New Ways to Deliver Drugs : Part 2

by Food and Drug Administration (FDA)

(Page 2 of 2)

With the nitroglycerin patch, however, it was discovered that maintaining constant blood levels is not advantageous. Studies showed that when patches are worn continuously, drug tolerance develops within 24 hours and the medication is no longer effective. Revised labeling recently approved by FDA recommends a dosing schedule alternating a daily patch-on period of 12 to 14 hours a day with a patch-off period of 10 to 12 hours.

Another extended-release preparation that did not prove as successful as originally expected is Ocusert, a reservoir system in a wafer-like disk, designed to treat glaucoma. Glaucoma is characterized by increased pressure in the eye that can cause blindness. At the time Ocusert was developed, the standard treatment for glaucoma was application four times a day of eye drops containing the pressure-lowering drug pilocarpine. The drops often caused side effects, however, and patients sometimes did not take them as prescribed. Ocusert, on the other hand, placed in the lower eyelid, where it floats in the tear film, delivers low-dose pilocarpine continuously for one week.

Although it was seen as having the potential to solve patient compliance problems, Ocusert was never widely used, in part because older patients were reluctant to place the object in their eyes. Also, Ocusert costs the patient approximately five times more than the pilocarpine drops. A new drug, timolol, has since been developed, which, although not a controlled-release preparation, requires only two applications of drops a day instead of the four needed with pilocarpine.

Implants and Intrauterine Devices

Devices implanted under the skin are also being developed to deliver drugs at a controlled rate. FDA approved one such device for contraception in December 1990. The Norplant system is implanted under the skin and protects against pregnancy for five years, unless removed sooner. It consists of six flexible silicone tubes filled with a five-year supply of the hormone levonorgestrel. It is implanted in the upper arm, and small amounts of the hormone continuously seep through the permeable tubes into the bloodstream, providing contraception. (For more on this device, see "Norplant: Birth Control at Arm's Reach" in the May 1991 FDA Consumer.)

Similarly, an intrauterine device called Progestasert releases the hormone progesterone directly into the uterus for one year to prevent pregnancy. An advantage of these controlled-release contraceptives over contraceptive pills is convenience; their effectiveness does not depend on remembering to take a daily pill.

The Mechanical Pump

Although the advantages of a steady rate of drug release are evident, some drugs are more effective given in intervals. Infusion pumps can be programmed to deliver drugs at very precise dosages and delivery rates. These pumps may have a feedback device that controls drug delivery according to need.

"I think we're going to see more complex dosing patterns that are going to be more difficult to regulate orally," says Amidon. "With further development of electronics and miniaturization of pumps and sensors, we'll be able to monitor various vital signs, and that will lead to feedback systems." Such a feedback system could monitor blood glucose levels and deliver insulin when needed.

Amidon explains that the size of the pump depends on the amount of drug and the intended length of treatment. Some pumps are portable, some wearable. For miniaturized, implantable pumps, methods will have to be devised to refill the device externally, perhaps once a month or once a year, through a catheter.

"I would say that 50 years from now we're going to have implantable pumps with multiple drugs that we can externally program once a month and, rather than going to the doctor for checkups, we will plug ourselves into a telephone monitoring device," Amidon predicts. "To solve problems like drug tolerance, we're going to have to develop drug delivery programs that are not constant, but programmed with time or circadian doses. We're going to see more complicated therapy in order to be able to reduce the amount of drug exposure and increase its efficacy."

If Amidon's vision is to become reality, several technological roadblocks will have to be solved first. Donald Marlowe, director of FDA's division of mechanics and material science, points out just one, as an example. Before feedback technology can be applied in humans, problems with the pump's sensor mechanism must be overcome, Marlowe says. "For example," he explains, "contact with body proteins causes reduced sensitivity of the sensors, compromising [feedback] reliability."

One implanted pump, approved by FDA in 1982, allows chronic infusion of the liver cancer drug FUDR directly into the artery leading to that organ, thereby delivering a high concentration of the drug to the target organ.

William Ensminger, M.D., Ph.D., Professor of Internal Medicine and Pharmacy at the University of Michigan Medical School in Ann Arbor, says that people live and function with implanted pumps quite well. One of his patients had a pump for eight years, which was refilled every couple of weeks. "We've had other people who have had them in for four years and a few people who have had them taken out when the liver tumor was eradicated."

Last July, FDA approved a concentrated form of morphine specially developed for microinfusion pumps that can be implanted under the skin of the abdomen or worn outside the body. Given this way, the drug can provide more constant relief to people in severe pain, such as terminal cancer patients. Programmed with dosing information before it is filled with the concentrated morphine, the pump constantly delivers fractional doses of the drug. The dose can be changed by beaming information through skin and tissues to the implanted pump.

Concentrated morphine can have severe side effects, such as seizures and respiratory depression if the starting dose is misjudged. Therefore, patients must be monitored in a fully equipped and staffed facility for at least 24 hours after the initial "test" dose. Patients may then go home and return periodically — sometimes as seldom as once a month — for a physician to refill the reservoir in the pump.

It's clear that we're witnessing an evolution — or revolution — in drug delivery, with many innovations in administering drugs to improve safety and effectiveness. The process continues, using techniques as varied as advanced electronics and genetic engineering.

About the Author

www.fda.gov
FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.