a report by

Priya Batheja ,1 Diksha Kaushik ,1 Longsheng Hu2 and Bozena B Michniak-Kohn 1

1. Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey; 2. Johnson & Johnson Consumer Healthcare Companies

The skin is the largest organ in the body and, with its large surface area,

represents an attractive route for drug administration. Several

transdermal systems have been developed and marketed for the relief

of pain, contraception, hormone replacement, motion sickness,

hypertension and angina. Transdermal drug delivery systems provide

distinct benefits due to elimination of hepatic first-pass effects,

reduction in systemic side effects by decrease in initial dose size and

increased patient compliance. However, development of formulations

and systems for transdermal delivery has been hindered by poor tissue

permeability – predominantly in the outermost layer of the skin –

known as the stratum corneum (SC).

The SC consists of a well-organised layer of dead corneocytes intercalated

with lipids, which present a significant barrier to the diffusion of agents

into the body. In order to overcome this barrier and enhance permeation,

a number of chemical and physical enhancement techniques have been

developed either alone or in combination. Though chemical enhancers

increase delivery of agents by perturbing the SC barrier through

interaction with proteins or by fluidisation of the SC lipids, their extensive

use is limited by their potential skin irritation.1–3 Similarly, various physical

enhancement techniques such as iontophoresis,4 phonophoresis,5

electroporation6 and microneedles7 have also been examined.

Transdermal iontophoresis involves the use of a constant/pulsed current

to develop an electric potential gradient that forces the ionised drug into

the skin. Various transdermal iontophoretic devices have been

successfully developed and marketed, the latest being the LidoSite™

patch (Vyteris, Inc.)8 Transdermal iontophoresis has not only enabled the

successful delivery of small molecules such as fentanyl hydrochloride

(E-TRANS® patch, ALZA Corp.) for pain management,9 but also delivery

of peptides such as insulin, nafarelin and luteinising hormone-releasing

hormone (LHRH).11,12

Basic Principles of Transdermal 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.10 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.11 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.12 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 (see Figure 1). The efficiency of

transdermal iontophoresis can be calculated from the slope of a plot of

the iontophoretic drug delivery versus current applied.11 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.13

Theory of Drug Transport by Iontophoresis

Iontophoretic drug delivery occurs by a combination of:

• concentration gradient (diffusive/passive transport component) and

electrochemical potential gradient developed across the skin;

• increased skin permeability under applied electric current

(electromigration/electrorepulsion); and

• a current-induced water transport effect (electro-osmosis/convective

transport/iontohydrokinesis).12,14

It should be noted that iontophoretic drug transport is mainly through

electrorepulsion and electro-osmosis; the passive component plays an

insignificant role. Electrorepulsion refers to the drug transport across skin

due to either the repulsion of cations into the skin from the anode

(anodal iontophoresis) or the migration of anions into the skin from the

cathode (cathodal iontophoresis). On the other hand, electro-osmosis is a

phenomenon that occurs as a result of a net negative charge on the skin

at physiological pH (7.4) that subsequently leads to its cation

permselectivity. This results in induced solvent flow that facilitates cation

transport in anode-to-cathode direction, with inhibition of anion

transport enabling enhanced transdermal delivery of neutral and polar

solutes across the skin when an electric field is applied.14–16 It has been

reported in the literature that the iontophoretic delivery of small, highly

mobile ions such as sodium ions, which are efficient charge carriers, is

dominated by electrorepulsion. However, electro-osmosis is the primary

transport mechanism of larger and bulkier species, such as cationic

peptides of molecular weights in the order of 1,000 Daltons or more.10

Advantages and Limitations of Iontophoresis

Iontophoresis, like passive transdermal drug delivery, bypasses the first-

pass hepatic metabolism and gastrointestinal degradation. It maintains

controlled plasma levels of drugs, even those with short biological half-

lives, and also offers the benefit of delivering charged and high-

molecular-weight compounds, unlike passive transdermal delivery, which

Transdermal Iontophoresis

© T O U C H B R I E F I N G S 2 0 0 7

Transdermal Delivery

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47D R U G D E L I V E R Y 2 0 0 7

Transdermal Iontophoresis

is limited to small, non-polar and lipophilic solutes. Iontophoresis also

provides increased patient compliance due to less frequent dosing, ease

of terminating drug delivery at any stage of therapy and the capability of

tailoring drug therapy at pre-programmed rates according to individual

needs.12,17 The inter- and intra-subject variability is also reduced as the

rate of drug delivery is directly proportional to the applied current.

Though it offers numerous advantages, application of iontophoresis is

limited to drugs that can be formulated in the ionic form.18 Also, during

iontophoretic transport across the skin, the drug encounters potential of

hydrogen (pH) differences ranging from 4 to 7.3, leading to the possibility

of the drug molecule becoming uncharged and losing the major effect of

electric field. For peptides and proteins that undergo charge reversal in their

passage through skin, this phenomenon may lead to their delivery out of

the skin instead of into the skin. In addition, the delivery efficiency is

reduced by competition from interfering ions (of the same charge as the

drug ions). Lastly, increasing the current intensity or applications for long

periods can lead to pain, burning sensations, skin irritation, erythema,

blister formation and skin necrosis,18 and iontophoresis is not

recommended for underarm or facial/head hyperhidrosis.17 Also, the high-

energy requirement in iontophoresis for sustained therapeutic delivery

influences the size and cost of the dosage form making its use less

economical.18

Pathways of Skin Transport by Iontophoresis

Despite the use of an electric current, iontophoresis primarily enhances

transport via the already existing pathways in the skin, mainly the

transappendageal (hair follicles and sweat glands) and the paracellular

route.19 This was demonstrated by Cullander and Guy,20 who used

vibrating probe electrodes to identify site-specific ionic flows occurring in

hairless mouse skin. The iontophoretic pathways were found to be

appendageal and certain appendages, mainly the small hairs, appeared

to carry the most current. Others have used visualisation techniques, such

as confocal laser scanning microscopy (CSLM),21 to view the pathway of

iontophoretic transport post-iontophoresis and passive treatment of

hairless mouse skin with fluorescently labelled poly-L-lysines (FITC-PLLs).

The enhanced penetration due to iontophoresis was observed mainly

along the hair follicles in the skin especially in the deeper layers (20–40µ

below the skin surface). Involvement of non-appendageal pathways for

iontophoretic transport has also been suggested,20 which includes the

creation of artificial shunts due to disruption of the stratum corneum

structure,12 a temporary pore formation due to ‘flip-flop’ movement in

the polypeptide helices in the stratum corneum22 or pathways of least

resistance created by damaged skin areas. In addition, other factors such

as the source and structure of skin and the density of hair follicles will

contribute to the determination of the transport pathways.23

Factors Influencing Iontophoretic Transport

Several factors play a role in influencing iontophoretic transport, the most

important being the physicochemical properties of the active agent

(concentration, molecular charge, size), formulation factors (pH, ion

competition, type of buffer), the iontophoretic system (amount and time

of applied current, electrodes) and the membrane used.12,17 One of the

most critical factors is pH, as this influences the amount of drug available

in its ionised form. Iontophoretic transport of lidocaine was found to be

highest at pH 8.5 where the molecule exists mainly in the ionised form,24

and similar trends have been demonstrated with other solutes;25 pH is also

very significant for peptides as it can control the amount of charge on the

molecules based on their isoelectric point. In addition, the pH changes that

occur at the electrodes concurrent with the iontophoresis process can

affect drug transport. Electromigration of the ions also increases with their

rising concentration in solution, and is negatively influenced by the

presence of other ions of similar charge (often a result of added buffers)

or opposite charge. Influence of the molecular size on iontophoretic

transport has been described by a linear relationship between the

logarithm of the iontophoretic permeability coefficient and the molal

volume. However, solutes of high-molar volumes, such as insulin and

other hormones, have also shown significant iontophoretic transport.

Besides the properties of the molecule and the formulation, various

aspects of the iontophoretic system affect the transport across

membranes. The iontophoretic flux has been shown to be proportional to

the current intensity, and this phenomenon has been reported in vitro for

thyrotropin-releasing hormone (TRH),26 sodium and lithium11 and

verapamil,27 and also in vivo for pyridostigmine.11 However, the

increasing flux may reach a plateau, implying presence of saturation.28

Moreover, the amount of current is also restricted by the skin irritation

and discomfort it may cause.

Though most studies have used continuous direct current, the choice of

pulsed current has led to equally effective or better transport efficiency

while giving the skin time to recover in between the pulses, at the same

time preventing accumulation of charges.29 The type of electrodes used

also influences the transport rate, hence they should be of good

conductive material and should contour well on the skin surface.

Silver/silver chloride (Ag/AgCl) electrodes are most commonly used

because they are reversible and resist changes in pH. Other electrodes

used are platinum or zinc/zinc chloride wires.12 Last, physiological factors

such as age, race, thickness and permselectivity of the skin, injuries and

blood flow impart some variations in iontophoretic transport.

Applications of Transdermal Iontophoresis

Transdermal iontophoretic systems have the potential to produce

reproducible enhancement of transdermal delivery of molecules at

Figure 1: Iontophoresis Using a Silver/Silver Chloride Electrode System

Anode (+)

Skin

Cathode (–)

Constant currentsource

e e

Ag Ag Ag Ag Ag Ag Ag

Ag Ag Ag Ag Ag Ag Ag

Ag(s)+Cl-(aq) AgCl (s) +e-

AgCl AgCl AgCl AgCl

AgCl

AgCl(s)+e- Ag(s)+Cl-(aq)

AgCl AgCl AgCl

Cl-

Cl-

Cl-

Cl- Cl-Cl-

Cl-

Cl-

Cl-Cl-

Cl-Na+

Na+ Na+

Na+

Na+

Na+

Na+

Na+

Na+Na+

Na+

D+ A-

Electromigration transports the cations, including the drug molecule, from the anodalcompartment into the skin, while the endogenous anions, primarily Cl-, move into the anodal compartment.

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48 D R U G D E L I V E R Y 2 0 0 7

Transdermal Delivery

levels that are therapeutically significant. They also enable the

programming or control of the drug kinetics through the device. These

properties make the system suitable for the delivery of a wide range of

molecules, including several macromolecules that demonstrate limited

passive permeation.

Enhancement of transdermal permeation by iontophoresis has been

demonstrated for several small molecules such as apomorphine,30,31

sumatriptan,32 5-fluorouracil,33 rotigotine34 and buspirone hydrochloride.35

Combination of iontophoresis of small molecules with other enhancement

strategies has also successfully led to significant permeation enhancement

through the skin. Tiwari and Udupa36 found that the combination of

chemical and physical enhancer pre-treatment (ultrasound, iontophoresis

and pre-treatment with 5% D-limonene in ethanol) gave rise to a flux

(136.11±9.10µg/cm2/h) that was significantly different from iontophoresis

alone (flux: 62.80±6.78µg/cm2/h) as well as from treatment with the

chemical enhancers and ultrasound alone.

Iontophoretic drug delivery systems have also generated interest in

enhancing the delivery of macromolecules such as peptides, which are

often polar, carry a charge and cannot be administered via the oral route

due to poor absorption and stability. Insulin has been a popular candidate

for iontophoretic delivery and has been investigated extensively, mostly

in combination with chemical enhancer pre-treatment or other

enhancement techniques.37–39 Most of these studies have led to

significant flux enhancement of insulin and in many cases delivery of the

therapeutic dose. Recently, Akimoto et al. reported similar results and

found that the iontophoretically enhanced skin permeation of insulin

increased linearly with the density of pulsed direct current applied.40

Several other macromolecules such as LHRH and nafarelin have also been

investigated for iontophoretic transport.41,42 The effectiveness of

transdermal iontophoresis of peptides, just like smaller molecules, is

influenced by several factors such as the charge, molecular weight,

lipophilicity and, above all, the physical and chemical stability of the

peptides in the delivery system and the proteolytic activity of the skin.43

Commercial Systems

The unique advantages of iontophoresis technology have led to

successful commercial applications in the pharmaceutical, as well as

physical therapy, industry. The key factors in commercialisation are the

net efficiency of the device, its portability and convenience of

administration. Some of the best-known devices are the GlucoWatch®

Biographer44 for monitoring glucose, the LidoSite® Patch (Vyteris, Inc.),8

the E-TRANS iontophoretic system with Fentanyl hydrochloride, IONSYS®

for pain management45 and IOMED’s new Hybresis™ Iontophoresis Drug

Delivery System.46

Vyteris, Inc. has received US Food and Drug Administration (FDA)

approval of a first-of-a-kind system called LidoSite (lidocaine

hydrochloride and epinephrine bitartrate) patch. This system consists of

a LidoSite Patch, a LidoSite Controller and a portable microprocessor-

controlled battery-powered direct current source, and is indicated for

local analgaesia during superficial dermatological procedures. ALZA

Corp’s45 E-TRANS fentanyl hydrochloride system is an FDA-approved

patient-controlled alternative for acute pain management in a medically

supervised setting. One of the major advantages of this device is the

ability to programme it to deliver fixed amounts and an on-demand

button enabling the patient to administer the drug when needed. The

Hybresis System by IOMED46 is an integrated mini-controller and patch

system that uses no lead wires and can deliver in-clinic treatment in as

little as three minutes. The three-minute Skin Conductivity

Enhancement feature provides rapid decrease of skin resistance and

normalises or reduces its variability, and makes the patch-only wear

time shorter and more predictable.

Conclusions

Iontophoretic drug delivery systems form a major group of the relatively

few physically enhanced transdermal delivery systems that have been

successfully developed and commercialised. The electrically driven

penetration enhancement provided by this method has succeeded in

overcoming the formidable barrier presented by the SC, and has shown

to be a promising technique for various agents, including

macromolecules. Combination strategies with other physical

enhancement techniques such as electroporation or ultrasound or with

chemical enhancers have led to the observation of significantly higher

flux levels compared with passive transdermal delivery. However, the

resulting irritation caused to the skin due to combined strategies may be

a cause for concern. Also, electrically assisted delivery systems provide

the advantage of controlled drug delivery with customised drug input

rates, and an option of ceasing drug transport when desired. In

addition, iontophoresis is also finding value in drug delivery via other

drug administration routes such as transcorneal and trans-scleral

routes,47 and also through bone for delivery of antibiotics to prevent

infection during allograft implantation.48 ■

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