WO2008040458A1

WO2008040458A1 - Cosmetic or dermatological preparations with a content of 2-isopropyl-5- methyl-cyclohexanecarbonyl-d-alanine methyl ester and one or more skin bleaching agents for treating unwanted pigmentation of the skin in particular postinflammatory hyperpigmentation

Info

Publication number: WO2008040458A1
Application number: PCT/EP2007/008231
Authority: WO
Inventors: Julia Eckert; Ludger Kolbe; Gitta Neufang
Original assignee: Beiersdorf Ag
Priority date: 2006-09-29
Filing date: 2007-09-21
Publication date: 2008-04-10
Also published as: DE102006047157A1

Abstract

The invention relates to cosmetic or dermatological preparations with a content of 2-isopropyl-5- methyl-cyclohexanecarbonyl-D-alanine methyl ester and one or more skin bleaching agents.

Description

description

Cosmetic or dermatological preparations containing 2-1 percent Py1-5 methyl cyclohexanecarbonyl-D-alanine methyl ester and one or more skin lightening agents against unwanted skin pigmentation, in particular postinflammatory hyperpigmentation

The present invention relates to cosmetic cosmetic or dermatological preparations containing 2-isopropyl-5-methyl-cyclohexanecarbonyl-D-alanine methyl ester and one or more skin lightening agents against unwanted pigmentation of the skin, in particular postinflammatory hyperpigmentation.

Responsible for the pigmentation of the skin are the melanocytes, which are found in the lowest layer of the epidermis, the stratum basale, in addition to the basal cells - depending on the skin type either isolated or more or less frequently occurring - pigment-forming cells.

Melanocytes contain as characteristic cell organelles melanosomes, in which the melanin is formed. Among other things, upon excitation by UV radiation melanin is increasingly formed. This is transported via the living layers of the epidermis (keratinocytes) ultimately in the horny layer (corneocytes) and causes a more or less pronounced brownish to brown-black skin color.

Melanin is formed as the final stage of an oxidative process in which tyrosine is converted by means of the enzyme tyrosinase via several intermediates to the brown to brown-black eumelanins (DHICA and DHI melanin) or with the involvement of sulfur-containing compounds to the reddish phaeomelanin. DHICA and DHI melanin are produced via the common intermediates dopaquinone and dopachrome. The latter is reacted, sometimes with the participation of other enzymes, either in indole-5,6-quinone carboxylic acid or in indole-5,6-quinone, resulting in the two mentioned Eumelanine arise.

Phaeomelanin is produced, inter alia, by the intermediates dopaquinone and cysteinyldopa. The expression of the melanin-synthesizing enzymes is controlled by a specific transcription factor (microphthalmia-associated transcription factor, MITF). In addition to the described enzymatic processes of melanin synthesis, further proteins are important for melanogenesis in the melanosomes. An important role here seems to be the so-called p-protein, the exact function is still unclear.

In addition to the process of melanin synthesis in the melanocytes described above, in the pigmentation of the skin and the transfer of melanosomes, their retention in the epidermis and their degradation and degradation of melanin is of crucial importance. It has been shown that the transport of melanosomes from the melanocytes into the keratinocytes, the PAR-2 receptor is significant (Seiberg M. et al., 2000, J. Cell, Sci., 113: 3093-101).

Furthermore, the size and shape of the melanosomes influence their light-scattering properties and thus the color appearance of the skin. In black Africans, for example, large spheroidal, isolated melanosomes are increasingly found, whereas in Caucasus, smaller, grouped melanosomes are found.

Problems with hyperpigmentation of the skin have many causes or are accompanying effects of many biological processes, e.g. UV radiation (e.g., freckles, ephelides), genetic predisposition, skin malignancy in wound healing (postinflammatory hyperpigmentation), or skin aging (e.g., lentigines seniles).

After inflammatory reactions, the pigmentation system of the skin reacts with partially opposite reactions. Both postinflammatory hyper- and hypopigmentation can occur. Postinflammatory hypomelanoses are often associated with atopy, lupus erythematosus and psoriasis. The different reactions tion forms of the pigmentation system of the human skin as a result of inflammatory phenomena are understood only very incompletely.

Problems with postinflammatory hyperpigmentation often occur in darker skin types. The problem of pseudofolliculitis barbae, which is associated with cosmetically undesired pigmentation of the pigmentation or leads to it, is known in particular in male colored individuals. Also forms of melasma, which occur especially in women of Asian affiliation in the face and décolleté area, as well as various forms of irregular pigmentation of the skin are counted among the postinflammatory hyperpigmentations. In addition, dark circles are also considered to be a form of postinflammatory hyperpigmentation, with the underlying inflammation usually subclinical.

In many cases, such postinflammatory Fehlpigmentierung by the action of sunlight (UV light) is enhanced without causing a UV-induced inflammation (sunburn).

Active ingredients and preparations are known which counteract skin pigmentation. In practical use are essentially preparations based on hydroquinone, but on the one hand only after several weeks of application show their effect, the excessively long use on the other hand is of concern for toxicological reasons. By Albert Kligman et al. a so-called triformula was developed, which represents a combination of 0.1% tretinoin, 5.0% hydroquinone, 0.1% dexamethasone (A. Kligman, 1975, Arch. Dermatol., 111: 40-48). However, this formulation is also very controversial because of possible irreversible changes in the pigmentation system of the skin.

Skin peeling methods (chemical and mechanical "peelings") are also used, however, which often lead to inflammatory reactions and may even lead to greater rather than reduced pigmentation due to postinflammatory hyperpigmentation, all of which are also used to treat post-inflammatory hypergigmentation become, are characterized by crucial side effects. The aim of the invention below was therefore to remedy the disadvantageous state of the art.

In a very particular embodiment, the present invention relates to cosmetic and dermatological preparations with reduced skin irritation.

The cooling effect of cosmetic preparations is based on two basic principles:

Use of components that volatilize after topical application gaseous and the required amount of energy, the so-called evaporation enthalpy, to a large part of the skin surface. Therefore, suitable liquid components are used in corresponding non-occlusive cosmetics. Ethanol has proved to be particularly suitable here, in addition formulations with a high water content likewise show a clear cooling effect.

Use of so-called "cooling agents", which interact with the heat receptors of the skin and thus trigger a feeling of cold without generating any measurable physical cooling, in particular menthol and various menthol derivatives (Frescolate, Physcool, Questice L _1, etc.) In particular, high content of ethane, as well as menthol and its derivatives, are not suitable for numerous uses under olfactory aspects in addition to the irritative potential, in particular due to their distinct inherent odor Frequently enough, such substances also increase blood circulation at the same time causes.

In the literature, for example, ionic compounds, in particular ammonium salts, are described as cooling agents. As cooling preparations are also widely used isopropanolic gels with camphor and menthol additive.

The use of these substances, especially on irritated skin, is in any case problematic. In addition, many of these compounds are poorly water-soluble. Their use is therefore limited to a few cosmetics and dermatics. It was therefore an object of the present invention to provide nourishing cosmetic and medical preparations which do not have the disadvantages of the prior art, in particular those which, applied to the skin or mucous membranes, have a moisturizing and / or cooling action.

DE 43 12 656 describes the use of cosmetically or pharmaceutically acceptable substances with positive enthalpy of solution in cosmetic or medical topical preparations, characterized in that the substance or substances in the preparations are present in a largely anhydrous medium and / or by a material barrier of one be shielded aqueous medium.

Although this procedure can in principle lead to cosmetically satisfactory preparations, they are galenically extremely expensive to produce.

It was therefore the object of the present invention to remedy the evils of the prior art and to provide cooling cosmetic or dermatological preparations which are easy to prepare, exert no irritating effect on skin or mucous membranes - for example, unpleasant tingling or itching - as well as intended Application pleasant cooling donate.

For example, in view of the hitherto incompletely understood reactions of the pigmentation system of the skin, it has surprisingly been found, surprisingly, that cosmetic or dermatological preparations containing 2-isopropyl-5-methylcyclohexanecarbonyl-D-alanine methyl ester and one or more skin-lightening active compounds undesirable pigmentation of the skin are extremely effective and contribute to a more even pigmentation - and simultaneous cooling of the skin.

In a particularly preferred form of use, this is for the treatment of the following hyperpigmentation conditions: postinflammatory hyperpigmentation after inflammatory reactions, in particular those associated with shaving, melasma, uneven skin tone, in particular as a result of excessive exposure to the sun.

It has been found that in a particularly preferred embodiment, 2-isopropyl-5-methylcyclohexanecarbonyl-D-alanine methyl ester is used in combination with UV filters become. In addition to the prevention and treatment of postinflammatory hyperpigmentation by the preparations according to the invention as a particularly preferred embodiment, a preferred embodiment of the formulations of the invention were also effective in the treatment of hypogigments.

Particularly preferred indications would be postinflammatory hyperpigmentation due to the pseudofollicularis barbae and melasma.

2-Isopropyl-5-methylcyclohexanecarbonyl-D-alanine methyl ester is characterized by the following structure:

The synthesis of 2-isopropyl-5-methyl-cyclohexanecarbonyl-D-alanine methyl ester [synonom: (R) -2 - [((1 R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] Propionic acid methyl ester can be made according to the following instructions:

1, 0 g of D-alanine methyl ester hydrochloride (from Aldrich Chemical Co received) 1 ml of double distilled water, diethyl ether and in 28 ml and cooled to 0 ⁰ C. A spatula tip of the catalyst diaminopyrimidine was added. 1, 62 ml of p-menthyl chloride was added dropwise, followed by 2 ml of triethylamine. Flakes of a no-mist precipitate formed in the mixture, which was stirred overnight at room temperature. The precipitate was dissolved in ethyl acetate, washed with double-distilled water and dried over sodium sulfate. The organic phase was evaporated under reduced pressure to give 2 g of the final product, which crystallized at room temperature. The expected molecular mass and structure were confirmed by mass spectrometer or NMR spectrum. Particularly advantageous is a use according to the invention, characterized in that the preparations 0.0001 to 5 wt .-%, in particular 0.001 to 1 wt .-%, most preferably 0.005 to 0.15 wt .-% of 2-isopropyl-5-methyl Cyclohexanecarbonyl-D-alanine methyl ester, based on the total weight of the preparation.

Furthermore, a use according to the invention is particularly advantageous, characterized in that the preparations contain from 0.001 to 10% by weight, in particular from 0.05 to 5% by weight, very particularly preferably from 0.01 to 2% by weight, of one or more of the skin containing lightening agents, based on the total weight of the preparation.

Of the skin lightening agents used in the invention, can be selected advantageously:

8-hexadecene-1, 16-dicarboxylic acid, ursolic acid, agouti peptides, liquorice root extract, hydroquinone, green tea extract, arbutin, biotin, mulberry extract (Uvae ursii), glycyrrhizin, placental extract, ascorbyl glucosides, endothelin antagonists from chamomile extract.

Cosmetic and dermatological preparations according to the invention can be present in various forms. So they can e.g. a solution, an anhydrous preparation, an emulsion or microemulsion of the water-in-oil (W / O) type or of the oil-in-water (O / W) type, a multiple emulsion, for example of the water-in-oil type in water (W / O / W), a gel, a solid stick, an ointment or even an aerosol. It is also advantageous in the invention to provide folic acid and / or its derivatives in encapsulated form, e.g. in collagen matrices and other common encapsulating materials, e.g. as cellulase encapsulations, in gelatin, wax matrices or liposomally encapsulated. In particular wax matrices as described in DE-OS 43 08 282, have been found to be favorable.

It is also possible and advantageous for the purposes of the present invention to incorporate folic acid and / or derivatives thereof into aqueous systems or surfactant preparations for cleaning the skin and hair. <

The cosmetic and dermatological preparations according to the invention may contain cosmetic adjuvants such as are conventionally used in such preparations For example, preservatives, bactericides, perfumes, foaming inhibitors, dyes, pigments that have a coloring effect, thickeners, surfactants, emulsifiers, softening, moisturizing and / or moisturizing substances, fats, oils, waxes or other conventional ingredients a cosmetic or dermatological formulation such as alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents or silicone derivatives.

The lipid phase can advantageously be selected from the following substance group: mineral oils, mineral waxes

Oils such as triglycerides of capric or caprylic acid, further natural oils such as e.g. Castor oil;

Fats, waxes and other natural and synthetic fats, preferably esters of fatty acids with lower C-number alcohols, e.g. with isopropanol, propylene glycol or glycerol, or esters of fatty alcohols with alkanoic acids of low C number or with fatty acids; benzoates;

Silicone oils such as dimethylpolysiloxanes, diethylpolysiloxanes, diphenylpolysiloxanes and mixed forms thereof.

The oil phase of the emulsions, oleogels or hydrodispersions or lipodispersions in the context of the present invention is advantageously selected from the group of esters of saturated and / or unsaturated, branched and / or unbranched alkanecarboxylic acids having a chain length of 3 to 30 carbon atoms and saturated and / or or unsaturated, branched and / or unbranched alcohols having a chain length of 3 to 30 carbon atoms, from the group of esters of aromatic carboxylic acids and saturated and / or unsaturated, branched and / or unbranched alcohols having a chain length of 3 to 30 carbon atoms. Such ester oils can then advantageously be selected from the group isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl stearate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-ethylhexyl laurate, 2-hexyldecyl stearate, 2 Octyldodecyl palmitate, oleyl oleate, oleyl erucate, erucyl oleate, erucyl erucate and also synthetic, semisynthetic and natural mixtures of such esters, eg jojoba oil. The aqueous phase of the preparations according to the invention optionally advantageously contains alcohols, diols or polyols of low C number, and their ethers, preferably ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl or -mob nobutyl ether, propylene glycol monomethyl, -monoethyl- or -monobutylether , Diethylene glycol monomethyl or monoethyl ether and analogous products, furthermore low C-number alcohols, for example ethanol, isopropanol, 1,2-propanediol, glycerol, and in particular one or more thickening agents, which may advantageously be selected from the group silicon dioxide, Aluminum silicates, polysaccharides or their derivatives, for example hyaluronic acid, xanthan gum, hydroxypropylmethylcellulose, particularly advantageously from the group of the polyacrylates, preferably a polyacrylate from the group of the so-called carbopols, for example Carbopols of the types 980, 981, 1382, 2984, 5984 , each individually or in combination.

In particular, mixtures of the abovementioned solvents are used. For alcoholic solvents, water can be another ingredient.

Emulsions of the invention are advantageous and contain e.g. the said fats, oils, waxes and other fatty substances, as well as water and an emulsifier, as commonly used for such a type of formulation.

Gels according to the invention usually contain low C number alcohols, e.g. Ethanol, isopropanol, 1, 2-propanediol, glycerol and water or an above-mentioned oil in the presence of a thickener which is preferably silica or an aluminosilicate in oily-alcoholic gels, in aqueous-alcoholic or alcoholic gels, preferably a polyacrylate.

Suitable propellants for preparations which can be sprayed from aerosol containers according to the invention are the customary known highly volatile, liquefied propellants, for example hydrocarbons (propane, butane, isobutane), which can be used alone or mixed with one another. Also, compressed air is advantageous to use.

Compositions according to the invention can also advantageously contain substances which absorb UV radiation in the UVB range, the total amount of the filter substances being, for example, from 0.1% by weight to 30% by weight, preferably from 0.5 to 10% by weight, in particular 1, 0 to 6.0 % By weight, based on the total weight of the preparations, in order to provide cosmetic preparations which protect the hair or the skin from the entire range of ultraviolet radiation. They can also serve as a sunscreen for hair or skin.

The following examples are intended to illustrate the present invention without limiting it. All amounts, proportions and percentages are, unless otherwise stated, percentages by weight, based on the weight and the total amount or on the total weight of the preparations.

Example 1: W / O cream

Example 2: Hydrodispersion / gel cream

Claims

claims:

1. Cosmetic or dermatological preparations containing 2-isopropyl-5-methylcyclohexanecarbonyl-D-alanine methyl ester and one or more skin lightening agents.

2. Preparations according to claim 1, characterized in that the or the skin-lightening agents is selected or are from the group octadecenedioic acid, 8-hexadecene-1, 16-dicarboxylic acid, ursolic acid, agouti peptides, licorice root extract, hydroquinone, green tea extract , Arbutin, biotin, mulberry extract (Uvae ursii), glycyrrhizin, placental extract, ascorbyl glucosides, endothelin antagonists from chamomile extract.

3. Preparations according to one of the preceding claims, characterized in that it contains from 0.001% by weight to 10% by weight, preferably from 0.01% by weight to 1.0% by weight, in particular 0.05-0, 5% by weight, based on the total weight of the preparations, of 2-isopropyl-5-methylcyclohexanecarbonyl-D-alanine methyl ester.

4. Use of preparations according to one of the preceding claims for lightening the skin.