The skin is elastic and quite rugged despite the fact that it is only approximately 3 mm thick. It consists of three anatomical layers, the epidermis, the dermis and a subcutaneous fat layer (Figure 8.1).
Apocrine Sweat Gland
Hair Smooth Eccrine Lymphatic
Follicle Muscle Sweat Gland Vessel
Figure 8.1 Structure of the skin
Apocrine Sweat Gland
Hair Smooth Eccrine Lymphatic
Follicle Muscle Sweat Gland Vessel
Figure 8.1 Structure of the skin
The epidermis is a thin, dry and tough outer protective outer layer. It forms a barrier to water, electrolyte and nutrient loss from the body, and at the same time is also responsible for limiting the penetration of water and foreign substances from the environment into the body. Damage or removal of the epidermis allows diffusion of small water-soluble non-electrolytes to occur approximately 1000 times faster than in the intact skin2.
The epidermis is made up of two layers; a basal layer known as the stratum germinativum, which is living, and an outer dead layer called the stratum corneum. The primary cell type in the stratum germinativum is the corneocyte or keratinocyte, which grows from the basal layer outwards to the skin surface. The journey to the surface takes between 12 to 14 days, during which time the cells synthesise the various proteinaceous materials called keratin, they become thin, hard and dehydrated and begin to die. The lifespan of such a cell on the surface is two to three weeks. These cells, together with intercellular lipids synthesized by the keratinocyte, form the outer stratum corneum or horny layer, which is dead. The stratum corneum is the primary protective layer and consists of eight to sixteen layers of flattened, stratified and fully keratinised dead cells. Each cell is about 34 to 44 pm long, 25 to 36 pm wide and 0.15 to 0.20 pm thick, and they are continuously replaced from the basal layer. The water content of the normal stratum corneum is 15 to 20% of its dry weight, but when it becomes hydrated it can contain up to 75% water.
Because the stratum corneum is the main barrier to drug absorption its structure has been closely studied. The most widely used description is the 'bricks and mortar' model (Figure 8.2) in which the keratinocytes form the hydrophilic bricks and the intercellular lipid is the mortar, so that there is a continuous hydrophobic path through the stratum corneum. There is no direct hydrophilic path since the lipid effectively 'insulates' the keratinocytes from each other, and techniques such as electroporation (q.v.) are required to form a continuous hydrophilic path. The lipids consist mainly of ceramides, fatty acids, and cholesterol. Alkanes are commonly present although they are almost certainly derived from environmental sources. It is particularly difficult to study the intercellular lipids since they are easily contaminated with lipids from the sebaceous glands (squalane and triglycerides) or from epidermal fat3.
The basal layer also contains melanocytes which produce the pigment melanin, which imparts colour to the skin and also protects it from the effects of ultraviolet radiation. Other cells found in the epidermis include Langerhans cells, which play a role in the body's immune defences, and Merkel cells, which are involved in sensory reception. Structures such as hair follicles, nails, and sweat and sebaceous (oil-producing) glands are appendages that develop from the epidermis and extend into the dermis.
The dermis is a fibrous layer which supports and strengthens the epidermis. It ranges from 2-3 mm thick and in man constitutes between 15% to 20% of the total body weight. The dermis consists of a matrix of loose connective tissue composed of fibrous protein collagen, embedded in an amorphous ground substance. The ground substance consists primarily of water, ions, and complex carbohydrates such as glycosaminoglycans that are attached to proteins (proteoglycans). The ground substance helps to hold the cells of the tissue together and allows oxygen and nutrients to diffuse through the tissue to cells.
There are two distinct layers in the dermis; the papillary layer, which is adjacent to the epidermis, which contains mainly reticulin fibres, with smaller amounts of collagen and elastin, and the reticular layer, which provides structural support since it has extensive collagen and elastin networks, and few reticulin fibres. Elastin is more flexible than collagen and it serves to anchor the epidermis to the dermis, which helps the skin return to its original form after it has been stretched.
The dermis contains blood vessels, nerves, hair follicles, sebum and sweat glands. A deep plexus of arteries and veins is found in the subcutaneous tissue, and this sends out branches to the hair follicles and various glands. A second network of capillaries is located on the sub-papillary region of the dermis. From this plexus, small branches are sent towards the surface layers of the skin. The capillaries do not enter the epidermis, but they come within 150 to 200 pm from the outer surface of the skin. In man, dermal blood flow is approximately 2.5 ml min-1100 g-1, but it can reach 100 ml min-1100 g-1 in the fingers.
Three different types of cells are scattered throughout the dermis. These are fibrocytes which synthesize collagen, elastin, and ground substance, histiocytes which are a type of macrophage, and mastocytes, or mast cells which are located near blood vessels; they release histamine in response to irritation, fever, oedema, and pain.
The subcutaneous fat layer acts both as an insulator, a shock absorber, reserve depot of calories and supplier of nutrients to the other two layers. This subcutaneous tissue or hypodermis is composed of loose, fibrous connective tissue which contains fat and elastic fibres. The base of the hair follicles are present in this layer, as are the secretory portion of the sweat glands, cutaneous nerves and blood and lymph networks. It is generally considered that the drug has entered the systemic circulation if it reaches this layer; however the fat deposits may serve as a deep compartment for the drug and this can delay entry into the blood.
Unlike other large land mammals, humans lack extensive body hair apart from epigamic areas which are concerned with social and sexual communication, either visually or by scent from glands associated with the hair follicles. The hair shaft consists of differentiated horny cells and it is the only part which breaks the surface of the skin. Hair follicles have a diameter of approximately 70 pm and occur at fixed intervals, and hence their separation increases during growth. The density of hair varies over the body surface and it is normally absent from certain areas such as the lips and palms. The extent of hair growth plays an important role in fastening a transdermal delivery system to the skin.
Nails are a modification of the epidermal structure. They are plates of hard keratin which lie along a nail bed, which is composed of modified skin and is very vascular.
Sebaceous glands vary in size from between 200 to 2000 pm in diameter and are found in the upper third of the hair follicle. Sebaceous glands secrete sebum into the hair follicle, which eventually ends up on the surface of the skin. Sebum consists, on average, of 58% triglycerides, 26% waxy esters, 12% squalene, 3% cholesteryl esters and 1% cholesterol. The lipids maintain a pH of about 5 on the skin surface, and can cause problems for the adhesives in transdermal delivery systems.
Eccrine sweat glands are simple tubular glands which possess a coiled section located in the lower dermis. There are approximately 3,000,000 on the body. The normal diameter of the surface opening is 70 pm, but the average width of the ducts are between 5 and 14 pm. They make up 1/10,000 of the total body surface area. Eccrine sweat glands secrete fluid which consists of 99% water with other minor components such as proteins, lipoproteins, lipids and several saccharides. The pH of the secretion is about 5. Apocrine sweat glands are ten times larger than eccrine sweat glands and they open into the hair follicle; however, the apocrine glands secrete a lower volume of sweat than the eccrine glands.
The characteristic features of skin change from the time of birth to old age. In infants and children it is velvety, dry, soft, and largely free of wrinkles and blemishes. The sebaceous glands in children up to the age of two years function minimally and hence they sweat poorly and irregularly. Adolescence causes sweating and sebaceous secretions to increase dramatically and the hair becomes longer, thicker, and more pigmented, particularly in the scalp, axillae, pubic eminence, and the face in males. General skin pigmentation increases and acne lesions often develop. As the skin ages, it loses elasticity and exposure to the environment, particularly sun and wind, cause the skin to become dry and wrinkled.
The human skin displays remarkable regional and racial differences, for example, skin of the eyebrows is thick, coarse, and hairy; that on the eyelids is thin, smooth, and covered with almost invisible hairs. Lips are hairless, whilst males have coarse hair over the upper lip and cheeks and jaws. Freckles, also called ephelides (singular ephelis), can also be found on the skin. They are small, brownish, well-circumscribed, stainlike spot on the skin, occurring most frequently in red- or fair-haired people. Freckles do not form on surfaces that have not been exposed to the sun. The ultraviolet radiation in sunlight causes the production of melanin to increase, however, the number of melanocytes remains the same.
The skin is driest at its surface, with a water content of 10 to 25%, and a pH of between 4.2 and 5.6. The lower epidermal layers contain up to 70% water and the pH gradually increases to 7.1 to 7.3. The "acid mantle" derives from the lactic acid and carboxylic amino acids in the sweat secretions mixed with the sebaceous secretions. The lower fatty acids (propionic, butyric, caproic or caprylic) have been demonstrated to have fungistatic and bacteriostatic action, possibly due to the low pH which they produce. The isoelectric point of keratin is between 3.7 and 4.5 and hence materials applied to the skin should have a pH greater than this value.
PASSAGE OF DRUG THROUGH THE SKIN Model systems for skin
A number of systems are available for studying transdermal drug absorption. In humans, cadaver skin is widely used, as is breast skin from mammary reduction operations. An alternative is the porcine skin model. Pigs have a marked advantage in studies of this type since their sebaceous glands are inactive, which can be particularly useful for the study of epidermal lipids. Large areas of full thickness epidermis can be removed by applying an aluminium block heated to 60°C for 30 seconds. The hamster cheek pouch also appears to be free of follicles and may be a useful model for absorption studies4.
There is much interest in drug absorption through the appendageal pathway, but it is hampered by a lack of reliable techniques allowing direct and appendageal absorption to be studied. Hairless rodents still possess underdeveloped follicles, and attempts to study burn scar tissue as follicle-free skin5 have obvious weaknesses. The Syrian hamster ear is rich in follicles, and a stratification procedure may allow the various routes of absorption to be separated in this model6.
Drug diffusion from a transdermal delivery system to the blood can be considered as passage through a series of diffusional barriers. The drug has to pass first from the delivery system through the stratum corneum, the epidermis and the dermis, each of which has different barrier properties. Differences in composition of these layers cause them to display different permeabilities to drugs, depending on molecular properties such as diffusion coefficient, hydrophobicity, and solubility.
The first limiting factor is the vehicle or device. In a transdermal device, the primary design goal is the maintenance of the desired constant drug concentration at the skin surface for a suitable length of time. This has been achieved with a wide variety of technologies. The second and major barrier for most compounds is the stratum corneum. Skin from which stratum corneum has been removed is highly permeable, while the removed stratum corneum is nearly as impermeable as the entire skin7. Skin from cadavers has approximately the same permeability as living skin, suggesting that the underlying tissues present little resistance to drug adsorption8.
Absorption can occur through several possible routes on an intact normal skin. It is widely accepted that the sebum and hydrophilic secretions offer negligible diffusional resistance to drug penetration. Drug molecules may penetrate not only through the skin but also via the eccrine glands and the sebaceous apparatus; this is known as transappendageal absorption. This route is often neglected since it is difficult to study. The most useful techniques are autoradiography of labelled drugs9 although several studies have used confocal microscopy with fluorescent drug models. As the openings of glands comprise only a fraction of a percent of the skin surface, transappendageal absorption is often considered unimportant; however it is likely that some materials do penetrate readily by this route. It has been suggested that this route is more rapid than transepidermal transport, and so provides a loading dose, which is sustained by slower diffusion through the epidermis10.
There are two possible routes of passage of drugs through the stratum corneum; these are via the hydrophilic keratinised cells or the lipid channels organized largely in bilayers between the cells. The lipoidal nature of the lipid channels favours passage of hydrophobic molecules, and since many drugs are hydrophobic, this is their major route of entry11. Transdermal drug absorption is influenced considerably by the degree of hydration of the skin, probably due to a combination of several factors including improved contact or wetting, and hydration of the lipid channels of the stratum corneum. Application of oily materials can improve the skin hydration by reducing the evaporation of moisture from underlying tissues. Hydration increases the penetration of polar molecules more than nonpolar ones12 so it is possible that hydration of the lipid channels is more important than hydration of keratinised cells. It is possible to hydrate the lipids in the stratum corneum (despite their hydrophobic nature) because they contain a large fraction of surface-active 'polar lipids' which are surfactant-like in nature (for example, phospholipids), and the phase behaviour of these materials depends strongly on the hydration of their polar groups.
The stratum corneum can act as a reservoir for drugs, causing the pharmacological response to continue for a short time after the device has been removed. If the skin is then allowed to dry out, the drug will diffuse into underlying tissues more slowly, and application of an occlusive patch which rehydrates the skin can cause release of the drug at a later time.
The final barrier is the living portion of the epidermis and the dermis. Diffusion rates in these viable tissues are much higher than in the stratum corneum and consequently they offer little resistance to absorption. However, the tissues are much more hydrophilic than the stratum corneum, and so act as a barrier to extremely hydrophobic compounds which cannot partition into them. As a result transdermal absorption is optimal for compounds with intermediate polarity which can pass through both the stratum corneum and dermal tissues.
Advantages and disadvantages of transdermal delivery
Drugs applied transdermally avoid the chemically hostile gastrointestinal environment containing acid, food and enzymes. Consequently, this route is useful if there is gastrointestinal distress, disease, or surgery, and one of the first applications of this delivery method was for the treatment of travel sickness. The most attractive feature of transdermal delivery is that first-pass metabolism of the drug is avoided since the blood drains directly into the main venous return. Patient compliance is good since a single device can administer drug for several days, and so is not subject to the problems of multiple daily dosing with tablets. Transdermal devices are usually well accepted, although they can cause irritation to the skin, the degree of which depends both on the drug and the formulation. Finally, the devices have major pharmacokinetic benefits; they can provide a sustained plasma profile over several days, without severe dips occurring at night, and without the potential for dosedumping which can be a hazard with orally administered sustained release devices. Because the drug is delivered continuously, it can have a short biological half-life. Removal of the device causes the plasma levels to fall shortly thereafter, although some drugs can be stored in the hydrophobic regions of the skin and be released slowly into the blood.
There are however several disadvantages. Drugs may be metabolised by bacteria on the skin surface. Epithelial bacteria can in fact be more prevalent under a transdermal device, since the increased hydration and uniform temperature can encourage growth. Enzymatic activity in the epithelium may be different to that in the gastrointestinal tract, leading to unexpected routes of breakdown of drugs13. However, once the enzyme systems are understood they have the potential to activate pro-drugs to active species. It appears that it is possible to influence the metabolism of the drug in the skin by the use of host-guest inclusion complexes; thus for example the incorporation of PGE1 into a cyclodextrin complex reduced the rate of metabolism to other prostaglandins in the epidermis, leading to more efficient delivery14.
Maintaining contact between a drug delivery device and the skin can present problems. Application of the device occludes the skin, trapping water and sebum from the glands. This, together with the flexing of the skin, can lead to loss of contact and discomfort. The choice of adhesive is restricted since irritation must be minimised, and in early devices, for example those used for clonidine, the drug had to be transported through the adhesive. In many modern devices the adhesive is loaded with drug thus becoming an integral part of the sustained release device. Irritation is often attributed to acrylic adhesives15. Silicone-based adhesive disks are a good alternative in this case.
One of the primary functions of the skin is as a protective barrier to foreign agents, and hence it is not surprising that a complex relationship exists between the skin and the body's immune system. A number of cell types (e.g. Langerhans cells and keratinocytes of the epidermis, indeterminant cells, tissue macrophages, mast cells, neutrophilic granulocytes and vascular endothelial cells of the dermis) are directly involved with the immune system and the transdermal route can cause drug sensitization. If an individual becomes sensitized to drug which has been delivered transdermally, it may become impossible to administer that drug by any other route16.
Finally, transdermal technology is often uneconomical compared to the simple oral tablet, and so is only used where specific advantages are gained.
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