A Comprehensive Review on Transungual Drug Delivery: From Nail Anatomy to Treatment of Onychomycosis

Transungual drug delivery refers to a system designed for transporting drugs through the nail to achieve targeted treatment for nail diseases. The term "transungual" is derived from "trans," meaning "through," and "unguis," meaning “nail” ^[1]. The hardness and low permeability of the nail have traditionally made it a difficult path for drug delivery. Improving topical drug delivery for nail conditions like onychomycosis and nail psoriasis could reduce the reliance on systemic medications and their associated side effects. This strategy may also shorten treatment time and decrease the chances of recurrence ^[2]. Compared to oral versions like pills, ungual treatment has several advantages over oral or systemic medication delivery, including easier preparation. Additionally, it gets rid of systemic adverse effects and drug interactions. Local side effects, such as periungual erythema (redness around the nail fold), are uncommon but usually go away within minutes, as the body adapts to the drug. Because ungual treatment uses a topical preparation that is simple to remove if needed, it has little systemic absorption. It helps prevent possible drug interactions, enhances patient adherence, and is appropriate for people who are unable to take systemic medications, such as the elderly or those on many medications. Despite its benefits, ungual therapy faces challenges, including the nail plate’s composition, which restricts drug penetration. This means only a small fraction of the topical medication can penetrate, preventing the attainment of the desired therapeutic concentration ^[3].

Anatomy of a Nail

The human nail acts as an essential organ, like the claws of other mammals. It serves multiple functions, including protecting the tips of the fingers and toes from injury, enhancing tactile sensitivity, and assisting in object manipulation. Nails vary in size, shape, and texture, creating a thicker barrier that increases the distance drugs must travel for diffusion. The nail's physicochemical properties suggest it behaves like a hydrophilic gel membrane, while the stable disulfide bonds responsible for its hardness are thought to restrict drug penetration ^[4]. The nail plate is mainly composed of keratin molecules, which are linked by numerous disulfide bonds, and contains very little lipid content ^[5].

The human nail consists of the following parts (as shown in Fig 1):

Figure 1. Parts of a Nail

Nail Plate

The firm, keratinized structure on the surface of the fingers and toes is called the nail plate. It acts as the primary barrier to medication entry and is composed of densely packed keratin layers. Because of its thick nature, it is challenging to absorb drugs via the nail plate.

Nail Bed

Beneath the nail plate is the nail bed, a soft tissue rich in blood vessels that provide nutrients to the nail. For effective treatment, medications need to reach the nail bed in order to treat infections or conditions beneath or within the nail plate.

Perionychium

The perionychium refers to the skin around the edges of the nail, providing added protection. However, it does not play a direct role in drug absorption. The unique structure and function of each layer of the nail influence how effectively medications can be delivered for the treatment of nail disorders ^[6].

Hyponychium

The hyponychium is the skin located beneath the free edge of the nail, serving as a protective barrier to prevent pathogens and foreign substances from entering beneath the nail. This layer can also influence the application and absorption of topical medications.

Eponychium

The eponychium, or cuticle, is found at the base of the nail plate. It serves as a protective barrier against infections and environmental elements. Like the hyponychium, it can affect the effectiveness of topical treatments applied to the nail area.

Nail Matrix

The nail matrix, situated beneath the cuticle at the base of the nail, is where nail growth originates. It produces new keratin cells, which allow the nail to grow. Targeting the matrix is vital when treating conditions that impact nail growth, like psoriasis or fungal infections.

Nail Root

The germinal matrix, also known as the nail root (radix unguis), is located several millimetres into the finger, beneath the skin at the lower edge behind the fingernail. Together with the nail bed, the nail root contributes to the nail's volume. This area lacks melanocytes, the cells responsible for producing melanin. The lunula, a white, crescent-shaped structure, is believed to represent the boundary of the germinal matrix ^[7-8].

Figure 2. Illustration showing Human Nail Anatomy

Factors Affecting Drug Diffusion Through Nail

The effectiveness of nail drug treatments depends on factors like molecule size, solubility, and formulation. Larger molecules face resistance from the nail's keratin structure, limiting their ability to penetrate, while smaller molecules can diffuse more easily. Hydrophilic drugs struggle to pass through the nail’s hydrophobic surface, whereas lipophilic drugs penetrate more readily. The pH of the formulation affects drug ionization, with neutral, uncharged molecules generally penetrating better than charged ones. Solvent choice is also important; hydrophilic solvents hydrate the nail, expanding keratin fibers to improve absorption. Application techniques, such as ensuring thorough contact, and longer treatment durations can increase drug penetration. Nail thickness can act as a barrier, and the condition of the nail, whether damaged or infected, further impacts drug absorption and overall effectiveness.

Types of Nail Diseases

Nail diseases encompass a wide range of conditions affecting the structure, appearance, and health of nails. These include infections like fungal onychomycosis, inflammatory disorders such as psoriasis, and deformities like ingrown nails. Nail diseases can arise from infections, trauma, systemic diseases, or nutritional deficiencies, often impacting quality of life. Understanding their types, causes, and symptoms is essential for accurate diagnosis and effective treatment strategies. Table 1 gives a summary on various nail diseases, their causes, and symptoms.

Table 1. Detailed Description of Nail Diseases, their Causes and Symptoms

Onychomycosis

Onychomycosis is a fungal infection affecting nails, resulting in changes to their appearance, texture, and structure as shown in Figure.3. While it predominantly impacts toenails, fingernails can also be affected. The infection is caused by various fungi, including dermatophytes, yeasts, and molds, with T. rubrum being the most common culprit. Fingernail infections are often associated with Candida species, particularly C.albicans, and frequently co-occur with paronychia. This chronic condition can affect both toenails and fingernails, accounting for 50% of nail infections and 30% of superficial fungal skin infections. It is a globally occurring disease with diverse presentations and prevalence rates influenced by geographic, climatic, and demographic factors ^[20].

Epidemiology

Onychomycosis accounts for half of all nail diseases and affects about 5.5% globally, with earlier studies showing 2–8%. Prevalence is highest in Europe (23%) and East Asia (20%), with North America reporting up to 14%. Rates in Greece range from 15.7% in the south to 20% in the north. Gender disparities are notable; toenail infections are more common in men (81.49%) due to nail trauma and sports injuries, while fingernail infections are more frequent in women (39.74%), linked to prolonged moisture exposure from housework, manicures, and nail care, which may damage the protective eponychium.

Figure 3. Clinical image of Onychomycosis

Symptoms

The condition typically presents with nail discoloration, thickening, brittleness, and distortion. In severe cases, the nail may separate from the nail bed, making it difficult to trim and more vulnerable to damage.

Causes and Risk Factors

Onychomycosis is caused by fungi that thrive in warm, moist environments, such as public showers or poorly ventilated footwear. Risk factors include:

• Advanced age
• Diabetes
• Immunosuppression
• Foot or nail injuries
• Poor hygiene

Etiology

Dermatophytes are the leading pathogens, responsible for approximately 90% of toenail infections and 50% of fingernail cases. T.rubrum is the most common pathogen, followed by T. mentagrophytes. Dermatophyte-related nail infections are collectively referred to as tinea unguium. Non-dermatophyte molds (NDMs) also contribute to onychomycosis, primarily affecting toenails. NDMs account for 1.5–6% of cases and include consistently pathogenic fungi (S. dimidiatum, S. hyalinum) and opportunistic fungi (S. brevicaulis, A. sydowii, O. canadensis). Yeasts, particularly Candida albicans, are increasingly recognized as significant pathogens in fingernail infections. C. albicans is responsible for about 70% of cases, with other species such as C. parapsilosis, C. tropicalis, and C. krusei also implicated. Candida infections are more prevalent among individuals with weakened immune systems due to vascular diseases, diabetes, immunosuppression, aging or the use of broad-spectrum antibiotics.Certain conditions, including agammaglobulinemia, DiGeorge syndrome, and thymus dysplasia, further increase susceptible.

Types of Onychomycosis

There are six primary forms of onychomycosis, each of which affects the nails differently: white superficial, distal and lateral subungual, candidal, proximal subungual, total dystophic and endonyx. Table.2 gives a summary on the above-mentioned types of onychomycosis, their common causes, affected areas and their clinical features ^[21].

Table 2. Types of Onychomycosis, causative organism, areas affected and clinical features

Methods of Transungual Drug Delivery

The following are the various methods of transungual drug delivery

1. Surgical Delivery
2. Systemic Drug Delivery
3. Topical Drug Delivery

1. Passive Drug Delivery
2. Device Based Drug Delivery

4. Biophysical Therapy

1. Laser Therapy
2. Carbondioxide Lasers
3. Photodynamic Therapy
4. Etching

Surgical Delivery

In both cases of total and partial nail avulsion, the affected nail plate is surgically removed, either completely or partially, while under local anesthesia. Salicylic acid and urea are examples of keratolytic agents that soften the nail plate in preparation for avulsion. For nonsurgical avulsion, urea or urea and salicylic acid in combination have been utilized ^[22].

Systemic Drug Delivery

A relatively small amount of drug may reach the site of action when taken orally or parenterally. While this approach is better in an emergency, it is not the best option for long-term nail treatment ^[23].

Topical Drug Delivery

1. Passive Topical Drug Delivery

In cases of lateral and distal subungual onychomycosis, lacquer is the recommended treatment. Infection of the nail matrix, however, renders it ineffective. Nail lacquer is recommended to be applied once or twice a week for a duration of five to ten months. When the nail matrix treatment is not used, the complete and mycological cure rates for this lacquer have been reported to range from 38–54% and 60–76%, respectively.Burning, irritation, itching, redness, and discomfort are the most frequent negative side effects ^[24].

2. Device Based Topical Drug Delivery

1. Iontophorosis: It is the process of applying an electric field (electromotive force) to transfer a substance across a membrane. Iontophoresis may improve drug diffusion through a nail's hydrated keratin.
2. Ultrasound technique: The canine hoof model has been used to test the effectiveness of this technique in delivering medications across the nails. The canine hoof membrane was marked with blue dye and subjected to three energy levels for 120 seconds at 1.5 W/cm² power, with blue dye as a marker. Drug absorption increases by 1–5 times when compared to alternative methods ^[25].
3. UV photodynamic therapy: In treating conditions relating to the skin, photodynamic therapies have demonstrated remarkable results.When alpha linolenic acid (10 mM) was added to dermatophytes like Candida albicans and Trichophyton interdigitale, and the organisms were then exposed to light, their viability reduced.

Biophysical Therapy

1. Laser Therapy

The target tissues can be directly heated by lasers with wavelengths in the near-infrared (780–3000 nm) range. A microsurgical laser device that creates nail holes and applies topical antifungals to treat onychomycosis has been patented. There is a lot of work left to characterize this invention named ‘onycholaser’.

2. Carbondioxide Laser

Topical antifungal medication and fractional carbon dioxide laser therapy should be used in combination. A topical application of antifungal cream after nail plates were perforated with ablative carbon dioxide improved the look. ^[26].

3. Photodynamic Therapy

The fundamental idea behind this treatment is the way photosensitizers and visible spectrum light interacts. The product of the reaction between photosensitizing chemicals and visible spectrum light is singlet oxygen. Fungal cells can die because of a reaction between singlet oxygen and their biological components ^[27].

4. Etching

Tiny micropores are created on the nail plate's surface during the etching process. By creating microporosities on the nail surfaces, certain surface-modifying substances like tartaric acid and phosphoric acid or tools like path former reduce the contact angle and improve the surface on which the medication can attach. An FDA-approved tool called a path forming helps drain subungual hematomas by making tiny pinholes in the nails without damaging the nail bed. The gadget does not require anesthetic because it uses the electrical resistance of the nail as feedback. A 400-μm tissue cutter is used to drill the nail plate, and once it has entered the nail plate, it is retracted.

Topical Therapeutic Approaches

Therapeutic approaches for transungual delivery focus on the development of treatments that effectively penetrate the nail plate to target infections or conditions beneath the nail. This method aims to overcome the natural barrier of the nail, enhancing the absorption of antifungal agents or other medications. Advances in formulations like nail lacquers, gels, and nanoparticles are improving the efficacy of transungual drug delivery for conditions like onychomycosis. The topical therapeutic approaches are shown in the following Figure 4:

Figure 4. Topical Therapeutic Approaches

Gels

Gels or hydrogels are created from natural or synthetic hydrophilic polymers that dissolve in a solvent, forming a three-dimensional structure ^[28]. Due to their ability to retain significant amounts of water and hydrate the nail plate, thereby improving drug absorption, they are commonly used in the treatment of nail disorders ^[29]. Gels are difficult to apply because of their viscosity, and they tend to wear off the nail surface during daily activities. These are some disadvantages of using gels to treat nail diseases. These issues have prompted the creation of in situ gelling solutions, which, when certain parameters (temperature, pH, and ionic strength) are changed, such as after being applied to the nail, transform from a liquid state into a gel (Sol–Gel Transition) ^[30]. One well-known example of a material that changes because of temperature changes is polxamers. Additionally, gels can be used in conjunction with iontophoresis to transfer charged drug molecules across the nail plate because they are hydrophilic ^[31].

Nail Lacquer

In general, nail illnesses cannot be effectively treated using conventional pharmaceutical topical systems such gels, lotions, creams, suspensions, or solutions because they cannot remain at the application site long enough to allow drug penetration. In these situations, nail lacquers or paints are usually applied to improve the efficacy of antifungal drugs ^[32]. The primary ingredients of nail lacquers are volatile solvents and film-forming polymers, which are either water-soluble or insoluble resins. These substances dry rapidly, leaving a smooth layer on the nail plate that serves as a drug release depot ^[33]. Ciclopirox and Amorolfine, antifungal medications, are sold as nail lacquers. They are recommended to be administered following nail abrasion. The FDA-approved hydro-lacquer Penlac R includes 8% ciclopirox, whereas the water-insoluble nail lacquer Loceryl R has 5% amorolfine ^[34]. The addition of various polymers to nail lacquers, such as dual acrylate–silicone hybrid copolymer and hydroxyl propyl chitosan, increased ciclopirox and ketoconazole penetration, respectively ^[35].

Patches and Films

Since nail patches offer a delayed release of medication, they have become a better option than nail lacquers for reducing treatment durations and enhancing patient compliance. Typically, it consists of a release liner, a drug-impermeable backing membrane, and a pressure-sensitive adhesive matrix that serves as a medication reservoir. For two days, ALA patches are able to maintain the drug release ^[36]. Transungual films, which are made using hot melt extrusion or film casting techniques, offer prolonged drug release. Mididoddi et al. used hot melt extrusion to create a film of the ketoconazole medication based on hydroxy propyl cellulose ^[37].

Nano Emulsions

An isotropic biphasic mixture of two phases—oil and water—in which one phase is distributed as nanoparticles in the other is called a nano-emulsion. An interfacial layer of surfactants is used to stabilize the system ^[38]. The appearance of these nano-emulsion systems is translucent or transparent. Nano-emulsions have a higher thermodynamic stability than other lipid carriers. When compared to simple micelle solutions, nano-emulsions show a higher solubilization capacity ^[39-40].

Nano-Emulgel Drug Delivery System

By combining the nano-emulsion with a hydrogel matrix, nano-emulgel is created, which lessens the emulsion's thermodynamic instability. Because of the greater consistency of the external medium, the non-aqueous phase's mobility is reduced, which results in improved thermodynamic stability. The formulation can release the drug over time due to its improved retention time and thermodynamic stability, which makes nano-emulgel a controlled release dosage form for topical administration that is advantageous for medications with a short half-life ^[41-42]. These systems also benefit from pharmacokinetic characteristics including improved absorption and fewer adverse effects. The hydrogel matrix, uniformity, and consistency have contributed to the increased interest in nano-emulgels ^[43].

Drugs Used for Treatment of Different types of Onychomycosis

The kind and intensity of the fungal infection determine how onychomycosis is treated. Antifungal medications, both topical and systemic, are commonly used to target the underlying fungal organisms. Drugs like terbinafine, itraconazole, and fluconazole are often prescribed to treat different forms of onychomycosis, aiming to eliminate the infection and restore healthy nail growth ^[44]. The drugs used for treatment of Onychomycosis are as shown in Table 3.

Table 3. Medications used in the treatment