Efficacy and safety of a new medicated nail hydrolacquer in the treatment of adults with toenail onychomycosis: A randomised clinical trial

A new water‐soluble formulation with ciclopirox has shown a higher penetration than other ciclopirox nail lacquers currently marketed, thus providing a higher concentration of ciclopirox into the nail.


| INTRODUC TI ON
Onychomycosis is a chronic fungal nail infection caused by dermatophytes, non-dermatophyte moulds and yeasts with negative consequences for patients as a result of pain or physical impairment. [1][2][3] Onychomycosis is the most common nail condition. The prevalence is 2%-20% in developed countries and its frequency increases with age in relation to the presence of a weakened immune system, poor peripheral circulation and slower growth of the nail plate. Around 20% of patients between 40 and 60 years of age and more than 50% of patients with 70 years suffer from onychomycosis. 1,4 Treatment of onychomycosis consists of eradicating the causative pathogens so that the healthy nail can be restored to prevent recurrence or spread of infection. 5 The therapeutic options are multiple, but the rates of therapeutic failure and recurrence are not negligible. Therefore, this disorder should be conveniently treated and addressed in the earliest stages. 4 Topical drug delivery systems to treat nail disorders are often preferred to avoid the adverse effects of systemic drugs, are well accepted by patients, and cost-effective. 6 They are indicated in the early stages of the disease when there is no involvement of the nail matrix and few nails are affected. 4 But its main drawback is low drug absorption due to the limited permeability of the nail structure, which reduces drug access and therefore therapeutic concentrations in the nail bed. 6 For this reason, the main challenge of research with lacquers is to obtain vehicles capable of solubilising the active ingredients, achieving greater permeability and longer residence time in the nail plate and consequently improving its efficacy, either as monotherapy or as an adjunct to systemic therapy. 7 Furthermore, since both the nail bed and the nail plate are involved in most cases, the effective antifungal drug must provide sufficient concentrations throughout the nail surface during the time of growth into a healthy nail. 8 Treatment of toenails is also challenging as they have a slower growth rate and require up to 12 months or more of treatment to complete replacement. 9 Several studies conducted throughout the world demonstrate the efficacy and good safety profile of ciclopirox when applied topically for the treatment of onychomycosis. 10 Ciclopirox is both fungicidal and fungistatic, and also has sporicidal activity. It has a broad-spectrum activity against dermatophytes (Trichophyton spp., Microsporum spp. and Epidermophyton spp.), yeasts (Candida spp.) and moulds, which reduces the probability of resistance development. 10,11 In more than 20 years of use no resistance to ciclopirox has been reported. [12][13][14] It inhibits the transport of essential elements into the fungal cells, leading to the disruption of DNA, RNA and protein synthesis. 14,15 Ciclopirox acts as a chelating agent for polyvalent cations (Fe 3+ or Al 3+ ), which causes the inhibition of metaldependent enzymes responsible for the degradation of reactive oxygen species in the fungal cell. This property seems to be decisive in its antifungal action. 13 In vitro studies have shown that the minimal inhibitory concentration of ciclopirox is almost unaltered when incubated in keratin-containing media as opposed to other topical drugs. 16 Ciclopirox also exhibits antibacterial activity against many Gram-positive and Gram-negative bacteria. 14,16 Also, it has been shown that ciclopirox exerts anti-inflammatory activity on human polymorphonuclear cells, inhibiting the synthesis of prostaglandins and leukotrienes. 17 In the treatment of onychomycosis, ciclopirox remains the antifungal drug of choice due to its broad antifungal spectrum and multiple properties mentioned before, 10 but its therapeutic efficacy can only be enhanced if it permeates and is subsequently retained on the nail plate. 15 To overcome the limitations of topical nail treatment, a new vehicle (Cyclo-Tech® technology) 18 was developed to improve the solubility parameters of the active ingredient which at the same time increases the permeability and consequently the hydration of the nail, maintaining effective concentrations of the ingredient active in the nail plate throughout the recommended treatment period.
The Ciclo-Tech® technology is based on the interaction of a solubilising and moisturising agent -hydroxypropyl--cyclodextrin-, with a permeability-enhancing substance -sodium lauryl sulfate-, and with a film-forming agent -poloxamer 407-. β-cyclodextrins encapsulate the active ingredient in a hydrophilic medium, 19,20 increasing its diffusion through the keratin of the nail and, at the same time, promoting nail hydration, [21][22][23] and therefore healthy nail replacement. [Correction added on 13 April 2023, after first online publication: "growth and healing' was changed to 'healthy nail replacement' in the preceding sentence.] Sodium lauryl sulfate (SLS) increases the pore of the nail surface, facilitating the penetration, concentration and time of permanence and action of the active ingredient. 24 Lastly, poloxamer-407 which has the property to solidify gels, when the ciclopirox, mycological cure, onychomycosis, water-soluble nail lacquer body temperature is stimulated, forms a uniform layer that increases the action time of the active ingredient, favouring the isolation of the nail surface and reducing the evaporation of water. 20 The preparation of these three components in an aqueous solution forms a supramolecular structure called polypseudorotaxane, 25 which facilitates the solubilisation of active ingredients, through the formation of inclusion complexes, as well as the formation of a hydrogel-type film on the nail. 19,20 With this, it is possible to significantly increase the concentration of the active ingredient compared to lacquers that do not incorporate cyclodextrins in their composition. 19,21 Likewise, the addition of ethanol further improves the solubility profile, the spreadability, the vehicle penetration into the nail, the drug permeation rate and the accumulation profile of the active ingredients in the nail. 26 A study carried out with the new vehicle (Ciclo-Tech® technology 27 ) solubility and better results in cosmetic alterations of the nails, which translates into a higher degree of patient satisfaction with this treatment.
In this context, a new water-soluble ciclopirox nail lacquer containing 80 mg/g of ciclopirox was developed, that confers moisturising and film-forming properties to the nail, allowing greater penetration of the active ingredient and thus provides a higher concentration of ciclopirox in the nail.
The release profile of the above-mentioned water-soluble ciclopirox nail lacquer was evaluated in an in vitro study carried out in a Franz cell assay and tested in parallel with a reference product (hydroxypropyl chitosan [HPCH]-based 80 mg/g ciclopirox nail lacquer). The new water-soluble ciclopirox nail lacquer had a permeability 3.25 times higher than the reference lacquer and it was also consistent with the determination of the drug in the nail model. The drug concentration reached from the investigational product was 1.6 times higher than the HPCH-based 80 mg/g ciclopirox nail reference lacquer. 28 A phase III clinical study has assessed the efficacy and safety of the new ciclopirox formulation in adults with toenail onychomycosis. The aim of this study was to evaluate the efficacy and safety of a new medicated nail hydrolacquer compared with its vehicle and an active comparator (ciclopirox 80 mg/g with HPCH nail lacquer) for the treatment of toenail fungal infection.

| PATIENTS AND ME THODS
Eligible patients were adult men and women aged ≥18 to ≤75 years with distal mild to moderate onychomycosis (involving ≥20% to ≤60% of the distal bed adherent nail plate without the involvement of the lunula) due to dermatophyte fungi affecting at least one big toenail. At screening disease positivity confirmed before randomisation was proven by culture and with the positive dermatophyte test strip-DTS (Diafactory Tinea unguium, JNC Corporation, Japan).
Exclusion criteria included allergy to ciclopirox or any component of the study medication, life expectancy less than 2 years at screening, regular use of cosmetic lacquer on the toenails unwilling to interrupt, pregnancy or breast-feeding and systemic or topical antifungal drugs.
This multicenter study was approved by the institutional review board of each participating institution and the corresponding national regulatory authorities. All patients provided written informed consent prior to enrollment.
All study drugs were identical/indistinguishable and had the same administration regimen. To keep them blind all were equally labelled.

| Study design
This was a multicenter, prospective, randomised, double-blinded, parallel-group and controlled study to assess the clinical effect of a ciclopirox nail hydrolacquer compared with its vehicle and the reference product in the treatment of patients with toenail fungal infection. Patients were recruited in a total of 31 centres from Spain (14), Mexico (12) and Latvia (5). week 52. Secondary outcomes were a rate of improvement, defined as patients with at least a 20% decrease of diseased nail area versus baseline, and conversion to negative DTS/KOH and culture (mycological cure).
The following safety endpoints were also considered: adverse events recorded during the whole treatment period and follow-up, and plasma ciclopirox levels and analytical parameters (haematology, clinical chemistry and urinalysis) of the safety laboratory subgroup (n = 36; n = 12 in each treatment group).

| Statistical analysis
To demonstrate the superiority of ciclopirox nail hydrolacquer versus the vehicle, the sample size calculation was based on the 1:1 allocation, a level of statistical significance of α = 0.05 (or 5% two-sided) and required power of at least 1 − β = 0.80 (80%), based on a normal approach. The patients were assigned to a group of ciclopirox nail hydrolacquer, vehicle or reference product with an equal allocation ratio of 1:1:1 using a table of random numbers generated by a computer. Differences between variables were compared using parametric (Student's t-test for paired samples or ANOVA) or non-parametric (Mann-Whitney, Kruskal-Wallis and Wilcoxon signed-rank) tests.
The Chi-squared test or Fisher's exact test was used for the analy-

| Assessments
The study included a total of 11 visits for up to 52 weeks (screen-

| Ethics statement
The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to and the appropriate ethical review committee approval has been received.

| RE SULTS
A total of 1430 patients were screened, 381 treated, 376 analysed for efficacy (ITT set), 381 analysed for safety and 255 completed the study (Figure 1). Overall, the demographic characteristics collected at baseline were similar between patient groups (Table 1) and there were no significant differences between the three study groups in these variables in the ITT population. week 52, although the differences were not statistically significant (Table 3). PP population analyses (220 patients) showed similar results in terms of conversion to negative to dermatophyte by culture (66.2% vs. 44.7%, respectively; p < .008; Figure 3). Mycological cure and improvement data are shown in Table 4.  population). The rate of AEs found in the study was low and most of them were of mild intensity. A summary of AEs is shown in Table 5. Ciclopirox levels in both active groups (ciclopirox nail hydrolacquer and the reference product) were found to be below the limit of detection or significantly low and at the same order of magnitude (range 1-2 ng/ml).

| DISCUSS ION
The main goal of onychomycosis treatment is to eradicate the organism, restore healthy nails and prevent the recurrence or spread of infection. 5 However, eradicating the causative pathogen is challenging because the penetration of the active ingredient through the nail is extremely low. 6  Published data have shown that the role of cyclodextrins is not limited to just improving solubility and bioavailability in antifungal formulations. 34 Specifically, its capacity to interact with the fungal membrane by extracting sterols (as ergosterol) and lipids, has been associated with its biological effect on the fungi homeostasis and so mimicking the action of some antifungals drugs. 35 Consequently, it is reasonable to assume that the vehicle included in this phase III clinical trial has played a role, more as an active pharmaceutical product than as a placebo-controlled group, and it may be explained by the active effect of the technology behind the vehicle. Apart from that, the high level of hydration and solubility showed by the inclusion of cyclodextrins in nail lacquers formulations, [20][21][22][23]28 which promotes quicker healthy nail growth, may have contributed to a more favourable clinical evaluation by the independent investigator during the study and especially in distal onychomycosis.
On the other hand, fungal culture represents one of the most specific method to diagnose onychomycosis, 36 and an essential tool to identify the etiological agent and test the efficacy of a treatment.
In this study, the topical formulation of the ciclopirox nail hydrolacquer showed optimal efficacy in mycological cure (conversion to negative dermatophyte by culture and DTS/KOH) and in improve- In conclusion, this study shows that the new water-soluble ciclopirox nail lacquer is effective and well tolerated, with a positive benefitrisk profile making it a good alternative for the topical treatment of onychomycosis. patients with adverse events leading to death 0 (0.0%) 0 (0.0%) 0 (0.0%)
Concerning AEs of severe intensity, one patient (0.8%) in the reference product group reported bladder cancer, another subject (0.8%) in the vehicle group reported pancreatic carcinoma and one patient (0.8%) in the ciclopirox nail hydrolacquer arm reported an acute myocardial infarction. None of them were considered related to the study treatment.