This material may be protected by Copyright law (Title 17 U.S. Code)
`
`J. DRUG DEL. SCI. TECH., 24 (3) 301-310 2014
`
`Transungual drug delivery: an update
`H.N. Shivakumar1,2, MA Repka3, S. Narasimha Murthyl, 3*
`
`'Institute for Drug Delivery and Biomedical Research (IDBR), Bangalore, India
`'Department of Pharmaceutics, KLE University's College of Pharmacy, Bangalore, India
`'Department of Pharmaceutics, The University of Mississippi, University, MS-38677, United States
`*Correspondence: murthy@olemiss.edu
`
`Topical therapy continues to be the treatment of choice for the patients and clinicians in treating certain infections of the nails. Topical treat-
`ment is widely accepted as an adjunct with oral therapy to improve the cure rates, reduce the treatment duration, cut down the treatment cost and
`enhance the therapeutic outcomes. However, effectiveness of topical therapy continues to pose a challenge owing to the poor permeability of the
`nail plate to many therapeutic agents and the prolonged treatment periods. Research over the past one decade has been focused to improve the
`transungual permeation using chemical penetration enhancers, mechanical methods and physical methods. Disrupting the dorsal surface of the
`nail by treating with penetration enhancers or etching agents or abrasion or filing of the nail plate has proved to drastically improve the efficacy
`of topical therapy. The present review is an effort to update the different chemical enhancers and etching agents used to enhance the transungual
`permeability.
`
`Key words: Transungual Onychomycosis — Penetration enhancers — Etching agents — Screening methods.
`
`I. NAIL:ANATOMY
`The human nail apparatus is made of nail folds, nail matrix, nail
`plate and the nail bed. The nail folds are the wedge-shaped fold of the
`skins surrounding the sides of the nail plate. The nail fold present at
`the proximal end of the nail is termed as the proximal nail fold while
`those situated on either sides of the nail are called the lateral nail folds
`(Figure 1).
`The dorsal surface of the proximal nail fold covers a part of the
`nail matrix and continues as the eponychium or the cuticle [1]. The
`nail folds that form soft keratinized flaps are made up of cornified
`epithelium which is similar to the normal skin. The nail matrix that
`is present just beneath the proximal nail plate basically consists of
`living, rapidly multiplying epidermal cells. The nail matrix is seen as
`a semilunar area totally recessed under the proximal nail fold or may
`extend as the lanula that may be more evident on the thumb and the
`toes rather than the fingers. The nail plate originates from the highly
`germinative nail matrix and is found to cover almost the entire nail
`bed. The nail plate is a hard, elastic, translucent and convex structure
`made of about 25 layers of flattened, dead, keratinized tightly bound
`cells and ranges in thickness of 0.25 to 0.6 mm. The nail plate is dif-
`ferentiated into the upper dorsal, the middle intermediate and the inner
`ventral layer that differ in thickness in a ratio of 3:5:2 respectively [2].
`The dorsal layer is hard, whereas germinative epithelial intermediate
`layer is softer and more flexible. The ventral layer is soft and connects
`the nail plate to the underlying nail bed. The dorsal surface of the nail
`plate is considered to be the rate limiting barrier for the permeation of
`topically applied therapeutics. The human nail is uniquely designed
`as it is curved along the transverse as well as the longitudinal axes
`[3]. The unique design and composition of the nail plate contributes
`to its strength and physical characteristics.
`
`Figure 1 - Different parts of the nail apparatus.
`
`301
`
`The nail plate contains 7 to 12 % of water under normal ambient
`conditions that maintains the opacity, elasticity and flexibility of the
`nail while the content may increase to about 25 % at a relative humid-
`ity (%RH) of 100 % [4]. The nail plate also contains traces of lipids
`(0.1-1.0 %), composed of long chain fatty acids, free fats, cholesterol,
`squalene and phospholipids that are organized as bilayers and oriented
`parallel to the nail surface in the dorsal and ventral layers of the nail
`plate [5]. The dorsal and ventral layers of the nail plate contains
`relatively higher amounts of calcium, phospholipids and sulphydryl
`groups while the intermediate layer has more number of disulphide
`bonds but lower number of bound sulphydryl groups, phospholipids
`and calcium. The size, shape, thickness, surface ridging, curvature
`and the flexibility of the nail plate tends to vary within and among
`individuals depending on the site, age, disease states and seasons [1].
`Nail bed is found to have a rich supply of nerves and lymphatic vessels
`and appears pink in color due to the underlying vascular network [6].
`
`II. DISEASES OF THE NAIL
`The two most common infectious diseases that can affect the
`nails are onychomycosis and nail psorioisis. Onychomycosis is the
`fungal infection of the nail that contributes to 50 % of the total nail
`disorders [7]. The main pathogens in 90 % of these cases is usually
`Trichophyton rubrum while the other causative organisms include
`yeasts mainly Candida albicans and non-dermatophyte moulds. The
`infection is more prevalent in certain groups like the elderly, diabetics,
`miners and sports-active individuals. [8]. The other risk factors are
`immunosuppression owing to human immunodeficiency virus (HIV)
`infections, cancer and other atopic disorders. Based on the part of the
`nail affected and the pathophysiology, onychomycosis may be: (i)
`distal subungual which involves infection of the nail plate tip and the
`underlying nail bed; (ii) proximal subungual that affects the cuticle
`and the nail bed; (iii) superficial infection which is confined only to
`the nail plate; (iv) total dystrophic that infects the whole nail [9]. The
`infected nails appear ugly, discolored and thickened thereby posing
`serious cosmetic, medical social and emotional problems [10].
`Onychomycosis is an infection that is difficult to treat since it is
`chronic, hard to eradicate and tends to commonly relapse. The only
`treatment option for onychomycosis in the past was surgical avulsion of
`the nail that would be extremely traumatic and painful [11]. However,
`currently the infection is treated with systemic and/or local antifungal
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`J. DRUG DEL. SCI. TECH., 24 (3) 301-310 2014
`
`Transungual drug delivery: an update
`H.N. Shivakumar, M.A Repka, S. Narasimha Murthy
`
`agents, considering the severity, patient population and choice, and
`cost effectiveness [12]. Systemic treatment involves prolonged oral
`dosing of powerful antifungal agents while the topical treatment is
`indicated only in cases where few nails are involved [13]. Moreover,
`the topical monotherapy, is generally recommended in the treatment
`of mild and distal infections, for superficial white onychomycosis
`and in cases where the nail matrix may not be involved [14]. Despite
`multiple therapeutic options, treatment failure has been common as
`about 20 % of the patients fail to respond to treatment due to which
`onychomycosis is considered as a "stubborn clinical problem" [15].
`The therapeutic failures are due to the indiscriminate and extensive
`use of systemic antifungals which have increased the numbers of
`emerging resistant strains. Owing to the development of resistant
`strains, relapse of onychomycosis is common with a recurrence rates
`varying from 10 to 53 % [16].
`Nail psoriasis is the other important disease of the nail that is found
`to be prevalent in 80-90 % of the patients with skin psoriasis which
`affects about 1 to 3 % of the total population [17]. The nail matrix,
`nail plate, and nail folds may get affected by psoriasis rendering the
`nails pitted, transversely ridged or thickened. Nail loss can also result
`in some cases from active shredding due to nail bed disease such as
`onycholysis or subungual hyperkeratosis [1]. Nail psoriasis warrants
`long term treatment durations and it is difficult to cure . The main treat-
`ment for psoriasis of nail plate is topical steroids vitamin D analogs,
`and 5-fluorouracil (5-FU), [18]. Systemic treatment for psoriatic nail
`has been recommended when the disease affects the skin or in case
`the function and quality of life has been drastically affected by the
`disease. In severe conditions, steroid injections are used while the
`other treatment options like superficial radiotherapy and electron beam
`therapy are found to be useful in some cases.
`For many years the human nail plate was considered to be an
`impermeable barrier and the only treatment modalities adopted by
`clinicians were systemic therapy or surgical avulsion of the affected
`nail prior to topical application. Unfortunately systemic administration
`of antifungals would be hampered by the limited blood circulation to
`the affected nail bed leading to sub-therapeutic concentrations at the
`infected sites. The low drug concentration at the infected site invari-
`ably needs high oral doses of the drug for prolonged periods [19].
`The high oral doses have been associated with severe adverse effects
`but most often the clearance of the infections has been temporary. In
`this context, the oral therapy in the treatment of nail disorders suffers
`from several limitations owing to severe side effects, contraindications,
`toxicities, drug interactions and long treatment periods that eventually
`incurs high treatment cost [20].
`In contrast, the topical therapy to the nail would be an attractive
`therapeutic option as it obviates the systemic adverse effects and
`drug interactions commonly associated with oral therapy. The topical
`therapy has been the treatment of choice in children under 2 years
`due to its high efficacy owing to the low thickness of the nails. The
`topical treatment options remains inevitable when systemic treatment
`is strictly contradicted as in case of pregnant women [1]. Topical
`therapy is often recommended by clinicians in combination with oral
`therapy (Booster treatments) to improve the cure rates, reduce the
`treatment duration, cut down the treatment cost and thereby enhance
`the therapeutic outcomes [4].
`The fate of the drug following topical application to the surface of
`the nail plate has been pictorially portrayed in Figure 2.A significant
`pre-absorptive loss is prone to occur following topical application
`of the formulation due to routine day-to-day activities. In addition,
`considerable amount of the drug may get bound to the keratin of the
`nail plate, eventually reducing the amount of drug delivered to the nail
`bed. Therefore, in order to maintain therapeutic drug concentrations
`at the target site, the rate at which the drug is delivered to the nail
`bed must suffice for the loss owing to tissue binding, metabolism and
`systemic clearance from the nail bed [21].
`
`Topical
`Formulation
`
`Pre absorptionJoss
`
`Permeability Coefficient
`
`Nail Thickness
`
`Keratin Cement
`
`Drug-keratin Binding
`
`4:110
`
`411110
`
`Tissue Metabolism Systemic
`Gradation
`Binding (cid:9)
`issilssue (cid:9)
`
`Figure 2 - The fate of the drug following topical application of the drug
`to the nail plate.
`
`Figure 3 -The Franz diffusion cell with the nail adapter used for ungual
`permeation studies. The right side picture shows the individual parts.
`
`III. IN VITRO TRANSPORT STUDIES
`In order to predict the permeation of the therapeutic agents into
`and across the human nail plate a number of in vitro models have
`been developed and assessed. The in vitro data generated is a valid
`predictor of the in vivo performance of the topical nail products. The
`data also serves as a useful index to compare the newly developed
`topical products and helps to optimize the composition of the topical
`nail products. The vertical Franz Diffusion Cells (FDC) set up used
`at present to determine the permeability of the nail plate is as shown
`in portrayed in Figure 3.
`The barrier across which permeability has to be assessed is mounted
`on a custom made nail adapter usually made of Teflon. The nail
`adapter with the nail plate is sandwiched between the donor and the
`receptor compartments of the vertical FDC. Hoof membranes sourced
`from bovine [22], porcine [23], Horse [24], or sheep [25], are used as
`barriers to predict the permeation across the nail plate. In addition to
`these, keratin films [26] , nail clippings from healthy human volunteers
`[27] and human cadaver nail plates [28] are also used as barriers for
`the in vitro studies. The solution of the permeant is charged into the
`donor compartment while the receptor compartment is composed of
`a suitable buffer measuring about 5 mL. The contents of the receptor
`compartment are maintained at a temperature of 37 °C and a stirring
`speed of 600 rpm with a magnetic bead. The drug permeated across
`the barrier is determined at predetermined time points during the
`study. The drug loaded following the in vitro permeation studies into
`the barrier is determined by estimating the drug content of the barrier.
`
`IV. FACTORS INFLUENCING THE DRUG
`PERMEATION ACROSS THE NAIL PLATE
`By virtue of its thickness, unique chemical composition and rela-
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`
`Transungual drug delivery: an update
`H.N. Shivakumar, M.A. Repka, S. Narasimha Murthy
`
`J. DRUG DEL. SCI. TECH., 24 (3) 301-310 2014
`
`lively compact and dense nature, human nail is known to considerably
`hinder the penetration of topically applied drugs .The clinical evidence
`documented so far has suggested that the success in treatment of fungal
`nail infections by topical antifungals lies in effectively overcoming
`the barrier of the nail plate [4] .The diffusion of the topically applied
`therapeutic agents is determined by the physicochemical properties
`of the permeant, formulation characteristics, presence of permeation
`enhancers, nail properties and interaction between the permeant and
`the nail keratin [29] _Some of the important factors are discussed below
`
`1. Molecular size
`Smaller molecules are known to penetrate well through the nail
`plate compared to the larger molecules. The dense keratin network is
`known to increase the path length of the permeant owing to its greater
`pore tortuosity. In addition, penetration rate would drop owing to the
`increased friction between the between the diffusing molecules and
`the keratin network as the molecular size of the permeant increases.
`Attempt was made to establish a meaningful correlation between the
`molecular weight of a series of therapeutic agents and the permeability
`coefficient. Further, the correlation established was used to predict the
`therapeutic efficacy of a series of antimycotics considering the aque-
`ous solubility and minimum inhibitory concentration (MIC) [30]. An
`inverse relationship is known to prevail between permeability of nail
`plate for several model permeants and the molecular size of diffusing
`molecules [31]. Generally, molecules that exceed 300 Daltons in size
`may face hindrance while permeating the nail plate and therefore are
`likely to demonstrate a poor clinical efficacy [32].
`
`2. Polarity of the permeant
`The human nail is known to behave like a hydrogel with a high
`ionic strength to the diffusing molecules. However, owing to the traces
`of lipids in the nail plate (-1 %), researchers speculate the possibility
`of existence of a minute lipid pathway that could assist the transport
`of lipophilic molecule across the nail plate. By and large, the permea-
`tion of the molecules through the nail plate is dictated by the partition
`coefficient of the diffusing molecule. The permeation of homologous
`alcohols (C2 to C5) across the nail plate was found to decrease with
`increase in the hydrophobicity or the alkyl chain length [33]. The
`reduction in the permeation of the long chain alcohols was ascribed to
`the hydrophilic nature of the nail plate. However, the better transport
`of extremely long chain alcohols like decanol and dodecanol was
`attributed to the utilization of the lipid pathway prevalent in the nail
`plate by these molecules. In this context, lipid formulations which
`have the potential to exploit the lipid pathway have been proposed
`off late for lipophilic therapeutic agents [34, 35].
`
`3. Nature and pH of the vehicle
`The human nail is found to be 1000 times more permeable to water
`than the skin [36]. Permeability studies across cadaver nail plates
`indicated that the permeability coefficient of water was found to be
`approximately three times higher for water compared to ethanol sug-
`gesting that hydrated nail is more permeable to water than to ethanol
`[33]. The nail is known to swell and soften on contact with water or
`a hydroalcoholic solution. As a result, the keratin network is likely to
`expand leading to the formation of larger pores that would ease the
`transport of the permeant across the nail plate.
`The pH of the aqueous vehicle along with the pKa value of the
`permeant determines the extent of ionization and therefore its aqueous
`solubility. Generally, acidic compounds are in the ionized or soluble
`state at higher pH values while the basic compounds are more soluble
`at low pH values. The saturation solubility and hence the thermody-
`namic activity of the drug is determined by the pH of the aqueous
`vehicle in such cases. The amount of drug permeated across the nail
`plate is eventually a function of its thermodynamic activity in the
`vehicle. Based on this hypothesis, aqueous solvents are considered
`
`to be ideal for lipophilic drugs whereas hydrophilic drugs require
`lipophilic solvents in order to ensure a high thermodynamic activity
`[37]. However, considering hydrophobic nature of most antimycotics
`agents, lipophilic vehicles have been investigated in the past for topi-
`cal applications to the nail [38]. Though the lipophilic vehicles fail to
`neither hydrate or soften the nail plate nor expand the keratin network,
`they have been successful in enhancing the transport of certain drugs
`across the nail plate.
`
`4. Surface charge of the permeant
`The charge the permeant carries is known to determine its diffu-
`sion through the nail plate [39]. The nail keratin having an isoelectric
`point (pi — 5.0), is known to carry a net positive charge at a pH values
`below 5.0 while it bears a negative charge at a pH values higher than
`5.0. It is likely that a negatively charged molecule is repelled from
`the nail surface at pH values of above 5.0 while a positively charged
`molecule is repelled at pH values lower than 5.0. The electrostatic
`interaction between the charged nail surface and the surface charge
`of the diffusing ions is termed as "Donnan effect" [21].
`
`5. Nail plate effect
`The nail plate is known to be about 100 times thicker than the
`stratum corneum of the skin though both the membranes are rich in
`keratin [4]. Due to its thickness, the nail plate is known to pose con-
`siderable obstacle to the transport of permeants to the infected nail
`bed. Further, nails infected with onychomycosis are found to be thicker
`than the healthy human nail plates due to the presence of the fungi
`and owing to the damage caused. An inverse relationship is known to
`exist between the thickness of the nail plate and the penetration of the
`topically applied therapeutic agents. Wetting of the nail plate or filing
`of the nail plate surface was found to cause a significant increase in
`the TOWL, which is usually considered as a measure of permeability
`through the nail plate [40]. Abrasion of the dorsal surface of the nail
`plate was found to increase the permeation of terbinafine hydrochlo-
`ride (THC) by — 4 fold, which proved that the dorsal layer is the rate
`limiting barrier for the transport of permeants [41]. Filing or vigorous
`debridement of the dorsal surface of the nail prior is likely to enhance
`the success of the topical therapy [42].
`
`V. METHODS TO ENHANCE TRANSUNGUAL DRUG
`DELIVERY
`A better understanding of the barrier properties on the nail plate
`has been helpful to rationally design topical formulations that can
`improve the ungual and trans-ungual delivery of therapeutic agents.
`Topical therapy is the most preferred mode of transungual drug de-
`livery as it is noninvasive and helps in regional delivery of actives
`to the infected sites. It has to be noted that most of the transdennal
`permeation enhancers have proved to be ineffective in enhancing the
`transungual drug delivery owing to the low lipid content in the nail
`plate (0.1-1 %) when compared to that in the skin (-10 %). Owing
`to its thickness, compactness and unique composition, the nail acts
`as a formidable barrier to the penetration of topically applied drugs.
`Further, binding of the drug to the nail plate keratin further decreases
`the free (active) drug and eventually the concentration gradient thereby
`limiting the drug penetration into deeper tissues [39]. Despite these
`constraints, the drug penetration into the nail plate can be improved
`using agents that break the physical and chemical bonds that maintain
`the integrity of the nail plate keratin. The disulfide, peptide, hydrogen
`and polar bonds in the nail plate keratin appear to be potential soft
`targets which could be breached by transungual penetration enhancers
`[43]. Exploiting this attempts have been made to enhance the efficacy
`of topical therapy using chemical penetration enhancers and etching
`agents.
`The transungual chemical permeation enhancers identified till date
`can be classified into:
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`J. DRUG DEL SCI. TECH., 24 (3) 301-310 2014
`
`Transungual drug delivery: an update
`H.N. Shivakumar, MA Repka, S. Narasimha Murthy
`
`1) solvents:
`a) water,
`b) other solvents: dimethyl sulfoxide (DMSO), methanol;
`2) keratolytic agents: urea, salicylic acid, papain, etc.;
`3) thiolytic agents:
`a) thiols: N-acetylcysteine, thioglycolic acid ,2-mercaptoethanol,etc.,
`b) sulfites: sodium sulfite, sodium metabisulfite etc.,
`c) hydrogen peroxide;
`4) enzymes: keratinase;
`5) etchanting agents:
`a) phosphoric acid,
`b) tartaric acid;
`6) miscellaneous penetration enhancers:
`a) inorganic salts,
`b) hydrophobins,
`c) dioxalane,
`d) polyethylene glycols,
`e) lipid vehicles.
`
`1. Solvents as permeation enhancers
`1.1. Water
`The trace amount of lipids in the nail plate and good number of
`experimental evidences has collectively indicated that the aqueous
`pathway plays a predominant in the penetration of drug through the
`nail plate [29]. Water is known to be the principle plasticizer present
`in the nail plate that imparts a certain degree of opacity, elasticity and
`flexibility to the nail. The degree of hydration of the nail is known to
`govern the permeability of the nail plate as demonstrated in number
`of studies. Nail plate has a tendency to hydrate, soften and swell
`similar to hydrogels on coming in contact with aqueous solutions.
`The permeability coefficients of the homologous alcohol diluted with
`saline was found to be five-fold higher when compared to the neat
`alcohols suggesting the facilitating role of water in increasing the
`permeation of water soluble permeants through the human nail plate
`[44]. Further, the permeation of methanol a hydrophilic alcohol and
`n-hexanol a hydrophobic alcohol was reduced when the proportion
`of water in the donor solution was decreased. A five-fold drop in the
`permeability coefficient of n-hexanol was noted as the concentration
`of dimethyl suphoxide in the binary mixture with water was increased
`to 86 % [45]. A similar reduction in the permeability coefficient of
`n-hexanol was observed when the donor contained traces or no water
`in isopropanol-water binary mixture. The decrease in the permeation
`of the two solutes on depletion of the water in the donor clearly con-
`firmed the role of water in promoting the permeation of compounds
`of varied polarity through the nail plate.
`The permeability of the nail plate at different states of % RH, has
`shown that diffusivity of water increased logarithmically by nearly 400
`folds as the % RH increased from 15 to 100 % [46]. Scanning electron
`microscopy (SEM) analysis undertaken recently has revealed that
`hydration of the finger nails was found to increase the pores size and
`promote the interconnection of the pores that in turn could enhance the
`drug transport. Mercury intrusion porosimetric (MIP) studies further
`confirmed the modification in the porous microstructure of the nail
`plate [47].
`The hydration of the nail was found to play a key role in tran-
`sungual delivery of topically applied water insoluble actives as well.
`The effect of hydration of the nail plate on the in vitro permeation of
`ketoconazole a poorly water-soluble drug through excised human nails
`was assessed [48]. The steady state flux of radiolabeled ketoconazole
`which was solvent carted on the nail plate increased by nearly three-
`fold as the % RH to which the nails were exposed increased from 15
`to 100 % with a drastic 2-fold enhancement as the % RH increased
`from 80 to 100 %. Considering the poor aqueous solubility of keto-
`conazole, the increased flux can be explained by increased flexibility
`and structural expansion of the keratin matrix on hydration with
`
`water, that would have allowed the high molecular weight (Mol. wt:
`531.44) to diffuse with ease. The results conclusively suggested that
`the formulations or treatment modalities that improve the nail hydra-
`tion have the potential to improve the penetration of topically applied
`therapeutic agents. Considering the ability of water to enhance the
`transportof topically applied actives across the nail plate, water soluble
`nail lacquers composed of hydrogels were developed for molecules
`of vivid polarity [22, 49-51].
`
`1.2. Other solvents
`Dimethyl sulfoxide (DMSO) is known to interact with the lipid
`domains of the stratum corneum thereby increasing their fluidity and
`promoting the partitioning of drug into the skin. Though, the solvent
`is not expected to demonstrate the same efficacy as a transungual
`penetration enhancer, considering the traces of lipids in the nail plate,
`there are few papers that report increase in the transungual penetration
`with DMSO. DMSO was found to increase the penetration of topi-
`cally applied antimycotics [52]. Further, pretreatment of the nail with
`DMSO was found to increase the penetration of amorolfine [53]. A
`maximum penetration depth of one fourth the depth of the total nail
`plate was observed compared to other lipophilic solvents in a human
`subject study when DMSO was used as an enhancer [54].
`The depth of penetration of urea, salicylic acid and ketoconazole
`into the human nail plate from test formulations containing DMSO was
`2-fold higher compared to control formulations containing saline [55].
`With salicylic acid in particular, greater amount of drug was bound
`to the dorsal surface of the nail plate for the control that limited the
`drug availability to the deeper areas. On the contrary, higher amount
`of salicylic acid was delivered to deeper areas of the nail plate with
`the formulation composed of DMSO.
`An increase in permeation of the caffeine across cadaver human
`nail plate was noted when DMSO or methanol was used as an enhancer
`in formulations [56] . The test formulations of caffeine (2 %w/v) with
`DMSO (5 %) or methanol (5 %) in either water or 20 % v/v ethanol
`while the reference formulations had similar compositions but were
`devoid of any enhancers. When DMSO was used as an enhancer, the
`permeability coefficients of caffeine increased by -.33 and 2-fold in
`ethanolic and aqueous systems respectively, when compared to the cor-
`responding reference formulations. Likewise, the caffeine loaded into
`the nail plates following the permeation studies were 155 and 1.18-fold
`higher for ethanolic and aqueous systems respectively, in presence of
`DMSO compared to the corresponding reference formulations.
`Similarly, in presence of methanol, the permeability coefficients
`of caffeine through the human cadaver nail plate increased by a factor
`of 4.8 and 3.2 fold for ethanolic and aqueous systems respectively
`when compared to the corresponding reference formulations. Corre-
`spondingly, the caffeine content in the nail plate after the permeation
`studies increased by —1.7 and 1.61-fold from ethanolic and aqueous
`systems respectively for the test formulations compared to the cor-
`responding references. The surface topography revealed an increase
`in the roughness of the dorsal nail surface treated with the test for-
`mulations compared to that treated with the reference formulations.
`The mechanism of action of DMSO and methanol as a transungual
`penetration enhancer continues to remain unclear though the authors
`attribute the penetration enhancement to the depletion of the lipids
`present in the dorsal surface of the nail plate.
`
`2.Keratolytic agents
`Keratolytic agents are known to disrupt the tertiary structure
`and the hydrogen bonds present in the keratin thereby enhancing the
`permeation of therapeutic agents through the nail plate. These agents
`are known to act by softening and swelling the nail plate especially in
`presence of water [37]. The swelling and softening of the nail plate is
`likely to enhance the drug permeation as a consequence of formation
`of a less dense keratin structure with large pores.
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`Transungual drug delivery: an update (cid:9)
`H.N. Shivakumar, MA Repka, S. Narasimha Murthy
`
`J. DRUG DEL SCI. TECH., 24 (3) 301-310 2014
`
`The effect of keratolytic agents like papain, urea and salicylic acid
`on the in vitro permeation of miconazole nitrate, ketoconazole and
`itraconazole through human nail were studied [57]. The permeation
`studies across nail plates carried out in side by side diffusion cells with
`60 % ethanol as donor and receiver fluid indicated no permeation of
`the three antimycotics in 60 days in the absence of keratolytic agents.
`Moreover, a 'single-step pretreatment' with salicylic acid (20 %) alone
`for 10 days nor addition of urea (40 %) to the donor solution failed
`to induce any permeation of the antimycotics. However, a "2-step
`pretreatment" with papain (15 %) for one day followed by salicylic
`acid (20 %) for 10 days resulted in a steady state flux of 6.66 x 105,
`1.15 x !Wand 0.13 x 105mg/cm2/s for miconazole nitrate ,ketoconazole
`and itraconazole respectively with an effective diffusion constants of
`629 x 108,3.60 x 108 and 3 x 108 cm2 sec.', respectively. Further, the
`lag times for miconazole, ketoconazole and itraconazole were found
`to be 32.15, 56.22 and 67.5 min, respectively. SEM revealed that the
`"2-step pretreatment" procedure was found to damage and fracture
`the dorsal nail surface, which in turn would have created pathways
`for drug penetration.
`Concentrated solutions of urea and salicylic acid have been used as
`hydrating and softening the nail in topical treatment of onychomycosis.
`The benefits of using urea (40 %) for non-surgical nail avulsion are
`low risk of infection, hemorrhage, a quick improvement after avulsion
`and absence of pain during and after treatment. In clinical trials, urea
`in combination with salicylic acid was found to effective in increasing
`the penetration of bifonazole penetration into the nail plate [58].
`Urea and salicylic acid are known to increase the permeation
`of tritiated water through human nail in combination with N-(2-
`mercaptopropionyl) glycine from aqueous gel formulations [59] . Urea
`in combination with other cysteine derivatives is reported to improve
`the penetration of penneants from aqueous formulations through hu-
`man nail [43]. Cysteines are thiols that act on disulfide bonds in the
`nail keratin whereas urea acts on the hydrogen bonds to facilitate the
`cleavage of disulfide linkages. Urea (20 %) in combination with N-
`acetyl cysteine (NAC) (5 or 10 %) was found to enhance the in vitro
`permeation of miconazole nitrate through the nail plate by 2 to 25
`fold. Further, the concentration of miconazole in the nail following
`the studies exceeded the MIC [60].
`
`3. Compounds that cleave the disulfide bonds
`3.1. Thiols
`Thiols are a group of compounds containing sufhydryl groups (-SH)
`that have shown promise as transungual penetration enhancers. The
`mechanism involved in the enhancement of the transungual permeation
`is