Introduction

The skin is the largest organ of the body, accounting for more than 10% of body mass, and the one that enables the body to interact most intimately with its environment. Figure 1 shows a diagrammatic illustration of the skin. In essence, the skin consists of four layers: the stratum corneum (nonviable epidermis), the remaining layers of the epidermis (viable epidermis), dermis, and subcutaneous tissues. There are also several associated appendages: hair follicles, sweat ducts, apocrine glands, and nails. Many of the functions of the skin can be classified as essential to survival of the body bulk of mammals and humans in a relatively hostile environment. In a general context, these functions may be classified as protective, maintaining homeostasis, or sensing. The importance of the protective and homeostatic role of the skin is illustrated in one context by its barrier property. This allows the survival of humans in an environment of variable temperature; water content (humidity and bathing); and the presence of environmental dangers, such as chemicals, bacteria, allergens, fungi, and radiation. In a second context, the skin is a major organ for maintaining the homeostasis of the body, especially in terms of its composition, heat regulation, blood pressure control, and excretory roles. It has been argued that the basal metabolic rate of animals differing in size should be scaled to the surface area of the body to maintain a constant temperature through the skin's thermoregulatory control (1). Third, the skin is a major sensory organ in terms of sensing environmental influences, such as heat, pressure, pain, allergen, and microorganism entry. Finally, the skin is an organ that is in a continual state of regeneration and repair. To fulfill

Stratum corneum Stratum granulosum

Stratum spinosum Stratum basale

Blood vessel Sweat duct Sebaceous gland

Erector muscle Hair follicle

Fat tissue

Connective tissue

Figure 1 Components of the epidermis and dermis of human skin.

each of these functions, the skin must be tough, robust, and flexible, with effective communication between each of its intrinsic components.

Many agents are applied to the skin either deliberately or accidentally, with either beneficial or deleterious outcomes. The use of topical products was evident in ancient times, and there are reports of systemic benefits of topical anti-infective and hormonal agents in the 1940s. Modern transdermal patch technology was introduced in the late 1970s. The main interests in dermal absorption assessment are in the application of compounds to the skin (a) for local effects in dermatology (e.g., cor-ticosteroids for dermatitis); (b) for transport through the skin for systemic effects (e.g., nicotine patches for smoking cessation); (c) for surface effects (e.g., sunscreens, cosmetics, and anti-infectives); (d) to target deeper tissues (e.g., nonsteroidal antiinflammatory agents [NSAIDs] for muscle inflammation); and (e) unwanted absorption (e.g., solvents in the workplace, agricultural chemicals, or allergens). Figure 2 summarizes these processes and sites of effect of compounds applied to the skin. The skin became popular as a potential site for systemic drug delivery because it

Figure 2 (A) Structure of the skin and processes of percutaneous absorption and transdermal delivery. Absorption can occur through sweat ducts (1), intercellular regions of the stratum corneum (2), and through the hair follicles (3). (B) Dermal absorption, sites of action and toxicity.

Transdermal Absorption

Fat tissue

Connective tissue

Figure 1 Components of the epidermis and dermis of human skin.

Enzyme Regulation Stomach

was thought to (a) avoid the problems of stomach emptying, pH effects, and enzyme deactivation associated with gastrointestinal passage; (b) to avoid hepatic first-pass metabolism; and (c) to enable control of input, as exemplified by termination of delivery through removal of the device. In practice, as discussed later in this book, delivery of solutes through the skin is associated with various difficulties, such as (a) the variability in percutaneous absorption owing to site, disease, age, and species differences; (b) the skin's "first-pass" metabolic effect; (c) the reservoir capacity of the skin; (d) irritation and other toxicity caused by topical products; (e) heterogeneity and inducibility of the skin in both turnover and metabolism; (f) inadequate definition of bioequivalence criteria; and (g) an incomplete understanding of the technologies that may be used to facilitate or retard percutaneous absorption. However, the controlled delivery of solutes through the skin continues to be of interest, with the further development of technologies, such as chemical penetration enhancement, sonopho-resis, transferosomes, and electroporation. The extent to which these are translated into practice will be defined by time.

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