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`NATIONAL LIBRARY OF MEDICINE
`
`VOL334N05-1‘2v15.lANUARY2010
`
`CONTENTS
`
`(
`
`I
`
`I
`
`H
`
`.I.I
`NLM oasnvmaa 5
`
`Cited in: BIOSIS/Biological Abstracts, CAB Abstracts, Chemical Abstracts Service, Current Contents (Life Sciences. Clinical Medicine), EMBASE/Excerpta Medicd. Elsevier
`BIOBASE/Current Advances in Biological Sciences, international Pharmaceutical Abstracts. PUBMED/ MEDLINE/Index Medicus. PASCAL M, Science Citation Index.
`Also covered in the abstract and citation database SCOPU5“. Full text available on ScienceDirect®
`
`
`Review
`Transungual drug delivery: Current status
`R. Elkeeb, A. AliKhan, L. Elkeeb. X. Hui. H.l. Maibach (USA)
`
`Research papers
`Delivery of fullerene-containing complexes via microgel swelling and shear-induced release
`E. Tarabukina. Z. Zoolshoev. E. Melenevskaya. T. Budtova (Russia, France)
`MRP isoforms and BCRP mediate sulfate conjugate efflux out of Bewo cells
`P. Mitra, K.L Audus (USA)
`An improved kinetics approach to describe the physical stability of amorphous solid dispersions
`J. Yang, K. Grey,j. Doney (USA)
`identification and functional characterization of breast cancer resistance protein in human bronchial epithelial cells (Calu—3)
`D.K. Paturi. D. Kwatra. H.K. Ananthula, D. Pal, A.K. Mitra (USA)
`An investigation into the kinetic (sliding) friction of some tablets and capsules
`B.C. Hancock, N. Mojica, K. St._lohn-Green,_l.A. Elliott, R. Bharadwaj (USA, UK)
`Characterization and pharmacokinetic analysis of tacrolimus dispersion for nebulization in a lung transplanted rodent model
`A.B. Watts, A.M. Cline. AR Saad, S.B.Johnson. J.l. Peters. R.O. Williams III (USA)
`Three-layered microcapsules as a long-term sustained release injection preparation
`Y. lto, Y. Ochii, K. Fukushima, N. Sugioka, K. Takada (japan)
`The roles of acidifiers in solid dispersions and physical mixtures
`T.T.-D. Tran, P.H.-L. Tran, H.-G. Choi. H.-K. Han. B.-]. Lee (Republic of Korea)
`Oxybutynin permeation in skin: The influence of drug and solvent activity
`P. Santos. A.C. Watkinson.j. Hadgraft. M.E. Lane (UK. Australia)
`The relationship between transepidermal water loss and skin permeability
`M. Machado, T.M. Salgado,]. Hadgraft, M.E. Lane (UK)
`PLGA/PVA hydrogel composites for long-term inflammation control following s.c. implantation
`U. Bhardwaj, R. Sura, F. Papadimitrakopoulos. DJ. Burgess (USA)
`Mechanical properties of excipients do not affect polymer matrix formation
`L Chatterjee. T. Rades, l.G. Tucker (New Zealand)
`Influence of temperature on the solubilization of thiabendazole by combined action of solid dispersions and co-solvents
`S. Muela, B. Escalera. M.A. Pena, P. Bustamante (Spain)
`Surface charged temoporfin-loaded flexible vesicles: in vitro skin penetration studies and stability
`N. Dragicevic—Curic. S. Grafe. B. Gitter. S. Winter. A. Fahr (Germany)
`Characterization of physical and viscoelastic properties of polymer films for coating applications under different temperature of drying and storage
`G. Perfetti, K.M.B. Jansen, W._l. Wildeboer, P. van Hee, G.M.H. Meesters (The Netherlands)
`Novel microencapsulation of potential drugs with low molecular weight and high hydrophilicity: Hydrogen peroxide as a candidate compound
`S.-M. Ng.].-Y. Choi. H.-S. Han,J.-S. Huh.J.0. Lim (Republic of Korea)
`Surface active drugs significantly alter the drug output rate from medical nebulizers
`A. Arzhavitina. H. Steckel (Germany)
`
`Note
`Wistar rat skin as surrogate for human skin in nortriptyline hydrochloride patch studies
`A. Melero, C.-M. Lehr, U.F. Schélfer, T.M. Garrigues (Spain)
`
`137
`
`(Contents continued on page 196)
`
`nFr212W 545$
`06-39-1113278
`XL ""‘
`
`IIIIHIII lllllll
`
`IIIIIIIIIIIIIIII
`
`0378-5173 (2o1oo115) 394 : 1/2; 1-1.
`
`Available online at
`
`Tfiejeedirectcom
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`

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`This material may be protected by Copyright law (Title 17 US. Code)
`
`International journal of Pharmaceutics 384 (2010) 1-8
`
`Contents lists available at ScienceDirect
`
`
`
`Review
`
`International journal of Pharmaceutics
`
`journal homepage: www.elsevier.com/locate/ijpharm
`
`
`
`Transungual drug delivery: Current status
`
`Rania Elkeeb M‘ . Ali AliI<han bv‘, Laila Ell<eeb°’1,Xiaoying Hula, Howard 1. Maibacha
`3 Department of Dermatology, School of Medicine, University of California, San Francisco, CA 94143-0989, USA
`“School of Medicine, University of California, Davis, CA, USA
`‘ Department ofDermatology, School of Medicine, University of California. Irvine. CA. USA
`
`
`ARTICLE INFO
`
`
`ABSTRACT
`
`Topical therapy is highly desirable in treating nail disorders due to its localized effects, which results
`in minimal adverse systemic events and possibly improved adherence. However, the effectiveness of
`topical therapies is limited by minimal drug permeability through the nail plate. Current research on nail
`permeation that focuses on altering the nail plate barrier by means of chemical treatments, penetration
`enhancers as well as physical and mechanical methods is reviewed. A new method of nail sampling is
`examined. Finally limitations of current ungual drug permeability studies are briefly discussed.
`© 2009 Elsevier B.V. All rights reserved.
`
`/lm'Cl9’1"5f0Ty-'
`Received 9 June 2009
`Received in revised form
`22 September 2009
`Accepted 1 October 2009
`Available online 9 October 2009
`
`Keywords:
`Ungual drug delivery
`Onychomycosis
`Nail penetration
`Antifungal
`Onychopharmacokinetics
`
`
`Contents
`
`5.2.
`
`5.3.
`
`Introduction ........................................................................................................................................ ..
`1.
`Topical drug delivery to the nail and available formulations ..................................................................................... ..
`2.
`3. Human nail ......................................................................................................................................... ..
`4.
`Nail sampling ....................................................................................................................................... ..
`5.
`Enhancing nail penetration ........................................................................................................................ ..
`5.1. Mechanical methods to enhance nail penetration ......................................................................................... ..
`5.1.1.
`Nail abrasion ............................................................ ..
`
`Nail avulsion ...................................................................................................................... ..
`5.1.2.
`Chemical methods to enhance nail penetration ........................................................................................... ..
`5.2.1.
`N-acetyl-L—cysteine and mercaptan compounds ................................................................................. ..
`5.2.2.
`2-n-nonyl-1,3-dioxolane ......................................................................................................... ..
`5.2.3.
`I(eratoIytic enhancers ............................................................................................................ ..
`5.2.4. Keratinolytic enzymes ............................................................................................................ ..
`Physical methods to enhance nail penetration ............................................................................................ ..
`5.3.1.
`Iontophoresis ..................................................................................................................... ..
`Etching ............................................................................................................................ ..
`5.3.2.
`
`5.3.3.
`Carbon dioxide laser ......................................................................................................... ..
`5.3.4. Hydration and occlusion .......................................................................................................... ..
`New frontiers in physical penetration enhancement ...................................................................................... ..
`5.4.1.
`lasers ............................................................................................................................. ..
`5.4.2.
`Phonophoresis .................................................................................................................... ..
`5.4.3. Ultraviolet light ................................................................................................................... ..
`5.4.4.
`Photodynamic therapy of onychomycosis with aminolevulinic acid ............................................................ ..
`
`5.4.
`
`2
`2
`2
`2
`3
`3
`3
`3
`3
`3
`3
`4
`4
`4
`4
`5
`5
`5
`6
`6
`6
`6
`6
`
`* Corresponding author at: C/O Dr. H.I. Maibach, Department ofDermatology. School of Medicine. UCSF. 90 Medical Center Way. San Francisco, CA 9414-0989.
`USA. Tel.: +1 415 476 4997/7138 8523; fax: +1 415 753 5304.
`.
`E-mailaddresses: relkeeb@yahoo.com (R. Elkeeb). MaibachH@derm.ucsf.edu (H.l. Maibach).
`‘ Rania Elkeeb. Ali Alikhan and Laila Elkeeb have contributed equally to the work.
`
`0378-5173/$ — see front matter © 2009 Elsevier B.V. All rights reserved.
`d°i=10-1016/iiivharm-2009-10-002
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`R. Elkeeb et al./Intemationaljoumal ofPharmaceuti'cs 384 (2010) 1-8
`
`Formulations may improve penetration .............................. ..
`6.
`7. New drugs .................................. .._ ...... ..' ............... ..
`8.
`Limitations of current ungual drug permeability studies ._ ............ ..
`8.1.
`Use of animal hooves as a model for nail penetration ......... ..
`8.2. Use of nail clippings as a model of nail penetration ........... ..
`8.3.
`Super hydration method‘. . . .'....... ..’.......................... ..
`8.4.
`Correlation of in vitro to in vivo studies ....................... ..
`References ............................................................. .
`.
`
`
`\l\l\l\lO‘IO‘)O70‘)
`
`1. Introduction
`
`The importance of nail permeability to topical therapeutics
`has been realized, primarily in the treatment of onychomycosis,
`which affects approximately 19% of the population (Gupta and
`Scher, 1998). Topical therapy is highly desirable due to its localized
`effects, which results in minimal adverse systemic events and pos-
`sibly improved adherence. Recent advances in topical transungual
`delivery have led to the development of antifungal nail lacquers.
`However, the effectiveness of topical therapies is limited by mini-
`mal drug permeability through the nail plate (Baran and Kaoukhov,
`2005). Current research on nail permeation focuses on altering the
`nail plate barrier by means of chemical treatments (Kobayashi et al.,
`1998; Malhotra and Zatz, 2002) and penetration enhancers (Hui et
`al., 2003). Physical and mechanical methods are also under exami-
`nation.
`
`of clinical signs of disease); furthermore, recurrence is common
`after discontinuing therapy (Gupta et al., 2000).
`In Europe, amorolfine and ciclopirox (nail lacquer 8% solution)
`have been approved for onychomycosis treatment. Amorolfine,
`available as a nail lacquer, acts by inhibiting the biosynthesis of
`ergosterol, a component of the fungal cell membranes. Amorolfine
`is fungistatic and fungicidal and most effective against dermato-
`phytes, but can be used for yeast and molds with lesser efficacy
`(Haria and Bryson, 1995).
`The clinical efficacy of amorolfine therapy in 727 patients with
`toenail or fingernail onychomycosis was evaluated. A mycological
`and clinical cure was achieved in 45-50% of the patients treated
`with 5% amorolfine lacquer once or twice weekly for 6 months at 3
`months post-treatment (Zaug and Bergstraesser, 1992).
`
`3. Human nail
`
`2. Topical drug delivery to the nail and available
`formulations
`
`Mycotic nail infections infrequently resolve spontaneously, and
`may have a substantial impact on quality of life. Current treatment
`modalities include surgery, as well as oral and topical antifun-
`gal agents. However, a meta-analysis of randomized trials found
`little high quality evidence that any topical therapy is effective
`(Crawford and Hollis, 2007). Topical therapy is indicated when the
`nail matrix is not involved (in ~74% of patients) (Effendy et al.,
`2005). It is preferred in elderly patients or patients receiving mul-
`tiple medications, in order to minimize drug—drug interactions.
`Topical therapy is also preferred in patients with mild-to-moderate
`disease and for those unwilling to use systemic medications.
`Topical therapy minimizes adverse systemic drug reactions, like
`those associated with oral antifungal agents (Elewski and Hay,
`1996).
`Multiple classes of antifungal medications have been utilized;
`these include: polyenes (e.g. nystatin) which have both fungistatic
`and fungicidal properties in vitro; imidazoles (e.g. clotrimazole, tio—
`conazole, econazole, ketoconazole, miconazole, sulconazole, and
`oxiconazole), which have fungistatic properties in vitro; and ally-
`Permeation studies with modified in vitro diffusion cells com-
`lamines/benzylamines (e.g. naftifine, terbinafine, and butenafine),
`which have fungistatic and fungicidal properties in vitro (Tom and
`monly utilized for flux determination. Drug is initially applied to
`Kane, i999).
`the nail dorsal surface. Permeation is measured by sampling the
`solution on the ventral nail plate at successive time points, and cal-
`Only one topical therapy has been FDA approved for onychomy—
`culating drug flux through the nail. This method bears similarities
`cosis: ciclopirox nail lacquer 8% solution. Ciclopirox inhibits the
`to skin penetration studies. However, skin penetration studies are
`transport of essential elements into the fungal cell, thus disrupting
`not limited simply to determination of flux, but also include the
`DNA, RNA, and protein synthesis. It is a broad-spectrum antifungal
`with activity against dermatophytes and some non—dermatophyte
`separation of skin layers to quantify drug concentration in each
`molds.
`layer.
`Two randomized, controlled trials suggest that complete resolu-
`A novel technique developed by Hui et al. enables the determi-
`tion occurs in approximately 7% of treated patients compared with
`nation of drug concentration within the plate, where fungi reside.
`This method relies on a drilling system which samples the nail core
`0.4% using placebo.Thus, only 1 of 1 5 patients using the lacquer will
`have a favorable outcome which involved reaching a clinically and
`without disturbing its surface (Fig. 1). This is achieved by the use
`of a micrometer-precision nail sampling instrument that enables
`mycologically cured target nail (treatment cure). Treatment cure
`finely controlled drilling into the nail with collection ofthe powder
`comprised of a negative culture and negative potassium hydroxide
`created by the drilling process. Drilling of the nail occurs through
`(KOH) as well as global evaluation score=cleared (l00% clearance
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`The chemical composition of the human nail differs signifi-
`cantly from other body membranes. The plate, composed of keratin
`molecules with many disulphide linkages and low associated lipid
`levels, does not resemble any other body membrane in its bar-
`rier properties — it behaves more like a hydrogel than a lipophilic
`membrane.
`
`Drug transport into the nail plate is influenced by: physico—
`chemical properties of a drug molecule (size, shape, charge, and
`hydrophobicity), formulation characteristics (nature of the vehicle
`and drug concentration), presence of permeation enhancers, nail
`properties (thickness and hydration), and interactions between the
`permeant and the keratin network of the nail plate. The chem-
`ical composition and some experimental evidence indicate that
`the aqueous pathway plays the dominant role in drug penetration
`through the nail. Furthermore, water is the principle nail plasticizer.
`Once hydrated, the nail becomes more elastic and possibly more
`permeable to topically applied substances. However, the effects
`of hydration on nail permeation requires elucidation (Gunt and
`Kasting, 2006).
`
`4. Nail sampling
`
`
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`3
`
`
`
`Fig. 1. The sampling device.
`
`the ventral surface. The dorsal surface and ventrally-accessed nail
`core can be assayed separately. The dorsal surface sample con-
`tains residual drug, while the core from the ventral side provides
`drug measurement at the site of disease. This method permits drug
`measurement in the intermediate nail plate. which was previously
`impossible (Bronaugh and Maibach, 2005).
`
`5.1.1. Nail abrasion
`
`Simply stated, nail abrasion involves sanding of the nail plate
`to reduce thickness or destroy it completely. Sandpaper number
`150 or 180 can be utilized, depending on required intensity. Sand-
`ing must be done on nail edges and should not cause discomfort
`(Di Chiacchio et al.. 2003). An efficient instrument for this proce-
`dure is a high—speed (350,000 rpm) sanding hand piece (Baran et al.,
`2008). Additionally, dentist’s drills have been used to make small
`holes in the nail plate. enhancing topical medication penetration
`(Di Chiacchio et al.. 2003).
`Nail abrasion thins the nail plate, decreasing the fungal mass of
`onychomycosis, and exposing the infected nail bed. In doing so. it
`may enhance the action of antifungal nail lacquer. The procedure
`may be repeated for optimal efficacy (Behl, 1973).
`
`5.1.2. Nail avulsion
`Total nail avulsion and partial nail avulsion involve surgical
`removal of the entire nail plate or partial removal of the affected
`nail plate, and under local anesthesia.
`Keratolytic agents such as urea and salicylic acid soften the nail
`plate for avulsion. Urea or a combination of urea and salicylic acid
`have been used for nonsurgical avulsion (chemical avulsion) in clin-
`ical studies. prior to topical treatment of onychomycosis (Hettinger
`and Valinsky, 1991). Nail abrasion, using sandpaper nail files, prior
`to antifungal nail lacquer treatment may decrease the critical fungal
`mass and aid penetration (Di Chiacchio et al.. 2003 ).
`
`5. Enhancing nail penetration
`
`5.2. Chemical methods to enhance nail penetration
`
`Physical, chemical and mechanical methods have been used
`to decrease the nail barrier. Within each of these broad cate-
`gories. many techniques exist to enhance penetration. Mechanical
`modes of penetration enhancement are typically straightforward,
`and have the most in vivo experience associated with them. In con-
`trast, many of the chemical and physical methods discussed are
`still in the in vitro stages of development; laboratory studies are
`currently examining these techniques using human nail samples.
`The goal of topical therapy for onychomycosis is drug pene-
`tration into deep nail stratums at amounts above the minimal
`inhibitory concentration (MIC). Effective penetration remains chal-
`lenging as the nail
`is believed by some to be composed of
`approximately 25 layers of tightly bound keratinized cells. I00—fold
`thickerthan the stratum corneum (SC) (Hao and Li, 2008b). Further-
`more, De Berker et al. have observed increase in toe nail thickness
`along the nail. Mean nail plate thickness increased progressively
`along the entire length of the nail ranging between 590 um and
`1080 um (De Berker et al.. 1996). While there is disagreement on
`the exact thickness of the nail there is consensus that the nail struc-
`ture is difficult to penetrate. In addition, poor permeability and
`prolonged transport lag time contribute to disappointing topical
`efficacy in nail diseases (Hao and Li, 2008b).
`Chemical and physical modes of penetration enhancement may
`improve topical efficacy. There are two main factors to consider:
`physicochemical properties of the drug (polar compounds are more
`permeable) and binding of the drug to keratin within the nail. Bind-
`ing to keratin reduces availability of the active (free) drug, weakens
`the concentration gradient, and limits deep penetration (Murthy et
`al., 2007b).
`
`Studies examining the efficacy of chemical compounds with
`transungual penetration properties are currently underway. As
`would be expected, skin penetration enhancers do not usually have
`the same effect on nails (Walters et al.. 1985). Thus far. only a few
`chemicals which enhance drug penetration into the nail plate have
`been described.
`
`5.2.1. N—acetyl-L—cysteine and mercaptan compounds
`Kobayashi et al. demonstrated that N—acetyl-L—cysteine and 2-
`mercaptoethanol. in combination, enhanced permeability of the
`antifungal drug tolnaftate into nail samples (I(obayashi et al., 1998).
`They suggested that these compounds may be generally useful in
`enhancing drug permeation across the nail plate.
`Hoogdalem et al. evaluated the penetration—enhancing proper-
`ties of N—acetyl-L—cysteine with the antifungal drug oxiconazole in
`vivo. N—acetyl-L—cysteine promoted oxiconazole retention in upper
`nail layers (Hoogdalem et al., 1997).
`Malhotra and Zatz screened nail penetration enhancers, includ-
`ing: mercaptan compounds, sulfites, bisulfites. keratolytic agents
`and surfactants in vitro. N—(2-mercaptopropionyl) glycine. demon-
`strated superior penetration enhancement to all other compounds,
`urea acted synergistically to increase nail permeation to the great-
`est extent (Malhotra and Zatz, 2002). However, post—treatment
`barrier integrity studies demonstrated that changes induced in
`the nail keratin matrix by these effective chemical modifiers were
`irreversible. It is believed that these enhancers act by breaking
`disulphide bonds, which are responsible for nail integrity thus pro-
`ducing structural changes in the nail plate (Malhotra and Zatz,
`2002; Murdan, 2007).
`
`5.1. Mechanical methods to enhance nail penetration
`
`Mechanical methods including nail abrasion and nail avulsion,
`have been used by dermatologists and podiatrists for many years —
`with varying results. Additionally, they are invasive and potentially
`painful. Thus, current research focuses on less invasive chemical
`and physical modes of nail penetration enhancement.
`
`5.2.2. 2—n-nonyl-1,3-dioxolane
`Hui et al. have showed that 2-n-nonyl-1.3—dioxolane (SEPA®)
`enhances penetration of econazole (from a lacquer formulation)
`into the human nail (Hui et al., 2003). They demonstrated that
`econazole penetrates the nail six times more effectively in a lacquer
`containing 2—n—nonyl—1,3-dioxolane than in an identical lacquer
`without enhancer. Concentrations of econazole in the decay nail
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`layer and nail bed were significantly higher in the ‘enhancer’ group
`than in the control group. Furthermore, in the ‘enhancer’ group,
`econazole concentration in the deep nail layer was 14,000 times
`greater than the MIC necessary to inhibit fungal growth.
`
`5.2.3. Keratolytic enhancers
`Guerrero et al. described the effect of keratoiytic agents (papain,
`urea, and salicylic acid) on the permeability of three imida-
`zole antifungal drugs (miconazole, ketoconazole, and itraconazole)
`(Quintanar-Guerrero et al., 1998). In the absence of l<eratolytic
`agents, no transungual antifungal permeation was detected over
`a period of60 days. Despite these findings, it is likely that the spec-
`trophotometric method of analysis was insufficiently sensitive to
`accurately measure drug concentrations.
`Permeation of these agents did not improve by pre—treatment
`with 20% salicylic acid (for 10 days) and the addition of 40% urea to
`the donor solution. However, pre—treatment with both 15% papain
`(for 1 day) followed by 20% salicylic acid (for 10 days), enhanced
`antimycotic permeation. Presence of ethanol (as a co-solvent) did
`not promote flux. Although ethanol is an effective skin permeation
`enhancer, it does not have a similar effect on the nail. Ethanol acts
`on the SC by altering intercellular lipids; however, the lipid con-
`tent of the nail comprises just 0.15—0.76% of its total weight. The
`authors proposed that aggressive pre—treatment (with papain and
`salicylic acid) produced pore formation in the nail matrix, allow-
`ing for effective drug permeation which was supported by the SEM
`images they obtained.
`Brown et al. investigated the effect of two novel penetration
`enhancers (PEs), thioglycolic acid (TA) a reducing agent and urea
`hydrogen peroxide (urea H202) an oxidizing agent on the in vitro
`nail permeability of penetrants of varying lipophilicity caffeine,
`methylparaben and terbinafine. TA increased the flux of CF and MP
`~4— and ~2—fold, respectively. while urea H202 proved ineffective
`at enhancing permeability. Effects of the PES were penetrant spe-
`cific, but the use of a reducing agent (TA) followed by an oxidising
`agent (urea H202) dramatically improved human nail penetration
`while reversing the application order of the PEs was only mildly
`effective. Both nail PEs are likely to function via disruption of
`keratin disulphide bonds and the associated formation of pores
`that provide more ‘open’ drug transport channels (Brown et al.,
`2009).
`
`5.2.4. Keratinolytic enzymes
`Due to an abundance of keratin filaments, keratinic tissues like
`the SC, are effectively hydrolyzed by keratinase (Gradisar et al.,
`2005).
`Mohorcic et al. hypothesized that keratinolytic enzymes may
`hydrolyze nail keratins, thereby weakening the nail barrier and
`enhancing transungual drug permeation. This group conducted
`permeation studies using modified franz diffusion cells and met-
`formin hydrochloride as a model drug and found keratinase to
`markedly enhance drug permeation through bovine hoof mem-
`branes (Mohorcic et al., 2007).
`In another study, human nail clippings were incubated in kerati-
`nase for 48 h. and subsequently examined with scanning electron
`microscopy. Keratinase clearly disrupted the nail plate, acting on
`both the intercellular matrix that holds the cells of the nail plate
`together and the dorsal nail corneocytes by corroding their surface
`(Mohorcic eta1.,2007).
`
`5.3. Physical methods to enhance nail penetration
`
`Physical permeation enhancement may be superior to chemi-
`cal methods in delivering hydrophilic and macromolecular agents
`(Murthy et al.. 2007b). We discuss several physical enhancement
`methods, both established and experimental.
`
`lontophoresis
`5.3.1.
`lontophoresis involves delivery of a compound across a mem-
`brane using an electric field (electromotive force). The principle
`has been applied clinically for cutaneous anesthesia. hyperhidrosis
`management, antibiotic penetration, and herpes simplex treat-
`ment (Kassan et al., 1996). Currently both LidoSite® (lidocaine
`HCI/epinephrine topical iontophoretic patch) and GlucoWatch®
`(iontophoretic measurement of glucose in diabetics) are FDA
`approved. lontophoresis has been used for various applications
`different from transdermal ophthalmic, dental, orthopaedic. etc.
`(Horwath—Winter et al.. 2005; Nowicki et al.. 2002; Chen et al.,
`2008). Drug diffusion through the hydrated keratin of a nail may
`be enhanced by iontophoresis.
`Several factors contribute to this enhancement: electrorepul-
`sion/electrophoresis, interaction between the electric field and
`the charge of the ionic permeant; electroosmosis, convective sol-
`vent flow in preexisting and newly created charged pathways;
`and permeabilization/electroporation, electric field-induced pore
`induction(Murthy etal., 2007b; Hao and Li, 2008b).While transport
`enhancement of neutral permeants relies on electroosmosis, trans-
`port enhancement ofi