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Painless Drug DeliveryContents
Transdermal patches—medicated adhesive pads placed on the skin that release drugs gradually for up to a week—have been available in the U.S. for more than 20 years. The first transdermal patch, approved by the U.S. Food and Drug Administration in 1979, delivered scopolamine to treat motion sickness. Since then, more than 35 transdermal patch products have been approved. Examples include the nicotine patch that helps people quit smoking, the lidocaine patch for relieving pain, and a patch containing hormone derivatives for preventing pregnancy. Transdermal patches have several advantages compared with other methods of drug delivery: they are painless, the drugs are not degraded in the gastrointestinal tract, and they provide a constant dosage without the need for patients to remember to take their medications. In addition, delivering drugs by way of patches can reduce the side effects of some drugs. For example, estrogen patches, unlike estrogen pills, do not cause adverse effects on the liver when used to treat menopausal symptoms. However, due to permeability constraints of the outer skin layer, the number of drugs that can be administered via transdermal patches is limited. Microneedle Arrays Expand Transdermal ApplicationsTo expand the number of compounds that can be delivered via the skin, researchers are developing novel transdermal technologies, including microneedle arrays that consist of tiny needles with diameters smaller than a strand of hair. The microneedles create micrometer-scale holes in the outer skin layer, thereby allowing passage of large molecules and other compounds that ordinarily could not traverse the skin. The microneedles are painless because they are too small to touch the nerves located deeper in the skin.Although microneedles were first proposed in the 1970s, the technology needed to make microneedles did not become widely available until the 1990s. Using techniques developed in the microelectronics industry, NIH-supported researchers devised methods for inexpensively mass-producing microneedles from materials such as silicon, metals, and glass. The researchers also showed that microneedles can be made from polymers that will harmlessly degrade in the body, thereby preventing problems should a microneedle break off in the skin. The investigators further demonstrated that microneedles can be constructed to be solid or hollow, and both types can be made with different geometries to allow the administration of different-sized compounds, including drugs, proteins, and vaccines. One drug-delivery technique uses solid microneedles to create micropores in the skin, and then the drug is applied over this area. NIH-funded scientists recently used this technique to administer insulin to diabetic rats. An array of solid metal microneedles was pressed into the skin, and then a glass chamber filled with insulin solution was placed over the microneedle array. Over a 4 hour time period, blood glucose levels steadily dropped by as much as 80 percent. Another drug-delivery method involves coating solid microneedles with a drug, which is then released from the needles when they are embedded in the skin. Still another method employs hollow microneedles, which allow drug solutions to be infused through the needles using a microprocessor-controlled pump. NIH-supported scientists recently inserted hollow glass microneedles into the skin of diabetic rats to deliver insulin for 30 minutes. Over a 5 hour period after the insulin was administered, the blood glucose level dropped by as much as 70 percent. Because people would require minimal training to apply microneedles, these devices may prove useful for immunization programs in developing countries or for mass vaccination or antidote administration in bioterrorism incidents. Increasing Skin Permeability With Low-Frequency UltrasoundAnother transdermal technology being developed is low-frequency sonophoresis (LFS), which uses low-frequency ultrasound to create pores in the skin that stay open for several hours. In studies with animals, LFS has delivered insulin to diabetic rabbits and the anticoagulant heparin to rats. Recently, scientists used LFS to administer local anesthetics through the skin to human volunteers. To improve the design of LFS systems, NIH-funded researchers have been studying the mechanisms by which LFS increases skin permeability. Scientists found that an ultrasound frequency of 20 kilohertz induces the formation of low-pressure air bubbles on the skin surface. These bubbles grow rapidly and then collapse violently, producing microjets and shock waves that create temporary micropores in the skin. With this understanding of the mechanism of pore formation, investigators can design LFS systems to focus the ultrasound waves so that they maximize bubble formation on the skin surface.Researchers have also experimented with viscous substances known as porous resins to increase skin permeability during sonophoresis. When dissolved in a solution of water and alcohol, these resins release air bubbles that trigger the formation of larger bubbles when LFS is applied. Investigators discovered that adding a porous resin to the solution surrounding pig skin increased permeability to the drug mannitol during sonophoresis. Mannitol promotes urine excretion, which is useful for treating brain swelling and other conditions that involve excess fluid. The results of this study suggest that adding a porous resin to the fluid that bathes the skin might enhance drug administration by sonophoresis. Transporting Drugs Using ElectroporationStill another transdermal technology under development is electroporation, the application of short, high-voltage electrical pulses to create temporary micropores in the skin. Electroporation has been used to transport several drugs through the skin in humans, including insulin, heparin, and the local anesthetic lidocaine. Studies also suggest that electroporation could be used to deliver compounds that would ameliorate skin aging, such as particular genes or Vitamin C. NIH-supported scientists have found that transdermal drug delivery via electroporation can be enhanced through the use of mild heat, alkaline solutions, and sodium dodecyl sulfate (a detergent used in various household products, including toothpaste, shampoo, and cosmetics).Because the drug reservoir remains outside the body, transdermal drug delivery devices provide the opportunity to easily adjust the quantity and delivery rate of medications. Transdermal systems could be controlled by a miniature computer, which would allow for accurate dosing as needed by the patient. These systems might also include sensors that monitor blood levels of compounds, such as glucose in diabetics, and then adjust the release of a drug, such as insulin. These and other developments in transdermal drug delivery technologies hold promise for improving patient compliance by making drug administration effortless and painless. References
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