Just What the Doctor Ordered

By John Langone

Following the doctor's prescription used to be simple enough. You dutifully swallowed your pills, smeared on your ointment or gulped down your medicine. And that was it. But physicians are finding that the old-fashioned ways of delivering medication can render treatment hopelessly ineffective -- even dangerous. Some people just forget to take pills, and repeated trips to the doctor for shots can be unpleasant and expensive. Tablets and injections can flood the bloodstream with drugs and disperse them unevenly through the system. And drugs can have toxic side effects. With an array of potent, highly specialized new therapeutic drugs on the market, scientists are busy developing a dazzling assortment of space-age techniques that promise to deliver the drugs to the body in safe and effective dosages.

The new methods, many still in the experimental stage, are myriad and mind boggling. Tiny biodegradable capsules are under development that can be embedded in a woman's thigh or arm and will automatically dispense contraceptive hormones for a year. Researchers at the Massachusetts Institute of Technology are experimenting with dissolvable plastic wafers that are implanted in the brain and slowly release an antitumor drug for cancer victims. The day is not far off when most diabetics will be able to give themselves insulin with a nasal spray. In California doctors are working on drug-loaded bubbles of fat that bind themselves to diseased cells. Says Robert Langer, a biomedical engineer at M.I.T.: "It's an explosive field with enormous potential."

Controlled-release systems first appeared in the 1950s with the introduction of Dexedrine's "tiny time capsules." Variations have included slowly dissolving wax-coated pills and small adhesive skin patches capable of delivering doses of medication. The new drug-delivery systems, based on advances in molecular biology, represent a dramatic improvement over their predecessors. Take the plastic wafer, about the size of a quarter, that can carry powerful drugs to brain-cancer victims. Researchers have known for some time that disks formed of chemical structures called polymers work well for dispensing small molecules like nitroglycerin, a pain reliever commonly used for heart patients. But the polymers seemed stubbornly resistant to releasing larger molecules of substances like insulin and growth hormones in the slow, steady doses needed for diabetics and underdeveloped children.

To solve the problem, Langer and his colleagues reconfigured the structure of polymers to enable drugs to be dispensed in measured doses. Explains Langer: "Because its route is so tortuous, the drug gets out, but slowly." Langer is now testing an injectable system for diabetics in which enzymes sensitive to glucose in the bloodstream are placed in microscopic polymers along with insulin. The drug is released through the complex, porous polymer structure. Because the solubility of insulin increases in the presence of glucose, the more glucose in the blood, the more drug is released. This "intelligent" method represents a potential revolution in the treatment of diabetes, since blood-sugar levels in diabetics are thought to be best controlled by the continuous release of insulin each day, supplemented by increased doses around mealtimes.

In Mountain View, Calif., a biotechnology company is developing a nasal spray for diabetics that uses "enhancer molecules" to coat and carry insulin through the mucous membranes and into the bloodstream. Preliminary tests show that a wisp of the spray at mealtime may mimic the healthy body's response to rising blood-sugar levels. According to the company, the insulin can take full effect in less than 15 minutes, in contrast to two to three hours for an injection.

While the polymer and spray systems stress control and timing, others -- such as those being tested at the Cancer Research Institute of the University of California at San Francisco -- attempt to deliver specific drugs to specific cells. To accomplish this, microscopic bubbles of fat, called liposomes, are filled with a cancer drug and attached to antibodies that have the ability to distinguish cancer cells from healthy cells. Injected, the package ignores normal cells and attaches to diseased ones. But getting the liposomes to stay in the blood long enough to do their job has been difficult until now. Researchers seem to have solved the problem by changing the surface chemistry of liposomes so that they can circulate for longer periods. Says UCSF Pharmacologist Demetrios Papahadjopoulos: "It's an entirely new beast. We beat the system."

Not all of the new delivery systems are directed at life-threatening diseases. Scientists at Advanced Polymer Systems of Redwood City, Calif., have turned to a more consumer-oriented line: synthetic microsponges averaging one- thousandth of an inch in size and containing 10 ft. to 20 ft. of drug- filled intertwining tunnels. When the sponges, which are as fine as dust, are rubbed on the skin, they squeeze out controlled bursts of sunscreen, local anesthetic, aftershave, insect repellent or antidandruff ingredients. Quips | A.P.S. Senior Vice President Martin Katz: "We're only beginning to scratch the surface." The next generation of drug-delivery systems is already on the drawing board: implantable microscopic mechanical devices, including gears and motors produced like computer chips.

With reporting by Robert Buderi/Boston and Dennis Wyss/San Francisco