Iontophoresis

Introduction
Iontophoresis (phoresis (transfer) of ions (ions)) also called Electromotive Drug Administration is a technique which uses an electric current to deliver a medicine or other chemical through the skin (basically an injection without needle). This is not a new technique, there is recorded Iontophoresis activity way back to the 1700's, however most authorities agree that it was not until the work of Le Duc in the early 1900's that the technique really gained momentum, since that time has been sporadic used. Formally can be defined thus a non-invasive method of propelling high concentrations of a charged substance transdermally, (normally a medication or bioactive agent), by using a small electrical charge applied to an iontophoretic chamber containing a same charged active agent and vehicle.

Principle of Iontophoresis
This technique is based on the principle that application of electric current provides external energy to drug ions for passage across the skin, thereby increasing drug permeability through the membrane. A typical iontophoretic drug delivery system consists of an anode, a cathode and two reservoirs, one comprising drug ions and the other containing biocompatible salt such as sodium chloride. For delivering positively charged and negatively charged ions, two iontophoretic approaches have been developed, namely anodal and cathodal iontophoresis. In anodal iontophoresis, cationic drug ions are placed under the anode at the desired site of application and the cathode (receiving electrode) is placed at a different site on the skin, whereas in cathodal iontophoresis the electrode orientation is reversed. The movement of ions in iontophoresis follows the basic rule of electricity, i.e. like charges repel each other. In anodal iontophoresis, on application of current, all drug cations (and other positively charged ions) placed at the anode move away from the anode (positive electrode) and pass into the skin, and at the same time anions from the body are repelled from the cathode and migrate into anodal reservoir. The efficiency of transdermal iontophoresis can be calculated from the slope of a plot of the iontophoretic drug delivery versus current applied. The amount of permeant delivered across the skin is directly proportional to the quantity of charge passed through the membrane, which in turn depends on the amount and duration of the applied current and the skin surface area in contact with the electrode compartment.

Factors affecting Iontophoresis results
Many factors have been shown to affect the results of iontophoresis. These include the physicochemical properties of the compound (molecular size, charge, concentration), drug formulation (types of vehicle, buffer, pH, viscosity, presence of other ions), equipment used (available current range, constant vs. pulsed current, type of electrode), biological variations (skin site, regional blood flow, age, sex), skin temperature and duration of iontophoresis. The following factors have to be considered:

Influence of pH The pH is of importance for the iontophoretic delivery of drugs. When the pH decreases, the concentration of hydrogen ion increases and a vascular reaction (vasodilatation) is initiated because of C-fiber activation, thus it is important to keep the pH as close as possible to 7 at least when working with vasodilators. At pH 5.5 and below, there is an increasing risk for vascular reaction due to the high concentration of hydrogen ions rather than the compound used. Since hydronium ions are small they penetrate the skin more easily than larger drug ions.

Current strength With increasing current, the risk of non specific vascular reactions (vasodilatation) increases. At a current of 0.4-0.5 mA/cm2, such a vascular reaction is initiated after a few seconds of iontophoresis with deionised or tap water. This latter effect is probably due to current density being high enough within a small area to stimulate the sensory nerve endings, causing reactions such as the release of substance P from C-fiber terminals.

Ionic competition When using iontophoresis, it is important to know that pH adjustment is performed by adding buffering agents. The use of buffering agents as co-ions, which are usually smaller and more mobile than the ion to be delivered results in a reduction of the number of drug ions to be delivered through the tissue barrier by the applied current. The use of a buffer system should be avoided in iontophoresis, but if this is not possible, alternative buffers, consisting of ions with low mobility or conductivity are preferred.

Drug concentration Depending on the drug used, the steady-state flux (ion movement) has been shown to increase with increasing concentration of the solute in the donor compartment, i.e. in the delivery electrode. A limiting factor to be considered is the strength of the current used. At higher drug concentration, the transport may become independent of concentration, probably because of the saturation of the boundary layer relative to the donor bulk solution.

Molecular size When the molecular size increases, the permeability coefficient decreases. However, there are certain solutes with a relatively high molecular size (e.g. insulin, vasopressin and several growth hormones), which have also been to penetrate the skin barrier into the systemic circulation.

Connective or electro-osmotic transport When performing iontophoresis with a specific current, the flow of ions across the membrane induces a flow of solvent called electro-osmosis. Compared to the ion transport, the electro-osmotic contribution is small. The penetration of uncharged substances (e.g. bovine serum albumin) has been shown to be facilitated by the volume flow effect induced by an applied potential difference across the membrane. Iontophoresis has also been observed to enhance the penetration of a number of dipolar ions (zwitter ionic substances like phenylalanine). Most of these substances have been shown to be delivered in significantly higher amounts by anodic delivery than by cathodic delivery. In general, iontophoresis is more effective for charged compounds, especially monovalent ions.

Current-continuous vs. pulsed mode Continuous DC current may result in skin polarization, which can reduce the efficiency of iontophoretic delivery in proportion to the length of current application. This polarization can be over come by using pulsed DC, a direct current that is delivered periodically. During the ‘off time” the skin becomes depolarization and returns to its initial unpolarised status. Enhanced iontophoretic transport has been reported for peptides and proteins by using pulsed Dc compared to convenient DC. Most of the drug ions used for diagnostic purposes in combination with iontophoresis and LDPM are small in size. As a result, the time needed for an effect is relatively short (5-20 s) compared to when iontophoresis is used for therapeutic purposes (20-40 min).

Physical factors Iontophoresis reduces intra and inter-subject variability in the delivery rate. This is an inherent disadvantage with the passive absorption technique. Experiments in vivo iontophoretic give support for clinical findings that there are small differences in the flux rate following transdermal iontophoresis between males and females, as well as between hairy and hairless skin. The status of the vascular bed is also important; for instance, a pre-constricted vascular bed decreases the flux through the skin while a dilated vascular bed increases the yield of the drug through the skin.

Optimising Iontophoretic Transport
Iontophoretic transport can be regulated by varying the applied current density and area of application. A current density that is too high maybe unpleasant for the patient. If possible avoid using current that result in more than 500 mA/cm2. At high current densities there is a significant risk for unspecific electrically mediated vasodilatation that is not drug related.

To prevent pH drifts during iontophoresis, the choice of electrodes is of importance. With a correct electrode material, decreased solubility and precipitation of the compound are avoided.

Before starting iontophoresis, we should clean carefully the skin area to be used. Cleaning will decrease the current and minimise the risk for local spots of high current density, which could result in C-fiber activation, vasodilatation and local burns.

Advantages of Iontophoresis
When compared with injections

Free from pain and invasion. Minimizes the needle-pricking accidents. Allows the drug delivery by skin contact itself. Can be used outside hospitals.

When compared to pills

Minimizes the on-set time. Adverse effects alleviation. Through this process, it is possible to delivery the drugs which dissolve and lose their potency and efficacy in the digestive organs.

When compared to patches (adhesives)

Shortens the on-set time. Drugs can be delivered quantitatively. Reduces the residual drug amount.

Contraindications for Iontophoresis
Contraindications for iontophoresis are important in patients with higher susceptibility to applied currents. Such patients include those carrying electrically-sensitive implants like cardiac pacemakers, those who are hypersensitive to the drug to be applied or those with broken or damaged skin surfaces.