Pharmaceutical Dosage
stratum corneum, epidermis, and dermis:
Chapter 11: Transdermal Drug Delivery Systems
Topical Dermatological Products
Drugs delivered into the skin for treatment of
dermal disorders
For local effects
Skin as the target organ
Transdermal Products
Drugs delivered through the skin (percutaneous
absorption) to the general circulation
For systemic effects
Skin: not the target organ
Transdermal Drug Delivery System (TDDS)
Facilitate the passage of therapeutic quantities of
drug substances through the skin and into the
general circulation for their systemic effects
Transderm scop
First transdermal (Ciba, now Novartis)
approved by the FDA in 1979
Prevents motion sickness, nausea, and
vomiting resulting from the use of certain Cadaver Skin Permeation Testing
anesthetics
Evidences of Percutaneous Drug Absorption
Evidences of percutaneous drug absorption
Measurable blood levels of the drug
Detectable excretion of the drug and/or
its metabolites in the urine
Clinical response of the patient to the
therapy
Blood concentration needed to achieve (with
TDDS) therapeutic efficacy determined by:
Comparative analysis of the patients
response to the drug blood levels
Ideal for the drug
To migrate through the skin: blood supply
without build up in the dermal layers
Stratum Corneum
Skin is composed of:
Stratum corneum (the outer layer)
Living epidermis
Dermis: provide the skin barrier
(blockade) layers to penetration by
external agents
Stratum corneum (keratinized tissue: major rate
limiting barrier of TDDS)
Behaves as a semipermeable artificialPhysical Methods to Enhance TDDS
membrane drug molecules penetrate by
passive diffusion
Drug Penetration in the Barrier
Drug molecules through the stratum corneum:
deeper epidermal tissues: dermis: vascularized
dermal layer,
Becomes available for absorption into the
general circulation
Good candidates for diffusion through the
aqueous and lipid soluble substances
Factors Affecting Percutaneous Absorption
Physical and chemical properties of drugs
including its molecular weight, solubility, partition
coefficient, and dissociation constant, the nature
of the carrier vehicle, and the conditioning of the
skin
Drug concentration
Area of application: the larger, the more drug is
absorbed
Greater physiochemical attraction to the skin
than to the vehicle
Can permeate skin: with molecular weights
ranging from 100 to 800 (ideal molecular weight
for TDDS: 400 or less) and adequate lipid and
aqueous solubility
Hydration of the skin favors percutaneous
absorption
Site with a thin horny layer than with a thick one
The longer the medicated application is
permitted to remain in contact with the skin and
the greater is the total drug absorption
Helps determine the feasibility of a compound to
be incorporated into a TDDS
Chemical Enhancers
Chemical skin permeation enhancer: increases
skin permeability by damaging or altering the
physiochemical nature of the stratum corneum to
reduce its diffusion substance
Among the alterations of the stratum corneum
are:
Increased hydration of the stratum
corneum
Change in the structure of lipids and
lipoproteins in the intercellular channels
through solvent action or denaturation or
both
Some drugs inherent capacity to permeate the
skin without chemical enhancer.
Chemical permeation enhancer: render
impenetrable substance useful in TDDS
More than 275 chemical compounds have cited
as skin penetration enhancers that include:
acetone, azone, dimethyl acetamide, dimethly
formamide, dimethyl sulfoxide, ethanol, oleic
acid, PEG, PG, and sodium lauryl sulfate
Iontophoresis
Delivery of charged chemical compounds
across the skin membrane using an
applied electrical field
Drugs examined: lidocaine,
dexamethasone, amino acids, peptides,
insulin, verapamil, propanolol,
Delivered by rapid injection
because of rapid metabolism and
poor absorption in oral delivery
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 and from TDDS (large molecular
size, ionic character)
Enhance TDDS for peptide or protein
administration Two Categories of the TDDS
Sonophoresis
Studied as a means to enhance TDDS
Influence integrity of stratum corneum
and thus affect penetrability
Agents examined: hydrocortisone,
lidocaine, and salicylic acid in such
formulations as gels, creams and lotions
Different Purposes for In-Vivo Skin Penetration Studies
To verify and quantify:
Cutaneous bioavailability of a topically
applied drug
Systemic bioavailability of a transdermal
drug
To establish bioequivalence of different topical
formulations of the same drug substance
To determine the incidence and degree of
systemic toxicological risk following topical
application of a specific drug or drug product
To relate resultant blood levels of drug in human
to systemic therapeutic effects
In-Vivo Skin Penetration Studies
Most relevant studies performed in humans and
animal models (predictors of human response)
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 The Transderm-Nitro System Comprises of Four Layers
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
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
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
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
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Different Layers of the Transdermal Drug Delivery System Therapy with a single application
Activity of drugs having a short half- life
Occlusive or blockade backing membrane through the reservoir of drug in the
Protects the system from environmental therapeutic delivery system and its controlled
entry and from loss of drug from the release
system or moisture from skin Drug therapy may be terminated rapidly by
Drug reservoir or matrix system removal of the application from the surface of the
Stores and releases the drug at the skin skin
site Identified easily and rapidly in emergencies
Release liner
Removed before application and enables Disadvantages of TDDS
drug release
Only relatively potent drugs are suitable
candidates for transdermal delivery
Some patients develop contact dermatitis at the
Adhesive layer site of application
Maintains contact with the skin after
application

Backing Layer

Must be occlusive Examples of Transdermal Drug Delivery Systems

To retain the skin moisture and hydrate
the site of application for increase drug Transdermal Scopolamine (transderm scop
penetration system)
Used as backing liners Patch is worn (at least 4 hours before the
Transparent or pigmented films of anti-nausea effect is required) in a
propylene, polyethylene, and polyofelin hairless area behind the ear
Prevents motion sickness, nausea and
vomiting resulting from the use of certain
anesthetics and analgesics used in surgery
Adhesive Layer Transdermal Nitroglycerin
For prophylactic treatment of angina
Must be pressure sensitive When taken sublingually: relatively low
Adheres to the skin with minimal dose, short plasma half-life, high peak
pressure and remains in place for plasma levels, and inherent side effects
intended period of wear Examples: Deponit (Schawarz), Minitram
Should be non-irritating, permit unimpeded drug (3M Pharmaceuticals), Nitro-Dur (Key),
flux to the skin, compatible with all other and Transderm-Nitro (Novartis)
systems, allow easy peel-off after use Transdermal Clonidine (Catapres TTS)
Commonly used as adhesive: polybutyl acrylate First trandermal system for hypertension
Transdermal Nicotine (Nicotrol)
Different Design Objectives of TDDS As adjunct in smoking cessation
programs
Deliver the drug to the skin for percutaneous Effective aid in quitting smoking
absorption at therapeutic levels at an optimal Provides sustain blood levels of nicotine
rate replacement therapy
Contain medicinal agents having necessary Transdermal Estradiol
physiochemical characteristics to release from Treatment of moderate to severe
the system, and partition to the stratum vasomotor symptoms associated with
corneum menopause, female hypogonadism,
Occlude the skin to ensure one way flux of drug female castration, primary ovarian
into the stratum corneum failure, and atrophic conditions caused by
Have a therapeutic advantage over other dosage deficient endogenous estrogen
forms and drug delivery systems production (atrophic vaginitis and
No irritation or sensitize the skin kraurosis vulvae)
Adhere well to the patients skin and have size, Examples: Vivelle (Novartis)
appearance, and site placement that encourage Transdermal Testosterone
acceptance For optimal absorption, applied to clean,
dry scrotal skin that has been dry-shaved
Advantages of TDDS Placed on the scrotum (stretching the
scrotal skin with one hand and pressing
Avoid: the adhesive side of the TDDS against
Gastrointestinal absorption difficulties the skin with the other hand, holding it in
First-pass effect place for about 10 seconds)
Inconvenience of parenteral therapy Androderm TDDS: applied nightly to a
Substitute for oral administration of medication clean, dry unbraded area of the skin of
Provide extended:

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 the back, abdomen, upper arms, or Membrane
thighs Drug-in-adhesive
Liner
Other Transdermal Therapeutic Systems
Drug Reservoir-in-Adhesive
Include:
Diltiazem, isosorbide dinitrade, propranolol, Backing
nifedipine, mepindolol, and verapamil, Drug
cardiovascular agents
Membrane
Levonorgestrel with estradiol for hormonal
Adhesive
contraception
Physostigmine and xanomeline for Liner
Alzheimers disease therapy
Naltrexone and methadone for substanceDrug Matrix-in-Adhesive
addiction
Backing
Buspirone for anxiety
Bupropion for smoking cessation Adhesive
Papaverine for male impotence Drug liner

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

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Therapeut TDDS Design and Content Comments
ic Agent
Clonidine Catapres-TTS Four layer patch: Transdermal therapeutic system to
(Boehringer (a) Backing of pigment polyester deliver therapeutic dose of
Ingelheim) film antihypertensive drug at constant
(b) Reservoir of clonidine, mineral rate for 7 days. TDDS generally
oil, polyisobutylene, colloidal applied to hairless or shave are of
silicone dioxide upper arm or torso
(c) Microporous polypropylene
membrane controlling rate of
delivery
(d) Adhesive formulation of agents
Estradiol Estraderm Four layer patch: Transdermal system to release 12b-
(Novartis) (a) Transparent polyester film estradiol continuously. Patch is
(b) Reservoir of estradiol, alcohol generally applied to trunk, including
gelled with hydroxypropyl cellulose, abdomen and buttocks, alternating
(c) Ethylene vinyl acetate sites twice a weekly over 3-week
copolymer membrane cycle with dosage frequency
(d) Adhesive formulation of light adjusted as required
mineral oil, polyisobutylene

Vivelle Three-layer patch:

(Novartis) (a) Translucent ethylene vinyl Use and application similar to
alcohol copolymer film Estraderm TDDS
(b) Estradiol in matrix of medical
adhesive of poly isobutylene,
ethylene vinyl acetate copolymer
(c) Polyester release liner, removed
prior to application

Climara Three-layer patch:

(Berlex ) (a) Translucent polyethylene film Use and application similar to
(b) Acrylate adhesive matrix Estraderm TDDS and system may
containing estradiol be applied weekly
(c) Protective liner of siliconized or
fluoropolymer-coated polyester
film, removed prior to use
Fentanyl Duragesic Four layer patch: Transdermal therapeutic system
(Janssen) (a) Backing layer of polyester film providing continuous 72 hour
(b) Reservoir of fentanyl, alcohol systemic delivery of potent opioid
gelled with hydroxyethyl cellulose analgesic and indicated in patients
(c) Rate controlling ethylene-vinyl with chronic pain requiring opioid
acetate copolymer membrane analgesia
(d) Fentanyl containing silicone
adhesive
Nicotine Habitrol Multilayer round patch: Transdermal therapeutic system
(Nivartis (a) Aluminized backing film providing continuous release
Consumer) (b) Pressure sensitive acrylate systemic delivery of nicotine to aid
adhesive smoking cessation. Patched
(c) Methacrylic acid copolymer somewhat vary in nicotine content
solution of nicotine dispersed in and dosing schedules.
pad of nonwoven viscose, cotton
(d) Acrylate adhesive layer
(e) Protective aluminized release
liner that overlies adhesive layer,
removed prior to use
Nicoderm CQ
(SmithKline
Beecham Multilayer rectangular patch:
Consumer) (a) Occlusive backing of aluminum,
polyester, ethylene-vinyl acetate
copolymer
(b) Reservoir of nicotine in
ethylene-vinyl acetate copolymer
matrix
Nicotrol (c) Rate-controlling polyethylene
(McNeil membrane
Consumer) (d) Polyisobutylene liner, removed
prior to application

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 Multilayer rectangular patch:
Prostep (a) Outer backing of laminated
(Lederie) 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
Nitroglyce Deponit Three-layer system:
rin (Schwarz (a) Covering foil
Pharma) (b) Nitroglycerin matrix with
polyisobutylene adhesive,
plasticizer, release membrane
(c) Protective foil, removed prior to
use
Nitroglyce Nitro- Dur Nitroglycerin in gel like matrix of
rin (Key) glycerin water , lactose polyvinyl
alcohol, povidone, sodium citrate
sealed in polyester, foil,
polyethylene laminate
Nitroglyce Transderm- Four-layer patch:
rin Nitro (a) Backing layer of aluminized
(Novartis) plastic
(b) Reservoir of nitroglycerin
absorbed on lactose, colloidal
silicone dioxide, ilicone medical
fluid
(c) Ethylene-vinyl acetate
copolymer membrane
(d) Silicone adhesive
Scopolami Transderm Four Layer patch: Continuous release of drugs over 3
ne Scop (a) Backing layer of aluminized days to prevent nausea, vomiting of
(Novartis polyester film motion sickness. Patch is placed
Consumer) (b) Reservoir of scopolamine, behind ear. For repeated
mineral oil, polyisobutylene administration, first patch is
(c) Microporous polypropylene removed and second placed behind
membrane for rate delivery of other ear. Also approved to prevent
scopolamine nausea of certain anesthetics and
(d) Adhesive of polyisobutylene, analgesics during surgery.
mineral oil, scopolamine
Testostero Testoderm Three-layer patch: Patch is placed on scrotum in
ne (Alza) (a) Backing layer of polyethylene treatment of testosterone
terephthalate deficiency
(b) Matrix film layer of testosterone,
ethylene-vinyl actetate copolymer
(c) Adhesive strips of
polyisobulylene, colloidal silicone
dioxide
Adroderm
(SmithKline Five-layer patch: Patch is placed on back, abdomen,
Beecham) (a) Backing film of ethylene-vinyl upper arms, or thighs for treatment
acetate copolymer, polyester of testosterone deficiency
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

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