Hyponychium
`
`Cuticle
`
`Nall plate
`
`Nail fold
`
`Hyponychium
`
`Cotton ball well
`(Nail supporting bed)
`
`Te on one chain re ex open)
`
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`Topical Nail Products
`and lingual Drug Delivery
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`Topical Nail Products
`and Ungual Drug Delivery
`
`EDITED BY
`S. Narasimha Murthy
`Howard I. Maibach
`
`CRC Press
`
`Taylor &Francis Group
`Boca Raton London Newyork
`
`CRC Press is an imprint of the
`Taylor & Francis Group, an informa business
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`CRC Press
`Taylor & Francis Group
`6000 Broken Sound Parkway NW, Suite 300
`Boca Raton, FL 33487-2742
`
`© 2013 by Taylor & Francis Group, LLC
`CRC Press is an imprint of Taylor & Francis Group, an Informa business
`
`No claim to original U.S. Government works
`
`Printed in the United States of America on acid-free paper
`Version Date: 20120809
`
`International Standard Book Number: 978-1-4398-1129-0 (Hardback)
`
`This book contains information obtained from authentic and highly regarded sources. Reasonable efforts
`have been made to publish reliable data and information, but the author and publisher cannot assume
`responsibility for the validity of all materials or the consequences of their use. The authors and publishers
`have attempted to trace the copyright holders of all material reproduced in this publication and apologize to
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`a separate system of payment has been arranged.
`
`Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used
`only for identification and explanation without intent to infringe.
`
`Library of Congress Cataloging-in-Publication Data
`
`Topical nail products and ungual drug delivery / editors, S. Narasimha Murthy and
`Howard I. Maibach.
`P. ; cm.
`Includes bibliographical references and index.
`ISBN 978-1-4398-1129-0 (alk. paper)
`I. Murthy, S. Narasimha (Sathyanarayana Narasimha), 1971- 11. Maibach, Howard I.
`[DNLM: 1. Nail Diseases--drug therapy. 2. Administration, Topical. 3. Nails--drug
`effects. WR 475]
`
`616.5'47061--dc23 (cid:9)
`
`2012031355
`
`Visit the Taylor & Francis Web site at
`http://www.taylorandfrancis.com
`
`and the CRC Press Web site at
`http://www.crcpress.com
`
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`

`Contents
`
`Preface (cid:9)
`Editors (cid:9)
`Contributors' Biographies (cid:9)
`
`Chapter 1 The Nail: Anatomy, Physiology, Diseases, and Treatment (cid:9)
`
`Sudaxshina Murdan
`
`Chapter 2 Permeability of the Nail Plate (cid:9)
`
`Jinsong Hao and S. Kevin Li
`
`Chapter 3 Topical Nail Formulations (cid:9)
`
`H. N. Shivakumar, Michael A. Repka, Sudaxshina Murdan, and
`S. Narasimha Murthy
`
`Chapter 4 Approaches to Enhance Ungual and Trans-Ungual
`Drug Delivery (cid:9)
`
`H. N. Shivakumar, Abhishek Juluri, Michael A. Repka,
`and S. Narasimha Murthy
`
`Chapter 5
`
`In Vitro and In Vivo Models to Evaluate Topical Nail
`Formulations (cid:9)
`
`Anroop B. Nair, Xiaoying Hui, Majella E. Lane,
`and S. Narasimha Murthy
`
`Chapter 6 Hydration-Controlled Nail System for the Evaluation of
`Topical Formulations and a Novel Nail Sampling Device (cid:9)
`
`Rania Elkeeb, Xiaoying Hui, and Howard I. Maibach
`
`vii
`ix
`xi
`
`1
`
`37
`
`61
`
`87
`
`123
`
`149
`
`Chapter 7 Bioengineering of the Nail: Transonychial Water Loss and '
`Imaging Techniques, an Overview (cid:9)
`
`157
`
`Rania Elkeeb and Howard I. Maibach
`
`Chapter 8 Trans-Ungual Iontophoresis and Physical Drug Delivery
`Enhancement (cid:9)
`
`165
`
`Jinsong Hao and S. Kevin Li
`
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`vi (cid:9)
`
`Contents
`
`Chapter 9 Pharmacokinetics of Drugs in the Nail Apparatus (cid:9)
`
` 187
`
`Daniele Debruyne and Antoine Carteret
`
`Chapter 10 Onychopharmacokinetics: Proposed Model Insight (cid:9)
`
`215
`
`Rania Elkeeb, Xiaoying Hui, Laila Elkeeb, Ali Alikhan, and
`Howard I. Maibach
`
`Chapter 11 Photodynamic Therapy of Nail Diseases (cid:9)
`
`Ryan F. Donnelly, Corona M. Cassidy, and Michael M. Tunney
`
`Chapter 12 Nail as a Surrogate for Investigating Drug Use (cid:9)
`
`Katarzyna Madej
`
`Index (cid:9)
`
`225
`
`245
`
`259
`
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`Preface
`
`Nail diseases, which include infections and inflammatory disorders, could affect
`human beings at any age. The diseases can result in feelings of inadequacy and
`depression in patients and affect their quality of life significantly.
`Oral and topical delivery of drugs have been the most common approaches to
`treat nail diseases. Topical therapy is the most preferred mode of drug delivery,
`due to patient compliance and convenience. Development of topical formulations
`to deliver effective amounts of drugs into the nail apparatus is highly challenging.
`This book provides a comprehensive review regarding the various nail diseases,
`topical formulations, drug delivery approaches, and unguokinetics of drugs. The
`chapters are contributed by pioneers in ungual drug delivery.
`
`vii
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`

`Editors
`
`S. Narasimha Murthy, PhD, is an associate professor at the University of Mississippi
`School of Pharmacy, University, Mississippi. After obtaining his PhD in pharmaceu-
`tics from Bangalore University, India, Dr. Murthy worked as a research associate at
`the Roswell Park Cancer Institute, Buffalo, New York, and as an assistant professor
`at Ohio Northern University, Ada, Ohio. He has published more than 60 research
`articles in the field of dermal and ungual drug delivery. Dr. Murthy also edited
`the textbook Dermatokinetics of Therapeutic Agents. He has been on the editorial
`boards of several pharmaceutical journals.
`
`Howard I. Maibach, PhD, is currently serving as a professor of dermatology at
`the University of California, San Francisco, California. He obtained his MD from
`Tulane University, New Orleans, Louisiana, in 1955. Later, he served in faculty posi-
`tions in various levels at the University of California, San Francisco. Dr. Maibach
`has published more than 2520 articles. He has been on the editorial board of more
`than 30 scientific journals and is a member of 19 professional societies including the
`American Academy of Dermatology, San Francisco Dermatological Society, and the
`Internal Commission on Occupation Health.
`
`ix
`
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`UN 1111 11111 IN ell del NB MIN VIII 1111 MI NMI ell MN 1111 GO III MO all
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`Contributors' Biographies
`
`Ali Alikhan, MD, is a resident in dermatology at the Mayo Clinic Department of
`Dermatology. He received his Bachelors in Science from Kent State Univserity and
`Medical Degree from University of California Davis School of Medicine, in addi-
`tion to completing a transitional residency at MacNeal Hospital in Berwyn, Illinois.
`He has published well over 60 journal articles and book chapters, and has presented
`at several national meetings. He has published on melanoma, vitiligo, hidradenitis
`suppurativa, onychomycosis, medical education, psoriasis, acne, rosacea, allergic
`contact dermatitis, Fox-Fordyce disease, and dermatopharmacology, among other
`topics. He holds several local and national leadership positions, and is a reviewer for
`numerous dermatology and non-dermatology journals.
`
`Corona M. Cassidy, PhD, is an honorary research fellow in the School of Pharmacy
`at Queen's University Belfast. She obtained an MPharm (First Class) in 2005 and a
`PhD in pharmaceutical microbiology in 2010, and has since held positions in com-
`munity pharmacy, academia, and the pharmaceutical industry, where she is based
`at present. She has research interests in clinical pharmacy and pharmaceutical
`manufacturing/production technologies.
`
`Antoine Coquerel, PhD, is a neurologist and pediatrician who holds a doctorate degree
`in neuropsychopharmacology. He has been the head of the Pharmacology Department
`and laboratory at the University Hospital of Caen, France, since 1999. Dr. Coquerel is
`also qualified to manage research in the fields of cell biology and neuropsychopharma-
`cology. Since 1999, he has been serving as the head of the Regional Pharmacovigilance
`Centre of Lower Normandy and the Centre for Evaluation and Information on Drug
`Dependence for the northwest of France. He is also the director of teaching of the
`pharmacology of Caen faculty of medicine. Dr. Coquerel does clinical research at
`the University of Caen as well as the University hospital. He leads a mixed research
`team at the University of Caen, Basse-Normandie, France. Her clinical research at the
`University of Caen is focused on "drug and driving," "aging and drugs," and chronobi-
`ology in healthy humans. He also performs experimental research on drug dependence
`in rats and mice. He has 57 publications and is also a coauthor of a French handbook of
`pharmacology (Masson, Paris, 2002). He is also an active member of French Society of
`Pharmacology and Therapeutics and the National College of Medical Pharmacology.
`He is an expert pharmacologist in the scientific committee of the regional clinical
`research management as well as an expert in the French drug safety agency (AFSSaPS).
`
`Daniele Debruyne, PhD, is a senior scientist in the Department of Pharmacology
`at the University Hospital Centre of Caen, France. Dr. Debruyne manages the thera-
`peutic monitoring of drugs mainly used in infectious and neurological diseases and
`in the prevention of graft rejection, with the objective being better efficacy and minor
`toxicity of the administered treatments owing to an optimal management; according
`
`xi
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`xii (cid:9)
`
`Contributors' Biographies
`
`to an agreement with the French Office of Drugs and Drug Addiction, Dr. Debruyne
`assumed the scientific responsibility of the analysis of illicit and licit recreational
`drugs that circulate in France to evaluate their dangerousness. Within the research
`team entitled "Laboratory of Methodological Developments for Positron Emission
`Tomography (PET)," Dr. Debruyne coordinates the biological characterization
`(including blood and tissue distribution, metabolism, evaluation of the in vitro and
`in vivo specific binding) of the new PET radiotracers developed by radiochemists.
`Dr. Debruyne has been recognized as an expert by the French Agency for the Safety
`of Health Products in the field of experimental pharmacokinetics. Dr. Debruyne has
`published five original research or review articles (on a total of 76 papers indexed in
`PubMed) concerning antifungal drugs.
`
`Ryan F. Donnelly, PhD, is reader in pharmaceutics in the School of Pharmacy at
`Queen's University Belfast, UK. Dr. Donnelly's research is centered on design and
`physicochemical characterization of advanced polymeric drug delivery systems for
`transdermal and topical drug delivery, with a strong emphasis on improving thera-
`peutic outcomes for patients. His bioadhesive patch design was used in successful
`photodynamic therapy of over 100 patients with neoplastic and dysplastic gyneco-
`logical conditions. This technology has now been licensed to Swedish Pharma AB,
`for whom Dr. Donnelly acts as a technical director. His microneedle technology is
`currently undergoing commercial development by two leading pharmaceutical com-
`panies. Still at a relatively early stage of his career, he has authored over 200 peer-
`reviewed publications, including three patent applications, three textbooks, seven
`book chapters, and approximately 90 full papers. He has been an invited speaker at
`several national and international conferences. Dr. Donnelly is the associate editor
`of Recent Patents on Drug Delivery & Formulation and a member of the editorial
`advisory boards of Pharmaceutical Technology Europe and Journal of Pharmacy
`and Bioallied Sciences and is a visiting scientist at the Norwegian Institute for
`Cancer Research, where he is an associate member of the Radiation Biology Group.
`Dr Donnelly is the current holder of the Royal Pharmaceutical Society's pres-
`tigious Science Award and is a previous winner of an Innovation Leader Award
`from the NHS Research & Development Office, a research scholarship from the
`Research Council of Norway, and the Pharmaceutical Society of Northern Ireland's
`Gold Medal.
`
`Laila Elkeeb, MD, is a fellow in dermatopathology at the University of Cincinnati
`Dermatology department. She completed her dermatology residency and a clini-
`cal trials fellowship from the University of California, Irvine. She also completed
`a Melanoma and Cutaneous Oncology fellowship from the University of California,
`San Francisco. Dr. Elkeeb has several years of research experience in the field of der-
`matology. She was a co-investigator on several studies that involved; skin cancer biol-
`ogy, laser and light therapy of dermatological diseases, psoriasis, rosacea, acne, and
`dermatopharmacology. She has published several journal articles, and has presented
`at several national meetings. Dr. Elkeeb has published in the field of skin cancer biol-
`ogy, laser and light therapy of dermatological diseases, phototoxicity, photoallergic
`dermatitis, dermatopharmacology, rosacea, onychomycosis, and dermatopathology.
`
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`Contributors' Biographies (cid:9)
`
`xiii
`
`Rania Elkeeb, PhD, is a researcher at Surge Lab, Department of Dermatology,
`University of California, San Francisco, California. She received her bachelor of
`pharmacy from Petra University, formerly Jordan University for Women, Amman,
`Jordan, in 1997. Dr. Elkeeb obtained her PhD in pharmaceutics and industrial phar-
`macy from the Massachusetts College of Pharmacy and Health Sciences, Boston,
`Massachusetts, in May 2005. She has done her postdoctoral training in dermato-
`phartScokinetics and onychopharmacokinetics as relates to their biologic/clinical
`effects in man and animals in the Department of Dermatology at the University
`of California, San Francisco, California, in 2008. She served as an adjunct assis-
`tant professor of pharmaceutical sciences at the Massachusetts College of Pharmacy
`and Health Sciences, Worcester, Massachusetts. Her current research interests are
`trans-ungual and transdermal drug delivery and their absorption efficiency; derma-
`topharmacokinetic and onychopharmacokinetics analysis; and transfollicular drug
`delivery.
`
`Jinsong Hao, PhD, obtained her PhD in pharmaceutics from Shenyang
`Pharmaceutical University, China. After her graduation, she worked at Shenyang
`Pharmaceutical University (China), National University of Singapore (Singapore),
`and Nova Southeastern University (United States). She is currently a research assis-
`tant professor in the College of Pharmacy at the University of Cincinnati (United
`States). Her research is in the field of drug delivery. She has published more than 40
`research articles in transdermal, transscleral, transcorneal, and trans-ungual drug
`delivery.
`
`Xiaoying Hui, MD, is an associate research dermatologist in the Department of
`Dermatology at the University of California, San Francisco, California. He has
`worked as a principal investigator in Dr. Howard Maibach's laboratory for 20 years.
`His major interests are dermatotoxicokinetics and risk assessment modeling of
`environmental chemicals following human skin absorption; antifungal drugs trans-
`ungual delivery and absorption efficiency; dermal absorption and transdermal
`delivery; and dermatopharmacokinetic analysis. He has published more than 60
`peer-reviewed research articles and is the author of 17 book chapters.
`
`Abhishek Juluri, is a graduate student in the Department of Pharmaceutics at the
`University of Mississippi, University, Mississippi. He is an NIH predoctoral fellow
`and a member of the American Association of Pharmaceutical Scientists and Rho
`Chi. Mr. Juluri received his bachelor's degree in 2009 from Kakatiya University,
`India.
`
`Majella E. Lane, PhD, is a senior lecturer of pharmaceutics in the School of
`Pharmacy at University College London. To date, she has been involved in the
`supervision of over 20 PhD students. She is a visiting professor in the Department
`of Pharmaceutical Sciences at the University of Michigan, Ann Arbor, Michigan.
`Over the years, she has contributed to more than 60 peer-reviewed articles and 10
`book chapters and serves on the editorial boards of several pharmaceutical science
`journals. Her major research interests are in the application of physical chemistry to
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`xiv (cid:9)
`
`Contributors' Biographies
`
`tissue characterization and modulation with special reference to the skin and nail.
`Her research group collaborates worldwide and uses a range of biophysical tech-
`niques (attenuated total reflectance-Fourier transform infra-red spectroscopy, confo-
`cal Raman spectroscopy, high-speed differential scanning calorimetry) to probe the
`mechanisms of skin penetration and its modulation. She also coordinates the Skin
`Forum, which evolved from an Engineering and Physical Sciences Research Council
`funded network on skin permeability.
`
`S. Kevin Li, PhD, is an associate professor of pharmaceutics in the College of
`Pharmacy at the University of Cincinnati, Cincinnati, Ohio. He is also an adjunct
`associate professor in the College of Pharmacy at the University of Utah, Salt Lake
`City, Utah. Dr. Li graduated summa cum laude from Brigham Young University,
`Provo, Utah, where he obtained his bachelor's degree in chemistry. Subsequently, he
`earned his PhD in pharmaceutics and pharmaceutical chemistry from the University
`of Utah under the supervision of Dr. William Higuchi and with the support of a pred-
`octoral fellowship from Pharmaceutical Research and Manufacturers of America
`(PhRMA) Foundation. Dr. Li has published more than 80 articles, patents, and book
`chapters on transdermal, ocular, and trans-ungual drug delivery and noninvasive
`pharmacokinetic study using MRI. He is a principal investigator and coinvestigator
`of research grants funded by the National Institutes of Health (NIH) in the United
`States. He has frequently served as a reviewer for scientific journals in pharma-
`ceutical sciences, ophthalmology, and MRI research and a member in grant review
`panels.
`
`Katarzyna Madej, PhD, graduated from the Faculty of Chemistry at the Jagiellonian
`University, Krakow, Poland, where she defended her master thesis. Her postgraduate
`study took place at the Faculty of Chemistry in J987-1991. In 1993, she defended
`her doctoral thesis on "Development of computerized-aid potentiometric multi-
`component titration methods." Then, she was employed in the Institute of Forensic
`Research, Krakow, Poland, for 7 years. In 1999, she began her career in the Faculty
`of Chemistry at the Jagiellonian University as an assistant and from 2002 as an assis-
`tant professor. Dr. Madej's scientific work mainly concerns development and opti-
`mization of analytical procedures for medicaments, especially psychotropic drugs,
`in biological samples. Her research interests include clinical and forensic toxicology,
`biological sample preparation techniques, and development of chromatographic and
`capillary electrophoretic methods. She also participated actively in many national
`and international conferences and symposia.
`
`Howard I. Maibach, PhD, is currently serving as a professor of dermatology at
`the University of California, San Francisco, California. He obtained his MD from
`Tulane University, New Orleans, Louisiana, in 1955. Later, he served in faculty posi-
`tions in various levels at the University of California, San Francisco. Dr. Maibach
`has published more than 2520 articles. He has been on the editorial board of more
`than 30 scientific journals and is a member of 19 professional societies including the
`American Academy of Dermatology, San Francisco Dermatological Society, and the
`Internal Commission on Occupation Health.
`
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`Contributors' Biographies (cid:9)
`
`xv
`
`Sudaxshina Murdan, PhD, is a senior lecturer in Pharmaceutics at the University
`College London School of Pharmacy. She studied pharmacy at The University of
`Nottingham and gained her PhD from The School of Pharmacy, University of London
`(now UCL School of Pharmacy). Her research is in the fields of ungual drug delivery,
`vaccine delivery, and in pharmacy and development education, and she has authored
`over 40 peer-reviewed papers, over 70 conference papers, a number of book chap-
`ters and articles in industry newsletters and student newspaper. She teaches on the
`MPharm, MSc and PhD programs and is a fellow of the Higher Education Academy.
`
`S. Narasimha Murthy, PhD, is an associate professor at the University of Mississippi
`School of Pharmacy, University, Mississippi. After obtaining his PhD in pharmaceu-
`tics from Bangalore University, India, Dr. Murthy worked as a research associate at
`the Roswell Park Cancer Institute, Buffalo, New York, and as an assistant professor
`at Ohio Northern University, Ada, Ohio. He has published more than 60 research
`articles in the field of dermal and ungual drug delivery. Dr. Murthy also edited
`the textbook Dermatokinetics of Therapeutic Agents. He has been on the editorial
`boards of several pharmaceutical journals.
`
`Anroop B. Nair, PhD, is an assistant professor in the College of Clinical Pharmacy
`at King Faisal University, Al Ahasa, Saudi Arabia. He received his PhD in pharma-
`ceutics from Jadavpur University, Kolkata, India. He was a postdoctoral fellow in
`S. N. Murthy Research group at the University of Mississippi, University, Mississippi,
`during which he worked extensively on the iontophoretic drug delivery in nail. He
`is an active member of several pharmaceutical councils/forums and a reviewer for
`several peer-reviewed journals in the field of pharmaceutics. He has authored more
`than 50 peer-reviewed articles.
`
`Michael A. Repka, PhD, is chair and professor of the Department of Pharmaceu-
`tics at the University of Mississippi, University, Mississippi, as well as the director
`of the Center for Pharmaceutical Technology. Dr. Repka joined the faculty at Ole
`Miss after receiving his PhD from the University of Texas College of Pharmacy and
`founded a pharmaceutical research/development company that specializes in drug
`delivery. His research interests include oral transmucosal and transdermal/transnail
`delivery systems, as well as other novel dosage forms. Many of these systems are
`directed toward the solubilization and delivery of poorly soluble bioactives via hot-
`melt extrusion technology, which is a primary focus of his research. In the nail drug
`delivery area, Dr. Repka worked on development of bioadhesive nail patches and nail
`etching technology. Her publications include more than 70 peer-reviewed journal
`articles and book chapters and well over 250 presentations at national/international
`scientific meetings. She serves on the editorial advisory boards of six prestigious
`journals, is an associate editor for AAPS PharmSciTech, and has been credentialed
`as a member of the U.S. Pharmacopeial Convention.
`
`H. N. Shivakumar, PhD, is currently working as professor and head in the Depart-
`ment of Pharmaceutics at the KLE University's College of Pharmacy, Bangalore,
`India. Dr. Shivakumar received his doctoral degree in pharmacy from Rajiv Gandhi
`
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`xvi (cid:9)
`
`Contributors' Biographies
`
`University of Health Sciences, Bangalore, India. He completed his postdoctoral
`research in S. N. Murthy Research Group at the University of Mississippi, University,
`Mississippi. His postdoctoral research was focused on passive targeting of micropar-
`ticulate systems to the lymphatics for various therapeutic interventions. He was also
`involved in developing innovative drug delivery strategies for transdermal and trans-
`ungual applications. He holds an appointment as a principal scientist with DermPerm
`Research Inc., Bangalore, India. Dr. Shivakumar has around 25 research articles in
`peer-reviewed journals and two book chapters to his credit.
`
`Michael M. Tunney, PhD, is a reader of clinical pharmacy in the School of Pharmacy
`at Queen's University Belfast. His research interests are centered on clinical pharmacy
`and pharmaceutical microbiology. His current work focuses on the detection and treat-
`ment of polymicrobial infection in a range of respiratory diseases including cystic
`fibrosis and chronic obstructive pulmonary disease. Other key areas of interest include
`treatment of biofilm infection of indwelling implants and determination of the fac-
`tors associated with success or failure of methicillin-resistant Staphylococcus aureus
`decolonization in hospital inpatients. Dr. Ilinney has published more than 50 research
`papers and has contributed to a number of microbiology and biomaterials textbooks.
`
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`

`1 The Nail
`Anatomy, Physiology,
`Diseases, and Treatment
`
`Sudaxshina Murdan
`
`CONTENTS
`
`1.1 (cid:9) The Nail Unit (cid:9)
`1.1.1 Nail Matrix, Nail Bed, Hyponychium, Nail Folds, and Cuticle (cid:9)
`1.1.2 The Nail Plate (cid:9)
`1.1.2.1 Nail Plate Surfaces (cid:9)
`1.1.2.2 Nail Plate Layers (cid:9)
`1.1.2.3 Nail Plate Cells (cid:9)
`1.1.2.4 Nail Plate Composition (cid:9)
`1.1.2.5 Nail Plate pH (cid:9)
`1.2 (cid:9) Nail Diseases and Current Treatment Approaches (cid:9)
`1.2.1 Disorders of the Nail Plate Size and Shape (cid:9)
`1.2.1.1 Disorders of the Nail Plate Surface (cid:9)
`1.2.1.2 Disorders of the Nail Plate Color (cid:9)
`1.2.1.3 Disorders of the Nail Plate's Mechanical Properties (cid:9)
`1.2.1.4 Disorders of the Nail Plate's Attachment to Underlying
`Tissues (cid:9)
`1.2.1.5 Disorders of the Perionychium (cid:9)
`1.2.1.6 Treatment of Nail Disorders (cid:9)
`1.2.2 Onychomycosis (cid:9)
`1.2.2.1 Treatment of Onychomycosis (cid:9)
`1.2.3 Psoriasis (cid:9)
`1.2.3.1 Topical Treatment of Nail Psoriasis (cid:9)
`1.2.3.2 Intralesional Therapy (cid:9)
`1.2.3.3 Photochemotherapy (cid:9)
`1.2.3.4 Systemic Treatment (cid:9)
`1.3 (cid:9) Topical Ungual Formulations (cid:9)
`1.4 Conclusions (cid:9)
`References (cid:9)
`
`2
`3
`4
`5
`7
`7
`9
`13
`15
`15
`16
`17
` 18
`
` 18
`19
`19
`20
`23
`25
`27
`28
`28
`28
`28
`29
`29
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`Anacor Exhibit 2030
`Flatwing Pharmaceuticals, Inc. v. Anacor Pharmaceuticals, Inc
`IPR2018-00168
`
`

`

`2 (cid:9)
`
`Topical Nail Products and Ungual Drug Delivery
`
`1.1 (cid:9)
`
`THE NAIL UNIT
`
`The nail plate lies on the nail bed, is produced by the nail matrix, and is framed
`and ensheathed by the nail folds and the hyponychium (Figure 1.1). All these com-
`ponents, that is, nail plate, nail bed, nail folds, matrix, and hyponychium, make up
`the nail unit (Gonzalez-Serva 1997) and are described below. The nail unit starts to
`develop in the tenth week of embryogenesis and is almost completely formed by the
`17th week, after which changes in the nail unit are mainly associated with growth;
`it is well perfused by blood and lymphatic vessels, has a rich nerve supply, and is
`anchored in place by attachment to the distal phalanx (Dawber et al. 2001; Fleckman
`2005; de Berker et al. 2007; de Berker and Forslind 2004; Zaias 1990).
`The functions of the nail unit are manifold. Equivalent to claws and hooves in other
`mammals, the nail allows one to manipulate objects, enhances the sensation of fine touch,
`protects the delicate tips of fingers and toes against trauma, and is used for scratching
`and grooming (Barron 1970; Dawber and Baran 1984; Chapman 1986; Gonzalez-Serva
`1997). The multibillion dollar industry devoted to nail cosmetics and nail salons attests to
`our use of the nail as a cosmetic organ, even to the extent of sacrificing function for beauty.
`
`Lunula
`
`Onychodermal band
`
`Eponychium
`
`Proximal nail fold
`
`Nail plate
`
`Nail bed
`
`Nail plate
`Nail bed
`
`Hyponychium
`Distal groove
`
`Eponychium
`
`Distal phalanx
`
`Matrix
`
`Dorsal proximal nail fold
`
`Ventral proximal nail fold
`
`Proximal nail fold
`subdivisions
`
`FIGURE 1.1
`(See color insert.) Nail structure. ( Reproduced from Jiarav uthisan et al., J. Am.
`Acad. Dermatol. 57, 1, 2007. With kind permission from the American Academy of Derma-
`tology, Inc.)
`
`Page 18
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`Flatwing Pharmaceuticals, Inc. v. Anacor Pharmaceuticals, Inc
`IPR2018-00168
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`

`

`The Nail
`
`For example, the use of the computer keyboard is hampered by long nails, and yet, many
`of us are happy to cope with such difficulties. Such extremes of a prerogative of beauty
`over function have even been actively cultivated to communicate social status, exempli-
`fied by Chinese mandarin culture. At the other extreme of beauty versus function, nail
`biting, which severely compromises the beauty of nails, is known to serve several needs,
`including providing a sense of relief as well as alleviating boredom (Williams et al. 2007).
`
`1.1.1 NAIL MATRIX, NAIL BED, HYPONYCHIUM, NAIL FOLDS, AND CUTICLE
`
`The nail matrix—also called the root of the nail—is the germinative epithelial tis-
`sue whose cell division gives rise to the nail plate. Its distal portion is sometimes
`(especially in the thumbs and great toes) visible through the transparent nail plate as
`a white, semilunar area, called the lunula. The nail bed is a very thin epithelium on
`which the nail plate rests (and strongly adheres to), and slides over during its growth.
`The nail bed's dorsal surface is characterized by longitudinal ridges, and a comple-
`mentary set of ridges is also found on the underside of the nail plate (though not at its
`free edge), which has led to the nail plate being described as led on rails as it grows
`out (Dawber et al. 1994), and to the suggestion that the ridges contribute to adhesion
`between the nail plate and the nail bed (Rand and Baden 1984). It has, however, been
`pointed out that it is unclear whether the ridges seen on the nail plate actually belong
`to the nail bed epithelium and remain attached to the undersurface of the nail plate
`or whether they are etchings on the nail plate (Fleckman 2005). There has also been
`vigorous debate for more than a century about whether or not the nail bed contributes
`to production of the nail plate. The interested reader should refer to Branca (1910)
`and Johnson et al. (1991), and references within.
`The hyponychium is the region underneath the free edge of the nail plate where
`the latter starts to separate from the nail bed. It includes the space, the epithelium
`bordered by the nail bed and the distal groove, and the keratinous products of that
`area. The distal groove (Figure 1.2) marks the most distal boundary between the nail
`
`i,
`_,___,- Nail plate
`
`'N, Distal groove
`
`Fing