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`demanding conditions are met, transdennal therapy offers an excellent means of sustaining the
`action of a drug. Transdermal delivery also skirts frequently encountered oral delivery prob(cid:173)
`lems, such as first-pass metabolic inactivation and gastrointestinal upset. Transdermal therapy
`is actually an old medical strategy, as compresses and poultices have been used for centuries,
`although never with certainty of effect. The current, effective use of small adhesive patches to
`treat systemic disease or its symptoms has revolutionized the practice.
`
`A. Therapeutic Stratification of the Skin
`
`How does a person best organize his or her thinking relative to these different rationales? One
`can start by asking what the topical drug is supposed to do. Is it to be applied to suppress
`inflammation?-eradicate infectious cnicroorganisms?-provide protection from the sun?(cid:173)
`stop glandular secretions?-provide extended relief from visceral pain? Regardless of which
`feat tbe drug is to perform, the answer to the question directs us to where and sometimes how
`the drug must act to be effective or to a target for the drug. Once knowing the locus of action,
`one can then consider its accessibility. Clearly, if the drug cannot adequately access its target,
`little or no therapeutic benefit will be realized.
`Sundry drug targets exist on, within. or beneath the skin. These include (a) the skin surface
`itself (external target), (b) the stratum comeum, (c) any one of several levels of the live epi(cid:173)
`dermis, (d) the avascular, upper dermis. (e) any one of several deeper regions of the dermis,
`(f) one or another of the anatomically distinct domains of the pilosebaceous glands, (g) eccrine
`glands, (h) apocrine glands, (i) the local vasculature, and, following systemic absorption, (j)
`any of numerous internal tissues. As these targets become increasingly remote, delivery to
`them becomes sparser as the result distributional dilution and, consequently, adequacy of de(cid:173)
`livery becomes less certain. Moreover, the specific properties of these targets and their nego(cid:173)
`tiability are very much determined by the state of health of the skin. Disease and damage alter
`the barrier characteristics of the skin and, therefore, target accessibility itself.
`Causes of skin damage or eruptions are diverse and may alternatively be traced to mechan(cid:173)
`ical damage, irritant or allergic reactions. an underlying pathophysiological condition, or an
`infection. Depending on the problem, the entire skin, or only a small part of it, may be involved.
`Moreover, disease may be manifest in one part of a tissue as a consequence of a biochemical
`abnormality in another. For instance, the cardinal expression of psoriasis is its thickened, sil(cid:173)
`very, malformed stratum comeum (psoriatic scale), but the disease actually results from mav(cid:173)
`erick proliferation of keratinocytes in the germinal layer of the epidermis. Mankind suffers
`many skin problems, such as this. each unique in expression to the well-trained eye. The names
`of some common afflictions are listed in Table 6. with indication of the tissue source of the
`problems. Table 7 adds to the lexicon pathophysiological terms used to describe the expressions
`of disease. Irrespective of their fundamental tissue origins, most diseases fan out and involve
`other tissue components. Inflammation and skin eruption are common sequelae. The nature and
`developing pattern of a skin eruption become the determinants of its diagnosis. There are
`subtleties, and it often takes a dermatologist to make a proper differential diagnosis.
`The pharmacist will, from time to time, be called on to examine an eruption or condition
`and make recommendation for treatment. If, and only if, the condition is unmistakable in origin,
`delimited in area, and of modest intensity, should the pharmacist recommend an over-the(cid:173)
`counter (OTC) remedy for its symptomatic relief. Physicians neither need nor want to see
`inconsequential cuts, abrasions, or mosquito bites. nor unremarkable cases of chapped skin,
`sunburn, or poison ivy eruption, and so on. However, if infection is present and at all deep(cid:173)
`seated, or if expansive areas of the body are involved, otherwise minor problems can pose a
`
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`Table 6 Common Afflictions: Brief Outline of Common Dermatological Disorders and Other
`Common Skin Problems
`
`Skin problems
`
`Examples
`
`I. General involvements
`A. Physical damage
`1. Blunt instrument
`2. Sharp instrument
`3. Scraping. rubbing
`4. Heat
`5. Uluaviolet radiacion
`6. Insects
`B. Chemical damage
`1. Contact dermatitis
`2. Contact allergy
`3. Solvent extraction
`n. Abnormalities of the epidermis
`A. Stratum comeum
`1. Tardigrade sloughing and thickening
`2. Hyperdryness
`3. Hyperproliferative thickening, abnormal
`structural organization
`8 . Viable epidermis
`1. Cell damage and inflammation
`2. Fluid collection
`3. Abnormal cell growth (not division)
`4. Thickening of granular layer
`5. Hyperproliferation, incomplete keratinization
`6. Malignancy
`III. Abnormalities of the dermis and dermal-epidermal
`interface
`A. Melanocyte abnormalities
`l. Hyperfunction
`2. Hypofunction
`3. Abnormal growth
`4. Malignancy
`B. Dermal-epidermal interface
`1. Lifting of the epidermis
`2. Overgrowth of papillary layer
`C. Dermis
`l. Vascular reactions
`2. Abnormal growth of fibrinocyte
`3. Abnormal polymerization
`IV. Abnormalities of the glands (appendages)
`A. Hair follicle
`l. Hyperactivity
`2. Hypoactivity
`B. Sebaceous glands
`l. Hyperactivity
`2. Occlusion
`C. Eccrine sweat gland
`1. Hyperactivity
`2. Occlusion, inflammation
`V. Infectious diseases
`A. Bacterial
`B. Fungal
`C. V1Cal
`D. Protozoa!
`
`Source: Refs. 16 and 19.
`
`Contusion, bruise
`Cut, nick, animal bite
`Abrasion, blister
`Bums (1°, 2°, 3°), blister
`Sunburn
`Mosquito bite, bee sting, ticks, mites
`(chiggers), lice, crab lice
`Poison ivy, poison oak
`Cosmetic dermatitis
`" Dishpan hands''
`
`lchthyosis
`Chapping, windburn
`Psoriasis
`
`Eczema, general dermatitis
`Blister
`Keratosis
`Lichen planus
`Psoriasis
`Ep ithelioma
`
`Tanning, chloasma, freckles
`Vitiligo
`Mole
`Melanoma
`
`Dermatitis hypetiformis
`Warts
`
`Urticaria, hives
`Scar, keloid
`Scleroderma. lupus erythematosus
`
`Hirsutism
`Alopecia, baldness
`
`Seborrhea
`Acne. pimples
`
`Hyperhidrosis
`Miliaria (pricky heat, heat rash)
`
`Carbuncles (boils)
`Athlete's foot, ringworm
`Chickenpox, herpes simplex (cold sores)
`To pical amebiasis
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`Table 7 Pathophysiological Terms: Brief Definitions of Select PathophysiologicaJ Terms
`
`Tenn
`
`Acne
`
`Alopecia
`Bulla
`Chloasma
`
`Comedo (pl. comedones)
`Dermatitis
`Dermatitis herpetiformis
`
`Eczema
`
`Hirsutism
`lchthyosis
`
`Infiltration
`Keloid
`
`Keratosis
`Lichen planus
`
`Lupus erythematosus
`
`Miliaria
`
`Nodule
`Papilla
`Psoriasis
`
`Pustule
`Scleroderma
`
`Seborrhea
`Urticaria
`
`Vesicle
`Vitiligo
`
`Definition
`
`Inflammatory disease of the sebaceous glands characterized by
`papules. comedones, pustules. or a combination thereof
`Deficiency of hair
`Large blister or vesicle filled with serous fluid
`Cutaneous discoloration occurring in yellow-brown patches and
`spots
`Plug of dried sebum in the sebaceous duct; blackhead
`Inflammation of the skin
`Dermatitis marked by grouped erythematous, papular, vesicular,
`pustular, or bullous lesions occurring in varied combinations
`An inflammatory skin disease with vesiculation, infiltration,
`watery discharge, and the development of scales and crusts
`Abnormal, heavy hairiness
`A disease characterized by dryness. roughness, and scaliness of
`the skin caused by hypertrophy of the stratum comeum
`An accumulation in a tissue of a foreign substance
`Growth of the skin consisting of whitish ridges, nodules, and
`plates of dense tissue
`Any horny growth
`Inflammatory skin disease with wide, flat papules occurring in
`circumscribed patches
`A superficial inflammation of the skin marked by disklike
`patches: with raised reddish edges and depressed centers.
`covered with scales or crusts
`An acute inflammation of the sweat glands, characterized by
`patches of small red papules and vesicles, brought on by
`excessive sweating
`Small node that is solid to the touch
`Small, nipple-shaped elevation
`A skin disease characterized by the formation of scaly red
`patches, particularly on the extensor surfaces of the body
`(elbows, knees)
`Small elevation of the skin filled with pus
`A disease of the skin in which thickened, hard, rigid, and
`pigmented patches occur with thickening of the dermal
`connective tissue layer
`A disease of the sebaceous glands marked by excessive discharge
`Condition characterized by the appearance of smooth. slightly
`elevated patches, whiter than the surrounding skin
`Small sac containing fluid; a small blister
`A skin disease characterized by the fonnation of light-colored
`(pigment-free) patches
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`serious threat, and physician referral is mandatory. Patients should also be directed to counsel
`with a physician whenever the origins of a skin problem are in question.
`a. Surface Effects
`Of the many possible aforementioned dermatological targets, the skin surface is clearly the
`easiest to access. Surface treatment begins at the fringe of cosmetic practice. Special cosmetics
`are available to bide unsightly blemishes and birthmarks. These lessen self-consciousness and
`are psychologically uplifting. Applying a protective layer over the skin is sometimes desirable.
`For example, zinc oxide pastes are used to create a barrier between an infant and its diaper
`which adsorbs irritants found in urine, ameliorating diaper rash. These same pastes literally
`block out the sun and, at the same time, hold in moisture, protecting the ski enthusiast from
`facial sun and wind burns on the high slopes. Transparent films containing ultraviolet light(cid:173)
`absorbing chemicals are also used as sunscreens. Lip balms and like products lay down occlu(cid:173)
`sive (water-impermeable) films over the skin, preventing dehydration of the underlying stratum
`corneum and, thereby. allaying dry skin and chapping. The actions of calamine lotion and other
`products of the kind are limited to the skin' s surface. The suspended matter in these purportedly
`binds urushiol. the bapten (allergen) found in poison ivy and oak. However, these may best
`benefit the patient by drying up secretions, relieving itchiness. In all these instances for which
`the film itself is therapeutic, bioavailability bas little meaning.
`Bioavailability does matter with topical antiseptics and antibiotics, even though these also
`act mainly at the skin's surface. These anti-infectives are meant to stifle the growth of surface
`microflora; thus, formulations that penetrate into the cracks and fissures of the skin where the
`microorganisms reside are desirable. The extent to which the surface is sanitized then depends
`on uptake of the anti-infective by the microbes themselves. Slipshod formulation can result in
`a drug being entrapped in its film and inactivated. For instance, little to no activity is to be
`expected when a drug is placed in a vehicle in which it is highly insoluble. Ointment bases
`that contain salts of neomycin. polymyxin, and bacitracin are suspect here, in that hydrocarbon
`vehicles are extremely poor solvents for such drugs. Inunction (rubbing in) may release such
`drugs, but the pharmacist should seek evidence that such formulations are effective before
`recommending them.
`Deodorants are also targeted to the skin surface to keep microbial growth in check. Here
`they slow or prevent rancidification of the secretions of apocrine glands found in and around
`the axillae (armpits) and the anogenital regions. Medicated soaps also belong in this family.
`
`C. Stratum Comeum Effects
`The stratum corneum is the most easily accessed part of the skin itself, and there are two
`actions targeted to this tissue: namely, emoUiency, the softening of the horny tissue, which
`comes about through remoisturizing it; and keratolysis, the chemical digestion and removal of
`thickened or scaly horny tissue. Tissue needing such removal is found in calluses, corns, and
`psoriasis, and as dandruff. Common agents such as salicylic acid and, to a lesser extent, sulfur,
`cause lysis of the sulfbydral linkages holding the keratin of the horny structure together, leading
`to its disintegration and sloughing.
`It has been mentioned that elasticity of the stratum comeum depends on its formation and
`on the presence of adequate natural lipids, hygroscopic substances, and moisture (19,20). Re(cid:173)
`moisturization (emolliency) can be induced by simply occluding the surface and blocking
`insensible perspiration. However, it is best accomplished by lotions, creams, or waxy formu(cid:173)
`lations, or combinations thereof (e.g., lip balms) that replenish lost lipid constituents of the
`stratum comeum. The fatty acids and fatty acid esters these contain partly fill the microscopic
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`cracks and crevices in the horny layer, sealing it off, stabilizing its bilayer structures, and
`allowing it to retain moisture. Many emollient products also contain hygroscopic glycols and
`polyols to replenish and augment natural moisturizing factors of this kind, also assisting the
`stratum comeum in retaining moisture.
`The introduction of moisturizing substances into the stratum comeum is ordinarily a straight(cid:173)
`forward process. Deposition of keratolytics, on the other hand, is not as easily achieved, as
`these agents must penetrate into the horny mass itself. Some salicylic acid-containing corn
`removers, therefore, are made up as concentrated nonaqueous solutions in volatile solvents. As
`these volatile solvents evaporate, drug is concentrated in the remaining vehicle and, thereby,
`thermodynamically driven into the tissue. These many examples illustrate that when the ther(cid:173)
`apeutic target is at the skin's surface or is the stratum corneum, the therapeutic rationale behind
`the treatment usually involves enhancing or repairing or otherwise-modulating barrier functions
`(see Table 5).
`
`o. Drug Actions on the Skin's Glands
`A few products moderate operation of the skin's appendages. These include antiperspirants (as
`opposed to deodorants), which use the astringency of chemicals such as aluminum chloride to
`reversibly irritate and close the orifice of eccrine glands [21), impeding the flow of sweat.
`Astringents also decimate the population of surface microbes. explaining their presence in
`deodorants. The distinction between antiperspirants and deodorants is legally significant, as
`antiperspirants after a body function and are regulated as drugs, whereas deodorants are clas(cid:173)
`sified as cosmetics. Thus, measurably reduced sweating has to be scientifically proved before
`it can be claimed for a product. Nevertheless, given the similarities in the compositions of
`deodorants and antiperspirants. they are likely functionally equivalent. Since eccrine glands are
`mediated by cholinergic nerves. sweating also can be shut off by anticholinergic drugs admin(cid:173)
`istered systematically (22) or topically. However, such drugs are too toxic for routine use as
`antiperspirants even when administered topically.
`Acne is a common glandular problem arising from hyperproliferative closure of individual
`glands in the unique set of pilosebaceous glands located in and around the face .and across the
`upper back. Irritation of cells lining the ducts of such glands initiates the formation of a lesions.
`Sheets of sloughed, sebum-soaked, keralinized cells that grow out from the walls surrounding
`the sebaceous duct are what clog the duct. Still-forming sebum is then trapped behind the
`obstruction. oftentimes bulging out the skin and giving rise to an observable lesion (papule).
`This may become infected and fill with a purulent exudate (pustule) or, after infection has set
`in. it may internally rupture and thereby begin the processes that lead to ulceration and scarring.
`Alternatively, the buildup of concentric sheets of sloughed cells may widen the glandular
`opening, with melanin in the widening plug darkening to the point of being black (blackhead).
`Soap and water is considered a therapeutic treatment in acne when it is used to unblock the
`pores. Sebum is emulsified, and it and other debris is removed. Alcoholic solvents, often
`packaged as moistened pledgets, are used for the same purpose. With either treatment care
`must be exercised not to dry out and further irritate the skin. Both loca! and systemic antibiotics
`and antiseptics suppress the formation of lesions. It is believed these attenuate the population
`of anerobic microorganisms that are deep-seated in the gland, the metabolic by-products of
`which irritate the lining of the gland, setting off lesion formation. Mild cases of acne improve
`and clear under the influence of astringents, possibly for the same reason. Retinoids, oral and
`topical, reset the processes of epidermal proliferation and differentiation. Through such dra(cid:173)
`matic influences on cell growth patterns, they actually prevent the formation of lesions. How-
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`ever, because of concerns over toxicity, they tend to be used only in the most severe cases of
`acne and thus are prescribed for those patients whose acne lesions progress to cysts.
`Hair is a product of the pilosebaceous appa.ratus and in this sense is glandular. It often grows
`out visibly in places where such display is unwanted. It may be shaved, but chemical hair
`removers (depilatories) along with other products are also used to remove it. In the main, the
`use of depilatories is cosmetic, rather than therapeutic. However, depilatories may be prescribed
`in hirsutism, when the existence of coarse, dark facial hair is psychologically distressing to the
`female patient for whom shaving is an anathema. Hair, like the stratum comeurn is composed
`of layers of dead, keratinized cells. However, its keratin is more susceptible to the action of
`keratolytics because it is structured in ways that make it more chemically pervious. Tbiogly(cid:173)
`colate-containing, highly alkaline creams generally dissolve hair in short order, without doing
`great harm to surrounding tissues. Facial skin is delicate, however, and depilatories must be
`used carefully here.
`
`E. Effects in Deep Tissues
`
`Local, Regional, and Systemic Delivery
`When the target of therapy lies beneath the stratum comeum, topical drug delivery is more
`difficult and becomes more uncertain. Therefore, many potentially useful drugs find no place
`in topical therapy owing to their inability to adequately penetrate the skin. Nevertheless, a
`number of pathophysiological states can be controlled through local administration and sub(cid:173)
`sequent percutaneous absorption. For example, most skin conditions are accompanied by in(cid:173)
`flammation of the skin; topical corticosteroids and nonsteroidal anti-inflammatory drugs alike
`are used to provide symptomatic relief in such instances. Corticosteroids are also used in
`psoriasis for which, in addition to suppressing inflammation, they somehow act on the basal
`epidermal layer to slow proliferation and restore the skin's normal tum9ver rhythm (23). Pain
`originating in the skin can be arrested with locally applied anesthetics. Over-the-counter ben(cid:173)
`zocaine and related prescription drugs are used for this purpose. Hydroquinone is applied to
`the skin to lighten excessively pigmented skin by oxidizing melanin deep within the surface.
`Another treatment that involves percutaneous absorption is the application of fluorouracil (5-
`FU) for the selective eradication of premalignant and basal eel] carcinomas of the skin (22).
`In all of these examples, the key to success is the ability we have to get therapeutic amounts
`of the drugs through the stratum corneum and into the viable tissues.
`Systemic actions of some drugs can also be achieved by local application, in which case,
`their delivery is known as transdermal delivery. The application of warmed, soft masses of
`medicated bread meals and clays over wounds or aching pa.rts of the body dates to antiquity.
`However, few such plasters and poultices (cataplasms) have survived into modern medicine.
`When analytical developments just past the middle of the twentieth century made it possible
`to measure the exceedingly low circulating levels of drugs that build up in the body during
`the course of therapy, resea.rch was begun on ways drugs might be delivered to lower their
`risks and extend their durations of action. Novel delivery systems involving nontraditional
`routes of administration were subsequently conceived, constructed, and put to test. Transdermal
`delivery with adhesive patches evolved as one of the innovations.
`The possibilities for transdermal delivery might have been seen long ago in the systemic
`toxicities of certain topically contacted chemicals. As long as a century ago it was known _that
`munitions workers who handle nitroglycerine suffered severe headaches and ringing in the ears
`(tinnitus). These same effects are experienced to a degree by those taking nitroglycerin to
`alleviate angina. The association between therapy and the inadvertent percutaneous absorption
`of nitroglycerin was finally made in the 1970s and a nitroglycerin ointment was introduced,
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`producing peak blood levels comparable with those attained on sublingual administration of
`traditional tablet triturates. but levels that were also sustained. Since the permeability of human
`skin is highly variable and patient needs themselves vary, patients using nitroglycerin ointments
`were (and are) instructed to gradually lengthen the ribbon of ointment expressed from the tube
`and rubbed into the skin until tinnitus and headache are experienced, and then back off on the
`dosage. The lastingness of the effects of nitroglycerin administered in this fashion freed patients
`from a fear of wakening in the middle of the night with a heart attack (angina). Consequently,
`nitroglycerin ointments became the first commercially successful, therapeutically proved trans(cid:173)
`dermal delivery systems. But ointments are greasy and, as with all semisolids, suffer variability
`in their dosing, even with dose titration, given that different patients apply semisolids more or
`less thinly and, therefore, over more or less area.
`Since about 1980, sophisticated adhesive patches for transdermal delivery of scopolamine
`(motion sickness), nitroglycerin (anginal symptoms), clonidine (regulation of blood pressure),
`13-estradiol (menopausal symptoms), and fentanyl (cancer pain) have been introduced into med(cid:173)
`icine (24- 26]. These patches are affixed to an appropriate body location and deliver drug
`continuously for periods ranging from a day (nitroglycerin) to a week (clonidine). To achieve
`such long periods of delivery, the patches contain reservoirs of their respective drugs. In one
`early type of system, nitroglycerin was formulated into a liquid-filled sponge held in direct
`contact with the skin by an adhesive band around the periphery of the patch. In more recent
`patch designs a membrane is placed over the delivery surface of the patch. Adhesive covering
`this membrane anchors the patch to the skin over the entire contact area of the patch. This
`interfacing membrane can be turned into a rate-controlling membrane to regulate delivery and
`prevent dose dumping, should the patch be inadvertently placed over a site of inordinately high
`permeability. Actually, this rate-controlling concept was used in the design of the first patch,
`the scopolamine transdermal system. The development of transdermal patches for yet other
`drugs is an active research area.
`It is obvious from the foregoing 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 suffi(cid:173)
`ciency 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 oc-currence, except when massive areas
`of application are involved. 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 by
`the local vasculature. Indeed, the levels of drug reached in deep local tissues have proved to
`be only a few multiples higher than those obtained after 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 variability in skin permeability
`between patients, which may be as much as tenfold. 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(cid:173)
`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, pre(cid:173)
`mature neonates have inordinately permeable skins. The incubators used to sustain such infants
`provide a humidified environment- which abates insensible perspiration- and a warm one,
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`conditions that not only make the baby comfortable, but that 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 much in permeability. However, there are established
`differences in the barrier properties of skin across the races of man. Although the horny layers
`of whites and blacks are of equal thickness, the latter 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, there(cid:173)
`fore, are placed over applications on occasion to seal off water loss, hydrate the horny layer,
`and increase drug penetration. In the absence of such intervention. the· state of dryness of the
`stratum corneum is determined by the prevailing humidity, explaining why the condition " dry
`skin' ' is exacerbated in the winter mon~hs in northern climates.
`Temperature influences skin permeability in both physical and physiological ways. For in(cid:173)
`stance, activation energies for diffusion of small nonelectrolytes across the stratum corneum
`lie between 8 and 15 kcal/mot (4,32). Thus thermal activation alone can double the rate of
`skin permeability when there is 10° change in the surface temperature of the skin (33J. Ad(cid:173)
`ditionally, 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. No clear-cut evidence exists that this is so, however, which
`seems to teach us that even the reduced blood flow of chilled skin is adequate to efficiently
`clear compounds from the underside of the epidermis.
`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(cid:173)
`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 1 or 2 days, 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 permea(cid:173)
`bility 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. Although . the
`stratum corneum may appear normal following such damage, the skin may be only marginally
`less permeable than denuded tissue (35). Furthermore, permeability remains high during the
`full duration of wound repair and until a competent stratum comeum is laid down over the
`injured surface. Other chemicals are deliberately added to formulations to raise the permeability
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`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, although fully capable of deep tissue destruction in seconds, leave the structure
`of the stratum comeum itself relatively unscathed. Burn wounds of this kind remain imper(cid:173)
`meable until tissue repair and restructuring processes get under way and the necrotic tissue
`with its horny capping is sloughed. The differences in permeability state of burned skin im(cid:173)
`mediately follow ing the trauma can be highly consequential in terms of drug delivery. In the
`instance of deep bu.ens obtained at lower than keratin-denaturing temperatures, topical delivery
`of antibiotics and antiseptics into a wound, as may be necessary to control wound sepsis,
`remains difficult for as long as the stratum comeum over the wound slays in place, and ag(cid:173)
`gressive use of antiseptics is warranted. ln the other extreme, there is risk of toxic systemic
`accumulation of the antiseptics and antibiotics, particularly in major bums covering 20% or
`more of the body surface area. Conservative treatment is warranted. Since burns are rarely well
`characterized relative to their permeability dimension, attending physicians and pharmacists
`need to monitor antiseptic usages carefully to control wound sepsis without poisoning the
`patient. Finally, if not surgically debrided, the necrotic tissue is eventually walled off. enzy(cid:173)
`matically digested, loosened. and sloughed, producing a denuded, open. granulating surface.
`Small full-thickness wounds are cl