Transdermal Drug Delivery

System
Human skin receives about one third of the blood
circulating through the body and serves as a
permeability barrier against the transdermal
absorption of various drugs.

Figure: Various routes of drug absorption

 Different Levels of Drug Effect Seen after
Percutaneous Drug Delivery
A drug applied to the skin may elicit effect at any
one of four different levels:
1. An effect on the skin surface.
2. An effect within the stratum corneum.
3. A more deep seated effect requiring
penetration into the living epidermis.
4. A systemic effect resulting from sufficient
delivery of drug across the layers of
skin into the vascular system.
 Percutaneous Absorption
(referred as Transdermal Absorption)
The absorption of substances from outside the skin into
the blood stream is referred to as percutaneous
absorption.
In Other Words- Percutaneous absorption involves the
transfer of drug from the skin surface into the
stratum corneum and its subsequent diffusion
through the underlying epidermis & the dermis and
into the microcirculation.
Although the skin has been divided histologically into the
stratum corneum, the living epidermis and the
dermis collectively, it can be considered as a
laminate of barriers.
Passage through this laminate of barriers can occur
by diffusion via: -
 1.Transcellular penetration (across the cells)
2.Intercellular penetration (between the cells)
3.Transappendageal penetration (via hair
follicles, sweat and sebum glands)
The major routes of penetration is through the
intercellular channels. The role of
transappendageal penetration is very minor
because the areas of the skin occupied by these
appendages is relatively small.
The skin behaves as a passive barrier to diffusing
molecules. The diffusional resistances are
encountered against penetrations of molecules
through various regions of skin.
The total diffusional resistance (Rskin) can be given by:
Rskin = Rsc + Re + Rpd
Where R is the diffusional resistance and the
subscripts sc, e and pd refers to the stratum
corneum, epidermis and papillary layer of the dermis
respectively.
By and large, the greatest resistance to penetration is met
in the stratum corneum, i.e. diffusion through the
stratum corneum tends to be rate limiting step.
Once through the stratum corneum, the molecules
may then pass through the deeper epidermal tissues
and into the dermis.
When the drug reaches the vascularized dermal layer
it is available for absorption into general circulation.
Factors Affecting Percutaneous Absorption
Among the factors playing a part in the percutaneous
absorption of drugs are: the nature of the drug itself,
the nature of the vehicle, the condition of the skin
and the presence of moisture.
Although it is difficult to draw general statements, a
summarized account covering majority of research
findings can be given as follows:
1. Drug Concentration: Generally the amount of drug
percuteneously absorbed per unit of surface area per
time interval increases as the concentration of the
drug substance in the vehicle is increased.
2. Surface area of the application site: More drug is
absorbed through percutaneous absorption when
the drug substance is applied to a larger surface
area.
3. Aqueous solubility and partition co-efficient of drug:
The drug substance should have a greater
physicochemical attraction to the skin then to the
vehicle in order for the drug to leave the vehicle in
favor of the skin.
In fact, the aqueous solubility of the drug and the
partition coefficient strongly influences the rate of
transport across the absorption site.
Solutes with mol. Wt. below 800 to 1000 with
adequate solubility in water can permeate the skin.
4. Vehicle characteristics: Drug absorption appears to be
enhanced from vehicles that easily cover the skin
surface, mix readily with the sebum and bring the
drug into contact with the tissue cells for
absorption.
5. Occlusion of the skin: Occluding the skin surface with
oleaginous vehicles (e.g. HC base) or occlusive
bandages causes increased percutaneous absorption
as a result of increased hydration of the skin and
increased skin temperature (~2-3C).
6. The degree of rubbing or inunctions: In general the
degree of rubbing or inunctions of the topical
application will have a bearing on the amount of drug
absorbed. The greater the period of inunction, the
greater the absorption.
7. Thickness of stratum corneum in the application site: The
degree of absorption from a skin site with a thin horny
layer appears to be greater than one with a thick layer.
Thus the degree of absorption from the palms of the
hands and the soles of the feet is comparatively slower
than the body horny layers.
8. The length of the application period: Generally the longer
the period of time the drug is permitted to remain in
contact with the skin, the greater will be the absorption.
(However, changes in the hydration of the skin or the
saturation of skin with the drug could decrease
absorption with increasing time).
9. Number/frequency of application per day: Multiple-
application dosing rather than single bolus application
can increase the absorption and bioavailability.
10. Percutaneous absorption/penetration enhancer: The term
“penetration enhancers” is used to describe materials
that have a direct effect on the permeability of the skin.
Among them: surfactants, dimethyl sulfoxide (DMSO),
dimethyl acetamide (DMA), propylene glycol,
polyethelene glycol.
But in view of its effectiveness and safety, water is
probably the best ultimate penetration enhancer.
 Transdermal Drug Delivery Systems
Transdermal drug delivery systems are designed to support
the passage of drug substances from the surface of the
skin, through its various layers into the systemic
circulation. Physically, these systems are sophisticated
patches.
There are two basic types of transdermal dosing systems:
1. Those that allow the skin to control the rate of drug
absorption.
2. Those that control the rate of drug delivery to the skin.
The first type is useful for drugs for which a wide range of
plasma concentration is effective, but not toxic. For
them, transdermal dosage forms may be developed of
various size and concentrations, with increasing the
dose until the desired effect is obtained.
However, for many drugs, it is important to
control the predictable rate of drug delivery
and percutaneous absorption.
In these instances, effective transdermal drug
delivery systems deliver uniform quantities of
drug to the skin over a period of time.
The amount of drug delivered may varied
with different types of skin and thus, the drug
delivery system, and not the skin, controls the
amount of drug entering the circulation.
 TYPES OF TRANSDERMAL PATCHES
There are various types of transdermal
patches:
1. Single layer drug in adhesive
In this type, the adhesive layer contains the
drug. The adhesive layer not only serves to
adhere the various layers together but also
responsible for releasing the drug to the skin.
The adhesive layer is surrounded by a
temporary liner and a backing.
2. Multi-layer drug in adhesive
This type is also similar to the single layer
but it contains an immediate drug release
layer and other layer will be a controlled
release along with the adhesive layer.
The adhesive layer is responsible for the
releasing of drug.
This patch also has a temporary liner-layer
and a permanent backing.
3. Vapour patch
In this type of patch, the role of adhesive
layer not only serves to adhere the various
layers together but also serves as release
vapour.
These are new to the market, commonly
used for releasing of essential oils in
decongestion.
Various other types of vapor patches are
also available in the market used to improve
the quality of sleep and reduces the cigarette
smoking conditions.
4. Reservoir system
In this system, the drug reservoir is
embedded between an impervious backing
layer and rate controlling membrane. The
drug releases only through the rate
controlling membrane, which can be micro
porous or non porous.
In the drug reservoir compartment, the
drug can be in the form of a solution,
suspension or gel.
5. Matrix system
In this type, the drug is dispersed
homogenously in a hydrophilic or
lipophilic polymer matrix. This drug
containing polymer disc is fixed in
between an adhesive layer and an
impervious backing layer.
The drug release is controlled by the
nature of the polymer in which drug is
dispersed.
6. Micro-reservoir system
In this type, the drug delivery system is a
combination of reservoir and matrix-
dispersion system.
The drug reservoir is formed by first
suspending the drug in an aqueous
solution of water soluble polymer and then
dispersing the solution homogeneously in
a lipophilic polymer to form microscopic
spheres of drug reservoirs.
Figure: Representative designs of transdermal drug
delivery systems
 BASIC COMPONENTS OF TDDS
1. Polymer matrix
Polymer is an integral and foremost important
component of transdermal drug delivery
systems. Different classes of polymeric
materials have been used to achieve rate
controlled drug delivery.
The mechanism of drug release depends
upon the physicochemical properties of the
drug and polymer used in the manufacture of
the device.
2. Drug substance
The selection of drug for transdermal drug delivery
depends upon various factors. Some of the desirable
properties of a drug suitable for transdermal delivery are:
i. Physicochemical properties
•The drug should have some degree of solubility in both
oil and water.
•The substance should have melting point less than
200°F.
•Substances having a molecular weight of less than
1000 units are suitable.
•A saturated aqueous solution of the drug should have a
pH value between 5 to 9.
•Hydrogen bonding groups should be less than 2.
ii. Biological properties
•Drug should be very potent, i.e. ideally effective in less
than 25 mg/day.
•The drug should have short biological half life.
•The drug should be non irritant and non allergic to
human skin.
•The drug should be stable when in contact with the skin.
•The drug should not stimulate an immune reaction to
the skin.
•Tolerance to drug must not be developed.
•The drug should not get irreversibly bound in the
subcutaneous tissue.
•The drug should not get extensively metabolized in the
skin.
3. Penetration enhancers
These are the compounds, which promote skin
permeability and are considered as an integral part
of most transdermal formulations. To achieve and
maintain therapeutic concentration of drug in the
blood, the resistance of skin to diffusion of drugs
has to be reduced.
These may conveniently be classified under the
following main headings:
a. Solvents: These compounds increase
penetration possibly by swelling the polar pathway.
Examples include methanol and ethanol; dimethyl
sulfoxide, dimethyl acetamide; dimethyl pyrrolidone,
propylene glycol etc.
b. Surfactants: These compounds are proposed
to enhance polar pathway transport, especially of
hydrophilic drugs.
Examples of commonly used surfactants are:
Anionic surfactants: Dioctyl sulphosuccinate,
Sodium lauryl sulphate etc.
Nonionic surfactants: Poloxamer.
Bile salts: Propylene glycol-oleic acid.

c. Miscellaneous chemicals: These include urea,

a hydrating and keratolytic agent; dimethyl
tolumide and calcium thioglycolate as anti-
cholinergic agents.
4. Drug reservoir components
It must be compatible with the drug and must
allow for drug transport at the desired rate.

If an ointment is used, the drug reservoir must

possess the desired viscosity attributes to
ensure reliable manufacturing process. It must
possess the desired adhesive and cohesive
properties to hold the system together.

Materials used are: mineral oils, colloidal silica,

poly isobutylene, HPC etc.
Figure: Different layers of TDDS.
5. Backing laminates
The primary function of the backing laminate is to
provide support. They should be able to prevent drug
from leaving the dosage form through top.
They must be impermeable to drugs and permeation
enhancers; should have a low moisture vapor
transmission rate; must have optimal elasticity,
flexibility, and tensile strength; must be chemically
compatible with the drug or other excipients; must be
relatively inexpensive and allow printing and
adhesive lamination.
Backing layers are composed of a pigmented layers,
a plastic film (polyethylene, polyvinyl chloride,
polyester) and a heat seal layer.
6. Rate controlling membrane
Rate controlling membranes in transdermal
devices govern drug release from the dosage
form.
Membranes made from natural polymeric
material such as chitosan show great promise for
use as rate controlling membranes.
Recently composite polyhydroxyethyl
methacrylate membranes have been evaluated
as rate controlling barriers for transdermal
application.
7. Adhesive layer
The fasting of all transdermal devices to the skin
using a pressure sensitive adhesive that can be
positioned on the face or back of the device is
necessary.
It should not cause irritation, sensitization or
imbalance in the normal skin during its contact. It
should adhere to the skin aggressively.
The three major classes of polymers evaluated for
potential medical applications in TDDS include:
Polyisobutylene, Acrylic and Silicone type pressure
sensitive adhesives.
8. Temporary/Release liners
The release liner has to be removed before the
application of transdermal system, and it
prevents the loss of the drug that has migrated
into the adhesive layer during storage. It also
helps to prevent contamination.

It is composed of a base layer, which may be

non-occlusive or occlusive, and a release coating
layer made of silicon or Teflon
Other materials include polyesters, foil and
metallized laminates.
Technology of Transdermal Drug Delivery System
(Basic manufacturing Designs)
Technically, transdermal drug delivery systems may
be categorized into two types:
1. Monolithic systems
2. Membrane controlled systems
1. Monolithic system: Monolithic systems
incorporate a drug matrix layer between backing
and frontal layers.
The drug matrix layer is composed of a polymeric
material in which the drug is dispersed. The
polymer matrix controls the rate at which the
drug is released for percutaneous absorption.
Nitro-Dur (Key) and Nitrodisc (Searle) are the
examples of monolithic systems.
In the preparation of monolithic systems, the drug
and the polymer are dissolved or blended
together, cast as the matrix and dried.
The gelled matrix may be produced in sheet or
cylindrical form, with individual dosage units cut
and assembled between the backing and frontal
layers.
Most transdermal drug delivery systems are
designed to contain an excess of drug and thus
have drug releasing capacity beyond the time-
frame recommended for replacement.
This ensures continued drug availability and
absorption as used patches are replaced on
schedule with fresh ones.
2. Membrane Controlled Transdermal System: This system is
designed to contain a drug reservoir, usually in liquid or
gel form, a rate controlling membrane and adhesive or
protective backing.
Here, a small quantity of drug is placed in the adhesive
layer to initiate prompt drug absorption, and therapeutic
effects.
This device may be prepared by pre-constructing the
delivery unit, filling the drug reservoir and sealing or
lamination with controlling membrane.
Transderm – Nitro (Sumit) and Transderm – Scop (CIBA)
are the examples of this technology.
Advantage of this system over monolithic systems is that,
as long as the drug solution in the reservoir remains
saturated, the release rate of drug through the
controlling membrane remains constant.
 General considerations in the use of TDDS
Some general points applicable to the use of transdermal
patches include the following:
1. The site selected for the application should be clear,
dry and hairless. [Nitroglycerin patches are generally
applied to the chest, estradiol to the buttocks or
abdomen, scopolamine behind the ear and nicotine
to the upper trunk or upper outer arm].
Because of the possible occurrence of skin irritation,
the site of application for replacement patches is
rotated. Skin sites generally are not reused for a
week.
2. The transdermal patch should not be applied to skin
that is oily, irritated, cut or abraded. (This is to
assure the intended amount and rate of transdermal
drug delivery and absorption).
3. The patch should be removed from its
protective package, being careful not to tear
or cut it. The patch's protective backing
should be removed to expose the adhesive
layer, and it should be applied firmly with
the palm or heel of the hand until securely in
place (about 10 seconds).
4. The patches should be worn for the period of
time stated in the product's instructions.
Following that period the patch should be
removed and a fresh patch applied as
directed. The used patch should be folded in
half with the adhesive layer together so that
it cannot be reused.
5. Patches generally may be left on when
showering, bathing or swimming. Should a
patch prematurely dislodge, an attempt may
be made to reapply it, or it may be replaced
with a fresh patch.
6. The patient should be instructed to clean the
hands thoroughly before and after applying
the patch. Care should be taken not to rub the
eyes or touch the mouth during handling the
patch.
7. As with all medications, if the patient exhibits
sensitivity or intolerance to the drug, or if
undue skin irritation results, the patient should
seek re-evaluation.
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