FR2844197A1 - Pharmaceutical or cosmetic solution for ungual or peri-ungual application, e.g. antifungal nail varnish, comprising synergistic pro-penetrant mixture of urea, acid and/or ethoxydiglycol - Google Patents

Abstract

A pharmaceutical or cosmetic solution (A) comprises a synergistic mixture (I) of pro-penetrants, containing urea, an acid and/or ethoxydiglycol. An Independent claim is also included for the solutions (A).

Description

The present invention relates to the use of pro-penetrating agents

  acting in synergy for the preparation of a solution for nail and peri-nail application for use

  dermatological or cosmetic and the resulting solution.

  The nails can be the subject of disorders, deficiencies or pathologies of nature and

  of various origins (Baran R. et al., Diseases of the nails and their management. 3nd.

  Editing. 2001). Mention may be made, for example, of paronychias, the causes of which can be bacterial, fungal, parasitic, viral, derived from dermatological or systemic diseases, or else result from a drug treatment. Fungal pathologies 10 can occur specifically at the nail level, such as onychomycosis, or which, like herpes or syphilis, affect other parts of the body, but can also affect the physiology of the nail. . Fungal nail infections are commonly caused by dermatophytes but can also be caused by mold, fungi and yeast. 15

  The treatments used today are either local treatments or general treatments and the two are often combined for optimal effectiveness. Indeed, a treatment to be effective must be long, in order to follow the time of regrowth of a nail. In addition, the yeasts can be located in the nail or in the nail bed, which requires that the active agent penetrate the entire nail.

  General treatments often have harmful side effects and topical treatments are often less effective alone because of the difficult penetration

through the nail.

  To date, nail varnishes or film-forming solutions are more particularly used for the treatment of onychomycosis and similar fungal infections of the nails in humans or mammals. Many compositions containing active agents with antifungal activity are described in the literature for the prevention and treatment of these conditions, such as, for example, 1 hydroxy-2-pyridone in a film-forming agent insoluble in water (US 4, 957,730), an active agent in a composition containing a 2-n-nonyl-1,3dioxolane as propenetrant (WO 99/39680), terbinafine (US 6, 214,360), itraconazole (US 4,267,179), amorolfine HCI

  (EP 0 389 778) or tioconazole (US 5,916,545).

  The effectiveness of a nail varnish as a delivery vehicle, for topical application of an active agent has been described by Marty in J. Eur. Acad. Dermatol. Venerol., 45 (suppl. 1), S17-S21, (1995). This is the study of the delivery of an antifungal agent, amorolfine HCl. The basic combination of a varnish, consisting of a solvent, a plasticizer and a film-forming agent, as described in the literature, does not allow

  unfortunately not optimal penetration of the active agent into the nail.

  It is therefore essential to develop a dermatological or cosmetic composition of the solution type for nail and peri-nail application allowing better penetration of the active agents through the nail, thereby providing better

  effectiveness of active agents and a reduction in application time.

  We now know the use of urea as a keratolytic agent. It has also been the subject of studies concerning its penetrating power through the skin (Wohlrab

  W. J. Appl. Cosmetol. 9.1-7 (Jan. March 1991)) and also at the nail level in association with the mercaptans (US 5,696,164). A combination of urea as a keratolytic agent and N- (2-mercaptopropionyl) glycine is described by Malhotra GGet Zatz JL (J. Pharm. Sciences, vol 91, 2, (2002)), as giving a very good penetration of 20 l active agent in the nail.

  No prior art describes the use of an acid or of ethoxydiglycol as propenetrant agent in a solution for nail and peri-nail application. In addition, nothing in the compositions described in the prior art could encourage a person skilled in the art to mix urea and an acid or urea and ethoxydiglycol for the manufacture of a solution for nail application and peri- ungual, in which the mixture would have an effect

  synergistic on the penetration of the active agent through the nail.

  Now, the Applicant has unexpectedly discovered that the presence of an adequate mixture of propenetrating agents, consisting of at least urea and at least one acid, or by at least urea and at least 1 ethoxydiglycol, allowed to have a better

  bioavailability of the active agent within the nail thanks to their synergistic action.

  Synergy means an effect greater than the sum of the effects obtained

  independently with each of the pro-penetrating agents.

  The invention therefore relates to the use of a mixture of penetrating agents acting in synergy chosen from urea, an acid and ethoxydiglycol for the preparation of a solution for nail and peri-nail application for use. pharmaceutical or cosmetic.

  By solution for nail and peri-nail application is meant a film-forming solution (or nail varnish) or not for application to the nails and their periphery.

  The invention preferably relates to the use of a mixture of propenetrating agents consisting of at least urea, and at least one acid for the preparation of a solution for nail and peri-nail application to pharmaceutical or cosmetic use.

  The invention also relates to the use of a mixture of pro-penetrating agents consisting of at least urea, and at least ethoxydiglycol for the preparation of a solution for nail application and peri-nail for pharmaceutical or cosmetic use.

  The use of a mixture of pro-penetrating agents acting in synergy is more particularly carried out for the manufacture of a solution for nail application and

peri-nail antifungal.

  The term “acid” preferably means a mono or polycarboxylated carboxylic acid, and in particular hydroxy acids such as hydroxymonocarboxylic acids, hydroxydicarboxylic acids, or free acids, as well as lactones, salts and esters being derived therefrom. Mention may be made, for example, without limitation, of methanoic acid, 2-methylbutanoic acid, propanoic acid, 2-methylpropanoic acid, 2,2-dimethylpropanoic acid, decanoic acid, octanoic acid, hex-2-enoic acid, heptanoic acid, 6methylheptanoic acid, 3-ethylpentanoic, 3-

4 2844197

  chloropentanoic, 2-hydroxypropanoic acid, 2-chloro4hydroxyhexanoic acid, hexanedioic acid, octadecanoic acid, 4-oxopentanoic acid, 6hydroxy-4-oxonanoic acid, 2cetopropanoic acid, acid tartronic, malic acid, tartaric acid, glucaric acid, citric acid, isocitric acid, tropic acid, 5-hydroxylauric acid, 3-hydroxy-4methoxymandelic acid or their mixtures . To give an order of magnitude, the solution for nail and peri-nail application, in particular a nail varnish, used according to the invention preferably comprises a concentration of less than 15% by weight of urea relative to the weight of the non-volatile part 10 of the composition, in particular a concentration of less than 14% by weight of urea relative to the weight of the non-volatile part of the composition, preferably between 7 and 14%, and more particularly between 9 and 13% by weight of urea relative to the weight of the

  non-volatile part of the composition.

  The proportion by weight of acid relative to the total weight of the composition is between 0.01% and 10% (weight / weight), and preferably between 1 and 7%.

  The weight proportion of ethoxydiglycol relative to the total weight of the composition is

  between 0.01% and 20% (weight / weight), and preferably between 1 and 10%.

  The present invention also relates to a solution for nail and peri-nail application comprising a mixture of pro-penetrating agents chosen from urea, acid

and ethoxydiglycol.

  In particular, it relates to a solution for nail and peri-nail application characterized in that the mixture of penetrating agents comprises at least urea and ethoxydiglycol and to a solution for nail and peri-nail application characterized in that the mixture of pro-penetrating agents comprises at least urea and

an acid.

  In one embodiment of the invention, the solution for nail and peri-nail application, in particular nail varnish, comprises: a) at least one active agent, b) a mixture of synergistic penetrating agents according to the invention,

2844197

  c) a mixture of organic solvents / co-solvents,

  d) and optionally a plasticizing agent.

  The solvents and co-solvents can be chosen from the family of organic solvents, and 5 are Class 3 solvents with low toxic potential according to ICH (Impurities: Guideline for Residual Solvents, International Conference of Harmonization) standards, such as ethanol, acetone, methyl acetate, ethyl acetate, butyl acetate, alkylmethyl sulfoxides such as dimethyl sulfoxide, propanol-2, methylisobutyl ketone, butanol-1, dichloromethane, or their mixtures. Among the solvents / co-solvents as described above, use will preferably be made of volatile organic solvents / co-solvents, and more preferably a mixture

  consisting of ethanol, ethyl acetate, and butyl acetate.

  The solvents / co-solvents can be used at preferential concentrations ranging respectively from 30 to 90% and from 0 to 30% by weight relative to the total weight of the composition, and more preferably, ranging from 35 to 60% and from 10 at

  % by weight relative to the total weight of the composition.

  For the preparation of the compositions according to the invention of the nail varnish type which requires the presence of a film-forming agent, this is advantageously insoluble in water and chosen from: - the copolymers of monoalkyl esters of polyvinylether methyl and of malic acid such as the butylester copolymer of polyvinylether of methyl and of malic acid (Copolymer Butyl Ester of PVM / MA) sold under the name of Gantrez ES 425 sold by the company ISP, - the copolymers of esters of acrylic and methacrylic acids with a low content of quaternary ammonium groups derived from acrylic acid such as the copolymer of acrylates and ammonium methacrylate (Acrylates / Ammonium Methacrylate Copolymer) sold under the name Eudragit RL 100 by the company Rôhm Pharma , - or cellulose derivatives, such as nitrocellulose, or ethylcellulose sold by the company Aqualon,

  - polyurethane derivatives such as Avalures sold by the company Noveon).

  The film-forming agent as described above can be used at the concentrations

  preferential ranging from 0.01 to 20% by weight relative to the total weight of the composition.

  The plasticizing agent is preferably at concentrations ranging from 0.001 to 10.00% by weight relative to the total weight of the composition and more particularly ranging from 0.01 to 5.00%. Among the plasticizing agents, there are used, without this list being limiting, compounds such as phthalates, triacetates, citrates or their mixtures. The active agent can be, by way of nonlimiting example, an antibiotic agent, an antibacterial agent, a steroid anti-inflammatory agent, a nonsteroidal anti-inflammatory agent, an antiparasitic agent, an antiviral agent, an immunosuppressive agent, a nuclear receptor modulating agent, an antifungal agent or their mixtures. Among the antibiotic agents, mention may be made, for example, of fluoroquinolones, rifamycin, josamycin, sulfadiazine, virginiamycin, fusidic acid or their mixtures.

  Among the antibacterial agents that may be mentioned, for example, benzoyl peroxide.

  Examples of steroidal anti-inflammatory agents include clobetasone butyrate, hydrocortisone, fluocinolone acetonide, desonide, betamethasone,

dexamethasone or mixtures thereof.

  Among the non-steroidal anti-inflammatory agents, mention may be made of indole derivatives,

  arylcarboxylic derivatives, oxicams, pyrazoles or mixtures thereof.

  Among the antiparasitic agents, mention may be made, for example, of crotamiton. 30

  Among the antiviral agents, there may be mentioned for example vidarabine.

  Among the immunosuppressive agents, there may be mentioned for example methotrexate,

  cyclosporine, tacrolimus or their mixtures.

  Among the modulators of nuclear receptors, there may be mentioned, for example, retinoids, or vitamin D and its analogs or their mixtures. Among the antifungal agents, there may be mentioned for example econazole, ketoconazole or miconazole belonging to the classes of imidazoles; azole compounds such as itraconazole, clotrimazole; bistriazole compounds such as fluconazole; compounds of the allylamine family, such as terbinafine, pyridones, such as ciclopirox olamine, morpholines, such as amorolfine and its salts; the compounds

  polyenes, such as amphotericin B; griseofulvin or their mixtures.

  The active agent is preferably chosen from antifungal agents. Thus, the solution for nail and periungual application according to the invention is preferably antifungal, in particular, it contains amorolfine or one of its salts. The preferred active agent concentrations are between 0.001 and 10% by weight

  relative to the total weight of the composition.

  The solution for nail and peri-nail application, in particular nail varnish, according to the invention can also comprise any additive usually used in the cosmetic or pharmaceutical field, such as sequestrants, wetting agents, adhesion agents , spreading agents, antioxidants, sunscreens, preservatives, fillers, electrolytes, humectants, pigments, dyes, bases or common acids, mineral or organic, essential oils, active ingredients cosmetics, moisturizers, vitamins, essential fatty acids, sphingolipids. Of course, those skilled in the art will take care to choose this or these optional additional compounds, and / or their quantity, in such a way that the advantageous properties of

  the composition according to the invention is not, or not substantially, altered.

  The solutions for nail and peri-nail application, in particular nail varnish, according to the invention are particularly suitable for the following dermatological treatment fields: onychomycosis, chloronychia, paronychia, erysipelode, onychorexia, gonococcal disease, swimming pool granuloma, migra larvae, leprosy , Orf nodule, milker nodule, herpetic paronychia, acute bacterial perionyxia, chronic perionyxia, sporotrichosis, syphilis, tuberculosis verrucosa cutis, tularemia, tungiasis, peri- and subungual warts, shingles, dystrophy of the twenty nails (trachyonychia), and dermatological diseases affecting the nails such as psoriasis, pustular psoriasis, alopecia aerata, pustular parakeratosis, contact dermatitis, Reiter syndrome, pustular parakeratosis, acreal psoriasiform dermatitis, lichen planus, idiopathic nail atrophy, lichen nitidus, lichen striatus, linear inflammatory verrucous epidermal nevus (NEVIL), pel ade, pemphigus, bullous pemphigode, acquired bullous epidermolysis, Darier's disease, pityriasis rubra pilaris, palmoplantar keratoderma, contact eczema, erythema multiforme, scabies, Bazex syndrome, systemic scleroderma, lupus

  systemic erythematosus, chronic lupus erythematosus, dermatomyositis.

  The solutions for nail and peri-nail application, in particular nail varnish, according to the invention are more particularly suitable for the treatment and prevention of onychomycosis.

  The object of the present invention also relates to the use of a solution for nail and peri-nail application as described above for the preparation of a medicament intended for the treatment of fungal pathologies such as onychomycosis The solutions for nail and peri-nail application, in particular nail varnishes, according to the invention also find application in the cosmetic field, in particular for the treatment of nail irregularities, koilonychia, Beau lines, lines. longitudinal by alteration of the relief, ingrown toenails. The examples below illustrate the invention without, however, limiting its scope. In the formulation examples (examples 1 to 8), the amounts of the constituents

  are expressed in% by weight relative to the total weight of the composition, unless otherwise stated.

  Examples illustrating the release-penetration of the active ingredient in compositions according to the invention are also described.

Example 1:

  Ingredients% Ethanol 43.85 Ethyl acetate 17.00 Butyl acetate 6.00 Urea 2.50 Lactic Acid 4.25 Amorolfine HC1 6.40 Butyl Ester copolymer of PVM / MA 20.00

  This solution can be applied for 9 months once a week to the nails of the 10 feet in the treatment of onychomycosis.

Example 2:

  Ingredients% Ethanol 51.90 Ethyl acetate 17.00 Butyl acetate 6.00 Glycerol triacetate 1.20 Urea 2.5 Ethoxydiglycol 5.00 Amorolfine HC1 6. 40 Acrylates / Ammonium copolymer 10.00 Methacrylate This solution can be applied for 9 months once a week on the nails

the treatment of onychomycosis.

Example 3:

  Ingredients% Ethanol 53.85 Ethyl acetate 17.00 Butyl acetate 6.00 Urea 2.50 Lactic Acid 4.25 Miconazole 6.40 Acrylates / Ammonium copolymer 10.00 Methacrylate

  This solution can be applied for 1 to 2 months twice a day on the nails in the treatment of acute bacterial perionyxia.

Example 4:

  Ingredients% Ethanol 43.10 Ethyl acetate 17.00 Butyl acetate 6.00 Urea 2.50 Ethoxydiglycol 5.00 Amorolfine HC1 6.40 Butyl Ester copolymer of PVM / MA 20.00

  This solution can be applied once a week for 6 months to the nails of the 15 hands in the treatment of onychomycosis.

Example 5:

  Ingredients% Ethanol 48.10 Acetone 28.00 Urea 2.50 Ethoxydiglycol 5.00 Amorolfine HC1 6.40 Acrylates / Ammonium Methacrylate Copolymer 10.00 This solution can be applied for 9 months once a week on the toenails in the treatment of onychomycosis.

Example 6:

  Ingredients% Ethanol 45.65 Acetone 20.00 Glycerol triacetate 1.20 Urea 2.50 Lactic acid 4.25 Amorolfine HC1 6.40 Butyl Ester copolymer of PVM / MA 20.00 This solution can be applied for 6 to 8 months once a week on the nails in the treatment of onychomycosis

Example 7:

  Ingredients% Dichloromethane 52.65 Ethyl acetate 17.00 Butyl acetate 6.00 Glycerol triacetate 1.20 Urea 2.50 Citric acid 4.25 Amorolfine HCl 6.40 Acrylates / Ammonium copolymer 10.00 Methacrylate This solution can be applied for 9 months twice a week on the toenails treatment of onychomycosis

Example 8:

  Ingredients% Dichloromethane 66.85 Acetone 20.00 Glycerol 5.00 Urea 2.50 Lactic acid 4.25 Amorolfine HCl 8.00 This solution can be applied for 6-12 months once a week on the toenails in the treatment of onychomycosis Example 9: Release-Penetration Method release - penetration studies of the active agent are carried out on a pig's hoof, using diffusion cells, more particularly Frantz cells (Pittrof F et al. Clin. Exp. Dermatol. 17 (suppl 1 ): 26-28, (1992)). The active agent is incorporated into a

nail varnish according to the invention.

  101i of the nail polish to be tested (containing a radiolabelled active ingredient) are applied to

  the hoof every day for 3 consecutive days on an area of 1 cm2.

  The active ingredient is then dosed in the hoof by assaying the radioactivity found, using a

scintillation counter.

  This experiment is carried out on 6 cells in parallel against a reference varnish in comparison. This reference varnish (Reference) contains no penetrating agent and consists of 55.20% ethanol, 17.20% ethyl acetate, 5.70% butyl acetate,

  1.20% glycerol triacetate, 14.30% Eudragit RI 100, 6.40% amorolfine HC1.

  The control varnishes contain only a single penetrating agent, which is either urea, lactic acid or ethoxydiglycol.

  Results Compositions Reference Witness 1 Witness 2 Witness 3 Example 1 Example 4 Ethanol 55.20 44.40 54.40 54.40 43.85 43.10 Ethyl acetate 17. 20 17.00 17.00 17.00 17.00 17.00 Butyl acetate 5.70 6.00 6.00 6.00 6. 00 6.00

  Glycerol triacetate 1.20 1.20 - - -

  Ethoxydiglycol 5.00 - - 5.00 Urea - 2.50 - 2.50 2.50 Lactic Acid - 4. 25 4.25 EudragitRl 100 14.30 - 10.00 10.00 Gantrez ES 425 - 20.00 - - 20. 00 20.00 Amorolfine HC1 6.40 6.40 6.40 6.40 6.40 6.40 Increase in 1 1 1 1 3.06 2.16 Release-Penetration The nail varnishes according to the invention make it possible to significantly increase the penetration of the active agent through the nail compared to the reference nail varnish (more than twice with the example 4 and more than three times with Example 1). While each of the penetrating agents tested alone (Control Compositions) does not at all increase the passage of the active agent in the pig's hoof (difference in release-penetration

  not significant compared to the reference varnish).

  These results show significantly that the associations of the urea and ethoxydiglycol or urea and acid propenetants according to the invention synergistically increase the passage of the active agent through the nail.

Claims (11)

  1. Use of a mixture of pro-penetrating agents acting in synergy chosen from   urea, an acid and ethoxydiglycol for the preparation of a solution for nail and peri-nail application for pharmaceutical or cosmetic use.   2. Use according to claim 1, characterized in that the solution is a solution film-forming or nail polish.   3. Use according to claim 1 or 2 characterized in that one uses a mixture of pro-penetrating agents consisting of at least urea and at least ethoxydiglycol.   4. Use according to claims 1 to 3 characterized in that one uses a mixture of pro-penetrating agents consisting of at least urea and at least one acid.   5. Solution for nail and peri-nail application comprising a mixture of agents   pro-penetrants chosen from urea, acid and ethoxydiglycol.   6. Solution according to claim 5, characterized in that the mixture of penetrating agents comprises at least urea and ethoxydiglycol.   7. Solution according to claim 5 or 6, characterized in that the mixture of penetrating agents comprises at least urea and an acid. 25 8. Solution for nail and peri-nail application according to any one of   Claims 5 to 7, characterized in that it comprises:   a) at least one active agent, b) a mixture of synergistic penetrating agents, c) a mixture of organic solvents / co-solvents,   d) and optionally a plasticizing agent.   9. Solution according to any one of claims 5 to 8, characterized in that it is antifungal.   10. Solution according to any one of claims 5 to 9, characterized in that it   contains amorolfine or one of its salts. 11. Use of a solution for nail and peri-nail application according to one of the   previous claims for the preparation of a medicament for treatment   fungal pathologies such as onychomycosis.