Noven’s DOT Matrix^Ž Technology

Juan Mantelle, a chemical engineer, has been with Noven since 1990 and serves as Vice President & Chief Technical Officer. Beginning in the 1980s with the first drug-in-adhesive nitroglycerin patch, through the development of Vivelle^Ž, Vivelle-Dot^®, CombiPatch^Ž, Daytrana^® and DOT Matrix^Ž patch technology itself, Juan has seen and done it all in transdermal drug delivery – usually before anyone else. There is no better person to explain the advantages of DOT Matrix^Ž over competitive patch technologies.

The circular image is a digital photograph of the adhesive layer of a DOT Matrix^Žpatch taken with a scanning electron microscope.

Small, adherent and non-irritating – those have been the three goals in patch development for as long as I can remember. Any approved patch will deliver a therapeutic dose, but what will differentiate your patch among patients and physicians? That is where small size, proper adhesion and low irritation come in. DOT Matrix^Ž, a third generation design, is the first technology to achieve all three goals.

Generation One: Reservoir
First generation transdermals, developed in the 1980s, fall short of these goals. They use a reservoir system filled with drug typically solubilized in alcohol. Skin irritation from the alcohol is the biggest problem, and they fail to meet any of the three goals particularly well.

In fairness to reservoir patches, they were designed at a time when the goal was simply to get the drug through the skin. The market was not developed enough to require manufacturers to refine the design. In hindsight, it is unfortunate that they were not more patient-friendly. Lasting impressions were formed in those early days, and the patch market is still working to overcome them.

Generation Two: Drug-in-Adhesive
Most second generation patches do much better than reservoir patches, but they still make compromises. Called "drug-in-adhesive" patches, the drug is usually solubilized in an acrylic adhesive. Our original Vivelle estrogen patch uses this generation technology.

Fig. 1 – Noven's Vivelle-Dot^® patch is much smaller, holds far less drug, and depletes a greater percentage of drug held, giving it the highest delivery efficiency on the market.

The acrylic serves two roles – it holds the drug, and it holds the patch on the skin. That creates a dilemma for a patch developer. A small patch needs high drug concentrations, but loading the acrylic with drug compromises its ability to stick. So drug concentrations are kept relatively low, which dictates a greater patch area. The only choice to keep it small is to add a skin permeation enhancer, but then irritation issues can arise. So a patch developer working with ordinary drug-in-adhesive technology can generally achieve any two of the three goals, but not all three.

The New Standard: DOT Matrix^®
It took several years and a wide range of patch formulations for Noven to develop the third generation technology, called DOT Matrix^Ž. With it, we can consistently meet all three goals without compromise.

In a DOT Matrix^® patch, the acrylic serves only one purpose – to hold a lot of drug. We load it with such high drug concentrations that it would never stick on its own. We then add a silicone adhesive whose only job is to make the patch stick.

The silicone essentially repels the drug/acrylic blend much like oil in water. We end up with a semi-solid suspension of microscopic, concentrated drug cells evenly dispersed through an uncompromised silicone adhesive. The high diffusion gradient between each drug cell and the skin causes the drug to penetrate the skin with extremely high efficiency. The uncompromised silicone keeps the patch in place through exercise, swimming – you name it. And the precise ratios of drug, acrylic and silicone permit us to fine tune the delivery profile.

As a result of our technology, DOT Matrix^Ž patches are the most efficient transdermal delivery systems in the category. For example, Vivelle-Dot^® is about one-third to one-quarter the size of competing estrogen patches delivering the same daily dose (see Fig. 1). It carries only a fraction of the drug contained in the other patches, and has a higher depletion rate. So with less drug in a smaller patch, we deliver the same amount of drug into the system.

Of course, the high-efficiency of DOT Matrix^® technology permits us to do more than just shrink patches. It lets us make patch versions of drugs that otherwise will not fit into an acceptable patch size. For example, a methylphenidate patch using older technology would be bigger than a compact disc; DOT Matrix^® makes the patch size commercially viable.

Also, we can squeeze therapeutic doses of two drugs into a patch no bigger than an ordinary one-drug patch. Our combination estrogen/progestin patch was the first patch of its kind on the U.S. market. So, as we have decreased patch size, Noven has increased the universe of molecules (and combinations of molecules) that can be delivered transdermally, and that gives us access to large markets that others cannot even consider.

–	Juan Mantelle