`reference
`
`from the room.
`
`For Not to be taken
`~~ reference
`
`from the room.
`
`1
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`AMN1028
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`·-------
`
`The Property ot
`Sterne, Kessler, Goldstein & Fox, P.L.L.C.
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`21 ST EDITION
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`Remington
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`The Science and Practice
`of Pharmacy
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`2 3 4 56 7 8 9 10
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`-
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`- --.....,
`
`3
`
`
`
`Medkated Topicals
`Lawrence H Block, PhD
`
`CHAPTER 44
`
`I
`
`The application of medicinal substances to the skin or various
`body orifices is a concept as old as humanity. The papyrus
`records of ancient Egypt describe a variety of these medications
`for external use. Galen described the use in Roman times of a
`forerunner to today's vanishing creams.
`Medications are applied in a variety of forms reflecting the
`ingenuity and scientific imagination of pharmacists through
`the centuries. New modes of drug delivery have been developed
`to remedy the shortcomings of earlier vehicles or, more re(cid:173)
`cently, to optimize drug delivery. Conversely, some external
`
`medications have fallen into disuse because of changes in the
`practice of medicine.
`Medications are applied to the skin or inserted into body
`orifices in liquid, semisolid, or solid form . Ophthalmics
`and topical aerosol products will not be discussed in this chap(cid:173)
`ter. Ophthalmic use imposes particle size, viscosity, and steril(cid:173)
`ity specifications that require separate, detailed discus(cid:173)
`sion (see Chapter 43). The complexity of pharmaceutical
`aerosol systems necessitates their inclusion elsewhere (see
`Chapter 50).
`
`~
`(<:_..
`
`- BIGPHARMAEiEUTIC ASPECTS·Of.THE ROUTES OF ADMINISTRATION
`'
`.
`· .. :.
`'
`.
`
`EPIDERMAL AND TRANSDERMAL
`DRUG DELIVERY
`The Skin
`The skin often has been referred to as the largest of the body or(cid:173)
`gans: an average adult's skin has a surface area of about 2m2
`.
`It is probably the heaviest organ of the body. Its accessibility
`and the opportunity it affords to maintain applied preparations
`intact for a prolonged time have resulted in its increasing use
`as a route of drug administration, whether for local, regional, or
`systemic effects.
`Anatomically, human skin may be described as a stratified
`organ with three distinct tissue layers: the epidermis, the der(cid:173)
`mis, and the subcutaneous fat layer (Fig 44-1).
`Epidermis, the outermost skin layer, comprises stratified
`squamous epithelial cells. Keratinized, flattened remnants of
`these actively dividing epidermal cells accumulate at the skin
`surface as a relatively thin region (about 10 f.Lm thick) termed
`the stratum corneum, or horny layer. The horny layer is itself
`lamellar with the keratinized-cells overlapping one another,
`linked by intercellular bridges and compressed into about 15
`layers. The lipid-rich intercellular space in the stratum
`corneum comprises lamellar matrices with alternating hy(cid:173)
`drophilic layers and lipophilic bilayers formed during the pro(cid:173)
`cess of keratinization. The region behaves as a tough but flexi(cid:173)
`ble coherent membrane.
`The stratum corneum also is markedly hygroscopic-far
`more so than other keratinous materials such as hair or nails.
`Immersed in water the isolated stratum corneum swells to
`about three times its original thickness, absorbing about four to
`five times its weight in water in the process. The stratum
`corneum functions as a protective physical and chemical bar(cid:173)
`rier and is only slightly permeable to water. It retards water
`
`loss from underlying tissues, minimizes ultraviolet light pene(cid:173)
`tration, and limits the entrance of microorganisms, medica(cid:173)
`tions, and toxic substances from without. The stratum corneum
`is abraded continuously. Thus, it tends to be thicker in regions
`more subject to abrasion or the bearing of weight. Its regenera(cid:173)
`tion is provided by rapid cell division in the basal cell layer of
`the epidermis. Migration or displacement of dividing cells to(cid:173)
`ward the skin surface is accompanied by differentiation of the
`epidermal cells into layers of flat, laminated plates, as noted
`above. An acidic film (pH ranging between 4 and 6.5, depending
`on the area tested) made up of emulsified lipids covers the sur(cid:173)
`face of the stratum corneum.
`The dermis apparently is a gel structure involving a fi(cid:173)
`brous protein matrix embedded in an amorphous, colloidal,
`ground substance. Protein, including collagen and elastin
`fibers, is oriented approximately parallel to the epidermis.
`The dermis supports and interacts with the epidermis, facili(cid:173)
`tating its conformation to underlying muscles and bones.
`Blood vessels, lymphatics, and nerves are found within the
`dermis, though only nerve fibers reach beyond the dermal
`ridges or papillae into the germinative region of the epider(cid:173)
`mis. Sweat glands and hair follicles extending from the der(cid:173)
`mis through the epidermis provide discontinuities in an oth(cid:173)
`erwise uniform integument.
`The subcutaneous fat layer serves as a cushion for the der(cid:173)
`mis and epidermis. Collagenous fibers from the dermis thread
`between the accumulations of fat cells, providing a connection
`between the superficial skin layers and the subcutaneous
`layer.
`HAIR FOLLICLES AND SWEAT GLANDS-Human
`skin is sprinkled liberally with surface openings extending well
`into the dermis. Hair follicles, together with the sebaceous
`glands that empty into the follicles, make up the pilosebaceous
`unit. Apocrine and eccrine sweat glands add to the total.
`
`871
`
`4
`
`
`
`872
`
`PART 5: PHARMACEUTICAL MANUFACTURING
`
`Figure 44-1 . Vertical section of human skin.
`
`VEIN
`
`PILOSEBACEOUS UNITS-Human hair consists of
`compacted keratinized cells formed by follicles. Sebaceous
`glands empty into the follicle sites to form the pilosebaceous
`unit. The hair follicles are surrounded by sensory nerves;
`thus, an important function of human hair is sensory. Human
`hair varies enormously within the same individual, even
`within the same specific body area. Follicular density varies
`considerably as well, from values of about 250 follicles per cm2
`for the scalp to 50 per cm2
`, or less, for the thigh and other rel(cid:173)
`atively nonhirsute areas. Follicular density is determined ge(cid:173)
`netically, ie, no new follicles are formed after birth. One char(cid:173)
`acteristic human trait is that although most of the body hairs
`never develop beyond the rudimentary vellus state, the only
`hairless areas are confined, primarily, to the palmar and plan(cid:173)
`tar surfaces. Individual hairs can vary in microscopic appear(cid:173)
`ance, diameter, cuticle appearance, and even presence or ab(cid:173)
`sence of medulla.
`Sebaceous glands are similar anatomically and functionally
`but vary in size and activity according to location. Population in
`the scalp, face, and anogenital areas may vary from 400 to
`900/cm2
`. Fewer than 100/cm2 are found in other areas. Seba(cid:173)
`ceous glands are richly supplied with blood vessels.
`Sebaceous cells syntnesize and accumulate lipid droplets.
`This accumulation results in enlarged cells that fragment to
`form sebum. Sebum is made up of a mixture of lipids, approxi(cid:173)
`mately as shown in Table 44-1.
`The sebaceous gland, containing sebum, cell debris, and mi(cid:173)
`croorganisms such as Propionibacterium acnes, is connected to
`the pilosebaceous canal by a duct of squamous epithelium.
`When access to the surface is blocked and bacteria multiply, the
`result is the comedo of acne.
`SWEAT GLANDS-Sweat glands are classified as apocrine
`and eccrine. Apocrine glands are secretory but are not neces(cid:173)
`sarily responsive to thermal stimulation. Such glands do not
`produce sweat in the normal sense of the word. Apocrine
`glands, however, often are associated with eccrine sweat
`glands, particularly in the axilla.
`Eccrine sweat glands are coiled secretory glands, equipped
`with a blood supply, extending from the dermis to the epider(cid:173)
`mal surface. Eccrine sweat glands function to regulate heat ex(cid:173)
`change in man. As such, they are indispensable to survival.
`About 3 million eccrine glands are thought to be distributed
`over the human body. Distribution varies from less than 100 to
`more than 300/cm2
`. Gland counts after thermal stimulation do
`not always agree with anatomical counts.
`
`Drug Effects and the Extent of
`Percutaneous Drug Delivery
`Drugs are applied to the skin to elicit one or more of four gen(cid:173)
`eral effects: an effect on the skin surface, an effect within the
`stratum corneum, a more deep-seated effect requiring penetra(cid:173)
`tion into the epidermis and dermis, or a systemic effect result(cid:173)
`ing from delivery of sufficient drug through the epi~ermis an_d
`the dermis to the vasculature to produce therapeutic system1c
`concentrations.
`SURFACE EFFECTS-An activity on the skin surface
`may be in the form of a film, an action against surface microor(cid:173)
`ganisms, or a cleansing effect. Film formation on the skin sur(cid:173)
`face may be protective (eg, a zinc oxide cream or a sunscreen).
`Films may be somewhat occlusive and provide a moisturizing
`effect by diminishing loss of moisture from the skin surface. In
`such instances, the film or film formation per se fulfills the ob(cid:173)
`jective of product design. The action of antimicrobials against
`surface flora requires more than simple delivery to the site. The
`vehicle must facilitate contact between the surface organisms
`and the active ingredient. Skin cleansers employ soaps or sur(cid:173)
`factants to facilitate the removal of superficial soil.
`STRATUM CORNEUM EFFECTS-Drug effects within
`the stratum corneum are seen with certain sunscreens; p(cid:173)
`aminobenzoic acid is an example of a sunscreening agent that
`both penetrates and is substantive to stratum corneum cells.
`Skin moisturization takes place within the stratum corneum.
`Whether it involves the hydration of dry outer cells by surface
`films or the intercalation of water in the lipid-rich intercellular
`laminae, the increased moisture results in an apparent soften(cid:173)
`ing of the skin. Keratolytic agents, such as salicylic acid, act
`within the stratum corneum to cause a breakup or sloughing of
`stratum corneum cell aggregates. This is particularly impor(cid:173)
`tant in conditions of abnormal stratum corneum such as psori(cid:173)
`asis, a disease characterized by thickened scaly plaq~es.
`The stratum corneum also may serve as a reservoLr phase or
`depot wherein topically applied drug accumulates due to parti(cid:173)
`tioning into or binding with skin components. This interaction
`can limit the subsequent migration of the penetrant unless the
`interaction capacity of the stratum corneum is surpassed by
`providing excess drug. Examples of drugs that exhibit signifi(cid:173)
`cant skin interaction include benzocaine, estrogens, scopo(cid:173)
`lamine, and corticosteroids.
`EPIDERMAL, DERMAL, LOCAL, AND SYSTEMIC
`EFFECTS-The penetration of a drug into the viable epider(cid:173)
`mis and dermis may be difficult to achieve, as noted above. But,
`once transepidermal permeation has occurred, the continued
`diffusion of drug into the dermis is likely to result in drug trans(cid:173)
`fer into the microcirculation of the dermis and then into general
`circulation. Nonetheless, it is possible to formulate drug deliv(cid:173)
`ery systems that provide substantial localized delivery without
`achieving correspondingly high systemic concentrations. Lim(cid:173)
`ited studies in man of topical triethanolamine salicylate, mi(cid:173)
`noxidil, and retinoids demonstrate the potential of this
`approach.
`Unwanted systemic effects stemming from the inadvertent
`transdermal penetration of drugs have been reported for a wide
`variety of compounds (eg, hexachlorophene, lindane, corticos(cid:173)
`teroids, or N,N-diethyl-m-toluamide) over the years. With the
`commercial introduction of transdermal drug delivery systems
`for scopolamine, nitroglycerin, clonidine, 1713-estradiol, fen(cid:173)
`tanyl, nicotine, testosterone, lidocaine, and oxybutynin, trans(cid:173)
`dermal penetration is being regarded increasingly as an oppor(cid:173)
`tunity rather than a nuisance.
`
`Table 44-1. Composition of Sebum
`CONSTITUENTS
`
`CONSTITUENTS
`
`Cholesterol esters
`Cholesterol
`
`Triglycerides
`"- Wax esters
`"-<;qualene
`
`% W/W
`57.5
`26.0
`12.0
`
`%W/W
`3.0
`1.5
`
`Percutaneous Absorption
`Percutaneous absorption involves the transfer of drug from the
`skin surface into the stratum corneum, under the aegis of a con(cid:173)
`centration gradient, and its subsequent diffusion through the
`stratum corneum and underlying epidermis, through the der-
`
`5
`
`
`
`mis, and into the microcirculation. The skin behaves as a pas(cid:173)
`sive barrier to diffusing molecules. Evidence for this includes
`the fact that the impermeability of the skin persists long after
`the skin has been excised. Furthermore, Fick's Law is obeyed in
`the vast majority of instances.
`Molecular penetration through the various regions of the
`skin is limited by the diffusional resistances encountered.
`The total diffusional resistance (Rski,J to permeation through
`the skin has been described by Chien as
`Rskin = Rsc + Re + Rpd
`where R is the diffusional resistance, and the subscripts sc, e,
`and pd refer to the stratum corneum, epidermis, and papillary
`layer of the dermis, respectively. In addition, resistance to
`transfer into the microvasculature limits the systemic delivery
`of drug.
`By and large, the greatest resistance to penetration is met in
`the stratum corneum (ie, diffusion through the stratum corneum
`tends to be the rate-limiting step in percutaneous absorption).
`The role ofhair follicles and sweat glands must be considered;
`however, as a general rule their effect is minimized by the rela(cid:173)
`tively small fractional areas occupied by these appendages. On
`the other hand, liposomal vehicles and micro bead (3 to 10 fLm di(cid:173)
`ameter) suspensions appear to accumulate selectively in pilose(cid:173)
`baceous and perifollicular areas. In the very early stages of ab(cid:173)
`sorption, transit through the appendages may be comparatively
`large, particularly for lipid-soluble molecules and those whose
`permeation through the stratum corneum is relatively low. Sur(cid:173)
`factants and volatile organic solvents such as ethanol have been
`found to enhance drug uptake via the transfollicular route.
`Rather than characterizing drug transfer into and through
`the skin in terms of the diffusional resistances encountered, one
`could define permeation in terms ofthe pathways followed by the
`diffusing species. Drug permeation through the intact skin of hu(cid:173)
`mans involves either an intercellular or transcellular path in the
`stratum corneum, for the most part, rather than the so-called
`shunt pathways (transglandular or transfollicular routes).
`The conventional wisdom is that for the most part, lipophilic
`compounds transfer preferentially into the lipoidal intercellu(cid:173)
`lar phase of the stratum corneum, while relatively more hy(cid:173)
`drophilic compounds transfer into the intracellular domain of
`the stratum corneum. One should keep in mind that the often(cid:173)
`postulated biphasic character of the horny layer- with hy(cid:173)
`drophilic cells in a lipophilic matrix-is overly simplistic: the
`hydrophilic cells themselves are enclosed within lipid bilayer
`membranes, while the lipophilic matrix comprises intercellular
`lipids that are, in fact, present in lamellar structures that sand(cid:173)
`wich in hydrophilic layers. As Bodde et al1 have suggested, the
`intercellular pathway is bicontinuous, consisting of a nonpolar
`and a polar diffusion pathway between the corneocytes. The
`implications for dermatopharmacokinetic modeling are clear.
`The stratum corneum can be regarded as a passive diffusion
`membrane but not an inert system; it often has an affinity for
`the applied substance. The adsorption isotherm is frequently
`linear in dilute concentration ranges. The correlation between
`external and surface concentrations is given in terms of the sol(cid:173)
`vent membrane distribution coefficient Km . The integrated
`form of Fick's Law is given as
`
`and
`
`J = KJJCs
`0
`s
`
`K = K,JJ
`0
`p
`
`where Kp is the permeability coefficient, Js is the steady state
`flux of solute, Cs is the concentration difference of solute across
`membrane, o is the membrane thickness,
`solute sorbed per cm3 oftissue
`_ Cm
`. h
`K
`m IS t e solute in solution per cm3 of solvent - Cs '
`
`and Dis the average membrane ,diffusion coefficient for solute.
`
`CHAPTER 44: MEDICATED TOPICALS
`
`873
`
`Permeability experiments have shown that the hydrated
`stratum corneum has an affinity for both lipophilic and hy(cid:173)
`drophilic compounds. The bifunctional solubility arises from
`the hydrophilic corneocytes and the lipid-rich lamellar struc(cid:173)
`tures in the intercellular space. Thus, attempts to predict per(cid:173)
`meability constants from oil:water or solvent:water partition
`coefficients have had limited success.
`The effect of regional variation on skin permeability can be
`marked. It has been suggested that one ought to differentiate
`between two species of horny layer: the palms and soles (up to
`600 fLm thick), adapted for weight-bearing and friction; and the
`body horny layer ( -10 fLm thick), adapted for flexibility, imper(cid:173)
`meability, and sensory discrimination.
`Overall, data suggest the following order for diffusion of sim(cid:173)
`ple molecules through the skin: plantar < palmar < arms, legs,
`trunk, dorsum of hand < scrotal and postauricular < axillary <
`scalp. Electrolytes in solution penetrate the skin poorly. Ioniza(cid:173)
`tion of a weak electrolyte substantially reduces its permeability
`(eg, sodium salicylate permeates poorly compared with salicylic
`acid). The development of iontophoretic devices in recent years
`may minimize this problem with ionic penetrants. For any spe(cid:173)
`cific molecule, the predictability of regional variations in skin
`permeability continues to elude investigators. This will con(cid:173)
`tinue to be true as long as dermatopharmacokinetic models do
`not adequately reflect the anisotropicity of the skin's composi(cid:173)
`tion and structure, its interactions with the drug and the vehi(cid:173)
`cle, and the physiological parameters that affect transfer.
`
`In Vitro and In Vivo Studies
`Classically, percutaneous absorption has been studied in vivo us(cid:173)
`ing radioactively labeled compounds or by in vitro techniques us(cid:173)
`ing excised human or animal skin. In vivo studies in recent years
`have made use of the skin-stripping method, which permits the
`estimation of the concentration or amount of the penetrating
`species as a function of depth of the stratum corneum. Layers of
`the stratum corneum can be removed or stripped successively
`away by the repeated application and removal of cellulose adhe(cid:173)
`sive tape strips. Skin penetration of a drug and the effect of ad(cid:173)
`ditives may be studied and evaluated through analysis of indi(cid:173)
`vidual skin strips, which provide a profile of skin penetration.
`Rougier et al2 have championed the use of the skin-stripping
`method, in conjunction with short-term exposure to the topically
`applied penetrant, as a predictor of skin permeation.
`Clearly, the evaluation of new chemical entities (NCEs) of
`indeterminate toxicity mandates in vitro testing. A diffusion
`cell frequently used for in vitro experiments is shown in Figure
`
`Figure 44-2. Schematic representation of diffusion cell. Top is open to am ·
`bient laboratory environment. (From Franz TJ . J Invest Dermatol
`1975;64: 191.)
`
`6
`
`
`
`874
`
`PART 5: PHARMACEUTICAL MANUFACTURING
`
`250
`
`zoo
`
`)(
`
`O'l
`0 ......
`.... 150
`.e 0. .,
`(.) .,
`.. .!!
`-= 100
`
`D:
`
`0
`::IE
`
`50
`
`0
`
`5
`
`10
`
`15 20 25 30 35
`Days
`
`Figure 44-3. Change in cortisone penetration by alternately drying (D)
`and humidifying (W) the stratum corneum. (From Scheuplein RJ, Ross LW.
`J Invest Dermatol 1974;63:353 .)
`
`44-2. 3 In this system, the intact skin or the epidermis is treated
`as a semipermeable membrane separating two fluid media. The
`transport rate of a particular drug is evaluated by introducing
`the drug in solution on the stratum corneum side of the mem(cid:173)
`brane, then measuring penetration by periodic sampling and
`analysis of the fluid across the skin membrane.
`Investigators have recognized that transport across an im(cid:173)
`mersed, fully hydrated stratum corneum may not represent the
`absorption system or rate observed in in vivo studies. Percuta(cid:173)
`neous absorption across a fully hydrated stratum corneum may
`be an exaggeration. It may be more representative of enhanced
`absorption that is seen after in vivo skin is hydrated by occlu(cid:173)
`sive wrapping.
`Using separated epidermal skin mounted in diffusion cells,
`Scheuplein and Ross4 varied the atmosphere above the skin
`strip by use of Drierite to simulate dry conditions and wetted
`paper strips to simulate the effect of occlusion and observed
`marked reduction in penetration of cortisone under dry condi(cid:173)
`tions but greatly enhanced penetration on humidifying the
`stratum corneum (Fig 44-3).4
`The studies ofScheuplein and Ross, 4 and ofFranz,3 demon(cid:173)
`strate that in vitro studies of percutaneous absorption under
`controlled conditions are relevant to in vivo drug penetration.
`As stated by Franz, "whenever a question is asked requiring
`only a qualitative or directional answer, the in vitro technique
`appears perfectly adequate."
`
`Relevance of Animal Studies
`PERCUTANEOUS ABSORPTION-Any evaluation of a
`study of percutaneous absorption in animals must take cog(cid:173)
`nizance of species variation. Just as percutaneous absorption in
`man will vary considerably with skin site, so will absorption in
`various animal species. Bartek et al5 investigated percutaneous
`absorption and found a decreasing order of permeability, thus,
`rabbit > rat > swine > man. They studied the in vivo absorp(cid:173)
`tion of radioactively labeled haloprogin, N -acetylcysteine,
`testosterone, caffeine, and butter yellow; their results with
`testosterone, shown in Figure 44-4,6 illustrate the penetration
`differences observed with different animal skins.
`Subsequently, using a similar in vivo technique, Wester and
`Maibach 7 investigated the percutaneous absorption of benzoic
`acid, hydrocortisone, and testosterone in the rhesus monkey.
`Radioactively tagged compounds were applied to the ventral
`surface of the forearm, and absorption was quantified on the
`
`basis of radioactivity excreted in the urine for 5 days following
`application. The investigators concluded that the percutaneous
`penetration of these compounds in the rhesus monkey is simi(cid:173)
`lar to that in man and regarded the data as encouraging be(cid:173)
`cause of the similarity.
`The consensus is that rhesus monkeys and miniature pigs are
`good in vivo models for human percutaneous absorption, while
`smaller laboratory animals (eg, mouse, rat, rabbit) are not.
`It should be stressed again that percutaneous absorption
`studies in animals, either in vivo or in vitro, only can be useful
`approximations of activity in man. The effect of species varia(cid:173)
`tion, site variability (about which little is known in animals),
`skin condition, experimental variables, and, of major impor(cid:173)
`tance, the vehicle, must be kept in mind.
`As Bronaugh8 notes, although human skin is preferable for
`in vitro permeation studies, its availability is limited. Addi(cid:173)
`tional constraints apply if one is only willing to use freshly ob(cid:173)
`tained viable human skin from surgical specimens or biopsies,
`as opposed to skin harvested from cadavers.
`Concern has been voiced over the notorious variability in bar(cid:173)
`rier properties of excised skin, whether animal or human. Fac(cid:173)
`tors responsible for the variability include the source and char(cid:173)
`acteristics of the donor skin (eg, elapsed time from death to
`harvesting of the skin, age and gender of the donor, health ofthe
`skin prior to the donor's death), exposure of the skin to chemi(cid:173)
`cals or mechanical treatment (eg, shaving or clipping prior to
`harvesting of the skin), etc. The availability of a living skin
`equivalent-comprising a bilayered system ofhuman dermal fi(cid:173)
`broblasts in a collagenous matrix upon which human corneo(cid:173)
`cytes have formed a stratified epidermis-offers an alternative,
`less variable, model for evaluating human skin permeation and
`biotransformation.
`Skin-flap methods represent in vivo and in vitro techniques
`for evaluating percutaneous absorption in animals or animal
`models: the general approach entails the surgical isolation of a
`skin section of an animal such that the blood supply is singular;
`this ensures that drug can be collected and assayed in the vas(cid:173)
`cular perfusate as it undergoes absorption from the skin sur(cid:173)
`face. The perfused skin flap can be maintained in the intact an(cid:173)
`imal or mounted in an in vitro perfusion system, all the while
`maintaining its viability.
`Animals also have been used to detect contact sensitization,
`measure antimitotic drug activity, measure phototoxicity, and
`evaluate the comedogenic and comedolytic potential of sub-
`
`100
`90
`
`..... ~i::::---o-
`u~
`
`o -o
`
`...... ___
`..
`., 80
`·-·-·
`-·-·-·-·
`.. ..0
`0~ -·-·-·-.
`0 60 ~ o-_
`.. .. 50
`0 - 40
`0::: ..
`.. 0.. .,
`
`70
`
`...
`
`30
`
`..0
`....
`0
`
`<t
`
`z
`
`0
`0
`
`~
`
`~
`u
`~
`
`0
`()
`
`0 - -
`
`0
`
`·~
`...
`Testo~i<--
`*
`------·-·
`
`Rat o-o-o
`Rabbit ..._.__.,.
`Pig
`Man o-o-o
`
`20
`0
`
`Days
`
`5
`
`Figure 44-4. Percutaneous absorption of testosterone in rats, rabbits,
`swine and man for 5 days after application. (From Maibach HI, ed. Ani(cid:173)
`mal Models in Dermatology. Edinburgh: Churchill Livingstone, 1975.)
`
`7
`
`
`
`stances. In each ofthese test procedures, be it a safety test or as(cid:173)
`say model, the animal is considered a substitute for man. It is,
`therefore, important to realize that the animal is not man, even
`though man is the ultimate test animal. Animal-testing pre(cid:173)
`sents the investigator with unique advantages; lack of appreci(cid:173)
`ation of the variables involved can destroy these advantages.
`Mershon and Callahan9 recorded and illustrated the consid(cid:173)
`erations involved in selecting an animal test model. They in(cid:173)
`terpreted the rabbit irritancy data of several investigators and
`impressively visualized different possible interpretations of the
`differing response between rabbit and man.
`While the ultimate system for establishing therapeutic effi(cid:173)
`cacy is man, there are specific animal test models that are rec(cid:173)
`ognized to be valuable as prehuman~use screens predictive of
`drug activity in humans. For example, the rat-ear assay and
`the granuloma-pouch procedure in rats are recognized proce(cid:173)
`dures for the estimation of steroid anti-inflammatory activity.
`Lorenzetti 10 tabulated the potency of various topical
`steroids, comparing the rat-ear-edema assay with potency mea(cid:173)
`sured in humans by use of the vasoconstrictor procedure of
`Stoughton and McKenzie; the results are given in Table 44-2.11
`Animal assay models of this kind, particularly the steroid anti(cid:173)
`inflammatory assays, are most useful as preliminary activity
`screens. The simplicity, safety, and reproducibility of the vaso(cid:173)
`constrictor assay in humans recommend it over any corre(cid:173)
`sponding animal procedure. However, a number of concerns
`have been raised over the years that need to be addressed, par(cid:173)
`ticularly if this bioassay is to be used to assess the bioequiva(cid:173)
`lence of topical corticosteroid formulations. These concern.s in(cid:173)
`clude the linearity of the vasoconstrictor response-drug
`concentration relationship and the visual assessment of the
`blanching or vasoconstrictor response.
`As the in vivo vasoconstrictor response generally approaches
`a maximum, one must know whether the microcirculation of the
`skin has exceeded its..capacity to respond linearly to the corticos(cid:173)
`teroid concentration attained in the skin. It may be that only rel(cid:173)
`atively minimal responses will be elicited by relatively high con(cid:173)
`centrations. At the other end of the response-dose relationship,
`what is the minimum dose that will produce a reliable, replica(cid:173)
`ble response? Rather than relying on the somewhat subjective vi(cid:173)
`sual evaluation of the response, investigators ought to make use
`of chromometers to provide objective, quantifiable data.
`PILOSEBACEOUS UPTAKE-The study of the targeted
`delivery of drugs to follicles and/or sebaceous glands has be(cid:173)
`come necessary in view of the selective uptake or deposition of
`antiacne drugs such as tretinoin in pilosebaceous units. Fortu(cid:173)
`nately, the anatomical and physiological correspondence of
`
`Table 44-2. Relative Potency of Anti-Inflammatory
`Agents
`
`RAT-EAR EDEMA ASSAY
`73.2 (49.4-110)
`117.3 (85.9-1 06)
`
`TOPICAL
`ANTI-INFLAMMATORY
`POTENCY HUMAN ASSAY
`VASOCONSTRICTOR
`10-20
`10-20
`
`2.44 (1.54-7.76)
`5.43 (4.05-7.70)
`
`1-2
`3
`
`COMPOUND
`Dexamethasone
`Dexamethasone
`21-acetate
`Prednisolone
`Prednisolone
`21-acetate
`Betamethasone
`Betamethasone
`21-acetate
`Fluorometholone
`Fluorometholone
`acetate
`Fluprednisolone
`Fluprednisolone
`acetate
`Hydrocortisone
`() = 95% confidence limits.
`From Maibach HI. In Maibach HI, ed. Animal Models in Dermatology.
`Edinburgh: Churchill Livingstone, 1.975, p 221.
`
`97.3 (16.7-141)
`1 072.0 (876-1179)
`
`138.3 (57.9-333)
`219.5 (9.15-536)
`
`31 .8 (13.3-76.1)
`61.3 (25.6-147)
`
`3-5
`18-33
`
`30--40
`
`4-6
`
`1
`
`CHAPTER 44: MEDICATED TOPICAL$
`
`875
`
`hamst