TRANSDERMAL DRUG DELIVERY SYSTEM

Facilitates the passage of therapeutic quantities

of drug substances through the skin into the
general circulation for their systemic effects.
Skin is not the target organ
1965 Stoughton first conceived of the percutaneous
absorption of drug substances.
First transdermal system
Transderm Scop (Baxter) approved by FDA
(1979)
Used to prevent nausea and vomiting
associated with travel, particularly at the sea.
EVIDENCE OF PERCUTANEOUS DRUG ABSORPTION:
Measurable bood levels of the drug
Detectablexcretion of the drug and/or its
metabolites in the urine
Clinical response of the patient to the
therapy
The blood concentration needed to achieve
therapeutic efficacy may be determined by
comparative analysis of the patients response
to drug blood levels.
Ideally, the drug should migrate through skin
to the underlying blood supply without buildup
in the dermal layers.
Composition of the Skin provides the skins barrier
layers to penetration by external agents
1. Dermis
2. Living Dermis
3. Stratum corneum
10 15 m thick layer of flat, partially
dessicated nonliving tissue. (15-25 layer
flattened corneocytes)
Composed of approximately 40% protein
(mainly keratin) and 40% water, with the
balance being lipid, principally as
triglycerides, free fatty acids,cholesterol
and phospholipids.
Lipid content concentrated in
extracellular phase of stratum corneum and
forms a large extent the membrane
surrounding the cells.
Lipid component considered an important
determinant in the first step of absorption.
Once the drug molecules may pass through the
deeper epidermal tissues and into the dermis.
Vascularized Dermal Layer
When drug reaches this layer, it
becomes available for absorption into
the general circulation.
Stratum corneum
A kertanizid tissue which behaves as a
semi-permeable artificial membrane
Drug molecules penetrate by passive
diffusion
It is the major rate-limiting barrier to
trandermal drug transport.
Rate of Drug Movement in Stratum corneum depends
on:
Concentration in the vehicle
Aqueous solubility
Oil-water partition coefficient between the
stratum corneum and the vehicle.
Substances with both Aqueous and Lipid
solubility are good candidates for diffusion
though the stratum corneum, epidermis, and
dermis.
FACTORS AFFECTING PERCUTANEOUS ABSORPTION:
Not all drug substances are suitable for
transdermal delivery.
1. Drug concentration amount of drug
percutaneously absorbed per unit of SA/
time interval increases with an increase in
the concentration of the drug in the TDDS.
2. Larger area of application (the larger
TDDS), the more drug is absorbed.
3. Drug should have a greater physiochemical
attraction to the skin than to the vehicle so
that the drug will leave the vehicle in favor
of the skin.
Aqueous solubility of a drug
determines the concentration presented
to the absorption site
Partition coefficient influences the rate
of transport across the absorption site.
Generally, drugs penetrate the skin better
in their unionized form.
Non-polar drugs through lipid-rich
regions (transcellular route)
Polar drugs- favor transport between
cells (intercellular route)
Erythromycin base demonstrates better
percutaneous absorption than
erythromycin ethyyl succinate.
4. Drugs with MWs of 100-800 and adequate lipid and
aqueous solubility can permeate skin.
The ideal MW of a drug in TDD is believed to be
400 or less.
5. Hydration of the skin generally favors percutaneous
absorption.
The TDDS acts as an occlusive moisture barrier
through which sweat cannot pass, increasing skin
hydration.
6. Percutaneous absorption appears to be greater
when the TDDS applied to a site with a thin horny layer
than with a thick bone.
7. The longer the medicated application is permitted to
remain in contact with the skin, the greater is the total
drug absorption.
These general statements apply to the skin in the
normal state.
Skin that is abraded or cut permits drugs to gain
direct access to the subcutaneous tissues and the
capillary netweork, defeating the function of TDDS.
Cadaver Skin Permeation Testing
Helps determine the feasibility of a compounds to be
incorporated into a TDDS.
PERCUTANEOUS ABSORPTION ENHANCERS:
Chemical Enhancers increases skin permeability by
reversibly damaging or altering the physiochemical
nature of the stratum corneum to reduceits diffusional
resistance.
Among the alterations are increased hydration
hydration of the startum corneum, a change in the
structure of the lipid and lipoproteins in the
intercellular channels through solvent action or
denaturation, or both.
Some drugs have an inherent capacity to permeate
the skin without chemical enhancers.
Chemical permeation enhancers may render an
otherwise impenetrab;e substance useful in TDDS.
More than 275 chemical compounds have been
cited in the literature as skin penetration
enhancers

Acetone Ethanol
Azone Oleic acid
Dimethyl acetamide Polyethylene glycol
Dimethyl formamide Propylene glycol
Dimethyl sulfoxide Sodium lauryl sulfate
The selection of a permeation enhancer should
be based not only on its efficacy in enhancing
skin permeation but also on its:
1. dermal toxicity (low)
2. its physiochemical and biologic
compatibility with the systems other
components.
PHYSICAL METHODS TO ENHANCE TDDS:
A. Iontophoresis
delivery of a charged chemical compound
across the skin membrane using an electrical
field.
Drugs examined: lidocaine, amino acids,
peptides, insulin, dexamethasone, verapamil
and propanolol. (LAPIDVP)
Agents are delivered by injection because of :

1. rapid metabolism
2. poor absorption after oral delivery
because of their large molecular size and ionic
character and the general impenetrability of
the skin
Iontophoresis-enhanced transdermal delivery
shown some promise as a means of:
1. peptide
2. protein administration.
B. Sonophoresis
aka high-frequency ultrasound
means to enhance TDD.
Agents Examined: hydrocostisone, lidocaine,
salicylic acid (ASA) in such formulations as gels,
creams, and lotions.
HF-U can influence the integrity of the stratum
corneum and thus affect penetrability.
PERCUTANEOUS ABSORPTION MODELS
In Vivo Studies
Different Purposes for In-Vivo Skin Penetration
Studies:
Verify and quantify:
The cutaneous bioavailability of a
topically applied drug
Systemic bioavailability topical
formulations of the same drug substances
Establish bioequivalence of different topical
formulations of the same drug substance
Determine the incidence and degree of
systemic toicologic risk following topical
application of a specific drug or drug product
Relate resultant blood levels of drug in human
to systemic therapeutic effects

The most relevant studies are performed in
humans. Animal models may be used insofar as
they may be effective as predictors of human
response.
Weanlig pig
Rhesus monkey
Hairless mouse or rat
Materials Used In-Vitro Skin Penetration Studies
Skin penetration may be tested in vitro using:
Various skin tissues (human or animal) in a
diffusion cell
Using human skin: limited because of
difficulties of procurement, storage,
expense, and variation in permeation
Animal skin: shown to be effective like
shed snakeskin (Elaphe obsolete, black rat
snake) which is nonliving, pure stratum
corneum, hairless and similar to human
skin but slightly less permeable
Living Skin Equivalent (LSE) Test Skin
(Organogenesis Inc.)
Product developed as an alternative for
dermal absorption studies
An organotypic culture of human
dermal fibroblasts in a collagen-
containing matrix and stratified
epidermis composed of human
epidermal keratinocytes.
Diffusion Systems and Principle Utilized
Diffusion cell systems
Employed in vitro to quantify the
release rates of drugs from topical
preparations
Skin membranes or synthetic
membranes employed as barriers to the
flow of drug and vehicle to stimulate
the biologic system
Two Categories of the TDDS
1. Monolithic system
Incorporate a drug matrix layer between
backing and frontal layers
Drug matrix layer
Composed of polymeric material (drug is
dispersed)
Controls the rate at which the drug is
released for percutaneous absorption
2 types either with or without an excess
of drug with regard to its equilibrium
solubility and steady: state concentration
gradient at the stratum corneum
As the concentration of the drug in the device
diminishes below the skins saturation limit
Transport of drug from device to skin
declines
Most TDDs designed to contain an excess of
drug
Drug-releasing capacity beyond the time
frame recommended for replacement

2. Membrane-controlled transdermal system
Designed to contain drug reservoir or pouch (in
liquid or in gel form, a rate controlling
membrane)
Backing, adhesive, and protecting layers
Examples of this technology: TransdermNitro
(Novartis) and Transderm-Scop (Novartis)
Advantage over monolithic systems: release
rate of drug remains constant when the drug
solution in the reservoir remains saturated
Prepared by preconstruction of the delivery
unit filling the drug reservoir: sealing or
lamination
Continuous process
Serves as a rate-controlling mechanism or
factor:
Drug delivery device
o If the drug is delivered to the
stratum corneum at a rate less than
the absorption capacity
Skin
o If the drug is delivered to the skin
area to
The Transderm-Nitro System Comprises of Four Layers
A tan-colored backing layer (aluminized plastic)
that is impermeable to nitroglycerin
A drug reservoir or matrix system containing
nitroglycerin adsorbed on lactose, colloidal
silicon dioxide, and silicon medical fluid
An ethylene-vinyl acetate copolymer
membrane that is permeable to nitroglycerin
A layer of hypoallergenic silicon adhesive: a
protective peel strip that is removed from the
adhesive surface prior to use
Different Layers of the Transdermal Drug Delivery
System
1. Occlusive or blockade backing membrane
Protects the system from environmental entry
and from loss of drug from the system or
moisture from skin
2. Drug reservoir or matrix system
Stores and releases the drug at the skin site
3. Release liner
Removed before application and enables drug
release
4. Adhesive layer
Maintains contact with the skin after
application
Example: Polybutyl acrylate
Backing Layer
Must be occlusive
To retain the skin moisture and hydrate the
site of application for increase drug
penetration
Used as backing liners
Transparent or pigmented films of propylene,
polyethylene, and polyofelin
Adhesive Layer
Must be pressure sensitive
Adheres to the skin with minimal pressure and
remains in place for intended period of wear
Should be non-irritating, permit unimpeded drug
flux to the skin, compatible with all other systems,
allow easy peel-off after use
Commonly used as adhesive: polybutyl acrylate
Different 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
physiochemical characteristics to release from
the system, and partition to the stratum
corneum
Occlude the skin to ensure one way flux of drug
into the stratum corneum
Have a therapeutic advantage over other
dosage forms and drug delivery systems
No irritation or sensitize the skin
Adhere well to the patients skin and have size,
appearance, and site placement that encourage
acceptance
Advantages of TDDS
Avoid:
Gastrointestinal absorption difficulties
Inconvenience of parenteral therapy
First-pass effect
Substitute for oral administration of
medication
Provide extended:
Therapy with a single application
Activity of drugs having a short half- life
through the reservoir of drug in the
therapeutic delivery system and its
controlled release
Drug therapy may be terminated rapidly by
removal of the application from the surface of
the skin
Identified easily and rapidly in emergencies
Disadvantages of TDDS
Only relatively potent drugs are suitable
candidates for transdermal delivery
Some patients develop contact dermatitis at the
site of application
Examples of Transdermal Drug Delivery Systems
Transdermal Scopolamine (transderm scop
system)
Patch is worn (at least 4 hours before the
anti-nausea effect is required) in a
hairless area behind the ear
Prevents motion sickness, nausea and
vomiting resulting from the use of certain
anesthetics and analgesics used in
surgery
Transdermal Nitroglycerin
For prophylactic treatment of angina
When taken sublingually: relatively low
dose, short plasma half-life, high peak
plasma levels, and inherent side effects
Examples: Deponit (Schawarz),
Minitram (3M Pharmaceuticals), Nitro-
Dur (Key), and Transderm-Nitro
(Novartis)
Transdermal Clonidine (Catapres TTS)
First trandermal system for
hypertension
Transdermal Nicotine (Nicotrol)
As adjunct in smoking cessation
programs
Effective aid in quitting smoking
Provides sustain blood levels of nicotine
replacement therapy
Transdermal Estradiol
Treatment of moderate to severe vasomotor
symptoms associated with menopause, female
hypogonadism, female castration, primary
ovarian
failure, and atrophic conditions caused
by deficient endogenous estrogen
production (atrophic vaginitis and
kraurosis vulvae)
Examples: Vivelle (Novartis)
Transdermal Testosterone
For optimal absorption, applied to
clean, dry scrotal skin that has been
dry-shaved
Placed on the scrotum (stretching the
scrotal skin with one hand and pressing
the adhesive side of the TDDS against
the skin with the other hand, holding it
in place for about 10 seconds)
Androderm TDDS: applied nightly to a
clean, dry unbraded area of the skin of
the back, abdomen, upper arms, or
thighs
Other Transdermal Therapeutic Systems
Include:
Diltiazem, isosorbide dinitrade,
propranolol, nifedipine, mepindolol, and
verapamil
o cardiovascular agents
Levonorgestrel with estradiol
o hormonal contraception
Physostigmine and xanomeline
o Alzheimers disease therapy
Naltrexone and methadon
o substance addiction
Buspirone
o anxiety
Bupropion
o smoking cessation
Papaverine (from opium)
o male impotence
General Clinical Considerations in the Use of TDDSs
Percutaneous absorption varies with the site of
application
Applied to clean, dry skin: relatively free of hair
and not oily, irritated, inflamed, broken, or
callused
Use of skin lotion: avoided at the application
site: affect skin hydration and can alter the
partition coefficient between the drug and the
skin
Should not be physically altered by cutting
since it destroys the integrity of the system
Should be removed from its protective
package or backing
Placed at a site not subjected to being rubbed
off by clothing or movement
Worn for full period stated in the products
instructions
The patient or caregiver should clean the
hands thoroughly before and after applying
TDDS.
In case of sensitivity or intolerance, the patient
should seek revaluation
TDDS should be folded in half: cannot be
reused
Crystal Reservoir Technology
Resulted in smaller patches with a more
controlled and sustained drug release
Single Layer Drug-in-Adhesive
Backing
Drug-in-adhesive
Liner
Multilayer Drug-in-Adhesive
Backing
Drug-in-adhesive
Membrane
Drug-in-adhesive
Liner
Drug Reservoir-in-Adhesive
Backing
Drug
Membrane
Adhesive
Liner
Drug Matrix-in-Adhesive
Backing
Adhesive
Drug liner

Therapeutic
Agent
TDDS Design and Content Comments
Clonidine Catapres-TTS
(Boehringer
Ingelheim)
Four layer patch:
(a) Backing of pigment polyester film
(b) Reservoir of clonidine, mineral oil,
polyisobutylene, colloidal silicone dioxide
(c) Microporous polypropylene membrane
controlling rate of delivery
(d) Adhesive formulation of agents
Transdermal therapeutic system to
deliver therapeutic dose of
antihypertensive drug at constant rate
for 7 days. TDDS generally applied to
hairless or shave are of upper arm or
torso
Estradiol Estraderm
(Novartis)







Vivelle
(Novartis)







Climara
(Berlex )
Four layer patch:
(a) Transparent polyester film
(b) Reservoir of estradiol, alcohol gelled with
hydroxypropyl cellulose,
(c) Ethylene vinyl acetate copolymer
membrane
(d) Adhesive formulation of light mineral oil,
polyisobutylene

Three-layer patch:
(a) Translucent ethylene vinyl alcohol
copolymer film
(b) Estradiol in matrix of medical adhesive of
poly isobutylene, ethylene vinyl acetate
copolymer
(c) Polyester release liner, removed prior to
application

Three-layer patch:
(a) Translucent polyethylene film
(b) Acrylate adhesive matrix containing
estradiol
(c) Protective liner of siliconized or
fluoropolymer-coated polyester film,
removed prior to use
Transdermal system to release 12b-
estradiol continuously. Patch is
generally applied to trunk, including
abdomen and buttocks, alternating
sites twice a weekly over 3-week cycle
with dosage frequency adjusted as
required



Use and application similar to
Estraderm TDDS







Use and application similar to
Estraderm TDDS and system may be
applied weekly
Fentanyl Duragesic
(Janssen)
Four layer patch:
(a) Backing layer of polyester film
(b) Reservoir of fentanyl, alcohol gelled with
hydroxyethyl cellulose
(c) Rate controlling ethylene-vinyl acetate
copolymer membrane
(d) Fentanyl containing silicone adhesive
Transdermal therapeutic system
providing continuous 72 hour
systemic delivery of potent opioid
analgesic and indicated in patients
with chronic pain requiring opioid
analgesia
Nicotine Habitrol
(Nivartis
Consumer)








Multilayer round patch:
(a) Aluminized backing film
(b) Pressure sensitive acrylate adhesive
(c) Methacrylic acid copolymer solution of
nicotine dispersed in pad of nonwoven
viscose, cotton
(d) Acrylate adhesive layer
(e) Protective aluminized release liner that
overlies adhesive layer, removed prior to use


Transdermal therapeutic system
providing continuous release systemic
delivery of nicotine to aid smoking
cessation. Patched somewhat vary in
nicotine content and dosing
schedules.
Nicoderm CQ
(SmithKline
Beecham
Consumer)





Nicotrol
(McNeil
Consumer)



Prostep
(Lederie)
Multilayer rectangular patch:
(a) Occlusive backing of aluminum, polyester,
ethylene-vinyl acetate copolymer
(b) Reservoir of nicotine in ethylene-vinyl
acetate copolymer matrix
(c) Rate-controlling polyethylene membrane
(d) Polyisobutylene liner, removed prior to
application

Multilayer rectangular patch:
(a) Outer backing of laminated polyester film
(b) Rate-controlling adhesive nonwoven
material, nicotine
(c) Disposable liner, removed prior to use

Multilayer round patch:
(a) Beige foam tape acrylate adhesive
(b) Backing foil gelatin low density
polyethylene coating
(c) Nicotine gel matrix
(d) Protective foil with well
(e) Release liner removed prior to use
Nitroglycerin Deponit
(Schwarz
Pharma)
Three-layer system:
(a) Covering foil
(b) Nitroglycerin matrix with polyisobutylene
adhesive, plasticizer, release membrane
(c) Protective foil, removed prior to use

Nitroglycerin Nitro- Dur
(Key)
Nitroglycerin in gel like matrix of glycerin
water , lactose polyvinyl alcohol, povidone,
sodium citrate sealed in polyester, foil,
polyethylene laminate

Nitroglycerin Transderm-
Nitro
(Novartis)
Four-layer patch:
(a) Backing layer of aluminized plastic
(b) Reservoir of nitroglycerin absorbed on
lactose, colloidal silicone dioxide, ilicone
medical fluid
(c) Ethylene-vinyl acetate copolymer
membrane
(d) Silicone adhesive

Scopolamine Transderm
Scop
(Novartis
Consumer)
Four Layer patch:
(a) Backing layer of aluminized polyester film
(b) Reservoir of scopolamine, mineral oil,
polyisobutylene
(c) Microporous polypropylene membrane for
rate delivery of scopolamine
(d) Adhesive of polyisobutylene, mineral oil,
scopolamine
Continuous release of drugs over 3
days to prevent nausea, vomiting of
motion sickness. Patch is placed
behind ear. For repeated
administration, first patch is removed
and second placed behind other ear.
Also approved to prevent nausea of
certain anesthetics and analgesics
during surgery.
Testosterone Testoderm
(Alza)


Three-layer patch:
(a) Backing layer of polyethylene
terephthalate
(b) Matrix film layer of testosterone, ethylene-
Patch is placed on scrotum in
treatment of testosterone deficiency






Adroderm
(SmithKline
Beecham)
vinyl actetate copolymer
(c) Adhesive strips of polyisobulylene,
colloidal silicone dioxide

Five-layer patch:
(a) Backing film of ethylene-vinyl acetate
copolymer, polyester laminate
(b) Reservoir of testosterone, ,alcohol,
glycerin, glyceryl monoleate, methyl laureate
gelled with acrylic acid copolymer
(c) Microporous polyethylene membrane
(d) Acrylic adhesive
(e) Adhesive polyester laminate




Patch is placed on back, abdomen,
upper arms, or thighs for treatment of
testosterone deficiency