Download The use of electric current – Iontophoresis for transcutaneous drug

Mohammad Younis Bhat, et al / Int. J. of Res. in Pharmacology & Pharmacotherapeutics Vol-3(3) 2014 [237-245]
International Journal of Research in
Pharmacology & Pharmacotherapeutics
ISSN Print: 2278-2648
ISSN Online: 2278-2656
IJRPP |Vol.3 | Issue 3 | July-Sep-2014
Journal Home page: www.ijrpp.com
Review article
Open Access
The use of electric current – Iontophoresis for transcutaneous drug
delivery – Novel drug delivery system (NDDS)
*Mohammad Younis Bhat1, Samina Farhat2,Vineeta Sawhney3, ShabirAhmd Mir4
1
Senior Resident, Department of Pharmacology, Govt. Medical College Srinagar.
2
Associate Professor and Head, Department of Pharmacology, Govt. Medical College Srinagar.
3
Assistant Professor, Department of Pharmacology, Govt. Medical College Srinagar.
4
PG Scholar, Department of Surgery, Govt. Medical College Srinagar.
.*Corresponding author: Mohammad Younis Bhat.
E-mail id:
[email protected]
ABSTRACT
The method by which a drug is delivered can have a significant effect on its efficacy. Some drugs have an optimum
concentration range within which maximum benefit is delivered, and concentrations above or below this range can
be toxic or produce no therapeutic benefit at all. On the other hand, the very slow progress in the efficacy of the
treatment of severe diseases, has suggested a growing need for a multidisciplinary approach to the delivery of
therapeutics to the targets in tissues with new ideas on controlling the pharmacokinetics, pharmacodynamics, nonspecific toxicity, immunogenicity, bio recognition, and efficacy of drugs. These new strategies often called drug
delivery system (DDS) are based on interdisciplinary approaches that combine polymer science, pharmaceutics, bio
conjugate chemistry, and molecular biology and have generated much attention during the last decades. Drugs
administered through these systems escape first-pas metabolism and maintain a steady state scenario similar to a
continuous intravenous infusion for up to several days. However, the excellent impervious nature of the skin offers
the greatest challenge for successful delivery of drug molecules by utilizing the concepts of iontophoresis. The
rationale behind using these techniques is to reversibly alter the barrier properties of skin, which could possibly
improve the penetration of drugs to increase the systemic delivery with controlled input kinetics and minimum intersubject variability.
Keywords: Pharmacokinetics, Pharmacodynamics, Immunogenicity, Bio recognition, Iontophoresis.
INTRODUCTION
The design of a dosage form, whether in the form of
a tablet, capsule, pill, cream, liquid, ointment,
aerosol, injectables, suppositories or patch, to deliver
the exact amount of medicine at right time to the
specific target becomes complicated if each
medication were not to be delivered in an optional
and preferred manner to the individual patient 1.
Newer dosage forms and drug delivery systems
providing excellent improvement in drug therapy are
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termed novel drug delivery system (NDDS) because
of recent development with satisfactory results in the
field of drug delivery2.The NDDS are being
investigated so as to alter the body distribution of
drug(s) with a view to reduce the toxicity of drug
and/or deliver them more efficiently to their site of
action to improve therapeutic index and lower the
toxological risks from the dosage of drug3,4. The
increased attention on patients compliance and
reduction in dose frequency has led to the
development of an alternative and desirable approach
of taking medicine, other than oral route for drug
action, which is to deliver them through the skin4 – a
major barrier to the delivery of transcutaneous
drugs5,6,7,8 and pharmaceutical companies are
continually involved in research to try to find new
ways to enhance the delivery of topical drugs8. Some
of the novel advanced transdermal technologies
include9:
In recent times, there has been a growing interest in
simulating the advantages of intravenous drug
infusion by using intact skin as the port of drug
administration5,6,7. Skin is one of the most extensive
and readily accessible organs of the human body. In
modern day pharmaceutical practice, therapeutic
compounds are applied to the skin for dermatological
(within the skin), local (regional) and transdermal
(systemic) delivery. For transdermal delivery of
drugs, stratum corneum is the main barrier layer for
permeation of drug10which is the uppermost layer of
the epidermis with a thickness of between 10and consists of several layers of corneocytes
(nucleate keratin filled cells) in laid in a lipid matrix,
a continuous medium through the SC, arranged in
bilayers11,12. So to circumvent the stratum corneum
and to increase the flux through skin membrane,
different approaches for enhancement of penetration
are used13.Much effort has been dedicated to
improving impermeability14 and one of the ways for
circumventing the stratum corneum barrier include
iontophoresis.
Iontophoresis
Iontophoresis, derived from the Greek “ionto”
meaning ‘ion’ and “phoresis” meaning ‘to bear’
involves enhancing the permeation of a topically
applied therapeutic agent by the application of a low
level electric current either directly to the skin or
indirectly via the dosage form15,16,17,18.
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Historical Background of Iontophoretic
Process
Clinical application of current can be traced back to
the ancient time of the golden age of the Greek
civilization and was probably originated by Varatti in
1747. Galvani and Vota in 18th century combined the
knowledge that the electricity can move different
metal ions and the movement of the ions produce
electricity.
This
method
of
administering
pharmacological agents by iontophoresis became
popular at the beginning of 20th century due to work
of Leduc (1900) who introduced the term
iontotherapy and formulated the laws for this process.
Until the early 20th century, current medicated drug
delivery was known as “cataphories”. Frankenhauses
is said to have introduced the term “iontophoresis”
before 1908. The phoresor device was the first
iontophoretic system to be approved by the FDA in
the late 1970’s as a physical medicine therapeutic
device in order to enhance patient’s compliance, the
use of patient-friendly, portable and efficient
iontophoretic systems have been under intensive
development over the years. Such improved systems
include the Vyteris and E-TRANS iontophoretic
devices19,20,21.
Iontophoretic Research and Drug Delivery
The physiochemical properties of the molecule have
an effect on the contribution of the follicular and nonfollicular routes of penetration. Hydrophilic
molecules tend to localize in the hair follicles,
whereas lipophilic molecules are mostly distributed
in the lipid intercellular organs of the SC and the
lipid membrane of the epidermal keratinocytes22.
Since passive transdermal permeation of the majority
of the drugs needs enhancement to achieve clinically
relevant plasma concentration, both chemical and
physical enhancement methods have been developed.
Iontophoresis is one of the physical methods. There
are three major enhancing mechanisms for drug
reflux through the skin, which include: Iontophoresis
(also known as electro repulsion, electro migration or
Nernest-Planck effect), electro-osmotic flow23-27 and
current induced increase in skin permeation, also
known as damage effect28. Electro repulsion is the
direct effect of the applied electric field on a charged
permeant and gives the largest enhancement to the
flux of small lipophilic cations29. The second
mechanism, electro osmosis, results from the fact that
the skin supports a net negative charge at
physiological pH30,31,the counter ions are cations and
the electro osmotic flow is thus from anode to
cathode. Therefore, the cathodic delivery of anions is
hindered and the anodic delivery of cations is assisted
by electro osmosis which has a positive contribution
to the transport of cations and a negative contribution
to the transport of anions under normal physiological
conditions. The impact of electro osmosis ion transfer
increases with the size of the ion32. The contribution
of electro osmosis can be so significant that the
delivery of large anion from the anodic compartment
can be more efficient than delivery from cathode, this
is called wrong way iontophoresis25. The other
mechanism is current induced increase in skin
permeation, also known as damage effect. In the
presence of an electric field, electro migration and
electro osmosis are the dominant forces in mass
transport33.
Diagram of iontophoretic technique: as current is applied the drug cations are repelled and move through the skin
and eventually they are absorbed in the systemic circulation.
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Because of the complex nature of iontophoretic
delivery, a number of attempts have been made to
define the rate of iontophoretic delivery. Abramson
and Gorin derived an equation to compare the
iontophoresis flow to electric mobility, electro
osmosis and simple diffusion. The increased flux
during iontophoresis includes:
 Flux due to the electrochemical potential
gradient across the skin.
 Change in the skin permeability due to the
electric field applied.
 Electro-osmotic water flow and resultant solvent
drag.
Jionto = Jelectric+ Jpassive + Jconnective
Jelectric = The flux due to electric current
application.
Jelectric–The flux due to electric current application.
Jpassive –
The flux due to passive delivery
through the skin.
Jconnective – The flux due to connective transport
due to electro Osmosis34.
Iontophoresis as Drug Delivery Module
Iontophoresis has been exploited for the transdermal
delivery of many drugs with poor penetration
properties e.g. high molecular weight electrolytes
such as proteins, peptides and oligonucleotides which
are normally difficult to administer except through
parenteral route35. An iontophoretic drug delivery
system has their basic components:
 An energy source of electronic current, which
usually consists of a battery and controlled
electronics.
 An active reservoir which contains the ionic
therapeutic agent.
 An indifferent or return reservoir system which
contains an electrolyte and serves to complete
the electric circuit.
 Also a control system to monitor the overall
process.
When the active and indifferent reservoir
systems are placed on the skin, the current source
causes electronic current flow to the active reservoir
where the electric current is transformed into ionic
current. The ionic current flows through the active
reservoir, through the skin, beneath the skin, towards
the indifferent reservoir, and back through the skin
into the indifferent reservoir. At the indifferent
reservoir, it is transformed back into electronic
current, completing the circuit at opposite pole of
current source36,37.
Factors Affecting Iontophoretic Delivery
System
Many factors including the physiochemical properties
of the compound, drug formulation, equipment used,
biological factors, skin temperature and duration of
iontophoresis effect the transport and can be divided
into operational and biological factors.The following
factors have to be considered:
1) Influence of pH: For optimum iontophoresis, it is
desired to have a relatively large proportion of the
drug in ionized state. However, this must be
counterbalanced with delivery of a drug at a pH
that is tolerable and safe for the patient38.
2) Current strength: The current is usually limited
to 1 mA due to patients comfort considerations
and should not be applied for more than 3 min
because of local skin irritation and burns39,40.
3) Ionic competition: The use of buffering agents as
co-ions (anion of equal charge but of different
type is referred as co-ion) which are usually
smaller and more mobile than the ion to be
delivered results in reduction of number of drug
ions to be delivered through the tissue barrier by
applied current, that is when a positively charged
drug is diluted in saline, the sodium ions will
compete with the amount of drug ions to be
delivered. Ideally the use of buffer system should
be avoided, but if this is not possible, alternative
buffers consisting of ions with low mobility or
conductivity are preferred41.
4) Drug concentration: Depending on the drug
used, the steady-state flux (ion movement) has
been shown to increase with increasing
concentration of the solute in the donor
compartment, i.e, in the delivery electrode.
Increased uptake by the skin during and after IP
with an increase in drug concentration has been
reported42,43.
5) Molecular size: In general when the molecular
size increases, the permeability coefficient
decreases. However, there are certain solutes
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with a relatively high molecular size (eg insulin,
vasopressin and several growth hormones), which
have also been shown to penetrate the skin barrier
into the systemic circulation44.
6) Drug salt form: It has been reported that
different salt forms have different specific
conductivities and that conductivity experiments
in vitro will provide information concerning the
general solubility of a drug and must be
considered along with the pH of the solution for
determining the amount of drug in the ionized
state45.
7) Biological factors: Patient anatomical factors that
influence the depth of penetration that is variable
from patient to patient include skin thickness at
the site of application, presence of subcutaneous
adipose tissue and size of other structures
including skeletal muscle. Additionally, the
presence and severity of inflammation can
influence drug penetration due to the increased
temperature46.
hyperhydrosis54, pilocarpine in diagnosis of cystic
fibrosis55,56,57, ketoprofen in subcutaneous tissues and
joints58, fentanyl59, arginine and vasopressin (AVP)60,
atenolol61, buprenorphine62, leuprolide63, piroxicam64,
rotigotine65, salbutamol66, thiocolchicoside67 and
timolol maleate68.
Merits and demerits
iontophoretic system
Merits
of
transdermal
It is a non-invasive technique that could serve as
substitute for chemical enhancer, eliminates problems
like toxicity problems, adverse reaction, formulation
problems associated with presence of chemical
enhancers in pharmaceuticals, permits lower
quantities of drug compared to use in TDDS, thereby
decreasing side effects, eliminate the chance of over
or under dosing by continuous delivery of drug
programmed at required therapeutic rate, permit a
rapid termination of the modification, simply by
stopping drug input from iontrphoretic delivery
system and self administration is possible.
Selection Criteria For Drug Candidate
Transdermal route of drug administration has certain
inherent difficulties that make it unsuitable for a large
number of drugs and an ideal characteristic drug
should be posses following criteria:
A TDDS should not cover an area more than 50 cm2
and daily dose should be of order of few mg, the
effective concentration of drug should be low,
presumably in the ng/ml, the active ingredients
should not cause any skin toxicity or irritation, the
drug should preferably be on low molecular weight
as diffusion is dependent on molecular size, the drug
should have a low melting point so that it acts on
normal body temperature, drugs, which degrade in
the GI tract or are inactivated by hepatic first pass
effect, should have adequate hydrophilic and
lipophilic balance to negotiate the lipid barrier of
stratum corneum before being partitioned into the
aqueous viable tissue and the half life of the drug
should be short47,48,49,50,51.
There is a wide variety of drugs that has been
investigated is reported recently for iontophoretic
delivery and include delivery of anaesthetics (eg
lidocaine)52, steroids and retinoids to treat acne
scarring53, for the relief of palmar and plantar
Demerits
Arrangement to protect electric shock needed, an
excessive current density usually results in pain,
burns may be caused by electrolyte changes within
the tissues, ionic form of drug in sufficient
concentration is necessary for iontophoretic delivery
and the treatment is somewhat costly49,69,70,71.
Clinical applications of iontophoresis in other
disciplines
Dentistry
Iontophoresis has been used for treatment of
hypersensitivity dentin (in teeth sensitive to air and
cold liquids) using negatively charged fluoride ions,
treatment of oral ulcers and herpes lesions using
negatively charged corticosteroids and antiviral
drugs, respectively72.
Dermatology
Iontophoresis with lidocaine, tap water or
anticholinergic compounds has been used for
treatment of patients with hyperhidrosis of palms,
feet and axillae73.
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CONCLUSION
Transdermal technology ensures as much as 95% of a
supplement reaches the cells where it is needed.
Doctors around the world are calling Transdermal
delivery “The delivery system of the future” and
found fantastic alternatives to pills and tablets.
Considerations that are all important for design and
development of pharmaceutical products intended
for application into the skin require an ideal skin
penetration enhancer, for which continual research
has occurred over a number of decades. Although
many potent enhancers have been discovered, their
clinical application has been limited because of their
toxic side effects. However, the recent approaches for
penetration enhancement do not compromise skin
barrier function as do chemical and physical
penetration enhancement technique, and hence
iontrophoresis and phonophoresis can serve as better
alternative. The iontrophoretic delivery of macromolecules allows the strategy for non-invasive
transdermal
delivery
of
peptide-based
pharmaceuticals, and contributes to further future
advancement toward recombinant DNA technology.
Although iontophoresis provides many benefits and
seems to be more effective than other techniques,
there is a need for further research and judicious use
of technology with microelectronics devices which
could prove it to be a ‘potential emergence to
transdermal drug delivery’.
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