|This article was published in FDA Consumer magazine several years ago. It is no longer being maintained and may contain information that is out of date. You may find more current information on this topic in more recent issues of FDA Consumer or elsewhere on the FDA Website, by checking the site index or home page, or by searching the site.|
Patches, Pumps and Timed Release: New Ways to Deliver Drugs by Marian Segal If, 25 years ago, someone tried to sell you an adhesive patch, telling you to stick it behind your ear and it would keep you from getting sick on the high seas, you could make a safe bet that you were being sold up the river by a modern-day snake oil salesman. Today, however, a similar patch can be legitimately prescribed by your doctor. Technological advances over the last 20 to 30 years have enabled scientists to develop new forms of delivering drugs to our bodies, including a transdermal patch containing the drug scopolamine to prevent motion sickness. Drug dosage forms are keeping pace with the high-tech times. Indeed, the ubiquitous tablet of 1990 may one day become obsolete, going the way of the spirits, powders and tinctures of a century ago. What might replace the tablet? How about pills that are pumps and implanted drug-filled devices with or without tiny computers to regulate the time and amount of drug dispensed? These and other unconventional dosage forms already exist, heralding advances in drug delivery that promise even safer and more effective treatments. One of the most active areas of research and development in drug delivery involves "controlled-release" products. Rather than develop new drug entities at great cost, some drug therapies already on the market can be improved simply by controlling the rate at which they enter the bloodstream. "Virtually all the delivery systems marketed are initially in what we would call 'immediate-release preparations'--things that disintegrate and dissolve in 5 or 10 minutes," says FDA visiting scientist Gordon Amidon, Ph.D. "For some drugs, dissolution may take longer because of drug or dosage form properties, but the controlled release is not designed in." Timing Is Everything "Drugs that are released rapidly produce a relatively rapid and high concentration in the body, followed by a sharp decline--a peak and valley effect," says Amidon. "We know that at too low a blood level the drug is not effective, at optimum level it's effective, and at too high a level undesirable effects are produced. The objective is to try to maintain the range in between." Controlled-release systems deliver a drug at a slower rate for a longer period. The dosage form contains more drug than a conventional tablet or injection, for example, but delivers the medication far more slowly--over a period of hours, days, or even years, rather than seconds or minutes. Depending on the mechanism, the delivery system may simply release the drug at a variable, but slower, rate, or release it at a constant rate over the period of release. Sometimes, by decreasing the variability of blood levels, it may reduce side effects. The Ways to Delay Milo Gibaldi, Ph.D., dean of the University of Washington's School of Pharmacy in Seattle, writes in Biopharmaceutics and Clinical Pharmacokinetics: "The early history of the prolonged-release oral dosage form is probably best forgotten. Products were developed empirically, often with little rationale, and ... problems were common. Today, the situation has improved; many of the available products are well-designed drug delivery systems and have a defined therapeutic goal. In some cases, the prolonged-release dosage form is the most important and most frequently used form of the drug." Prolonged-release preparations usually require less frequent dosing. Being able to take a pill once a day instead of four times or more, for example, can help improve patient compliance. That is, it's often easier and less bothersome for patients to remember to take fewer doses of medications. There are a number of ways of controlling the rate of delivery of oral medicines. One system uses the principle of osmosis to release the drug. The drug and an osmotic agent are surrounded by a semipermeable membrane pierced by one or more small, laser-drilled holes. As water from the digestive tract is drawn through the membrane, the osmotic layer expands, pushing the drug through the holes. In other systems, the drug simply diffuses through a polymer coating of the pill. The drug may be contained in a reservoir surrounded by a polymer film, or it may be uniformly distributed through the polymeric material. "Most of the polymers used in human pharmaceuticals are derivatives of natural products such as gelatin and cellulose, or the synthetic polymer silicone," says Amidon. "When designing a drug delivery system, you select the polymer best suited for that particular system based on the properties of the specific polymer." An erosion-controlled release system uses a polymer that is relatively water-soluble with the drug incorporated in it. As the polymer dissolves, it releases the drug. The formulation of Contac's "tiny time pill" capsules is based on an erosion system. It consists of coated and uncoated granules that erode at various rates, thus releasing the drug at varying rates and providing relief for an extended period. Skin Patches Some drugs that have the right properties to penetrate the skin and are potent enough to be effective at low doses can be delivered transdermally (through the skin). The first transdermal patch was approved by FDA in 1979. It contained the drug scopolamine, used to treat motion sickness. Scopolamine can cause dry mouth, drowsiness, blurred vision and other eye problems, and sometimes more serious side effects, including dizziness and confusion, hallucinations, difficulty urinating, and rashes. Delivered through the skin at a slow rate in small amounts over three days, however, the drug can protect against motion sickness with fewer or less severe side effects. One patch design consists of four layers of thin, flexible membranes: an impermeable backing, a drug reservoir, a rate-controlling membrane, and an adhesive. When the patch is applied, the drug begins flowing through the skin into the bloodstream at a rate regulated by the membrane, pre-programmed to keep the drug at levels that provide effectiveness with acceptable adverse effects. Another transdermal preparation is a nitroglycerin patch for patients with angina pectoris (chest pain). Unlike nitroglycerin tablets placed under the tongue at the onset of an attack to relieve pain, the patch is applied once a day (usually to the chest) to help prevent angina attacks. As with scopolamine, a goal of delivering a steady concentration of nitroglycerin was to provide the lowest effective blood level of the drug while minimizing adverse effects, such as headaches in the case of nitroglycerin. 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. n Marian Segal is a member of FDA's public affairs staff.