Insights into drug delivery across the nail plate barrier

http://informahealthcare.com/drtISSN: 1061-186X (print), 1029-2330 (electronic)

J Drug Target, 2014; 22(9): 769–789! 2014 Informa UK Ltd. DOI: 10.3109/1061186X.2014.929138

REVIEW ARTICLE

Insights into drug delivery across the nail plate barrier

Manish V. Saner, Abhijeet D. Kulkarni, and Chandrakantsing V. Pardeshi

Department of Pharmaceutics, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, North Maharshtra University,

Maharashtra, India

Abstract

Topical therapy is at the forefront in treating nail ailments (especially onychomycosis and nailpsoriasis) due to its local effects, which circumvents systemic adverse events, improves patientcompliance and reduces treatment cost. However, the success of topical therapy has beenhindered due to poor penetration of topical therapeutics across densely keratinized nail platebarrier. For effective topical therapy across nail plate, ungual drug permeation must beenhanced. Present review is designed to provide an insight into prime aspects of transungualdrug delivery viz. nail structure and physiology, various onychopathies, techniques of nailpermeation enhancement and in vitro models for trans-nail drug permeation studies. Updatedlist of drug molecules studied across the nail plate and key commercial products have beenfurnished with sufficient depth. Patents pertinent to, and current clinical status of transungualdrug delivery have also been comprehensively reviewed. This is the first systematic critiqueencompassing the detailed aspects of transungual drug delivery. In our opinion, transungualdrug delivery is a promising avenue for researchers to develop novel formulations, augmentingpharmaceutical industries to commercialize the products for nail disorders.

Keywords

Nail permeation, nail plate, onychomycosis,penetration enhancement, topical therapy,transungual drug delivery

History

Received 3 April 2014Revised 9 May 2014Accepted 25 May 2014Published online 25 June 2014

Introduction

Humans and animals alike are commonly plagued by the

infiltration of microorganisms beneath the nail [1]. Topical

therapeutics are desirable in the treatment of nail ailments like

onychomycosis, a fungal nail infection, and nail psoriasis.

These nail ailments are widely spread in the population,

among elderly and immunocompromised patients. The topical

treatment is an attractive option owing to its non-invasiveness,

drug targeting to the site of action, elimination of adverse

effects associated with systemic therapy, thereby raising the

patient compliance and cutting back the treatment costs.

However, topical therapy had limited success, primarily due

to poor permeability of the nail plates to the topically applied

therapeutics. For effective topical therapy across nail plate,

ungual drug permeation must be enhanced [2].

Certainly, enhancement of ungual drug permeation can be

accomplished by physical techniques (iontophoresis, acid

etching, carbon dioxide laser, hydration and occlusion,

electroporation, UV-light, photodynamic therapy, sonophor-

esis/phonophoresis), mechanical methods (nail avulsion and

nail abrasion) or by use of various chemical penetration

enhancers (sulfites, mercaptans, hydrogen peroxides, urea,

water, keratolytic agents, keratinolytic enzymes). In the past

decade or so, several findings have been reported for

transungual delivery of ticonazole [3], econazole [4],

oxiconazole [5], ketoconazole [6,7], sertaconazole [8],

miconazole [9], terbinafine [10–12], ciclopirox [13], and so

on. The increased attention of researchers in this particular

area may be ascribable to the infancy in the field, launch and

success of several commercial topical antifungal nail lacquers

like Loceryl�, Penlac�, Curanil�, and the obvious opportu-

nities for research and development of new products in this

previously neglected area.

There are but few reports highlighting the crucial aspects

of ungual and transungual drug delivery and associated

limitations. Present review is a state-of-the-art collection of

prominent facets that embodies the anatomy of nail apparatus,

factors affecting drug transport into and through the nail plate,

various diseases of nails, in vitro models to study transungual

drug permeation and methods of nail penetration enhance-

ment. Furthermore, various drug formulations studied, till

date, across the nail plate and key commercial products

marketed for nail disorders also contributes to the outline of

this review. List of chemical enhancers has been updated to

the most recent one. Patents pertaining to transungual drug

delivery have also been listed systematically, for the first time.

No literature available at present stating the current clinical

perspectives on transungual drug delivery and our efforts are

first endeavor in this direction. The prime objective behind

designing of this manuscript is to present these latest updates

before the scientific community.

Address for correspondence: Chandrakantsing V. Pardeshi, AssistantProfessor, Department of Pharmaceutics, R. C. Patel Institute ofPharmaceutical Education and Research, Shirpur (425405), Dist.-Dhule, Maharashtra, India. Tel: +91 2563 255189. Fax: +91 2563251808. E-mail: [email protected]

To reach to a valid conclusion, authors desires to mention

here that the field of transungual drug delivery is relatively

young, and vibrant and is a promising avenue for researchers

to develop novel topical formulations for transungual drug

delivery, augmenting pharmaceutical industries to commer-

cialize the products for topical therapy of nail disorders.

The human nail apparatus: structure and physiology

The nail apparatus, as illustrated in Figure 1, is composed of

the proximal nail fold (PNF), nail matrix, nail bed, and the

hyponychium, which altogether formulates the nail plate. The

nail plate (corpus unguis), produced mainly by the matrix,

emerges via PNF and is held in place by lateral nail folds.

It covers the nail bed and detaches from the latter at

hyponychium (skin under the free edge of the nail plate)

[14]. The nail plate is a thin (0.25–1 mm), hard, slightly elastic,

translucent, convex-shaped structure and is made up of

approximately 80–90 layers of dead, keratinized, flattened

cells which are tightly bound to one another via numerous

intercellular links, membrane-coating granules, and desmo-

somes. Based on the differential ultrasound transmission, the

nail plate can be divided into three macroscopic layers, namely

dorsal, intermediate and ventral. The dorsal layer is few cells

thick, while intermediate layer is softer, more flexible and

represents the thickest layer of the nail plate. The ventral layer

is very thin (consists of only 1–2 cells thick), and it connects the

nail plate to the underlying nail blade [14,15]. Often within the

proximal aspect of the nail plate, most notably on thumbs, are

the white crescent-shaped areas, called lanulae. Rich vascular

network of the underlying nail bed imparts visibly pink color to

the dorsal surface of nail unit [16]. According to Kobayashi

et al. [17], the thickness ratio of nail plate layers (dorsal,

intermediate, and ventral) is 3:5:2, respectively. On average,

the dimensions of the flattened corneocytes in the upper nail

layer are 34� 60� 2.2 mm, while those in the lower nail layer

are thicker, at 40� 53� 5.5 mm.

The chemical composition of the nail plate is depicted in

Table 1 [1]. Chemically, nail plate consists mainly of the

fibrous proteins, keratins, 80% of which are of ‘‘hard’’ hair

type keratin while the remainder is of ‘‘soft’’ skin type keratin

[18]. The hair-type keratin filaments are only concentrated in

intermediate nail layers, whereas skin-type keratin filaments

are found in the dorsal and ventral layers [19]. The keratin

filaments are thought to be held together by globular,

cysteine-rich proteins, whose disulfide links act as ‘‘glue’’

and responsible for the toughness and barrier properties of

nails [20]. The nail plate contains 7–12% of water under

normal conditions while the water content can rise up to 35%

at a relative humidity of 100%. Water content is important for

elasticity, flexibility, and opacity of the nail [21,22]. The nail

plate also contains very small amounts of lipids (0.1–1%),

Figure 1. The schematic illustration of nail apparatus. Reprinted from [16], with kind permission of the copyright holder, Elsevier, Amsterdam.

Table 1. Chemical composition and other characteristicsof nail plate [data from 1].

Characteristics Normal values

Water content 9–35%Lipid content 0.1–1%Disulfide linkage 10.60%Thickness 50–1000mMaximum swelling capacity 25%Water loss rate 1.94 mg/cm2/h

770 M. V. Saner et al. J Drug Target, 2014; 22(9): 769–789

which are organized as bilayers, oriented parallel to the nail

surface and concentrated in the dorsal and ventral nail layers

[23,24].

The nail matrix (matrix unguis) (a highly proliferative

epidermal tissue), along with minor contribution from the nail

bed, forms the entire length of the nail plate (Figure 2). It is

likewise called the nail root and lies beneath the PNF. Cell

division of nail matrix results in continuous development of

onychocytes (nail plate cells), which grows throughout the

life [25]. The nail matrix also contains melanocytes, which

pigment surrounding keratinocytes and appears as longitu-

dinal bands across the nail plate, which are often easily visible

in dark-skinned individuals [26].

The PNF has a dorsal and a ventral epithelial surface. It is a

continuation of the skin of each digit (the dorsal surface) that

folds underneath itself, resting above the nail matrix

(the ventral surface) as shown in Figure 1. At the junction

between dorsal and ventral surfaces, there exists the

eponychium (cuticle), which serves to seal off the potential

space between the PNF and the nail plate, shielding the matrix

from environmental damage [26].

The nail bed (area underneath the nail plate) is a thin, soft

and non-cornified epithelium that extends from the lanulae to

the eponychium. The nail bed serves as a holder and slide for the

growing nail plate and plays a predominant role in forming

deeper layers of the nail plate. In relation to other nail

structures, there is a noticeable decrease in cell division among

the keratinocytes within the epidermis of the nail bed [27]. Rich

vascular network of the underlying nail bed imparts visibly pink

color to the dorsal surface of the nail unit. In addition, the nail

bed is well perfused with lymphatic vessels [28].

The hyponychium is situated underneath the free edge of

the nail plate. Anatomically, it indicates the transition of the

nail bed to the normal epidermis of the fingers and toes.

A component of the hyponychium, that reflects onto the

ventral surface of the nail plate called ‘‘onychodermal band’’.

This band serves to protect the nail parenchyma from the

outside environment by providing a barrier to chemical agents

and infectious organisms.

The growth rate of nails is highly variable from individual

to individual. The average growth rate is 3 mm per month for

fingernail and 1 mm per month for toenail. A fingernail grows

out completely in around 6 months while a normal toenail in

12–18 months [20]. The growth rate of nails is highly

influenced by various factors viz. age (ageing slows the rate),

gender (growth rate is higher in males), climate (slower in

cold climate), dominant hand (growth rate is faster), preg-

nancy (faster), diseased condition (the rate may be increased

or decreased; rate is faster in psoriasis, slower in fever),

malnutrition (slower), drug administration (may increase or

decrease the rate) [14].

Physiologically, human nails have been developed to grasp

and manipulate objects. It protects the terminal phalanx and

fingertip from traumatic injury. Nails also provide enhance-

ment of fine touch and fine digital movements and also aid in

scratching and grooming. Nails are often modified or

decorated to become a cosmetic accessory. Nails are also

capable of conveying information about individual’s social

standing [29].

Disease targets for transungual drug delivery

Nails can suffer from a very wide array of diseases which can

range from relatively harmless conditions like pigmentation as

in case of heavy smokers to more painful, and devastating

conditions characterized by dystrophied, hypertrophied,

inflamed or infected nails [28]. Most commonly occurring

nail diseases and their description have been presented in Table

2 [26,30]. The two most common infectious diseases affecting

the nail apparatus are onychomycosis (a fungal infection of the

nail plate and/or nail bed) and nail psoriasis.

Onychomycosis

Onychomycosis (Tinea unguium) is a fungal nail infection,

which accounts for about 50% of nail disorders. It affects

approximately 5% of the population worldwide [31,32]. The

principal pathogens are dermatophyte fungi (Trichophyton

rubrum, T. interdigitale, and T. mentagrophyte,

Figure 2. Schematic representation of subdivisions of nail matrix and their contribution to different layers of the nail plate. The dorsal section (a) of thenail matrix contributes to the most superficial layers of the nail plate whereas the intermediate region (b) of the nail matrix forms the deeper layers.The ventral subdivision (c) is the most distal part of the nail matrix and it is contributed by the nail bed. Reprinted from [16], with kind permission ofthe copyright holder, Elsevier, Amsterdam.

DOI: 10.3109/1061186X.2014.929138 Drug delivery across the nail plate barrier 771

Epidermophyton floccosum), the non-dermatophyte molds

(Scopulariopsis brevicaulis and Scytalidium dimidiatum), and

yeasts (Candica albicans) [33]. Majority (90–95%) of the

infections are caused by dermatophytes, while the rest being

caused by yeast and molds. Toenails are affected more than

fingernails [34]. Onychomycosis is found to be more preva-

lent in elderly patients and diabetics [35]. The other risk

factor associated with onychomycosis are immunosupression,

as in Human Immunodeficiency Virus (HIV) infection and

cancer, and atopic disorders. Therefore, the incidence of

onychomycosis seems to increase due to rising elderly

population, extensive use of immunosuppressant in infections

with HIV. Current lifestyle factors such as wearing of tight-

fitting clothings, use of communal recreational facilities and

health clubs have too led to the increased prevalence of

onychomycosis [36–39].

Clinically, onychomycosis can be categorized into four

types depending on the site of infection and pathophysiology:

namely (i) distal and lateral subungual onychomycosis: fungal

infection begins at hyponychium and distal or lateral nail bed,

(ii) superficial white onychomycosis: fungal infection begins

at nail plate and white chalky patches appears on the nail

plate, (iii) proximal subungual onychomycosis: fungal infec-

tion invades via PNF and penetrate the nail plate, producing

white discoloration in the lanulae, (iv) total dystrophic

onychomycosis: entire nail plate and nail bed are attacked

by the fungus and this is the endpoint of all forms of

onychomycosis [40].

Clinical diagnosis of onychomycosis is based on the

patient’s history, physical examination, direct microscopy,

and culture of nail specimens. Direct microscopy serves

only as a screening technique for the presence or absence

of fungi; culture can actually assist in differentiating among

the pathogens and identifying the etiological agents [32].

Onychomycosis is difficult to treat since it is chronic, hard

to eradicate and tends to relapse. In the past, surgical avulsion

was the only treatment option for onychomycosis. Surgical

avulsion, is, however, extremely traumatic and painful [41].

Treatment of onychomycosis is known to be challenging;

failure to achieve ‘‘disease-free nail’’ is fairly common with

one course of therapy [42] and a high relapse rate (22.2%) is

reported by Tosti et al. [43]. Such treatment failure has been

attributed to a possible lack of diagnostic accuracy, incorrect

antifungal or delivery strategy, presence of dormant spores

(not killed by antifungals, thereby acting as a reservoir of

fungus and germinate to relapse the infection, after

the conclusion of the treatment), concentrated zones of

fungi (into which drug diffusion is inadequate) or resistant

fungi [44]. Currently, the pharmacotherapy for onychomy-

cosis involve the use of systemic (terbinafine, itraconazole,

fluconazole, griseofulvin, etc.) and topical (amorolfine,

ciclopirox, tioconazole, etc.) antifungal agents, either alone

or in combinations, depending on the severity of the

condition. Mechanical treatments (surgical/mechanical nail

avulsion or debridement) are also on current treatment

strategy options. Topical treatment avoids problems asso-

ciated with systemic therapy. However, in case of former,

drug diffusion into highly keratinized nail plate is poor

and duration of treatment is long. Currently, topical therapy

is recommended only in early stages of the disease and

when only a few nails are affected, due to its limited success

rate [2].

Table 2. Most commonly occurring nail diseases and their description [26,30].

Disease/disorder Description

Onychomycosis It is a fungal nail infection caused by dermatophytes, yeasts or non-dermatophyte molds. The prevalence rate ofonychomycosis is determined by age, occupation, social class, climate and living environment.

Nail psoriasis It is characterized by pitting (presence of small shallow holes in the nail plate), nail fragility, crumbling and nail loss.It may also result in onycholysis (separation of the nail plate from the nail bed), subungual hyperkeratosis, splinterhemorrhages and paronychia (inflamed and swollen nail folds).

Nail patella syndrome It is also known as HOOD (hereditary onycho-osteodysplasia) syndrome. It is a genetic disorder and the majorhallmarks of this syndrome are poorly developed fingernails and toenails. The lack of growth or complete absence offingernails results from the mutations in the LMX1B gene.

Subungual hematoma It is a collection of blood underneath a fingernail or toenail. It is sometimes known as runner’s toe or tennis toe. It maybe caused by horizontal separation of the nail plate from the nail bed. It is characterized, clinically, by reddish-blackdiscoloration of the nails. The nail plate may also get more compact and more brittle as a consequence of the injury(onychochauxis).

Beau’s lines Beau’s lines are deep grooved horizontal lines of darkened cells that run from side to side on the fingernail. It may beinduced by injury, illness, malnutrition or major metabolic condition or due to chemotherapy. It may be the result ofany interruption in the protein formation of the nail plate.

Pterygium unguis It is also known as dorsal Pterygium. It is the inward advance of skin over the nail plate usually the result of trauma tothe matrix due to a surgical procedure or by a deep cut to the nail plate. It results in the loss of nail plate due to thedevelopment of scar tissue.

Onychatrophia Onychatrophia is a scarring process. It is an atrophy or wasting away of the nail plate which causes it to lose its luster,shrinks and falls off. Once it is damaged, the nail won’t recover.

Onychogryposis It is also known as ram’s horn nails. It is a hypertrophy that may produce nails resembling claws or ran’s horn. It ischaracterized by thickened nail plate and often a result of trauma. It represents the inward curved nail plate, pinchingthe nail bed.

Obychorrhexis Onychorrhexis are also known as brittle nails, in which nail plate often split vertically, peel and/or have vertical ridges.It may be hereditary or may result from excessive use of strong soaps, water exposure or nail polish remover.

Leuconychia It is characterized by white lines or spots in the nail plate. The most common cause is the injury to the nail matrix.It may be caused by entrapment of tiny air bubbles in the nail plate layers due to trauma or it may be hereditary.

Melanonychia It is characterized by vertical black or brown pigmented bands, often termed as ‘‘nail moles’’, which usually form in thenail matrix. It may be a result of trauma.


Nail psoriasis

Nail psoriasis is the second most important disease target for

the development of topical nail products as it is alleged to be

prevalent in 80–90% of patients with skin psoriasis and affects

about 1–3% of the entire population. The disease can affect

the nail plate, nail matrix, nail bed, nail folds and the

surrounding soft tissues. The psoriatic nail matrix results in

pitting (presence of small shallow holes in nail plate), nail

fragility, crumbling or nail loss. Nail bed involvement causes

onycholysis (separation of the nail plate from the nail bed),

subungual hyperkeratosis (deposition and collection of cells

under the nail plate) and splinter hemorrhages (as a result of

trauma). Psoriatic nail folds results in paronychia (inflamed

and swollen nail folds) which leads to transverse ridging of

the nail plate [45].

Nail psoriasis tends to be persistent and refractory to

treatment and hence, it is understandable that a standardized

therapeutic regimen does not currently exist. Although,

intralesional injections of cortisone into the nail fold,

topical application of corticosteroids, vitamin D3 analogs,

5-fluorouracil (5-FU), anthralin, tazarotene, phototherapy and

photochemotherapy, systemic administration of immunosup-

pressants, combination therapies and biological therapies have

shown some success [16,46]. Diseased nails may also be

chemically extracted using urea ointment. Urea ointment

(40%) upon application softens the diseased nail plate and,

after 5–10 d, the entire nail plate may be lifted off the nail bed

and trimmed behind the PNF. A disease-free nail may then

grow back [14,47].

Biofate of therapeutics following transungualapplication

The biofate of topical therapeutics after transungual applica-

tion has been pictured in Figure 3. Following topical

application, the drug is expected to partition out of the

formulation into the nail plate, diffuse through the latter,

and finally, partition into the nail bed. However, routine day-

to-day activities results in significant pre-absorptive losses of

transungually applied therapeutics. Binding of transungually

absorbed drug to the nail plate keratin reduces the amount of

regionally available drug. The absorbed drug has to partition

into the nail bed and maintain the concentrations in excess of

minimum inhibitory concentration (MIC) to be effective. The

rate at which the drug is delivered into nail plate must

compensate for the losses due to tissue binding, metabolism

and clearance of the drug from the nail bed. High drug

loading into nail and nail bed will most likely gain the success

of topical monotherapy [28].

Factors affecting drug permeation across thenail plate

The transungual drug permeation following topical applica-

tion is thought to be influenced by the permeant properties

(molecular size of permeant, lipophilicity and charge of

permeant), the formulation characteristics (nature and pH of

vehicle) and nail plate properties (disease state of nail,

hydration of nail, nail thickness and keratin content) as well as

drug–keratin interactions [2,14].

Figure 3. Biofate of topical therapeutics following transungual application. (Bulleted points show various factors related to permeant properties,formulation characteristics, and nail plate properties, which influence the permeation of topical therapeutics across the nail plate.) Modified after [28].


Permeant properties

The most significant permeant property that has marked

influence on the permeation of diffusing molecules is the

molecular weight. As likely, molecular weight has an inverse

relationship with the drug permeation into nail plate. Higher

the molecular weight, harder it is for permeating molecule to

diffuse through the keratin network, and lower is the

permeation [48]. Kobayashi et al. [49] reported that the

dense keratin network of nail is found to increase the path

length of diffusing molecules by virtue of its greater pore

tortuosity. The permeation rate was found to decrease, on

account of increased friction between diffusing molecules and

the keratin network, as the molecular size of permeant

increased. Permeation of larger molecules through the pores

in the close-meshed keratin network of the nail plate is

obviously more difficult than the permeation of smaller

molecules. There exists an inverse relationship between

the permeability coefficient of several ionic and non-ionic

model drugs across human nail plate and their molecular

weight.

The permeability of diffusing molecules through nail plate

is influenced by the permeability coefficient of the permeant.

In most instances, the permeation rate was found to decrease

with an increase in carbon-chain length or lipophilicity of the

permeant. The decrease in permeability coefficient with

increase in lipophilicity of permeant was attributed to

hydrophilic nature of the nail plate [14,28]. Walters et al.

[50] studied the permeation of a series of homologous

alcohols (C1–C12), diluted in saline, through avulsed human

nail plates. Increasing chain length from single carbon to

eight carbon atoms resulted in decreased permeability coef-

ficient, after which, increasing chain length (up to C12)

resulted in an increased permeability coefficient. The nail

plate seems to be a hydrophilic gel membrane when the

permeation of lower alcohols (5C8) is considered. The

authors have concluded that the nail plate behaves like a

concentrated hydrogel and this indicates a facilitating role of

water towards the diffusion of alcohol molecules. It is

possible that when an aqueous formulation is applied, nails

swell due to water uptake into the nail plate. Consequently,

the keratin network expands, leading to the formation of

larger pores through which diffusing molecules can permeate

more easily. Still, the increase in permeation of higher

alcohols (C10–C12) with increasing lipophilicity was sug-

gested to take place through a lipidic pathway. Despite the

lower lipid content (0.1–1%) in the nail plate, this lipidic

pathway appears to be important rate-controlling barrier to

the passage of highly hydrophobic permeant.

A surface charge of permeant seems to be a key

consideration for passive diffusion of molecules through the

nail plate. Regardless of the nature of the charge, non-ionic

permeants were found to have approximately 10-fold greater

permeability as compared to their ionic counterparts [49]. The

low permeability of the charged species was thought to be

caused by a small increase in molecular size due to the

hydration of the charged species. Reduced permeation of

the charged species was attributed to the ‘‘Donnan effect’’,

i.e. electrostatic repulsion between the charged keratin

membrane and like-charged diffusing molecule [51,52].

The nail keratin has an isoelectric point (pI) of 5.0 [53],

thus carries a net negative charge at pH 7.4 while net positive

charge at pH 2.0. At pH 7.4, the negatively charged benzoate

ion is repelled by the negatively charged keratin, resulting

in decreased diffusion of the solute through the nail

plate and thereby lowered permeability coefficient. This

reduced permeability was attributed to the decreased keratin

swelling due to charge inversion of keratin, when the

environment was altered from an acidic to a neutral or basic

one [54]. Similarly, at pH 2.0, the positively charged

pyridinium ion is repelled by the positively charged keratin,

resulting in lower permeability coefficient of the pyridinium

cation [14].

Formulation characteristics

Water plays a facilitating role in enhancing the diffusion of

water soluble permeants through the nail plate. The perme-

ability coefficients of alcohols diluted in saline through nail

plates was 5 times greater than the permeability coefficient of

neat alcohols [55]. Water hydrates the nail plate, resulting in

subsequent swelling. Considering the nail plate to be a

hydrogel, swelling results in expansion of keratin network,

leading to the formation of larger pores. Permeant molecules

can diffuse through these pores easily resulting in increased

permeability coefficient. Replacing water with non-polar

solvent, which does not hydrate the nail plate, is therefore

expected to reduce the drug permeability into nail plate. This

was demonstrated by Walters et al. [55], whose results

suggested that the addition of non-polar co-solvent such as

dimethyl sulfoxide (DMSO) and isopropanol decreased the

transungual permeation of hexanol. In short, increasing

concentration of co-solvent or decreasing concentration of

water in the medium results in decreasing permeability

coefficient of hexanol. The precise mechanism behind this has

not been well documented.

The molecules in soluble form and unionized state, in

general, have good permeation across nail plate. The pH of

the aqueous vehicle governs the extent of ionization, aqueous

solubility of the permeant and its interaction with nail plate

keratin fibers. The extent of ionization is influenced by pKa

value of the permeant and the pH of the vehicle. As a general

rule, acidic drugs are unionized at lower pH values while

basic drugs remain unionized at higher pH values. Thus, it is

estimated that acidic drugs are well permeated at low pH

values while basic drugs exhibit better permeation at higher

pH values. Soong [56] studied the permeation of benzoic acid

through a human nail plate at different pH. The donor

compartment contained a saturated solution of permeant

and receptor compartment contained permeation medium of

the same pH as of the donor. It was observed that, as the

pH of the medium increased from 2.0 to 8.5, the permeability

coefficient of benzoic acid decreased by 95.5%. This

was attributed to greater permeation of uncharged molecules

(at pH 2.0) through the nail plate compared to charged

molecules (at pH 8.5). Further, Mertin and Lippold

(1997b) [54], also observed the greater permeation of

undissociated benzoic acid at pH 2.0 across the bovine

hoof membrane compared to dissociated benzoate ion at

higher pH.


Nail plate properties

The various nail plate properties which have significant

influence on the permeation of drug across the nail plate

includes the nail plate’s diseased state, hydration, thickness,

keratin content and permeant–keratin interactions. The nail

plate’s diseased state is expected to have an enormous

influence on nail permeability. Kobayashi et al. [49] demon-

strated comparable permeation of 5-FU in healthy nail plates

and in nail plates with mild fungal infection. Nail plate with

heavy fungal infections were not used due to their uneven

thickness and as such plates ‘‘collapsed’’ when placed in

water. However, the diseased nail plate may be heavily

thickened, which increases the distance the drug has to

permeate through the nail plate before reaching the nail bed;

this would have a negative influence on the success of topical

therapy. Also, presence of dermatophytoma (a dense focus of

fungi with thick shortened hyphae) in onychomycotic nails is

likely to change the drug diffusion through nail plate; thereby

is thought to melt off the success of topical therapy. Diseased

nail plates may also be more ‘‘crumbly’’, which could

increase the nail porosity and thereby increase the nail

permeability. The diseased nail plate can also detach from the

nail bed, and such detachment presents a huge barrier to drug

movement into the nail bed if the detachment is surrounded

by ‘‘non-detached’’ nail areas. On the other hand, if

onycholysis occurs at the proximal edge of the nail plate,

drug formulation can be applied within the detached space,

which would facilitate drug delivery into the nail bed [2].

Hydration of nail plate increases the ungual permeability

of polar compounds as the nail plate is thought to behave like

a concentrated hydrogel and the mechanism behind this fact

has already been discussed earlier [55]. De Berker et al. [57]

observed the increased toenail thickness along the nail. Mean

nail plate thickness increased progressively along the entire

length of the nail ranging between 590mm and 1080 mm. This

high thickness poses the difficulty for the permeant to

penetrate the nail structure.

Binding of permeant to keratin within the nail also

contribute to disappointing topical efficacy in nail diseases.

Binding to keratin reduces the availability of permeant,

weakens the concentration gradient and thereby limits the

deep penetration [58].

Enhancement of drug permeation into nails

Nail disorders can be successfully treated only when applied

topical therapeutics are able to permeate through the dense

keratinized nail plate and reach the deeper layers of nail

apparatus at amounts above the MIC. This can be made

practically possible using different techniques of ungual

penetration enhancement viz. physical, chemical and mech-

anical methods (Figure 4). However, effective penetration

remains challenging as the nail is thought to be made of

approximately 80–90 layers of tightly bound keratinized cells,

100-folds thicker than the stratum corneum (SC) [59].

Therefore, high nail thickness, poor drug permeation and

prolonged transport lag time contribute to unsatisfactory

outcomes in ungual topical therapy. Physical, chemical and

mechanical modes of penetration enhancement may improve

topical efficacy.

Mechanical methods of nail penetration enhancement

Mechanical methods of nail penetration enhancement

(nail abrasion and avulsion), although invasive and extremely

painful, have been used by dermatologists and podiatric

physicians since long time. Thus, current research focuses on

less invasive physical and chemical modes of nail penetration

enhancement.

Nail abrasion

Out of three layers of nail (dorsal, intermediate and ventral,

that vary in thickness in the proportion of 3:5:2, respectively),

the dorsal layer is found to be the major barrier for permeation

of drug into the nail plate. One of the methods employed to

mechanically enhance the transungual drug delivery is filing

the surface of the nail plate using an abrasive. Filing removes

the dorsal layer of nail plate, thus reduces the barrier that

drugs have to permeate through to reach the deeper nail

layers. Filing has shown to double the permeability

coefficient of 5-FU and flurbiprofen through the nail plate

in vitro [17]. In clinical trials, filing the nail plate prior to the

application/re-application of drug-loaded formulations were

found to be indispensable for the success of topical therapy

[60,61]. Nail abrasion, sometimes, involves sanding of the

nail plate to thin out its thickness or destroy it completely.

Depending on the required intensity, sandpaper number 150

or 180 can be utilized for sanding purpose. The sanding must

be performed on nail edges and should not cause discomfort.

An efficient instrument for sanding is a high-speed

(350 000 rpm) sanding hand piece. Nail abrasion, using

sandpaper nail files, prior to antifungal nail lacquer treatment

may reduce the critical fungal mass and thereby aids in

effective penetration [62,63].

More aggressive abrasion of dorsal surface of nail plate

using electrical equipment or nail drilling using dentist’s drill

has proved to be beneficial in clinics for improving the

efficacy of topical antifungal treatment [63–66]. Sumikawa

et al. [67] performed the drilling to reduce nail thickness to

1–2 mm in thickened nail areas and studied the influence of

foot care intervention on topical therapy of distal-lateral

subungual onychomycosis in diabetic patients.

Nail avulsion

Total nail avulsion (surgical removal of entire nail plate) or

partial nail avulsion (partial removal of the affected nail plate)

is usually carried out under local anesthesia. Keratolytic

agents (urea or a combination of urea and salicylic acid),

which softens the nail plate, have been utilized for non-

surgical nail avulsion in clinical studies, prior to topical

treatment of onychomycosis [68].

Physical methods of nail penetration enhancement

Iontophoresis

The application of electric current (electromotive force) has

proved to enhance the diffusion of charged molecules through

the hydrated keratin network of a nail and found to cause a

large increase in ungual drug flux compared to passive

transport [58,69]. Transungual transport of uncharged per-

meants depends on electroosmosis while that of ionic


permeants relies on electrophoresis, with a small contribution

from electroosmosis. Influence of electric current on nails are

reversible in vitro; nail plates return to their normal after

iontophoretic treatment [59]. Several factors responsible for

enhancement of iontophoretic drug flux includes: electro-

phoresis/electrorepulsion (interaction between electric field

and charge of ionic permeant), electroosmosis (convective

solvent flow in preexisting and newly charged pathways),

permeabilization/electroporation and electric-field induced

pore induction [58,59].

Murthy et al. (2007a) was the first to demonstrate the

feasibility of transungual iontophoresis. The authors system-

atically studied in vitro transport of salicylic acid (SA) across

the human nail plate using specifically-designed diffusion

cells [58]. Iontophoresis significantly enhanced drug flux

through the nail compared to passive transport. Iontophoretic

trans-nail flux improved with higher SA concentration

(up to 2 mg/ml), higher current density (up to 0.5 mA/cm2),

higher buffer ionic strength (50–100 mM) and higher pH.

Findings of Murthy et al. (2007b) stated increased

transungual glucose and griseofulvin flux with higher pH

(pH45) in anodal iontophoresis [69]. Cathodal iontophoresis

followed the opposite trend for pH-dependent transport

(i.e. increased drug flux at lower pH). SA flux was enhanced

�16-fold while of griseofulvin �8-fold with iontophoresis

[58,69].

Hao and Li (2008a) accomplished in vitro iontophoresis

experiments on human nails with neutral and charged

molecules. Anodal iontophoresis at 0.3 mA enhanced manni-

tol (MA) and urea (UR) transport compared to passive

transport. Also, findings suggested only a marginal contribu-

tion of electroosmosis in anodal iontophoretic transport

of MA and UR at low electric currents (�0.3 mA). The

contribution of electroosmosis increased with permeant’s

molecular size and current strength [59]. For a positively

charged permeant, tetraethylammonium ion (TEA), pene-

tration was significantly enhanced �29-fold with anodal

iontophoresis at only 0.1 mA. Moreover, the contribution

of electroosmosis was less than 10% of electrophoresis in

TEA [59].

Figure 4. Illustrative representation of the various techniques of nail penetration enhancement.


Hao and Li (2008b) [70] also examined the influence of

pH and ionic strength on the electro-osmotic transungual

transport of neutral molecules. When pH was below pI

(pH55), the nail plates were positively charged and electro-

osmotic flow occurred from cathode to anode. On the

contrary, when pH was above pI (pH 45), the nail plates

were negatively charged and electro-osmotic flow occurred

from anode to cathode. In addition, electroosmosis improved

significantly from pH 7.4 to 9.0 in anodal iontophoretic

transport. As discussed earlier, electro-osmosis contribution

was greater in MA than UR due to increased molecular size.

Furthermore, the significant electro-osmotic enhancement

was seen only in MA, not UR, with pH changes (anodal

transport at pH 7.4 and 9.0 and cathodal transport at pH 3.0).

Electroosmosis correlated inversely with ionic strength,

decreasing former by four times when the solution ionic

strength increased from 0.04 to 0.7 M.

Manda et al. [71] investigated the plausibility of ionto-

phoretic delivery of terbinafine hydrochloride (TH) to the nail

matrix via PNF. In vitro drug permeation studies were

performed in Franz diffusion cell across folded porcine

epidermis as a model for PNF. A custom-designed foam-pad-

type patch system was used for iontophoresis across excised

cadaver toenails. The amount of drug delivered into the nail

matrix following iontophoresis for 3 h at 0.5 mA/cm2 was

significantly higher than the MIC of TH. The study concluded

that the iontophoresis across the PNF could be developed as a

potential method to target drugs to nail matrix.

Acid etching

Application of surface-modifying chemical etchants (10%

phosphoric acid gel or 20% tartaric acid solution) onto the

dorsal surface of nail clippings was used in vitro to modify the

nail plate surface, resulting in formation of profuse micro-

porosities, prior to application of topical formulations, such as

adhesive polymeric films [7,72]. These microporosities

increases the wettability and surface area and decreases the

contact angle; thereby provide an ideal surface for bonding

materials. They improve interpenetration and bonding of a

polymeric delivery system and facilitate interdiffusion of

topical therapeutics [7]. Atomic force microscopy (AFM)

revealed that application of abovementioned etchants

increased the mean surface roughness by 1.3 and 1.7 times,

respectively. Etching the nail plate surface with phosphoric

acid gel also increased the adhesion of drug-loaded polymeric

films onto the nail plate surface and drug diffusion

(the latter by �6-fold) through the nail plate. Improved

bioadhesion and drug permeation were thought to be

attributed to the increased nail plate surface area, providing

‘‘greater opportunity for the polymer chains (of therapeutic

films) to bond with the nail plate and for drug diffusion’’. The

latter also benefited from a decreased membrane thickness of

the etched nail plate, as studied on hot-melt extruded (HME)

hydroxypropyl cellulose (HPC) films loaded with ketocon-

azole as a model drug, across human nails in vitro [72,73].

Pulsed laser/carbon dioxide (CO2) laser

Natural barriers that limits the permeation of topical

therapeutics have been abandoned by pulsed laser systems.

Following topical application, laser energy would be

absorbed by the keratin network in the nail plate and

scattered heat lead to vaporization and thus, removal of nail

layers.

Laser application on the nail plate in vitro resulted in the

formation of craters whose shape, size and other properties,

such as crater wall smoothness, the presence of cracks and of

melted and re-solidified tissue depended on the nature of laser

system employed. The effect of different laser systems on nail

plate ablation rates, ablation efficiencies and subsequent

crater morphologies has been studied by Neev et al. [74].

Among four laser systems studied, the ultrashort pulsed laser

system was found to display best ablation efficiencies without

cracks or thermal damage to the nail plate. However, the

efficacy of laser on transungual drug permeation in vivo is yet

to be established [74].

CO2 laser treatment may produce positive, but unpredict-

able, results. One method involves avulsion of diseased nail

portion followed by laser treatment at a density of 5000 W/

cm2. Thus, underlying tissue is exposed to direct laser

therapy. Penetrating the nail plate with CO2 laser beam

followed by daily topical antifungal treatment, penetrating

laser-induced puncture holes is another method of nail

penetration enhancement based on CO2 laser-treated ablation

of nail plate [75].

Microporation

PathFormer is an FDA-approved hand-held microcutting

(nail trephination) device (developed by Path Scientific,

Carlisle, USA) used to drill a hole (microconduite) of specific

depth in the nail plate without affecting the nail bed in order

to drain subungual hematomas [76]. Figure 5 depicts the

PathFormer device, its components and the microconduites

drilled in toenail using PathFormer [77]. This device uses

the electrical resistance of the nail bed as a feedback to stop

and retract the drill when it has penetrated through the nail

plate. Besides, it eliminated the need for anesthesia. The nail

plate is drilled using a 400-mm diameter tissue cutter in a

hand-held device driven by two small electrical motors.

The depth of the hole created by the device is said to be

precisely controlled by the electrical resistance; the electrical

resistance of the highly keratinized nail plate decreases upon

microcutting from 5 MX (undrilled) to 10–20 kX (upon

reaching the nail bed) as each successive layer of nail tissue

is removed [78]. Microconduites of varying depths corres-

ponding to the electrical resistances ranging from 90 to 25 kXwere drilled to assess the tolerability of the technique

in healthy adult subjects. The procedure was well tolerated,

with regard to pain and pressure felt by the volunteers,

when five microconduites (of diameter 400 mm and depths

corresponding to electrical resistance of 90–25 kX) were

drilled in each patient’s toenail, without penetrating the

nail bed.

Boker and co-workers employed the same device in their

clinical studies to drill microconduites prior to application of

terbinafine cream and placebo cream. Though transungual

permeation of terbinafine was increased, the number of

microconduites drilled and the extent of enhancement

obtained is not revealed [79].


Low-frequency ultrasound

The potential of low frequency ultrasound as a physical nail

penetration enhancement technique has been evaluated on

whole nail plates and on bovine hoof membranes [80,81].

Torkar and co-workers applied a low frequency ultrasound

(20 kHz) to the hoof membranes using a 13-mm ultrasound

probe held at a distance of 13 mm from the surface through a

liquid coupling medium and employed a 50% intensity level

as a pretreatment procedure for 1 min in a pulsatile fashion.

Their findings suggested an enhanced drug permeation

through hoof membrane and it was attributed to the

ultrasound-induced disruption of the hoof membrane [81].

Although the mechanism of membrane disruption has not

yet been clearly interpreted, it is possible that inertial

cavitation or pit formation is involved, as has been proposed

for low frequency ultrasound-assisted transdermal drug

delivery [82,83]. Cavitation (formation and collapse of gas

bubbles) occurs when low frequency ultrasound waves are

applied in a liquid. Cavitation may be stable (periodic bubble

growth and oscillations) or inertial (violent growth and

collapse). The violent collapse of a very large number of gas

bubbles in the liquid medium generates shock waves, which

travel through the membrane and impact on the membrane

(Figure 6a). This results in asymmetrical pressure and the

formation of liquid microjects which impact on (Figure 6b)

and penetrate through the membrane (Figure 6c). This leads

to the formation of pits on the membrane surface, which could

act as conduites or microconduites for ungual drug flux.

Hydration and occlusion

Hydration may increase the pore size of nail matrix, thereby

enhances the transungual penetration. Again, hydrated nails

are more elastic and permeable. Hydration aids in enhanced

iontophoretic transungual drug delivery [59], whereas solu-

tion pH and ionic strength have no significant influence on

nail hydration [70].

Human nails can retain water �25% of its weight, twice of

its normal water content (10–15%), and has a pronounced

effect on drug penetration in the region of high water content

(RH480%) [84]. Gunt and Kasting reported that increasing

ambient relative humidity (RH) from 15% to 100% enhanced

permeation of [3H]-ketoconazole by �3-folds in vitro, as

studied on excised human nail plates. Flux increased from

0.175 mg/cm2/h at 15% RH to 0.527 mg/cm2/h at 100% RH [85].

Figure 5. Diagram demonstrates: (a) the PathFormer (nail trephination) device, consisting of power supply circuite, foot of PathFormer, and sensingelectrodes. (b) Application of PathFormer on a fingernail: The sensing electrodes are attached to the skin prior to the procedure. The circuite verifiesthat the electrodes are in good contact with the skin. The foot of the PathFormer stabilizes the device during 3–5 s procedure. (c) Close up view of thePathFormer’s foot (shown in inset). The electrically conducting foot encloses, but does not contact the cutter. The cutter is held tightly by the chuck.The blue switch on the top activates the device, and (d) a row of five openings (microconduites) drilled in toenail with PathFormer. Each opening is0.4 mm in diameter, and created in less than 3 s. Reproduced from [77], with kind permission from PathScientific, Carlisle, MA.


Susilo et al. revealed in their in vivo experiments

examining sertaconazole-loaded nail patches, a remarkable

enhanced nail penetration (40–50%) with mean sertaconazole

concentrations above the MIC at 2, 4 and 6 weeks [8].

Transonychial water loss, decrease in ceramide concentration

and water binding capacity may result from onychomycosis.

Occlusion may resolve these changes via reconstitution of

water and lipid homeostasis in dystrophic nails. In addition,

sertaconazole was able to amass in substantial subungual

concentrations under occlusion [8].

Miscellaneous methods

A patent has been filed on ONYCHOLASER� – a micro-

surgical laser unit which is used to make holes in tissues,

especially fingernails and toenails [86]. Antifungals are then

topically applied to these holes for the treatment of

onychomycosis.

A recent patent on the application of heat and/or UV light

to fingernails or toenails that are afflicted by onychomycosis,

discusses the different devices and methodologies which may

effectively provide exposure. It involves heating the nail,

exposing it to UV light and subsequently treating with topical

antifungal therapy [87].

5-Aminolevulinic acid-mediated photodynamic therapy

(ALA-PDT) is a medical treatment based on a combination

of a sensitizing drug and a visible light used together for

destruction of cells. Donnelly et al. [88] developed a

novel bioadhesive patch containing ALA and conducted

in vitro penetration studies across the human nail. Their

findings suggested that, if sufficient concentrations of ALA

could be achieved within the nail matrix and at the nail

bed, PDT may open the new vistas for treatment of

onychomycosis.

Chemical methods of nail penetration enhancement

Many chemical permeation enhancers that facilitate

transdermal penetration have not been effective in enhancing

the transungual drug permeability. As earlier mentioned

in ‘‘The nail apparatus’’, the lipid content of the nail plate is

0.1–1%. This very low lipid levels explain why transdermal

enhancers, many of which are known to act by fluidizing

the skin lipids, have been unsuccessful as transungual

penetration enhancers. Chemical enhancement of nail

plate permeability has therefore been focused on the cleavage

of chemical and physical bonds that maintain the integrity

of nail plate keratin. The disulfide, peptide, hydrogen and

polar bonds were identified as potential targets for

ungual chemical penetration enhancers. The chemical

enhancer may be applied to the nail plate prior to or

concomitantly with the drug formulation. The various

chemical enhancers exploited till date have been quoted in

Table 3.

Figure 6. Proposed mechanism of transungual penetration enhancement by low-frequency ultrasound. Cavitation of gas bubbles in the liquid mediumresults in generation of shockwaves which impact on the membrane (a), while gas bubbles collapse near the membrane results in the formation of liquidmicrojets which impact on membrane (b), and even penetrate through the membrane (c). Reprinted from [83] after slight modifications, with kindpermission of the copyright holder, Elsevier, Amsterdam.

Table 3. Chemical enhancement of ungual drug permeation (Modified after [2]).

Chemical enhancer Permeant Methodology Ref

Sodium sulfite 5,6-Carboxyfluoresceine Diffusion cells [2]2-n-Nonyl-1,3-dioxolane Econazole EcoNail� lacquer [4]N-acetylcysteine (15%) Oxiconazole Drug applied on human nail

plates for 6 weeks[5]

N-(2-mercaptopropionyl) glycine (MPG, 10%) Water Diffusion cells [89]Mercaptoethanol (3%) Tolnaftate; 5-FU Diffusion cells [90]N-acetylcysteine (3%) 5-FU, Tolnaftate Diffusion cells [90]Thioglycolic acid & Urea- H2O2 Caffeine, Methylparaben, Terbinafine ————— [91]Cysteine Mannitol Diffusion cells [93]Thioglycolic acid (5%) Caffeine, Mannitol Diffusion cells [93]H2O2 (35%) Mannitol Diffusion cells [93]Keratinolytic agents (Keratinase) Metformin HCl Diffusion cells [97]Keratolytic agents (Papain, Urea & salicylic acid) Ketoconazole, Miconazole, Itraconazole Diffusion cells [98]N-acetylcysteine (5%) Itraconazole Nail immersed in drug solution [99]


Reducing agents that cleaves the nail disulfide bond

Thiols

Thiols, compounds containing sulfhydryl groups (-SH), are

the agents that reduce the disulfide linkage in the keratin

matrix of the nail [89], as exhibited below:

Nail�S�S�Nailþ2R�SH$ 2Nail�SHþR�S�S�R

Where, R–SH represents a thiol. The thiols which have been

used as transungual penetration enhancers include N-

acetylcysteine, mercaptoethanol, N-(2-mercaptopropionyl)

glycine (MPG), pyrithone and thioglycolic acid (TGA) [89].

Once cleaved, disulfide bonds are unlikely to be reformed in

the dead nail plate. Thus, nail plates may be pretreated with

the enhancer prior to drug application (rather than being used

in drug formulation). Pretreatment with the enhancer would

resolve drug-enhancer compatibility problems, if any, and

enable higher drug and enhancer concentrations to be

employed.

Hoogdalem et al. evaluated the penetration-enhancing

properties of N-acetylcysteine in vivo and revealed an

enhanced retention of antifungal agent oxiconazole in upper

nail layers [5]. Kobayashi et al. demonstrated that

N-acetylcysteine and 2-mercaptoethanol enhanced the per-

meability of antifungal drug tolnaftate in upper layers of nail

clippings, attributed to swelling and softening of nail plate

[90]. TGA is known to increase the transungual drug flux and

reduce the lag time of compounds with varied polarity.

TGA-mediated redox reaction involving nail disulfide linkage

overcome the barrier integrity of the nail, facilitating the drug

flux [91].

Sulfites

Incubation of proteins and peptides containing disulfide bond

with sodium sulfite is known to cleave disulfide bond to

produce thiols and thiosulfates, as depicted in following

reaction:

R� S� S� Rþ Na2SO3 ! R� S� Hþ R� S� SO3H

Thus, it was hypothesized that incubation of nail plates

with sodium sulfite could reduce the nail plate’s barrier

properties and enhance ungual drug flux [2]. Certainly, the

penetration of 5,6-carboxyfluoresceine (as a model drug)

through nail clippings from a healthy volunteer was found

to be significantly enhanced in the presence of sodium

sulfite [92]. It was found to enhance the transungual

permeation on pretreatment and on co-application as well.

Oxidizing agent that cleaves the nail disulfide bond

Much less attention has been given on the use of oxidizing

agents for cleavage of nail disulfide bonds and to enhance

transungual drug permeability. Hydrogen peroxide has been

used alone or in combination with urea, as urea hydrogen

peroxide (UHP), to enhance transungual drug flux.

Pretreatment of nails with hydrogen peroxide (35% wt in

water) alone for 20 h increased mannitol permeation �3-fold

following a 120 h permeant application [93]. MedNail�

technology consists of pretreatment of nails with reducing

agent TGA, followed by oxidizing agent UHP.

Nail pretreatment with MedNail increased ungual drug flux

of terbinafine �18-fold, with concomitant increased fungal

eradication by Penlac and Loceryl [94].

Water

The pivotal role of water as a transungual permeation

enhancer for alkanols is well documented in the literature

[55]. Nail hydration and swelling, on contact with water, have

been thought to be a probable mechanism for the higher drug

flux from aqueous vehicle. The permeability coefficient of

C2-C10 n-alkanols (but not methanol) from a saline solution

through the nail was �5 times greater than from neat alcohols

[50]. The role of water in the donor medium was confirmed

when its replacement with an organic solvent (isopropanol or

DMSO) reduced the permeability of hexanol (but not

methanol) in a concentration-dependent manner [55].

Kobayashi et al. revealed higher drug flux of the hydro-

philic 5-FU from aqueous drug formulation (compared

with lipophilic) drug-saturated formulations containing

N-acetylcysteine and mercaptoethanol [90]. Gunt and

Kasting reported that increasing ambient RH from 15% to

100% enhanced permeation of [3H]-ketoconazole by �3-folds

in vitro, as studied on excised human nail plates and the

diffusivity of water increased by more than 400-folds. This is

attributed to increase in nail plate hydration by nail incubation

in environments of increasing RH [85,95]. An increase in

ungual flux of hydrophilic drugs from aqueous vehicles is

associated with an increase in nail weight. The flux of

hydrophilic drugs was found to be higher from aqueous

vehicle compared to their lipophilic counterparts.

However, increased nail swelling and enhanced drug flux

do not always occur together, as in case of resorcinol [93] and

urea [89], which caused nail swelling but failed to signifi-

cantly enhance the flux of mannitol. On the contrary,

enhanced flux of tolnaftate has not been associated with

nail swelling owing to the lipophilic nature of the vehicle

used [90]. Therefore, nail hydration and swelling by a

formulation cannot always be considered as an indication

for the enhanced transungual drug permeation.

Keratinolytic enzymes

Keratinolytic enzymes are known to hydrolyze the keratin

matrix of nail plate, thereby altering its barrier properties and

subsequently enhancing the transungual permeation [96].

Mohorcic et al. conducted permeation studies using modified

Franz diffusion cells and found keratinase to markedly

enhance the permeation (more than double) of metformin

HCl (model drug) through bovine hoof membranes (model

nail plate). Indeed, the keratinase intensely affected the

surface of human nail clippings (on incubation for 48 h),

acting on the intercellular cement that holds the nail

corneocytes together. This resulted in the separation of

corneocytes on the dorsal surface of the nail and ‘‘lifted

off’’ the nail plate (Figure 7A). The surface of the corneocytes

was corroded as well, as revealed by scanning electron

microscopy (SEM) (Figure 7B), suggesting enzyme action on

the interfilamentous matrix [97].

Papain, an endopeptidase that contains a highly reactive

sulfhydryl group, has also shown some promising action as a


transungual penetration enhancer [98]. Incubation of nail in

papain solution (15% w/v) for 1 d, followed by soaking

salicylic acid solution (20% w/v) for 10 d enabled the

permeation of antifungals, miconazole, ketoconazole and

itraconazole. The aggressive pretreatment regime fractured

the nail surface and possibly created pathways (pores) for

ungual drug penetration, as revealed by SEM analysis.

Keratolytic enhancers

The Guirrero et al. demonstrated the influence of keratolytic

agents (papain, urea and salicylic acid) on the permeability of

three imidazole antifungals (miconazole, ketoconazole and

itraconazole). In the absence of keratolytic agents, no

transungual antifungal permeation was detected over a

period of 60 d [98]. Urea and salicylic acid are known to

soften and hydrate the nail plate [90]. The swelling and

hydration of nail plate would enhance the drug permeation as

a consequence of the formation of a less dense structure with

large pores. Keratolytic agents were found to damage and

fracture the nail plate surface [98]. The drug load in nail was

found to increase on incubation with drug solution containing

urea, but failed to enhance ungual drug flux when used alone

in many cases. In fact, it has been found to reduce the ungual

flux of 5-FU. This is due to an alteration in pH of the solution

(from pH 4.7 to 7.2) upon inclusion of urea, which resulted in

ionization of the acidic 5-FU (pKa¼ 8.0, 13.0) into negatively

charged species and repulsion between the like-charged drug

and the nail (which also carries a negative charge above pH

5.0 due to its pKa of �5) [90].

Urea has a synergistic effect on ungual drug flux when

used in combination with other penetration enhancers [89].

Sun et al. reported that itraconazole concentration in nail

plates in the presence of both N-acetylcysteine and urea

was 94 times higher than that of the control (no enhancer),

compared to 20 times in the presence of urea only and

49 times in the presence of N-acetylcysteine only [99].

Interestingly, the beneficial effect of combining urea with

proven transungual enhancers was observed even when urea

did not enhance the ungual drug permeation alone; transun-

gual flux of water being enhanced by 3.5-fold in the presence

of urea and MPG, compared with an increase of 2.5-fold in

the presence of MPG only [89].

Urea is a keratolytic agent that acts by unfolding,

solubilizing and denaturing the nail keratin. The process of

keratin unfolding by urea (probably via interaction with their

hydrogen bonds) would facilitate the cleavage of disulfide

bonds. The dismantling of disulfide bonds promote the

disruption of the nail plate barrier and subsequently enhance

the ungual drug permeation. Thus, urea has been included in

nail lacquers [100]. Urea has been employed at high

concentrations (40%) to chemically avulse the diseased nail

plates [47,101].

2-n-nonyl-1,3-dioxolane (SEPA�)

2-n-nonyl-1,3-dioxolane (a skin penetration enhancer) is as

well known as SEPA (Soft enhancement of percutaneous

absorption), which has proven to be efficient in increasing

transdermal drug delivery [101–103]. Hui et al. examined the

delivery of econazole across human nail from a lacquer

formulation (EcoNail�) with a penetration enhancer,

2-n-nonyl-1,3-dioxolane. Findings of Hui et al. suggested

that the addition of 2-n-nonyl-1,3-dioxolane (18%) to

econazole nail lacquer (test group) delivered six times more

drug through human nail than an identical lacquer formulation

without enhancer (control group). Concentrations of econa-

zole in the deep nail layer and nail bed were significantly

higher in the ‘‘test group’’ than in ’’control group’’.

Moreover, the concentration of econazole in the deep nail

layer in the test group was 14 000 times higher than the MIC

necessary to inhibit the fungal growth [4].

Miscellaneous enhancers

N-methyl-2-pyrrolidone, polypropylene glycol 400, DMSO,

Labrasol, mercaptoethanol, Transcutol are found to increase

the ungual drug permeation through the bovine hoof mem-

brane. Inorganic salts such as sodium metabisulphite, sodium

citrate, potassium phosphate and ammonium carbonate were

found to increase the drug load as well as the drug uptake rate

of terbinafine HCl. Additionally, sodium dodecyl sulfate and

Figure 7. SEM photomicrographs showing influence of keratinase solution on nail plate. (A) Nail corneocytes ‘‘lift off’’ the nail plate, owing toenzyme action on the intercellular cement after incubation of nail clippings in a keratinase solution. (B) Keratinase seems to ‘‘corrode’’ the surface ofindividual corneocytes, possibly due to the action of keratinase on the interfilamentous matrix. Reprinted from [97], with kind permission of thecopyright holder, Elsevier, Amsterdam.


polyethylene glycols were identified as potential transungual

enhancers. Sodium phosphate was found to be the most

effective inorganic salt to enhance the transungual permeation

of terbinafine HCl, due to increased hydration of the nail plate

and higher thermodynamic activity of the drug in the presence

of inorganic salt [104].

Murthy and co-workers [105] assessed the influence of

polyethylene glycols (PEGs) on the in vitro transungual

permeation of terbinafine by passive and iontophoretic

processes using gel formulations containing different molecu-

lar weight PEGs (30% w/w). Passive delivery using low

molecular weight (LMW) PEGs (200 and 400 MW) indicated

moderate enhancement of drug permeation and drug load in

the nail plate whereas iontophoresis delivery significantly

enhanced the drug permeation and drug load into the nail

plate. Little or no effect on drug permeation and was observed

with high molecular weight PEGs (1000–3350 MW) in

passive or iontophoretic processes. This study concluded

that the enhancement in drug permeation by LMW PEGs is

likely due to their ability to lead to greater water uptake and

swelling of nail and LMW PEGs are indeed a promising

transungual permeation enhancer.

TranScreen-N�: Method for rapid screening oftransungual penetration enhancers

Topical monotherapy of nail diseases (onychomycosis and

nail psoriasis) has been abandoned due to poor permeability

of the human nail plate to topical therapeutics. Chemical

enhancers are likely to improve the drug delivery across

the nail plate. Selecting the most effective chemical

enhancer for the given drug and formulation is highly

crucial in determining the efficacy of topical therapy of nail

diseases [106].

Nail swelling alone cannot always be considered as an index

for the increased transungual permeation since, many transun-

gual penetration enhancers are not likely to promote the

swelling of the nail plate. Besides, most of the screening

methods cannot be used to predict the extent of permeation

from lipophilic systems, which may fail to hydrate or swell the

nail plate. Screening the big pool of enhancers using currently

followed diffusion cell experiments would be tedious and

expensive. In this context, TranScreen-N was devised as a high

throughput method of screening transungual penetration

enhancers. It is a rapid microwell plate-based technique

which involves two different procedures; the simultaneous

exposure treatment and sequential exposure treatment [107].

Murthy and co-workers (2009c) screened several chemical

enhancers using TranScreen-N employing diffusion studies

using Franz diffusion cell. In TranScreen-N technique, the

enhancers can be categorized according to whether they need

to be applied before or concomitantly with drugs (or by either

procedure) to enhance the transungual drug delivery.

TranScreen-N technique can significantly reduce the cost

and duration required to screen transungual drug delivery

enhancers. The treatment procedures adopted by Murthy and

co-workers for screening of chemical enhancers is presented

in Figure 8 [106].

Vaka et al. [108] studied the effect of pretreatment using

five different chemical etchants on the delivery of TH and

5-FU into and across the human cadaver fingernail plates

using TranScreen-N technique. The dorsal surface of nail

plate was pretreated with these chemical etchants in gel

formulation for a period of 60 s and evaluated for drug load

and in vitro permeation. Of the five chemical etchants – lactic

acid (LA), tartaric acid (TTA), glycolic acid (GA), citric acid

(CA) and phosphoric acid (PA) – evaluated, PA was identified

as the most potent transungual etchant while LA did not

demonstrated any etching properties. Optical microscopy and

AFM revealed that the PA enhanced the transungual drug

delivery by decreasing the keratin density of the dorsal layer

of the nail plate and by microstructural alterations. The study

demonstrated that pretreatment of the nail plate with PA

(1% or 10% w/w) for short duration could be a potential

method of improving the efficiency of topical monotherapy in

treatment of nail disorders.

In vitro models to study transungual drug permeation

Nail is considered to be a stringent barrier to the permeation

of topical therapeutics owing to its thickness, chemical

composition, and relatively compact nature. In spite of this,

good number of experiments exhibit permeability of drugs

through the keratinized nail plate. Several models have been

developed and evaluated to predict the permeation of drug

through and across the human nail plate, some of which are

conferred below:

Animal hoof membranes

Animal hooves and human nail plate are reported to possess

analogous properties in regard to the content of keratin and

the release of soluble protein on incubation with keratinase,

and thus offer an alternative to human nails in permeation

studies [109]. Therefore, bovine [110], porcine [111] and

horse [93] hooves have been used by many researchers as

in vitro models to assess the nail permeability of topical

therapeutics.

Khengar et al. compared the swelling behavior of human

nail and horse’s hooves as a consequence of solvent uptake in

presence of penetration enhancers. When immersed in control

solution, an increase in weight by hooves was 40 ± 9%

compared to 27 ± 3% weight increase by human nails. Results

of Khengar suggested that the mammalian hoof is capable of

taking up and retaining more water than human nail, as

animal hoof keratin is thought to be less dense than human

nail plate (provides support to the findings of Mertin &

Lippold, 1997a) [48,93].

Animal hoof is more permeable than the human nail plate.

Hoof proteins have a significantly less disulfide linkage

compared to human nail plate [21]. As a result, the hoof may

be less susceptible to transungual permeation enhancers that

cleaves disulfide linkages. In such cases, enhancement of

perungual absorption in the hoof may be less than the

enhancement that could be achieved in human nail plate.

These findings may indicate that animal hooves do not

necessarily provide a representative model in which diffusion

through the nail can be evaluated.

Predominantly, hydrophilic gel membrane property of

human nail plate is similar to that of bovine hoof membrane,

which indeed made bovine hoof membrane a more suit-

able in vitro model for transungual permeation studies. Mertin

and Lippold (1997a) evaluated the in vitro permeability of


several antifungals through bovine hoof membranes using

diffusion cell. The relationship between permeability coeffi-

cients through human nail plate for the screened antifungals

was predicted and reported (r¼ 0.971) on the basis of their

permeation rates through the hoof membranes and their water

solubilities using the following equation:

log PN ¼ 3:723þ 1:751 log PH

where PN is the nail plate permeability coefficient and PH is

the permeability coefficient through the bovine hoof mem-

brane obtained experimentally [48].

Nail clippings

Nail clippings from fingers and toe nails of healthy human

volunteers are widely used as in vitro models to evaluate the

transungual formulations. Nail clippings can be hydrated by

soaking in water or other media prior to experimentations.

Permeation studies are carried out by mounting the hydrated

nail clippings on a nail adaptor, which is then sandwiched

between the donor and receiver compartments of diffusion

cell. Kobayashi et al. have established a relationship between

physicochemical properties and permeability of several

therapeutics across nail clippings [49]. Physical penetration

enhancement techniques such as iontophoresis were also

studied by several researchers using nail clippings as a

permeation barrier [58,69,112]. However, nail clipping is

short of the nail bed, so it might not be the best in vitro model

for ungual permeation studies.

Cadaver nail plates

A human finger and toe nail plates are, not surprisingly the

model considered to simulate, very closely, the in vivo

conditions. Hence, cadaver nail plate samples were used very

frequently to evaluate several topical antifungal formulations

containing transungual enhancers [89]. Physical enhancement

techniques were also being investigated using human cadaver

nail plates [11].

Murthy et al. (2009b) have revealed an improvement in the

permeation of terbinafine HCl when sodium sulfite and other

inorganic salts were used as penetration enhancers. Permeation

studies were performed across human cadaver nail plates

mounted on the nail adapter in the vertical Franz diffusion cell.

They observed that permeation was enhanced by�3–5-folds in

the presence of salts [104].

Figure 8. Schematic representation of sequence of procedures in TranScreen-N. It is micro-well plate-based technique of screening transungualpermeation enhancers. This involved ‘‘simultaneous exposure’’ and ‘‘sequential exposure’’ procedures run in parallel for screening of chemicalenhancers. Reprinted from [106] after slight modifications, with kind permission of copyright holder, John Willey and Sons Ltd., Hoboken, NJ.


Recently, Vejnovic et al. performed the permeation studies

across human cadaver nail plates using specially designed

modified Franz diffusion cell. Hydrophobins were used as

permeation enhancers and caffeine was employed as model

permeant. The permeability coefficient of caffeine was found

to increase by �3.6-folds in the presence of salts [113].

Hao and Li (2008a) studied the passive and the

iontophoretic transport of model permeants such as mannitol,

urea and tetraethylammonium ion across fully hydrated,

excised human cadaver nail plates with respect to location

(fingernail or toenail) and concluded that there is large

individual variability in nail permeation [59].

Nair et al. [114] evaluated the effect of iontophoresis on

the transungual delivery of TH using two ex vivo models viz.

nail on agarose model with human cadaver toe nails and a

surrounding ‘‘skin-like’’ barrier membrane and separately

with intact cadaver toe model. The drug was loaded into two

different applicator (nail-only and nail-and-skin applicator).

In the nail on agarose model, the amount of TH permeated

through the nail or nail and skin increased linearly with an

increase in the electrical dose for both the applicators, with

higher permeation observed using the nail-and-skin applicator

because of the increased skin delivery. The study concluded

that the iontophoresis improved TH permeation through and

load into the nail, and achieved levels above the MIC of TH

for dermatophytes. This may offer a novel treatment option

for onychomycosis.

Intact toes

Murthy et al. (2009a) have used excised toe as a model for

in vivo transungual permeation studies [11]. However, the

drug clearance from the nail bed and the nail matrix is lacking

in this model. Nonetheless, the cadaver toes simulate the

in vivo in many aspects and is one of the most appropriate

model for transungual drug delivery experimentations [28].

Opto-thermal transient emission radiometry(OTTER): Tool for estimation of solvent diffusioninto nails in vivo

Xiao et al. first described an infrared remote sensing

technique, Opto-Thermal Transient Emission Radiometry

(OTTER), to probe the extent to which solvents permeate

through the human nail plate in vivo. They examined the

efficiency of OTTER using decanol, glycerol and butyl

acetate as model solvents. Preliminary experiments have been

conducted on human volunteers using OTTER to examine the

uptake of the solvents that could potentially be used to deliver

active ingredients across the nail plate. Their findings

demonstrated the potential of OTTER as a tool to investigate

and optimize excipients to target drugs to the human nail

tissues in vivo [115].

Drug formulations studied across nail plate

A plenty of literature supports the investigational studies

being undertaken by scientists working particularly on

transungual drug delivery systems. The prime objective

might be the treatment of major onychopathies, in particular,

onychomycosis and nail psoriasis. Table 4 highlights a current

outlook on the role of various pilot molecules loaded in a

variety of topical formulations applied across the nail plate as

investigated in different research laboratories around the

globe.

Key commercial products available on market fornail disorders

A wide range of formulations has been developed for ungual

and transungual applications. In Table 5, authors have tried to

present a comprehensive coverage of all key commercial

products available on market for addressing the treatment of

nail disorders. Promising success to the development of

topical nail formulations and a good response to such

products in the pharmaceutical market enrolled these on the

list of pharmaceutical industries which have been looking for

further development to bring better therapeutic outcomes in

topical therapies.

Patents pertaining to transungual drug delivery

Despite the fact that many of them have not reached the

pharmaceutical market so far, a good number of patents have

been received on transungual drug delivery. Due to the

challenge of poor permeation across nail plate, only few

patents have been transferred into commercial marketed

products. However, there are some patents on the methods

Table 4. Drug formulations studied across nail plate as investigated indifferent research laboratories (Modified after [28]).

Pilot molecule Formulation/s Ref

Tioconazole Topical nail solution [3]Econazole Nail lacquer [4]Oxiconazole Nail lacquer [5]Ketoconazole Gel [6]Ketoconazole Films [6,7]Sertaconazole Nail patch [8]Miconazole Powder [9]Terbinafine Combination of oral &

topical solution[10]

Terbinafine Aqueous solution [11]Terbinafine HCl Topical gel [11]Terbinafine HCl Bilayered nail lacquer [12]Ciclopirox Topical gel [13]Chloramphenicol Nail lacquer [48]5-aminolevulinic acid Nail patch [88]Clobetasol-17-ropionate Nail lacquer [101]Caffeine Solution [113]Tioconazole & Griseofulvin Topical nail solution [116]Dimethyl sulfoxide Topical nail solution [117]Panthenol Non-lacquer film &

nail solution[118]

Glutaraldehyde Topical nail solution [119]Amorolfine/Ciclopirox Nail lacquer [120–123]Naftifine HCl Gel [124]Clotrimoxazole Cream [124]Ketoconazole/Ciclopirox Cream [125]Juglans regia

(Walnut hulls extract)Cream [126]

Voriconazole Nail lacquer [127]Keratin Thick film [128]Ketoconazole Nail lacquer [129]Triamcinolone &

Ciclopirox olamineAqueous nail lacquer [130]

Terbinafine HCl Liposome gel,Ethosome gel

[131]

Geraniol & Nerol Gel [132]


and devices employed to enhance the transungual permeabil-

ity and they would, no doubt, handover new formulations, in

the near future with major nail ailments at their crux. Selected

patents related to transungual drug delivery systems are

briefly outlined in Table 6.

Clinical status of transungual drug delivery

Substantial advancement has been built in this expanse of

research at the clinical level and some topical formulations

have been approved by FDA for clinical purpose. Table 7 lists

the transungually applied therapeutics that are either clinically

approved or in advanced phases of clinical trials [149].

Concluding remarks and future directions

Transungual drug delivery is indeed a reality, but its

therapeutic value is still under question. The permeability of

the dense, highly keratinized nail plate to topical therapeutics is

quite poor as such. This demonstrates poor delivery of

permeant molecules into the nail bed, which is believed to be

a primary site for many onychopathies (more often onycho-

mycosis and nail psoriasis). The permeant molecule must have

low molecular weight and remain undissociated in order to

permeate through the nail plate. However, there have been

contradictory findings and conflicting reports in the literature

about the influence of other variables relevant to permeant

(size, surface charge and hydrophilicity/hydrophobicity) and

formulation (nature and pH of the vehicle) on the transungual

drug permeation. This may be due to inadequate exploration of

factors affecting, and mechanisms involved in transungual

permeation. Under these circumstances, nail plate permeabil-

ity is modulated by an array of permeation enhancement

techniques that overcome the relatively impermeable nail plate

barrier and improve the therapeutic potential of topical cargos.

Table 5. Key commercial products available on market for transungual drug delivery.

Pilot molecule Formulation Brand name Manufacturer

Ciclopiroxamine (8%) Topical solution Onylac Cipla (Mumbai, India)Ciclopiroxamine (8%) Topical solution; Nail lacquer Penlac� Dermik Laboratories (Mississauga, Canada)Ciclopirox Nail lacquer Loprox� Aventis Pharma. Ltd. (Mumbai, India)Ciclopirox Gel (0.77%), Cream (0.77%), Solution (8%),

Topical suspension (0.77%)Loprox� Medicis Pharmaceutical Corp. (Scottsdale, AZ)

Ciclopirox Cream (1%) Loprox� Sanofi-Aventis (Paris, France)Ciclopirox olamine Cream (0.77%) Fougera� Fougera Pharmaceutical Inc. (Melville, NY)Ciclopirox Topical solution (8%) Rejuvenail� Menarini (Florence, Australia)Ciclopirox (8%) Nail lacquer Ciclopoli� Polichem SA (Pazzallo, Switzerland)Amorolfine (5%) Nail lacquer Loceryl� Roche Laboratories (Basel, Australia)Amorolfine (5%) Nail lacquer Curanil� Galderma (Lausanne, Switzerland)Econazole (5%) Nail lacquer EcoNail� Macrochem Corp. (Lexington, MA)Urea (40%) Nail film Umecta� Jsj Pharmaceuticals (Charleston, SC)Sertaconazole nitrate Nail patch Zalain� Labtec GmbH (Langenfeld, Germany)Sertaconazole nitrate (2%) Cream Ertaczo� OrthoNeutorgena (Los Angeles, CA)Tazarotene (0.1%) Gel Tazorac� Allergan Inc. (Irvine, CA)Tazarotene (0.05% & 0.1%) Topical gel Zorac� Allergan Inc. (Irvine, CA)Tazarotene Cream Avage� Allergan Inc. (Irvine, CA)Ticonazole Topical solution Trosyl� Pfizer Ltd. (Tadworth, UK)Salicylic acid Nail paint Phytex� Pharmax Healthcare Ltd. (Bexley, UK)Methyl undecenoate Nail paint Monphytol� LAB (UK)

Table 6. Patents pertaining to ungual and transungual drug delivery systems.

Drug Therapeutic application Drug delivery system Patent no. Ref

Griseofulvin Onychomycosis Nail lacquer US 005487776 A (1996) [133]Ciclopirox olamine Onychomycosis Topical solution US 005840283 A (1998) [134]Butenafine HCl Onychomycosis Gel US 006143794 A (2000) [135]Fluconazole NS Nail lacquer, Solution US 006585963 B1 (2003) [136]Antifungal topical agents Onychomycosis Topical gel & cream US 006846837 B2 (2005) [137]Antimycotic agents Onychoschizia Nail lacquer US 0134039 A1 (2006) [138]Benzalkonium chloride NS Lotion, ointment, nail polish US 7198794 B1 (2007) [139]Clotrimazole, Amorolfine, Terbinafine NS Topical solution & Cream US 0166249 A1 (2007) [140]Terbinafine HCl Onychomycosis Dual action nail coat US 7462362 B2 (2008) [141]Antifungal agents Onychomicosis Solution, Solid/semisolid implants,

Microparticles & crystalsUS 0132442 A1 (2008) [142]

Terbinafine HCl, Fluconazole Onychomicosis Gel (Iontophoresis) US 0319371 A1 (2008) [143]Terbinafine Nail psoriasis Hydrogel US 0175945 A1 (2009) [144]Antifungal agents Onychomicosis NS US 0215888 A1 (2009) [145]Terbinafine Onychomicosis NS US 7820720 B2 (2010) [146]Hydrogen peroxide Onychomicosis Gel US 0098645 A1 (2010) [1]Terbinafine HCl, Clotrimazole Onychomicosis Cream US 0083692 A1 (2011) [147]Antifungal agents Onychomicosis,

Nail psoriasisThermogel US 0010227 A1 (2012) [148]

NS, not specified.


Nail abrasion and surgical avulsion (albeit invasive and

painful) have been used by dermatologists and podiatric

physicians since long time but, current research focuses on

less invasive physical and chemical modes of nail permeation

enhancement. Physical penetration enhancement techniques

like iontophoresis have displayed promising results in

facilitating transungual drug delivery. Although, thiols/mer-

captans (N-acetylcysteine, mercaptoethanol) and keratolytic

agents (urea) have shown remarkable permeation enhance-

ment, but efforts to endeavor the transungual permeation

using other chemical enhancers have not been convincing

so far.

The field of transungual drug delivery is relatively young

and there is ample opportunity for researchers to develop

novel topical formulations for transungual drug delivery,

urging pharmaceutical industries to commercialize the prod-

ucts for topical therapy. In addition, late-stage clinical trials of

topical antimycotics authenticate the research in this field.

The escalated filing and granting of patents on drug delivery

devices, permeation enhancers, and enhancement techniques

necessitates radical advancements in transungual drug deliv-

ery system so as to boost the therapeutic outcome. The

authors strongly believe that the future will lie in the

comprehensive resolution of unhampered challenges of nail

penetration enhancement. Aforementioned research perspec-

tives on transungual drug delivery are currently under

investigation of our research group.

Declaration of interest

The authors report no conflicts of interest. The authors alone

are responsible for the content and writing of the article.

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NS, not specified.


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Insights into drug delivery across the nail plate barrier

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