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Human skin is a uniquely engineered organ that permits terrestrial life by regulating heat and water loss from the body whilst preventing the ingress of noxious chemicals or microorganisms. It is also the largest organ of the human body, providing around 10% of the body mass of an average person, and it covers an average area of 1.7 m2. Whilst such a large and easily accessible organ apparently offers ideal and multiple sites to administer therapeutic agents for both local and systemic actions, human skin is a highly efficient self-repairing barrier designed to keep 'the insides in and the outside out'.

Human skin is a highly complex organ though in many transdermal drug delivery studies it is often regarded somewhat simplistically as merely a physical barrier. In vivo, skin is in a process of continual regeneration, it has immunological and histological responses to assault (as would be the case if an exogenous chemical, such as a drug, were applied to the surface) and is metabolically active. Due to experimental and ethical difficulties, most transdermal drug delivery studies tend to utilise skin ex vivo (in vitro) which inherently reduces some of the above complexity ' regeneration stops, immune responses cease and metabolic activity is usually lost in these studies. However, it should always be borne in mind that data obtained from excised skin may not translate directly to the in-vivo situation.

For the purpose of transdermal drug delivery, we can examine the structure and function of human skin categorised into four main layers :

' the innermost subcutaneous fat layer (hypodermis)
' the overlying dermis
' the viable epidermis
' the outermost layer of the tissue (a non-viable epidermal layer) the stratum corneum.

The subcutaneous fat layer

The subcutaneous fat layer, or hypodermis, bridges between the overlying dermis and the underlying body constituents. In most areas of the body this layer is relatively thick, typically in the order of several millimetres. However, there are areas of the body in which the subcutaneous fat layer is absent, such as the eyelids. This layer of adipose tissue principally serves to insulate the body and to provide mechanical protection against physical shock. The subcutaneous fatty layer can also provide a readily available supply of high-energy molecules, whilst the principal blood vessels and nerves are carried to the skin in this layer.

The dermis

The dermis (or corium) is typically 3'5 mm thick and is the major component of human skin. It is composed of a network of connective tissue, predominantly collagen fibrils providing support and elastic tissue providing flexibility, embedded in a mucopolysaccharide gel (Wilkes et al.,1973). In terms of transdermal drug delivery, this layer is often viewed as essentially gelled water, and thus provides a minimal barrier to the delivery of most polar drugs, although the dermal barrier may be significant when delivering highly lipophilic molecules. The dermis has numerous structures embedded within it; blood and lymphatic vessels, nerve endings, pilosebaceous units (hair follicles and sebaceous glands), and sweat glands (eccrine and apocrine).

The epidermis

The epidermis is itself a complex multiply layered membrane, yet varies in thickness from around 0.06 mm on the eyelids to around 0.8 mm on the load-bearing palms and soles of the feet. The epidermis contains no blood vessels and hence nutrients and waste products must diffuse across the dermo-epidermal layer in order to maintain tissue integrity.

Likewise, molecules permeating across the epidermis must cross the dermo-epidermal layer in order to be cleared into the systemic circulation. The epidermis contains four histologically distinct layers which,from the inside to the outside, are the stratum germinativum, stratum spinosum, stratum granulosum and the stratum corneum.

A fifth layer, the stratum lucidum, is sometimes described but is more usually considered to be the lower layers of the stratum corneum. The stratum corneum, comprising anucleate (dead) cells, provides the main barrier to transdermal delivery of drugs and hence is often treated as a separate membrane by workers within the field. The term 'viable epidermis' is often used to describe the underlying layers, although the viability of cells within, for example, the stratum granulosum is questionable as the cell components degrade during differentiation.

Epidermal enzyme systems

As well as the cellular component of the epidermis, the tissue contains many drug-metabolising enzymes. Histochemical and immunohistochemical methodologies suggest that the majority of these are localised in the epidermis, sebaceous glands and hair follicles. Although present at relatively small quantities in comparison to the liver, they do allow metabolic activity that can effectively reduce the bioavailability of topically applied medicaments; a common misconception is that the skin is an 'inert' tissue. Indeed, most phase 1 (e.g. oxidation, reduction, hydrolysis) and phase 2 (e.g. methylation, glucuronidation) reactions can occur within the skin, though these tend to be at http://www.skin-disorders.info