WO2012110430A1

WO2012110430A1 - Novel composition for topical use on a nail

Info

Publication number: WO2012110430A1
Application number: PCT/EP2012/052354
Authority: WO
Inventors: Åke LINDAHL; Peter Kaufmann; Peter Wolpert
Original assignee: Moberg Derma Ab
Priority date: 2011-02-10
Filing date: 2012-02-10
Publication date: 2012-08-23

Abstract

A composition for topical application on a nail comprising urea, a diol and lactic acid or an ester thereof and a volatile vehicle characterized in that urea is soluble in the solvent in the absence of the volatile vehicle, and that urea is in the solid state in the solvent in the presence of the volatile vehicle. Furthermore, a method for the stabilization of urea in a liquid formulation is shown.

Description

NOVEL COMPOSITION FOR TOPICAL USE ON A NAIL

Technical field

[0001 ] The present invention generally relates to novel compositions comprising urea for topical application on nails.

Background

[0002] Urea is a useful agent for the treatment of several skin conditions and is often included in formulations for the treatment of nails. Urea can also be used as a penetration enhancer in formulations for skin and can be included in formulations for the treatment of nails.

[0003] Several patent applications teach the possibility of increasing penetration of an active pharmaceutical ingredient through skin by evaporation of solvents. For example US2007/01 96453 (Zars Inc, Zhang Jie et al.) concerns adhesive solidifying formulations, methods of drug delivery, and solidified layers for dermal delivery of a drug. The formulation can include a drug, a solvent vehicle, and a solidifying agent. The solvent vehicle can include a volatile solvent system comprising at least one volatile solvent, and a non-volatile solvent system comprising at least one non-volatile solvent, wherein at least one non-volatile solvent is a flux- enabling non-volatile solvent(s) capable of facilitating the delivery of the drug at therapeutically effective rates over a sustained period of time. The formulation can have a viscosity suitable for application to a skin surface prior to evaporation of the volatile solvents system . When applied to the skin, the formulation can form a solidified layer after at least a portion of the volatile solvent system is evaporated. The application mention the use of urea for the treatment of warts.

[0004] Previously, formulations comprising urea, lactic acid and a diol are known . WO87/0461 7 describes such a formulation for the treatment of skin and fungal infections of the nail. However, the current shelf life of that formulation is limited to about two years. The reason for this is that urea is unstable - degrading over time resulting in the loss of activity of the product. This is a major obstacle to achieving cost-efficient production as new batches of the product have to be produced frequently.

[0005] The major degradation products of urea are carbon dioxide and ammonia. Factors that promote the degradation process include light, heat and the presence of certain enzymes.

[0006] Because of the short shelf-life, there is a need for novel stable

formulations comprising urea.

[0007] Moreover, a general problem when treating fungal infections of the nail is to achieve sufficient penetration of the pharmaceutical composition to and into the keratin layer of the nail. Dermatological formulations for application on the nail must therefore be designed in such a way that maximum penetration is achieved.

Definitions

[0008] The term "about" is used to indicate a deviation +/- 1 0% of the stated value, where applicable. By way of example, "about 20%" denotes a value of from 1 8% to 22%.

[0009] The term "soluble" refers the ability of the solvent to dissolve an amount of the active pharmaceutical ingredient that is relevant for its pharmacological effect.

[001 0] As used herein, unless stated otherwise, the amounts of components in percent refer to percent by weight and are based on the total weight of the composition .

[001 1 ] Before the present invention is described, it is to be understood that the terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims and equivalents thereof.

Summary

[001 2] It is an object of the invention to address the problem of urea stability mentioned above. It would be desirable to have a composition for topical application on nails where urea has an increased stability.

[001 3] Therefore it is provided, in a first general aspect of the invention, a urea-comprising composition for topical application on a nail comprising urea, a diol, lactic acid or an ester thereof, and a volatile vehicle, characterized in that urea is soluble in the composition in the absence of the volatile vehicle, and that urea is in the solid state in the composition in the presence of the volatile vehicle.

[001 4] The composition is intended for cosmetic and/or pharmaceutical use on discolored, deformed, thick, brittle and/or crumbly nails or nails suffering from infection, trauma or psoriasis.

[001 5] The invention presents a novel way to maximize the chemical activity of urea and thereby the penetration rate through nail and preserving the urea so that it is not degraded. The inventive formulations and method minimizes the chemical degradation of urea as the whole composition contains very little water and the urea is in the solid state. Furthermore, the invention also results in an increased concentration of urea on the application site when the volatile vehicle evaporates, thereby facilitating penetration. This results in higher penetration of urea.

[001 6] One important advantage of the present invention is that the

composition will have a high stability and therefore a long shelf life. The longer shelf-life increases cost-efficiency, as larger batches can be produced, distributed and stored.

[001 7] Another advantage is that, because the urea component is stable, the composition will contain a low amount of degradation products when it is used by the consumer.

[001 8] Yet another advantage is that the formulation lacks an antifungal agent, in particular an antifungal agent with strong antifungal activity. This enables the production and sale of a non-prescription product and/or over the counter product.

[001 9] Thus, the composition does not comprise an antifungal agent selected among imidazoles, triazoles, thiazoles, allylamines, and echinocandins examples of which are miconazole, ketoconazole, econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole,

voriconazole, terconazole, abafungin, terbinafine, amorolfine, naftifine, butenafine, anidulafungin, caspofungin, and micafungin .

[0020] In particular, the lactic acid or ester thereof may be lactic acid. The diol in the composition is preferably propylene glycol.

[002 1 ] Preferably, the volatile vehicle comprises, consists essentially of, or consists of, at least one selected from the group consisting of ethyl acetate and butyl acetate and mixtures of ethyl acetate and butyl acetate.

[0022] One suitable composition comprises from 2.5% to 32% of a diol, from 0.25% to 6% of lactic acid or an ester thereof and from 0.5% to 8% of urea and from 55% to 95% of a volatile vehicle.

[0023] Another suitable composition comprises from 2.5% to 32% of a diol, from 0.25% to 6% of lactic acid or an ester thereof, from 0.5% to 8% of urea; the remainder of the composition being ethyl acetate or butyl acetate, or a mixture of ethyl acetate and butyl acetate, and optionally, other components selected from the group consisting of a gelling agent or thickener, a surfactant, a chelating agent, sodium hydroxide, water and glycerol.

[0024] Yet another suitable composition consist- or consist essentially of - from 2.5% to 32% of propylene glycol, from 0.25% to 6% of lactic acid, from 0.5% to 8% of urea, from 0.05% to 1 .5% of a surfactant; from 0. 1 % to 1 % of a chelating agent, from 2% to 1 6% of a gelling agent or thickener, from 0.01 % to 0.8% of sodium hydroxide and from 0. 1 % to 1 % of water and from 1 % to 5% of glycerol; the remainder of the composition being ethyl acetate or butyl acetate, or a mixture of ethyl acetate and butyl acetate.

[0025] In a second general aspect of the invention there is provided a composition for use in the treatment of discolored, deformed, thick, brittle and/or crumbly nails or nails suffering from infection, trauma or psoriasis.

[0026] In a third general aspect of the invention there is provided use of a composition according to the invention for the treatment of discolored, deformed, thick, brittle and/or crumbly nails or nails suffering from infection, trauma or psoriasis.

[0027] In a fourth general aspect of the invention there is provided a method for increasing the stability of urea. The method comprises the steps of dissolving urea in a solvent comprising a diol and lactic acid and adding a volatile vehicle which precipitates the urea.

[0028] In a fifth general aspect of the invention there is provided a method for the treatment of discolored, deformed, thick, brittle and/or crumbly nails or nails suffering from infection, trauma or psoriasis, comprising the step of topically administering a composition according to the invention on a nail. The method comprises the steps of applying the inventive composition to a nail, allowing the volatile vehicle to evaporate so that urea dissolves in the remaining solvents, and leaving the composition on the nail and allowing the urea exert its function.

Preferably, the amount of urea present in the composition after evaporation of the volatile vehicle is from 2% to 30%. Preferably, the application is carried out at least once a week.

[0029] Yet another aspect of the invention is a composition comprising a precipitation or suspension of urea obtainable according to the method described herein .

Detailed Description

[0030] In the following, a detailed description of the invention will be provided.

[003 1 ] The composition comprises a suspension of urea particles in a solvent comprising a diol and lactic acid or an ester thereof and a volatile vehicle that precipitates urea. The solvent has a lower vapor pressure than the volatile vehicle such that the composition comprises a suspension of urea particles during storage when the volatile vehicle is present. When the composition is applied to a nail the volatile vehicle evaporates. The urea the dissolves in the remaining components (mainly lactic acid and a diol), so that it becomes accessible for penetration into the nail.

[0032] Preferably, at least 30%, more preferably at least 50%, more preferably at least 60% and most preferably at least 70% of the urea is solu the composition in the absence of the volatile vehicle. [0033] The composition includes lactic acid or an ester thereof. Suitable esters of lactic acid include butyl lactate and ethyl lactate. Mixtures of two or more of lactic acid, butyl lactate and ethyl lactate are also suitable.

[0034] The disclosed formulation allows high penetration of urea to, through and into the nail.

[0035] Preferably, at least 5%, more preferably at least 1 0%, more preferably at least 20%, more preferably 30%, more preferably 40% more preferably 50%, more preferably 60 %, more preferably 80% and most preferably at least 95% of the urea is in the solid state in the presence of the volatile vehicle at a temperature from 2°C to 25°C.

[0036] The composition does not comprise an antifungal agent, that is, a compound with strong antifungal activity. A list of such antifungals can be found in Goodman & Gilmans The pharmacological basis of therapeutics, 2001 , 1 295- 1 3 1 2, McGraw-Hill. In particular, the composition does not comprise imidazoles, such as miconazole, ketoconazole, econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole; triazoles, such as fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole, and terconazole; thiazoles, such as abafungin; allylamines, such as terbinafine, amorolfine, naftifine, and butenafine; and echinocandins, such as anidulafungin, caspofungin, and micafungin .

[0037] Furthermore, the composition does not comprise polyenes or miscellaneous compounds such as griseofulvin, benzoic, salicylic, propionic, undecylenic or caprylic acid, or clotimtrazole, potassium iodide, tolnaphtate, ciclopirox olamine, amphotercin C, nystatin, flucytosine, or haloprogine.

[0038] Thus, one further advantage is that the formulation lacks an antifungal agent with strong antifungal activity. This enables the production and marketing of a product that can be sold as a non-prescription and/or over-the-counter product. Furthermore, the use of antifungal drugs will cause antifungal agents to be released to the environment. The use of antifungals may result in the development of resistance to these drugs which would result in reduced efficacy of available treatment. One further aspect is that antifungal drugs are expensive to produce and handle. All of these drawbacks are avoided by excluding an antifungal drug.

[0039] The amount of urea present in the invented composition after evaporation of the volatile vehicle is in the range of from 2% to 40%, more preferably from 2% to 30%. The amount of diol, preferably propylene glycol, in the composition after evaporation of the volatile part is preferably from 40% to 90%. These concentrations are suitable for the treatment of fungal infection of nails and the treatment of discolored, deformed, thick, brittle and/or crumbly nails or nails suffering from infection, trauma or psoriasis.

[0040] The composition comprises a diol, of which in particular propylene glycol is suitable. Other suitable diols are butanediol, pentanediol and hexanediol.

[0041 ] The combined amount of urea, diol and lactic acid in the composition is preferably from about 5% to about 40% of the total composition, more preferably from 1 0% to 30% and most preferably from 1 5% to 25%.

[0042] The volatile vehicle is chosen so that urea is precipitated in the presence of the volatile vehicle. When the composition is applied on a nail the volatile vehicle evaporates and the urea becomes dissolved in the remaining components.

[0043] Suitably the volatile vehicle has a vapor pressure of more than 1 kPa at 25°C. The volatile vehicle should be pharmaceutically acceptable. [0044] A non-limiting list of suitable compounds for the volatile vehicle includes ethyl acetate and butyl acetate and mixtures thereof. When a mixture of ethyl acetate and butyl acetate is used, the weight ratio of ethyl acetate to butyl acetate is preferably from 3 : 1 to 1 : 1 , most preferably about 2: 1 . The amount of volatile vehicle is preferably from 60% to 95%, more preferably from 70% to 90% and most preferably from 75% to 85%.

[0045] The diol is preferably present in concentrations from 2% to 36%, more preferably from 2.5% to 32%, even more preferably from 3% to 30% and most preferably from 6% to 28%. The lactic acid or ester thereof is preferably present in concentrations from 0.05% to 1 2%, more preferably from 0.25% to 8%, even more preferably 0.25% to 6% and most preferably from 0.25% to 4%. Urea is preferably present in concentrations from 0. 1 % to 1 2%, more preferably from 0.5% to 1 0%, even more preferably from 0.5% to 8%, even more preferably from 1 % to 6% And most preferably from 1 % to 4%, while the volatile vehicle is preferably present in concentrations from 55% to 95%, more preferably from 60% to 95%, more preferably from 70% to 90%, more preferably from 75% to 85%, even more preferably from 77% to 83% and most preferably from 78 to 82%.

[0046] In addition, the composition may include additional components well known to a person skilled in the art which are pharmaceutically acceptable.

[0047] In order to modify the viscosity of the composition it may comprise a pharmaceutically acceptable gelling agent or thickener, preferably selected from the group of gelling or thickening agents that are soluble in the preferred volatile vehicle, e.g. ethyl acetate and butyl acetate. Non-limiting examples of such gelling or thickening agents are carbomers, carboxyethylene or polyacrylic acids such as carbomer 980 or 940 NF, 981 or 941 NF, 1 382 or 1 342 NF, 5984 or 934 NF, ETD 2020, 2050, 934P NF, 971 P NF, 974P NF and carbomer derivatives;

cellulose derivatives such as ethylcellulose, hydroxypropylmethylcellulose (HPMC), ethyl-hydroxyethylcellulose (EHEC), carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), etc; natural gums such as arabic, xanthan, guar gums, alginates, etc; polyvinylpyrrolidone derivatives; polyoxyethylene polyoxypropylene copolymers, etc; others like chitin, chitosan, polyvinyl alcohols, pectins, veegum grades, and the like. Yet other suitable thickeners are represented by methacrylates exemplified by but not limited to different types of Eudragit. Alternatively, other gelling agents or viscosants known by those skilled in the art may also be used. A preferred group of thickeners is polymethacrylates (copolymers derived from esters of acrylic and methacrylic acids). Alternatively, other gelling agents or viscosants known by those skilled in the art may also be used.

[0048] The gelling agent or thickener is present from about 0.2% to about 20% depending on the type of polymer, as known by one skilled in the art. Preferably, the gelling agent or thickener, which suitably is a polymethacrylate, is present at a concentration of from 2% to 1 6%, more preferably from 3 % to 1 2%, even more preferably from 4% to 1 0%.

[0049] Preferably, the gelling agent or thickener is selected so that the composition, when applied on a nail, forms a film within a reasonable time, such as within 1 0 minutes, preferably within 5 minutes, more preferably within 2 minutes, more preferably within 1 minute. Preferably the film is not formed within a shorter time than 30 seconds.

[0050] Furthermore, the gelling agent or thickener preferably forms a film so that the non-evaporating components of the composition remain on the application site.

[005 1 ] The composition may comprise a pharmaceutically acceptable base, preferably sodium hydroxide. Suitably the base, which preferably is sodium hydroxide, is present in a concentration of from 0.01 % to 0.8%, more suitably 0.05% to 0.6%, even more suitably from 0. 1 % to 0.4%.

[0052] The water content of the composition depends on the selection of the included compounds. The composition may include small amounts of added water in order to enable the inclusion of sodium hydroxide. The water content may be from 0. 1 % to 1 %, more preferably from 0.2% to 0.4%. Alternatively, the

composition may include no added water. Nevertheless, the composition may then still include water contained in the excipients. For example, various commercially available qualities of lactic acid may contain water. Alternatively, the composition does not contain water.

[0053] Also the composition may further comprise pharmaceutically acceptable buffers such as carbonate buffers, citrate buffers, phosphate buffers, acetate buffers, hydrochloric acid, tartaric acid, diethylamine, triethylamine, diisopropylamine or aminomethylamine. However, other buffers, as known in the art may be included.

[0054] The composition can be prepared with pharmaceutically acceptable chelating agents exemplified by, but not limited to, EDTA or its derivatives and phosphonic acids. The concentration of EDTA is suitably from 0. 1 % to 1 %, even more suitably from 0.3% to 0.7% and most preferably from 0.45% to 0.65%.

[0055] Preferably, the composition may further comprise a pharmaceutically acceptable surfactant. The surfactant is selected so that suitable flocculation of the suspended urea particles occurs. The surfactant is preferably polar and is soluble in the volatile vehicle and should be able to wet the urea particles. Examples of suitable surfactants can be found in Handbook of Pharmaceutical Excipients

Pharmaceutical Press 6^th edition, 2009, and the most suitable surfactants for the system can selected by a person skilled in the art. The concentration of the surfactant is preferably from 0.05% to 1 .5%, more preferably from 0.25% to 0.75% and most preferably from 0.4% to 0.6%. A preferred surfactant is polysorbate (Tween), in particular polysorbate 80 (Tween 80). One advantage with adding a surfactant is to achieve suitable flocculation of the suspended particles in order to prevent caking of the suspension .

[0056] Preferably, the non-evaporating components, that is, the components that remain on the nail after evaporation of the volatile vehicle, can be washed away using only water or soap and water. This property is referred to as

"washability" herein . In order to improve the washability, agents that improve the water miscibility and/or solubility of the non-evaporating components may be included in the composition. Glycerol is an example of such an agent. The concentration of glycerol is suitable from 1 % to 5%

[0057] The following are non-limiting examples of compositions.

[0058] In general the composition comprises from 2% to 36%, more preferably from 2.5% to 32%, and most preferably from 3% to 30% of a diol which preferably is propylene glycol; from 0.05% to 1 2%, more preferably from 0.25% to 8% and more preferably from 0.25% to 6% and most preferably from 0.25% to 4% of lactic acid; from 0. 1 % to 1 2%, more preferably 0.5% to 1 0%, more preferably from 0.5% to 8% and most preferably from 1 % to 6% of urea; and optionally one or more of the following components: from 0.05% to 1 .5%, more preferably from 0.25% to 0.75% and most preferably from 0.4% to 0.6% of a surfactant which preferably is polysorbate 80; from 0. 1 % to 1 %, preferably 0.3% to 0.7% and most preferably from 0.45% to 0.65% of a chelating agent, which preferably is EDTA; from 2% to 1 6%, more preferably from 3 % to 1 2%, even more preferably from 4% to 1 0% of a gelling agent or thickener, from 0. 1 % to 1 %, more preferably from 0.2% to 0.4% of water and from 0.01 % to 0.8%, more preferably 0.05% to 0.6%, even more preferably from 0. 1 % to 0.4% of NaOH, the remainder of the composition being ethyl acetate or butyl acetate, or a mixture of ethyl acetate and butyl acetate. [0059] Thus, in general the composition consists of from 2% to 36%, more preferably from 2.5% to 32%, and most preferably from 3% to 30% of a diol which preferably is propylene glycol; from 0.05% to 1 2%, more preferably from 0.25% to 8% and more preferably from 0.25% to 6% and most preferably from 0.25% to 4% of lactic acid; from 0. 1 % to 1 2%, more preferably 0.5% to 1 0%, more preferably from 0.5% to 8% and most preferably from 1 % to 6% of urea; and optionally one or more of the following components: from 0.05% to 1 .5%, more preferably from 0.25% to 0.75% and most preferably from 0.4% to 0.6% of a surfactant which preferably is polysorbate 80; from 0. 1 % to 1 %, preferably 0.3% to 0.7% and most preferably from 0.45% to 0.65% of a chelating agent, which preferably is EDTA; from 2% to 1 6%, more preferably from 3 % to 1 2%, even more preferably from 4% to 1 0% of a gelling agent or thickener, from 0. 1 % to 1 %, more preferably from 0.2% to 0.4% of water and from 0.01 % to 0.8%, more preferably 0.05% to 0.6%, even more preferably from 0. 1 % to 0.4% of NaOH, the remainder of the

composition being ethyl acetate or butyl acetate, or a mixture of ethyl acetate and butyl acetate.

[0060] The composition includes urea, lactic acid or an ester thereof, a diol and a volatile vehicle and may in addition include other pharmaceutically

acceptable excipients. Thus, the composition may consist of urea, a diol, lactic acid, a volatile vehicle and a gelling agent or thickener.

[0061 ] Alternatively, the composition may consist of urea, a diol, lactic acid, a volatile vehicle, a gelling agent or thickener and a chelating agent.

[0062] Also, the composition may consist of urea, a diol, lactic acid, a volatile vehicle, a gelling agent or thickener, a chelating agent and a surfactant.

[0063] Furthermore, the composition may also consist of urea, a diol, lactic acid, a volatile vehicle, a gelling agent or thickener, a chelating agent, a surfactant and water. [0064] The composition may also consist of urea, a diol, lactic acid, a volatile vehicle, a gelling agent or thickener, a surfactant and water.

[0065] The composition may also consist of urea, a diol, lactic acid, a volatile vehicle, a gelling agent or thickener and water.

[0066] Also, the composition may consist of urea, a diol, lactic acid, a volatile vehicle, a gelling agent or thickener, water and chelating agent.

[0067] The composition may also consist of urea, a diol, lactic acid, a volatile vehicle, a gelling agent or thickener and a surfactant.

[0068] One preferred composition comprises from 5% to 1 0%, more preferably from 6% to 8% of a diol, from 0.5% to 2%, more preferably from 0.75% to 1 .5% of lactic acid, from 1 .5% to 3%, more preferably 1 .8% to 2.5% urea, and optionally other components, such as, for example, a gelling agent or thickener in the amounts described herein, the remainder being ethyl acetate or butyl acetate or a mixture of ethyl acetate and butyl acetate.

[0069] A preferred composition consists of from 5% to 1 0%, more preferably from 6% to 8% of a diol which preferably is propylene glycol; from 0.5% to 2%, more preferably from 0.75% to 1 .5% of lactic acid; from 1 .5% to 3%, more preferably 1 .8% to 2.5% of urea; and optionally one or more of the following components: from 0.05% to 1 .5%, more preferably from 0.25% to 0.75% and most preferably from 0.4% to 0.6% of a surfactant which preferably is polysorbate 80; from 0. 1 % to 1 %, preferably 0.3% to 0.7% and most preferably from 0.45% to 0.65% of a chelating agent, which preferably is EDTA; from 2% to 1 6%, more preferably from 3% to 1 2%, even more preferably from 4% to 1 0% of a gelling agent or thickener, from 0. 1 % to 1 %, more preferably from 0.2% to 0.4% of water and from 0.01 % to 0.8%, more preferably from 0.05% to 0.6%, even more preferably from 0. 1 % to 0.4% of NaOH, the remainder of the composition being ethyl acetate or butyl acetate, or a mixture of ethyl acetate and butyl acetate.

[0070] However, it may be suitable to increase the concentration of urea, lactic acid and diol while keeping the ratio of the concentrations of these

compounds constant.

[0071 ] Thus, a composition may be prepared with higher concentrations of urea, lactic acid and diol as follows.

[0072] Thus, a preferred composition with a higher proportion of urea, lactic acid and diol comprises from 1 0% to 20%, more preferably from 1 2% to 1 6% of propylene glycol, from 1 % to 4%, more preferably from 1 .5% to 3% of lactic acid, from 3% to 6%, more preferably from 3.6% to 5% urea, and optionally other components, such as, for example, a gelling agent or thickener in the amounts described herein, the remainder being ethyl acetate or butyl acetate or a mixture of ethyl acetate and butyl acetate.

[0073] A preferred composition comprises about 1 4% propylene glycol, about 2% lactic acid, about 4% urea and the remainder, preferably about 80% of a volatile vehicle, which preferably is ethyl acetate, butyl acetate, or a mixture of butyl acetate and ethyl acetate.

[0074] A preferred composition with a even higher proportion of urea, lactic acid and diol comprises from 1 5% to 30%, more preferably from 1 8% to 25% of propylene glycol, from 1 .5% to 6%, more preferably from 2.25% to 4.4% of lactic acid, from 4.5% to 9%, more preferably 5.4% to 7.5% urea, and optionally other components, such as, for example, a gelling agent or thickener in the amounts described herein, the remainder being ethyl acetate or butyl acetate or a mixture of ethyl acetate and butyl acetate. [0075] When used on a nail, the composition is suitably applied and the volatile vehicle is allowed to evaporate. The urea then dissolves in the remainder of the composition (the solvent comprising a diol and lactic acid). The urea is then able to penetrate into the keratinous layer of the nail.

[0076] Application of the composition on the infected nail suitably takes place at least once a week, more preferably once every two days, and even more preferably once daily. Thus, there is also provided the use of a composition according to the invention for the treatment of a fungal infection of a nail and the use of a composition according to the invention for the treatment of discolored, deformed, thick, brittle and/or crumbly nails or nails suffering from infection, trauma or psoriasis.

EXAMPLES

Example 1

[0077] 9.96 g of propylene glycol was weighed into a 1 00 ml beaker. 0.54 g of 1 0 M sodium hydroxide was added to the propylene glycol and the mixture was allowed to stir with a magnetic stir bar for 5 min . 1 .5 g of lactic acid was dissolved before 3.0 g of urea was added. After the urea had dissolved, 0.75 g of polysorbate 80 was added and the solution was stirred for 5 min before the addition 0.075 g of EDTA. In a separate flask 1 3.5 g of the polymethacrylate polymer Eudragit® RS PO (Evonik Industries) was dissolved in a mixture of 93 ml of ethyl acetate and 41 ml of butyl acetate. The resulting composition was as foil

Propylene glycol 6.67%

Sodium hydroxide 10M 0.36%

Lactic acid 1.00%

Urea 2.01%

Polysorbate 80 0.50%

EDTA 0.05%

Eudragit SPO 9.04%

Ethyl acetate 56.19%

Butyl acetate 24.17%

Total 100.00%

[0078] The propylene glycol solution containing urea was added to the solution containing the polymer in ethyl acetate/butyl acetate solution. Upon addition of the propylene glycol phase, the solution turned opaque as a

consequence of the precipitation of urea. After sedimentation, the particles formed a loose sediment that was easily shaken to form a suspension.

Example 2

[0079] 9.96 g of propylene glycol was weighed into a 1 00 ml beaker. 0.56 g of 1 0 M sodium hydroxide was added to the propylene glycol and the mixture was stirred with a magnetic stir bar for 5 min. 1 .50 g of lactic acid was dissolved before 3.00 g of urea was added. After the urea had dissolved 0.75 g of polysorbate 80 was added and the solution was stirred for 5 min before the addition 0.075 g of EDTA. In a separate flask, 1 3.5 g of the polymethacrylate polymer Eudragit® RS PO (Evonik Industries) was dissolved in a mixture of 66.5 ml of ethyl acetate and 68 ml of butyl acetate. [0080] The resulting composition was as follows:

Propylene glycol 6.68%

Sodium hydroxide 10M 0.38%

Lactic acid 1.01%

Urea 2.01%

Polysorbate 80 0.50%

EDTA 0.05%

Eudragit SPO 9.05%

Ethyl acetate 40.21%

Butyl acetate 40.12%

Total 100.00%

[0081 ] The propylene glycol solution containing urea was added to the solution containing the polymer in ethyl acetate/butyl acetate solution. Upon addition of the propylene glycol phase, the solution turned opaque as a

consequence of the precipitation of urea. After sedimentation, the particles formed a loose sediment that was easily shaken to form a suspension .

Example 3

[0082] 9.96 g of propylene glycol as weighed into a 1 00 ml beaker. 0.55 g of 1 0 M sodium hydroxide was added to the propylene glycol, and the mixture was allowed to stir with a magnetic stir bar for 5 min . 1 .50 g of lactic acid was dissolved before 3.00 g of urea was added. After the urea had dissolved, 0.75 g of polysorbate 80 was added and the solution was stirred for 5 min before 0.079 g of EDTA was added. In a separate flask, 1 3.5 g of the polymethacrylate polymer Eudragit® RS PO (Evonik Industries) was dissolved in 1 33.8 ml of ethyl acetate. [0083] The resulting composition was as follows:

Propylene glycol 6.64%

Sodium hydroxide 10M 0.37%

Lactic acid 1.00%

Urea 2.00%

Polysorbate 80 0.50%

EDTA 0.05%

Eudragit SPO 9.00%

Ethyl acetate 80.44%

Butyl acetate 0.00%

Total 100.00%

The propylene glycol solution containing urea was added to the solution containing the polymer in ethyl acetate solution. Upon addition of the propylene glycol phase, the solution turned opaque as a consequence of precipitation of urea. After sedimentation, the particles formed a loose sediment that was easily shaken to form a suspension.

Example 4

[0084] 9.96 g of propylene glycol as weighed into a 1 00 ml beaker. 0.56 g of 1 0 M sodium hydroxide was added to the propylene glycol, and the mixture was stirred with a magnetic stir bar for 5 min. 1 .50 g of lactic acid was dissolved before 3.00 g of urea was added. After the urea had dissolved, 0.77 g of polysorbate 80 was added and the solution was stirred for 5 min before 0.077 g of EDTA was added. In a separate flask, 1 3.5g of the polymethacrylate polymer Eudragit® RS PO (Evonik Industries) was dissolved in 1 37.2 ml of butyl acetate.

[0085] The resulting composition was as follows:

Propylene glycol 6.64%

Sodium hydroxide 10M 0.37%

Lactic acid 1.00%

Urea 2.00%

Polysorbate 80 0.51%

EDTA 0.05%

Eudragit SPO 8.99%

Ethyl acetate 0.00%

Butyl acetate 80.44%

Total 100.00%

[0086] The propylene glycol solution containing urea was added to the solution containing the polymer in butyl acetate solution . Upon addition of the propylene glycol phase, the solution turned opaque as a consequence of

precipitation of urea. After sedimentation, the particles formed a loose sediment that was easily shaken to form a suspension .

Example 5

[0087] 9.97 g of propylene glycol as weighed into a 1 00 ml beaker. 0.54 g of 1 0 M sodium hydroxide was added to the propylene glycol and the mixture was allowed to stir with a magnetic stir bar for 5 min . 1 .50 g of lactic acid was dissolved before 3.01 g of urea was added. After the urea had dissolved, 0.76 g of polysorbate 80 was added and the solution was stirred for 5 min before 0.080 g of EDTA was added. In a separate flask, 7.5 g of the polymethacrylate polymer Eudragit ® RS PO (Evonik Industries) was dissolved in 72.3 ml of ethyl acetate and 49.4 ml of butyl acetate.

[0088] The resulting composition was as follows:

Propylene glycol 6.64%

Sodium hydroxide 10M 0.37%

Lactic acid 1.00%

Urea 2.00%

Polysorbate 80 0.50%

EDTA 0.05%

Eudragit SPO 9.00%

Ethyl acetate 60.32%

Butyl acetate 20.12%

Total 100.00%

The propylene glycol solution containing urea was added to the solution containing the polymer in ethyl acetate/butyl acetate solution. Upon addition of the propylene glycol phase, the solution turned opaque as a consequence of precipitation of urea. After sedimentation, the particles formed a loose sediment that was easily shaken to form a suspension.

Example 6

[0089] The following procedure was applied for example formulations 6A-6F

[0090] Propylene glycol was weighed into a beaker. 1 0 M sodium hydroxide (when present) was added to the propylene glycol and the mixture was allowed to stir with a magnetic stir bar for 5 min. Lactic acid was dissolved into the propylene glycol and urea was then added. After the urea had dissolved, polysorbate 80 was added. The solution was stirred for 5 min and optionally EDTA was added. In a separate flask, the polymethacrylate polymer Eudragit ® RS PO (Evonik Industries) was dissolved in ethyl acetate and/or butyl acetate. [0091 ] The propylene glycol solution containing urea was added to the solution containing the polymer in ethyl acetate/butyl acetate solution. Upon addition of the propylene glycol phase, the solution turned opaque as a consequence of precipitation of urea. After sedimentation, the particles formed a loose sediment that was easily shaken to form a suspension .

Example 6A Batch size 1 00 g.

Propylene glycol 1 7.5 g

Lactic acid 5.0 g

Urea 2.5 g

Polysorbate 80 0.3 g

Ethyl acetate 70.7 g

Eudragit RS PO 4.0 g

Example 6B

Batch size 500 g.

Propylene glycol 49.8 g

Lactic acid 7.52 g

Urea 1 5.01 g

Polysorbate 80 2.5 g

Ethyl acetate 382.27g

Eudragit RS PO 40.0 g

EDTA 0.25 g

NaOH 1 0 M 2.7 g [0092] The percentage of the composition was as follows:

Example 6C

Batch size 150 g.

Propylene glycol 14.94 g

Lactic acid 2.3 g

Urea 4.51g

Polysorbate 80 0.75 g

Ethyl acetate 80.28g

Butyl acetate 34.41g

Eudragit RS PO 12.0g

EDTA 0.078g

NaOH 10 M 0.84 g

[0093] The percentage of the composition was as follows:

Example 6D

Batch size 40 g.

Propylene glycol 8.4 g

Lactic acid 1 -2 g

Urea 2.4 g

Polysorbate 80 0.1 2 g

Ethyl acetate 26.3 g

Eudragit RS 1 .6 g

[0094] The percentage of the composition was as follows:

% (W/W)

Propylene glycol 21 .0

Lactic Acid 6.0

Urea 3.0

Polysorbate 80 0.3

Ethyl acetate 65.7

Eudragit RS PO 4.0 Example 6E

Batch size 40 g .

Lactic Acid 1 .4 g

Propylene glycol 9.8 g

Urea 2.8 g

Polysorbate 80 0. 1 2 g

Ethyl acetate 24.3 g

Eudragit RSPO 1 .6 g

[0095] The percentage of the composition was as foil

% (w/w)

Lactic acid 3.5

Propylene glycol 24.5

Urea 7

Polysorbate 80 0.3

Ethyl acetate 60.7

Eudragit RS PO 4.00

Total 1 00

Example 6F

Batch size 5 g .

Lactic Acid 0.22 g

Propylene glycol 1 .54 g

Urea 0.44 g

Butyl acetate 2.8 g

[0096] The percentage of tta composition was as follows:

% (w/w)

Lactic acid 4.4

Propylene glycol 30.8

Urea 8.8

Butyl acetate 56

Total 1 00 Example 7

[0097] The following composition was manufactured by dissolving propylene glycol, urea, NaOH, water and lactic acid and an antifungal in one vessel and the remaining compounds in ethyl acetate in another vessel.

[0098] When mixing the propylene glycol solution into the ethyl acetate solution a suspension was formed. The suspension was packed in clear glass bottles with a polypropylene cap.

[0099] The suspension was stored at 2°-8°, 25°, 30° and 40°C for up to 1 2 months and analysis of urea content demonstrated that the invented formulation is stable at the tested temperatures. The urea concentration after storage is shown in Table 1 . The fact that the concentration appears to be higher can be explained by an acceptable error in the method. The testing conditions comply with drug regulatory requirements (ICH). Storage assays was carried out in a GMP unit. The assay for urea was performed with an HPLC method. [001 00] The stability data show that the urea content is within 1 .8 and 2.2 %, which is 2% ± 1 0%. Thus, it can be concluded that the urea is stable in the composition. The presence of an antifungal component is not expected to influence the stability of urea.

Table 1 . Urea stability.

Example 8

[001 01 ] In order to determine the amount of urea present in the solid state, the amount of urea present in the solid phase after centrifugation was determined in the following composition :

Ethyl acetate 90%

Propylene glycol 7%

Urea 2%

Lactic acid 1 % [001 02] Lactic acid and urea were dissolved in propylene glycol and ethyl acetate was added and a suspension was formed.

[001 03] 5 g of the suspension was centrifuged at 1 5.000 rpm for 60 minutes at 20°C. The supernatant was removed and analysis of the solid phase was made after dissolution and dilution with water. Analysis was performed by HPLC and resulted in a fraction of urea in the solid state of 64.2%. The remainder was either in solution or in colloidal form .

Example 9

[001 04] An important property of a formulation intended for the nail is its ability to deliver the medically or cosmetically useful substance to the nail. This can be studied in vitro using human cadaver nails or bovine hoof material. The advantage of the bovine hoof material is that penetration of most compounds is much faster than through nail.

[001 05] The following composition was used for test of permeability of urea through hoof membranes:

Substance Content (%) (w/w)

Ethyl acetate 48.87

Butyl acetate 32.58

Eudragit RS PO 8.00

EDTA 0.05

Polysorbate 80 0.50

NaOH 0. 1 1

Water 0.25

Lactic acid 1 .00

Propylene glycol 6.64

Urea 2.00

Total % 1 00.00 [001 06] Equipment for the determination of penetration through nail or hoof membranes is commercially available. A Franz cell equipment from PermeGear Inc. (USA) was used (model V9-CB which has 9-station stirrer with black anodized aluminum cell holders for jacketed Franz cells). The glass cells were 9 mm jacketed Franz cells with flat ground joints, a receptor volume of 3 ml, stir-bar and cell top. The temperature in the receptor fluid was set to 32°C. Hoof membranes were collected from bovine hoofs from an abattoir (SLP, Helsingborg, Sweden). Only membranes from the sole of the bovine hoof were used. The thickness of the membranes were 1 00 μηη and they were prepared by gluing 3 *3 cm cubes of the hoof sole to a methacrylate block and making slices of 1 00 μηη thickness with a dermatome. The hoof membranes were frozen and stored at -80°C until use.

[001 07] The samples were prepared by evaporation of weighed amounts of product on filter paper discs to a dry weight of 1 20 to 1 30 mg. The reason for this procedure is that the evaporation in the penetration chamber is slow and the solvents may otherwise interact with the membrane and the receptor fluid.

[001 08] After hydration of the hoof membrane for a suitable time the hoof membranes were mounted in the Franz cells and the evaporated preparations were applied. The experiment was terminated after 6 hours whereupon the amount urea that had penetrated to the receptor fluid was determined by HPLC. After 6 hours, almost half the applied dose, about 45%, had penetrated through the membrane as shown in Table 2. This means that urea, although being in solid form when stored, is readily available when the volatile vehicle has evaporated. Table 2.

Sample Amount Average penetration, Standard

% of dose of deviation, triplicate experiments triplicates

1 1 23 mg 48.61 % 0.70

2 1 35 mg 42.81 % 3.36

Claims

1 . A composition for topical application on a nail comprising urea, a diol, lactic acid or an ester thereof and a volatile vehicle, characterized in that urea is soluble in the composition in the absence of the volatile vehicle, and that urea is in the solid state in the composition in the presence of the volatile vehicle.

2. The composition according to claim 1 wherein said compostion does not comprise an antifungal agent selected among miconazole, ketoconazole,

econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole, and terconazole, abafungin,

terbinafine, amorolfine, naftifine, butenafine, anidulafungin, caspofungin, and micafungin

3. The composition according to claim 1 , wherein said composition does not comprise an antifungal agent selected among imidazoles, triazoles, thiazoles, allylamines, and echinocandins.

4. The composition according to claim 1 , wherein said composition does not comprise an antifungal agent.

5. The composition according to any one of claims 1 to 4 where the lactic acid or ester thereof is lactic acid.

6. The composition according to any one of claims 1 to 5, wherein the volatile vehicle comprises at least one compound selected from the group consisting of ethyl acetate and butyl acetate and mixtures of ethyl acetate and butyl acetate.

7. The composition according to any one of claims 1 to 6, wherein the diol is selected from the group consisting of propylene glycol, butanediol, pentanediol and hexanediol or mixtures thereof.

8. The composition according to claim 7, wherein the diol is propylene glycol.

9. The composition according to any one of the previous claims additionally comprising a base.

1 0. The composition according to claim 9, wherein the base is sodium hydroxide.

1 1 . The composition according to any one of claims 1 to 1 0, comprising from

2.5% to 32% of a diol, from 0.25% to 6% of lactic acid or an ester thereof and from 0.5% to 8% of urea and from 55% to 95% of a volatile vehicle.

1 2. The composition according to claim 1 , comprising from 2.5% to 32% of a diol, from 0.25% to 6% of lactic acid or an ester thereof, from 0.5% to 8% of urea; the remainder of the composition being ethyl acetate or butyl acetate, or a mixture of ethyl acetate and butyl acetate, and optionally other components selected from the group consisting of a gelling agent or thickener, a surfactant, a chelating agent, sodium hydroxide, water and glycerol.

1 3. The composition according to claim 1 consisting of from 2.5% to 32% of propylene glycol, from 0.25% to 6% of lactic acid, from 0.5% to 8% of urea, from 0.05% to 1 .5% of a surfactant; from 0. 1 % to 1 % of a chelating agent, from 2% to 1 6% of a gelling agent or thickener, from 0.01 % to 0.8% of sodium hydroxide and from 0. 1 % to 1 % of water and from 1 % to 5% of glycerol; the remainder of the composition being ethyl acetate or butyl acetate, or a mixture of ethyl acetate and butyl acetate.

1 4. A method for increasing the stability of urea in a liquid formulation, comprising the steps of a) dissolving urea in a solvent comprising a diol and lactic acid, b) adding a volatile vehicle which precipitates the urea.

1 5. A composition comprising a precipitation or suspension of urea obtainable according to claim 1 4.

1 6. Use of a composition according to any one of claims 1 to 1 3 or claim 1 5 for the treatment of fungal infection of the nail.

1 7. Use of a composition according to any of claims 1 to 1 3 or claim 1 5 for the treatment of discoloured, deformed, thick, brittle and/or crumbly nails or nails suffering from infection, trauma or psoriasis.

1 8. A method for treating discoloured, deformed, thick, brittle and/or crumbly nails or nails suffering from infection, trauma or psoriasis comprising the steps of a) applying a composition according to any one of claims 1 to 1 3 or claim 1 5, b) allowing the volatile vehicle to evaporate so that urea dissolves in the remaining solvents, and c) leaving the composition on the nail and allowing the urea to exert its function.

1 9. The method according to claim 1 8 where the amount of urea present in the composition after evaporation of the volatile vehicle is from 2% to 30%.

20. The method according to claim 1 8 or 1 9 where the application is carried out at least once a week.