Dosage - Chapter 11

7/30/2019 Dosage - Chapter 11

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Pharmaceutical Dosage

Chapter 11: Transdermal Drug Delivery Systems

Topical Dermatological Products

Drugs delivered into the skin for treatment of dermaldisorders

For local effects Skin as the target organ

Transdermal Products

Drugs delivered through the skin (percutaneousabsorption) to the general circulation

For systemic effects Skin: not the target organ

Transdermal Drug Delivery System (TDDS)

Facilitate the passage of therapeutic quantities of drugsubstances 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, andvomiting 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 responseto 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 limitingbarrier of TDDS)

Behaves as a semipermeable artificialmembrane drug molecules penetrate by

passive diffusion

Drug Penetration in the Barrier

Drug molecules through the stratum corneum: deeperepidermal tissues: dermis: vascularized dermal layer,

Becomes available for absorption into thegeneral circulation

Good candidates for diffusion through the stratumcorneum, epidermis, and dermis: aqueous and lipid

soluble substances

Factors Affecting Percutaneous Absorption

Physical and chemical properties of drugs including itsmolecular 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 tothe vehicle

Can permeate skin: with molecular weights ranging from100 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 beincorporated into a TDDS

Chemical Enhancers

Chemical skin permeation enhancer: increases skinpermeability 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 skinwithout chemical enhancer.

Chemical permeation enhancer: render impenetrablesubstance useful in TDDS

More than 275 chemical compounds have cited as skinpenetration enhancers that include: acetone, azone,

dimethyl acetamide, dimethly formamide, dimethy

sulfoxide, ethanol, oleic acid, PEG, PG, and sodium laury

sulfate

Physical Methods to Enhance TDDS

Iontophoresis Delivery of charged chemical compoundsacross the skin membrane using an applied

electrical field

Drugs examined: lidocaine, dexamethasone,amino acids, peptides, insulin, verapamil,

propanolol,

Delivered by rapid injection becauseof rapid metabolism and poor

absorption in oral delivery and from

TDDS (large molecular size, ionic

character)

Enhance TDDS for peptide or proteinadministration


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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 systemictoxicological risk following topical application of a

specific drug or drug product

To relate resultant blood levels of drug in human tosystemic therapeutic effects

In-Vivo Skin Penetration Studies

Most relevant studies performed in humans and animalmodels (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 ofdifficulties of procurement, storage, expense,

and variation in permeation

Animal skin: shown to be effective like shedsnakeskin (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 (OrganogenesisInc.)

Product developed as an alternative fordermal absorption studies

An organotypic culture of human dermalfibroblasts 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 membranesemployed 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

(d i di d)

Controls the rate at which the drugis released for percutaneous

absorption

2 types either with or without anexcess 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 devicediminishes below the skins saturation limit

Transport of drug from device toskin declines

Most TDDs designed to contain an excess ofdrug

Drug-releasing capacity beyond thetime 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 deliveryunit filling the drug reservoir: sealing or

lamination

Continuous process Serves as a rate-controlling mechanism or

factor:

Drug delivery deviceo If the drug is delivered to

the stratum corneum at a

rate less than the

absorption capacity

Skino 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 isimpermeable to nitroglycerin

A drug reservoir or matrix system containingnitroglycerin adsorbed on lactose, colloidal silicon

dioxide, and silicon medical fluid

An ethylene-vinyl acetate copolymer membrane that ispermeable to nitroglycerin

A layer of hypoallergenic silicon adhesive: a protectivepeel 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


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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 drugpenetration

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 tothe skin, compatible with all other systems, allow easy

peel-off after use

Commonly used as adhesive: polybutyl acrylateDifferent Design Objectives of TDDS

Deliver the drug to the skin for percutaneousabsorption at therapeutic levels at an optimal rate

Contain medicinal agents having necessaryphysiochemical characteristics to release from the

system, and partition to the stratum corneum

Occlude the skin to ensure one way flux of drug into thestratum corneum

Have a therapeutic advantage over other dosage formsand 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 ofthe application from the surface of the skin

Identified easily and rapidly in emergenciesDisadvantages of TDDS

Only relatively potent drugs are suitable candidates fortransdermal delivery

Some patients develop contact dermatitis at the site ofapplication

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 vomitingresulting 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 (3MPharmaceuticals), 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, dryscrotal skin that has been dry-shaved

Placed on the scrotum (stretching the scrotalskin 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,

cardiovascular agents

Levonorgestrel with estradiol for hormonacontraception

Physostigmine and xanomeline for Alzheimersdisease 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 ofapplication

Applied to clean, dry skin: relatively free of hair and notoily, irritated, inflamed, broken, or callused

Use of skin lotion: avoided at the application site: affectskin hydration and can alter the partition coefficient

between the drug and the skin

Should not be physically altered by cutting since itdestroys the integrity of the system

Should be removed from its protective package orbacking

Placed at a site not subjected to being rubbed off byclothing 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 shouldseek revaluation

TDDS should be folded in half: cannot be reusedCrystal Reservoir Technology

Resulted in smaller patches with a more controlled andsustained 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

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 toapplication

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 totrunk, 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)

Nicoderm CQ

(SmithKline

Beecham

Consumer)

Nicotrol

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

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:

Transdermal therapeutic system providing

continuous release systemic delivery of

nicotine to aid smoking cessation. Patched

somewhat vary in nicotine content and

dosing schedules.


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(McNeil

Consumer)

Prostep

(Lederie)

(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, iliconemedical 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)

Adroderm

(SmithKline

Beecham)

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

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 scrotum in treatment of

testosterone deficiency

Patch is placed on back, abdomen, upper

arms, or thighs for treatment of

testosterone deficiency


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Dosage - Chapter 11