After modest beginnings, transdermal patches are now taking advantage of nanotechnology and other novel techniques to improve drug delivery.
Thomas Morrow, MD
The simply designed transdermal patch has undergone a dramatic transformation over the past decade. In its strictest sense, all transdermal systems attempt to create a balance between a number of key factors including size of patch or coverage area, concentration of the drug, duration of therapeutic drug level, and use of an enhancer.
The advantages of transdermal delivery are obvious — even delivery of a therapeutic level of drug is painless, the patient does not need to inject himself, there are no bulky delivery devices to manage or dangerous needles to dispose of, and there are few or no gastrointestinal effects from the drug itself. Peak plasma levels of the drug are reduced, leading to decreased side effects. In addition, transdermal delivery is useful for those drugs that have a high first pass effect through the liver, have poor oral uptake, need frequent administration, or that interact with stomach acid. The first pass effect results in the destruction of a significant amount of the drug. Drugs absorbed through the skin, however, enter the general circulation directly — avoiding the liver, with less total drug absorption occurring.
These benefits have not been lost on clinicians. As a result, the patch business is growing at a healthy annual revenue rate of 12 percent with a current worldwide market of about $3 billion, with the U.S. making up 56 percent of the market. Unless you are in the transdermal patch business, you will not be aware of the advances under development.
The first transdermal systems were simply pieces of plastic dipped into a drug that was dissolved in alcohol. The plastic had an adhesive around the edges. Although revolutionary in their day, they created a significant number of skin reactions, more often than not fell off, and had a number of other limitations. These problems gave a lasting negative impression of the whole sector.
The next generation — still in use today — uses a "drug in the adhesive" model. This is a significant improvement, as the skin irritation is diminished and in many cases eliminated. The adhesive serves two functions: It is the glue that keeps the patch attached to the skin, and it acts as the suspension that holds the drug. But it creates a major challenge: The concentration of the drug within the adhesive directly affects the "stickiness" of the adhesive. Thus, if there is a need for large quantities of drug, either the size of the patch must be increased or the patch needs to be reapplied more frequently. Basically, the patch would not stick, as it would be primarily made up of the drug.
Next generation patches
Third generation patches have solved some of these issues by using an acrylic reservoir that holds the drug. Silicon adhesive is added to create a semisolid suspension of microscopic, concentrated drug cells.
Now, fourth generation transdermal systems involve the addition of an enhancer — a mechanism to increase the permeability of the skin — and in some of the technology, a mechanism to time the delivery and create bolus dosing. There are a number of enhancers to drug delivery. These include iontophoresis, ultrasound, chemicals including gels, microneedles, sonophoresis, lasers, and electroporatic methods.
Some delivery systems avoid the patch altogether. These use a gel that is rubbed into the skin. This method, mastered by Antares Pharma, tailors the kinetic profile of the drug to the gel. CombiGel consists of a hydro alcoholic gel containing a combination of enhancers. This gel is totally invisible and is designed to be rapidly absorbed through the skin. The first transdermal testosterone gel for men, released in 2000, used this approach. The gel was fraught with challenges, including cost, irritancy, delivery efficacy, cosmetic issues, smell, and color. Many other drugs will soon be delivered using this method.
Nanotechnology gaining hold
Another enhancer that is gaining advancement is microneedles. Why should a needle that is a few inches long be used to deliver a drug that is only a few atoms large? This technology combines the advantage of a needle and the transdermal patch. The devices are dime-sized pieces of polymer with hundreds of hollow microneedles between 100 and 1,000 micrometers long. These small needles penetrate the top layers of skin and allow the drug to pass through with ease. This size of needle does not penetrate deeply enough to stimulate the nerves and hence ... no pain!
This technology can be combined with an electronically controlled micropump that delivers the drug at specific times or upon demand. Once approved by the FDA, these devices would allow the patient or physician to control the time and dose of the drug being delivered. These devices have the potential to place drugs precisely into the area where special immune cells reside, making these drugs capable of modulating the immune system, with relative ease.
Alza is using a slightly different variation on the use of needles. The company has developed the patented Macroflux transdermal technology that uses microprojections to create superficial pathways through the dead skin barrier. The tips of the projections contain active drug — a quick bolus. Interestingly, the Alza Web site displays a study where human growth hormone, a rather large protein, was able to reach therapeutic levels hours after the application of the patch.
Pain relief routinely benefits from transdermal patch technology. Most of the readers are aware of the Duragesic patch. There are several others now on the market. One is Lidoderm, a lidocaine 5 percent patch, which is used for post herpetic neuralgia. Other exciting advancements in pain control include the E-Trans fentanyl HCl patch. This credit card-size patch is an active delivery device that has a self-contained battery that delivers pulses of fentanyl HCl, a strong narcotic. This mimics the use of intravenous self-controlled analgesic systems that are very expensive, cumbersome, and require considerable nursing care. A study just published in the Journal of the American Medical Association demonstrated that this patch does the job about as well as conventional intravenous devices. Alza is hoping for approval in 2004.
Finally, SonoPrep offers a topical anesthetic system with an ultrasound enhancer. This system uses a small ultrasound generator to transport 4 percent lidocaine HCl into the skin in an area just big enough to place a catheter into a vein or artery. It anesthetizes the area in less than a minute and can allow for prolonged application for several hours.
These advances will revolutionize the delivery of many drugs, enhancing the application of nanotechnology and giving new options to patients needing biologic drugs. Soon, polypeptides and even proteins will not need to be injected or infused.
These advances will soon fuel Tomorrow's Medicine!
Thomas Morrow, MD, is president of the National Association of Managed Care Physicians and vice president and medical director of Matria Health Care. He has 19 years of managed care experience at the payer or health plan level.