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 patient’s 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 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

Good candidates for diffusion through the stratum corneum, epidermis, and dermis: 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

Cadaver Skin Permeation Testing

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

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

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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 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

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 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

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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: 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

Other Transdermal Therapeutic Systems

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 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)

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, 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)

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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