Formulation And Evaluation of Transdermal Drug Delivery System for Treatment of Onychomycosis

Sakshi Bharane; Karan  Bharane; Vinayak Mahesh Nagare; Mulani Jahir Husen; Akanksha Bharane

doi:10.5281/zenodo.19548410

Review Paper | Open Access
Volume 04 | Issue 04 | Article Id IJPS/260404274

Formulation And Evaluation of Transdermal Drug Delivery System for Treatment of Onychomycosis
Sakshi Bharane* Karan Bharane Vinayak Mahesh Nagare Mulani Jahir Husen Akanksha Bharane
Dattakala College Of Pharmacy, swami chincholi.

Abstract

Onychomycosis is a common fungal infection of the nail that accounts for nearly half of all nail disorders worldwide. It is primarily caused by dermatophytes, yeasts, and non-dermatophyte molds, leading to nail discoloration, thickening, and structural damage. Conventional treatment strategies mainly include systemic antifungal therapy and topical antifungal formulations. Although systemic antifungal drugs such as terbinafine and itraconazole demonstrate good efficacy, their use is often associated with systemic side effects, drug–drug interactions, and hepatotoxicity. On the other hand, topical therapies frequently exhibit limited therapeutic success due to the highly keratinized structure of the nail plate, which acts as a strong barrier to drug penetration.Transungual and transdermal drug delivery systems have emerged as promising approaches to improve the treatment of onychomycosis by enhancing drug permeation through the nail plate and providing localized drug action. Recent advancements in drug delivery technologies, particularly nanotechnology-based systems such as nanoparticles, nanoemulsions, liposomes, and nanostructured lipid carriers, have demonstrated significant potential in improving antifungal drug solubility, stability, and penetration across the nail barrier. In addition, physical enhancement techniques including iontophoresis, microneedles, ultrasound, and laser-assisted drug delivery have been explored to further improve transungual drug transport.This review summarizes the pathophysiology of onychomycosis, limitations of conventional therapies, and recent advances in transungual drug delivery systems. Particular emphasis is placed on nanotechnology-based approaches and physical enhancement techniques that can improve drug penetration and therapeutic efficacy. These emerging strategies hold great promise for developing more effective and patient-friendly treatments for onychomycosis

Keywords

Onychomycosis , Transdermal drug delivery , Antifungal therapy , Nanotechnology , Nail drug delivery , Nano carriers , Nail lacquer formulations

Introduction

Onychomycosis is a chronic fungal infection that affects the fingernails and toenails and represents nearly half of all nail disorders worldwide. The condition is primarily caused by dermatophytes, particularly Trichophyton rubrum and Trichophyton mentagrophytes, although non-dermatophyte molds and yeasts such as Candida species may also contribute to infection. Epidemiological studies suggest that approximately 5–10% of the global population is affected by onychomycosis, with prevalence increasing significantly with age. Elderly individuals, patients with diabetes mellitus, immunocompromised individuals, and those with peripheral vascular disease are particularly susceptible to infection. Additional risk factors include nail trauma, poor foot hygiene, excessive moisture exposure, and the use of occlusive footwear. Clinically, onychomycosis presents with nail discoloration, thickening, brittleness, subungual hyperkeratosis, and separation of the nail plate from the nail bed (onycholysis). These symptoms can lead not only to cosmetic concerns but also to pain, discomfort, and impaired quality of life.The pathogenesis of onychomycosis involves the invasion of keratinized nail tissue by fungal organisms capable of producing keratin-degrading enzymes known as keratinases. These enzymes enable fungi to penetrate the dense keratin structure of the nail plate and colonize deeper layers such as the nail bed and nail matrix. Once established, fungal growth can be persistent because the nail plate provides a protective environment that shields pathogens from external treatments and host immune responses.

Current treatment strategies for onychomycosis include systemic antifungal therapy and topical antifungal formulations. Oral antifungal drugs such as terbinafine and itraconazole are widely prescribed due to their relatively high clinical efficacy and ability to reach the nail bed through systemic circulation. However, long-term systemic therapy is often associated with adverse effects including hepatotoxicity, gastrointestinal disturbances, and potential drug–drug interactions. Furthermore, systemic therapy may not be suitable for elderly patients or individuals with liver disease.Topical antifungal treatments, including ciclopirox and amorolfine nail lacquers, offer a safer alternative with fewer systemic side effects. However, their therapeutic effectiveness is often limited by poor drug penetration through the nail plate, which is composed of tightly packed keratin fibers with low lipid content. This structure forms a strong barrier that restricts the diffusion of many antifungal agents.To overcome these limitations, advanced drug delivery approaches such as transdermal and transungual drug delivery systems have been developed. These strategies aim to enhance the permeation of antifungal drugs across the nail plate and surrounding tissues while maintaining sustained drug release at the site of infection. Techniques including penetration enhancers, medicated nail lacquers, physical enhancement methods (such as iontophoresis and microneedles), and nanotechnology-based drug delivery systems have shown promising potential. By improving drug penetration and retention within the nail unit, these innovative systems may enhance therapeutic efficacy, reduce treatment duration, and minimize systemic adverse effects, thereby offering improved management of onychomycosis.

1. Epidemiology

Onychomycosis is one of the most common nail disorders worldwide and accounts for nearly 50% of all nail diseases. The global prevalence of onychomycosis is estimated to be around 5–10% of the general population, although the frequency varies depending on geographic region, climate, and population characteristics. The infection occurs more frequently in adults and elderly individuals, with prevalence increasing significantly after the age of 60 years, where rates may reach 20–30%.The disease is relatively uncommon in children due to faster nail growth and lower exposure to fungal pathogens. However, the incidence in younger populations has gradually increased in recent years. Several systemic and environmental factors contribute to the epidemiology of onychomycosis. Individuals with diabetes mellitus, peripheral vascular disease, immunosuppressive conditions, and nail trauma are at greater risk of developing the infection.Geographical and climatic conditions also influence the occurrence of onychomycosis. The infection is more common in humid and temperate climates, where fungal organisms can thrive in warm and moist environments. Lifestyle factors such as wearing occlusive footwear, poor foot hygiene, and frequent exposure to communal areas such as swimming pools and gyms further increase the risk of transmission.Dermatophytes are responsible for the majority of cases, accounting for approximately 70–90% of infections, with Trichophyton rubrum being the most frequently isolated pathogen worldwide. Non-dermatophyte molds and yeasts contribute to a smaller proportion of cases but are increasingly recognized as important causative agents.Overall, the prevalence of onychomycosis continues to increase globally due to factors such as aging populations, rising rates of diabetes, and increased use of immunosuppressive therapies, making it an important public health concern.

Conventional therapies for onycomycosis

Conventional treatment strategies for Onychomycosis primarily involve systemic (oral) antifungal medications and topical antifungal formulations. These therapies aim to eradicate fungal pathogens from the nail plate, nail bed, and surrounding tissues while promoting the growth of healthy nails. The choice of treatment generally depends on the severity of infection, number of nails involved, causative organism, and patient health status.

2.Systemic (Oral) Antifungal Therapy

Systemic antifungal therapy is commonly used for moderate to severe infections, especially when multiple nails are affected or when the infection involves the nail matrix. Oral antifungal drugs reach the site of infection through the bloodstream and accumulate in the nail keratin, thereby inhibiting fungal growth.The most commonly prescribed oral antifungal agents include Terbinafine and Itraconazole. Terbinafine acts by inhibiting fungal squalene epoxidase, which disrupts ergosterol synthesis in fungal cell membranes. Itraconazole, a triazole antifungal agent, inhibits fungal cytochrome P450 enzymes involved in ergosterol biosynthesis. These medications generally require treatment durations ranging from 6 weeks for fingernails to 12 weeks or longer for toenails.Although systemic therapy is considered highly effective, it may cause adverse effects such as hepatotoxicity, gastrointestinal disturbances, and potential drug–drug interactions, particularly in elderly patients or individuals with liver disease.

2. Topical Antifungal Therapy

Topical antifungal agents are commonly used for mild to moderate infections or when systemic therapy is contraindicated. These formulations are applied directly to the affected nail surface and surrounding skin to inhibit fungal growth locally.Common topical agents include Ciclopirox, Amorolfine, Efinaconazole, and Tavaborole. These drugs are often formulated as medicated nail lacquers or topical solutions, which form a thin film on the nail surface and allow gradual diffusion of the drug into the nail plate.Despite their safety and minimal systemic toxicity, topical treatments often show limited therapeutic success due to poor drug penetration through the dense keratinized nail plate. As a result, treatment durations may extend for 6–12 months, and patient adherence becomes a significant challenge.

3. Mechanical and Surgical Approaches

In some cases, mechanical or surgical interventions may be used alongside pharmacological treatment. These methods include nail debridement, chemical nail avulsion, or surgical removal of the infected nail plate. Debridement helps reduce fungal load and improves the penetration of topical antifungal drugs.

Limitations of Conventional Therapies

Despite the availability of several therapeutic options, the management of Onychomycosis remains challenging due to multiple limitations associated with conventional treatment approaches. Both systemic and topical antifungal therapies often show suboptimal clinical outcomes, mainly because of the unique structure and physiology of the nail unit. One of the major limitations of topical antifungal therapy is poor drug penetration through the nail plate. The nail plate is composed of densely packed keratinized cells with low lipid content, forming a rigid barrier that significantly restricts the diffusion of antifungal agents to the deeper infected regions such as the nail bed and nail matrix. As a result, achieving therapeutic drug concentrations at the site of infection becomes difficult.Another important challenge is the prolonged duration of treatment required for successful therapy. Since nail growth is relatively slow, particularly in toenails, treatment often needs to be continued for several months or even up to a year to allow the infected nail to grow out completely. This extended treatment period may reduce patient adherence and overall therapeutic success. In the case of systemic therapy, commonly prescribed antifungal agents such as Terbinafine and Itraconazole are associated with potential systemic adverse effects, including hepatotoxicity, gastrointestinal disturbances, and possible drug–drug interactions. These safety concerns may limit their use in certain patient populations, particularly elderly individuals or those with pre-existing liver disorders.Furthermore, recurrence and reinfection are frequently observed after completion of therapy. Fungal spores may persist within the nail environment or surrounding tissues, leading to relapse even after apparent clinical improvement.Due to these limitations, there is a growing need for advanced drug delivery strategies capable of enhancing antifungal drug penetration through the nail plate and maintaining effective drug concentrations at the site of infection. Consequently, novel approaches such as transungual drug delivery systems, nanotechnology-based formulations, and physical permeation enhancement techniques are being explored to improve therapeutic outcomes in onychomycosis treatment.

Transdermal drug delivery system

Transdermal drug delivery systems (TDDS) have emerged as an important therapeutic approach for improving the treatment of Onychomycosis and other dermatological conditions. These systems are designed to deliver therapeutic agents across the skin or nail apparatus in a controlled and sustained manner, allowing the drug to reach the site of infection while minimizing systemic exposure. Unlike conventional oral therapies, transdermal delivery bypasses the gastrointestinal tract and hepatic first-pass metabolism, which can reduce systemic side effects and improve patient safety. The principle of transdermal drug delivery involves the diffusion of drug molecules through the outer barrier layers of the skin or nail unit. In the context of onychomycosis, the drug must penetrate the highly keratinized nail plate and reach the infected tissues such as the nail bed and nail matrix. However, the nail plate acts as a strong physical barrier due to its compact keratin structure and low lipid content. Therefore, transdermal drug delivery systems are often designed with specialized formulations and permeation enhancement strategies to improve drug transport through the nail barrier. Various transdermal and transungual drug delivery systems have been investigated to enhance antifungal drug penetration and therapeutic effectiveness. These include medicated nail lacquers, gels, creams, films, patches, and nanoparticle-based formulations. Medicated nail lacquers are among the most commonly used systems, as they form a thin polymeric film on the nail surface after solvent evaporation. This film acts as a drug reservoir, allowing sustained drug release and gradual diffusion into the nail plate. In addition to conventional topical formulations, advanced transdermal delivery technologies have been developed to overcome the limitations of poor nail permeability. These strategies include the use of chemical penetration enhancers, nanocarriers, liposomes, nanoemulsions, and polymeric nanoparticles, which can improve drug solubility and facilitate deeper penetration into the nail structure. Furthermore, physical enhancement techniques such as iontophoresis, microneedles, ultrasound, and laser-assisted drug delivery have also been explored to increase drug permeation through the nail plate. Transdermal drug delivery systems offer several advantages compared to conventional treatments. These systems can provide controlled and sustained drug release, improved drug bioavailability at the target site, reduced systemic toxicity, and enhanced patient compliance. By maintaining therapeutic drug concentrations at the infected site for prolonged periods, transdermal systems may improve clinical outcomes and reduce the duration of treatment. Overall, the development of advanced transdermal and transungual drug delivery systems represents a promising strategy for the effective management of onychomycosis. Continued research in formulation technologies, nanotechnology-based carriers, and permeation enhancement techniques is expected to further improve the efficiency and reliability of these drug delivery approaches.

5. Advanced Transdermal Strategies For Onycomycosis

The treatment of Onychomycosis remains challenging due to the highly keratinized structure of the nail plate, which significantly restricts the penetration of conventional topical antifungal agents. To overcome this barrier and improve therapeutic outcomes, several advanced transdermal and transungual drug delivery strategies have been developed. These approaches focus on enhancing drug permeation through the nail plate, improving drug stability, and maintaining sustained drug release at the site of infection. Recent advancements in formulation technologies, nanotechnology-based carriers, and physical enhancement methods have demonstrated considerable potential in improving antifungal drug delivery to infected nail tissues.

5.1 Nail Lacquer Systems

Medicated nail lacquers are among the most widely used topical formulations for the treatment of onychomycosis. These formulations consist of antifungal drugs dissolved or dispersed in a volatile solvent system containing film-forming polymers. Upon application to the nail surface, the solvent evaporates, leaving behind a thin, adherent polymeric film that acts as a drug reservoir. This film allows the gradual and sustained release of the antifungal agent, facilitating diffusion into the nail plate over an extended period.Nail lacquers provide several advantages, including prolonged drug contact with the nail surface, improved drug stability, and enhanced patient compliance due to ease of application. Common antifungal agents formulated as nail lacquers include Ciclopirox and Amorolfine, which have demonstrated broad-spectrum antifungal activity against dermatophytes, yeasts, and non-dermatophyte molds. Despite their benefits, the effectiveness of nail lacquers may still be limited by incomplete drug penetration through thickened or severely infected nails, which has encouraged further research into improved delivery systems.

5.2 Nanoparticle-Based Drug Delivery

Nanotechnology-based drug delivery systems have attracted considerable attention in recent years due to their ability to improve the physicochemical properties and therapeutic performance of antifungal drugs. Nanoparticles typically range in size from 1 to 1000 nanometers and can be engineered using various materials such as polymers, lipids, or inorganic substances. These nanoscale carriers enhance antifungal therapy by improving drug solubility, stability, and controlled release characteristics.The small particle size and high surface area of nanoparticles facilitate deeper penetration into the nail plate and surrounding tissues, enabling higher drug concentrations to reach the infected site. Polymeric nanoparticles, solid lipid nanoparticles, and nanostructured lipid carriers are among the most commonly investigated systems for antifungal drug delivery. These systems not only enhance drug permeation but also protect the active drug from degradation and allow sustained release, thereby improving therapeutic efficacy and reducing dosing frequency.

5.3 Liposomes and Nanoemulsions

Lipid-based nanocarriers such as liposomes and nanoemulsions have been extensively studied as potential delivery systems for antifungal drugs. Liposomes are spherical vesicles composed of phospholipid bilayers that can encapsulate both hydrophilic and lipophilic drugs. These vesicles enhance drug penetration by interacting with biological membranes and facilitating drug transport across the nail barrier.Nanoemulsions are thermodynamically stable dispersions of oil and water stabilized by surfactants, typically with droplet sizes ranging from 20 to 200 nanometers. Their small droplet size and large surface area improve drug solubility and enhance permeation through the nail plate. Both liposomes and nanoemulsions have demonstrated promising results in improving antifungal drug delivery and increasing antifungal activity against pathogenic fungi associated with onychomycosis.

5.4 Microneedle-Based Delivery

Microneedle technology represents a minimally invasive approach for enhancing transungual drug delivery. Microneedles are microscopic needle-like structures designed to create tiny microchannels in the nail plate or surrounding skin without causing significant pain or tissue damage. These microchannels facilitate the direct transport of antifungal drugs into deeper nail layers, thereby overcoming the barrier properties of the nail plate.Microneedle systems can be fabricated from various materials including metals, polymers, and biodegradable substances. When combined with topical antifungal formulations, microneedles significantly improve drug permeation and therapeutic effectiveness. This technique also offers the advantage of targeted drug delivery, which may reduce treatment duration and enhance patient outcomes.

5.5 Physical Enhancement Techniques

Several physical enhancement techniques have been explored to improve the permeation of antifungal drugs across the nail plate. One such technique is iontophoresis, which uses a low electrical current to drive charged drug molecules through the nail barrier, thereby enhancing drug transport into the infected tissues. Another approach is sonophoresis, which utilizes ultrasound waves to temporarily disrupt the keratin structure of the nail plate, increasing its permeability.In addition, laser-assisted drug delivery has gained attention as an innovative technique for improving transungual drug penetration. Laser treatment creates microchannels in the nail plate, allowing antifungal drugs to diffuse more effectively into deeper layers of the nail unit. These physical enhancement methods, either alone or in combination with advanced drug delivery systems, have shown significant potential in improving the treatment outcomes of onychomycosis. Overall, the integration of advanced formulation technologies and physical enhancement techniques offers promising opportunities for overcoming the limitations associated with conventional antifungal therapies and improving the effectiveness of transdermal drug delivery in the management of onychomycosis.

Clinical Studies on Transungual/Transdermal Drug Delivery Systems for Onychomycosis

Sr.No	Drug/Formulation	Delivery System	Study Type	Key Findings	Reference
1	Efinaconazole 10%	Topical solution (transungual delivery)	Phase III clinical trial	Demonstrated high nail penetration and improved complete cure rates compared with placebo	Elewski et al., 2013
2	Tavaborole 5%	Topical oxaborole antifungal solution	Randomized clinical trial	Effective nail penetration with significant improvement in distal subungual onychomycosis	Gupta et al., 2014
3	Ciclopirox 8%	Medicated nail lacquer	Clinical study	Provided sustained drug release but required long treatment duration for complete cure	Gupta & Paquet, 2015
4	Amorolfine 5%	Film-forming nail lacquer	Clinical study	Broad-spectrum antifungal activity with improved nail plate diffusion	Baran et al., 2007
5	Terbinafine	Nanoparticle-based topical formulation	Experimental clinical evaluation	Nanocarriers improved drug penetration and antifungal activity	Murdan, 2012
6	Itraconazole	Liposomal topical formulation	Preclinical/clinical evaluation	Enhanced drug permeation through nail keratin compared with conventional formulation	Vaka et al., 2013

Physical Enhancement Techniques for Transungual Drug Delivery

Sr.No	Technique	Principle	Drug/Example	Advantages	Limitation	Reference
1	Lontophoresis	Uses a low electrical current to drive charged drug molecules across the nail plate	Terbinafine, Ciclopirox	Enhances drug penetration, controlled delivery	Requires electrical device, possible irritation	Murdan, 2012
2	sonophoresis (Ultrasound)	Ultrasound waves disrupt keratin structure and enhance drug permeation	Ketoconazole, Amorolfine	Non-invasive technique, improves permeability	Limited penetration depth, equipment required	Polat et al., 2011
3	Laser-Assisted Drug Delivery	Laser creates microchannels in the nail plate allowing drug entry	Topical antifungal agents	Rapid drug penetration, targeted therapy	Expensive equipment, requires trained personnel	Waibel et al., 2013
4	Microneedle Technology	Microneedles create micro-pores in the nail plate to enhance drug diffusion	Terbinafine nanoparticles	Improves transungual drug transport	Possible discomfort, limited commercial availability	Bhatta et al., 2017
5	Nail Abrasion/Drilling	Mechanical thinning or perforation of the nail plate	Ciclopirox lacquer	Improves drug diffusion through nail	May damage nail plate, risk of infection	Murdan, 2008
6	Hydration/Occlusion Technique	Hydration swells the nail keratin structure, increasing permeability	Various antifungal formulations	Simple and inexpensive method	Limited enhancement compared to advanced techniques	Walters et al., 2012

Recent Advances in Transungual Drug Delivery (2020–2025)

In recent years, significant advancements have been made in the field of transungual drug delivery to overcome the limitations associated with conventional antifungal therapies. Researchers have focused on developing innovative drug delivery systems capable of enhancing drug penetration through the dense keratin structure of the nail plate while ensuring sustained antifungal activity. One of the most promising developments is the use of nanotechnology-based formulations, such as polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, and nanoemulsions. These nanosystems improve drug solubility, stability, and permeation across the nail plate. Due to their small particle size and high surface area, nanocarriers can penetrate deeper into the nail layers and deliver antifungal agents directly to the site of infection. Another notable advancement is the development of medicated nail lacquers with improved permeation enhancers. Modern nail lacquers incorporate keratolytic agents such as urea, salicylic acid, and thioglycolic acid, which help disrupt keratin networks and enhance drug diffusion. These formulations also provide prolonged drug contact with the nail surface, improving therapeutic efficacy. Researchers have also explored microneedle-based systems, which create microscopic channels in the nail plate to facilitate drug delivery. Microneedle-assisted drug delivery has shown promising results in increasing the permeability of antifungal drugs such as terbinafine and itraconazole. Additionally, laser-assisted drug delivery and iontophoresis have gained attention as physical enhancement techniques for improving drug penetration through the nail plate. These technologies create microchannels or utilize electrical current to transport drug molecules across the nail barrier more effectively. More recently, stimuli-responsive nanocarriers and smart drug delivery systems have been investigated for their ability to release antifungal drugs in response to specific environmental triggers such as pH changes or enzymatic activity. These systems may provide controlled and targeted drug release, improving treatment outcomes while minimizing drug wastage.

Evaluation Parameter

The development of effective transungual drug delivery systems requires comprehensive evaluation to ensure adequate drug permeation, antifungal efficacy, formulation stability, and patient safety. Due to the highly keratinized and compact structure of the nail plate, specialized evaluation techniques are employed to assess the performance of these systems. The key evaluation parameters are discussed below.

10.1 Physicochemical Characterization of Formulations

Physicochemical properties play a crucial role in determining the performance of transungual formulations. Parameters such as drug content uniformity, viscosity, drying time, and pH are commonly evaluated. Drug content analysis ensures uniform distribution of the active pharmaceutical ingredient within the formulation. Viscosity influences the spreadability and film-forming ability of nail lacquers, while drying time affects patient compliance. The pH of the formulation should be compatible with the nail and surrounding skin to prevent irritation

10.2 In Vitro Drug Release Studies

In vitro drug release studies are performed to evaluate the rate and extent of drug release from the formulation. These studies are typically conducted using Franz diffusion cells with appropriate membranes. The release profile provides insight into the controlled or sustained release behavior of the formulation, which is essential for maintaining therapeutic drug concentrations over prolonged

Transungual permeation studies are critical for assessing the ability of the drug to penetrate the nail plate. These studies are carried out using human or animal nail samples mounted on diffusion cells. The amount of drug permeated over time is quantified, and parameters such as permeation flux and permeability coefficient are calculated. These studies help in comparing different formulations and optimization of penetration enhancers.

10.3 Transungual Permeation Studies

10.4 Drug Uptake and Nail Penetration Studies

Drug uptake studies evaluate the accumulation of the drug within the nail plate. These studies provide information on drug distribution across different layers of the nail, including the dorsal, intermediate, and ventral layers. Advanced analytical techniques such as confocal laser scanning microscopy and spectroscopic methods are often employed to visualize and quantify drug penetration.

10.5 Antifungal Activity Evaluation

The antifungal efficacy of the formulation is assessed against common causative organisms such as trichophyton rubrum and trichophyton mentagrophytes. Standard microbiological methods, including the determination of minimum inhibitory concentration (MIC) and zone of inhibition studies, are used. These studies confirm whether the drug maintains its activity after formulation and penetration through the nail plate.

10.6 Mechanical Properties of Film-Forming System

For nail lacquer formulations, mechanical properties such as film adhesion, flexibility, and resistance to cracking are evaluated. Good adhesion ensures prolonged contact of the drug with the nail surface, while flexibility prevents film breakage during daily activities. Water resistance is also an important parameter, as frequent exposure to water may reduce drug retention.

10.7 Stability Studies

Stability studies are conducted according to International Council for Harmonisation (ICH) guidelines to evaluate the physical and chemical stability of the formulation. Parameters such as drug content, viscosity, color, and drying time are monitored under various temperature and humidity conditions. Stability studies help determine the shelf life and storage conditions of the formulation.

10.8 Safety and Irritation Studies

Safety evaluation is essential to ensure that the formulation does not cause irritation or toxicity. Skin irritation studies are conducted using animal models or human volunteers to assess any adverse reactions. These studies are particularly important for formulations containing penetration enhancers or novel nanocarriers.

10.9 Clinical Evaluation

Clinical studies provide the ultimate assessment of the efficacy and safety of transungual drug delivery systems. Parameters such as clinical cure rate, mycological cure rate, and recurrence rate are evaluated in patients with onychomycosis. These studies validate the therapeutic potential of the developed formulation under real-world conditions.

10.10 Nail Hydration and Swelling Studies

Hydration studies assess the effect of the formulation on nail swelling, which can significantly influence drug permeation. Increased hydration leads to loosening of the keratin network, thereby enhancing drug diffusion. These studies are important for evaluating formulations containing humectants or occlusive agents.

10.11 Advanced Characterization Techniques

Advanced analytical techniques are increasingly used to study drug–nail interactions and penetration mechanisms. Scanning electron microscopy (SEM) is employed to examine changes in nail surface morphology, while Fourier-transform infrared spectroscopy (FTIR) is used to detect chemical interactions between the drug and nail keratin. Confocal microscopy provides detailed visualization of drug distribution within the nail structure.

Future Perspectives of Nanotechnology in Onychomycosis Treatment

Nanotechnology has emerged as a promising approach for improving the treatment of onychomycosis by addressing many of the limitations associated with conventional therapies. Nanocarrier-based drug delivery systems, including nanoparticles, nanoemulsions, liposomes, and nanostructured lipid carriers, offer significant advantages such as improved drug solubility, enhanced permeation, and controlled drug release.One of the key advantages of nanotechnology-based formulations is their ability to penetrate the dense keratin structure of the nail plate more effectively than conventional formulations. Due to their extremely small particle size and high surface area, nanocarriers can facilitate deeper drug penetration and increase drug retention within the nail unit. This improved drug localization may lead to higher antifungal activity while minimizing systemic side effects.Nanotechnology also enables the development of targeted drug delivery systems that can specifically deliver antifungal agents to infected nail tissues. These systems can be designed to provide sustained drug release over extended periods, reducing the need for frequent drug application and improving patient compliance.Another promising area is the integration of nanocarriers with physical enhancement techniques such as microneedles, iontophoresis, and laser-assisted delivery. Such combination strategies can further improve drug penetration through the nail plate and enhance therapeutic outcomes. In the future, advanced technologies such as stimuli-responsive nanocarriers, smart drug delivery systems, and bioadhesive nanoparticle formulations may provide more effective and patient-friendly treatments for onychomycosis. Continued research in nanotechnology, along with clinical validation, will be essential for translating these innovative approaches into safe and effective therapeutic options.

CONCLUSION

Onychomycosis continues to represent a persistent and therapeutically challenging fungal infection, largely due to the unique structural and biochemical properties of the nail unit. The dense keratinized architecture of the nail plate, characterized by tightly packed keratin fibers and extensive disulfide cross-linking, significantly restricts drug permeation and limits the effectiveness of conventional topical therapies. Although systemic antifungal agents such as terbinafine and itraconazole have demonstrated clinical efficacy, their long-term use is often constrained by systemic toxicity, drug–drug interactions, and the need for prolonged treatment regimens. Consequently, these limitations highlight a critical need for alternative, safer, and more effective therapeutic strategies.In this context, transungual and transdermal drug delivery systems have emerged as promising approaches for improving antifungal therapy by enabling localized drug delivery directly to the site of infection. These systems offer several advantages, including enhanced drug penetration, reduced systemic exposure, and improved patient compliance. Various formulation strategies such as medicated nail lacquers, chemical penetration enhancers, and physical enhancement techniques—including iontophoresis, microneedles, ultrasound, and laser-assisted delivery—have demonstrated significant potential in overcoming the nail barrier and enhancing drug bioavailability.Among these, nanotechnology-based drug delivery systems represent a particularly transformative advancement in the management of onychomycosis. Nanocarriers such as polymeric nanoparticles, liposomes, nanoemulsions, and nanostructured lipid carriers provide improved drug solubility, enhanced permeation across the nail plate, and controlled or sustained drug release profiles. Moreover, these systems can potentially target fungal biofilms and deliver antifungal agents more effectively to deeper layers of the nail unit, thereby improving therapeutic outcomes while minimizing adverse effects.Despite these promising developments, several challenges remain to be addressed before these advanced delivery systems can be widely translated into clinical practice. Issues related to formulation stability, scalability, regulatory approval, cost-effectiveness, and long-term safety require further investigation. Additionally, variability in nail morphology among patients and the presence of fungal biofilms necessitate the development of more personalized and targeted treatment approaches.Future research should focus on the integration of nanotechnology with smart and stimuli-responsive drug delivery systems, as well as combination therapies that utilize both chemical and physical enhancement techniques. Advances in these areas, coupled with robust clinical validation, are expected to significantly improve treatment efficacy and reduce recurrence rates.In conclusion, transungual drug delivery systems, particularly those incorporating nanotechnology, hold substantial promise for revolutionizing the treatment of onychomycosis. Continued interdisciplinary research and innovation will be essential for translating these emerging technologies into safe, effective, and patient-friendly therapeutic solutions for this widespread and often recalcitrant condition.

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S.H. Rao et al.Testing the Efficacy of Transungual Drug Delivery System (Nail Lacquer) Containing Terbinafine against Aspergillus brasiliensis for the Topical Treatment of Onychomycosis(2022)
Y. YangA novel drug delivery gel of terbinafine hydrochloride with high penetration for external useDrug Deliv.(2015)There are more references available in the full text version of this article.Cited by (3)
ormulation and evaluation of herbal essential oil based nail lacquer for management of onychomycosis2024, Journal of Medical Mycology Show abstract
Drug delivery systems2024, Current Trends and Future Developments on Bio Membranes Advances on Membrane EngineeringShow abstract
hytochemicals as potential active principal components for formulation of alternative antifungal remedies against Trichophyton spp.: a systematic review
C. AjitTerbinafine-associated hepatotoxicitym. J. Med. Sci.(2003)
. I. AlbertiEffevt of ethanol and isopropyl myristate on the availability of topica? terbinafine in human stratum corneum, in vivoInt. J. Pharm.(2001)
. AlbertiIn vivo assessment of enhanced topical delivery of terbinafine to human stratum corneumJ. Controlled Release(2001)
G. BetzIn vivo comparison of various liposome formulations for cosmetic applicationInt. J. Pharm.

(2005)

. BogatajInfluence of phsicochemical and biological parameter on drug release from microspheres adhered on vesical and intestinal mucosaInt. J. Pharm.(1999)
M.B. Brownvercoming the nail barrier: a systematic investigation of ungual chemical penetration enhancementInt. J. Pharm.(2009)
A.K. DashDevelopment of a rectal nicotine delivery system for the treatment of ulcerative colitisInt. J. Pharm.(1999)
.-P. FangComparison of 5-aminolevulinic acid-encapsulated liposome versus ethosome for skin delivery for photodynamic therapyInt. J. Pharm.(2008)
E. FuglsethChiral derivatives of butenafine and terbinafine: synthesis and antifungal activity

Tetrahedron(2009)

M.A. GhannoumA large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patternsJ. Am. Acad. Dermatol.(2000)
H.B. Gunt et al.Effect of hydration on the permeation of ketoconazole through human nail plate in vitroEur. J. Pharm. Sci.(2007)
A.K. Gupta et al.Terbinafine: an update
. Am. Acad. Dermatol.(1997)
D.S. JonesTextural analysis and flow rheometry of novel, bioadhesive antimicrobial oral gelsInt. J. Pharm.(1997)
Y. KobayashiIn vitro permeation of several drugs through the human nail plate: relationship between physicochemical properties and nail permeability of drugsEur. J. Pharm. Sci.

(2004)

J.M. Lopez-PintoEffect of cholesterol and ethanol on dermal delivery from DPPC liposomes

Int. J. Pharm.(2005)

F. Maestrellireparation and characterisation of liposomes encapsulating ketoprofen–cyclodextrin complexes for transdermal drug delivery

Int. J. Pharm.(2005)

P. MuraDevelopment, characterization and in vivo evaluation of benzocaine-loaded liposomesEur. J. Pharm. Biopharm.(2007)
S. MurdanDrug delivery to the nail following topical applicationInt. J. Pharm.(2002)
A. PaavolaControlled release injectable liposomal gel of ibuprofen for epidural analgesiaInt. J. Pharm.(2000)
M.A. Repka et al.Influence of human nail etching for the assessment of topical onychomycosis therapiesInt. J. Pharm.(2004)
R.G. Rileyn investigation of mucus/polymer rheological synergism using synthesised and characterised poly(acrylic acid)sInt. J. Pharm.

(2001)

SunPreparation and evaluation of N3-O-toluyl-fluorouracil-loaded liposomesInt. J. Pharm.

(2008)

E. Van HoogdalemNail penetration of the antifungal agent oxiconazole after repeated topical application in healthy volunteers, and the effect of acetylcysteineEur. J. Pharm. Sci.(1997)
I. VejnovicInvestigation of different formulations for drug delivery through the nail plateInt. J. Pharm.(2010)
I. VejnovicPermeation studies of novel terbinafine formulations containing hydrophobins through human nails in vitroInt. J. Pharm.(2010)
S. Wessel et al.Hydration of human nails investigated by NIR-FT-Raman spectroscopyBiochim. Biophys. Acta(1999)Semin. Dermatol.(1991)

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Electrospun polyurethane/Eudragit® L100-55 composite mats for the pH dependent release of paclitaxel on duodenal stent cover applicationInt. J. Pharm.(2015)
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M.B. Delgado-CharroA pharmaceutics perspective on drug delivery to the nail: recent advances and challengesTher. Deliv.(2015)
T.S. Ahn et al.Effect of pressure sensitive adhesive and vehicles on permeation of terbinafine across porcine hoof membraneArch Pharm. Res. (Seoul)(2013)
S.H. Rao et al.Testing the Efficacy of Transungual Drug Delivery System (Nail Lacquer) Containing Terbinafine against Aspergillus brasiliensis for the Topical Treatment of Onychomycosis(2022)
Y. YangA novel drug delivery gel of terbinafine hydrochloride with high penetration for external useDrug Deliv.(2015)There are more references available in the full text version of this article.Cited by (3)
ormulation and evaluation of herbal essential oil based nail lacquer for management of onychomycosis2024, Journal of Medical Mycology Show abstract
Drug delivery systems2024, Current Trends and Future Developments on Bio Membranes Advances on Membrane EngineeringShow abstract
hytochemicals as potential active principal components for formulation of alternative antifungal remedies against Trichophyton spp.: a systematic review
C. AjitTerbinafine-associated hepatotoxicitym. J. Med. Sci.(2003)
. I. AlbertiEffevt of ethanol and isopropyl myristate on the availability of topica? terbinafine in human stratum corneum, in vivoInt. J. Pharm.(2001)
. AlbertiIn vivo assessment of enhanced topical delivery of terbinafine to human stratum corneumJ. Controlled Release(2001)
G. BetzIn vivo comparison of various liposome formulations for cosmetic applicationInt. J. Pharm.

(2005)

. BogatajInfluence of phsicochemical and biological parameter on drug release from microspheres adhered on vesical and intestinal mucosaInt. J. Pharm.(1999)
M.B. Brownvercoming the nail barrier: a systematic investigation of ungual chemical penetration enhancementInt. J. Pharm.(2009)
A.K. DashDevelopment of a rectal nicotine delivery system for the treatment of ulcerative colitisInt. J. Pharm.(1999)
.-P. FangComparison of 5-aminolevulinic acid-encapsulated liposome versus ethosome for skin delivery for photodynamic therapyInt. J. Pharm.(2008)
E. FuglsethChiral derivatives of butenafine and terbinafine: synthesis and antifungal activity

Tetrahedron(2009)

M.A. GhannoumA large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patternsJ. Am. Acad. Dermatol.(2000)
H.B. Gunt et al.Effect of hydration on the permeation of ketoconazole through human nail plate in vitroEur. J. Pharm. Sci.(2007)
A.K. Gupta et al.Terbinafine: an update
. Am. Acad. Dermatol.(1997)
D.S. JonesTextural analysis and flow rheometry of novel, bioadhesive antimicrobial oral gelsInt. J. Pharm.(1997)
Y. KobayashiIn vitro permeation of several drugs through the human nail plate: relationship between physicochemical properties and nail permeability of drugsEur. J. Pharm. Sci.

(2004)

J.M. Lopez-PintoEffect of cholesterol and ethanol on dermal delivery from DPPC liposomes

Int. J. Pharm.(2005)

F. Maestrellireparation and characterisation of liposomes encapsulating ketoprofen–cyclodextrin complexes for transdermal drug delivery

Int. J. Pharm.(2005)

P. MuraDevelopment, characterization and in vivo evaluation of benzocaine-loaded liposomesEur. J. Pharm. Biopharm.(2007)
S. MurdanDrug delivery to the nail following topical applicationInt. J. Pharm.(2002)
A. PaavolaControlled release injectable liposomal gel of ibuprofen for epidural analgesiaInt. J. Pharm.(2000)
M.A. Repka et al.Influence of human nail etching for the assessment of topical onychomycosis therapiesInt. J. Pharm.(2004)
R.G. Rileyn investigation of mucus/polymer rheological synergism using synthesised and characterised poly(acrylic acid)sInt. J. Pharm.

(2001)

SunPreparation and evaluation of N3-O-toluyl-fluorouracil-loaded liposomesInt. J. Pharm.

(2008)

E. Van HoogdalemNail penetration of the antifungal agent oxiconazole after repeated topical application in healthy volunteers, and the effect of acetylcysteineEur. J. Pharm. Sci.(1997)
I. VejnovicInvestigation of different formulations for drug delivery through the nail plateInt. J. Pharm.(2010)
I. VejnovicPermeation studies of novel terbinafine formulations containing hydrophobins through human nails in vitroInt. J. Pharm.(2010)
S. Wessel et al.Hydration of human nails investigated by NIR-FT-Raman spectroscopyBiochim. Biophys. Acta(1999)Semin. Dermatol.(1991)