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Pharmaceutical Dosage
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 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

Factors Affecting Percutaneous Absorption

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 artificial 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

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 physicochemical 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

Cadaver Skin Permeation Testing

Helps determine the feasibility of a compound to be


incorporated into a TDDS

Chemical Enhancers

Stratum Corneum

Good candidates for diffusion through the stratum


corneum, epidermis, and dermis: aqueous and lipid soluble
substances

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

Physical Methods to Enhance TDDS

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 and from TDDS (large
molecular size, ionic character)
Enhance TDDS for peptide or protein
administration

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
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

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

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

Occlusive or blockade backing membrane


Protects the system from environmental entry and
from loss of drug from the system or moisture
from skin
Drug reservoir or matrix system
Stores and releases the drug at the skin site
Release liner
Removed before application and enables drug
release

Adhesive layer
Maintains contact with the skin after application

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
First-pass effect
Inconvenience of parenteral therapy
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

Other Transdermal Therapeutic Systems

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 antinausea 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

Include:
Diltiazem,
isosorbide
dinitrade,
propranolol,
nifedipine, mepindolol, and verapamil, cardiovascular
agents
Levonorgestrel with estradiol for hormonal
contraception
Physostigmine and xanomeline for Alzheimers
disease therapy
Naltrexone and methadone for substance addiction
Buspirone for anxiety
Bupropion for smoking cessation
Papaverine for 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

Multilayer Drug-in-Adhesive

Drug Reservoir-in-Adhesive

Crystal Reservoir Technology

Resulted in smaller patches with a more controlled and


sustained drug release

Estradiol

Backing
Drug-in-adhesive
Liner

Therapeutic
Agent
Clonidine

TDDS

Backing
Drug
Membrane
Adhesive
Liner

Drug Matrix-in-Adhesive

Single Layer Drug-in-Adhesive

Backing
Drug-in-adhesive
Membrane
Drug-in-adhesive
Liner

Backing
Adhesive
Drug liner

Design and Content

Comments

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
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

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

Vivelle
(Novartis)

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

Use and application similar to Estraderm


TDDS

Climara
(Berlex )

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
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
Multilayer round patch:

Use and application similar to Estraderm


TDDS and system may be applied weekly

Catapres-TTS
(Boehringer
Ingelheim)

Estraderm
(Novartis)

Fentanyl

Duragesic
(Janssen)

Nicotine

Habitrol

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

Transdermal therapeutic system providing


continuous 72 hour systemic delivery of
potent opioid analgesic and indicated in
patients with chronic pain requiring opioid
analgesia
Transdermal therapeutic system providing

(Nivartis
Consumer)

(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

Nicoderm CQ
(SmithKline
Beecham
Consumer)

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

Nicotrol
(McNeil
Consumer)

Multilayer rectangular patch:


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

Prostep
(Lederie)

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
Three-layer system:
(a) Covering foil
(b) Nitroglycerin matrix with polyisobutylene
adhesive, plasticizer, release membrane
(c) Protective foil, removed prior to use
Nitroglycerin in gel like matrix of glycerin
water , lactose polyvinyl alcohol, povidone,
sodium citrate sealed in polyester, foil,
polyethylene laminate
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
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
Three-layer patch:
(a) Backing layer of polyethylene
terephthalate
(b) Matrix film layer of testosterone,
ethylene-vinyl actetate copolymer
(c) Adhesive strips of polyisobulylene,
colloidal silicone dioxide

Nitroglycerin

Deponit
(Schwarz
Pharma)

Nitroglycerin

Nitro- Dur
(Key)

Nitroglycerin

TransdermNitro (Novartis)

Scopolamine

Transderm Scop
(Novartis
Consumer)

Testosterone

Testoderm
(Alza)

Adroderm

Five-layer patch:

continuous release systemic delivery of


nicotine to aid smoking cessation. Patched
somewhat vary in nicotine content and dosing
schedules.

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.
Patch is placed on scrotum in treatment of
testosterone deficiency

Patch is placed on back, abdomen, upper

(SmithKline
Beecham)

(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

arms, or thighs for treatment of testosterone


deficiency