WO2010069519A1 - Topical compositions comprising at least one active ingredient poorly soluble in water and biopolymers such as hyaluronic acid with a pka-value between 5-7 - Google Patents

Abstract

The present invention relates to compositions comprising one or more active ingredients poorly soluble in water and an biopolymer having at least one carboxylic group, selected from acid polysaccharides such as hyaluronic acid, alginic acid, polymaleic acid or a derivative thereof having a pKa-value of between 5 and 7 in a water or water - alcoholic mixture. Surprisingly such active ingredients remain in a suitable (solvated) form in the composition without rapid crystallisation of the active/s. Moreover when topically applied to skin or parts thereof, e.g. nails, hair and scalp in need of a treatment, the compositions as described surprisingly form an essentially anti-abrasive film which can be removed by action of water. The compositions have a good skin compatibility with excellent adhesive properties and are especially suitable for treatment of skin, hair or nails in need of an anti-infective, anti-mycotic, anti-inflammatory / or related treatment.

Description

TOPICAL COMPOSITIONS COMPRISING AT LEAST ONE ACTIVE INGREDIENT POORLY SOLUBLE IN WATER AND BIOPOLYMERS SUCH AS HYALURONIC ACID WITH A PKA-VALUE BETWEEN 5-7

Description 5 Field of the invention

The present invention relates to compositions comprising one or more active ingredients poorly soluble in water and a biopolymer having at least one carboxylic group, selected from acid polysaccharides such as hyaluronic acid, alginic acid; a dicarboxylic acid such as a polymaleic acid or a derivative thereof, having a pKa-0 (=pks) value of between 5 and 7, in a water or water - alcoholic mixture. Such compositions may comprise an amount of active ingredient(s) sufficient for an improved action inspite of the spare solubility thereof. The reason therefore is that surprisingly such active ingredients remain in a suitable / solvated form in the composition without rapid crystallisation of the active/s. Moreover when topically5 applied to skin or parts thereof, e.g. nails, hair and scalp in need of a treatment, the compositions as described surprisingly form an essentially anti-abrasive film which can be removed by action of water.

The compositions have a good skin compatibility with excellent adhesive properties and are especially suitable for treatment of skin, hair or nails in need of e.g.0 an anti-infective, anti-mycotic, or an anti-inflammatory treatment, e.g. in case of nail and skin psoriasis, tinea capitis, tinea barbae, tinea faciei, tinea manum, onychomycosis, tinea pedis.

Background of the invention and prior art 5 Topical treatment of skin or parts thereof is depending on various factors such as actual availability of the active ingredient, permeability and the trans- or intradermal delivery thereof as well as the stability and solubility of the active ingredient within the formulation. Also the applicability to the customer and consequently the kind of the formulation such as a fluid, a cream, an ointment, a gel is a decisive0 factor to achieve good results. Various pharmaceutical dosage forms have hitherto been used for the care or treatment of skin. These forms usually comprise spreadable preparations, e.g. in the form of ointments, creams, pastes, gels, lotions or fluids. Often, specific carriers in dependence of the desired application form and / or active ingredients are incorporated, e.g. lipids, solvents. However, with regard to the applicability, stability and activity of such individual dosage forms a large number of auxiliary substances may also be necessary. Such auxiliary substances however may often entail an unwanted skin feel and / or sensitisation / allergic reactions. Furthermore, also an - often unwanted - absorptive effect can occur with a possible sys- temic action.

Numerous publications relate to compositions for application to skin describing different approaches to solve the problems mentioned above. EP B 1 308 169 discloses topically administrable water containing preparations, with formation of an external active ingredient depot, containing sparingly soluble active ingredients, and poly-oxy-ethylene copolymer surfactants. Thus, within this system a specific delivery shall be achieved via the action of a specific emulsifier system thus avoiding systemic action of the active ingredient. A further delivery system for pharmaceutical actives is described in EP 0368 253 wherein chitosan which is a non-acidic polyaminoglycosid is used as a filmforming agent.

In another attempt (EP B 0 928 192) it has been suggested to use gel compositions to have a better activity of the active ingredient (hydroxyl-pyridines as anti- mycotics) using gelforming agents such as gelatine, pectine, agar, hydroxypropyl- cellulose, alginates. Herein the active ingredient action is said to be specifically related to the gel form.

The composition "Loceryl®" (an anti-mycotic nail lacquer) comprises amorolfinhy- drochloride as the active ingredient together with poly(ethylacrylat), polymethyl- methacrylat, polytrimethylammoniumethyl-methycrylatchlorid as film-forming agents. However, such filmforming agents are sparingly soluble in water and therefore have to be removed with the aid of organic solvents such as acetone, isopropanol before the next application may follow. Likewise, US 2007/0122366 A1 discloses a specific terbinafine hydrochloride composition for treatment of nails further comprising poly(methyl vinylether)alt- maleic monobutyl ester which is not soluble in water, in 50% ethanol solution, as a film forming agent at about 20-75 wt.%. Another method for topically applying active ingredients comprises the use of hyaluronic acid and derivatives thereof, respectively. Thereby the hyaluronic acid shall act as a carrier or penetration promoter / enhancer. For example, US Patent 4,636,524 is concerned with hyaluronic acid gels cross-linked with divinylsulfon showing a high swelling property and providing thereby a cage for active ingredi- ents. EP 0 626 894 B1 discloses the use of hyaluronic acid or a derivative thereof as a penetration enhancer for a medical and / or therapeutic agent whereby such combination shall be used in an amount of at least 5 mg / cm² of the skin or exposed tissue to which the dosage amount is to be applied. The hyaluronic acid shall have a molecular mass of about 150 000 to 750 000 D, and be used in the compositions in an amount of about 1- 3 % by weight in the treatment of various disorders in different application forms such as a gel or a cream comprising e.g. diclophenac, water, and additives like wax, methoxypolyethylene. Hyaluronic acid itself may also be used as active for skin treatment. In this connection EP A 1 837 347 A1 describes a specific process for the preparation of a cross linked - hyaluronic acid gel having a molecular weight of between 600 000 and 1 800 000 D. Such gels shall exhibit an only poor water absorption capacity and shall be quite stable against enzyme degradation and be incorporated in cosmetic / or pharmaceutical compositions of various forms. Thus, the state of the art provides different systems aiming a better active ingredi- ent activity, namely either the use of penetration enhancers, or of specific application forms and / or solvent surfactants. However, nothing is said about the actual availability of the active ingredient in relation to the amount incorporated in the composition and the stability thereof (active agent balance), especially when being poorly soluble in the solvent system. Object of the invention

In view the various possible systems and difficulties in preparing topical compositions with a good ingredient delivery / activity, the object of the invention is the provision of a composition suitable for topical application to the skin and / or re- lated tissue showing sufficient stability on the one hand and also a sufficient active agent balance -which means a sufficiently available agent concentration for a good activity - as well as a good skin compatibility including an appropriate and easy removability. It is a further object of the invention to provide a composition wherein the active agent although being sparingly soluble in water or a watery solvent system is present and available for activity in an amount suitable and sufficient to provide the desired treatment effect, especially an antimycotic or anti-inflammatory effect or an effect related thereto. Another object of the invention is the preparation of such composition as well as the use thereof in the manufacture of a cosmetic / pharmaceutical agent and the use thereof and methods therewith in cosmetic or pharmaceutical / medical treatment of skin and / or related tissue in need of a treatment, especially of nails and nail related tissue like nail bed, in view of disorders occurring therein such as mycotic, fungal disorders or inflammatory disorders or skin / hair tissue and inflam- matory / related disorders such as disorders related to androgenetically based effects like acne, alopecia. Furthermore, also tinea capitis, tinea barbae, tinea faciei, tinea manum, onychomycosis, tinea pedis may be treated with the compositions according to the invention.

Achievement of the objects

These objects are achieved by the following subjects. In one aspect of the invention there is provided a composition for topical application comprising: a biopolymer or derivate thereof comprising at least one carboxylic acid group, selected from acid polysaccharides such as hyaluronic acid or a derivative thereof, alginic acid or a derivative thereof, and polymers of dicarboxylic acids or a derivative thereof, preferably polymaleic acid or polyfumaric acid or derivatives thereof, having a pKa (=pks-) value of 5.0 to 7.0 and being present in an amount of up to 5 %, or in another embodiment of less than 5 %, especially less than 1 % by weight of the composition;

0.01 to 12% by weight (of the composition) of (at least one) an active ingredient sparingly (poorly) soluble in water; a solvent system comprising water, or especially a mixture of water and at least one alcohol; whereby such composition exhibits an pH - value of between 3 and

7.

The active ingredient is preferably a pharmaceutical or pharmaceutically / cos- metically acceptable agent which is used in an amount which is non - toxic to the subject receiving it, but sufficient to provide the desired effect. In another aspect there is provided a composition as described above further comprising 0 to 40 %, preferably 0.1 to 30 wt. %, especially 0.1 to 15 % by weight, of additives useful for such composition. Such additives may be selected from the group consisting of pH-modifiers, buffering substances, emulsifiers, penetration enhancers, smell adjustments (perfumes, fragrances), naturally occurring and synthetically produced water or ethanol soluble pigments / colouring agents, water or ethanol soluble preservatives, body care substances, such as mentioned in detail below. Another embodiment of the invention concerns a biologically active composition as described above comprising components as described above. In another embodiment according to the invention there is provided a method for preparing compositions as described above by mixing the biopolymer and additives if present in a part of the solvent system and thereafter adding the active ingredient premixed in another part of the solvent system.

Yet another object of the invention is the use of such compositions as cosmetic agents for skin, hair, nails and related tissue or their use in the preparation of pharmaceutical agents for treating a condition of the skin or related tissue such as hair in need of such treatment, especially in the treatment of nails and nail related tissue like nail bed of human beings such as finger or foot nails, nail beds, hair and scalp such as fungal or anti-inflammatory diseases therein. In a further embodiment of the invention there is provided a method for treating a condition of the skin or related tissue in need of such treatment, especially in the treatment of nails, nail beds of human beings such as finger or foot nails, nail beds such as fungal or anti-inflammatory diseases. Such methods comprise the provision of compositions as described above and the administration / application to the skin or tissue as required.

Applicants have found out that compositions as described are essentially biocompatible / and / or pharmaceutically acceptable so that the risk of skin or related skin or nail tissue irritation can be reduced. Also an improved active ingredient balance can be achieved. This means within the scope of invention an improved ratio between the amount of active substance and the action thereof which is surprisingly achieved by a reduced crystallisation of the active ingredient.

Description of the figures The figures 1-4 show the ratio of crystallisation of the composition of example 5 of the invention at different times measured by stop watch in comparison (Fig. 5-7) with the known composition "Loceryl", comprising also 5 % amorolfine hydrochloride, acrylatic filmforming agents in contrast to the present biopolymers. As can clearly be seen the present composition benefits from a lack of crystallisation after solvent evaporation after application.

Fig. 8 shows the surprisingly higher bioavailability of claimed compositions in comparison with state of the art formulations ("Loceryl", "Penlac.Batrafen").

Detailed explanation of the invention The compositions according to the present invention are topically applicable fluids or gel-like agents, which can be applied to the skin and related areas, especially nails / nail beds such as foot and finger nails of human beings or hair and scalp. When applying such composition to the area in need thereof, it will remain on the area for a sufficient time for action without a greater loss of activity of the active due to crystallization. This means e.g. with regard to the application to nails (or hair, skin), the composition comprising as active ingredient at least one anti- infective, especially anti-mycotic (antifungal) agent can remain for a longer period of time at the area in the soluble state so that there is sufficient time for a sufficient mode of action of the active ingredient in areas sensitive to easy removal of the composition form. Surprisingly it has been found out that with such a composi- tion the biopolymer such as the polysaccharide is acting as a film forming agent which however may also be removed by simply applying water thus avoiding specific solvents like acetone. Moreover, it has surprisingly been found out, that although the pH-value of the composition is not alkaline, which normally is considered being necessary in view of sparingly water - soluble active ingredients, a considerable amount of the active ingredient (e. g. up to 8 wt% terbinafine) can be incorporated into the composition while as pointed out avoiding a crystallisation thereof and consequently a loss of possible activity resulting insofar in a stable product. In addition it has surprisingly been found out that with the compositions described above the active ingredient release can also be controlled via the pH value of the composition, as further shown in the experimental part below. The composition in one aspect of the invention can therefore be considered, when applied to nail or nail related tissue area, as a lacquer, e. g. as an anti-mycotic (naturally removable) lacquer.

Description of the ingredients of the composition 1. Biopolymers

The biopolymers of the composition according to the invention are selected from biopolymers with one or more carboxylic acid groups. Preferably they are selected from the group comprising acid polysaccharides, such as hyaluronic acid and alginic acid or a derivative thereof. Derivatives in the sense according to the invention means salts, such as alkaline metal salts such as sodium salt, potassium salt, alkaline earth metal salt such as calcium, magnesium, aluminium, barium salt, as well as cross-linked derivatives thereof. Cross-linked within the sense of the invention means cross-linked in such a way that at least one or more free car- boxyl groups is/are available also resulting in pKa- (=pKs)-values of 5.0 - 7.0.

Within the composition conditions (pH values) the biopolymers used can be considered as water soluble. The amount of the biopolymer as indicated is chosen such as to provide film forming properties to the composition. Thereby, the pKa-(=pKs) value and the amount of / the molecular mass of the biopolymer will define certain performance characteristics such as viscosity or film forming properties, or both. For example, the final viscosity of a composition to be applied to nail is low to provide good application properties for the damaged nail. For a composition to be applied to skin or hair the amount of the biopolymer might be chosen in such a way that the final product viscosity allows a local application. Consequently, the resulting viscosity values of the claimed compositions may differ between 0.01 Pas up to 10 Pas, preferably between 0.01 and 6 Pas, and particularly between 0.015 and 4 Pas (values of 1% solution measured with Brookfield apparatus).

The biopolymers preferably have a pKa (=pKs) value of 5.5-6.8 and an average molecular weight of between 30000 to 3 MioD, preferably 100000 to less than 2.0 MioD. In a specific embodiment hyaluronic acid or a derivative thereof, especially a salt thereof, e.g. a sodium salt, is used, especially preferred in an amount of 0.01 up to less than 1 wt. %, such as 0.1 to 0.95 wt.%. Preferably the hyaluronic acid or salt, e. g. sodium salt thereof as used in the claimed composition may have a molecular mass (weight) of ≤ 3 Mio D and a pKa(=pKs) value of 6.0 -7.0. Since hya- luronic acid (as the other biopolymers) can be considered as a natural agent - namely a glycosaminoglycan - no adverse effects should occur therewith. Such substance is commercially available or can be prepared according to known methods as described in Acta Chem. Scand. 18 (1964) No. 1 , 274-275. In another specific (preferred) embodiment a cross-linked hyaluronic acid is used having a molecular mass of about 2.3 -2.6 Mio Dalton having a pKa (=pKs)- value of 6.6-6.9 and being cross-linked by 1 ,2,3,4-Diepoxybutan as the cross-linking agent, preferably in an amount of from 0.1 up to 0.95 wt.%. In another embodiment alginic acid is used or a salt thereof as mentioned above. This biopolymer consists of (1→4) linked β-D-mannuronic acid (M) and α-L- guluronic acid (G) residues of widely varying composition and sequence. It derives from stipes of Laminaria hyperborean. For the current product a G-content of about 40% and a M-content of about 60% used having a pKa (=pks)- value of about 6.7 was used. Preferably, the alginic acid biopolymer can be used in an amount of between 0.1 and 3.5 wt. %, or even between 0.1 and 0.95wt%. In another embodiment a cross-linked alginic acid is used having a pKa(=pks-) value of 5.0-7.0 and a molecular mass of about ≥ 200 kg / MoI (laser light scatter- ing photometer) and being cross-linked by Bariumchlorid and Calciumchlorid, respectively, as the cross-linking agent, each in an amount of between 0.1 and 2.5, preferably 0.1 to 0.95 wt.%.

In another embodiment polymaleic acid e.g. poly(methyl vinyl ether)-alt-maleic acid) having a molecular mass Mw (Weight average) of ≤ 1 980 000 and Mn (number average) < 960 000, e.g. MW 216000 and Mn 80000, and a pKa(=pks)- value of 5.3-5.7 is used. Preferably, the amount of this compound is between 0.1 and 5.0 wt. %, preferably 0.1 to 3.5, or even to 0.95 wt.%. The biopolymers or derivatives thereof are either soluble in neutral water or if not can be solved by altering the pH value to higher values and thereafter lowering the same to the desired value, e.g. neutral value.

Especially preferred amounts of the biopolymers in the composition are between 0.1 and 0.95 % by weight, especially 0.2 to 0.95 % by weight.

2. Solvent system The solvent system of the composition according to the invention is composed of water or a mixture of water and an alcoholic compound. The alcoholic compound can be selected from the group consisting of C₂- Ce aliphatic mono- or divalent or trivalent alcohols such as ethanol, propanol, isopropanol, 1 ,2-propandiol or 1 ,3- propandiol or mixtures thereof; divalent alcohols such as ethylenglykol, poly- ethylenglycol, or glycerol. The water - alcohol - ratio can be between 8:1 and 1 :8 or 2:1 and 1 :1.5, especially in regard to water-ethanol mixtures. In a specific embodiment according to the invention the solvent system is selected from water or a mixture of water and a C₂- C₃ aliphatic monovalent alcohol, selected from ethanol, isopropanol or mixtures thereof. In another specific embodiment the solvent system comprises water and water / alcoholic mixtures, wherein the alcohol is selected from monovalent alcohol, preferably ethanol. The amount of the solvent system is between 70 and 95% or more appropriate, between 80 and 95% by weight of the composition. In specific cases such solvent or solvent mixture can comprise small amount of a ketone, e.g. up to 5 % by wt., such as acetone. By the use of highly potent active ingredients, such as clobetasol, the amount of the solvent system could be up to 99.8%.

3. The active ingredients

The active ingredient is selected from the group consisting of ingredients poorly soluble in water, and amongst these of anti-infective active ingredients, especially anti-mycotic agents, hormones, anti-inflammatory agents, and amongst these agents with at least an anti-inflammatory activity or a related activity as explained below. In a specific embodiment according to the invention the active ingredient is se- lected from anti-mycotic ingredients of the group consisting of iodopovidone, keto- conazole, climbazaole, gentamycin, nystatin, acyclovir; ciclopirox, amorolfine, naftifine, terbinafine, itraconazole, fluconazole, itraconazole, econazole nitrate, clotrimazole, bifonazole, griseofluvin, tolnaflate or combinations thereof. In another specific embodiment according to the invention the active ingredient is selected from substances with anti-psoriatic properties, preferably anti-inflammatory properties, such as corticosteroids like clobetasol, cortisone, clobutinol, betamethasone acetate, - dipropionate, hydrocortisone and the esters thereof (except of their solved forms e.g. hydrocortisone natrium phosphat), triamcinolone acetonide, fluprednilydene acetate and combinations thereof, or dithranol, diflora- sone, halobetasol, halcinonide, fluocinolone, desoximetasone, fluocinonide (and other derivates of cyclopentanoperhydrophenanthren).

In another embodiment the active ingredient is preferably chosen amongst agents with in the broadest sense at least anti- inflammatory properties. Such agents may be selected from the group comprising benzonitrile derivatives, sparingly soluble in water, of the general formula I

(I) or a stereoisomeric form or a pharmaceutically acceptable salt thereof wherein:

R¹ CN; NO₂; Ci.₄-Alkyl-C(O)-OH or halogen; R² is halogen; CN or CF_3; R³ is =O; =S or =NH

X is a radical of the formula — C=O or X and Y form a group of the formula — N=C-S-R⁴; wherein Y is a radical of the formula R⁵R⁶ — C(CH₃)CH₃ wherein R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl of up to 12 carbon atoms, aryl and aralkyl of up to 12 carbon atoms, all optionally substituted with at least one member of the group consisting of -OH₁ halogen, -SH, -CN, acyl and acyloxy of up to 7 carbon atoms, —aryl, -O- aryl, - O-aralkyl -S- aryl of up to 12carbon atoms, the aryl and aralkyl being optionally substituted with a member of the group consisting of halogen, -CF3, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl and alkynyloxy with the sulfur being optionally oxidized to sulfone or sulfoxide, free, esterified, amidified or salified carboxy, — NH2, mono and dialkylamino and heterocyclic of 3 to 6 ring members and containing at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, the alkyl, alkenyl and alkynyl being optionally interrupted with at least one member of the group consisting of oxygen, nitrogen and sulfur optionally oxidized to sulfoxide or sulfone, and acyl and acyloxy of an organic carboxylic acid of 1 to 7 carbon atoms; wherein R⁵ is independently of R⁶ selected from hydrogen, Ci-₄-Alkyl wherein the alkyl is unsubstituted or mono- to tetra-substituted, independently of each other by halogens; and R⁶ is independently of R⁵ selected from hydrogen, Ci-₄-Alkyl wherein the alkyl is unsubstituted or mono- to tri-substituted, independently of one another by halogens, phenyl-(CH)₂)m wherein the phenyl is unsubstituted or mono- to trisubstituted, independently of one another by -COOH, -CN, or CF3; and m is an integer from zero to 6; or wherein Y is a radical of the formula — N — R⁴ in which R⁴ is as defined above; and wherein Z is =O or a radical of the formula C(CH₃)CH₃.

Such compounds are also disclosed e.g. in US 5,411 ,981 , US 2009/0093487, EP 0580459 A1.

Representatives of compounds of formula I are e.g. Trifluoro-cyano- Benzimidazoles wherein R¹ and / or R² are CN, CF₃, respectively; wherein X, R³ are =O; Y is — N— R⁴ and Z is — C(CH₃)CH₃; with R₄ = hydrogen or alkyl, in particular alkyl substituted by hydroxy such as 4-(3-(4-Hydroxybutyl)-4,4-dimethyl- 2,5-dioxo-1-imidazolyl-2(trifluoromethyl)benzonirile of the formula Ia.

(Ia).

Such compounds can be used within the present formulations in combination with the aforementioned biopolymers, especially in combination with hyaluronic acid having a molecular mass of preferably 100000 to less than 2.0 Mio and a pka- value of 6.0 to 7.0,or polymaleic acid, e.g. poly(methyl vinyl ether)-alt-maleic acid, especially having a molecular mass (weight average) of less than 2.0 Mio and and > Mn 80 000 as well as a pka- value of between 5.3 and 5.7, each in amounts of e.g up to 5% wt., especially 0.5 to 5 % wt. A suitable solvent system were water or water- alcohol with an alcohol as mentioned before, in particular water- ethano- lic mixtures with a ratio of water - alcohol / ethanol of between 8:1 and 1 :8 or 2:1 and 1 :1.5. Due to the excellent solubility of the active ingredient further additives in this regard, especially plasticizers (such as ethoxylated compounds like ethoxy- lated oils etc.) are not necessary in such benzonitrile compositions. Such compositions may be applied to the area of the skin in need thereof, especially to hair whereby also an anti - androgenetic effect may be achieved, such as desired in case of the treatment of an androgenetic alopecia, acne, hirsutism. Preferably, the active ingredient is selected from naftifine, terbinafine, amorolfine, and clobetasol.

In another embodiment the active ingredient may be selected from benzonitriles as indicated above, especially from those preferred ones such as 4-(3-(4-Hydro- xybutylH^-dimethyl^.S-dioxo-i-imidazolyl^trifluoromethyObenzonirile. The active ingredient is incorporated in the composition in an amount between 0.01 and 12 % by weight, especially 0.05 to 8 wt. %, or even 0.1 and 8 wt.%, and more preferred 4 to 8 % by weight. Highly potent active ingredients, like the corticosteroid clobetasol are incorporated in the composition in an amount between 0.01 and 0.2 % by weight.

4. Additives

Additives can be added where desired. These are selected from the group comprising pH-modifiers, buffering substances, emulsifiers, penetration enhancers, smell adjustments, naturally occurring and synthetically produced water or ethanol soluble pigments / colouring agents, water or ethanol soluble preservatives, body care substances, or mixtures thereof.

The pH regulators can be selected from indifferent und less irritated salts e.g. calcium chloride; barium chloride; or from acids, especially organic acids, salts, buffering substances, e.g. citric acid, acetic acid, salicylic acid, lactic acid and other alpha hydroxy acids as well as inorganic acids e.g. HCL, phosphate buffer, citric buffer and etc., NaOH, KOH and other bases. These regulators are used in amounts sufficient to provide the desired pH value of the composition of the invention.

The pH value of the claimed composition is between 3 and 7, and in a preferred embodiment between 4.5 and 5.5. Insofar the composition is especially skin com- patible and does not exhibit an alkaline milieu which is often the case concerning aqueous (watery) agents comprising active ingredients poorly soluble in water in order to assure stability thereof. Buffering substances may also be added, e.g. citrate buffer, phosphate buffer, lactate buffer.

Emulsifiers can be chosen among alkylglycosides (glucose- or alkyl-glucose-) ethers of saturated, partially unsaturated or unsaturated alcohols of C₈-C₂o-fatty acids such as decyl-, stearyl-, palmityl-, lauryl-, oleyl, caprylic, caprinic, myristyl acid, CioCu-glucosidic ethers such as decylglucosid, which is commercially available under the trade name Plantacare^® 2000 UP, Plantacare^® 818 UP, sugar esters, such as esters of Cβ-C₂o-fatty acids and sugars like glucose, saccharose, alkyl glucose such as methylglucose. Among the emulsifiers alkylglucosides can be used in an amount between 0.1 and 40 % by weight, preferably between 0.1 and 30 % by weight. Such alkylglucosides can also act as penetration enhancers. In a specific embodiment alkylglucosides are selected from sugar (glucose- or alkyl-glucose-) ethers of saturated, partially unsaturated or unsaturated, Cβ-C2o-fatty alcohols (such as decyl-, stearyl-, palmityl-, lauryl-, oleyl alcohol and the like). Especially preferred are CioCu-glucosidic ethers such as decylglucosid (which is commercially available under the trade name Plantacare^® 2000 UP, Plantacare^® 818 UP). A further group of emulsifiers according to another embodiment of the invention may be selected from hydrated lecithins such as hydrated phosphatidylcholine, Probiol N03031. Such emulsifier is used to a further embodiment as preferred additive to enhance good skin compatibility and avoid the often unwanted absorptive effect of the active substances with a possible systemic action (skin product). Yet, in another embodiment emulsifiers can be selected from one or more of lecithins such as phosphatidylcholin or phosphatidylserin to enhance good skin com- patibility and penetration enhancing effects if wanted (nail product).

Penetration enhancers can be chosen amongst polyvalent alcohol(s) and derivatives thereof preferably esters, such as glycerol alone or with its esters or suitable combinations thereof; mono- or polyvalent glycols or derivatives thereof, such as propylenglycol, ethoxydiglycol, preferably Transcutol^®, or azocycloheptanone, preferably 1-dodecyl azocycloheptan-2-one as in Azone^®.

Smell adjustments: can be selected from fragrances, perfumes, essential oils and terpenes e.g. d-limonene, terpineol, acyl terpineol, 1,8-cineole, ascaridole, anethole, geraniol and linalool esters, menthone, limonene oxide, carvone, nerol, eugenol, octahydro-1 ,8-dimethyl-7-(1-methylethenyl)-naphthalene, β-bisabolene, α- panasinsen, octahydro-1 ,8-dimethyl-7-(1-methylethenyl)-naphthalene and cis- α- copaene-8-ol or suited combinations thereof. Naturally occurring and synthetically produced water or ethanol soluble pigments / colouring agents can be chosen amongst Acid Blue 7, disodium salt of 1-(3-sulfo- 1-phenylazo)-2-naphthol-6-sulfonic acid (Food Orange 2), disodium salt of 1-(4- sulfo-1-phenylazo)-2-naphthol-6-sulfonic acid (Food Orange 3), Acid Orange 10 (Food Orange 4) or derivatives thereof, trisodium salt of 1-(4-sulfo-1-naphthylazo)- 2-naphthol-6,8-disulfonic acid (Acid Red), trisodium salt of 1-(4-sulfo-1-naphthyl- azo)-2-naphthol-3,6-disulfonic acid (Acid Red 27), tetrasodium salt of 1-(4-sulfo-1- naphthylazo)-2-naphthol-3,6,8-disulfonic acid (Acid Red 41), quinophthalonedisul- fonic acid or suited combinations thereof. The composition may contain water or ethanol soluble preservatives such as imi- dazolidinyl urea, glutaraldehyde, formaldehyde, 2-phenoxyethanol, 1-phenoxy- propan-2-ol, undec-10-enoic acid, sorbic acid, dehydracetic acid, benzoic acid, salicylic acid, propionic acid, formic acid or other acids and salts or esters or combinations thereof, benzyl alcohol or ester such as p-hydroxy benzoic acid ester, such as methylparabene, ethylparabene, propylparabene, butylparabene, isobu- tylparabene or suited combinations thereof.

Body care substances may be chosen from cholesterol, panthenol, allantoin, camomile, azulene such as cham-azulene or guja-azulene or other substances known to the expert. Furthermore, vitamins, especially those related to skin or nail treatment, such as retinol, retinolacetate / -palmitate (vitamin A), thiaminnitrate (Bi), biotin, Ca- pantothenate (Bs), vitamin C (ascorbic acid) and its calcium, sodium and potassium salts may be chosen in this regard.

Specific embodiments of the invention Specific embodiments of the invention can be the following:

A composition for topical application comprising a biopolymer exhibiting at least one carboxylic acid group, selected from polysaccharides e.g. hyaluronic acid, alginic acid, and polymers of a dicarboxylic acid e.g. polymaleic acid, polyfumaric acid or derivatives thereof in an amount of 0.01 up to 5 %, or in another embodiment of 0.01 up to less than 5 % by weight, preferred up to 3 %, by weight, pref- erably 0.1 to 0.95 wt.%, being essentially water soluble at suitable pH- values, and having a pKa(=pKs)-value of between 5 -7, preferably 5.5-6.8.; 0.01 to 12 % by weight of (at least one) an anti-infective, anti-inflammatory active ingredient sparingly soluble in water; 0 to 40%, preferably 0.1 to 30%, by weight of additives selected from pH regulators, buffering agents, emulsifiers, penetration enhancers, pigments / or dyes, body care agents, preservatives, or mixtures thereof; a solvent system comprising water or a mixture of water and a C₂- Cβ aliphatic mono,- di- or trivalent alcohol; especially comprising a mixture of water and ethanol, in a preferred ratio as indicated above of between 2:1 and 1 :1.5, whereby such composition exhibits a final pH-value of between 3 and 7. The solvent system is preferably chosen from a water / alcohol system which can contain up to 5% of a ketone, e.g. acetone.

In another embodiment such composition comprises 0 to 40 %, preferably 0.1 to 30 % by weight of additives, selected from pH modifiers, body care agents and emulsifiers or mixtures thereof. Preferably a composition is used wherein the biopolymer is selected from cross- linked hyaluronic acid or cross-linked alginic acid, in an amount of 0.1 to 0.9 % by weight having a pKa(=pKs-) value of 5-7, especially between 6.6 and 6.9, as well as derivates of polymers of hydroxycarboxylic acid e.g. poly(methyl vinyl ether-alt- maleic acid), in an amount of 0.1 to 5.0, preferably 0.1 to 0.95 % by weight having a pKa(=pks)-_value of 5 - 7, especially between 5.0 and 6.0.

In another preferred embodiment such composition comprises 0.1 to 0.9 % by weight of hyaluronic acid or a salt thereof, preferably selected from sodium salt, having a pKa(=pks-) value of 5.5 up to 7 independent of its molecular mass, which is less than 3 Mio Da. In a further embodiment such a composition comprises as the biopolymer water soluble poly(methyl vinyl ether-alt-maleic acid) having a molecular mass of ≤ Mw (Weight average) =1 980 000 and > Mn 80 000, in an amount of preferably up to 5% by wt, especially 0.1 to 0.95 % by wt., having a pKa(=pks-) value of 5.0-6.0. Yet in another embodiment such composition comprises one or more active ingredients selected from anti-fungal agents or hormones or mixtures thereof. Amongst such ingredients those of the group consisting of naftifine, amorolfine, terbinafine, fluconazole, itraconazole, econazole nitrate, clotrimazole, bifonazole, griseofluvin, ketokenazole, nystatin, tolnaflate, clobetasone, clobetasol, cortisone, clobutinol, betamethasone acetate; hydrocortisone and the esters thereof, triamcinolone acetonide, fluprednilydene acetate, or dithranol, diflorasone, halobetasol, halcinonide, fluocinolone, desoximetasone, fluocinonide or combinations thereof are preferred.

Also another embodiment of the invention are compositions as described above wherein the solvent system is composed of water or a mixture of water and C2- Ce aliphatic mono- di- or trivalent alcohols, especially ethanol, or isopropanol. e.g, in a preferred ratio as indicated above. Such solvent systems may be present in compositions of the invention in an amount of between 70 and 95 % by weight The composition can be a fluid, liquid or a semi-solid system, preferably a gel as a film forming composition that can be removed by water. Insofar it can be a nail lacquer which can be applied to nails, nail beds of fingers or foot, e. g. of human beings.

In another embodiment of the invention a biopolymer as described above, exhibiting at least one carboxylic group, selected from hyaluronic acid, alginic acid, and polymers of hydroxycarboxylic acid, polymaleic acid, polyfumaric acid or derivatives thereof in an amount of 0.1 up to 5 %, or in another embodiment of 0.1 up to less than 5 %, preferred up to 3 %, by weight, preferably 0.1 to 0.95 wt.%, being essentially (neutral, acidic or basic) water soluble at suitable pH- values, and having a pKa(=pks)-value of between 5-7; 0.01 to 12% by weight of an active (anti- infective, hormones or combinations) ingredient sparingly soluble in water; a solvent system comprising water or a mixture of water and an alcohol; and 0 to 40% by weight of additives selected from pH modifiers, buffering agents, perfumes, dyes, emulsifiers, penetration enhancers, body care agents, whereby such composition exhibits an phi-value of between 3 and 7 are used for preparing a me- dicament for treating an infective, especially mycotic disorder of skin or skin related tissue, and for treating nail/nail tissue disorders.

Such compositions can be used as cosmetic agents or in the treatment of infective, especially mycotic, skin or skin related tissue disorders, especially nail disor- ders such as psoriasis, nail psoriasis, onychomycosis and nail psoriasis, brittle nail syndrom or tinea capitis, tinea barbae, tinea faciei, tinea manum, onychomycosis, tinea pedis.

Another embodiment of the invention concerns a method for treating an infective, especially mycotic skin or skin related tissue disorder, the method comprising preparing and obtaining a composition according to the invention comprising a biopolymer as described, an active ingredient, solvent system and if desired additives as described, applying said composition to the skin or skin related tissue in need of an anti-infective / anti-mycotic treatment and leaving it there for a time sufficient for the desired action. In another embodiment such disorder is selected from mycotic nail disorder like onychomycosis, nail psoriasis, skin psoriasis.

Preparation of the compositions according to the invention

The compositions according to the invention can be prepared by admixing in a first vessel the desired amount of the biopolymer and if present one or more of the additive(s) such as emulsifier, penetration enhancer, body care agent, etc, in an appropriate part of the solvent system sufficient to achieve a clear to opaque fluid or gel. Normally about 30 to 70 % of the complete amount of the solvent system can be used. In case the biopolymer is poorly soluble in the solvent solution sys- tern actually present, then the pH value can appropriately be altered (within the desired range) by adding an acid and / or an alkaline compound, e. g. citric acid / lactic acid or / and Na/KOH.

This mixture can be stirred at ambient temperature (such as 20 - 30 ° C) or heated to enhance dissolution. In another vessel the (the at least one or more) active ingredient(s) is admixed in the remaining part of the solvent system. Thereafter, the active ingredient mixture is added to the biopolymer /additive(s) mixture and after stirring the desired composition is obtained. Alternatively, the compositions can also be prepared by adding components in the following order: the biopolymer is dissolved in water, than the solvent system, e.g. alcohol or water-alcohol mixture or ketone or water-ketone-alcohol mixture is added, and after stirring the active ingredient(s) (probably with additives) are added. The pH value can be adjusted directly after adding the polymer to water if necessary and / or suitable or even after the preparation of the admixture. Preferably the biopolymer is mixed with water as the solvent system and the ac- tive ingredient(s) is (are) mixed with a water- alcoholic, preferably water-ethanol and /or water-isopropanol, mixture, with an excess of alcohol, e.g. 1.5:1 to 5:1 alcohol:water.

The sum of the solvent system of the 2 mixtures referred above corresponds to the amount of the solvent system of the composition of the invention. The composition as prepared above results in a quite clear to opaque fluid having a sufficient viscosity for the desired application purpose. It can be packed into suitable vessels such as glass container or tubes.

In a specific embodiment according to the invention the following preparation method is used: In a separate vessel a cross-linked biopolymer, especially hyaluronic acid, having an average molecular mass of between 2.2-2.6 Mio. Dalton is added to water, containing an alkaline compound, such as KOH, NaOH, or the like to achieve a pH value of about 4.0. After stirring the pH value is decreased by adding an acid, preferably an organic acid such as citric acid. In another vessel the at least one active ingredient(s) is admixed with the solvent system consisting of a water / alcohol -, preferably water-ethanol and / or water- isopropanol, mixture (in a preferred ratio as indicated above). Stirring of the mixtures can be performed at ambient temperatures. Packaging is as described hereinbefore. The compositions are stable, in general preservatives are not necessary, especially as regards the present nail lacquers, but might be incorporated where desired. Use and application methods of the compositions of the invention The compositions according to the present invention are topically applicable fluids or gel- like agents, which can be applied to the skin and related areas, especially nails, nail beds such as foot and finger nails of human beings or animals. Such compositions as described hereinbefore might be pharmaceutical compositions or cosmetic compositions depending on the active ingredient(s). When applying such composition to the area in need thereof, it will after solvent evaporation remain on the area, parts of it will penetrate, remaining parts can be removed by action of water. This means e.g. with regard to the application to nails, the composition comprising as active ingredient at least one anti-mycotic (antifungal) agent can remain for a longer period of time at the area so that there is sufficient time for a sufficient mode of action of the active ingredient in areas sensitive to easy removal of the composition form which moreover is present in sufficiently / high amounts without a greater loss of activity of the active due to crystallization.

The present compositions might therefore be used for the preparation of or as agents for treating a condition or disorder of the skin or related tissue in need of such treatment, especially in the treatment of nails or nail related tissue like nail bed of human beings such as finger or foot nails / nail beds. The treatment espe- cially includes infective disorders of the skin or related tissue like psoriasis, nail psoriasis, furthermore infective, especially mycotic or inflammatory disorders of the nails especially like skin / nail psoriasis, onychomycosis. Such methods comprise the provision of compositions as described above and the administration / application to the skin as required. When applied to exposed tissue the composi- tion of the invention will remain thereon due to the film forming properties which applicants believe (without being bound to that theory) could be related to the small amounts of the acidic groups containing biopolymer. Furthermore in spite of the favourable, especially skin compatible pH value of the composition the active ingredient will not crystallize out. Consequently there is a double effect concerning the active ingredient balance since on the one hand a great amount thereof can be incorporated into the skin or through the nail and on the other hand it remains on the area to be treated more available for a longer time. This is a special advan- tage, e.g. as regards mycotic nail disorders (like onychomycosis) which normally require a long time of treatment since the active ingredient can crystallize out and / or the composition is easily removed. In the present case applicants' composition can remain at the area for a time sufficient to act and can be removed by wa- ter. That means solvents which are not skin compatible or at least poorly skin compatible like acetone are avoided.

This is also a special advantage in regard to active ingredients such as agents with an at least an anti- inflammatory and / or related / additional effect such as an anti- androgenetic effect e.g. of the aforementioned benzonitrile derivatives in the treatment of hair (conditions like alopecia, acne, hirsutism) exhibiting undesired side effects which might occur especially upon cystallisation out of the formulation onto the treated tissue.

The composition is applied one or more a day, as necessary and remains at the area treated for a sufficient time, e. g. one night. Thereafter it can be removed and another treatment circle is started. Thereby it can be applied to a nail in an amount of between 32 μl and 145 μl.

Applicants have found out that compositions as described are essentially biocompatible and / or pharmaceutically acceptable so that the risk of skin or related skin tissue irritation can be reduced. Also an improved active ingredient balance can be achieved. This means within the scope of invention an improved ratio between the amount of active substance used and the action thereof due to an essential avoidance of crystallisation thereof.

Examples The following examples describing some embodiments of the invention are merely illustrative without limiting. Herein, the water as used in the preparation of the composition was purified water, ethanol was 96% ethanol.

Example 1: (Rez.107) Composition comprising cross-linked hyaluronic acid (as described herein above), with pKa (=pKs)- value of 6.6 and Mw = 2,2-2,6 MDa. In a separate beaker 0.125 g (0.5%) of cross- linked hyaluronic acid having an average molecular mass of between 2.2 and 2.6 MDa was added to 8.68 g (34.74%) water, containing 0.04 g (0.18%) NaOH (10%ig) to achieve a pH value of about 11.8. After stirring the pH value of this hyaluronic acid solution (a) was decreased to 4.4 by adding 0.145 g (0.58%) 10% citric acid. In a second beaker 1.25 g (5%) naftifine was mixed with 3 g (12%) water / 11.75 g (47%) ethanol (mixture b).

Then, the hyaluronic acid solution (a) and the naftifine (mixture b) were combined and shortly stirred at ambient temperature. The resulting composition was a clear solution exhibiting a pH value of 4.5.

Example 2 (Rez. 105): Composition comprising hyaluronic acid 100 000 Da.

In a vessel / beaker 0.9 g (0.9%) of hyaluronic acid, having an average molecular mass of about 100 000 Da, having a pKa-(=pKs-)value of 6.0 was dissolved in 49.1 g (49.1%) water. Thereafter, 45.00 g (45%) ethanol (96 %) was added and the mixture stirred until it was clear homogeneous. Finally, 5.00 g (5%) naftifine was admixed and stirred resulting in a clear solution.

Example 3 (Rez. 136): Composition comprising hyaluronic acid 1 700 000 Da. In a vessel/beaker 0.9 g (0.9 %) of hyaluronic acid, having an average molecular mass of about 1 700 000 Da and having a pKa-(=pKs-)value of 6.9 was dissolved in 47 (47%) ethanol (96 %). After the addition of 47.1 (47.1%) water the resulting solution was stirred until it was clear and homogeneous. Then, 5.0 g (5%) naftifine were admixed until a clear solution had been formed.

Example 4 (Rez.117): Composition comprising hyaluronic acid, 1 700 000 Dalton In a vessel / beaker 0.1 g (0.4%) of hyaluronic acid, having an average molecular mass of about 1 700 000 Da_having a pKa-(=pKs-)value of 6.9 was dissolved together with 0.75 g (3%) Plantacare® 2000 UP in 8.15 g (32.6%) water. In another vessel 1.25 g (5%) naftifine was mixed with 3 g (12%) water / 11.75g (47%) ethanol (96%) until a solution was formed. Both solutions were combined and stirred shortly at ambient temperature. The resulting composition was a solution and showed a pH value of 5.3. Example 5 (Rez.141): Composition comprising poly(methyl vinyl ether-alt-maleic acid) Mw=216 000 (LS) Mn=80 000.

In a vessel 4.3 g water (43%) was added to 0.5 g (5%) of poly(methyl vinyl ether- alt-maleic acid) having a pka-(pks-)value of 5.6. After stirring until a clear solution is formed, amorolfine hydrochloride 0.5 g (5%) and 4.7 g (47%) ethanol 96% were added to the mixture and stirred further until an opaque solution was formed.

Example 6 (004): Composition comprising hyaluronic acid 1.7 MDa. In a vessel 12.68 g water (50.75%) was added to 0.05 g (0.2%) of hyaluronic acid having a pka-(pks-)value of 6.9. After stirring until a clear solution is formed, clobetasol propionate 0.0125 g (0.05%) and 11.00 g (44.00%) ethanol 96% with 1.25 g (5.00%) acetone were added to the mixture and stirred further until clearly dissolved.

Example 7: Determination of ratio of crystallisation of the active ingredient

The following figures 1-4 show the ratio of crystallisation of the composition of example 5 at different times measured by stop watch. As can clearly be seen the present composition benefits from a lack of crystallisation after solvent evaporation after application, especially in comparison (Fig. 5-7) with the known composi- tion "Loceryl", comprising also 5 % amorolfine hydrochloride, acrylatic film forming agents in contrast to the present biopolymers.

Example 8: Determination of film forming properties

The film forming properties are determined by means of viscosity measured with a Brookfield Viscosimeter, Model LVTDV-TI serial D0669I, arbor 61 and 62, respectively:

Examples 9 to 11

The following examples 9 to 11 have been prepared in accordance with the procedure as described in examples 2 and 5.The compositions thereof are summa- rized in the following table 1 :

Table 1 :

Example 12 Bioavailability studies

The formulations of examples 9 to 11 as indicated in table 1 and two products of the state of the art, namely the aforementioned product Loceryl, comprising poly- acrylate filmformers as indicated hereinbefore, water, ethanol, 5wt.% of amorolfine hydrochloride, exhibiting a pH value of 3.40, representing comparison A; and the product Batrafen, comprising water, ethanol, 8wt % of ciclopirox, exhibiting a pH value of 5.20, representing comparison compound B, have been used to determine the bioavailability of the active compounds by measuring the drug concentration (accumulation) and the drug penetration as well as the overall sum thereof using the human ex- vivo nail model at Cetera Research, Protocol No. R08-1311 , as follows: specially designed diffusion cells allowing the nails to be maintained at a temperature and humidity that match in vivo conditions test formulations were each evaluated on one fingernail from 5 different donors over a 28-day study period applied once daily for 21 days, + 7 days of collecting receptor solution samples. Samples were analysed by HPLC.

It should be noted that the procedure as explained above can serve as a general model regarding penetration, accumulation of active compounds in keratinous fibers both regarding skin and nails since nails are composed of about 100 to 150 layers of horny cells (=keratinocytic cells) which also represent the main cell type of the epidermis.

The results obtained are summarized in the following tables 2 to 4 wherein table 2 represents the drug concentration of the active compound within the nail; table 3 shows the cumulative penetration data and table 4 summarizes the overall activity regarding the mean content of the active compound in nail and to the nail bed matrix which represent the amount of active compound as available. Such bioavailability data are further documented in Fig. 8.

Table 2: Drug concentration in the nail (cumulative concentration, accumulation data at day 28)

Table 3. Cumulative penetration data at days 2 to 28

These data clearly show that the comparison B compound does not penetrate at all and is accumulated within the nail. However, in order to achieve best results in skin / nail treatment, not only the damaged area, but also the surrounding area (e. g. the nail bed) has to be treated which treatment may only be affected by penetration. Thus, the sum of accumulation and penetration ability, the bioavailability, at best proves the effectiveness of active compounds. Table 4 shows the results as an overall activity, namely the mean nail content of active compound in nail and to the nail bed matrix at study day 28 after 21 days of applications.

Table 4: Bioavailability (mean content of active compounds in nails /nail bed matrix)

Formulation /example Drug concentration

Comparison A (Loceryl) 163.7 ± 146.1

Comparison B (Batrafen) 120.9 ± 61.8

Example 9 (F2) 5021.3 ± 997.7

Example 10 (F3) 6054.1 ± 3660.1

Example 11 (F9) 491.2 ± 153.8

As can be seen the formulations of examples 9, 10 and 11 according to the present invention exhibit a much more higher bioavailability of the active compounds both in the nail and in the nail bed matrix than the products according to the state of the art (comparisons A and B). As can also be seen therefrom the content of the active ingredient in the area treated may be controlled in relation to the pH value of the composition: the more acidic the formulation the more of active ingredient may be found within the nail, and the less acidic the formulation the more of active ingredient may be found within the nail bed matrix. Thus, the mode of action and of the release of the active ingredient may be controlled by modulating the pH values.

Claims

Claims:

1) A composition for topical application comprising:

- a biopolymer selected from acid polysaccharides of the group of hyaluronic acid, alginic acid, polymaleic acid or polyfumaric acid, or an alkaline / earth alkaline metal salt or a cross-linked derivative thereof, having a pKa- value of 5.0 to 7.0 and being present in an amount of up to 5 % by weight of the composition;

- 0.01 to 12% by weight (of the composition) of (at least one) an active ingredi- ent sparingly (poorly) soluble in water, selected from anti-infective active ingredients, agents with an anti-inflammatory activity / or related activity, hormones or mixtures thereof;

- 70 and 95 % by weight of a solvent system comprising a mixture of water and ethanol; - 0 to 40 % by weight of additives; whereby such composition exhibits an pH- value of between 3 and 7 and a viscosity of from 0.01 Pas up to 10 Pas.

2) The composition of claim 1 characterized in that it further comprises 0.1 to 40% of additives, selected from pH-modifiers, buffering substances, emulsifi- ers, penetration enhancers, smell adjustments, pigments / colouring agents, preservatives, body care substances or mixtures thereof.

3) The composition according to any of claims 1 or 2 characterized in that it com- prises a mixture of water and ethanol in a ratio of between 2:1 and 1:1.5.

4) The composition of any of claims 1 to 3 characterized in that the biopolymers are essentially water soluble within the pH value range of the claimed compositions.

5).The composition according to any of claims 1 to 4 characterized in that it comprises 0.1 to 0.9 % by weight of hyaluronic acid or a salt thereof having a pKa- value of 6.0 and an average molecular weight of < 3 Mio.D; or 0.1 to 0.95 % by weight of cross linked hyaluronic acid having a pka- value of 6.6 having a molecular mass of 2.2-2.6 MioD.

6) The composition according to claims 1 to 4 characterized in that it comprises poly(methyl vinyl ether-alt-maleic acid) having a pka- value of 5.6 and a molecular mass Mw (Weight average) of ≤1 980 000 and an Mn (number average) of >80 000 in an amount of from 0.1 and 5.0 wt, %, preferably 0.1 to 0.95 wt.%.

7) The composition according to one of claims 1 to 4 characterized in that it comprises alginic acid a salt thereof consisting of (1→4) linked β-D-mannuronic acid (about 60%) residues and of α-L-guluronic acid (about 40 %) residues derived from stipes of Laminaria hyperborean having a pKa- value of 6.7 or alginic acid having a molecular mass of about > 200 kg / MoI being cross- linked by Bariumchlorid as the cross-linking agent, having a pKa- value of 6.9.

8) The composition according to any of claims 1 to 7 characterized in that the active ingredient is present in an amount of 0.05 to 8 wt.% and is selected from naftifine, amorolfine, terbinaflne, fluconazole, itraconazole, econazole nitrate, clotrimazole, bifonazole, griseofluvin, ketokenazole, nystatin, tolnaflate; clobe- tasone, clobetasol, cortisone, clobutinol, betamethasone acetate , - dipropion- ate; hydrocortisone and the esters thereof, triamcinolone acetonide, triamcinolone acetonide, fluprednilydene acetate, or dithranol, diflorasone, halobe- tasol, halcinonide, fluocinolone, desoximetasone, fluocinonide, 4-(3-(4-

Hydroxybutyl)-4,4-dimethyl-2,5-dioxo-1-imidazolyl-2(trifluoromethyl)benzonirile and combinations thereof.

9) The composition according to any of claims 1 to 8, characterized in that the active ingredient is selected from anti-infective ingredients, anti-mycotic ingredients, hormones or mixtures thereof. 10)The composition according to any of claims 1 to 9, characterized in that the active ingredient is selected from naftifine, terbinafine, clobetasol, betamethasone acetate.

11)The composition according to any of claims 1 to 10, characterized in that the pH value thereof is between 4.5 and 5.5.

12)The composition according to any of claims 1 to 11 characterized in that it is a film forming composition which is removable by water wherein the biopoly- mer(s) is (are) essentially water soluble film forming agents.

13)The composition according to any of claims 1 to 12 for topical (pharmaceutical or cosmetic) application to finger or foot nail, nail related tissue or hair of human beings.

14)The composition according to any of claims 1 to 13 characterized in that is a nail lacquer.

15) The composition of claim 13 for topical application to hair comprising a benzo- nitrile of the formula Ia

Ri- ( >— N Y

(Ia) wherein R¹ and / or R² are CN, CF₃, respectively; wherein X, R³ each are - C=O; Y is — N— R⁴ and Z is — C(CH₃)CH₃; with R₄ = hydrogen or Ci_-6- alkyl, in particular alkyl substituted by hydroxyl.

16)A method for preparing a composition according to any of claims 1 to 15 characterized in by admixing the desired amount of the biopolymer and suitable additives if present in an appropriate part of water or the solvent system, and admixing in separate step the (at least one or more) active ingredient(s) in the solvent system or a remaining part thereof and combining both mixtures while stirring at ambient temperature thus obtaining the desired composition.

17)Use of a composition according to any of claims 1 to 15 as a cosmetic skin or nail or hair treating agent.

18)Use of a composition according to any of claims 1 to 15 for manufacturing a medicament for treating an anti- inflammatory /related disorder, an infective, especially mycotic skin or skin tissue related disorder, nail disorders, hair disorders.

19) A pharmaceutical composition according to any of claim 1 to 15 for the treatment of an infective, especially mycotic skin or skin tissue related disorder, nail disorders, hair disorders.

20) Use according to claim 18 characterised in that the disorder is nail, skin and / or nail / skin related tissue disorder selected from nail psoriasis, onychomycosis, brittle nail syndrome, skin psoriasis, tinea capitis, tinea barbae, tinea faciei, tinea manum, tinea pedis or a hair disorder such as alopecia or hirsutism.