Transdermal drug delivery systems are designed to support the passage of drug substances from the surface of the skin, through its various layers, and into the systemic circulation,

offering a more sophisticated

and more reliable means of

administering drug through

the skin.

TRANSDERMAL DRUG DELIVERY SYSTEMS

​

1. Avoids gastrointestinal drug absorption difficulties caused by gastrointestinal pH, enzymatic activity, drug interactions with food, drink, or other orally administered drugs.

2. Substitutes for oral administration in cases of vomiting and/or diarrhea.

3. Avoids first-pass effect avoiding the drug's deactivation by digestive and liver enzymes.

ADVANTAGES OF TRANSDERMAL DRUG DELIVERY SYSTEMS:

4. Avoids the risks of parenteral therapy.

5. Provides the capacity for multiday therapy with a single application.

6. Provides capacity to terminate drug effect rapidly.

7. Provides ease and rapid administration of the medication in emergencies.

Disadvantages of transdermal drug delivery systems:

1. The transdermal route of administration is unsuitable for drugs that irritate or sensitize the skin.
2. Only relatively potent drugs are suitable for transdermal delivery due to the natural limits of drug entry by the skin's impermeability.
3. Technical difficulties with the adhesion of the systems to different skin types and under various environmental conditions.

The Skin

The skin has a wide variety of functions:

• Protect the organism from water loss and

mechanical, chemical, microbial, and physical

influences.

Structure of the Skin

The skin is the largest human organ and is composed of:

• A film of emulsified material present upon the surface of

the skin composed of a complex mixture of sebum, sweat.

• Three functional layers:
• Epidermis,
• Dermis (true skin)
• Hypodermis

(Subcutaneous fat layer).

​

• Blood capillaries and

nerve fibers.

• Sweat glands.
• Hair follicles.

The epidermis is the outermost layer of the skin

​

• 0.02 to 5 mm thickness
• It has five layers,

• Barrier layer (stratum germinativum).
• Beneath the hornylayer
• Composed of living epidermal cells.

• Horny layer

(stratum corneum).

• The uppermost layer

• Composed of dead epidermal cells forms the permeability barrier

The stratum corneum consists of:

Horny skin cells (corneocytes) which are connected via protein-rich attachments of the cell membrane.

​

​

​

​

The corneocytes are embedded in a lipid matrix in “Brick and mortar” structure.

The corneocytes of hydrated keratin comprise the bricks and the epidermal lipids fill the space between the dead cells like mortar.

Routes of skin Penetration

Include transport via:

1- Hair follicles and sebaceous

glands

2- Sweat glands

• These routes avoid penetration through the stratum corneum and therefore known as shunt routes.

The Transappendageal route:

There are two diffusional routes to penetrate intact skin:

• Although these routes offer high permeability, they are of

minor importance because of their relatively small area,

0.1% of the total skin area.

• The transappendageal route seems to be most important for ions and large polar molecules which hardly permeate through the stratum corneum.

Transepidermal transport means that molecules cross the intact horny layer.

The transepidermal route :

Two potential micro-routes are exist

The transcellular (or intracellular) rout.

The intercellular pathways.

The principal pathway taken by drugs is decided by its partition coefficient.

Hydrophilic drugs partition into the intracellular pathways, whereas lipophilic drugs traverse the stratum corneum via the intercellular route.

Factors Affecting Percutaneous Absorption

• Factors concerning the nature of the drug
• Factors concerning the nature of the vehicle
• Factors concerning the condition of the skin

Percutaneous absorption is the absorption of substances from outside the skin to positions beneath the skin, including entrance into the blood stream.

1. Spreadability of the vehicle

Percutaneous absorption

​

2. Mixing with the sebum

Percutaneous absorption

​

3. Hydration of the skin Percutaneous absorption

​

Oleaginous vehicles act as moisture barriers through which the sweat from the skin cannot pass, thus increased hydration of the skin beneath the vehicle and increase Percutaneous absorption.

• Factors concerning the nature of the vehicle

• Factors concerning the condition of the skin

Transdermal absorption follow Fick’s First Law of Diffusion

Js = Km D Cs

E

Js = Flux of solute through the skin

Km = Distribution coefficient of drug between vehicle and

stratum corneum

Cs = Concentration difference of solute across the

membrane

D = Membrane Diffusion coefficient for drug in stratum

corneum

E = Thickness of stratum corneum

1. The thickness stratum corneum

Percutaneous absorption

​

2. Multiple application dosing

Percutaneous absorption than single Application

​

3. Time of contact with the skin

Percutaneous absorption

​

4. Broken skin permit (remove of the stratum corneum)

Percutaneous absorption

There are two basic types of transdermal dosing systems: (1) those that control the rate of drug released to the skin, (2) those that allow the skin to control the rate of drug absorption.

Drug delivery systems have been developed to control the rate of drug delivery to the skin over a period of time for subsequent absorption.

Percutaneous Absorption Enhancers

Mechanisms of action by which Materials enhance absorption through stratum corneum is either by

• Enhancing drug release from the formulation to the skin.
• Reduction of the resistance of the stratum corneum by

altering it physicochemical properties

• Alteration of the hydration of the stratum

corneum using occlusive formulations.

• Carrier mechanisms in the transport of ionisable

drugs.

• Enhance absorption by directly influencing

the stratum corneum

(CHEMICALLY or PHYSICALLY).

This can be achieved by the following mechanisms:

Chemicals used to enhance absorption by directly influencing the stratum corneum

• Chemicals interact with the keratin structure in the stratum

corneum and open the tight protein structure, this leads

increase the diffusion coefficient D for substances which use

the transcellular route:

Surfactants, Dimethylsulfoxide (DMSO) and Urea.

​

• Solvents extract lipids and making the stratum corneum more

permeable: Dimethylsulfoxide (DMSO) and Ethanol.

• Chemical enhancers which intercalate into the structured

lipids of the horny layer and disrupt the packing. Thus

make the regular structure more fluid and increases the

diffusion coefficient of drugs:

Azone, Oleic acid, and isopropyl myristate

​

• Solvents increase solubility and improve partitioning:

Alcohol, acetone, polyethylene and propylene glycol

Physical methods can enhance drug flux up to several orders of magnitude above that allowed by passive diffusion (as conventional skin patches).

The effective delivery range for passive diffusion across the skin is limited to small, hydrophobic agents,

However, Physical delivery can be used for larger hydrophilic molecules as peptide drug administration.

IONTOPHORESIS

A physical method to enhance transdermal drug delivery

and penetration.

It involves the delivery of charged chemical compounds across the skin membrane using an applied electrical field.

Mechanisms of Transport

Iontophoresis uses two electrodes, the anode and the cathode, each of which is in contact with a reservoir containing the drug to be delivered as an electrically conductive aqueous solution.

The reservoir containing the drug is in contact with the electrode of the same charge which is (the active electrode), while the other electrode named (passive electrode).

An electrical potential is applied across the electrodes, causing current to flow across the skin and facilitating delivery of the therapeutic agent by repulsion.

Variables affecting iontophoresis:

The electrical current.

Which may be direct, alternate or pulsed

Biological factors:

Involve the presence of thickness,

permeability and porous of the skin.

Physicochemical factors:

Include charge, size, structure and lipophilicity of the drug with small or large molecular size.

The drug should be water soluble, of low dose and ionizable with high charge density.

Formulation factors:

Include dug concentration, pH, ionic strength and viscosity.

• Increasing drug concentration results in greater drug delivery.
• The inclusion of buffer ions in a formula will compete with the drug for the delivery current and decrease the quantity of drug delivered, especially since buffer ions are smaller and more mobile than the large active drug. The pH of the solution can be adjusted and maintained by large molecules as ethanolamine : ethanolamine HCL.
• An increase in the ionic strength of the system will increase the competition for the available current especially when the active drugs are potent and present in small concentration.

They are also poorly absorbed from the transdermal route, because of their large molecular size, ionic character, and impenetrability of the skin.

A number of drugs have been used including, lidocaine, amino acids, peptides and insulin.

These agents are presently delivered by injection, because of their rapid metabolism and poor absorption following oral delivery.

SONOPHORESIS

Sonophoresis (Phonophoresis)

in which High-frequency ultrasound,

is used to enhance transdermal drug delivery.

Among the drugs used are hydrocortisone, lidocaine, and salicyclic acid in the form of gels, creams, e lotions (coupling agents) followed by ultrasound unit.

The high-frequency ultrasound (1 MHZ at 0.5 to 1 W/cm²) can disrupt the stratum corneum which influence the integrity of and thus affect its penetrability.

Involves the formation and collapse of very small air bubbles in a liquid in contact with ultrasound waves.

These air bubbles can disperse the ultrasound waves resulting in heating at the liquid air interfaces.

Three effects are results from ultrasound include:

Cavitation, microstreaming and heat generation.

Cavitation:

Micro-streaming:

Closely associated with cavitation results in efficient mixing by inducing vortexes (currents) in small volume elements of a liquid, this may enhance dissolution of suspended drug particles results in s higher concentration of drug near the skin for absorption.

​

Heat generation:

Heat results from the conversion of ultrasound energy to heat energy and can occur at the surface of the skin and deeper layers of the skin.

The vehicle containing the drug must be formulated to

provide good conduction of the ultrasonic energy to the skin.

• The product must be smooth and non-gritty as they will be rubbed into the skin by the head of the transducer.
• The product should have low viscosity for easy of application and easy of movement of the transducer (as gels).
• Emulsions can be used but the oil/ water interfaces can disperse the ultrasonic waves, resulting in a reduction of the intensity of the energy reaching the skin. It may case some localized heat.

Requirements for rate-controlling transdermal

drug delivery systems:

l. 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 release of the drug 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 systems.

5. The system's adhesive, vehicle, and active agent should be nonirritating and non-sensitizing to the skin of the patient.

6. The patch should adhere well to the patient's skin.

7. The system should not permit the proliferation of skin bacteria beneath the occlusion.

Technology of Transdermal Delivery Patches

Technically, transdermal drug delivery systems may be categorized into two types:

Monolithic systems

membrane-controlled systems

The drug-matrix layer is composed of a polymeric material in which the drug is dispersed.

The polymer matrix controls the rate at which the drug is released for percutaneous absorption.

Monolithic Transdermal Patches

Incorporate a drug matrix layer between backing and frontal layers.

NicoDerm® CQ®

nicotine transdermal system

Polymer Matrix

�The Polymer controls the release of the drug from the device.

�Possible useful polymers for transdermal devices are:

​

A-Natural Polymers:

e.g. Cellulose derivatives, Gelatin, Shellac, Waxes, Proteins, Gums and their derivatives, Natural rubber, Starch.

​

B- Synthetic Elastomers:

e.g. Polybutadieine, Styrene butadieine, Polysiloxane, Silicone rubber, Acrylonitrile, Butyl rubber, Neoprene.

​

C- Synthetic Polymers:

e.g. Polyvinyl alcohol, Polyvinyl chloride, Polyacrylate, Polyvinylpyrrolidone, Polymethylmethacrylate, Epoxy.

The matrix may be with or without an excess of drug with regard to its equilibrium solubility and steady-state concentration gradient at the stratum corneum.

• In types having no excess, drug is available to maintain the saturation of the stratum corneum only as long as the level of drug in the device exceeds the solubility limit of the stratum corneum.

As the concentration of drug in the device diminishes below the skin's saturation limit, the transport of drug from device to skin gradually declines.

• In monolithic systems that have an excess amount of drug present in the matrix, a drug reserve is present to assure continued drug saturation at the stratum corneum, this assures continuous drug availability and absorption.

The rate of drug decline is less than in the type designed with no drug reserve.

Examples of monolithic systems are NitroDur (Key) and Nitrodisc (Searle).

In the preparation of monolithic systems, the drug and the

polymer are dissolved or blended together, cast as the

matrix, and dried.

The gelled matrix may be produced in sheet or cylindrical

form, with individual dosage units cut and assembled

between the backing and frontal layers.

Designed to contain a drug reservoir, usually in liquid or gel form, a rate-controlling membrane, and backing, adhesive, and protecting layers.

Examples are Transderm-Nitro (Summit) and Transderm-Scop (CIBA)

and levonorgestrel/estradiol

for hormonal contraception.

Membrane-controlled Transdermal Patches

Membrane-controlled systems have the advantage over

monolithic systems:

• As the drug solution in the reservoir remains saturated, the release rate of drug through the controlling membrane remains constant.
• In membrane systems, a small quantity of drug is frequently placed in the adhesive layer to initiate prompt drug absorption and pharmaco-therapeutic effects upon skin placement.
• Membrane controlled systems may be prepared by preconstructing the delivery unit, filling the drug reservoir, and sealing, or by a process of lamination, which involves a continuous process of construction, dosing, and sealing.

General Considerations in the proper Use

of Transdermal Drug Delivery Patches:

1. The site for application should be clean, dry, and hairless (but not shaved).

Nitroglycerin patches are generally applied

to the chest, estradiol to the abdomen,

scopolamine behind the ear,

nicotine to the upper trunk or upper outer arm for smoking cessation.

Because of the possible of skin irritation, the site of application must be rotated, that skin sites must not reused for a week.

2. The transdermal patch should not be applied to skin that is oily, irritated, cut or abraded 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 it. The patch's protective backing should be removed to expose the adhesive layer, and it should be applied firmly with the palm or heal of the hand until securely in place.

4. The patient should be instructed to cleanse the hands before and after applying the patch.

​

5. Care should be taken not to rub the eyes or touch the mouth during handling of the patch.