PALO ALTO, Calif.— Ten years ago, the Alza Corporation introduced the first skin patch that delivered controlled amounts of a drug continuously over a long time. Now, Alza and other companies are working on improving the technology of such transdermal therapeutic systems to deliver new drugs that have resisted this method, to provide greater amounts of existing drugs and to exert greater control over dosage and timing.

Several companies are exploring iontophoresis, or electrotransport, an active system in which a small electrical current is used to propel drugs through the skin. Though several years away, electrotransport could be used to treat patients with genetically engineered drugs that cannot be taken in pill form and whose molecules are too big to work in the passive system.

Transdermal drug delivery has the advantage of being both highly precise and consistent, like a closely monitored intravenous drip, but noninvasive because there is no needle. Drug levels stay at concentrations that maximize therapeutic effects and minimize side effects. The worldwide market in 1991 for transdermal drugs is about $800 million, and it expected to grow to $5 billion by the year 2000.

Although the skin is a barrier to foreign substances, some drugs penetrate it readily. One of Alza's key patents is on a rate-controlling membrane, which forms an interface between a liquid drug and the skin to slow the penetration. Other drugs enter the skin slowly and must be mixed with penetration-enhancing substances, like alcohol, to be used transdermally. Some drugs, like the large proteins developed by biotechnology, will not normally pass through the skin at all.

The premise behind electrotransport is that the current acts as a kind of penetration enhancer, which may be the only way to get proteins and other large-molecule drugs through the skin to the bloodstream. With timing and pulsing of the electrical current, drug delivery could also be controlled to a degree not possible with passive systems.

"If you move drugs in the presence of an electrical field -- very low current; you wouldn't feel any tingling -- they will carry the current," said Jane Shaw, Alza's president and chief executive. "The current can move any drugs which have a charge, and most of them do."

She continued, "The miniaturization of chips and battery technology has advanced so that we can put all the logic and power we need into a Band-Aid." Indeed, the electronics are the easy part of electrotransport, little more than a timer and a low-voltage power supply. The biology of moving current through the skin will be more challenging.

Alza has formed a subsidiary, Bio-Electro Systems Inc., to develop products based on electrotransport, aided by money from the companies whose drugs would be encapsulated in the patches. Bio-Electro initially plans three different systems: a steady-state delivery system, which would deliver a continuous amount of drug; a patterned delivery system, which could, for example, provide periodic high doses with intervening small doses, and a patient-controlled system.

Dr. Shaw said these products are not likely to be available for at least five years. Other companies actively pursuing electro transport include Cygnus Therapeutic Systems of Redwood City, Calif., and the Elan Corporation of Athlone, Ireland.

One challenge in perfecting electro transport is that the skin turns out to be an effective barrier between electrical charges and the bloodstream, said Russell O. Potts, Cygnus's associate director for biophysical research. Lipid bilayers, which are the fatty molecules that form the mortar between skin cells, "are excellent capacitors -- they resist the flow of ions," he said. The result is that the electrical charge and the drug tend to concentrate at hair follicles, which limits the charge that can be used.

"Yes, it's true you can increase delivery, but there is an inherent upper limit," said Dr. Potts. While Cygnus is looking for ways to diffuse the charge and raise the limits, "one of the best advantages of electrically controlled delivery is not so much delivering more drug but the very specific control possible," he said. One likely application of such programmed delivery is providing diabetics with just the right amount of insulin.

Dr. Potts said electrotransport might also be used in reverse, to extract compounds from the body with an electrical charge that is opposite the charge of the substance being extracted. One application being explored is a glucose monitor, which could determine a patient's blood sugar without a needle.

Cygnus is also developing transdermal systems based on sonophoresis, which uses ultrasound to move drug molecules through the skin, and electroporation, which uses electrical currents to alter the skin's permeability temporarily.

In the near term, Cygnus is working on ways to improve passive transdermal patches. The main thrust of its efforts has been to eliminate the rate-controlling membrane used in Alza's products. Instead of a liquid in a pouch with the membrane on one side, a Cygnus patch uses a spongy reservoir layer impregnated with a much smaller amount of drug. This layer is faced with a porous adhesive and is placed directly on the skin.

"In comparison to Alza, which has a liquid patch, ours is a solid-state patch," said Gary W. Cleary, Cygnus's chairman and chief technical officer. Cygnus analyzes each drug's physical chemistry and desired therapeutic effect and develops a reservoir layer to match; the adhesive is also tailored to each drug. The benefits include greater control over dosage and patches that can be worn longer, he said.

One frustration for developers of transdermal drug delivery has been the length of time required for the systems to gain F.D.A. approval and reach the market. Alza has five transdermal drugs on the market, but more than a dozen still await approval. Cygnus was founded in 1985, specifically to develop transdermal systems, but it will introduce its first product only this year. Analysts say the expectation that these products would get speedy approval was unrealistic.

"There has always been this impression out there in the world that because you're using a drug already approved" for conventional delivery, "the approval process should be easier and shorter," said James McCamant, publisher of Medical Technology Stock Letter. "That just isn't true."

Another factor that could slow the progress of transdermal delivery is patent litigation. Elan filed suit last week against Cygnus, charging that the company's nicotine patch infringes Elan patents. At the same time, Alza holds a patent on transdermal delivery of fentanyl, a powerful pain reliever, which could block a fentanyl-delivering patch being developed at Cygnus.

Much of the published data on electro transport is based on work done by scientists in the Soviet Union, and this may prevent any company from obtaining a dominant patent, said Dr. Shaw. But, she added, there is ample room for refinements and patents on specific applications.

Diagram: "From the Skin to the Bloodstream," shows how electric currents promote the movement of the drug through the stratum corneum and epidermis to the dermis, where it is picked up by the capillaries and carried into the bloodstream.