European Journal of Cardiovascular Medicine

Nail fungal infections are prevalent diseases throughout the world particularly in tropics. Human nails are extremely vulnerable to several nail diseases like onychomycosis onychogryphosis, Onycholysis, Koilonychia caused not only by fungus but also different bacteria, viruses & nutritional diseases [1,2]. Out of that onychomycosis is quite common. Another term of onchomycosis is Tinea unguinum  .Several different fungus like dermatophytes, Fusarium even yeast causes onchomycosis. Amongst dermatophytes Trichophyton & Epidermophyton generas are mainly responsible but Trichophyton rubrum is the commonest [4]. Here nails are distorted, brittle, discoloured, yellowish, sometimes detachment of nail from nail bed is possible [5]. Due to cosmetic defect nail infections generally causes mental stress & disfigurement [Figure 1] [3].

In India Warm, humid climates are responsible for spread of Infections. Several studies revealed that the disease is more prevalent amongst men spcially (elderly >70).

But the real problem lies with the treatment of this Infections. especially due to rigid, tough, impenetrable structure of nail. The impenetrability of nail attributed to highly stable & strong disulphide linkages & hydrogen bonds in the keratin network structure. Therefore, antifungal drugs take a longtime for absorption and penetration. Moreover, treatment requires a long course of 3 months for finger nails & 6 months for the toe nails, which aggregates many side effects like hepatotoxicity, hepatic first pass metabolism etc, as well as rise in treatment cost (like terbinafine) [2,6,7].

Most frequent conventional therapy with oral medicines used previously were by Griseofulvin, Terbinafine, itraconazole, ketoconazole etc.

Figure 1: Onchomycosis occur in human toe nails

In 1996 FDA approved oral therapy with terbinafine followed by in 1996 Ciclopirox olamine [8].

Later topical therapy was preferred instead of oral therapy due to its local actions, less side effects & increased tolerance & inexpensive cost. However, due to high amount of water with less lipid content (3%) nail reveals hydrophilic gel membrane with a hydrophobic base. This obstructs permeability of hydrophobic or moderately lipophilic drugs. Thus, this problem of inadequate drug permeability limits the efficacy of topical treatment. There are generally three important methods to increase nail permeability before application of topical therapy by mechanical, physical & chemical methods.

In mechanical methods by removal of nail layers or parts of nail plate by nail avulsion and nail abrasion. Physical methods to increase nail permeability are phonophoresis, hydration, occlusion, electroporation, photodynamic therapy.

Chemical methods that improve penetration by keratolytic agents, ammonia, sodium thiosulfate, hydrogen peroxide, mercaptans, USG approach [9].

But all those invasive procedures are painful and causes severe nail disfigurement. In this concern noninvasive topical therapy   by nail lacquer combined with antifungals like cyclopirax olemine can be an alternative to local management of onchomycosis.

But again, due to tough keratrin structures, hydrogen bonding drug delivery through nail is really an obstacle   for absorption of drugs for effective topical therapy. So there was ongoing research to invent some novel transdermal drug delivery systems with nanoparticles, microemulsions, hydrogels etc.  Encapsulation of oral antifungal drugs within nanoparticles facilitates site specific prolonged release, to achieve adequate concentration & capable of reducing toxicity also.

Other novel systems like in situ gels, microemulsion, polymeric fibres are also in pipeline [10].

This review will focus various novel strategies that favours transungal drug delivery system for treatment of persistent onchomycosis.

Nail Anatomy Structure of Human Being:

Nail anatomy was different from other body parts. It is a lipophilic substance; cholesterol is the main lipid layer. Nail plate is made of 25 layers of flattened, dead and keratinized (0.25-0.6 mm) cells. It is convex in shape and rigid and transparent. The nail plate is made up of hyponychium, nail substrate, nail bed and proximate to nail fold (all jointly make up the nail plate).

The nail plate laterally held together by fingernail folds.  Ectodermal band (hyponychium) also form the nail structures in anterior side. The nailplate act as a barrier against chemical agents and pathogenic organisms shielding nail tissue from other part [11]. Figure 2 represent the structure of nail. 

Figure 2: Structure and different part of finger nail in this figure

The composition of nail pack includes 7 to 12% fluid, 100% moisture, liquid more than 35%. Water percentage determines the opaqueness and suppleness of nail. In addition to water it contains little lipids (0.1 to 1%), disulphide linkage (10.60% ), Keratin (80% fibrous protein) protect them from damage and make  the nail  hard [12].

Nails are always developing, but them. expansion drops as they are aged and have poor circulation [13]. Figure 3 represent various factor affect the nail growth. If blood circulation is delayed

Figure 3: Different factors that affect the nail growth

oxygen supply will be reduced and delay the nail growth. Trauma also causes nail damage .. Different nutrients, proteins and minerals deficiency also retarded nail growth. Chemotherapeutic medicine also affects the nail growth. Nail location also affect its growth [14].

Different diseases and treatment of the nail:

Common nail disease are given in Table1.

Table 1: Representation of different diseases causes by different microorganism and its treatment by drugs

Conventional therapy use in the treatment of onchomycosis :

Oral and local drug delivery both essential for the treatment of onchomycosis. Mechanical, chemical and physical methods were used for the treatment of local drug delivery. Oral antifungal drugs were used for the treatment for local fungal infections [15]. But long oral therapy causes hepatotoxicity, cardiac and gastric disturbances [16]. Drug-drug interactions was a big inconvenience [17]. On the contrary local / topical therapy can provide minimum inhibitory concentration required to treat Dermatophytes, moreover [18]. they do not harm geniatric, pediatric and pregnant patients [19]. But the main problem of local treatment that improper penetration, this attributed to higher relapse rate.

Drugs can be administered transungally in the form of nail lacqurers  ,  solutions & gels . Terbinafine and ciclopirox olamine nail lacquer has already been popularised .

Nanoparticles in the treatment of onchomycosis:

Nanoparticleso have gained much discussed in case of drug delivery. Though it is small enough to penetrate the skin and nail coating [20, 21]. Below we will discuss about some nanoparticles help in the treatment of onchomycosis. Figure 4 represent images of some nail polish coated with silver nanoparticle.

Figure 4: Nail polish in the treatment of onchomycosis

Nanoparticle as nanocapsule:

Nanocapsule s are nanoparticles that contain a solid or liquid core surrounded by a polymeric shell on the outside. Generally oily core of nanocapsules can engulf and bind lipophilic or hydrophobic drugs. Poly [lactic acid] [ PLA] and poly [lactide-co-glycolide] [PLGA] are generally use as synthetic polymeric materials for the preparation of nanocapsules [22]. Antifungal drugs were encapsulated in nanocapsules so it can cause sustained release, more efficacious and enhanced penetration. Flores et al evaluated Melaleuca alternifolia   an essential tree tea oil that used to produce nanocapsules and nanoemulsions. Zone of Inhibition measured against T. rubrum. in onychomycosis. Nanocapsules containing tea tree essential oil performed better.

Tioconazole loaded nanocapsule   suspension with a coating of cationic polymer also used in transungual drug delivery. Cationic coated polymer presented a greater zone of inhibition   compared to uncoated particles.

Pullulen nano-based nail formulation demonstrated good viscosity is also essential for nail application [9]. IVRT means in vitro release tests and IVPT means in vitro permeation tests are also supplemented to establish this hypothesis. Series of experiments with Nile Red and confocal microscopy utilizing fluorescent marker into the nail guplate was employed to observe the pathway and depth of nail penetration. Tioconazole loaded-nanocapsule result in greater drug release. After 7 days, a depth of 90-160 µm was measured as depth of the penetration [24].

Polymeric Nanoparticles:

Since in past many years polymeric nanoparticles were used in drug delivery systems in various diseases. It is biocompatible, flexible designing, stable and have longer action. Polymeric nanoparticles also found in the treatment of onchomycosis [25]. Chiu.et al formulated Poly-[€-caprolactone] loaded nanoparticles with Nile Red for visualisation after topical therapy under confocal microscopy. Nails before dye treatment porated with microneedle pores to facilitate better   penetration of fluorescent labelled probe loaded nano paricles . Confocal laser microscope was used to visualise the depth of penetration. The results support that polymeric nanoparticles act as a sustained release drug reservoirs in the deeper region of nail [26].

Wang et al. in 2018 presented the action of ketoconazole encapsulated polymeric nanoparticle under fluorescent microscopes to study the controlled release penetration for treating onchomycosis. In vivo studies the nanoparticle coated drugs were delivered through mouse model through tattoo marks Nanoparticle characterised good encapsulation efficiency and sustained release of Ketoconazole. The results support the use of ketoconazole-encapsulated crosslinked fluorescent supramolecular nanoparticles as an intradermal controlled release solution for treating onchomycosis [27].

Onchomycosis, a persistent fungal infection of nail is difficult to treat as lack of penetrability of drugs and   requires prolonged course of antifungals with lots of side effects. Physical, chemical and mechanical therapies used in the past years as is involved in conventional methods with lots of systemic hazards. In recent years nail lacquers incorporated with   nanoparticles coated antifungals acts as excellent drug delivery system to replace conventional therapy with lesser side effects.

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