Implants May Vary Drug Delivery : 2 Techniques Promise Dosage Control According to Need

Two new techniques that may allow implanted drug-delivery systems to vary dosage according to need were described here Tuesday by a scientist from the Massachusetts Institute of Technology.

The new systems represent a potentially significant step toward the controlled administration of drugs, which is considered more effective than periodic administration for certain diseases like diabetes, MIT chemical engineer Robert Langer said at a meeting of the American Chemical Society here.

One of the new systems would allow the patient to decide when an increased quantity of the drug is needed. The other would respond automatically by, in effect, monitoring the concentration of certain chemicals in the blood.

Systems Already in Use

Existing systems that release drugs at a controlled rate are already in use. One such system is based on polymeric skin patches that release nitroglycerin for treatment of angina pectoris or certain agents for treatment of high blood pressure. Another such system, an implant that releases hormones for birth control and remains effective for as long as five years, is now used in Europe and may be approved soon in the United States.

But all of these systems have two limitations. They are only effective with small molecules, so they cannot be used for many of the peptide drugs, such as insulin, that have been developed by genetic engineering. They also release drugs at a constant rate, whereas a diabetic, for example, typically needs a higher dose of insulin after a meal.

Langer, a founding father of controlled drug release, had addressed the first problem by producing biodegradable polymers, which are large molecules that can be broken down into smaller harmless chemicals by the body. The Eli Lilly Co. of Indianapolis, for example, is working with his polymer to develop aspirin tablet-sized implants that would release insulin for up to 100 days.

Two years ago, Langer reported on a system that addressed the second problem by incorporating magnetic beads into the drug-filled polymer. When an alternating magnetic field was applied to the polymer from outside the body, the beads squeezed pores of the polymer, causing extra drug to be released. This system has also been licensed to drug companies.

But Langer reported here Tuesday that he has two new systems that are even better.

Ultrasound Radiation

He has found that the biodegradation of the polymers he has previously developed can be speeded up if they are subjected to a short burst of ultrasound radiation of the type that is used for fetal monitoring.

When the ultrasound is turned off, the drug release returns to normal. “All of our work suggests that there are no ill effects associated with this procedure,” Langer said.

He envisions a system in which diabetics, for example, would wear small ultrasonic generators on their belts or wristwatches. After a meal, they could activate the system to release extra insulin. Langer has so far tried the system only in a few mice.

The second system is more sophisticated because it would control itself. Langer has found that the acidity within the polymer implant controls the rate of release of drugs. As the acidity increases, drug release increases.

He has therefore developed a system in which an enzyme called glucose oxidase is attached to beads within the polymer. The enzyme triggers the conversion of sugar in the blood to gluconic acid, which increases the acidity within the polymer so that more insulin is released.

When blood sugar is lowered, the enzyme becomes inactive because the chemical it normally operates on is no longer present. The acidity of the implant and the release of insulin both return to normal.

Langer has shown in animals that the small change in acidity produced by the blood sugar levels normally present after a meal can cause a 200%increase in the rate of insulin release. The main advantage of this system, Langer said, is that the patient does not have to do anything.

Although the enzyme system has been studied in mice, Langer cautions that both systems “are clearly at an early stage and years away from practical use.”