Transdermal Permeation Enhancement by Iontophoresis : A Review
Garala Jasmin1,3*, Tank H. M.2, Shiroya Umesh3, Fadadu S.D.4
1
School of Pharmacy, RK University, Rajkot, Gujarat.
2
V. B. Manavar College of Pharmacy, Dumiyani, Rajkot, Gujarat.
3
Astra Lifecare (India) Pvt. Ltd., Ahmedabad, Gujarat.
4
Shree Swaminarayan College of Pharmacy, Kalol, Gandhinagar.
*Corresponding
Author: Garala Jasmin
E-mail: jasmingarala@gmail.com
Contact No. +91-7600563947
1
ABSTRACT
The skin is an attractive route for drug administration due to its large surface area.
Several transdermal systems have been developed and marketed now a days. Iontophoresis is one
of transdermal approach in enhancement of transdermal permeation of drug. Iontophoresis 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 skin. Transdermal
iontophoretic drug delivery provides steady state drug concentration in blood, elimination of
hepatic first-pass effects, increased patient compliance and dose dumping never occurs.
However, transdermal delivery by iontophoresis has been hindered by poor Permeability from
stratum corneum of the skin. This article is an overview of the theory, mechanism, principles and
factors influencing iontophoresis.
Key words: Iontophoresis, Transdermal, External energy, Permeability.
2
Introduction
Drug delivery through skin has become one of the most successful and innovative focus for
research in drug delivery, with around 40% of the drug candidate being under clinical evaluation
related to transdermal or dermal systems.1 Transdermal delivery of drugs through the skin to the
systemic circulation provides a convenient route of administration for a variety of drugs.2 The
benefits of using transdermal drug delivery include improved systemic bioavailability resulting
from by passing the first pass metabolism.3 Variables due to oral administration, such as pH, the
presence of food or enzymes and transit times can be eliminated.4 In the development of new
transdermal drug delivery devices the object is to obtain controlled, predictable and reproducible
release of drugs into the blood stream of the patient. The transdermal device acts as a drug
reservoir and controls the rate of drug transfer.5
Transdermal delivery of drug prevents the degradation of drugs in the gastrointestinal tract and
their subsequent metabolism due to hepatic first pass effects. It also allows controlled drug
delivery to the target tissues, thereby reducing the potential adverse effects associated with oral
route. The outermost layer of the skin, stratum corneum is the rate limiting step for the entry of
drug through skin. As a result only a small number of drugs commercially available using
transdermal systems with limited daily drug dosage to about 10 mg via an acceptable sized patch.
Moreover, transdermal drug delivery is not suitable to all drugs.6 Currently most of drugs
transdermally administered have been small in molecular weight (≤500 Da), highly lipophilic
and require small dosages.7 (Table 1)
It has been even more challenge to exploit the transdermal route to deliver hydrophilic drugs and
large molecules such as peptides and macromolecules into blood circulations, including new
genetic treatment of DNA or small-interfering RNA.8
3
In order to extend the application of transdermal delivery to more agents encompassing different
therapeutic areas, various penetration enhancement techniques have been investigated over the
years. Several different strategies have been explored to increase permeability of the skin.9
Various physical and chemical enhancement methods or their combination have been
investigated to enhance efficiency of transdermal drug delivery.10
Chemical enhancement methods involve the use of various chemical enhancers such as organic
solvents, surfactants, etc.11
Physical methods include Iontophoresis, Electroporation, Sonophoresis, stratum Corneum
ablation, microneedles.12
Chemical enhancement methods have been widely studied and they work to increase the drug
flux by one or a combination of the following mechanisms:13,14
i)
Disruption of the lipid structure in the stratum corneum,
ii)
Opening up the dense protein structure in the corneocytes,
iii)
Altering the chemical environment in the stratum corneum, thereby increasing the
partitioning of a second active agent into skin.
However, the type and amount of chemical enhancers that can be used in transdermal
applications is restricted by their skin irritation potential.
Physical
enhancement
methods
include
electrically assisted
methods
(Iontophoresis,
Electroporation), mechanical methods (Microneedles), velocity-based techniques such as jetpropulsion, or other methods such as ultrasound, laser and photomechanical waves.15,16 Out of
the various enhancement methods, transdermal iontophoresis, which uses low level electric
current (~0.5 mA/cm2) to enhance the transdermal delivery of charged substances through skin,
4
has been extensively studied in the past years. Various Devices for non-invasive blood
monitoring have been developed and successfully commercialized. 17
Iontophoresis has also demonstrated great value for delivery of macromolecules like proteins and
peptides as it enhances their transdermal permeation while protecting them from the harsh
proteolytic environments encountered with oral delivery.18
Principle of Iontophoretic drug delivery
Iontophoresis is based on the simple principle of any electrically based system, that is, “Like
charges repel while opposite charges attract.”
An iontophoretic drug delivery system has three basic components:19
1. Energy source: Usually consists of a battery or low voltage direct current generator.
2. Electrodes:
a) Active electrode: An electrode containing ionic drug
b) Reference electrode: An electrode containing salt or buffer solution.
3. Lead wires: Consisting of positive and negative lead
A set of electrode systems is used to create these repulsive and attractive forces that provide
external energy to drug ions for passage across the skin, thereby increasing drug permeability
through the membrane.20 These principles have led to the development of two types of
iontophoresis: Anodal iontophoresis and Cathodal iontophoresis. Positively charged ions can
be delivered by placing them under the positive electrode (anode) creating repulsion and at the
same time creating an attractive force by placing the negative electrode on the skin. This system
is called anodal iontophoresis, and a typical setup is illustrated in Figure 1. For cathodal
iontophoresis, the electrodes are reversed so that a negatively charged drug is delivered through
skin. Figure-1 illustrates a system that comprises of silver-silver chloride (Ag/AgCl) electrodes,
the most commonly used electrodes in iontophoretic systems.21 The Ag+ and Cl- react at the
5
anode-solution interface to form insoluble AgCl which is deposited at the electrode. In order to
maintain electroneutrality, either a cation moves out of this compartment into the skin or an
anion from the skin is taken up in this chamber. Similarly, in the cathodal compartment,
reduction of the AgCl to Ag+ at the electrode leads to release of a Cl- ion into solution, which
necessitates the uptake of a cation from the skin or loss of an anion from the chamber.22
(Figure-1)
Drug Transport in Iontophoresis
A large portion of iontophoretic permeation enhancement occurs due to the effect of the applied
electric current on the migration of charged molecules across the skin, a phenomenon called
electromigration or electrorepulsion. The applied electric current also gives rise to a water
transport phenomenon, called electroosmosis,23 which also contributes to iontophoretic transport
of molecules. While electrorepulsion occurs due to repulsion of similarly charged molecules,
electroosmosis is a facet of the cation permselectivity that occurs as a result of the net negative
charge on the skin at physiological pH (7.4).24 This cation permselectivity can facilitate cation
transport, present an electrostatic barrier to anion transport and enhance the transport of neutral
or polar solutes. This results in a net volume flow, called electroosmosis, in the direction of
movement of the positive ions, and neutral molecules, such as water can be transported by this
process. Electroosmostic flow is favored in the anode to cathode direction while catholic delivery
is retarded. Iontophoretic transport is primarily driven by electrorepulsion and electroosmosis,
and to a smaller extent by passive diffusion. Thus the total iontophoretic flux, JTotal can be
described as:25
J Total = Je + Jc + Jp …………… (1)
Where,
6
Je = Flux contribution due to electrorepulsion,
Jc= Flux contribution due to electroosmosis
Jp= Flux contribution due to passive diffusion.
It has been considered that in all practical iontophoretic applications, J p will form a negligible
fraction of JTotal with the contribution becoming even smaller with increasing molecular weight
of agents.
Je is a function of charge, mobility, concentration of the drug in the membrane and applied
current density.
Jc = v·cx …………… (2)
where cx is the concentration of the compound and v is the electroosmotic solvent velocity.
Quantification of the contributions of each processes is difficult, it has been suggested that
electrorepulsion enhances the transport of small cations such as Na+ and then falls off sharply
with increasing molecular weight of the species, and electroosmosis becomes the more dominant
mechanism, especially with bulkier cations of higher molecular weights (≥ 1000 daltons).26,27
Similarly, for anions, there will be a point where the increase in molecular weight will lead to the
effects of electrorepulsion and electroosmosis cancelling out and the cathodal delivery will
become prominent.
The contribution that each component makes to the total flux is depends on several factors such
as the physiochemical properties of the permeant including the degree and type of charge, the
properties of the solution and the properties of the membrane.
7
Mechanism of iontophoresis 28,29,30
Iontophoresis enhances transdermal drug delivery by various mechanisms. Mechanism depends
on various factors like type of ion, property of skin, applied electric current etc. (Table-2)
Pathways for Iontophoretic Transport
There are three primary routes of passive skin permeation are transcellular, paracellular or
transappendageal pathway. Iontophoretic transport is said to occur primarily through the
transappeandageal (shunt pathway) and the paracellular route, however the appendageal pores
such as the hair follicles and the sweat glands are most efficient in iontophoresis and major
transport occurs through this route. The efficiency of iontophoretic transport is frequently below
100% due to several variables influencing the transport efficiency.38,39 (Figure -2)
Advantages40,41,42,43,44,45
Advantages of iontophoretic technique can be summarized as follows:
1. Avoids the risk and inconveniences of parenteral therapy.
2. Delivery of ionized, unionized and macro molecules like Insulin.
3. Non invasive administration with improved bioavailability.
4. Controlled administration of drugs through unbroken skin for systemic medication.
5. Termination and modification of therapy is possible in case of toxicity.
6. Controlled drug delivery is possible since the amount of drug delivered depends on
applied current, duration of applied current, and area of skin exposed to the current.
7. Variation in the absorption and metabolism is less as compared with oral administration.
8. Inter and intra individual variability is less because drug delivery is more dependent on
applied current than on stratum corneum characteristics.
9. Drug with narrow therapeutic index and short biological half life can be administered.
8
10. Reduces dosage regiment i.e. dose and dosing frequency
11. Depending on the current applied both continuous and pulsatile delivery of drug possible.
12. In combination with other permeation enhancer delivery of polar molecules as well as
high molecular weight compounds possible.
13. Enhanced safety, efficacy, reliability and acceptability.
Disadvantages46,47,48,49
1. After iontophoretic application, sometime produce pigmentation or skin irritation.
2. Drugs which produce skin irritation, cannot delivered by iontophoresis.
3. Low dose of dreg can be delivered usually 5 to 10mg/hr.
4. High current strength or applications for longer periods can lead to pain, burning
sensation, blister formation and skin necrosis.
5. Iontophoresis is not suggested for under arm or facial / head hyperhydrosis.
6. High drug concentration in blood is not possible with iontophoresis.
7. Skin disease can alter permeation of drug.
8. Iontophoresis is restricted to drugs that can be formulated in ionized form.
9. The high current density and time of application would generate extreme pH, resulting in
a chemical burn.
10. Ionic form of drug in sufficient concentration is necessary for iontophoretic delivery.
Factors Affecting Iontophoresis
Structural arrangement of human skin is same in all people. There are numerous differences
among patient groups as well as between various regions of the body, age and ethnicity. Various
factors have been shown to affect the results of iontophoresis. The following factors have to be
9
considered because they may improve the drug delivery from the device and drug release
kinetics.50,51,52,53
1. Physiochemical Properties (Table-3)
2. Drug formulation related factors (Table-4)
3. Experimental factors (Table-5)
4. Biological factors (Table-6)
Synergistic Effect of other Enhancers with iontophoresis
To improve transdermal drug delivery, various physico‐chemical penetration enhancers are used
other than iontophoresis that includes ultrasound, chemical enhancers, and electroporation. The
following combinations of iontophoresis with other techniques have been used for transdermal
drug delivery:
i)
Iontophoresis + Chemicals
ii)
Iontophoresis + Ultrasound
iii)
Iontophoresis + Electroporation
iv)
Iontophoresis + Microneedles
1. Iontophoresis and chemical enhancer
Iontophoresis enhances transdermal drug delivery via electrorepulsion, electroosmosis, or
enhanced diffusion. On the other hand, chemical enhancers increase transdermal drug delivery
via several different mechanisms, including increased drug solubility, increased drug partitioning
into the Stratum corneum fluidization of lipid bilayers, and disruption of the intracellular
proteins.91,92
Propylene glycol, Oleic acid etc. enhances transdermal transport of various drugs synergistically
in combination with iontophoresis. Application of propylene glycol and oleic acid enhances
10
transdermal flux of Zidovudine by about 200‐fold. On the other hand, application of
iontophoresis alone enhances Zidovudine flux by 7‐fold. However, the combination of propylene
glycol and iontophoresis enhances Zidovudine flux by about 400‐fold.93
2. Iontophoresis and Ultrasound
The synergistic effect of ultrasound and iontophoresis on transdermal transport was attributed to
ultrasound‐induced structural changes in the skin. Application of ultrasound should alter lipid
bilayers of the skin, thereby introducing iontophoresis and ultrasound result in enhancement of
transdermal drug delivery.94,95
3. Iontophoresis and Electroporation
The mechanism for the synergistic effect of iontophoresis and electroporation is likely to be
similar to that of iontophoresis and ultrasound. Electroporation may create new transport
pathways in the stratum corneum. Thus helps to produce synergistic effect along with
iontophoresis.96
4. Iontophoresis in conjunction with microneedles
Few studies have reported the combination of iontophoresis with microneedle technologies.
Microneedles produces micro pores in stratum corneum which helps to increase drug transport
through skin. This combination may provide the possibility of macromolecule transdermal
delivery with precise electronic control.13,35
Application of iontophoresis
Transdermal iontophoretic systems have the potential to produce reproducible enhancement of
transdermal drug delivery. Also programming or control of the drug kinetics through the device
makes this delivery system ideal for various treatment. Enhancement of transdermal permeation
11
by iontophoresis has been demonstrated for several small molecules such as Apomorphine,
sumatriptan, 5-fluorouracil, rotigotine and buspirone hydrochloride.97,98,99,100,11,67
Application of iontophoresis various fields includes Treatment of hyperhydrosis,101 Diagnostic
purpose,102 Ophthalmology,103 Otorhinolaryngology,101 Dentistry,104 Peptide delivery18 and Noninvasive monitoring of glucose104 etc.
List of iontophoretic products under development stage are tabulated in Table-7.3
Conclusion
The electrically driven penetration enhancement provided by this method has succeeded in
overcoming the formidable barrier presented by the Stratum Corneum, 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 led to the significantly higher flux levels compared with passive transdermal delivery.
Electrically assisted delivery systems provide the advantage of controlled drug delivery with
customised drug input rates, and an option of termination of drug transport when desired. It
seems that iontophoresis is close to commercialization. But till iontophoretic delivery of polar,
non ionic, and macromolecules like proteins and peptides is a challenging field.
12
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23
Figure 1: Anodal iontophoresis.
24
Figure-2: Pathways for Iontophoretic Transport of drug across skin: 1. Through the sweat ducts;
2. Directly across the stratum corneum; 3. via the hair follicles.
25
Table-1: Formulation considerations for passive transdermal delivery and ideal limits.
Aqueous solubility
Lipophilicity
Molecular weight
Melting point
pH of saturated aqueous solution
Dose deliverable
Abbreviation: Ko/w = Oil-Water partition coefficient.
> 1 mg / ml
10 < Ko/w < 1000
< 500 Dalton
< 200 oC
pH = 5 - 9
< 10 mg / day
26
Table -2: Various Reported Mechanisms for Iontophoratic Transport
Electromigration / Electric field provide external energy to drug ions for passage across the
skin, thereby increasing drug permeability through the membrane31
Electrorepulsion
Electroosmosis produces bulk motion of solvent that carries ions or
Electroosmosis /
neutral molecules with the solvent stream. The skin is negatively charged
Convective force
at pH values above 4, to maintain electroneutrality positively charged
small ionic drug easily penetrate in to the skin to neutralize the charge.32
The molecular arrangement of skin is altered by applied electric current.
“Flipflop” gating
This alteration leads to change in the skin permeability.33,34
When an electric current is applied across a cellular membrane a
voltage‐dependent “flip‐flop” of polypeptides helices occurs. This causes
a voltage dependent rearrangement of the helices and pore formation in
the stratum corneum.35,36,37
27
Table-3: Physiochemical Properties Affecting Iontophoresis.
Molecular size
 Smaller and more hydrophilic ions are transported at a faster rate than
larger ions.54
 When the molecular size increases, the permeability coefficient
decreases.55
 Transport of compounds decreased with increase in molecular weight
(chloride> amino acid >nucleotide > tripeptide >insulin)56,57,58,59,60
Charge of drug
 Transport of cations has been shown to be better than anions for amino
acids and peptides.61,62,63
 An increased positive charge on peptide, cause it to bind tightly to the
membrane creating a reservoir which in turn can decrease the rate at
which the steady state flux will be achieved.64
Polarity
 Compounds which are hydrophilic are considered ideal candidates for
optimum flux.65
Drug
 An increase in concentration was shown to increase the apparent steady
Concentration
state flux of a number of drugs e.g., metoprolol.66
 Iontophoretic transport of drug increase with increase in drug
concentration.67
 O’malley et al., showed the flux of solute was non-linearly proportional
to its concentration.68
 Permeation of drug through iontophoresis increases with increase in
reservoir system concentration.
28
Table-4: Drug Formulation Related Factor Affecting Iontophoresis.
pH
 pH is an important factor governing the iontophoretic delivery of drugs.52,69
 The pH of the donor solution influences the pH of the skin and thus makes
the skin a permselective membrane especially if the pH of the skin rises
above 4.
 The pH of the donor solution also affects the ionization of the drug itself.
 A weakly basic drug will be ionized to a lower extent at pH higher than its
pKa and will not permeate by electromigration in presence of
iontophoresis.
 Several authors reported the pH dependent penetration enhancement of
insulin, Lidocaine, enalaprilate and acetate ions.70,71,72,73
Ionic
 The ionic strength of a drug delivery system is directly related to the
strength
iontophoretic permeation of drugs
 Increase in the ionic strength of the system decreases the permeation rate of
drug and has no significant effect on penetration up to the 0.5 V.74,75
 Many peptides widely studied for ionic strength showed a higher flux
occurring at low electrolyte concentration.76,77,78
 However tiwari et. al. showed increased flux at low ionic strength.79
Presence of
 The presence of a co-ion (ion with the similar charge as the drug) results in
co-ions
competition between the drug and the co-ion, can reduce the fraction of the
current carried by the drug and thus a reduction in the transdermal
iontophoretic flux of the drug.80
29
Table-5: Experimental Factors Affecting Iontophoresis
Current
 There is a linear relation between the current and flux
 Current should not be applied for more than 3 min because of local skin
irritation and burns.
 Iontophoretic current which should be used on human beings will be
between 0.1 - 0.5 mA/cm2.81
Current
 The current density should be sufficiently high to provide a desired drug
density
delivery rate but should not produce any harmful effect to the skin.
Pulsed
 The continuous use of direct current (DC), proportional to time, can reduce
current
the iontophoretic flux because of its polarization effect on the skin. This
can be overcome by the use of pulsed DC which is a direct current
delivered in a periodic manner.82
Duration of
 The transport of drug delivery depends on the duration of current applied in
application
iontophoretic drug delivery.83
 The iontophoretic penetration of drug linearly increased with increasing
application time in case of insulin delivery, 2-3 fold reduced the blood
glucose levels with increase in duration of iontophoretic application.84
Electrode
 The most common electrodes are aluminum foil, platinum and silver/silver
materials
chloride electrodes used for iontophoretic drug delivery.85,86
 The iontophoretic penetration of drug within the skin depends on the size,
type and position of electrodes.
 Larger electrode introduce the greater amounts of drug but produces local
skin irritation
 Metal electrodes touching to the skin produce burns
 A loose contact between the padded electrode and skin also produce burn
due to uneven distribution of current.87
30
Table-6: Biological Factors Affecting Iontophoresis
Intra and inter
 Small differences in the flux rate following transdermal
subject
iontophoresis between males and females, as well as between hairy
variability
and hairless skin.88
Regional blood
 Greater blood flow at drug delivery site helps to maintain high
flow
concentration gradient and supports osmotic flow.
 Roberts et al.,showed that blood did not affect the penetration of
drug through the epidermis.89
Condition of skin
 Passive diffusion of drug using skin from different areas of human
body observed the following rank order: abdomen> forearm>
instep> heel> planter, for all subjects.90
31
Table -7: Iontophoretic products under different development stages
Drug/Delivery system
Development stage
Glucose monitoring system based on reverse iontophoresis Awaiting US FDA approval
Reusable power supply controllers Lidocaine patches
Under development Phase III
clinical trials
On-demand delivery system of fentanyl for acute pain
Phase III clinical trial
management.
IontoDexdexamethasone sodium phosphate system for
Phase III clinical trials
acute local inflammatory conditions
Hydromorphone for pain management.
Phase IIb clinical trials
Disposable and reusable systems for delivery of antiUnder development
emetics and analgesics
Local delivery of antimicrobials to the skin.
Under development
Wearable iontophoretic patches
Under development
32