Transdermal Drug

Delivery Systems
Prepared by : Tejas J Patel
Associate Professor
Department of Pharmaceutics
SNLPCP, Umrakh.
Introduction
Transdermal delivery may be defined as the delivery of
a drug through ‘intact’ skin so that it reaches the
systemic circulation in sufficient quantity, to be
beneficial after administration of a therapeutic dose.
It lying under the category of controlled drug delivery,
in which the aim is to deliver the drug through the skin
in a predetermined and controlled rate.
TDDS are adhesive drug-containing devices of defined
surface area that deliver a predetermined amount of
drug to the surface of intact skin at a programmed rate
to reach the systemic circulation.
Transdermal systems are ideally suited for diseases
that demand chronic treatment. Hence, anti-diabetic
agents of both therapeutic and prophylactic usage have
been subjected to transdermal investigation.
Currently transdermal delivery is one of the most
promising methods for drug application.
It reduces the load that the oral route commonly
places on the digestive tract and liver.
It enhances patient compliances and minimizes
harmful side effects of a drug caused from temporary
over dose and is convenience in transdermal delivered
drugs that require only once weakly application.
Transdermal delivery not only provides controlled,
constant administration of drugs, but also allows
continuous input of drugs with short biological half
lives and eliminates pulsed entry into systemic
circulation, which often causes undesirable side effects.
The first transdermal system, Transderm SCOP was
approved by FDA in 1979 for the prevention of nausea
and vomiting associated with travel.
Advantages
Self-administration is possible and continuous,
sustained release of drug.
Avoids first-pass hepatic metabolism.
Avoids Enzymatic degradation by the gastrointestinal
tract and also avoids gastrointestinal irritation.
Less frequent dosing improves patient compliance.
Avoids peak and trough drug levels and longer and
multiday dosing intervals.
Alternate route for patients who are unable to take
oral medication.
Dose delivery unaffected by vomiting or diarrhea.
Drug administration stops with patch removal.
Disadvantages
Only small lipophilic drugs can be delivered
currently
through the skin.
Drug molecule must be potent because patch size
limits the amount that can be delivered.
Not suitable for high drug doses.
It cannot deliver drugs in a pulsatile fashion.
Adhesion may vary with patch type and
environmental conditions.
Skin irritation and hypersensitivity reactions may
occur.
Long time adhere is difficult.
Skin and drug permeation
The objective of TDDS is to achieve systemic
medication through topical application on intact skin;
therefore, it is important to review the structural and
biochemical features of the human skin.
Anatomically, the skin can be divided into two layers:
epidermis and dermis or corium [Figure], penetrated
by hair shafts and gland ducts.
The skin is one of the most extensive organs of the
human body, covering an area of about 2 m2 in an
average human adult.
The major skin layers, from inside to outside,
comprise the fatty subcutaneous layer (hypodermis),
the dermis of connective tissue and the stratified a
vascular cellular epidermis.
o The dermis or corium consists of a dense network of
connective tissue in which bundles of collagen fibers
predominate, mingled with elastic tissue in the
superficial levels.
o The dermis contains fine plexuses of blood vessels,
lymphatic, nerves, hair follicles, sweat glands and
sebaceous glands.
o The structure of the SC is often depicted as a bricks and
mortar arrangement, where the keratin-rich corneocytes
(bricks) are embedded in the intercellular lipid-rich
matrix (mortar).

Routes of penetration
o There are critically three ways in which a drug
molecule can cross the intact SC: via skin appendages
(shunt routes), through the intercellular lipid
domains or by a transcellular route [Figure].
 1) The trans appendageal routes are also known as the shunt
routes, and include permeation through the sweat glands and
across the hair follicles with their associated sebaceous glands.
2) Drugs entering the skin via the transcellular route pass
through the corneocytes.
3) The intercellular route involves drug diffusion through the
continuous lipid matrix.
o The transcellular and intercellular route is collectively
known as trans-epidermal route.
 Factor affecting on TDDS
A) Physiochemical Factor
1) Molecular size:
o There is an inverse relationship existed between
transdermal flux and molecular weight of the molecule.
The drug molecule selected as candidates for
transdermal delivery tend to lie within narrow range of
molecular weight (100-500 Dalton).
2) Solubility:
Lipophilicity is a desired property of transdermal
candidates as lipophilic molecules tend to permeate
through the skin faster than more hydrophilic
molecules.
3) Melting point:
Drugs with higher melting point have relatively low
aqueous solubility at normal temperature and pressure.
It permeate slower than lower melting point containing
 4) pH and Ionization Constant:
o The pH mainly affects the rates of absorption of acidic
and basic drugs whereas unchanged form of drug has
better penetrating capacity.
o According to pH partition hypothesis, only the
unionized form of the drugs can permeate through
the lipid barrier in significant amounts.
5)Partition co-efficient:
Drug possessing both water and lipid solubility are
favorably absorbed through the skin. Transdermal
permeability co-efficient shows a linear dependence on
partition coefficient. Varying the vehicle may also alter
a lipid/water partition co-efficient of a drug molecule.
The partition co-efficient of a drug molecule may be
altered by chemical modification without affecting the
pharmacological activity of the drug.
B) Physiological factor
1) Skin age :
It is seen that the skin of adults and young ones is more
permeable than that of the older ones. but there is no
dramatic difference.
Children show toxic effects because of the greater
surface area per unit body weight. Thus, potent
steroids, boric acid and hexachlorophene have produced
severe side-effects.
2) Skin condition :
The intact skin itself acts as a barrier, but many agents
like acids and alkali cross the barrier cells and
penetrate through the skin.
Many solvents open the complex dense structure of the
horny layer: solvents like methanol and chloroform
remove the lipid fraction, forming artificial shunts
through which drug molecules can pass easily.
 3) Hydration of skin :
Generally, when water saturates the skin, it swells
tissues, softens wrinkles on the skin and its
permeability increases for the drug molecules that
penetrate through the skin.
4) Temperature of the skin :
The penetration rate varies if the temperature varies
and the diffusion coefficient decreases as the
temperature falls;, however adequate clothing on the
body prevents wide fluctuations in temperature and
penetration rates.
5) Pathological injury to the skin:
o Injuries to the skin can cause the disturbance in the
continuity of SC and leads to increase in skin
permeability.
Polymer used in TDDS
Natural Polymer Synthetic Elastomers Synthetic polymer
Cellulose Polybutadiene, Polyvinyl alcohol,
derivatives, zein, hydrin rubber, polyvinylchloride,
gelatin, waxes, polysiloxanes polyethylene,
proteins and their silicone rubber, polypropylene,
derivatives, nitrile, acrylonitrile, polyacrylate,
natural rubber, butyl rubber rubber, polyurea,
starch, chitosan, styrene–butadiene polyvinyl
Etc. rubber, neoprene, pyrrolidone,
Etc. polymethyl
methacrylate,
epoxy, ethyl
cellulose,
hydroxy propyl
cellulose,
polyamide, etc.
 Basic components of TDDS
1) Polymer matrix/drug reservoir
2) Membrane
3) Drug
4) Permeation enhancers
5) Pressure-sensitive adhesives (PSA)
6) Backing laminates
7) Release liner
8) Other excipients like plasticizers and solvents.
1) Polymer matrix/drug reservoir :
Polymers are the backbone of TDDS, which control the
release of the drug from the device. A polymer matrix can be
prepared by dispersion of drug in a liquid or solid state
synthetic polymer base.
Polymers used in TDDS should have biocompatibility and
chemical compatibility with the drug and other components
of the system, such as penetration enhancers and PSAs.
Additionally, they should provide consistent and effective
delivery of a drug throughout the product’s intended shelf-
life, and should be safe,
The polymer should be stable, nonreactive with the drug,
easily manufactured and fabricated into the desired product,
and should be inexpensive.
The polymer and its degradation products must be nontoxic
or nonantagonistic to the host.
2) Membrane :
A membrane may be sealed to the backing to form a pocket
to enclose the drug-containing matrix or used as a single
layer in the patch construction.
The diffusion properties of the membrane are used to
control availability of the drug and/or excipients to the skin.

For example, ethylene vinyl acetate, silicone rubber,

polyurethane, etc. are used as a rate-controlling membrane.
3) Drugs:
For successfully developing a TDDS, the drug should be
chosen with great care.
Transdermal patches offer many advantages to drugs that
undergo extensive first-pass metabolism, drugs with
narrow therapeutic window or drugs with a short half-life,
Ideal properties of drugs for TDDS
Parameters Properties
Dose Should be low (less than 20 mg/
day)
Half-life 10 hr or less
pH Between 5.0 to 9.0
Molecular weight Less than 400 Da
Partition coefficient Between 1.0 and 4.0
Skin permeability coefficient >0.5 × 10-3 cm/h
Lipophilicity 10 < Ko/w < 1000
Oral bioavailability Low
Therapeutic Index Low
Melting Point <200°C
4) Permeation enhancers :
One long-standing approach for improving TDDS uses
penetration enhancers also called sorption promoters or
accelerants, which increase the permeability of the SC so as
to attain higher therapeutic levels of the drug candidate.
Penetration enhancers interact with structural components
of the SC thus modifying the barrier functions, leading to
increased permeability.
Three pathways are suggested for drug penetration through
the skin: polar, nonpolar and polar/nonpolar.
The key to altering the polar pathway is to cause protein
conformational change or solvent swelling.
The key to altering the nonpolar pathway is to alter the
rigidity of the lipid structure and fluidize the crystalline
pathway.
Some enhancers (binary vehicles) act on both polar and
nonpolar pathways by altering the multilaminate pathway
for penetrants.
 The methods employed for modifying the barrier properties
of the SC to enhance the drug penetration through the skin
can be categorized as (a) chemical and (b) physical methods
of enhancement.

a) Chemical enhancers :
Chemicals that promote the penetration of topically applied
drugs are commonly referred to as accelerants, absorption
promoters or penetration enhancers.
It increasing (and optimizing) the thermodynamic activity of
the drug when functioning as a co-solvent.
It Increasing the partition coefficient of the drug to promote
its release from the vehicle into the skin.
b) Physical enhancers :
Iontophoresis and ultrasound (also known as phonophoresis
or sonophoresis) techniques are examples of physical means
of enhancement that have been used for enhancing
percutaneous penetration (and absorption) of various
therapeutic agents.
Some of more desirable properties for penetration
enhancers acting within skin have been given as:

•They should be nontoxic, nonirritating and nonallergenic.

•They should ideally work rapidly, and the activity and
duration of the effect should be both predictable and
reproducible.
•They should have no pharmacological activity within the
body.
•The penetration enhancers should work unidirectionally.
•When removed from the skin, barrier properties should
return both rapidly and fully.
•The penetration enhancers should be appropriate for
formulation into diverse topical preparations and, thus,
should be compatible with both excipients and drugs.
•They should be cosmetically acceptable with an
appropriate skin “feel”.
5) Pressure-sensitive adhesives (PSA) :
PSAs are the material that adhere to a substrate, in
this case skin, by application of light force and leave no
residue when removed.
They form interatomic and intermolecular attractive
forces at the interface, provided that the intimate
contact is formed.
To obtain this degree of contact, the material must be
able to deform under slight pressure, giving rise to the
term “pressure sensitive.”
Adhesion involves a liquid-like flow, resulting in
wetting of the skin surface upon the application of
pressure, and, when the pressure is removed, the
adhesive sets in that state.
Widely used PSA polymers in TDDS are
polyisobutylene-based adhesives, acrylics and silicone-
based PSAs, hydrocarbon resin, etc.
6) Backing laminates :
Backings are chosen for appearance, flexibility and
need for occlusion; hence, while designing a backing
layer, the consideration of chemical resistance of the
material is most important.
Excipient compatibility should also be considered
because the prolonged contact between the backing
layer and the excipients may cause the additives to
leach out of the backing layer or may lead to diffusion
of excipients, drug or penetration enhancer through the
layer.
The most comfortable backing will be the one that
exhibits lowest modulus or high flexibity, good oxygen
transmission and a high moisture vapor transmission
rate.
Examples of backing materials are vinyl, polyethylene,
polyester films, aluminium and polyolefin films.
7) Release liner :
During storage, the patch is covered by a protective
liner that is removed and discarded before the
application of the patch to the skin.
It is therefore regarded as a part of the primary
packaging material rather than a part of dosage form
for delivering the drug.
Because the liner is in intimate contact with the
TDDS, the liner should be chemically inert.
Typically, a release liner is composed of a base layer
that may be non-occlusive (e.g, paper fabric) or
occlusive (e.g, polyethylene, polyvinyl chloride) and a
release coating layer made up of Silicone & Teflon.
Other materials used for TDDS release liner are
polyester foil and metalized laminates.
8) Other excipients like plasticizers and
solvents :
Various solvents such as chloroform, methanol,
acetone, isopropanol and dicholoromethane are used
to prepare drug reservoir.
In addition, plasticizers such as dibutylphthalate,
triethyl citrate, polyethylene glycol and propylene
glycol are added to provide plasticity to the
transdermal patch.
Types of transdermal drug delivery system:
1)Polymer membrane permeation controlled TDD
system / Reservoir system :
o Drug reservoir sandwiched between drug impermeable
backing laminate and rate controlling polymeric
membrane.
o In drug reservoir compartment drug is dispersed
homogeneously in a solid polymeric matrix(e.g.
polyisobutylene), suspended in a unleachable viscous
liquid medium(e.g. silicon fluid) to form a paste like
suspension.

o Rate controlling membrane is either a microporous or

a nonporous polymeric membrane e.g. ethylene-vinyl
acetate copolymer.

o Example of this type of patch are Estraderm(twice a

week in treatment of postmenopausal syndrome) and
Duragesic(management of chronic pain for 72 hrs).
2) Polymer matrix diffusion controlled TDD system:

o Drug reservoir is formed by homogeneously dispersing

the drug solids in hydrophilic or lipophilic matrix and
the medicated polymer formed is than moulded into
medicated disk with defined surface area and controlled
thickness.
o e.g. Nitro-dur system once-a-day medication for angina
pectoris.
3) Drug reservoir gradient controlled TDD system:

o To overcome nonzero order drug release profile from

polymer matrix TDD system can be modified to have
drug loading level varied in incremental manner.
o forming a gradient of drug reservoir along the
diffusional path across the multilaminate adhesive
layer. e.g. Deponit system.
 4) Microreservoir dissolution controlled TDD
system :
o Considered as the hybrid system of reservoir and
matrix dispersion type drug delivery.
o In this system the drug reservoir is formed by first
suspending the drug solids in aqueous solution of
water-miscible drug solubiliser.e.g. polyethylene glycol
and than homogeneously dispersing the drug
suspension with controlled aqueous soluble lipophilic
polymer by high shear mechanical force to form
thousands of unleachable microscopic drug reservoir.
 Evaluation of tdds :
1. Thickness of the patch :
The thickness of the drug loaded patch is measured in
different points by using a digital micrometer and the
average thickness and standard deviation is determined
to ensure the thickness of the prepared patch.
The thickness of transdermal film is determined by
travelling microscope dial gauge, screw gauge or
micrometer at different points of the film.
2. Weight uniformity :
The prepared patches are dried at 60°c for 4hrs before
testing.
A specified area of patch is to be cut in different parts of
the patch and weigh in digital balance.
The average weight and standard deviation values are to
be calculated from the individual weights.
3. Folding endurance :
A strip of specific area is to be cut evenly and
repeatedly folded at the same place till it breaks.
The number of times the film could be folded at the
same place without breaking gives the value of the
folding endurance.
4. Percentage Moisture content :
The prepared films are to be weighed individually and
to be kept in a desiccators containing fused calcium
chloride at room temperature for 24 hrs.
After 24 hrs the films are to be reweighed and
determine the percentage moisture content from the
below mentioned formula.
%Moisture content = Initial wt – Final wt / Final wt
*100
5. Content uniformity test :
10 patches are selected and content is determined for
individual patches.
If 9 out of 10 patches have content between 85% to 115%
of the specified value and one has content not less than
75% to 125% of the specified value, then transdermal
patches pass the test of content uniformity.
But if 3 patches have content in the range of 75% to 125%,
then additional 20 patches are tested for drug content. If
these 20 patches have range from 85% to 115%, then the
transdermal patches pass the test.
6. Drug Content :
A specified area of patch is to be dissolved in a suitable
solvent in specific volume. Then the solution is to be
filtered through a filter medium and analyze the drug
contain with the suitable method (UV or HPLC technique).
7. Moisture Uptake :
Weighed films are kept in desiccators at room
temperature for 24 h.
These are then taken out and exposed to 84% relative
humidity using saturated solution of Potassium chloride
in desiccators until a constant weight is achieved.
% moisture uptake is calculated as given below.
%Moisture uptake : Final wt – Initial wt / Initial wt * 100
8. Shear Adhesion test :
This test is to be performed for the measurement of
cohesive strength of an adhesive polymer.
An adhesive coated tape is applied onto a stainless steel
plate; a specified weight is hung from the tape, to affect
it pulling in a direction parallel to the plate.
Shear adhesion strength is determined by measuring
the time it takes to pull the tape off the plate. The
longer the time take for removal, greater is the shear
9. Peel Adhesion test :
In this test, the force required to remove an adhesive
coating form a test substrate is referred to as peel
adhesion.
A single tape is applied to a stainless steel plate or a
backing membrane of choice and then tape is pulled
from the substrate at a 180º angle, and the force
required for tape removed is measured.
10. Rolling ball tack test :
This test measures the softness of a polymer that
relates to talk.
In this test, stainless steel ball of 7/16 inches in
diameter is released on an inclined track so that it rolls
down and comes into contact with horizontal, upward
facing adhesive.
The distance the ball travels along the adhesive
provides the measurement of tack, which is expressed
in inch.
11. Quick Stick (peel-tack) test :
In this test, tape is pulled away from the substrate at
90ºC at a speed of 12 inches/min.
The peel force required breaking the bond between
adhesive and substrate is measured and recorded as
tack value, which is expressed in ounces or grams per
inch width.
12. Probe Tack test :
In this test, the tip of a clean probe with a defined
surface roughness is brought into contact with
adhesive, and when a bond is formed between probe
and adhesive.
The subsequent removal of the probe mechanically
breaks it. The force required to pull the probe away
from the adhesive at fixed rate is recorded as tack and
it is expressed in grams.
13. In vitro drug release studies :
The paddle over disc method (USP apparatus V) is
employed for assessment of the release of the drug from
the prepared patches.

14. In vitro skin permeation studies :

An in vitro permeation study can be carried out by
using diffusion cell.

15. Stability Studies :

Stability studies are to be conducted according to the
ICH guidelines by storing the TDDS samples at
40±0.5°c and 75±5% RH for 6 months.
The samples are withdrawn at 0, 30, 60, 90 and 180
days and analyze suitably for the drug content.
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