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11

Transdermal Delivery andCutaneous Reactions

JAGDISH SINGH

North Dakota State University, Fargo, North Dakota

HOWARD I. MAIBACH

University of California School of Medicine, San Francisco, California

I. INTRODUCTION

Drugs and excipients have different sensitization capacities for inducing contact al-lergy. The risk of skin reactions produced by chemicals depends on their inherentallergenicity and ability to penetrate into the normal skin or damaged skin. As fullydescribed in earlier chapters, the penetration of chemicals into the skin depends onskin condition, anatomical site, chemical characteristics of the substance, lipid sol-ubility and concentration of the chemical. Penetration is also influenced by externalfactors, especially solvents, surface-active agents, alkalies, moisture, temperature,extreme dehydration, and mechanical effects. The length of time that a substancecontacts the skin is of great importance. Skin irritation influences the cells of theskin and results in an increased sensitization risk. Such cell damage can be producedby variety of chemicals or by mechanical means.

Irritation is the nonimmunological evocation of normal or exaggerated reactionin a tissue by application of a stimulus. Irritation may be subjective or objective.Subjective irritation refers to transient pruritus, stinging, burning, or related sensa-tions without subsequent visible inflammation (e.g., alcohol on an open wound). Achemical substance that evokes inflammation on initial exposure is called an acute(primary) irritant but, on repeated exposure to an identical site, will cause cumulativeirritation. In the past, soaps, cosmetic materials, and pest control chemicals have

Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.

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been recognized as potential sources of cutaneous irritation. More recently it hasbeen recognized that a multitude of occupational and environmental factors, such asorganic dyes and solvents or industrial waste material contribute to this topical skindisorder.

The most common reaction consists of a local inflammatory response charac-terized by erythema or edema, or a corrosive reaction characterized by local tissuedestruction or necrosis. Other reactions, sometimes referred to as irritation, do notdisplay visible signs of inflammation. Subtle increases in epidermal thickness, with-out visible or histological inflammation, may be produced by a variety of substancesusually thought to be nonirritating (1).

The occlusive nature of many transdermal delivery systems provides an idealmodel for inducing sensitization. Potential allergens include the adhesive, the dif-fusion membrane, the solvent, the enhancer, and the drug. Allergic contact dermatitiswith redness, swelling, and sometimes vesiculation, is the most overt presentationof skin sensitivity from transdermal delivery systems. The reaction is usually local-ized to the site of application of the current patch, but may also occur at the sitesof previous applications, the flare-up reaction (2). Spread of the eczematous reactionto sites not associated with the application of patches may occur (3). Urticaria andangioedema are rare allergic reactions to transdermal therapeutic systems (4).

This chapter deals with the skin reactions caused by topical drug deliverysystems.

II. PREDICTIVE TESTING

A. Irritation

There is not yet an adequately validated in vitro model available to predict skinirritation of topical chemicals. Details of the current state of development of thesepotentially useful assays were summarized (5). The standard method to forecast skinirritation is by so-called predictive tests on humans or animals. The most widelyused test for predicting potential skin irritants to humans, using animal models, waspublished by Draize et al. (6), and has been refined by many groups (7). The testwas initially designed to classify chemicals that cause primary (acute) irritation.However, in designing a test that would eliminate false-negative reactions (type 2errors), Draize permitted the introduction of a significant number of false-positivereactions (type 1 errors). The rabbit Draize test, properly performed and interpretedby experienced scientists, still remains valuable.

Transepidermal water loss (TEWL) is a well-accepted method for quantifyingalterations in stratum corneum function (8), and it provides a robust method forassessing stratum corneum damage. Irritation tends to reduce the efficiency of thestratum corneum barrier function and may result in an increase in TEWL. This issometimes associated with a decrease in skin water content (9). Hence, measurementof skin capacitance or skin hydration (10) may also be used to assess irritation(11,12). Measurements of carbon dioxide emission from human skin can also beused to determine the degree of irritation (13). Rates of carbon dioxide emissionfrom irritated skin increase roughly in proportion to the degree of irritation (14).


Transdermal Delivery Reactions

Four techniques (skin color reflectance, TEWL, laser Doppler flow (LDF) mea-surement, and visual scores) have been compared for their ability to quantify sodiumlauryl sulfate irritant dermatitis in humans (9). The study concluded that, althoughTEWL measurements may be an accurate and sensitive method in evaluating skinirritation when stratum corneum damage is present, color reflectance measurementsmay be a useful complimentary tool in the evaluation of skin damage. Detaileddocumentation on these bioengineering tools can be found in recent text books (15–17).

B. Allergic Contact Dermatitis

Allergic contact dermatitis testing is widely performed, with both human subjectsand laboratory animals, to determine the irritant potential of various chemicals. Theoldest of these assays is the Draize guinea pig test. The Draize test with animalmodels requires careful planning and performance. Buehler (18) and Magnusson andKligman (19) used five chemicals (benzocaine, formalin, monobenzyl ether of hy-droquinone, potassium chromate, and tetrachlorosalicylanilide) to compare sensiti-zation rate by the Draize test, closed patch test, and guinea pig maximization test(GPM test). The percentage of sensitized animals was about 5% with the Draize test,38% with the closed patch test, and 61% with the GPM test. This provides a roughestimate of the relative capacity of the three techniques to identify contact sensitizers.

Marzulli et al. (20) tested eight compounds using various modifications of theDraize guinea pig and human sensitization techniques (21). Skin sensitization wasobserved both in humans and guinea pigs with p-phenylenediamine and dinitro-chlorobenzene, and in humans, but not in guinea pigs, with neomycin, benzocaine,hexachlorophene, furacin, and a mixture of methyl and propyl parabens. The authorsstated that a negative result with guinea pigs provide an insufficient basis for con-cluding that a human is not likely to be sensitized by a substance.

The GPM test, the human maximization test,and the Draize repeat insult patchtest (22) have been used for extensive comparisons of contact sensitizers in guineapigs and humans (19). Contact sensitizers were rated in the five grades such thatweak (I), mild (II), moderate (III), strong (IV), and extensive (V) corresponded to0–8%, 9–28%, 29–64%, 65–80%, and 81–100% sensitized. The results are givenin Table 1. Neither technique produced sensitization with very weak allergens, suchas hexachlorophene and lanolin. Substances that did not sensitize humans, such asaluminum chloride, sodium lauryl sulfate, and polysorbate 80, did not sensitize theguinea pigs either. Quantitative structure activity relations (QSAR) analysis providesa powerful tool for predicting not only sensitization potential, but also how to defineappropriate testing parameters (23–26).

Guinea pig testing constitutes the first step in evaluating the allergenicity ofnew compounds or products. There is a reasonable degree of correspondence betweenthe results obtained with the GPM test and the human maximization test. These twotests rate the allergenicity of common human sensitizers in a similar fashion. Sub-stances that sensitize in the human test also do so in the animal test (27). Detaileddiscussions of animal and human sensitization assays and interpretation can be found(28,29). Skin reactions from topical drug delivery systems, including chemicals, met-als, and textiles, have been extensively investigated and may be found in series ofpublications (30–73).


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Table 1 Comparative Sensitization in Humans and Guinea Pigs by the Guinea PigMaximization Test and Human Maximization Test from the Following Chemicals

Chemicals

Guinea pigmaximization test

Positive (%) Grade

Humanmaximization test

Positive (%) Grade

Aluminum chlorideApresolineAtabrineBenzocaineFormalinHexachloropheneLanolinMalathionMercaptobenzothiazoleMercuric chlorideMonobenzyl ether of hydroquinoneNeomycinNickel sulfatePenicillin GPolysorbate 80Potassium dichromateSodium lauryl sulfateSulfathiazoleStreptomycinTetrachlorosalicylanilideTurpentineVioform

080902880

00

544032507255

1000

750

3672726420

IIVVIIIVII

IIIIIIIIIIIIIVIIIVI

IVI

IIIIVIVIIIII

0100

782272

00

100389292284867

0100

04

808872

0

IIVIVIIIVIIVIIIVVIIIIIIVIVII

IVIVIVI

Source: Ref. 8.

III. REACTIONS TO DRUG DELIVERY SYSTEMS

A. Transdermal Therapeutic Systems

Transdermal drug delivery systems for systemic effect are feasible for small, potent,and lipophilic drug molecules (74–76). Transdermal drug delivery systems are pres-ently marketed in the United States for seven drugs (estradiol, clonidine, nitroglyc-erin, scopolamine, nicotine, fentanyl, and testosterone), and others are under devel-opment. As the drug is the most frequently identified allergen, human subjects canbe patch-tested with the drug at an appropriate concentration in a suitable vehicle(Table 2). Skin irritation at the application site is the most common adverse effectaccompanying the use of transdermal therapeutic systems, occurring in as many as5–24% of women (77–89). Although generally mild and transient, it appears to bethe most common reason for discontinuation of treatment during published efficacyand tolerability studies (90). The following are adverse reactions related to the useof commercially available transdermal drug delivery systems.



Table 2 Concentration of Drug in Appropriate Vehicle Used in Patch Tests

Drug Vehicle Concentration (%) Ref.

Clonidine PetrolatumPetrolatum

19

7677

Estradiol Petrolatum 5 75Fentanyla

Nicotine Water 10 84Nitroglycerin Petrolatum

Water20.02

79,8081–83

Scopolamine PetrolatumWater

1.80.25

478

Testosterone Petrolatum 5

aTo be determined.

1. Estradiol

Estradiol is available as transdermal therapeutic systems, licensed for hormone re-placement in postmenopausal women. After assessing data from those trials involvingmore than 100 patients (and up to 15,194 patients), the reported incidence of skinreactions to the transdermal therapeutic system was between 5 and 35% (91–96).Most reactions consisted of mild erythema or pruritus at the application site, whichgenerally resolved after system removal. However, a small percentage of cases havebeen of sufficient severity to cause patients to discontinue treatment. Erkkola et al.(92) noted that 8.8% of patients withdrew from transdermal estradiol therapy becauseof skin irritation, although the number of patients withdrawing from treatment forthis reason in other studies has been less than 5% (91,93,95–97). The most commonadverse effect observed using transdermal estradiol was local irritation at the appli-cation site (98,99).

Similar results have been found in long-term (1-year) studies. Nachtigall (100)reported skin irritation in 14% of 138 patients receiving transdermal estradiol ther-apy; 3% of patients discontinued treatment for this reason. Randall (101) reportedon 29 patients, 10% withdrawing because of skin irritation.

Unpublished tolerability data involving 11,562 patients using estradiol trans-dermal therapeutic systems have shown a comparable incidence of dermatologicaladverse experiences. Treatment was either cyclic or continuous and, in some cases,included concomitant oral administration of progestogen. Duration of treatment var-ied from 8 to 52 weeks. Pooled results showed that, on average, the incidence oflocal skin reactions was 14.2%. Skin reactions were the most commonly reportedadverse experience, accounting for 47% of all reported adverse experiences. Thesereactions caused 6.3% of the patients, on average, to withdraw from treatment (dataon file, Ciba Geigy).

Several studies have specifically investigated the effects of the estradiol trans-dermal therapeutic system on skin. In many cases, the cutaneous adverse effectsreported have been overcome by changing application site. Allergic contact dermatitishas been induced by the components of the patch, as well as from the estrogen. Thecomponents of the patch, such as adhesive (102), hydroxypropyl cellulose (103),


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enhancer, such as alcohol, present in the reservoir (102,104); as well as the estrogen(102,105,106) have been shown to cause contact dermatitis, but this is uncommon(107,108).

2. Clonidine

Clonidine is a centrally acting �-agonist used primarily as an antihypertensive agent.A common adverse effect associated with transdermally administered clonidine isthe development of local skin reactions to the clonidine preparation. Reports of suchdermatological reactions range in incidence between 5 and 42% (109–112). Thesereactions vary in severity from mild erythema and pruritus to vesiculation and in-flammatory infiltration of the skin beneath the transdermal patch. Rarely, develop-ment of a generalized maculopapular rash has also been reported to occur followingtransdermal clonidine therapy. The majority of the skin reactions requiring discon-tinuation of therapy are mediated by a delayed-type IV hypersensitivity reaction(allergic contact dermatitis), which can be confirmed with patch testing using com-ponents of the clonidine transdermal device. In most of these patients the allergicreaction is due to clonidine specifically, whereas in other patients, a specific com-ponent of the transdermal system (polyisobutylene) functions as the allergen(79,109).

There is an effect of race and gender on the irritation rates from clonidine patchsystems. For example, occlusive transfermal clonidine patch systems show sensiti-zation rates of 34% in white women, 18% in white men, 14% in black women, and8% in black men (113). Itchiness under the patch and contact dermatitis were re-ported from clonidine transdermal patches (114). The long-term safety and efficacyof transdermal clonidine was evaluated in 102 patients for over 5 years. Transientlocal side effects occurred, mainly between weeks 4–26; thereafter, the incidenceclearly diminished and adverse events did not cause any withdrawal related to skinreactions from 1 year up to 5 years. Overall the long-term transdermal clonidinetreatment was highly accepted and was well tolerated by the patients (115). It isimportant to point out that predictive patch testing for allergic contact dermatitispotential requires special techniques, not only for clonidine systems but for trans-dermal systems in general (79,116).

3. Scopolamine

Scopolamine, a belladonna alkaloid indicated for nausea and vomiting associatedwith motion, radiotherapy, anesthesia, and surgery, was the first drug approved foruse as a transdermal patch-type delivery system. There are three reports of allergiccontact dermatitis to scopolamine. In a group of 164 sailors, 10% developed allergiccontact dermatitis after 1.5–15 months of use (117). Patch testing with 1.8% sco-polamine in petrolatum (2) or 0.25% in water (80) has been used to confirm allergiccontact dermatitis. Patch testing with structurally related alkaloids has failed to dem-onstrate cross-sensitivity, indicating the specific nature of the antigenic site for sco-polamine (2,118).

4. Nitroglycerin

Nitroglycerin is an organic nitrate used for the prevention and treatment of anginapectoris caused by coronary artery disease. Erythema under the nitroglycerin trans-dermal patch is frequent and represents the capacity of nitroglycerin to cause vaso-



dilation. Rubefaction at the margins of covered skin, noticed with a similar frequencyin placebo and active nitrate patches, is indicative of mild irritation (119). Irritantreddening disappeared spontaneously within a few hours. A more severe reaction,localized to the site of nitroglycerin and subsequently placebo patches, has beendescribed (120).

Allergic contact dermatitis to nitroglycerin, both in ointments and patch-typetransdermal drug delivery systems, has been reported (81,83,85,121,122). Some de-livery systems have employed acrylate adhesives, which have been implicated as theallergen in several of these cases (123).

5. Nicotine

The pharmacological side effects of transdermally absorbed nicotine have assumedgreater significance following recent research in alkaloid delivery through the skin.Percutaneous administration of nicotine may reduce the craving experienced duringabstinence from cigarette smoking and, thereby, serve as useful supplementationregimen during the behavioral modification process (124). Percutaneous nicotine ad-ministration induces predominant sudorific and rubiform responses in the skin thatmay be accompanied by subtle pyloerection, hyperalgesia, and pruritus (125).

The most common adverse effects of nicotine patches are cutaneous, charac-terized by itching (16–29% of patients), erythema (7–25%), and edema (2–7%).Poor cutaneous tolerability is a significant problem, resulting in withdrawal of thetreatment in 2–5% of patients (126,127). Bircher et al. (86) investigated 14 volun-teers with a history of adverse skin reactions to nicotine transdermal therapeuticsystems. Five of 14 demonstrated contact sensitivity to 10% aqueous nicotine solu-tion. Irritant reactions in 9 individuals were due to occlusion. The safety, tolerability,and efficacy of transdermal nicotine patch was studied in 80 patients who smoked.Side effects, such as itch and local erythema, were reported in 4 patients (128).

6. Testosterone

Testosterone transdermal therapeutic systems are used in the treatment of hypo-gonadism in men. One system is designed to be applied to the scrotum and requireschanging daily. Three male subjects of nine reported transient pruritus with the pla-cebo patch; however, none reported this with the use of testosterone transdermaltherapeutic systems (129). An alternative system for application to glabrous skin wasrecently been commercialized in the United States. The package insert lists blisterdevelopment in 11.5% of the phase I–III clinical study population (130).

7. Fentanyl

Fentanyl is a narcotic analgesic used for medication before surgical procedures. Ad-verse effects on skin (erythema) have been reported (131,132). The physicochemicalproperties and adverse effects of transdermally administered fentanyl have been de-scribed. Dermatological reactions to the fentanyl patch are generally transient andmild (133).

B. Iontophoresis

Iontophoresis increases the penetration of ionized substances into or through a tissueby application of an electric field (76,134–137). Iontophoresis has the potential to


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overcome many limitations associated with conventional transdermal systems andcould be feasible for ionic, hydrophilic, and higher molecular weight drugs. Skinirritation, however, has been reported following iontophoresis, but extensive toxi-cological studies are still required (138). Such studies are underway in our laboratory(139).

1. Barrier Properties and Skin Reactions

Skin irritation and stratum corneum integrity following 1- and 4-h saline iontopho-resis in human subjects were evaluated using several response measurements:

1. A visual scoring system2. Transepidermal water loss3. Skin capacitance4. Skin color5. Skin temperature

Saline iontophoresis for 1 or 4 h did not produce significant changes in skinwater loss and skin water content, suggesting that skin function was unaffected bytranscutaneous electrical stimulation. However, the occurrence of transient changesin skin structure (papules) was observed (unpublished data).

Papules are observed following iontophoresis, indicating that the electrical cur-rent occasionally induced short-term, transient changes in skin. Direct effects ofelectrical stimulation on vascular permeability were reported. For example, macro-molecular capillary leakage was demonstrated following stimulation of the hamstercheek pouch and the rabbit tibia with direct current of 5–50 �A for 30–160 min(140). Several types of sweat retention (miliaria) have been described. Iontophoresisproduces miliaria rubra with distilled water after 10 min of current delivery at 0.5mA/cm2 (141). The same study showed that vesicles had a different aspect than thosewe have observed, in that they were uniformly scattered and their walls were fragileenough to be rubbed off with a towel. Also, physiological saline did not producevesicles under the same conditions.

The effect of 4-h saline iontophoresis at the current density of 0.2 mA/cm2 wasinvestigated on skin barrier function and irritation in four ethnic groups (whites,Hispanics, blacks, and Asians) (142). The results suggested that iontophoresis waswell tolerated in all four groups, and that skin barrier function, as determined byTEWL and skin capacitance measurements, was not irreversibly affected by ionto-phoresis in any group. There was no significant difference (p > 0.05) in skin tem-perature, compared with baseline at all observation points in the ethnic groups. Noedema was observed in any group. However erythema was higher than the baselineowing to iontophoresis in all the four groups (Table 3). The subjects also demon-strated papules. The highest number of subjects exhibiting papules were in the Asiangroup followed by Hispanics, whites, and blacks (142). The results of skin reactionsto iontophoresis in four ethnic groups are given in Table 4. Details of differences inethnic skin can be found in Berardesca and Maibach (143).

Solvents remove intercellular lipids resulting in cutaneous barrier disruption.In a study on the effect of alcohol, acetone, and electrode gel swabbing and ionto-phoresis on skin irritation, the skin integrity was not affected. However, erythemaand papules were observed, but these were virtually resolved 24 h after patch removal(144).



Table 3 Draize Erythema Scoresa from Iontophoresis inEthnic Groups

Ethnic group Active site Control site

WhiteBlackHispanicAsian

8E1 (3E1); 2E29E1 (3E1); 1E23E1 (4E1); 7E2

4E1; 6E2

2E12E12E11E1

aEntries are frequencies of subjects experiencing the level of theerythema (E). Entries are listed such that for example: 8E1 (3E1)indicates eight subjects developed erythema score of ‘‘1’’ which wasnot resolved in three subjects 1440 min after patch removal. Ery-thema score was not significantly different (p > 0.05) among ethnicgroups.Source: Ref. 142.

Table 4 Skin Reactionsa to 4-h Iontophoresis: Influence ofEthnic Group

Ethnic group

Observation time

Patchremoval 60 min 1440 min

White PA 1pAA 3p AA 2p AA 1p

Black AA 3p AA 3p AA 1cHispanic AA 8p

AC 1pAA 7p AA 3c

Asian AA 8pAC 5p

AA 10pAC 5p

AA 6c

aEntries are frequencies of subjects (n = 10) experiencing papules (p)and papules in dry state [i.e., crust (c)]. Entries are listed as activeanode, AA; active cathode, AC; passive anode, PA; and passive cath-ode, PC: for example, PA 1p at patch removal immediately afteriontophoresis indicates one subject developed papules at the passiveanode site at observation time immediately after patch removal andAA 1c at 1440 min (24 h) indicates one subject still had papules indry state (crust) 1440 min after iontophoresis at the active anode site.Source: Ref. 142.

2. Sensation and Itching

The range of sensations evoked by transcutaneous electrical stimulation have variedfrom tactile (touch, vibration, or other) to pricking pain and itch. Thermal sensations,however, have rarely been reported (145–152). A high-voltage low-current transcu-taneous electrical stimulating device was tested for prickle sensation in 162 subjects.The initial sensation experienced by subjects was prickle (153).

Itching is felt in certain subjects during and after iontophoresis. The way thatitch is signaled to the central nervous system (CNS) remains incompletely under-


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stood. A general theory proposes that the whole spectrum of cutaneous sensations issignaled by differences in the patterns of activity; hence, any particular neuron cansignal a variety of sensory modalities. However, the finding that high-frequency,electrical stimulation of large myelinated axons in the peripheral nerves of conscioushumans consistently evokes painless sensations argues against such models (154).An alternative view proposes that an individual neuron transmits a specific type ofsensory information. Itch sensation evoked by percutaneous microiontophoresis ofhistamine on hairy human skin was studied (155). Iontophoresis of histamine evokedsensations of itch in human subjects; therefore, itch sensation may be implicatedowing to release of histamine during iontophoresis.

Under proper conditions, touch sensations, such as thumping, vibration, andpulsing, can be elicited by electrical stimulation of hairy skin (156–158). In contrastwith hairy skin, the threshold sensations on glabrous skin are touch instead of pruritus(159). With electrode paste used on six subjects as a conductive medium, half re-ported painful sensation, similar to acid burn, but with saline they felt itch (160).Changes in electrode size may alter the quality of sensation from itch to pain (161).Recent advances in defining C-fiber function is described (162).

3. Burns

Burns occur if the patient uses excessive stimulation with small-area electrodes orif the interface between the skin and electrode is dry (163). Shealy and Maurer (164)demonstrated that the electrode surface area must be more than 4 cm2 for a 500-�s85-mA–pulse, 185-pps stimulus. The heat produced must be less than 250 mcal/cm2

s�1 to avoid localized burns. Burton (165) described another type of injury, micro-punctate burns. The explanation was that current flow is not distributed over a widesurface area, but is concentrated in small punctate areas (usually hair follicles). Be-cause of the concentration of the large volume of current in small areas, currentdensity is high, resulting in skin burns. These micropunctate skin burns representtrue thermal damage to the skin, but Burton (165) feels that they are of little clinicalsignificance, in themselves, as with allergic reactions, simple discontinuation of useof the electrodes permit recovery.

4. Virus Activation

In humans, one isolated case of an outbreak of molluscum contagiosum, a DNAvirus of the pox group, at the site of hydrocortisone iontophoresis has been described(166). It appears that the phenomenon is more related to the drug being deliveredthan to iontophoretic mode of delivery.

C. Electroporation

Electroporation involves alteration of lipid bilayers when transient and pulsed electricfields lead to the reversible formation of nonlamellar lipid phases: a pore. Iontopho-resis utilizes existing pathways, such as hair follicles or sweat glands. These sweatglands and hair follicles comprise only about 0.1% of the total skin surface area.Thus, a high-charge density occurs around sweat glands and hair follicles, whichmay potentially lead to localized skin irritation. In electroporation, the other 99.9%of the skin’s surface area is reversibly altered using a brief pulse of electricity. As a



consequence, the current density is distributed more uniformly across the surface;thus, potential for irritation may be reduced (167).

The effect of current and voltage on pig skin was evaluated under conditionsof iontophoresis and electroporation (167). Pigs were treated with either an ionto-phoresis or an electroporation protocol. The study evaluated irritation, not drug de-livery. Current densities used were in the range from 0 to 10 mA/cm2, and the appliedvoltage ranged from 0 to 1000 V. The potential was a single pulse followed by 30min of iontophoresis. Irritation was measured at 0 and 4 h after treatment. Skinbiopsies were taken for histological examination. Irritation was measured by thevisual scoring system of Draize et al. (6). Use of conventional iontophoresis, whenthere was no applied voltage pulse and current density was near 0.2 mA/cm2, resultedin no significant difference from the no-pulse values in either of these measures. Theskin response was measured in terms of erythema at the anode and the cathode.Again iontophoresis produced a value not significantly different from that of a pulseplus iontophoresis at both the cathode and the anode. These results showed that apulse voltage of up to 1000 V had no effect on erythema or edema. Erythema andedema are equivalent for iontophoresis and electroporation. Thus, one can concludethat electroporation under these test conditions produced no measurable damage toskin or tissue.

IV. CONCLUSIONS

Adequate evaluation of irritation potential of chemical substances depends on a thor-ough understanding of the variables influencing the irritant response. Guinea pigtesting and the local lymph node assays constitute a first step in evaluating theallergenicity of new compounds or products. With the traditional Draize test, potentirritants can be detected. Substances that irritate in humans also do so in someanimals. More sensitive animal tests will identify weak irritants. The comparativesensitivity of these various tests is still under examination. There is a reasonabledegree of correlation between the GPM test and the human maximization test.

Transdermal therapeutic systems have proved to be a useful adjunct for ad-ministration of systemic medications. Their potential for future applications seemsexcellent. However, the systems carry a risk of either irritant or allergic skin sensi-tivity. Avoidance of reapplication of patches directly over the previous site, shouldhelp minimize the incidence and severity of such irritation. Keep in view that withthe delayed onset of some allergic reactions, safety data based on short-term expe-rience should be considered with caution.

There is increasing interest in the use of iontophoresis. Such therapy may re-quire long-term delivery and the extended wearing of delivery systems. Irritations insuch patients may be greater than those found with the more brief applications forwhich iontophoresis is most widely used today. There is no doubt that iontophoresiscan be a safe and effective method of drug delivery by the innovative application ofmodern electronics and material science; however, extensive skin toxicological stud-ies are warranted. Alternatively, electroporation followed by iontophoresis can beused to lower the skin irritation. With electroporation, new pathways are created. Asa consequence, there is more even distribution of charge; hence, there may be alower potential for irritation.


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22. Kligman AM. The identification of contact allergens by human assay. III. The maxi-mization test: a procedure for screening and rating contact sensitizers. J Invest Dermatol47:393–409, 1966.

23. Lepoittevin J–P, Benezra C, Sigman CC, Bagheri D, Fraginals R, Maibach HI. Mo-lecular aspects of allergic contact dermatitis. In: Textbook of Contact Dermatitis. Berlin:Springer-Verlag, p 105, 1995.

24. Menne T, Flyvholm MA, Maibach HI. Prevention of allergic contact sensitization. In:Vos JG, Younes M, Smith E, eds. Allergic Hypersensitivities Induced by Chemicals.Boca Raton: CRC Press, p 287, 1996.

25. Marzulli FN, Maibach HI. Allergic contact dermatitis. In: Marzulli FN, Maibach HI,eds. Dermatotoxicology. 5th ed. Washington: Hemisphere, p 143–146, 1996.

26. Marzulli FN, Maibach HI. Test methods for allergic contact dermatitis in humans. In:Marzulli FN, Maibach HI, eds. Dermatotoxicology. 5th ed. Washington: Hemisphere,pp 477–483, 1996.

27. Magnusson B, Kligman AM. Usefulness of guinea pig tests for detection of contactsensitizers. In: Marzulli FN, Maibach HI, eds. Advances in Modern Toxicology. Vol 4.Dermatotoxicology and Pharmacology. New York: John Wiley & Sons, p 551, 1977.

28. Marzulli FN, Maibach HI, eds. Dermatotoxicology. 5th ed. Washington: Hemisphere,1996.

29. Anderson R, Maibach HI, eds. Guinea Pig Sensitization Assays. New York: Karger,1987.

30. Welthriend S, Kwangsukstith C, Maibach HI. Contact urticaria from cucumber pickleand strawberry. Contact Dermatitis 32:173–174, 1995.

31. Hardy MP, Maibach HI. Contact urticaria syndrome from sorbitan sesquioleate in acorticosteroid ointment. Contact Dermatitis 32:114, 1995.

32. Maibach HI. Contact urticaria syndrome from mold on salami casing. Contact Der-matitis 32:120–121, 1995.

33. West I, Maibach HI. Contact urticaria syndrome from multiple cosmetic components.Contact Dermatitis 32:121, 1995.

34. Elsner P, Maibach HI, eds. Irritant Dermatitis, New Clinical and Experimental Aspects.Current Problems in Dermatology. Vol. 23. Basel: Karger, 1995.

35. Holness DL, Nethercott JR, Adams RM, Belsito D, Deleo V, Emmett EA, Fowler J,Fisher AA, Larsen WG, Maibach HI, Marks J, Reitschel RL, Rosenthal LE, SchorrWF, Storrs FJ, Taylor JS. Concomitant positive patch test results with standard screen-ing tray in North America 1985–1989. Contact Dermatitis 32:289–292, 1995.

36. Maibach HI. Dermatologic vehicles: science and art. Cutis 55(4S):4, 1995.37. Funk JO, Dromgoole SH, Maibach HI. Sunscreen intolerance: contact sensitization,

photocontact sensitization, and irritancy of sunscreen agents. Dermatol Clin 13:473–481, 1995.

38. Hatch KL, Maibach HI. Textile dermatitis: an update (1) resins, additives and fibers.Contact Dermatitis 32:319–326, 1995.

39. Hardy M, Maibach HI. Contact urticaria syndrome from sorbitan sesquioleate in acorticosteroid ointment. Contact Dermatitis 32:114, 1995.

40. Lee CH, Maibach HI. The sodium lauryl sulfate model: an overview. Contact Der-matitis 33:1–7, 1995.

41. Hostynek JJ, Lauerma AI, Magee PS, Maibach HI. A local lymph-node assay validationstudy of a structure–activity relationship model for contact allergens. Arch DermatolRes 287:567–571, 1995.

42. Hui X, Wester RC, Magee PS, Maibach HI. Partitioning of chemicals from water intopowdered human stratum corneum (callus): a model study. In Vitro Toxicol 8:159–167, 1995.


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43. Tur E, Aviram G, Zeltser D, Brenner S, Maibach HI. Regional variations of humanskin blood flow response to histamine. In: Exogenous Dermatology, Advances in Skin-Related Allergology, Bioengineering, Pharmacology and Toxicology. Basel: Karger, p59, 1995.

44. Ale SI, Maibach HI. Clinical relevance in allergic contact dermatitis, an algorithmicapproach. Occup Environ Dermatoses 43:119–121, 1995.

45. Liden C, Maibach HI, Wahlberg JE. Skin. In: Metal Toxicology. New York: Academic,p 447, 1995.

46. Kwangsukstith C, Maibach HI. Contact urticaria from polyurethane membrane hy-poallergenic gloves. Contact Dermatitis 33:200–201, 1995.

47. Patil S, Harvell J, Maibach HI. In vitro skin irritation assays: relevance to human skin.In: Gali CL, Goldberg AM, Marinovich M, eds. Modulation of Cellular Responses inToxicity. Berlin: Springer-Verlag, p 283, 1995.

48. Effendy I, Maibach HI. Surfactants and experimental irritant contact dermatitis. ContactDermatitis 33:217–225, 1995.

49. Lauerma AI, Aioi A, Maibach HI. Topical cis-urocanic acid suppresses both inductionand elicitation of contact hypersensitivity in BALB/C mice. Acta Derm Venereol 75:272–275, 1995.

50. Andersen PH, Maibach HI. Skin irritation in man: a comparative bioengineering studyusing improved reflectance spectroscopy. Contact Dermatitis 33:315–322, 1995.

51. Tur E, Eshkol Z, Brenner S, Maibach HI. Cumulative effect of subthreshold concen-trations of irritants in humans. J Contact Dermatitis 6:216–220, 1995.

52. van der Valk PGM, Maibach HI, eds. The Irritant Contact Dermatitis Syndrome. BocaRaton: CRC Press, 1995.

53. Ophaswongse S, Maibach HI. Allergic contact cheilitis. Contact Dermatitis 33:365–370, 1995.

54. Effendy I, Loeffler H, Maibach HI. Baseline transepidermal water loss in patients withacute and healed irritant contact dermatitis. Contact Dermatitis 33:371–374, 1995.

55. Kwangsukstith C, Maibach HI. Effect of age and sex on the induction and elicitationof allergic contact dermatitis. Contact Dermatitis 33:289–298, 1995.

56. Frosch PJ, Pilz B, Andersen KE, Burrows D. Carnarasa JG, Dooms–Goossens A, Du-combs G, Fuchs T, Hannuksela M, Lachapelle JM, Lahti A, Maibach HI, Menne T,Rycroft RJG, Shaw S, Wahlberg JE, White IR, Wilkinson JD. Patch testing with fra-grances: results of multicenter study of the European Environmental and Contact Der-matitis Research group with 48 frequently used constituents of perfumes. Contact Der-matitis 33:333–342, 1995.

57. Maibach HI. Possible cosmetic dermatitis due to mercaptobenzothiazole. Contact Der-matitis 34:72, 1996.

58. Patil S, Singh P, Maibach HI. Radial spread of sodium lauryl sulfate after topicalapplication. Pharm Res 12:2018–2023, 1995.

59. Amin S, Maibach HI. Cosmetic intolerance syndrome: pathophysiology and manage-ment. Cosmet Dermatol 9:34, 1996.

60. Smith JD, Odom RB, Maibach HI. Contact urticaria from cobalt chloride. Arch Der-matol 111:1610, 1995.

61. Effendy I, Kwangsukstith C, Lee JY, Maibach HI. Functional changes in human stratumcorneum induced by topical glycolic acid: comparisons with all-trans-retinoic acid.Acta Derm Venereol 75:455, 1995.

62. Nangia A, Andersen PH, Berner B, Maibach HI. High dissociation constants (pKa) ofbasic permeants are associated with in vivo skin irritation in man. Contact Dermatitis34:237–242, 1996.

63. Maibach HI. Acne necrotica varioliformis (P. acnes folliculitis); resolution with iso-tretinoin. Eur J Dermatol 6:153, 1996.



64. Mitchell JC, Maibach HI. Difficulties to investigate dermatitis from plants, a practicalapproach to office-based diagnosis. Dermatosan 44:29, 1996.

65. Effendy I, Weltfriend S, Patil S, Maibach HI. Differential irritant skin responses totopical retinoic acid and sodium lauryl sulfate: alone and crossover design. Br J Der-matol 134:424, 1996.

66. Flyvholm MA, Menne T, Maibach HI. Skin allergy: exposure and dose–response re-lationships. In: Vos JG, Younes M, Smith E, eds. Allergic Hypersensitivities Inducedby Chemicals. Boca Raton: CRC Press, p 261, 1996.

67. Weltfriend S, Bason M, Lammintausta K, Maibach HI. Irritant dermatitis (irritation).In: Marzulli FN, Maibach HI, eds. Dermatotoxicology. 5th ed. Washington: Hemi-sphere, pp 87–118, 1996.

68. Menne T, Veien N, Maibach HI. Systemic contact-type dermatitis. In: Marzulli FN,Maibach HI, eds. Dermatotoxicology. 5th ed. Washington: Hemisphere, pp 161–175,1996.

69. Patil SM, Hogan DJ, Maibach HI. Transdermal drug delivery systems: adverse der-matologic reactions. In: Marzulli FN, Maibach HI, eds. Dermatotoxicology. 5th ed.Washington: Hemisphere, pp 389–396, 1996.

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