WO2010069519A1 - Compositions topiques comprenant au moins un ingrédient actif difficilement soluble dans l'eau et des biopolymères, tels que l'acide hyaluronique, présentant une valeur pka située entre 5 et 7 - Google Patents

Compositions topiques comprenant au moins un ingrédient actif difficilement soluble dans l'eau et des biopolymères, tels que l'acide hyaluronique, présentant une valeur pka située entre 5 et 7 Download PDF

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Publication number
WO2010069519A1
WO2010069519A1 PCT/EP2009/008872 EP2009008872W WO2010069519A1 WO 2010069519 A1 WO2010069519 A1 WO 2010069519A1 EP 2009008872 W EP2009008872 W EP 2009008872W WO 2010069519 A1 WO2010069519 A1 WO 2010069519A1
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WIPO (PCT)
Prior art keywords
composition
acid
water
nail
skin
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PCT/EP2009/008872
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English (en)
Inventor
Sigrid Drewes
Alexander Linko
Martina Heberer
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Merz Pharma Gmbh & Co. Kgaa
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Application filed by Merz Pharma Gmbh & Co. Kgaa filed Critical Merz Pharma Gmbh & Co. Kgaa
Publication of WO2010069519A1 publication Critical patent/WO2010069519A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on

Definitions

  • 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.
  • the compositions as described form an essentially anti-abrasive film which can be removed by action of water.
  • 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.
  • 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.
  • 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.
  • auxiliary substances may also be necessary.
  • Such auxiliary substances may often entail an unwanted skin feel and / or sensitisation / allergic reactions.
  • an - often unwanted - absorptive effect can occur with a possible sys- temic action.
  • 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.
  • an external active ingredient depot containing sparingly soluble active ingredients, and poly-oxy-ethylene copolymer surfactants.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 / cm 2 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • tinea capitis, tinea barbae, tinea faciei, tinea manum, onychomycosis, tinea pedis may be treated with the compositions according to the invention.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • FIG. 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.
  • 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”).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • biopolymers of the composition according to the invention are selected from biopolymers with one or more carboxylic acid groups.
  • 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.
  • 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.
  • the final viscosity of a composition to be applied to nail is low to provide good application properties for the damaged nail.
  • 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).
  • 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.%.
  • the hyaluronic acid or salt e. g.
  • alginic acid is used or a salt thereof as mentioned above.
  • This biopolymer consists of (1 ⁇ 4) linked ⁇ -D-mannuronic acid (M) and ⁇ -L- guluronic acid (G) residues of widely varying composition and sequence. It derives from stipes of Laminaria hyperborean.
  • 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%.
  • Mw Weight average
  • Mn number average
  • 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.
  • 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 C 2 - 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.
  • the solvent system is selected from water or a mixture of water and a C 2 - C 3 aliphatic monovalent alcohol, selected from ethanol, isopropanol or mixtures thereof.
  • 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.
  • such solvent or solvent mixture can comprise small amount of a ketone, e.g. up to 5 % by wt., such as acetone.
  • the amount of the solvent system could be up to 99.8%.
  • 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.
  • 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.
  • 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, bifonazo
  • 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).
  • the active ingredient is preferably chosen amongst agents with in the broadest sense at least anti- inflammatory properties.
  • agents may be selected from the group comprising benzonitrile derivatives, sparingly soluble in water, of the general formula I
  • 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.
  • the active ingredient is selected from naftifine, terbinafine, amorolfine, and clobetasol.
  • 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.
  • 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.
  • 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.
  • the pH value of the claimed composition is between 3 and 7, and in a preferred embodiment between 4.5 and 5.5.
  • 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 C 8 -C 2 o-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 C ⁇ -C 2 o-fatty acids and sugars like glucose, saccharose, alkyl glucose such as methylglucose.
  • alkylglycosides alkylglycosides (glucose- or alkyl-glucose-) ethers of saturated, partially unsaturated or unsaturated alcohols of C 8
  • 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.
  • alkylglucosides are selected from sugar (glucose- or alkyl-glucose-) ethers of saturated, partially unsaturated or unsaturated, C ⁇ -C2o-fatty alcohols (such as decyl-, stearyl-, palmityl-, lauryl-, oleyl alcohol and the like).
  • 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).
  • 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).
  • 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 ® .
  • 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, ⁇ -bisabolene, ⁇ - panasinsen, octahydro-1 ,8-dimethyl-7-(1-methylethenyl)-naphthalene and cis- ⁇ - copaene-8-ol or suited combinations thereof.
  • terpenes e.g. d-limonene, terpineol, acyl terpineol, 1,
  • 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-napht
  • 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.
  • 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,
  • 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.
  • 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.
  • 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 C 2 - C ⁇ aliphatic mono,- di- or trivalent alcohol; especially comprising a mixture of water and
  • 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.
  • additives selected from pH modifiers, body care agents and emulsifiers or mixtures thereof.
  • such composition comprises one or more active ingredients selected from anti-fungal agents or hormones or mixtures thereof.
  • active 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.
  • 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.
  • 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.
  • 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.
  • a composition according to the invention 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.
  • such disorder is selected from mycotic nail disorder like onychomycosis, nail psoriasis, skin psoriasis.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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).
  • 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.
  • 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.
  • 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.
  • 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 ⁇ l and 145 ⁇ l.
  • 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.
  • the water as used in the preparation of the composition was purified water, ethanol was 96% ethanol.
  • pKa pKs
  • Mw 2,2-2,6 MDa.
  • 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.
  • pH value of this hyaluronic acid solution (a) was decreased to 4.4 by adding 0.145 g (0.58%) 10% citric acid.
  • naftifine was mixed with 3 g (12%) water / 11.75 g (47%) ethanol (mixture b).
  • Example 2 Composition comprising hyaluronic acid 100 000 Da.
  • Example 3 Composition comprising hyaluronic acid 1 700 000 Da.
  • Example 6 Composition comprising hyaluronic acid 1.7 MDa.
  • 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.
  • 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.
  • the following figures 1-4 show the ratio of crystallisation of the composition of example 5 at different times measured by stop watch.
  • 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:
  • 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.
  • table 2 represents the drug concentration of the active compound within the nail
  • table 3 shows the cumulative penetration data
  • 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.
  • bioavailability data are further documented in Fig. 8.
  • 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).
  • 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.
  • the mode of action and of the release of the active ingredient may be controlled by modulating the pH values.

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Abstract

La présente invention concerne des compositions comprenant les éléments suivants : un ou plusieurs ingrédients actifs difficilement solubles dans l'eau ; et un biopolymère possédant au moins un groupe carboxylique, sélectionné parmi les polysaccharides acides tels que l'acide hyaluronique, l'acide alginique, l'acide polymaléique ou un dérivé de ceux-ci, présentant une valeur pKa située entre 5 et 7 dans un mélange d'eau ou d'eau et d'alcool. De manière surprenante, de tels ingrédients actifs restent sous une forme adaptée (solvée) dans la composition sans cristallisation rapide du ou des ingrédients actifs. En outre, lorsqu'elles sont appliquées de manière topique sur la peau ou des parties de la peau - par exemple ongles, cheveux et cuir chevelu - ayant besoin de ce traitement, lesdites compositions telles que décrites forment, de manière surprenante, une pellicule sensiblement anti-abrasive qui peut être retirée sous l'action de l'eau. Ces compositions présentent une bonne compatibilité cutanée et d'excellentes propriétés adhésives, et elles sont particulièrement adaptées au traitement d'une peau, de cheveux ou d'ongles ayant besoin d'un traitement anti-infectieux, antifongique, anti-inflammatoire et/ou d'un traitement afférent.
PCT/EP2009/008872 2008-12-18 2009-12-11 Compositions topiques comprenant au moins un ingrédient actif difficilement soluble dans l'eau et des biopolymères, tels que l'acide hyaluronique, présentant une valeur pka située entre 5 et 7 WO2010069519A1 (fr)

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Cited By (7)

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WO2015179729A1 (fr) * 2014-05-23 2015-11-26 Paz Garcia Juan Préparation utilisée pour régénérer l'os, le cartilage, les dents et le parodonte, et traitement des tumeurs et des kystes
US9433629B2 (en) 2014-05-23 2016-09-06 Juan Paz Garcia Formulation for regeneration of bone, cartilage, teeth, and periodontium and treatment of tumors and cysts
US9669074B2 (en) 2014-05-23 2017-06-06 Juan Paz Garcia Formulation for regeneration of bone, cartilage, teeth, and periodontium and treatment of tumors and cysts
US9877983B2 (en) 2007-11-27 2018-01-30 Algipharma As Use of alginate oligomers in combating biofilms
CN108997987A (zh) * 2018-07-16 2018-12-14 唐山市金沙工贸有限公司 一种油气田开发带压作业管柱封堵剂及其制备方法
US20220110859A1 (en) * 2016-09-22 2022-04-14 Cmpd Licensing Llc Composition and method for treating fungal skin conditions and inflammation
US12102712B2 (en) * 2021-05-03 2024-10-01 Cmpd Licensing Llc Composition and method for treating fungal skin conditions and inflammation

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9877983B2 (en) 2007-11-27 2018-01-30 Algipharma As Use of alginate oligomers in combating biofilms
US10624920B2 (en) 2007-11-27 2020-04-21 Algipharma As Use of alginate oligomers in combating biofilms
WO2015179729A1 (fr) * 2014-05-23 2015-11-26 Paz Garcia Juan Préparation utilisée pour régénérer l'os, le cartilage, les dents et le parodonte, et traitement des tumeurs et des kystes
US9433629B2 (en) 2014-05-23 2016-09-06 Juan Paz Garcia Formulation for regeneration of bone, cartilage, teeth, and periodontium and treatment of tumors and cysts
US9669074B2 (en) 2014-05-23 2017-06-06 Juan Paz Garcia Formulation for regeneration of bone, cartilage, teeth, and periodontium and treatment of tumors and cysts
JP2017516852A (ja) * 2014-05-23 2017-06-22 ガルシア，ホアン パズ 骨、軟骨、歯、および歯周組織の再生と、腫瘍および嚢胞の処置のための製剤
US20220110859A1 (en) * 2016-09-22 2022-04-14 Cmpd Licensing Llc Composition and method for treating fungal skin conditions and inflammation
CN108997987A (zh) * 2018-07-16 2018-12-14 唐山市金沙工贸有限公司 一种油气田开发带压作业管柱封堵剂及其制备方法
US12102712B2 (en) * 2021-05-03 2024-10-01 Cmpd Licensing Llc Composition and method for treating fungal skin conditions and inflammation

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