Advances in Transdermal Technologies - Pharmaceutical Technology

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Advances in Transdermal Technologies
Transdermal delivery takes up once-forbidden compounds, reviving markets and creating formulation opportunities.

Pharmaceutical Technology

Gaining approval
"If the drug requires a long time to permeate the skin, then the potential advantages of using an active system is to get a rapid onset of action," says Rashmi Upasani, research scientist, at Cirrus Pharmaceuticals (RTP, NC). Other advantages include the ability to achieve pulsatile or patient-controlled delivery and the ability to reduce inter-individual variability in drug delivery. (Passive permeation depends on the thickness of the skin and type, but iontophoresis depends on how much electric potential is used across the skin, so the variability is comparatively less than with passive patches).

Figure 3: Schematic of iontophoresis delivery. (FIGURE ADAPTED FROM Y. WANG ET AL, EUR. J. PHARM. SCI., 2005)
The structure of an electrical iontophoresis TDDS includes a DC power source and an adhesive electrode with a reservoir on the dermal side. An electric current is passed through the drug solution, which drives the drug into the skin. Iontophoresis systems take advantage of the fact that like charges repel. Therefore, a negatively-charged drug or compound is delivered using the cathode, and positively-charged drugs are delivered using the anode. It is also believed that drug delivery is enhanced not only by these electro-repulsive forces but also by the opening of transdermal pathways such as pores and sweat glands by the application of the current. Battery-powered iontophoresis TDDS (see Figure 3) require the drug to be placed on only one side and others allow placement on either the positive or negative side. In anode iontophoresis, the drug has a positive charge. When placed near the anode, electro-repulsion pushes it through the skin.

The history of using electricity to transdermally deliver drugs dates back to the late 1800s, with the first demonstration of the delivery of strichnine to rabbits. The implementation as a drug delivery system was impractical, however, until the past 20 years. Drug delivery by electrical stimulation now has a wide application in the physical therapy market to treat injuries such as tendonitis as well as localized inflammation. One such drug is dexamethasone. "The more you get away from systemic delivery of these drugs, the better off you're going to be," says Jim Pomonis, director of medical affairs, at Empi (St. Paul, MN).

Iontophoretic delivery systems present more complex challenges than passive systems. For iontophoresis systems in which the drug is dissolved in water before it is applied to the reservoir on the electrode, there is an added concern. "Whereas for passive transdermal systems you worry about adhesion, skin irritation, and allergic reactions to the gel, we have the additional issues that as you pass current through water you're going to get hydrolysis, which can change the pH level," says Pomonis. Empi developed buffered electrode systems to prevent the change in pH. Hydrolysis is still allowed to occur, but it is buffered. Iomed (Salt Lake City, UT) took a different approach to this problem and developed a silver-silver-chloride electrode that prevents hydrolysis and prevents the pH from changing.

Defining the dose
Formulation. The amount of drug that can be loaded into a device and the amount that can actually cross the skin can be two different values. The volume that can be loaded into the device depends on the device and the technology. The amount that traverses the skin depends on the formulation and the drug.

"We try to select molecules that are already charged by their nature," says Upasani. "It is possible to transport neutral molecules with electro-osmosis and iontophoresis. If the molecule is charged, however, there are two forces acting on the molecule, electrorepulsion and electro-osmosis, which helps the drug pass into the skin."


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