Adhesives Magazine

Adhesives In Transdermal Drug Delivery Systems

November 1, 2005
Many transdermal drug delivery systems require the use of adhesives, and current TDD technology advances suggest a bright future for this segment of the medical market.

The ORTHO EVRA birth control patch. Photo courtesy of Ortho-McNeil Pharmaceutical.
As traditional applications for pressure-sensitive adhesives begin to mature, manufacturers are beginning to explore niche markets to enter and grow their business. In some cases, niche applications are high-tech and require development of new adhesives. These adhesives command a greater price and can result in large streams of revenue for adhesive manufacturers. The growth from such applications is further compounded if the products they are used in exhibit a high growth rate. One such area is transdermal drug delivery. Many, but not all, transdermal drug delivery (TDD) systems require the use of adhesives, and current TDD technology advances suggest a bright future for this segment of the medical market.

Product Roots

Transdermal drug delivery comes in several forms. Among the most popular are creams and gels, and adhesive patches. Adhesive patches entered the U.S. market for TDD in the late 1970s. They were approved by the FDA in 1979 and originally used for the treatment of motion sickness. You can still identify seasickness-prone passengers on cruise liners by the small adhesive patch worn behind their ear.

Two years after the introduction of motion-sickness patches, a nitroglycerin patch to treat angina was approved. Today, TDD systems have reached the limits expected by drug manufacturers 20 years ago. Because of the lipophilic nature of skin, only certain types of drugs are suitable for transdermal delivery.

The skin's function is to keep blood and other bodily elements within, all the while protecting these inner elements from outside pathogens and irritants. The outer layer of the skin, known as the stratum corneum, has been compared to brick and mortar. Skin cells are connected with lipid bilayers that repel water; in the past, this excluded water-soluble drugs from use in the TDD market. Because of the barriers imposed by the functions of human skin, it was once thought that only lipophilic drugs of small molecular mass could pass through the skin via these lipid bilayers.



Advantages of TDD

TDD systems bring with them many benefits that have contributed to their success in the marketplace both with healthcare providers and patients. Among these benefits are reduced gastro-intestinal incompatibility, steady drug levels, self-administration, non-invasive procedure and ability to remove the drug source.

Gastrointestinal incompatibility has varying degrees of severity. Some medications may be more likely to cause a patient to have an upset stomach. This is often countered by instructing the patient to take the medication on a full stomach. On the more severe end, the drug is not able to enter the patient's blood stream via the stomach. These types of drugs are not available in oral form because of the body's inability to process them. TDD systems offer a method of depositing drugs more directly into a patient's bloodstream and delivering some drugs that the digestive system cannot process.

Steady drug levels often contribute to the effectiveness of a prescribed drug regimen. Maintaining proper drug levels requires multiple doses to be synchronized to carefully planned schedules. Oral or injection drug administration causes the body to experience sudden bursts of drug levels that taper down as the drug passes through a patient's body. TDD systems allow longer periods of drug administration, and therefore minimize the peaks and valleys otherwise seen in a patient's drug levels. Before TDD systems were available, the most effective method of maintaining steady drug levels required intravenous drips administered by a healthcare professional.

A patient's ability to take drugs in a way that maintains steady drug levels in the body has opened up the option of self-administration. Because TDD systems allow a patient to maintain drug levels and bypass needles, several roadblocks to self-administration have been removed. Now patients who may not be educated in self-administering injections are able to take their medication without the assistance of doctors or nurses.

Because TDD systems have in some instances offered an alternative to syringes, they have also increased patient compliance. Many patients experience anxiety when faced with a shot of medicine. The non-invasive method of drug delivery that TDD systems offer allows patients to take their prescribed medications without the anxiety caused by needles.

Another benefit of TDD systems is the ability to remove the drug source. In some instances, time-release drugs taken orally or through injections cause allergic or otherwise unwanted reactions in patients. In these instances, there is no recourse but to wait out the ill effects of the drug. With adhesive patches, a patient has the ability to stop drug administration anytime an allergic reaction should occur.

There are two main drawbacks to this method of drug administration. As previously discussed, there are limitations to which drugs can be administered through the skin. The second shortcoming of the TDD systems is skin irritation. Patients' skin can sometimes have adverse reactions to the drug, the adhesive, or some other component of the TDD system. In spite of the possibility of skin irritation, TDD systems continue to be a common method of drug delivery because the benefits outweigh the drawbacks. Some patients who experience skin irritation can also minimize this effect by applying the patch to varying locations of the body so the same piece of skin is not in constant contact with the TDD system.

State of the Market

At the turn of the century, transdermal patches on the market included nicotine patches for smoking cessation, estradiol patches for treating symptoms of menopause, and nitroglycerin patches for angina, a type of chest pain that occurs when there is limited blood flow to the heart. Other drugs available in TDD systems included testosterone, clonidine, fentanyl, and the first "patch" drug, scopolamine. In 2004, one of the new patches approved by the FDA was norelgestromin/ethinyl estradiol, more frequently known as Ortho Evra. TDD systems have been projected to see a 12% growth rate in the U.S. Compared to the documented North American adhesives and sealants market growth of 3.9%, TDD systems are a lucrative niche market for adhesives manufacturers.

In addition to delivering prescription drugs, transdermal patches can be used to deliver over-the-counter (OTC) drugs and herbs to the body. These include Neoskin facial masks, Dr. Scholl's Clear Away Wart Removal patches, Neutrogena On-The-Spot Acne patches and Curad Scar Therapy patches. There are also herbal and weight-loss patches readily available on the Internet.

With many prescription and OTC products already available, there is a steady demand for bioadhesives. Currently there are three prevalent types of pressure-sensitive bioadhesives in use in the U.S. TDD system market: polyacrylate copolymers (acrylics), polysiloxanes (silicones) and polyisobutylenes (PIBs). Each of these types of adhesive can be modified according to the drug being administered, the length of application time desired and dosage strength.

A Closer Look

PIBs are elastomeric polymers commonly used in pressure sensitive adhesives (PSAs). Their molecular structure provides chemical stability and high resistance to weathering and aging. PIBs can be used as both primary base polymers and tackifiers in the PSAs used in TDD systems. As primary-base polymers, PIBs have weak adhesion to many surfaces and will often need to have tackifiers added to the adhesive formulation. Added tackifiers can be PIBs of lower molecular density.

Many adhesive and raw material manufacturers do not formulate PIBs to be used in TDD systems. Patch makers therefore must often create their own PIB PSAs for TDD use. They achieve this by either combining both low- and high-molecular-weight PIBs, or by adding other tackifiers such as rosin ester resins to a high-molecular-weight PIB. Two adhesive companies that do supply the TDD system market with ready-to-use PSAs are Adhesives Research Inc. and MACtac.

With use dating back to the 1950s, silicones have the longest and most documented history of PSA use in the healthcare field, therefore it is a natural choice for PSAs in TDD systems. Silicone PSAs in TDD systems are based on two key components, a silicone polymer and a silicate resin, which are dissolved together in a solvent, forming a network of crosslinked polymer chains. Silicone PSAs are therefore single-component systems, unlike PIBs, which feature polymers and tackifiers physically blended together. Dow is the primary supplier of silicone PSAs to the pharmaceutical market.

Though acrylates have been recognized for their adhesive properties since the 1920s, they were not used in PSAs until the 1950s, and in the medical field even later. They have proven themselves to be favorable materials for TDD system PSAs because of their biocompatibility, excellent skin adhesion and their compatibility with a wide range of drugs and permeability enhancers. Acrylates are also resistant to oxidation and translate more easily into ready-to-use adhesives than PIBs and silicones. Acrylate PSAs are comprised largely of primary and modifying monomers, the primary monomers contributing to the flexibility and tack to the adhesive.

Adhesive manufacturers may also crosslink acrylic monomers to prevent the adhesive from oozing or seeping out from under the TDD system during storage or wear. Crosslinking also helps the adhesive maintain tack, adhesion and cohesive properties even after the drug and any permeation enhancers have been loaded into the TDD system. Major manufacturers of pharmaceutical grade acrylic PSAs include the National Starch and Chemical Company and Adhesives Research, Inc.

TDD System Structures

Currently, there are two main types of TDD system structures: drug-in-adhesive (DIA) and reservoir. These two types of TDD systems also have their own variations, creating multiple potential TDD system structures.

DIA systems are the easiest to manufacture because all of their components are combined. They are, however, the most complicated for adhesive manufacturers because the addition of the drug and possibly chemical-permeation enhancers is likely to affect the potency of the adhesive, and vice versa.

DIA systems are available in monolithic or multilaminate structures. Monolithic TDD system structures contain only one layer of drug-adhesive solution between the patch backing and the patch lining. Multilaminate structures contain both a drug-adhesive layer and an adhesive-only layer. A membrane that controls the release rate of the drug separates these two layers.

Reservoir systems keep the drug and adhesive separated by one of two methods. In the basic liquid reservoir system, a membrane separates the drug/permeation enhancer combination from the adhesive. The membrane usually acts as a method of controlling the drug flow. In liquid reservoir systems, the drug must pass through the adhesive layer, so precautions must be taken to ensure that the drug and adhesive do not react with each other.

A variation of the liquid reservoir system is the polymer matrix system. In this design, the adhesive surrounds the periphery of the patch and therefore does not come into contact with the drug. With these types of patches, only the adhesives' adhesive properties and skin compatibility are a concern.

The Future of TDD Systems

One of the most exciting projects currently underway in the area of TDD systems is microporation, a method of altering the skin via micro-needles, which allows a greater variety of drugs to enter the body through the skin. The micro-needles are located on the surface of the patch that comes in contact with the skin. They are so small, though, that they do not reach nerve endings, and thus do not cause pain for the user. The needles are reported to feel similar to sandpaper, but they facilitate the entry of drugs into the body without the use of injections. Currently, 3M and Alza provide microporation designs to the U.S. market.

Ultimately, there is enough growth in this market, as well as research and development on the part of drug manufacturers, to warrant continued research and development on the part of adhesive manufacturers.

Frost & Sullivan, a global growth consulting company, has been partnering with clients to support the development of innovative strategies for more than 40 years. The company's industry expertise integrates growth consulting, growth partnership services, and corporate management training to identify and develop opportunities. Frost & Sullivan serves an extensive clientele that includes Global 1,000 companies, emerging companies and the investment community by providing comprehensive industry coverage that reflects a unique global perspective and combines ongoing analysis of markets, technologies, econometrics, and demographics. For more information, visit www.frost.com or e-mail Trisha Bradley at trisha.bradley@frost.com.