International Journal of Pharmaceutics 586 (2020) 119584

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Review

Iontophoretic skin delivery systems: Success and failures T

a a b a,⁎
P. Bakshi , D. Vora , K. Hemmady , A.K. Banga
a
Center for Drug Delivery Research, Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA 30341, United States
b
Dermatologist, Frimley Park Hospital NHS Foundation Trust, Frimley, Surrey, United Kingdom

A R T I C LE I N FO A B S T R A C T

Keywords: Iontophoretic transdermal delivery uses a small electric current to push charged molecules into the skin under an
Iontophoresis electrode of same polarity and offers an attractive option to facilitate the delivery of macromolecules or hy-
Macromolecules drophilic molecules and to improve patient compliance. This technique has been used in physical therapy clinics
Hydrophilic molecules for several decades, though the science was not always there to support claims of clinical effectiveness. Recently,
Controlled drug delivery
this modality of treatment has undergone more systematic and rigorous investigations to withstand the scrutiny
Iontophoretic patches
of regulatory authorities. In recent years various drugs have gained FDA approval for iontophoretic patches. This
technique is gaining recognition due to better compliance rates, non-invasive drug delivery leading to fewer side
effects, and sustained release of the drug. Furthermore, programmed delivery and bolus delivery systems have
helped with customizing the drug dosage and frequency of dosage based on the patient's need.

1. Introduction
Transdermal drug delivery (TDD) offers multiple advantages over
traditional oral drug delivery route. These include non-invasive de-
livery, bypass of first-pass metabolism, patient compliance, and less
systemic side effects. The TDD industry has grown and has seen a sig-
nificant upward trend over the past decade. The global TDD market was
worth $32,516 million in 2016 and is expected to reach $61,689 mil-
lion by the end of 2023 with a compound annual growth rate of 9.5%
during 2016–2023 (ReportLinker, 2019; Prateeksha Kaul and Garima
Chandra, 2017).
For a drug to permeate through the skin, it should ideally be
moderately lipophilic with a molecular weight < 500 Daltons. The
stratum corneum acts as a barrier and limits the entry of substances into
the skin. Large and hydrophilic molecules such as peptides and poly-
saccharides cannot cross this barrier, which has resulted in the devel-
opment of different strategies to enhance drug transport into and
through the skin. Several enhancement technologies, such as ionto-
phoresis, electrophoresis, and sonophoresis, have been developed to
assist the transdermal delivery of such molecules (Siddoju et al., 2011).
In recent years, numerous hydrophilic macromolecules have gained
FDA approval for therapeutic use. This trend is expected to continue
and possibly even increase. Iontophoretic transdermal delivery offers
an attractive option to facilitate the delivery of these molecules and to
improve patient compliance. In theory, this modality is promising as it
has been validated by multiple clinical trials. The technique has been
used in physical therapy clinics for several decades, though the science
was not always there to support claims of clinical effectiveness.
History of iontophoresis can be traced back to more than 250 years
ago when electrical transport was performed on therapeutic agents in
the mid-18th century by Giovanni Battista Bianchi. It was found that
purgatives delivered using electricity had the same laxative effect when
administered orally. The method of delivering pharmacological agents
using iontophoresis was later recognized by Leduc (1900), who in-
troduced the term iontotherapy and formulated laws for this process
(Chien and Banga, 1989). Since then, iontophoresis has been used to
treat acute local inflammatory conditions and to deliver local an-
esthesia and a variety of drug molecules percutaneously.
Iontophoresis is an enhancement technique that involves the ap-
plication of low current intensities to the skin. This technique helps to
enhance the topical and transdermal delivery of charged or neutral
molecules (Singh and Roberts, 1989). Iontophoresis involves the use of
small intensity of the current (usually less than 0.5 mA/cm2) to push
charged drug molecules into the skin when placed under an electrode of
like polarity. Iontophoresis shows an excellent enhancement effect on
hydrophilic molecules with molecular weight less than 15 kDa (Kalluri
and Banga, 2011). Iontophoresis works on the principle of electro-
migration, i.e., like repels like, driving charged molecules through the
skin (Ita, 2016). Application of current through the electrodes results in
electromigration of the charged drug molecules causing the drug mo-
lecule to be driven into or through the skin. The movement of the drug
molecule is accompanied by the flow of water, which is known as

⁎
Corresponding author.
E-mail address: banga_ak@mercer.edu (A.K. Banga).

https://doi.org/10.1016/j.ijpharm.2020.119584
Received 1 May 2020; Received in revised form 17 June 2020; Accepted 23 June 2020
Available online 27 June 2020
0378-5173/ © 2020 Elsevier B.V. All rights reserved.
P. Bakshi, et al.
electroosmosis. The transport of neutral molecules also occurs at the
anode by electroosmosis along with the bulk water flow from anode to
cathode. Thus, iontophoresis enables transport of several hydrophilic
drugs that cannot otherwise be delivered passively (Singh et al., 1995).
In recent times this modality of treatment has undergone more
systematic and rigorous investigations to withstand the scrutiny of
regulatory authorities. Products for iontophoretic delivery of lidocaine,
fentanyl, and sumatriptan have been approved by FDA, though some
were later recalled due to lack of sales or issues relating to device or
skin burns.
2. Mechanism of drug transport by iontophoresis:
Iontophoresis transports the drug across the skin by two main me-
chanisms: Charged solutes are transported primarily by electrical re-
pulsion from the electrode, and electroosmosis may enable transport of
unionized molecules (Barry, 2001). The trans-appendageal path plays a
vital role in drug transport through electroosmosis and electromigration
(Bath et al., 2000). During iontophoresis, ions prefer the pathway with
least electrical resistance, i.e., through the pores such as sweat glands or
hair follicles (Grimnes, 1984; Burnette and Marrero, 1986). The ionic
flow through stratum corneum is negligible hence the dominant ionic
path is sweat duct units or trans-appendageal pathway. As iontophoretic
delivery takes place via the appendageal pathway, the technique would
be useful for the treatment of some follicular diseases, such as acne or
androgenetic alopecia (Illel, 1997; Banga, 2011).
Fig. 1 illustrates the basic principle of iontophoresis. A typical
iontophoretic delivery system consists of a current source and two
electrodes. The drug reservoir is placed under the appropriate elec-
trode, while the other electrode serves as a counter electrode to com-
plete the circuit (Singh et al., 2012). Negatively charged ions are pro-
pelled into the skin under the influence of cathode, and positively
charged ions are transferred through the skin under the influence of
anodal delivery. The isoelectric point (pl) of the human skin is around
4–4.5, which is below the pH of physiological conditions (pH-7.4).
Therefore, skin is negatively charged, which favors the flow of water
from anode to cathode. Thus, facilitating the transport of positively
charged drugs. Also, electroosmosis plays an essential role in the
transport of neutral molecules. This is because carboxylate groups
present in the skin are ionized at physiological pH. When an electric
current is passed across such charged membranes, they favor the pas-
sage of counterions, usually cations, and thus electroosmosis occurs
from anode to cathode (Kalia and Guy, 2004). Therefore, skin is
permselective to cations under the imposition of an electrical field
(Naik et al., 2000).
For delivery under anode, the role of electroosmosis becomes sig-
nificant with increasing molecular weight, and this enables
Fig. 1. Basic principle behind iontophoretic drug delivery. Charged ions are propelled into the skin under the influence of electrode of like charge, while the
counter electrode completes the circuit – Reproduced from Naik et al., 2000; with permission from Elsevier.
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International Journal of Pharmaceutics 586 (2020) 119584
iontophoretic delivery of macromolecules, irrespective of their charge
(Kanikkannan, 2002). Neutral molecules can also be carried by elec-
troosmosis mechanism using anodal delivery (Kalia and Guy, 2004).
Another mechanism by which iontophoresis can be performed or
applied is reverse iontophoresis. Reverse iontophoresis involves the
extraction of a molecule from the body by electroosmotic flow. This
technique has a significant medical application and can be used for non-
invasive sampling. One such product based on this technique was an
automatic glucose biographer device, GlucoWatch® G2™ Biographer,
and its application is discussed later in this review (Pandey et al., 2019;
Banga, 2011).
3. Factors affecting iontophoretic transport
Various factors affect the iontophoretic delivery, such as current
density, pH, duration, salts and drug concentration in formulation,
ionic strength, drug concentration, molecular size, and type of current
[continuous, pulse current, AC (alternating current) and DC (direct
current)]. Physiochemical properties such as charge, size, and lipophi-
licity of the drug also influence the rate of delivery across the skin. Drug
candidates with higher water solubility and charge are favorable for
iontophoretic delivery. The transport of the molecules across the skin is
also dependent on the current. Thus an increase in current density is
expected to deliver a higher amount of drug (Banga, 2011). The phy-
siologically acceptable current considered safe for humans is considered
to be 0.5 mA/cm2 or less (Dixit et al., 2007). Iontophoresis has the
advantage of delivering the drugs in a controlled manner where de-
livery can be initiated or terminated. The application of iontophoresis
further reduces the lag time of the drugs administered by passive dif-
fusion (Kalluri and Banga, 2011). Delivery can also be modulated by
controlling the current profiles. In DC, the current is continuous and is
in one direction. Whereas, in AC, the current changes periodically.
Leuprorelin acetate, a potent luteinizing-hormone-releasing hormone
(LHRH) receptor agonist used in various clinical applications, was
successfully delivered across porcine skin by using pulsed iontophoresis
(Smyth et al., 2002).
The choice of drug reservoir or formulation and its pH control the
charge on the drug and competitive ions. Therefore, these factors are
critical for the successful transport of the drug during iontophoresis.
While choosing the formulation, it is essential to consider the type of
buffer incorporated in the formulation since buffer ions compete with
the drug molecules and thus affect the drug permeation (Krishnan et al.,
2011). Iontophoretic patches typically have hydrogel formulations as
they provide an aqueous environment to carry the current and also hold
drug formulation in place. The type of polymer used for hydrogel for-
mulation can influence the rate of delivery of the drug across the skin.
Banga and Chien investigated the iontophoretic delivery of insulin,
P. Bakshi, et al.
calcitonin, and vasopressin by using hydrogels of polyacrylamide, poly
hydroxyethyl methacrylate, and carbopol 934 (Banga and Chien, 1993).
Gupta et al. reported that ionic polymers decrease the flux of sodium
cromoglycate, but nonionic polymers like hydroxypropyl cellulose and
polyvinyl alcohol did not affect the flux (Gupta et al., 1994).
Experimental variables that can be adjusted to modify iontophoretic
transfer include the quantity of charge, skin area, and drug con-
centration. A linear relationship between drug concentration and
transport during iontophoresis has been reported until it reaches sa-
turation (Kalia and Guy, 2004), although this may not always be the
case (Banga, 2011). Similarly, another factor influencing the delivery of
drugs across the skin is the pH of the formulation. An appropriate pH
will ensure the ionization of the drug and cause maximum delivery
during iontophoresis (Kalia and Guy, 2004).
Experimental variables such as the use of another active or passive
delivery technique may influence the delivery by compromising the
barrier. Iontophoresis has also been used in combination with other
enhancement technologies. For example, microneedles create hydro-
philic channels and application of iontophoresis with microneedles can
enhance the delivery of large hydrophilic macromolecules through
these channels (Banga, 2011; Katikaneni et al., 2009; Katikaneni et al.,
2010). Similarly, the barrier function of stratum corneum can be
overcome by using physical and chemical enhancers (Liu et al., 2013).
Singh et al. investigated the effect of penetration enhancer and ionto-
phoresis on surface characteristics of human epidermis (Singh and
Singh, 1995). In another study by Lee et al., barrier properties of
stratum corneum in rats was affected by permeation enhancers such as
oleic acid and propylene glycol. This study showed that co-application
of oleic acid with iontophoresis further enhanced the effect of oleic acid
and thus resulted in higher drug delivery (Jiang et al., 2000).
Furthermore, the type of electrodes used in the study is also a sig-
nificant factor. Typical electrodes used for iontophoretic delivery are
Ag/AgCl as they resist changes in pH. The typical reaction occurring at
the anode and cathode is:
Anode:Ag + Cl− → AgCl + e−
Cathode:AgCl + e− → Ag + Cl−
The electron is released to the circuit, and insoluble AgCl pre-
cipitates at the anode surface.
4. Iontophoretic delivery of peptides and proteins:
Peptides and proteins play an increasingly vital role in medicine
today. Their potency and specificity make them excellent therapeutic
agents; however, their physicochemical properties and stability ne-
cessitate their administration by parenteral route. Transdermal delivery
offers an alternative route of drug delivery, avoiding pain associated
with parenteral administration, and avoid the need for frequent injec-
tions due to their typically short half-life (Parasrampuria and
Parasrampuria, 1991). Techniques such as iontophoresis can be used to
enhance the delivery of these large molecules across the skin.
The charge on the peptide can be controlled by changing the pH
relative to the isoelectric point of the peptide. The pH and ionic
strength of the buffer, current density, and electrode configuration, as
discussed previously, are some of the factors that are important for
iontophoretic delivery of peptides.
Iontophoretic delivery has typically been used to deliver small
peptides. Iontophoretic delivery of various peptides through the skin
has been widely studied. Gayathri et al. investigated the iontophoretic
delivery of 5-aminolevulinic acid and a dipeptide L-alanine-L-trypto-
phan across human epidermis. Iontophoresis enhanced the permeation
of 5- aminolevulinic acid and the dipeptide by up to 15 and 22 fold,
respectively, compared to passive delivery (Krishnan et al., 2011 Jan 1).
However, there are some reports for in vitro delivery of larger proteins
such as Ribonuclease A (13.6 KDa, pI 8.64) and daniplestim (12.76
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International Journal of Pharmaceutics 586 (2020) 119584
KDa, pI 6.2) to hairless rat and porcine skin (Burnette and Marrero,
1986; Dubey and Kalia, 2010; Katikaneni et al., 2009). Iontophoretic
delivery of insulin has also been studied widely (Zhang et al., 2020).
As mentioned previously, the delivery of these macromolecules can
be further enhanced in combination with other enhancement technol-
ogies. For instance, Pawar et al. observed a multiple fold enhancement
in transdermal permeation of Lysine-Proline-Valine (KPV) peptide by
microneedle pretreatment followed by iontophoresis as compared to
microneedle or iontophoresis alone (Pawar et al., 2017). Similarly, in
vivo delivery of daniplestim was most efficient and resulted in the
highest plasma concentration in a hairless rat model using a combina-
tional approach with maltose microneedles and iontophoresis, as
compared to iontophoresis, sonophoresis, and microneedles alone
(Banga, 2011; Katikaneni et al., 2010).
Proteolytic activity of skin is low compared to mucosal delivery
(Kanikkannan, 2002). However, to minimize potential proteolytic de-
gradation of peptides in skin, protease inhibitors can be added. This was
also observed in one of the in vivo studies, which demonstrated en-
hanced iontophoretic delivery of salmon calcitonin in rats by the use of
protease inhibitors (Morimoto and Tojima, 1992). In clinical studies,
leuprolide, luteinizing hormone-releasing hormone (LHRH), and calci-
tonin analog have been reported to be successfully delivered in human
volunteers using iontophoresis (Meyer and Kreis, 1988; Green, 1996).
Even though iontophoretic transdermal delivery of peptides has been
successfully investigated with proteins of molecular weight up to
~13KDa, many challenges still need to be investigated and resolved.
Issues such as quantity and cost of peptides to be formulated in
patches, physical and chemical stability of peptides in the patch during
shelf life, the proteolytic activity of the skin, safety, and efficacy of
iontophoresis for extended duration still needs further investigation.
5. Skin irritation and safety
It has been suggested in the literature that physiologically accep-
table current, which could be applied, is 0.5 mA/cm2 or less (Warden,
2007). Sometimes, a higher intensity of current or the properties of the
drug molecule can cause mild to moderate skin erythema or skin irri-
tation on the application of the iontophoretic patch (Curdy et al., 2001).
Minor reactions such as itching, erythema, tingling sensation, or minor
irritation on the skin surface where the iontophoresis is performed are
common. However, these minor reactions can be of the increased risk if
the current density and exposure time is increased. In the past, there
have been reports of sustaining burns or scars on the skin due to the use
of an iontophoretic sumatriptan patch (Zecuity). Though such cases are
not common, the FDA has investigated these events (Medscape, 2020).
One of the ways this problem can be addressed is by avoiding the ap-
plication of patch on broken or damaged skin (Singh et al., 2001).
However, apart from mild skin erythema or skin irritation, there are no
side effects of iontophoretic delivery.
6. Commercialized iontophoretic devices
6.1. Iontophoretic devices in the pharmaceutical industry
During the 1990 s, various transdermal companies such as ALZA,
Cygnus, and Theratech underwent acquisition or merger, affecting the
development of iontophoretic patches. ALZA Corporation developed an
E-TRANS system used for iontophoretic delivery of fentanyl for post-
operative pain management, and its pipeline/developmental activities
were affected by the Johnson & Johnson acquisition (Kasha and Banga,
2008). Fig. 2 shows some of the FDA approved iontophoretic devices in
the pharmaceutical and cosmetic industry. These iontophoretic devices
are discussed further in this review.
Even though some of the products were approved or marketed in the
US, several had some limitations or setbacks, and hence were with-
drawn from the market. LidoSite™, 10% lidocaine hydrochloride (HCl),
P. Bakshi, et al.
and 0.1% epinephrine was available till 2008 and Iontocaine, 2% li-
docaine hydrochloride (HCl) and 0.01 mg/ml epinephrine topical
system till 2005. LidoSite™, an iontophoretic patch delivering lidocaine
and epinephrine, could achieve dermal analgesia in 10 min that was
faster compared to topically applied analgesics such as EMLA (eutectic
mixture of lidocaine and prilocaine), which takes 60 min to achieve
analgesia (Barry, 2001). Epinephrine/Lidocaine iontophoretic patch
(LidoSite™ from former Vyteris, Inc.) was designed for children to
achieve fast local action of analgesics. Despite achieving a fast onset of
action compared to topical cream, it had limited commercial success. In
2008, Vyteris, Inc., withdrew the product after being two years in the
market (Yeoh, 2012). In addition to the patch, another lidocaine pro-
duct on the market was a topical iontophoretic solution (Lidopel, Empi.
Inc., 2004) to produce an anesthetic effect. The topical iontophoretic
solution of lidocaine HCl 2% and Epinephrine 1:100,000 (Lidopel,
Empi. Inc., 2004) consisted of empi dupel iontophoretic system and
bilayer ultra-electrodes. The direct current was generated by the bat-
tery-powered device, and the drug was delivered through the electrodes
into the skin. However, this product was also withdrawn from the
market in 2011 (Federal Register, 2011).
Similarly, IONSYS®, an iontophoretic transdermal patch for fentanyl
delivery, has been withdrawn from the market more than two times.
This iontophoretic fentanyl patch is a self-activating delivery system for
patients to control acute postoperative surgical pain. In 2006, both the
US FDA and European Medicines Agency approved the iontophoretic
fentanyl patch (IONSYS®) for acute postoperative pain. However, cor-
rosion in the circuit system was identified in one of the lots of ionto-
phoretic fentanyl patches. This malfunction could potentially self-
trigger the device and could result in a patient overdose. Due to the
danger of overdosing, the European Medicines Agency recommended
the suspension of the product from the market in 2008 (European
Medicines Agency, 2008). However, the iontophoretic fentanyl patch
(IONSYS®) was later re-introduced to the market by The Medicines
Company after FDA approval (Businesswire, 2015) but has again been
discontinued, and all the products were withdrawn from the market in
July 2017.
Another product that was marketed is GlucoWatch® G2™
Biographer, an automatic glucose biographer device, developed by
former Cygnus, Inc. The product was a glucose monitoring device based
on the principle of reverse iontophoresis, which was discussed earlier.
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International Journal of Pharmaceutics 586 (2020) 119584
Fig. 2. Iontophoretic devices introduced in
US market for therapeutic and cosmetic use.
A) NuPathe's Zecuity® (FDA approved suma-
triptan iontophoretic transdermal system)
(ZECUITY 0000) B) IONSYS®, FDA approved
iontophoretic transdermal patch for fentanyl
(USFDA, 2018) C) Wrinkle MD®, hydrogel patch
to deliver hyaluronic acid and peptides (Eye
wrinkle treatment, 2019) D) FDA approved Fa-
cial spa device by NuFace using galvanic current
(NuFACE, 2018).
Reverse iontophoresis is essential in medical diagnostics as it can allow
noninvasive sampling of biological fluids. However, the product was
discontinued from the market; it had low demand due to high cost and
the inconvenience of still needing one finger prick each day to calibrate
the device (Tierney et al., 2001; Wang and Lee, 2015).
Class 2 category devices approved by FDA are considered “life-
supporting/sustaining/substantially relevant to human health“ but in-
volve enough potential risk that ”special controls“ are required for their
clearance (MiriamTucker, 2014). As of April 2020, FDA has classified
iontophoretic devices under class 2 devices, which are approved via a
510(k) application (Accessdata.fda.gov, 2020). Overall, FDA has
cleared 63 iontophoresis devices, mostly under 510(k) clearance. FDA
approved iontophoretic drug delivery combinations for the treatment of
local dermal anesthesia using epinephrine/ lidocaine, acute post-
operative pain management using fentanyl, and acute migraine pain
using sumatriptan delivery. At the time they were cleared, only safety
relative to a product already on the market needed to be shown. FDA
also approved NuPathe's sumatriptan iontophoretic transdermal patch
for migraine (Zecuity®). Following the successful approval of Zecuity by
FDA, Teva Pharmaceuticals acquired NuPathe Inc. for $144 million
(BioSpace 2013). However, after the brief commercial success of the
product, Teva pharmaceuticals suspended their sales for Zecuity and
investigated the cause and risk of severe burns and potential scarring
due to sumatriptan iontophoretic patch (Zecuity®) (FDA Drug Safety
Communication, 2016).
6.2. Iontophoretic devices in the cosmetic industry
The cosmetic industry primarily focuses on restoration [acne and
hyperpigmentation] and structural repair (scar treatments and anti-
wrinkle) of the skin. Cosmetic agents are usually applied topically and
delivered at the site of action, which is usually the viable epidermis and
dermis. For efficient delivery of these agents, enhancement techniques
like iontophoresis, microporation (laser and microneedles), sonophor-
esis, and microdermabrasion are being used (Scott and Banga, 2015).
This technique is also gaining recognition due to better compliance
rates and noninvasive drug delivery hence fewer side effects.
The application of iontophoresis in the cosmetic industry started in
early 1935 when iontophoresis was used in salon practice. Earlier
iontophoresis was used for cosmetic applications in dermatological
P. Bakshi, et al.
clinics, but now with the advancement in technology, smaller cosmetic
devices, and iontophoretic patches, the technology can be used at
home. Cosmetic devices marketed in the US are regulated under class I
device; a classification that does not need FDA approval before mar-
keting or class II where safety and efficacy are compared with the
commercially available cosmetic device and are approved via 510(k)
application (Newburger, 2006; Cosmetics and Skin, 2020; Class I/II
Exemptions. Health C for D and R, 2019; Wang and Lee, 2015).
WrinkleMD™ and Patchology® are examples of cosmetic ionto-
phoretic patches on the market. Cosmetic manufacturers generally refer
to galvanic microcurrent to describe the technology. The microcurrent
is provided from the electric unit that delivers cosmetic agents in the
skin through the flexible patch when placed on the skin (Patchology,
2020). NuFACE Trinity®, an FDA approved product and Nu Skin’s
Galvanic Spa System are iontophoretic devices on the market that use
microcurrent technology on skin. The current, when applied improved
facial toning and also claims to reduce the appearance of wrinkles and
fine lines on the skin. Fig. 2 shows iontophoretic devices currently on
the US market used for cosmetic purposes. These cosmetic ionto-
phoretic devices with built-in integrated battery and circuits are con-
sumer-friendly and also cost-effective compared to treatments in der-
matological clinics.
6.3. Other iontophoretic devices:
Other applications of iontophoresis include the delivery of local
anesthetic drugs. In November 2019, FDA approved the most recent
iontophoretic device, the Tula® System, by Tusker Medical Inc. (Tula®
System - P, 2020). This system consists of the Tula iontophoresis system
with the Tula tube delivery system used to deliver a solution of amide
local anesthetic and an α and β adrenergic agonist to the eardrums. The
system is approved to be used in both adults as well as children above
six months of age for the treatment of persistent fluid or infections in
the middle ear (Accessdata.fda.gov, 2020; Tula® System - P, 2020;
Crotti, 2020).
Transdermal iontophoresis is also used for the topical delivery of
anti-inflammatory agents (Costello and Jeske, 1995), analgesics, and in
the treatment of hyperhidrosis (Reinauer et al., 1993; Vlahovic, 2016).
Hyperhidrosis is the condition of excessive sweating and affects 2–3%
of the population. Tap water iontophoresis seems to offer a viable op-
tion for long-term treatment that does not require any medications.
Some of the FDA approved devices to treat hyperhidrosis currently on
the market are Hidrex PSP1000, Idromed 5 PS, and Fischer Galvanic
MD-2. These devices use direct and pulsed current to process ionto-
phoresis, and current applied induces ions to pass through the skin and
block or turn off the sweat ducts temporarily (Nawrocki and Cha, 2019;
Fischer Product, 2020; Hidrex, 2019; IontoCentre, 2020; Hyperhidrosis,
2020).
One iontophoretic product on the market that can be filled with any
drug solution is IontoPatch™ , an iontophoretic patch for extended time-
release of drugs placed in this patch and is manufactured by Travanti
Medical (IontoPatch®, 2020). It can provide noninvasive drug delivery
and is designed for use in physical medicine and rehabilitation centers.
It has a self-contained battery producing low levels of electric current,
which stops after the prescribed dose (mA-minute) is delivered. These
patches are for single-use and disposable (Banga, 2011; Costello and
Jeske, 1995). Other such devices that are on the market include Tri-
varion®, Trivarion® Butterfly, and ActivaDose® II (ActivaTek Inc., USA).
This technology allows precise dosing in a unique integrated circuit in a
device that has controls for current and time of application (Trivarion®,
2014).
7. Clinical relevance and future of iontophoresis-based drug
delivery
This section will discuss drugs that are either approved or in clinical
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International Journal of Pharmaceutics 586 (2020) 119584
development for delivery by iontophoresis.
7.1. Systemic drugs
7.1.1. Fentanyl
Approximately 75% of surgical patients suffer from moderate to
severe postoperative pain (Wells et al., 2008). This happens despite
clinical advancements and constant efforts made to the development of
better standards for pain management (Apfelbaum et al., 2003; Gan
et al., 2014). FDA approval of IONSYS®, iontophoretic fentanyl patch by
The Medicines Company, USA, was expected to provide an alternative
to the traditional IV-PCA (patient-controlled analgesia). It was the first
needle-free, patient-controlled, pre-programmed fentanyl delivery
system for patients suffering from post-operative pain. It was a short-
term pain management system for the replacement of opioid analgesia
in the hospital (The Medicines Company, 2020). In the past, it has been
demonstrated that fentanyl iontophoretic transdermal delivery provides
more tolerability and postoperative pain relief (Saffer et al., 2015).
Clinical trials for the iontophoretic fentanyl transdermal system showed
that it was equally effective and as safe as morphine intravenous [IV]
patient-controlled analgesia (PCA).
IONSYS® offered control over the analgesic dosing by double-
pressing a button to provide on-demand dosing of fentanyl by an im-
perceptible electric current. It was administered only in hospitalized
patients and not intended for use at home. However, it had the potential
to improve acute post-operative surgical pain for patients by optimizing
nursing care (The Medicines Company, 2020).
Due to the presence of fentanyl, a Schedule II controlled substance
with high abuse potential, IONSYS® was available under the Risk
Evaluation and Mitigation Strategy (REMS) program required by the
FDA. The aims of this program included a desire to reduce the risk of
respiratory depression that results from accidental exposure to non-
prescribed people (The Medicines Company, 2020). However, the
product was discontinued (July 2017), and was withdrawn from the
market based on a business decision by The Medicines Company and
was claimed to have no quality or safety issues with the product for
withdrawal.
7.1.2. Sumatriptan
Migraine is a common condition affecting 10% of the adult popu-
lation worldwide (Morillo, 2002). One class of drugs, triptans, are
commonly used as anti-migraine agents and are an agonist of 5-HT1
family receptors (Brandt et al., 2020). Sumatriptan is the most widely
prescribed triptan. Currently, marketed formulations of sumatriptan,
with other routes of delivery, have their respective advantages and
disadvantages. Parenteral delivery provides a good response, but the
patient suffers from more adverse side effects compared to other routes
of administration. Moreover, injections bring discomfort to the pain.
Oral formulations are more patient compliant, but most of the
people suffering from migraines experience nausea or vomiting during
their migraine attacks, making oral absorption unreliable (Vikelis et al.,
2012). The half-life of sumatriptan is only 2 h, and most of the active
drug is eliminated within 4–6 h in the majority of the patients (Tfelt-
Hansen, 1998). Nasal and oral formulations of sumatriptan suffer from
poor bioavailability, whereas subcutaneous administration in the form
of injections leads to rapid effect. Thus, due to reasons discussed,
transdermal delivery offers advantages over other routes of adminis-
tration. Sumatriptan is a relatively hydrophilic drug (Ahn and Basbaum,
2005); hence transdermal iontophoretic delivery of the drug is ideal.
Iontophoresis delivers a steady-state of therapeutic drug levels over a
more extended period. This sustained therapeutic level is helpful for
patients to avoid recurrence that is likely to occur due to its short half-
life. It yields lower Cmax with comparable AUC, yielding a safer de-
livery profile with fewer side effects (Siegel et al., 2020; Siegel, 2005).
Fig. 3 illustrates the pharmacokinetic profile of sumatriptan following
iontophoretic delivery. Plasma levels are maintained around 20 ng/ml
P. Bakshi, et al.
Fig. 3. Sumatriptan plasma concentration over time for each formulation.
Iontophoretic delivery of Sumatriptan shows a maintained level of 20 ng/ml
until the cessation of iontophoretic delivery at 4 h. Reproduced from (Pierce
et al., 2009 Jun 1) with permission from Elsevier.
until the termination of iontophoretic delivery at 4 h. Thus, ionto-
phoresis based transdermal delivery of sumatriptan offers rapid but
steady and non-invasive drug delivery approach (Pierce, 2010; Siegel,
2005).
The maximum plasma concentration (Cmax) achieved with the su-
matriptan patch was 30% lower than that achieved by the subcutaneous
route. Lower Cmax reduces the adverse effects of the patch as compared
to S.C. administration (Rapoport et al., 2010). FDA had approved a new
drug application of iontophoretic patch containing Sumatriptan (Ze-
cuity®, formerly NP101- Zelrix™, Nupathe Inc., Conshohocken, PA,
USA) (BioSpace 2013). The iontophoretic device for sumatriptan was
designed to reach therapeutic dose (with 4 mA for 1 h followed by 2 mA
for 3 h) within four hours. As discussed previously, iontophoretic de-
livery of sumatriptan maintained a constant level of 20 ng/ml until the
termination of iontophoretic delivery at 4 h (Pierce et al., 2009;
ZECUITY®, 2015). However, the product is currently discontinued, as
discussed earlier.
7.2. Local treatment- Lidocaine/Epinephrine
LidoSite™ (from former Vyteris Inc., Fair Lawn, NJ, USA) was ap-
proved by FDA in 2004 and was a lidocaine patch in combination with
epinephrine. The combination with epinephrine helps reduce the blood
flow at the delivery site, thereby decreasing systemic uptake and in-
creasing the dermal concentration. The current density used in
LidoSite™ patch was 0.35 mA/cm2 and was to be applied for 10 min,
with the patch formulation designed to be at pH 4.5, at which both
lidocaine and epinephrine are positively charged (USFDA Drug
Approval Package, 2004; Lidosite, 2007). However, the product also
has been discontinued since 2006 due to the reasons discussed earlier in
this review.
7.3. Other potential applications
The development of integrated circuits and miniaturized or coated
batteries will enable the design and manufacture of compact credit-
card-sized patches, further improving patient acceptance of this tech-
nology. The industry will do a better if they focus on niche products
with significant unmet needs to use this technology so that there are no
insurance reimbursement issues. More product approvals are expected,
and approval will be easier to obtain for drugs that are intended for
localized effects on the skin. As iontophoresis shows a preference for a
trans-appendageal route, this widens horizons with regards to the
treatment of follicular diseases or hair treatments. The cost of the
6
International Journal of Pharmaceutics 586 (2020) 119584
product is a challenging factor. Other challenges involve avoiding dose
dumping and formulating an electronically safe device.
Cigarette smoking is harmful to health and is a primary contributing
factor for lung cancer. Therefore, smoking cessation is highly desired to
reduce health risks. Currently, nicotine replacement products such as
nicotine patches and bupropion are being used to address the problem
of smoking cessation (Nicotine Transdermal Patch: MedlinePlus Drug
Information, 2019,). However, to explore other drugs for transdermal
delivery, combinational approaches with iontophoresis are being in-
vestigated. This novel approach will help the investigation of more
drugs for smoking cessation. One such drug for smoking cessation,
nortriptyline hydrochloride delivery, has been delivered by ionto-
phoresis along with permeation enhancers, isopropyl myristate (20%,
w/w), and propylene glycol (15%, w/w). The efficient delivery of
nortriptyline hydrochloride was observed by the combinational ap-
proach of iontophoresis with permeation enhancers (Escobar-Chávez
et al., 2009; Merino et al., 2008).
Iontophoresis has been explored for use in the treatment of skin
cancers in order to avoid the significant side effects associated with
anti-cancer drugs. One such study was carried out on cetuximab, an
anti-EGFR monoclonal antibody for the treatment of non-melanoma
skin cancer. Therapeutically relevant concentrations of cetuximab were
obtained in the epidermis, upper dermis, and lower dermis after 1 h,
4 h, and 8 h, respectively proving the potential of anti-cancer drugs for
non-invasive transdermal delivery. (Lapteva et al., 2020)
Also, iontophoresis technology has been explored for the treatment
of skin diseases like psoriasis. Psoriasis is an inflammatory skin disorder
associated with the uncontrolled growth of epidermis. One of the sig-
nificant challenges in the conventional treatment of psoriasis is the
inability of the therapeutic drug to penetrate the layers of the skin.
These barriers can be overcome by iontophoresis, and iontophoretic
delivery of methotrexate has been investigated for the treatment of
psoriasis (Dhote et al., 2012; Vemulapalli et al., 2008; Vemulapalli
et al., 2008).
8. Clinical investigations with iontophoresis
Iontophoretic delivery of lidocaine has been thoroughly in-
vestigated. Draper et al. were able to deliver 2% lidocaine and epi-
nephrine with iontophoresis within 10 min in a clinical setting at
40 mA/min. Lidocaine was detected at a depth of 5 mm below the skin
surface. The total concentration delivered was more than 18% (Draper
et al., 2011). In another study, the effectiveness of lidocaine ionto-
phoresis was investigated to inactivate trigger points in the treatment of
myofascial pain syndrome. Anxiety and depression scores were sig-
nificantly improved by using direct current with and without lidocaine
iontophoresis at three mA for 10 min (Kaya et al., 2009). The Pulsed
dye laser is a therapy used for the treatment of port-wine stains, but the
treatment is painful and requires repeated sessions. Iontophoresis of
lidocaine with and without epinephrine was observed to be a safe and
effective method of local anesthesia and does not affect the treatment
efficacy (Kennard and Whitaker, 1992).
Iontophoretic delivery of lidocaine was also investigated for the
treatment of chronic arthritis in children, Juvenile Idiopathic Arthritis
(JIA). A clinical study performed on children showed delivery of 2%
lidocaine with local anesthetic (EMLA®) cream provides an excellent
alternative to painful joint injections (ClinicalTrials.gov, 2019). Topi-
cally applied drugs for the treatment of herpes labialis (cold sores)
exhibit lower levels of efficacy due to limited permeability through the
skin. Iontophoresis offers enhanced drug delivery through the skin by
using low levels of electric current. Clinical studies performed on ion-
tophoretic Zovirax (acyclovir) Cream was achieved, having 5% delivery
(ClinicalTrials.gov, 2007).
Further, in one of the clinical studies, transdermal delivery by ion-
tophoresis of prokinetic agents like neostigmine and glycopyrrolate was
investigated for the promotion of bowel evacuation. Bowel care can be
P. Bakshi, et al.
a cumbersome process for patients suffering from spinal cord injury.
Successful delivery of neostigmine and glycopyrrolate was observed
across the skin by anodal iontophoresis (ClinicalTrials.gov, 2015). Pa-
tients suffering from spinal cord injury are at risk of metabolic disorders
and sometimes suffer from resistance to insulin. In one clinical study,
patients suffering from spinal cord injury and having resistance to in-
sulin were given insulin by iontophoretic delivery (La Fountaine et al.,
2013). However, as insulin is a large molecule with an isoelectric point
similar to skin pH, there is also literature reporting several challenges in
the transdermal delivery of insulin (Banga, 2011).
Several more clinical studies have been performed recently for
iontophoretic delivery of therapeutic agents like terbinafine on nails
and corticosteroids in the eye, but only studies relevant to the skin are
summarized in this review.
9. Conclusion
Iontophoresis has been known for its therapeutic applications,
particularly in physical therapy and dermatology. An iontophoretic
device, though more complicated than an adhesive passive diffusion
patch, can enable the delivery of hydrophilic small and large molecules
that would not usually permeate the skin. There have been numerous
publications investigating this mode of delivery for both localized and
systemic drug delivery. Several companies have successfully commer-
cialized this technology. The combination of iontophoresis with other
technologies is also being investigated and has proven to be successful.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
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