Transdermal Drug Delivery System (TDDS)

Transdermal Drug Delivery System (TDDS)

• TDDS involves drug passage through skin into general circulation for systemic effects.
• Evidence of percutaneous drug absorption includes measurable blood levels, detectable excretion of metabolites in urine, and clinical response.
• Dosage forms include gels, creams, patches, and ointments.

Transdermal Patch Formulation

• Backing: Protects the patch and provides flexibility. Made of polyester, polyethylene, or polyurethane.
• Membrane: Controls drug release, it is made of natural/synthetic polymer. Thickness ranges from 2 mm to 7 mm.
• Adhesive: Binds the patch to the skin; made of silicone or polyvinyl acetate. Permeation enhancers may be present.
• Liner: Protects the patch during storage; peeled off before use.

TDDS Advantages

• Non-invasive and promotes patient compliance due to ease of use.
• Provides extended therapy; drug therapy can be terminated by patch removal.

TDDS Disadvantages

• TDDS bypasses the first-pass effect and the hostile gastrointestinal drug environment.
• The stratum corneum is the rate-limiting barrier of drug absorption.
• Can cause allergic contact dermatitis or skin irritation (API, excipients).

Dermatological Formulations

• Dermatological formulations produce a local drug effect, either on or in the skin.
• They serve as protectants, lubricants, and emollients.
• Treatments for minor skin infections, itching, burns, diaper rash, insect stings/bites, athlete's foot, corns/calluses, and dandruff use dermatological formulations.
• Percutaneous absorption depends on the potential of the drug to cross the stratum corneum, leave the formulation, and the influence of the formulation on the stratum corneum.
• Increasing the surface area of application and the hydration of the skin enhances percutaneous absorption.
• Frequently compounded products due to wide range of uses include solutions like liniments, aqueous and oleaginous solutions, suspensions and gels, emulsions, lotions, and creams.
• Lotions can be either suspensions or emulsions, used for lubricating effects.
• Creams are emulsions, usually opaque and thick, and are used as emollients.

Skin Structure and Function

• The largest/heaviest organ, comprising 17% of body weight, has a surface area of 1.2-2.2 m2, and a thickness of 3-5 mm.
• The epidermis is the outermost layer, the dermis is the middle layer, and the hypodermis is the innermost layer.
• The skin regulates body temperature and fluids.
• Protective functions are microbiological, chemical, radiation, thermal, and electrical barriers.

Epidermis

• The epidermis is the major barrier to transdermal drug absorption.
• Composed of five layers, with the stratum corneum being the primary barrier to drug absorption.
• The stratum corneum has a "brick wall" structure, the penetration through which is rate-limiting.

Dermis

• Contains an extensive lymphatic network and is the site for transdermal drug absorption into systemic circulation and its the thickness is 2-3 mm

Hypodermis

• Composed of loose connective tissue and fat, serves as a major fat storage site (50% of body fat), and provides a mechanical cushion and thermal barrier.

Skin Absorption

• Occurs across the intact stratum corneum, through hair follicles with sebaceous glands, and via sweat glands.
• Hair follicle/sweat gland routes contribute negligibly, with ~0.1% available area.
• Percutaneous absorption results from direct drug penetration through the stratum corneum.
• The stratum corneum is a 10-15 μm thick layer.
• The stratum corneum is 40% protein (keratin) and 40% water, with lipids, triglycerides, free fatty acids, cholesterol, and phospholipids.
• Once past the stratum corneum, drug molecules traverse deeper epidermal tissues into the dermis.
• Upon reaching the vascularized dermal layer, the drug is available for general circulation absorption.

Skin Permeability & Fick's Law

• Transdermal absorption is a passive-diffusion process that follows Fick's first law.
• dM/dt = APΔC

Variables of Fick's Law

• dM/dt = total flux transported through per unit skin area in steady state (μg/hr).
• A = area of skin.
• P = permeability coefficient.
• ΔC = drug concentration gradient across the skin.

Permeability Enhancement

• Permeability can be enhanced by altering the structure of the skin.

Factors Affecting Transdermal Absorption

• Molecular weight (<400 Da is preferable).
• Solubility (in lipid and water is essential).
• Partitioning coefficient.
• Melting point (<200 °C is preferable).
• Liposomes can improve the absorption.

Factors

• Longer TDDS exposure increases drug absorption.

Enhancing Transdermal Absorption

• Chemical techniques (penetration enhancers).
• Physical techniques.
• DMSO extracts lipids and makes the stratum corneum more permeable.
• Azone partitions into the bilayer lipid to disrupt it.

Water as a Penetration Enhancer

• Hydration increases penetration of active compounds.
• It opens the compact structure of the stratum corneum.

Hydration

• Swelling of the stratum corneum increases to approximately three times its original size and absorbs to about five times its weight in water.
• To increase hydration, prevent water loss from the skin using TDDS.

Physical Techniques for Transdermal Delivery

• Skin abrasion (microdermabrasion).
• Electroporation.
• Iontophoresis.
• Sonophoresis.
• Microneedles.

Microdermabrasion:

• Microdermabrasion removes the stratum corneum by light abrasion.

Electroporation

• Electroporation creates small pores in the phospholipid bilayer of the stratum corneum via pulses of high voltage current.

Other Physical Techniques

• Iontophoresis: Facilitates drug delivery through the skin using an applied electrical current. Charged drugs are moved via electrophoresis. and LidoSite ® patch system delivers lidocaine quickly for dermal anesthesia.
• Sonophoresis: Uses ultrasound energy to enhance transdermal drug delivery by disrupting the stratum corneum lipid structure, which increases skin permeability.
• Microneedles: Penetrate the stratum corneum and epidermis without reaching the nerve endings.

Other Methods

• Dissolving Microneedles (MicroHayala®) are made from pure hyaluronate and collagen, and they dissolve in the skin in 60-90 minutes, effectively releasing compounds (API) for maximum penetration.
• Macroflux® Patch (Alza) is used to deliver protein, small molecule drugs, and vaccines transdermally.
• RF-MicroChannel Technology uses high-frequency alternating current through microelectrodes to penetrate the outer skin layer. It creates microchannels within milliseconds that remain open for over 24 hours.