J. DFIUG DEL SCI. TECH. 24 (3} 301-310 2014
`
`i T
`
`his material may be prolected thupyrlgltl law {Title 1? US. Code]
`
`Transuugual drug delivery: an update
`
`HN. Shivakumar'-z, MA Repka3, S. Narasimha Murthyh’“
`
`'lnstirute for Drug Delivery and Biomcdical Research (IDBR). Banylorc. India
`chpm-tmcnt of Pharmaceutics KLE University’s College of Pharmacy. Bangalore, India
`’Dopartmcnt of Pharmaceutics. The University of Mississippi. University, his-3867?. United Sistcs
`*Corrcspondcncc: murthy®olcmissodu
`
`Topical therquy contimtes to be the trmunettt of choicefor the patients and clinicians in treating certain infections oft-he nails. Topical treat—
`ment is widely accepted as an adjunct with oral therapy to improve the cure rates. reduce the treatment duration. ctrt down the treatment cost and
`enhance the therapeutic outcomes. However: efectt'veness cftopt'cal therapy continues to pose a challenge owing to the poorpemeohility afthe
`nail plate to many therapeutic agents and the prolonged rrcmnt periods. Research over the past one decade has beenfocused to improve the
`transungttai pemeation using chemical penetration enhancers. mechanical methods andphysicai methods. Disrrqpting the dorsal surface afthe
`rmii by {mating with penetration enhancers or etching agents or abrasion orfiling ofthe nailplate has proved to drastically improve the cjfimt')‘
`aftopimt therapy. The present review is an efl'ort to update the difiersnt chemical enhancers and etching agents used to enhance the trmungml
`permeability.
`
`Key words: Transmgucl — Onychomycosis — Penetration enhancers — Etching agents - Screening methods.
`
`I. NAJL‘ANATOMY
`The human nail apparatus is made of nail folds. null matrix. nail
`plate and the nail bed. The nail folds are the wedgc-shapcd fold of the
`skins surrounding the sides of the nail plate. Thc nail fold present at
`the proximal end of the call is tanned as tho proximal mall fold while.
`most: situated on either sidcs ofthe nail arc called the lateral uajl folds
`(Figm i].
`The dorsal stufacc of the. proximal nail fold COVCI’S a part of the
`nail matrix and continues as the eponychium or the cuticle [l].Thc
`nail folds that form soft keratinized flaps are made up of cornified
`epithelium which is similar to the normal skimThc nail matrix that
`is present just bcncuth the proximal nail platc basically consists of
`living. rapidly multiplying spider-Incl cells. Thc nail matrix is soon as
`a sernilunat area totally rcccssod under the proximal nail fold or may
`extend as the lauula that may bc more evident on tho thumb and the
`toes rather than the fingers. The nail plate originates from the highly
`genuluadve 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. kcratinizcd tightly bound
`cells and ranges in thickness of 025 to 0.6 mm. The nail placc is dif-
`ferentiated into the upper dorsal .thc middle intermediate and tho inner
`ventral Iaycrthat differin thickness in a ratio of3:5:2 respectively [2].
`The dorsal layer is hard, whereas gct'tninativc epithelial intcnnndiale
`layer is softer and more flexiblcil'he Ventral layer is soft and com-toms
`the nail plate to the underlying nail bed. The dorsal surfaoc ofthe nail
`plate is considered to be the rate limiting barrier for the permeation of
`topically applied drenpeutics. The human nail is uniquely designed
`as it is curved along d1: msvcrsc as well a the longitudinal axes
`{3] . The unique dwign and composition of the nail plate conu-ihulcs
`to its smgdt and physical characteristics.
`
`
`
`
`Figure 1 - Different ports or the nail apparatus.
`
`The nail plate contains 7 to 12 9’0 of water under normal ambient
`conditions that maintains the opacity, elasticity and flexibility of the
`null while. the content may increase to about 25 do at a rclativc humid-
`ity ('56an of [DO % [41.1113 nail plate also contains traces of lipids
`(U. I l (l ‘35). composed oflong chain fatty acids, fiufats.cholcstcro|.
`squalcne and phospholipids that one organism as hilayers and oriented
`parallel to file nail surface[[1 the dorsal and ventral layers of the nail
`plan: [5]. The dorsal and ventral layers of the nail plate: contains
`relatively higncr amounts of calcium. phospholipids and sulphydryl
`groups while the intermediate layer has more number of disulphide
`bonds but lower numbct 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 [I].
`Nail bed is found to have a rich supply ofnerves and lymphatic vessels
`and appears pink in color due to the underlying vascular network [6].
`
`ll. DISEASES OF THE NAIL
`The two most common infectious discascs that can affect the
`nails are ouychomycosis and nail psorioisis. Ouychoruyoosis is the
`fungal infection of the nail that contributes to 50 9% of the total nail
`disorders [7]. The main pathogens in 9G ‘5: of these cases is usually
`Trichoplvton rubrtun while the timer causative organisms include
`yeasts mainly Candida ethical-ts and non—dcrmalophytc moulds. The
`infection is more provalcnt in ccnaiu groups like drealderlyfilabetics.
`miners and sports—active individuals. [8}.1116 other risk factors arc
`immunosupprcssiou owing to human immunodeficiency virus (HIV)
`infcctions. cancer and other atopic disordm. Based on the part of the
`nail affected and the pathophysiology. onychomycosis my be: (i)
`distal subungual which involves infection of the nail plane tip and the
`underlying nail bed: (ii) proximal subunguul 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 trail [9]. The
`iufocncd nails appear ugly. discolored and thickened thereby posing
`serious cosmetic. medical social and emotional problems [l0].
`Onychomycosis is an infection that 'Is difficult to [teat since it is
`chronic. hard to cradicatc and tends to commonly relapse. The only
`treammnloption fotonychomyoosisin the psstwas surgical avulsion of
`the nail that would becxu'cmely traumatic and painful [l 1]. However.
`currently the infection is treated widr systemic andlor local audfuugal
`
`301
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`

`J. DRUG DEL. SCI.TECH.. 24(31301-3102014
`
`Transmgual' drug delivery: an update
`H. N. Shivakumal: MA. Repka. S. Narasimha Mutthy
`
`
`
`agents, considering the severity. patient population and choice. and
`cost effectiveness [12]. Systemic treatment involves prolonged oral
`dosing of powerful antifungal agents whiIc the topical treatment is
`indicated only in cases where t‘ew nails are involved [[3] . 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 [[4]. Despite
`multiple therapeutic options. treatment failure has been common as
`about 20 % of the patients fall to respond to treatment due to which
`onychornycosis 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 S3 ‘35: [16}.
`Nail psodasis is the other important disease of the nail that is found
`to be prevalent in 80—90 We of the patients with skin psoriasis which
`affects about 1 to 3 % of the total population [1?]. The nail matrix.
`nail plate, and nail folds may get affected by psoriasis rendering die
`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 hypcrkeratOSis [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~tluorouracil (S-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 afiected by the
`disease. In severe conditions. steroid injections are used while the
`othertreatment 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
`impenneable ban-let and the only treatment modalities adopted by
`clinicians were systemic therapy or surgical avulsion of the affected
`nail priorto 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 owingto severe side effects.contra.i ndications.
`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 diet-apeutlc 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
`pro-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 die amou nt of drug delivered to the nail
`bed. Therefore, in order to maintain therapeutic drug concentrations
`at the target site, the rate at which file 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].
`
`T‘nsuc
`Binding
`
`Sme‘
`Met-wim-
`in'l'hmo Won
`
`Figure 2 - The fate of the drug following topical application of the dmg
`to the nail plate.
`
`
`
`
`
`
`brethren-um
`
`Figure 3 - The Franz difiusion cell with the nail adapter used for ungual
`permeation studies. The right side picture shows the individual parts.
`
`III. IN WTRO TRANSPORT STUDIES
`In order to predict the permeation of die therapeutic agents into
`and across die 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 viva performance of die 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 pcnneability has tobeassessed 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 oftbe 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 composod of
`a suitable buffer measuring about 5 mL. The contents of me receptor
`compartment are maintained at a temperature of 37 0C 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.
`
`W. FACTORS INFLUENCING THE DRUG
`PERMEATION ACROSS THE NAIL PLATE
`By virtue of its thickness, unique chemical composition and rela—
`
`302
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`

`

`Transmgual drug delirium an update
`HEN. fitnekm'tar. MA. Rooks. S. Natasimha Mitrthy
`
`J. DRUG DEL. SCI. TECH. 2d {3) 1301-3102014
`
`tively compact and dense nature, human nail is known to considerably
`hinder-the penetrationoftopicallyapplieddrugs.’l‘hcclinicalevidenoc
`docu mentedso farhas suggested thatthe success in treatmenroffungal
`nail infections by topical anrifungals lies in effectively overcorrtirlg
`the barrier of the nail plate [4] .The diffusion of the topically applied
`drerapeutic agents is determined by the physioochemical properties
`of the permeant, formulation characteristics, presence ofpcrmearion
`enhancers, nail properties and utter-action between the pcrmeant and
`lltenail keratin [29] .Some ofthe important factors arediseussed 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
`brown to inm‘ease the path length of the penneant 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 perineum increases.
`Attempt was made to establish a meaningful correlation between the
`molecular weight ofa series oftherapeutic agents and the permeability
`coefficient. Fuflher,the correlation established was used to predict the
`therapeutic efficacy ofa 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 pennants 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 poorclinical efficacy [32].
`
`2. Polarity of the permeant
`The human nail is known to behave like a hydrogel with a high
`ionic strength to the difl’using molecules. However,owingto the Ill-aces
`of lipids in the nail plate (~l %), 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 largenhe permea-
`tion of the molecules through the nail plate is dictated by the partition
`coefficient of the diffusing moleculc.The permeation of homologous
`alcohols (C2 to C5) across the nail plate was found to decrease with
`increase in the hydmphobicity or the alkyl chain length [33]. The
`reduction in the pcrtueationof the long chain alcohols was ascribed to
`the hydmmilic namre 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 forlipophilic therapeutic agents [34. 35].
`
`3. Nature and pH of the vehicle
`The human nail is found robe [000 times more permeable to warm-
`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 wawr compared to ethanol sug-
`gestingthathydrasednailismorepermeahletowsterdtautoefltanol
`[33]. The nail is known to swell and soften on contact with wateror
`a hydroalcoholic solution. As a result, the keratin network is likely to
`expand leading to the formation of larger pores that would case due
`transport of the penneant across the nail plate.
`The pH of the aqueous vehicle along with the pKa value of the
`penneant determines the extent ofionizatiou and dietefore its aqueous
`solubility. Generally, acidic compounds are in the ionized or soluble
`state at higherpH 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
`lipopltilic 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 thenail plate norexpand the keratin network.
`they have been successful in enhancing the nansport of certain drugs
`across the nail plate.
`
`4. Surface charge of the mount
`The charge the penneant carries is known to dctennine its diffu-
`sion through the nail plate [39].The nail keratin having an isoclectric
`point (pl ~ 5.0), is knovtm to carry a net positive charge at a pH values
`below 51] while it bears a negative charge at a pH values higherthan
`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 tanned as “Donnan effect" [21].
`
`5. Nail plate effect
`The nail plate is known to be about [00 times thicker than the
`stratum cor-newt: of the skin though both the membranes are rich in
`keratin [4]. Due to its ducimess.thc nail plate is known to pose con-
`siderable obstacle to the transport of porn-reams to the infected nail
`bed.Furlher,nails infected wim onychomycosis arefound robe thicker
`than the heraldry human nail plates due to the presence of the fungi
`and owing to the damage caused. Au inverse relationship is known to
`exist between the thickness oflhe 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 10W]... which is usually considered as a measure of permeability
`through the nail plate [40]. Abrasion of the dorsal smface of the nail
`plate was found to increase the pennearion of tethinafine hydrochlo-
`ride (THC) by ~ 4 fold, which proved that the dorsal layer is the rate
`limiting banier for the transport of penrteanls [41]. filing or vigorous
`debridcment of the dorsal surface of the nail prior is liluely to enhance
`the success of the topical therapy [42].
`
`V. METHODS TO ENHANCE THANSUNGUAL DRUG
`DELIVERY
`A better understanding oflhe barrier properties on the nail plate
`has been helpful to rationally design topical formulations that can
`improve the ungual and trans-Lingual delivery ofWrit: agents.
`T0pical 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 u-ansderrnal
`permeation enhancers have proved to be ineffective in enhancing the
`transungual drug delivery owing to the low lipid content in the nail
`plate (OJ-l %) when compared to that in the skin (~l0 ‘59). Owing
`to its thickness. compactness and unique composition, the nail acts
`as a fonnidable barrier to the penetration of topically applied drugs.
`Further, binding of the drug to the nail plate keratin funherdecreases
`thefree(active)drug andevenniallytheconcentrationgradienrdlereby
`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 beme by o-ansungua] penetration enhancers
`[43]. Exploiting this attempts have been made to enhance the efficacy
`of topical therapy using chemical penetration enhancers and etching
`agents.
`The Ltansungual chemical permeation enhancers identified tilldate
`can be classified into:
`
`

`

`J. DRUG DEL SCI. TECH. 24 (3) 301-310 2014
`
`Transongual drug WW: an cadets
`H.N. Sitivalrtrmar; MA Raptor. S. Natasimha Mirth)!
`
`l) 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.drioglyoolicacid,2—mercaptoethanol,etcu
`b} sulfites: sodium sulfite. sodium metabisulfite etc.,
`c) hydrogen peroxide;
`4) enzymes: keratinase;
`5) enchanting agents:
`a) phosphoric acid,
`b) tartaric acid;
`6} miscellaneous penetration enhancers:
`a) inorganic salts.
`b) hydrophobins,
`c) dioxalarte,
`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 dnrg 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.Thc 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 soltttions.
`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 dimcthyl suphoxide in the binary minute with water was increased
`to 86 % [45L A similar reduction in the permeability coefficient of
`n—hexancl was observed when the donor cantaincd traces or no water
`in isopropanol-waner binary mixnuefl'he decrease in the permeation
`of the two solutes on depletion of the water in the danor 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 near-U400
`foldsasthe %RHiucreasedfrom lSto [00 %[46].Scanningelecn-ort
`microscopy (SEM] analysis undertaken recently has revealed that
`hydration of the finger nails was found to increase the pores size and
`promotedie interconneaion of the pores that in turn could enhancedie
`drug transport. Mercury intrusion porosimctric (MIP) studies further
`confirmed the modification in the porous microstmcture 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 penneation of
`ketocooazolea poorly water—soluble drug through excised human nails
`was assessed [481.Thc steady state flux of radiolabcled ketoconazole
`which was solvent casted on the nail plate increased by nearly direc—
`foldasthefiiRHtowhich thenails mesposedincreased from l5
`to 100 96 with a drastic 2-fold enhancement as the ‘3: RH increased
`from 80 to [00 %. Considering the poor aqueous solubility of ketc-
`oonazole. the increased flux can be explained by increased flexibility
`and mutual expansion of the keratin matrix on hydration with
`
`water, that would have allowed the high molecular weight (Mol. wt:
`531.44) to diffirse with ease.‘I'he 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 or:
`transportoftopically applied activesacrosa the nail plate,water soluble
`nail lacquers composed of hydrogcls we develOped for molecules
`of vivid polarity [22,49-5l].
`
`1.2. Other solvents
`
`Dimethyl sulfoxide (DMSO) is known to interact with the lipid
`domains of the stratum con-rem 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 u-ansungual
`penetration enhancer. considering the traces of lipids in the nail plate,
`there arefew papers that report increase in then-ansurrgual penetration
`with DMSO. DMSO was found to increase the penetration of topi—
`cally applied autimycotics [52]. Further, pretreatment of the nail with
`DMSO was found to increase the penetration of amorolfine [531.A
`maximum penetration depth of one fourth the depth of the total nail
`plate was obseerd compared to other lipophilit: solvents in a human
`subject study when DMSO was used as an enhancer [54].
`The depth of penetration of urea. salicylic acid and ltctoconazole
`into diehuman nail platefrom testformulations containingDMSO was
`2-fold higher oomparedtoconnol formulations containing saline [55] .
`With salicylic acid in particular, greater mm of dmg was bound
`to die dorsal surface of the nail plate for the control that limited the
`drug availability to the deeper areas. 0n 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 usedas an enhancer
`in formulations [56]. The test formulations of caffeine (2 %wlv) with
`DMSO (S '52) or methanol (5 9b) in either water or 20 94.1 vr'v ethanol
`while the reference formulations had similar compositions but were
`devoid ofany enhanca's.When DMSO wasusedasanenhanceedre
`permeability coefficients of (caffeine increased by ~33 and 2-fold in
`ethanolicand aqueous systems respectively. whencompared tothe cor-
`responding reference fonnulations. LikewiseJhe caffeine loaded into
`the nail platesfollowing the permeation studies were l55andl.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
`ofcaffeioe 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 componding reference formulations. Corre-
`spondingly, the caffeine content in the nail plate after the permeation
`studies increased by ~15? and [oi-fold from edianolic and aqueous
`systems teapectively for the test formulations compared to the cor-
`responding references. The surface topography revealed an increase
`in the roughnfis of the dorsal nail surface heated with the test for-
`mularions compared to that treated with the reference formulations-
`The mechanism of action of DMSO and medianol as a n'ansungual
`penetration enhancer continues to remain unclear though the audiots
`attribute die penetration enhancement to the depletion of the lipids
`present in the dorsal surface of the nail plate.
`
`2.Keratolytlc agents
`Keratolytic agents are known to disrupt the tertiary structure
`and the hydrogen bonds present in the keratin thereby enhancing die
`permeation of therapeutic agents through the nail plate. Them agents
`are known to act by softening and smelling 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 offonnation
`of a less dense keratin structure with large pores.
`
`

`

`Transunguai‘ drug detiveqc an update
`HEN. Shwakumar, MA Repka. S. Narasrhrha Martin!
`
`.l. DRUG DEL SCI. TECH. 24 (3) nor-31o 2014
`
`The effect of licratolytic agents like papain, ureaand salicylic acid
`on the in vitro moon of rniconazole nitrate. ketoconazole and
`inaconazole drmugh human nail were studied {57]. The permeation
`studies across nail plates carried out in side by sided'rffusion cells with
`60 % ethanol as donor and receiver fluid indicated no permeation of
`the three antimyeotics in 60 days in the absence of keratolytic agents.
`Moreover,a ‘s ingle-steppreoeatment’ with salicylic acid (20 '5») alone
`for ID days nor addition ofurea (-10 fir) to the donor solution failed
`to induce any permeation of the antimyootics. However, a “2-step
`pretreatment" with papain (15 its) for one day followed by salicylic
`acid (20 ‘32) for [0 days resulted in a steady state flux of6.66 x105,
`1.15 x10’aad0J3 x lo’mplcm‘ts formieonazolenitrateketoconazole
`and itraconazole respectively with an effective diffusion constants of
`629 x 10'. 3.60 x10' aad3 x 10‘ cm2 sec", respectively. Further. the
`lag times for miconazole, ketoconazole and innconazole were found
`to be 32.15. 56.22 and 675 min, respectively. SEM revealed that the
`“2-step preueaorrent” procedure was found to damage and fracture
`the dorsal nail surface, which in turn would have creased pathways
`for drug penetration.
`Concentrated solutions ofureaand salicylic acid have been usedas
`hydratingandsofiening the nailin topical treatment ofonychomycosis.
`The benefib of using urea {40 %) for non—surgical nail avulsion are
`low risk of infection,hemorrhage,aqtlick improvement afheravulsion
`and absence of pain during and after nutrient. In clinical trials, urea
`in combination with salicylic acid was found to effective in increasing
`the penetration of bifouazole penetration into the nail plate [58].
`Urea and salicylic acid are known to increase the permeation
`of tritiated water dlrough human nail in combination with N-(Z-
`mercapropmpionyl) glycine from aqueous gel formulations [59].Ureu
`in combination with othercysteine derivatives is reported to improve
`the penetration of pennearns from aqueous formulations though hu-
`man null [43]. Cysteines are thiols that act on disulfldc bonds in the
`nail keratin whereas urea acts on the hydrogen bonds ID facilitate the
`cleavage of disulfide linkages. Urea (20 %) in combination with N»
`acetyl cysteine (NAC) (5 or 10 %) was found to enhance the in mm
`permeation of rniconazrole nitrate through the nail plate by 2 to 25
`fold. Further, the concentration of miconazole in the nail following
`the studies exceeded me MIC [60].
`
`3. Compounds that cleave the dieullide bonds
`3.1.Thiols
`‘Ihiolsareagroupofcompoundscontainingsuflrydrylgroups(—SH)
`that have shown promise as transungual penetration enhancers. The
`mechanism involvedinflicenhaneementofthe transungual permeation
`is the reduction of the disulfide linkage in the nail keratin matrix as
`shown below [60]. 'I‘hiols are Imown to get oxidized while reducing
`the disulfidc linkage of the nail keratin asshown in Equation 1:
`
`Nail-S-S-Nail -t— R-SH (-3- 2 Nail-SH + R-Séi—R
`
`Eq. 1
`
`where Nail-S-S-Nail represents for the dieullidc linkage of the nail
`plate keratin while R-SH stands for a thiol. The reduction of the
`keratin is known to destabilize the disulphide bonds, compromise the
`barrier integrity oflhe nail plate and thereby promote the transungual
`permeation [61]. Thiols are found to be more effective in aqueous or
`hydroalcoholic vehicles which tend to hydrate, swell and soften the
`nail plate. Once the disulfide bonds are broken, they are less likely to
`be reformed in the dead nail plate and hence the action of the thiols
`as transu ngual penetration enhancers is irreversiblefllrioloompounds
`which have been investigated as u-ansungual penetration enhancers
`are pyrithione (P10), N—CZ-mercaptopropionyl) glycine (MPG).
`N—acetyl cysteine (NAG), cysteine. 2-mmpt0ethanol (MPE) and
`thioglycolic acid (TGA).
`Thiol compounds like P10 and MPG Were found to act as