The document discusses transdermal patches, which deliver medication through the skin in a time-released manner. It covers the structure of skin and absorption mechanisms, the history and components of transdermal patches, different types of patches including polymer membrane and matrix patches, evaluations of patches, recent advances like iontophoresis and sonophoresis, and some marketed preparations. The key advantages of transdermal patches are avoiding presystemic metabolism, maintaining drug levels, and improving compliance through extended duration of action.

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Contents
1. Introduction
2.Structure of skin
3.Absorption mechanism
4.History of patches
5.Components of Transdermal Devices
6.Types of Transdermal Patches
7.Evaluation of TDDS
8.Recent Advances
9.Marketed preparations
10.References

3. Transdermal Patch or Skin Patch is a medicated
adhesive patch that is placed on the skin to deliver a
time released dose of medication through the skin and
into the bloodstream.
The delivery rate is controlled by the skin or membrane
in the delivery system. 3

4. Advantages of TDDS
1. Avoidance of presystemic metabolism.
2. Reduced inter- & intra-patient variability.
3. Maintained systemic drug level.
4. “Peak & Valley” effect of oral or injectable
therapy is avoided.
5. Extended duration of action.
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5. 6. Improved patient compliance.
7. Drug input terminated by simple removal of
patch.
8. Reduced dosage related side-effects.
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6. Disadvantages of TDDS
Limitations of TDDS are principally associated
with the barrier function of skin.
1. Method is limited only to potent drug
molecules.
2. Physicochemical properties of drug should
allow to be absorbed percutaneously.
3. Molecular wt should be reasonable.
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7. 4. Solubility should be in both lipophilic and
hydrophilic environments. Absence in either
phase will preclude permeation.
5. Drugs with short biological half-lives cannot
be delivered by TDDS.
6. Drugs must not be locally irritating or
sensitizing.
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8.  The most extensive and readily accessible organ
 Covers a surface area of approximately 2 m2
 Receives about one-third of the blood circulation.
Composed of three tissue layers:
– Epidermis
– Dermis
–Subcutaneous fat tissue or hypodermis.
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9. Fig: Structure of Skin
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10. Epidermis:
Comprises of stratum corneum and stratum germinativum.
Stratum corneum (10-15 m thick) is dry.
Consists of blocks of cytoplasmic protein
matrices(keratins) embedded in extracellular lipid.
Corneocytes are arranged in an interlocking structure.
Stratum corneum cells formed and continuously
replenished by slow upward migration of cells produced by
basal cell layers of Stratum germinativum.
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11. Stratum corneum lipids consists of ceramides and neutral
lipids like free sterols , free fatty acids and triglycerides &
phospholipids.
Despite low phospholipid levels Stratum corneum lipids
form bilayers.
All above points contribute to tightness and impermeability
characteristics of intact skin.
Molecules with molecular mass greater than 200-350 Da are
inefficient to cross the intact skin.
Removal of upper 3 epidermal layers results into water loss
and an enhancement of the transdermal permeability.
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12. Dermis:
 Composes of network of collagen and elastic fibers
embedded in mucopolysaccharide matrix.
It provides physiological support for epidermis.
Blood vessels approach the interface of 2 layers hence is
not considered significant barrier to inward drug permeation
in vivo.
Beneath the dermis fibrous tissue opens out and merges
with the fat-containing subcutaneous tissue.
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13. Percuteneous Absorption & its Mechanistic
Aspects
Designing TDDS requires:
1. Understanding permeation behavior of drug through skin.
2. The flux through the skin into the systemic circulation.
3. Mechanism of permeation.
Route Relative surface
area (%)
Diffusional
pathlength ( m)
Relative viscosity
of ST (%)
Transcellular 99.0 25 90-99
Intercellular 0.7 350 1-10
Transfollicular 0.1 200 0.1
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Fig : Various routes of drug absorption

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• The stratum corneum – limited skin permeation.
For a systematically active drug to reach a target tissue remote
from the site of drug administration on the skin surface, it must
posses physicochemical properties that facilitate the sorption of
drug by the stratum corneum, the penetration of drug through the
viable epidermis, and also the uptake of drug by microcirculation in
the dermal papillary layer.
The rate of permeation dQ/dt across various layers of skin tissue
can be expressed mathematically as
Mechanism of Rate-Controlled Transdermal Drug
Delivery

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Where,
Cd = conc. of drug in donor phase.
Cr = conc. of drug in the receptor phase.
Ps = the overall permeability coefficient of the skin tissues to the drug.
Ks/d = the partition coefficient for the interfacial partitioning of the drug
molecule from a TDD system onto the stratum corneum .
Dss = the apparent diffusivity for the steady-state diffusion of the drug
through the skin tissues.
hs = overall thickness of the skin tissues for penetration.
To achieve a constant rate of drug permeation one needs to maintain a
condition in which the drug concentration on the surface of stratum corneum
Cd is consistently and substantially greater the drug concentration in the body
Cr, i.e. Cd >> Cr.
So, if the magnitude of Cd value remains fairly constant throughout the course
of skin permeation, the rate of skin permeation should be constant.

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To maintain Cd at a constant value, it is necessary to deliver the drug at a rate Rd
that is either constant or always greater than Ra the rate of skin absorption, i.e.
Rd >>Ra. By making Rd greater than Ra the drug concentration on the skin surface
Cd is maintained at a level equal to or greater than the equilibrium solubility of
the drug in the stratum corneum Cs
e , i.e. Cd > Cs
e.
A maximum rate of skin permeation (dQ/dt)m can be expressed as
Membrane – limited drug release.
In such systems the drug delivery is controlled by the use of rate-limiting
membrane. The bioavailability of the drug does not depend only on this, but also
on its absorption through the stratum corneum, and its subsequent uptake into
the systemic circulation.

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Historically, the Chinese medicated plaster can be
viewed as the first development of transdermal drug
delivery; it is designed to bring medication into close
contact with the skin, so drug can be delivered
transdermally.
Medicated plasters were also very common in Japan as
OTC dosage forms – called Cataplasms, Salonpas.
In Western countries – Allock’s porous plasters of
England and the ABC plaster of Germany.
In the US – 3 medicated plasters have been listed in
the official compendia since 40 yrs ago Belladonna
plaster, Mustard plaster, and Salicylic acid plaster.
History of patches

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Components of transdermal devices
There are 2 basic types of transdermal dosing systems
1. Those that control rate of drug delivery to skin
2. Those that allow the skin to control the rate of drug absorption.
The basic components of transdermal devices include:
 Polymer matrix
 Drug
 Penetration Enhancers
 Other Excipients
 Adhesive/Packaging

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Polymer matrix
Polymers used in TDDS should fulfill:
1. Mol wt, physical & chemical characteristics must allow diffusion
of drug.
2. Should be chemically non-reactive (inert drug carrier).
3. Must not decompose on storage.
4. Polymer & its decomposed product should be nontoxic.
5. Polymer must be easy to manufacture and fabricate .
6. Cost should not be excessively high.
Polymers used in TDDS are
 Poly-propylene
 Poly vinyl carbonate
 Cellulose acetate nitrate
 Polyacrylonitrle
 Ethylene vinyl acetate copolymer
 Polyethylene terephthalate
 Hydroxypropyl cellulose
 polyesters
Ethylene vinyl
acetate
copolymer

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Drug
Choice of drug is critical in successful development of
transdermal product.
Important properties of drug that affect its diffusion include
1. Molecular weight
2. Chemical functionality
3. Partition coefficient
4. Skin metabolism
Skin irritation & clinical need should also be considered.
The drug should be non-irritating and non-allergic to human
skin.

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Penetration enhancers
Skin permeation enhancers are considered as integral part of
most TDDDS.
Penetration enhancers are classified into mainly 3 categories:
1. Lipophilic solvents
e.g. Dimethyl sulfoxide
2. Surface-active agents
e.g. Sodium lauryl sulfate (SLS)
3. Two component systems
e.g. oleic acid and propylene glycol

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Other excipients
Solvents such as:
Chloroform,
Methanol,
Acetone,
Isopropanol and
Dichloromethane are used to prepare drug reservoir.
Plasticizers such as:
•Dibutylpthalate,
•Triethylcitrate,
•Polyethylene glycol and
•Propylene glycol are added to provide plasticity to the
transdermal patch.

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Adhesive and packaging:
•Adhesion of all transdermal devices to skin is an essential
requirement.
•Pressure-sensitive polymeric adhesives are generally used.
•The adhesive system should posses following characteristics:
1. Should not cause irritation, sensitization & imbalance to skin.
2. Should adhere to skin strongly.
3. Should resist to normal routine disturbances like
bathing, abrasion and exercise.
4. Should be easily removable.
5. Should have intimate contact with the skin.

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Pressure-sensitive adhesive:
It is defined as a material that adheres to a substance when a light
pressure is applied and leaves no residue when removed.
There are 3 different categories of adhesives:
1. Butyl Rubbers
e.g. It is a copolymer of isobutylene & isoprene.
2. Polyisobutylenes
differ from butyl rubber in terminal unsaturation.
used in polyolefin plaster surface.
3. Butyl rubber and Polyisobutylenes
Combination of above two.

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Types of Transdermal
Patches
Polymer Membrane Permeation – Controlled
Transdermal Patch
Polymer Matrix Diffusion – Controlled Transdermal
Patch
Drug Reservoir Gradient – Controlled Transdermal
Patch
Micro reservoir Dissolution – Controlled Transdermal
Patch

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1. Polymer Membrane Permeation – Controlled
Transdermal Patch
Drug reservoir - sandwiched between a drug impermeable
backing laminate and a rate-limiting polymeric membrane.
The drug molecules are permitted to release only through
the rate-controlling polymeric membrane.

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 In the drug reservoir compartment the drug solids are :-
•dispersed homogeneously in a solid polymer matrix – polyisobutylene
•suspended in a unleachable, viscous liquid medium – silicone fluid
•dissolved in a releasable solvent – alkyl alcohol
The rate-controlling membrane can be either a microporous or a
nonporous membrane – ethylene-vinyl acetate copolymer.
On the external surface of the polymeric membrane a thin layer of
drug-compatible, hypoallergenic pressure-sensitive adhesive polymer
may be applied to provide intimate contact of the TDD system with the
skin surface. These adhesives are usually based on silicones, acrylates
or polyisobutylene.
Examples – Scopolamine releasing TDD system –
Transderm-Scop system,
Clonidine releasing TDD system –
Catapress-TSS system

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2. Polymer Matrix Diffusion – Controlled
Transdermal Patch
2 types of systems
1. Drug-in-adhesive system
2. Matrix-dispersion system
1. Drug-in-adhesive system:
Drug reservoir – drug dispersed in hydrophilic or lipophilic
polymer matrix
Drug reservoir is then mounted on a baseplate over which is
the drug-impermeable plastic backing with an absorbent pad.
Adhesive rim surrounds the reservoir disc.

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2. Matrix-dispersion system
Drug reservoir – drug is directly dispersed in a pressure-
sensitive adhesive polymer, e.g. polyacrylate
This is then coated onto a flat sheet of a drug-impermeable
backing laminate.
 Additionally Release liner is present.
Examples – Nitroglycerin releasing TDD system –
the Minitran system
Isosorbide dinitrate releasing TDD system –
Frandol tape.

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3. Drug Reservoir Gradient – Controlled
Transdermal Patch
Zero order release
Drug reservoir – drug loading level is varied in an incremental
manner, forming a gradient of drug reservoir along the
Diffusional path across the multilaminate adhesive layers.
Example – Nitroglycerin
releasing TDD system
the Deposit system

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4. Micro reservoir Dissolution – Controlled
Transdermal Patch
It is a hybrid of the reservoir and matrix dispersion- type
drug delivery systems.
Drug reservoir - formed by first suspending the drug
solids in an aq. solution of drug solubilizer, e.g.
polyethylene glycol, and then homogeneously dispersing
the drug suspension, in a lipophilic polymer to form
thousands of unleachable microscopic drug reservoirs.
This thermodynamically unstable dispersion is quickly
stabilized by immediately cross-linking the polymer chains
in situ. A TDD system is then produced by mounting the
medicated disc at the centre of adhesive pad.

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Example – Nitroglycerin releasing TDD system –
Nitrodisc system
Progestin-estrogen releasing TDD system –
Transdermal contraceptive system

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Evaluation of Transdermal Drug Delivery
Systems
Evaluation of Adhesives
1. Peel adhesion properties : Tested by measuring the
force required to pull single coated tape.
2. Tack properties
a) Thumb tack test
b) Rolling ball tack test
c) Quick-stick (or peel-tack) test
d) Probe tack test
3. Shear Strength Properties: Measurement of cohesive
strength of adhesive polymer.

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Evaluation of Patches
1. Interaction study
2. Thickness of patch
3. Weight uniformity
4. Folding Endurance of patch
5. % Moisture content
6. % Moisture uptake
7. Drug content
8. Uniformity of unit dosage form test
9. Skin irritation studies
10. Stability studies

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In-vitro drug release studies:
Paddle over disc method is used.(USP apparatus V)
In-vitro skin permeation studies:
1. Keshery-Chien Diffusion Cell

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2. Franz diffusion cell

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3. Valia – Chien Diffusion Cell

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Recent Advancements in TDD Systems
Iontophoresis :-
• It can be defined as the facilitation of ionizable drug
permeation across the skin by an applied electrical potential, the
driving force of which may be simply visualized as electrostatic
repulsion.
• Technique involves application of small electric current(0.5
mA/cm2)
Example :- Piroxicam

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Sonophoresis :-
• It is the enhancement of migration of drug molecules through the skin by
ultrasonic energy.
• Mechanism of drug permeation involves disruption of stratum corneum
lipids.
• The acoustic waves that reduce the resistance offered by stratum
corneum lie in the frequency range of 20 KHz to 20 MHz.
Example :- Salicylic acid

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Electroporation
It involves application of high voltage pulses to the skin which
induces formation of transparent pores.
High voltages of Direct Current 100 volts for few milliseconds are
employed.
The technology has been successfully used to enhance skin
permeation of molecules differing in lipophilicity & size.
Example :- metoprolol, lidocaine, tetracaine, etc

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Marketed Preparations :-
 Scopolamine-releasing TDD system for 72 hrs prophylaxis or
treatment of motion-induced nausea (Transderm-Scop)
 Nitroglycerine-releasing TDD system (Deponit, Nitrodisc,
Transderm-Nitro) and other isosorbide dinitrate-releasing
TDD system for once-a-day medication of angina pectoris
 Clonidine-releasing TDD system for the weekly therapy of
hypertension (Catapres-TTS)
 Estradiol-releasing TDD system for the twice-a-week
treatment of postmenopausal syndromes (Estraderm)
 Fentanyl-releasing TDD system for the twice-a-week
analgesic in cancer patients (Duragesic).

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1. Chien Y.W; “Novel Drug Delivery System” ; 2nd edition;
volume 50; Informa healthcare; pg no 301-380.
2. Jain N.K; “Controlled and Novel Drug Delivery” ; 1st edition;
CBS Publishers; pg no 100-129.
3. Wokovich Anna M. “Transdermal drug delivery system
(TDDS) adhesion as a critical safety, efficacy and quality
attribute” European Journal of Pharmaceutics and
Biopharmaceutics 64 (2006) 1-8
4. Mark Gibson; “PHARMACEUTICAL PREFORMULATION AND
FORMULATION- A practical guide for candidate drug
selection to commercial dosage form” CRC press LLC 331-
353.

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5. Keleb E, et al; “Transdermal Drug Delivery System-
Design and Evaluation”; International Journal of Advances
in Pharmaceutical Sciences
1 (2010) 201-211.
6. Prabhakar V et al; “Transdermal drug delivery system:
Review”; International Resarch Journal of Pharmacy 2012 3
(5).
7. Arunachalam. A. et al; “Transdermal Drug Delivery
System: A Review”; Current Pharma Research vol 1, issue 1,
Oct-Dec 2010.
8. J. Ashok Kumar et al; “Transdermal Drug Delivery
System: A Overview”; International Journal of
Pharmaceutical Sciences Review and Research; Volume 3,
Issue 2, July – August 2010; Article 009

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