Transdermal Drug Delivery Systems

Transdermal drug delivery
systems
1
• Transdermal drug delivery systems (TDDSs) facilitate
the passage of therapeutic quantities of drug
substances through the skin and into the general
circulation for their systemic effects.
• In 1965, Stoughton first conceived of the percutaneous

absorption of drug substances.
• The first transdermal system, Transderm Scop

(Baxter), was approved by the Food and Drug
Administration (FDA) in 1979 for prevention of nausea
and vomiting associated with travel, particularly at sea.
2
Routes of penetration
• Simplified diagram of skin structure and routes of
drug penetration,
• (a) Macroroutes:
(1) via the sweat ducts;
(2) across the continuous stratum corneum;
(3) through the hair follicles with their
associated sebaceous glands,
• (b) Representation of the stratum corneum

membrane, illustrating two possible Microroutes for
permeation ( Transcellular or Intercellular) across the
continuous stratum corneum between these
appendages
3
Routes of drug absorption through skin
4
4
Skin appendages
• Their fractional area available for absorption is small
(about 0.1%) and this route usually does not contribute
appreciably to the steady-state flux of a drug.
• However, the route may be important for ions and

large polar molecules that cross intact stratum
corneum with difficulty.
• For electrolytes and large molecules with low diffusion

coefficients, such as polar steroids and antibiotics, and
for some colloidal particles, the appendages may
provide the main entry route.
5
the slope = - P
Epidermal route
• The epidermal barrier function resides mainly in
the stratum corneum.
• The corneocytes, consisting of hydrated keratin,

are embedded in the in a complex lipid mixture of
ceramides, fatty acids, cholesterol and cholesterol
esters, formed into multiple bilayers.
• Most molecules penetrating through the skin use

this intercellular microroute.
7
FACTORS AFFECTING
PERCUTANEOUS ABSORPTION
• Not all drug substances are suitable for Transdermal
delivery.
• Among the factors playing a part in percutaneous
absorption are the physical and chemical properties
of the drug, including its molecular weight, solubility,
partitioning coefficient and dissociation constant
(pKa), the nature of the carrier vehicle, and the
condition of the skin.
8
Physicochemical factors
• Skin hydration.
• Temperature and pH
• Diffusion coefficient
• Drug concentration
• Partition coefficient
• Molecular size and shape
9
Penetrate (Drug) concentration
• Drug concentration is an important factor.
• Generally, the amount of drug percutaneously
absorbed per unit of surface area per time
interval increases with an increase in the
concentration of the drug in the TDDS.
10
Higher the concentration of the drug in vehicle
faster the absorption.
 At higher concentrations than solubility the

excess solid drug will function as a reservoir and
helps to maintain a constant drug constitution for
prolonged period of time.
11
the area and time of application
• The larger the area of application (the larger the
TDDS), the more drug is absorbed.
• Percutaneous absorption appears to be greater when

the TDDS is applied to a site with a thin horny layer
than with a thick one.
• Generally, the longer the medicated application is

permitted to remain in contact with the skin, the
greater is the total drug absorption.
12
solubility of the drug in
both lipid and water
• The drug should have a greater physicochemical
attraction to the skin than to the vehicle so that the
drug will leave the vehicle in favor of the skin.
• Some solubility of the drug in both lipid and water is

thought to be essential for effective percutaneous
absorption.
• the aqueous solubility of a drug determines the

concentration presented to the absorption site, and
the partition coefficient influences the rate of
transport across the absorption site.
13
• Generally, drugs penetrate the skin better in
their unionized form. Nonpolar drugs tend to
cross the cell barrier through the lipid-rich
regions (transcellular route),
• whereas the polar drugs favor transport

between cells (intercellular route) (6). For
example, erythromycin base demonstrates
better percutaneous absorption than does
erythromycin ethyl succinate.
Drugs molecular weight
• Drugs with molecular weights of 100 to 800
and adequate lipid and aqueous solubility can
permeate skin.
• The ideal molecular weight of a drug for

Transdermal drug delivery is believed to be
400 or less.
15
Hydration of the skin
• Hydration of the skin generally favors percutaneous
absorption.
• It can be achieved by covering skin with plastic

sheeting, which leads to accumulation of sweat,
condensed water vapors, increase hydration and
increase porosity.
• The TDDS acts as an occlusive moisture barrier

through which sweat cannot pass, increasing skin
hydration.
16
Temperature
• The penetration rate of material through human skin
can change tenfold for a large temperature variation,
as the diffusion coefficient decreases as the
temperature falls.
• Clothing on most of the body would usually prevent

wide fluctuations in temperature and penetration
rates.
• Occlusive vehicles increase skin temperature by a few

degrees, but any consequent increased permeability is
small compared to the effect of hydration.
17
PH condition
• Only unionized molecules pass readily across lipid
membranes. So when weak acids and bases dissociate to
different degrees, depending on the pH and their pKa or pkb
values. Thus, the proportion of unionized drug in the applied
phase mainly determines the effective membrane gradient,
and this fraction depends on pH.
• Moderate pH is favorable because if solutions with high or

low pH will result in destruction to the skin.
18
Partition coefficient
• Polar cosolvent mixtures, such as propylene glycol with water,
may produce saturated drug solutions and so maximize the
concentration gradient across the stratum corneum.
• However, the partition coefficient of a drug between the

membrane and the solvent mixture generally falls as the
solubility in the solvent system rises.
• Thus, these two factors - increase in solubility and decrease in

the magnitude of the partition coefficient - may oppose each
other in promoting flux through the membrane, when the
system is not saturated.
• Hence it is important not to over solubilize a drug if the aim is

to promote penetration: the formulation should be at or near
saturation.
19
Biological factors
• Skin condition.
• Skin age.
• Blood flow.
• Regional skin sites.
• Skin metabolism.
20
Skin condition
• The intact, healthy skin is a strong barrier but many agents can
damage it.
• acids and alkalis injure barrier cells and thereby promote

penetration, as do cuts, abrasions and dermatitis.
• skins may lose their reactivity or 'harden' because of frequent
contact with irritant chemicals.
• Disease commonly alters skin condition; In diseases characterized

by a defective stratum corneum ( e.g. psoriasis), percutaneous
absorption usually increases.
• permeability increases: the skin inflamed, with loss of stratum

corneum and altered keratinization.
• permeability decreases: the organ thickened, with corns, calluses
and warts,
21
22
Skin age
• It is often assumed that the skin of the young and
the elderly is more permeable than adult tissue
• Children are more susceptible to the toxic effects of

drugs and chemicals, partly because of their greater
surface area per unit body weight; thus potent
topical steroids, boric acid and hexachlorophane
have produced severe side-effects and death.
23
Blood flow
• an increased blood flow could reduce the amount of
time a penetrant remains in the dermis, and also
raise the concentration gradient across the skin
( Sink condition ) .
Regional skin sites

• Variations in cutaneous permeability around the
body depend on the thickness and nature of the
stratum corneum and the density of skin
appendages.
24
Skin metabolism
• The skin metabolizes steroid hormones, and some
other drugs.
• Such metabolism may determine the therapeutic

efficacy of topically applied compounds (particularly
prodrugs)
25
The nature of the carrier vehicle :
A vehicle can influence absorption by its effect on

physical state of drug and skin. Example greases,
paraffin bases are more occlusive while water in oil
bases are less. Humectants in bases will dehydrate the
skin and decrease percutaneous absorption.
26
FACTORS AFFECTING
TRANSDERMAL PERMEABILITY
Physico-chemical properties of drug delivery system
Release characteristic
 Solubility of drug in vehicle determines the release rate.
Composition of drug delivery system

 It not only effects the rate of drug release but also the
permeability of STC by means of hydration mixing with
skin lipids. Example methyl salicylate is more lipophilic
than its parent acid (Salicylic acid). When applied to skin
from fatty vehicle methylsalicylate yielded higher
absorption.
27
PERCUTANEOUS ABSORPTION
ENHANCERS
• Increase percutaneous absorption of
therapeutic agents:
1.chemical permeation enhancers

2.physical methods
28
CHEMICAL ENHANCERS
• increases skin permeability by reversibly
damaging or altering the physicochemical
nature of the stratum corneum to reduce its
diffusion resistance
• Among the alterations are:

• increased hydration of the stratum corneum,
• a change in the structure of the lipids and
lipoproteins in the intercellular channels through
solvent action or denaturation, or both
29
skin penetration enhancers
• Water
• Sulphoxides (especially dimethylsulphoxide) and
their analogues
• Pyrrolidones
• Fatty acids and alcohols
• Azone and its derivatives
• Surfactants - anionic, cationic and non-ionic
• Urea and its derivatives
• Alcohols and glycols
• Essential oils, terpenes and derivatives
• Synergistic mixtures.
30
• The selection of a permeation enhancer
should be based on:
• its efficacy in enhancing skin permeation
• its dermal toxicity (low)
• its physicochemical and biologic compatibility
with the system’s other components
31
Physical methods
• Iontophoresis and Sonophoresis.
• Iontophoresis is delivery of a charged chemical compound
across the skin membrane using an electrical field.
A number of drugs have been the subject of iontophoretic
studies; they include Lidocaine; dexamethasone; amino
acids, peptides, and insulin ; Verapamil; and propranolol.
• Sonophoresis, or high-frequency ultrasound,

Among the agents examined are hydrocortisone, lidocaine,
and salicylic acid in such formulations as gels, creams, and
lotions. It is thought that high frequency ultrasound can
influence the integrity of the stratum corneum and thus affect
its penetrability.
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Transdermal drug delivery

• In 1965, Stoughton first conceived of the percutaneous

• The first transdermal system, Transderm Scop

• (b) Representation of the stratum corneum

• However, the route may be important for ions and

• For electrolytes and large molecules with low diffusion

• The corneocytes, consisting of hydrated keratin,

• Most molecules penetrating through the skin use

 At higher concentrations than solubility the

• Percutaneous absorption appears to be greater when

• Generally, the longer the medicated application is

• Some solubility of the drug in both lipid and water is

• the aqueous solubility of a drug determines the

• whereas the polar drugs favor transport

• The ideal molecular weight of a drug for

• It can be achieved by covering skin with plastic

• The TDDS acts as an occlusive moisture barrier

• Clothing on most of the body would usually prevent

• Occlusive vehicles increase skin temperature by a few

• Moderate pH is favorable because if solutions with high or

• However, the partition coefficient of a drug between the

• Thus, these two factors - increase in solubility and decrease in

• Hence it is important not to over solubilize a drug if the aim is

• acids and alkalis injure barrier cells and thereby promote

• Disease commonly alters skin condition; In diseases characterized

• permeability increases: the skin inflamed, with loss of stratum

• Children are more susceptible to the toxic effects of

Regional skin sites

• Such metabolism may determine the therapeutic

A vehicle can influence absorption by its effect on

Composition of drug delivery system

1.chemical permeation enhancers

• Among the alterations are:

• Sonophoresis, or high-frequency ultrasound,

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