HU213865B - Cosmetical composition, for decreasing the greasiness of the skin, process for its preparation and its use - Google Patents

Abstract

 The composition of the present invention comprises, as an active ingredient, a total compound of from 0.05 to 1% by weight, or a metabolisable acid addition salt thereof, wherein R is methyl tube coat or coarse powder. ŕ

Description

The present invention relates to a cosmetic composition for controlling the sebum content of the skin, to the preparation thereof, and to the regulation of the fatness of the skin.

The appearance of the skin is of great importance for man. Oily skin, for example after a busy day or after physical exertion, often causes discomfort, even if it is temporary and not a health problem. FIELD OF THE INVENTION The present invention relates to an active ingredient which, in particular in a new physical form, is advantageously used to control the fatness of the skin. The present invention relates to cosmetic compositions containing such an active ingredient, to the manufacture of the compositions and to a method for controlling the sebum content of the skin.

Accordingly, the present invention relates to a lipid-lowering cosmetic composition comprising 0.05 to 1% by weight, based on the total weight of the composition, of a compound of formula (I) or a cosmetically acceptable acid addition salt thereof, wherein R is methyl or ethyl in a cosmetic carrier.

The present invention relates to the preparation of the above composition comprising 0.05 to 1% by weight, based on the total weight of the composition, of a compound of formula (I) or a cosmetically acceptable acid addition salt thereof, wherein

R is methyl or ethyl, mixed with a cosmetic carrier.

The invention further relates to a method for controlling the fatness of a human skin comprising applying to the skin a composition comprising a compound of formula (I) or a cosmetically acceptable acid addition salt thereof.

The compound of formula (I) may be applied to the skin whenever it appears necessary or desirable, for example, during or after each wash. Topical treatment may be repeated as desired until cosmetically satisfactory reduction of skin fat is achieved. There are no unusual restrictions on the normal use of cosmetic products.

The compounds of formula (I) used in the present invention have the chemical name (±) -methyl or -ethyl- [cis -4- [4 - [[2- (2,4-dichlorophenyl) -2- (1 imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] -methoxy] -phenyl-1-piperazinecarboxylate] and these compounds and their preparation are known from US 4,335,125.

However, these compounds are not known to regulate the sebum content of human skin.

The compounds of formula (I) may be used alone or in the form of an acid addition salt which may be cosmetically used. The salt may be prepared in a conventional manner by treating the base with an appropriate acid. Suitable acids include, for example, hydrogen halides such as hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and organic acids such as acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, diacid, propanedioic acid, butanedioic acid, (Z) -2-butenedioic acid, (E) -2-butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2- hydroxy-1,2,3-propane tricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid.

The term "acid addition salt" also encompasses solvates of the compounds of formula (I) and their acid addition salts. Examples of such solvates are hydrates and alcoholates.

The compounds of the formula I are keratinophilic substances and bind keratin in the upper layers of the epidermis. In cosmetic formulations, the sterol has an inhibitory effect on the skin of 0.05 to 1% by weight, preferably 0.1 to 0.5%, more preferably 0.1 to 0.2% by weight, based on the total weight of the composition. derivatives such as cholesterol. Since this affects the lipid content of the epidermis, the application of a compound of formula (I) to the skin has a favorable effect on the fatiness of the skin. More specifically, it appears to reduce the biosynthesis of some free fatty acids and alter the composition of free fatty acids. The compound of formula (I) also influences the concentration of phospholipids in the skin. In addition to their effect on lipid content, the compounds of formula I inhibit the growth of microorganisms such as bacteria and fungi at the concentrations used.

Because these microorganisms are dependent on the lipids present in the skin, the dual effect of the compounds of formula I on the lipid content of the skin and the growth of the microorganisms ensures control of the skin flora and avoid the formation of unpleasant odors.

The compounds of formula (I) may be prepared as described in US 4,335,125. Preferably, the starting material is commercially available cis-1-acetyl-4- [4 - [[2- (2,4-dichlorophenyl) -2- (1H-imidazole)] -1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] piperazine was used. In this process, the compound of formula (II) is hydrolyzed and the resulting product is reacted with a compound of formula (III):

R is methyl or ethyl and W is a leaving group such as halogen, preferably chlorine, methoxy or ethoxy.

The hydrolysis is preferably carried out when the cis-1-acetyl-4- [4 - [[2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) methyl] is represented by the formula (II) ) -1,3-dioxolan-4-yl] -methoxy] -phenyl] -piperazine is stirred and heated in water in the presence of a base or an acid, preferably concentrated hydrochloric acid. The product of hydrolysis is isolated by extracting the reaction mixture (neutralized with a base such as sodium or potassium hydroxide) in an organic solvent. Suitable solvents are, for example, a halogenated hydrocarbon such as dichloromethane or an alcohol such as methanol or ethanol and mixtures thereof. The organic phase is then evaporated and the crude hydrolyzed product is converted into the compound of formula I without further purification. This is solved in halogenated hydrocarbons such as dichloromethane2

It is treated with methyl or ethyl chloroformate in the presence of a base such as sodium or potassium carbonate. The degree of conversion of the reaction can be improved by stirring the mixture, and the process is preferably carried out at room temperature.

According to the invention, the compound of formula I can be used in any physical form, such as crystalline, microcrystalline, micronized or dissolved.

The compound of formula (I) is preferably used in micronized form with an average particle size of up to 100 µm, preferably up to 75 µm, in particular up to 15 µm.

The micronized form of the compound of formula (I) has the advantage that it has a high specific surface area which dissolves better and faster and penetrates the upper layers of the epidermis more easily. The micronized form of the compounds of formula (I) is novel and can be prepared by conventional micronization techniques, such as milling in a suitable mill and sieving in a suitable screen.

The free base form of the compound of formula (I) wherein R is ethyl may exist in two polymorphic forms. Polymorph Form I (Polymorph I), which has a higher melting point than crystallographically pure material, is characterized by a maximum at 127.6 ° C in differential scanning calorimetry (DSC) and a maximum at 110.9 ° C at lower melting point (Polymorph II). Polymorph I is more stable and slightly less soluble than polymorph II, so polymorph I is preferably used in the present invention.

Polymorph I is readily prepared by recrystallization of the free base form of a compound of formula I from a suitable solvent. Suitable solvents are a ketone or an ester such as acetone or ethyl acetate. For recrystallization, the free base form of the compound of formula (I) is preferably dissolved in a hot solvent, the resulting solution is concentrated and the concentrate is allowed to cool and the precipitated crystals are separated. Preferably, the solution is treated with activated carbon prior to concentration. It may also be advantageous to inoculate the supersaturated solution for crystallization of polymorph I with previously prepared corresponding polymorph I crystals. Polymorph I can be micronized as described above, for example by milling in a suitable mill and sieving the resulting product. The screening can advantageously be carried out, for example, with an air flow screening screen of suitable size, such as 100 and 74 µm screens. The AII polymorph can be prepared by recrystallization of the free base form of a compound of formula I from a solvent such as 2-propanol, hexane or methylbenzene. Selective crystallization of polymorph II is induced by inoculating the supersaturated solution used for crystallization. The AII polymorph can also be micronized, but this must be done carefully to avoid the conversion of polymorph II to polymorph I.

Preferably, the compound of formula (I) is applied in the form of a suitable composition, such as a cosmetic composition, to the affected body. Such a composition will generally contain from 0.05 to 1% by weight, preferably from 0.1 to 0.5% by weight, particularly preferably from 0.1 to 0.2% by weight, of the compound of the formula I in addition to the usual dermatologically acceptable carriers. The preparation is prepared in the usual form. Examples include liquid formulations such as solutions, emulsions, gels or suspensions in aqueous, alcoholic or oily media, lotions, lotions or milk lotions, and shampoos. It may also be a semi-liquid preparation such as a cream, hydrogel, gel, paste, ointment or tincture, as well as a solid preparation such as a powder.

Such compositions contain, in addition to the compounds of formula (I), the customary components. Examples include oils, fats, waxes, surfactants, wetting agents, penetration enhancers, thickeners, lipid absorbents, antioxidants, viscosity stabilizers, chelating agents, buffering agents, preservatives, fragrances, alcohols, alcohols, and low carbon chains. If desired, other active ingredients may be included in the composition, such as an anti-inflammatory agent, bactericide, fungicide, wound healing agent, disinfectant, vitamin, sunscreen, antibiotic and anti-dandruff.

The compounds of formula (I) are preferably used in the form of a skin care cosmetic composition. Examples include anti-blemishes, anti-blackheads and acne preparations. The cosmetic composition may be of any form, for example, sun-tanning preparations applied before, during or after sun-tanning, sun-tanning preparations, skin-whitening preparations, anti-wrinkle preparations, daytime sanitary preparations such as soaps, shampoos, baths. - and shower preparations, shaving creams, foams and lotions, baby care preparations, sanitary towels, intimate hygiene preparations such as lotions and daytime cosmetics such as creams, emulsions, gels, oils, lotions, skin lotions, skin lotions, deodorants, antiperspirant preparations, perfumes, colognes, depilatory preparations, after shave preparations, and face lotions such as creams, tinted bases, powders, mouth lotions lipsticks, top creams, eye exfoliating preparations, make-up removing preparations, hair care preparations such as hair dyes and bleaches, hair waving, straighteners and hair straighteners, hair fasteners, hair rinses, conditioners and hairdressing preparations.

Liquid form preparations may be packaged with any topical application device, such as a bottle, bottle or spray, which may contain an inert propellant such as nitrogen or carbon dioxide or an aerosol dispensing pump. The solid compositions may be in powder or cream form, alternatively in the form of granules, tablets or bath salts. Semi-solid formulations may be packaged in a suitable container, such as a plastic, glass or ceramic crucible or tube, such as a PVC-coated aluminum tube.

HU 213 865 Β

The compounds of formula (I) may also be formulated as a liposome-containing composition. Various types of liposomes can be used, such as coarse (multilayer) liposomes or monolayer liposomes, which may be formed, for example, with phosphatidylcholine, ethanolamine, various serines, swingomyelins, cardiolipins, plasmacogens, phosphatidic acid and the like. The viscosity of the liposome may be increased by the addition of one or more thickening agents, such as xanthan gum, hydroxypropylcellulose, hydroxypropylmethylcellulose or mixtures thereof. The aqueous composition may contain water, optionally electrolytes, buffers and other components such as preservatives. Preferred electrolytes are calcium, sodium and potassium chloride. The organic component may be a solvent such as ethanol, glycerol, propylene glycol, polyethylene glycol, or a suitable phospholipid such as lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, lysophosphatidyl. The selective properties of liposomes can be modified by lipophilic additives such as stearylamine, phosphatidic acid, tocopherol, cholesterol and lanolin.

For the preparation of ointments, creams, aqueous compositions and lotions, the compound of formula I is thoroughly mixed with the cosmetic carrier. For ointments and creams, the carrier composition is, for example, 1-20% by weight, preferably 5-15% by weight of a wetting agent, 0.1-10% by weight, preferably 0.5-5% by weight of a thickener and water; 70-9% by weight, preferably 80-95% by weight of surfactant and 0-20%, preferably 2.5-15% by weight of fat; and 80-99.9% by weight, preferably 90-99% by weight thickening agent, or 5-15% by weight surfactant, 2-15% by weight wetting agent, 0-80% by weight oil, and a small amount up to 2% by weight preservative, coloring agent, and / or perfume and water. For aqueous compositions, the carrier may comprise, for example, 2-10% by weight of a lower alcohol, 0.1-10% by weight, preferably 0.5-1% by weight of a surfactant, 1-20% by weight, preferably 3-7% by weight of a wetting agent, 5% by weight of buffer, water and a small amount of preservatives, dyes and / or fragrances, up to 2% by weight. The gelled composition, the carrier composition is preferably 50-80 wt%, especially 70-80 wt% water, 8-20 weight ⁰ / », especially 10-15% by weight of alcohol, 1-10%, particularly 2-5% by weight of surfactant 0.5-2% by weight of one or more thickening agents and 0-3% by weight of preservatives, moisturizers, skin nourishing factors, vitamins, astringens and / or fragrances. The amount of further active compounds is generally 0.005-0.5% by weight, preferably 0.01-0.1% by weight.

A typical gel composition will contain 0.02% of the active ingredient as defined above and water, one or more gelling agents or thickeners, such as cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, or carboxyvinyl polymer 0.02. -4% by weight, preferably 0.2-2% by weight, particularly preferably 0.2-1.5% by weight, 0.02-50% by weight, preferably 0.5-30% by weight, particularly preferably 0.5- 20% by weight with one or more alcohols such as ethanol, propanol, butanol, pentanol, glycerol, propylene glycol or dodecatrienol. Such a gel composition may further comprise, for example, from 0.1 to 35% by weight, preferably 0.5 to 12% by weight, of plant extracts such as agave, amica, birch, carnation, cyan, ginseng, hazelnut, hawthorn, quinine, lemon, fasting or rosemary extract. %, particularly preferably 1-3% by weight; fats such as paraffin in an amount of 0.1 to 30% by weight, preferably 0.2 to 10% by weight, particularly preferably 1 to 5% by weight; vitamins such as vitamin E and its derivatives such as tocopherol acetate, panthenol and the like in amounts of 0.01 to 10% by weight, preferably 0.1 to 8% by weight, especially 0.5 to 2% by weight; synthetic or natural anti-inflammatory agents, such as bisabolol 0-5% by weight, preferably 0.1-3 parts by weight ⁰ / ", in particular in an amount preferably from 0.2 to 0.5% by weight; preservatives in an amount of 0 to 2% by weight, preferably 0.1 to 1% by weight, particularly preferably 0.3 to 0.5% by weight, and optionally the amount of preservative and / or antioxidant needed to preserve the composition.

The colored preparations are generally emulsion formulations containing water, one or more emulsifiers, such as ethoxylated fatty alcohol in an amount of 0.1 to 10% by weight, preferably 0.5 to 5% by weight, with one or more fats such as 8- C22 fatty alcohol, preferably C12-18 fatty alcohol in an amount of 0.1-10% by weight, preferably 0.5-5% by weight, mineral oil in an amount of 0.1-80% by weight, preferably 1-30% by weight, or polyoxyethylated or propylated fatty alcohol ethers such as polyoxypropylated stearyl ether in an amount of from 1 to 40% by weight, preferably from 5 to 30% by weight, particularly preferably from 10 to 20% by weight, and one or more alcohols such as ethanol, propanol, butanol, pentanes, glycerol, propylene glycol, butylene glycol or dodecatrienol in an amount of 0.1 to 25% by weight, preferably 0.5 to 20% by weight. Of course, such colored compositions contain one or more pigments, for example, zinc oxide, kaolin, mica, iron oxide and titanium dioxide. The colored preparations may further comprise from 0.1 to 35% by weight, preferably from 0.5 to 12% by weight, of plant extracts such as agave, amica, birch, carnation, cyan, ginseng, hazelnut, hawthorn, quinine, lemon, locust or rosemary extract. particularly preferably in amounts of 1-3% by weight, and gelling agents such as cellulose derivatives or carboxyvinyl polymers in amounts of 0.1-1% by weight, vitamins such as vitamin E or derivatives thereof such as tocopheryl acetate or panthenol 0.01% by weight. -10% by weight, preferably 0.1-8% by weight, particularly preferably 0.5-2% by weight, in an amount of ⁰ to ⁴ % by weight of synthetic or natural anti-inflammatory agents, for example bisolol 0-5% by weight, preferably 0.1-3% by weight, % of a particular, thickeners, such as xanthan gum 0.1-1% by weight, preferably 0.2 to 0.5 parts by weight ⁰ / "amount of perfume 0-2% by weight, preferably 0.1- preferably 0.2 to 0.5 parts by weight 1% by weight, particularly preferred n in an amount of 0.3 to 0.5% by weight, and a preservative and / or antioxidant in an amount necessary to preserve the composition. The pH of the composition is a base such as sodium hydroxide or an acid such as milk

It can be adjusted by adding acid, citric acid or phosphoric acid or a buffer such as citrate buffer, phosphate buffer, lactate buffer or acetate buffer.

The cream-based formulations contain the active ingredient in the above amounts, the further component being one or more fats or mineral oils in an amount of 1-70% by weight, preferably 30-60% by weight, or paraffin 0.1-30% by weight, preferably 5-20% by weight. in an amount of from 0.1% to 30% by weight of triglyceride, preferably from 1 to 10% by weight, from 0.1 to 40% by weight of fatty alcohol having from 8 to 22 carbon atoms, preferably from 12 to 18 carbon atoms, preferably from 1 to 10% by weight, In an amount of 1 to 10% by weight, and optionally in the amount necessary to preserve the consistency of the composition and / or antioxidant. Such compositions may further contain a perfume, a wound healing agent and a pigment.

Suitable moisturizing agents, surfactants, oily components and further active ingredients in the composition of the present invention are those commonly known in the cosmetics industry. If one or more components are the major component of the formulation, the other components are used in amounts less than the maximum.

Example 1 Preparation of compounds of formula (I)

a) 50 g of cis-1-acetyl-4- [4 - [[2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) methyl] -1,3-dioxolane A mixture of -4-yl] -methoxy-phenyl] -piperazine, 105 g of water and 35 g of concentrated hydrochloric acid was stirred at 80-90 ° C for 16 hours, then diluted with 112 g of water and stirred for 4 hours. The reaction mixture was then cooled to room temperature (about 20-25 ° C) and diluted with dichloromethane (70 mL) and methanol (30 mL). Subsequently, 25 ml of a 50% w / w aqueous solution of sodium hydroxide are added dropwise with stirring, while cooling with ice-water the temperature of the reaction mixture is kept below 30 ° C. After stirring for half an hour, the reaction mixture was diluted with additional 130 ml of dichloromethane and 170 ml of methanol. After stirring for a further half an hour, the organic phase was separated, the solvent was distilled off under reduced pressure and the residue was taken up in 200 ml of dichloromethane.

b) To the residue was added 52 g of potassium carbonate and 12.25 g of ethyl chloroformate was added dropwise, keeping the reaction temperature below 25 ° C. It is then stirred for 2 hours at room temperature. The organic layer was separated, dried, filtered and concentrated under reduced pressure. The residue was dissolved in 4 mL of 4-methyl-2-pentanone with heating and allowed to cool to room temperature. After cooling in ice-water for 4 hours, the precipitate was filtered off and dried at 40 ° C under vacuum. 44.84 g (84.9%) of (±) -ethyl- [cis -4- [4 - [[2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) methyl) -l, 3-dioxolan-4-yl] methoxy] phenyl]

-1-piperazinecarboxylate] is obtained.

c) 6.5 g of (±) -ethyl- [cis -4- [4 - [[2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) methyl] -1 A mixture of 3-dioxolan-4-yl] -methoxy] -phenyl] -1-piperazinecarboxylate] in 51.5 ml of acetone was heated to boiling and 3.23 g of activated carbon (Norit A supra) was added. It is boiled under reflux for half an hour and then heated on diatomaceous earth. The filter was washed with hot acetone and the combined filtrate was concentrated to about 25 mL. This was allowed to cool to 40 ° C and inoculated with polymorph I. Allow to cool to room temperature and stir over ice water for one hour. The precipitate was collected and dried under vacuum at 40 ° C. Thus, 5.35 parts (82.1%) of (±) -ethyl- [cis -4- [4 - [[2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) methyl] is obtained. -1,3-Dioxolan-4-yl] -methoxy] -phenyl] -1-piperazinecarboxylate] is obtained (polymorph I).

127.6 ° C.

The composition of the cosmetic compositions of the present invention is illustrated in the following examples, wherein the active ingredient is a compound of formula (I) or a cosmetically acceptable acid addition salt thereof.

Example 2

0.1% by weight cream

In a double-walled vessel, 75 ml of stearyl alcohol, 2 mg of cetyl alcohol, 20 mg of sorbitan monostearate and 10 mg of isopropyl myristate are weighed and melted. The mixture was added to a mixture of distilled water, 200 mg of propylene glycol and 15 mg of polysorbate 60 at 70-75 ° C and homogenized. The resulting emulsion was allowed to cool to 25 ° C while stirring continuously. The emulsion is further mixed with 1 mg of the active ingredient, 1 mg of polysorbate 80 and distilled water, and a solution of 2 mg of sodium sulfite in distilled water. The resulting cream composition is homogenized and filled into suitable containers.

Example 3

0.2% liposome preparation

0.2 g of microparticulate active ingredient, 20 g of phosphatidylcholine, 5 g of cholesterol and 10 g of ethyl alcohol are stirred at 55-60 ° C until complete dissolution, followed by 0.2 g of methyl paraben, 0.02 g of propyl paraben, , Add 15 g of disodium edetate and 0.3 g of sodium chloride in a solution of distilled water and homogenize. 0.15 g of hydroxypropylmethyl cellulose in distilled water are added per 100 g and the swelling is stirred until completion.

Example 4

0.1% liposome composition g phosphatidyl chlorine, 1 g cholesterol and 7.5 g ethyl alcohol were stirred at 40 ° C until complete dissolution. 0.2 g of the microparticulate active compound are dissolved in distilled water at 40 ° C. The alcoholic solution was slowly added to the aqueous solution and homogenized for 10 minutes. 1.5 g of a mixture of hydroxypropylmethyl cellulose in distilled water are added and the swelling is stirred until the process is complete. The solution was adjusted to pH 5.0 with 1N sodium hydroxide and made up to 100 g with distilled water.

Claims (4)

PATENT CLAIMS CLAIMS 1. A cosmetic composition for reducing skin fat, comprising as an active ingredient 0.05 to 1% by weight, based on the total weight of the composition, of a compound of formula (I) or a cosmetically acceptable acid addition salt thereof. R is methyl or ethyl in addition to a cosmetic carrier. Cosmetic composition according to claim 1, characterized in that it contains from 0.1 to 0.2% by weight, based on the total weight of the composition. 3. A process for the preparation of a cosmetic composition according to claim 1 or 2, characterized in that 0.05 to 1% by weight, based on the total weight of the composition, of a compound of formula I or a cosmetically acceptable acid addition salt thereof, wherein R is methyl or ethyl. Mix with 10 cosmetic carriers. A method for controlling the sebum content of the skin, comprising applying to the skin a cosmetic composition according to claim 1 or 2.