application by the end of the year.
In the future, researchers say, drug delivery will be the limiting factor in the use of wonder compounds. Scientists are still puzzled over how to administer such high-tech drugs as monoclonal antibodies, which target specific proteins on diseased cells, or how to deliver gene-targeting drugs that home in on faulty DNA. Solving those problems will keep the drug-delivery pioneers busy for years--and the big drug houses hungry for help.