Iontophoresis to Overcome the Challenge of Nail Permeation: Considerations and Optimizations for Successful Ungual Drug Delivery

Abstract

Iontophoresis is a widely used drug delivery technique that has been used clinically to improve permeation through the skin for drugs and other actives in topical formulations. It is however not commonly used for the treatment of nail diseases despite its potential to improve transungual nail delivery. Instead, treatments for nail diseases are limited to relatively ineffective topical passive permeation techniques, which often result in relapses of nail diseases due to the thickness and hardness of the nail barrier resulting in lower permeation of the actives. Oral systemic antifungal agents that are also used are often associated with various undesirable side effects resulting in low patient compliance. This review article discusses what is currently known about the field of transungual iontophoresis, providing evidence of its efficacy and practicality in delivering drug to the entire surface of the nail for extended treatment periods. It also includes relevant details about the nail structure, the mechanisms of iontophoresis, and the associated in vitro and in vivo studies which have been used to investigate the optimal characteristics for a transungual iontophoretic drug delivery system. Iontophoresis is undoubtedly a promising option to treat nail diseases, and the use of this technique for clinical use will likely improve patient outcomes.

INTRODUCTION

Nail diseases such as onychomycosis and nail psoriasis are very common, the former affecting nearly 5.5% of all people worldwide (1) and the latter about 1 to 3% of people worldwide (2). Both diseases cause a significant decrease in quality of life of patients (3–5), but often go untreated due to a lack of safe and effective treatment methods. Currently, existing therapies for the treatment of these diseases are either ineffective or undesirable. In the case of onychomycosis, there are both systemic and topical treatments. Systemic treatments are usually in the form of oral antifungals, which have high cure rates but have numerous side effects including hepatotoxicity and cardiac effects, reducing patient compliance (6–8). Commercially available topical lacquers such as Loceryl® and Penlac® have less side effects and better patient compliance but suffer from low cure rates due to poor penetration of drug through the nail plate (9,10). Oral and topical treatments are often combined to treat more severe cases of onychomycosis in order to address these issues (11). Nail psoriasis is also treated using systemic or topical treatments, both of which suffer problems similar to the treatment methods for onychomycosis. Typically, immunosuppressant drugs (such as corticosteroids, methotrexate, infliximab) are used to treat nail psoriasis, which have a wide variety of side effects depending on which drug is used. The majority of these drugs require parenteral administration, which is an inconvenient route of administration, particularly in an outpatient setting (12). Topical antipsoriatic drugs suffer similar problems to that of anti-onychomycotic ones, featuring poor penetration of drug through the nail (13).

Iontophoresis is the use of an electrical current to drive ionizable molecules through biological membranes. This technique has most widely been used for transdermal drug delivery and has also found some success recently in ocular delivery (14,15). It was first attempted in nails in a 1986 study which described the delivery of prednisolone through the nail (16), but the idea of transungual iontophoresis was not revisited until nearly 30 years later, when research in the field then picked up rapidly. Iontophoresis has been shown to improve transungual permeation of drugs (such as terbinafine hydrochloride), improving drug permeation over passive formulations by up to 37 times in onychomycotic toenails (17). It has also been shown to enhance drug loading into the nail by up to tenfold (18).

This review aims to consolidate relevant novel studies related to transungual iontophoresis in a systematic manner and highlights specificities to be considered when designing such a system. Since Delgado-Charro’s review published in 2012 on this topic (19), more advancements have been made that further demonstrate the potential of this technique to be used in the clinical setting. This work aims to elucidate areas in need of more research in this field so that iontophoresis may be utilized clinically to enhance topical treatments of nail disease.

THE NAIL AND NAIL MODELS IN TRANSUNGUAL IONTOPHORESIS

The Nail Plate

The nail plate (or nail body) is essentially a modified stratum corneum composed of intracellular protein keratin. The protein molecules are very tightly packed into a dense network maintained by many strong disulfide bonds (20,21). The nail plate is divided into three layers—the dorsal, the intermediate, and the ventral layers, which each represent 30%, 50%, and 20% of the nail, respectively. An early study has reported that the dorsal layer is the most difficult barrier to permeate because it has the lowest diffusion coefficients out of the three layers (22). However, recent studies have suggested that this may not be the case; rather, the nail has a porous external layer and a less porous intermediate layer (23,24). The intermediate layer has the lowest lipid content of the three layers, and the ventral layer has the highest lipid content. The nail’s main lipid is cholesterol, but the nail is only about 0.1–1% lipid, which is in contrast with the ~ 10% lipid content found in the stratum corneum of the skin. On the other hand, the water content of the nail is around 12% (25), and it is also extremely permeable to water, being 1000-fold more permeable to water than the skin (26). These properties both suggest that water-soluble permeants are favorable for transungual delivery, which has been demonstrated in a study in which the drug loading of 5-fluorouracil, a hydrophilic drug, had a concentration 300-fold higher than flurbiprofen, a hydrophobic drug (22). Therefore, in terms of permeability, the nail is often compared to a hydrophilic gel membrane (22,26).

The pathways for permeants to travel through the nails is very different from that of the skin, primarily due to the lack of appendageal pathways, which is the main route utilized for iontophoretic transport across the skin (10,26). The appendageal pathway is the path of least resistance, making it more favorable than the other paracellular and transcellular pathways in the skin. Unlike the skin, the paracellular and transcellular pathways are the only option for transungual drug delivery, which has been demonstrated by the use of laser scanning confocal microscopy (19,24). The pore size of these pathways is quite small, which results in hindered transport of larger molecules. Besides charge, which is critical for iontophoresis, molecular weight is often seen as the most significant property of a drug, with higher molecular weight drugs having lower permeation (27).

The lack of a clear pathway for current to travel through the tissue matrix contributes to the high electrical resistance of the nail plate. The electrical resistance of the nail plate when completely dry was found to be too high to measure; however, it quickly drops if the nail is hydrated. This is believed to be happening because of the swelling of the nail plate in its hydrated state, loosening the keratin network which then forms channels for drug transport. This is also helpful for passive ungual drug delivery (28). It has also been reported that the use of iontophoresis does not affect the electrical resistance of the nail (29,30). This essentially requires that the nail is hydrated before transungual iontophoresis can be applied. Oftentimes, hydration is a pretreatment and is also built into the drug delivery system by the usage of an aqueous formulation.

Alternative Nail Delivery Routes

Different parts of the nail can also be targeted as routes for drug delivery, some of which have been studied in conjunction with iontophoresis (see Figure 1 for a depiction of nail anatomy). Manda et al. investigated the use of iontophoresis across the proximal nail fold to directly target the nail matrix where the stem cells that create the nail plate reside. Like the nail itself, the proximal nail fold lacks appendageal pathways, which was emulated using a porcine folded epidermal model. It was seen that iontophoresis increased the amount of permeant (terbinafine hydrochloride) loaded into the folded epidermis by more than fivefold (passive, 0.08 ± 0.01 μg/mg; iontophoresis, 0.45 ± 0.12 μg/mg), and it increased the amount that penetrated through the folded epidermis by around 150 times compared to that of passive application. This enhancement of permeation across the proximal nail fold directly to the nail matrix is expected to reduce the likelihood of recurrence of nail disease once the nail plate and bed have achieved complete cure (31).

Fig. 1.

Nail anatomy. Image source: Integumentary Levels of Organization. Authored by: Open Learning Initiative. Provided by: Carnegie Mellon University.

Kushwaha et al. studied iontophoretic drug delivery into the nail unit through the hyponychium, which would deliver drug from the ventral layer of the nail plate upward into the dorsal layer rather than the other way around. The electrodes for iontophoresis were placed on the hyponychium and proximal nail fold, and 0.5 mA/cm² current was run through the nail for 3 days, 8 h a day. In the passive experiment without iontophoresis, 0.17 ± 0.10 μg/mg of terbinafine hydrochloride was loaded into the nail plate, and an undetectably low amount into the nail bed and nail matrix, while iontophoresis delivered 3.43 ± 1.34 μg/mg into the nail plate, and 0.173 ± 0.124 μg/mg into the nail bed and nail matrix. Despite the positive results, the limitation of this method is the small available surface area of the hyponychium, limiting the amount of formulation that can be applied (32).

Nail Models

Many nail models have been used in order to study transungual drug delivery and emulate in vivo conditions as closely as possible, each featuring their own pros and cons. The ones that have been used to study iontophoretic delivery are discussed here. Note that in vivo models reportedly have higher initial electrical resistance than in vitro models, which eventually becomes the same after hydration (28). However, this fact is mostly irrelevant since nail hydration is critical to enhancing transungual permeation, which means that the nails are often hydrated before the iontophoretic treatment.

Animal Hooves

Animal hooves or animal-derived keratin slices are the easiest nail models to procure and use for testing. They are large, flat, and much easier to work with in comparison to human nails (33) but have many chemical differences from the human nail. Bovine hooves, for example, have a lower proportion of disulfide bridges as compared to the human nail and are nearly 30-fold more permeable than the healthy human nails (34). Bovine hooves feature parallelism to human infected toenails, meaning extrapolation of data is possible (33). However, as a result of having less disulfide bridges, chemical permeation enhancers are less effective (35), since many permeation enhancers function to enhance drug permeation by breaking down keratin bonds. In horse hooves, the hydration capacity is much higher than in human nails, leading to large amounts of swelling and potentially an overestimation of permeability (36). Due to these differences, these models are mostly suitable for preliminary studies (37,38), although in some instances they have been used to conduct full studies even recently in studies involving iontophoretic transungual drug delivery (39).

Human Nail Clippings

Human nail clippings are the most frequently used in vitro models for studying transungual iontophoresis because they are relatively easy to obtain over full nail plates and are more representative of the in vivo nail than animal hooves. However, they are often small, thick, and curved, which can make them difficult to incorporate into permeation equipment such as a modified Franz diffusion cell. Additionally, they have been shown to have different iontophoretic transport characteristics as compared to the in vivo case, which was seen when the transport of sodium was compared between the two cases (40). Due to the lack of a nail bed, the receptor medium of a vertical a Franz diffusion cell is altered in order to emulate a nail bed. The most important factor to emulate is the circulatory system of the underlying epithelium underneath the nail. Most studies do this by establishing sink conditions and making the receptor solution highly favorable for the dissolution of the permeant. For instance, Nair et al. used a receptor solution of pH 3 in their experiments order to fully solubilize the antifungal drug terbinafine hydrochloride (41).

Human Nail Plates

The human nail plates/human cadaver nails are more difficult to obtain than nail clippings. However, they are a more accurate representation of in vivo drug delivery situation in terms of barrier function. The nail plate is firmly attached to the nail bed and is hence hydrated differently from the distal nail clippings resulting in different transonychial water loss (TOWL) and barrier functions (40). Like human nail clippings, the receptor medium of a Franz diffusion cell can be altered to achieve sink conditions and emulate in vivo conditions. The plates could be even closer to in vivo conditions if diseased nails can be obtained; however, it should be kept in mind that the difference in extent of the disease progression and, hence, in nail irregularities will limit the reproducibility of studies.

Human Cadaver Nail Unit

The ex vivo human cadaver nail is closest to in vivo in terms of permeability characteristics because it has a nail bed, but it is difficult to obtain and needs to be stored well. A major problem with this model is that it lacks a circulatory system, making sink conditions under the nail difficult to establish. This presents as decreased permeation through the nail over time, as seen in Kushwaha’s comparison of the porcine hoof membrane model and the excised toe model in a transungual iontophoresis permeation experiment. There was a high correlation (r² = 0.93) between the drug load into the hoof membrane and nail plate, but there was a much lower correlation in the permeation of the two models (r² = 0.56) (38). The same was seen by Nair et al., in which the correlation between iontophoretic current density and permeation was investigated. Normally, an increase in current density results in a linear increase in permeation, but this linear correlation was not present in this model due to the lack of sink conditions (42).

Keratin Films

Keratin films derived from the human hair have been explored as a potential nail model. The human hair and human nails have similar physical and chemical properties (43), and the use of these films as a valid model is further validated by their similarity to hooves. However, similar to hooves, ungual penetration enhancers seem to misrepresent the effects of these compounds on the keratin films (44). An advantage of these models is that they are manufactured, and therefore would not have high internal variability, which is a major problem with the other nail models. These films have not yet been tested in transungual iontophoresis in published studies, so their applicability as a model for iontophoresis is not yet established.

Nail Models of Diseases

Whether or not the nail model has the disease condition of interest is very important in relevance to permeation characteristics. Onychomycotic nails are thicker, have reduced tensile strength, have larger pores, and are considerably more permeable than the healthy human nails (45,46). This is because fungi release keratinases which break apart the structure of the nail (47,48). It has been shown that keratin films can be “infected” with T. rubrum and can function as a model of onychomycotic nails, which may be a very useful screening tool prior to starting clinical studies (49).

While no in vitro studies have been performed on psoriatic nails, the disease is inflammatory in nature and causes nail pitting, onychodystrophy, and in severe cases, onycholysis (12). Such psoriasis-affected nails are, therefore, expected to have different permeability characteristics than healthy nails. Currently, there is no animal model reported in the literature that can serve as a model for nail psoriasis. Considering the importance of the disease state on the nail model, the development of a model that mimics nail psoriasis could assist in making in vitro results much more applicable to the clinical setting. It would be difficult to adjust the structure of the nail in order to emulate inflammation, so the most reasonable approach to achieve a nail psoriasis model is to obtain them by inducing psoriasis in animal keratin membranes such as bovine hooves or by receiving psoriatic human nails. Both methods would be difficult, as the former would require induction of a disease that has no clear pathogenesis (12), and the latter suffers from ethical and availability issues.

Inter-nail Variability

A major obstacle in studying transungual drug delivery is inter-nail variability, presenting as statistically significant differences between nails despite no other differences being present (50). A common variable used in studying the nail barrier is TOWL, the nail counterpart of transepidermal water loss (TEWL) that depicts the effects of formulations and/or disorders on the skin barrier (51). Many of the observations described below have been observed due to differences in TOWL or due to a difference of nail thickness.

Nail plates are very different between individuals, with significant differences in thickness and TOWL (51). Furthermore, as people age, nail plates thicken because the cells of the nail plate increase in size (52). Whether or not the nails used were frozen for storage or if the patient has used cosmetics can influence TOWL, and oftentimes, investigators do not know if the patient has used cosmetics (53). There are also pH differences that seem to be correlated with gender (54). While thickness can be adjusted for samples, there are too many differences between the nail plates of different individuals to produce statistically significant results without a large sample size.

Even if the nails are from the same donor, differences still exist between the nails. Fingernails and toenails are quite different structurally (55) and have different permeabilities as a result. In a comparison of onychomycotic fingernails and onychomycotic toenails, it was found that the fingernails were significantly more permeable than the toenails. It also found that iontophoresis assisted the permeation through toenails to a greater extent (18). Between an individual’s fingernails, the nail plate thickness is different among all five nails. In the order from thickest to thinnest, the nail thickness goes from thumb, to the index, to the middle, to the ring, and lastly the little finger (56). Unfortunately, attempting to account for this by using opposite digits (i.e., a left index fingernail and a right index fingernail) is also not recommended (51), as the TOWL of left digits appears to significantly be higher than that of the right hand, which is presumably linked to handedness, with the dominant hand possessing the lower TOWL (40). This difference may be linked to the fact that nails of the dominant hand tend to grow faster (57). While not officially studied, it is likely that the TOWL of right digits would be lower in left-handed individuals, meaning the difference persists.

The only reliable way, therefore, to obtain a good control group for a study is to use the same nail from the same individual for multiple tests, but this may be impractical. Certain treatments such as nail abrasion have irreversible effects on nail morphology, and it may be necessary to destroy or permanently damage the nail to evaluate certain nail characteristics, such as the amount of drug loaded into the nail. However, even this must be done with caution, since nail plate hydration greatly affects TOWL, and relative humidity has been shown to cause differences in TOWL among individuals within the same day of testing (51). As the nails lose hydration, the TOWL also changes, suggesting a change in barrier function over time.

One approach to address the variability between nail samples is to systematically study a large number of nail samples, but due to the difficulty of obtaining human tissue, this is viewed as unfeasible (58). Another approach is to measure the variability between the samples using another method to study the nail variability before conducting the study of interest (24). Regardless, the issue of inter-nail variability makes quantitative comparison of data between studies a challenge. Overall, a transungual drug delivery system should be able to address the differing nail barrier functionalities present in an in vivo setting. Iontophoresis is particularly well-suited to serve this purpose, as the current applied can be easily altered, which can change the permeation of the drug through the nail.

MECHANISMS OF IONTOPHORESIS

Iontophoresis enhances transungual drug delivery primarily by two mechanisms: electromigration and electroosmosis. A summary of these mechanisms as relevant to transungual iontophoresis is presented below. The total transungual flux is represented as the total of these two forces, plus the natural passive flux, giving Eq. 1 (15):

$$J_{TOT}=J_P+J_{EM}+J_{EO}$$ (1)

where J_EM is the flux caused by electromigration; J_P is the passive flux; and J_EO is the flux caused by electroosmosis. As suggested by Eq. 1, the three fluxes are independent of one another.

Electromigration

Electromigration, also known as electrorepulsion, is based on the familiar electrical concept that like charges repel one another and opposite charges attract. When the electrodes are placed onto a membrane, electrolytes (including the permeant of interest) will attempt to move across the membrane in order to balance charges. Electromigration can be explained and predicted using Faraday’s Law, which states that (59):

$$J_{EM}=\frac{I{t}_i}{AF{z}_i}$$ (2)

where I is the applied current in amperes; t_i is the transport number of the ion; A is the cross-sectional area; F is Faraday’s constant; and z_p is the valence of the ion. Analyzing the equation, F is a constant, and the majority of charged drugs have a valence of 1, making the only remaining variables of interest I, A, and t_i.

The combination of terms I/A is often referred to as the current density and is directly proportional to the flux contributed by electromigration. Due to the fact that electromigration is the largest contributor of the fluxes in charged permeants, a change in current density can appear to result in a linear change in flux. However, a linear correlation is not always observed (15), possibly due to the other contributing factors to total flux. Nair et al. reported on this phenomenon in terms of voltage, stating that permeation is a function of applied voltage (r² = 0.98). The programmability of this was also confirmed, as instantaneous changes in voltage were associated with an instantaneous change of rate of drug permeation. This included completely turning off the device (voltage = 0), in which the flux would immediately return to that of passive permeation alone (30).

The transport number t_i is a fraction of the total charge carried by the ion in question. It measures the ability of a permeant to carry charge compared to other ions in the system. There are three main factors that influence transport number: ion molar fraction, electric mobility, and valence. Intuitively, the higher the ion concentration relative to other ions in the system, the more charge it will carry relative to competing ions. However, electrical balance will still mostly be achieved by endogenous ions such as sodium and chloride, which are highly mobile due to their small size and hydrophilicity. Since drug molecules are often significantly larger than their primary competition (endogenous ions), and size is inversely proportional with electromobility (60), they will by default not be as mobile (and thus carry less charge). Therefore, minimizing co-ion competition is critical in optimizing electromigration (15,19).

Electroosmosis

Electroosmosis, also known as convective solvent flow, is the force that results from solvent flow within a system that has a fixed charge within its structure. Imposing an electrical field on such a system causes solvent to flow, creating a momentum which causes ion movement in a specific direction. The flux of the solvent that results is a function of many different factors, most of which relate to the penetration pathways (61), which practically can only be manipulated with chemical enhancers. In general, interactions between the ions and the penetration pathways should be minimized in order to maximize electroosmotic solvent flow. The solvent’s flux is also proportional to the applied voltage and therefore current density (15), making a higher current density favorable for electroosmosis, similar to electromigration. The amount of flux that is given to a specific drug, then, is the solvent flux (J_solvent) multiplied by the concentration of the drug in that solvent (C_d), giving Eq. 3 (62):

$$J_{EO}=J_{\mathit{\text{solvent}}}\times C_d$$ (3)

The direction of electroosmosis depends on the permselectivity of the membrane in question. Figure 2 explains the direction of electroosmosis depending on the pH of the nail. Note that the nail has an isoelectric point (pI) of around 5 (62).

Fig. 2.

The direction of electroosmosis depends on the permselectivity of the nail, which is determined by its pH

Unlike electromigration, electroosmosis can be applied to neutral permeants, as tested by Hao and Li [29]. Anodal iontophoresis was used to enhance the transport of mannitol and urea, albeit marginally. This transport enhancement was proportional to the electric current. When cathodal iontophoresis was used instead, the transport of neither ion was significantly different from the passive transport, as the electroosmotic solvent flow was opposing permeation through the nail. This study also suggested that the effects of electroosmosis are stronger on larger molecules, as the enhancement of mannitol (182.17 g/mol) transport was higher than that of urea (60.06 g/mol) (29).

Comparison of Electromigration and Electroosmosis

The direction of electroosmosis creates a problem with many drugs used in transungual drug delivery of ions. In order to ionize a drug into a cation, for example, terbinafine hydrochloride (pK_a = 6.7 ± 0.3 (63)), a low pH is often necessary. A cationic drug will preferentially utilize anodal iontophoresis (anode-to-cathode) in order to take advantage of electromigration. However, using a low pH means that the nail will become anion permselective, and electroosmosis will flow from cathode to anode, which is the opposite direction of electromigration. The only situation in which electromigration and electroosmosis will flow in the same direction is if a drug is positively charged at a high pH or negatively charged at a low pH.

As aforementioned, the contributions of electromigration are much more significant than that of electroosmosis in the nails (19,29,64). In one study by Murthy et al., anodal iontophoresis was applied to salicylic acid. Electroosmosis favored transport across the nail, while electromigration worked in the opposite direction. The resulting transport flux was approximately 2 times less than the passive transport flux, showing that the opposing electromigration effect is much stronger than the electroosmotic effect (62). As will be further explained in the discussion of formulation pH, the two forces often oppose one another. If electromigration and electroosmosis are competing, electromigration should always dictate whether cathodal or anodal iontophoresis is utilized.

Electroosmosis should mainly be considered for neutral permeants, as electromigration has no effect on neutral permeants. In this case, assuming a formulation with a physiologic pH of ~ 7 is being used, anodal iontophoresis should be applied, as this is the direction that assists in permeation.

Electropermeabilization

Electropermeabilization, also known as electroporation, is a phenomenon in which small current pathways open up as a result of iontophoresis in the skin (65). However, as mentioned previously, iontophoresis itself has little to no effect on the nail structure; rather, the increase in hydration that results from iontophoresis is what enhances permeation. Hao et al. demonstrated this by comparing the electric resistance profiles during constant voltage iontophoresis and with hydration alone. These authors concluded that the electric current had no significant effect on nail electric resistance (28). This decrease in nail resistance that results from increased hydration as a result of electric current is occasionally still referred to as electropermeabilization (30).

Fungicidal Effects of Current Application

In addition to the ability of iontophoresis to enhance transungual transport, treatment of onychomycosis using transungual iontophoresis is benefited from the fact that low-voltage direct current is fungicidal, particularly to T. rubrum and T. mentagrophytes (66). While current can kill fungi at 0.5 mA, the effect at this current is only mild and often requires higher currents to have much of an effect.

PRACTICALITY OF TRANSUNGUAL IONTOPHORESIS

All transungual iontophoresis studies have reported a significant increase of both permeation and drug loading into the active site of diffusion, but therapy cannot be successful unless the drug is delivered to the entire nail unit that is affected by disease. It must also stay in the affected area for an extended period of time.

Drug Loading into Different Layers of the Nail

Iontophoresis assists in delivering drug into deeper layers of the nail in comparison to passive delivery, which primarily delivers only to the dorsal layer (17,30). This is crucial because in both onychomycosis and nail psoriasis, the entire nail is affected by the disease and requires drug, not just the dorsal layer (12). It was found that in the passive delivery of terbinafine, the dorsal layer contained 0.362 ± 0.064 μg/mg and the ventral layer contained 0.008 ± 0.002 μg/mg, despite the fact that the maximum drug load in each layer was quite similar (dorsal, 1.34 ± 0.22 μg/mg; ventral, 1.19 ± 0.10 μg/mg). Iontophoresis, on the other hand, had a much higher proportion of drug delivered into the ventral layer, with the dorsal layer containing 1.002 ± 0.327 μg/mg and the ventral layer containing 0.644 ± 0.086 μg/mg (41).

Drug Loading into the Peripheral Area of the Nail

The ability of a drug delivery system to deliver drug into the peripheral areas of the nail is important in effectively treating the entirety of the affected nail, as the active diffusion site of the delivery system is rarely as large as the nail (67). The amount of drug delivered to all peripheral areas of the nail is higher in iontophoretic delivery than passive delivery, including the left and right lateral nail folds, the proximal nail fold, the distal nail fold, and the nail bed (42). Like the increase in delivery in the active diffusion area, an increase in current density results in a proportional increase in drug loading into the peripheral area, which was seen when a twofold increase in current density resulted in a twofold increase in peripheral nail drug loading (0.25 mA/cm², 0.020 ± 0.014 μg/mg; 0.5 mA/cm², 0.039 ± 0.015 μg/mg) (18). However, the increase in drug load into the peripheral area when using iontophoresis is slightly less than the increase in drug load into the active diffusion area. In one study, the increase in drug loading in the active diffusion area in onychomycotic toe nails was 11-fold while the increase in the peripheral areas of the nail was only ninefold (17). Nevertheless, the ability of iontophoresis to also enhance permeation into the peripheral areas of the nail is a critical component in its ability to improve treatment of nail diseases.

Drug Release from the Nail

Once the drug is loaded into the nail, the nail acts as sort of a drug reservoir that slowly releases drug to the surrounding tissue (18). The longer it stays in the nail, the longer it can treat the disease within the nail plate as well. A nail loaded with drug from passive drug delivery releases a very small amount of drug in a short, single, slow phase, while a nail loaded with drug from iontophoretic drug delivery releases drug in a biphasic manner: an initial fast release phase (~ 1–3 weeks long) followed by a long, slow phase of release (as long as 10 weeks long) (17,41,42). These release profiles are likely related to the fact that most of the drug in passive delivery are confined in the dorsal layer of the nail, while iontophoresis effectively delivers drug into all layers of the nail. The initial fast release in the iontophoretically loaded nails is likely the drug that is in the ventral layer, which releases drug much better than the dorsal layer, which is likely responsible for the slow release of both the iontophoretically loaded nail and the passively loaded nail (18). The proportion of drug that is released from iontophoretically loaded nails (60–65%) is also higher than that of passively loaded nails (15–25%), which makes the iontophoretically loaded nail more advantageous as a drug reservoir than a passively loaded nail (42).

FORMULATION DEVELOPMENT AND DESIGN FOR A TRANSUNGUAL IONTOPHORETIC DRUG DELIVERY SYSTEM

Drug Choice

Many of the factors considered while selecting a drug for transungual iontophoresis are intuitive once the mechanisms are known. To maximize electromigration, the drug selected should be ionized at a reasonable pH range, have a low molecular weight, and be highly soluble (19). A drug must be ionized for electromigration to be successful, and ionization also imparts hydrophilicity which is ideal for transungual permeation (35). A low molecular weight both increases the transport number for electromigration and increases passive permeation through the nail (27), but it has a much greater effect on the latter (68). Molecular weight has a much greater importance in the nail than in the skin as well, as mentioned previously due to hindered transport in the nail. Baswan et al. describe in detail how one can predict how successful transport will be based on the hydrodynamic radius of the drug (68). Solubility should be high in order to maximize the molar fraction in the formulation and therefore maximize the transport number (19). Selected drugs should also be relatively potent and be able to treat the disease at low concentrations, especially for topical delivery in which transport is challenging. Lastly, the activity of a drug may be reduced if there is an affinity between keratin and the drug (69).

Drugs Used with Transungual Iontophoresis for Treatment of Onychomycosis

Terbinafine hydrochloride has been the most frequently studied for the transungual iontophoretic treatment of onychomycosis, as it is widely regarded as the most effective systemic antifungal agent for treating onychomycosis (70). It is potent against many different dermatophytes, particularly T. rubrum (71), the main dermatophyte that causes onychomycosis among many others (72). It is moderately sized for an antifungal agent (327.89 g/mol), but it has low aqueous solubility. It has a pK_a of 6.7 ± 0.3 such that it becomes cationic at pHs below this value (63). While the drug experiences considerable difficulty in permeating the nail barrier, its mycological effectiveness makes it a promising choice for topical delivery, and its ability to assume a positive charge at reasonable pHs makes it suitable for iontophoresis. Terbinafine does bind to keratin, causing it to temporarily lose its antifungal activity, but the drug is eventually released without a change in activity (69).

Ciclopirox olamine is another commonly used topical antifungal that has been used for transungual iontophoresis. It is often used as a local antimycotic that inhibits cellular activities of a wide variety of fungal organisms. In comparison to terbinafine hydrochloride, it is considerably smaller (207.25 g/mol), has much better water solubility (8.6 mg/mL), and is thus more hydrophilic (logP ~ 2.6). It has a pK_a of 8.07 ± 0.05 and becomes anionic at pHs above this value (73,74) which makes it suitable for usage with cathodal iontophoresis. Other favorable characteristics of ciclopirox are its tendency to accumulate the nail and be released over long periods of time and its tendency to not induce fungal resistance (i.e., its minimum inhibitory concentration does not change over time) (75).

Some larger drugs have also been used for transungual iontophoresis, namely, itraconazole hydrochloride and nystatin. Itraconazole (molecular weight: 705.65 g/mol) is typically used to systemically treat onychomycosis and can also be synthesized into itraconazole hydrochloride. The latter is advantageous for transungual iontophoresis because it carries a charge at reasonable pH values (itraconazole’s pK_a is 3.7, requiring extremely low pHs to achieve protonation), has better transungual permeation, and has improved aqueous and organic solubility, while not having significantly different antifungal activity. However, itraconazole HCl is not normally manufactured as a salt, so it needs to be manually synthesized using the process described by Kushwaha et al. (38). Considering the improved characteristics of the salt version of itraconazole, it may be advantageous for transungual iontophoresis of other drugs by making them into their salt forms. Nystatin (molecular weight: 926.1 g/mol) is very large and has low aqueous solubility. The main issue with both of these drugs for transungual permeation is their large size, making their permeation low (39). A direct comparison of these agents, along with other antifungal drug candidates and their physical and chemical properties, is shown in Table I.

Table I.

Potential Transungual Iontophoresis Drug Candidates

Drug	MW (g/mol)	pKa	Iontophoresis type	Water solubility	Source
Amorolfine	353.51	6.6	Anodal	9.2 ± 0.06 mg/mL	(73)
Ciclopirox olamine	268.35	8.07 ± 0.05	Cathodal	32.8 ± 0.6 mg/mL	(73,74)
Fluconazole	306.27	1.76 ± 0.1	Anodal	8 mg/mL	(76)
Itraconazole	706.65	3.7	Anodal	Essentially insoluble	(38,77)
Itraconazole HCl	743.11	3.7	Anodal	0.01 mg/mL (pH 7)	(38)
				0.04 mg/mL (pH 3)
Naftifine HCl	323.86	8.0 ± 0.2	Anodal	Essentially insoluble	(78)
Nystatin	926.1	5.12; 8.89a	Anodal	∼0.3 mg/mL	(39)
Terbinafine HCl	327.89	6.7 ± 0.3	Anodal	0.02 mg/mL (pH 6.8)	(63)

^aNystatin is amphoteric, with a carboxyl functional group (pK_a ∼5.12) and an amino functional group (pK_a ∼8.89)

Data and references for some entries are obtained directly from Delgado-Charro’s 2012 review (19).

The drug used should consider the aforementioned properties, as well as the clinical indication for which it is being considered. Potential drug candidates have been listed and detailed in the table; however, suggesting a choice of drug based on clinical application is out of the scope of this article.

Electrodes

The electrodes selected for transungual iontophoresis depend primarily on the permeant in question. Table II summarizes permeants and their electrodes that have been used for transungual iontophoresis.

Table II.

Permeants Tested with Transungual Iontophoresis and Associated Electrodes

Electrode	Permeant	Source
Ag/AgCl	Terbinafine hydrochloride	Several sources
	Glucose, griseofulvin	(62)
	Salicylic acid	(29,79)
	Mannitol	(29,58,64,80)
	Urea, triethylammonium, thioglycolic acid	(29,64,80)
	Chloride	(40,81)
	Sodium	(40,81,82)
	Lithium	(82)
	Sodium fluorescein	(24,32)
	Nile blue chloride	(24)
	Nystatin	(39)
Ag/Pt	Ciclopirox olamine	(83)
Pt/Pt	Ciclopirox olamine	(30)
Pt/AgCl	Itraconazole hydrochloride	(38)

Ag/AgCl electrodes are the preferred electrodes for iontophoresis and are used for the vast majority of permeants. However, the system must have sufficient chloride ions to avoid precipitation of silver which can stain the nail (28). Note that if chloride is a permeant of interest, the estimation of chloride flux while using Ag/AgCl electrodes can become difficult. The AgCl anode uses chloride ions to react with oxidized silver. The amount of chloride that the anode consumes must be theoretically calculated, which requires the assumption that the only process occurring at the anode is silver oxidation. This assumption does not account other agents in the nail that could oxidize the anode, leading to an overestimation of chloride consumption (40).

Ciclopirox olamine cannot be used with Ag/AgCl electrodes because ciclopirox olamine chemically reacts with the AgCl anode, causing the electrode to peel (83). Hao et al. used Ag/Pt to prevent this from occurring. However, Pt generates hydroxide, which caused a change in pH in the donor from 8.7 to over 10 throughout the course of the experiment. This pH change can cause two potential problems: a potential change in the ionization state of ciclopirox, decreasing transport efficiency, and additional hydroxide ions which compete with ciclopirox for electromigration, also decreasing transport efficiency (83). Pt/Pt is an alternative to Ag/Pt used by Nair et al. that does not significantly change the pH (30), making this the recommended choice for ciclopirox olamine.

Pt/AgCl was used by Kushwaha et al. for a study on itraconazole hydrochloride. Itraconazole hydrochloride reacted with the Ag electrode, causing a sharp pH change that caused precipitation of itraconazole. The use of a Pt electrode caused pH changes over time as well, but this was addressed by replacing the donor and receiver solutions periodically (38).

Drug Concentration

The main effect of drug concentration in transungual iontophoresis is on electromigration, as the transport number is in part determined by the proportion of the charge carried by the drug. It has been found that relative concentrations of ions (i.e., molar fractions) are more representative of an ion’s transport number than its concentration in the formulation (82). In cases in which there is a large amount of ion competition, drug concentration seems to have a linear correlation with drug flux. An early study by Murthy prepared salicylic acid solutions in PBS. It was concluded that the concentration of salicylic acid resulted in a linear increase in both passive and iontophoretic transungual flux (79). Since PBS is an ion-rich solution, an increase in salicylic acid concentration presumably had a dramatic effect on increasing its electromigration. The usage of a salt bridge to remove ion competition has been tested in the skin. When the cations in the donor compartment were removed, delivery became independent of drug concentration (10 mM rasagiline permeation, 1200 ± 155 μg/cm²; 40 mM rasagiline permeation, 1322 ± 3352 μg/cm²) (84). The usage of a salt bridge has not been attempted with transungual iontophoresis, but the effect will most likely be the same.

Drug concentration also directly affects the flux that results from electroosmosis (Eq. 3), but considering electromigration and electroosmosis frequently work in opposite directions, this is not necessarily desirable. In certain cases with larger drug molecules, an increase in concentration does not significantly increase permeation and in fact may even decrease permeation due to an increase in electroosmosis (37,39).

In this section, we will now consider and discuss ionic strength. There are numerous reports on the effects of formulation ionic strength, and there are both reasons why a lower ionic strength may be favorable and also why it should not be too low. A lower ionic strength means there is less ion competition for the drug and also results in favorable partitioning into the nail (80,85). However, if the ionic strength is too low, it may sacrifice the stability of the system. Using an ionic strength of < 40 mM is difficult to maintain and can result in a decrease of pH, decreasing transport (62,80). Low formulation ionic strengths are also prone to causing an asymmetric situation in which the tissue in question (nail ionic strength = 154 mM) has a much higher ionic strength than the formulation, which establishes a gradient that favors transport from the receiver to the donor (85). Also, if the drug being used is too large, it may not carry charge well enough to conduct current, as seen in a study with nystatin. In this case, increasing the ionic strength was favorable presumably because the additional ions helped to carry the current flow (39). Since the effect of ionic strength depends on drug choice and has a profound effect on the membrane, there is no universally optimal choice, but nail studies have seen success above 50 mM but not higher than 200 mM (39,79). While no articles have explicitly tested permeation at an ionic strength of 154 mM, this ionic strength is potentially a good choice due to having symmetry with the physiological ionic strength of the nail.

pH

pH is a critical factor in transungual iontophoretic nail delivery that can be changed relatively freely depending on the hydrating solution used in pretreatment and the pH of the formulation. The hydration step will determine the initial pH of the nail, but the pH of the formulation will eventually balance out with the pH of the nail. It is often best to make the nail pH and the formulation pH the same, mostly due to the electromigration effect. In the case of an ionizable drug, which is the most suitable drug choice for iontophoresis, a pH such that the drug in question is almost completely ionized should be used.

Another major factor determined by pH which is relevant to electromigration is the presence of hydronium and hydroxide, which serve as competition co-ions to drug delivery. They are highly mobile species that have a much higher equivalent conductance than both inorganic ions and ionized organic drugs, so it is advised to maintain a drug concentration higher than the concentration of hydronium or hydroxide (59). This was demonstrated when a pH of 1 was used with iontophoresis. At this pH, the transport of all drugs was very low relative to normal pHs, most likely due to the excessive competition for electromigration from hydronium ions (81).

As aforementioned, the ionization of the nail’s keratin membrane also depends on pH, which determines the direction of electroosmotic solvent flow. At physiologic pH (pH = 7.4), the nail carries a net negative charge and will be cation permselective, since the nail has a pH of around 5 (62). Most formulations used are this pH due to the risk of irritating the skin at non-physiologic pHs. However, the nail itself is usually around a pH of 5, which varies slightly if the nails are washed (54), meaning the nail normally bears low charge density. However, this effect contributes much less than electromigration and should mainly be considered if a neutral drug is being used.

The pH also influences the passive flux for ions, as the charge state of the drug influences its passive permeability. The passive permeability of non-ionic drug molecules is considerably higher than ionic drug molecules. The non-ionic form of benzoic acid was approximately 10 times more permeable than its ionic counterpart, and a similar trend was seen with lidocaine, a basic drug (86). Murthy et al. found that this relationship has less to do with charge, but thermodynamic activity of the drug solution. The thermodynamic activity is lower if the solubility of the drug at a given pH is higher, ionizing it further and, thus, negatively impacting passive delivery by having lesser free drug available at the interface (79).

Extreme pHs should not be used in conjunction with iontophoresis due to the significant co-ion competition that results, but extreme pHs may be able to increase the permeability of the nail for non-charged molecules. At pH 13 or higher, the nail appears to irreversibly disintegrate, which increased water permeation and therefore hydration. At a pH of 1 or lower, the transport pathways in the nail are chemically altered, which is only somewhat reversible. This chemical change highly favored the passive transport of negatively charged drugs (81). Neither of these pHs were tested clinically, however, as such extreme pHs are certainly unsafe for the surrounding skin.

Solvent

Formulations designed for transungual iontophoresis should try to maximize the use of water as the solvent and avoid the use of organic solvents. Organic solvents such as ethanol decrease permeation by dehydrating the nail, increasing nail resistance, and decreasing conductivity and by solvent interactions that reduce nail uptake by altering the barrier properties of the nail (87). They also decrease nail conductivity and considering that most drugs (particularly antifungals) are large and lipophilic, this is not always feasible, but surfactant can be used to decrease the proportion of organic solvent necessary.

NAIL PRETREATMENTS

Nail Hydration

The hydration of the nail plate is a major factor in determining its permeability and electrical resistance. When hydrated, the water is mainly protein-bound, implying a water-protein interaction (88). This results in the softening of the nail, possibly due to water-induced change in molecular structure, or a loosening of the structure due to hydration. When infrared and impedance spectroscopy were used to evaluate the effects of hydration, it was found that the presence of water affects the nature of amino acid side chains and the hydrogen bonding of the nail (50), further supporting the fact that a change in protein structure may be the mechanism. The most important effect of hydration is the increase of pore size in the nails, allowing for relatively large drug molecules to better permeate the nail (29).

Hydration also specifically enhances iontophoretic drug delivery through the nails by increasing the relative number of conductive sites as compared to capacitive sites (50), decreasing the electrical resistance of the nail. Marzec and Olszewski have conducted in-depth research on the effect of hydration on the dielectric properties of the nail, with the ultimate conclusion that the dielectric properties are considerably higher in wet nails due to the surface polar groups (OH, NH, etc.) from the interactions in the keratin-water system (89). Using a hydrating solution with modified pH can also change the permselectivity of the nail, which affects the direction of electroosmosis, one of the mechanisms of iontophoresis, and the ability for either cations or anions to permeate through the membrane more easily. The importance of pH is further explained later in this article.

In general, nail permeation increases the longer the nail is hydrated, with a saturation point at around 2 h (28). This time is too long for practical use in a clinical setting, but most relevant changes occur very quickly, typically within the first hour of hydration (50). If the nail was not hydrated prior to application, patients reported an initial “tingling effect,” but only about 3 min of hydration is necessary to overcome the initially high resistance of the nail (40). According to one test, nails approached 90% of their complete hydration state within 30 min of hydration (29). Many in vitro studies hydrate the nails overnight before use, and while this guarantees complete hydration, this amount of hydration is not practical in a clinical setting.

Physical Methods

Physical (mechanical) pretreatments to enhance transungual permeation include abrasion and avulsion. Abrasion is the use of a file to remove layers of the nail barrier and has been used clinically to improve the efficacy of passive permeation through the nail for pharmaceutical lacquers (90,91). Clinically, only the uppermost dorsal layer of the nail can be abraded, which, as mentioned previously, is a more relevant barrier to permeation than the ventral layer. This was confirmed in a study in which a dorsal abrasion and ventral abrasion were directly compared. In a passive permeation experiment, delivery through nails with an abraded ventral layer was not significantly different from the untreated control, while nails with an abraded dorsal layer resulted in almost fourfold higher permeation (67). However, the effects of abrasion are also subject to inter-nail variability, so there is no set number of filing strokes that will be equally effective for all nails (51). Avulsion is the full removal of the nail plate from the nail bed and obviously has no need to be followed by iontophoresis.

Chemical Methods

The discussion of chemical pretreatment methods revolves around ungual permeation enhancers. The mechanisms by which these chemicals work are often through increased hydration and/or disruption of the keratin network (35). There are many ungual permeation enhancers, but only a few have been used in conjunction with iontophoresis. Screening a potential permeation enhancer as a candidate can be done relatively easily by determining the hydration enhancement factor and drug uptake enhancement factor, as described by Chouhan and Saini (92). Hao and Li tested the effects of pretreating the nails in solutions of thioglycolic acid (TGA), glycolic acid, and urea and found that thioglycolic acid assisted the most in permeation. While urea is keratolytic and causes hydration and swelling, the data suggested that the pores created by urea were too small to enhance permeation of molecules larger than water, and glycolic acid primarily weakens lipid binding, which would not help much in permeation of the nail plate. Thioglycolic acid’s main mechanism is to break disulfide bonds and this compound has often been used for breaking keratin in the hair, which created large pores in the nail that increased nail permeability to permeants larger than water. At a concentration of 0.5 M (a further increase in concentration did not significantly help), TGA increased the effective pore size and decreased the electrical resistance of the nail, increasing the transference numbers from 0.15 ± 0.05 to 0.26 ± 0.07 μg/mg (64). Amichai et al. investigated the use of iontophoresis with 3% dimethyl sulfoxide (DMSO), which is similarly a keratolytic agent. DMSO significantly accelerated the penetration of the drug through the nail. The total amount of drug that penetrated through the nail after 120 h (70.4 ± 28.1 μg/cm²) was nearly 3× higher than the formulation without DMSO (25.3 ± 2.7 μg/cm²) (37). Polyethylene glycols (PEGs) were investigated in detail by Nair et al. in conjunction with iontophoresis. An iontophoresis experiment was performed to test and compare the nail permeability using 30% PEG 200 and PEG 400 (PEG 200, 2.51 ± 0.33 μg/mg; PEG 400, 2.69 ± 0.59 μg/mg) and 30% glycerin, which was used as the control in this experiment (1.46 ± 0.31 μg/mg). While both were simply nail softening agents that increased hydration, microscopy revealed that the PEGs were more efficient in hydrating the nail than glycerin (93).

Defatting is another chemical treatment, which it does not significantly enhance permeability of the nail presumably due to the low lipid content reported (67).

Ionto-keratolysis

Ionto-keratolysis is the pretreatment of nails using iontophoresis in conjunction with keratolytic agents. Essentially, the permeation of the permeation enhancer itself is being enhanced by using iontophoresis. Because iontophoresis is being used, the permeation enhancer in question should be charged, and an appropriate iontophoresis method should be used for pretreatment. Nair et al. used ionto-keratolysis with salicylic acid and sodium sulfite, permeation enhancers that can exist in negatively charged states. The pretreatment consisted of the use of cathodal iontophoresis with a constant current of 0.5 mA/cm² for 1 h. When the nails that had undergone ionto-keratolysis underwent a permeation experiment alongside of non-treated control nails, the nails that were pretreated with ionto-keratolysis with salicylic acid and sodium sulfite both had significant increases in permeation over the control nails (~twofold increase and ~threefold increase, respectively) (67). Despite the effectiveness of ionto-keratolysis, it has only been used for transungual iontophoresis in the aforementioned in vitro study by Nair et al. If the permeation enhancer has the same charge as the drug, it may be effective to include the permeation enhancer in the formulation to deliver both the enhancer and the drug at the same time. However, while this would be much more convenient and skip the pretreatment step, it would introduce significant ion competition for the transport of the drug. Whether or not such a system would be effective for improving transungual iontophoresis has not yet been tested.

CLINICAL USE OF TRANSUNGUAL IONTOPHORESIS

Clinical Efficacy of Transungual Drug Delivery

As one may surmise from the in vitro results, the ability of iontophoresis to improve transungual drug delivery has improved clinical efficacy of topical treatments for ungual diseases. Four controlled clinical studies regarding the efficacy of iontophoresis to treat nail diseases have been reported: two for onychomycosis and two for nail psoriasis. Some in vitro studies additionally had an in vivo element to evaluate safety in patients.

Onychomycosis

Amichai et al. conducted a study on thirty-eight patients with onychomycosis. The patients were divided into two groups: an iontophoresis group, which received treatment with a 1% terbinafine formulation and 0.1 mA iontophoresis, and a control group, which was treated only on the 1% terbinafine formulation. Each group was treated 5 days per week for 6–8 h overnight over a period of 4 weeks. Each week, nail growth and the presence of fungal elements (e.g., using potassium hydroxide microscopy to detect fungal cells) were measured. While the results of the nail growth study are not fully validated (94), there was a significantly lower amount of fungal elements in the nail in group A by the end of the 4 weeks (study group, 74% of patients negative for fungal elements; control group, 50% of patients negative for fungal elements). The fungal elements continued to decrease even after the treatment ended due to the large amount of drug that was still loaded into the nail, which is evident by a checkup that occurred 1 week after the initial 4 weeks of treatment (study group, 2.41 μg/cm²; control group, 0.15 μg/cm²) (95).

Another clinical study on forty patients used onychomycosis severity index (a scale from 0 to 35 that represents how much of the nail is affected by the disease), a visual analog scale (a scale from 0 to 10 based on patient-reported pain while walking with shoes on), and potassium hydroxide microscopy (to evaluate presence of fungal elements) to evaluate the efficacy of Lamisil® with iontophoresis. The iontophoresis group received 3–4 mA/min iontophoresis for 30 min 3 times a week for 4 weeks, while the control group received a placebo 0 mA/min iontophoresis. The study group was clearly superior to the control group in all three measured factors, which included onychomycosis severity index (study group, 4.6 ± 8.7; control group, 14.45 ± 6.95), the visual analog scale (study group, 1.25 ± 2.02; control group, 5.95 ± 2.46), and potassium hydroxide microscopy (study group, 80% of patients negative for fungal elements; control group, 15% of patients negative for fungal elements) (96).

Nail Psoriasis

Two clinical studies were reported in the literature about the use of iontophoresis to treat nail psoriasis. Both of them used nail psoriasis severity index (NAPSI) in order to measure outcomes, in which each nail was divided into eight sections—four quadrants for each nail bed and nail matrix—and given points depending on if a section was diseased or not (max score per nail = 8). Both treatments also used the same method of submerging the fingernails into drug solution and running the current through the solution and up the hand. A notable disadvantage of this is that the current is most likely to flow through the pathway of least resistance, which is through the water. It is less likely to travel through the skin, and even less likely through the nail (19). Despite this flaw, the treatment appears to be effective, as described below. Direct application of the drug onto the nail for treatment of nail psoriasis has not yet been attempted and would likely increase the efficacy of this treatment even further than what has been seen in the below studies.

The first was a retrospective study on 27 patients who were treated with dexamethasone solution in combination with 4 mA iontophoresis for 20 min once a week for 3 months (97). All patients had previously failed standard topical treatment before attempting iontophoresis. After the application of iontophoresis, 22 of the patients had a NAPSI score improvement (mean improvement: 8), but 5 of them did not. Of the 5 patients, 2 were still satisfied with the results, claiming their nails were stronger, 2 discontinued for miscellaneous reasons, and 1 was completely unresponsive to any treatment. It was seen that some of the patients who had improved NAPSI scores saw improvement very late into treatment, suggesting that treating the patients for longer than 3 months may have helped more.

The other study was a controlled clinical trial that compared triamcinolone acetonide with 4 mA iontophoresis (TI) with calcipotriol/betamethasone dipropionate ointment (CB) (98). Each patient enrolled in the study would have a random hand treated with TI and the other hand treated with the CB. Over a period of 6 months, the former was applied for just 20 min monthly, while the latter was applied daily. At the end of the treatment period, no statistical difference was seen in terms of change in NAPSI, but throughout the course of the study, the improvement was more rapid in the triamcinolone acetonide iontophoresis hands. This treatment was also preferred because the sessions were monthly. This made the procedure cheaper and more time efficient, which improved patient compliance.

Safety of Iontophoretic Technique

The effects of iontophoresis on the structure of the nail plate are primarily due to increased hydration of the nail (50). Any other effects to the nail barrier that may be caused by iontophoresis are reversible once application is stopped (29,39,40,82).

Transungual iontophoresis is well tolerated by patients at 0.5 mA/cm², which is the current density usually applied to the skin. The nail should be hydrated prior to application to avoid a potential tingling sensation that patients may feel (40). As mentioned previously, hydration lowers the initially very high electrical resistance of the nail that results in discomfort (28). However, even if the nail is not hydrated, the tingling sensation that is felt is tolerable, as patients who felt it did not feel a need to discontinue the current application (95). When current densities higher than 0.5 mA/cm² were utilized, patients felt a shock. The tissues underneath the nail plate presumably swelled, as a soreness was felt upon application of pressure. Brown stains were additionally found on the nail surface, the origin of which seems to be the precipitation of Ag from the AgCl electrode (28).

CONCLUSIONS

Despite the apparent effectiveness of iontophoresis in improving drug delivery through the nails, the technique is still not widely used in the clinic, and many patients with nail diseases are not treated due to lack of safety and efficacy of existing treatment methods. The technique has been tested in many different nail models and has been shown to significantly improve drug permeation in every model it has been tested in, including in vivo application. The mechanisms of iontophoresis and various methods of improving transungual permeation have been studied, and the underlying theory has been supported by several studies. The effectiveness of iontophoresis in delivering drug into the nail and maintaining drug concentrations for an extended period has been clearly demonstrated. Transungual iontophoresis is also safe at low currents, with either insignificant or readily reversible changes that result from the application of electric current. The mild irritation that some patients have reported is easily prevented by hydrating the nail prior to any topical formulation application, which is already a useful practice in enhancing nail permeability. Thus, transungual iontophoresis is a promising approach to address the issue of poor treatment options for nail diseases. Some areas in the field that could benefit from further studies are ionto-keratolysis, the application of a greater variety of permeation enhancers, the use of disease model keratin films to both emulate disease states and improve on inter-nail variability, and the use of a nail gel formulation for the treatment of nail psoriasis (the way in which transungual treatment of onychomycosis is typically treated). Figure 3 summarizes considerations that influence the development of a suitable transungual iontophoresis system.

Fig. 3.

Flow chart for development of a transungual iontophoresis delivery system