Page 1 of 4

Chapter 11: TRANSDERMAL DRUG DELIVERY SYSTEMS Percutaneous Absorption

The absorption of substances from outside the skin to positions

beneath the skin, including entrance into the blood stream

Penetration of the Skin by Drugs

Drugs may penetrate intact skin after topical application

(a) through the walls of the hair follicles,(b) through the sweat

glands or the sebaceous glands, (c) or between the cells of the

horny layer.

Are designed to support the passage of drug substances from the

surface of the skin, through its various layers, and into the

systemic circulation.

The main route for the penetration of drug is generally through

the epidermal layers, rather than through the hair follicles or the

gland ducts, because the surface area of the latter is rather

minute compared to the area of the skin.

The percutaneous absorption of a drug generally results from

direct penetration of the drug through the stratum corneum.

Permeation of the laminate barriers in stratum corneum can

occur by diffusion via:

1. Transcellular penetration (across the cells)

2. Intercellular penetration (between the cells)

3. Transappendageal penetration (via hair follicles, sweat and

sebum glands, and pilosebaceous apparatus)

Factors Affecting Percutaneous Absorption

1. Nature of the drug itself

2. Nature of the vehicle

3. The nature of the skin

4. Presence of moisture

RESEARCH FINDINGS ABOUT PERCUTANEOUS ABSORPTION

Drug concentration is an important factor

Most drug is absorbed through percutaneous absorption when

the drug substance is applied to a larger surface area.

The drug should have a greater physicochemical attraction to the

skin than to the vehicle in which it is presented in order for the

drug to leave the vehicle in favor the skin.

Drug absorption appears to be enhanced from vehicles that easily

cover the skin surface, mix readily with the sebum, and bring the

drug into contact with the tissue cells for absorption.

Vehicles that increase the hydration of the skin generally favor the

percutaneous absorption of drugs.

The amount of rubbing in or inunction of the topical application

will have a bearing on the amount of drug absorbed, the longer

the period of inunction, the greater the absorption.

Percutaneous absorption appears to be greater when the drug is

applied to skin with a thin horny layer than with one that is thick.

The longer the period of time the medicated application is

permitted to remain in contact with the skin, the greater will be

the absorption.

Multiple-application dosing rather than single bolus applications

can increase drug absorption

PERCUTANEOUS ABSORPTION ENHANCERS

Materials used to enhance absorption: surfactants, azone,

dimethylsulfoxide (DMSO), dimethylacetamide,

dimethylformamide, alcohol, acetone, propylene glycol, and

polyethylene glycol.

Mechanism Of Action For Percutaneous Absorption Enhancers

Mechanism Of Action

1. Reduction of the resistance of the stratum corneum by

altering its physicochemical properties

2. Alteration of the hydration of the stratum corneum

3. Effecting a change in the structure of the lipids and

lipoproteins in the cellular channels, through solvent action

or denaturation

4. Carrier mechanism in the transport of ionizable drugs

Percutaneous Absorption Models

2 Categories

1. In vivo - skin penetration; performed in humans

or animal models

Purposes:

a. To verify and quantify the cutaneous bioavailability of

a topical applied drug.

b. To verify and quantify the systemic bioavailability of a

transdermally delivered drug.

c. To establish bioequivalence of different topical

formulations of the same drug substanc

d. To determine incidence and degrees of systemic

toxicologic risk following the topical application of a

specific drug/drug product

2. In Vitro - penetration studies human skin are limited

because of difficulties of procurement, storage, expense,

and variability in permeation. Excised animal skins may

also variable in quality and permeation. Alternative dermal

absorption studies is Living Skin Equivalent (LSE)

Iontophoresis and Sonophoresis

Iontophoresis involves the delivery of charged chemical compounds

across the skin membrane using an applied electrical field.

Examples: lidocaine, amino acids/peptides/insulin, verapamil, and

propanolol

Sonophoresis, or high-frequency ultrasound, is also being studied as a

means to enhance transdermal drug delivery

Examples: hydrocortisone, lidocaine, and salicylic acid in such

formulations as gels, creams and lotions

2 Basic Types of Transdermal Dosing System

1. Those that control the rate of drug delivery to the skin.

2. Those that allow the skin to control the rate of drug

absorption

Objectives of Rate-Controlling TDDS

1. Deliver the drug substances at a controlled rate, to the

intact skin of patients, for absorption into the systemic

circulation.

2. The system should possess the proper physicochemical

characteristics to permit the ready release of the drug

DEPICTION OF FOUR LAYERED THERAPEUTIC

Uy, Alyssa V.

2BPh

Page 2 of 4

substance and facilitate its partition from the delivery

system into the stratum corneum.

3. The system should occlude the skin to ensure the one-way

flux of the drug substance.

4. The transdermal system should have a therapeutic

advantage over other dosage forms and drug delivery

system

5. The system’s adhesive, vehicle, and active agent should be

nonirritating and nonsensitizing to the skin of the patient.

6. The patch should adhere well to the patient’s skin and its

physical size and appearance and placement on the body

should not be a deterrent to use.

7. The system should not permit the proliferation of the skin

bacteria beneath the occlusion.

Advantages of TDDS

1. Avoids gastrointestinal drug absorption difficulties caused by

gastrointestinal pH, enzymatic activity, drug interactions with

food, drinks, or other orally administered drugs.

2. Substitutes for oral administration of medication when that

routes is unsuitable, as in instances of vomiting and/or diarrhea.

3. Avoids first-pass effect, that is, the initial pass of a drug substance

through the systemic and portal circulation following

gastrointestinal absorption (thereby possibly avoiding the drug’s

deactivation by digestive and liver enzymes).

4. Avoids the risks and inconveniences of parenteral therapy and the

variable absorption and metabolism associated with oral therapy.

5. Provides the capacity for multiday therapy with a single

application, thereby improving patient compliance over use of

other dosage forms requiring more frequent dose administration.

6. Extends the activity of drugs having short half-life through the

reservoir of drug present in the therapeutic delivery system and

its controlled release characteristics.

7. Provides capacity to terminate drug effect rapidly (if clinically

desired) by removal of drug application from the surface of the

skin.

8. Provides ease of rapid identification of the medication in

emergencies (e.g. non responsive, unconscious or comatose

patient)

Disadvantages of TDD Systems

1. The transdermal route administration is unsuitable for drugs that

irritate or sensitize the skin.

2. Only relative potent drugs are suitable candidates for transdermal

delivery due to the natural limits of drug entry imposed by the

skin’s impermeability.

3. Technical difficulties are associated with the adhesion of the

systems to different skin types and under various environment

conditions, and the development of rate-controlling drug delivery

features which are economically feasible and therapeutically

advantageous for more than a few drug substances.

General Considerations in the use of TDD Systems

1. The site selected for application should be clean clean, dry, and

hairless (but not shaved)

Example: nitroglycerin - chest; estradiol - buttocks or

abdoment; scopolamine - behind the ear; nicotine –upper

trunk or upper outer arm.

2. The transdermal patch should not be applied to skin that is oily,

irritated, cut, or abraded. This is to assure the intended amount

and rate of transdermal drug delivery and absorption.

3. The patch should be removed from its protective package, being

careful not to tear or cut.

4. The patch should be worn for the period of time stated in the

product’s instructions. Following period, the patch should be

removed and a fresh patch applied as directed.

5. Patches generally may be left on when showering, bathing, or

swimming. Should a patch premature dislodge, an attempt may

be made to reapply it, or it may be replaced with a fresh patch--

the latter being worn for a full time period before it is replaced.

6. The patient should be instructed to cleanse the hands thoroughly

before and after applying the patch. Care should be taken not to

rub the eyes or touch the mouth during handling the patch.

7. If irritation results, patient should seek re-evaluation.

Other Transdermal Therapeutic Systems

1. Testosteron transdermal system - Testoderm, is available

for hormone replacement in men who have an absence or

deficiency of testosterone.

Dose: 10 mg for delivery of 4 mg/day; 15 mg for

delivery of 6mg/day. The patches are applied to

scrotal skin where optimal absorption occurs. The

patches are worn 22 to 24 hours daily for 6 to 8 weeks.

2. Trans-Ver-Sal - contains 15% salicylic acid in a vehicle

consisting of karaya, a substance known for its non -

irritating and self-adhesive properties. It is use for the

treatment of viral wart infections

Technology Of Transdermal Delivery Systems (2 Types)

1. Monolithic systems - incorporate a drug matrix layer between

backing and frontal layers. The drug matrix layer is composed

of a polymeric material in which the drug is dispersed. The

polymer matrix controls the rate at which drug is released for

percutaneous absorption.

Ex.: Nitro-Dur and Nitrodisc

2. Membrane controlled transdermal system - are design to contain

a drug reservoir, usually in liquid or gel form, a rate controlling

membrane, and backing, adhesive, and protecting layers

Ex.: Transderm-Nitro and Transderm-Scop

Examples Of TDD Systems

1. Clonidine - Catapress –TTS

Four-layered patch:

a. backing layer of pigmented polyester film

b. drug reservoir of clonidine, mineral oil,

polyisobutylene, and colloidal silicon dioxide

c. a microporous polypropylene membrane controlling

the rate of drug delivery

d. an adhesive formulation of agents

Uses: antihypertensive clonidine at a constant rate for 7

days, once a week dosing in the upper arm or torso.

2. Estradiol - Estraderm

Four layered patch:

a. transparent polyester film

b. drug reservoir of estradiol and alcohol gelled with

hydroxypropyl cellulose

c. an ethylenevinyl acetate copolymer membrane

d. an adhesive formulation of light mineral and

polyisobutylene

Page 3 of 4

Uses: design to release 17 B-estradiol continuously. Applied

twice weekly over a cycle of 3 weeks. The patch is generally

applied to the abdomen, altering sites with each application.

3. Nicotine – Nicotrol

Multi-layered rectangular patch:

a. outer backing of laminated polyester film

b. rate-controlling adhesive, nonwoven material, and

nicotine, disposable liner removed prior to use - Aid

in smoking cessation programs

4. Nitroglycerin - Deponit

Nitroglycerin in a matrix of lactose, plasticizer,

polyisobutylene, and aluminized plastic

Use: to provide controlled release of nitroglycerin

continuously for a 24 hour period. Patches are applied to

inner part of upper arm, shoulders, or chest.

5. Nitroglycerin - Nitro - Dur

Nitroglycerin in a gel like matrix composed of glycerin,

water, lactose, polyvinyl alcohol, povidone and sodium

citrate sealed in a polyester foil polyethylene laminate

Use: same as # 4

6. Scopolamine - Transderm – Scop

Four layered patch:

a. backing layer of aluminized polyester film

b. drug reservoir of scopolamine, mineral oil &

polyisobutylene

c. a microporous polypropylene membrane for rate

delivery of scopolamine

d. adhesive of polyisobutylene, mineral oil, and

scopolamine

Use: for continuous release of scopolamine over a 3-day

period as required for the prevention of nausea and

vomiting associated with motion sickness. The patch is

placed behind the ear. When repeated administration is

desired, the first patch is removed and the second patch

placed behind the other ear

COMPONENTS

Liner - Protects the patch during storage. The liner is removed

prior to use.

Drug - Drug solution in direct contact with release liner

Adhesive - Serves to adhere the components of the patch

together along with adhering the patch to the skin

Membrane - Controls the release of the drug from the reservoir

and multi-layer patches

Backing - Protects the patch from the outer environment

VIVELLE-DOT

This contains estradiol in a multipolymeric adhesive that helps in the

development and maintenance of the female reproductive system and

secondary sexual characteristics.

NEUPRO

This is a skin patch designed to treat symptoms of early Parkinson's disease.

DENTI PATCH

Page 4 of 4

This is a band-aid-like patch inserted on your gum to numb it before an

injection

NITRO-DUR

This contains nitroglycerin which is a type of vasodilator. This is used to

prevent chest pain caused by angina. It will not help to stop an episode of

chest pain.

DAYTRANA

This is used to treat Attention Deficit Hyperactivity Disorder (ADHD) in

children six to 12 years of age.

ORTHO EVRA

It is a contraceptive used by women to prevent pregnancy

NICOTINE PATCH

It is used as a temporary aid for smoking-cessation programs. It helps to

control the symptoms of nicotine withdrawal (irritability, headache, fatigue,

insomnia) and thus helps you to concentrate on overcoming the

psychological and behavioral aspects of your smoking habit.

MYLAN ESTRADIOL PATCH

This patch is designed to release Estradiol continuously upon application to

intact skin for the treatment of moderate to severe vasomotor and

vulvovaginal symptoms associated with menopause, and for prevention of

postmenopausal osteoporosis.

NICORETTE PATCH

This contains a low dose of nicotine that is intended to help quit smoking by

reducing the unpleasant nicotine withdrawal effects.

ESTRADERM PATCH

This patch contains estradiol that is a form of estrogen in female sex

hormone the regulates many processes in the body.

NICOTROL PATCH

This helps avoid the discomfort of nicotine withdrawal symptoms when you

quit smoking by giving you a controlled, sustained dose of nicotine