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11 Transdermal Delivery and Cutaneous 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 allergy. The risk of skin reactions produced by chemicals depends on their inherent allergenicity and ability to penetrate into the normal skin or damaged skin. As fully described in earlier chapters, the penetration of chemicals into the skin depends on skin condition, anatomical site, chemical characteristics of the substance, lipid solubility and concentration of the chemical. Penetration is also influenced by external factors, especially solvents, surface-active agents, alkalies, moisture, temperature, extreme dehydration, and mechanical effects. The length of time that a substance contacts the skin is of great importance. Skin irritation influences the cells of the skin and results in an increased sensitization risk. Such cell damage can be produced by variety of chemicals or by mechanical means. Irritation is the nonimmunological evocation of normal or exaggerated reaction in a tissue by application of a stimulus. Irritation may be subjective or objective. Subjective irritation refers to transient pruritus, stinging, burning, or related sensations without subsequent visible inflammation (e.g., alcohol on an open wound). A chemical substance that evokes inflammation on initial exposure is called an acute (primary) irritant but, on repeated exposure to an identical site, will cause cumulative irritation. In the past, soaps, cosmetic materials, and pest control chemicals have Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved. Singh been recognized as potential sources of cutaneous irritation. More recently it has been recognized that a multitude of occupational and environmental factors, such as organic dyes and solvents or industrial waste material contribute to this topical skin disorder. The most common reaction consists of a local inflammatory response characterized by erythema or edema, or a corrosive reaction characterized by local tissue destruction or necrosis. Other reactions, sometimes referred to as irritation, do not display visible signs of inflammation. Subtle increases in epidermal thickness, without visible or histological inflammation, may be produced by a variety of substances usually thought to be nonirritating (1). The occlusive nature of many transdermal delivery systems provides an ideal model for inducing sensitization. Potential allergens include the adhesive, the diffusion membrane, the solvent, the enhancer, and the drug. Allergic contact dermatitis with redness, swelling, and sometimes vesiculation, is the most overt presentation of skin sensitivity from transdermal delivery systems. The reaction is usually localized to the site of application of the current patch, but may also occur at the sites of previous applications, the flare-up reaction (2). Spread of the eczematous reaction to sites not associated with the application of patches may occur (3). Urticaria and angioedema are rare allergic reactions to transdermal therapeutic systems (4). This chapter deals with the skin reactions caused by topical drug delivery systems. II. A. PREDICTIVE TESTING Irritation There is not yet an adequately validated in vitro model available to predict skin irritation of topical chemicals. Details of the current state of development of these potentially useful assays were summarized (5). The standard method to forecast skin irritation is by so-called predictive tests on humans or animals. The most widely used test for predicting potential skin irritants to humans, using animal models, was published by Draize et al. (6), and has been refined by many groups (7). The test was initially designed to classify chemicals that cause primary (acute) irritation. However, in designing a test that would eliminate false-negative reactions (type 2 errors), Draize permitted the introduction of a significant number of false-positive reactions (type 1 errors). The rabbit Draize test, properly performed and interpreted by experienced scientists, still remains valuable. Transepidermal water loss (TEWL) is a well-accepted method for quantifying alterations in stratum corneum function (8), and it provides a robust method for assessing stratum corneum damage. Irritation tends to reduce the efficiency of the stratum corneum barrier function and may result in an increase in TEWL. This is sometimes associated with a decrease in skin water content (9). Hence, measurement of 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 be used to determine the degree of irritation (13). Rates of carbon dioxide emission from irritated skin increase roughly in proportion to the degree of irritation (14). Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved. Transdermal Delivery Reactions Four techniques (skin color reflectance, TEWL, laser Doppler flow (LDF) measurement, and visual scores) have been compared for their ability to quantify sodium lauryl sulfate irritant dermatitis in humans (9). The study concluded that, although TEWL measurements may be an accurate and sensitive method in evaluating skin irritation when stratum corneum damage is present, color reflectance measurements may be a useful complimentary tool in the evaluation of skin damage. Detailed documentation 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 subjects and laboratory animals, to determine the irritant potential of various chemicals. The oldest of these assays is the Draize guinea pig test. The Draize test with animal models requires careful planning and performance. Buehler (18) and Magnusson and Kligman (19) used five chemicals (benzocaine, formalin, monobenzyl ether of hydroquinone, potassium chromate, and tetrachlorosalicylanilide) to compare sensitization 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 rough estimate of the relative capacity of the three techniques to identify contact sensitizers. Marzulli et al. (20) tested eight compounds using various modifications of the Draize guinea pig and human sensitization techniques (21). Skin sensitization was observed both in humans and guinea pigs with p-phenylenediamine and dinitrochlorobenzene, and in humans, but not in guinea pigs, with neomycin, benzocaine, hexachlorophene, furacin, and a mixture of methyl and propyl parabens. The authors stated that a negative result with guinea pigs provide an insufficient basis for concluding that a human is not likely to be sensitized by a substance. The GPM test, the human maximization test,and the Draize repeat insult patch test (22) have been used for extensive comparisons of contact sensitizers in guinea pigs and humans (19). Contact sensitizers were rated in the five grades such that weak (I), mild (II), moderate (III), strong (IV), and extensive (V) corresponded to 0–8%, 9–28%, 29–64%, 65–80%, and 81–100% sensitized. The results are given in Table 1. Neither technique produced sensitization with very weak allergens, such as hexachlorophene and lanolin. Substances that did not sensitize humans, such as aluminum chloride, sodium lauryl sulfate, and polysorbate 80, did not sensitize the guinea pigs either. Quantitative structure activity relations (QSAR) analysis provides a powerful tool for predicting not only sensitization potential, but also how to define appropriate testing parameters (23–26). Guinea pig testing constitutes the first step in evaluating the allergenicity of new compounds or products. There is a reasonable degree of correspondence between the results obtained with the GPM test and the human maximization test. These two tests rate the allergenicity of common human sensitizers in a similar fashion. Substances that sensitize in the human test also do so in the animal test (27). Detailed discussions of animal and human sensitization assays and interpretation can be found (28,29). Skin reactions from topical drug delivery systems, including chemicals, metals, and textiles, have been extensively investigated and may be found in series of publications (30–73). Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved. Singh Table 1 Comparative Sensitization in Humans and Guinea Pigs by the Guinea Pig Maximization Test and Human Maximization Test from the Following Chemicals Guinea pig maximization test Human maximization test Positive (%) 0 100 78 22 72 0 0 100 38 92 92 28 48 67 0 100 0 4 80 88 72 0 Grade I IV IV II IV I I V III V V II III IV I V I I IV IV IV I Chemicals Aluminum chloride Apresoline Atabrine Benzocaine Formalin Hexachlorophene Lanolin Malathion Mercaptobenzothiazole Mercuric chloride Monobenzyl ether of hydroquinone Neomycin Nickel sulfate Penicillin G Polysorbate 80 Potassium dichromate Sodium lauryl sulfate Sulfathiazole Streptomycin Tetrachlorosalicylanilide Turpentine Vioform Source: Ref. 8. Positive (%) 0 80 90 28 80 0 0 54 40 32 50 72 55 100 0 75 0 36 72 72 64 20 Grade I IV V II IV I I III III III III IV III V I IV I III IV IV III II III. A. REACTIONS TO DRUG DELIVERY SYSTEMS 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 presently marketed in the United States for seven drugs (estradiol, clonidine, nitroglycerin, scopolamine, nicotine, fentanyl, and testosterone), and others are under development. As the drug is the most frequently identified allergen, human subjects can be 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 effect accompanying the use of transdermal therapeutic systems, occurring in as many as 5–24% of women (77–89). Although generally mild and transient, it appears to be the most common reason for discontinuation of treatment during published efficacy and tolerability studies (90). The following are adverse reactions related to the use of commercially available transdermal drug delivery systems. Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved. Transdermal Delivery Reactions Table 2 Drug Clonidine Concentration of Drug in Appropriate Vehicle Used in Patch Tests Vehicle Petrolatum Petrolatum Petrolatum Water Petrolatum Water Petrolatum Water Petrolatum Concentration (%) 1 9 5 10 2 0.02 1.8 0.25 5 Ref. 76 77 75 84 79,80 81–83 4 78 Estradiol Fentanyla Nicotine Nitroglycerin Scopolamine Testosterone a To be determined. 1. Estradiol Estradiol is available as transdermal therapeutic systems, licensed for hormone replacement in postmenopausal women. After assessing data from those trials involving more than 100 patients (and up to 15,194 patients), the reported incidence of skin reactions to the transdermal therapeutic system was between 5 and 35% (91–96). Most reactions consisted of mild erythema or pruritus at the application site, which generally resolved after system removal. However, a small percentage of cases have been of sufficient severity to cause patients to discontinue treatment. Erkkola et al. (92) noted that 8.8% of patients withdrew from transdermal estradiol therapy because of skin irritation, although the number of patients withdrawing from treatment for this reason in other studies has been less than 5% (91,93,95–97). The most common adverse effect observed using transdermal estradiol was local irritation at the application 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 therapy; 3% of patients discontinued treatment for this reason. Randall (101) reported on 29 patients, 10% withdrawing because of skin irritation. Unpublished tolerability data involving 11,562 patients using estradiol transdermal therapeutic systems have shown a comparable incidence of dermatological adverse experiences. Treatment was either cyclic or continuous and, in some cases, included concomitant oral administration of progestogen. Duration of treatment varied from 8 to 52 weeks. Pooled results showed that, on average, the incidence of local skin reactions was 14.2%. Skin reactions were the most commonly reported adverse experience, accounting for 47% of all reported adverse experiences. These reactions caused 6.3% of the patients, on average, to withdraw from treatment (data on file, Ciba Geigy). Several studies have specifically investigated the effects of the estradiol transdermal therapeutic system on skin. In many cases, the cutaneous adverse effects reported have been overcome by changing application site. Allergic contact dermatitis has been induced by the components of the patch, as well as from the estrogen. The components of the patch, such as adhesive (102), hydroxypropyl cellulose (103), Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved. Singh 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 is the development of local skin reactions to the clonidine preparation. Reports of such dermatological reactions range in incidence between 5 and 42% (109–112). These reactions vary in severity from mild erythema and pruritus to vesiculation and inflammatory infiltration of the skin beneath the transdermal patch. Rarely, development of a generalized maculopapular rash has also been reported to occur following transdermal clonidine therapy. The majority of the skin reactions requiring discontinuation of therapy are mediated by a delayed-type IV hypersensitivity reaction (allergic contact dermatitis), which can be confirmed with patch testing using components of the clonidine transdermal device. In most of these patients the allergic reaction is due to clonidine specifically, whereas in other patients, a specific component 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 patch systems. For example, occlusive transfermal clonidine patch systems show sensitization rates of 34% in white women, 18% in white men, 14% in black women, and 8% in black men (113). Itchiness under the patch and contact dermatitis were reported from clonidine transdermal patches (114). The long-term safety and efficacy of transdermal clonidine was evaluated in 102 patients for over 5 years. Transient local side effects occurred, mainly between weeks 4–26; thereafter, the incidence clearly diminished and adverse events did not cause any withdrawal related to skin reactions from 1 year up to 5 years. Overall the long-term transdermal clonidine treatment was highly accepted and was well tolerated by the patients (115). It is important to point out that predictive patch testing for allergic contact dermatitis potential requires special techniques, not only for clonidine systems but for transdermal systems in general (79,116). 3. Scopolamine Scopolamine, a belladonna alkaloid indicated for nausea and vomiting associated with motion, radiotherapy, anesthesia, and surgery, was the first drug approved for use as a transdermal patch-type delivery system. There are three reports of allergic contact dermatitis to scopolamine. In a group of 164 sailors, 10% developed allergic contact dermatitis after 1.5–15 months of use (117). Patch testing with 1.8% scopolamine in petrolatum (2) or 0.25% in water (80) has been used to confirm allergic contact dermatitis. Patch testing with structurally related alkaloids has failed to demonstrate cross-sensitivity, indicating the specific nature of the antigenic site for scopolamine (2,118). 4. Nitroglycerin Nitroglycerin is an organic nitrate used for the prevention and treatment of angina pectoris caused by coronary artery disease. Erythema under the nitroglycerin transdermal patch is frequent and represents the capacity of nitroglycerin to cause vaso- Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved. Transdermal Delivery Reactions dilation. Rubefaction at the margins of covered skin, noticed with a similar frequency in placebo and active nitrate patches, is indicative of mild irritation (119). Irritant reddening disappeared spontaneously within a few hours. A more severe reaction, localized to the site of nitroglycerin and subsequently placebo patches, has been described (120). Allergic contact dermatitis to nitroglycerin, both in ointments and patch-type transdermal drug delivery systems, has been reported (81,83,85,121,122). Some delivery systems have employed acrylate adhesives, which have been implicated as the allergen in several of these cases (123). 5. Nicotine The pharmacological side effects of transdermally absorbed nicotine have assumed greater significance following recent research in alkaloid delivery through the skin. Percutaneous administration of nicotine may reduce the craving experienced during abstinence from cigarette smoking and, thereby, serve as useful supplementation regimen during the behavioral modification process (124). Percutaneous nicotine administration induces predominant sudorific and rubiform responses in the skin that may be accompanied by subtle pyloerection, hyperalgesia, and pruritus (125). The most common adverse effects of nicotine patches are cutaneous, characterized by itching (16–29% of patients), erythema (7–25%), and edema (2–7%). Poor cutaneous tolerability is a significant problem, resulting in withdrawal of the treatment in 2–5% of patients (126,127). Bircher et al. (86) investigated 14 volunteers with a history of adverse skin reactions to nicotine transdermal therapeutic systems. Five of 14 demonstrated contact sensitivity to 10% aqueous nicotine solution. 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 hypogonadism in men. One system is designed to be applied to the scrotum and requires changing daily. Three male subjects of nine reported transient pruritus with the placebo patch; however, none reported this with the use of testosterone transdermal therapeutic systems (129). An alternative system for application to glabrous skin was recently been commercialized in the United States. The package insert lists blister development 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. Adverse effects on skin (erythema) have been reported (131,132). The physicochemical properties and adverse effects of transdermally administered fentanyl have been described. Dermatological reactions to the fentanyl patch are generally transient and mild (133). B. Iontophoresis Iontophoresis increases the penetration of ionized substances into or through a tissue by application of an electric field (76,134–137). Iontophoresis has the potential to Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved. Singh overcome many limitations associated with conventional transdermal systems and could be feasible for ionic, hydrophilic, and higher molecular weight drugs. Skin irritation, however, has been reported following iontophoresis, but extensive toxicological 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 iontophoresis in human subjects were evaluated using several response measurements: 1. 2. 3. 4. 5. A visual scoring system Transepidermal water loss Skin capacitance Skin color Skin temperature Saline iontophoresis for 1 or 4 h did not produce significant changes in skin water loss and skin water content, suggesting that skin function was unaffected by transcutaneous electrical stimulation. However, the occurrence of transient changes in skin structure (papules) was observed (unpublished data). Papules are observed following iontophoresis, indicating that the electrical current occasionally induced short-term, transient changes in skin. Direct effects of electrical stimulation on vascular permeability were reported. For example, macromolecular capillary leakage was demonstrated following stimulation of the hamster cheek 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. Iontophoresis produces miliaria rubra with distilled water after 10 min of current delivery at 0.5 mA/cm2 (141). The same study showed that vesicles had a different aspect than those we have observed, in that they were uniformly scattered and their walls were fragile enough to be rubbed off with a towel. Also, physiological saline did not produce vesicles under the same conditions. The effect of 4-h saline iontophoresis at the current density of 0.2 mA/cm2 was investigated on skin barrier function and irritation in four ethnic groups (whites, Hispanics, blacks, and Asians) (142). The results suggested that iontophoresis was well tolerated in all four groups, and that skin barrier function, as determined by TEWL and skin capacitance measurements, was not irreversibly affected by iontophoresis in any group. There was no significant difference (p > 0.05) in skin temperature, compared with baseline at all observation points in the ethnic groups. No edema was observed in any group. However erythema was higher than the baseline owing to iontophoresis in all the four groups (Table 3). The subjects also demonstrated papules. The highest number of subjects exhibiting papules were in the Asian group followed by Hispanics, whites, and blacks (142). The results of skin reactions to iontophoresis in four ethnic groups are given in Table 4. Details of differences in ethnic 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 iontophoresis on skin irritation, the skin integrity was not affected. However, erythema and papules were observed, but these were virtually resolved 24 h after patch removal (144). Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved. Transdermal Delivery Reactions Table 3 Draize Erythema Scoresa from Iontophoresis in Ethnic Groups Active site 8E1 (3E1); 2E2 9E1 (3E1); 1E2 3E1 (4E1); 7E2 4E1; 6E2 Control site 2E1 2E1 2E1 1E1 Ethnic group White Black Hispanic Asian a Entries are frequencies of subjects experiencing the level of the erythema (E). Entries are listed such that for example: 8E1 (3E1) indicates eight subjects developed erythema score of ‘‘1’’ which was not resolved in three subjects 1440 min after patch removal. Erythema score was not significantly different (p > 0.05) among ethnic groups. Source: Ref. 142. 2. Sensation and Itching The range of sensations evoked by transcutaneous electrical stimulation have varied from tactile (touch, vibration, or other) to pricking pain and itch. Thermal sensations, however, have rarely been reported (145–152). A high-voltage low-current transcutaneous 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 that itch is signaled to the central nervous system (CNS) remains incompletely under- Table 4 Skin Reactionsa to 4-h Iontophoresis: Influence of Ethnic Group Observation time Ethnic group White Black Hispanic Asian a Patch removal PA 1p AA 3p AA 3p AA 8p AC 1p AA 8p AC 5p 60 min AA 2p AA 3p AA 7p AA 10p AC 5p 1440 min AA 1p AA 1c AA 3c AA 6c Entries are frequencies of subjects (n = 10) experiencing papules (p) and papules in dry state [i.e., crust (c)]. Entries are listed as active anode, AA; active cathode, AC; passive anode, PA; and passive cathode, PC: for example, PA 1p at patch removal immediately after iontophoresis indicates one subject developed papules at the passive anode site at observation time immediately after patch removal and AA 1c at 1440 min (24 h) indicates one subject still had papules in dry state (crust) 1440 min after iontophoresis at the active anode site. Source: Ref. 142. Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved. Singh stood. A general theory proposes that the whole spectrum of cutaneous sensations is signaled by differences in the patterns of activity; hence, any particular neuron can signal a variety of sensory modalities. However, the finding that high-frequency, electrical stimulation of large myelinated axons in the peripheral nerves of conscious humans consistently evokes painless sensations argues against such models (154). An alternative view proposes that an individual neuron transmits a specific type of sensory information. Itch sensation evoked by percutaneous microiontophoresis of histamine on hairy human skin was studied (155). Iontophoresis of histamine evoked sensations of itch in human subjects; therefore, itch sensation may be implicated owing to release of histamine during iontophoresis. Under proper conditions, touch sensations, such as thumping, vibration, and pulsing, can be elicited by electrical stimulation of hairy skin (156–158). In contrast with 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 reported 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 or if 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-␮s 85-mA–pulse, 185-pps stimulus. The heat produced must be less than 250 mcal/cm2 sϪ1 to avoid localized burns. Burton (165) described another type of injury, micropunctate burns. The explanation was that current flow is not distributed over a wide surface area, but is concentrated in small punctate areas (usually hair follicles). Because of the concentration of the large volume of current in small areas, current density is high, resulting in skin burns. These micropunctate skin burns represent true thermal damage to the skin, but Burton (165) feels that they are of little clinical significance, in themselves, as with allergic reactions, simple discontinuation of use of the electrodes permit recovery. 4. Virus Activation In humans, one isolated case of an outbreak of molluscum contagiosum, a DNA virus 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 delivered than to iontophoretic mode of delivery. C. Electroporation Electroporation involves alteration of lipid bilayers when transient and pulsed electric fields lead to the reversible formation of nonlamellar lipid phases: a pore. Iontophoresis utilizes existing pathways, such as hair follicles or sweat glands. These sweat glands 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, which may 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 Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved. Transdermal Delivery Reactions 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 conditions of iontophoresis and electroporation (167). Pigs were treated with either an iontophoresis or an electroporation protocol. The study evaluated irritation, not drug delivery. Current densities used were in the range from 0 to 10 mA/cm2, and the applied voltage ranged from 0 to 1000 V. The potential was a single pulse followed by 30 min of iontophoresis. Irritation was measured at 0 and 4 h after treatment. Skin biopsies were taken for histological examination. Irritation was measured by the visual scoring system of Draize et al. (6). Use of conventional iontophoresis, when there was no applied voltage pulse and current density was near 0.2 mA/cm2, resulted in no significant difference from the no-pulse values in either of these measures. The skin 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 pulse plus iontophoresis at both the cathode and the anode. These results showed that a pulse voltage of up to 1000 V had no effect on erythema or edema. Erythema and edema are equivalent for iontophoresis and electroporation. Thus, one can conclude that electroporation under these test conditions produced no measurable damage to skin or tissue. IV. CONCLUSIONS Adequate evaluation of irritation potential of chemical substances depends on a thorough understanding of the variables influencing the irritant response. Guinea pig testing and the local lymph node assays constitute a first step in evaluating the allergenicity of new compounds or products. With the traditional Draize test, potent irritants can be detected. Substances that irritate in humans also do so in some animals. More sensitive animal tests will identify weak irritants. The comparative sensitivity of these various tests is still under examination. There is a reasonable degree of correlation between the GPM test and the human maximization test. Transdermal therapeutic systems have proved to be a useful adjunct for administration of systemic medications. Their potential for future applications seems excellent. However, the systems carry a risk of either irritant or allergic skin sensitivity. Avoidance of reapplication of patches directly over the previous site, should help minimize the incidence and severity of such irritation. Keep in view that with the delayed onset of some allergic reactions, safety data based on short-term experience should be considered with caution. There is increasing interest in the use of iontophoresis. Such therapy may require long-term delivery and the extended wearing of delivery systems. Irritations in such patients may be greater than those found with the more brief applications for which iontophoresis is most widely used today. There is no doubt that iontophoresis can be a safe and effective method of drug delivery by the innovative application of modern electronics and material science; however, extensive skin toxicological studies are warranted. Alternatively, electroporation followed by iontophoresis can be used to lower the skin irritation. With electroporation, new pathways are created. As a consequence, there is more even distribution of charge; hence, there may be a lower potential for irritation. Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved. Singh REFERENCES 1. 2. 3. 4. 5. 6. Sarkany I, Gaylarde PM. Thickening of guinea pig epidermis due to application of commonly used ointment bases. Trans St John’s Hosp Dermatol Soc 59:241, 1973. Trozak DJ. Delayed hypersensitivity to scopolamine delivered by a transdermal device. J Am Acad Dermatol 13:247–251, 1985. Weickel R, Frosch PJ. Kontaktallergie auf Glycerotrinitrat (Nitroderm TTS). Hautarzt 37:511, 1986. Chandraratna PAN, O’Dell RE. Allergic reactions to nitroglycerin ointment: a report of five cases. Curr Ther Res 25:481, 1979. Rougier A, Goldberg A, Maibach HI, eds. In Vitro Skin Toxicology: Irritation, Phototoxicity and Sensitization. New York: Mary Ann Liebert, 1994. Draize JH, Woodard G, Calvery HO. Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J Pharmacol Exp Ther 83:377–390, 1944. Patrick E, Maibach HI. Predictive assays: animal and man, and in vitro and in vivo. 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