INTRODUCTION:

Nail fungal infections are said to be the most common diseases of the nail. The most common toe nail fungal infection is Onychomycosis, also known as Tinea unguium, which is caused by a kind of fungus known as dermatophyte. More than 40% people worldwide are affected by Onychomycosis^3,4. Onychomycosis has been more prevalent in males and the predisposing factors include diabetes, obesity, peripheral arterial disease and smoking. This toenail fungal infection is responsible for over half of all nail diseases, which are characterized by discoloration and thickening of the nail, as well as the nail plate, nail bed and nail fold. Onychomycosis is regarded as an important cosmetological health problem due to it high prevalence and associated morbidity. In fact, it undesirably affects the patient’s quality of life⁵. There are a range of topical formulations for the treatment of nail infections such as gels, creams and ointments, but their effectiveness is restricted due to their low nail permeability⁵. Dermatophytes are the most frequent cause of Onychomycosis, which accounts for 50% of all nail disease cases. It was mostly seen as an aesthetic issue in cosmetics⁶.

The current review entails the development of a transungual drug delivery system, which is a novel drug delivery system for treating nail infections with successful penetration. Topical transungual administration of therapeutic agents has many advantages over conventional and invasive methods of drug delivery and allows for controlled drug release over a longer period of time. Topical antifungal medicines delivered through the human nail have various advantages over oral therapy, including a decreased rate of adverse effects and a lower risk of drug-drug interactions with diabetics, HIV/AIDS and psoriasis medications⁶.

The transungual drug delivery system has been widely accepted as an effective non-invasive drug medication, with benefits such as prolonged therapeutic effect, reduced side effects, improved bioavailability, decreased hepatic metabolism, predetermined rate of drug permeation, improved patient compliance and ease of drug therapy. Onychomycosis treatment are quite limited due to the impermeable nature of the nail. The word “Transungual” is derived from two Greek words: “Trans” means through and “unguis” means nails. A transungual drug delivery system is a system that involves delivering drugs through the nail to achieve a specific drug delivery mode for treating nail illness. The principal route for drug penetration through the nail plate and drug administration through the nail is known as transungual drug delivery^7-9.

In India, most of the states are quite hot in summer season and humid in monsoon season. Apart from varying climatic conditions, Agriculture sector constitutes the most important Industry in Indian economy having higher population density consisting of farmers, construction workers and labors etc.^10-12 So, development of dermatophytosis are common in the overcrowding unhygienic life style of the community with low socio-economic background. The nail patches containing antifungal drugs can aid with onychomycosis clinical circumstances. The treatment strategies and approaches assist in overcoming issues such as infection recurrence and irreversible loss of the diseased nail. The transungal patches can deeply permeate through nail cuticle and helps to prevent the spread of infection to the blood stream and other areas of the body. Onychomycosis is much prevalent in HIV infected patients with fungal invasions in the nail plate and leads to total dystrophy. This newly developed nail patches will help these immunosuppressed patients with better treatment.

Types of nail fungal disorders

Nail disorders are condition that affects the appearance of finger nail and toenail. These are mainly caused by fungal organism. There are mainly three types of fungus that can infect toenails namely yeast, moulds and dermatophytes. Among these dermatophyte infections are more common and toe nail infection caused by yeast Candida albicans is relatively rare.

Yeast infection

Candida albicans, can cause toenail infection. This is a relatively uncommon condition that affects children with a genetic immune system disease results in a wide spread candida infection affecting the different parts of the body like scalp, lip and nails.

White islands

This is a superficial toenail fungus that can extend to the nail bed and cause foggy "white islands" on the nail, which is a very frequent illness (also on fingernails).

Distal toenail infection

When the tip of the nail lifts from the nail bed, allowing the fungus to penetrate the tissue, this is the most prevalent cause of toenail infection.

Onychomycosis

Onychomycosis is also known as Tinea unguium, is a fungus that attacks the nail. It may start as yellow discoloration on the tip of the nail, and leads to progressive loss of nail thickness and crumbled edges.

It is generally classified as various groups according to the morphological design and method of nail invasion.

The different groups are;

Distal and lateral sublingual^13-17

Causative organism: Epidermophyton floccosum, Trichophyton mentagrophytes, Trychophyton rubrum.

It starts distally at the hyponychium and progresses to the nail plate and bed, hyper keratotic debris causing onychomycosis.

Mode of infection: invasion of fungus through a skin breach on the lateral or distal underside of the nail.

Endonyx sublingual

Causative organism: Trychophyton soudanense, Trychophyton violaceum.

There is no hyperkeratosis or onycholysis, but the nail develops a milky appearance, lamellar cracking and indentation.

Mode of infection: fungus infects the entire thickness of the nail without infecting the nail bed because it enters through the nail.

Proximal sublingual

Causative organism: Tinea rubrum, Aspergillus spp., Fusarium spp.

Debris gathered under the proximal section of the nail, creating onychomycosis and a distal spread white shade.

Mode of infection: The fungus infects the proximal nail folds and cuticles, and it’s can also be caused by paronychia.

Superficial

Causative organism: Tinea mentagrophytes, Tinea rubrum, Acremonium spp., Fusarium spp., Scytalidium spp.

The surface of the nail looks to have powder like spots of transverse striae.

Mode of infection: It may occur on the surface of the nail plate or arise from beneath the fold of the nail .it may represent deep penetration of the superficial infection.

Total dystrophic

Long term infection causes complete nail destruction. The thickness of the nail and the nail structure is lost^18-20.

Treatment methods for the management of onychomycosis

Onychomycosis is a cosmetologically related fungal infection which is affected in the nails. There are various treatment methods available for the treatment of onychomycosis

Oral and topical medication delivery are currently available treatments for onychomycosis. Mechanical, physical and chemical approaches can all be used to improve topical medication delivery.

Oral antifungal medications have a high cure rate; however, they are not suitable for usage in patients who are elderly or immune-compromised. Oral antifungal medication for a longer period of time has major side effects such as hepatotoxicity, cardiac and gastrointestinal disturbances. Topical antifungal medicines work by passing into the systemic circulation and have little, if any, negative effects. They are easy to apply due to their non-invasive nature and more compliance. The main problem with topical therapy is that it does not penetrate through the nails, resulting in a higher rate of infection relapse.

Topical therapy also provides direct and localized therapy, with the lowest inhibitory concentration required to combat dermatophytes.

Challenges faced in treating onychomycosis.

Slow growth of the nail
Extended therapy
Persistent nature
Penetration inabilities of drugs

Oral therapy

Antifungal medications taken orally are the initial line of treatment for onychomycosis. As an oral therapeutic alternative, terbinafine or itraconazole are commonly used in traditional treatment. In the event of fingernail onychomycosis, terbinafine is given at a dose of 250mg per day for 6 weeks and 12 weeks in the case of toe nail onychomycosis.

Itraconazole is given in pulses of 200mg twice a day for a week followed by a 3 week respite, or it is given as a single dose of 200mg twice daily for 3 months. Fluconazole is another oral medicine that is rarely used due to its low success rate and the need for extended treatment.

Many more innovative oral antifungal medicines, such as luliconazole, ravuconazole and posaconazole, are being developed specifically for onychomycosis.

Topical therapy

Oral medicines have negative effects when compared with topical therapy. However, topical therapy for nail illness is limited due to their poor permeation through nail plates. If the systemic circulation is accessed an effective penetration enhancer would boost drug delivery through the nail plate opening up new possibilities for treating surrounding target sites. The goal of topical therapy is to develop and test medicated nail patches for the treatment of onychomycosis. This topical delivery of drug reduces the risk of systemic effects and allows more interaction time at the site of action²⁰.

The most commonly used formulations include ciclopirox and amorolfine. Ciclopirox is considered to be one of the most effective topical broad spectrum antifungal activities. 8% of ciclopirox is used as lacquers. Amorolfine is considered to be a synthetic antifungal drug which is used against yeast dermatophytes and molds. It is also used as 5% lacquer.

Systemic antifungal therapy

This medication is used when the infection becomes severe or non dermatophytic onychomycosis. The common factors used for selecting antifungal therapy is based on the organism, adverse effects, interaction, cost and availability.

Systemic drugs that are widely used for the treatment of onychomycosis are;

Terbinafine
Itraconazole
Fluconazole

Strategical Cosmetic Approaches for the treatment of Onychomycotic Nail.

Onychomycosis is considered as the most prevalent cosmetic problem which affects the quality of life of patients. Therefore, a successful treatment strategy is essential for the eradication of Onychomycosis. Among oral and Topical treatment, the use of Oral antifungal agents is not recommended for patients who have liver, kidney or heart diseases or who taking medications that may cause significant drug-drug interactions. So Topical agents are more preferred and it has more patient acceptance. The development of an efficient well-tolerated topical antifungal would be very beneficial. In order to overcome the challenges that prevents adequate drug penetration to the infection site of the nail plate, various preparations are used prior to treatment and also during the treatment period.^21-23. Nano-formulations are intended for targeted drug delivery and long-term or delayed drug release. Based on the benefits of bridging keratinase and bridging nano-formulation in the treatment of Onychomycosis, combining all three as a single topical combinational formulation might result in a more successful treatment regimen.^24-26

Nail Avulsion

Nail Avulsion is the removal of a portion or all of the infected nail plate. It is used prior to topical Onychomycosis treatment. Nail avulsion may be beneficial to investigate the nail unit for diagnostic or therapeutic purposes in certain nail diseases²⁷.

Nail Abrasion

Nail Abrasion with sandpaper nail files is done prior to antifungal nail lacquers. Nail abrasion is performed by sanding of the nail plate which reduces the thickness. It is an effective and inexpensive method when compared to others²⁷.

Nail Lacquers

Nail lacquers have long been used as a cosmetic product to protect and adorn the nails. Medicated nail lacquers are a new type of formulation that have been utilized to delivery drugs transungually. It contains specific antifungal drug in a transparent film forming polymer, penetration enhancer, and an organic solvent to make up the nail lacquer. It can be simply applied on the nail plate, just like a nail polish and also as a transparent layer of antifungal drug. Since this layer is water resistant, it remains for longer period and is successful in treating toe nail infection. The effective nail lacquers are Ciclopirox and Amorolfine.

Ciclopirox [Penlac 8%] nail lacquers

Ciclopirox attack the fungal cells metabolic activities in a number of ways. It chelates with the polyvalent cations [Fe³⁺and Al³⁺] involved in fungal enzymatic activity, causing intracellular energy production and harmful peroxide decomposition to be disrupted. Ciclopirox may also limit fungal food uptake, resulting in amino acid and nucleotide depletion as well as a decrease in protein synthesis.

Amorolfine [5%] nail lacquers

Amorolfine is a fungicidal antimycotic [antifungal]medication used topically. It inhibits sterol production, causing cell death by disrupting the fungal cell membrane. Amorolfine is a broad spectrum antimycotic that kills wide range of bacteria and fungi.

Nail creams

Nail creams are applied to the nail plate. This allows the drug to penetrate the hard nail surface and reach the fungus beneath. Bifonazole, an antifungal agent is found in the cream.

Nail polishes

Many people start by using a colorless nail lacquer to treat their nail infection. The effected nail must be trimmed and filed down as much as possible before applying the nail paint. The nail paint contains antifungal and growth inhibiting chemical amorolfine and ciclopirox.

One to two times each week, amorolfine is administered. In the first month, ciclopirox products are normally administered every other day, at least twice a week in the second month, and once a week in the third month.

Before applying the new layer of polish, the previous layer must be removed with an alcohol swab in both cases. On top of the medicated nail paint, you can use cosmetic nail polish. Water-soluble ciclopirox nail paints are now available. They are applied once a day, and any leftover polish is washed away with water before each new application.

Nail patches

Nail patches are also considered to be a cosmetic product which contain the suitable medicament for the treatment of Onychomycosis. Its application is quite similar to the cosmetic nail patches. Nail patch increases the contact time of drug and thereby produces the maximum therapeutic efficacy. It can be easily removed, when there is any irritation or itching. So, nail patch has an improved patient acceptance.

Other than these formulations, Antifungal Creams, Solutions, Gels, Ointments are used. But due to poor penetration into infected area and lack of bioavailability, Nail patches and Nail lacquers are more preferred over these formulations^28-30

Impairment of quality of life in onychomycosis affected patients

Disease manifests itself in a variety of ways, including social, behavioral, psychological, morphological, and molecular. The condition has a number of issues, including physical and financial difficulties. Feelings of neglect and loss of importance in the family, as well as environmental issues, have been recognized as issues. These issues exacerbate emotions of loneliness, unwontedness, inadequate Onychomycosis psychologically and socially affect the work and the life of patients. ^31-32A range of risk factors contribute to the disease’s prevalence, including age, aberrant nail morphology, immune deficiency and genetic factors. Onychomycosis is said to be a serious health problem because of its wide spread incidence, as it can cause pain, discomfort and physical impairment. It is characterized by nail thickening, splitting, roughening, discoloration and its effects toe nails more frequently than finger nails. Onychomycosis is the most common nail condition, and it can have a negative impact on a patient’s quality of life. The goal of this study is to examine how toe nail onychomycosis affected the quality of life.

Despite the fact that onychomycosis is not life-threatening, it is more than just a cosmetic issue. Patients will experience pain and discomfort if their nails become infected. When standing, walking, doing physical activity, or wearing shoes, toe nails dystrophy will cause discomfort.

Infection of the fingernails will hinder daily activities. In addition to the physical aspect, onychomycosis affects the social, psychological, and emotional well-being of patients. Several studies have found that onychomycosis has a negative impact on patient quality of life, particularly physically, socially, and emotionally.

Patients were separated in to sub groups based on sex, education level, residence, kind of onychomycosis, number of involved toe nails, fingernails involvement, length of illness, and previous antimycotic medication. Patients with advanced toe nails and finger nails onychomycosis were more severely impacted. Female patients had larger social and emotional impairment than male ones. Patients with a higher educational level and those who lived in towns or cities were also more emotionally and socially affected by onychomycosis, despite the fact that those who lived in the country or had a lower education level had more severe symptoms. Onychomycosis is still a serious medical disease that can have a substantial impact on a patient’s quality of life^33-35

Prevalence of Onychomycosis in patients in various clinical conditions

The prevalence of Onychomycosis in psoriasis patients has been reported to vary. The occurrence of Onychomycosis among inpatients with psoriasis are very much common. When compared to healthy people, smokers and people with peripheral artery disease may have a higher prevalence of Onychomycosis. Diabetic patients have a significant prevalence of Onychomycosis, according to several research. Diabetic patients were more likely to develop Onychomycosis, especially those who were older and had severe nail abnormalities. Onychomycosis is an age-related infection that is becoming more common as people get older. It is common in children, with Down syndrome and immunodeficiencies, who are more susceptible to fungal nail infections. Onychomycosis in youngsters has been reported in a modest number of cases.^35-36

Medicated nail patches-A promising approach for onychomycosis

Transungal drug delivery system is used for various nail disorders like green nail syndrome, paronychia, onycholysis and bacterial nail infections etc. This helps to improve the quality and provide better patient convenience. This newer drug delivery system helps to provide an overview of the various approaches for treating nail infections. If the systemic circulation of the drug is accessed, an effective penetration enhancer would boost drug delivery through the nail plate, opening up new possibilities for treating surrounding target sites. The challenge behind the transungal delivery system is to manage the drug delivery to nail, because nails are made of keratin, which is non-vascular and is impermeable. So, the eradication of onychomycosis is difficult to achieve. Anti-fungal agents are an alternative first line therapy for dermatophtyic infections, with intermittent pulse dosing is safe and effective for a continuous short-term therapy. Most of the antifungal drugs comes under the category of BCS Class II, with very low water solubility and low availability. Due to increase in untoward side effects and highest risk of liver injury occurred in the oral therapy, there is a demand for a newer therapeutic approach. Patients with diabetics and immunodeficiency disorders are in the high risk of onychomycosis. So, it is difficult to achieve therapeutic activity of the drug, if it is in the form of conventional dosage form. So, in-order to get effective drug delivery and to maximize the effectiveness of the drug to the right place by using drug loaded transungal patches are designed. These patches are aesthetically acceptable which can permeate the drug to the nail cuticle.

CONCLUSION:

Dermatophytosis that occur in fingernails and toe nails are difficult to eradicate with conventional dosage form. Due to treatment limitation of oral and topical medicines, the development of anti-onychomycotic nail patches using the antifungal helps to target the medication to the nail cuticle. Onychomycosis is a frequent fungal infection that requires specialized treatment. It takes several months to complete therapy because the nail grows slowly, especially in the elders. The kind and severity of Onychomycosis as well as the patient’s condition influence drug selection. Topically applied medicines have poor permeability through keratinized nail plates and drug absorption into the nail apparatus is exceedingly low. Treatment of onychomycosis using nail patches helps to improve the individualized treatment plans. The optimized drug loaded patches helps to achieve maximum therapeutic effect and also helps to provide controlled release of the drug for an extended period of time. The designed patches will show superior clinical and mycological outcomes in patients with onychomycosis. Therefore, this novel drug delivery is an effective approach for the treatment of Onychomycosis with better penetration and effective bioavailability^37-46.

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Received on 02.12.2021 Accepted on 14.12.2021

Research J. Topical and Cosmetic Sci. 2021; 12(2):125-131.

DOI: 10.52711/2321-5844.2021.00017