Renz

Name:

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 circulationFor systemic effectsSkin: not the target organTransdermal 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 drugDetectable excretion of the drug and/or its metabolites in the urineClinical response of the patient to the therapyBlood 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 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 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 TDDSChemical Enhancers

Chemical skin permeation enhancer: increases skin permeability by damaging or altering the physiochemical nature of the stratum corneum to reduce its diffusion substanceAmong 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 cellUsing human skin: limited because of difficulties of procurement, storage, expense, and variation in permeationAnimal 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 permeableLiving 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 systemsEmployed 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 systemIncorporate 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

If the drug is delivered to the stratum corneum at a rate less than the absorption capacity

Skin

If the drug is delivered to the skin area to

The Transderm-Nitro System Comprises of Four LayersA tan-colored backing layer (aluminized plastic) that is impermeable to nitroglycerinA 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 membraneProtects 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 sensitiveAdheres to the skin with minimal pressure and remains in place for intended period of wearShould 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 difficultiesFirst-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 deliverySome patients develop contact dermatitis at the site of applicationExamples 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 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 TDDSsPercutaneous 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

Therapeutic AgentTDDSDesign and ContentComments

ClonidineCatapres-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 agentsTransdermal 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

EstradiolEstraderm (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 useTransdermal 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

FentanylDuragesic

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

NicotineHabitrol

(Nivartis Consumer)

Nicoderm CQ

(SmithKline Beecham Consumer)

Nicotrol

(McNeil Consumer)

Prostep

(Lederie)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:

(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 useTransdermal therapeutic system providing continuous release systemic delivery of nicotine to aid smoking cessation. Patched somewhat vary in nicotine content and dosing schedules.

NitroglycerinDeponit

(Schwarz Pharma)Three-layer system:

(a) Covering foil

(b) Nitroglycerin matrix with polyisobutylene adhesive, plasticizer, release membrane

(c) Protective foil, removed prior to use

NitroglycerinNitro- Dur

(Key)Nitroglycerin in gel like matrix of glycerin water , lactose polyvinyl alcohol, povidone, sodium citrate sealed in polyester, foil, polyethylene laminate

NitroglycerinTransderm- 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

ScopolamineTransderm 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, scopolamineContinuous 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.

TestosteroneTestoderm

(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 laminatePatch 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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