RU2648763C2 - Topical use of 1-hydroxy 3,5-bis(4′ hydroxystyryl)benzene - Google Patents

Abstract

FIELD: cosmetology.

SUBSTANCE: invention relates to cosmetology and is a topical anti-aging skin care composition containing 1-hydroxy 3,5-bis(4'hydroxystyryl)benzene or a cosmetically acceptable salt thereof and a cosmetically acceptable carrier for topical use comprising a softener and an emulsifier.

EFFECT: invention provides an effective inhibition of the nuclear transcription factor of kappa-bi (NF-ĸB).

11 cl, 9 ex, 12 tbl

Description

FIELD OF TECHNOLOGY

The present invention relates to compositions and methods for topical application of 1-hydroxy 3,5-bis (4’-hydroxystyryl) benzene.

BACKGROUND OF THE INVENTION

Active substances are known that act on the skin in order to eliminate the signs of aging, to provide anti-inflammatory action or lightening.

A separate class of anti-inflammatory drugs are substances that inhibit the nuclear transcription factor kappa-bi (NF-ĸB). For example, it is known that some substituted resorcinol, such as 4-hexylresorcinol and tetrahydrocurcuminoids, are NF-ĸB inhibitors. Such compositions when applied to the skin provide an effect that slows down its aging. However, only a relatively small group of compounds was identified as both effective and cosmetically acceptable.

It is known that when anti-inflammatory compounds are applied to the skin, they provide anti-pigmentation effect. A separate class of anti-inflammatory drugs used for this purpose are substances that reduce the melanin content in melanocytes by inhibiting the molecules of inflammatory mediators. However, only a relatively small group of formulations has been identified as topical for regulating the formation of melanin in the skin.

SUMMARY OF THE INVENTION

Currently, the inventors have unexpectedly found that 1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene is a potential NF-ĸB inhibitor and is suitable for topical application to the skin and that 1-hydroxy 3,5-bis (4'-hydroxy-styryl) benzene and its cosmetically acceptable salts can be used to eliminate signs of skin aging, are inhibitors of the formation of melanin in melanocytes and can be applied to skin that needs lightening.

In one aspect, the present invention provides a composition comprising 1-hydroxy 3,5-bis (4′-hydroxystyryl) benzene or a cosmetically acceptable salt thereof; and a cosmetically acceptable carrier for topical application, including an ingredient selected from the group consisting of moisturizers, emulsifiers, softeners, moisture-retaining agents and fragrances.

In addition, the present invention provides a method for caring for human skin, comprising topically applying to a human skin a composition comprising 1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene or a cosmetically acceptable salt thereof.

The present invention also provides a method of skin care with signs of aging, comprising topically applying to a skin in need of such care a composition comprising 1-hydroxy 3,5-bis (4′-hydroxystyryl) benzene or a cosmetically acceptable salt thereof.

The present invention provides a skin lightening method comprising the step of topically applying to a skin in need of lightening a composition comprising 1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene or a cosmetically acceptable salt thereof.

In addition, the present invention provides a method of inhibiting the growth of a microorganism, comprising the use of the aforementioned microorganism 1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene or its cosmetically acceptable salt.

Other features and advantages of the present invention will become apparent from the detailed description of the invention and the claims.

DETAILED DESCRIPTION OF THE INVENTION

It is assumed that a specialist in this field, based on this description, will be able to use the present invention in its fullest extent. The following typical embodiments of the invention should be considered only as examples, which in no way limit the disclosed nature of the present application for invention.

All technical and scientific terms used herein, unless otherwise indicated, have a generally accepted meaning that is understood by any person skilled in the art to which the present invention relates. In addition, all publications, patent applications, patents and other references referred to herein are incorporated herein by reference. Unless otherwise indicated, the percentage or concentration is indicated as a weight percentage or concentration (i.e.,% weight). Unless otherwise specified, all ranges are inclusive of end points, for example, the range “4 to 9” includes points 4 and 9.

The products described herein may also be in packaged form. In one embodiment of the invention, the package is a container, for example, a plastic, metal or glass tube or jar containing the composition. The product may also have additional packaging, for example plastic or cardboard, in which said container is placed. In one embodiment of the invention, the product comprises a composition of the invention and instructions for applying the composition to the skin to treat signs of aging, as described below. Such instructions may be printed on the container, on the enclosed annotation, or on any additional packaging.

As used herein, the term “topical application” means the direct application or distribution over the surface of the skin, skin of the scalp or hair, in particular by hand or using special means such as a wipe, roller or aerosol.

As used herein, the term “cosmetically acceptable” means that the ingredients to which the term refers are suitable for use in contact with body tissues (eg, skin or hair) without toxic effects, without incompatibility, instability, without causing irritations, allergic reactions, etc.

As used herein, the term “cosmetic” refers to a composition or substance that improves appearance, which preserves, restores, imparts, mimics or enhances physical attractiveness or creates an effect of increasing attractiveness or youth, especially with respect to the appearance of tissue or skin.

As used herein, the phrase “skin in need of reducing the signs of aging” means skin having, among others, the following characteristics: saggy, flabby, sluggish, uneven, wrinkled, thinned, and having an uneven tone. Reducing the signs of aging means increasing skin elasticity, improving skin texture, reducing wrinkles on the skin, improving skin tone or eliminating skin defects caused by aggressive environmental influences.

As used herein, “increasing skin firmness” means improving skin firmness or elasticity, preventing the loss of skin firmness or elasticity, or preventing or eliminating sagging, sagging and lethargic skin. The firmness or elasticity of the skin can be measured with a cutometer. See Handbook of Non-Invasive Methods and the Skin, Ed. J. Serup, G. Jemec & G. Grove, chap. 66.1 (2006). Loss of skin elasticity or firmness may result from a number of factors, including but not limited to aging, environmental damage, or the application of cosmetics to the skin.

As used herein, “improving skin texture” means smoothing the skin surface to eliminate bumps or depressions on the skin surface.

As used herein, “improving the appearance of wrinkles on the skin” means preventing, slowing, stopping or reversing the process of wrinkling on the skin. As used herein, “wrinkles” include fine lines, fine wrinkles, and large wrinkles. Examples of wrinkles include, but are not limited to, fine lines around the eyes (for example, crow's feet), wrinkles on the forehead and cheeks, eyebrow wrinkles, and facial wrinkles around the mouth.

As used herein, the term “uneven skin” means a condition of the skin associated with diffuse or spotty pigmentation, which can be classified as hyperpigmentation, for example post-inflammatory hyperpigmentation.

As used herein, the term “spotting” means a condition of the skin associated with its redness or erythema.

In this document, “the elimination of skin defects due to aggressive environmental influences” means the reduction or prevention of skin damage due to aggressive environmental influences. Examples of aggressive environmental influences include, but are not limited to, damage to the skin when using cleaners (e.g. topical cleaners containing surfactants), makeup, shaving, and environmental factors such as UV radiation (e.g. damage due to solar radiation or damage due to UV radiation from artificial sources, e.g. UV lamps and solar radiation simulators), ozone, air emissions, pollution medium, chlorine and chlorine compounds, as well as cigarette smoke. The effects of aggressive environmental influences include, among others, oxidative or nitrosative damage and modifications of lipids, carbohydrates, peptides, proteins, nucleic acids and vitamins. The effects of aggressive environmental influences also include, among others, loss of cell viability, loss or alteration of cellular functions, alteration of gene and / or protein expression.

As used herein, “improving skin tone” means visually brightening the skin (for example, brightening age spots or defects, decreasing the yellowish color of the skin and / or evening out skin color).

As used herein, “skin in need of reducing signs of inflammation” means skin showing redness or erythema, swelling, or showing reactivity or sensitivity to external elements. External elements include, among others, sun rays (UV radiation, visible radiation, IR radiation), microorganisms, atmospheric pollutants such as ozone, exhaust gases, chlorine and compounds that produce chlorine, cigarette smoke, cold, the heating. Inflammatory disorders and related conditions that are to be treated or prevented using the compositions of the present invention include, but are not limited to, arthritis, bronchitis, contact dermatitis, atopic dermatitis, psoriasis, seborrheic dermatitis, eczema, allergic dermatitis, polymorphic lung rashes, inflammatory dermatoses, folliculitis, alopecia, exposure to poisonous sumac, insect bites, acne inflammation, irritation under the influence of external factors, including, but not limited to sneeze, chemicals, trauma, pollutants (such as cigarette smoke) and sun exposure, secondary conditions associated with inflammation, including, inter alia, xerosis, hyperkeratosis, pruritus, postinflammatory hyperpigmentation, scarring, etc. Preferably, the inflammatory disorders and related conditions that are to be treated or prevented using the methods of the present invention are arthritis, inflammatory dermatoses, contact dermatitis, allergic dermatitis, atopic dermatitis, polymorphic lung rashes, irritation, including erythema due to external factors, acne inflammation, psoriasis, seborrheic dermatitis, eczema, exposure to poisonous sumac, insect bites, folliculitis, alopecia, as well as secondary standing, etc.

As used herein, the term “skin lightening” refers essentially to lightening, whitening and / or equalizing skin tone, skin color and / or skin tone, and / or reducing yellowish skin color, and / or lightening or reducing hyperpigmented spots and / or defects, including, but not limited to, pigment spots, melanin spots, age spots, sun spots, senile lentigo, freckles, simple lentigo, pigmented solar keratosis, seborrheic keratosis, melanosis, acne marks, post-inflammatory hyperpigmentation, lentiginosis , ephelids, combinations of two or more kinds of defects, etc. In certain embodiments, “skin lightening” also refers to an increase in skin radiance, translucency and luminosity and / or to obtain a more radiant, luminous, translucent or visually highlighted skin tone or to reduce a yellowish skin color. In certain preferred embodiments, “skin lightening” refers to lightening and evening skin tone, increasing skin radiance and / or lightening age spots.

As used herein, the term “skin requiring whitening” refers essentially to skin showing one or more properties selected from the group consisting of: skin having a measured color classification of human skin color (individual typological angle, ITA) of less than 41 as defined in the COLIPA GUIDE: GUIDELINE FOR THE COLORIMETRIC DETERMINATION OF SKIN COLOR TYPING AND PREDICTION OF THE MINIMAL ERYTHEMAL DOSE (MED) WITHOUT UV EXPOSURE, published in 2007, which is incorporated herein by reference and further described below; darkened and / or yellowish skin, including skin darkened by exposure to UV radiation; uneven skin or skin with one or more hyperpigmented spots and / or lesions, including but not limited to age spots, melanin spots, age spots, sun spots, senile lentigo, freckles, simple lentigo, pigmented solar keratosis, seborrheic keratosis, melanosis, acne spots, post-inflammatory hyperpigmentation, lentiginosis, ephelids, combinations of two or more of them, etc. In the COLIPA manual, skin color is determined depending on the ITA value as follows: very fair skin -> 55; fair skin - 41–55, average skin color - 28–41, dark skin - <28. In certain preferred embodiments, the term “skin in need of lightening” refers to skin with an ITA value of less than 41, such as about 40 or less, about 35 or less, about 30 or less, or more preferably about 28 or less. In other specific preferred embodiments, the present invention relates to compositions and methods for using them to lighten a skin with a tone selected from yellowish and / or darkened skin. In other specific preferred embodiments, the present invention relates to compositions and methods for using to lighten skin with defects selected from the group consisting of age spots, freckles, acne marks and combinations of two or more defects.

In this document, unless otherwise indicated, all percentages of ingredients in the compositions represent the weight percent of active / solid ingredient of the total weight of the composition.

As used herein, a “substantially free” ingredient means that the content of such an ingredient is less than about 1% by weight, for example, less than about 0.5% by weight, for example, less than about 0.25% by weight. for example, less than about 0.1% weight. In one embodiment of the present invention, “substantially free” means the complete absence of such an ingredient.

The compositions of the present invention are suitable for the care of human skin, for example, skin of the face or body, for example, to eliminate signs of aging or inflammation of the skin. In a particularly preferred embodiment of the present invention, the composition of the present invention is used to treat lines and wrinkles and / or loss of skin elasticity. Compositions that are the subject of the present invention are suitable for the care of human skin, for example, skin of the face or body, for example, for lightening the skin.

1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene

The compositions of this invention contain 1-hydroxy 3,5-bis (4'-hydroxystyrene) benzene or a cosmetically acceptable salt thereof.

1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene is an analog of curcumin and has the structure shown below:

As described in US Pat. No. 7,745,670, 1-hydroxy 3,5-bis (4′-hydroxystyryl) benzene can be prepared by reacting 1- (bromomethyl) -4-methoxybenzene with triethyl phosphate using the Arbuzov reaction to produce diethyl [(4-methoxyphenyl) methyl] phosphonate. It is combined with 5-methoxybenzene-1,3-dicarbaldehyde with sodium hydride as a base in THF, followed by reaction with boron trichloride and dichloromethane to replace methoxy groups with hydroxyl groups.

Salts of 1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene can be prepared, for example, by reacting 1-hydroxy 3,5-bis (4'-hydroxy-styryl) benzene with a base such as piperazine or another to produce at least at least, salts of 1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene phenolate.

Topical Compositions

In general, 1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene or its salt is present in the composition in a cosmetically effective amount, for example, from about 0.01% to about 10%, mainly from about 0.1% up to about 5%, more preferably from about 0.2% to about 2%, and even more preferably from about 0.5% to about 1.5% weight. composition.

Compositions that are the subject of the invention are applied topically, applying to the skin and (or) human hair.

These compositions may be pasty products. They can be applied topically by spreading, for example, spreading on the skin or hair, in particular on the skin of the face or hands.

In one embodiment of the present invention, the composition of the present invention is applied topically without stress.

In addition to 1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene, the composition may also include a cosmetically acceptable topical carrier, which may be from about 50% to about 99.99% by weight. compositions (e.g., from about 80% to about 99% by weight of the composition). In a preferred embodiment of the present invention, a cosmetically acceptable topical carrier comprises water.

Said cosmetically acceptable topical carrier may be unsuitable for oral administration.

The specified cosmetically acceptable carrier for topical application may include an ingredient selected from one or more of the following five classes: moisturizers, emulsifiers, softeners, moisture-retaining agents and perfumes. In some embodiments, implementation of the present invention, the specified cosmetically acceptable carrier for topical application includes ingredients from two or more of the above classes, for example, ingredients from at least three or more of these classes.

In one embodiment of the present invention, said cosmetically acceptable topical carrier comprises water, an emulsifier, and a softener.

The compositions can be prepared in the form of a wide range of products, which include, but are not limited to, lotions, creams, gels, pencils, sprays, ointments, cleansing liquids and solid washing bars, shampoos and hair conditioners, hair fixers, pastes, foams , powders, mousses, shaving creams, wipes, plasters, hydrogels, film-forming products, face and skin masks, films and decorative cosmetics, such as foundation creams and mascaras. These types of products may contain several types of cosmetically acceptable carriers for topical application, including but not limited to solutions, suspensions, emulsions, for example, microemulsions and nanoemulsions, gels, solids and liposomes.

Compositions used in the framework of the present invention can be made in the form of solutions. Solutions typically include aqueous or organic solvents (for example, from about 50% to about 99.99%, or from about 90% to about 99% of a cosmetically acceptable aqueous or organic solvent). Examples of suitable organic solvents include water-retaining agents (eg, water-retaining or hygroscopic materials) such as propylene glycol, pentylene glycol, polyethylene glycol, polypropylene glycol, glycerin, 1,2,4-butanetriol, sorbitol esters, 1,2,6-hexanetriol; as well as ethyl alcohol and mixtures thereof. The solutions may further include a moisturizer, for example, to obtain a foam, for example, an anionic, nonionic or cationic moisturizer.

The compositions used in the framework of the present invention can be prepared in the form of a solution containing a softener. Such preparations preferably contain from about 2% to about 50% of the softener (s). As used herein, the term “softeners” refers to materials used to prevent or eliminate dry skin, for example, by preventing transepidermal water loss. Examples of softeners include hydrophobic compounds such as vegetable oils, mineral oils (e.g., liquid paraffin), fatty esters (e.g. isopropyl palmitate, c12-c15 alkyl benzoate), including glycerol fatty esters, silicon oils (e.g. dimethicone), and etc.

A lotion can be made from such a solution. Lotions typically contain from about 1% to about 20% (e.g., from about 5% to about 10%) of softener (s) and from about 50% to about 90% (e.g., from about 60% to about 80 %) water.

Another type of product that can be made from a solution is a cream. The cream typically contains from about 5% to about 50% (e.g., from about 10% to about 20%) of the softener (s) and from about 45% to about 85% (e.g., from about 50% to about 75%) ) water.

Although the composition of the present invention should preferably contain water, the composition may also be anhydrous or an ointment containing not water, but organic and (or) silicone solvents, oils, fats and waxes. The ointment may contain a simple base of animal or vegetable oils or semi-solid carbohydrates. The ointment may contain from about 2% to about 10% of the softener (s) plus from about 0.1% to about 2% of a thickening (gelling) agent.

The composition may be prepared in the form of an emulsion. If the topical carrier is an emulsion, then from about 1% to about 10% (for example, from about 2% to about 5%) of this carrier will constitute the emulsifier (s). Emulsifiers can be nonionic, anionic or cationic. Examples of suitable emulsifiers include those emulsifiers that are usually identified as such in the field of personal care and cosmetic preparations, for example, cationic emulsifiers such as distyryldimonium chloride, non-ionic emulsifiers such as steareth-2, steareth-21; anionic emulsifiers such as cetyl potassium phosphate; polymer emulsifiers such as acryloyl dimethyl taurate / VP copolymers, etc.

Lotions and creams can be made in the form of emulsions. Typically, such lotions contain from about 0.5% to about 5% emulsifier (s). Such creams typically contain from about 1% to about 20% (for example, from about 5% to about 10%) of softener (s); from about 20% to about 80% (for example, from 30% to about 70%) of water; and from about 1% to about 10% (e.g., from about 2% to about 5%) of emulsifier (s).

Single emulsion based skin care products, such as lotions and creams such as oil-in-water and water-in-oil, are well known in the cosmetic industry and can be used within the scope of the present invention. Multiphase emulsion compositions such as water-in-oil-in-water or oil-in-water-in-oil can also be used within the scope of the present invention. In general, such single-sided or multiphase emulsions contain water, softeners and emulsifiers as the main ingredients.

Compositions that are the subject of the present invention, can also be made in the form of a gel (for example, an aqueous, alcoholic, aqueous-alcoholic or oily gel using suitable gelling agent (s)). Suitable gelling agents for aqueous and / or alcoholic gels include, but are not limited to, natural gums, acrylic acid (thickened with a crosslinked polymer), acrylate polymers and copolymers, as well as cellulose derivatives (e.g., hydroxymethyl cellulose and hydroxypropyl cellulose). Suitable gelling agents for oils (e.g., mineral oil) include, but are not limited to, a hydrogenated butylene / ethylene / styrene copolymer and a hydrogenated ethylene / propylene / styrene copolymer. In such gels, the content of gelling agents, as a rule, is from about 0.1% to 5% by weight.

Compositions that are the subject of the present invention can also be made in solid form (for example, in the form of sticks based on wax, bars of soap, powder or napkins containing powder).

Compositions that can be used in the framework of the present invention may contain, in addition to the above components, a wide range of additional oil-soluble materials and / or water-soluble materials traditionally used in skin and hair care compositions in concentrations known to those skilled in the art.

Additional cosmetically active substances

In one embodiment of the present invention, said composition comprises an additional NFĸB inhibitor such as substituted resorcinol, (E) -3- (4-methylphenylsulfonyl) -2-propenitrile (such as “Bay 11-7082”, commercially available from Sigma-Aldrich from St. Louis, Missouri), tetrahydrocurcuminoid (such as Tetrahydrocurcuminoid CG, commercially available from Sabinsa Corporation from Piscataway, New Jersey), paulownia, Paulownia extracts (e.g., Paulownia tomentosa), Paulownia fortune, Paulownia elongate, Paulownia taiwaniana and / or Paulownia kawakamii), as well as combinations thereof.

In one embodiment, the composition also contains another cosmetically active substance. As used herein, “cosmetically active agent” means a compound (eg, a synthetic compound or a compound isolated from a natural source or natural extract) that has a therapeutic or cosmetic effect on the skin, including, but not limited to, anti-aging actives, anti-inflammatory agents, tropoelastin stimulants, acne remedies, antimicrobial agents, antifungal agents, external analgesics, sunscreens, antioxidants, keratolytic agents CTBA, vitamins, skin brighteners and means of strengthening the skin.

In one embodiment of the present invention, such a compound includes a skin brightener such as a tyrosinase inhibitor, a melanin reduction agent, a melanosome transfer inhibitor, including PAR-2 antagonists, retinoids, antioxidants, tranexamic acid, transexamic acid hydrochloride, a skin whitening agent, linoleic acid, adenazine monophosphate disodium salt, chamomilla extract, allantoin, opacifier, talc or silica, zinc salt, etc. or another agent described in Solano et al. Pigment Cell Res. 19 (550-571) and Ando et al. Int J Mol Sci 11 (2566–2575).

Examples of suitable tyrosinase inhibitors include, but are not limited to, vitamin C and its derivatives, vitamin E and its derivatives, kojic acid, arbutin, resorcinol, hydroquinone, flavones (e.g. licorice flavonoids, licorice root extract, mulberry root extract, root extract dioscorea coposita, saxifrage extract, etc.), ellagic acid, salicylates and derivatives, glucosamine and derivatives, fullerene, quinocithiol, dicarboxylic acid, acetylglucosamine, 5,5'-dipropyl diphenyl-2,2'-diol (magnolignan), 4 - (4-hydroxyphenyl) -2-butanol (4-HPB), a combination of two or more of them, etc.

Examples of vitamin C derivatives include, but are not limited to, ascorbic acid and its salts, ascorbic acid 2-glucoside, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, and a natural extract rich in vitamin C.

Examples of vitamin E derivatives include, but are not limited to, alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, delta-tocotrienol and mixtures thereof, tocopherol acetate, tocopherol phosphate and natural extracts enriched with derivatives of vitamin E.

Examples of resorcinol derivatives include, but are not limited to, resorcinol, 4-substituted resorcinol such as 4-alkylresorcinol such as 4-butylresorcinol (rucinol), 4-hexylresorcinol (SYNOVEA HR, SYNTHEON), phenylethylresorcinol (SYMWHITE, SYMRISE) 1- (2,4-dihydroxyphenyl) -3- (2,4-dimethoxy-3-methylphenyl) propane (Nivitol, UNIGEN), etc., as well as natural extracts enriched in resorcinol.

Examples of salicylates include, but are not limited to, 4-methoxysalicylic acid, potassium salts, salicylic acid, acetylsalicylic acid, 4-methoxysalicylic acid, and salts thereof.

In certain preferred embodiments, tyrosinase inhibitors include 4-substituted resorcinol, a vitamin C derivative, or a vitamin E derivative. In more preferred embodiments, tyrosinase inhibitors comprise phenylethylresorcinol, 4-hexylresorcinol, or ascorbyl-2-glucoside.

Examples of suitable melanin degradation promoting agents include, but are not limited to, peroxides and enzymes such as peroxidases and ligninases. In certain preferred embodiments, melanin inhibiting agents include peroxide or ligninase.

Examples of suitable melanosome transfer inhibitors include PAR-2 antagonists, such as a soybean trypsin inhibitor or a Bauman-Birk inhibitor, vitamin B3 and its derivatives, such as niacinamide, soybean essence, whole soybean, soybean extract. In certain preferred embodiments, melanosomal transfer inhibiting agents include soybean extract or niacinamide.

Examples of retinoids include, but are not limited to, retinol (vitamin A alcohol), retinal (vitamin A aldehyde), retinyl acetate, retinyl propionate, retinyl linoleate, retinoic acid, retinyl palmitate, isotretinoin, tazarotene, bexarotene, adaptale, a combination of two or more etc. In certain preferred embodiments, the retinoid is selected from the group consisting of retinol, retinal, retinyl acetate, retinyl propionate, retinyl linoleate, as well as combinations of two or more substances. In certain more preferred embodiments, the retinoid is retinol.

Other skin lightening agents include vitamin B5, vitamin B12, glycolic acid, and paulownia extracts (e.g., Paulownia felted (Paulownia tomentosa), Paulownia fortunei, Paulownia elongate, Paulownia taiwaniana, and / or Paulownia kawakamii).

Examples of antioxidants include, but are not limited to, water-soluble antioxidants such as sulfhydryl compounds and their derivatives (e.g. sodium metabisulfite and N-acetylcysteine, glutathione), lipoic acid and dihydrolipoic acid, stilbenoids such as resveratrol and derivatives, lactoferrin, agents chelating iron and copper, as well as ascorbic acid and derivatives of ascorbic acid (for example, ascorbyl-2-glucoside, ascorbyl palmitate and ascorbyl polypeptide). Oil-soluble antioxidants suitable for use in the compositions of this invention include, but are not limited to, butylated hydroxytoluene, retinoids (e.g. retinol and retinyl palmitate), tocopherols (e.g. tocopherol acetate), tocotrienols, and ubiquinones. Natural extracts containing antioxidants suitable for use in the compositions of the present invention include, without limitation, extracts containing flavonoids and isoflavonoids, as well as derivatives thereof (e.g., genistein and diadzein), extracts containing resveratrol, etc. . Examples of such natural extracts include grape seed extract, green tea extract, black tea, white tea, pine bark, girl’s feverfew, girl’s parthenolide extract, oat extract, blackberry extract, scumpia extract, soy extract, pomelo extract, wheat germ extract, hesperidin, grape extract, portulaca extract, lycochalcon, chalcon, 2,2'-dihydroxychalcon, primrose extract, propolis, etc.

Other materials

Other various materials known to those skilled in the art may be present in the formulations. They include water-retaining agents, pH adjusters, chelating agents (e.g., EDTA), flavors, colorants and preservatives (e.g., butylhydroxytoluene, benzyl alcohol).

In one embodiment of the present invention, the composition is essentially absent, mainly preservatives are completely absent. This is due to the fact that 1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene and its salts are predominantly actively involved in the processes of suppression and destruction of microorganisms. Accordingly, the compositions that make up the subject of the present invention can be formulated with little or no conventional preservatives. Conventional preservatives are selected, for example, from the group consisting of parabens, benzoic acid and its salts, phenoxyethanol, isothiazolones, imidazolidinyl urea, iodopropinyl butyl carbamate, hydantoin DMDM, caprylycol glycol, dehydroacetic acid, glycine chloroferin, levine phenylate, laphenyl laphenylphenolate, its salt sodium, anisic acid, ethylhexylglycerol, benzyl alcohol, and combinations thereof.

Such compositions, as well as compositions and products containing these compositions, can be made using methods well known to those of ordinary skill in the art.

Application methods

The compositions of the invention can be applied topically by application to human skin, for example to skin that needs to be treated with one or more of the signs of aging described above. In one embodiment of the invention, the compositions are applied to the skin, which needs to be treated with furrows, wrinkles and / or in the treatment of loss of elasticity. The compositions can be applied to the skin in need of such treatment as part of an appropriate treatment regimen, for example, monthly, weekly, every other day, daily, twice a day, etc.

1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene, its cosmetically acceptable salts and compositions containing it, can be used to provide antimicrobial effects (for example, bactericidal, antifungal, antiviral or antiparasitic effects).

In one embodiment, the invention provides a method of inhibiting the growth of a microorganism, comprising the use of 1-hydroxyl 3,5-bis (4'hydroxylstyryl) benzene, a cosmetically acceptable salt or composition containing them for the aforementioned microorganism.

Microorganisms that can be suppressed or destroyed by this use include gram-positive bacteria, gram-negative bacteria and fungi, including Staphylococcus aureus, Staphylococcus epidermidis, Propionibacterium coli, (Propionibacterium coli, Acnes) ), Pseudomonas aeruginosa (Pseudomonas aeruginosa), white candida (Candida albicans) and black mold (Aspergillus niger).

It is assumed that a specialist in this field, based on this description, will be able to use the present invention in its fullest extent. The following typical embodiments of the invention should be considered only as examples, which in no way limit the disclosed nature of the present application for invention. The following non-exclusive examples are further illustrative of the invention.

Example 1. Inhibition of NF-ĸB

NF-ĸB INHIBITION TESTS were performed for various concentrations of 1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene and carrier control medium (DMSO). 1-hydroxy 3,5-bis (4′-hydroxystyryl) benzene was prepared as described in US Pat. No. 7,745,670.

NF-ĸB INHIBITION TEST was performed as follows. H9c2 rat cardiac muscle cells were purchased from ATCC (Manasas, Virginia). The cultures were maintained in the Dulbecco Modified Eagle Medium (DMEM) (Invitrogen Life Technologies, Carlsbad, Calif.) Supplemented with 10% fetal bovine serum, 100 units / ml penicillin and 50 μg / ml streptomycin (Invitrogen life technologies , Carlsbad, California). 1 × 104 cells grown on 96-well plates were temporarily transfected with 0.45 μg of total DNA injected into each well using Lipofectamine 2000 (Invitrogen life technologies, Carlsbad, California). In all transfection cases, in addition to the NF-kB luciferase promoter, a construct with the thymidine kinase promoter and the Renilla luciferase reporter gene (pRL-TK, Promega, Madison, Wisconsin) was used as an internal control. One day after transfection, the cells were treated with the indicated samples (in DMSO as a carrier medium) at the indicated concentrations and stimulated with 100 ng / ml tumor necrosis factor-alpha (TNF-α, Sigma-Aldrich, St. Louis, Missouri) in for about 24 hours, then they were lysed for luciferase analysis using the Promega Dual-Luciferase Reporter System (Madison, Wisconsin) according to the manufacturer's protocol. In other words, firefly luciferase activity (reflecting the activity of the NF-kB promoter) was measured first, then Renilla luciferase activity (internal control) using an LMAX lumenometer manufactured by Molecular Devices (Sunnyvale, California). To assess the activity of each promoter, the ratio of the activities of the two given luciferase (RLU) was used:

Inhibition of NF-ĸB = [1- (RLU sample / RLU control)] * 100

where the RLU sample and RLU control are normalized indicators of luciferase activity for the sample and control, respectively.

The results are shown in table 1, which shows the value of the activation of the reporter gene for NF-kB (luminescence, L). The percentage inhibition of NF-kB is also provided.

TABLE 1 Activation of the reporter gene for NF-kB (luminescence, L) The percentage of inhibition of NF-kB No processing 131.5 ± - Stimulation with TNFα (100 ng / ml), “L _control ” 452.4 - TNFα + carrier medium (0.1% DMSO) 588.3 0% TNFα + 1-hydroxy 3,5-bis (4’-hydroxystyryl) benzene (0.2 μg / ml) 585.5 ± 0.5% TNFα + 1-hydroxy 3,5-bis (4’s hydroxy-styryl) benzene (0.5 μg / ml) 458.6 ± 22.1% TNFα + 1-hydroxy 3,5-bis (4’-hydroxystyryl) benzene (1 μg / ml) 283.8 ± 51.7% TNFα + 1-hydroxy 3,5-bis (4’-hydroxystyryl) benzene (2 μg / ml) 170.5 ± 71.0%

TNFα + 1-hydroxy 3,5-bis (4’-hydroxystyryl) benzene (4 μg / ml) 22.6 ± 96.1%

1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene showed a strong reduction in the inflammatory response with the help of factor NF-kB in human skin cells.

Example 2. Anti-inflammatory activity

The anti-inflammatory activity with topical administration of 1-hydroxy 3,5-bis (4’-hydroxystyryl) benzene and its paperazine salt was evaluated as follows.

Epidermal equivalents (EPI 200 HCF), a multilayer and differentiated epidermis consisting of normal human epidermal keratinocytes, were purchased from MatTek (Ashland, Massachusetts). After preparation, epidermal equivalents were incubated for 24 hours at 37 ° C in a stabilizing medium without hydrocortisone. The equivalents were topically treated with (2 mg / cm ² ) 1-hydroxy 3,5-bis (4'-hydroxystyryl) benzene in a carrier medium ethanol + propylene glycol 70:30 two hours before exposure to sunlight in the ultraviolet range (1000W-Oriel sunlight simulator, equipped with a Schott WG 320 filter 1 mm; applicable dose of UV radiation: 70 kJ / m ² at a wavelength of 360 nm). Equivalents were incubated for 24 hours at 37 ° C in a stabilizing medium, then the supernatant was analyzed for release of the cytokine IL-8 using commercially available kits (Millipore Corp., Billerick, Massachusetts).

The results are shown in table 2.

TABLE 2 Sample Change of one carrier medium (reduced to 100) % inhibition after UV treatment Carrier Medium (70/30: Ethanol + Propylene Glycol) 100 ± 28 -

Carrier Medium + UV 134 ± 42 - UV + 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene - free phenol (0.5%) 82 ± 21 39% UV + 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene - free phenol (1%) 80 ± 26 40% UV + 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene - paperazine salt (0.5%) 85 ± 14 37% UV + 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene - paperazine salt (1%) 81 ± 31 40%

1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene and its paperazine salt showed a strong reduction in inflammation of human skin cells caused by UV radiation.

Example 3. Induction of gene expression of elastin and collagen 1A

Primary human skin fibroblast (Lifeline Cell Technologies, Frederick, Maryland) was grown to confluence in DMEM (Invitrogen Life Technologies, Carlsbad, California) supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin per A 24-well plate with tissue cultures was then treated with 1-hydroxy 3,5-bis (4'-hydroxystyryl) benzene (0.1 μg / ml) with TNF-a and without TNF-a for 48 hours. After treatment, the cells were lysed using an RLT buffer, and total RNA was isolated using an RNeasy mini-kit (Qiagen, Valencia, California). Quantitative PCR was performed using the Gene Amp PCR System 9700 PCR system and the real-time PCR system cycler 7500 Real Time PCR System (Applied Biosystems) / Life Technologies, Carlsbad, California). The primers used were elastin (Qiagen) and collagen 1α1 (customer sequence - semantic: 5'-TCC-CCA-GCT-GTC-TTA-TGG-CT-3 'and antisense: 5'-CAG-GCA-CGG-AAA-TTC-CTC -C-3 '). The constitutive GAPDH gene was used for normalization (customer primer sequence: F 5'-ATC-TCT-GCC-CCC-TCT-GCT-G-3 'and R 5'-ATG-GTT-CAC-ACC-CAT-GAC-GA- 3 '; Invitrogen / Life Technologies, Carlsbad, CA). The multiplicity of changes in PCR (normalized to GAPDH) was calculated from the data without processing.

The results obtained are shown in tables 3A and 3B.

TABLE 3A Collagen 1A Normalized rate of changes in PCR (Medium) Elastin Normalized rate of changes in PCR (Medium) No processing 1,0 1,0 1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene (0.1 μg / ml) 2.96 6.23

TABLE 3B Collagen 1A Normalized rate of changes in PCR (Medium) Elastin Normalized rate of changes in PCR (Medium) No processing 1,0 1,0 TNF-α (10 ng / ml) 0.52 0.41 TNF-α (10 ng / ml) + 1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene (0.1 μg / ml) 1.36 1.12

1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene increased the expression of genes associated with the production of collagen and elastin.

Example 4. Inhibition of TNFα-induced levels of MMP-9

The ability of 1-hydroxy 3,5-bis (4'-hydroxystyryl) benzene to inhibit TNF-a induced levels of MMP-9 was tested at various concentration levels as follows. The formation of TNFα-induced MMP-9 is involved in the undesired destruction of the extracellular matrix of human skin.

Epidermal equivalents (EPI 200 HCF) were purchased from MatTek (Ashland, Mass.). After preparation, epidermal equivalents were incubated for 24 hours at a temperature of 37 ° C in a stabilizing medium without hydrocortisone. The equivalents were topically treated (2 mg / cm ² ) with extracts of 1-hydroxy 3,5-bis (4'-hydroxystyryl) benzene in a carrier medium 70% ethanol / 30% propylene glycol for 2 hours before treatment with TNFα (100 ng / ml ) Equivalents were incubated for 48 hours at 37 ° C in a stabilizing medium, then MMP-9 was analyzed in the supernatant using commercially available kits (R&D Systems, Minneapolis, Minnesota).

The results are shown in table 4.

TABLE 4 Processing (dose in% weight / volume) The average release of MMP-9 (ng / ml) The percentage of inhibition of the production of MMP-9 (from one TNFα) No processing 1422 ± 611 - TNFa only 3557 ± 1181 - TNFa + 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene (0.25%) 1392 ± 627 60.9 TNFα + 1-hydroxy 3,5-bis (4’-hydroxystyryl) benzene (0.5%) 1012 ± 249 71.6

1-hydroxy 3,5-bis (4'-hydroxystyryl) benzene inhibited the formation of MMP-9 induced by TNFα.

Example 5. Melanogenesis Inhibition Test

The ultraviolet (UV) radiation of the sun is the most important external irritant for the formation of melanin, which causes darkening of the skin. Reducing the formation of melanin in the skin can be achieved by inhibiting several steps of the melanin biogenesis process. Tyrosinase is a key regulatory enzyme in melanogenesis. Tyrosinase inhibiting agents will reduce melanin synthesis.

1-hydroxy 3,5-bis (4’-hydroxystyryl) benzene (0.0001, 0.001 and 0.01% w / v) was tested for tyrosinase inhibition as follows.

Samples of fungal tyrosinase (Sigma, T7755, 10 U / reaction) were tested using samples of 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene and reference samples. The reaction was initiated by adding 10 millimoles of L-dihydroxyphenylalanine (Research Organics, # 2111D) at 37 ° C. Tyrosinase activity was measured by measuring light absorption (optical density) at a wavelength of 492 nm after 30 minutes in both reference samples (not exposed to the test composition) and test samples that were exposed to the test composition.

The percentage of tyrosinase inhibition was determined by the decrease in absorption at 492 nm (relative to the reference sample) according to the following formula:

Tyrosinase Inhibition Percentage = [T _reference -T _test / T _reference )] * 100

where the T _reference is the tyrosinase activity of the reference sample and the T _test is the tyrosinase activity in the presence of the test composition. Two parallel testing of the samples was carried out, and the mean percent inhibition of tyrosinase and standard deviation were calculated. The average optical density of the reference sample was 0.622.

The results are presented in table 5.

TABLE 5 Tyrosinase activity inhibition percentage (mean ± SD) 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene - free phenol (0.0001%) 3.3 ± 1.95 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene - free phenol (0.001%) 8.21 ± 1.27 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene - free phenol (0.01%) 11.84 ± 3.22 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene - piperazine salt (0.0001%) 2.03 ± 3.94 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene - piperazine salt (0.001%) 11.52 ± 3.16 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene - piperazine salt (0.01%) 16.64 ± 2.76

1-hydroxy 3,5-bis (4′-hydroxystyryl) benzene showed a significant and dose-dependent inhibition of tyrosinase enzyme activity.

Example 6. Inhibition of melanogenesis induced by UV radiation.

One or more B16 (F10) cell samples were prepared, each of which was pretreated with a test sample followed by UVB treatment as described below. When exposed to UVB, cell melanogenesis was stimulated, after which the test compounds were evaluated for their ability to inhibit or slow down the rate of melanogenesis. Cells were lysed to measure protein at 595 nm and melanin at 470 nm. The potential of the test compounds was determined by comparing the% inhibition achieved in the test compounds relative to the treated reference sample.

On the first day, mouse B16 (F10) melanoma cells were seeded onto 60 mm plates with a density of ~ 1 million cells per plate and incubated for 48 hours at 37 ° C in an environment containing 5% CO ₂ . On the second day, cells with a confluency level of 90-100% were treated with a test compound with a given concentration (for example, 25 μg / ml) for two hours (only for samples with a test compound), followed by UVB treatment of 200 mJ / cm ² (for test samples and processed reference sample). Cells were taken on the third day (24 hours after UVB treatment for the test samples and the processed reference sample) and lysed in a protein lysis buffer solution (50 mmol Tris, pH 8.2 mmol EDTA, 150 mmol NaCl and 1% Triton X 100 - nonionic surfactant manufactured by BioRad, catalog number: 161-0407), and also centrifuged.

The resulting supernatant was well mixed with a protein dye for analysis (Bio-rad protein reagent), and then the optical density (OD) of the sample was measured at a wavelength of 595 nm using a Molecular Devices VERSAmax spectrophotometer, which was recorded as “OD for protein analysis. ” The cell mass remaining after removal of the supernatant was dissolved in DMSO alkaline buffer, and then the absorption coefficient of the resulting solution was measured on a spectrophotometer at a wavelength of 470 nm to determine the melanin content. The absorption coefficient was recorded as "OD for analysis of the content of melanin."

Reference samples of murine melanoma B16 (F10) cells were prepared and collected as described above, but without the addition of any test sample and without UVB (untreated reference sample). Other samples were prepared and collected as described above, but without the addition of a test sample and with UVB, as described below (processed reference sample).

Three samples were prepared for untreated reference samples, processed reference samples and for each test sample, and the optical density was measured in all samples to determine the content of melanin and proteins. Normalized melanin for each untreated reference sample (3 samples), the processed reference sample (3 samples) and the test sample (3 samples for each test compound) were determined from the following equation:

Normalized melanin = OD for analysis of melanin content / OD for analysis of protein content.

The average values of normalized melanin were calculated for untreated reference samples and processed reference samples (the sum of the three obtained values divided by three).

The exposure values for the reference sample (which can be understood as the increase in melanin caused by exposure to UV radiation without using any test sample to reduce melanogenesis) were defined as the difference between the average value of the normalized melanin of the processed reference sample and the average value of the normalized melanin of the untreated reference sample . Similarly, the exposure value for each test sample (which can be understood as the additional amount of melanin relative to the base level of the sample not treated with UV radiation) was defined as the difference between the normalized melanin value of the test sample and the average normalized melanin value of the untreated reference sample. Then, the percent inhibition for each test sample was obtained from the following equation:

Inhibition percentage = 100 × [(exposure value for the reference sample - exposure value with the test sample) / exposure value for the reference sample].

The average percent inhibition was calculated as the sum of the three obtained percent inhibitions for each test sample divided by three.

The sequence for calculating the percent inhibition is shown by the example of 1-hydroxy 3,5-bis (4'-hydroxystyryl) benzene-free phenol (0.0001%) in table 6A below.

TABLE 6A Example of calculating the percentage of inhibition of melanogenesis caused by exposure to UV radiation Average normalized melanin, untreated reference sample 0.122 Average normalized melanin, reference sample treated with UVB 0.234 Impact value for the reference sample 0.234-0.122 = 0.112 The value of normalized melanin (double test sample S1 and S2) 0.19 (S1)
0.187 (S2) Impact value for test sample 0.19-0.122 = 0.068
0.187-0.122 = 0.065 Percent Inhibition for Test Sample [(0,112-0,068) / 0,112] × 100 = 39.05% (S1)
[(0,112-0,065) / 0,112] × 100 = 41.93% (S2)
Average = (39.05 + 41.93) / 2 = 40.49%

1-hydroxy 3,5-bis (4’-hydroxystyryl) benzene and its piperazine salt were evaluated in terms of inhibition of melanogenesis caused by UV radiation. The test is described above. The results are presented in table 6B.

TABLE 6B The percentage of inhibition of melanogenesis caused by UV radiation Percentage inhibition of melanogenesis due to UV radiation (mean ± SD) 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene - free phenol (0.00001%) 18.93 ± 5.92 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene - free phenol (0.00005%) 33.27 ± 4.39 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene - free phenol (0.0001%) 40.49 ± 2.04 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene - piperazine salt (0.00001%) 13.93 ± 11.33 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene - piperazine salt (0.00005%) 33.52 ± 1.54 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene - piperazine salt (0.0001%) 55.70 ± 4.44

1-hydroxy 3,5-bis (4’-hydroxystyryl) benzene and its piperazine salt showed strong inhibition of melanogenesis caused by UV radiation.

Example 7. Inhibition of pigmentation

Matter Tek's epidermal skin equivalents fabricated using the MelanoDerm ™ system were used as follows. MatTek's MelanoDerm ™ system consists of normal human epidermal keratinocytes (NHEK) and melanocytes (NHM), which were cultured to form a multilayer and highly differentiated model of the human epidermis. In particular, the following tests used 9 mm diameter MEL-300-B fabrics.

1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene and its piperazine salt were prepared in an appropriate carrier medium and applied daily topically to a skin model. The experiment lasted 8 days. The measurement was carried out on day 9.

The degree of clarification for each tissue of the skin model (L-value) was determined using a spectrophotometer (Konica Minolta CM-2600d). ΔL (degree of clarification compared to a reference sample treated with a carrier medium (inert substance)) for each test sample was calculated by the following formula:

ΔL = L-value of the processed sample – L-value of the reference sample

The results are shown in table 7.

TABLE 7 The degree of clarification (ΔL) 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene - piperazine salt (0.1%) 1.46 ± 0.71 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene - piperazine salt (0.25%) 2.83 ± 0.41 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene - piperazine salt (0.5%) 4.60 ± 0.61 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene - free phenol (0.5%) 4.23 ± 0.64

1-hydroxy 3,5-bis (4’-hydroxystyryl) benzene and its piperazine salt showed inhibition of melanogenesis in epidermal tissue equivalents.

Example 8

The activity of 1-hydroxy 3,5-bis (4'-hydroxystyryl) benzene was evaluated based on the analysis of gram-positive bacteria, gram-negative bacteria and two representatives of the fungal species as follows.

An initial 4% solution (40 mg / ml) was prepared by weighing 200 mg of 1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene powder (test preparation) in a yellow test tube and dissolving it in 5 ml of DMSO by vigorous stirring with room temperature.

Antimicrobial sensitivity testing was performed to determine the minimum inhibitory concentration (MIC) of the test drug by culture medium analysis based on the standard protocol of the National Committee for Clinical and Laboratory Standards (NCCLS) (NCCLS, 2000). MIC in this analysis was defined as the lowest concentration of the test drug, which inhibited the visible growth of the studied microorganisms.

Seven different microorganisms were tested: three (3) gram-positive bacteria (Staphylococcus aureus Staphylococcus aureus (MO-012-015), Staphylococcus epidermidis (Staphylococcus epidermidis) (MO-012-045), and Propionic Acne Bacteria (Propionibacterium acnes) (ATCC # 6919)), two (2) gram-negative bacteria (E. coli (Escherichia coli) (ATCC # 8739) and Pseudomonas aeruginosa (Pseudomonas aeruginosa) (ATCC # 9027)) and two (2) representatives of the fungal species (candida white (Candida albicans) (ATCC # 10231) and black mold (Aspergillus niger) (ATCC # 16404)). All samples, with the exception of staphylococci, were obtained from the American Type Culture Collection (ACCT). Two (2) samples of staphylococci were obtained as clinical isolates.

MIC for each of the seven strains was determined for the test drug using solution titers prepared from the original 4% w / v solution of the test drug to obtain formulations for the study with initial concentrations of 1.00% w / v and 0.25% weight ./volume.

The antimicrobial susceptibility test was performed in a 96-well microtiter plate. During this test, two titers of the starting concentration of the test drug solution were sequentially prepared in the first 10 rows of the microplate (rows 11 and 12 served as positive and negative control samples for the test organism).

An inoculum suspension was prepared for each organism, which was adjusted for optical density at a wavelength of 600 nm (OD600). The indicated suspension was diluted in a ratio of 1: 100, and 100 μl was added to each well of the microplate to obtain a final suspension of ~ 1 * 10 ⁶ CFU / well.

The plates were closed and incubated at a temperature of 35 ° C for bacteria (propionic bacteria acne (Propionibacterium acnes) was incubated under anaerobic conditions) and at a temperature of 25 ° C for fungal. Microplates were incubated for 48 hours, after which MICs were counted (tablets with propionic acne bacterium (Propionibacterium acnes) were incubated for ~ 72 hours, fungal plates were incubated for ~ 120 hours). MIC was the lowest concentration of antimicrobial agent that did not produce visually verified growth after incubation.

The analysis of the minimum concentration of biocide (ICD) is designed to determine the lowest concentration at which the test drug shows bactericidal and fungicidal properties in relation to a particular microorganism. After analyzing the plate on the MIC, the Multi-Blot replicator on 96 solid-state pipettes was sterilized on fire, cooled and centered so that each pipette was immersed in a separate well of the MIC plate. Then the replicator was used to create a tablet with fresh agar so that a small aliquot of the volume from the microtiter well for the MIC was introduced into the agar matrix of the ICD plate. The microplates were incubated for 48 hours, after which the ICD was counted (tablets with propionic acne bacterium (Propionibacterium acnes) were incubated for ~ 72 hours, fungal tablets were incubated for ~ 120 hours). The minimum concentration of biocide (ICD) was defined as the minimum concentration of biocide at which there was no growth of bacteria or fungi.

The MIC and ICD values were calculated for the test drug in relation to each test organism. The results are shown in table 8.

TABLE 8 Test Staphylococcus aureus Epidermal staphylococcus Propionic Acne Bacteria E. coli Pseudomonas aeruginosa Candida White Black mold MIC 0,0004% 0,0008% 0,0008% 0.031% 0.25% ≤0.002% 0.50% ICD 0,0008% 0,0008% 0,0008% ≥1.0% ≥1.0% ≥0.002% ≥1.0%

The data are presented as the values (%, weight / volume) of MIC and ICD (minimum inhibitory concentration and minimum concentration of biocide), and show that 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene found inhibition of the growth of gram-positive bacteria, gram-negative bacteria and representatives of the fungal species. The composition also showed biocidal activity against gram-positive bacteria and yeast. In addition, these data give reason to conclude that 1-hydroxy 3,5-bis (4'hydroxystyryl) benzene increased activity against gram-positive bacteria and yeast compared with gram-negative bacteria and molds.

Example 9

The composition of this invention is prepared by mixing the ingredients in table 9.

TABLE 9 Tradename Name by INCI % the weight Deionized water Water 70.64 Sodium chloride Sodium chloride 0.01 1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene 1.00 Snow White Vaseline Oil Petroleum jelly 4.00

ISOFOL 28 Dodecylhexadecanol 2,50 DOW CORNING Q7-9120 (20 cSt) Dimethicone 1.25 KESSCO IPP Isopropyl palmitate 0.00 VARISOFT TA-100 Distearyldimonium chloride 5.00 Glycerol Glycerol 12.00 Benzyl alcohol Benzyl alcohol 0.60

Water is added to the reaction vessel. Mixing is started and salt is added, stirring is continued until the salt is dissolved. Turn on the heat and continue stirring until a temperature of 85 ° C is reached. 1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene is dissolved in glycerol, then added, but stirring continues and the temperature is maintained at 85 ° C. Distearyldimonium chloride, as well as liquid paraffin and dodecylhexadecanol, dimethicone and isopropyl palmitate are added. The composition is stirred at a temperature of 85 ° C for another 10-15 minutes. Then the composition stops heating, it is mixed and cooled. At 40 ° C benzyl alcohol is added, if necessary with water, the composition is mixed and cooled to 30-35 ° C. Then the composition fills the package.

The composition of this invention is prepared by mixing the ingredients in table 10.

TABLE 10 Tradename Name by INCI % the weight. Deionized water Water 70.55 Snow White Vaseline Oil Petroleum jelly 4.00 ISOFOL 28 Dodecylhexadecanol 2,50 DOW CORNING Q7-9120 (20 cSt) Dimethicone 1.25 OSH OSH 0.10 KESSCO IPP Isopropyl palmitate 3.00 VARISOFT TA-100 Distearyldimonium chloride 5.00

1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene 1,0 Glycerol Glycerol 12.00 Retinol 10S Soy glycine (soy) oil and retinol 1.00 Benzyl alcohol Benzyl alcohol 0.60

Water was added to the reaction vessel and a temperature of 85 ° C. was set. Mixing is started and glycerin is added, stirring is continued until glycerol is dissolved. Add VARISOFT TA-100, as well as liquid paraffin and ISOFOL 28, DOW CORNING Q7-9120 20 CS and isopropyl palmitate. The composition is stirred at a temperature of 85 ° C for another 10-15 minutes. Then the composition stops heating, it is mixed and cooled.

The composition of this invention is prepared by mixing the ingredients in table 11.

TABLE 11 Tradename Name by INCI % the weight. Deionized water Water 73 HYDROLITE 5 Pentylene glycol 5 1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene 5 NATRULON OSF Oleosome safflower dyeing 10 FINSOLV TN Alkyl benzoate C12-15 four ARISTOFLEX AVC Ammonium Acryloyl Dimethyl Taurate / VP Copolymer 2 Tanacetum parthenium extract Juice of leaves / flowers / stems of Chrysanthemum Parthenium (feverfew) one

1-hydroxy 3,5-bis (4'-hydroxystyryl) benzene was weighed and dissolved in HYDROLITE 5, deionized water was added until phase A was formed. Oleosomes and FINSOLV TN were mixed until phase B was formed. Phase B was very slowly added to phase A with continuous stirring. . Stirring was continued for 15 minutes until a homogeneous emulsion was obtained. ARISTOFLEX AVC was added to the emulsion with continuous rapid stirring until a thick and uniform composition was obtained.

The composition of this invention is prepared by mixing the ingredients in table 12.

TABLE 12 Tradename Name by INCI % the weight. Deionized water Water 67.70 Carbomer Crosslinked Polyacrylic Acid 0.60 VERSENE NA Disodium EDTA 0.20 Brij 72 Stareth 2 0.75 Brij 721 Stareth 21 1,50 FINSOLV TN Alkyl benzoate C12-15 2.00 Dimethicone NF Silicone fluid Dow corning Q7-9120 (20 cSt) 5.00 PHENONIP XB Phenoxyethanol, methylparaben, ethylparaben, propylparaben 1.00 LYS'LASTINE Peucedanum graveolens (10% active substance) 10.00 SYMMATRIX Maltodextrin, Rubus fruticosus 10.00 Leaf (Blackberry) Extract (10% Active) 1-hydroxy 3,5-bis (4'hydroxy-styryl) benzene 0.25 Glycerol Glycerol 1,0

The oil phase was prepared by adding FINSOLV TN to a clean glass beaker. Mixing begins, and the vessel is heated to a temperature of 55-60 ° C. When the oil phase reaches a temperature of 55 ° C or higher, Brij 72 and Brij 721 are added. When the oil phase reaches a temperature of 55-60 ° C, it is continued to withstand at this temperature and stirred for 15 minutes (or until uniform). The temperature is then maintained at 55-60 ° C, and stirring is continued until added to the aqueous phase.

The aqueous phase is obtained by adding water to a clean glass beaker. Mixing begins, and the vessel is heated to a temperature of 55-60 ° C. Disodium EDTK is added. At a temperature of 55-60 ° C, the ingredients are mixed for 15 minutes or until uniform. The temperature is then maintained at 55-60 ° C, and stirring is continued to mix the phases.

The oil phase is added to the aqueous phase with increased stirring, then they are mixed at high speed for 10–20 minutes. At a temperature of 50 ° C or lower, dimethicone is added. At a temperature of 40 ° C or lower, PHENONIP XB is added. Then the phases are mixed for 10 minutes or until uniform. Sodium hydroxide is added (target pH is 5.4). The composition is then mixed for 10 minutes or until uniform. Then add LYS’LASTINE and SYMMATRIX. 1-hydroxy 3,5-bis (4′-hydroxystyryl) benzene was weighed and dissolved in glycerol and added to the mixture, which was stirred until uniform. Then sufficient water was added, and the composition was mixed for another 10 minutes.

Although the disclosure of the present invention is accompanied by its detailed description, it is understood that the above description was intended to illustrate, but not limit the scope of the present invention, which is determined by the scope of the attached claims. Other aspects, advantages and modifications are included in the scope of the claims.

Claims (13)

1. A topical anti-aging cosmetic composition comprising 1-hydroxy 3,5-bis (4’-hydroxystyryl) benzene or its cosmetically acceptable salt and a cosmetically acceptable topical carrier including a softener and an emulsifier. 2. The composition according to claim 1, further comprising an inhibitor of NF-ĸB. 3. The composition according to claim 1, wherein said composition comprises from about 0.01 wt.% To about 10 wt.% Of the above 1-hydroxy 3,5-bis (4’-hydroxystyryl) benzene. 4. The composition according to claim 1, additionally containing an agent for lightening the skin. 5. The composition according to claim 1, essentially not containing preservatives. 6. The composition according to claim 5, wherein the aforementioned preservatives are selected from the group consisting of parabens, benzoic acid and its salts, phenoxyethanol, isothiazolones, imidazolidinyl urea, iodopropinyl butylcarbamate, hydantoin DMDM, caprylyl glycol, its hydrochloric acid acetic acid, dehydroacetic acid, sorbitol, acetic acid, hydrochloride, acetic acid, , glycerylcaprylate, phenylpropanol, sodium levulinate, anisic acid, ethylhexylglycerol, benzyl alcohol, and combinations thereof. 7. A method of cosmetic care for human skin, comprising topical application to a human skin of a composition comprising 1-hydroxy 3,5-bis (4’-hydroxy-styryl) benzene or a cosmetically acceptable salt thereof. 8. The method according to claim 7, wherein said composition is applied using an applicator selected from the group consisting of masks and wipes. 9. A method of cosmetic skin care with signs of aging, including topical application to the skin in need of such care, a composition comprising 1-hydroxy 3,5-bis (4’s hydroxy-styryl) benzene or a cosmetically acceptable salt thereof. 10. The method according to claim 9, wherein the aforementioned sign of skin aging is selected from the group consisting of lines and wrinkles, loss of elasticity, uneven skin and spotting. 11. A method of cosmeticly brightening a skin, comprising the step of topically applying to a skin in need of such care a composition comprising 1-hydroxy 3,5-bis (4’-hydroxystyryl) benzene or a cosmetically acceptable salt thereof.