Transdermal Iontophoresis

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Transdermal Delivery
Transdermal Iontophoresis
a report by
P r i y a B a t h e j a , 1 D i k s h a K a u s h i k , 1 L o n g s h e n g H u 2 and B o z e n a B M i c h n i a k - K o h n 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,
cations (and other positively charged ions) placed at the anode move
represents an attractive route for drug administration. Several
away from the anode (positive electrode) and pass into the skin, and at
transdermal systems have been developed and marketed for the relief
the same time anions from the body are repelled from the cathode and
of pain, contraception, hormone replacement, motion sickness,
migrate into anodal reservoir (see Figure 1). The efficiency of
hypertension and angina. Transdermal drug delivery systems provide
transdermal iontophoresis can be calculated from the slope of a plot of
distinct benefits due to elimination of hepatic first-pass effects,
the iontophoretic drug delivery versus current applied.11 The amount of
reduction in systemic side effects by decrease in initial dose size and
permeant delivered across the skin is directly proportional to the
increased patient compliance. However, development of formulations
quantity of charge passed through the membrane, which in turn
and systems for transdermal delivery has been hindered by poor tissue
depends on the amount and duration of the applied current and the skin
permeability – predominantly in the outermost layer of the skin –
surface area in contact with the electrode compartment.13
known as the stratum corneum (SC).
Theory of Drug Transport by Iontophoresis
The SC consists of a well-organised layer of dead corneocytes intercalated
Iontophoretic drug delivery occurs by a combination of:
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
• concentration gradient (diffusive/passive transport component) and
electrochemical potential gradient developed across the skin;
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
• increased skin permeability under applied electric current
(electromigration/electrorepulsion); and
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.
• a current-induced water transport effect (electro-osmosis/convective
transport/iontohydrokinesis).12,14
Transdermal iontophoresis involves the use of a constant/pulsed current
to develop an electric potential gradient that forces the ionised drug into
It should be noted that iontophoretic drug transport is mainly through
the skin. Various transdermal iontophoretic devices have been
electrorepulsion and electro-osmosis; the passive component plays an
successfully developed and marketed, the latest being the LidoSite™
insignificant role. Electrorepulsion refers to the drug transport across skin
patch (Vyteris, Inc.)8 Transdermal iontophoresis has not only enabled the
due to either the repulsion of cations into the skin from the anode
successful delivery of small molecules such as fentanyl hydrochloride
(anodal iontophoresis) or the migration of anions into the skin from the
(E-TRANS® patch, ALZA Corp.) for pain management,9 but also delivery
cathode (cathodal iontophoresis). On the other hand, electro-osmosis is a
of peptides such as insulin, nafarelin and luteinising hormone-releasing
phenomenon that occurs as a result of a net negative charge on the skin
hormone (LHRH).11,12
at physiological pH (7.4) that subsequently leads to its cation
permselectivity. This results in induced solvent flow that facilitates cation
Basic Principles of Transdermal Iontophoresis
transport in anode-to-cathode direction, with inhibition of anion
This technique is based on the principle that application of electric
transport enabling enhanced transdermal delivery of neutral and polar
current provides external energy to drug ions for passage across the skin,
solutes across the skin when an electric field is applied.14–16 It has been
thereby increasing drug permeability through the membrane. A typical
reported in the literature that the iontophoretic delivery of small, highly
iontophoretic drug delivery system consists of an anode, a cathode and
mobile ions such as sodium ions, which are efficient charge carriers, is
two reservoirs, one comprising drug ions and the other containing
dominated by electrorepulsion. However, electro-osmosis is the primary
biocompatible salt such as sodium chloride.11 For delivering positively
transport mechanism of larger and bulkier species, such as cationic
charged and negatively charged ions, two iontophoretic approaches
peptides of molecular weights in the order of 1,000 Daltons or more.10
10
have been developed, namely anodal and cathodal iontophoresis. In
anodal iontophoresis, cationic drug ions are placed under the anode at
Advantages and Limitations of Iontophoresis
the desired site of application and the cathode (receiving electrode) is
Iontophoresis, like passive transdermal drug delivery, bypasses the first-
placed at a different site on the skin, whereas in cathodal iontophoresis
pass hepatic metabolism and gastrointestinal degradation. It maintains
the electrode orientation is reversed.12 The movement of ions in
controlled plasma levels of drugs, even those with short biological half-
iontophoresis follows the basic rule of electricity, i.e. like charges repel
lives, and also offers the benefit of delivering charged and high-
each other. In anodal iontophoresis, on application of current, all drug
molecular-weight compounds, unlike passive transdermal delivery, which
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Transdermal Iontophoresis
is limited to small, non-polar and lipophilic solutes. Iontophoresis also
provides increased patient compliance due to less frequent dosing, ease
Figure 1: Iontophoresis Using a Silver/Silver Chloride
Electrode System
of terminating drug delivery at any stage of therapy and the capability of
tailoring drug therapy at pre-programmed rates according to individual
Constant current
source
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.
e
e
Anode (+)
Though it offers numerous advantages, application of iontophoresis is
Cathode (–)
AgCl AgCl AgCl AgCl
Ag Ag Ag Ag Ag Ag Ag
Ag Ag Ag Ag Ag Ag Ag
limited to drugs that can be formulated in the ionic form.18 Also, during
iontophoretic transport across the skin, the drug encounters potential of
-
AgCl AgCl AgCl AgCl
AgCl(s)+e- Ag(s)+Cl-(aq)
-
Ag(s)+Cl (aq) AgCl (s) +e
Na+
Cl-
hydrogen (pH) differences ranging from 4 to 7.3, leading to the possibility
Cl-
Na+
of the drug molecule becoming uncharged and losing the major effect of
Cl-
Cl-
Na+
Cl-
D+
electric field. For peptides and proteins that undergo charge reversal in their
Na+
Na+
A-
Cl-
Na+
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
Na+
Skin
Na+
ClNa+
Cl-
Na+
Cl-
Na+
Cl-
Cl-
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-
Electromigration transports the cations, including the drug molecule, from the anodal
compartment into the skin, while the endogenous anions, primarily Cl-, move into the
anodal compartment.
energy requirement in iontophoresis for sustained therapeutic delivery
influences the size and cost of the dosage form making its use less
very significant for peptides as it can control the amount of charge on the
economical.18
molecules based on their isoelectric point. In addition, the pH changes that
occur at the electrodes concurrent with the iontophoresis process can
Pathways of Skin Transport by Iontophoresis
affect drug transport. Electromigration of the ions also increases with their
Despite the use of an electric current, iontophoresis primarily enhances
rising concentration in solution, and is negatively influenced by the
transport via the already existing pathways in the skin, mainly the
presence of other ions of similar charge (often a result of added buffers)
transappendageal (hair follicles and sweat glands) and the paracellular
or opposite charge. Influence of the molecular size on iontophoretic
route.
who used
transport has been described by a linear relationship between the
vibrating probe electrodes to identify site-specific ionic flows occurring in
logarithm of the iontophoretic permeability coefficient and the molal
hairless mouse skin. The iontophoretic pathways were found to be
volume. However, solutes of high-molar volumes, such as insulin and
appendageal and certain appendages, mainly the small hairs, appeared
other hormones, have also shown significant iontophoretic transport.
19
This was demonstrated by Cullander and Guy,
20
to carry the most current. Others have used visualisation techniques, such
as confocal laser scanning microscopy (CSLM),21 to view the pathway of
Besides the properties of the molecule and the formulation, various
iontophoretic transport post-iontophoresis and passive treatment of
aspects of the iontophoretic system affect the transport across
hairless mouse skin with fluorescently labelled poly-L-lysines (FITC-PLLs).
membranes. The iontophoretic flux has been shown to be proportional to
the current intensity, and this phenomenon has been reported in vitro for
The enhanced penetration due to iontophoresis was observed mainly
thyrotropin-releasing hormone (TRH),26 sodium and lithium11 and
along the hair follicles in the skin especially in the deeper layers (20–40µ
verapamil,27 and also in vivo for pyridostigmine.11 However, the
below the skin surface). Involvement of non-appendageal pathways for
increasing flux may reach a plateau, implying presence of saturation.28
iontophoretic transport has also been suggested,20 which includes the
Moreover, the amount of current is also restricted by the skin irritation
creation of artificial shunts due to disruption of the stratum corneum
and discomfort it may cause.
structure,12 a temporary pore formation due to ‘flip-flop’ movement in
the polypeptide helices in the stratum corneum22 or pathways of least
Though most studies have used continuous direct current, the choice of
resistance created by damaged skin areas. In addition, other factors such
pulsed current has led to equally effective or better transport efficiency
as the source and structure of skin and the density of hair follicles will
while giving the skin time to recover in between the pulses, at the same
contribute to the determination of the transport pathways.23
time preventing accumulation of charges.29 The type of electrodes used
also influences the transport rate, hence they should be of good
Factors Influencing Iontophoretic Transport
conductive material and should contour well on the skin surface.
Several factors play a role in influencing iontophoretic transport, the most
Silver/silver chloride (Ag/AgCl) electrodes are most commonly used
important being the physicochemical properties of the active agent
because they are reversible and resist changes in pH. Other electrodes
(concentration, molecular charge, size), formulation factors (pH, ion
used are platinum or zinc/zinc chloride wires.12 Last, physiological factors
competition, type of buffer), the iontophoretic system (amount and time
such as age, race, thickness and permselectivity of the skin, injuries and
of applied current, electrodes) and the membrane used.12,17 One of the
blood flow impart some variations in iontophoretic transport.
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
Applications of Transdermal Iontophoresis
highest at pH 8.5 where the molecule exists mainly in the ionised form,24
Transdermal iontophoretic systems have the potential to produce
and similar trends have been demonstrated with other solutes;25 pH is also
reproducible enhancement of transdermal delivery of molecules at
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Transdermal Delivery
levels that are therapeutically significant. They also enable the
Biographer44 for monitoring glucose, the LidoSite® Patch (Vyteris, Inc.),8
programming or control of the drug kinetics through the device. These
the E-TRANS iontophoretic system with Fentanyl hydrochloride, IONSYS®
properties make the system suitable for the delivery of a wide range of
for pain management45 and IOMED’s new Hybresis™ Iontophoresis Drug
molecules, including several macromolecules that demonstrate limited
Delivery System.46
passive permeation.
Vyteris, Inc. has received US Food and Drug Administration (FDA)
Enhancement of transdermal permeation by iontophoresis has been
approval of a first-of-a-kind system called LidoSite (lidocaine
demonstrated for several small molecules such as apomorphine,30,31
hydrochloride and epinephrine bitartrate) patch. This system consists of
sumatriptan,32 5-fluorouracil,33 rotigotine34 and buspirone hydrochloride.35
a LidoSite Patch, a LidoSite Controller and a portable microprocessor-
Combination of iontophoresis of small molecules with other enhancement
controlled battery-powered direct current source, and is indicated for
strategies has also successfully led to significant permeation enhancement
local analgaesia during superficial dermatological procedures. ALZA
through the skin. Tiwari and Udupa36 found that the combination of
Corp’s45 E-TRANS fentanyl hydrochloride system is an FDA-approved
chemical and physical enhancer pre-treatment (ultrasound, iontophoresis
patient-controlled alternative for acute pain management in a medically
and pre-treatment with 5% D-limonene in ethanol) gave rise to a flux
supervised setting. One of the major advantages of this device is the
(136.11±9.10µg/cm2/h) that was significantly different from iontophoresis
ability to programme it to deliver fixed amounts and an on-demand
alone (flux: 62.80±6.78µg/cm2/h) as well as from treatment with the
button enabling the patient to administer the drug when needed. The
chemical enhancers and ultrasound alone.
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
Iontophoretic drug delivery systems have also generated interest in
little as three minutes. The three-minute Skin Conductivity
enhancing the delivery of macromolecules such as peptides, which are
Enhancement feature provides rapid decrease of skin resistance and
often polar, carry a charge and cannot be administered via the oral route
normalises or reduces its variability, and makes the patch-only wear
due to poor absorption and stability. Insulin has been a popular candidate
time shorter and more predictable.
for iontophoretic delivery and has been investigated extensively, mostly
in combination with chemical enhancer pre-treatment or other
Conclusions
enhancement techniques.37–39 Most of these studies have led to
Iontophoretic drug delivery systems form a major group of the relatively
significant flux enhancement of insulin and in many cases delivery of the
few physically enhanced transdermal delivery systems that have been
therapeutic dose. Recently, Akimoto et al. reported similar results and
successfully developed and commercialised. The electrically driven
found that the iontophoretically enhanced skin permeation of insulin
penetration enhancement provided by this method has succeeded in
40
increased linearly with the density of pulsed direct current applied.
overcoming the formidable barrier presented by the SC, and has shown
Several other macromolecules such as LHRH and nafarelin have also been
to be a promising technique for various agents, including
investigated for iontophoretic transport.41,42 The effectiveness of
macromolecules.
transdermal iontophoresis of peptides, just like smaller molecules, is
enhancement techniques such as electroporation or ultrasound or with
influenced by several factors such as the charge, molecular weight,
chemical enhancers have led to the observation of significantly higher
lipophilicity and, above all, the physical and chemical stability of the
flux levels compared with passive transdermal delivery. However, the
peptides in the delivery system and the proteolytic activity of the skin.43
resulting irritation caused to the skin due to combined strategies may be
Combination
strategies
with
other
physical
a cause for concern. Also, electrically assisted delivery systems provide
Commercial Systems
the advantage of controlled drug delivery with customised drug input
The unique advantages of iontophoresis technology have led to
rates, and an option of ceasing drug transport when desired. In
successful commercial applications in the pharmaceutical, as well as
addition, iontophoresis is also finding value in drug delivery via other
physical therapy, industry. The key factors in commercialisation are the
drug administration routes such as transcorneal and trans-scleral
net efficiency of the device, its portability and convenience of
routes,47 and also through bone for delivery of antibiotics to prevent
administration. Some of the best-known devices are the GlucoWatch®
infection during allograft implantation.48 ■
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Aungst BJ, et al., Int J Pharma, 1986;33(1–3):225.
Marjukka Suhonen T, et al., J Control Release, 1999;59(2):
149–61.
Smith EW, et al., Percutaneous Penetration Enhancers, Boca
Raton, Florida: CRC Press, 1995;1–4.
Chang SL, et al., J Pharm Pharmacol, 1998;50(6):635–40.
Mitragotri S, et al., J Control Release, 2000;63(1–2):41–52.
Lombry C, et al., Pharm Res, 2000;17(1):32–7.
Tao SL, et al., Adv Drug Deliv Rev, 2003;55(3):315–28.
http://www.vyteris.com/home/Our_Products/Lidosite.php
Viscusi ER, et al., JAMA, 2004;291(11):1333–41.
Guy, RH, et al., Skin Pharmacol Appl Skin Physiol, 2001;
14(Suppl. 1):35–40.
Phipps JB, et al., J Pharm Sci, 1989;78(5):365–9.
Singh P, et al., Crit Rev Ther Drug Carrier Syst,
1994;11(2–3):161–213.
Kalia YN, et al., Adv Drug Deliv Rev, 2004;56(5):619–58.
Pikal MJ, et al., Adv Drug Deliv Rev, 2001;46(1–3):281–305.
Guy RH, et al., J Control Release, 2000; 64(1–3):129–32.
Merino V, Pharm Res, 1999;16(5):758–61.
48
17. Batheja P, et al., Expert Opin Drug Deliv, 2006;3(1):127–38.
18. Burton HS Jr, et al. In: Smith EW, Maibach HI (eds),
Percutaneous Penetration Enhancers, Boca Raton, Florida: CRC
Press, 1995;351–68.
19. Burnette RR, Transdermal Drug Delivery, NY: Marcel Dekker,
1988.
20. Cullander C, et al., J Invest Dermatol, 1991;97(1):55–64.
21. Turner NG, et al., Pharm Res, 1997;14(10):1322–31.
22. Jung G, Physical Chemistry of Transmembrane Ion Motion, NY:
Elsevier, 1983.
23. Riviere JE, et al.,Pharm Res, 1997;14(6):687–97.
24. Siddiqui O, et al., J Pharm Pharmacol, 1985;37(10):732–5.
25. Siddiqui O, et al., J Pharm Pharmacol, 1989;41(6):430–32.
26. Burnette RR, et al., J Pharm Sci, 1986;75(8):738–43.
27. Wearly LL, et al., Int J Pharma, 1990;59(2):87.
28. Kasting GB, et al., J Control Release, 1989;8(3):195–210.
29. Bagniefski T, J Control Release, 1990;11(1–3):113–22.
30. van der Geest R, et al., Pharm Res, 1997;14(12):1798–1803.
31. van der Geest R, et al., Pharm Res, 1997;14(12):1804–10.
32. Patel SR, et al., Eur J Pharm Biopharm, 2007;66(2):296–301.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
Fang JY, et al., Int J Pharm, 2004;270(1–2):241–9.
Nugroho AK, et al., J Control Release, 2004;96(1):159–67.
Meidan VM, et al., Int J Pharm, 2003;264(1–2):73–83.
Tiwari SB, et al., Int J Pharm, 2003;260(1):93–103.
Zakzewski CA, et al., J Control Release, 1998;50(1–3):267–72.
Pillai O, et al., Skin Pharmacol Physiol, 2004;17(6):289–97.
Pillai O, et al., J Control Release, 2003;88(2):287–96.
Akimoto M, et al., Progress In Electromagnetics Research
Symposium 2006, Cambridge, US, 26–29 March 2006;157.
Raiman J, et al., Eur J Pharm Sci, 2004;21(2–3):371–7.
Hirvonen J, et al., Nat Biotechnol, 1996;14(13):17103.
Abla N, et al., Pharm Res, 2005;22(12):2069–78.
Potts RO, et al., Diabetes Metab Res Rev, 2002;18(Suppl. 1):
S49–53.
http://www.alza.com/alza/etrans
Parkinson TM, et al., Drug Delivery Technology, 2007:54.
Eljarrat-Binstock E, et al., J Control Release, 2005;106(3):
386–90.
Khoo PP, et al., J Bone Joint Surg Br, 2006;88(9):1149–57.
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