Marie Lodén - Howard I. Maibach
`
`Editors
`
`Treatment of Dry Skin
`Syndrome
`
`The Art and Science of Moisturizers
`
`@ Springer
`
`Page 1 of 19
`
`Kaken Exhibit 2021
`Acrux V. Kaken
`
`IPR2017-00190
`
`Kaken Exhibit 2021
`Acrux v. Kaken
`IPR2017-00190
`
`

`

`
`
`Editors
`Marie Lodén. M.SC. Pharm-
`Eviderm Institute
`Solna, Sweden
`
`Howard I. Maibach. MD-
`Department of Dermatology
`A
`V
`University of California
`San Francisco School of Medicine
`San Francisco. Califmnifl
`USA
`
`
`
`"nap-fit->¢'4v'Q-A4"f\‘!>..MD.h~‘fi
`
`ISBN 978-3-642-27606-4
`ISBN 978-3-642-27605-7
`DOI 10.1007/978-3-642-27606-4
`.
`Springer Heidelberg Dordrecht London New York
`
`(eBook)
`
`Library of Congress Control Number: 2012937364
`———?\f§
`
`© Springer-Verlag Berlin Heidelberg 2012
`
`This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or
`part of the material is concerned, specifically the rights of translation, reprinting, reuse of illus-
`trations. recitation, broadcasting. reproduction on microfilms or in any other physical way, and
`transmission or information storage and retrieval, electronic adaptation, computer software. or
`by similar or dissimilar methodology now known or hereafter developed. Exempted from this
`legal reservation are brief excerpts in connection with reviews or scholarly analysis or material
`supplied specifically for the purpose of being entered and executed on a computer system, for
`exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is
`permitted only under the provisions of the Copyright Law of the Publisher's location, in its cur-
`rent version, and permission for use must always be obtained from Springer. Permissions for use
`may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to
`prosecution under the respective Copyright Law.
`The use of general descriptive names, registered names, trademarks, service marks. etc. in this
`publication does not imply, even in the absence of a specific statement, that such names are
`exempt from the relevant protective laws and regulations and therefore free for general use.
`While the advice and information in this book are believed to be true and accurate at the date of
`publication, neither the authors nor the editors nor the publisher can accept any legal responsibil-
`ity for any errors or omissions that may be made. The publisher makes no warranty, express or
`implied, with respect to the material contained herein.
`
`Printed on acid-free paper
`
`Springer is part of Springer Science+Business Media (www.springer.com)
`
`Page 2 of 19
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`

`

`Contents
`
`
`
`Part I The Marketplace and Treatment Aspects
`
`1 Moisturizers as Cosmetics, Medicines, or Medical Device?
`The Regulatory Demands in the European Union .
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`Amy Sorensen. Peter Landvall, and Marie Lodén
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`3
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`2
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`90
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`Design of Claims Support for Moisturizers .
`Judith K. Woodford
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`17
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`Educational Interventions for the Management
`of Children with Dry Skin .
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`Steven J. Ersser and Norecn lleer Nicol
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`27
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`4 Dry Skin in Childhood and the Misery of Eczema
`and Its Treatments .
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`Susan Lewis—Jones
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`41
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`5
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`Use of Moisturizers in Patients with Atopic Dermatitis .
`Kam Lun Ellis lion and Alexander K.C. Leung
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`59
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`Part [1 Skin Essentials
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`6
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`Sensory Systems of Epidermal Keratinocytes .
`Mitsuhiro Denda
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`77
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`95
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`7
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`8
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`9
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`Sensitive Skin: Intrinsic and Extrinsic Contributors .
`Miranda A. Farage and Michael K. Robinson
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`Electron Tomography of Skin .
`Lars Norlén
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`111
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`Filaggrin Gene Defects and Dry Skin Barrier Function .
`Martin Willy Meyer and Jacob P. Thyssen
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`119
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`10 Molecular Organization of the Lipid Matrix
`in Stratum Corneum and Its Relevance for
`the Protective Functions of Human Skin .
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`Mila Boncheva
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`ll Desquamation: It Is Almost All About Proteases .
`Rainer Voegcli and Anthony V. Rawlings
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`125
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`149
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`XXXV
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`Page 3 of 19
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`

`

`Contents
`xxxvi
` -*-
`
`V,‘
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`12
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`13
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`14
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`15
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`Endogenous Retroviral-Like Aspartic Protease,
`SASPase as a Key Modulator of Skin Moisturization .
`Takeshi Matsui
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`Vemix Caseosa and Its Substitutes:
`Lipid Composition and Physicochemical Properties .
`Many O. Visscher and Steven B. Hoath
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`179
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`193
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`The Role of Tight Junctions and Aquaporins
`in Skin Dryness .
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`J.M. Brandner
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`Biomechanics of the Barrier Function of Human
`Stratum Corneum .
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`Kemal Levi and Reinhold H. Dauskardt
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`215
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`233
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`Part III Dry Skin Disorders and Treatments
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`Update on Atopic Eczema with Special Focus
`on Dryness and the Impact of Moisturizers .
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`Eric Simpson
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`. 269
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`Update on Hand Eczema with Special Focus
`on the Impact of Moisturisers .
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`Christina Williams and Mark Wilkinson
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`18
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`19
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`20
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`Update on Ichthyosis with Special Emphasis on Dryness
`and the Impact of Moisturizers .
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`Johannes Wohlrab
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`Psoriasis and Dry Skin: The Impact of Moisturizers .
`Joachim W. Fluhr, Enzo Berardesca, and Razvigor Darlenski
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`. 285
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`Update on Infant Skin with Special Focus on Dryness
`and the Impact of Moisturizers .
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`Georgios N. Stamatas and Neena K. Tierney
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`Part IV Ingredients and Treatment Effects
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`21
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`22
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`25
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`26
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`The Composition and Development of Moisturizers .
`Steve Barton
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`Ungual Formulations: Topical Treatment of Nail Diseases. .
`Kenneth A. Walters
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`Preservation of Moisturisers .
`D. Godfrey
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`Potential Allergens in Moisturizing Creams. .
`Ana Rita Travassos and An Goossens
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`~
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`Formulating Moisturizers Using Natural Raw Materials
`Swamlata Saraf
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`V
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`Chemical and Physical Properties of Emollients
`Jari T. Alander
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`313
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`341
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`355
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`367
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`Page 4 of 19
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`

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`
`
`xxxvii
`Contents
`___j
`
`27 Polyfunctional Vehicles by the Use of Vegetable Oils .
`Luigi Rigano and Chiara Andolfatto
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`. 419
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`28 The Effect of Natural Moisturizing Factors on the Interaction
`Between Water Molecules and Keratin .
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`Noriaki Nakagawa
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`29 Impact of Stratum Comeum Damage on Natural
`Moisturizing Factor (NMF) in the Skin .
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`Lisa M. Kroll, Douglas R. Hoffman,
`Corey Cunningham, and David W. Koenig
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`. 441
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`30 Water and Minerals in the 'I1'eatment of Dryness .
`Ronni Wolf, Danny Wolf, Donald Rudikoff,
`and Lawrence Charles Parish
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`31 Hyaluronan Inside and Outside of Skin .
`Aziza Wahby, Kathleen Daddario DiCaprio, and Robert Stern
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`32 Glycerol as a Skin Barrier Influencing Humectant .
`Laurene Roussel, Nicolas Atrux—Tallau, and Fabrice Pirot
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`481
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`33 The Use of Urea in the Treatment of Dry Skin .
`Marie Lodén
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`34 Urea and Skin: A Well-Known Molecule Revisited .
`Alessandra Marini, Jean Krutmann, and Susanne Grether-Beck
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`35 The Influence of Climate on the Treatment of Dry Skin
`with Moisturizer .
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`C. Stick and E. Proksch
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`36 Emollient Therapy and Skin Barrier Function .
`Majella E. Lane
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`37 Skin Barrier Responses to Moisturizers: Functional
`and Biochemical Changes .
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`Izabela Buraczewska-Norin
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`525
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`38 Changes in Stratum Comeum Thickness, Water Gradients
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`and Hydration by Moisturizers .
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`Jonathan M . Crowther, Paul J. Matts, and Joseph R. Kaczvinsky
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`545
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`561
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`39 Skin Moisture and Heat Transfer .
`Jerrold Scott Petrofsky and Lee Berk
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`581
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`Appendix .
`
`Index .
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`Page 5 of 19
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`

`

`
`
`Ungual Formulations: Topical
`Treatment of Nail Diseases
`
`Kenneth A. Walters
`
`
`
`22.1
`
`Introduction
`
`have been indicative of the in vivo situation.
`
`The human nail can be afflicted by several disease
`states including paronychia, psoriasis and infec-
`tions due to bacteria, viruses or fungi. While rarely
`life threatening, these generate self—consciousness
`and psychological stress. Approximately 50% of
`all problems result from fungal infections, onycho—
`mycoses, and the prevalence of these may be as
`high as 27% in Europe [27] and 10% in the USA
`[15]. Brittle nail syndrome affects approximately
`20% of the population, with occurrence in females
`being twice that of males. Brittle nails can be the
`result of both internal and external factors, includ-
`
`ing aging, other nail problems such as psoriasis
`and fungal infections, exposure to irritants, such as
`solvents, and excessive water exposure. Although
`
`the precise pathogenesis leading to brittle nails is
`unknown,
`the involvement of nail coenocytes
`intercellular adhesion factors seems the most likely
`
`explanation [67]. There is certainly evidence to
`suggest that dry nails are brittle [17], but earlier
`work indicated that the water content of normal
`
`and brittle nails was similar [61]. In the latter work,
`however, the authors found that nail samples were
`
`losing water between clipping and analysis and
`that the moisture content determinations may not
`
`K.A. Walters, Ph.D.
`An-ex Analytical Services Ltd,
`14/16 CBTC2, Capital Business Park, Cardiff
`CF3 2PX, UK
`e-mail: kaw@an-ex.co.uk
`
`Overall, however, the advice of many derrnato1o—
`gists is that the strength and flexibility of brittle
`nails can be improved using humectant compounds
`that will increase the water content of the nail plate
`(see e.g. [31]). For the topical treatment of nail
`diseases, however, it is a prime requirement that
`the active ingredient, be it a humectant or an
`
`antifungal agent, is capable of penetrating into and
`diffusing though the nail plate.
`Experimental techniques for investigation of
`the penetration and distribution of chemicals into
`and through the nail plate have demonstrated that
`it is possible to deliver drugs to the nail following
`topical application. This research has led the
`development of newer more effective topical
`products and regimens for treatment of onycho-
`mycoses and other nail diseases (see examples in:
`[16, 39, 44, 53, 57, 65]). In this chapter, nail
`structure and chemical composition will be dis-
`cussed together with an overview of the perme-
`ation of molecules through the nail plate, and this
`will be followed by a review of selected clinical
`studies designed to determine the efficacy of top-
`ical treatment for nail diseases.
`
`22.2 Nail Structure
`
`The nail plate is composed of layers of flattened
`keratinized cells fused into a dense but some-
`
`what elastic mass set within periungual grooves
`(Fig. 22.1). Nail plate cells grow distally from
`the germinative nail matrix at a rate of about
`
`M. Lodén, H.I. Maibach (eds.), Treatment of Dry Skin Syndrome.
`DOI 10.1007/978-3-642-27606-4_22, © Springer-Verlag Berlin Heidelberg 2012
`
`Page 6 of 19
`
`341
`
`

`

`K.A. Walters
`342
`
`
`Fig. 22.1 Anatomical
`features of the human nail
`
`a
`
`plate. (a) Top view showing
`the area of the gerrninative
`nail matrix. (b) Cross section
`of the matrix
`
`Flee margin
`
`Nan mate
`
`Eponychium
`
`Proximal end of
`nail matrix
`
`Dorsal matrix
`
`Lunula
`
`b
`
`Dorsal nail plate
`
`Ventral nail plate
`
`
`
`2-3 mm per month. During keratinization, cells
`undergo shape and other changes similar to
`those experienced by the epidermal cells form~
`ing the stratum comeum. There are three very
`tightly knit keratinized layers, a thin outermost
`dorsal lamina, a thicker intermediate lamina and
`an innermost ventral layer [54]. Keratins in hair
`and nail are classified as
`‘hard’
`trichocyte
`keratins.
`
`As a cornified epithelial structure, the chemical
`composition of the nail plate has many similarities
`to hair
`[2]. The major components are hard
`(80—90%) and soft
`(l0—20%) keratin proteins
`with small amounts (0.l—1.0%) of lipid, the latter
`presumably located in the intercellular spaces. In
`addition,
`intermediate filament-associated pro-
`teins and trichohyalin are also found within the
`nail [7]. Sulphur content of the nail amounts to
`about 10% and is mainly present within the cys-
`tine disulphide bonds that contribute to nail ten-
`sile strength by linking the keratin fibres. The nail
`contains significant amounts of phospholipid,
`mainly in the dorsal and intermediate layers,
`which contribute to its flexibility. Glycolic and
`stearic acids are also found in the nail. The total
`
`Table 22.1 Water content of human fingernails as a
`function of relative humidity (RH). RH was controlled
`using saturated salt solutions, and nail clippings were
`positioned above the saturated solutions and exposed for
`at least 48 h (Data from [l7])
`
`.1
`
`M
`
`0
`33
`50
`65
`75
`85
`100
`
`Nail waterucontent (96)
`6
`9
`13
`18
`25
`37
`64
`
`lipid content of the nail plate is between 0.1% and
`1%, which is considerably different to that of the
`stratum comeum (~l0%). The principal plasti-
`cizer of the nail is water, the content of which var-
`ies widely dependent on prevailing relative
`humidity (Table 22.1), but it is normally present
`at around 18%. When the water content is 1655
`
`than 16%, the nail plate becomes brittle, and Whfifl
`the nail is hydrated to water levels of ~25%, it
`becomes soft. Minerals are also important con-
`stituents of nails. Lack of selenium and magnesium
`
`Page 7 of 19
`
`

`

`
`
`343
`22 Ungual Formu|ations:Topical Treatment of Nail Diseases
`
`
`can have a profound effect on the health of the
`nail plate [4, 35].
`
`
`
`22.3 Nail Plate Permeability
`
`30
`
`10
`
`Early investigations of nail plate permeability
`indicated that the nail was significantly more per-
`meable to water than was the stratum comeum [6,
`60, 71]. Indeed, when the relative thicknesses
`were taken into account, water was found to dif-
`
`fuse through the nail plate at approximately 100-
`fold faster than through the stratum comeum.
`Given our current knowledge on the role of lipids
`in the barrier function of the stratum comeum,
`this is perhaps not surprising. However, at the
`time the finding that hydrophilic materials could
`pass through the nail plate with relative ease was
`viewed with scepticism.
`
`22.3.1 In Vitro Investigations
`
`The first systematic studies on nail plate perme-
`ability were carried out in the late 1970s [72—74].
`These studies indicated that there were marked
`
`differences between the penneability characteris-
`tics of the nail plate and stratum comeum. These
`differences were attributed to the relative amounts
`
`of lipid and protein within the structures and pos-
`sible differences in the physicochemical nature of
`the respective phases. The nail plate was perme-
`able to dilute aqueous solutions of a series of low
`molecular weight homologous alcohols, but per-
`meation decreased as a function of increasing
`
`alkyl chain length up to octanol (Fig. 22.2). It
`was suggested that the nail plate possessed a
`highly ‘polar’ penetration route that was capable
`of excluding permeants on the basis of their
`hydrophobicity. The existence of a minor ‘lipid’
`pathway through the nail plate, which could
`become rate controlling for hydrophobic solutes,
`was suggested based on the significant decrease
`in permeation of hydrophobic n-decanol follow-
`ing nail plate delipidization.
`In the mid—l990s, Mertin and Lippold [40—42]
`studied nail and hoof penetration in vitro.
`Permeability coefficients through both nail plate
`
`Page 8 of 19
`
`Ca)
`
`
`
`
`
`.4.
`
`Permeabilitycoefficient(cmh-1)x103 OOL.be
`
`1
`
`2
`
`6
`4
`Alkyl chain length
`
`8
`
`10
`
`Fig. 22.2 Permeation rates for the n-alkanols crossing
`full—thickness human nail plates mounted in stainless steel
`side-by-side diffusion chambers in vitro. The alkanols
`(methanol through decanol) were applied as dilute aque-
`ous solution, and samples taken from the receptor cham-
`ber over an 8—h period. Note that the y-axis is logarithmic
`(Data from [72])
`
`and hoof membranes did not
`
`increase with
`
`increasing oil-water partition coefficient (range 7
`to >51,000) or lipophilicity, indicating that these
`barriers behaved like hydrophilic gel membranes
`rather than lipophilic partition membranes (as in
`
`stratum corneum). Further studies with paraceta-
`mol and phenacetin showed that maximum flux
`was a function of drug solubility in water or in
`the swollen keratin. Merlin and Lippold were
`able to predict the maximum flux of ten antimy-
`cotics through the nail plate on the basis of their
`water solubilities and their penetration rates
`through hoof membrane. Their
`speculative
`extrapolation on permeation of amorolfine was in
`remarkably close agreement to the value obtained
`
`by Franz [18] using human nail plate. Bovine
`hoof membranes were also used by Monti et al.
`
`

`

`344
`K.A. Walters
`
`[44] to evaluate the effect of formulation on the
`
`transungual permeation of ciclopirox . Comparison
`of an experimental water-soluble lacquer (based
`on hydroxypropyl chitosan) with the marketed
`water-insoluble lacquer (Penlac) showed that,
`although steady-state permeation rates were sim-
`ilar,
`lag times were considerably less for the
`experimental lacquer. This was tentatively attrib-
`
`uted to a strong adhesion between hydroxypropyl
`chitosan and nail plate keratin. Further work con-
`firmed the validity of using bovine hoof slices as
`a model for infected human toenails [45, 46].
`
`This group also used bovine hoof membrane to
`determine penetration of piroctone olamine into
`keratinous matrices [1 1]. Although no transmem—
`brane permeation was observed, following 30 h
`exposure, approximately 11% of the drug pene-
`trated into the hoof.
`
`Measurement of the nail permeation of several
`model compounds, including a series ofp—hydroxy-
`benzoic acid esters, indicated that, in broad agree-
`ment with earlier work, permeation decreased with
`increasing hydrophobicity (Table 22.2). It was
`suggested that molecular size was the principal
`determinant of the rate and extent of permeation
`across nail plate [38]. Very importantly,
`their
`studies also showed that, for the model permeant
`5-lluorouracil, normal nail plate had similar
`permeation characteristics to infected nail plate,
`suggesting that nonnal plates can be used to predict
`drug distribution in diseased plates.
`Recognizing the possibility of photodynarnic
`therapy for onychomycosis [32, 59], Donnelly et al.
`[10] investigated the delivery of 5—aminolevulinic
`acid (ALA) to the nail from a bioadhesive patch
`in vitro. After 72 h, approximately 90% of the
`applied drug had penetrated the nail, with an aver-
`age flux of 2.S4><10" mg/cm’/s. This was quite a
`remarkable rate of penetration and, given that ALA
`is a small highly polar molecule, further confirma-
`tion of the hydrophilic nature of the nail banier.
`Hui et al. [30] developed a drilling technique
`for assessing drug delivery to the inner nail plate
`in vitro and used it to determine the effect of dim-
`
`ethyl sulfoxide (DMSO) on the penetration of
`urea, salicylic acid and ketoconazole. Nail plate
`composition suggests that it would be compara-
`tively insensitive to the effects of stratum corneum
`
`(K ) and
`Table 22.2 Nail penneability coefficients
`molecular weights (MWt) for several model c0mppounds_
`Note that for the p—hydroxybenzoic acid esters, permea.
`bility rates tend to decrease with increasing lipophilicity.
`Penneation studies were carried out over 5-17 days, and
`K“ calculated from steady-state regions of cumulative
`permeation plots (Data from [38])
`
`' Model permeant
`Methyl
`p-hydroxybenzoale
`Ethyl
`p-hydroxybcnzoate
`Propyl
`p-hydroxybenzoate
`Butyl
`p-hydroxybenzoate
`Amyl
`p-hydroxybenzoate
`Hexyl
`p-hydroxybenzoatc
`Pyridine
`Benzoic acid
`Sodium benzoate
`5-Fluorouracil
`
`Antipyrine
`Aminopyrine
`Lidocaine
`Lidocaine HCI
`Procaine HCl
`lsosorbide dinitrate
`Sodium nicotinate
`Barbital sodium
`Mexiletine HCI
`
`Isoproterenol HC1
`Croconazole HC1
`
`MWt
`152.2
`
`1 66.2
`
`1 80.2
`
`I 94.2
`
`208.3
`
`222.3
`
`79.]
`122.1
`121.1
`130.1
`
`188.2
`232.3
`234.3
`235.3
`237.3
`236.1
`122.1
`183.2
`179.3
`
`21 1.2
`311.8
`
`8. ‘IE;”(”>‘<i_l07 cm/s)
`3.68 20.08
`
`2.43 20.48
`
`2.01 20.35
`
`2.38 2032
`
`22420.39
`
`l.2420.32
`
`6.36 20.40
`12.84 20.05
`0.91 20.14
`2.08 20.13
`0.53 20.07
`0.09 20.02
`0.39 20.14
`0.03120.003
`0.11 20.02
`1.51 20.29
`0.61 20.20
`0.14 20.02
`02020.06
`008420.013
`0.017 20.009
`
`penetration enhancers that produce their effects
`mainly by delipidization or fluidization of inter-
`cellular lipids. The nail plate is incapable of
`absorbing DMSO to any great degree [36], and a
`decrease in absorption of methanol and hexanol
`applied with DMSO has been noted [74]. On I116
`other hand, an increase in nail plate content of
`econazole when applied in a formulation contain-
`ing DMSO was reported [62], and following pre-
`treatment with DMSO, an increase in the nail
`absorption of the antifungal amorolfine was dem-
`onstrated [l8]. Hui et al. [28] determined that
`DMSO was capable of enhancing the concentra-
`tion of all three permeants in the ventral region of
`
`Page 9 of 19
`
`
`‘,.-'fr;ETj§’*z\‘>w=f6*:c~3}':7\Y1:=!1r'.9‘1'~a{t.y:vtf;I5dumI(
`
`
`l4v"‘VA‘.'~.."-/A.~.J.-:».-.,~.*:;';
`..n"w:r.‘....W.2-‘-’"tr...."W-r-uaa-.4...-.«_v_‘.1.
`
`
`
`
`"Y";-3.“'J.
`
`

`

`345
`22 Ungual Formulations: Topical Treatment of Nail Diseases
`—____
`
`the nail plate but, paradoxically, reduced the con-
`centration of ketooonazole and salicylic acid in
`the dorsal regions. The data for the effects of
`DMSO on the nail, therefore, remain ambiguous.
`In later experiments, Hui et al. determined the
`
`effects of the lipophilic skin penetration enhancer
`2-n-nonyl-1,3-dioxolane on the in vitro nail
`delivery of econazole [29] and evaluated the nail
`penetration of ciclopirox from three topical
`formulations [30]. In the first study, lacquer for-
`mulations containing econazole with and without
`the enhancer (18%) were applied twice daily for
`14 days to human nail plates. The amounts of
`econazole in the inner part of the nail plate were
`11.1 mg/mg and 1.78 mg/mg nail powder (with
`and without enhancer, respectively). The amounts
`of econazole that had permeated through the nail
`plates with the enhancer were 48 mg and without
`enhancer 0.2 mg. In a separate study, radiola-
`belled 2-n-nonyl-1,3-dioxolane was found not to
`significantly penetrate the nail, and the mecha-
`nisms of penetration enhancement were pre-
`sumed to be at the formulation/nail interface. In
`
`the subsequent study over 14 days, Penlac lac-
`quer (8% ciclopirox) was evaluated alongside the
`gels Loprox (0.77% ciclopirox) and an experi-
`mental formulation containing 2% ciclopirox.
`Ciclopirox delivery into and through the nail was
`greater from the marketed gel than from either
`the experimental gel or the nail
`lacquer. The
`amount of drug that penetrated into and through
`the nail was also greater from the marketed gel. It
`was concluded that the delivery of ciclopirox was
`
`influenced by the nature of the applied formula-
`tion. Notwithstanding the differences
`in the
`amount of ciclopirox delivered, all three formula-
`tions delivered sufficient drug to generate ‘in
`nail’ concentrations far in excess of the minimum
`
`inhibitory concentrations (MICS) for most nail
`invasive dermatophytes and yeasts.
`In our laboratory, we have modified the nail
`drilling technique to allow detennination of drug
`distribution in three layers of the nail plate
`(dorsal, intennediate and ventral) and success-
`
`fully adapted the technology as a rapid in vitro
`formulation-screening tool. More recently, opto-
`thermal transient emission radiometry (OTTER)
`has been shown to be capable of monitoring
`
`diffusion in nails [77]. The permeation rates of
`decanol, glycerol and butyl acetate were success-
`fully monitored, and it is interesting to note that
`the rates of permeation increased with increasing
`solvent polarity. An advantage of the OTTER
`technique is that it provides a means of monitor-
`ing diffusion into nails in vivo.
`
`The influence of keratolytic agents (papain,
`urea and salicylic acid) on the permeability of
`three imidazole antimycotics (miconazole nitrate,
`
`ketoconazole and itraconazole) using healthy
`human nails in vitro has been evaluated [51]. In
`the absence of any keratolytics, the nail was rela-
`tively
`impermeable
`to
`these
`antimycotics.
`Furthermore, permeation of these antimycotics
`was not improved by pretreatment with salicylic
`acid alone (20% for 10 days) or by application of
`the drug in a 40% urea solution. The combined
`effects of papain (15% for 1 day) and salicylic
`acid (20% for 10 days) were capable of enhanc-
`ing nail plate permeability.
`In contrast, Mohorcic et al. [43], evaluating
`the use of keratinolytic enzymes to decrease bar-
`rier properties, found that keratinase acted on the
`intercellular regions and caused comeocytes on
`the dorsal surface to separate. Permeation studies
`using bovine hoof membranes showed that the
`enzyme doubled the flux and membrane-vehicle
`
`partition coefficient of the model penetrant, met-
`formin, but had little effect on the diffusion coef-
`
`the effect of the
`ficient. This suggested that
`enzyme was confined to the outer surface layers
`of the hoof membrane.
`
`Brown et al. [5] investigated the nail permea-
`bility of caffeine, methylparaben and terbinafine
`and determined the effect of two novel penetra-
`tion enhancers (thioglycolic acid and urea hydro-
`gen peroxide) on their permeation using human
`nails in vitro. The penetrants were applied as
`saturated solutions. In the absence of penetration
`enhancement, steady-state flux through nails was
`more dependent on penetrant molecular weight
`than lipophilicity. While thioglycolic acid increased
`the flux of caffeine and methylparaben, urea
`hydrogen peroxide proved ineffective. Interest-
`ingly, sequential application of thioglycolic acid
`followed by urea hydrogen peroxide increased
`terbinafine flux considerably, but when the
`
`Page 10 of 19
`
`

`

`
`
`'i’7lT3f'§".l7s-._-.u:r:-_
`
`
`
`.“‘.‘f"..‘.“‘!*'v‘.““""?""‘.'7"‘t"§‘,t'-.”.'?.A--«-,..
`
`(llycmz/h,
`terbinafine
`rates of
`Table 22.3 Flux
`mean:SD, n=3—8) across nails pretreated with either
`thioglycolic acid (TA) or urea hydrogen peroxide (UP) or
`both TA and UP sequentially. Single enhancers were
`applied (0.5 ml) in solution for 20 h, nails were washed
`with water, and, if applicable. the second enhancer was
`applied for a further 20 h. Terbinafine was applied in satu-
`rated solution (in 50% ethanol
`in phosphate-buffered
`saline), and permeation monitored over about 9 days (Data
`from [5])
`
`l
`
`Terbinafine fiux
`'
`(Hg/cm’/h)
`‘Pretreatment regimen
`O.5S:O.7l
`None
`4.73tl.01
`5% TA
`04310.29
`17.5% UP
`10.22:5.22
`5% TA then 17.5% UP
`17.5% UP then 5% TA 1.25 10.80
`
`—
`8.6
`0.8
`18.6
`2.3
`
`penetration enhancer application order was
`reversed, the enhancement effect was consider-
`
`ably reduced (Table 22.3). These findings led to
`the development and in vitro evaluation of a
`potential treatment modality for onychomycosis
`consisting of a pretreatment dose of thioglycolic
`acid followed by application of a formulation
`containing urea hydrogen peroxide and the anti-
`fungal agent terbinafine [64]. It was clearly dem-
`onstrated that this system (MedNail"’, MedPharm
`Ltd) was effective at delivering therapeutic levels
`of terbinafine to the nail. Furthermore,
`the
`
`enhancer system was also shown to enhance the
`efficacy of existing antifungal topical formula-
`tions. Both thioglycolic acid and urea hydrogen
`peroxide most likely alter barrier function by dis-
`rupting the ot-keratin disulfide links. The authors
`went on to determine how the altering of the
`reduction/oxidation environment of nail keratin
`
`using thioglycolic acid and urea hydrogen perox-
`ide influenced the barrier properties of the nail
`[34]. The investigation demonstrated that the nail
`permeability of terbinafine was greatest when
`relatively low concentrations of the thiolate ion
`
`were present in the applied solution and that free
`radical generation was fundamental in facilitat-
`
`K.A. Walters
`
`They are extremely surface active and form an
`amphipathic film at interfaces that render hydro-
`philic surfaces hydrophobic and hydrophobic
`surfaces hydrophilic. They possess eight cysteine
`residues that form four disulphide bridges that
`
`prevent self-assembly of the hydrophobin in the
`absence of a hydrophilic-hydrophobic interface.
`Hydrophobins are subdivided into classes I and
`II, in which the amino acid sequences diverge
`considerably. This is reflected in the biophysical
`properties of these proteins such that assemblages
`of class I hydrophobins are highly insoluble,
`while those of class II hydrophobins readily dis-
`solve in a variety of solvents. These proteins have
`been evaluated as potential enhancers to increase
`drug delivery to the nail plate. Vejnovic et al. [69]
`evaluated several nail plate permeation enhancers
`using caffeine as the model drug. Formulations
`were prepared in water and 20% (v/v) ethanoll
`water solutions. The potential enhancers evalu-
`ated were urea, DMSO, methanol, N-acety1-L-
`cysteine,
`sodium docusate, boric
`acid and
`hydrophobins. Cadaver nails were used in modi-
`fied Franz—type diffusion cells. The permeability
`coefficients of caffeine were
`increased by
`
`N-acetyl-L-cysteine, but formulations containing
`methanol generated the highest permeability
`coefficients for the model drug. The enhancers
`were classified according to their permeation
`enhancement. Methanol generated the greatest
`increase in caffeine permeability over class II
`hydrophobins. DMSO was more effective than
`
`class I hydrophobins and urea. Vejnovic et al.
`[70] went on to determine the amount of terbin-
`
`afine that permeated through the human nail
`plate, from formulations containing hydropho-
`
`bins at 0.1% (w/v), again using cadaver nails and
`Franz diffusion cells. Terbinafine remaining in
`
`the nail was extracted using 96% ethanol. The
`hydrophobins tested increased terbinafine perme-
`ation after 10 days with a maximum enhancement
`factor of 13-fold over the reference vehicle (10%
`terbinafine in a 60% v/v ethanol in water solu-
`
`ing the redox-mediated keratin disruption of the
`nail plate.
`Hydrophobins are fungal proteins, of about
`100 amino acids, that function by self-assembly
`at hydrophobic-hydrophilic interfaces [9, 76].
`
`tion). The authors concluded that hydrophobins
`could be included in the list of potential enhanc-
`ers for treatment of fungal nail infections.
`There is certainly little doubt that effective
`topical treatment of nail diseases will require
`
`Page 11 of 19
`
`

`

`347
`22 Ungual Formulations: Topical Treatment of Nail Diseases
` ___j:___j__
`
`Table 22.4 Emhancement ratios (ER) of terbinafine hydrochloride penetration into nails pretreated with several
`enhancer candidates (sequential ER) or simultaneous application of drug and enhancer candidate (simultaneous ER)
`using the Transcreen-‘NTl\/I method, compared with enhancement ratios obtained for permeation across nails using a
`simultaneous application In Franz diffusion cells (permeation ER) (Data from [48])
`Enhancer candidate
`Sequential ER
`1.121 0.03
`0.87 10.20
`0.2410.07
`0.891 0.11
`1.101 0.24
`0.94 10.08
`1.43 1 0.34
`2.24 1 0.03
`1.111004
`1.011 0.1 1
`0.95 10.01
`1.25 10.02
`1.6510. 17
`2.74 1 0.34
`1.91 10.52
`1.751-0.22
`
`Simultaneous 1
`1.411038
`0.841002
`0.301 0.12
`0.9910.09
`0.841002
`0.9210.16
`1.291039
`1.6510.42
`O.641O.14
`O.4410.04
`O.9910.08
`99811.44
`9.311 1.14
`99811.02
`8.851006
`6.901 1.15
`
`' Perriieationil-112' ’ ii
`l.l610.1l
`1.031006
`0.831006
`l.l010.01
`1.51 10.09
`l.lO10.02
`1.81 10.08
`1.761031
`1.001 0.16
`0.6010.08
`l.l010.07
`8.4910.70
`9.3310.85
`8.321064
`6.5710.33
`4.9810.20
`
`Hydrogen peroxide
`Salicylic acid
`Glycolic acid
`Thioglycolic acid
`Urea
`Thiourea
`
`Cysteine
`Sodium lauryl sulphate
`Ethanol
`Citric acid
`
`Polysorbate 20
`Ammonium phosphate
`Ammonium carbonate
`
`Potassium phosphate
`Sodium phosphate
`Sodium carbonate
`
`some form of penetration and/or permeation
`enhancement to facilitate drug delivery [47]. It is
`important
`to note that selecting an effective
`
`chemical enhancement system for a given drug
`and a gi