Vol. 50
`
`No. 1
`
`January/February 1999
`
`/Vt/M3
`
`i§ToURNAL OF COSMETIC SCIENCE
`TH: Official Journal of the Society of Cosmetic Chemists
`
`~ Ea+—~—————
`
`Contents
`
`ORlG|NAL PAPERS
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`A rheological study on microemulsion gels of isopropyl myristate,
`polysorbate 80, glycerol, and water
`C. A. Ayannides and G. Kfistis .
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`The etiect of preparation technique on droplet size in silicone emulsions
`V. Gal/orcio, A. Hernandez, A. Parera, and M. A. Ruiz .
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`A stucly ol B-cycloolextrin-staloilizecl parattin oil/water emulsions
`Serge Laurent, Michel Serpelloni, and Daniel Pioch .
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`Human hair cuticle: Biologically conspired to the owner's advantage
`J. A. Swift
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`Papers presented at the Annual Scientific Meeting of the Society of
`Cosmetic Chemists, New York, December lO—l l, 1998 .
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`49
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`

`
`Journal of
`
`Cosmetic Science
`The Ofiicial Journal of the Society of Cosmetic Chemists
`
`(ISSN ()0,57—9832)
`VOLUME 50 0 NUMBER 1
`
`JANUARY./FEBRUARY 1999
`Published by the Society of Cosmetic Chemists
`33;" *‘
`Editor:
`
`Associate Editor:
`
`Production:
`
`Editorial Advisory Board:
`
`Joel Zatz, Ph.D., Rutgers University, College of Pliarniacy, 160 Freling-
`huysen Road, Pascntaway, NJ 08854-8020
`Linda Rhein, Ph.D., Srnithkline Beecham Consumer, 1500 Littleton Road,
`Parsippany,
`0703/1
`SCC, 120 \)(/all Street, Suite 2400, New York, NY 10003-4088
`Daniel Brannan, Ph.D., Abilene Christian University, Abilene, TX 79699
`Genji Imokawa, Ph.D., Kao Corporation, 2606 Akahrane, Ichikai—n1achi, Haga,
`Toch ig i, 3 21-34 Japan
`Janusz Jachowicz, Ph.D., ISP, 1361 Alps Road, \Wayne, NJ (7470
`Kenneth Klein, Cosmetech Labs, Inc., 39 Plymouth Street St 4, Fairfielcl, NJ
`07004-1681
`
`T. Joseph Lin, Ph.D., TJL Associates, 628 Enchanted \‘(/ay, Pacific Palisades, CA
`90272
`
`Robert Lochhead, Ph.D., University of Southern Mississippi, 1 59 Pompano Road,
`Hzittieshurg, MS 59402
`Martin Rieger, Ph.D., 3041 Mountain \Way, Morris Plains, NJ 07930
`R. Randall W1C1i6tt, Ph.D., University of Cincinnati, 3223 Eden Avenue, Cincin—
`nati, OH 45267
`
`Executive Director:
`President:
`
`Theresa Ccsario, 120 \Vall Street, Suite 2400, New York, NY 10005-4088
`Karl F. Popp, R.Ph., A.C. Stiefel Research Institute, Route 143, Oak Hill, NY
`12/160, (518) 259-6901, Fax: (318) 239-8402
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`3:,,
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`
`PREPRINTS OF THE 1998 ANNUAL SCIENTIFIC MEETING
`
`71
`
`AN NAIL AND ITs TOPICAL TREATMENT: BRIEF REVIEW OF
`CIIRVNT RESEARCH AND DEVELOPMENT or TOPICAL ANTIFUNGAL
`DRUG DELIVERY FOR ONYCHOMYCOSIS TREATMENT
`Jonas C.T. Wang and Ying Sun, Ph.D.
`
`Jo.=';.-won and Johnson Topical Formulation and Drug Delivery Technology Resource Center,
`Johnson and Johnson Consumer Products, Skillman, New Jersey, USA
`
`B’ hemical Properties of the Nail
`
`., human nail plate is composed of approximately 25 layers of flattened, keratinized
`'1";
`cells fused into a dense, hard yet slightly elastic plate, with a typical thickness of 0.5 —
`l.u mm (1). These cells have their origin in the nail matrix, a living highly proliferative
`erifhelia tissue (Figure 1). Human nail compared with human stratum comeum has less
`lipid (1% versus 20%) and higher percentage of disulfide linkages (10.6% versus 1.2%)
`a’.
`- is thicker (750 p. versus 301.1) but holds less water (25% versus 300%) (ref. 2-4). The
`high disulfide bond content confers toughness to the nail (3). Nail consists of three layers
`(1; ..gure 1): (i) hard dorsal nail plate 0.5mm thick in finger nails and 1.3mm for toe nails,
`(ii), nail bed of noncomified soft tissue, and (iii) nail matrix which is the thick, highly
`proliferative tissue at the root of the nail.
`
`History of Topical Nail Delivery
`
`In contrast to the abundant literature available on chemical skin penetration enhancers,
`i...fbnnation on chemical nail penetration enhancers is rather scarce. Due to the different
`nature of the barriers, the likelihood of success would not be very high if one simply used
`a proven-effective skin penetration enhancer for nail delivery. The working mechanism
`3”’ a vast majority of skin penetration enhancers involves the lipid domains or pathways
`in the stratum comeum., either by increasing the fluidity, or by increasing the drug
`; vrtitioning into it. These skin penetration enhancers are unlikely to have the same
`penetration enhancement effect on the nail simply because the nail contains much less
`-.pid, probably has much less well-developed lipid pathways. The aforementioned
`differences between the nail and stratum comeum, both physical and chemical, are
`probably responsible for the lack of efficacy of the topical nail antifungal products on the
`':.arket (5), as well as for the ineffectiveness of some well known skin penetration
`enhancers, such as dimethyl sulfoxide and homologous alcohols, on nail permeation
`nhancement (6).
`
`.vv'alters and his associates (2, 6, 7) discovered that, as a permeation barrier, a human
`aailplate does not mimic the behavior of a lipophilic membrane, which has been the case
`for almost all the other body membranes, such as the skin, vaginal and gastrointestinal
`‘,”ll.lCOl.lSal membranes. Instead a hydrated nail plate behaves more like a hydrogel
`membrane in its barrier properties.
`
`Mertin and Lippold (7,8,9) pointed out that for onychomycosis treatment (nail fungal
`Infections), not only the flux of an antimycotic drug through the nail plate is of
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`72
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`JOURNAL OF COSMETIC SCIENCE
`
`importance, but also the antifungal potency, which expressed as minimum inhibitory
`concentration (MIC). An efficacy coeff1cientE is therefore introduced, which should be
`maximum for high therapeutic effectiveness (9):
`
`E = Flux\MlC
`
`Thus one wishes to obtain a high flux of drug through the nail and a low MIC for
`maximum efficacy. Flux is also directly proportional to molecular size of the drug(9).
`
`Recent Progress of the Research of Topical Drug Delivery to the Nail for
`Onychomycosis Treatment
`
`Fungal infections of the nails (onychomycosis) makes up about 30% of fungus infections
`of the skin. Onychomycosis involves about 2-5% of general population. Of the 245
`million people in the United States, between 4.9 and 12.3 million are infected with
`onychomycosis. Onychomycosis takes a profound psychosocial toll on the sufferer.
`Although there are many potent antifimgal drugs currently available, nail fungal
`infections remain a disease very difficult to treat. In the U.S., only oral administration of
`three antifungal drugs is approved by FDA as effective therapy for nail fungal infection:
`itraconazole (Sporanox®), terbinaflne (Larnisil®), and an old drug, griseofulvin.
`Because of the long duration of oral treatment for onychomycosis (3-12 months),
`potential adverse effects, such as hepatotoxicity and drug interactions, are ofien of
`concern. In addition, relapse rate is rather high. To minimize the undesirable side effects
`associated with systemic treatment, it is highly desirable to have an efficacious topical
`product to treat onychomycosis. However, ability for a topical drug to penetrate the nail
`plate has hampered this approach.
`
`Keratolyic agents, such as urea and salicylic acid are ofien used to soften nail plates.
`Urea and a combination of urea and salicylic acid were reported to be used for
`nonsurgical avulsion of nail dystrophies in clinical studies prior to topical treatment of
`onychomycosis with satisfactory results (10-12). Lauharanta (13) reported another
`favorable clinical study of using an amorolfine-containing nail lacquer (Loceryl nail
`lacquer) with a special nail preparation procedure (cleaning, filing and cutting) to treat
`onychomycosis in clinical trials. Clinical trials demonstrated that this special procedure
`was essential. The physical elimination of a part of the nail barrier certainly facilitated
`the drug penetration for a better efficacy. Similar results were also observed from a
`Cilcopirox lacauer product.
`
`By exploiting target sites on the nail keratin (Figure 2), we discovered a novel way of
`using chemical enhancers that act directly on the nail keratin to increase nail elasticity,
`and consequently, to enhance drug permeation through the nail (14). Certain sulfhydryl
`compounds, such as cysteine, a natural amino acid, or its derivative acetylcysteine
`(NAC), cleave the disulfide bonds of nail keratin. Urea was used to interact with
`hydrogen bonds of nail keratin to facilitate the disulfide bond breaking (Figure 2). The
`chemical reaction that occurs between the cystine linkages in nail keratin and cysteine is
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`PREPRINTS OF THE 1998 ANNUAL SCIENTIFIC MEETING
`
`73
`
`;.,‘l0wn in the reaction below. Both cysteine and acetylcysteine have been used in Japan
`hair-waving agents (15).
`
`“‘hemical Reaction Sequence:
`
`fail-S-S-Nail
`
`"’ Nail-SH
`
`+
`
`+
`
`2HSCH2(NH2)COOH —>
`Cysteine
`(-
`
`HOOCH(NH2)CH2-S—S-CH(NH2)COOH
`Cystine
`
`Reducing the disulfide bonds in the nail along with sofiening the nail plate could serve to
`open up the nail plate to drug penetration.
`
`in vitra methodologies
`fo demonstrate enhanced penetration of anti-fungals into nail,
`such as nail swelling test, drug partitioning test, and drug penneation through human
`nails were used. The ability of a drug in a formulation to penetrate nail plate should be
`Lieflected by the rate and extent of the nail uptake of the formulation (i.e., nail swelling in
`the formulation), as well as by the amount of the drug migration into the nail (drug
`partitioning). Nail swelling and drug partitioning tests were conducted by immersing
`human nail clippings in a topical drug formulation at 32°C for two days. Alter washing
`off the surface-bond formulation, the nail clippings were first examined for weight gain,
`men digested and analyzed for drug analysis with a high pressure liquid chromatography
`method.
`
`Figures 3 and 4 show the effect ofNAC and urea as penetration enhancers on the nail
`swelling and itraconazole partitioning. All four itraconazole formulations contained 1%
`itraconazole and different enhancer compositions: Formulation A was the control,
`containing neither NAC nor urea; Formula B contained 10% urea but no NAC; Formula
`C contained 5% NAC but no urea; and Formulation D contained both 5% NAC and 10%
`urea. The numbers over the bars are the enhancement factors, i.e., the ratio of the nail
`weight gain (Figure 3) or nail itraconazole content (Figure 4) from the test formulations
`to those from the control (Fonnulation A). Figure 3 shows that Formulation D produced
`the highest nail swelling, which corresponds to the highest drug uptake into the nail, 93.6
`fold higher than the control.
`
`The benefits of incorporating nail penetration enhancers into topical antiftmgal
`formulations are clearly demonstrated by these examples. The amount of antifungal
`drugs penetrated through the nail in these in vitro studies are over a thousand fold higher
`than that required to have therapeutic effect.
`
`Conclusions
`
`In surmnary, the chemical composition of human nail is significantly different from the
`other body membranes such as the skin, vaginal and gastrointestinal membranes. In
`topical delivery of actives to the nail, the nail plate does not mimic the behavior of a
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`74
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`JOURNAL OF COSMETIC SCIENCE
`
`lipophilic membrane, which has been the case for almost all the other body membranes,
`including the skin. Instead, a nail plate behaves more like a hydrogel membrane in its
`barrier properties. Effectiveness of topical formulation at treating nail disease is
`increased dramatically by enhancers that disrupt protein structure of the nail plate.
`
`REFERENCES
`
`1. Fleckman, P. (1990). Basic science of the nail unit. In Nails: therapy, diagnosis,
`surgery. edited by Scher, R.K. and Daniel, C.R. W.B. Saunders Company,
`Philadelphia, pp. 42-43.
`_
`2. Walters, K.A., Flynn, G.L., and Marvel, J.R. (1983b). Physiochemical chemical
`characterization of the human nail: permeation pattern for water and the homologous
`alcohols and difference with respect to the stratum comeum. J.Pharm.Pharmcol.
`35:28-33.
`
`3. Baden, H.P., Goldsmith, L.A., and Fleming, B. (1973). A comparative study of the
`physicochemical properties of human keratinized tissues. Biochim. Biophys. Acta.
`322:269-278.
`
`4. Scheuplein, R.J. and Morgan, LJ. (1967). Bound water in keratin membranes
`measured by a microbalance technique. Nature. 2142456.
`5. Haneke, E. (1991). Fungal infections of the nail. Seminars in Derrntol. 10:41-53.
`6. Walters, K.A., Flynn, F.L., and Marvel, J.R. (l985a). Penetration of the human nail
`plate: the effects of vehicle pH on the permeation of miconazole. J. Pharm. Pharmcol.
`37:498-499.
`
`7. Mertin, D. and Lippold, B.C. (1997b). In-vitro permeability of the human nail and a
`keratin membrane from bovine hooves: penetration of clrlorarnphenicol from
`lipophilic vehicles and a nail lacquer. J. Pharm. Pharmacol. 49:241-245.
`8. Mertin, D. and Lippold, B.C. (1997a). In-vitro permeability of the human nail and a
`keratin membrane from bow'ne hooves: influence of the partition coefficient
`octanol/water and the water solubility of drugs on their permeability and maximum
`flux. J. Pharm. Pharmacol. 49:30-34.
`
`9. Mertin, D. and Lippold, B.C. (19970). In-vitro permeability of the human nail and a
`keratin membrane from bovine hooves: prediction of the penetration rate of
`antimycotics through the nail plate and their efficacy. .l.Pharm. Pharmacol. 49:866-
`872.
`
`10. Farber, E.M. and South, D.A. (1978). Urea ointment in the nonsurgical avulsion of
`nail dystrophies. CUTIS.22:689-692.
`1 1. South, D.A. and Farber, E.M. (1980). Urea ointment in the nonsurgical avulsion of
`nail dystrophies - a reappraisal. CUTIS.25.609-612.
`. Buselmeier, T.J. (1980). Combination urea and salicylic acid ointment nail avulsion
`in nondystrophic nails: a follow-up observation. CUTIS.25:397-405.
`. Lauharanta, J. (1992). Comparative efficacy and safety of amorolfine nail lacquer 2%
`and 5% once weekly. Clin. Exp. Dermatol. 17 (Suppl. 1): 41-43.
`. Sun, Y., Liu, J.C., Kimbleton, E. and Wang, J. (1977). Antifungal treatment of nails.
`US patent No. 5,696,164.
`. Iwaski, A. (1994). Cysteine Waving Lotions - Past Improvement and Future
`Prospects. Cosmetics & Toiletries. 109:69-78.
`
`-—n-n:->-tll&UJB.)
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`

`
`PREPRINTS OF THE 1998 ANNUAL SCIENTIFIC MEETING
`
`75
`
`EPONYCHIUM
`
`NAIL PLATE
`
`
`
`NAIL MATRIX
`
`HYPONYCHIUM
`
`Figure 1.
`A ,..mernatic diagram of a human nail. The target sites of topical onychomycosis treatment are nail plate, nail
`bed and nail matrix. where a topically administered antifiingal drug should be able to reach with a concentration
`am. we its fimgicidal level. The ‘arrows indicate the potential points of entry for drug delivery.
`
`CHEMICAL BONDS OF KERATIN MOLECULE
`
`Dlsulfide linkage
`
`I
`\:
`
`I 1
`
`/
`
`
`
`Karatln Protein Chain
`
`Peptide linkage
`
`Q00
`/'aH+
`Polar linkage
`
`I
`N
`
`Figuw 2.
`Diagram depicting the types of bonds in nail protein that represent potential targets for nail
`pene‘ ‘ation enhancers.
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`76
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`JOURNAL OF COSMETIC SCIENCE
`
`NAILSWELIJ
`(45
`
`N
`s.
`
`Fonuuumons
`.n-:!)
`
`WEIGHT
`00)
`
` INITIAL
`
`Figure 3.
`The effect ofNAC and urea as nail penetration enhancer on nail swelling.
`enhancement
`, i.e., the ratio of percentage weight gain in the nail sam
`in the control
`lation without NAC and/or urea.
`
`umbers above the bars are the
`in the testing fonnulation to that
`
`ITRACONAZOLE PARTITI
`I43 HHS. 32C.
`
`N6 INTO NAIL
`- 3)
`
`ITRACONAZOLE
`GONG. IN NAIL
`
`(W9)
`
`Figure 4.
`The efiect ofNAC and urea on itraeonazole partitioning into nai .
`enhancemmt factor, l.e.. the ratio ofthe itraeonazole concentrati
`to that in the eontrol formulation without NAC and/or urea.
`
`e numbers above the bars are the
`the nail sample in the testing formulation
`
`'
`
`CFAD V. Anacor, |PR20’|5-01776 ANACOR EX. 2165 - 8/8
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2165 - 8/8