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Please cite this article in press as Archana Sharma et al, Transdermal Drug Delivery: A Way for Better
Tomorrow, Indo Am. J. P. Sci, 2017; 4(10).
5. The barrier function of the skin changes from Ps = Ks Dss /Hs ------[2]
one site to another on the same person, from
person to person and with age. Where,
Ks = Partition coefficient of the penetrant
SKIN AS SITE OF DRUG INFUSION Dss = Apparent diffusivity of penetrant
The skin of an average adult body covers a surface hs = Thickness of skin
area of approximately two square meters and
receives about one-third of the blood circulating Thus, permeability coefficient [PS] may be a
through the body. The skin is a multilayered organ constant since Ks; Dss and hs terms in equation [2]
composed of many histological layers. It is are constant under the given set of conditions.
generally described in terms of three major tissue A constant rate of drug permeation achieved, if
layers: the epidermis, the dermis, and the Cd>Cr, then the equation [1] may be reduced to
hypodermis [Fig 1]. Microscopically, the epidermis
further divided into five anatomical layers with dQ/dt = Ps .Cd -----[3]
stratum corneum forming the outer most layer of
the epidermis, exposing to the external And the rate of skin permeation [dQ/dt] becomes a
environment. An average human skin surface is constant, if the Cd value remains fairly constant
known to contain, on the average, 40-70 hair throughout the course of skin permeation. To
follicles and 200-250 sweat ducts on each square maintain the Cd at a constant value, it is critical to
centimeter of skin area. These skin appendages, make the drug to be released at a rate [Rr] which is
however, actually occupy, grossly, only 0.1% of always greater than the rate of skin uptake [Ra], i.
the total human skin surface. Even though the e., Rr>>Ra
foreign agents, especially the water-soluble ones,
may be able to penetrate into the skin via these skin Relationship between the rate of drug release
appendages at a rate which is faster than through [Rr] from a transdermal drug delivery system
the intact area of the stratum corneum, this trans- [TDDS] and the rate of drug uptake [Ra] by
appendage route of percutaneous absorption has, at the skin.
steady state, a very limited contribution to the By doing so, the drug concentration on the skin
overall kinetic profile of transdermal permeation. surface [Cd] is maintained at a level which is
Therefore, the transdermal permeation of most always greater than the equilibrium [or saturation]
neutral molecules can, thus, be considered as, a solubility of the drug in the stratum corneum [Ces],
process of passive diffusion through the intact i.e., Cd>>Ces; and a maximum rate of skin
stratum corneum in the inter follicular region. So, permeation [dQ/dt]m, as expressed by equation
for the sake of mechanistic analysis of transdermal [4],is thus reached:
drug infusion, the various skin tissue layers can be
represented by a simplistic multilayer model. In the [dQ/dt]m = Ps . Cse
case that the skin serves as the point of
administration for systemically active drugs, the Apparently, the magnitude of [dQ/dt] m is
drug applied topically will be absorbed, first into determined by the skin permeability coefficient
the systemic circulation and then transported to [PS] of the drug and its equilibrium solubility in the
target tissues. stratum corneum [Ces].
the rate controlling membrane, Pm is the sum of solution or suspension which is in direct contact
permeability coefficients simultaneous with the release liner. The component responsible
penetrations across the pores and the polymeric for skin adhesion is incorporated in an overlay and
material. Pm and Pa, respectively, are defined as forms a concentric configuration around the
follows. semisolid matrix. The rate of drug release from this
Pm = Km/r. Dm /hm type of system is defined as,
Pa = Ka/m. Da /ha
DQ/dt = ACp Dp /2t
where Km/r and Ka/m are the partition
coefficients for the interfacial partitioning of drug Where A is the initial drug loading dose dispersed
from the reservoir to the membrane and from the in the polymer matrix and Cp and Dp are the
membrane to adhesive respectively; Dm and Da solubility and diffusivity of the drug in the polymer
are the diffusion coefficients in the rate respectively. Since, only the drug species dissolved
controlling membrane and adhesive layer, in the polymer can release, Cp is essentially equal
respectively; and hm and ha are the thicknesses of to Cr, where Cris the drug concentration in the
the rate controlling membrane and adhesive layer, reservoir compartment. [8, 9]
respectively.
BASIC COMPONENT OF TDDS [1,2,8,11,12]
Multi-layer Drug-in-Adhesive Polymer matrix / Drug reservoir
The Multi-layer Drug-in-Adhesive is similar to the Drug
Single-layer Drug-in-Adhesive in that the drug is Permeation enhancers
incorporated directly into the adhesive. However, Pressure sensitive adhesive [PSA]
the multi-layer encompasses either the addition of a Backing laminates
membrane between two distinct drug-in-adhesive
Release liner and other excipients like
layers or the addition of multiple drug-in-adhesive
plasticizers and solvents
layers under a single backing film. The rate of drug
release in this system is defined by,
1. Polymer matrix / Drug reservoir
Polymers are the backbone of TDDS, which control
dQ/dt = Ka/r. Da /Ha * Cr the release of the drug from the device. Polymer
matrix can be prepared by dispersion of drug in
Where Ka/r is the partition coefficient for the
liquid or solid state synthetic polymer base.
interfacial partitioning of the drug from the
Polymers used in TDDS should have
reservoir layer to adhesive layer. biocompatibility and chemical compatibility with
the drug and other components of the system such
Drug Reservoir-in-Adhesive
as penetration enhancers and PSAs. Additionally
The Reservoir transdermal system design is
they should provide consistent and effective
characterized by the inclusion of a liquid
delivery of a drug throughout the products intended
compartment containing a drug solution or
shelf life and should be of safe status. Companies
suspension separated from the release liner by a
involved in the field of transdermal delivery
semi-permeable membrane and adhesive. The
concentrate on a few selective polymeric systems.
adhesive component of the product responsible for
For example, Alza Corporation mainly concentrates
skin adhesion can either be incorporated as a
on ethylene vinyl acetate [EVA] copolymers or
continuous layer between the membrane and the
microporous polypropylene and Searle Pharmacia
release liner or in a concentric configuration around
concentrates on silicon rubber. Similarly Colorcon,
the membrane. The rate of drug release from this
UK uses HPMC for matrix preparation for
drug reservoir gradient controlled system is given
propranolol transdermal delivery and Sigma uses
by,
ethyl cellulose for isosorbide dinitrate matrix. The
DQ/dt = Ka/r. Da /ha[t] *A [ ha ]
polymers utilized for TDDS can be classified as,
In the above equation, the thickness of the
adhesive layer for drug molecules to diffuse
through increases with time ha [t]. To compensate Natural Polymers: e.g. cellulose derivatives, zein,
for this time dependent increase in the diffusional gelatin, shellac, waxes, gums, natural rubber and
path due to the depletion of drug dose by release, chitosan etc.
the drug loading level is also increased with the Synthetic Elastomers: e.g. polybutadiene, hydrin
thickness of diffusional path A [ha]. rubber, polyisobutylene, silicon rubber, nitrile,
acrylonitrile, neoprene, butyl rubber etc.
Pressure sensitive adhesives Teflon. Other materials used for TDDS release
A PSA is a material that helps in maintaining an liner include polyester foil and metallized
intimate contact between transdermal system and laminates.
the skin surface. It should adhere with not more
than applied finger pressure, be aggressively and Other excipients
permanently tachy, and exert a strong holding Various solvents such as chloroform, methanol,
force. Additionally, it should be removable from acetone, isopropanol and dichloromethane are used
the smooth surface without leaving a residue. to prepare drug reservoir. In addition plasticizers
Polyacrylates, polyisobutylene and silicon based such as dibutylpthalate, triethylcitrate, polyethylene
adhesives are widely used in TDDSs. The selection glycol and propylene glycol are added to provide
of an adhesive is based on numerous factors, plasticity to the transdermal patch.
including the patch design and drug formulation.
For matrix systems with a peripheral adhesive, an APPROACHES TO DEVELOP TD SYSTEMS
incidental contact between the adhesive and the [2,8,11,12]
drug and penetration enhancer should not cause Several technologies have been successfully
instability of the drug, penetration enhancer or the developed to provide a rate control over the
adhesive. In case of reservoir systems that include a release and the transdermal permeation of drugs.
face adhesive, the diffusing drug must not affect These technologies can be classified into four
the adhesive. In case of drug-in-adhesive matrix approaches as follows:
systems, the selection will be based on the rate at 1. Membrane permeation controlled
which the drug and the penetration enhancer will systems
diffuse through the adhesive. Ideally, PSA should 2. Adhesive dispersion type systems.
be physic chemically and biologically compatible
and should not alter drug release. 3. Matrix diffusion controlled systems.
4. Micro reservoir type or micro sealed
Backing Laminate dissolution controlled systems.
While designing a backing layer, the consideration
of chemical resistance of the material is most 1. Membrane Permeation Controlled Systems
important. Excipients compatibility should also be In this type of system, drug reservoir is
considered because the prolonged contact between encapsulated in a shallow compartment moulded
the backing layer and the excipients may cause the from a drug-impermeable metallic plastic laminate
additives to leach out of the backing layer or may and a rate controlling polymeric membrane which
lead to diffusion of excipients, drug or penetration may be micro porous or non-porous. The drug
enhancer through the layer. However, an molecules are permitted to release only through the
overemphasis on the chemical resistance may lead rate controlling polymeric membrane. In the drug
to stiffness and high occlusive to moisture vapor reservoir compartment, the drug solids are either
and air, causing patches to lift and possibly irritate dispersed homogenously in a solid polymer matrix
the skin during long wear. The most comfortable [e.g. Polyisobutylene adhesive] or suspended in an
backing will be the one that exhibits lowest unbleachable, viscous liquid medium [e.g. Silicon
modulus or high flexibility, good oxygen fluids] to form a paste like suspension. The rate of
transmission and a high moisture vapor drug release from this type of system can be
transmission rate. Examples of some backing tailored by varying the polymer composition,
materials are vinyl, polyethylene and polyester permeability coefficient and thickness of the rate
films. limiting membrane and adhesive. The constant
release rate of the drug is the major advantage of
Release Liner membrane permeation controlled system. However,
During storage the patch is covered by a protective a rare risk also exists when an accidental breakage
liner that is removed and discharged immediately of the rate controlling membrane can result in dose
before the application of the patch to skin. It is dumping or rapid release of entire drug content.
therefore regarded as a part of the primary Examples of this system are
packaging material rather than a part of dosage
form for delivering the drug. However, as the liner Transderm Nitro
is in intimate contact with the delivery system, it Nitroglycerin releasing transdermal system for
should comply with specific requirements once a day medication in angina pectoris.
regarding chemical inertness and permeation to the
drug, penetration enhancer and water. Typically, Transderm Scop
release liner is composed of a base layer which Scopolamine releasing transdermal system for 72
may be non-occlusive [e.g. paper fabric] or hrs. Prophylaxis of motion
occlusive [e.g. polyethylene, polyvinylchloride] sickness.
and a release coating layer made up of silicon or
carry out studies in humans. Some of the species described in the literature. It can be concluded that
that have been used for in vivo testing include; many techniques for in-vivo evaluation of
mouse, rat, guinea pig, rabbit, hairless mouse, transdermal systems have been put forward there is
hairless rat, hair less dog, cat, dog, miniature pig, scope for further refinement. Some of the
pig, horse, goat, squirrel, monkey, rhesus monkey, unresolved issues include the barrier function of the
chimpanzee, etc. Various experiments have been skin with age, skin metabolism, in-vivo functioning
carried out to determine which of the animal of penetration enhancers etc.
models provide the best prediction of the behavior
of the device, being tested, in humans. METHODS TO ENHANCE TRANSDERMAL
DELIVERY [31, 32,33]
B. Human volunteers 1.Chemical enhancers- Because the skin provides
The final stage in the development of transdermal such a formidable barrier to the delivery of most
device involves collection of pharmacokinetic and drugs, a broad range of different chemical additives
pharmacodynamic data following application of the have been tested to enhance transdermal
device to human volunteers. An in vivo evaluation penetration. chemical penetration enhancers
using human subjects should give pertinent provide certain advantages, including design
information with minimum risk to the subjects flexibility with formulation chemistry and an easier
within a reasonable period of time. In vivo possibility of patch application over a large area
evaluation using human models involve [>10 cm2]. Chemical penetration enhancers can
determination of percutaneous absorption by an increase skin permeability by various mechanisms,
indirect method of measuring radio activity in including enhancing solubility, increasing
excreta following topical application of the labeled partitioning into the stratum corneum, fluidizing
drug. C-14 is generally used for radio-labelling the crystalline structure of stratum corneum and
Determination of absorption following topical causing dissolution of stratum corneum lipids.
administration requires the investigator to know the Example - Surfactants [Tween], fatty acids/esters
amount of radioactivity retained in the body, or [oleic acid], terpenes [limonene], and solvents
excreted by routes not monitored. This necessitates [dimethyl sulphoxide and ethanol].
measurement of dose absorbed. However this
method has certain limitations, to overcome the limitation - potent chemical enhancers are usually
limitations inherent in this method, various potent irritants to the skin at concentrations
refinements have been made. These are described necessary for achieving useful levels of penetration
below enhancement and are therefore physiologically
incompatible
1. Reservoir Technique
This method involves a simple, short exposure of 2.Iontophoresis: - Rates of transdermal transport
the skin to the [radio-labeled] compound under can also be increased through Iontophoresis, which
study followed by removal of the stratum corneum uses an electric field to move both charged and
by tape stripping and analysis of the content of the uncharged species across the skin. Transdermal
compound in the stratum corneum. From this iontophoresis has been most extensively applied to
analysis, it is possible to predict the amount of drug the delivery of anti-inflammatory agents and other
that will penetrate over a longer period of time. compounds for local effects in the context
of physical therapy. Other FDA-approved uses
2. Mass balance Technique include pilocarpine delivery to induce sweating as
This method involves the application site is part of a cystic fibrosis diagnostic test, tap-water
covered with an occlusive chamber, the chamber delivery to treat hypperhydrosis, lidocaine delivery
being replaced by a new one after a particular time for local anesthesia, especially before venipuncture,
interval. The site is also subjected to washing at and extraction
these times. Radio-labeling techniques are used and of interstitial fluid for monitoring glucose levels in
the chambers, washings and the faces and urine of diabetics. Typically, a few milli amperes of current
the patients are subjected to analysis. Advantage of are applied to a few square centimeters of skin,
this technique include achievement of mass balance which generally causes no pain or irritation beyond
between the applied dose and excretion levels and mild erythema. Iontophoresis can enhance transport
the use of surface wash measurements for across skin by a number of possible mechanisms,
predicting percutaneous absorption. including an electrophoretic driving force, an
electro osmotic driving force, and transiently
C. Biophysical Models increased skin permeability. The electrophoretic
Models based on steady-state mass balance mechanism can drive charged compounds across
equation, solution of Ficks second law of diffusion the skin by a direct interaction with the electric
for the device, stratum corneum and viable field. Species with greater charge and smaller
epidermis, as well as linear kinetics have been molecular mass are generally delivered more
hydration of skin and can alter partition manufacturer also recommends close monitoring
coefficient of drug. for opioid side effects in patients who have
3. Patient should not physically alter TDDS, developed fevers while wearing a Duragesic patch.
since this destroys integrity of the system. Heat-induced increased absorption of transdermally
4. The protecting backing should be removed delivered drugs is well documented. However,
with care not to touch fingertips. The TDDS many patients are not aware of the possibility of
should be pressed firmly against skin site with overdosing on transdermally delivered drugs when
the heel of hand for about 10 seconds. the application site is exposed to heat. It is
5. A TDDS should be placed at a site that will important to educate patients about this possibility
not subject it to being rubbed off by clothing to prevent drug overdose and/or compromise
or movement. TDDS should be left on when efficacy. Patients should be advised to avoid
showering, bathing or swimming. exposing the patch application site to external heat
6. A TDDS should be worn for full period as sources including, but not limited to, heating pads
stated in the products instructions followed or electric blankets, heat lamps, saunas, hot tubs,
by removal and replacement with fresh heated water beds, hot water bottles, hot whirlpool
system. spa baths, and intensive sun-bathing. They should
7. The patient or caregiver should clean the also be advised that fever and an increase in body
hands after applying a TDDS. Patient should temperature from intense physical activity may also
not rub eye or touch the mouth during increase the absorption of transdermally delivered
handling of the system. drugs. In the event of drug overdose, the drug patch
8. If the patient exhibits sensitivity or should be removed immediately and appropriate
intolerance to a TDDS or if undue skin treatment measures should be employed. Patients
irritation results, the patient should seek should also be reminded to store transdermal drug
reevaluation. patches in their original packaging and keep in a
9. Upon removal, a used TDDS should be cool, dry place until they are ready to be used.
folded in its half with the adhesive layer
together so that it cannot be reused. The used APPLICATION OF TRANSDERMAL
patch discarded in a manner safe to children PATCHES [1,2,8]
and pets. The highest selling transdermal patch in the
EFFECT OF HEAT ON TRANSDERMAL United States is the nicotine patch, which
PATCH [35] releases nicotine in controlled doses to help
Heat is known to increase skin permeation of drugs with cessation of tobacco smoking.
by several mechanisms. Higher temperatures Two opioid medications used to provide
increase microcirculation and blood vessel round-the-clock relief for severe pain are often
permeability, which facilitates drug transfer into prescribed in patch form: Fentanyl [marketed
the systemic circulation. A rise in temperature may as Duragesic] and Buprenorphine [marketed as
also increase drug solubility both in the patch BuTrans].
formulation and within the skin, thus increasing the Estrogen patches are sometimes prescribed to
release rate of the drug from local skin tissue into treat menopausal symptoms as well as post-
the systemic circulation. In fact, a new technology menopausal osteoporosis. Other transdermal
utilizing heat's ability to increase transdermal patches for hormone delivery include the
permeation called the controlled, heat-aided drug contraceptive patch [marketed as Ortho Evra or
delivery [CHADD] system is currently under Evra].
review by the FDA. Since heat increases skin Nitroglycerin patches are sometimes
permeation, there are concerns that excessive prescribed for the treatment of angina in lieu of
exposure to heat will increase absorption of sublingual pills.
transdermally delivered drugs and lead to The anti-hypertensive drug Clonidine is
overdosage. In fact, the U.S. prescribing available in transdermal patch form.
information for Duragesic warns patients to avoid Transdermal form of the MAOI selegiline,
exposing the application site to direct external heat became the first transdermal delivery agent for
sources, such as heating pads or electric blankets, an antidepressant.
heat lamps, saunas, hot tubs, and heated water beds, Transdermal delivery agent for the Attention
etc., while wearing the patch. In addition, the Deficit Hyperactivity Disorder [ADHD].
Canadian Duragesic drug monograph also warns
patients to avoid hot water bottles, hot whirlpool TRANSDERMAL MARKET PRODUCT
spa baths, and intensive sun-bathing. A [13,14]
pharmacokinetic model showed that serum fentanyl The market for transdermal products has been in a
concentrations could theoretically increase by significant upward trend that is likely to continue
approximately one-third for patients with a body for the foreseeable future. An increasing number of
temperature of 40C [104F]. Therefore, the TDD products continue to deliver real therapeutic
benefit to patients around the world. More than 35 two areas of formulation research are focused on
TDD products have now been approved for sale in adhesives and excipients. Adhesive research
the US, and approximately 16 active ingredients are focuses on customizing the adhesive to improve
approved for use in TDD products globally. Drug skin adhesion over the wear period, improve drug
in adhesive technology has become the preferred stability and solubility, reduce lag time, and
system for passive transdermal delivery; two areas increase the rate of delivery. Because a one-size-
of formulation research are focused on adhesives fits-all adhesive does not exist that can
and excipients. Adhesive research focuses on accommodate all drug and formulation chemistries,
customizing the adhesive to improve skin adhesion customizing the adhesive chemistry allows the
over the wear period, improve drug stability and transdermal formulator to optimize the
solubility, reduce lag time, and increase the rate of performance of the transdermal patch. A rich area
delivery. Because a one-size-fits-all adhesive does of research over the past 10 to 15 years has been
not exist that can accommodate all drug and focused on developing transdermal technologies
formulation chemistries, customizing the adhesive that utilize mechanical energy to increase the drug
chemistry allows the transdermal formulator to flux across the skin by either altering the skin
optimize the performance of the transdermal patch. barrier [primarily the stratum corneum] or
A rich area of research over the past 10 to 15 years increasing the energy of the drug molecules. These
has been focused on developing transdermal so-called active transdermal technologies include
technologies that utilize mechanical energy to iontophoresis [which uses low voltage electrical
increase the drug flux across the skin by either current to drive charged drugs through the skin],
altering the skin barrier [primarily the stratum electroporation [which uses short electrical pulses
corneum] or increasing the energy of the drug of high voltage to create transient aqueous pores in
molecules. These so-called active transdermal the skin], sonophoresis [which uses low frequency
technologies include iontophoresis [which uses low ultrasonic energy to disrupt the stratum corneum],
voltage electrical current to drive charged drugs and thermal energy [which uses heat to make the
through the skin], electroporation [which uses short skin more permeable and to increase the energy of
electrical pulses of high voltage to create transient drug molecules]. Even magnetic energy, coined
aqueous pores in the skin], sonophoresis [which magnetophoresis, has been investigated as a means
uses low frequency ultrasonic energy to disrupt the to increase drug flux across the skin.
stratum corneum], and thermal energy [which uses
heat to make the skin more permeable and to CONCLUSION:
increase the energy of drug molecules]. Even Successful transdermal drug application requires
magnetic energy, coined magnetophoresis, has numerous considerations. Bearing in mind that the
been investigated as a means to increase drug flux basic functions of the skin are protection and
across the skin. containment, it would seem exceptionally difficult
Examples of marketed transdermal drug to target the skin for drug delivery. However, with
delivery system:- our greater understanding of the structure and
function of the skin, and how to alter these
S. Therapeutic TDDS Design properties, more and more new drug products are
No agent being developed for transdermal delivery. The
1. Clonidine Catapres- Four-layer properties of the drug, the characteristics of the
TTS patch transdermal device, selection of in-vivo model and
[Boehringer the status of patients skin are all important for safe
Ingelheim] and effective drug delivery. Taking into account the
2. Estradiol Estraderm Four layer advantages of TDDS, it can be considered a perfect
[Novartis] patch alternative for drugs whose enteral and parenteral
3. Estradiol Vivelle Three-layer dosages forms having drawbacks in performance
[Novartis] system and also in patient compliance. After rectifying the
4 Estradiol Climara Three-layer presently excisting short-comings TDDS can surely
[Novartis] system introduce new dimentions in the field pf drug
5 Fentanyl Duragesic Four-layer delivery.
[Janssen] patch
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