2. 2
Anatomy and Physiology
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
3. 3
Anatomy and Physiology
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
4. 4
Anatomy and Physiology
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
5. 5
Anatomy and Physiology
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
7. 7
Conventional formulations for transdermal
drug delivery
The formulations used for transdermal drug delivery
include ointments, creams, and gels
Nitroglycerin, testosterone, estrogen and progesterone are
delivered systemically as ointments and gels
These Formulations are relatively inexpensive and easy
to manufacture
They are associated with less local skin reactions than
with patches
8. 8
Conventional formulations for transdermal
drug delivery
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
9. 9
Transdermal Delivery Systems
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:
matrix system
reservoir system
10. 10
Transdermal Delivery Systems: Matrix
System
Matrix systems are also referred to as monolithic System
The simplest type of matrix system is the three-layer
system
11. 11
Transdermal Delivery Systems: Matrix
System
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
12. 12
Transdermal Delivery Systems: Matrix
System
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.
13. 13
Transdermal Delivery Systems: Matrix
System
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
14. 14
Transdermal Delivery Systems: Reservoir
System
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
15. 15
Transdermal Delivery Systems: Reservoir
System
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
16. 16
Transdermal Delivery Systems: Reservoir
System
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; 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
17. 17
Transdermal Delivery Systems: Reservoir
System
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.
18. 18
Components of a Transdermal Therapeutic
System
Backing layer
Adhesives
Penetration Enhancement
19. 19
Components of a Transdermal Therapeutic
System: Backing layer
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
20. 20
Components of a Transdermal Therapeutic
System: Adhesives
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
21. 21
Components of a Transdermal Therapeutic
System: Adhesives
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
22. 22
Components of a Transdermal Therapeutic
System: Penetration Enhancement
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.
23. 23
Components of a Transdermal Therapeutic
System: Penetration Enhancement
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
24. 24
Components of a Transdermal Therapeutic
System: Penetration Enhancement
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.
25. 25
Active Transdermal Drug Delivery
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
26. 26
Active Transdermal Drug Delivery
1. Iontophoresis
2. Phonophoresis (or Sonophoresis)
3. Electroporation
4. Microneedle- or Micro projection- Based Devices
28. 28
Iontophoresis
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.
29. 29
Iontophoresis
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.
30. 30
Iontophoresis: Examples
The LidoSite TM
Topical System delivers lidocaine and
epinephrine topically by iontophoresis: lidocaine 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
Ionsys TM
(fentanyl iontophoretic transdermal system).
Ionsys is a patient-activated transdermal system that is
used to deliver Fentanyl into the systemic circulation.
32. 32
Phonophoresis (or Sonophoresis)
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.
33. 33
Electroporation
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
34. 34
Microneedle- or Micro projection- Based
Devices
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
