AAPS PharmSciTech (2020) 21:67

DOI: 10.1208/s12249-019-1591-9

Review Article

Mechanistic Insights of Formulation Approaches for the Treatment of Nail

Infection: Conventional and Novel Drug Delivery Approaches

Agrawal Vikas,1,2,4 Patel Rashmin,1 Patel Mrunali,1 Rahul B. Chavan,2 and Thanki Kaushik3

Received 6 July 2019; accepted 25 November 2019

Abstract. Onychomycosis is a chronic disorder that is difficult to manage and hard to eradicate
with perilous trends to relapse. Due to increased prevalence of HIV, use of immunosup-
pressant drugs and lifestyle-related factors, population affected with fungal infection of nail
(Onychomycosis) happens to increase extensively in last two decades. Modalities available
for the treatment of onychomycosis include systemically administered antifungals, mechanical
procedures, and topical drug therapy. But the efficacy of the most of approaches to deliver
drug at targeted site, i.e., deep-seated infected nail bed is limited due to compact and highly
keratinized nail structure. A series of advanced formulation approaches, such as
transfersomes, liposomes, nano/micro emulsion, nail lacquers etc., have been attempted to
improve the drug penetration into nail plate more efficiently. The manuscript reviews these
formulation approaches with their possible mechanisms by which they improve the drug
penetration.Comparative analysis of available treatment modalities for onychomycosis has
been provided with pros and cons of each alternatives. Additionally, ongoing research about
the application of biological materials such as modified cationic antimicrobial peptides
(AMPs), plant-derived proteins, and synthetic antimicrobial peptidomimetics have also been
explored.
KEY WORDS: onychomycosis; microemulsion; topical drug delivery; nail infection; nail lacquer.

INTRODUCTION clear [5]. In 1972, Zaias classified the onychomycosis based on

their clinical appearances, which helped in describing and
About 19% of the global population is affected by the grouping common patterns of fungal infection affecting the
fungal infection of the human nail, which is known as nail plate [6]. Baran et al. further revised the classification
onychomycosis. Its occurrence seems to be increasing with system of onychomycosis (Fig. 1), but this time based upon
the spread of HIV infection, higher frequency of immuno- the pattern of nail plate involvement by mode and site of
suppression due to excessive use of immunosuppressant invasion rather than by fungal etiology [7]. This new more
drugs, lifestyle-related factors like wearing tight-fitting cloth- comprehensive classification system covers the latest updates
ing and shoes [1]. More than 90% of cases of onychomycosis about the onychomycosis disease such as identification of
of the toenails are caused because of dermatophytes. List of endonyx onychomycosis in which the core of the nail plate is
causative pathogens for this nail infection includes dermato- infected. Benefits of this revised classification system include
phytes (Microsporum, Epidermophyton, and Trichophyton) clear differentiation between primary and secondary total
and non-dermatophytes (e.g. Neoscytalidium, Scopulariopsis, dystrophic onychomycosis. In primary total dystrophic
Aspergillus, and Fusarium) [2–4]. Additionally, mixed infec- onychomycosis, all tissues of the nail apparatus involved in
tions have been reported, although their significance is less chronic mucocutaneous candidiasis are included, while sec-
ondary total dystrophic onychomycosis comprise the different
1 types of destructive nail dystrophy.
Department of Pharmaceutics, Ramanbhai Patel College of Phar-
Allyl amines, azoles, benzoxaboroles, and echinocandins
ma cy, C h a r o t a r U ni v e r s i t y o f S ci e n ce & Tec hn o l o g y
(CHARUSAT), CHARUSAT Campus-Changa, Anand, Gujarat are the broad anti-fungal agent categories, until now,
388 421, India. explored for the treatment of onychomycosis [12]. Allylamine
2
Department of Pharmaceutical Science, Amneal Pharmaceuticals class of anti-fungal drugs act by inhibiting the squalene
Pvt. Ltd, Office No. 901-911, 9th Floor, Iskon Elegance, epoxidase [13]. This class includes terbinafine, naftifine, and
S.G.Highway, Ahmedabad, Gujarat 380 015, India. butenafine [14]. Anti-fungal agents that belong to azoles
3
Section for Biologics, University of Copenhagen, Copenhagen, category inhibit CYP450, which eventually blocks the con-
4
Denmark. version of lanosterol into ergosterol by C14 α-demethylase
To whom correspondence should be addressed. (e–mail: and prevents fungal cell growth [15]. Posaconazole,
vikas2845agrawal@gmail.com)

1530-9932/20/0000-0001/0 # 2020 American Association of Pharmaceutical Scientists

 67 Page 2 of 12 Vikas et al. (2020) 21:67

Fig. 1. Classification of onychomycosis [7–11]

ravuconazole, voriconazole, and ketoconazole are the widely very thin (consists of only 1–2 cells thick) and connects it to
explored azoles in onychomycosis treatment. Compared to the underlying nail blade. Often within the proximal aspect of
azoles and allyl amines, benzoxaboroles are the newest the nail plate, most notably on thumbs, a white cresent-
category of anti-fungal drugs. Basically, benzoxaborole mol- shaped area known as lanulae is present. The highly vascular
ecules are made up from a 1,3-dihydro-2,1-benzoxaborole network of nail bed imparts pink color to the dorsal surface of
lead compound [16,17]. Tavaborole and AN-2718 are the two nail.
examples of this category, which are being clinically tested for Onychomycosis mainly infects the area underneath the
onychomycosis treatment [18–20]. Their mechanism of action nail plate. Infection generates thick hyperkeratotic nodule
is different than azoles and allyl amines, since they target which contains the clusters of branching filaments (hyphae)
protein synthesis, as opposed to fungal cell wall synthesis, called dermatophytoma. Also, nail becomes severly deformed
providing an alternate means of targeting fungi in and causes nail lifting, brittleness, and discoloration, which is
onychomycosis. They inhibit the fungal LeuRS tRNA syn- the main reason behind acute pain in onychomycosis.
thetase which causes an imbalance in the cell’s tRNA Additionally, this abnormal thickness of nail may result into
reserves. This imbalance blocks protein synthesis in vivo soft tissue breakdown, inflammation of subcutaneous tissues,
[21,22]. and ulceration in the nail bed. From drug delivery point of
Onychomycosis is a not life-threatening infection, but if view, thick abnormal thickness further decreases the drug
not treated properly can transform into an exasperating penetration into the nail bed or infected region.
problem, which may consume more time to restore its
reasonable condition. The preferred therapy for treating the
onychomycosis involves a combination of systemic drug CHALLENGES TO THE THERAPY OF
delivery with topical treatment. Numerous formulation ap- ONYCHOMYCOSIS
proaches have been reported in the literature which aims to
increase the diffusion of the anti-fungal agent through the The chroninc and relapsing nature makes onychomycosis
dense ungula keratin layers. This review article provides an a challenging infection to treat successfully. On the other side,
overview of such formulation approaches along with the infected nails appear discolored, ugly, dystrophic, and thick-
mechanism by which they improve the penetration of drug in ened, which negatively impact the social life of the patient
the nail bed and treat onychomycosis. Additionally, chal- [23]. Since the infecting pathogens are embedded in the nail
lenges involved in the treatment of onychomycosis have been bed, treatment of onychomycosis becomes a challenging task
described with the special dialog on the advanced formulation [24]. Treatment modalities available for onychomycosis
approaches such as a colloidal drug delivery system. include systemically administered anti-fungals, mechanical
procedures, and topical drug therapy.

ANATOMY OF NAIL
Conventional Treatment
The nail plate comprises the proximal nail fold, nail
matrix, nail bed, and the hyponychium. The nail plate The most common way of treating onychomycosis is oral
generates from the matrix, emerges via proximal nail fold, administration of anti-fungal agents. Orally administered anti-
and is held in place by lateral nail folds. Nail plate covers the fungal agents include terbinafine, itraconazole, and flucona-
nail bed and detaches from the latter at hyponychium. The zole. Due to higher efficacy and lesser drug-drug interactions,
nail plate is found to be thin, slightly elastic, hard, translucent, terbinafine is the most preferred drug for the treatment of
and convex shaped. These cells are tightly attached with each onychomycosis. After oral administration of terbinafine, it
other through intercellular links, desmosomes, and mem- undergoes absorption into the systemic circulation, followed
brane coating granules. Furthermore, the nail plate is divided by its diffusion from the blood vessels into the nail plate via
into macroscopic layers such as dorsal, intermediate, and the nail bed. The most common regimen of terbinafine
ventral based upon the differential ultrasound transmission. encompasses administration of 250 mg daily for 6 weeks for
These layers named as dorsal, intermediate, and ventral. The fingernails and 12–16 weeks for toenails. While itraconazole is
dorsal layer of nail plate is only few cells thick, while usually taken intermittently as it accumulates in the nail, its
intermediate layer which represent the thickest layer is soft dosing regimen involves 200 mg twice a day administration
and more flexible. However, the third layer of nail plate is for first week, followed by 3 weeks off between successive
Conventional and Novel Drug Delivery Approaches (2020) 21:67 67 Page 3 of 12

pulses [25]. Fluconazole is recommended to be taken once in onychomycosis [41]. Short-pulse neodymium yttrium-
a week (150 mg) until the diseased nail plate has grown out. aluminum garnet (Nd: YAG) 1064 device is the first approved
However, oral therapy of anti-fungal agents faces laser therapy-based device for the treatment of
limitations such as high percentage of treatment failure and onychomycosis. It acts as fungistatic or fungicidal due to its
relapse occurrences, which makes onychomycosis a difficult thermal effect [25]. Ti/sapphire laser is another example
infection to treat [24,26–28]. Nearly 22.2% of patients treated under this laser category which was explored for the
with an oral anti-fungal agent have reported of experiencing a treatment of onychomycosis. This is a modelocked laser that
relapse during a 3-year follow-up period [29]. For getting the emits 200-fs length pulses at a frequency of 76 MHz at the
proper effect of an anti-fungal drug, its distribution through- near-infrared wavelength, of 800 nm [12]. Microporation is
out the nail bed is necessary so that it can eradicate the another physical method employed to improve drug penetra-
pathogens. Nail bed of an infected patient shows a negative tion into nail bed. Path Scientific, Carlisle, USA, developed
culture and negative microscopy, which is termed a mycolog- hand-held nail trephination (micro-cutting) device, known as
ical cure; however, a clinical cure involves not only the PathFormer [42]. This device helps in creating holes of
elimination of the fungi from the nail bed but also the specific depth (micro-conduite) into the nail plate without
formation of clear, new nail growth with the complete affecting the nail bed. The electrical resistance of nail bed acts
absence of dystrophic characteristics. Since the growth of as a feedback to stop this device from drilling.
toenails is prolonged (∼ 1 mm/month), evidence of a clinical Using these local therapies, the removal of infected nails
cure can take about 9–12 months. Because of this, the can be possible, but the onychomycosis recurs again once the
treatment period for onychomycosis is prolonged and re- new nail grows back, which limits the application of these
quires minimum 3–12 months. local procedures in achieving the disease-free period. Addi-
Due to varied anatomy of the nail, fungal pathogens get tionally, local therapies involve traumatic avulsion procedure;
the opportunity to invade and proliferate deeply into the nail hence, it is rarely used today. Historically, removal of the nail
plate, the nail bed, and the surrounding tissues. So, for by using chemicals such as urea ointment was also utilized to
systemically administered drugs, two different hurdles have to treat the infection. However, these days, the medical practi-
be overcome, first one is to reach up to nail bed and the tioner does not prefer this method of nail removal. In the first
second one is to achieve sufficient concentration in the nail place, podiatrists try to reduce symptoms by performing
plate to remove dermatophytes at this location. Most periodic trimming and debridement of the affected nails. In
common pathway for permeation of systemically adminis- comparison to surgical procedures to treat onychomycosis
tered drugs to nail plate goes through a continually prolifer- with marginal benefit to the patient, drug therapies are
ating epidermal tissue (called as nail matrix), which serves as promising in an attempt to treat this disease effectively;
the origin of new nail growth. Since the growth rate of however, 100% success in treating onychomycosis is still not
toenails lengthens, permeation of drug to nail plate through achieved.
these newly grown nail matrices is a slow process [30]. As a
result of this slow growth rate, the treatment period of
onychomycosis by oral therapy takes quite a long time and Topical Drug Delivery
this may have the inherent disadvantage of causing systemic
adverse effects. Ciclopirox is the most popular drug molecule for the
topical treatment of onychomycosis. This hydroxypyridone
analog is active against many pathogenic fungi such as
Local Interventions dermatophytes, M. furfur and Candida spp. [43,44]. Mecha-
nism of action of ciclopirox involves inhibition of metal-
Drug permeation to nail bed can be accomplished using dependant enzymes through chelation of the polyvalent
local intervention techniques, which comprises physical cations (Fe3+ or Al3+). Its treatment regimen includes daily
techniques like laser treatment, photodynamic therapy [31], administration to the infected nails up to ≥ 6 months.
iontophoresis [32], hydration and occlusion, microporation Ciclopirox persists in the nail for 14 days after the therapy
[33,34], and ultrasound therapy [35], mechanical methods is completed. Amorolfine is the second most preferred drug
(etching/mesoscissioning), and using chemical penetration molecule for topical therapy of onychomycosis. This synthetic
enhancers (keratolytic agents, urea, hydrogen peroxides, anti-fungal drug belongs to the morpholine group. It showed
sulfites, keratinolytic enzyme mercaptans, and water) fungicidal activity against T. mentagrophytes and C. albicans.
[36,37]. Among these local therapies, iontophoresis is the Its dose regimen involves once or twice weekly administra-
most frequently used technique to increase the drug diffusion/ tion to the infected nails for 6–12 months. Similar to
permeation through the dense keratin layer of the nail plate. ciclopirox, it persists in the nail for 14 days after completion
Briefly, the procedure involves drug depot formation into of the therapy [45,46]. Both the drugs are formulated as nail
keratin layers of the nail using iontophoresis, from which drug lacquers, which are applied onto the infected nails. The
will release slowly with time. Murthy et al. first time water-insoluble film formed after drying of nail lacquers on
investigated the use of iontophoresis for transungual drug top of the infected nail acts as a drug depot.
delivery. In this technique, low density electric current is used Topically administered drugs face even more difficult
to deliver charged drug molecules through the dense keratin challenges such as penetration up to all infected sites of these
layer of nail plate [32,38–40]. Laser-based therapy is also deep-seated infections. This challenge of achieving relevant
popular for the treatment of the onychomycosis. Near- concentrations of anti-fungal drug to kill pathogens through-
infrared region (780–3000 nm) of laser light can heat the out the nail unit is mainly governed by the nail plate’s
target tissue and is approved by US-FDA for the treatment of thickness and compact structure of cells. Hard and convex
 67 Page 4 of 12 Vikas et al. (2020) 21:67

structure of nail plate contains nearly 25 layers of dead, Nail Lacquer

flattened, and keratinized cells which are tightly bound
together. The main barrier for drug diffusion across the nail In the field of cosmetics, nail lacquers are quite famous
plate is the upper (dorsal) layer, which is a few cell layers for decorating and protecting the nails. Formulation of
thick and consists of hard keratin [47]. While the middle layer medicated nail lacquers have become immensely popular for
made up of soft keratin cells comprises 75% of the whole nail drug delivery to nail. Table I provides a brief idea about the
thickness. The ventral layer of soft keratin present just below reported nail lacquers in the literature along with their
the middle layer is few cells thick, which connects to the composition. Nail lacquers mainly comprise a solution of a
underlying nail bed in which many pathological changes can drug with film forming polymer. After application of this
occur [48–50]. Thus, penetration of drug up to ventral nail solution on nail plate, the solvent evaporates and forms a film
plate and the nail bed and attaining the effective drug on the nail plate which works like drug depot [54]. Drug
concentration is of the prime requirement for the treatment release and permeate across the nail from this drug depot.
of nail diseases. Chemically, the nail plate mainly consists of But for permeation of drug across the nail plate, high
keratins (fibrous protein), which are highly cross-linked with diffusion gradient is required as a driving force. Film formed
disulfide bonds. Coupled with the highly compact structure of after solvent evaporation generates a driving force on account
the keratinized cells in the nail plate, these highly cross-linked of hyper hydration of the upper nail plate layer by preventing
proteins act as a formidable barrier for the topically water loss from the nail surface into the atmosphere. This
administered anti-fungal [1,35,51,52]. This may result in poor hyper hydration of nail plate improves the drug diffusion.
drug penetration up to inner ventral layer, and drug Additionally, incorporation of penetration enhancers (for
concentration remains below effective therapeutic concentra- example, keratolytic agents, hydrating agents, and thiol
tion. Another factor contributing to the hurdles of topically compounds), in the film further, enhances drug permeation
applied anti-fungal drugs to penetrate the nail plate is the across nail plate through various mechanisms [55]. Figure 3
apparent mismatch of drug physicochemical properties with highlights the different mechanism of drug permeation via
the biophysical properties of the nail plate. Most existing anti- nail lacquer.
fungal drugs were originally designed for oral and/or skin In general, nail lacquer comprises volatile organic
applications and are consequently fairly lipophilic molecules, solvent to solubilize the drug [56], film-forming agent, and
only sparingly soluble in water and have molecular weights of plasticizer. Plasticizer is added to the nail lacquers to form a
≥ 300 Da. On the other hand, with its dense keratin fabric film with proper flexibility and durability. Purposes of
network and a high capacity for flux of water, the nail plate addition of resins, suspending agents, and surfactant to the
has been described as a hydrophilic gel. Thus, most of the nail lacquers are to enhance the adhesive property of the film,
known anti-fungal agents will not find a compatible environ- increase the viscosity of enamel, and improve drug’s wetta-
ment in traversing the nail plate. Summary of challenges bility and solubility, respectively. Humectants are also a part
involved in topical delivery of an anti-fungal agent to nail bed of nail lacquer composition to improve the drug solubility and
is depicted in Fig. 2. permeation.
Film-forming agents are an essential component of nail
lacquers. After application of nail lacquers, the volatile
Formulation Options solvent evaporates and leaves behind a thin polymeric film
on the nail surface. This film acts as a drug reservoir from
The proce ss of drug discovery with desired which drug releases slowly and penetrates into and through
pharmacologic/pharmacokinetic properties is a lengthy, te- the nail. Films formed after the application of nail lacquers
dious, and costly process. Therefore, researchers are more are categorized as water soluble/insoluble films. This classifi-
focused towards the development of formulation, which cation is mainly based upon the polymer used for film
would help in achieving desired drug penetration and formation. Water-soluble films are easily removed once
effective therapeutic concentration in the ventral layer of exposed to water. Hence, there is no need for periodic
the nail plate and nail bed [53]. removal of film using organic solvent and prevent a recur-
The conventional formulation approaches like oral/ rence. Water-soluble films mainly contain hydroxypropyl
topical solutions, ointments, and creams possess short resi- chitosan (HPCH), which was derived from alkylated chitosan
dence time on the nail surface. For any topical formulation and hydroxyl groups. Higher film adhesion property of
approach, it is desired that formulation must hydrate or HPCH was attributed to its ability to form a hydrogen bond
enhance the hydration of nail bed so that permeation of drug with the keratin and capacity to hydrate the nail plate for
through it gets enhanced. However, formulations like proper adhesion [57]. Ciclochem Unas and Ciclopoli/Onytech
ointments and creams failed to achieve this because of their are the two marketed nail lacquers developed using water-
hydrophobic nature, which limited their applicability in the soluble film former. Additionally, HPCH has also shown the
treatment of nail disorders. Therefore, there was a need to ability to promote nail growth, which helps in reducing the
develop formulations having the ability to increase the treatment period. On the other side, water-insoluble nail
residence time of drug on the nail surface, improve the lacquers like methacrylic polymers and vinyl resins-based
hydration level of the nail plate, or provide an occlusive films are known for providing sustained drug release and
effect. Nail lacquers, adhesive patches, and films have the have wash-resistant nature. But these films possess limitation
ability to increase nail hydration owning to their occlusive such as the requirement of weekly removal using either
properties which ultimately improve the drug diffusion organic solvents or mechanically (nail filing), which adversely
through the nail plate. On the other hand, gels enhance drug affect surrounding skin adversely [58].
permeation by increasing residence time [5].
Conventional and Novel Drug Delivery Approaches (2020) 21:67 67 Page 5 of 12

Fig. 2. Challenges involved in topical delivery of anti-fungal agent [47]

Penlac is a FDA-approved nail lacquer formulation that compliance. Hence, there is a need to a design drug delivery
contains 8% ciclopirox for the treatment of onychomycosis. system which requires less frequent administration and
Amorolfine (5%) nail lacquer (Loceryl®) is approved in ultimately improves patient compliance and comfort. This
Australia and United Kingdom for the same purpose. List of problem can be solved by formulating patches as they offer
marketed nail lacquers is provided in Table II, along with the advantages like sustained/controlled drug release for a long
active and base component. Optimization is necessary as duration with a single application. A transungual drug
permeation of drug(s) from the nail lacquers is governed by delivery patch formulation contains a pressure-sensitive
solubility and diffusion coefficient of the drug in the adhesive matrix, drug-impermeable backing membrane, a
polymeric film as well as in the nail plate. Few investigators release liner, and other excipients. In addition to nail
have observed that the penetration of drug increases with the adhesion, pressure-sensitive adhesive matrix serves as a drug
increase in its concentration in the formulation. However, reservoir. Critical parameters in the selection of PSA
other researchers have inferred that the type of formulation (pressure sensitive adhesive) matrix include desired release
affects the effective delivery of drugs. pattern of the drug from the matrix, the ability of the drug to
Major advantages of topical nail lacquers involve permeate through the nail plate and compatibility of formu-
lation components (drug, polymer, and other additives).
1. Nail lacquer prevents reinfection at the beginning of Myoung et al. studied the impact of different PSA
the treatment as it inhibits adhesion of fungal spores polymers (polystyrene-polyisoprene-polystyrene, acrylic,
(propagules) on and underneath nail plate. polystyrenepolybutadiene-polystyrene, silicone, and
2. Nail lacquers form an occlusive lacquer film and polyisobutylene) on drug release pattern from the matrix
increase nail plate hydrations, which ultimately help and drug permeation through the nail plate. Highest
in enhancing the diffusion of anti-fungal drug across ciclopirox permeation was observed with acrylic adhesive
the nail plate. Hydration enhances anti-fungal drug with a hydroxyl functional group. With the help of structure-
diffusion through the nail plate. activity relationship author concluded that the presence of
3. Additionally, this hydration benefit of nail lacquer hydroxyl functional group in polymer caused the highest
helps in germination of drug susceptible fungal permeation and while, PSA with PEO grafted acrylic
hyphae and limits formation and persistence of drug- adhesives resulted in the lowest permeation rate [77].
resistant fungal spores. Donnelly et al. developed a bioadhesive patch of 5-
Recent time has witnessed the advancement in conven- aminolevulinic acid (ALA). An aqueous mixture of two
tional nail lacquers to improve the penetration of anti-fungal polymers, i.e. tripropylene glycol methyl ether and poly
agent into the nail bed. For example, Hui et al. from (methyl vinyl ether/maleic anhydride), was used for the
Maibach’s group developed nail lacquers using SEPA® (2- preparation of patch. Approximately 5-h lag time was
n-nonyl 1,3-dioxolane) to improve the drug penetration into observed for the permeation of ALA followed by improve-
nail. This nail lacquer formulation is now termed as ment in the rate of permeation. After 24 and 48 h of
Econail™. The author reported that incorporation of SEPA® application, 2.8 and 6.9 mM drug concentration was detected
into nail lacquer showed 6-fold improvements in drug in the ventral layer of nail, respectively [78].
permeation through nail than the control. Dioxalones,
permeation enhancer, act by modifying the lipid diffusion Films
pathway of the skin. The exact mechanism by which
dioxalone promotes drug influx into the nail was not Transungual films provide better adherence and proved
explained clearly by the author, but they proposed that to have superior penetration and efficacy compared to
SEPA® acts as an adhesion promoter and plasticizer for the conventional nail formulations like lotions, gels etc. Drug-
nail which facilitated enhanced penetration of the drug into loaded films used for transungual applications are normally
the nail [75,76]. produced using hot melt extrusion (HME) or film casting
method. Mididoddi et al. evaluated the influence of instru-
Patches ment variables and etching on the bioadhesion of the film on
the human nail. Film contaning ketoconazole was prepared
A major limitation of nail lacquers and creams is that using HPC and/or poly(ethylene oxide). Bioadhesion param-
they are too easily wiped or washed off from the nails. This eters (peak adhesion force and area under the curve) were
results in application of nail lacquers and creams to nails up found to be higher for HPC-based film on etched nails as
to 6 months for complete cure and affects the patient compared to the non treated control nails [79]. In further
 67 Page 6 of 12 Vikas et al. (2020) 21:67

Table I. Examples of Nail Lacquer Reported in the Literature

Drug name Component of formulation Outcomes Ref

T e r b i n a fi n e H C l Hydrophilic lacquer-hydroxypropyl methylcellulose High drug load, reduced drug loss due to repeated [59]
(bilayered nail lacquer) (HPMC) E-15 contained polyethylene glycol (PEG) washing
400
Water-resistant film former- poly (4-vinyl phenol)
Terbinafine HCl Combination of Eudragit RL 100 (hydrophobic High permeation and drug retention in the nail plate [60]
polymer) and Hydroxypropyl cellulose (HPC) LF
(hydrophilic polymer)
Naftifine HCl Eudragit RL100, Eudragit RS100, and ethyl cellulose Release of drug directly proportional to the [61]
concentration of Eudragit RL100 in the formulation
Ciclopirox olamine or Poloxamer 407, methyl- β-cyclodextrin, N- Low concentration of Poloxmer and use of hydro- [62]
clobetasol propionate acetylcysteine and hydro-ethanolic mixture ethanolic mixtures as solvent improved the efficacy of
nail lacquer through rapid drying and easy film
formation
Isotretinoin Ethyl cellulose and thioglycolic acid Improvement in permeation [63]
Ciclopirox olamine or Sodium lauryl sulpha te (SLS), PEG 300, Impact of base component on the microstructure, nail [64]
clobetasol propionate carbocysteine, N-acetylcysteine, lactic acid, surface and drug permeability studied
potassium phosphate, Labrasol® and Labrafil®
Ciclopirox Solvent-isopropyl alcohol (IPA), alkalizing agent- Enhanced retention of drug and high permeation [65]
potassium hydroxide, permeation enhancer- urea compared to marketed formulation
Ciclopirox Film former- Eudragit RLPO, penetration enhancer- Three fold enhancement in permeation [66]
papain
Terbinafine HCl Film former-Eudragit RLPO Nail lacquers showed higher retention time as [67]
In situ gel-Pluronic® F68 compared to the marketed cream formulation.
Terbinafine HCl Polyurethanes Polyurethanes based lacquers showed good wettability [68]
properties, biocompatibility with keratinocytes, and
adequate free volume.
Te r b i n a fi n e H C l Film former- nitrocellulose Permeability of terbinafine HCl through liposome- •
(liposome-loaded nail Adhesive resin-toluene sulfonamide loaded nail lacquer was found to be significantly higher [69]
lacquer) Formaldehyde than nail lacquer with a permeation enhancer
Ciclopirox Water-soluble film-forming agent HPCH Due to intimate contact and strong adhesion property [57]
of HPCH lacquer for keratin responsible for increased
permeation of drug.
Ciclopirox and N-acetylcysteine, partially methylated β-cyclodextrin Addition of methylated β-cyclodextrin into lacquers [70]
triamcinolone and urea were incorporated as penetration en- improved thermogelling property, solubilization and
hancers and polypseudorotaxanes of Pluronic F-127 accelerated the drug penetration.
[14C]-Ketoconazole Ethanol, polysilicone-8, panthenol, acrylates Cumulative concentrations of ketoconazole achieved in [71]
copolymer, tocopheryl acetate, phytantriol, butylene the deep ventral layer of nail plate and the nail bed
glycol, benzophenone-3, and calcium chloride, and using nail lacquers were significantly higher than
fragrance commercial ketoconazole cream
Natural coniferous resin Resin content in nail lacquer-30%. Clinical efficacy of resin based nail lacquer proved. [72]
from the Norway spruce Other component- Monopropylene glycol, glycerol
(Picea abies) and alcohol
Luliconazole HPMC, PEG-400, glycerol, and thioglycolic acid Formulation stable for 1 month, low drying time, [73]
appreciable nonvolatile content, and minimal skin
irritation with suitable esthetic coverage
Ketoconazole Hydrophobic (Eudragit RL 100) and hydrophilic Optimized formulation showed 2.81 fold higher [74]
polymer (Klucel LF; HPC) penetration and 2.98 fold retention time compared to
the marketed formulation

study, Mididoddi et al. prepared HPC-based film of ketoco- significant increase in the drug permability as compared to
nazole drug using HME with and without tartaric acid and control [81].
evaluated for moisture sorption, bioadhesive, and mechanical
properties. The author demonstrated that tartaric acid acts as Colloidal Ungual Formulations
an effective plasticizer, increased percent elongation, and
decreased the tensile strength of the HPC films [80]. Repka Conventional systemic drug delivery options discussed
et al. also developed HPC and poly(ethylene oxide)-based before for the treatment of nail infection has been associated
film of ketoconazole and evaluated for drug permeability and with severe side effects and has the potential for drug-drug
bioadhesion property using tensile and peel tests. In vitro interactions which has clear implications for patients’ safety,
permability study of HME film of ketoconazole showed the pharmaco-economic impact of monitoring patients at risk
Conventional and Novel Drug Delivery Approaches (2020) 21:67 67 Page 7 of 12

of these adverse reactions. On the other hand, topical anti- Ghannoum et al. reported the ultrastructural changes in
fungal therapy bypasses the systemic side effects of oral anti- T. rubrum hyphae treated with TDT 067 or conventional
fungal agents, but the efficacy rates are poor for topical terbinafine hydrochloride using transmission electron micros-
therapy as compared to oral therapy. Novel topical prepara- copy (TEM) and scanning electron microscopy (SEM)
tions comprising colloidal/ nano formulations offer high rate analysis. Author reported that transfersome potentiates the
of efficacy with less systemic effects of anti-fungal agents and action of drug by delivering it to the site of action more
may benefit patients with onychomycosis. Colloidal drug effectively where it disrupts the intracellular matrix. Through
delivery systems have gained a lot of importance in recent SEM analysis, the author demonstrated that TDT 067 caused
past as they try to cure diseases/disorders at the cellular and rapid and more extensive disruption of fungal hyphae in
molecular levels. comparison to conventional terbinafine. Author further
proved the higher potency of TDT 067 against plain
Transfersomes terbinafine and terbinafine spray. It showed MIC range of
0.00003–0.015 mg/ml against dermatophyte strains which was
The transfersome was developed by Targeted Delivery 8-fold and 60-fold lower than those of plain terbinafine and
Technologies Ltd. This colloidal drug delivery system is a terbinafine spray, respectively [83].
highly deformable drug carrier, consisits of complex lipid as a Naumann et al. demonstrated the effectiveness of
vesicle, and was originally formulated for the non-invasive colloidal formulations in improving the penetration of a novel
drug delivery through the skin. These vesicles possess ability anti-fungal drug EV086K through the nail plate in compar-
to permeate through skin, driven by the transcutaneous water ison to the conventional formulations (hydrogel, nail lacquer,
gradient. The carrier-mediated drug delivery through hydro- and topical solution). Author investigated the pharmacoki-
philic channels in the skin achieves a high concentration of netic data of drug penetration using animal hooves in the
drug in sub-dermal tissues, unlike conventional topical online diffusion cell. Colloidal formulation of EV-086K was
preparations [82]. prepared using an oily excipient (Pelemol® BIP), emulsifiers
TDT 067 is one such colloidal/vesicular drug delivery system (Tagat®), and an aqueous component consisting of a water–
which is extensively researched in recent time. It is a sprayable propylene glycol mixture. In vitro studies revealed that the
ultra-deformable vesicle of terbinafine HCl for the treatment of penetration rate of EV-086K into the human nail plate using
nail infection. This vesicular system has also been referred in colloidal formulation was significantly higher than other
literature as ‘transfersomes’ [83,84]. They possess ability to formulations and a significant amount of drug was deposited
transport drug molecules through the narrow pathways of skin into the nail plate. Also, the time required for penetration
cell membrane (5–10 times narrower than cell diameter) without into the nail barrier was quite short, which is desirable for
significant loss. By mimicking same mechanism, vesicles of onychomycosis therapy [85].
terbinafine HCl penetrate through the skin and diffuse rapidly
into the fungal cell wall leading to its destruction. This vesicular Micro/Nano-emulsion
system deliver drug into the nail bed at therapeutic concentration
via lateral diffusion through the skin. Excipients used in the An antimicrobial oil in water (O/W) nano-emulsion (NB-
preparation of TDT 067 have all been used widely in pharma- 002) consisiting of extremely stable positively charged,
ceutical products for topical use and are generally recognized as nanosized droplets was developed and reported by Pannu
safe [84]. et al. The emulsion was prepared using purified oil, ethanol,

Fig. 3. Various formulation approaches for onychomycosis treatment along with probable
mechanism of drug permeation enhancement
 67 Page 8 of 12 Vikas et al. (2020) 21:67

Table II. Marketed Nail Lacquers

P r o d u c t Active ingredient Base Company

name

Loceryl® Amorolfine 5% w/v Ammonio methacrylate copolymer type A (Eudragit® RL), triacetin (plasticizer), G a l d e r m a
ethyl acetate, butyl acetate, and ethanol International SAS
Penlac® Ciclopirox 8% w/w Butyl monoester of poly[methylvinyl ether/maleic acid], IPA and ethyl acetate Aventis Pharma
Ciclopoli® Ciclopirox 8% w/w HPCH, cetostearyl alcohol, ethyl acetate, ethanol, and purified water Polichem SA
EcoNail™ Econazole 5% w/w 2-n-nonyl-1,3-dioxolane (SEPA®) 18% w/w, Eudragit® RL/PO, ethanol A c c e s s
Pharmaceuticals,
Inc.
MycoVa™ T e r b i n a fi n e Dodecyl 2-(N, N dimethylamino)-propionate A p r i c u s
hydrochloride 10% HCl (DDAIP HCl, NexACT®), benzyl alcohol, PVP, and ethanol Biosciences, Inc.
P-3058 Terbinafine HPCH Polichem SA

polysorbate 20, cationic quaternary ammonium compound Liposomal Drug Delivery System
cetylpyridinium chloride (CPC), and water. The average
droplet size of the nano-emulsion was 180 nm. The formu- Liposome is a colloidal phospholipidic vesicular drug
lated nanoemulsion has CPC oriented as O/W interface delivery system which comprises a phospholipid bilayer
responsible for its solubility. It also contributed to the anti- membrane identical to that of natural cell membranes.
infective activity and served as a marker of activity. Through Liposomes are promising carrier for many drugs which
in vitro studies, author demonstrated that NB-002 eradicated enhances their penetration into the skin. Among their several
both mycelia and microconidia even when the fungal forms possible pharmaceutical applications, they have been widely
were dormant or not actively growing [86]. applied in topical drug delivery. Tanrıverdi et al. developed
Barot et al. formulated terbinafine as the micro-emulsion the liposome and liposomal gel formulation of terbinafine
based gel for the treatment of onychomycosis. Composition HCl. Phospholipon 90 G was used as a lipid for preparation
of micro-emulsion was optimized using D-optimal design. of this vesicular system. Liposomal poloxamer gel showed
Optimized composition of terbinafine was composed of better accumulation of drug in nail bed and was easier in
26.87% Labrasol, 26.87% Transcutol P, 5.75% oleic acid, application due to its added adhesive properties. This
and 40.5% water (w/w). Author observed that the optimized formulation remained on nail plate for longer duration and
gel showed improvement in anti-fungal activity as compared could result into sustained release of terbinafine HCl [90].
to marketed formulation due to better retention in the skin. In addition, same author further developed terbinafine
This was attributed to the special characteristics of micro- HCl liposome film formulation using two different film
emulsion such as smaller droplet size, low interfacial tension, formers (Eudragit L100 and pullulan) and compared their
and large interfacial area, which resulted into the concentra- efficacy with the liposome-based gel. Liposome film showed
tion and localization of large amount of drug within the same higher efficacy, penetration, and ease in application compared
isotropic medium, thus providing improved anti-fungal activ- to liposome-based gel, which was attributed to the better
ity in comparison to commercial cream [87]. adhesion properties of the film as compared to gel [91].
Mahtab et al. studied the potential of nano-emulgel
with permeation enhancer as vehicle for the transungual
drug delivery of ketoconazole. Author also explored the Penetration Enhancing Vesicles
efficacy of formulation for inhibiting the growth of
onychomycotic dermatophytes using in vitro study. Nano- Apart from nanoemulsion, liposomes, and
emulsion was comprised of Labrafac™ Lipophile WL 1349 transferosomes, penetration enhancing vesicles are a new
as the oil phase and Tween 80 and PEG 400 as the class of nanovesicular system having potential in anti-fungal
surfactant and co-surfactant, respectively. Nano-emulsion- drug delivery to nail [92]. Bseiso et al. prepared and
based gel showed improved in vitro anti-fungal activity on characterized the penetration enhancing vesicular drug deliv-
T. rubrum and C. albicans as compared to drug solution in ery system for sertaconazole. Preparation of this nano
DMSO [88]. penetration enhancing vesicles [nPEVs] involves use of
Kesrin Amra et al. developed ketoconazole micro- various nail penetration enhancers. Developed nPEV formu-
emulsion-loaded hydrogel containing nigella oil as perme- lation was compared with the marketed Dermofix cream.
ation enhancer. Composition of oils, surfactants, and cosur- Among the screened penetration enhancers, N-acetyl cysteine
factants in micro-emlusion was indentified using pseudo- showed optimum nail penetration enhancing potential. Vesic-
ternary phase diagrams. The optimized micro-emulsion ular size of nPEVs was in range between 38 and 538 nm,
comprised 54.97% capryol/nigella (2:1), 36.07% transcutol/ while encapsulation efficiency was found to be between 77
propylene glycol (2:1), and 7.13% water (w/w). This opti- and 95%. nPEVs with N-acetyl cysteine showed 1.4-fold
mized microemulsion was incorporated in polymeric gel base. enhancement in drug uptake as compared to marketed cream
The hydrogel showed sustained release up to 10 h as [93]. In another study, Elsherif et al. developed the
compared to the marketed cream [89]. terbinafine hydrochloride-loaded spanlastic nanovesicular
carrier which showed enhanced drug uptake [94]. Elsherif
Conventional and Novel Drug Delivery Approaches (2020) 21:67 67 Page 9 of 12

Table III. Examples of Advanced Biological Therapeutics in the Treatment of Onychomycosis

Therapeutic agent Activity against Mechanism of anti-fungal activity Benefits

S y n t h e t i c C. albicans and Peptide act by plasma membrane disruption or membranolytic Effective towards resistant
antimicrobial T. rubrum activity pathogen
peptidomimetics
Novel cationic T . r u b r u m , Membranolytic activity Ra p id ly im p ro ve t he n ai l
anti-fungal peptide Scopulariopsis appearance
brevicaulis
P l a n t d e f e n s i n C. albicans Peptide enter the cytoplasm of fungal cell by membrane Rapid killing of fungal cell, no
peptide permeabilization, followed by hyperproduction of reactive oxygen resistance and higher nail
species, and killing cell by oxidative damage penetration

et al. further loaded spanlastic nanovesicular system into two developed a novel cationic anti-fungal peptide, Novexatin®
different dosage forms (in situ gel and the nail lacquer) and (NP213) for the treatment of onychomycosis. The main
evaluated their ability to deliver terbinafine HCl encapsulated component of this product is NP213 (cyclic arginine-based
in spanlastic carriers to the nail plate. In situ gel formulation heptamer) which showed potent fungicidal activity. It showed
showed higher retention time in nail as compared to Lamisil® rapid fungicidal activity through a membranolytic mode of
cream 1% [67]. action that targets both non-metabolizing and metabolically
active nail fungal pathogens. Safety, effectiveness, and
tolerability of NP123 were already established through phase
ADVANCED THERAPY IN TREATMENT OF I and IIa clinical studies in patients with toenail infections
ONYCHOMYCOSIS treated for 1 month.
In addition to SAMPs (Table III), plant-derived proteins
In recent time, application of modified cationic antimi- and peptides are also explored for the treatment of
crobial peptides (AMPs) obtained from the innate immune onychomycosis. Hexima, a clinical stage company, developed
system against bacteria which are resistant to conventional a potent anti-fungal plant defensin peptide HXP124. This
antibiotics has been explored. Since these AMPs act through plant peptide rapidly kills a broad range of fungal pathogen,
numerous permeabilizing routes on the bacterial membrane, more specifically, than those that cause onychomycosis. It
ultimately reduce the chances of resistance development. possesses rapid penetration power to human nails and ability
AMPs selectively act on anionically charged bacterial cell to retain activity in the nail environment. Currently, it is being
membrane and kill bacterial cell rather than zwitterionic evaluated in phase I/IIa for safety, tolerability, and efficacy in
mammalian cell membrane [95]. However, careful attention patient with mild to moderate onychomycosis.
should be provided for generation of optimal AMP with
proper combination of hydrophobic and cationic structural
elements for efficient bacterial membrane association [96]. PATENTS RELATED TO DRUG DELIVERY
Haug et al. and Strøm et al. developed a class of membrane APPROACHES EXPLORED IN THE TREATMENT OF
active synthetic antimicrobial peptidomimetics (SAMPs). ONYCHOMYCOSIS
These SAMPs possess good cellular selectivity and high
antibacterial potential. Among these compounds, LTX-109 Even though there is complexity in evaluating the drug
showed promising results during initial study, hence currently delivery system for their penetration potential in the nail bed,
is undergoing clinical trials against topical infections (Lytix many patents are granted in this field but, only few of them
Biopharma AS, Norway) [97,98]. Inspired from AMP activity have reached to the market. Table IV provides information of
against pathogens, Stensen et al. synthesized five SAMPs and granted patents along with the drug delivery system. The
tested them against a 24 different fungal isolates. Among researchers are still exploring the new drug delivery ap-
these five SAMPs, compound 5 exhibited potent activity proaches to improve the drug penetration capacity in the nail
against C. albicans and T. rubrum [99]. Nova Biotics bed. Since most of the techniques and processes involved in

Table IV. List of Granted Patents

Patent No. Drug delivery system Drug Reference

US6143794A Gel Butenafine HCl [100]

US585963B1 Nail lacquer, solution Fluconazole [101]
US6846837B2 Topical gel and cream Anti-fungal agent [102]
US7198794B1 Lotion, ointment, nail polish Benzalkonium chloride [103]
US7462362B2 Dual action nail coat Terbinafine HCl [104]
US319371A1 Gel (iontophoresis) Terbinafine HCl [105]
US83692A1 Cream Terbinafine HCl [106]
 67 Page 10 of 12 Vikas et al. (2020) 21:67

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