L6 - Transdermal

What are dermatological formulations?

Preparations designed for application on the skin to treat, manage, or improve various skin conditions

Give some examples of dermatological formulations

Solutions, suspensions, gels, emulsions, lotions (suspensions or emulsions), creams, transdermal drug delivery systems, etc.

What is a Transdermal Drug Delivery System?

The passage of drug substances through the skin and into the general circulation for systemic effects

How is the amount of drug that passes through the skin measured?

The blood levels of the drug, detectable secretion of the drug in the urine, and the clinical response of a patient to the therapy

Give the different dosage forms of Transdermal Drug Delivery Systems (TDDS)

Gels, creams, patches, ointments, etc.

What are the four major components of a transdermal patch?

Backing, membrane, adhesive, and liner

Backing

Protects the patch from the outer environment and impermeable to the transdermal patch components. Provides flexibility

Membrane

Controls the release of the drug. Thickness ranges from 2-7 mm

Adhesive

Binds the patch to the skin. May contain permeation enhancers to promote skin permeability

Liner

Protects the patch during storage and is peeled off before use

What are the advantages of TTDS?

Non-invasive, patient compliance, extended therapy, terminate drug therapy rapidly, avoid GI environment, and bypasses the first pass effect

What are the disadvantages of TTDS?

Permeation through the skin is limited, stratum corneum is a rate-limiting barrier, allergic contact dermatitis is possible, skin irritation, etc.

What kinds of drugs are suitable candidates for TDDS?

Potent drugs

Where do TDDS produce local effects?

On or in the skin

Besides the specific therapeutic action of incorporated active drugs, dermatological formulations also serve as:

Protectants, lubricants, and emollients

Give some conditions treated with dermatological formulations

Minor skin infections, itching, burns, diaper rash, insect bites, athletes foot, corns, calluses, dandruff, acne, psoriasis, and eczema

What is percutaneous absorption?

Absorption through the skin

Percutaneous absorption is the result of what three processes?

The potential of the drug to cross the stratum corneum

The potential of the drug to leave the formulation

The influence of the formulation on the stratum corneum

Name some factors that increase percutaneous absorption

Larger surface area, hydrated skin, rubbing the formulation, and longer contact with the skin

What is the outermost layer of the skin called?

The epidermis

What is the middle layer of the skin called?

The dermis

What is the innermost layer of the skin called?

The hypodermis

Name three functions of the skin

Regulates body temperature, regulates body fluids, and has protective function

Describe the epidermis and its relation to drug delivery through the skin

The outermost layer of the skin composed of 5 layers. It is the major barrier for skin absorption due to the stratum corneum. Rate-limiting step

Describe the stratum corneum and its relation to drug delivery through the skin

The outermost layer of the epidermis that is the primary barrier for skin absorption. Acts as a brick wall

Describe the dermis

The middle layer of the skin with an extensive lymphatic network. Site for absorbed drug to enter the systemic circulation. 2-3 mm thick

Give the four components of the dermis

Collagen, elastin, reticulin, and ground substance

Describe the hypodermis (subcutaneous layer)

The innermost layer of the skin composed of loose connective tissue and fat. Major site for fat storage and acts as a mechanical cushion and thermal barrier

Describe the three mechanisms of transdermal drug absorption

1. Across the stratum corneum

2. Through hair follicles in sebaceous glands

3. Through sweat glands

How much do hair follicle and sweat gland absorption contribute to total transdermal drug absorption?

Very little. Fractional area for absorption available (0.1%)

Percutaneous absorption mainly occurs through:

Direct penetration of the drug through the stratum corneum

How thick is the stratum corneum?

10-15 micrometers

What is the stratum corneum composed of?

40% protein (mainly keratin) and 40% water with the balance being lipids

What is skin permeability?

The ability of substances to pass through the skin and enter the body.

What equation helps determine the skins permeability?

Ficks first law of diffusion

Give Ficks first law of diffusion

dM/dt = APΔC

What is dM/dt?

The rate of mass transfer (M) over time (t) — essentially, how much of the substance crosses the membrane per unit of time (µg/hr)

What is A?

Surface area of the membrane

What is P?

Permeability coefficient — a measure of how easily the substance crosses the membrane. The higher, the more lipophilic, the easier it crosses (not too high though or it could get stuck in membrane)

What is ΔC?

Concentration gradient — the difference in concentration of the substance on either side of the membrane. A higher gradient drives more diffusion

How can permeability be enhanced?

Alerting the structure of the skin and increasing the solubility of the drug in the skin

What three factors mainly affect transdermal absorption?

Physical and chemical properties of the drug, formulation, and exposure time

What physical and chemical properties of a drug increase transdermal absorption?

Low MW, solubility in both lipid AND water is essential, high partitioning coefficient, and lower melting point

What formulation characteristics can increase transdermal absorption?

Liposomes

How can exposure time increase transdermal absorption?

The longer the TDSS remains in contact with the skin, the greater the absorption

Enlist two methods to enhance the transdermal absorption

Chemical and physical enhancement techniques

How can chemical techniques enhance transdermal absorption?

By altering the structure of skin lipids, decreasing their diffusion resistance, and enhancing the solubility of the drug within the skin

Give two examples of chemical techniques enhancing transdermal absorption

DMSO and Azone

DMSO (Dimethyl sulfoxide)

Extracts lipids and makes the stratum corneum more permeable

Azone

Partitions into bilayer lipid to disrupt the packing arrangement (increases the fluidity of the membrane)

How can water enhance transdermal absorption?

It can act as a penetration enhancer by opening the compact structure of the stratum corneum or swelling the stratum corneum (3x)

Name five physical techniques that enhance transdermal absorption

Skin abrasion, electroporation, iontophoresis, sonophoresis, and microneedles

Skin abrasion (microdermabrasion)

The stratum corneum is partially removed by light abrasion

Electroporation

Short pulses of high voltage current are applied to create small pores in the bilayer of stratum corneum

Iontophoresis

An electrical current is applied to the skin to allow charged drugs to move (charged molecules move under the influence of uniform electric field)

Give two examples of iontophoresis

Phoresor and Lidosite

Sonophoresis

Ultrasound energy is used to enhance the transdermal delivery by disrupting the stratum corneum lipid structure

Microneedles

Penetrate the stratum corneum and epidermis without reaching the nerve endings present in the upper dermis (painless)

Give three examples of other methods to increase transdermal drug delivery

MicroHayala, Macroflux Patch (Alza), and RF-MicroChannel Technology

MicroHayla

Dissolving micro-needles made from pure hyaluronate and collagen that dissolve in the skin (60-90 min) to effectively release API

Macroflux Patch (Alza)

Can be used for transdermal delivery of protein, small molecule drug, and vaccine

Microneedle skin roller dermatology therapy system

Improves the elasticity of the skin and makes you look younger in a pain free way

RF-MicroChannel Technology

High frequency alternating current is transferred through microelectrodes localized in the skin. Penetrate the outer layer with no pain or blood

What is RF-MicroChannel Technology used to treat?

Osteoporosis