RU2776073C2 - Cosmetic compositions and skin treatment method - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to the treatment of skin pathologies. A method for the treatment of skin pathologies caused by aging under the impact of internal processes, exogenous factors or skin diseases includes the application to the skin of a composition including a compound of the formula (I)

,

where dotted lines are a single or double bound; R₁ is H or a carbon chain, which is linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; R₂ is a carbon chain, which is linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; A is an unsubstituted carbon chain, which is linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms.

EFFECT: invention allows for avoiding unfavorable effect from the use of retinoids.

10 cl, 4 dwg, 2 tbl, 5 ex

Description

FIELD OF THE INVENTION

The present invention relates to compositions having retinol-like activity and methods of using these compositions to treat the skin.

DESCRIPTION OF THE PRIOR ART

Human skin is subject to certain aging processes, some of which are internal (eg age-related aging) and some are exogenous (eg photoaging). In addition, temporary or even chronic skin changes may occur, such as acne, oily or dry skin, keratoses, rosacea, photosensitivity, inflammatory, erythematous, and allergic or autoimmune reactions such as dermatosis and photodermatosis.

The consequences of the aforementioned aging processes may include thinning of the skin, weakening of the epidermis-dermis bond strength, and reduction in the number of cells and the blood vessels that feed them. This often leads to the formation of fine lines and wrinkles, and pigmented defects may appear.

Retinoids are used to treat skin pathologies caused by aging under the influence of internal processes, exogenous factors or skin diseases. However, despite the beneficial effects of retinoids, their benefits are limited due to their irritating effects on the skin. These side effects may limit their use.

To date, the search for alternative compounds to replace retinoids has achieved limited success in the treatment of skin pathologies associated with aging, such as skin atrophy, acne, photoaging, and in reducing the appearance of wrinkles, fine lines, stretch marks or cellulite.

A number of aromatic compounds have been identified and used on the skin to provide a number of personal care benefits. For example, US Pat. No. 4,939,171 assigned to Henkel describes the use of compounds comprising 3-(4-farnesyloxyphenyl)-propionic acid to provide anti-seborrheic properties. The patent, however, does not establish anti-aging properties associated with the compositions described therein.

In addition, US Patent Application No. 2011/0318439, assigned to Ecobiotics LTD., describes compounds derived from plants of the genus Acronychia , including 3-(4-farnesyloxyphenyl)-propionic acid, for use as antioxidants, antibacterial agents, anthelmintic agents, anti-inflammatory agents, agents for cancer chemoprevention, nutritional supplements and/or flavoring agents. The patent, however, does not establish the anti-aging properties associated with the compositions described therein.

US Pat. No. 7,173,062 describes a compound having anti-aging activity by condensing vitamin A and retinoic acid. WO2005/066116 describes retinoid-like compounds with a chalcone oxime functional group. EP1723952 describes compositions that are less irritating to the skin and prevent the formation of wrinkles. EP0983992 contains information on RXR and RAR selective retinoid compounds.

Thus, the purpose of this invention is to provide such new compositions and methods for the treatment of skin pathologies, which avoid the adverse effects of the use of retinoids.

SUMMARY OF THE INVENTION

It is believed that, based on the description provided herein, a person skilled in the art will be able to use this invention to the fullest extent. The following specific embodiments can be considered only as examples, which in no way limit the rest of the present description.

Unless otherwise indicated, all technical and scientific terms used herein have the common meaning understood by any person of ordinary skill in the field to which the invention pertains. In addition, all publications, patent applications, patents and other materials mentioned in this document are incorporated herein by reference. All percentages in this document are by weight of the total composition unless otherwise noted.

As used herein, a composition "substantially free" of an ingredient means a composition containing about 2% or less of that ingredient by weight, based on the total weight of the composition. Preferably, the composition substantially free of the ingredient contains about 1% or less, more preferably about 0.5% or less, more preferably about 0.1% or less, more preferably about 0.05% or less, more preferably about 0 01% or less of an ingredient by weight, based on the total weight of the composition. In certain more preferred embodiments, a composition substantially free of an ingredient is free of an ingredient, i.e., the ingredient is not present in the composition.

As used herein, the term "cosmetically/dermatologically acceptable" means that the ingredients that the term describes are suitable for use in contact with tissues (e.g., skin or hair) without exhibiting non-specific toxicity, incompatibility, instability, irritation, allergic reaction, etc. n. As will be understood by any person skilled in the art, cosmetically/dermatologically acceptable salts are acidic/anionic or alkaline/cationic salts.

As used herein, the term "safe and effective amount" means an amount of an extract or composition sufficient to induce the desired effect, but sufficiently low to prevent serious side effects. The safe and effective amount of a compound, extract or composition will vary depending on, for example, the age, health and environmental conditions of the end user, the duration and nature of the treatment, the particular extract, ingredient or composition used, the particular pharmaceutically acceptable carrier used, and to similar factors.

In general, this document applies the rules of the International Union of Pure and Applied Chemistry (IUPAC) nomenclature in accordance with the following definitions of terms.

The term "C1-8 alkyl", whether used alone or as part of a substituent group, refers to a saturated aliphatic branched or straight chain monovalent hydrocarbon radical having 1-8 carbon atoms. For example, "C1-8 alkyl" specifically includes methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, t-butyl, 1-butyl, 1-pentyl, 2-pentyl, 3 -pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 1-octyl, 2-octyl, 3-octyl, etc. The term may also refer to the corresponding alkyldiyl radical. The alkyl and alkyldiyl radicals can be attached to the parent molecule via a terminal carbon atom or via an intrachain carbon atom. Similarly, any number of variable substituents allowed by the available valences may be attached to the alkyl or alkyldiyl radical.

The term "C1-4 alkyl", whether used alone or as part of a substituent group, refers to a saturated aliphatic branched or straight chain monovalent hydrocarbon radical or alkyldiyl linking group having the number of carbon atoms indicated, the radical obtained by removing one hydrogen atom from a carbon atom, and the alkyl diyl linking group is obtained by removing one hydrogen atom from each of the two carbon atoms in the chain. The term "C1-4 alkyl" refers to a radical having 1-4 carbon atoms in a linear or branched configuration. For example, "C1-4 alkyl" specifically includes methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, t-butyl, 1-butyl, and the like radicals. Alkyl and alkyldiyl radicals may attach to the main molecule through a terminal carbon atom or through a carbon atom inside the chain. Similarly, any number of variable substituents allowed by the available valences may be attached to the alkyl or alkyldiyl radical.

The term "C2-4 alkenyl" refers to an alkenyl radical having 2-4 carbon atoms. For example, specifically includes ethenyl, propenyl, allyl (2-propenyl), butenyl, and the like radicals. As described above, an alkenyl radical can be similarly attached to the parent molecule and further substituted where indicated.

The term "halogen", alone or in combination with other terms, means a halogen atom such as fluorine, chlorine, bromine or iodine.

The term "substituted" refers to a base molecule in which one or more hydrogen atoms have been replaced by the number of substituents allowed by the available valences. Substitution is not limited to the parent molecule, but can also occur on a substituent radical, whereby the radical is converted to a linking group.

The term "independently selected" refers to two or more substituents which may be selected from a group of variable substituents, the selected substituents being the same or different.

The term "dependently selected" refers to one or more variable substituents that are given in the specified combination for substitution in the main molecule (for example, variables that refer to groups of substituents listed in the tabular list of compounds).

Acceptable salts prepared using inorganic bases include, for example, sodium or potassium salts, etc. Acceptable salts prepared using organic bases include, for example, salts formed by reaction with primary, secondary, or tertiary amines, etc. P.

The invention relates to a compound of formula (I):

where -

dotted lines show a single or double bond; preferably one of the dotted lines represents a double bond;

R ₁ represents H, a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms;

R ₂ represents H, a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; preferably a methyl (-CH3) or methylene (=CH ₂ ) functional group;

A represents a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; preferably 1 to 10 carbon atoms; more preferably 6 carbon atoms; preferably an aromatic functional group, preferably a phenyl functional group; preferably 2-methyl-prop-1,3-diene.

The compounds include the corresponding salts, including, without limitation, Li ⁺ , Na ⁺ , K ⁺ , Ca ²⁺ or Mg ²⁺ .

In more preferred embodiments, the compounds are:

(2 E ,4 E ,6 E )-7-(1,1,2,2,3,3-hexamethyl-2,3-dihydro- 1H -inden-5-yl)-3-methylocta-2, 4,6-trienoic acid

or

4-(1-(1,1,2,2,3,3-hexamethyl-2,3-dihydro- 1H -inden-5-yl)vinyl)benzoic acid.

The present invention relates to compounds such as (2E,4E,6E)-7-(1,1,2,2,3,3-hexamethyl-2,3-dihydro-1H-inden-5-yl)-3- methylocta-2,4,6-trienoic acid and 4-(1-(1,1,2,2,3,3-hexamethyl-2,3-dihydro-1H-inden-5-yl)vinyl)benzoic acid and derivatives thereof which exhibit retinoid-like activity in the skin at a reduced irritant potential. These compounds can be used as an alternative to retinoids for topical application to the skin, which has a reduced irritant effect. These compounds can be used, without limitation, to care for aging skin and improve texture, minimizing fine lines and wrinkles, age spots, skin pigmentation and uneven skin tone, dry skin, acne, psoriasis and papillomas.

BRIEF DESCRIPTION OF GRAPHICS

FIG. 1 is a graph showing the dose-dependent effect on RARγ receptors in both agonist (AG) and positive allosteric modulator (PAM) modes for compounds (1) and (2).

FIG. 2 is a bar graph showing the results of induced expression of the CRABP2 (cellular retinoic acid-binding protein-II) gene in human skin explants after 48 hours.

FIG. 3 is a bar graph showing the results of induced expression of the HBEGF (heparin-binding growth factor like epidermal growth factor) gene in human skin explants after 48 hours.

FIG. 4 is a bar graph of the results of the test for the release of the inflammatory mediator interleukin 8 (IL-8 mRNA) in a skin explant after 48 hours.

Preferably, the methods of the invention involve the application to the skin of an effective anti-aging amount of a compound of formula I, preferably a safe and effective amount. In one embodiment, the methods involve applying to the skin to be treated a compound of Formula I in an amount of greater than zero to about 20%. In another embodiment, the methods include applying to the skin to be treated about 0.0001% to about 20%, about 0.001% to about 10%, about 0.01% to about 5%, about 0.1% to about 5% or about 0.2% to about 2% of a compound of formula I. In yet another embodiment, the methods involve applying to the skin more than zero to about 1%, about 0.0001 to about 1%, about 0.001 to about 1%. or from about 0.01% to about 1% of a compound of formula I.

Any suitable carrier may be used in the compositions of the present invention. Preferably, the carrier for the skin care composition is a cosmetically acceptable carrier. As will be appreciated by one of ordinary skill in the art, cosmetically acceptable carriers include carriers that are suitable for use in contact with the body, in particular the skin in the application of anti-aging agents, without exhibiting non-specific toxicity, incompatibility, instability, irritation, allergic reaction, and etc. The safe and effective amount of the carrier is from about 50% to about 99.999%, preferably from about 80% to about 99.9%, more preferably from about 99.9% to about 95%, most preferably from about 99.8% to about 98% composition. The carrier may be present in a wide variety of forms. For example, emulsion carriers are used within the scope of this invention, including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and oil-in-water-in-silicone emulsions. These emulsions may have a wide range of viscosities, such as from about 100 centipoise to about 200,000 centipoise. Examples of suitable cosmetically acceptable carriers include cosmetically acceptable solvents and agents for cosmetic solutions, suspensions, lotions, creams, serums, essences, gels, toners, pomades, sprays, ointments, washes and soap bars, shampoos, hair conditioners, pastes, foams, mousses, powders, shaving creams, wipes, patches, strips, patches with a power source, microneedle patches, bandages, hydrogels, film-forming products, face and skin masks, color cosmetics, liquid drops, etc. These types of products may encompass several types of cosmetically acceptable carriers including, without limitation, solutions, suspensions, emulsions such as microemulsions and nanoemulsions, gels, solids, liposomes, products from other encapsulation technologies, and the like.

The following are non-limiting examples of such carriers. Ordinary specialists in this field can enter into the compositions and other carriers. In one embodiment, the carrier comprises water. In a further embodiment, the carrier may also contain one or more aqueous or organic solvents. Examples of organic solvents include, without limitation: dimethyl isosorbide; isopropyl myristate; surfactants of cationic, anionic and non-ionic nature; vegetable oils; mineral oils; waxes; gums; synthetic and natural gelling agents; alkanols; glycols; and polyols. Examples of glycols include, without limitation, glycerol, propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, polyethylene glycol, polypropylene glycol, diethylene glycol, triethylene glycol, capryl glycol, glycerol, butanediol, and hexanetriol, and copolymers or mixtures thereof. Examples of alkanols include, without limitation, alkanols having about 2 carbons to about 12 carbons (eg, about 2 carbons to about 4 carbons), such as isopropanol and ethanol. Examples of polyols include, without limitation, polyols having about 2 carbons to about 15 carbons (eg, about 2 carbons to about 10 carbons), such as propylene glycol. Organic solvents may be present in the carrier in an amount based on the total weight of the carrier from about 1 percent to about 99.99 percent (for example, from about 20 percent to about 50 percent). Water may be present in the carrier (prior to use) in an amount based on the total weight of the carrier from about 5 percent to about 95 percent (eg, from about 50 percent to about 90 percent). The solutions may contain any suitable amount of solvent, including from about 40% to about 99.99%. Certain preferred solutions contain from about 50% to about 99.9%, from about 60% to about 99%, from about 70% to about 99%, from about 80% to about 99%, or from about 90% to 99%.

From this solution, you can make a lotion. Typically, lotions contain at least one emollient in addition to the solvent. Lotions may contain from about 1% to about 20% (e.g., about 5% to about 10%) emollient(s) and about 50% to about 90% (e.g., about 60% to about 80%) water. . In this document, the term "emollients" refers to materials used to prevent or reduce dryness, as well as to protect the skin or hair. Examples of emollients include, without limitation, those listed in International Cosmetic Ingredient Dictionary and Handbook, eds. Wenninger and McEwen, pp. 1656-61, 1626, and 1654-55 (The Cosmetic, Toiletry, and Fragrance Assoc., Washington, D.C., 7th Edition, 1997) (hereinafter ICI Handbook).

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

Another type of product that can be prepared from a solution is an ointment. The ointment may contain a simple base of animal, vegetable or synthetic oils or semi-solid hydrocarbons. The ointment may contain from about 2% to about 10% emollient(s) plus from about 0.1% to about 2% thickener(s).

The compositions used in the present invention may also be formulated as emulsions. If the carrier is an emulsion, then it contains from about 1% to about 10% (eg, from about 2% to about 5%) of the emulsifier(s). Emulsifiers can be non-ionic, anionic or cationic. Examples of emulsifiers include, without limitation, those listed in ICI Handbook, pp. 1673-1686.

Lotions and creams can be prepared as emulsions. Typically, such lotions contain from 0.5% to about 5% emulsifier(s), while such creams typically contain from about 1% to about 20% (for example, from about 5% to about 10%) softener(s); about 20% to about 80% (eg, 30% to about 70%) water; and about 1% to about 10% (eg, about 2% to about 5%) emulsifier(s).

Single phase emulsion skin care preparations such as oil-in-water and water-in-oil type lotions and creams are well known in the art and are used in the claimed invention. The claimed invention also uses compositions based on a multi-phase emulsion of the water-in-oil-in-water or oil-in-water-in-oil type. Typically, such one- or multi-phase emulsions contain water, softeners and emulsifiers as main ingredients.

The compositions of this invention may also be formulated as a gel (eg, an aqueous, alcoholic, hydroalcoholic, or oily gel using the appropriate gelling agent(s)). Suitable gelling agents for aqueous and/or alcoholic gels include, without limitation, natural gums, acrylic acid, and cellulose-derived acrylate polymers and copolymers (eg, hydroxymethylcellulose and hydroxypropylcellulose). Suitable gelling agents for oils (such as mineral oil) include, without limitation, hydrogenated butylene/ethylene/styrene copolymer and hydrogenated ethylene/propylene/styrene copolymer. Such gels typically contain from about 0.1% to 5% by weight of such gelling agents.

The compositions of the present invention may also be formulated in solid form (eg, wax-based lipstick, soap bar composition, powder, or wipe). The composition of the present invention may also be combined with a solid, semi-solid, or soluble substrate (eg, wipe, mask, pad, glove, or strip).

The compositions of the present invention may further contain any of a number of additional cosmetically active agents. Examples of suitable co-active agents include: skin lightening co-agents, darkening agents, anti-acne agents, gloss control agents, anti-microbial agents such as anti-yeast agents, anti-fungal and anti-bacterial agents, anti-inflammatory agents, anti-parasitic agents, external analgesics, sunscreens, photoprotectors. , antioxidants, keratolytic agents, detergents/surfactants, humectants, nutrients, vitamins, energy boosting agents, antiperspirants, astringents, deodorants, hair removers, hair growth enhancing agents, hair growth retardants, sealants, hydration enhancers, performance enhancers, anti-corn agents, skin conditioning agents, anti-cellulite agents, fluorides, teeth whitening agents, antiplaque agents and plaque dissolving agents, odor control agents ha, such as odor-masking or pH-adjusting agents, and the like. Examples of various suitable additional cosmetically acceptable actives include hydroxy acids, benzoyl peroxide, D-panthenol, UV filters including, but not limited to, avobenzone (Parsol 1789), disodium bisdisulizole (Neo Heliopan AP), diethylaminohydroxybenzoylhexyl benzoate (Uvinul A Plus), ecamsul (Mexoryl SX), methyl anthranilate, 4-aminobenzoic acid (PABA), cinoxate, ethylhexyl triazone (Uvinul T 150), homosalate, 4-methylbenzylidene camphor (Parsol 5000), octyl methoxycinnamate (Octinoxate), octyl salicylate (Octisalate), padimate O (Escalol 507) , phenylbenzimidazole sulfonic acid (Ensulizole), polysilicon-15 (Parsol SLX), trolamine salicylate, bemotrizinol (Tinosorb S), benzophenones 1-12, dioxybenzone, drometrizole trisiloxane (Mexoryl XL), iscotrisinol (Uvasorb HEB), octocrylene, oxybenzone (Eusolex 4360) , sulisobenzone, bisoctrizol (Tinosorb M), titanium dioxide, zinc oxide, carotenoids, free radical scavenger, spin traps, retinoids and retinoid precursors, so such as retinol, retinoic acid and retinyl palmitate, ceramides, polyunsaturated fatty acids, essential fatty acids, enzymes, enzyme inhibitors, minerals, hormones such as estrogens, steroids such as hydrocortisone, 2-dimethylaminoethanol, copper salts such as copper chloride, copper containing peptides such as Cu:Gly-His-Lys, coenzyme Q10, amino acids such as proline, vitamins, lactobionic acid, acetyl coenzyme A, niacin, riboflavin, thiamine, ribose, electron carriers such as NADH and FADH ₂ , and other plant extracts such as extracts of oats, aloe vera, feverfew, soybean, shiitake mushroom, and their derivatives and mixtures.

In one embodiment, the compositions of the present invention are skin care compositions that contain a compound of Formula I and at least one active skin lightening agent. Examples of suitable skin lightening active agents include, but are not limited to, tyrosinase inhibitors, melanin inhibitors, melanosome transfer inhibitors including PAR-2 antagonists, scrubs, sunscreens, retinoids, antioxidants, tranexamic acid, skin whitening agents, allantoin, opacifiers, talcs and silicas, zinc salts, and the like. and other agents as described in Solano et al . Pigment Cell Res. 2006, 19(550-571). Examples of suitable tyrosinase inhibitors include, without limitation, vitamin C and derivatives thereof, vitamin E and derivatives thereof, kojic acid, arbutin, resorcinols, hydroquinone, flavones, e.g. licorice flavonoids, licorice root extract, mulberry root extract, Dioscorea coposita root extract , saxifrage extract (Saxifraga) and the like, ellagic acid, salicylates and derivatives, glucosamine and derivatives, fullerene, hinokitiol, dicarboxylic acid, acetylglucosamine, magnolignan, combinations of two or more of them, and the like. 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 natural extract enriched with 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 vitamin E derivatives. Examples of resorcinol derivatives include , without limitation, resorcinol, 4-substituted resorcinols such as 4-alkylresorcinols such as 4-butylresorcinol (rucinol), 4-hexylresorcinol, phenylethylresorcinol, 1-(2,4-dihydroxyphenyl)-3-(2,4-dimethoxy -3-methylphenyl)-propane, and the like. and natural extracts enriched with resorcinols. Examples of salicylates include, without limitation, salicylic acid, acetylsalicylic acid, 4-methoxysalicylic acid, and salts thereof. In some preferred embodiments, the tyrosinase inhibitors include a 4-substituted resorcinol, a vitamin C derivative, or a vitamin E derivative. In more preferred embodiments, the tyrosinase inhibitor comprises phenylethylresorcinol, 4-hexylresorcinol, or ascorbyl-2-glucoside.

Examples of suitable melanin degradation agents include, without limitation, peroxides and enzymes such as peroxidases and ligninases. In some preferred embodiments, the melanin inhibitory agents include peroxide or ligninase.

Examples of suitable melanosome transfer inhibiting agents include PAR-2 antagonists such as soy trypsin inhibitor or Bowman-Birka inhibitor, vitamin B3 and derivatives such as niacinamide, soy essence, whole soy, soy extract. In some preferred embodiments, the melanosome transfer inhibiting agents include soy extract or niacinamide.

Examples of exfoliants include, without limitation, alpha hydroxy acids such as lactic acid, glycolic acid, malic acid, tartaric acid, citric acid, or any combination of any of these, beta hydroxy acids such as salicylic acid, polyhydroxy acids such as lactobionic acid and gluconic acid; and mechanical exfoliating agents such as microdermabrasion agents. In certain preferred embodiments, the scrub includes glycolic acid or salicylic acid.

Examples of sunscreens include, but are not limited to, avobenzone (Parsol 1789), disodium bisdisulizole (Neo Heliopan AP), diethylaminohydroxybenzoylhexyl benzoate (Uvinul A Plus), ecamsul (Mexoryl SX), methyl anthranilate, 4-aminobenzoic acid (PABA), cinoxate, ethylhexyltriazone (Uvinul T 150), homosalate, 4-methylbenzylidene camphor (Parsol 5000), octylmethoxycinnamate (Octinoxate), octyl salicylate (Octisalate), padimate O (Escalol 507), phenylbenzimidazole sulfonic acid (Ensulizole), polysilicon-15 (Parsol SLX), trolamine salicylate, bemotrizinol (Tinosorb S), benzophenones 1-12, dioxybenzone, drometrizole trisiloxane (Mexoryl XL), iscotrizinol (Uvasorb HEB), octocrylene, oxybenzone (Eusolex 4360), sulisobenzone, bisoctrizol (Tinosorb M), titanium dioxide, zinc oxide, etc. .

Examples of retinoids include, without limitation, retinol, retinaldehyde, retinoic acid, retinyl palmitate, isotretinoin, tazarotene, bexarotene, and adapalene. In certain preferred embodiments, the retinoid is retinol.

Examples of antioxidants include, without limitation, 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, and ascorbic acid. acid and derivatives of ascorbic acid (for example, ascorbyl-2-glucoside, ascorbyl palmitate and ascorbyl polypeptide). Fat-soluble antioxidants suitable for use in the compositions of this invention include, but are not limited to, butylated hydroxytoluene, retinoids (eg, retinol and retinyl palmitate), tocopherols (eg, tocopherol acetate), tocotrienols, and ubiquinone. Natural extracts containing antioxidants suitable for use in the compositions of this invention include, without limitation, extracts containing flavonoids and isoflavonoids and their derivatives (eg, genistein and diadzein), extracts containing resveratrol, and the like. Examples of such natural extracts include grape seed, green tea, pine bark, feverfew, parthenolide-free feverfew, oat extract, pomelo extract, wheat germ extract, hesperidin, grape extract, purslane extract, lycochalcone, chalcone, 2, 2'-dihydroxychalcone, evening primrose extract, propolis, and the like.

The additional cosmetically active agent may be present in the composition in any suitable amount, such as from about 0.0001% to about 20% by weight of the composition, such as from about 0.001% to about 10%, such as from about 0.01% to about 5%. In certain preferred embodiments, in an amount of from 0.1% to 5%, and in other preferred embodiments, from 1% to 2%.

A number of other materials may also be present in the compositions of the present invention. These include, for example, chelating agents, humectants, opacifiers, conditioners, preservatives, fragrances, and the like. The compositions may include surfactants, for example, selected from the group consisting of anionic, nonionic, amphoteric, cationic surfactants, or combinations of two or more of these.

In certain preferred embodiments, the present invention provides for the application of a compound or composition of the present invention via a substrate containing such material. Any suitable substrate can be used in the present invention. Examples of suitable substrates and substrate materials are described, for example, in US Published Applications Nos. 2005/022683 and 2009/0241242, the contents of which are incorporated herein by reference in their entirety.

In certain preferred embodiments, the substrate is a wipe or face mask. Such embodiments preferably comprise a water-insoluble substrate, as specifically defined in the above references. In certain embodiments, the water-insoluble substrate may be sized and shaped to cover the face of a human user to facilitate placement of the water-insoluble substrate on the user's face as a mask substrate. For example, the water-insoluble mask substrate may have openings for the user's mouth, nose, and/or eyes. Alternatively, the water-insoluble mask substrate may not have such holes. Such a non-perforated configuration may be suitable for embodiments of the invention in which the water-insoluble substrate is intended to be wrapped around areas of skin that are not on the face, or the water-insoluble substrate is intended to be used as a wipe. The water-insoluble substrate may have various shapes such as an angled shape (eg rectangular) or a curved shape such as round or oval.

In one embodiment of the invention, the product includes a plurality of water-insoluble substrates in various forms. In one embodiment of the invention, the product includes a first water-insoluble substrate and a second water-insoluble substrate. The first water-insoluble substrate is shaped for application to the forehead, and the second water-insoluble substrate is shaped for application near the mouth, in particular to the areas above and/or below the lips, chin and/or cheeks. In one embodiment of the invention, the first water-insoluble substrate is also applied to the nasal region of the face. The first water-insoluble substrate may have a surface area of from about 100 cm ² to about 200 cm ² , in particular from about 120 cm ² to about 160 cm ² , and the second water-insoluble substrate has a surface area of from about 100 cm ² to about 300 cm ² , in particular from about 150 cm ² to about 250 cm ² . In one embodiment of the invention, the water-insoluble substrate has a low rigidity so that it can, for example, be easily wrapped around or shaped around the user's face or other body parts.

The present invention may include application to any area of skin requiring care on the human body. For example, it can be applied to one or more areas of the face, neck, chest, back, arms, underarms, hands and/or legs. In certain preferred embodiments, the method comprises applying a compound of formula I to the skin of the face.

Any suitable method of applying the extract to the skin to be treated can be used in accordance with the present invention. For example, the extract can be applied to the skin to be treated directly from the package, by hand or by transfer from a substrate such as a wipe or mask, or by a combination of two or more of these methods. In other embodiments, the extract may be applied by pipette, tube, roller, spray, patch, or added to a bath or otherwise to water for application to the skin, or the like.

In certain embodiments, the methods of the present invention further comprise the step of leaving the compound of formula I in contact with the skin for a period of time. For example, in certain preferred embodiments, after application, the compound is left in contact with the skin for about 15 minutes or more. In certain more preferred embodiments, the extract is left in contact with the skin for about 20 minutes or more, more preferably about 1 hour or more.

In certain embodiments, the implementation of the method of the present invention includes a regimen that involves multiple application of the compounds of formula I to the skin after a selected period of time. For example, in certain embodiments, the present invention provides a method for reducing signs of aging, comprising applying to skin in need of anti-aging a composition containing a compound of formula I once or twice daily for at least 12 weeks, preferably at least 8 weeks, and more preferably for at least 2 weeks.

In certain preferred embodiments, the methods of the present invention include applying to the skin at least two different compositions or products containing a compound of formula I. For example, the methods may include applying to skin requiring anti-aging, a first composition containing a compound of formula I , followed by application to the skin requiring the prevention of aging, the second composition containing the compound of formula I, but different from the first composition. In certain preferred embodiments, the first and second compositions may be independently selected from the group consisting of lotions, cleansers, masks, wipes, creams, serums, gels, and the like. In certain preferred embodiments, at least one of the first and second compositions is a cleanser, lotion, cream, essence, or serum, and the other is a face mask or wipe. In certain other preferred embodiments, at least one of the first and second compositions is a cleanser and the other is a lotion or cream.

In certain other preferred embodiments, the method comprises applying to skin in need of anti-ageing at least three products containing a compound of formula I. Such three products are preferably selected from the group consisting of cleansers, lotions, creams, essences and masks for faces.

The composition according to the present invention can be used to treat a variety of skin diseases and pathologies, in particular to reduce the appearance of signs of skin aging, skin inflammation and skin pigmentation.

Examples of signs of skin aging that can be reduced by topical or oral application of the compositions of this invention include, without limitation, skin wrinkles, loss of skin firmness or elasticity, sagging, laxity. As used herein, the term "wrinkle" includes fine lines, fine lines, coarse lines, cellulite, scars, and stretch marks. Examples of wrinkles include, but are not limited to, fine lines around the eyes (eg, crow's feet), wrinkles on the forehead and cheeks, frown lines, and expression lines around the mouth.

Examples of inflammatory diseases of the skin that can be treated by topical or oral application of the compositions of this invention include, without limitation, arthritis, contact dermatitis, atopic dermatitis, psoriasis, seborrheic dermatitis, eczema, allergic dermatitis, polymorphic light rashes, inflammatory dermatoses, folliculitis , alopecia, poison sumac exposure, insect bites, irritation due to environmental factors including, but not limited to, chemicals, trauma, pollutants (such as cigarette smoke), and exposure to UV rays or wind, and secondary conditions associated with inflammation, including , without limitation, xerosis, hyperkeratosis, pruritus, post-inflammatory hyperpigmentation, scarring, and the like.

Examples of skin pigmentation that can be treated by topical or oral application of the compositions of this invention include, without limitation, hyperpigmentation of the skin, light areas of the skin, uneven skin tone, discoloration and puffiness around the eye. Discoloration and puffiness around the eye include, but are not limited to, dark circles and bags under the eye. In one embodiment, the dark circles under the eye to be eliminated are the result of an increased concentration of blood in the skin under the eye.

Methods of topical application

Methods for topical application of the compositions of this invention, containing at least one compound of formula (I) and a cosmetically acceptable carrier, are intended for the treatment of signs of aging in human skin, dry skin, pigmentation defects, skin damage from UV rays, skin irregularities such as wrinkles, fine lines, rough skin or skin with wide pores, and diseases associated with skin aging such as defective keratinization, acne, eczema, inflammation and skin atrophy.

As used herein, the terms "topical application" and "topical application" refer to direct application or distribution to the skin, hair or nails, for example by hand or with an applicator such as a wipe.

Additional cosmetic active agents

In one embodiment, the topical composition further comprises a cosmetically active agent. What is meant by "cosmetic active agent" is a compound that has a cosmetic or therapeutic effect on the skin, hair or nails, e.g. brightening agents, darkening agents such as artificial tanning agents, anti-acne agents, agents for shine, antimicrobial agents, anti-inflammatory agents, antifungal agents, antiparasitic agents, topical analgesics, sunscreens, sunscreens, antioxidants, keratolytic agents, detergents/surfactants, humectants, nutrients, vitamins, energy boosting agents, antiperspirants , astringents, deodorants, hair removers, firming agents, anti-calf agents and hair, nail and/or skin conditioning agents.

In one embodiment, the cosmetically active agent is selected, without limitation, from the group consisting of hydroxy acids, benzoyl peroxide, sulfuric resorcinol, ascorbic acid, D-panthenol, hydroquinone, octylmethoxycinnamate, titanium dioxide, octyl salicylate, homosalate, avobenzone, polyphenolic compounds, carotenoids, free radical scavengers, ceramides, polyunsaturated fatty acids, essential fatty acids, enzymes, enzyme inhibitors, minerals, hormones such as estrogens, steroids such as hydrocortisone, 2-dimethylaminoethanol, copper salts such as copper chloride, coenzyme Q10, lipoic acid , amino acids such as proline and tyrosine, vitamins, lactobionic acid, acetyl coenzyme A, niacin, riboflavin, thiamine, ribose, electron carriers such as NADH and FADH2, and other plant extracts such as aloe vera, feverfew and soy , and their derivatives and mixtures. The cosmetically active agent will generally be present in the composition of the invention in an amount of from about 0.001% to about 20% by weight of the composition, such as from about 0.01% to about 10%, in particular from about 0.1% to about 5%. .

Examples of vitamins include, without limitation, vitamin A, vitamin B (such as vitamin B3, vitamin B5 and vitamin B12), vitamin C, vitamin K and vitamin E and their derivatives.

In one embodiment, the composition also contains one or more antioxidants. Examples of antioxidants include, without limitation, water-soluble antioxidants such as sulfhydryl compositions and their derivatives (e.g., sodium metabisulfite and N-acetylcysteine), lipoic acid and dihydrolipoic acid, resveratrol, lactoferrin, ascorbic acid, and ascorbic acid derivatives (e.g., ascorbyl palmitate). and ascorbyl polypeptide). Fat-soluble antioxidants suitable for use in the compositions of this invention include, but are not limited to, butylated hydroxytoluene, tocopherols (eg, tocopheryl acetate), tocotrienols, and ubiquinone. Natural extracts containing antioxidants suitable for use in the compositions of this invention include, without limitation, extracts containing flavonoids and isoflavonoids and their derivatives (eg, genistein and diadzein), extracts containing resveratrol, and the like. Examples of such natural extracts include grape seed, green tea, pine bark, and propolis. Other examples of antioxidants can be found on pages 1612-13 of the ICI Handbook.

Mineral water

The compositions of the present invention can be prepared using mineral water, such as naturally mineralized mineral water, such as Evian® mineral water (Evian, France). In one embodiment, the mineral water has a mineralization of at least about 200 mg/L (eg, from about 300 mg/L to about 1000 mg/L). In one embodiment, the mineral water contains at least about 10 mg/l calcium and/or at least about 5 mg/l magnesium.

Other materials

Various other materials may also be present in the compositions used as the subject matter of the invention. They include humectants, proteins and polypeptides, preservatives and an alkaline agent. Examples of such agents are described in ICI Handbook, pp. 1650-1667.

The compositions of the present invention may also contain chelating agents (eg, ethylenediaminetetraacetic acid - EDTA) and preservatives (eg, parabens). Examples of suitable preservatives and chelating agents are listed on pages 1626 and 1654-55 of the ICI Handbook. In addition, the compositions used in the present invention may contain conventional cosmetic adjuvants such as colorants, in particular dyes and pigments, opacifiers (eg titanium dioxide) and fragrances.

The composition and products containing such compositions of the present invention can be prepared using techniques well known to those of ordinary skill in the art.

EXAMPLES

In the examples, the following test methods were used.

Test Method 1: Cellular RARγ transactivation assay

This assay system uses non-human cells engineered to provide constitutive, high-efficiency expression of the human retinoic acid gamma receptor, a ligand-dependent transcription factor. The cells include a luciferase reporter gene operably linked to a RARγ sensitive promoter. Thus, quantification of changes in luciferase expression in treated reporter cells is a sensitive parameter for changes in RARγ activity.

The modified cells are seeded in 96-well plates and treated with the evaluated compounds at 3 concentrations: 0.1 µmol, 1 µmol and 10 µmol. After 24 hours of incubation, the treatment medium is removed and a luciferase detection reagent is added. The light emission from each sample well is quantified with a plate luminometer. Compounds (1) and (2) both demonstrated RARγ transactivation in a cell-specific RARγ transactivation assay from Indigo Biosciences (article no. IB02001).

Test Method 2: RARγ receptors in both agonist (AG) and positive allosteric modulator (PAM) modes

Dose-dependent effects on RARγ receptors in both agonist (AG) and positive allosteric modulator (PAM) modes were tested using the RAR-gamma GenBLAzer® cellular assay from Invitrogen according to the manufacturer's instructions.

Test Method 3: Gene Expression of CRABP2 (Cellular Retinoic Acid-Binding Protein II) and HBEGF (Heparin-Binding Growth Factor Like Epidermal Growth Factor) in Human Explants

Cellular retinoid-binding proteins (CRABPs) are a family of cytoplasmic binding proteins that have been shown to facilitate retinol uptake and prevent spontaneous non-enzymatic retinol isomerization and oxidation. It has been shown that the production of CRABP2 transcripts is activated in human skin upon treatment with retinol, both in vivo and in vitro. Moreover, the results showed that epidermal growth following topical retinoid exposure was at least partially induced by HB-EGF released from suprabasal keratinocytes.

Human skin explants were prepared as described in Bellemère et al . (Journal of Investigative Dermatology (2008) 128, 542-548), treated with 4 μl of compound (1) or (2) (compound (1) and compound (2) in the figure) at 2 concentrations: 10 μmol and 100 μmol and incubated at 37°C, 5% CO2 in 6-well plates containing 1.5 ml of medium for 48 h. After 48 h, the epidermis of each explant was separated from the dermis and (i) lysed for RNA extraction using the Qiagen Rneasy kit, (ii) reverse transcribed using iCycler from Biorad and Applied Biosystems, and (iii) analyzed for gene expression by quantitative polymerase chain reaction (qPCR) using the CFX96 Biorad Q-PCR system and polymerase chain reaction master mix (PCR) Power Sybergreen from Applied Biosystems. All steps were performed according to the manufacturer's instructions. Both compounds induced gene expression of CRABP2 (cellular retinoic acid-binding protein II) and HBEGF (heparin-binding growth factor like epidermal growth factor) in human skin explants when applied topically. Compounds (1) and (2) used at doses of 10 µmol and 100 µmol cause retinol-like bioactivity as demonstrated by induction of CRABP2 and HB-EGF gene expression.

Test Method 4: Expression of the Inflammatory Mediator Interleukin 8 Gene (IL-8 mRNA)

The skin explant used in test method 3 was used to measure the mRNA expression of the IL-8 gene.

Both compounds demonstrated this activity with less retinoid-specific skin side effects, such as release of the inflammatory mediator interleukin 8, compared to a positive Neutrogena Rapid Wrinkle Repair standard (retinol 0.1%). As shown in the figure below, IL-8 mRNA expression is less in the explant treated with both compounds (1) and (2) compared to Neutrogena RWR.

Material Source: Compounds 1 and 2 were purchased from Sigma, who originally obtained them from MolMall SARL.

Example 1

Compounds 1 and 2 demonstrated transactivation of the retinoic acid gamma receptor using Test Method 1. The results are shown in Table 1 below.

Concentration, µmol Researched material ten one 0.1 A Compound 1 6.506 8.4578 10.6988 B Compound 2 6.7229 3.253 5.5663 C Retinoic acid standard sample 8.3529

Table 1 RARγ receptor transactivation values (ratio: test material RLU/control RLU), RLU is a relative light unit.

Example 2

Compounds 1 and 2 showed a dose-dependent effect on RARγ receptors in both agonist (AG) and positive allosteric modulator (PAM) modes using test method 2. The results are shown in FIG. one.

On FIG. 1 shows 4 graphs: A, B, C and D. These graphs show the dose-dependent effects on RARγ receptors in agonist mode (plots A and C) and positive allosteric modulator mode (plots B and D); for compounds (1) and (2).

The vertical axis is indicated by the ratio: (radiation at 460 nm - background) / (radiation at 530 nm - background).

The horizontal axis is indicated logarithmically in µmol.

Graph A shows the dose-dependent effect on RARγ in agonist mode for Compound (1). Each displayed diamond indicates an experimental result; the corresponding curve is monitored and the average EC50 value is calculated: 8.31 * 10 ^-5 ± 1.15 * 10 ^-5 .

Graph B shows the dose-dependent effect on RARγ in positive allosteric modulator mode for Compound (1). Each displayed diamond indicates an experimental result; the corresponding curve is monitored and the average EC50 value is calculated: 3.01 * 10 ^-5 ± 3.27 * 10 ^-6 .

Graph C shows the dose-dependent effect on RARγ in agonist mode for Compound (2). Each displayed diamond indicates an experimental result; the corresponding curve is monitored and the mean EC50 value is calculated: 0.0071 ± 0.0007.

Plot D shows the dose-dependent effect on RARγ in positive allosteric modulator mode for Compound (2). Each displayed diamond indicates an experimental result; the corresponding curve is monitored and the mean EC50 value is calculated: 0.0067 ± 0.0027.

Example 3

Samples were tested using test method 3

Topical treatment of human skin explants with compounds (1) and (2) used at 10 µmol and 100 µmol doses induces retinol-like bioactivity as demonstrated by induction of CRABP2 and HB-EGF gene expression. Both compounds demonstrated this activity with less retinoid-specific skin side effects, such as release of the inflammatory mediator interleukin 8, compared to a positive Neutrogena Rapid Wrinkle Repair standard (retinol 0.1%).

On FIG. 2 is a histogram showing CRABP2 mRNA expression in a skin explant after 48 hours.

The vertical axis is indicated by mRNA concentration (% of control).

Column A represents the result for the untreated control sample, the value in % is 100.

Column B represents the result for the carrier sample (PG70/EtOH30), the % value is 102.

Column C represents the result for a sample with compound (1) according to the present invention at 10 ^-5 mol in vehicle, the % value is 256. The result is significant compared to the untreated control and compared to the vehicle.

Column D represents the result for a sample with compound (1) according to the present invention) at 10 ^-4 mol in vehicle, the % value is 496. The result is significant compared to the untreated control and compared to the vehicle.

Column E represents the result for a sample with compound (2) according to the present invention at 10 ^-5 mol in vehicle, the % value is 191. The result is significant compared to the untreated control and compared to the vehicle.

Column F represents the result for a sample with compound (2) according to the present invention at 10 ^-4 mol in vehicle, the % value is 340. The result is significant compared to the untreated control and compared to the vehicle.

Column G represents the result for a sample of the commercially available product Neutrogena Rapid Wrinkle Repair, the active compound is retinol, the 0.1% value is 597. The result is significant compared to the untreated control.

On FIG. 3 is a histogram showing the expression of the HB-EGF gene in a skin explant after 48 hours.

Column A represents the result for the untreated control sample, the value in % is 100.

Column B represents the result for the carrier sample (PG70/EtOH30), the % value is 81.

Column C represents the result for a sample with the compound (1) according to the present invention at 10 ^-5 mol in a carrier medium, the value in % is 218).

Column D represents the result for the sample with the compound (1) according to the present invention) at 10 ^-4 mol in vehicle, the % value is 513. The result is significant compared to the untreated control and compared to the vehicle.

Column E represents the result for a sample with compound (2) according to the present invention at 10 ^-5 mol in a carrier medium, the value in % is 173.

Column F represents the result for a sample with compound (2) according to the present invention at 10 ^-4 mol in vehicle, the % value is 358. The result is significant compared to the untreated control and compared to the vehicle.

Column G represents the result for a sample of the commercially available product Neutrogena Rapid Wrinkle Repair, the active compound is retinol, the 0.1% value is 902. The result is significant compared to the untreated control.

Example 4

Samples were tested using test method 4. The results are shown in FIG. four.

The vertical axis is indicated by mRNA concentration (% of control).

Column A represents the result for the untreated control sample, the value in % is 100.

Column B represents the result for the carrier sample (PG70/EtOH30), the % value is 194.

Column C represents the result for a sample with compound (1) according to the present invention at 10 ^-5 mol in vehicle, the % value is 422. The result is significant compared to the untreated control.

Column D represents the result for a sample with compound (1) according to the present invention) at 10 ^-4 mol in vehicle, the % value is 410. The result is significant compared to the untreated control.

Column E represents the result for a sample with compound (2) according to the present invention at 10 ^-5 mol in vehicle, the % value is 334. The result is significant compared to the untreated control.

Column F represents the result for a sample with compound (2) according to the present invention at 10 ^-4 mol in vehicle, the % value is 690. The result is significant compared to the untreated control.

Column G represents the result for a sample of the commercially available product Neutrogena Rapid Wrinkle Repair, the active compound is retinol, 0.1% value is 597. The result is significant compared to the untreated control.

Example 5

A cosmetic composition comprising Compounds 1 or 2 is made according to the following composition

Ingredient Quantity (%) Water 87.4 Cross-linked polymer of C10-30 alkyl alkylates 0.4 Disodium salt EDTA 0.1 Methylparaben 0.2 Propylparaben 0.15 Phenoxyethanol 0.5 Sodium hydroxide 10% - water 90% one Glyceryl stearate - polyethylene glycol (PEG) stearate 2 Butylated hydroxytoluene (BHT) 0.1 cetyl alcohol one Isononyl isononanoate 7 Connection (1) or (2) 0.1 Vitamin C 0.05 Total 100

Although the present invention has been described above with reference to specific embodiments thereof, it is clear that many changes, modifications and variations are possible without departing from the spirit of the concept having the features of the invention presented herein. Thus, it is intended to cover all such changes, modifications and variations that fall within the spirit and scope of the broadly appended claims.

Claims (15)

1. A method for treating skin pathologies caused by aging under the influence of internal processes, exogenous factors or skin diseases, including applying to the skin a composition comprising a compound of formula (I)

where dotted lines show a single or double bond; R ₁ represents H or a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; R ₂ represents a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; A represents an unsubstituted carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms. 2. The method according to claim 1, in which the dotted lines represent double bonds, R ₂ represents a methyl or methylene functional group. 3. The method of claim 2, wherein A is a carbon chain containing 6 carbon atoms. 4. The method of claim 3 wherein A is an aromatic functional group. 5. The method of claim 4 wherein A is a phenyl functional group. 6. The method of claim 1 wherein said compound is (2E, 4E , 6E )-7-( 1,1,2,2,3,3 -hexamethyl-2,3-dihydro- 1H -inden-5-yl)-3-methylocta-2,4,6-trienoic acid. 7. The method of claim 1 wherein at least one of the dotted lines represents a double bond. 8. The method according to p. 1, in which R ₂ represents a methyl or methylene functional group. 9. The method of claim 1 wherein A is an unsubstituted carbon chain containing from 1 to 10 carbon atoms. 10. The method of claim 1 wherein said compound is 4-(1-(1,1,2,2,3,3-hexamethyl-2,3-dihydro- 1H -inden-5-yl)vinyl ) benzoic acid.

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