Novemberfflecember 1999
`
`JOURNAL OF COSMETIC SCIENCE
`
`e Official Journal of the Society of Cosmetic Chemists
`
`Contents
`
`5| IGINAL PAPERS
`
`Effect of coconut oil on prevention of hair damage. Part I
`Audi 5. Rate and R. B. Mohtte .
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`DNA damage, repair, and tanning acceleration
`A. A. ‘fink, R I M. Van den Berg, and L Roza
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`RI-Ieoiogical properties of aerosol Foams containing aqueous cationic polymer
`and anionic surfactant
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`Yoshitumi Yamagata .
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`Structural characteristics and permeabiiity properties of the
`human nail: A review
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`Gouri V. Gupcttup and Joei' L Zatz .
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`Author index to Volume 50 .
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`Subject index to Volume 50 .
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`if-.‘.-£5 :1! STF:‘:’
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`Page 1 0f 25
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`"
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`‘
`
`Kaken Exhibit 2012
`Acrux V. Kaken
`
`IPR2017-00190
`
`Page 1 of 25
`
`Kaken Exhibit 2012
`Acrux v. Kaken
`IPR2017-00190
`
`

`

`Journal ol
`
`Cosmetic Science
`
`The Official Journal iii the society in cosmetic Chemists
`{ISSN (1037-9352)
`VOLUME 50 o NUMBER 6
`NOVEMBERJDECEMBER 1999
`
`fiissociate Editor:
`
`P1'DCll.lL‘[ ion:
`
`Editorial Advisory Board:
`
`Published by the Society of Cosmetic Chemists
`
`Editor:
`Joel Zatz, Ph.D., Rutgers University, College of Pharmacy, 160 F1-cling-
`huysen Road, Pzistziraway, NJ 08854-8020
`Linda Rheiri, Ph.D., Smirhklirie Bcetham Consumer.
`Parsippany, N__] 07054
`SCC, 120 Wall Street, Suite 24l)0, New York, NY 10005-4088
`Daniel Brannon, Ph.D., Abilene Christian Uriiversity, Abilene, TX W69“)
`Genji Irnokawa, Ph.D., Kao Corporation, 2606 Akzibane,
`lchilou'—machi. Hfigfl,
`Tochigi, 521-34 _]:1pan
`l;-‘>61 Alps Road. Wayne, NJ U'r’=l'r'fI
`Janus: jachowiez, Ph.D., [S‘P.
`Kenneth Klein. Cosrnetcch Libs.
`lru.'.. 59 Plymouth Street St 4.
`l'l7U04—l68l
`T. Joseph Lin, Ph.D., T_]L Associates, 628 Enchanted Way, Pacific P&l.llS:i:Ll("S, CA
`90272
`Robert Lochheatl, Ph.D.. UI1iVl':ISity of Southern Mississippi, 159 PUl'l'l111l'I0 Road,
`l-Iritriesbuxg, MS 39102
`Martin Rieger, Ph.D., _"§['J—’l Mountain W/ay, Morris Plains, Nj ll‘i'950
`R. Randall Wicken, Ph.D., University ofCiricirinari, 5223 Eden Avenue. Cincin-
`l‘|£l.l.'l, OH ~’i52(i7
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`l5{l(_l I.i[tli'."(Dl'I Road.
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`I:i1ll'f1E‘lLi. N]
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`Vice President:
`
`Executive Director: Theresa (Jcsario, I20 Wall Street, Suite 2400, New York. NY l()()05—4(J38
`President: Karl F. Popp, R.Ph.. A.C. Stit-Fel RCSl;1].l1‘_l‘l Institute, Route 145, Oak Hill, NY
`12460. (318) 239-690], Fax: (518) 239-3402
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`Vice President-Elect: Michael Smith. Cusmziir, lnt., 189 Territirial Avenue, Clark, NJ 07066. (‘.1 52)
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`TN 38151. (901) 520-2060. Fax: (901) 320-5152
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`Treasurer.
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`0'
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`suimepnm; _J(_‘|LillN.i\L or tLv.~‘.iiE'I'It. §CIEN(ZF.. the onion: jnimi ii‘ Ill‘
`Sociny ind" EIRJDEUK Cheriiisis J5 puihlivdieil six iimu ire:
`limit’ with j:iiiii.iry.-
`I’-chriury. March-‘April. llvliiyfliiiii-. _]ul_i--‘Au;-,-usi, Sepu-rnl:icir()cm-her. Nmvt-m1x'ta'
`lJl‘-i.'I:l!1bCI' imzs. Yflrly ssiihiitnptinn prim 1') l.!ll¢}J..'l}.
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`1*_l|-P} by the Sorii-i_ii nl Cusruciic Clit-misra. Pl‘fll'llS51IIlI
`gr-.u1m.l m rmilen. and rioiiiwi-iii liliuiriui Ming lbr ihein Fur lairmr ii lhu i-mm-ial
`turiimncil in (IIIS_I(!Ill'|hll. Permission is lunhei gamed in iiiiore lmm ihiijiairml
`in stientiiit wurlo: with the rusn-.iniiin- urkmwludigrnciu iii the 9oi.|nl:. CKEBLTIK
`him EACH {IF THE ORIGINAL .i\lJ'I'I‘lURh' illnng with mcifiatatiori no rlic‘
`iiI'("na.nit1ii (Tl icmisix is rrqujml in it-print a tiiiuir. i-.il1lt- or urliw rioterpi.
`The ii-piibliuiruau. si-sreriiarii ii: multiple |'|.’1'I|'Y¥-lw-Tim] of any material
`in this
`_1ciiirriiilIiritluiiiri,e, absrnittsi is perrriiiiul under wniieii ll(l.‘l'lSl.' lmrii the Sim-ry iii"
`Cusinmt Ch-_rrii_u.s. The Society iI('riiiiriei-it Oieini-its rriay iilaiti reqiuii: Uiu rur-
`riimsinii must be oliciiriud Iirum T.-IACl-I (IF THE r\U'I'l-IURS Addie-.5 inqiiims to
`the Eiilllllf.
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`JOLIE-lhl.»\L or cosaii:t'iic SCIENCE. [he Clllicisl _lI!u.rI'iil at my Sultry doi:-
`mvrii: Clasriiv-u is .i iqqiwen-i.l uudariailr of Kilt Sriciery of l"mtnm'i: ChI:lI1lSlS.
`P0.'§'I‘M.-\5'['ER. MEMBERS AND S|J'BSCR.I BERS. Send adilius cllaiign to Th;
`Sucii-ry of fxvmcut (Jianiiis,
`l.!{J W-.il1 Sin-iei, 5111!: 3-H10. New York. N.Y.
`Il|(|l'J5—l(‘lBFl.
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`til Cusniuic
`Responsibility fur S(alEl'I'l9l'|l.'i Published: The Soi'ic-n_,'
`Cliemi-«is, (HE (.;umi-iiitlne rm P\lblIE".Il’lI)|l'.i and rlir Brand of Dinrmrs :I$'iul!'l£'
`run
`it9pr.irisil\iJ.'iri- Fix srniuneiiir. or otiiniuris admired by iumribiiiniii [(3 ilii-i. juumal
`
`if LIilllT|‘)' are ll11:l‘l\L\l more iluii I'll
`rim be supplied.
`Missing numbers will
`days alter the clinic oldie issig, nir iflosa w.:i due to liiilurr to give riiiti-vi iftlhflige
`oi wlclri.-.is
`'1‘ht-JG!-' mi-inui iiioqit itspmsiluiliry fin Iiiirign ilcliwi-y when in
`ru'nrd5 llKll:.‘ll'I‘ .*ihIpFl'l|‘:'l'll wits Inaide.
`Edition iiritl Piibliiihen: l’\h§lI:ll.'l50¢ iliguus ind iirutliei nut i.-s«.i~cdiii,i_; -inn words may
`lie iaiblisllul, sluly crlsiirrd rri (he authial‘ uiil JUURNAI. ()1:
`K]-
`ENCE. the Ollitial jiiiiinil ul the Son i:‘r_i' at Cuiriuit [:l'|CFI'li5E'S.
`Auilinrs: W'ht-ii iisiiiia I“LlilT.|tlLl|a or qinniniins l".I.lOl'n Iium i-um-rigliii-ul pi.ilil:i-.i-
`tium. aiiihois must ii,-i-t wrim-n pi-rrnissian from the (I!|'>}'Tlj_:hr ho|.d.::r ru irprixlutr
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`liut priiiiscl ll'|.'l(l|.I:il.fl[1la'. TI»: autlwr will still be El5[]Jl'Blbl.r ltvr the mar innintd for
`the rmtiiini: of itilnr rilnxtigrzpiis. .I\rr_v irutrri.-I SN’ iniii t_\‘pc but iinluul deleted
`from the riulilittition at Ill‘ page prml -stage rniisr also bc iuiil liar by the auilur.
`'l'|u:ie ilurgu will be inviiiri-cl In the it-rucir aiirliur at the lirilt‘ of publication.
`MANL|SK‘3.'lP1'S: Miirius-mp: ahuiilil he pm-para] in a;mn.Eanci- with "lnfimniirir>11
`liar llurhurs," aipiit-infwhith an AImll£.|:I|l.' from I20 Wall Siren. Suite Zrlflll. New
`\"ri1'It_ NT Il'l(l(l5<1lllH8.I'_'3l2}(<63—l'§lKl, Iiuz I2|.2H"IlSN-l‘l(l-I
`Pmndiexls ritislaggv paid at New York. New York and ailiiliiarnial rriailiiii: olfias.
`Publicmoii iiflitir. I20 \llr'a|.l Sui-er. Suit: _’-iIJO. Ni-w York. NY 1{.'IfK)5—l-[II-ll-l
`talaiisriitistio. I-".1:-r. ms; mi:-isiid
`
`Page 2 of 25
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`Page 2 of 25
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`

`

`J. Crmrm‘. St'f.. 50, 363-385 (Noveml)er?December 1999}
`
`Structural characteristics and permeability properties at
`
`the human nail: A review
`
`GOURI V. GU PCHUP and JOEL L. ZATZ, Callege of P/xrwrsaty.
`Kiri’-‘get’: Unit.'i:r'tr'£y, I60 Fr£’;’h?_g’Ifrrz_].'5c.rr Road. Pi.tt'::!::ui.'rrj.'. N} 08854.
`
`/ictepredfnr prrnfiiwriarr Om;-¢'iei‘ I 5.
`
`I 999.
`
`Synopsis
`
`The human nail forms ll resistant barrier to the topical penetration of it.C(iVC5. Thus, treatment of nail
`disorders. such as fungal infections, remains a challenge because of the difficulty encountered in achieving
`therapeutic concentrations of drugs at
`the site of infection. The nail
`is primarily composed ofa highly
`cross-linked keratin network that contains several disulfide linkages. This unique structure results in a
`highly effective permeability barrier. Nail pt.‘I'lt'tr:.lti0n has been reported to be affected by molecular size and
`hyclrophilitity; smaller. water-soluble molecules are found to preferentially permeate the nail. Permeation
`of untiissociated drugs is favored in certain instances. Also. some studies indicate that the nature of the
`vehicle can influence drug penetration. Recent research has focused on imprtivetnent of penetration of
`topically applied actives into and througlt the nail. Studies have slttiwn that compounds containing sulf-
`hydryl groups in conjunction with keratolytic agents can significantly enhance drug penetration. relative to
`a control formulation (without enhancer). Such sulfhydryl cornpounds are tltnught to reduce the disulfide
`linkages in the nail keratin matrix. Thus, althnuglt some success has been achieved in enhancing penetration
`of drugs through the nail. further research is required to achieve successful topical proclticts for treatment
`of nail infections.
`
`INTRODUCTION
`
`The human nail acts as a protective covering to the delicate terminal phalanges of the
`fingers and toes and helps in grasping small objects. Changes in the appearance of the
`nail result from a variety of conditions such as Fungal, bacterial, and viral infections or
`dermatological disorders (1-3). Various cosmetic procedures such as application of ar-
`tificial acrylic nails, use of nail hardeners, and mimicures can also result in nail disorders
`(4).
`
`infections of the nail, called onychomycosis (OM), are some of the most com-
`Fungal
`monly encountered dermatological disorders, typically manifested as localized infections
`of the nail or nail bed. OM has widespread incidence and is thought to account for 40%
`of all nail disorders. It is estimated that «-/t.9—12.:"i million people are affected with OM
`in the United States. The incidence of OM increases with age, and toenails are infected
`about seven times more frequently than fingernails. Mycotic nail infections are caused by
`detrnatophyres, yeasts, and nondetmatophyte molds. although dermatophytes are be—
`lieved to he the principal Causative organisms in OM (3.5). Symptoms of OM include
`
`363
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`

`

`364
`
`JOURNAL OF COSMETIC SCIENCE
`
`discoloration of the nail, brittleness, pitting, splitting, hypertrophy, or even complete
`separation of the nail from its bed (onycholysis) (6). Thus, nail diseases may result in
`unaesthetic changes in nail appearance. Hence, these disorders require treatments that
`will eradicate the infection and allow the nails to return to a cosmetically acceptable
`state.
`
`treatment modalities for OM include surgery and oral antifungals. While
`Current
`surgical nail removal (avulsion) is invasive and painful, high doses oforal medication can
`lead to systemic side effects. These adverse effects combined with treatment
`times
`extending to several months, and frequent incidences of relapses observed with oral
`antifungals, often lead to patient noncompliance and interruption of therapy. Thus,
`topical therapy is the most desirable, but it has met with limited success to date. The
`primary reason for the resistance of the nail
`to topical
`therapy is the extremely low
`permeability of the nail plate and thus the inability of actives to reach the sire of
`infection (7). This review will outline the structure, chemical composition, and physical
`properties of the nail, and will also describe studies used to investigate and improve
`permeation of actives through the human nail.
`
`STRUCTURAL CHARACTERISTICS OF THE HUMAN NAIL
`
`STRUCTURE .i‘\ND ANJKTOMY OF THE NAIL
`
`The nail, shown schematically in Figure 1, consists essentially of the hard, flat, and
`roughly rectangular nail plate, which is closely connected to the nail bed. The nail bet!
`appears pink in color due to its extensive vascular network, and can be seen due to tilt‘
`translucency of the nail plate. The nail wall surrounds the nail proxim-ally, while the
`groove—shaped nail fold encloses the nail laterally. The nail root lies 3-5 mm deep within
`the nail fold and is invisible. The nail plate emerges from the matrix, the distal end of
`which appears as the whitish cte5cent~sh-aped lunula. The eponychiurn is formed from
`the epidermis of the proximal nail wall. The stratum cotneum of the eponychium forms
`the cuticle. Below the cuticle lies the matrix. The skin under the free edge of the nail
`is called the hyponychium (8-9).
`
`The mrzimix. The matrix is mainly responsible for the formation of the nail plate. During
`nail plate formation, the basal cells of the matrix flatten, and fragmentation ofcell nuclei
`and condensation of cytoplasm occur to form flat, keratinous cells whose cell borders, in
`contrast to hair, are retained. The lower cell layers of the matrix contain melanocytes.
`and this may cause varying degrees of pigmentation of the human nail plate, depending
`on race (8~9).
`
`The raw"! beta’. The nail bed extends from the lunula to the hyponychium. It does not
`contribute much to the formation of the nail plate; however, keratin production in the
`nail bed occurs synchronously with extension of the nail plate. The nail bed acts mainly
`as a holder and slide for the nail plate (8-9).
`
`T/as mzii’ plate. The nail plate consists of dead. cornified, adherent cells without nuclei.
`but with prominent cell borders. The nail plate is 0.5-1.0 mm thick, made of or-keratin.
`and consists of three layers: the dorsal and intermediate nail, formed from the matrix;
`and the ventral nail, formed from the nail bed (Figure 1). The dorsal nail is a few cell
`layers thick and contains hard keratin, while the intermediate nail contains softer keratin
`
`Page 4 of 25
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`

`STRUCTURE AND PERMEABILITY OF HUMAN NAIL
`
`3:65
`
`Eponychium
`
`I-lypnnyehium
`
`Nail Plate
`
`Lunula
`
`Matrix
`
`
`
`
`Dorsal Nail Plate
`
`Intermediate Nail Plate
`
`
`
`.-.-;-‘i'3-"13"
`
`'
`
`3"?-7‘.v:-_v:—,:-.:.,..;._. Ventral Nail Plate
`
`(A)
`
`(B)
`
`(C)
`
`Figure 1. SL'|1un1-.1riL- dizigr-dun nFtl1c hum.m nail. A: tup view. B:
`taf the nail p1;1l.'r:. Atiaprc-LI from rt-flwncc.-: 5. 51.
`
`lr.ungm1din-.1! view. C.’ lt_mgituL'lin-al 5<_'L'[il}Il
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`Page 5 of 25
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`566
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`JOURNAL OF COSMETIC SCIENCE
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`and accounts For three fourths of the whole nail thickness. The ventral nail is one to two
`cell layers thick and is comprised of soft, hyponychial keratin. The ventral nail serves to
`connect the nail plate securely to the substratum (9).
`
`BLOOD L-il_.'PPLY TO THE NAIL
`
`The nail matrix and nail bed have a rich blood supply that originates from two millll
`arterial arches lying below the nail plate. In addition, there is an extensive capillary
`blood supply to the tissues around the nail; in particular, a capillary loop system supplier.
`blood to the whole nail fold. Furthermore, the nail bed has a rich supply of lymphatic
`vessels and glomus bodies that are thought to be involved in regulating blood supply to
`the extremities in cold weather. Despite this extensive vascular network, defective
`peripheral circulation may be one of the main causes of nail deformities (10).
`
`GRO\l€’TI[ OF THE. NAIL
`
`The nail is formed continually from the matrix, unlike hair, which is formed cyclically
`The growth rate depends on matrix cell turnover. Toenails grow 3(l—'5{l‘/’?- more slowly
`than fingernails. Typically, the fingernail grows at an average rate of 5 mm per month,
`and nails of the dominant hand (i .e., right vs. left) exhibit a Faster rate ofgrowth. Growth
`rate of the nail
`is usually independent of nail thickness. However, growth occurs in -.i
`definite order in relation to the length of the fingers; in general, the longer the finger.
`the faster the growth. Various pathological conditions can cause either an increase or
`decrease in growth rate. The regeneration time of the nail is dependent on growth rate.
`The fingernails usually have a total regeneration time of about 160 days, while toenails
`take approximately a year to regenerate. Due to long regeneration times, treatment oi
`nail diseases requires several months (9).
`
`CHEMICAL COMPOSITION OF THE NAIL
`
`The main chemical constituent of the human nail is keratin, a scleroprotein containing
`large amounts ofsulfiir. Both epidermal— and hair-type keratins are present, although the
`latter make up more than 90% of the protein content. Recent studies using double-label
`imrnunofluotescence techniques have shown that the nail matrix contains three popu-
`lations ofcells: cells expressing either skin or hair type keratins and cells expressing both
`keratins (11-12). The oi-keratin filaments (helical) interact with the cystine-rich non-
`helical matrix keratins, and are oriented perpendicular to the direction of nail growth
`and parallel to the Free edge of the nail. This alignment of keratin filaments and the
`strong adherence of nail cells to each other are thought to contribute to nail hardness
`(8-9).
`
`The nail contains various amounts of amino acids that condense together to Form the
`polypeptide chains present in keratin. The amino acid composition of human nails is
`shown in Table I. For comparison, the amino acids present in human hair and stratum
`corneum, as well as those in sheep horn, hoof, and wool are included. As seen from Table
`I. the content ofglycine and half—cystine in hurnan nails is similar to that of human hair
`and sheep wool, rather than human stratum corneum. However, the amino acid com-
`
`Page 6 of 25
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`Page 6 of 25
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`

`

`FT
`
`STRUCTURE AND PERMEABILITY OF HUMAN NAIL
`
`%6'?
`
`Table 1
`Amino Acid Composition (as residues per 100 residues) of Human Nail, Human Hair, and 1-Iuman
`Stratum Corneurn, Compared Witli That of Sheep Wool, Horn. and 1-Iool’
`
`Human
`
`Sheep
`
`Stratum
`Hoof
`Horn
`Wool
`corneum
`Hair
`Nail
`Amino acid
`$1.0
`3.51
`.’.'i'
`4.2
`3.5
`3.1
`Lysine
`0.9
`1.3
`0.8
`1.":
`0.9
`1.0
`Histidine
`7.2
`6.?
`6.2
`3.8
`6.5
`6.3]
`Arginine
`8.11
`18
`5.9
`7.9
`5.41
`7.0
`Asparric acid
`3.0
`-1.3
`6.5
`3.0
`‘L6
`6.1
`Threunine
`9.5
`9.0
`10.8
`15.6
`12.2
`11.3
`Serine
`13.?
`12.9
`11.1
`12.6
`12.2
`13.13
`Glut-arnic acid
`4.1}
`5.3
`6.6
`5.0
`8.4
`5.9
`Proline
`9.1
`11.1
`8.6
`24.5
`3.8
`7.9
`Glycine
`6.31
`5.9
`5.2
`4.4
`4.3
`3.5
`Alanine
`5.7
`5.2
`3.7
`3.0
`5.5
`4.2
`Valine
`0.8
`0.8
`(L5
`I .1
`0.5
`0.?
`Methionine
`3.6
`3.3
`_’i.U
`2.7
`2.3
`2.7
`Isoleucine
`9.5
`9.1
`7.2
`6.9
`6.1
`8.5
`Leucine
`4.0
`5.0
`3.8
`_’n.4
`2.2
`3.2
`Tyrosine
`2.7
`2.7
`2.5
`"-3.2
`1.7’
`2.5
`Phenylalanine
`5.7
`6.2
`I 55.1
`1.2
`15.9
`10.6
`Half-cystine
`2.2
`2.1
`3.3
`1.51
`"-1.5
`5.2
`Su.11-l.lf(%-)
`______________________________________
`Adapted from references 13. 1-1.
`
`position of human nails differs considerably from that of horn or hoof derived from
`sheep. In general, significant amounts ofglutamic acid, half-cystine, arginine, aspartic
`acid, serine, and leucine are present in human nails (9.13—l S). The nail cellular envelope
`contains large amounts of proline, unlike the cell matrix, which contains numerous
`cysteinyl residues (16). Carbohydrates are also found to be present in the cell membrane
`complexes of human nails. Allen at an’. (1?) demonstrated by formic acid extraction and
`lectin-binding studies that sugar characteristics of membrane glycoprnteins (i.e., man—
`nose, galactose, N-acetylglucosamine, and N-acetylgalactosamine) were present in the
`cell membrane complexes of nails.
`The lipid content of nails is less than 5% (8-9), while the sulfur content is high, as in
`hair (Table 1) (13-4). Nitrogen is another major component. resulting from the presence
`ofhigh levels of keratin. The nail also contains low levels of Ca, Mg, Na, K, Fe. Cu, and
`Zn (18). The calcium content was earlier thought to be responsible for the hardness of
`the dorsal nail (19). However, it is now believed that the presence of disulfide linkages,
`rather than the calcium content, is responsible for nail hardness (8-9). Trace amounts of
`Cr, Se, Au. I-lg, Ag, and Co have also been reported in human thumbnails (20).
`
`l~'i"l‘RUf_TURlE OF KERATIN
`
`The main form of keratin resent in all mammalian hairs, wool, horns, claws, nails, and
`.
`.
`P
`quills is or-keratin. The presence ofcovalent disulhde cross—links. which occur due to the
`high proportions of cystine, confers an exceptional degree of physical and chemical
`stabilit on the keratins. in addition to the intermittent disulfide cross-links, there are
`Y
`
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`JOURNAL OF COSMETIC SCIENCE
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`other secondary bonds also present in the keratin structure. These include Van der Waaia.
`interactions, hydrogen bonds, and coulombic interactions. The coulombic interactions.
`arise because of the presence of negatively charged carboxylic acid groups (COO ') and
`positively charged amino groups (N1-Ii") formed on the side chains of acidic and basic
`residues. These secondary bonds and interactions play an important role in maintaining
`molecular order in the lteratins, which, in turn, control the freedom of movement and
`cooperation between molecular chains forming the keratin structure. These character-
`istics of keratins greatly influence the physical and mechanical properties of the nail (21),
`
`X-ray diffraction studies have revealed a high degree of order (crystallinity) in the
`keratin structure. The keratinous tissue is primarily composed of ot—keratin filaments
`(7-—1{') nm in diameter and several micrometers in length) embedded in an amorphous
`matrix. The oi-helix form constitutes about 35-55% of the keratin, and the rest is the
`non-helical amorphous form. The oi—helix portions have a low sulfur content; however,
`the amorphous sections are high in disulfide linkages (22-23). Apparent molecular
`weights of low-sulfur and high-sulfur proteins (estimated by electrophoresis) were re-
`ported to be in ranges of §5,0(l0—'i'6,[}00 and 26,50()—’i3v,000 daltons, respectively. The
`isoelectric points for hair and nail
`low-sulfur protein components are in the range of
`4.9—5/1 (24). The term "at" refers to the typical high-angle X-ray diffraction pattern
`obtained for Ct-l(E1“Eltil'1 filaments. Two reflections are obtained that are diagnostic for
`0:-I-teratins. The 0.516-nm reflection on the meridian corresponds to a repeat in the fiber
`direction, and the [).98-nm reflection on the equator corresponds to a spacing repeat -at
`right angles to the fiber direction (21,25).
`
`PHYSICAL PROPERTIES OF THE NAIL
`
`The water content of the nail is normally about 18% (9). Early work showed that the rats:
`of diffusion of water through toenails was essentially the same as that through the palm.»
`and soles. Moreover, increases in temperature or air currents led to increased diffusion.
`whereas changes in the humidity of the air influenced water diffusion to a smaller extent
`(26). Further studies on the water content of nails have revealed that nails are similar to
`hair in that they are much more permeable to water than the stratum corneum. Also, the
`uptake of water and rate of water loss seem to be unaffected by prior lipid extraction of
`the nails with a 3:1 chloroformtrnethanol mixture. This indicates that the lipid com-
`ponent of nails does not limit water loss from them. The modulus of elasticity of nails
`has been measured and is found to be dependent on water content of the specimen (27).
`Forslind and coworkers (28) measured effective elastic modulus (independent of par-
`ticular dimensions of a nail specimen) and concluded that the water content of finger-
`nails affects their rigidity and stiffness, while natural nail curvature does not affect
`effective elastic modulus. These authors indicate that contact with detergents, organic
`solvents, oils, etc., may also influence nail stiffness. In another study, the specific water
`vapor loss (a product of water vapor loss and nail thickness) was found to be independent
`of fingernail thickness (29).
`
`Nail flexibility has also been assessed, and has been found to be directly related to water
`content. Finlay at at’. (30) used a specially developed nail flexorneter to assess changes in
`properties of the nail it: 1..-rm after treatment with various agents. The flexometer spe-
`cifically measured the ability of the nail specimen to withstand repeated flexions, and
`
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`STRUCTURE AND PERMEABTLITY OF HUMAN NAIL
`
`369
`
`was thus a measure of nail flexibility. They found that during water immersion of nails,
`nail weight increased by 22% of its original value in two hours and then unexpectedly
`decreased. Flexibility of nails continuously increased with water immersion. Treatment
`of nails with mineral oil showed no increase in flexibility; however. mineral oil applied
`to previously hydrated nails prolonged their flexibility. A phospholipid-water prepara-
`tion was also found to increase nail flexibility of normal and lipid-extracted nails. It was
`postulated that this increased flexibility may be due to the ability of the phospholipids
`to bind water.
`
`transonychial water loss (TOW/I.) was measured using an
`In :1 more recent study,
`evaporimeter in 21 healthy adults, and was reported to be in the range of 1.17-3.35
`mg/cm‘,/h. This rate of water loss through the nail plate was not significantly different
`from the transepidermal water loss (TEWL) from the dorsum of the hand. The TO\Y/L
`appeared to decrease with age and was not affected by nail plate thickness (51).
`
`PERMEABILITY OF THE HUMAN NAIL
`
`By virtue of its chemical composition, the nail plate forms an effective barrier to the
`permeation of drugs. Thus, the diffusion of actives into and through the nail is extremely
`poor relative to other membranes such as the skin. Hence,
`topical medication for
`treatment of nail infections has been ineffective to date, and information on nail pet-
`meability still remains limited. Currently, only oral antifungal therapy is approved for
`treatment of OM in the United States. However, since efficacious topical nail therapy is
`most desirable, recent research has focused on characterizing and improving the perme-
`ation of drugs through the human nail. Some of the permeability properties and advances
`made in topical therapy of nail diseases are discussed in the remainder of this review.
`
`EFFECT OF MOLECULAR WEIGHT AND LIPOPHILICITY OF THE PERMEANT
`
`Walters et ul. designed the first diffusion cell. specially adapted to quantitatively mea-
`sure nail plate permeability in r/itro.
`in 1981 (32). This stainless steel diffusion cell
`permitted the exposure ofO.38 cm2 of the nail plate to the donor and receiver solutions.
`present on either side of the nail. The flux and permeability coefficients of the per-
`meants. based on Fick's Law. were reported. A water flux (determined by monitoring the
`permeation of tritiated water through cadaver nails) of 12.6 2 5.8 mg/cm‘,/h was
`obtained using this diffusion cell. This flux value was about five times higher than that
`reported by earlier researchers. This was explained by the fact that nails used in this
`study were hydrated, in contrast to dry nails used in earlier investigations. To check the
`integrity of the nail permeability barrier as a consequence of hydration, the permeability
`coefficient of methanol was monitored over a period of 49 days and was found to remain
`fairly constant. This indicated that the nail was a stable barrier and was not affected by
`the repeated application of pressure required to seal
`the nail
`in the diflitsion cell.
`Furthermore, the nail plate permeability was found to be almost inversely proportional
`to nail thickness.
`
`These diffusion cells were later used to study the in mm permeation of a series of dilute,
`homologous alcohols (from methanol to n-dodecanol) through the nail plate. A radio-
`active assay was used to analyze concentration of the active. and permeability coeffi-
`
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`JOURNAL OF COSMETIC SCIENCE
`
`lag times, and effective diffusion coefficients were calculated. The effix-1;.
`cients,
`increasing chain length on the permeability coefficients and diffusion coefficients of:
`:2-alkanols is depicted in Figure 2. Figure 2 shows that the permeability coefficients
`diffusion coefficients of the alcohols from methanol through ti-octanol decreased wjfl-I
`increasing chain length. The lag times also showed a corresponding increase (not shown};
`The authors thus concluded that the nail plate appeared to behave as a concentrated
`hydrogel in this case, and that the partitioning of the alcohols into the complex keratin
`matrix decreased with increasing hydrophobicity up to J:-octanol. However, with the
`higher alkanols from ri-octanol
`to iv:-dodecanol,
`it was found that
`the permeability
`coefficients through the nail plate increased exponentially {Figure 2}. The authors sug-
`gested the involvement ofa possible parallel lipid pathway to explain the permeability
`result for extremely hydrophobic molecules (33)- Neat (undiluted) alcohols were also
`found to demonstrate trends similar in permeation to the dilute alcohols. However, the
`permeability coefficients of the undiluted alcohols (except methanol) were about one
`fifth those of their dilute counterparts. It was observed that the rate of transfer for the
`lower alcohols increased through the lipid—extracted (with a 5:1 chlorofotm:mt~th-anol
`mixture) nail plate. On the other hand, a sixfold decrease in the permeation rate of
`:3-decanol was observed through the delipidized nail. The authors suggested that the
`decrease in permeation rate observed for the larger alkanols resulted because the rate-
`
`18.00
`
`l6.00
`
`14.00
`
`12.00
`
`10.00
`
`8.00
`
`6.00
`
`4.00
`
`2.00
`
`0.00
`
`
`
`PermeabilityCoefficientx10’(emfh)
`
`—i—-Permeability Coefficient
`
`' 9' Diffusion (Inefficient
`
`6.00
`
`5.00
`
`4.00
`
`3.00
`
`2.00
`
`1 .00
`
`0.00
`
`
`
`
`
`DiffusionCocfficienl110'llllllzffil
`
`0
`
`2
`
`4
`
`6
`
`8
`
`I0
`
`12
`
`14
`
`Figure 2. Effect of chain length on the permeability coefficients and diffusion coefficients of a series of
`diluted. homologous rt-all-zanols through the human nail plate. Mean 2 S.[)_, n = 4-26. Adapted from
`reference 55.
`
`Alcohol chain length
`
`Page 10 of 25
`
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`

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`
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`STRUCTURE AND PERMEABILITY OF HUMAN NAIL
`
`37’l
`
`tontrolling lipid pathway for the higher alcohols was interfered with by extraction of the
`?very low, but necessary, lipid level in the nail plate (34).
`In a study by Soong (35). the in virro penetration of acetic acid (molecular weight = 60),
`benzoic acid (molecular weight : 122), and suprofen (molecular weight = 260) through
`nails was investigated. Steady-state conditions were achieved in these experiments, and
`the permeated drug was assayed by HPLC. The results of this study showed that as the
`size of the permeant increased,
`the lag time increased and diffusion coefficients de-
`creased. The data from this detailed investigation indicated that small, lipophilic mol-
`ecules would be good candidates for topical nail therapy, both in terms of shorter lag
`times and faster penetration into the nail plate (due to effective drug partitioning).
`However, the author cautions against using a very highly lipophilic molecule since water
`has been shown to facilitate drug transport across the nail plate (53). In order to ascertain
`whether the dorsal part of the nail plate (which contains tight intercellular junctions)
`constituted the main barrier to drug penetration, the permeability of benzoic acid
`through intact as well as shaved (dorsal part removed by scraping) nails was studied (35).
`No dramatic increase in the permeability coefficie.nt occurred with the shaved nails
`(which was expected if the dorsal nail constituted the main barrier). Thus, the author
`speculated that the intracellular structured keratin was the main barrier to the perme-
`ation of drugs.
`A recent study has further attempted to explain the transport mechanism of permeants
`through the nail. In this investigation, Mertin and Lippoid (36) studied the in -vim:
`permeation of homologous nicotinic acid esters (with octanolfwater partition coefficients
`ranging from 7 to >5l.000) through human nail and a keratin membrane derived from
`bovine hooves. The diffusion cells used by these researchers were of the Fran2—type,
`temperature was maintained at 52°C,, and drug analysis was performed spectrophoto-
`metrically for studies with the hoof membrane, and by HPLC for studies with the nail
`plate. It was found that the permeability coefficients through both human nail and
`bovine hooves did not
`increase with increasing partition coefficient or lipophilicity.
`Thus, the authors stated that the nail appears to behave as a hydrophilic gel membrane
`rather than as a lipophilic partition membrane. Penetration of acetaminophen and
`phenacetiri showed that maximum drug flux was a function of solubility in water or the
`swollen keratin matrix. This study showed that water solubility of the drug is an
`important consideration in formulating a topical product for nail disorders, as increased
`water solubility can enhance maximum drug flux.
`The relationship between the molecular weight (MW) of several drugs (including a series
`of antirnycotics} and permeability through the nail plate and hoof membrane was also
`investigated (3?) The donor compartment consisted of a drug suspension in ethanol
`(42% vfv), pH 8.1. Due