Chapter 11: Transdermal Drug Delivery System

Ansels Pharmaceutical Dosage Forms and Drug Delivery Systems

Transdermal Drug Delivery Systems

- facilitate the passage of therapeutic
quantities of drug substances through the
skin.
- general circulation for systemic effect
- ideal for the drug to migrate through the
skin without buildup in the dermal layers.
- acts as an occlusive moisture barrier
through sweat cannot pass, increasing skin
hydration.
- should not be applied to skin that is
abraded or cut.
Stoughton
- conceived the first percutaneous
absorption of drug substances
- 1965
Transderm Scop (Baxter)
- first transdermal system
- approved on 1979
- prevention of nausea and vomiting
associated with travel (particularly at sea)
Evidence of percutaneous drug absorption
may be found through:
- measurable blood levels of the drug
- detectible excretion of the drug (e.g
metabolites in urine)
- clinical response of the patient to the
therapy
Drug Penetration
Skin
- composed of the stratum corneum (the
outer layer), the living epidermis, and
the dermis.
Stratum Corneum
- 10 to 15 mm thick layer of flat partially
desiccated keratinized nonliving tissue.
- composed of 40% protein and 40%
water
- behaves as a semipermeable artificial
membrane
- film that covers the stratum corneum
and hair follicle are not significant
factors in drug penetration.
Percutaneous Drug Absorption
- results from direct penetration of the
drug through the stratum corneum
- passive diffusion
- drugs major route of penetration:
intercellular channels
- lipid component: important determinant
in the first step of absorption
- when the drug reached the vascularized
dermal layer: drug becomes available
for absorption into the general
circulation
Factors affecting Percutaneous Drug
Absorption:
- drug concentration is important.
- the larger area of application, the more
drug absorbed.
- drugs physicochemical attraction to the
skin is greater than the vehicle.

- drugs penetrate the skin better in their

unionised form

- drugs with molecular weights of 100 to

800 and adequate lipid and aqueous

solubility can permeate the skin.
- Hydration of the skin generally favours
percutaneous absorption.
- absorption is greater when applied to a
site with a thin horny later than with a
thick one.
- the longer application permitted to
remain in contact with the skin, the
greater is the total drug absorption.
Absorption Enhancers
Chemical Enhancers
- increases skin permeability by
reversibly damaging or altering
physicochemical nature of the
stratum corner to reduce its
diffusional resistance.
- examples include: acetone, azone,
d i m e t h y l a c e t a m i d e ,
d i m e t h y l f o r m a m i d e ,
dimethylsulfoxide, ethanol, oleic
acid, polyethylene glycol, propylene
glycol, and sodium laureate
sulphate.
- toxicity should be low
Iontophoresis
- delivery of a charged chemical
compound across the skin
membrane using an electrical field.
- lidocaine, dexamethasone, amino
acids, peptides, insulin, verapamil,
and propanolol.
Sonophoresis
- high frequency ultrasound
- hydrocortisone, lidocaine, and
salicylic acid in gels, creams, and
lotions.
Percutaneous Absorption Models
In Vivo
- performed in humans and animals
- animal models include: weanling
pig, rhesus monkey, and hairless
mouse or rat
- Purposes:
To verify and quantify the
cutaneous bioavailability of a
topical applied drug.
To verify and quantify the
systemic bioavailability of a
transdermally delivered drug.
To establish bioequivalence of
different topical formulations of
the same drug substance
To determine incidence and
degrees of systemic toxicologic
risk following the topical
application of a specific drug/
drug product
In Vitro
- skin tissues are used
- animal skins are more permeable
than human skin
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- animal models include: elaphe

Polybutyl acrylate - commonly used

obsoleta or black rat snake.

- diffusion cell systems are employed
in vitro.

adhesive in TDDS
Types:
Peripheral - outer edge
Face - covers the entire face of
TDDS

Living Skin Equivalent Testskin

- is an
alternative for dermal
absorption studies.

- Organogenesis

Design Features of Transdermal Drug

Delivery Systems
Monolithic System
- incorporate a drug matrix layer between
the backing and the frontal layers
Drug Matrix Layer - polymeric material
in which the drug is dispersed.
Polymer Matrix - controls the rate at
which the drug is released for
percutaneous absorption
Two types of matrix:
no excess drug is available to
maintain the saturation of the stratum
corneum
with excess
- drug reserve is present to ensure
continued saturation
- rate of drug decline is less than no excess
- Examples include: Nitro-Dur and Nitrodisc
Membrane-controlled Transdermal System
- designed to contain a drug reservoir or
pouchm usually in liquid or gel form; a ratecontrolling membrane; and backing
adhesive; and protective layers.
- Examples include: Transderm-Nitro and
Transderm Scop
- have the advantage than Monolithic
System
Device - controlling factor if the drug is
delivered to the stratum corneum at a rate
less than the absorption capacity
Skin - controlling factor if the drug is
delivered to the skin area to saturation
Layers of TDDS
Occlusive backing membrane
- protect the system from environmental
entry and from loss of drug
Drug reservoir or matrix
- to store and release the drug at the skin
site
Release liner
- part that is removed that enables drug
release
Backing Layer
- must be occlusive to retain skin
moisture and hydrate the site of skin
penetration
Adhesive layer
- to maintain contact with the skin after
application
- must be pressure sensitive

Design Objectives of TDDS

deliver the drug to the skin for percutaneous
absorption at therapeutic levels at an
optimal rate
contain medicinal agents having necessary
physicochemical characteristics to release
from the system and partition into the
stratum corneum
occlude the skin to ensure one-way flux
have a therapeutic advantage over other
dosage forms
Advantages of TDDS
avoid gastrointestinal drug absorption
difficulties
substitute for oral administration of
medication
avoid first-pass effect
non invasive
provide extended therapy
having a short-life is extended through the
reservoir of the drug
drug therapy may be terminated rapidly
easily and rapidly identified in emergencies
Disadvantages of TDDS
only relative potent drugs are suitable
patients may develop contact dermatitis
General Clinical Considerations in the use of
TDDS

percutaneous absorption may vary with the

site of application.
- Example: nitroglycerin - chest; estradiol -
bu9ocks or abdoment; scopolamine -
behind the ear; nico;ne upper trunk or
upper outer arm.

should be applied to clean and dry skin that

is relatively free of hair.

use of skin lotion should be avoided
should not be physically altered
should be removed from its protective
package
placed on area rear we bot subject to being
rubbed off by clothing or movement
should be worn for the full period stated in
the products information
should have clean hands before applying
seek reevaluation when irritation or
intolerance happen
TDDS should be fold in half with the
adhesive layer after using
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Examples of TDDS

Transdermal Testosterone
Testoderm TDDS
two-layer system that is used to treat men who have an absence or are deficient in

testosterone

three-layer patch
applied in the scrotum (scrotal skin that is dry and shaved)
Androderm TTDS
also for men who have an absence or are deficient in testosterone
five-layer patch
applied nightly, to a clean, dry, unabridged area of the skin of the back, abdomen, upper

arms, or thigh.
not applied in scrotum
Trans-Ver-Sal

contains 15% salicylic acid in a vehicle consisting of karaya, a substance known for its non

- irritating and self-adhesive properties. It is use for the treatment of viral wart infections

Tapes
- dosage form that is suitable for delivering drugs to the skin.
- consist of drug that is impregnated into a flexible durable woven fabric or extruded
synthetic material that is coated with an adhesive agent.

- not designed to control the release rate

Patches

Lidoderm patch
consist of an adhesive material containing 5% lidocaine which is applied to a non-woven

polyester felt backing.

can only apply 3 patches once up for 12 hours within a 24 hour period

Other TDDS include:

dil;azem, isosorbide, dinitrate, propanolol, nifedipine, mepindolol, and verapimil.

Table 1.0 | Examples of TDDS

Therapeautic Agent

TDDS

Design Contents

Clonidine

Catapress - TSS
(Boehringer Ingelheim)

Four layer patch

a) backing layer of
pigmented polyester
film
b) drug reservoir of
clonidine, mineral oil,
polyisobutylene, and
colloidal silicon
dioxide
c) a microporous
polypropylene
membrane controlling
the rate of drug
delivery
d) an adhesive
formulation of agents

antihypertensive drug

first transdermal system

for hypertension

Four layer patch

a) transparent polyester
film
b) drug reservoir of
estradiol and alcohol
gelled with
hydroxypropyl
cellulose
c) an ethylenevinyl
acetate copolymer
membrane
d) an adhesive
formulation of light
mineral and
polyisobutylene

design to release 17 Bestradiol continuously.

applied twice weekly

over a cycle of 3
weeks.

to the abdomen,
altering sites with each
application.

Estradiol

Estraderm
(Novartis)

Comments

constant rate for 7 days

hairless upper arm or torso

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Therapeautic Agent

TDDS

Vivelle
(Novartis)
Climara
Fentanyl

Nicotine

Duragesic

Habitrol

Design Contents

Three layer patch

Three layer system
Four layer patch

Multilayer round patch

a) outer backing of
laminated polyester
film
b)

Nitroglycerin

Deponit

Nitro-dur

Comments

72 hour continuous
systemic delivery
potent opioid analgesic
chronic pain

smoking cessation

rate-controlling
adhesive,
nonwoven material,
and
nicotine, disposable
liner removed prior
to use

Three layer system

a) covering foil
b) nitroglycerin matrix
with polyisobutylene
adhesive, plasticizer,
release membrane
c) p r o t e c t i v e f o i l ,
removed before use
Nitroglycerin in a gel like
matrix composed of

Nitroglycerin
- treatment for angina
to provide controlled
release of nitroglycerin
continuously for a 24
hour period.

Patches are applied to

inner part of upper arm,
shoulders, or chest.

continous release of
drug for 3 days
prevent nausea and
vomiting
motion sickness
behind the ear

glycerin, water, lactose,

polyvinyl alcohol, povidone
and sodium citrate sealed in
a polyester foil polyethylene
laminate

Scopalamine

Transderm-Nitro

Four layered patch

Transderm sCOP

Four layered patch:

a)
b)

c)

d)

backing layer of

aluminized
polyester film

drug reservoir of

scopolamine,
mineral oil &
polyisobutylene
a microporous
polypropylene
membrane for rate
delivery of
scopolamine
adhesive of
polyisobutylene,
mineral oil, and
scopolamine

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