Pharmaceutics 2
Unit 4
Transdermal drug delivery systems
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• 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.
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• The stratum corneum, being
keratinized tissue, behaves as a
semipermeable membrane, and
drug molecules penetrate by
passive diffusion.
• It is the major rate-limiting
barrier to transdermal drug
transport.
• Once through the stratum
corneum, drug molecules may
pass
through
the
deeper
epidermal tissues and into the
dermis.
• When the drug reaches the
vascularized dermal layer, it
becomes available for absorption
into the general circulation.
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• The rate of drug movement across this layer
depends on its concentration in the vehicle, its
aqueous solubility, and the oil– water partition
coefficient between the stratum corneum and
the vehicle.
• Substances with both aqueous and lipid solubility
characteristics are good candidates for diffusion
through the stratum corneum, epidermis, and
dermis.
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Routes of penetration
• The diffusant has three potential entry routes to
the viable tissue:
• Through the hair follicles with their associated
sebaceous glands,
• Via the sweat ducts;
• ( Transcellular or Intercellular) across the
continuous stratum corneum between these
appendages
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Routes of drug absorption through skin
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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.
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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.
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10
• 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) .
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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.
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Physicochemical factors
•
•
•
•
•
•
Skin hydration.
Temperature and pH.
Diffusion coefficient
Drug concentration
Partition coefficient
Molecular size and shape
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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.
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the area and time of application
• The larger the area of application (the larger
the TDDS), the more drug is absorbed.
• Generally, the longer the medicated
application is permitted to remain in contact
with the skin, the greater is the total drug
absorption.
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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.
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• Generally, drugs penetrate
their unionized form.
the skin better in
• Non-polar drugs tend to cross the cell barrier
through the lipid-rich regions (intercellular
route), whereas the polar drugs favor transport
between cells (transcellular route).
• For example, erythromycin base demonstrates
better
percutaneous
absorption
than
erythromycin ethyl succinate.
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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.
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Hydration of the skin
• Hydration of the skin
percutaneous absorption.
generally favors
• The TDDS acts as an occlusive moisture barrier
through which sweat cannot pass, increasing
skin hydration.
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Temperature and pH
• 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.
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PH
• 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.
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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.
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Biological factors
•
•
•
•
•
Skin condition.
Skin age.
Blood flow.
Regional skin sites.
Skin metabolism.
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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,
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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.
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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.
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Skin metabolism
• The skin metabolizes steroid hormones, and some
other drugs.
• Such metabolism may determine the therapeutic
efficacy of topically applied compounds (particularly
prodrugs)
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PERCUTANEOUS ABSORPTION
ENHANCERS
• Increase percutaneous absorption of
therapeutic agents:
1.chemical permeation enhancers
2.physical methods
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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
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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.
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• 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
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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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