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`VOLUME 199 10 FEBRUARY 2015
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`1
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`ssu 0 63
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`-3659
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`——]
`Journal of controlled release
`v‘ 199 (Feb. 10 2015)
`General Collection
`W1 JOSQGC
`
`I
`2015—02-2413332158
`R» controlled
`release
`
`
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`OFFICIAL JOURNAL OF THE CONTROLLED RELEASE SOCIETY
`
`AND THE JAPANESE SOCIETY OF DRUG DELIVERY SYSTEM
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`COVER STORY
`Tissue penetration of bacteria into quiescent regions of tumors
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`journal of
`controlled
`release
`
`
`
`Official Journal of the Controlled Release Society and of the Japanese Society of Drug Delivery System
`
`
`The journal publishes innovative, original research involving the controlled release and delivery oi drugs and other biologically
`active agents. The terms “controlled release” and "delivery’ are used in their broadest sense to Include mechanisms such as
`diffusion, chemical and enzymatic reactions. dissolution. osmosis. targeting. as well as the utilization and manipulation of
`biological precesses. A broad spectrum of studies dealing with all aspects of controlled release and'delivery, including
`gene delivery. tissue engineering and diagnostic agents, is encouraged. The use of prodrugs and carriers such as water-
`solubie polymers, micro and nanoparticles. liposomes and micelles is included in the scope.
`
`in addition to original full length papers and reviews. the journal includes reports of future meetings and announcements per-
`taining to the activities of the Controlled Flelease Society. Persons considering writing a review are encouraged to contact the
`Review Editor.
`EDITORS
`
`.
`EDITOR-iN-CHiEF
`Prot. K. Park. Purdue University. Departments of Biomedical Engineering and Pharmaceutics, West Latayetle. IN, USA;
`Email; kpark©purdue.edu
`I
`.
`ASSOC!!! TE EDITORS FOP] THE AMERICAS
`Prof. Y.H. Eae, Dept. of Pharmaceutics and Pharmaceutical Chemistry. University of Utah. 421 Wakara Way. Salt Lake City, UT 84108. USA.
`.
`Email: you.bae@ utah.edu
`_
`Prof. S. Mltragmrl, Dept. or Chemical Engineering. University of California at Santa Barbara. Ma" 00d9 5059 Santa Ba'bara' CA 93106' USA'
`E—mail: sarnlr
`engineering.ucsb.edu
`.
`Prof. S.F. Schwendeman, Dept. of Pharmaceutical Sciences. University of Michigan, 428 Church Street, Ann Arbor. Ml 48109. USA.
`E-mail: schwende@ urnich.edu
`EDITORS FOFI“ EUROPE
`Editor
`Prof. T. Klssel. Dept. of Pharmaceutics 8i Biopharmacy. Universitat Marburg. Ketzerbach 63, 35032 Marburg. GB'many‘.
`Eemail: jcr@ statf.uni-marburg.de
`Associate Editors
`‘
`_
`7.
`Prof. 5.8. De Smedt. Lab. 01 Gen. Biochem. 8t PhySIcal Pharmacy. Universiteit Gent. Harelbeltestraat 72. 900i) Gent. Belgium
`Prof. J.-C- Lemur. Inst. of Pharmaceutical Sciences. Eidgenossische Technische Hochschule (Em) Z'Un'Ch. WO'IQanQ-Pani-S‘F 10. 3093 21mm: SW‘Venand
`EDiTOFiS FOR ASIA
`Editor
`Prot. LC. Kwon. Biomedirai Research Center. Korea lnst‘tutie of Science and Technology (KIST). 39-1 HawolgokDong. 136-791 Seongbuk—Gu. Seoul. South Korea;
`E-m ail: ilrwon @ Irist.re.kr
`.
`.
`.
`.
`Associate Editors
`Prof. H. Harashima, Lab. Moi. Design 01 Pharmaceutics. Fee. or Pharmaceutical Sciences. Holdtaidc Unwe'srw. I612: 12. Nishi 6. NIa—ku. 0600812 Sapporo. Japan;
`E—mail: harasima®pharmhokudaiacip
`‘
`I
`Prot. A. Kikuchi, Dept. of Materials Science and Technology. Tokyo University 01 Science. 2641 Yamazaici. 278-8510 Noda. Chiba. Japan:
`Email; kilruchia®rs.noda.tus.ac.ip
`FieView Editor
`Frot.V.P.Torchllin, Pharmaceutical Sciences. Northeastern University. 360 Huntington Ave. Boston. MA 02115-5000. USA;
`E-mail: v.torchilin@neu.edu
`.
`.
`.
`_
`_
`Speciai issue Editor
`Prof.W.E. Hennink. Dept. ct Pharmaceutics, Utrecht inst; for Pharmaceutical Sciences. Universiteit Utrecht. Unwersrteitsweg 9.9. 3584 CG Uliecht. Netherlands
`Concept Papers Editor
`.
`Frof.Y.H. Bae, Dept. ot Pharmaceutics and Pharmaceutical Chemistry, University of Utah. 421 Wakara Way. Salt Lake City. UT 34103. USA:
`E-mail: you.bae®utah.edu
`Adviser
`Prof. T. Nagal. E—mail: nagai-t@mbc.ocn.ne.jp
`Editorial Board
`
`M.J.Alonso, Santia 0 do Com ostela. Spain
`T.L. Bowersock. Ka amazoo. NH. USA
`X. Chen. Changchun. China
`P. Colombo, Parma, Italy
`P. Coovreur. Chatenay-Malabry. France
`M.C. Davies. Nottingham. UK
`A.J. Bomb, Jerusalem. israel
`R. Duncan, Cardiff. UK
`..
`.
`.
`E. Fattal, Chatenay-Malabry. France
`B. Gander. Zurich, Switzerland
`H. Ghandeharl, Salt Lake Ci
`. UT. USA
`G. Golomb. Jerusalem. Israe
`D.W. Grain er. Salt Lake City. UT. USA
`n. Gurny.
`eneva. Switzerland
`J. Hanes, Baltimore. MD. USA
`M. Hashida, K oto, Japan
`J.A.Hubbell, ausanne. Switzerland
`L. illum. Nottingham. UK
`S.Y. Jeong. Seoul. Korea
`T- Jln. Shan hai. China
`AT. Jones.
`arditf. UK
`A. Kabanov. Omaha. NE. USA
`Founding Editors
`Prof. J. Feijen, University of Twente. The Netherlands
`Dr. J. Heller. USA
`
`
`D. Putnam. Ithaca. NY. USA
`I
`T. Hades, Copenhagen. Denmark
`M.J. Rathbone, Kuala Lumpur. Malaysia
`A.P. Holland, San Diego. CA. USA
`K_ Roy, Austin, Tx' USA
`wgg, gamma", New Hauem CT. USA
`Ekategei, Minneapoiisl MN, USA
`J. stepmann! Lille! France
`RS. Stayton.
`.
`.
`Seame WA USA
`V sugiyama Tokyo Japan
`H'_W Sung “$th Taiwan
`K'Ta‘kayam'a Tok 0 ‘Japan
`I
`'Uche bu iondg'n' UK
`k Ulb 19h 'P
`'c ech Re "mic
`-
`[c r Faguei
`2
`p
`A. Urttil Helsmki, Finland
`.
`E-W39mn .MUNCh- Germ“?
`C.Wang. MinneaPOIIS- MN: USA
`C.—H. Wan , Slrlgiipm‘a
`C.O.Yun,
`soul, Korea
`0. Zhng. Beiiing. China
`2. Zheng. Suzhou. China
`
`K. Kataoka. Tokay. Ja an
`Y. Kawashin'ia.
`ifLi. Egan
`J. K0 eéek. Salt_Lake
`I
`. UT. USA
`G.S. wort, Madison. WI. USA
`T. Lammers, Aachen. Gummy
`S.J.Lee. Seoul. Korea
`CM. Lehr, Saarbrucken. Germany
`K.
`. Lear-i9. Baltimore. MD. USA
`.
`T. Li. Lexrn ton. KY. USA
`K. Méder.
`alle (Seals). Germany
`H. Maeda. igumamoto. Japan
`E. Mathlownz. Providence, RI. USA
`AG. Mikes. Houston. TX. USA
`T. Minko. Piscataway. NJ. USA
`Ft. Niven, Half Moon Bay, CA. USA
`H. Okada. Tokyo. Japan
`T.Okanc. Tok 0. Japan
`o.w. Pack. Ur aria. IL. USA
`D. Peer. Tel Aviv. Israel
`N.A. Peppas. Austin.Tx. USA
`Y. Perrie. Birmin ham. UK
`M. Prausnitz, At anta. GA. USA
`
`Page 2 of 20
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`

`

`journal of
`controlled
`release
`Volume 199 (2015)
`
`Amsterdam — Boston -— London — New York —Oxford - Paris —
`Philadelphia — San Diego - St. Louis
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`ELSE IER
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`journal of
`controlled
`release
`
`
`
`
`Official Journal 0! the Controlled Release Society and of the Japanese Society of Drug Delivery System
`
`EDITORS
`EDtTOH—W-CHIEF
`
`Prof. K. Park. Purdue University. Departments 01 Biomedicat Engineering and Pharmaceutics. West Lafayette. IN. USA;
`Email: kpark@purdue.edu
`.
`.
`ASSOCJATE EDITORS FOR THE AMERJCAS
`Prof. Y.H. Bae, Dept, cl Pharmaceutics and Pharmaceutical Chemistry. University of Utah, 421 Wakara Way. Salt Lake City. UT 84108. USA.
`l
`E-mail: you.bae@ utahedu
`Prof. S. Mitragotri. Dept. oi Chemical Engineering. University of California at Santa Barbara. Mail Code 5090. Santa Barbara. CA 93105. USA
`E-mail: samir@engineeringucsbodu
`Prot.s.P. Schwendeman. Dept. of Pharmaceutical Sciences. University of Michigan, 428 Church Street. Ann Nbflr. Ml 43109. USA:
`Email: schwende®umichedu
`EDITORS FOR EUROPE
`
`_
`Editor
`Prof. T. Kissel. Dept. Of Pharmaceutics & Biopharmacy, Universita't Marhurg, Ketzerbach 63. 35032 MarbUtt]. Germafil'.
`Eamaii: icr®stafi.uni-rnarburg.do
`.
`Associate Editors
`12 n M
`I
`_
`Prof. 3.6. De Smedt, Lab. of Gen. Biochem. a Physical Pharmacy. Universiteit Gent, Hareibekeatraat 72. 9000 Gent. BE'Q‘UW
`Prof. J.-C. Leroux. that of Pharmaceutical Sciences, Efdgenossische Technische Hochschule (ETH) Zunoh. WolfgangiPaull-Sfl'. 10. 3093 ZUI'ICh. 5““ e 3‘
`EDFTOHS FOH ASIA
`
`_
`Editor
`Prat. l.c. Kwon. Biomedical Flesearoh Center. Korea lnsfitute oi Sa'erloe and Temmlogy (Klsn. 39-1 Hawolgok-Dong. 136791 WWW”! 59°” - 50”“ Kma-
`E—mail: lkwon @ kist. re.l<r
`
`r
`.
`.
`.
`,
`_
`Associate Editors
`Prat. H. Harashima, Lab. Moi. Design of Pharmaceutics, Fee. or Pharmaceutical Seances. Hokkaido Urwerslty. We 12, News. Imam. 060-089 5609070. JaPat'l
`E-mail: harasima® pharmhokudaiaoip
`,
`r
`_
`Prot. A. Kikueht. Dept. cl Materials Science and Technology, Tokyo University of Science. 264i Yamazakl. 278-8510 Nada. Chiba. Japan,
`Email: kikuchia@rsnodatusacjp
`Review Editor
`Prot.V.P.Torchilin, Pharmaceutical Sciences. Northeastern University. 350 Huntington Ave. Boston. MA 02115-5000, USA;
`E—rrlaii: v_torchilin@neu.edu
`Speciat issue Editor
`Prot.W.E. Hennlnk, Dept. of Pharmaceutifi. Utrecht Inst. for Pharmaceutical Sciences. Universite'rt Utred1t. Universitailsweg QB. 3534 CG Utrecht. Netherlands
`Canoe We are Editor
`.
`.
`Prof. ‘lfl-l. Ego. Dept. of Pharmaceutics and Pharmaceutical Chemistry. University Of Utah. 421 Wakala Wain 33” Lake 0““ UT 34103' USA‘
`E-mail; you.bae@utah.edu
`Adviser
`Prot. T. Nagal. E-rnail: nagai-t@mbc.ocn.ne.]p
`Editorial Board
`M.J. Alonso, Sanlia 0 de Compostela. Spain
`“~- Elmer-$00k. K393018200. Ml. USA
`X. Chen. Changchun. China
`P. Colombo. Parma, Italy
`P. Couvreur, Chétenay-Malabry, France
`M.C. Davies. Nottingham. UK
`M. Dmb. Jerusalem. Israel
`Ft. Duncan, Cardiff. UK
`E. Fattal, Chatenayeltlalaory. France
`B. Gander, Zi'rr'rch, Switzerland
`H. Ghandeharl, Salt Lat-re City. UT. USA
`G. GDIOt‘nb. Jemsalem. lsrael
`D_W.Grainger. Salt Lake City. UT, USA
`“' GW'Y-Gammr SWi‘zemn“
`.1. Hanes. Baltimore. MD. USA
`til. Hashlda. Kyoto, Japan
`J.A. Hubbell. Lausanne, Switzerland
`L. Illum.Noitingham. UK
`5.7. Jecmg. Seoul. Korea
`T. .IlnI Shanghai. China
`M". Jones. Cardiff. UK
`A. Kebaan Omaha. NE. USA
`Founding Editors
`Prot.J. Fallen, University ofTwente, The Netherlands
`Dr. J. Heller, USA
`
`
`D. Putnam. Ithaca. NY. USA
`_
`T. Hades, Copenhagen, Denmark
`MJ. Hathbone. Kuala Lumpur. Malaysra
`AP. Rolland. San Diego, CA, USA
`K. Roy. Austin. TX, USA
`WM. Saitzman, New Haven, CT, USA
`Fm. siegei, Minneapolis, MN, USA
`J. slepmann, Lille, France
`:15, Stan“, seams, wa. USA
`Y. Sugwama’ Tokyo. Japan
`H'_w_ Sung. Hal-“Chm Taiwan
`KlTakawma Tokyo' Japan
`I Uchegbu condo” UK
`k Ulbrlch 'Prague 'Czech Republic
`A- Uml Héjsmki Finland
`E‘W I
`M “Eh Gama“
`' Wagnerr . u '
`-| MN 55A
`C-
`“"9. “William ‘5.
`i
`I3.-H.Wan9. Siflgapom
`C.O.'I"Lln. Seoul. Korea
`o. zhang. BE‘IIIl’lQ. China
`2. Zhong. Suzhou, China
`
`K. Kataeka. Tokyo. Japan
`Y. Kawashima, Gilli. Japan
`.1. Kopeoek, Salt Lake City, UT. USA
`6.5. Kwon. Madison. Wt. USA
`T. Lammers, Aachen. Germany
`S.J. Lee, Seoul, Korea
`c.lvl. Lehr. Saarnmcken. Germany
`K.W. Leong, Baltimore. MD. USA
`T. Li. Lexington. KY. USA
`K. Mia'der, Halle (Saaiej. Germany
`H. Manda, Kumamoto, Japan
`E. Mathlowitz, Provrdenca, HI. USA
`n.6, Mikes. Houston. TX. USA
`1" M'mmr Pimmwayr NJ' USA
`R. vaerl,t-lalt Moon Bay. CA, USA
`H. Okada. Tokyo. Japan
`T. Dkano. Tokyo, Japan
`D.W.Pack. Urbana. IL, USA
`D. Peer, Tel Aviv, Israel
`MA. Peppas, Austin, TX. USA
`v. Perrle. Birmingham. UK
`M. Prausnltz. Atlanta. GA. USA
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`_$1,
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`ELSER
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`

`

`journal ol'Controlled Release IBEI (2015] 132-144
`
`
`Contents lists available at SeieneeDireot
`
` journal homepage: www.elsevier.eomilocatelicvnffl|
`
`journal of Controlled Release
`
`Development of topical therapeutics for management of onychomycosis ®
`and other nail disorders: A pharmaceutical perspective
`
`Cm‘““‘k
`
`Mustafa NLA. Elsayed
`
`Department ofPha nnnceun‘cs, Faculty ofl’ltnmtoty. Alexandria University. til-Khartoum Square. Eli/12mm. Alexa ndn'tt 2l52] Egypt
`
`ARTICLE lNFO
`ABSTRACT
`
`Tlte human nail plate is a formidable b3 '
`-
`.
`rrlet to drug permeation. Development oftherapeutlcs for management
`of nail diseases thus remains a challenge. This article reviews the current knowledge and recent advances '
`field oftransungual drug deliveryand provides guidance on development oftopicalfungual therapeutics forIn the
`agement of nail diseases. with special emphasis on management of onychomycosis. the most common mini-m
`ease. Selection of drug candidates. drug delivery approaches. and evaluation of formulations are among ti?
`topics discussed. A comprehenstve mathematical description for transungual permeation is also introduced
`6
`© 2014 Elsevier BM A“ If
`Ems resel'ved_
`
`Article history:
`Received wartime-rm”
`I1°1ccepted 17 November 2014
`Availablconlinc 4 December 2014
`Keywords:
`Transungufl
`Nail lacquer
`Nail hydration
`Keratin binding
`Transungual penetration enhancer
`Detmatophytes
`Antifungal
`Amorolfine
`Ciciopirox
`Efinaconazole
`Luliconazole
`Tavaborole
`Terhinal'ine
`
`
`Contents
`
`45-53.“?
`
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`4.4. Sublimabiiity._......................:::: '
`4.5.
`Antifungalactiv'tty .
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`Nail lacquers
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`5.3. Colloidalcartiers....................::: '
`5.4.
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`6.
`
`E-rnil address: mu stafa.eisayed@alcxphannresmm.
`
`hllpszdxfloiorgflulfllfifljconrellflldj 1.01?
`UlGE-3GSQIO 20M Elsevier I3.V. All rights reserved.
`
`Page 6 of 20
`
`

`

`MMA. Elsoyed fjournal ofControlled Release 199 (2015) 132444
`
`I33
`
`1. Introduction
`
`The human nail plate is a resistant barrier that is difficult to pene—
`trate and. when afflicted. difficult to cure. Several disease conditions.
`such as infections and psoriasis. afflict the human nail. Of these diseases.
`onychornycosis. also known as tinea unguium. is the most common in
`adults:
`it accounts for approximately 50% of all nail diseases.
`Onychomycosis is the fungal infection of the nail. It involves one or
`more of the nail unit components. including the nail matrix. the nail
`bed. or/and the nail plate. Epidemiological studies suggest that the dis-
`ease affects 6.9—23.2% of the general population in North America and
`Europe {1—3}.
`Treatment of onychomycosis relies widely on long—duration
`systemic/oral antifungal therapy. which is often associated with serious
`side effects. drug interactions. and high recurrence rates. This raises a
`special need for effective topical therapy. Many broad-spectrum antie
`fungal agents are effective in vitro against fungi responsible for
`onychomycosis. The therapeutic outcome of topical formulations
`(Table I) is. however, often unsatisfactory [4] owing to the high nail re-
`sistance to drug permeation. Despite of shortcomings of available sys-
`temic and topical drug products. the dermatophylic onychomycosis
`
`market in 2010 was valued at US$11 billion [5]. Development of rather
`effective and safer drug products will expand this market to millions
`who do not receive treatment. The desire to capture a share of this mar—
`ket and the recent recognition that nail plate penetration is achievable,
`albeit difficult. have attracted several drug companies to join the race
`towards a successful topical drug product [Table ‘1). Until 2013 only
`three topical
`formulations were approved for management of
`onychomycosis in some countries worldwide and only one was ap—
`proved by the US FDA. In 2014 two new topical formulations were ap—
`proved by the US FDA (Table l J.
`This article reviews the current knowledge and recent advances in
`the field oftransungual drugdelivery with special emphasis on develop-
`ment oftopical/ungual therapeutics for management of onychomycosis.
`Selection of drug candidates. drug delivery approaches, and evaluation
`of formulations are discussed.
`
`2. The nail barrier
`
`The human nail plate is comprised of layers of flattened. keratinized
`cells fused into a dense but somewhat elastic mass. It is 0,571.0 mm
`thick and it grows distally from the matrix at a rate of about 2—3 mm
`
`Table 1
`Topical antil‘ungal drug products. currently approved or under development. for management of onychomycosis.
`
`Product name[s)
`Description
`_——.—-—.———_—_—_——..—————
`Approved in (dalc)fstatus
`Companyralliance "
`Galderma International SAS (1.2 Défense.
`Loceryltlil (also marketed
`Active: Amorolfine 5% will. as the hydrochloride salt
`UK 0991). Switzerland ([99] ). France
`as Curanailcsl) nail lacquer
`France)
`Base: Ammonia methacrylate copoly mer type A [ Eudragit®
`{1992 “j. and more than 50 other coun-
`tries
`RL. water insoluble film former). triacetin (plasticizer).
`butyl acetate. ethyl acetate. and ethanol (solvents)
`Not approved in USA and Canada
`Active: Ciclnpirox 8% wr‘w
`France (1991). Germany (1992 l’).
`Base: Butyl mun oester of polylmethylvinyl etherfrnaleic
`Austria (1995). USA (1999). Canada
`acid] (water insoluble film former). ethyl acetate. and
`[2004]. and more than 50 other
`countries
`isootopyl alcohol (solvents)
`Australia
`Each pack contains:
`1 tube of Canesten 40% Urea Ointment
`1 tube ofCanesten 1% Bifonazole Cream
`Active: Ciciopirox 8% WM
`Base: Hydroxypropyl chitosan (water soluble film former).
`cetoslearyl alcohol. ethyl alcohol. ethyl acetate. and purified
`water
`Active: Efinaconazole 10% WW
`Base: Alcohol. Cl2-15 alkyl lactate. cyclomethicone.
`diisopropyl adipate. citric acid. butylated hydroxytoluene,
`disodium edetate. and purified water
`Active: Tavaborole (ANZBDD) 5% who
`Base: alcohol, propylene glycol. and edetare calcium
`disodlum
`Active: Econa zolc 576 MW
`Base: 2-rr-nonyl-I.3-dioxolane [SEPA®) 18% wrw.
`Ammonio methacrylale copelymer type A [Eudragino
`RLrl’O). ethanol
`Active: Terbinafine hydrochloride 10%
`Base: Dodecyl 2-(N. N dimethylamino)-propionale
`hydrochloride (DDAIP llCI. NexACT®). benzyl alcohol.
`polyvinylpyrtolidonc. ethanol
`Active: Luliconazole (NND-EOZ) 102‘.“
`
`Penlac® (also marketed as
`Batrafcn®. Loprox®, or
`Mycostcr®) nail lacquer
`
`Can esten® Fungal Nail
`Treatment Set "
`
`Ciclopoli® (also marketed
`as RejuveNaiI®) nail
`lacquer ( P—3051)
`
`Jubliaro topical solution
`
`Kcrydinm topical solution
`
`EcoNailm nail lacquer
`
`Mycohl'aml nail lacquer
`(NMr‘l 00060 )
`
`Lulico nazole solution
`
`TD‘I' 067 liquid spray
`
`P3058 nail lacquer
`
`Active: Terbjnafine 15 mgrml
`Base: Soybean phosphatidylcholine — Tween 80 deformable
`lipid vesicles (Transfersomcs®) “
`Active: Terbinafinc
`Base: Hydroxypropyl chilosan (water soluble film former)
`solution ‘l
`
`Aventis Pharma (Frankfurt am Main.
`Germany)
`
`Bayer Australia Ltd.
`
`Germany (2008), Switzerland {2009).
`and other countries.
`
`Polichem SA {Lugano Switzerland)
`
`Canada (2013}. USA {2014)
`
`USA (2014)
`
`Valeant Pharmaceuticals International.
`Inc. (Laval. Quebec. Canada); Kaken
`Pharmaceutical Co.. Ltd. (Tokyo. Japan)
`
`Anacor Pharmaceuticals. Inc. {Palo Alto.
`California. USA)
`
`Phase II clinical studies completed in
`2008
`
`Access Pharmaceuticals. lnc. (Dallas.
`Texas. USA)
`
`Phase [1] clinical studies completed in
`2009
`
`Apricus Biosciences. Inc. (San Diego.
`California, USA)
`
`Phase llbrll] clinical studies are ongoing
`
`Phase II] clinical studies are ongoing
`
`Topica Pharmaceuticals. Inc. (Los Altos.
`California. USA); Nihon Nohyaku Co.. Ltd.
`(Tokyo. Japan)
`Celtic Pharmaceutical Holdings LP.
`(Hamilton. Bermuda)
`
`Phase ll clinical studies are ongoing
`
`Polichem SA (Lugano. Switzerland)
`
`
`
`" For prod ucts marketed in different trade names the company provided refers to the manufacturerfmarketing authorization holder ofthe main product only. Other marketed products.
`Whose trade names are referred to between parentheses. are not necessarily ploprietary producls of the same company.
`1’ Exact approval data was not found; launch date is given.
`‘ Canesten® Fungal Nail Treatment Set consists of a two-p hasc treatment. In the first phase (273 weeks). the infected nail parts are softened by applying Caneslen® urea ointment and
`then removed with the help ofa plastic nail scraper. In the second phase (4 weeks). the fungal infection is treated by applying CancstenflD bifonazole cream on the nail bed. CanesPI'O‘El
`Fungal Nail Treatment Set available in the UK consists only of 40% urea ointment. A follow-up treatment with an antifungal cream is advised.
`" Detailed composition is not available.
`rm: mnfurinl ms: rrlrlizlr'
`
`Page 7 of 20
`
`

`

`134
`
`MMA. Eisayed fJournal ofControlled Release mg (2015) 132-144
`
`per month. The main form of keratin in the human nail is tit-keratin. The
`nail plate sulfur content (-3.2% dry weight [5]) contributes to its tensile
`strength by linking the keratin fibers via cystine disulfide bonds. The
`densely packed tar-keratin filaments (helical) are embedded in qrstine-
`rich keratin matrix (amorphous) and oriented perpendicular to the di-
`rection of nail growth. Water is the principal nail plate plasticizer. The
`nail plate water content depends on the surrounding relative humidity
`and ranges under normal conditions from 10 up to 25% [6.7]. in this re—
`spect the nail plate contrasts to the stratum corneum. which may hold
`several times its dry weight in water. The lipid content of the nail
`plate ranges from 0.1% to 1% {8.9}. This is a second contrast to the strae
`tum comeum. having a lipid content ofabout 10%.
`
`3. Mathematical description of the nail permeability
`
`Fick's laws of diffusion can be used to model drug permeation
`through the nail plate. The flux is the permeant amount moving across
`a membrane ofunit area during unit time:
`
`13%.
`
`‘
`
`(1}
`
`') when an amounthin mol
`jis the flux (in mol of2 5—1 Of g n'i‘2 s'
`or g) of a permeant moves across a membrane with a cross—sectional
`areaA (in m2) during time t (in s). Flux is described by Fick‘s first law:
`
`6C
`1: —D§;:
`
`(2)
`
`where D is the permeant diffusion coefficient (or diffusivity, in
`rd2 5‘ 1) in the membrane [nail plate) and dC/Bx is the permeant con—
`centration gradient [in mol In"1 or g in") across the membrane.
`The negative sign indicates that the flux is in the direction ofdecreas~
`ing concentration. Steady state is reached when i) the permeant con—
`centration gradients. aC/dx. at all points across the membrane
`become constant. ii) the permeant concentration at any point across
`the membrane becomes constant. i.e. fiC/dt at any point is constant.
`and thus iii) the flusts. becomes constant. At steady state
`
`C mC
`AC,"
`JESEDTzflfld—h’fl‘
`
`(3)
`
`AC... is the difference (in mol In‘3 or g m”) between the permeant
`concentrations at the two faces of the membrane (nail plate). C”...
`and Cm are the permeant concentrations in the membrane at the
`donor and at the acceptor faces. h is the membrane thickness [in
`m). in this article we consistently use volume-based concentration
`units [e.g. mol m_3 or g m”). Assuming the same solvent is used
`as the donor and as the acceptor solvent. or in other words. the dis—
`tribution equilibrium (distribution constant). K.
`is the same on
`both sides of the membrane. Eq. [3) can be rewritten as
`
`Kmfd is the permeant membraneidonor solvent (or membrane/yew
`cle) distribution constant. The permeability coefficient is than de
`fined as:
`
`—
`
`
`nitmm
`h
`
`.
`
`(sink)
`
`(7)
`
`For steady-state diffusion. the total permeant amount crossing the
`membrane at time t is:
`
` if c
`
`Q.=]55At=D W" “At=PCdAr.
`h
`
`(sink)
`
`(8)
`
`Since a lag time. T (in s). is needed to establish pseudo—steady-state t
`_
`_
`ain-
`is replaced with the time over which pseudo-steady-state is m I
`talned. i.e. tar.
`
`
`Q. = gain—r) = oKmldchn—r) : PCdAU—T)
`h
`
`(sink)
`
`(9)
`
`The diffusional lag time. T. is obtained by linear extrapolation of the
`pseudo-steady—state portion ofthe Q. vs. t curve. Daynes' time lag 5m
`lution relates the diffusional lag time to the effective diffusion coeffi-
`cient [10]:
`
`h?
`
`Alternatively. a general. i.e. not limited to steady-state. solution of
`Fick's second law ofdiffusion can be used [1 1]:
`
`(—1)"
`2 ‘°
`i
`Dt
`QI =ijdcdi'dlh HiFE—F'E“ n2
`
`-Dn2n2t
`Exp T _
`
`(sink)
`
`(11)
`
`Eq. (11) allows fitting entire sets rather than only pseudo-steady-
`state portions ofdiffusion data (cf. Eq. (9)). lfwe assign