J UNE 2010
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`COPYRIGHT© 2010
`
`667
`ORIGINAL ARTICLLS
`
`VOLUME 9 • I SSUE 6
`
`JOURNAL O F DRUGS IN DERMAT O LOGY
`
`Harnessing the Anti-inflammatory Effects ofTopical
`Dapsone for Management of Acne
`Leon H. Kircik, MD
`Mount Sinai Medical Center, New York, NY; Indiana University School of M edicine, Indianapolis, IN
`
`ABSTRAC I
`
`Data continue to establish the role of inflammation, not only in the pathogenesis of acne but also in the development of its most dev(cid:173)
`astating sequelum, scarring. Although topical therapy is preferred by most acne patients and the physicians who treat them, histori(cid:173)
`cally no topical intervention has provided primarily anti-inflammatory effects . Topical dapsone 5% gel offers documented efficacy for
`the reduction of both inflammatory and non-infla matory aGne lesions. It has been proven safe, presenting none of the hematologic
`1
`risks associated with oral dapsone
`Data suggest the ve icle formulation enhances healing and contributes to tolerability, making
`topical dapsone 5% gel a w orthwffi e anti-inflammatory treatment fo r many patieflts wit mild-ta:-moderate acne vulgaris.
`
`A lthough acne
`
`IN I RODUC rtON
`is one of t e most com on skin
`disorders, its pathogenesis is not clearl y un derstood.
`Propionibacterium acnes (P. acnes) is a commensal
`organism that plays an active rol e in acne vu lgaris. P. acnes
`thrives in the presence of excess sebum and ha s been shown
`to mediate inflammatory processes at the site of the sebaceous
`follicle, contributing to the form atio n of free radical species
`and generating pro-infla m matory cytokines. 1 Co upled w ith
`faulty keratinization, excess sebum production and P. acnes
`colonization contribute to the formation of microcomedones,
`ultimately leading to development of the comedones, papules,
`pustules and cysts characteristic of acne.
`
`While the appearance of active acne vulgaris can have a sig(cid:173)
`nificant impact on a person's appearance and can be associ(cid:173)
`ated with potential physical discomfort, the scarring following
`acne is the most devastating sequelum to the patient. A better
`understanding of the pathophysiology of acne and associated
`scarring has been gained with the most recent in vivo research
`by Kang et al. 2 They reported a marked increase in inflamma(cid:173)
`tory cytokine gene transcripts in active acne lesions, including
`TNF-(cid:143) and IL-1 b. Importantly, these pro-inflammatory cytokines
`amplify NF-kB signaling pathways that originally led to their
`production while also stimulating nearby cells, according to the
`authors . This investigation also identified significant increases
`in 11.:-8 and 11.:-10. In addition to NF-kB, Activator Protein-1 (AP)-1
`is also elevated in acne lesions, leading to elevated matrix met(cid:173)
`alloproteinases, which degrade collagen-up to 2.5-fold com(cid:173)
`pared to normal skin. Furthermo re, the authors note that the
`inflammatory process is localized to the pilosebaceous unit. 2
`
`The most common sequelum of inflammatory acne is scarring,
`which is devastating to patients. The best way to prevent scar(cid:173)
`ring is, of course, to prevent and treat inflammatory lesions
`as early as possible. Also, any agent blocking (AP)-1, which in-
`
`creases matrix m etalloproteinases that cause scarring via col(cid:173)
`lagen degradatio n, wi ll be useful in scar prevention .
`
`Topical treatment options for acne include retinoids, antImI(cid:173)
`crobials, such as erythromycin ancl clindamycin, and benzoyl
`peroxide (BRO). Different combi nation formulations of retin(cid:173)
`oids, antibiotics and BPO are also available. Topical retinoids
`primarily act to normalize hyperkeratinization and have been
`suggested to confer mi ld anti-inflammatory effects. Topical
`antimicrobials and benzoyl peroxide target P. acnes, diminish(cid:173)
`ing colonization. Topical antimicrobials may also confer anti(cid:173)
`inflammatory effects.
`
`Despite the well-known and recently re-affirmed role of inflam(cid:173)
`mation in acne, no primarily anti-inflammatory topical therapy
`has been available for acne. Anti -inflammatory topical dapsone
`5% get (Aczone Gel 5%, Allergan, Irvine, CA) is now available
`for topical treatment of acne.
`
`Mechanisms of Action
`Although dapsone has proven to be a very powerful treatment
`in several neutrophilic dermatoses (such as dermatitis herpeti(cid:173)
`formis) through its anti-inflammatory effects, the mechanism of
`action of this effect is not well understood. There are several in
`vitro studies that show the anti-inflammatory effect of dapsone.
`The successful use of oral dapsone in several sub-epidermal
`blistering diseases is associated with anti-inflammatory effects
`by the suppression of neutrophil and eosinophil functions. This
`effect was demonstrated through dapsone's inhibition of IL-8
`release in cultured human keratinocytes. 3
`
`It also has been shown that dapsone suppressed leukocyte integ(cid:173)
`rin function, thus inhibiting migration of neutrophils to extravas(cid:173)
`cular sites.• Further, in vitro studies by Debo! et al. show that
`dapsone inhibits chemoattractant-induced G-protein activation
`and suppresses the subsequent signal transduction cascade. 5
`
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`J UNE 2010 • V OLUME 9 • ISSUE 6
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`L. H . Kircik
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`668
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`Other in vitro work revealed dapsone's inhibition of calcium(cid:173)
`dependent function of neutrophils6 and release of inflammatory
`mediators, such as prostagland ins, leukotrienes and lysosomal
`acid hydrolases.7 A study by Abe et al. revealed that dapsone
`may confer anti-inflammatory activity in cutaneous lupus
`erythematosis by decreasing TNF-a produced by activated
`mononuclear cells.• There is also a suggestion that dapsone's
`beneficial effects in inflammatory dermatological conditions
`come from its inhibition of 5-lipooxygenase metabolites.9
`
`Historical Context
`Systemic dapsone has a long history of use for numerous in(cid:173)
`flammatory diseases, such as peml!)higus vulgari s, leprosy and
`dermatitis herpetiformis. Although the chemical structure of
`dapsone is similar to that of th e sulfo nam ide antibi otics, it is
`distinctly different from the sulfon amides (Fi gure 1) and is actu(cid:173)
`ally classified as a sulfone. 10 Of not e, histo ry of allergic reaction
`to sulfonamide non-antibiotics o r sulfonamide anti biotics or
`history of adverse reactions to su lfon amides does not predict
`cross-reactivity with other sulfa drugs.11
`
`• It
`Dapsone confers anti-inflammatory and antipyretic effects .12
`1
`-
`also appears to have antioxidant effects and has been shown to
`target inflammatory proteinases and the oxidant hypochlorous
`acid. 15 Systemic dapsone has been associated w ith notable
`risks. Hemotoxicity (methem ogld binemia) has been reported .
`About 50 percent of the dose is excreted within 24 hours (mostly
`through urine). After absorption from the gastrointestinal tract,
`dapsone is metabolized to either by N-hydroxylation-producing
`hydroxylamine, a potentially toxic metabolite produced by
`cytochrome P-450 enzymes - or N-acetyltransferase, w hich
`yields non-toxic metabolites (monoacetyl dapsone and diacetyl
`dapsone).16 People with a glucose-6-phosphate dehydrogenase
`(G6PD) deficiency, methemoglobin reductase deficiency or
`hemoglobin M disease are at highest risk for hemotoxicity, and
`the package insert for oral dapsone requires regular screening
`offull blood counts, unlike in the case of topical dapsone, where
`no laboratory testing is required .
`
`FIGURE 1. Chemical structures.
`
`NH, ---0-so,-O-NH,
`ov~,0--
`
`Dapsone
`
`~
`
`#
`
`H2N
`Sulfa methoxazole
`
`In clinical tria ls, twice-daily topical application of dapsone as
`directed for the treatment of acne did not induce significant
`changes in hemoglobin or other hematologic indicators, even
`in G6PD-deficient patients. 11- 20 An analysis of data from two
`phase 1 pharmacokinetic studies and one phase 3 long-term
`safety study found that overall total system ic exposures to dap(cid:173)
`sone and its metabolites were approximately 100-fold less for
`dapsone gel than for oral dapson e (even with co-administration
`of trimethoprim/sulfamethoxazole) . Mean plasma dapsone
`concentrations associated with topical application ranged from
`7.5-11 ng/ml over 12 months in the long-term safety study.20
`Therefore, continuous use of dapsone 5% gel is not associated
`wi th an increase iri plasma concentrations of the drug. Con(cid:173)
`comitant use of topical BPO or adapalene has not been shown
`to affect the pha rmacokinetic profile of dapsone 5% gel. 18 A
`0.32-g/dl decrease in hemoglo bin concentration occurred from
`basel ine to two weeks during dapsone gel treatment. This was
`not accompa nied by changes in other laboratory parameters,
`includi ng reticul0cytes, haptoglobin, bilirubin and lactate de(cid:173)
`hydrogenase levels, and was no~ apparent at 12 weeks as treat(cid:173)
`ment co ntinued. Current labelin g for topical dapsone does not
`,i ncl ude requirements for glucose-6-p hosphate dehydrogenase
`(G6PD) screening or blood monitoring.
`
`Efficacy
`Dapsone 5% gel applied twice daily has been shown to de(cid:173)
`crease both the inflammatory and non-inflammatory lesions
`of acne vulgaris. In two 12-week, double-blind, randomized,
`parallel group, phase 3 studies conducted under identical pro(cid:173)
`tocols, a total of 3,010 patients age 12 or older were assigned
`to apply ei,ther dapsone gel 5% tw ice daily or vehicle gel to af(cid:173)
`fected areas of the face. 19 Pooled analysis of the data shows that
`treated patients experienced significantly greater reductions
`from baseline to 12 weeks in inflammatory, non-inflammato(cid:173)
`ry and total lesion counts compared to controls (Figures 2-4).
`The greatest reduction occurred in inflammatory lesion counts,
`which were reduced by nearly half in treated patients (47.5 ver(cid:173)
`sus 41.8 percent). Response to treatment was rapid, starting at
`week 2, and was maintained throughout the study. In fact, a
`slight difference in inflammatory lesion counts between the ac(cid:173)
`tive and vehicle groups that was evident by week 2 was highly
`statistically significant at week 4. Treated patients achieved su(cid:173)
`perior Global Acne Assessment Scores, regardless of whether
`baseline acne was more or less severe (as determined by acne
`lesion counts).
`
`Tolerability
`Importantly, topica l dapsone treatment was well tolerated with
`similar numbers of patients reporting adverse events in the
`active and control groups (58.2 percent of treated patients and
`58.6 percent of controls) . Most events were of mild to moderate
`intensity, resolved during treatment, and did not result in
`treatment discontinuation. Just 0.6 percent of treated patients
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`JO U RNAL OF DRUGS IN DERMATOLOGY
`JU NE 2010 • VOLUME 9 • ISSUE 6
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`L. H. Kircik
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`669
`
`discontinued participation due to lack of efficacy, while 0.4
`percent withdrew due to an adverse event.
`
`Long-term Study
`Similar efficacy and tolerability were evident in a one-year open(cid:173)
`label, non-comparative trial oftopical dapsone involving a total
`
`FIGURE 2. Mean percentage change in non-inflammatory lesion
`count.
`
`-10
`
`..,
`c::
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`~ ·, c::
`c::
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`0
`z
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`-40
`
`-so
`
`Dapsone Gel 5%
`~ Vehicle Gel
`(
`
`(
`
`32%
`
`0
`
`2
`
`8
`6
`4
`Time (weeks)
`
`10
`
`12
`
`FIGURE 3. Mean percentage change in inflammatory lesion-count.
`
`of 506 patients age 12 or older.'0 Patients applied dapsone for a
`mean of 253 days over the 12-month study period . The protocol
`directed twice-daily application to affected facial areas. Patients
`could discontinue application to a particular area once clear,
`but could reinitiate application to that site if necessary.
`
`Improvement in inflammatory lesions was more significant than
`improvement in non-inflammatory lesions, and was evident by
`week 4. Lesion counts continuously decreased through month 6;
`these improvements were mainta ined through 12 months. Mean
`inflammatory lesion counts decreased from 48.1 at baseline to
`23.1 at month 3, 20.4 at month 6 and 18.4 at 12 months. Mean
`non-inflamm at ory lesio ns cou_nts for the same respective periods
`were 38.5, 30.1 , 26 and 25.1. Twelve-month mean percent reduc-
`
`matory lesio ms a d 19.5 perce t for non-inflammatory lesions.
`At mo nth 3, 96 patients in itiated concomitant systemic or topical
`acne t herapy according to study protocols, but ad hoc analysis
`of the data revealed no clinically apparent differences in lesion
`count reductions for this sub-populatio n at month 3 or 12.
`
`/Approximately two-thirds of patient s (68 percent) experienced
`at least one adverse event du ring the course of the study, but
`investigators judg ecLj ust 9. 5 pe rcent of these to be treatment
`related . Reported application site reactions (reported by 13.8
`percent of patient s)
`ineluded dryness, rash and sunburn.
`Treatment was we ll tolerated: 0.8 percent of patients withdrew
`due to lack of efficacy, while 2.2 percent withdrew due to an
`adverse event.
`
`Combination Study
`There was also a combination trial comparing dapsone alone
`to dapsone plus adapalene and dapsone plus benzoyl peroxide
`4%. 18 Dapsone gel in the combinations investigated was found
`to provide greater mean percentage reduction in total lesion
`and in non-inflammatory lesion counts than dapsone alone,
`with the most significant decrease associated with dapsone
`plus adapalene. However, it is notable that there was no sta(cid:173)
`tistically significant difference between topical dapsone alone
`versus the combination regimens for inflammatory lesions.
`These findings actually reveal that topical dapsone alone is a
`very powerful agent against inflammatory lesions.
`
`Unique Vehicle
`These results support the efficacy of this new, patented
`formulation that is exclusively used with topical dapsone .
`Data confirm that optimally designed formulations work
`synergistically to deliver active agents into viable tissue while
`enhancing the barrier function essential for healthy skin.
`Aczone's gel formulation contain s diethylene glycol monoethyl
`ether (DGME), which facilitates the permeation of active
`ingredients into the skin and helps undissolved dapsone to
`remain in the pilosebaceous unit, according to in vitro data. 21
`
`JO0610
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`B
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`
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`
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`
`Dapsone Gel 5%
`vehicle Gel
`
`-
`
`35%
`
`48%
`
`40%
`44%
`-50% ._ _ __, ____ ___. _ _ __._ _ _ ....._ _ _ ..._ _ _..
`10
`12
`4
`6
`8
`Time (Weeks)
`
`FIGURE 4. Percentage of patients achieving GAAS success.
`P<0.001
`P<0.002
`P<0.001
`44.2%
`I
`
`42.5%
`
`I
`
`50%
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`a.. :i.
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`20%
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`Study 1
`
`Study 2
`
`Combined
`
`Dapsone Gel 5%
`
`-
`
`Vehicle
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`JOUR N AL O F DRUGS IN D ERMATOLOGY
`JUNE 2010 • VOLUME 9 • ISSUE 6
`
`L. H. Kircik
`
`670
`
`Penetration enhancers such as DGME have been shown to
`increase the efficacy of topical molecules. However, some
`penetration enhancers are limited by their potential toxicity
`and irritancy. DGME improved the skin penetration of topical
`steroids and its lower toxicity has been established, leading
`to approval by FDA for cosmetic use. 22 DGME is a hydroscopic
`liquid with an excellent solubilizing characteristic and
`cutaneous biocompatibility. One of its important functions is
`to increase cutaneous accumulation of topical compounds
`without increase of transdermal permeation, as shown in a
`study of ultraviolet absorbers. 23 Another study revealed skin
`retention of dexamethasone and hydrocortisone, creating an
`intracutaneous depot for these moleeules
`ithout incr!} sir(g
`transdermal delivery. 24
`
`These specific properties of DGME help topica l dapsone in this
`novel formulation to remain in the ~ilosebaceous unit and subse-
`quently increases its efficacy in the trea ment of acne vulgaris .
`
`C:ONCI USION
`Inflammation plays a significant ro l not onl y in t he pathogenesis
`of acne but also in the develop ent of its m ost d eva stating
`is preferred
`sequelae, scarring. Although topical
`th erapy
`by most acne patients and the physicia ns who treat tbem,
`historically no topical intervention has provided primarily anti(cid:173)
`inflammatory effects. Topical dapso ne 5% gel is a novel agent
`that targets inflammation w ith-proven efficacy for the reduction
`of both inflammatory and non-inflammatory acne lesions.
`
`While the risks of life-threatening hematologic events associ(cid:173)
`ated with oral dapsone require that clinicians institute therapy
`with caution, studies confirm that topical application of dap(cid:173)
`sone does not produce worrisome plasma concentrations. In
`fact, the safety of topical dapsone is sufficiently obvious that
`the FDA has withdrawn the requirement for baseline blood
`monitoring (particularly G6PD screening).
`
`Aczone gel 5% represents a valuable treatment option for
`patients with acne vulgaris. Studies document the excellent
`tolerability of the new aqueous gel formulation. Given the
`current understanding of the role of inflammation in the
`pathogenesis of acne and scarring, a targeted anti-inflammatory
`agent is a welcome addition to the treatment arsenal, especially
`for sensitive skin patients who cannot tolerate other topicals.
`
`DISCLOSURLS
`Dr. Kircik has served as an investigator, consultant or speaker
`for Allergan, Inc. and OLT.
`
`REl·LRLN( :FS
`1. Grange PA, Chereau C, Raingeaud J, et al. Production of superox(cid:173)
`ide anions by keratinocytes initiates P acnes-induced inflammation
`of the skin. PLoS Pa thog. 2009;5(7):e1000527.
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`4.
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`7.
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`2. Kang S, Cho S, Chung JH , et al. Inflammation and extracellular ma(cid:173)
`trix degradation mediated by activated transcription factors nuclear
`factor-B and activator protein-1 in inflammatory acne lesions in
`vivo. Am J Pathol. 2005;166:1691-1699.
`3. Schmidt E, Reimer S, Kruse N, et al . The ll.c8 releas e from cultured
`human keratinocytes, mediated by antibodies to bullous pemphi(cid:173)
`goid autoantigen 180, is inhibited by dapsone . Clin Exp /mmunol.
`2001 ;124:157-162.
`Sally A, Booth SA, Moody CE, et al. Dapsone suppresses integ(cid:173)
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`1992;98135-140.
`5. Debol SM, Herron MJ, Nelson RD. Anti-inflammatory action of
`dapso e: I hrb'itio of neutrophfl adherence is associated with inhi(cid:173)
`bition of chemoattractant-induced signal transaction . J Leukoc Biol.
`1997;62 :827-886.
`6. Suda T, SLJzuki Y, Matsw T Da sone suppresses human neutrophil
`su peroxide production and elastase release in calcium-dependent
`manner. Br J /Dermatol. 2005;152:8817-895.
`Bonney RJ, Wightman PD, Dah ren M E, et al. Inhibition of pros(cid:173)
`ta glandins, leukotrienes, and lysosoma l acid hydrolases from mac-
`,ophages by selective inhibitors of lecithin biosynthesis. Biocheml
`Pharm. 1983;32(2) :361 -366.
`8. Abe M, Shimizu A, Yokoyama Y, et al. A possible inhibitory action
`of diaminbd1Qhenyl sulfone--on tumour necrosis factor-a production
`from activated mononuclear cells on cutaneou s lupus erythemato(cid:173)
`sus, Clio Expe Dermatol. 2008;33:759-763 .
`9. Wozel G, Lehmann B. Dapsone inhibits the generation of 5-lipoxy(cid:173)
`genase products in human polymorphonuclear leukocytes. Skin
`Pharmacol. 1995;8:196-202.
`10. Zhu YI, Stiller MJ. Dapsone and sulfones in dermatology: Overview
`and update. J Am Acad Dermatol. 2001 ;45(3):420-434.
`Strom BL, Schinnar R, Apter AJ, et al. Absen ce of cross-reactivity
`between sulfonamide antibiotics and sulfonamide nonantibiotics.
`New EngJ Med 2003;349(17) :1628-1 635
`12. Lewis AJ, Gemmell DK, Stimson WH . The anti-inflammatory pro(cid:173)
`file of dapsone in animal models of inflammation. Agents Actions.
`1978;8(6) 578-586
`13. Williams K, Capstick RB, Lewis DA, Best R. Anti-inflammatory ac(cid:173)
`tions of dapsone and its related biochemistry. J Pharm Pharmacol.
`1976;28(7) 555-558
`14. Ottonello L, Dapino P, Scorpcco MC, et al. Sulphonamides as anti(cid:173)
`inflammatory agents: Old drugs for new therapeutic strategies in
`neutrophilic inflammation? C/in Sci (Land). 1995;88(3):331-336.
`15. Diaz-Ruiz A, Zavala C, Montes S, et al. Antioxidant, antiinflamma(cid:173)
`tory and antiapoptotic effects of dapsone in a model of brain isch(cid:173)
`emia/reperfusion in rats. J Neurosci Res. 2008.
`16. Tingle MD, Mahmud R, Maggs JL, et al. Comparison of the me(cid:173)
`tabolism and toxicity of dapsone in rat, mouse and man . Pharmcol(cid:173)
`ogy. 1997;283(2):817-823.
`17. Thiboutot DM, Willm er J, Sharata H, et al. Pharmacokinetics of
`dapsone gel, 5% for the treatment of acne vulgaris. C/in Pharma(cid:173)
`cokinet. 2007;46(8) :697-712
`18. Del Rosso JO. Newer topical th erapies for the treatment of acne
`
`11.
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`vulgaris. Cutis. 2007;80(5):400-410.
`19. Draelos ZD, Carter E, Maloney JM, et al.; United States/Canada
`Dapsone Gel Study Group . Two randomized studies demonstrate
`the efficacy and safety of dapsone gel, 5% for the treatment of
`acne vulgaris. J Am Acad Dermatol. 2007 ;56(3) :439.e1-10.
`20. Lucky AW, Maloney JM, Roberts J, et al.; Dapsone Gel Long-Term
`Safety Study Group. Dapsone gel 5% for the treatment of acne vul(cid:173)
`garis: Safety and efficacy of long-term ( 1 year) treatment. J Drugs
`Dermatol. 2007;6(10):981-987.
`21. Hadgraft J. Passive enhancement strategies in topical and trans(cid:173)
`dermal drug delivery. Int J Pharm. 1999;184(1 ):1-6.
`22 . Bonina FP, Montenegro L. Effects of some non-toxic penetration
`enhancers on in vitro heparin skin permeation fro m gel ve)1 icle~.
`Int J Pharm. 1994;111 :191 -196.
`23 . Godwin DA, Kim N, Felton LA. Influence of transcutol CG on the
`skin accumulation and transdermal permeation of ultraviolet ab(cid:173)
`sorbers. Eur J Pharm Biopharm. 2002;53:23-27.
`24 . Otto A, Wiechers JW, Kelly CL, et al. Effect of penetration modifi(cid:173)
`ers on the dermal and transdermal delivery of drugs and cosmetic
`active ingredients. Skin Pharmacol Physiol. 2008;21 :326-334.
`
`ADDRESS FOR CORRESPO
`
`CE
`
`Leon H. Kircik, MD
`Physicians Skin Care
`1169 Eastern Pkwy, Ste 2310
`Louisville, KY 40217
`.. . .............. ................. wedoderm@bellsouth .net
`E-mail :.
`
`I>R
`
`I DFRMAl(HO(
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