Pharmaceutical Dosage Factors Affecting Percutaneous Absorption

Chapter 11: Transdermal Drug Delivery Systems  Physical and chemical properties of drugs including its
molecular weight, solubility, partition coefficient, and
Topical Dermatological Products dissociation constant, the nature of the carrier vehicle,
and the conditioning of the skin
 Drugs delivered into the skin for treatment of dermal  Drug concentration
disorders  Area of application: the larger, the more drug is
 For local effects absorbed
 Skin as the target organ  Greater physiochemical attraction to the skin than to
the vehicle
Transdermal Products  Can permeate skin: with molecular weights ranging from
100 to 800 (ideal molecular weight for TDDS: 400 or
 Drugs delivered through the skin (percutaneous less) and adequate lipid and aqueous solubility
absorption) to the general circulation
 Hydration of the skin favors percutaneous absorption
 For systemic effects
 Site with a thin horny layer than with a thick one
 Skin: not the target organ
 The longer the medicated application is permitted to
remain in contact with the skin and the greater is the
Transdermal Drug Delivery System (TDDS)
total drug absorption
 Facilitate the passage of therapeutic quantities of drug
Cadaver Skin Permeation Testing
substances through the skin and into the general
circulation for their systemic effects
 Helps determine the feasibility of a compound to be
 Transderm scop incorporated into a TDDS
 First transdermal (Ciba, now Novartis)
approved by the FDA in 1979 Chemical Enhancers
 Prevents motion sickness, nausea, and
vomiting resulting from the use of certain  Chemical skin permeation enhancer: increases skin
anesthetics permeability by damaging or altering the physiochemical
nature of the stratum corneum to reduce its diffusion
Evidences of Percutaneous Drug Absorption substance
 Among the alterations of the stratum corneum are:
 Evidences of percutaneous drug absorption
 Increased hydration of the stratum corneum
 Measurable blood levels of the drug
 Change in the structure of lipids and
 Detectable excretion of the drug and/or its
lipoproteins in the intercellular channels
metabolites in the urine
through solvent action or denaturation or
 Clinical response of the patient to the therapy
both
 Blood concentration needed to achieve (with TDDS)
 Some drugs inherent capacity to permeate the skin
therapeutic efficacy determined by:
without chemical enhancer.
 Comparative analysis of the patient’s response
 Chemical permeation enhancer: render impenetrable
to the drug blood levels
substance useful in TDDS
 Ideal for the drug
 More than 275 chemical compounds have cited as skin
 To migrate through the skin: blood supply
penetration enhancers that include: acetone, azone,
without build up in the dermal layers
dimethyl acetamide, dimethly formamide, dimethyl
sulfoxide, ethanol, oleic acid, PEG, PG, and sodium lauryl
Stratum Corneum
sulfate
 Skin is composed of:
Physical Methods to Enhance TDDS
 Stratum corneum (the outer layer)
 Living epidermis
 Iontophoresis
 Dermis: provide the skin barrier (blockade)
 Delivery of charged chemical compounds
layers to penetration by external agents
across the skin membrane using an applied
 Stratum corneum (keratinized tissue: major rate limiting
electrical field
barrier of TDDS)
 Drugs examined: lidocaine, dexamethasone,
 Behaves as a semipermeable artificial
amino acids, peptides, insulin, verapamil,
membrane drug molecules penetrate by
propanolol,
passive diffusion
 Delivered by rapid injection because
of rapid metabolism and poor
Drug Penetration in the Barrier
absorption in oral delivery and from
TDDS (large molecular size, ionic
 Drug molecules through the stratum corneum: deeper
character)
epidermal tissues: dermis: vascularized dermal layer,
 Enhance TDDS for peptide or protein
 Becomes available for absorption into the
administration
general circulation
 Good candidates for diffusion through the stratum
corneum, epidermis, and dermis: aqueous and lipid
soluble substances

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  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
The Transderm-Nitro System Comprises of Four Layers
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
Different Layers of the Transdermal Drug Delivery System
 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 skin’s 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
 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
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  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 patient’s skin and have size,
appearance, and site placement that encourage
acceptance
Advantages of TDDS
 Avoid:
Other Transdermal Therapeutic Systems
 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
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
 Include:
 Diltiazem, isosorbide dinitrade, propranolol,
nifedipine, mepindolol, and verapamil,
cardiovascular agents
 Levonorgestrel with estradiol for hormonal
contraception
 Physostigmine and xanomeline for Alzheimer’s
disease therapy
 Naltrexone and methadone for substance addiction
 Buspirone for anxiety
 Bupropion for smoking cessation
 Papaverine for male impotence
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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

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

Vivelle Three-layer patch: Use and application similar to Estraderm

(Novartis) (a) Translucent ethylene vinyl alcohol TDDS
copolymer film
(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: Use and application similar to Estraderm

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

Nicoderm CQ Multilayer rectangular patch:

(SmithKline (a) Occlusive backing of aluminum,
Beecham polyester, ethylene-vinyl acetate copolymer
Consumer) (b) Reservoir of nicotine in ethylene-vinyl
acetate copolymer matrix
(c) Rate-controlling polyethylene membrane
(d) Polyisobutylene liner, removed prior to
application

Nicotrol Multilayer rectangular patch:

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

Prostep Multilayer round patch: (a) Beige foam tape

(Lederie) 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 Three-layer system:
(Schwarz (a) Covering foil
Pharma) (b) Nitroglycerin matrix with polyisobutylene
adhesive, plasticizer, release membrane
(c) Protective foil, removed prior to use
Nitroglycerin Nitro- Dur Nitroglycerin in gel like matrix of glycerin
(Key) water , lactose polyvinyl alcohol, povidone,
sodium citrate sealed in polyester, foil,
polyethylene laminate
Nitroglycerin Transderm- Four-layer patch:
Nitro (Novartis) (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 Four Layer patch: Continuous release of drugs over 3 days to
(Novartis (a) Backing layer of aluminized polyester film prevent nausea, vomiting of motion sickness.
Consumer) (b) Reservoir of scopolamine, mineral oil, Patch is placed behind ear. For repeated
polyisobutylene administration, first patch is removed and
(c) Microporous polypropylene membrane second placed behind other ear. Also
for rate delivery of scopolamine approved to prevent nausea of certain
(d) Adhesive of polyisobutylene, mineral oil, anesthetics and analgesics during surgery.
scopolamine
Testosterone Testoderm Three-layer patch: Patch is placed on scrotum in treatment of
(Alza) (a) Backing layer of polyethylene testosterone deficiency
terephthalate
(b) Matrix film layer of testosterone,
ethylene-vinyl actetate copolymer
(c) Adhesive strips of polyisobulylene,
colloidal silicone dioxide

Adroderm Five-layer patch: Patch is placed on back, abdomen, upper

(SmithKline (a) Backing film of ethylene-vinyl acetate arms, or thighs for treatment of
Beecham) copolymer, polyester laminate testosterone deficiency
(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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