Transdermal Drug Delivery Systems Transdermal drug delivery system are topically administered medicaments in the form of patches that deliver drugs for systemic effects at a predetermined and controlled rate.

Advantages of TTS Avoid first-pass effect in intestine and the acidic environment of stomach Transdermal systems are non-invasive and can be self-administered. They can provide release of drug for long periods of time (up to one week) without dose dumping. They can improve patient compliance since single application is administered for several days Easy removal or termination of the device if needed Avoid risks and inconvenience of IV therapy

Limitation of TTS Drug may be metabolized by bacteria on skin surface since the hydration of skin can encourage bacterial growth Enzymatic activity to certain drug by skin enzymes. Molecular size is critical (max size is 400D). The slow transport of drug across skin limit this approach for potent drugs (max conc. 20mg/day) Skin pores may be blocked and cause problems because of long term appliaction

The skin site for transdermal drug administration Skin is one of the most accessible organs of human body It has an average surface area of 2 m2 and few millimeters in thickness It also receives one third of circulating blood Physiologically it serves as a barrier against physical and chemical attacks and protects the vital organs from microbial invasions It is function as first line of defense of human body

Anatomy of human skin Skin is a multilayered organ composed of three layers: epidermis, dermis and subcutaneous fat Epidermis: - The outerlayer of the skin, composed of multilayered stratified squamous epithelial cells. - It is non vascular but contain amino acids. - Epidermis has varying thickness ranging from very thin covering the eyelids to thickest on the palms and soles - Normal epidermis is renewed as it is worn off Epidermis composed of two main parts: 1 - Stratum corneum ( Horny layer) 2 - The viable epidermis (stratum germinativum)

1. (Stratum corneum): The outermost layer of the epidermis Composed of many layers of compact flattened dehydrated, keratinized cells in stratified layers Cells have lost their nuclei and are inactive Thickness is variable, dependent on abrasion and pressure, swells several folds in water Cells are formed and replaced by migrating cells from stratum germinativum about every 2 weeks in adults Composition: only 20% water, keratin, lipids Stratum corneum requires min. of 10% moisture content to maintain softness and flexibility Considered as the main barrier for percutaneous absorption

2. (Startum germinativum): Cells of the deepest layer of the epidermis that divide and migrate upwards, as these migrate, the cells loose their nucleus and give rise to the dead keratinized outmost layer of the skin ( Stratum corneum) It is known as regenerative layer of the epidermis Contains 70% water content The germinativum zone to horny layer is made of three layers: 1. Stratum spinosum (pricky layer), 2. Stratum granulosum (granular layer) and 3. Stratum lucidum (clear layer)

2. Dermis layer Just below the epidermis Composition: it is made of network of collagen fibers of uniform thickness It gives the skin its elasticity It is the vascular part of the skin, where it contains blood vessels, lymphatics and nerve endings It is considered as the sink of the skin It also contains skin appendages (sweat glands, sebaceuos glands and hair follicles) 3. Subcutaneous fat Sheet of fat tissue attaching the dermis to underlying structures, It provide mechanical cushion and thermal insulator

The skin appendages Sweat glands: they aid in heat control and secrete sweat Hair follicles: develop all over the skin except the red part of the lips, the palms and soles. One or more sebaceous glands, and some times sweat glands open into the follicle. Sebaceous glands: most numerous on the face, forehead, in the ear. These produce sebum (principle components are glycerides, free fatty acids, cholesterol, cholesterol esters, wax esters and squalene).

Approaches to topical formulation Surface treatment Stratum corneum treatment Skin appendages treatment: hyperhydrosis, Acne, Depilatories Viable epidermis and dermis: psoriasis, anaesthetics, anti pruritics, Premalignant and malignant tumours Systemic treatment

Fundamentals of skin penetration Stratum corneum as skin permeation barrier - The barrier can be viewed as three layers: stratum corneum (15 µm thick), viable epidermis (150 µm thick), the papillary layer of the dermis (100-200 µm thick) - The above structure is pierced in various places by two types of shunts: sweat glands and hair follicles

Routes for skin penetration There are 3 potential entry routes of drug to the viable tissue (dermis): 1. Hair follicles and their associated sebaceous glands, 2. Via the sweat ducts, or 3. Across the continuous stratum corneum

Routes of Skin Penetration

Skin appendages The average human skin contains 40-70 hair follicles and 200-250 sweat ducts per square centimeter These only occupy 1% of the total cross sectional area of the skin. Water soluble and large molecules can penetrate into the skin via these appendages at a faster rate than through the intact area of the stratum corneum Skin appendages may act as shunts at short time period prior to steady state diffusion, nevertheless, very limited contribution in the overall profile of skin permeation

Epidermal route The main barrier is the stratum corneum Molecules may penetrate either intercellularly or transcellularly. Molecules partition into and diffuse through the network according to their polarity. The intercellular route is rich in neutral lipids

The percutaneous absorption of drugs can be considered as a series of three steps: Sorption of penetrant molecule onto the surface layers of stratum corneum Diffusion through stratum corneum and the viable epidermis At the papillary layer of dermis, the molecule is taken up by the capillaries for subsequent systemic absorption The viable tissue layer and capillaries are relatively permeable and rapid. The rate limiting step is often diffusion through stratum corneum. In SC no active transport as the cells are dead, but only simple passive diffusion.

Factors influencing penetration 1. Biological Factors Skin age Site of application State of the skin Hydration of the skin Ageing and environmental factors

2.Physicochemical Factors Drug/skin interactions: skin hydration, drug binding Vehicle/skin interactions: vehicle effects on skin hydration, effect of temperature, penetration enhancers Drug vehicle interactions

Evaluation of transdermal drug delivery systems In vitro drug release kinetics The release kinetics of drug from the TDDS technology can be evaluated using a two compartment diffusion cell assembly. Cellophan membrane is mounted on a vertical diffusion cell such as Franz diffusion cell. The skin permeation profile is followed by sampling the receptor solution at predetermined time intervals until steady state is reached. In vitro skin permeation kinetics The release and skin permeation kinetics of drug from the TDDS technology can be evaluated using a two compartment diffusion cell assembly. Skin is mounted on a vertical Franz diffusion

In vivo studies A. Animal models B. Human studies

Approaches to enhance skin permeability Physical approach Stripping of stratum corneum: SC is considered as the main barrier for drug absorption, its removal enhances drug permeation. Hydration of SC: SC can be hydrated and the dense structure of keratin opens up making permeation easier. SC can be hydrated by occlusion with water immiscible dressings Iontophoresis: Iontophoresis passes a few milli-amperes of current to a few square centimeters of skin through the electrode placed in contact with the formulation, which facilitates drug delivery across the barrier.

2. Chemical approach Synthesis of lipophilic prodrugs: a drug with poor skin permeability may be chemically modified to a prodrug with improved skin permeation characteristics. After SC permeation, the prodrug is transformed by the metabolic processes within the skin tissue to regenerate the active drug. E.g. ester type prodrugs of Estradiol

b.. Skin permeability promoters (absorption enhancers): Are Substances that temporarily diminish the impermeability of the skin. These should be safe and non toxic, pharmacologically inert, non irritating, non allergenic. Their action must be immediate and once removed the skin should immediately and fully recover to its normal barrier properties. The enhancement should not cause loss of body fluids, electrolytes or any endogenous material The mechanism of action of various skin permeability promoters may be due to their activity on the lipophilic lipid matrix and/or hydrophilic protein gel in stratum corneum

Examples: Solvents: Alcohols Alkylmethylsulfoxide: DMSO, DMF, DMA Azone, Pyrrolidones (NMF): free fatty acids, urea Surfactants(non-ionic SAA) Others: Cyclodextrins, glycolate salts