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of blood pressure), P-estradiol (menopausal symptoms), fentanyl (cancer pain), nicotine (smoking cessation), testosterone (hypogonadism), and others have been introduced into medicine since about 1980 (24-26). These patches, affixed to an appropriate body location, deliver drug continuously for periods ranging from about half a day (nitroglycerine) to a week (clonidine, P-estradiol). It is obvious from the above that the skin is a formidable barrier irrespective of whether therapy is to be local, regional, or systemic, and the first concern in topical delivery is sufficiency of delivery. With local therapy, the aim is to get enough drug into the living epidermis or its surroundings to effect a pharmacological action there without producing a systemically significant load of the drug. The latter is actually a rare occurrence except when massive areas of application are involved (overdose of methyl salicylate). Regional therapy involves effects in musculature and joints deep beneath the site of application. To be successful, this requires a greater delivery rate because an enormous fraction of the drug that passes through the epidermis is routed systemically via the local vasculature. Indeed, the levels of drug reached in deep local tissues have proven to be only a few multiples higher than those obtained upon systemic administration of the drug (27). Even more drug has to be delivered per unit area to transdermally effectuate a systemic action.

Factors Affecting Functioning of the Skin Barrier

A matter of considerable consequence in topical delivery is the variability in skin permeability between patients, which may be as much as 10-fold. This, however, has more to do with some patients having unusually impermeable skin rather than the reverse. Literature data suggest that the most permeable human skins are only twice the average in comparative studies, while the least permeable skins are fivefold below the average. The underlying sources of this high degree of variability are thought to be many and diverse. Humans differ in age, gender, race, and health, all of which are alleged to influence barrier function. Yet, insofar as can be told, a full-term baby is born with a barrier-competent skin and, barring damage or disease, the skin remains so through life. There is little convincing evidence that senile skin, which tends to be dry, irritable, and poorly vascularized, is actually barrier compromised (28). However, premature neonates have inordinately permeable skins. The incubators used to sustain such infants provide a humidified environment, which abates insensible perspiration, and a warm one, conditions that not only make the baby comfortable but also forestall potentially lethal dehydration and hypothermia (29).

Gender too affects the appearance of human skin. Nevertheless, there is little evidence that the skins of male and female differ greatly in permeability. However, there are established differences in the barrier properties of skin across the races of humans. While the horny layers of Caucasians and Blacks are of equal thickness, the latter population has more cell layers and is measurably denser (30). As a consequence, black skin tends to be severalfold less permeable (30,31).

Humidity and temperature also affect permeability. It has long been known that skin hydration, however brought about, increases skin permeability. Occlusive wrappings are therefore placed over applications on occasion to seal off water loss, hydrate the horny layer, and increase drug penetration. Temperature influences skin permeability in both physical and physiological ways. For instance, activation energies for diffusion of small nonelectrolytes across the stratum corneum have been shown to lie between 8 and 15 kcal/ mole (3,32). Thus, thermal activation alone can double the rate of skin permeability when there is a 10°C change in the surface temperature of the skin (33). Additionally, blood perfusion through the skin in terms of amount and closeness of approach to the skin's surface is regulated by its temperature and also by an individual's need to maintain the body's 37°C isothermal state. Since clearance of percutaneously absorbed drug to the systemic circulation is sensitive to blood flow, a fluctuation in blood flow might be expected to alter the uptake of chemicals. Above all else, the health of the skin establishes its physical and physiological condition and thus its permeability. Consequences attributable to an unhealthy condition of skin can be subtle or exaggerated. Broken skin represents a high permeability state, and polar solutes are several log orders more permeable when administered over abrasions and cuts. Irritation and mild trauma tend to increase the skin's permeability even when the skin is not broken, but such augmentation is far less substantial. Sunburn can be used to illustrate many of the barrier-altering events that occur in traumatized skin. Vasodilation of the papillary vasculature with marked reddening of the skin is among the first signs that a solar exposure has been overdone. In its inflamed state, the skin becomes warm to the touch. After a day or two, epidermal repair begins in earnest and the tissue is hyperproliferatively rebuilt in its entirety. It doubles in thickness, and a new stratum corneum is quickly laid down (34). Because the newly formed stratum corneum's anchorage to existing tissues is faulty, the preexisting horny layer often eventually peels. Of more importance, hyperplastic repair leads to a poorly formed horny structure of increased permeability to water (as measured by transepidermal water loss) and presumably other substances. Given these events surrounding irritation, since many chemicals found in the workplace and home are mildly irritating, including the soaps we use to bathe and the detergents we use to clean house and clothes, is it really a wonder that the permeability of human skin is so demonstrably variable?

Some chemicals have prompt, destructive effects on the skin barrier. Saturated aqueous phenol, corrosive acids, and strong alkali instantly denature the stratum corneum and destroy its functionality even as their corrosive actions stifle the living cells beneath. Though the stratum corneum may appear normal following such damage, the skin may be only marginally less permeable than denuded tissue (35). Other chemicals are deliberately added to formulations to raise the permeability of skin and improve drug delivery. For obvious reasons, these are referred to as skin penetration enhancers. More will be said of these later.

Thermal burning produces comparably high states of permeability immediately following burning, providing that the surface temperature of the skin is raised above 80°C, a temperature on the lower side of temperatures able to denature keratin (36). However, burning temperatures below 75°C, though fully capable of deep tissue destruction in seconds, leave the structure of the stratum corneum itself relatively unscathed. Burn wounds of this kind remain impermeable until tissue repair and restructuring processes get under way and the necrotic tissue with its horny capping is sloughed. In the later stage, all such wounds remain highly permeable until covered over again with a healthy, fully differentiated epidermis.

As with burns, physical disruption of the stratum corneum opens the skin in proportion to the extent of damage. Cuts and abrasions are associated with high permeability at and around such injuries. Eruption of the skin in disease has a similar effect to the extent that the stratum corneum's integrity is lost. The skin over eczematous lesions should be regarded as highly permeable. Not all skin diseases raise permeability, however. The states of permeability of ichthyosiform, psoriatic, and lichenified skin have not been well characterized, but in all likelihood are low for most drugs. It has been proven difficult to get potent corticosteroids through psoriatic plaque, for instance, and occlusive wrapping is often called for.

Percutaneous Absorption—The Process

The process of percutaneous absorption can be described as follows. When a drug system is applied topically, the drug diffuses passively out of its carrier or vehicle and, depending on where the molecules are placed down, partitions into either the stratum corneum or the sebum-filled ducts of the pilosebaceous glands. Inward diffusive movement continues from these locations to the viable epidermal and dermal points of entry. In this way, a concentration gradient is established across the skin up to the outer reaches of the skin's microcirculation where the drug is swept away by the capillary flow and rapidly distributed throughout the body. The volume of the epidermis and dermis beneath a 100-cm2 area of application, roughly the size of the back of the hand, is approximately 2 cm3. The total aqueous volume of a 75 kg (« 165 lb) person is about 50,000 cm3, yielding a systemic-to-local dilution factor well in excess of 10,000. Consequently, systemic drug levels are usually low and inconsequential. Thus, selectively high epidermal concentrations of some drugs can be obtained. However, if massive areas of the body 20% of the body surface) are covered with a topical therapeutic, systemic accumulation can be appreciable. For instance, corticosteroids have produced serious systemic toxicities on occasion when they have been applied over large areas of the body (37). Moreover, as has already been pointed out, if the stratum corneum is not intact, many chemicals can gain systemic entrance at alarming rates. Together these factors may place a patient at grave risk and should always be taken into account when topical drugs are put in use. The pharmacist should therefore carefully measure how topical systems are to be applied and be on alert for untoward systemic responses when body coverages are unavoidably extensive.

The events governing percutaneous absorption following application of a drug in a thin vehicle film are illustrated in Figure 2. The important processes of dissolution and

Figure 2 Events governing percutaneous absorption.

diffusion within the vehicle are cataloged. These will be discussed later. Two principal absorption routes are indicated in the sketch: (i) the transepidermal route, which involves diffusion directly across the stratum corneum, and (if) the transfollicular route, where diffusion is through the follicular pore. Much has been written concerning the relative importance of these two pathways. Claims that one or the other of the routes is the sole absorption pathway are groundless, since percutaneous absorption is a spontaneous, passive diffusional process that takes the path of least resistance. Therefore, depending on the drug in question and the condition of the skin, either or both routes can be important. There are temporal dependencies to the relative importance of the routes too. Corticosteroids breach the stratum corneum so slowly that clinical responses to them, which are prompt, are reasoned to be due to follicular diffusion (3).

Sight should not be lost of the fact that the chemical barrier of the skin actually consists of all skin tissues between the surface and the systemic entry point. While it is true that the stratum corneum is a source of high diffusional resistance to most compounds and thus the skin's foremost barrier layer, exceptional situations exist where it is not the only or even the major resistance to be encountered. For example, extremely hydrophobic chemicals have as much or more trouble passing across the viable tissues lying immediately beneath the stratum corneum and above the circulatory bed, because such drugs have little capacity to partition into these tissues. Backing for the latter assertion comes from extensive clinical experience as well as from physical modeling of percutaneous absorption. Consider that ointments can be used safely over open wounds for their hydrocarbon constituents are not transported significantly across even denuded skin. Similarly, the whole skin is considerably more impermeable to octanol and higher alkanols than is the stratum corneum alone because of the presence of the viable tissue layer beneath.

Model of the Skin Barrier

The percutaneous absorption picture can be qualitatively clarified by considering Figure 3, where the schematic skin cross-section is placed side by side with a simple model for

Figure 3 Skin cross-section beside a simple model.

percutaneous absorption patterned after an electrical circuit. In the case of absorption across a membrane, the current or flux is in terms of matter or molecules rather than electrons, and the driving force is a concentration gradient (technically, a chemical potential gradient) rather than a voltage drop (38). Each layer of a membrane acts as a diffusional resistor. The resistance of a layer is proportional to its thickness (symbol = h), inversely proportional to the diffusive mobility of a substance within it as reflected in a diffusion coefficient (D), inversely proportional to the capacity of the layer to solubilize the substance relative to all other layers as expressed in a partition coefficient (K), and inversely proportional to the fractional area of the membrane occupied by the diffusion route (/) if there is more than one route in operation (39). In general, an individual resistance in a set may be represented by

1 fiDJCi (fractional area) (diffusion coefficient) (partition coefficient)

The overall phenomenon of percutaneous absorption is describable upon recognizing that the resistances of phases in series (phases encountered serially) are additive and that diffusional currents (fluxes) through routes in parallel (differing routes through a given phase) are additive. Such considerations applied to skin allow one to explain, in semiquantitative terms, why percutaneous absorption through intact skin is slow for most chemicals and drugs and why disruption of the horny covering of the skin profoundly increases permeability of the ordinary run of solutes.

At the steady state and under sink conditions, the following equation describes that drug transport through the skin is primarily by parallel transepidermal (stratum corneum is the primary barrier) and follicular pathways:

where /total is the total flux and /sebum and /sc are fluxes through independent pathways (sebum/hair follicles and stratum corneum). A is the total area of application, P is the permeability coefficient, and C is the concentration of drug in the application. It follows that j ( A ^sebum^sebum C\ f D^K^C} . .

In these equations, /4sebum and Asc are the actual areas of the sebum and stratum corneum routes. Dsebum and Dsc are the effective diffusion coefficients (composite diffusion coefficients for heterogeneous phases) for the drug in question through sebum and the stratum corneum, while ifsebum and Ksc are the drug's partition coefficients in sebum/ water and stratum corneum/water, respectively. The terms, hsebum and hsc, refer to the functional thicknesses of the sebum and stratum corneum, respectively.

First, consider the transepidermal route. The fractional area of this route is virtually 1.0, meaning the route constitutes the bulk of the area available for transport. Molecules passing through this route encounter the stratum corneum and then the viable tissues located above the capillary bed. As a practical matter, the total stratum corneum is considered a singular diffusional resistance. Because the histologically definable layers of the viable tissues are also physicochemically indistinct, the set of strata represented by viable epidermis and dermis is handled comparably and treated as a second diffusional resistance in series.

Estimated diffusion coefficients in the stratum corneum are up to 10,000 times smaller than that found anywhere else in the skin, reflecting in part the considerable density of this tissue. If diffusion is almost exclusively through the intercellular lipid regime within the horny tissue, as most experts believe, then the estimates, which range between 1 x 10"13 cm2/sec and a low of 1 x 10~9 cm2/sec, have to be tempered with the knowledge that path tortuosity (nonlinearity) and excluded volume were not taken into account in calculating these values. Regardless, such low values still speak to the high resistance of the horny tissue (3), particularly given that the thickness of the stratum corneum is only about 1 x 10~3 cm (10 |im). The parameter exhibiting the most variability relative to the stratum corneum's diffusion resistance is the partition coefficient, Ksc, where the subscript sc denotes this specific tissue. The partition coefficient can take values several log orders less than 1 with highly polar molecules, for example, glucose, or values several log orders greater than 1 for hydrophobic molecules, for example, P-estradiol. The wedge of living tissue lying between the stratum corneum and the capillaries is on the order of 100 |im thick (1 x 10~2 cm). Permeation of this element of the barrier is facile and without great molecular selectivity. Where measured, diffusion coefficients through this cellular mass have proven to be no less than one-tenth of the magnitude of those found for the same compounds passing through water (40).

The follicular route can be analyzed similarly. The fractional area available for penetration by this route is on the order of one-one-thousandth (3), clearly a restricting factor. Here, partitioning is into sebum, and the distance that has to be traveled through sebaceous medium filling the follicular duct can be estimated as 200 to 500 |im, which is much greater than the thickness of the stratum corneum (41). Diffusion coefficients in the quasi-liquid sebum can be reasoned to be more than thousand times greater than found for the stratum corneum, however (3,9,42).

Net chemical penetration of the skin is simply the sum of the accumulations by each of the mentioned routes and by other routes, for instance, eccrine glands, where these contribute. The latter tiny glands are ubiquitously distributed over the body but are generally discounted in importance because of the limited fractional area they occupy and their unfavorable physiological states, either empty or profusely sweating.

For reasons that need not be elaborated here, water is invariably the solvent medium used to experimentally access permeability coefficients. Accordingly, water is assumed to be the vehicle used to apply a drug to the skin. This choice of vehicle effectively sets the partition coefficients between the aqueous tissues and the vehicle roughly to unity. Choosing water as the vehicle of consideration does not in any way invalidate insights that can be drawn from the model as long as saturated solutions, which operate at the thermodynamic activity of the solid drug, are brought into the analysis. Barring specific solvent-induced changes in the physical chemistry of the tissue, from the thermodynamic perspective, all saturated solutions should deliver drug at the maximal rate. Some parameter estimates are given in Table 5. The listed fractional areas, diffusion coefficients, and strata thicknesses reported in the table are based on the best information that is available.

Some scientists, including the authors, believe that the stratum corneum harbors a minor polar (aqueous pore) pathway,a mostly because of evidence that suggests that the stratum corneum offers higher fluxes to polar solutes the likes of methanol, ethanol, propylene glycol, glycerol, and glucose than one would otherwise expect. In this regard, it is also relevant that ions diffuse through the stratum corneum with deceptive ease considering their solution attributes. Sebum is generally taken to be an oily composite, which consists of wax esters, triglycerides, squalene, cholesterol/cholesteryl esters, and fatty acids. If the latter portrayal were apt, then sebum would have a thermodynamically limited ability to dissolve polar compounds. On these admittedly flimsy grounds, an argument can be mounted that the transepidermal route dominates the transfollicular route with respect to the permeation of small, polar nonelectrolytes and ions (3,7,9,42,43).

This supposition is hotly debated in scientific circles.

Table 5 Representative Parameters to Probe Model

Diffusion coefficient, D (cm2/sec)a (4,8)

Table 5 Representative Parameters to Probe Model

Diffusion coefficient, D (cm2/sec)a (4,8)

Stratum corneum

10"9-10"13

Water

«10-9

n-Alkanols (hydrated tissue)

«10-9

n-Alkanols(dry tissue)

«10-10

Small nonelectrolytes

10"9-10-10

Progesterone

«10"11

Cortisone

«10-12

Hydrocortisone

«10-13

Follicular pore (sebum)

10"7-10"9

Viable tissue

«10-6

Tissue thickness, h (|xm) (2,7,10)

Stratum corneum

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