VOL. 4, SUPPL. 1
`
`APRIL 1995
`
`ISSN:0926-9959
`
`JEAVEQ 4(Supp|. 1) S1 —s3o (1995)
`
`w1 40929
`
`1995
`3 V‘4
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`TI:
`JOURNAL OF THE EUROPEAN
`ACADEMY OF DERMATO
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`E Q D JOURNAL OF THE EUROPEAN ACADEMY /
`
`OF DERMATOLOGY AND VENEREOLOGY
`
`
`
`Elsevier
`
`/\~._
`
`Management of Superficial Mycosis
`
` Amorolfine: Progress in the
`
`Proceedings of a symposium at the 3rd
`European Academy of Dermatology and Venereology,
`Copenhagen, September 1993
`
`Guest Editor: H. Merk
`
`
`
`This material was {spied
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`am~e~LMaw=mav==e
`Sulzjescti US Emwright Laws
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`
`E JOURNAL or THE EUROPEAN ACADEMY
`OF DERMATOLOGY AND VENEREOLOGY
`
`Amorolfine: Progress in the Management of
`Superficial Mycosis
`
`Proceedings of a symposium at the 3rd European Academy of
`Dermatology and Venereology
`
`Copenhagen, September 1993
`
`Guest Editor.‘ H. Merk
`
`Supported by an educational grant by F. Hoffmann—La Roche Ltd.
`
`This text is brought to you by F. Hoffmann-La Roche Ltd. as a service to the medical profession. It does
`not necessarily reflect the views of the editors or an endorsement by the European Academy of
`Dermatology and Venerology. This supplement was subject to independent review.
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`JOURNAL OF THE EUROPEAN ACADEMY
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`JOURNAL OF THE EUROPEAN ACADEMY
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`Q I)
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`OF DERMATOLOGY AND VENEREOLOGY
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`EDITOR-IN-CHIEF
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`E[)]T()m,\L S’]‘;\F[«‘
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`Volume 4, Supplement 1 (1995)
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`Ndg.
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`ELSEVIER
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`Amsterdam — Lausanne — New York — Oxford — Shannon — Tokyo
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`JEAD OF DERMATOLOGY AND VENEREOLOGY
`
`JOURNAL OF THE EUROPEAN ACADEMY
`
`Volume 4, SUPP'- 1
`Apr” 1995
`
`Contents
`
`Cited in: Excerpta Medica; Oncology and Information Service; Core Journals of Dermatology
`
`Foreword
`
`H. Merk (Germany)
`
`Therapeutic strategies in onychomycosis
`I. Effendy (Germany)
`
`Mechanism of action of antifungals and combination therapy
`A. Polak-Wyss (Switzerland)
`
`Amorolfine nail lacquer: a novel formulation
`J .-P.L. Marty (France)
`
`Amorolfine nail lacquer: clinical experience in onychomycosis
`M. Zaug (Switzerland)
`
`S1
`
`S3
`
`S11
`
`S17
`
`S23
`
`/Vx
`
`This material was {copied
`at the NLM and may he
`Subject USC.Dpy‘right‘ Laws
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`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`
`
`Journal of the European Academy of Dermatology and Venereology
`4 (Suppl. 1) (1995) S17—S21
`
`JEADV
`
`Amorolfine nail lacquer: a novel formulation
`
`Unité de Recherche en Dermopharmaco/agic ct Cosniétologie, Faculté de Pharmacie, Urziuersité Paris Sud, 5 rue J.B. Clémcnt,
`92296 Cluitenay-Malabry, France
`
`Jean—Paul L. Marty *
`
`
`
`Abstract
`
`Onychomycosis is difficult to treat. Systemic therapy with the potent oral azoles may be restricted by
`their potential side-effects; an attractive alternative is topical application of an antifungal directly to the
`nail. Several such formulations have been developed,
`including creams and lotions which are largely
`ineffective due to poor drug penetration into and through the nail structure. Nail keratin is thick and
`compact; its permeability is low. Transungual drug diffusion depends on the characteristics of the nail
`(especially degree of hydration) and the properties of the chemical (molecular weight and size, and
`lipophilic/hydrophilic profile). A nail lacquer containing 5% amorolfine was recently introduced; the
`Volatile vehicle evaporates, leaving an occlusive film on the surface of the nail. The film acts as a drug
`depot, while at the same time increasing the hydration of the nail and the thermodynamic activity of the
`drug, thereby enhancing diffusion, particularly of hydrophilic compounds. Amorolfine has been shown to
`penetrate human nail from the film at clinically effective concentrations. In addition, the effect is long
`lasting: a single application of lacquer provides protection for 1 week. Release and rate of diffusion can
`be optimized by selecting the components of the lacquer formulation (solvent, polymer, plasticizer).
`Transungual drug delivery via nail lacquer is a major addition in the dermat0logist’s therapeutic arsenal.
`
`/\
`
`Keywords: Amorolfine; Nail lacquer; Transungual drug delivery; Nail diffusion
`
`
`1. Introduction
`
`therapy of onychomycosis is
`local
`Successful
`dependent on choosing an appropriate antifungal
`coupled with a method of delivery which maxi-
`
`* Corresponding author. Tel.: +33 1 4683 5351.
`
`mizes the effect of the active principle by aiding
`its diffusion into the nail bed at levels exceeding
`the minimum inhibitory concentration (MIC)
`against
`local
`infection by fungi, dermatophytes
`and molds.
`
`Local treatments are an interesting alternative
`to long-term systemic therapy, especially when
`the nail matrix is not affected. Transungual diffu-
`sion of the active principle is the necessary and
`
`0926‘-9959/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved
`SSDI 0926-9959(94)00075-1
`
`mimateflalmmpied CFAD v. Anacor, |PR20‘|5-01776
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`S18
`
`J.-P.L. Marty /J. Eur. Acad. Dermatol. Venereol. 4 (Suppl. 1) (1995) SI7—S2I
`
`limiting condition for all local application. Diffu-
`sion depends on the physicochemical composition
`of the nail and of the excipient containing the
`active principle.
`In addition to delivery of the active principle
`to the nail, other problems exist in applying drugs
`to the nail surface: how to apply the preparation
`evenly, how to maintain it in place long enough to
`ensure adequate penetration at fungicidal levels,
`and thereby avoiding multiple applications and
`enhance compliance.
`
`2. Differential permeabilityof nail
`
`The basic constituent of the nail is keratin, a
`scleroprotein responsible for the mechanical re-
`sistance of the nails. The hardness of the nail
`
`plate depends not only on the junctions between
`the cells and their architectural arrangement, but
`also on the tranverse orientation of the keratin
`
`filaments with respect to the axis of nail growth.
`The multiplicity of the lateral bonds between
`keratin fibers (disulfide bridges, hydrogen bonds,
`acid-base bonds, electrostatic bonds) accounts for
`the hardness of nail keratin and its high resis-
`tance to the diffusion of active principles.
`Nail contains little lipid (0.5 to 1.5%, depend-
`ing on age), in contrast to the stratum corneum
`(10%) [1]. The lipid comprises cholesterol, which
`appears to be responsible for maintaining nail
`elasticity and cell cohesion, hydrocarbons and
`mainly unsaturated fatty acids. The latter account
`for 2/3 of the total lipid, and consist mainly of
`oleic acid. Phospholipids tend to be found in
`abundance in the dorsal
`layer of the nail,
`in
`association with calcium. Solvent extraction of
`
`cholesterol leaves the nail dry and brittle.
`Water is the main nail plasticizer. Its concen-
`tration in nail
`tissue (7% to 12%)
`is directly
`related to ambient relative humidity, and is lower
`than in the stratum corneum (15% to 25% under
`normal conditions). In dry air, nails quickly lose
`water; they can be rehydrated up to a maximum
`concentration of 25% in high ambient humidity.
`Nail is less able to bind water than the stratum
`
`corneum, which can absorb several times its dry
`weight [1,2].
`
`Like the stratum corneum, nail tissue is con-
`
`stantly losing water; under normal conditions,
`transungual diffusion of water (1.8 to 3.1 mg/cmz
`-h) is similar to transepidermal water loss from
`the palms and soles (2.0 to 3.0 mg/cmz - h). It is
`10-fold higher than that from other anatomical
`areas (0.15 to 0.35 mg/cmz-h). Given the rela-
`tive thicknesses of stratum corneum and nail, the
`
`to water is some 1000-fold
`permeability of nail
`greater than that of the stratum corneum [3,4].
`The nail plate is also permeable to many polar
`and non-polar substances with widely differing
`molecular weights (30 to 665), as shown in toxico-
`logical studies (formaldehyde, phenol, fluoruracil,
`detergents, pesticides, mercurials, hydroquinone
`etc), therapeutic trials (antifungal agents, antipso-
`riasis drugs) and diffusion studies [5].
`Aliphatic alcohols are useful for analysing the
`mechanism of diffusion across biological mem-
`branes, owing to their respective solubility in wa-
`ter and lipids. The data reported by Walters et al.
`for dilute aqueous solutions of these alcohols
`with samples of human nail in vitro show that the
`permeability constant falls steadily from methanol
`to octanol, and then rises up to decanol. These
`results differ from those obtained with the same
`substances under identical experimental condi-
`tions in stratum corneum,
`in which membrane
`permeability increases with the length of the hy-
`drocarbon chain [6].
`These comparative data suggest that the stra-
`tum corneum is a lipophilic membrane;
`the in-
`crease in diffusion is due to a favorable partition
`
`coefficient of lipophilic alcohols in the hydropho-
`bic areas of the membrane. Nail, on the other
`hand, behaves primarily as a water gel (for alco-
`hols comprising 1 to 8 carbon atoms). A lipophilic
`route of diffusion has been demonstrated for the
`diffusion of alcohols with a longer hydrocarbon
`chain. Similar qualitative data have been ob-
`tained when aliphatic alcohols have been applied
`pure to the nail surface and not in dilute aqueous
`solution. However, permeability constants are on
`average five times lower than those obtained with
`the dilute aqueous solutions. The parallel diffu-
`sion profiles show that the concentration of the
`diffusing molecule is a predominant factor in the
`mechanism; the difference in degree of diffusion
`
`Tl‘: is mate rial wasionrp-ied
`at the HLM and may be
`2'-pubjeazt US tltzpw,-‘right Laws.
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`J.-P.L. Marty /J. Eur. Acad. Dermatal. Venereol. 4 (Suppl. 1) (1995) S17-S21
`
`S19
`
`Suggests that water facilitates diffusion through
`the nail [7].
`This physicochemical difference in the charac-
`teristics of nail permeability suggests that there
`are two routes by which substances penetrate
`nails:
`
`— The hydrophilic pathway, which is used by
`most compounds, particularly if polar, and
`which accounts for the diffusion of water, urea,
`electrolytes and the ionized forms of ionizable
`molecules; the water contained in the vehicle
`plays an important role in promoting diffusion.
`— A secondary lipophilic pathway,
`through the
`extracellular lipid network, for use by strictly
`non-polar compounds.
`
`This selective diffusion of hydrophilic substances
`through a water gel contrasts with that in the
`stratum corneum and restricts the diffusion of
`
`many active principles that were developed for
`dermatological use because their lipophilic prop-
`erties enabled them to diffuse through the extra-
`cellular lipids of the stratum corneum [8].
`The excipients developed for use on skin are
`thus inappropriate for releasing active principles
`on the nail, as shown by the inefficacy of diffu-
`sion promoters such as DMSO [9]. Where ioniz-
`able substances are concerned, water solubility is
`maximal when ionization is complete; given that
`the nail is hydrophilic, vehicle pH can thus play a
`fundamental role, as has been suggested in the
`case of miconazole [10], where a high concentra-
`tion of active principle is achieved in the vehicle
`for maximal diffusion.
`
`3. Transungual drug diffusion
`
`The topical formulations conventionally used
`in dermatology (creams, gels, water- or oil—based
`lotions, powders) are specifically adapted neither
`to the nail nor to the mean treatment duration (6
`to 12 months) required for the growth of a healthy
`nail. Following application to the nail, such for-
`mulations are readily removed by rubbing, wiping
`and washing; their impermanence at the site of
`application readily accounts for their inefficacy.
`
`Apparently simple formulations have been pro-
`posed instead: alcoholic solutions containing high
`concentrations of active principle,
`e.g. 28%
`ticonazole, and nail
`lacquers or film—generating
`solutions
`containing 8% ciclopirox or 5%
`amorolfine.
`
`A film-generating solution is a novel therapeu-
`tic formulation developed to deliver effective
`doses of antifungal to the entire nail tissue over a
`short duration (one day, in the case of ciclopirox)
`or for longer periods (up to 1 week, in the case of
`amorolfine). Because 5% amorolfine remains at
`the site of application, the number of applications
`can be reduced, while effective treatment is en-
`sured by high bioavailability of the active princi-
`ple.
`A film-generating solution basically consists, in
`addition to the active agent, of the following: a
`volatile solvent (ethanol, ethyl /butyl /methyl ac-
`etate, methylene chloride, methyl ethyl ketone,
`isopropanol) and a non-water-soluble polymer
`(methacrylic acid copolymers, vinyl polymers)
`which leaves a thin continuous film following
`evaporation of the solvent. Plasticizers (triacetin,
`dibutyl phthalate) can be added to give the film
`the characteristics required for molding to the
`nail,
`including enough mechanical
`flexibility to
`prevent flaking and removal. The solvent
`itself
`can be composed of a mixture of compounds to
`accelerate drying and result in an even and repro-
`ducible film.
`
`This formulation is very similar to that of a
`nail lacquer, one of the most widely used prod-
`ucts in cosmetics. It maintains the active principle
`in a polymer film depot on the nail surface, from
`which the antifungal evenly diffuses through the
`nail plate keratin to reach the nail bed. The
`concentration (or thermodynamic activity) of the
`active principle in the film after solvent evapora-
`tion is extremely high; by the laws of diffusion,
`this enhances penetration [8].
`According to Spruit [11], application of an 0.05
`mm film of nail lacquer reduces transungual wa-
`ter diffusion from 1.6 to 0.4 mg/cmz - h, leading
`to hyperhydration of the upper layers of the nail
`plate. This also enhances the diffusion of the
`amorolfine applied to the nail surface.
`The specific aims addressed in formulating a
`
`This material was {baled
`atthe NLM arm may be
`Subjeet US~€>ui:ag‘right Laws
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`ANACOR EX. 2196 - 9/11
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`CFAD v. Anacor, IPR2015-01776
`ANACOR EX. 2196 - 9/11
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`S20
`
`J.-P.L. Marty /J. Eur. Acad. Dermatal. Venereoi. 4 (Suppl. I)_(I995) S1 7—S2I
`
`film-generating solution were to give the active
`principle maximal affinity for nail keratin and
`obtain the highest possible thermodynamic activ-
`ity compatible with maintaining the active princi-
`ple in true or supersaturated solution. Thus,
`in
`the case of LocerylTM, the amorolfine concentra-
`tion in the film-generating solution is 5%; solvent
`evaporation leaves a film with a final amorolfine
`concentration of 25%. The high post-evaporation
`concentration enhances transungual diffusion of
`the active principle.
`The concern to maximize diffusion must take
`
`into account the stability of the active principle
`and any physicochemical
`incompatibilities. The
`final product must be as clinically effective as
`possible, at the same time as having a maximal
`risk/benefit ratio and zero systemic diffusion.
`This means that the vehicle constituents must be
`
`non-irritant and non-allergenic and be well toler-
`ated locally. The formulation chemist is also un-
`der purely technological constraints arising from
`the use of organic solvents: special
`techniques
`need to be employed, particularly in the choice of
`inner packaging, to ensure maximal stability dur-
`ing storage. Application of the lacquer to the nail
`surface requires a device coping with the viscosity
`of the solution and giving a consistent and repro-
`ducible dose. A calibrated spatula gives a uniform
`coat of 18 ,ul of solution per nail; thus 90 i 8 u]
`(mean i standard deviation) is required to treat
`five nails.
`
`in the case of
`The film-generating solution,
`amorolfine,
`is an excipient giving substantial in-
`traungual diffusion, which is enhanced by the
`hydrating effect of the film; the active principle
`penetrates rapidly following a single application.
`Thus 6 h after single application in vitro, the nail
`concentration of amorolfine is 56 ,u. g/g - cmz, with
`a residual concentration of 188 p.g/g-cmz after
`7 days. These tissue concentrations are 140- and
`470-fold higher,
`respectively,
`than the MIC
`against Candida albicans [12]. The vehicle compo-
`sition helps modulate the release of amorolfine
`into the nail and maintain it at high levels over 7
`days [13]. These data have been confirmed in
`vivo, after treatment for one month: two weeks
`after the last application, subungual
`tissue still
`
`showed an overall antifungal activity far exceed-
`ing the mean MICs against test organisms [14].
`
`4. Conclusion
`
`A nail lacquer is a novel formulation solution
`to the problem of a transungual drug delivery
`system for maximal antifungal efficacy. The film
`on the nail surface acts as a depot of active
`principle, permitting optimized and sustained dif-
`fusion of amorolfine (for up to 7 days). Continu-
`ous penetration of the active principle leads to
`the high tissue concentrations required for the
`effective treatment of onychomycosis.
`
`References
`
`[1] Baden HP, Goldsmith LA, Fleming B. A comparative
`study of the physicochemical properties of human kera-
`tinized tissues. Biochim Biophys Acta 1973;322:269—278.
`[2] Finlay AY, Frost P, Keith AD, Snipes W. An assessment
`of factors influencing flexibility of human fingernails. Br
`J Dermatol 1980;l03:357—365.
`[3] Spruit D. Measurement of water vapor loss through
`human nail in vivo. J Invest Dermatol 1971;56:359-361.
`[4] Walters KA, Flynn GL, Marvel JR. Physicochemical
`characterization of the human nail: 1. Pressure sealed
`apparatus for measuring nail plate permeability. J Invest
`Dermatol 1981;76:76—79.
`[5] Walters KA, Flynn GL. Permeability characteristics of
`the human nail plate. Int J Cosmet Sci l983;5:23l—246.
`[6] Walters KA, Flynn GL, Marvel JR. Physicochemical
`characterization of the human nail: Permeation pattern
`for water and the homologous alcohols and differences
`with respect to the stratum corneum. J Pharm Pharmacol
`1983;35:28—33.
`[7] Walters KA, Flynn GL, Marvel JR. Physicochemical
`characterization of the human nail: Solvent effects on the
`permeation of homologous alcohols. J Pharm Pharmacol
`1985;37:771-775.
`[8] Marty JP, Dervault AM. Voie percutanée. In: Dubertret
`L (ed.), Thérapeutique dermatologique. Paris: Médecine
`Sciences Flammarion, 1991;649-663.
`[9] Walters KA. Penetration of chemicals into, and through,
`the nail plate. Pharm Int l985;April:85—89.
`[10] Walters KA, Flynn GL, Marvel JR. Penetration of the
`human nail plate: the effects of vehicle pH on the perme-
`ation of miconazole. J Pharm Pharmacol 1985;37:498-
`499.
`
`[11] Spruit D. Effect of nail polish on the hydration of the
`fingernail. Amer Cosmet Perf 1972;87:57—58.
`
`Tl‘: is mate rial wascnplied
`at the HLM and may he
`2'-pubjeazt US -mzpw,-‘right Laws.
`
`CFAD v. Anacor, |PR20‘|5-01776
`ANACOR EX. 2196 - 10/‘I1
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`CFAD v. Anacor, IPR2015-01776
`ANACOR EX. 2196 - 10/11
`
`

`
`J.-P.L. Marty /J. Eur. Acad. Dermatol. Venereol. 4 (Suppl. 1) (I 995) SI7—S2I
`
`S21
`
`[12] Pittrof F, Gerhards J, Erni W, Klecak G. Locery1TM nail
`lacquer: realization of a new galenical approach to ony-
`chomycosis therapy. Clin Exp Dermatol
`l992;17(suppl
`1):26—28.
`[13] Franz TJ. Absorption of amorolfine through human nail.
`Dermatology l‘)92;184(suppl 1):18-20.
`
`[14]
`
`Mensing I-I, Polak-Weiss A, Splanemann V. Determina-
`tion of the subungual antifungal activity of amorolfine
`after 1 month’s treatment in patients with onychomyco—
`sis: comparison of two nail
`lacquer formulations. Clin
`Exp Dermatol 1992;l7(suppl 1):29—32.
`
`This material was {spied
`a1:t'h~e NLM and maytze
`Eu bjen US Eicrpyright Laws
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`CFAD v. Anacor, |PR2015-01776
`ANACOR EX. 2196 - 11/11
`
`CFAD v. Anacor, IPR2015-01776
`ANACOR EX. 2196 - 11/11