WO2017029387A1

WO2017029387A1 - Method of improving visual appearance of nails affected by onychomycosis

Info

Publication number: WO2017029387A1
Application number: PCT/EP2016/069677
Authority: WO
Inventors: Marlis SARKANY; Farzaneh SIDOU; Nabil Kerrouche
Original assignee: Galderma Sa
Priority date: 2015-08-20
Filing date: 2016-08-19
Publication date: 2017-02-23

Abstract

The invention relates to method of improving visual appearance of nails affected by onychomycosis comprising the steps of: applying an antifungal nail lacquer comprising amorolfine to the affected nails; and applying, on said nails coated with said nail lacquer, a cosmetic nail varnish.

Description

METHOD OF IMPROVING VISUAL APPEARANCE OF NAILS AFFECTED

BY ONYCHOMYCOSIS

The invention relates to a method of improving visual appearance of nails affected by onychomycosis by applying a cosmetic nail varnish on the affected nails, after treatment with an amorolfine nail lacquer, without reducing its antifungal efficacy, and a kit comprising such a nail lacquer. Onychomycoses are fungal infections of the nails, among which the most frequent are dermatophytic onychomycoses also called tinea unguium: onychomycosis constitutes about half of all nail abnormalities. Onychomycosis may affect toenails or fingernails, but toenails affections are particularly common. It occurs in about 10% of the adult population.

The most common symptom of an onychomycosis is the nail becoming thickened and discoloured (dyschromia; mostly white, yellow) detaching itself from the nail bed (onycholysis). As the infection progresses, the nail can become brittle, with pieces breaking off or coming away from the toe or finger completely. If left untreated, the skin can become inflamed. There is usually no pain or other bodily symptoms, unless the disease is severe.

People with onychomycosis may experience significant psychosocial problems due to the appearance of the nail, particularly when fingers, which are always visible, are affected (Szepietowski JC, Reich A., September 2008, "Stigmatisation in onychomycosis patients: a population-based study". Mycoses 52 (4): 343-9).

Onychomycosis is not spontaneously cured and should be treated with oral or topical antifungal agents according to the severity of the infection.

Treatment efficacy depends on the capacity of the antifungal agent to penetrate the infected area, down to the nail bed. Topical agents may include amorolfine. Amorolfine is a morpholine antifungal drug, fungicidal (killing fungi) against most species causing onychomycosis; it interferes with ergosterol biosynthesis at two steps: by inhibiting delta14 reductase and delta7-8 isomerase. As a consequence, ergosterol is depleted and causes ignosterol to accumulate in the fungal cytoplasmic cell membranes. Marketed for example as Loceryl™, amorolfine is commonly available in the form of a nail lacquer, containing 5% amorolfine as the active ingredient. It is generally used in once- weekly or twice-weekly applications. As the disease is unsightly and causes embarrassment, there is a strong demand among patients for concomitant use of a cosmetic nail varnish to mask the diseased nail until clinical improvement. Furthermore, prolonged treatment is often required as complete replacement of an infected toenail with a healthy one may take 12-18 months. However, studies were required to evaluate if the addition of cosmetic nail varnishes modified the antifungal efficacy of amorolfine under the nailbed, where the infection is most frequent.

Section 4.4 of the Summary of Product Characteristics of the Loceryl™ 5% nail lacquer, last revised on 24 October 2013, concerns special warnings and precautions for use of this nail lacquer. In the majority of countries, it was therefore recommended that, during the application of amorolfine, cosmetic nail varnishes shall not be used. In addition, Section 6.2 of this Summary concerns incompatibilities of this nail lacquer. It teaches that concurrent use of cosmetic nail varnishes or false nails should be avoided. Moreover, currently, there is a paucity of data on the effect of cosmetic varnish on the mycological and clinical cure rate of topical antifungal treatments. In the clinical studies demonstrating the efficacy and safety of amorolfine 5% Nail Lacquer, the concurrent use of cosmetic nail varnish was prohibited. As taught at the following User Resource Location http://mycose.comprendrechoisir.com/qr/voir/186712/le-traitement-d-une- onvchomvcose-et-vernis-a-onqles, a response of an expert to the question: "Does the treatment of onychomycosis imply that it is not possible to use nail varnish?" was "Nail fungus (onychomycosis) can be treated by applying a special nail lacquer that has antifungal properties. It is therefore excluded for the entire duration of the treatment to wear another type of varnish (cosmetic varnish)."

Accordingly, a need exists for improving the visual appearance of nails affected by onychomycosis, and onto which an antifungal nail lacquer comprising amorolfine was applied.

In this context, the inventors surprisingly demonstrated that a cosmetic nail varnish improved the nail surface appearance of nails affected by onychomycosis onto which an antifungal nail lacquer comprising amorolfine was applied. The present invention therefore concerns a method of improving visual appearance of nails affected by onychomycosis comprising the steps of: applying an antifungal nail lacquer comprising amorolfine to the affected nails; and

applying a cosmetic nail varnish.

According to a first particular embodiment of this method, the antifungal nail lacquer is first applied on the affected nails. More specifically, the antifungal nail lacquer is first applied on the affected nails and, then, the cosmetic nail varnish is applied.

According to a second particular embodiment of this method, the cosmetic nail varnish is first applied on the affected nails. More specifically, the cosmetic nail varnish is first applied on the affected nails and, then the antifungal nail lacquer is applied. According to this method and its different particular embodiments, there is no decrease of the antifungal nail lacquer efficacy related to the applied cosmetic nail varnish. One or more (if compatible) of the below embodiments is applied:

- the antifungal nail lacquer comprises amorolfine in an amount of about 0.25 to about 10 wt. %;

- the antifungal nail lacquer comprises amorolfine in an amount of about 5 wt.

%;

- the antifungal nail lacquer further comprises acrylates / ammonium methacrylate copolymer, triacetine, ethyl acetate, butyl acetate and ethanol; - the cosmetic nail varnish comprises nitrocellulose;

- the method further comprises, according to the first embodiment, the step of allowing the nail lacquer to dry before applying the cosmetic nail varnish; - according to the first embodiment, the cosmetic nail varnish is applied once the applied nail lacquer is dry;

- the cosmetic nail varnish is applied between 10 min and 24 hours after the nail lacquer was applied. The invention also concerns a use of a cosmetic nail varnish for improving visual appearance of nails affected by onychomycosis and treated by an antifungal nail lacquer comprising amorolfine. In a preferred embodiment, the antifungal nail lacquer comprises amorolfine in an amount of about 5 wt. % The invention further concerns a kit comprising, in a common package, an antifungal nail lacquer comprising amorolfine, preferably in an amount of about 5 wt. %, and a cosmetic nail varnish.

Thus, in proposing to apply a cosmetic varnish onto nails affected by onychomycosis and treated by an antifungal nail lacquer comprising amorolfine, the present invention overcomes a technical prejudice. Overcoming this technical prejudice is particularly emphasised, due to the fact that a man skilled in the art knows that cosmetic nail varnishes are not to be applied directly onto nails suspected of infection (http://www.naildoctors.com/nail%20 funqus.html). Indeed, cosmetic nail varnishes are known to trap moisture and fungi.

Other features and aspects of the present invention will be apparent from the following description and the accompanying drawings, in which:

Fig. 1 is a graphic which shows the disease improvement assessment of a panel of subjects treated by Loceryl™ nail lacquer alone or Loceryl™ nail lacquer plus a cosmetic nail varnish over time; and

Figs. 2, 3 and 4, are graphic representations of replies to various questions of subjects treated by Loceryl™ nail lacquer alone or such nail lacquer and a cosmetic nail varnish.

The invention relates to a method of improving the visual appearance of nails affected by onychomycosis. This method comprises the step of applying an antifungal nail lacquer comprising amorolfine to the affected nails.

Amorolfine, or (±)-(2R^*,6S^*)-2,6-dimethyl-4-{2-methyl-3-[4-(2-methylbutan-2- yl)phenyl]propyl}morpholine, is a morpholine antifungal drug. It has a broad antifungal spectrum. It is effective against dermatophytes (Trichophyton-, Microsporum-, Epidermophyton species), yeast (Candida, Cryptococcus-, Malassezia- or Pitysporum species), moulds and other fungus species. However, except for Actinomyces, bacteria are not sensitives. In the context of the present invention, the term "amorolfine" also comprises its pharmaceutical acceptable salts. The pharmaceutically acceptable salts include inorganic as well as organic acids salts. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, maleic, methanesulfonic and the like. In a preferred embodiment, the salt is a chlorhydrate.

In a preferred embodiment, amorolfine is present, in the nail lacquer, in an amount of about 0.25 to about 10 wt. %, preferably in an amount of about 5 wt. %.

All percentages used in the present application are expressed by weight relative to the total weight of the nail lacquer unless otherwise specified. For instance, the expression "amorolfine is present, in the nail lacquer, in an amount of about 5 wt. %" means that the nail lacquer comprises about 5 % of amorolfine by weight, relative to the total weight of the nail lacquer.

As used herein, the term "about" will be understood by a person of ordinary skill in the art and will vary to some extent on the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, "about" will mean up to plus or minus 20 %, preferably 10 % of the particular term.

In addition to amorolfine, the nail lacquer may comprise the following excipients: acrylates / ammonium methacrylate copolymer, triacetine, butyl acetate, ethyl acetate and ethanol.

As a suitable antifungal nail lacquer, Loceryl™ and its equivalents such as Curanail, Curanale, etc. may be cited.

Loceryl™ is marketed as a pack containing cleansing alcohol swabs, spatulas and nail files. Before applying the antifungal nail lacquer, the infected area of a nail can be filed down as thoroughly as possible using a nail file. The surface of the infected nail can then be cleaned with cleansing alcohol swabs. A spatula can be dipped into the lacquer and the nail lacquer can then be painted over the entire surface of the infected nail.

Amorolfine penetrates and diffuses through the nail plate and is accumulated in effective concentrations at the nail bed. Particularly, the nail lacquer is to be applied to the affected finger- or toe- nails once or twice weekly. More particularly, the lacquer is applied with one of the recyclable spatulas to the whole surface of the affected nails, and the lacquer is allowed to dry (3-5 minutes). In a particular embodiment, the method according to the invention further comprises the step of applying, on the nails coated with the nail lacquer, a cosmetic nail varnish. The cosmetic nail varnish is applied on top of the nail lacquer, for example, using a brush, and is allowed to dry. In a preferred embodiment, the cosmetic nail varnishes comprise a film- forming polymer dissolved in a volatile organic solvent. Particularly, the primary ingredient in cosmetic nail varnishes is nitrocellulose. Nitrocellulose acts as a film forming agent. It is dissolved, for example, in butyl acetate or ethyl acetate. This basic formulation is expanded to include the following: - plasticizers to yield non-brittle films, for example, dibutylphthalate and camphor;

- dyes and pigments, for example chromium oxide greens, chromium hydroxide, ferric ferrocyanide, stannic oxide, titanium dioxide, iron oxide, carmine, ultramarine, and manganese violet;

- opalescent pigments, the glittery/shimmer aspect in the colour being conferred for example, by mica, bismuth oxychloride, natural pearls, and aluminium powder; - adhesive polymers in order to ensure that the nitrocellulose adheres to the nail's surface. One modifier used is typically tosylamide-formaldehyde resin;

- thickening agents, which are added in order to maintain the sparkling particles in suspension while in the bottle, for example, stearalkonium hectorite; and - ultraviolet stabilizers resist colour changes, when the dry film is exposed to sunlight, for example benzophenone-1 .

In a preferred embodiment, the cosmetic nail varnish does not comprise any therapeutically active ingredient.

Particularly, treatment with an antifungal nail lacquer is continued without interruption until the nail is regenerated and the affected areas are cured. The required duration of treatment depends on the severity and localization of the infection. Preferably, treatment duration is six months for finger nails. Preferably, treatment duration is nine to twelve months for toenails.

The discoloration of the nails affected by onychomycosis, onto which is applied an antifungal nail lacquer comprising amorolfine and a cosmetic nail varnish according to the invention, as well as the surface irregularities of the nails affected by onychomycosis, are masked at the satisfaction of the users..

Other advantages and uses of the present invention will emerge on reading the examples which follow, which should be considered to be purely illustrative and non-limiting.

Example 1 : Evaluating the in vitro effect of a combination of eleven different cosmetic nail varnishes on the antifungal efficacy of Loceryl™ 5% nail lacguer The objective was to evaluate the in vitro effect of cosmetic varnish on the antifungal efficacy of Loceryl™ 5% nail lacquer using 1 1 different best-selling cosmetic nail varnishes marketed in various countries throughout the world (Germany, Venezuela, Korean Republic, Russia, Italy, Australia, Brazil, U.S.A., China, Hong-Kong) where Loceryl™ 5% nail lacquer represents the most widely used treatment for onychomycosis. This assay was performed in duplicate on 3 nails for each product (n=6). Untreated nails were included as controls.

Experimental procedure

Fresh human cadaver healthy big toenails from 3 multiple donors were prepared and treated in duplicate with each of the test devices (25 L/cm²). Loceryl™ 5% nail lacquer was applied and allowed to dry for either 10 min. or 24 hours after which one of 1 1 cosmetic nail varnishes was applied. Thirty minutes after application of the cosmetic nail varnish, 4-mm nails disks were taken from the nails using a biopsy punch (n=6). These nail disks were placed, treated side facing upwards onto agar plates seeded with Trichophyton rubrum conidia. Plates were incubated for 4 days at 30°C. The size of the zones of no fungal growth (inhibition zones) were then measured. The average diameters of the zone of inhibition ± SEM were compared to determine treatment efficacy. A zone of inhibition superior to 10 mm is categorized potent antifungal activity.

Results

The untreated control group showed no zones of inhibition while the Loceryl™ 5% nail lacquer showed a mean effective zone ± SEM of 57.67 ± 2.8 mm in diameter.

Application of cosmetic varnish 10 min. after that of Loceryl™ 5% nail lacquer

Table 1 hereunder shows effective zones of inhibition ± SEM (mm) for nails treated with Loceryl™ 5% nail lacquer 10 minutes prior to the application of various cosmetic nail varnishes. Table 1

All inhibition zones were larger than 10 mm in diameter.

There was no statistically significant difference between nails treated with Loceryl™ 5% nail lacquer alone and those treated with Loceryl™ 5% nail lacquer in combination with 9 of the 1 1 cosmetic nail varnishes tested (P- values > 0.05). Only nails treated with Loceryl™ 5% nail lacquer and either Christian Dior (3V02) or Max Factor (4202583002) cosmetic varnish, when compared to those treated with Loceryl™ 5% nail lacquer alone, showed slightly smaller zones of inhibition (P-values of 0.006 and 0.035, respectively).

Application of cosmetic varnish 24 hours after that of Loceryl™ 5% nail lacquer:

Table 2 hereunder shows effective zones of inhibition ± SEM (mm) for nails treated with Loceryl™ 5% nail lacquer 24 hours prior to the application of various cosmetic nail varnishes.

Table 2 Company Brand Lot number Effective zone

MeaniSEM

(mm)

N=6

Cosnova™ Essence™ DIAC 58.17 ± 2.8

Drocosca C.A.™ Valmy™ CPE0710197790 44.67 ± 2.5

Amopacific Corp.™ Mamonde™ L05M0220131224 45.17 ± 1.8

L'Oreal™ Color Rich™ 16L701 58.00 ± 3.3

Deborah™ Deborah™ A094 53.67 ± 4.1

Revlon™ Color Stay™ 14032 64.83 ± 2.6

Hypermarcas S.A.™ Risque™ P14C1 166 60.50 ± 3.6

Revlon™ Revlon™ FA12300 56.00 ± 4.9

LVMH™ Christian Dior™ 3V02 56.83 ± 1.8

P&G™ Max Factor™ 4202583002 64.67 ± 0.8

Maybeline™ Tenue & Strong 16K900 56.83 ± 5.5

Pro™

All inhibition zones were larger than 10 mm in diameter.

Nails treated with the cosmetic nail varnish Revlon™, Color Stay™ yielded the largest zones with mean effective zones of inhibition ± SEM of 64.83 ± 2.6 mm in diameter. Nails treated with the cosmetic nail varnish Drocosca CA™, Valmy™ yielded the smallest mean zones of inhibition ± SEM of 44.67 ± 2.5 mm in diameter. There was no statistically significant difference between nails treated with Loceryl™ 5% nail lacquer alone and those treated with Loceryl™ 5% nail lacquer in combination with 10 of the 1 1 cosmetic nail varnishes tested (P-values > 0.05).

Conclusion The results of the study confirm the potent antifungal activity of Loceryl™ 5% nail lacquer in an in vitro human nail penetration model. Overall, the results of the study indicate that Loceryl™ shows efficacy when used in combination with cosmetic nail varnishes, regardless of whether the cosmetic varnish was applied 10 min. or 24 hours after the Loceryl™ nail lacquer.

Example 2: Evaluating the in vivo effect of a combination of a cosmetic nail varnish on the antifungal efficacy of Loceryl™ 5% nail lacquer

Experimental procedure

Fifty male and female subjects with mild to moderate distal subungual onychomycosis on at least one great toenail without matrix involvement were included in the study. Subjects were randomized into two groups which were comparable in terms of demographic characteristics. Indeed, in both groups, the majority of the subjects were male, Caucasian, with skin phototype III and with a mean age of 54 years old. Both groups were also comparable in terms of mean number of affected toenails per subject, of around 6.

The affected great toenails of the 26 subjects of the first group were treated with Loceryl™ nail lacquer and a cosmetic nail varnish, Maybeline Forever Strong Super Stay 7 days™, whereas the affected great toenails of the 24 subject of the second group were treated with Loceryl™ nail lacquer alone. For both groups, Loceryl™ nail lacquer was applied once weekly in the morning for 12 weeks. For the subjects in the first group, the cosmetic nail varnish was applied around 24 hours after application of the Loceryl™ nail lacquer. Two subjects discontinued the study before the week-12 visit.

Study visits were carried out at week 4, week 8 and week 12. Investigators and subjects assessments were obtained at each study visit. Assessments of the visual aspects of the nails were performed according to the following scale: 1 = improved; 2 = stable and 3 = worse. At week 12, nail samples were taken from all subjects of both groups, and mycological analyses were performed.

Results As shown in Table 3 hereunder, toenails samples from all subjects in both groups demonstrated zones of inhibition > 10 mm in diameter indicating potent anti-fungal activity. The mean diameter of zones of inhibition in the Loceryl™ nail lacquer plus cosmetic nail varnish group was very similar to that of the active control of Loceryl™ nail lacquer alone. Mycological cultures for all subjects in both groups were negative for dermatophytes and non- dermatophyte nail pathogens.

Table 3

As shown in Fig. 1 , the rates of improvement, as assessed by the investigator, were similar for both groups. The majority of subjects (around 60 %), assessed an improvement in the aspect of their toenails from week 4 onwards, in both groups. Example 3: Evaluation of the effect of the cosmetic nail varnish by subjects

Procedure

At week 12, subjects of both groups completed a questionnaire as disclosed in Example 2.

The questionnaire comprised the following questions for both groups:

Q1 - Before treatment, how embarrassed did you feel about the appearance of your affected toenails?

Q2 - At the end of the treatment, how embarrassed did you feel about the visual appearance of your affected toenails?

Also, for Group 1 , the questionnaire comprised the following additional questions: Q3 - Do you think the cosmetic nail varnish masks your diseases toenails?

Q4 - Would you recommend the use of a cosmetic nail varnish with a nail lacquer to your family and friends? Q5 - Would you use again the same cosmetic nail varnish on top of Loceryl™?

Results

As shown in Fig. 2, concerning Q1 : 48% of the subjects of Group 1 (Loceryl™ + cosmetic varnish) replied: Not at all; 40% of the subjects of Group 1 replied: Yes, a little; 8% of the subjects of Group 1 replied: Yes, somewhat; and 4% of the subjects of Group 1 replied: Yes, a lot. Concerning Group 2 (Loceryl™ only), 34.8% of the subjects replied: Not at all; 39.1 % of the subjects replied: Yes, a little; and 26.1 % of the subjects replied: Yes, somewhat.

Concerning Q2, as shown in Fig. 2: 56% of the subjects of Group 1 replied: Not at all; 32% of the subjects of Group 1 replied: Yes, a little; 8% of the subjects of Group 1 replied: Yes, somewhat; and 4.3% of the subjects of Group 1 replied: Yes, a lot. As for Group 2, 65.2% of the subjects replied: Not at all; 30.4% of the subjects replied: Yes, a little; and 4.3% of the subjects replied: Yes, somewhat.

Concerning Q3, and as shown in Fig. 3, 12% of the subjects of Group 1 replied: Not at all; 1 6% of the subjects of replied: Yes, a little; 28% of the subjects replied: Yes, somewhat; and 44% of the subjects replied: Yes, a lot. Concerning Q4, and as shown in Fig. 4, 28% of the subjects of Group 1 replied: No; 68% of the subjects of replied: Yes; and 4% of the subjects did not reply or did not reply by Yes or No.

As for Q5, and as shown in Fig. 4, 32% of the subjects of Group 1 replied: No; 52% of the subjects of replied: Yes; and 1 6% of the subjects did not reply or did not reply by Yes or No.

Conclusion 52% (40% + 8% + 4%) of the subjects in Group 1 (Loceryl™ + cosmetic nail varnish), at the start of treatment, compared to 44% (32% + 8% + 4%) at week 12, were embarrassed with the appearance of their affected toenails, whereas 65.2% (39.1 % + 26.1 %) of the subjects in Group 2 (Loceryl™ only), at the start of treatment, compared to 34.7% (30.4% + 4.3%) at week 12, were embarrassed with the appearance of their affected toenails. The majority of the subjects of Group 1 , practically 88% (1 6% + 28% + 44%) thought that a cosmetic nail varnish masked their affected toenails. More than half of the subjects of Group 1 , 68% and 52%, would recommend and use again, respectively, a cosmetic nail varnish on top of the Loceryl™ nail lacquer.

Claims

1 . A method of improving visual appearance of nails affected by onychomycosis comprising the steps of:

applying an antifungal nail lacquer comprising amorolfine to the affected nails; and

applying a cosmetic nail varnish.

2. The method of claim 1 , wherein the antifungal nail lacquer is first applied on the affected nails.

3. The method of claim 1 , wherein the cosmetic nail varnish is first applied on the affected nails.

4. The method of any one of claims 1 to 3, wherein the antifungal nail lacquer comprises amorolfine in an amount of about 0.25 to about 10 wt. %.

5. The method of claim 4, wherein the antifungal nail lacquer comprises amorolfine in an amount of about 5 wt. %.

6. The method of any one of claims 1 to 5, wherein the antifungal nail lacquer further comprises acrylates / ammonium methacrylate copolymer, triacetine, ethyl acetate, butyl acetate and ethanol.

7. The method of any one of the preceding claims, wherein the cosmetic nail varnish comprises nitrocellulose.

8. The method of any one of claims 1 , 2 and 4 to 7, further comprising the step of allowing the nail lacquer to dry before applying the cosmetic nail varnish.

9. The method of any one of claims 1 , 2 and 4 to 8, wherein the cosmetic nail varnish is applied once the applied nail lacquer is dry.

10. The method of claim 9, wherein the cosmetic nail varnish is applied between 10 min and 24 hours after the nail lacquer has been applied.

1 1 . A use of a cosmetic nail varnish for improving visual appearance of nails affected by onychomycosis and treated by an antifungal nail lacquer comprising amorolfine.

12. The use of claim 1 1 , wherein the antifungal nail lacquer comprises amorolfine in an amount of about 5 wt. %.

13. A kit comprising, in a common package, an antifungal nail lacquer comprising amorolfine and a cosmetic nail varnish.

14. The kit of claim 13, wherein the antifungal nail lacquer comprises amorolfine in an amount of about 5 wt. %.