|
`
`r 1' Not to be taken
`
`reference
`
`from the room.
`
`'
`
`-m " The Science and
`* Practice of Pharmacy
`
`
`from the room. - 9.2'
`
`2 1 s t E D IT I 0 NA
`
`:.»::::.—:':':::.
`
`j
`
`'
`
`Not to be taken
`
`_-
`
`
`
`
`:
`
`
`
`
`
`WILLIAMS 8 WILKINS
`
`
`
`Iif.”
`
`1
`
`AMN1028
`
`

`

`ThePropettyof
`
`Sterne, Kessler, Goldstein & Fox, PJ. L c
`
`V ‘
`
`215T EDITION
`
`
`Remington
`
`The Science and Practice
`
`of Pharmacy
`
`
`V f LIPPINCOTT WILLIAMS 8 WILKINS
`A Wolters Kluwer Company
`
`Philadelphia - Baltimore - New York . London
`Buenos Aires - Hong Kong - Sydney - Tokyo
`
`2
`
`

`

`I
`
`—
`
`=.
`
`Editor: David B. Troy
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Marisa A. O’Brien
`
`Lippincott Williams & Wilkins 351 West Camden Street
`
`-'
`
`Baltimore, Maryland 21201-2436 USA
`
`530 Walnut Street
`
`Philadelphia, PA 19106
`
`All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any form or by any means,
`including photocopying, or utilized by any information storage and retrieval system without written permissmn from the copy-
`right owner.
`
`The publisher is not responsible (as a matter of product liability, negligence or otherwise) for any injury resulting from any
`material contained herein. This publication contains information relating to general principles of medical care which should not
`be construed as specific instructions for individual patients. Manufacturer’s product information and package inserts should be
`reviewed for current information, including contraindications, dosages and precautions.
`
`Printed in the United States of America
`
`Entered according to Act of Congress, in the year 1885 by Joseph P Remington, in the Office of the Librarian of Congress, at
`Washington DC
`
`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
`
`Copyright 1926, 1936, by the Joseph P Remington Estate
`
`Copyright 1948, 1951, by the Philadelphia College of Pharmacy and Science
`
`Copyright 1956, 1960, 1965, 1970, 1975, 1980, 1985, 1990, 1995, by the Philadelphia College of Pharmacy and Science
`
`Copyright 2000, 2006, by the University of the Sciences in Philadelphia
`
`All Rights Reserved
`Library of Congress Catalog Card Information is available
`ISBN 0-7817-4673-6
`
`The publishers have made every effort to trace the copyright holders for borrowed material. If they have inadvertently overlooked
`any, they will be pleased to make the necessary arrangements at the first opportunity.
`
`The use of structural formulas from USAN and the USP Dictionary ofDrug Names is by permission of The USP Convention. The
`Convention is not responsible for any inaccuracy contained herein.
`
`Notice—This text is not intended to represent, nor shall it be interpreted to be, the equivalent of or a substitute for the official
`United States Pharmacopeia (USP) and/ or the National Formulary (NF). In the event of any difference or discrepancy between the
`current official USP or NF standards of strength, quality, purity, packaging and labeling for drugs and representations of them
`herein, the context and effect of the official compendia shall prevail.
`
`To purchase additional copies of this book call our customer service department at (800) 638-3030 or fax orders to (301)
`824-7390. International customers should call (301) 714-2324.
`
`2345678910
`
`W
`
`3
`
`

`

`mastectopicals
`
`Lawrence H Block, PhD
`
`CHAPTER 44
`
`
`
`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—
`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-
`ter. Ophthalmic use imposes particle size, viscosity, and steril-
`ity specifications that require separate, detailed discus—
`sion (see Chapter 43). The complexity of pharmaceutical
`aerosol systems necessitates their inclusion elsewhere (see
`Chapter 50).
`
`
`
`EPIDERMAL AND TRANSDERMAL
`DRUG DELIVERY
`
`The Skin
`
`The skin often has been referred to as the largest of the body or-
`gans: an average adult’s skin has a surface area of about 2 m2.
`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-
`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 pm 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-
`drophilic layers and lipophilic bilayers formed during the pro-
`cess of keratinization. The region behaves as a tough but flexi-
`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-
`rier and is only slightly permeable to water. It retards water
`
`
`
`loss from underlying tissues, minimizes ultraviolet light pene-
`tration, and limits the entrance of microorganisms, medica-
`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-
`tion is provided by rapid cell division in the basal cell layer of
`the epidermis. Migration or displacement of dividing cells to-
`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-
`face of the stratum corneum.
`The dermis apparently is a gel structure involving a fi-
`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-
`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-
`mis. Sweat glands and hair follicles extending from the der-
`mis through the epidermis provide discontinuities in an oth-
`erwise uniform integument.
`The subcutaneous fat layer serves as a cushion for the der-
`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
`
`
`
`
`
`
`
`
`
`W
`
`4
`
`

`

`872
`
`PART 5: PHARMACEUTICAL MANUFACTURING
`
`STRATUM GRANULOSUM '
`STRATUM LUCIDUM—jfi'
`VEIN
`
`'
`
`ARTERY§—\
`SEBACEOUS GLAND
`\-
`HAIR FOLLICLE
`SWEAT GLAND
`PAPILLA OF HAIR
`
`
`
`
`
`_
`
`EPIDERMIS
`
`DERMiS
`
`'
`
`__'suacunmeous TISSUE
`WITH
`ADIPOSE CELLS
`
`Drug Effects and the Extent of
`Percutaneous Drug Delivery
`
`Drugs are applied to the skin to elicit one or more of four gen-
`eral effects: an effect on the skin surface, an effect within the
`stratum corneum, a more deep-seated effect requiring penetra—
`tion into the epidermis and dermis, or a systemic effect result-
`ing from delivery of sufficient drug through the epidermis and
`the dermis to the vasculature to produce therapeutic systemic
`concentrations.
`
`SURFACE EFFECTS—An activity on the skin surface
`may be in the form of a film, an action against surface microor-
`ganisms, or a cleansing effect. Film formation on the skin sur-
`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-
`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-
`factants to facilitate the removal of superficial soil.
`STRATUM CORNEUM EFFECTS—Drug effects within
`the stratum corneum are seen with certain sunscreens; p-
`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-
`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-
`tant in conditions of abnormal stratum corneum such as psori-
`asis, a disease characterized by thickened scaly plaques.
`The stratum corneum also may serve as a reservoir phase or
`depot wherein topically applied drug accumulates due to parti~
`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-
`cant skin interaction include benzocaine, estrogens, scopo-
`lamine, and corticosteroids.
`EPIDERMAL, DERMAL, LOCAL, AND SYSTEMIC
`EFFECTS—The penetration of a drug into the viable epider-
`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-
`fer into the microcirculation ofthe dermis and then into general
`circulation. Nonetheless, it is possible to formulate drug deliv-
`ery systems that provide substantial localized delivery without
`achieving correspondingly high systemic concentrations. Lim—
`ited studies in man of topical triethanolamine salicylate, mi-
`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-
`teroids, or MN-diethyl-m-toluamide) over the years. With the
`commercial introduction of transdermal drug delivery systems
`for scopolamine, nitroglycerin, clonidine, 17B-estradiol, fen-
`tanyl, nicotine, testosterone, lidocaine, and oxybutynin, trans-
`dermal penetration is being regarded increasingly as an oppor-
`tunity rather than, a nuisance.
`
`
`
`Figure 44-1. Vertical section of human skin.
`
`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—
`atively nonhirsute areas. Follicular density is determined ge-
`netically, ie, no new follicles are formed after birth. One char-
`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-
`tar surfaces. Individual hairs can vary in microscopic appear-
`ance, diameter, cuticle appearance, and even presence or ab-
`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
`9OO/cm2. Fewer than 100/cm2 are found in other areas. Seba-
`ceous glands are richly supplied with blood vessels.
`Sebaceous cells synthesize 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-
`mately as shown in Table 44—1.
`The sebaceous gland, containing sebum, cell debris, and mi—
`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-
`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-
`mal surface. Eccrine sweat glands function to regulate heat ex-
`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.
`
`Table 44-1. Composition of Sebum
` CONSTITuEIyTS % WNV CONSTITUENTS % W/W
`
`
`
`Triglycerides
`57.5
`Cholesterol esters
`3.0
`Wax esters
`26.0
`Cholesterol
`1.5
`Squalene
`12.0
`
`
`Percutaneous Absorption
`
`Percutaneous absorption involves the transfer of drug from the
`skin surface into the stratum corneum, under the aegis of a con-
`centration gradient, and its subsequent diffusion through the
`stratum corneum and underlying epidermis, through the der-
`
`~
`
`5
`
`

`

`7’
`
`mis, and into the microcirculation. The skin behaves as a pas—
`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 (Rskirj to permeation through
`the skin has been described by Chien as
`
`Rskin = Rsc + Re + de
`where R is the diffusional resistance, and the subscripts 3c, 3,
`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-
`tively small fractional areas occupied by these appendages. On
`the other hand, liposomal vehicles and microbead (3 to 10 um di-
`ameter) suspensions appear to accumulate selectively in pilose-
`baceous and perifollicular areas. In the very early stages of ab-
`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-
`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 of the pathways followed by the
`diffusing species. Drug permeation through the intact skin of hu-
`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-
`lar phase of the stratum corneum, while relatively more hy-
`drophilic compounds transfer into the intracellular domain of
`the stratum corneum. One should keep in mind that the often-
`postulated biphasic character of the horny layer—with hy-
`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-
`wich in hydrophilic layers. As Boddé 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-
`vent membrane distribution coefficient Km, The integrated
`form of Fick’s Law is given as
`
`
`J3 = KmDCS8
`
`and
`
`KmD
`Kp = T
`
`where KP is the permeability coefficient, JS is the steady state
`flux of solute, Cs is the concentration difference of solute across
`membrane, 8 is the membrane thickness,
`
`solute sorbed per cm3 of tissue
`Cm
`solute in solution per cm3 of solvent # Cs ’
`
`Km is the
`
`and D is 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-
`drophilic compounds. The bifunctional solubility arises from
`the hydrophilic corneocytes and the lipid—rich lamellar struc-
`tures in the intercellular space. Thus, attempts to predict per—
`meability constants from oilzwater or solventzwater 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 um thick), adapted for weight-bearing and friction; and the
`body horny layer (~10 pm thick), adapted for flexibility, imper-
`meability, and sensory discrimination.
`Overall, data suggest the following order for diffusion of sim-
`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-
`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-
`cific molecule, the predictability of regional variations in skin
`permeability continues to elude investigators. This will con-
`tinue to be true as long as dermatopharmacokinetic models do
`not adequately reflect the anisotropicity of the skin’s composi-
`tion and structure, its interactions with the drug and the vehi-
`L
`cle, and the physiological parameters that affect transfer.
`
`In Vitro and In Vivo Studies
`
`Classically, percutaneous absorption has been studied in viva us—
`ing radioactively labeled compounds or by in vitro techniques us-
`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-
`sive tape strips. Skin penetration of a drug and the effect of ad-
`ditives may be studied and evaluated through analysis of indi-
`vidual skin strips, which provide a profile of skin penetration.
`Rougier et alz 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
`
`Temperature
`Jac kei
`
`
`
`Stirring Bar
`
`—> Outflow
`To
`Water
`Bath
`
`<—-lnflow
`
`Figure 44—2. Schematic representation of diffusion cell. Top is open to am -
`bient
`laboratory environment. (From Franz TJ. J Invest Dermatol
`1975;611:191.)
`
`
`
`6
`
`

`

`874
`
`PART 5: PHARMACEUTICAL MANUFACTURING
`
`250
`
`200
`
`
`
`DRIERITE(D)
`
`
`
`MolesInReceptorx109
`
`Go
`
`'00
`
`0| 0
`
`N0 DRIERITE (w)
`
`
`
`
`DRIERITEiD)
`
`0
`
`5
`
`’IO
`
`15 20
`Days
`
`25 30 35
`
`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.)
`
`44-23 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-
`brane, then measuring penetration by periodic sampling and
`analysis of the fluid across the skin membrane.
`Investigators have recognized that transport across an im-
`mersed, fully hydrated stratum corneum may not represent the
`absorption system or rate observed in in vivo studies. Percuta—
`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-
`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—
`tions but greatly enhanced penetration on humidifying the
`stratum corneum (Fig 44~3).4
`The studies of Scheuplein and Ross,4 and of Franz,3 demon-
`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-
`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-
`tion of radioactively labeled haloprogin, N—acetylcysteine,
`testosterone, caffeine, and butter yellow; their results with
`testosterone, shown in Figure 444,6 illustrate the penetration
`differences observed with different animal skins.
`Subsequently, using a similar in viva technique, Wester and
`Maibach7 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-
`lar to that in man and regarded the data as encouraging be-
`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-
`tion, site variability (about which little is known in animals),
`skin condition, experimental variables, and, of major impor-
`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—
`tional constraints apply if one is only willing to use freshly ob»
`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-
`rier properties of excised skin, whether animal or human. Fac—
`tors responsible for the variability include the source and char-
`acteristics of the donor skin (eg, elapsed time from death to
`harvesting ofthe skin, age and gender ofthe donor, health of the
`skin prior to the donor’s death), exposure of the skin to chemi—
`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 of human dermal fi-
`broblasts in a collagenous matrix upon which human corneo-
`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-
`cular perfusate as it undergoes absorption from the skin sur-
`face. The perfused skin flap can be maintained in the intact an-
`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
`
`80
`
`70
`
`60
`
`50
`
`4O
`
`30
`
`Absorbed
`CorrectedPercentofDoseNot
`
`
`\Testosteronev i
`Rat O—O—O\*
`Rabbit ¥—¥-—¥
`Pig
`0—- -O—-—O
`Man D—D—D
`
`Days
`
`Figure 44-4. Percutaneous absorption of testosterone in rats, rabbits,
`swine and man for 5 days after application. (From Maibach HI, ed. Ani—
`ma/Mode/s in Dermatology. Edinburgh: Churchill Livingstone, 1975.)
`
`—7‘
`
`7
`
`

`

`
`
`stances. In each of these test procedures, be it a safety test or as-
`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-
`sents the investigator with unique advantages; lack of appreci-
`ation of the variables involved can destroy these advantages.
`Mershon and Callahan9 recorded and illustrated the consid-
`erations involved in selecting an animal test model. They in-
`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-
`cacy is man, there are specific animal test models that are rec—
`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-
`dures for the estimation of steroid anti-inflammatory activity.
`Lorenzetti10 tabulated the potency of various topical
`steroids, comparing the rat-ear—edema assay with potency mea»
`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-
`inflammatory assays, are most useful as preliminary activity
`screens. The simplicity, safety, and reproducibility of the vaso-
`constrictor assay in humans recommend it over any corre-
`sponding animal procedure. However, a number of concerns
`have been raised over the years that need to be addressed, par-
`ticularly if this bioassay is to be used to assess the bioequiva—
`lence of topical corticosteroid formulations. These concerns in-
`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 itacapacity to respond linearly to the corticos-
`teroid concentration attained in the skin. It may be that only rel-
`atively minimal responses will be elicited by relatively high con-
`centrations. At the other end of the response-dose relationship,
`what is the minimum dose that will produce a reliable, replica—
`ble response? Rather than relying on the somewhat subjective vi—
`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-
`come necessary in view of the selective uptake or deposition of
`antiacne drugs such as tretinoin in pilosebaceous units. Fortu—
`nately, the anatomical and physiological correspondence of
`
`
`
`Table 44-2. Relative Potency of Anti-Inflammatory
`Agents
`TOPICAL
`ANTI-INFLAM MATORY
`POTENCY HUMAN ASSAY
`
` COMPOUND RAT-EAR EDEMA ASSAY VASOCONSTRICTOR
`Dexamethasone
`73.2 (494—110)
`10—20
`Dexamethasone
`117.3 (859—106)
`10—20
`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, 1975, p 221.
`
`2.44 (1.54—7.76)
`5.43 (4.05—7.70)
`
`97.3 (16.7—141)
`1072.0 (876—1179)
`
`138.3 (57.9—333)
`219.5 (9.15—536)
`
`31.8 (13.3—76.1)
`61.3 (25.6—147)
`
`1
`
`1—2
`3
`
`3—5
`18-33
`
`30—40
`
`4—6
`
`1
`
`m
`
`
`
`
`
`
`
`CHAPTER 44: MEDICATED TOPICALS
`
`875
`
`a
`
`hamster ear pilosebaceous units to those in humans has facili-
`tated studies of the cutaneous and pilosebaceous disposition of
`drugs following topical application.”
`
`Other Factors Affecting Drug Absarption
`from the Skin
`
`Percutaneous absorption of a drug can be enhanced by the use
`of occlusive techniques or by the use of so-called penetration
`enhancers.
`SKIN HYDRATION AND TEMPERATURE—Occluding
`the skin with wraps of impermeable plastic film such as Saran
`Wrap prevents the loss of surface water from the skin. Since
`water is absorbed readily by the protein components of the skin,
`the occlusive wrap causes greatly increased levels of hydration
`in the stratum corneum. The concomitant swelling of the horny
`layer ostensibly decreases protein network density and the dif-
`fusional path length. Occlusion of the skin surface also in~
`creases skin temperature (~2 to 3°C), resulting in increased
`molecular motion and skin permeation.
`Hydrocarbon bases that occlude the skin to a degree will
`bring about an increase in drug penetration. However, this ef-
`fect is trivial compared with the effects seen with a true occlu-
`sive skin wrap. Occlusive techniques are useful in some clinical
`situations requiring anti-inflammatory activity, and occlusive
`wrappings are used most commonly with steroids. Since steroid
`activity can be enhanced so enormously by skin occlusi