EP1648378A2 - Antimycosic nail varnish - Google Patents

Antimycosic nail varnish

Info

Publication number
EP1648378A2
EP1648378A2 EP04767801A EP04767801A EP1648378A2 EP 1648378 A2 EP1648378 A2 EP 1648378A2 EP 04767801 A EP04767801 A EP 04767801A EP 04767801 A EP04767801 A EP 04767801A EP 1648378 A2 EP1648378 A2 EP 1648378A2
Authority
EP
European Patent Office
Prior art keywords
nail varnish
active substance
varnish according
nail
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04767801A
Other languages
German (de)
French (fr)
Inventor
Pascal Lefrancois
Roger Navaro
Marlène DELAUNOIS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pierre Fabre Dermo Cosmetique SA
Original Assignee
Pierre Fabre Dermo Cosmetique SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pierre Fabre Dermo Cosmetique SA filed Critical Pierre Fabre Dermo Cosmetique SA
Publication of EP1648378A2 publication Critical patent/EP1648378A2/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q3/00—Manicure or pedicure preparations
    • A61Q3/02—Nail coatings

Definitions

  • the present invention relates to a nail varnish having antimycotic activity.
  • Nail conditions due to fungi are stubborn forms of disease that have so far been unable to be satisfactorily treated.
  • fungi onychomycosis
  • Various types of nail fungus are grouped under the name of onychomycosis, including those caused by dermatophytes which are the most difficult to treat, while nail fungus caused by yeast has so far been easier to treat. .
  • Various routes have been used for the treatment of these yeast infections, but with little success.
  • the systemic method which consists of the administration of antifungal agents by the oral route, is a long-term treatment, which can lead to side effects and to the selection of resistant strains.
  • the antimycotic molecules used for the oral route are itraconazole, terbinafine and fluconazole (Effendy I. Therapeutic strategies in onychomycosis. Journal of the European Academy of Dermatology and Venereology. 1995, S3-S10). Nail removal by surgery or by chemical action is a very aggressive which gives no guarantee that the nails will grow back in their normal form; on the contrary, the regrowing nails are frequently deformed. Local treatment of the nails with specific substances with antimycotic action has also been envisaged.
  • varnishes have the advantage of being easy to apply and of forming a water-insoluble film on the surface of the nail allowing the release of the antimycotic agent within the nail.
  • the antimycotic molecules formulated in these nail varnish bases are amorolfine, ciclopiroxolamine and the bifonazole / urea combination (De Chauvin MF, Baran R. and Charasse D. Onychomycosis. III: treatment. Journal de Mycologie Médicale, 2001, 11 (4), 205-215; Fleckman P. Onychomycosis: diagnosis and topical therapy. Dermatologie Therapy, 2002, 15 (2), 71-77).
  • Patent EP 855 397 describes antimycotic agents which contain, as active substances, azole derivatives, in particular imidazole and triazole derivatives. These antimycotic agents can be applied in the form of a film soluble in water, manifest a deposition effect and allow a short-term treatment. They are suitable for the treatment of nail fungus and can be used both in solutions and in aerosols which form, after drying, a water-soluble film. The use of such binders in water obviously has the effect that the agent applied is more or less eliminated with each toilet. To facilitate the penetration of antimycotics through the nail, these varnishes often contain keratolytic substances such as urea.
  • EP 226 984 describes a nail varnish comprising a film-forming agent insoluble in water and an antimycotic agent.
  • the varnish may contain urea but the amount of urea is not specified.
  • Application EP 1 138 314 discloses an extended-release film-forming composition for nail varnish comprising an antifungal agent, urea, a humectant such as glycerol or sorbitol, water, a film-forming agent and a solvent comprising minus a volatile component.
  • the joint use of urea and glycerol improves the cross-nail passage of the antifungal molecule and the presence of glycerol allows urea to be used at concentrations of less than 1% relative to the total weight of the composition.
  • German application DE 10061801 describes a pharmaceutical composition which contains a hydrophilic film-forming agent, water and urea.
  • the hydrophilic film-forming agent is polyvinylpyrrolidone in concentrations of 15-25% by weight. Urea is present at a very high concentration, more particularly 75-85% by weight.
  • US Patent 5,346,692 describes a nail polish formulation for treating onychomycosis which contains a film-forming agent, an antimycotic agent, urea and a very specific mixture of solvents; the formulations contain a high proportion of urea, preferably 15 to 60% relative to the non-volatile compounds.
  • the present invention provides a nail varnish to treat onychomycosis, capable of being applied topically to the infected region of the nail in the form of a film, which allows good release of the active principle and good diffusion of this active principle over the infected regions without attacking the healthy regions of the nail and which contains a small amount of an absorption-promoting agent, preferably urea, despite the absence of a humectant.
  • the subject of the invention is therefore a nail varnish with antimycotic action containing: a) 2 to 80% by weight relative to the amount of volatile compounds of at least one l-hydroxy-2-pyridone of general formula ( I)
  • RI represents either a straight or branched alkyl group having from 6 to 9 carbon atoms, or a cycloalkyl group having from 3 to 6 carbon atoms
  • one of the substituents R2 and R4 represents a hydrogen atom and the other represents a hydrogen atom or a group chosen from methyl and ethyl groups
  • R3 represents a straight or branched alkyl group having from 1 to 2 carbon atoms, in free form or in salt form physiologically acceptable, as a substance with antimycotic action
  • the nail varnish is characterized in that the active substance with antimycotic action corresponds to formula (I) in which R2 and R4 are each a hydrogen atom.
  • the nail varnish contains an active substance with antimycotic action corresponding to formula (I) in which RI represents a cycloalkyl group having 3 to 6 carbon atoms, preferably a group -CH 2 -CH (CH 3 ) -CH 2 -C (CH 3 ) 3 , or a cyclohexyl group.
  • the absorption promoter is urea.
  • the nail varnish according to the invention relative to the amount of the non-volatile components, that is to say to the sum of the film-forming agents, pigments possibly present, plasticizers and other non-volatile additives, as well as the active substance, this one is generally contained in an amount going from 2 to 80, preferably from 10 to 60 and in particular from 20 to 40% in weight.
  • the active substance is contained in an amount ranging from 0.5 to 20, preferably from 2 to 15% by weight relative to the amount of non-volatile components.
  • the nail varnishes according to the invention additionally contain, as essential components, one or more film-forming agents which form on the nail after the preparation has dried, a film insoluble in water.
  • film-forming agents are chosen from the group comprising acrylic / methacrylic copolymers, polymethacrylate / butyl acrylate, acrylic / acrylate copolymers, polyvinyl alcohol, polyvinylpyrrolidones, polyvinylpyrrolidones / vinyl acetates and vinylpyrrolidones / dimethylaminoethyl methacrylates. It is known that the combination of solvents is of paramount importance for the drying time, the ease of application with a brush and other important properties of the varnish or of the varnish film.
  • the solvent system preferably consists of an optimal mixture of solvents with a low boiling point (less than 100 ° C.) and solvents with a medium boiling point (between 100 and up to 150 ° C); possibly with a small proportion of high boiling point solvents (between 150 and up to 200 ° C).
  • Water / ethanol, water / isopropyl alcohol or water / butanol mixtures will preferably be chosen as solvent in ratios ranging from 10/90 to 30/70, ratios taking account of the solubility of the active substance and of the film-forming agent chosen.
  • the nail varnishes according to the invention can also contain additives commonly used in cosmetics, such as plasticizers based on phthalate, camphor or urea, colorants or colored pigments, pearlescent agents, sedimentation retardants , sulfonamide resins, silicates, perfumes, wetting agents such as sodium dioctylsulfosuccinate, lanolin derivatives, light protection agents such as 2-hydroxy-4-methoxy-benzophenone, substances with antibacterial action .
  • the difficulty in carrying out this invention consisted in choosing film-forming agents which are insoluble in water, but soluble in the water / alcohol mixture so that, after drying, the film formed on the nail is insoluble in water. and therefore can resist the action of the toilet.
  • the nail varnish according to the invention is also suitable for the prophylactic use against fungal infections of the nail, a sufficiently large deposit of active substance which can be obtained in the nail so that, in the case of fungal contamination, does not notice the appearance of a nail disease caused by fungi.
  • the nail polish according to the invention it is possible to achieve a radical cure in the treatment of nail fungus, the nails usually repelling without deformation.
  • the present invention is illustrated in more detail with the aid of the following examples.
  • Procedure The activity of the compounds used according to the invention has been demonstrated by penetration tests on ox horn. These ox horns were cut so as to obtain keratin disks with a diameter close to 1 cm and a thickness standardized to 0.6 mm. These keratin discs were seeded by a dermatophyte (Trichophyton mentagrophytes). After about 30 days, these dermatophytes have completely colonized the horn discs, both on the surface than in the middle of the substrate, perfectly mimicking the nail fungus phenomenon.
  • a dermatophyte Trichophyton mentagrophytes
  • compositions according to the invention differ from preparations of the prior art known for the treatment of nails, in that 168 superficial horny layers allow the active substances contained in these preparations to pass in considerable proportion, and that these compositions according to the invention thus exert a lasting action at effective depth.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Birds (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cosmetics (AREA)

Abstract

Antimycosic nail varnish containing 2 to 80 wt. %, in relation to the amount of volatile compounds, of at least one 1-hydroxy-2-pyridone of general formula (I) as an antimycosic active substance and 0.1 to 20 wt. %, in relation to the amount of volatile compounds, of an absorption promoter.

Description

Vernis à ongles à action antimycosique Antimycotic action nail polish
La présente invention a pour objet un vernis à ongles présentant une activité antimycosique. Les affections des ongles dues à des champignons (onychomycoses) sont des formes de maladies tenaces qu'il n'a pas été possible jusqu'à présent de traiter de façon satisfaisante. Sous le nom d' onychomycoses, on groupe divers types de mycoses des ongles parmi lesquelles celles provoquées par des dermatophytes qui sont les plus difficiles à traiter, tandis que les mycoses des ongles provoquées par des levures ont pu jusqu'à présent être traitées plus facilement . On a utilisé diverses voies pour le traitement de ces mycoses, mais sans véritable succès. La méthode systémique qui consiste dans l'administration d'agents antifongiques par voie orale, est un traitement de longue durée, pouvant conduire à des effets secondaires et à la sélection de souches résistantes. Ces traitements nécessitant l'administration de fortes doses d'agent thérapeutique sont par conséquent réservés préférentiellement au cas sévères d' onychomycoses . Les molécules antimycosiques utilisées pour la voie orale sont 1 ' itraconazole, la terbinafine et le fluconazole (Effendy I. Therapeutic stratégies in onychomycosis . Journal of the European Academy of Dermatology and Venereology. 1995, S3-S10) . L'élimination des ongles par la chirurgie ou par action de produits chimiques est une méthode très agressive qui ne donne aucune garantie que les ongles repoussent sous leur forme normale; au contraire, les ongles qui repoussent sont fréquemment déformés. Le traitement local des ongles avec des substances spécifiques à action antimycosique a également été envisagé. Ainsi, dans un traitement combiné on a d'abord traité les ongles avec des solutions de substances à action antimycosique puis on a appliqué des pansements avec des crèmes pendant une nuit. Cette méthode de traitement est fort désagréable et psychologiquement éprouvante pour les patients. En effet, d'une part le traitement des ongles avec des solutions est nécessaire plusieurs fois par jour, d'autre part ceux-ci doivent être munis de pansements surtout la nuit. En outre, il est nécessaire de limer constamment les ongles malades, ce qui non seulement est pénible, mais contribue également à une propagation des germes pathogènes. Finalement, ce traitement qui dure plusieurs mois, n'est souvent pas poursuivi par les patients qui, au contraire, se découragent et deviennent négligents, ce qui conduit à l'échec du traitement. Le succès de ce traitement est en outre compromis par le fait que les solutions et les crèmes sont habituellement miscibles à l'eau ou hydrophiles, et peuvent par conséquent être éliminées de la surface de l'ongle ou entraînées par dissolution hors de l'ongle lors de la toilette et doivent donc être de nouveau appliquées . Plus récemment, des méthodes faisant appel à un vernis à ongles contenant une substance à activité antimycosique ont été mises au point. Ces dernières méthodes sont les plus efficaces. Le développement récent de nouveaux agents antimycosiques sous forme de vernis à ongle a permis d'obtenir de très bons résultats dans le cas des traitements des infections modérées sans recours à l'acte chirurgical (Goettman S. Treatment of dermatophytic onychomycosis . Journal de mycologie médicale. 1995, 5 (1) 11-16). Ces vernis ont pour avantage d'être faciles à appliquer et de former un film insoluble dans l'eau à la surface de l'ongle permettant la libération d l'agent antimycosique au sein de l'ongle. Les molécules antimycosiques formulées dans ces bases de vernis à ongle sont 1 ' amorolfine, la ciclopiroxolamine et la combinaison bifonazole/urée (De Chauvin M. F., Baran R. and Charasse D. Onychomycosis. III: treatment. Journal de Mycologie Médicale, 2001, 11 (4), 205-215; Fleckman P. Onychomycosis: diagnosis and topical therapy. Dermatologie Therapy, 2002, 15 (2), 71- 77) . Le brevet EP 855 397 décrit des agents antimycosiques qui contiennent en tant que substances actives des dérivés azole, en particulier des dérivés imidazole et triazole. Ces agents antimycosiques peuvent être appliqués sous forme de pellicule soluble dans l'eau, manifester un effet de dépôt et permettre un traitement de courte durée. Ils sont appropriés au traitement de mycoses des ongles et peuvent être utilisés aussi bien en solutions qu'en aérosols qui forment, après séchage, une pellicule soluble dans l'eau. L'utilisation de tels liants dans l'eau a évidemment pour effet que l'agent appliqué est plus ou moins éliminé à chaque toilette. Afin de faciliter la pénétration des antimycosiques à travers l'ongle, ces vernis contiennent souvent des substances kératolytiques comme l'urée. La demande EP 226 984 décrit un vernis à ongles comprenant un agent filmogene insoluble dans l'eau et un agent antimycotique. Le vernis peut contenir de l'urée mais la quantité d'urée n'est pas précisée. La demande EP 1 138 314 divulgue une composition filmogene à libération prolongée pour vernis à ongle comprenant une agent antifongique, de l'urée, un humectant tels que le glycerol ou le sorbitol, de l'eau, un agent filmogene et un solvant comprenant au moins un composant volatil. L'utilisation conjointe d'urée et de glycerol améliore le passage trans-ongle de la molécule antifongique et la présence de glycerol permet d'utiliser l'urée à des concentrations inférieures à 1 % par rapport au poids total de la composition. La demande allemande DE 10061801 décrit une composition pharmaceutique qui contient un agent filmogene hydrophile, de l'eau et de l'urée. L'agent filmogene hydrophile est la polyvinylpyrrolidone dans des concentrations de 15-25 % en poids. L'urée est présente à très forte concentration plus particulièrement 75-85 % en poids . Le brevet US 5 346 692 décrit une formulation de vernis à ongle pour traiter les onychomycoses qui contient un agent filmogene, un agent antimycosique, de l'urée et un mélange de solvants très particulier ; les formulations contiennent une forte proportion d'urée, de préférence 15 à 60 % par rapport aux composés non volatils . Compte-tenu de l'état de la technique précédemment décrit, la présente invention propose un vernis à ongles pour traiter 1 'onychomycose, susceptible d'être appliqué de manière topique sur la région infectée de l'ongle sous la forme d'un film, qui permet une bonne libération du principe actif et une bonne diffusion de ce principe actif sur les régions infectées sans attaquer les régions saines de l'ongle et qui contient une faible quantité d'un agent facilitateur d'absorption, de préférence de l'urée, malgré l'absence d'un humectant. L'objet de l'invention est donc un vernis à ongles à action antimycosique contenant: a) 2 à 80 % en poids par rapport à la quantité de composés volatils d'au moins une l-hydroxy-2- pyridone de formule générale (I)The present invention relates to a nail varnish having antimycotic activity. Nail conditions due to fungi (onychomycosis) are stubborn forms of disease that have so far been unable to be satisfactorily treated. Various types of nail fungus are grouped under the name of onychomycosis, including those caused by dermatophytes which are the most difficult to treat, while nail fungus caused by yeast has so far been easier to treat. . Various routes have been used for the treatment of these yeast infections, but with little success. The systemic method which consists of the administration of antifungal agents by the oral route, is a long-term treatment, which can lead to side effects and to the selection of resistant strains. These treatments requiring the administration of large doses of therapeutic agent are therefore preferably reserved for severe cases of onychomycosis. The antimycotic molecules used for the oral route are itraconazole, terbinafine and fluconazole (Effendy I. Therapeutic strategies in onychomycosis. Journal of the European Academy of Dermatology and Venereology. 1995, S3-S10). Nail removal by surgery or by chemical action is a very aggressive which gives no guarantee that the nails will grow back in their normal form; on the contrary, the regrowing nails are frequently deformed. Local treatment of the nails with specific substances with antimycotic action has also been envisaged. Thus, in a combined treatment, the nails were first treated with solutions of substances with antimycotic action and then bandages were applied with creams overnight. This method of treatment is very unpleasant and psychologically trying for the patients. Indeed, on the one hand the treatment of the nails with solutions is necessary several times a day, on the other hand these must be provided with dressings especially at night. In addition, it is necessary to constantly file sick nails, which not only is painful, but also contributes to the spread of pathogenic germs. Finally, this treatment, which lasts several months, is often not continued by patients who, on the contrary, become discouraged and become negligent, which leads to treatment failure. The success of this treatment is further compromised by the fact that solutions and creams are usually water-miscible or hydrophilic, and can therefore be removed from the surface of the nail or caused by dissolution out of the nail. when washing and must therefore be reapplied. More recently, methods using a nail varnish containing a substance with antimycotic activity have been developed. The latter methods are the most effective. The recent development of new antimycotic agents in the form of nail polish has made it possible to obtain very good results in the case of the treatment of moderate infections without recourse to the surgical act (Goettman S. Treatment of dermatophytic onychomycosis. Journal of medical mycology 1995, 5 (1) 11-16). These varnishes have the advantage of being easy to apply and of forming a water-insoluble film on the surface of the nail allowing the release of the antimycotic agent within the nail. The antimycotic molecules formulated in these nail varnish bases are amorolfine, ciclopiroxolamine and the bifonazole / urea combination (De Chauvin MF, Baran R. and Charasse D. Onychomycosis. III: treatment. Journal de Mycologie Médicale, 2001, 11 (4), 205-215; Fleckman P. Onychomycosis: diagnosis and topical therapy. Dermatologie Therapy, 2002, 15 (2), 71-77). Patent EP 855 397 describes antimycotic agents which contain, as active substances, azole derivatives, in particular imidazole and triazole derivatives. These antimycotic agents can be applied in the form of a film soluble in water, manifest a deposition effect and allow a short-term treatment. They are suitable for the treatment of nail fungus and can be used both in solutions and in aerosols which form, after drying, a water-soluble film. The use of such binders in water obviously has the effect that the agent applied is more or less eliminated with each toilet. To facilitate the penetration of antimycotics through the nail, these varnishes often contain keratolytic substances such as urea. EP 226 984 describes a nail varnish comprising a film-forming agent insoluble in water and an antimycotic agent. The varnish may contain urea but the amount of urea is not specified. Application EP 1 138 314 discloses an extended-release film-forming composition for nail varnish comprising an antifungal agent, urea, a humectant such as glycerol or sorbitol, water, a film-forming agent and a solvent comprising minus a volatile component. The joint use of urea and glycerol improves the cross-nail passage of the antifungal molecule and the presence of glycerol allows urea to be used at concentrations of less than 1% relative to the total weight of the composition. German application DE 10061801 describes a pharmaceutical composition which contains a hydrophilic film-forming agent, water and urea. The hydrophilic film-forming agent is polyvinylpyrrolidone in concentrations of 15-25% by weight. Urea is present at a very high concentration, more particularly 75-85% by weight. US Patent 5,346,692 describes a nail polish formulation for treating onychomycosis which contains a film-forming agent, an antimycotic agent, urea and a very specific mixture of solvents; the formulations contain a high proportion of urea, preferably 15 to 60% relative to the non-volatile compounds. In view of the state of the art previously described, the present invention provides a nail varnish to treat onychomycosis, capable of being applied topically to the infected region of the nail in the form of a film, which allows good release of the active principle and good diffusion of this active principle over the infected regions without attacking the healthy regions of the nail and which contains a small amount of an absorption-promoting agent, preferably urea, despite the absence of a humectant. The subject of the invention is therefore a nail varnish with antimycotic action containing: a) 2 to 80% by weight relative to the amount of volatile compounds of at least one l-hydroxy-2-pyridone of general formula ( I)
dans laquelle RI représente soit un groupe alkyle droit ou ramifié ayant de 6 à 9 atomes de carbone, soit un groupe cycloalkyle ayant de 3 à 6 atomes de carbone, l'un des substituants R2 et R4 représente un atome d'hydrogène et l'autre représente un atome d'hydrogène ou un groupe choisi parmi les groupes méthyle et éthyle et R3 représente un groupe alkyle droit ou ramifié ayant de 1 à 2 atomes de carbone, sous forme libre ou sous forme de sel physiologiquement acceptable, en tant que substance à action antimycosique, b) 0,1 à 20 % en poids par rapport à la quantité de composés volatils d'un promoteur d'absorption de la substance active, choisi dans le groupe comprenant l'urée, le sulfite d'ammonium, les esters et les sels de l'acide thioglycolique, l' allantoïne, les enzymes et l'acide salicylique. c) 5 à 40 % en poids par rapport à la quantité de composés volatils d'un agent filmogene soluble dans les solvants polaires et éventuellement d) un solvant physiologiquement acceptable, ainsi qu ' éventuellement e) des additifs acceptables en cosmétologie. Dans un mode de réalisation avantageux de l'invention, le vernis à ongles est caractérisé en ce que la substance active à action antimycosique répond à la formule (I) dans laquelle R2 et R4 sont chacun un atome d' hydrogène. Dans un mode de réalisation particulièrement avantageux de l'invention, le vernis à ongles contient une substance active à action antimycosique répondant à la formule (I) dans laquelle RI représente un groupe cycloalkyle ayant de 3 à 6 atomes de carbone, de préférence un groupe -CH2-CH (CH3) -CH2-C (CH3) 3, ou un groupe cyclohexyle. Dans un autre mode de réalisation particulièrement avantageux de l'invention, le promoteur d'absorption est 1 ' urée . Dans le vernis à ongles selon l'invention, par rapport à la quantité des composants non volatiles, c'est-à-dire à la somme des agents filmogènes, des pigments éventuellement présents, des plastifiants et des autres additifs non volatils, ainsi que de la substance active, celle-ci est en général contenue en une quantité allant de 2 à 80, de préférence de 10 à 60 et en particulier de 20 à 40 % en poids. Dans le vernis à ongles selon l'invention, la substance active est contenue en une quantité allant de 0,5 à 20, de préférence de 2 à 15 % en poids par rapport à la quantité de composants non volatils. Les vernis à ongles selon l'invention contiennent en outre, en tant que composants indispensables, un ou plusieurs agents filmogènes qui forment sur l'ongle après séchage de la préparation, une pellicule insoluble dans 1 ' eau. Ces agents filmogènes sont choisis dans le groupe comprenant les copolymères acryliques/méthacryliques, les polyméthacrylate/butyle acrylate, les copolymères acryliques/acrylates, l'alcool polyvinylique, les polyvinylpyrrolidones, les polyvinylpyrrolidones/vinyle acétates et les vinylpyrrolidones/diméthylaminoéthyle méthacrylates . Il est connu que l'association des solvants a une importance prépondérante pour le temps de séchage, la facilité d'application au pinceau et d'autres propriétés importantes du vernis ou de la pellicule de vernis. Selon la présente invention, le système de solvants est constitué de préférence d'un mélange optimal de solvants à bas point d'ébullition (inférieur à 100°C) et de solvants à point d'ébullition moyen (compris entre 100 et jusqu'à 150°C) ; éventuellement avec une faible proportion de solvants à point d'ébullition élevé (compris entre 150 et jusqu'à 200°C) . On choisira préférentiellement comme solvant des mélanges eau/éthanol, eau/alcool isopropylique ou eau/butanol dans des rapports allant de 10/90 à 30/70, rapports tenant compte de la solubilité de la substance active et de l'agent filmogene choisis. Les vernis à ongles selon l'invention peuvent contenir en outre des additifs utilisés couramment dans les cosmétiques, tels que des plastifiants à base de phtalate, de camphre ou d'urée, des colorants ou pigments colorés, des agents nacrants, des retardateurs de sédimentation, résines sulfonamide, silicates, des parfums, des agents mouillants tels que le dioctylsulfosuccinate de sodium, des dérivés de la lanoline, des agents de protection contre la lumière tels que la 2-hydroxy-4-méthoxy-benzophénone, des substances à action antibactérienne. La difficulté dans la réalisation de cette invention a consisté à choisir des agents filmogènes insolubles dans l'eau, mais solubles dans le mélange eau/alcool de telle manière qu'après séchage, la pellicule formée sur l'ongle soit insoluble dans l'eau et donc puisse résister à l'action de la toilette. Le vernis à ongles selon l'invention convient également pour l'utilisation prophylactique contre des mycoses de l'ongle, un dépôt suffisamment important de substance active pouvant être obtenu dans l'ongle pour que, dans le cas d'une contamination fongique, on ne constate pas l'apparition d'une maladie de l'ongle provoquée par des champignons. Avec le vernis à ongles selon l'invention, on peut aboutir à une guérison radicale dans le traitement des mycoses des ongles, les ongles repoussant habituellement sans déformation. La présente invention est illustrée plus en détail à l'aide des exemples qui suivent. in which RI represents either a straight or branched alkyl group having from 6 to 9 carbon atoms, or a cycloalkyl group having from 3 to 6 carbon atoms, one of the substituents R2 and R4 represents a hydrogen atom and the other represents a hydrogen atom or a group chosen from methyl and ethyl groups and R3 represents a straight or branched alkyl group having from 1 to 2 carbon atoms, in free form or in salt form physiologically acceptable, as a substance with antimycotic action, b) 0.1 to 20% by weight relative to the amount of volatile compounds of an absorption promoter of the active substance, chosen from the group comprising urea, ammonium sulfite, esters and salts of thioglycolic acid, allantoin, enzymes and salicylic acid. c) 5 to 40% by weight relative to the amount of volatile compounds of a film-forming agent soluble in polar solvents and optionally d) a physiologically acceptable solvent, as well as optionally e) additives acceptable in cosmetology. In an advantageous embodiment of the invention, the nail varnish is characterized in that the active substance with antimycotic action corresponds to formula (I) in which R2 and R4 are each a hydrogen atom. In a particularly advantageous embodiment of the invention, the nail varnish contains an active substance with antimycotic action corresponding to formula (I) in which RI represents a cycloalkyl group having 3 to 6 carbon atoms, preferably a group -CH 2 -CH (CH 3 ) -CH 2 -C (CH 3 ) 3 , or a cyclohexyl group. In another particularly advantageous embodiment of the invention, the absorption promoter is urea. In the nail varnish according to the invention, relative to the amount of the non-volatile components, that is to say to the sum of the film-forming agents, pigments possibly present, plasticizers and other non-volatile additives, as well as the active substance, this one is generally contained in an amount going from 2 to 80, preferably from 10 to 60 and in particular from 20 to 40% in weight. In the nail varnish according to the invention, the active substance is contained in an amount ranging from 0.5 to 20, preferably from 2 to 15% by weight relative to the amount of non-volatile components. The nail varnishes according to the invention additionally contain, as essential components, one or more film-forming agents which form on the nail after the preparation has dried, a film insoluble in water. These film-forming agents are chosen from the group comprising acrylic / methacrylic copolymers, polymethacrylate / butyl acrylate, acrylic / acrylate copolymers, polyvinyl alcohol, polyvinylpyrrolidones, polyvinylpyrrolidones / vinyl acetates and vinylpyrrolidones / dimethylaminoethyl methacrylates. It is known that the combination of solvents is of paramount importance for the drying time, the ease of application with a brush and other important properties of the varnish or of the varnish film. According to the present invention, the solvent system preferably consists of an optimal mixture of solvents with a low boiling point (less than 100 ° C.) and solvents with a medium boiling point (between 100 and up to 150 ° C); possibly with a small proportion of high boiling point solvents (between 150 and up to 200 ° C). Water / ethanol, water / isopropyl alcohol or water / butanol mixtures will preferably be chosen as solvent in ratios ranging from 10/90 to 30/70, ratios taking account of the solubility of the active substance and of the film-forming agent chosen. The nail varnishes according to the invention can also contain additives commonly used in cosmetics, such as plasticizers based on phthalate, camphor or urea, colorants or colored pigments, pearlescent agents, sedimentation retardants , sulfonamide resins, silicates, perfumes, wetting agents such as sodium dioctylsulfosuccinate, lanolin derivatives, light protection agents such as 2-hydroxy-4-methoxy-benzophenone, substances with antibacterial action . The difficulty in carrying out this invention consisted in choosing film-forming agents which are insoluble in water, but soluble in the water / alcohol mixture so that, after drying, the film formed on the nail is insoluble in water. and therefore can resist the action of the toilet. The nail varnish according to the invention is also suitable for the prophylactic use against fungal infections of the nail, a sufficiently large deposit of active substance which can be obtained in the nail so that, in the case of fungal contamination, does not notice the appearance of a nail disease caused by fungi. With the nail polish according to the invention, it is possible to achieve a radical cure in the treatment of nail fungus, the nails usually repelling without deformation. The present invention is illustrated in more detail with the aid of the following examples.
EXEMPLE 1 : Compositions quantitativesEXAMPLE 1: Quantitative compositions
EXEMPLE 2 : Mesure de 1 ' activité antimycosiqueEXAMPLE 2 Measurement of the Antimycotic Activity
1. Mode opératoire L'activité des composés utilisés selon l'invention a été mise en évidence par des essais de pénétration sur corne de bœuf. Ces cornes de bœufs ont été découpées de façon à obtenir des disques de kératine de diamètre voisin de 1 cm et d'une épaisseur standardisée à 0,6 mm. Ces disques de kératine ont été ensemencés par un dermatophyte { Trichophyton mentagrophytes) . Au terme d'environ 30 jours, ces dermatophytes ont totalement colonisé les disques de cornes, aussi bien en surface qu'au milieu du substrat, mimant parfaitement le phénomène de mycose de l'ongle.1. Procedure The activity of the compounds used according to the invention has been demonstrated by penetration tests on ox horn. These ox horns were cut so as to obtain keratin disks with a diameter close to 1 cm and a thickness standardized to 0.6 mm. These keratin discs were seeded by a dermatophyte (Trichophyton mentagrophytes). After about 30 days, these dermatophytes have completely colonized the horn discs, both on the surface than in the middle of the substrate, perfectly mimicking the nail fungus phenomenon.
On considère qu'un taux de germes de départ de 7,46 log de 10 spores/gramme de corne est un taux suffisamment élevé pour permettre de calculer la chute de log 10. Le vernis contenant le ciclopirox est alors déposé sur ce disque de corne 5 jours sur 7 et le septième jour, la corne est réduite en poussière afin de pouvoir compter les populations résiduelles en unité formant colonies. Ce traitement a été réalisé pendant 1 mois avec une cinétique de prélèvement réalisée à T7jours, T14jours et T21jours. Le passage à travers l'ongle est étudié en suivant la disparition de ces dermatophytes. Cette méthode permet à la fois de connaître le passage à travers" l'ongle du principe actif et son efficacité in vi tro . Un témoin de vigueur de la souche est réalisé en parallèle. La mise en évidence de la réduction logarithmique du nombre d'unités formant colonies est réalisé après neutralisation du vernis (un test préliminaire a permis de valider la neutralisation de la formule pour ce germe) . Dans les essais sur le pouvoir de pénétration, on a testé plusieurs formules préparées soit avec des agents filmogènes à tendance hydrophile dissous dans des milieux hydroalcooliques, soit avec des agents filmogènes à tendance hydrophobe dissous dans des solvants polaires. Les formules suivantes ont été testées : Formule n°l ciclopirox 8 g copolymère acrylique/méthacrylique 14 g alcool éthylique 59,1 g eau purifiée qsp 100 gIt is considered that a starting germ rate of 7.46 log of 10 spores / gram of horn is a rate high enough to allow the fall of log 10 to be calculated. The varnish containing the ciclopirox is then deposited on this horn disc 5 days a week and on the seventh day, the horn is reduced to dust in order to be able to count the residual populations in unit forming colonies. This treatment was carried out for 1 month with sampling kinetics performed at T7days, T14days and T21days. The passage through the nail is studied by following the disappearance of these dermatophytes. This method allows both to know the passage through " the nail of the active ingredient and its effectiveness in vi tro. A witness of vigor of the strain is carried out in parallel. The demonstration of the logarithmic reduction of the colony-forming units are produced after neutralization of the varnish (a preliminary test has made it possible to validate the neutralization of the formula for this germ). In the tests on the power of penetration, several formulas have been tested either with film-forming agents with hydrophilic tendency dissolved in hydroalcoholic media, or with film-forming agents with hydrophobic tendency dissolved in polar solvents The following formulas have been tested: Formula n ° l ciclopirox 8 g acrylic / methacrylic copolymer 14 g ethyl alcohol 59.1 g purified water qs 100 g
Formule n°2 ciclopirox 6 g urée 5 g copolymère acrylique/méthacrylique 14 g alcool éthylique 59,1 g eau purifiée qsp 100 gFormula n ° 2 ciclopirox 6 g urea 5 g acrylic / methacrylic copolymer 14 g ethyl alcohol 59.1 g purified water qs 100 g
Formule n°3 ciclopirox 8 g urée 5 g copolymère acrylique/méthacrylique 14 g alcool éthylique 59,1 g eau purifiée qsp 100 gFormula n ° 3 ciclopirox 8 g urea 5 g acrylic / methacrylic copolymer 14 g ethyl alcohol 59.1 g purified water qs 100 g
2. Résultats Le tableau suivant résume les résultats obtenus au 7è jour, au 14è et au 21è jour.2. Results The following table summarizes the results obtained on the 7th day, the 14th and the 21st day.
Il ressort de ces travaux que les formules avec urée (formules 2 et 3) sont les plus efficaces car la cinétique de destruction des dermatophytes est plus rapide ; on observe à 7 jours une chute de 5,79 et 6,4 respectivement pour les formules 3 et 2, alors que la chute est seulement de 3,12 pour la formule 1 sans urée. L'effet fongicide est atteint le plus rapidement (en 7 jours) pour les formules 2 et 3 et est total à 21 jours. En revanche, la cinétique de destruction est beaucoup plus lente avec la formule 1 qui ne contient pas d'urée et pour laquelle l'efficacité fongicide n'est pas atteinte au bout de 21 jours (chute de 4,44 en 21 jours). Il est connu que les couches cornées superficielles ont, entre autres, la fonction biologique d'empêcher la pénétration de substances étrangères. Les compositions selon l'invention se distinguent des préparations de l'état antérieur de la technique connues pour le traitement des ongles, par le fait que 168 couches cornées superficielles laissent passer en proportion considérable les substances actives contenues dans ces préparations, et que ces compositions selon l'invention exercent ainsi une action durable en profondeur efficace. It emerges from these works that the formulas with urea (formulas 2 and 3) are the most effective because the kinetics of destruction of dermatophytes is faster; at 7 days, a fall of 5.79 and 6.4 is observed respectively for formulas 3 and 2, while the fall is only 3.12 for formula 1 without urea. The fungicidal effect is reached most quickly (in 7 days) for formulas 2 and 3 and is total at 21 days. On the other hand, the kinetics of destruction is much slower with formula 1 which does not contain urea and for which the fungicidal efficacy is not reached after 21 days (drop from 4.44 in 21 days). It is known that the superficial horny layers have, among other things, the biological function of preventing the penetration of foreign substances. The compositions according to the invention differ from preparations of the prior art known for the treatment of nails, in that 168 superficial horny layers allow the active substances contained in these preparations to pass in considerable proportion, and that these compositions according to the invention thus exert a lasting action at effective depth.

Claims

REVENDICATIONS
1. Vernis à ongles à action antimycosique caractérisé en ce qu'il contient : a) 2 à 80 % en poids par rapport à la quantité de composés volatils d'au moins une l-hydroxy-2-pyridone de formule générale (I)1. Nail polish with antimycotic action, characterized in that it contains: a) 2 to 80% by weight relative to the amount of volatile compounds of at least one l-hydroxy-2-pyridone of general formula (I)
dans laquelle RI représente soit un groupe alkyle droit ou ramifié ayant de 6 à 9 atomes de carbone, soit un groupe cycloalkyle ayant de 3 à 6 atomes de carbone, l'un des substituants R2 et R4 représente un atome d'hydrogène et l'autre représente un atome d'hydrogène ou un groupe choisi parmi les groupes méthyle et éthyle et R3 représente un groupe alkyle droit ou ramifié ayant de 1 à 2 atomes de carbone, sous forme libre ou sous forme de sel physiologiquement acceptable, en tant que substance à action antimycosique, b) 0,1 à 20 % en poids par rapport à la quantité de composés volatils d'un promoteur d'absorption de la substance active choisi dans le groupe comprenant l'urée, le sulfite d'ammonium, les esters et les sels de l'acide thioglycolique, l' allantoïne, les enzymes et l'acide salicylique. c) 5 à 40 % en poids par rapport à la quantité de composés volatils d'un agent filmogene soluble dans les solvants polaires et éventuellement d) un solvant physiologiquement acceptable, ainsi qu ' éventuellement e) des additifs acceptables en cosmétologie. in which RI represents either a straight or branched alkyl group having from 6 to 9 carbon atoms, or a cycloalkyl group having from 3 to 6 carbon atoms, one of the substituents R2 and R4 represents a hydrogen atom and the another represents a hydrogen atom or a group chosen from methyl and ethyl groups and R3 represents a straight or branched alkyl group having from 1 to 2 carbon atoms, in free form or in the form of physiologically acceptable salt, as substance with antimycotic action, b) 0.1 to 20% by weight relative to the amount of volatile compounds of an absorption promoter of the active substance chosen from the group comprising urea, ammonium sulfite, esters and the salts of thioglycolic acid, allantoin, enzymes and salicylic acid. c) 5 to 40% by weight relative to the amount of volatile compounds of a film-forming agent soluble in polar solvents and optionally d) a physiologically acceptable solvent, as well as optionally e) additives acceptable in cosmetology.
2. Vernis à ongles selon la revendication 1, caractérisé en ce que la substance active à action antimycosique répond à la formule (I) dans laquelle R2 et R4 sont chacun un atome d'hydrogène.2. Nail varnish according to claim 1, characterized in that the active substance with antimycotic action corresponds to formula (I) in which R2 and R4 are each a hydrogen atom.
3. Vernis à ongles selon l'une quelconque des revendications 1 et 2, caractérisé en ce que la substance active à action antimycosique répond à la formule (I) dans laquelle RI représente un groupe cycloalkyle ayant de 3 à 6 atomes de carbone.3. Nail varnish according to any one of claims 1 and 2, characterized in that the active substance with antimycotic action corresponds to formula (I) in which RI represents a cycloalkyl group having from 3 to 6 carbon atoms.
4. Vernis à ongles selon l'une quelconque des revendications 1 et 3, caractérisé en ce que la substance active à action antimycosique répond à la formule (I) dans laquelle RI représente un groupe cyclohexyle.4. Nail varnish according to any one of claims 1 and 3, characterized in that the active substance with antimycotic action corresponds to formula (I) in which RI represents a cyclohexyl group.
5. Vernis à ongles selon l'une quelconque des revendications 1 à 3, caractérisé en ce que la substance active à action antimycosique répond à la formule (I) dans laquelle RI représente un groupe -CH2-CH (CH3) -CH2-C (CH3) 3.5. Nail varnish according to any one of claims 1 to 3, characterized in that the active substance with antimycotic action corresponds to formula (I) in which RI represents a group -CH2-CH (CH 3 ) -CH 2 -C (CH 3 ) 3.
6. Vernis à ongles selon l'une quelconque des revendications 1 à 5, caractérisé en ce que l'agent promoteur d'absorption de la substance active est l'urée. 6. Nail varnish according to any one of claims 1 to 5, characterized in that the promoter agent for absorption of the active substance is urea.
7. Vernis à ongles selon l'une quelconque des revendications 1 à 6, caractérisé en ce qu'il contient 10 à 60 %, de préférence 20 à 40 % en poids par rapport à la quantité de composants non volatils, de substance active à action antimycosique.7. Nail varnish according to any one of claims 1 to 6, characterized in that it contains 10 to 60%, preferably 20 to 40% by weight relative to the amount of non-volatile components, of active substance to antimycotic action.
8. Vernis à ongles selon l'une quelconque des revendications 1 à 6, caractérisé en ce qu'il contient 0,5 à 20 %, de préférence 2 à 15 % en poids par rapport à la quantité des composants non volatils et des composants volatils, de substance active à action antimycosique.8. Nail varnish according to any one of claims 1 to 6, characterized in that it contains 0.5 to 20%, preferably 2 to 15% by weight relative to the amount of the non-volatile components and of the components volatile, active substance with antimycotic action.
9. Vernis à ongles selon l'une quelconque des revendications 1 à 8, caractérisé en ce que l'agent9. Nail varnish according to any one of claims 1 to 8, characterized in that the agent
"filmogene est choisi dans le groupe comprenant les les copolymères acryliques/méthacryliques, les polyméthacrylate/butyle acrylate, les copolymères acryliques/acrylates, l'alcool polyvinylique, les polyvinylpyrrolidones, les polyvinylpyrrolidones/vinyle acétates et les vinylpyrrolidones/diméthylaminoéthyle méthacrylates ."film-forming agent is chosen from the group comprising acrylic / methacrylic copolymers, polymethacrylate / butyl acrylate, acrylic / acrylate copolymers, polyvinyl alcohol, polyvinylpyrrolidones, polyvinylpyrrolidones / vinyl acetates and vinylpyrrolidones / dimethylaminoethyl methacrylates.
10. Vernis à ongles selon l'une quelconque des revendications 1 à 9, caractérisé en ce que le solvant est constitué d'un mélange des solvants ayant un point d'ébullition inférieur à 100°C et de solvants ayant un point d'ébullition compris entre 100 et 150°C et éventuellement d'un solvant ayant un point d'ébullition compris entre 150 et 200°C.10. Nail varnish according to any one of claims 1 to 9, characterized in that the solvent consists of a mixture of solvents having a boiling point below 100 ° C and of solvents having a boiling point between 100 and 150 ° C and optionally a solvent having a boiling point between 150 and 200 ° C.
11. Vernis à ongles selon la revendication 10, caractérisé en ce que le solvant est un système hydrophile choisi dans le groupe comprenant les mélanges éthanol/eau, alcool isopropylique/eau et butanol/eau, de préférence dans des proportions allant de 10/90 à 30/70. 11. Nail varnish according to claim 10, characterized in that the solvent is a system hydrophilic chosen from the group comprising ethanol / water, isopropyl alcohol / water and butanol / water mixtures, preferably in proportions ranging from 10/90 to 30/70.
EP04767801A 2003-07-29 2004-07-28 Antimycosic nail varnish Withdrawn EP1648378A2 (en)

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PCT/FR2004/002019 WO2005011565A2 (en) 2003-07-29 2004-07-28 Antimycosic nail varnish

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FR2892023B1 (en) * 2005-10-14 2009-09-25 Galderma Sa PHARMACEUTICAL COMPOSITION BASED ON AMOROLFIN AND WATER-SOLUBLE FILMOGENIC AGENT FOR UNIGEAL AND PERI-UNGUEAL APPLICATION
FR2937250B1 (en) * 2008-10-21 2013-05-10 Fabre Pierre Dermo Cosmetique UREA-BASED FILMOGENOUS SOLUTION FOR THE TREATMENT OF NAIL PSORASIS
US8697753B1 (en) 2013-02-07 2014-04-15 Polichem Sa Method of treating onychomycosis
KR101580077B1 (en) * 2015-03-28 2015-12-24 한국콜마주식회사 Nail lacquer composition containing a ciclopirox
US11878023B2 (en) * 2017-10-25 2024-01-23 Arizona Board Of Regents On Behalf Of The University Of Arizona Compositions and methods for delivering pharmaceutical agents
WO2019084370A1 (en) * 2017-10-27 2019-05-02 Tenneco Inc. Combustion engine components with dynamic thermal insulation coating and method of making and using such a coating
ES2976036A1 (en) * 2024-03-06 2024-07-22 Univ Madrid Complutense Enhancement of intraungual accumulation of active ingredients (Machine-translation by Google Translate, not legally binding)

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DE3544983A1 (en) * 1985-12-19 1987-06-25 Hoechst Ag ANTIMYCOTIC EFFECTIVE NAIL POLISH
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