Transdermal drug delivery
Dr Mohammad Issa
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Anatomy and Physiology
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The site of administration of both topical and
transdermal delivery systems is the skin
surface
The skin is the largest single organ in the
human body
It serves a number of critical functions:
protection from pathogens and chemicals, act
as a sensor to inform the brain of changes in
the surroundings
It is divided into three layers: the epidermis,
the dermis, and the subcutaneous (fat) layer
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Anatomy and Physiology
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The uppermost layer of the skin is the
epidermis. The thickness of the epidermis
varies over the body, and is roughly 0.05 mm
on the eyelids and 1.5 mm on the palms and
soles of the feet
The outermost portion of the epidermis, the
stratum corneum, serves mainly as a
waterproof barrier. This layer, which is 10 to
15 um thick, consists of dead, flattened cells
embedded in a lipid bilayer. These cells are
composed of tough, fibrous protein called
keratin and are being continuously replaced
by newer cells that migrate upward
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Anatomy and Physiology
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The dermis is a thick layer that consists of
connective tissue and is responsible for the
strength and flexibility of the skin
The dermis contains nerve endings, sweat
glands, hair follicles, and blood vessels
The drug molecule that diffuse across the
epithelium are distributed systemically
because of the presence of a rich vascular
network in the dermis
Below the dermis is the subcutaneoous (fat)
layer. This layer helps to regulate body
temperature and also provides a protective
padding
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Anatomy and Physiology
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The fat layer varies in thickness across the
body. Some lipophilic drugs accumulate in the
adipose tissue, and this decrease the plasma
concentration of these drugs
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Anatomy and Physiology
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Conventional formulations for
transdermal drug delivery
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The formulations used for transdermal drug
delivery include ointments, creams, and gels
Nitroglycerin, testosterone, estrogen and
progesterone are delivered systemically as
ointments and gels
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These Formulations are relatively inexpensive
and easy to manufacture
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They are associated with less local skin
reactions than with patches
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Conventional formulations for
transdermal drug delivery
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Variability and poor reproducibility in the
amount of drug delivered result primarily
from improper application technique,
application of too little or too much of the
product, and removal of the product from the
site of application by its rubbing off on
clothes and other surfaces before all the drug
is absorbed
Another major concern is that the product
may be transferred from the individual who is
being treated to another individual through
direct skin contact
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Transdermal Delivery Systems
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The first transdermal
therapeutic system (TTS)
which contained scopolamine
to prevent nausea and
vomiting associated with
motion sickness, was
approved in 1981
The two major types of TTS
products are:
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matrix system
reservoir system
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Transdermal Delivery Systems: Matrix
System
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Matrix systems are also referred to as
monolithic System
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The simplest type of matrix system is the
three-layer system
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Transdermal Delivery Systems: Matrix
System
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The first layer is the backing film that helps
provide the integrity of the drug Layer and
keep it occluded and protected during storage
and use
In the second Layer the drug and other
excipients are uniformly distributed in an
adhesive polymer. The adhesive polymer (or
a combination of two or more adhesive
polymers) serves as both a means by which
the device is held to the skin and the vehicle
for the drug
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Transdermal Delivery Systems: Matrix
System
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The last layer consists of a protective liner
that is peeled off and discarded by the
patient before the patch is applied. It helps
protect the drug layer during transport and
storage of the patch
Some matrix systems may be more complex,
with the drug dispersed in a polymer, and the
adhesive layer comprising a separate layer.
Matrix systems can hold a large quantity of
drug, which is often in excess of the amount
that is delivered during the use of the patch.
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Transdermal Delivery Systems: Matrix
System
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The rate of drug release is controlled by the
polymeric matrix and also by the stratum
corneum
The drug is dispersed in a solid polymeric
matrix, and thus the integrity of the system
is generally maintained even if the system is
cut and there is less potential for dose
dumping as a result of intentional tampering
or unintentional damage to the system
Matrix systems are thinner than reservoir
systems and hence may be easier to use
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Transdermal Delivery Systems:
Reservoir System
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In these systems, the active ingredient is in a
solution or suspension located between the
backing layer and a rate-controlling
membrane
A reservoir system typically consists of five
layers
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Transdermal Delivery Systems:
Reservoir System
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The first layer is the backing film
The second layer is the reservoir that
includes the drug and excipients. Excipients
may include a solvent that helps dissolve or
disperse the drug, a polymer that acts as a
gelling agent, and surfactants that help
maintain the drug in solution. The solvents
and surfactants can also enhance the
percutaneous absorption of the drug
The third layer is a semipermeable
membrane that is made of polymers such as
polyethylene, polypropylene, or ethylene
vinyl acetate
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Transdermal Delivery Systems:
Reservoir System
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The semipermeable membrane regulates the
rate at which the drug diffuses from the
reservoir
The adhesive layer is the fourth layer. A small
quantity of drug may also be included in the
adhesive layer; for example. in Catapres
TTS®, which is a transdermal system
providing continuous systemic delivery
clonidine for 7 days, the drug in the adhesive
layer is released immediately, which helps
build the initial drug levels in the skin
The last layer is the protective layer or
protective liner
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Transdermal Delivery Systems:
Reservoir System
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The integrity of the system is not maintained
if the system is cut, and significant potential
exists for dose dumping if intentional
tampering or unintentional damage to the
system occurs.
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Components of a Transdermal
Therapeutic System
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Backing layer
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Adhesives
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Penetration Enhancement
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Components of a Transdermal
Therapeutic System: Backing layer
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The backing layer is the outermost layer of
the TTS
It primarily helps maintain the integrity of the
system and protects the product during its
period of use and throughout its shelf life.
The backing film must be occlusive, because
this helps keep the skin hydrated by retaining
moisture in the skin and thus improves
permeation
Transparent, pigmented, or aluminized films
of polymers such as polyethylene,
polyurethane, or polyester are used as
backing liners
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Components of a Transdermal
Therapeutic System: Adhesives
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Because a TTS must stay in contact with the
skin for the required period of time, the
adhesive and its appropriate selection are
crucial to the functioning of being used in
transdermal products, and very often these
compounds are combined
These compounds adhere to the skin by
application of light force and do not Leave a
residue when the system is removed
Adhesives should also exhibit substantial
strength of adhesion and duration of
adhesion and should not cause any skin
irritation or sensitization
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Components of a Transdermal
Therapeutic System: Adhesives
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The patch should be easy to remove from the
skin without causing pain
In many matrix types of TTSs, the adhesive
and the drug are mixed together. In such
cases, the solubility of the drug in the
adhesive and the impact of the adhesive on
the diffusion coefficient of the drug must be
studied thoroughly
The compatibility of the adhesive with the
drug and other excipients must be carefully
examined
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Components of a Transdermal
Therapeutic System: Penetration
Enhancement
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Most substances cannot permeate the skin at
sufficient rates to produce therapeutic
concentrations
This is due primarily to the barrier properties
of the stratum corneum
Occlusion increases the hydration of the
stratum corneum by inhibiting water loss
from the skin. Increasing skin hydration can
increase the permeation of some compounds,
and it thus acts as a natural penetration
enhancer.
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Components of a Transdermal
Therapeutic System: Penetration
Enhancement
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A number of chemical compounds have been
identified as penetration enhancers (also
called permeation enhancers, sorption
promoters, or accelerants) to improve the
permeation of drugs through skin
These include surfactants (eg. sorbitan
monooleate), fatty acids and esters (eg, oleic
acid), and solvents (eg. alcohol and
propylene glycol))
A penetration enhancer acts by reducing the
barrier resistance of the stratum corneum
without damaging the cells and may also
improve the solubility of the diffusing drug
within the skin
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Components of a Transdermal
Therapeutic System: Penetration
Enhancement
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These compounds thus allow drug molecules
to cross the straturn corneum at a faster
rate. Ideally, they should also improve drug
solubility and stability in the formulation.
Many of these penetration enhancers cause
dermal irritation. Ethanol is a permeation
enhancer that has been used in a number of
formulations.
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Active Transdermal Drug Delivery
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These delivery systems use energy to
increase the rate and extent of drug
movement across the skin
One advantage of these methods is that drug
penetration does not depend on the
concentration gradient to force the drug
molecule across the skin and therefore
molecules that are charged or hydrophilic can
also be delivered via these methods
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Active Transdermal Drug Delivery
1.
Iontophoresis
2.
Phonophoresis (or Sonophoresis)
3.
Electroporation
4.
Microneedle- or Micro projection- Based
Devices
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Iontophoresis
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Iontophoresis
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Iontophoresis involves application of a low
intensity electric current to facilitate the
permeation of a drug into the skin.
Iontophoresis can increase the rate of
transdermal penetration of hydrophilic
compounds.
A solution containing ionized drug is placed
into contact with an electrode of the same
charge as that of the ions.
These ions are thus repelled by the
electrode. This forces the ions into the skin.
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Iontophoresis
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A return electrode of the opposite charge in
contact with a second reservoir helps
complete the electrical circuit
The charge and concentration of the ion, the
surface area of the delivery electrode, and
the intensity and duration of current influence
the amount of drug that penetrates the skin.
Only a low level of current can be used to
force the drug, because this reduces the
chances of skin irritation or sensitization.
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Iontophoresis: examples
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The LidoSiteTM Topical System delivers
lidocaine and epinephrine topically by
iontophoresis: lidooine is a local anesthetic,
and epinephrine, because of its
vasoconstrictor properties, helps to maintain
anesthesia by decreasing the rate of removal
of the drug from the site.
Another system that has been approved by
the FDA is IonsysTM (fentanyl iontophoretic
transdermal system). Ionsys is a patientactivated transdermal system that is used to
deliver Fentanyl into the systemic circulation.
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LidoSiteTM Topical System
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Phonophoresis (or Sonophoresis)
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In phonophoresis (or sonophoresis) energy
from low frequency ultrasonic waves is used
to enhance drug absorption.
The method increases drug permeation
through temporary disruption of the barrier
layer as a result of cavitation
Cavitation causes the enlargement of
intercellular spaces. The increase in the
temperature of the skin surface caused by
sound waves enhances permeation of drug.
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Electroporation
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In electroporation, high-voltage pulses are
applied to the skin for a short period. This
increases the permeability of the stratum
corneum to the drug being administered. This
increase in permeation is thought to result
from the formation of pores, which usually
close within a very short time after the
removal of the pulse
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Microneedle- or Micro projectionBased Devices
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In microneedle- or microprojection-based
devices, tiny drug-coated projections or
needles are used to pierce the top layer of
skin and make superficial holes through
which the drug can be transported into the
skin
The projections are too small to penetrate
into the dermis and hence do not reach the
nerve endings
The Macro- flux® system by Alza Corporation
uses this principle
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Microneedle- or Micro projectionBased Devices
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