Composition for hormone-affected skin

Abstract

A composition comprising: (i) a monocyclic sesquiterpene alcohol; (ii) vitamin B or a derivative thereof; and (iii) an amide of formula (I) wherein X is CH or N, Y is CHR8 or O, n is 0, 1 or 2, preferably 1 or 2, R1, R2 and R3 are independently from each other selected from the group consisting of H, OH, a halogen atom, a carbamoyl group and a C1-C6 alkyl group, and R4, R5, R6, R7 and R8 are independently from each other H or a C1-C6 alkyl group. The composition is suitable for topical application to treat hormone-affected skin. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of skin care. More particularly, the present invention relates to compositions, methods and uses thereof for treating hormonally affected skin. Background Art

[0002] From a cosmetic perspective, healthy-looking skin is characterized by moisturized, smooth and flawless skin, a radiant and radiant complexion, and an even, non-greasy complexion. Throughout life, transient changes in factors such as lifestyle, mental health, sleep, nutrition, and environmental exposures can lead to transient fluctuations in skin appearance, primarily driven by changes in epidermal homeostasis. Hormones represent an additional exposome factor, whether produced naturally by endocrine glands coinciding with life stage or provided by supplements in contraceptives, performance enhancers, and hormone replacement therapy (HRT), and there is increasing evidence that hormones can influence dermatological mechanisms, which can have an impact on cosmetically healthy skin conditions.

[0003] The most well-studied hormonal or hormonally influenced skin disorder is acne. This skin disease involves a complex chain of events that are controlled by androgens, which have an impact on the pilosebaceous unit, leading to increased sebum production and inflammation. Sex hormone fluctuations have also been implicated in premenstrual "acne" outbreaks, with peaks in testosterone levels associated with the highest acne prevalence. However, the impact of hormonal fluctuations is not limited to acne. Although sun exposure and heredity are undoubtedly important causal factors in pigmentation, hormonal effects also play an important role in its pathogenesis, as seen in the increased incidence seen in pregnancy, oral contraceptive use, and other hormonal treatments. Increased susceptibility to melasma can also be associated with an increase in local progesterone and estrogen receptors in the skin. Summary of the Invention

[0004] According to a first aspect of the present invention, there is provided a composition comprising:

[0005] (i) monocyclic sesquiterpene alcohols;

[0006] (ii) vitamin B or its derivatives; and

[0007] (iii) Amides of formula (I)

[0008]

[0009] Wherein X is CH or N,

[0010] Y is CHR 8 or O, n is 0, 1 or 2, preferably 1 or 2,

[0011] R 1 、R2 and R 3 are independently selected from the group consisting of H, OH, a halogen atom, a carbamoyl group and a C1-C6 alkyl group, and

[0012] R 4 、R 5 、R 6 、R 7 and R 8 are independently H or a C1-C6 alkyl group.

[0013] The inventors have surprisingly discovered that compositions (e.g., cosmetic compositions) as defined herein have benefits for hormonally affected skin (e.g., skin conditions affected by hormones or hormone fluctuations). The compositions are suitable for topical application to hormonally affected skin. In particular, the compositions as defined herein have the benefit of reducing the sensitivity of hormonally affected skin, such as how the skin reacts to hormonal fluctuations. Skin sensitivity is a common condition in which, for example, the skin is prone to itching and irritation. This sensitivity can manifest, for example, as redness, dryness, increased sebum production, itching, and / or the appearance of blemishes.

[0014] According to a second aspect of the present invention, there is provided an in vitro method for evaluating the effect of a test composition on hormonally influenced skin, the method comprising:

[0015] a) applying hormonal insult to skin cells in vitro to produce skin cells affected by hormones;

[0016] b) applying a test composition to the skin cells affected by the hormone; and

[0017] c) measuring changes in properties of the cells affected by the hormone.

[0018] The inventors have developed an in vitro method for evaluating a target composition that has benefits over in vivo methods, such as avoiding the need for human volunteers. In addition, the method allows test compositions to be tested in a fair and consistent manner over a long period of time. Measuring changes in the properties of cells affected by hormones can include monitoring biomarkers. Biomarkers of cell health and performance include, but are not limited to, proliferation rate; oxidative stress (malondialdehyde (MDA) is a marker of oxidative stress; inflammatory biomarkers (e.g., inflammatory cytokines); and cell viability.

[0019] Figure 1is a schematic, theoretical diagram illustrating the method of the second aspect. A hormonal stimulus (e.g., Cortisol) is applied to skin cells in vitro to produce cells affected by the hormone. A test composition (e.g., Active A) is applied to the hormone-affected skin cells, and a characteristic (e.g., a marker of poor skin health) is measured. In this example, the test composition (Active A) mitigates the adverse effects of the hormone (Cortisol), as indicated by the "With Cortisol" row being higher than the "Cortisol + Active A" row.

[0020] The composition of the present invention may be used for purely cosmetic purposes, as defined in the third aspect of the invention. Alternatively, the composition may be used as a medicament, for example for use in humans suffering from a medical condition such as eczema, psoriasis, dermatitis, rosacea or acne, as defined in the fourth to sixth aspects of the invention.

[0021] According to a third aspect of the present invention, there is provided a cosmetic method comprising topically applying the composition of the first aspect, wherein the cosmetic method is used for preventing and / or treating skin allergies.

[0022] According to a fourth aspect of the present invention, there is provided the composition of the first aspect for use as a medicine.

[0023] According to a fifth aspect of the present invention, a kit is provided, comprising the composition of the first aspect and a pharmaceutical composition.

[0024] According to a sixth aspect of the present invention, there is provided the kit of the fifth aspect for use as a medicament, in particular for treating skin disorders such as eczema, psoriasis, dermatitis, rosacea or acne.

[0025] It should be understood that the composition of the first aspect can be used before the pharmaceutical composition; used simultaneously with the pharmaceutical composition; or used after the pharmaceutical composition.

[0026] According to a seventh aspect of the present invention, there is provided a method for treating a skin disorder, the method comprising

[0027] (i) topically administering the composition of the first aspect (to the skin of a person in need thereof); and

[0028] (ii) administering the pharmaceutical composition.

[0029] It should be understood that the composition of the first aspect can be used before the pharmaceutical composition; used simultaneously with the pharmaceutical composition; or used after the pharmaceutical composition. The pharmaceutical composition can be applied topically to the same area of skin as the first composition. Alternatively, the pharmaceutical composition can be administered orally (e.g., tetracyclines). DETAILED DESCRIPTION

[0030] Unless otherwise stated, references to compositions of the invention are references to compositions of all aspects of the invention.

[0031] Monocyclic sesquiterpene alcohol

[0032] Sesquiterpenes are a class of terpenes composed of three isoprene units and usually have the formula C 15 H 24 . Sesquiterpenes can be acyclic or contain rings. The present invention employs alcohol derivatives of monocyclic (single ring) sesquiterpenes. For example, the monocyclic sesquiterpene alcohol can be α-bisabolol (shown below, left) or β-bisabolol (shown below, right). Synthetic bisabolol is typically a racemic mixture: α-(±)-bisabolol

[0033]

[0034] The amount of monocyclic sesquiterpene alcohol (e.g., α-bisabolol or β-bisabolol) present in the composition may be at least 0.001%, at least 0.005%, at least 0.01%, at least 0.05%, at least 0.1%, at least 0.5%, or at least 1% by weight; and / or the amount of monocyclic sesquiterpene alcohol (e.g., α-bisabolol or β-bisabolol) present in the composition may be 2% or less, 1% or less, 0.5% or less, 0.1% or less, 0.05% or less, or 0.01% or less by weight.

[0035] In particular, the amount of monocyclic sesquiterpene alcohol (such as α-bisabolol or β-bisabolol) present in the composition may be 0.001% to 2%, 0.01% to 1% or 0.05% to 0.5% by weight.

[0036] Vitamin B or vitamin B derivatives

[0037] The composition includes vitamin B (e.g., vitamin B1 to vitamin B12) or a vitamin B derivative (e.g., a derivative of vitamin B1 to B12 such as vitamin B3). In particular, the composition may include a vitamin B3 compound such as niacinamide.

[0038] Vitamin B3 and niacin are the common names for nicotinic acid. Nicotinamide is the physiologically active form of niacin. Niacin and niacinamide (nicotinamide or nicotinic acid amide) function in the body as components of two coenzymes: nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP).

[0039] The compositions used in the present invention may include a safe and effective amount of a (natural or synthetic) vitamin B3 compound. As used herein, "vitamin B3 compound" means a compound having the formula:

[0040]

[0041] wherein R is -CONH2 (i.e., niacinamide), -COOH (i.e., nicotinic acid), or -CH2OH (i.e., nicotinyl alcohol); derivatives thereof; and salts of any of the foregoing. Exemplary derivatives of the foregoing vitamin B3 compounds include nicotinic acid esters, including non-vasodilating nicotinic acid esters, nicotinyl amino acid, nicotinyl alcohol esters of carboxylic acids, nicotinic acid N-oxide, and nicotinamide N-oxide.

[0042] Suitable nicotinic acid esters include nicotinic acid esters of C1-C22, preferably C1-C16, more preferably C1-C6 alcohols. The alcohol can be linear or branched, cyclic or acyclic, saturated or unsaturated (including aromatic), and substituted or unsubstituted. Preferred esters are those that do not produce a visible flushing reaction after application to the skin. Alternatively, nicotinic acid substances that do produce a flushing reaction can be used if used in lower doses to reduce the flushing effect. Non-flushing nicotinic acid esters include tocopheryl nicotinate and inositol hexanicotinate. Tocopheryl nicotinate is preferred.

[0043] Other derivatives of vitamin B3 compounds are derivatives of nicotinamide resulting from substitution of one or more hydrogens of the amide group. Non-limiting examples of derivatives of nicotinamide useful herein include nicotinyl amino acids, derived, for example, from the reaction of activated nicotinic acid compounds (e.g., nicotinic acid azide or nicotinyl chloride) with amino acids, and nicotinyl alcohol esters of organic carboxylic acids (e.g., C1-C18). Specific examples of such derivatives include nicotinylglycine and nicotinyl hydroxamic acid.

[0044] Exemplary nicotinyl alcohol esters include nicotinyl alcohol esters of carboxylic acids (salicylic acid, acetic acid, glycolic acid, palmitic acid, etc.). Other suitable vitamin B3 compounds are selected from the group consisting of 2-chloronicotinamide, 6-aminonicotinamide, 6-methylnicotinamide, n-methyl-nicotinamide, n,n-diethylnicotinamide, n-(hydroxymethyl)-nicotinamide, quinolinic acid imide, nicotinanilide, n-benzylinotinamide, n-ethylnicotinamide, nifenazone, nicotinaldehyde, isonicotinic acid, methylisonicotinic acid, thionicotinamide, nialamide, 1-(3-pyridylmethyl)urea, 2-mercaptonicotinic acid, nicomol, niaprazine, and mixtures thereof.

[0045] Examples of the above-mentioned vitamin B3 compounds are well known in the art and are commercially available from a number of sources, for example, Sigma Chemical Company (St. Louis, Missouri (MO)); ICN Biomedicals, Inc. (Irvin, California (CA)) and Aldrich Chemical Company (Milwaukee, Wisconsin (WI)).

[0046] The compositions of the present invention preferably include one or more vitamin B3 compounds. Preferred vitamin B3 compounds are niacinamide and tocopheryl nicotinate. Niacinamide is more preferred.

[0047] Salts of vitamin B3 compounds are also useful herein. Non-limiting examples of salts of vitamin B3 compounds useful herein include organic or inorganic salts, such as inorganic salts with anionic inorganic species (e.g., chlorides, bromides, iodides, carbonates, preferably chlorides), and organic carboxylates (including mono-C1-C18 carboxylates, di-C1-C18 carboxylates, and tri-C1-C18 carboxylates, e.g., acetates, salicylates, glycolates, lactates, malates, citrates, preferably monocarboxylates, such as acetates).

[0048] The vitamin B3 compound can be included as the substantially pure material, or as an extract obtained by suitable physical and / or chemical isolation from natural sources.The vitamin B3 compound is preferably substantially pure, more preferably essentially pure.

[0049] The amount of vitamin B or a vitamin B derivative (e.g., a vitamin B3 compound such as niacinamide) present in the composition may be at least 0.01%, at least 0.05%, at least 0.1%, at least 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, or at least 5% by weight; and / or the amount of vitamin B or a vitamin B derivative (e.g., a vitamin B3 compound such as niacinamide) present in the composition may be 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, 0.1% or less, or 0.05% or less by weight. When more than one vitamin B / vitamin B derivative is present, these values apply to the total amount of vitamin B or vitamin B derivatives.

[0050] In particular, vitamin B or a vitamin B derivative (e.g., niacinamide) may be present in the composition in an amount of 0.01 to 5%, 0.05% to 3%, 0.1% to 3%, 0.1% to 2%, 0.5% to 1%, or 0.5% to 2% by weight.

[0051] Amide of formula (I)

[0052] The composition includes an amide of formula (I)

[0053]

[0054] Wherein X is CH or N,

[0055] Y is CHR 8 or O, n is 0, 1 or 2, preferably 1 or 2,

[0056] R 1 、R 2 and R 3 are independently selected from the group consisting of H, OH, a halogen atom, a carbamoyl group and a C1-C6 alkyl group, and

[0057] R 4 、R 5 、R 6 、R 7 and R 8 are independently H or a C1-C6 alkyl group.

[0058] The amides of formula (I) may comprise only one residue selected from the group consisting of OH, a halogen atom and a carbamoyl group.

[0059] The C1-C6 alkyl group may be an unbranched C1-C3 alkyl group, more preferably a C1-C2 alkyl group, most preferably a methyl group.

[0060] The halogen atom may be F or Cl.

[0061] The amide of formula (I) may be selected from (4-methylpiperidin-1-yl)(3-(6-methylpyridin-3-yl)phenyl)methanone, (4'-hydroxy-[1,1'-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone, (4'-fluoro-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone, (3'-fluoro-4'-methyl-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone, (2'-chloro-[1,1'-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone , (4'-methyl-[1,1'-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone, (4'-chloro-[1,1'-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone, (3,3-dimethylpiperidin-1-yl)(3'-fluoro-4'-methyl-[1,1'-biphenyl]-3-yl)methanone, 3'-(4-methylpiperidine-1-carbonyl)-[1,1'-biphenyl]-4-carboxamide, (3'-hydroxy-[1,1'-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone, 3' -(4-methylpiperidine-1-carbonyl)-[1,1-biphenyl]-3-carboxamide, (2,2-dimethylmorpholino)(3'-fluoro-4'-methyl-[1,1-biphenyl]-3-yl)methanone, (2,6-dimethylmorpholino)(3'-fluoro-4'-methyl-[1,1-biphenyl]-3-yl)methanone, (2,6-dimethylmorpholino)(4'-methyl-[1,1-biphenyl]-3-yl)methanone, azepan-1-yl(3'-fluoro-4'-methyl-[1,1'-biphenyl]-3-yl)methanone, azepan -1-yl(4'-chloro-[1,1'-biphenyl]-3-yl)methanone, azepan-1-yl(4'-methyl-[1,1'-biphenyl]-3-yl)methanone, azepan-1-yl(4'-hydroxy-[1,1'-biphenyl]-3-yl)methanone, azepan-1-yl(3-(6-methylpyridin-3-yl)phenyl)methanone, [1,1'-biphenyl]-3-yl(azepan-1-yl)methanone or azepan-1-yl(3',4'-dimethyl-[1,1'-biphenyl]-3-yl)methanone.

[0062] The amide of formula (I) can be [1,1'-biphenyl]-3-yl(azepan-1-yl)methanone, also known as [1,1'-biphenyl]-3-yl(hexahydro-1H-azepan-1-yl)-methanone (INCI name: BiphenylAzepanyl Methanone, CAS number: 1910069-14-5, also known as BEL-EVEN (RTM)).

[0063] The amount of amide of formula (I) (e.g., biphenylazepanyl ketone) present in the composition may be at least 0.0005%, at least 0.001%, at least 0.005%, at least 0.01% or at least 0.05% by weight; and / or the amount of amide of formula (I) (e.g., biphenylazepanyl ketone) present in the composition may be 1% or less, 0.5% or less, 0.1% or less, 0.05% or less, 0.01% or less or 0.05% or less by weight.

[0064] In particular, the amount of amide of formula (I) (eg, biphenylazepanyl ketone) present in the composition may be 0.001% to 1%, 0.01% to 0.5%, or 0.05% to 0.1% by weight.

[0065] Methods for preparing amides of formula (I) are disclosed in WO 2017012890. WO 2021089501 describes methods for preventing and / or treating dry skin and loss of natural oils in humans in need thereof by topical application of amides of formula (I). WO 2021089501 teaches the use of amides of formula (I) to stimulate sebum production in sebaceous glands.

[0066] Annona Extract

[0067] The composition may additionally include an Annona extract.

[0068] Annona is a genus of flowering plants in the pawpaw / sugar apple family, Annonaceae. The Annona extract can be a cherimoya extract, a soursop extract, or a sugar-apple extract.

[0069] The Annona extract can be a fruit extract or a flower extract. In some cases, the Annona extract can be a seed or bark extract.

[0070] Preferably, the composition comprises Annona fruit extract, ie, an extract from the fruit of the Annona plant (rather than the seeds or bark, which may be toxic).

[0071] Custard apple (cherimoya) (Annona cherimola) is a species of edible fruiting plant in the genus Annona and is commonly described as a custard apple. The composition may include an Annona cherimoya fruit extract or flower extract. Preferably, the composition includes an Annona cherimoya fruit extract.

[0072] Soursop is the fruit of the soursop (Annona muricata). The composition may include a soursop fruit extract or flower extract.

[0073] Sugar-apple or sweet-sop is the fruit of Annona squamosa. The composition may include an extract of the sugar-apple fruit or flower.

[0074] The amount of Annona extract (e.g., Annona custard apple fruit extract) present in the composition may be at least 0.01%, at least 0.05%, at least 0.1%, at least 0.5%, or at least 1% by weight; and / or the amount of Annona extract (e.g., Annona custard apple fruit extract) present in the composition may be 6% or less, 4% or less, 2% or less, 1% or less, 0.5% or less, or 0.1% or less by weight.

[0075] In particular, the amount of Annona extract (eg, Annona chebula fruit extract) present in the composition may be 0.1% to 5%, 0.5% to 4%, or 1% to 3% by weight.

[0076] Panax ginseng extract

[0077] The composition may additionally include a Panax species extract.

[0078] Ginseng plants belong to the genus Panax. The compositions of the present invention may include Panax ginseng (Korean ginseng), Panax notoginseng (South China ginseng), or Panax quinquefolius (American ginseng). The composition preferably includes Panax ginseng.

[0079] The Panax species extract may be a root extract, such as a ginseng root extract.

[0080] The amount of Panax species extract (e.g., ginseng root extract) present in the composition may be at least 0.005%, at least 0.01%, at least 0.02%, or at least 0.03% by weight; and / or the amount of Panax species extract (e.g., ginseng root extract) present in the composition may be 1% or less, 0.5% or less, 0.1% or less, 0.08% or less, or 0.5% or less by weight.

[0081] In particular, the Panax species extract (eg, ginseng root extract) may be present in the composition in an amount of 0.01% to 1%, 0.02% to 0.5%, or 0.03% to 0.1% by weight.

[0082] Trifolium Extract

[0083] The composition may include a Trifolium extract.

[0084] Trifolium is a genus of plants commonly known as clover. The Trifolium extract can be, for example, an extract of Trifolium pratense (red clover) or Trifolium repens (white clover). The Trifolium extract can be, for example, a flower or leaf extract.

[0085] The Trifolium extract may be an extract from flowers of the genus Trifolium, such as Trifolium pratense (red clover) flower extract. The Trifolium extract may be an extract from leaves of the genus Trifolium, such as Trifolium pratense (red clover) leaf extract.

[0086] The amount of Trifolium extract (e.g., red clover flower extract) present in the composition may be at least 0.05%, at least 0.1%, at least 0.15%, or at least 2% by weight; and / or the amount of Trifolium extract (e.g., red clover flower extract) present in the composition may be 3% or less, 2% or less, 1% or less, 0.8% or less, or 0.5% or less by weight.

[0087] In particular, the amount of Trifolium extract (eg, red clover flower extract) present in the composition may be 0.05% to 2%, 0.1% to 1%, or 0.2% to 0.5% by weight.

[0088] Ceramide

[0089] Ceramides are a family of waxy lipid molecules. Ceramides are composed of sphingosine and fatty acids.

[0090] The composition may include at least one ceramide. The at least one ceramide may include ceramide 1 (ceramide EOP), ceramide 2 (ceramide NG), ceramide 3 (ceramide NP), and / or ceramide 6 (ceramide AP). The composition preferably includes ceramide 3 (ceramide NP), also known as N-oleoyl-4-hydroxysphinganine. The composition preferably includes ceramide 6 (ceramide AP).

[0091] The composition may include at least two ceramides, such as ceramide 3 and ceramide 6. The composition may include at least three ceramides, such as ceramide 1, ceramide 3, and ceramide 6.

[0092] The amount of at least one ceramide present in the composition (e.g., the combined amount of Ceramides 1, 3, and 6) can be at least 0.003%, at least 0.005%, at least 0.008%, or at least 0.01% by weight; and / or the amount of at least one ceramide present in the composition (e.g., the combined amount of Ceramides 1, 3, and 6) can be 0.1% or less, 0.05% or less, 0.03% or less, or 0.01% or less by weight.

[0093] In particular, the amount of at least one ceramide present in the composition (eg, the combined amount of Ceramides 1, 3, and 6) may be 0.003% to 0.03% or 0.005% to 0.02% by weight.

[0094] Sugar isomers

[0095] The composition may include saccharide isomerates. Saccharide isomerates are mainly composed of glucose, fructose, mannose and galactose.

[0096] Saccharide isomers mimic the NMF (natural moisturizing factor) found in human skin and are derived from plant-based glucose. Saccharide isomers are available from DSM Nutritional Products Ltd under the trade name PENTAVITIN Commercially available.

[0097] The amount of saccharide isomers present in the composition may be at least 0.05%, at least 0.1%, at least 0.2%, or at least 0.3% by weight; and / or the amount of saccharide isomers present in the composition may be 2% or less, 1% or less, 0.8% or less, 0.6% or less, or 0.4% or less by weight.

[0098] In particular, the amount of saccharide isomers present in the composition may be from 0.1% to 0.9% or from 0.2% to 0.6% by weight.

[0099] Hyaluronic acid or its salt

[0100] The composition may include hyaluronic acid or a salt thereof, such as sodium hyaluronate or potassium hyaluronate. The composition preferably includes sodium hyaluronate.

[0101] The amount of hyaluronic acid or a salt thereof (e.g., sodium hyaluronate) present in the composition can be at least 0.01%, at least 0.02%, at least 0.05%, or at least 0.1% by weight; and / or the amount of hyaluronic acid or a salt thereof (e.g., sodium hyaluronate) present in the composition can be 1% or less, 0.5% or less, 0.2% or less, or 0.1% or less by weight.

[0102] In particular, the amount of hyaluronic acid or a salt thereof (eg, sodium hyaluronate) present in the composition may be from 0.01% to 0.2% or from 0.03% to 0.1% by weight.

[0103] Other components

[0104] The compositions of the present invention may be aqueous or non-aqueous and include single-phase or multi-phase systems. (Cosmetic) compositions may include, but are not limited to, liquids, gels, balms, oils, or solids. Single-phase or multi-phase compositions are contemplated. Multi-phase systems include, but are not limited to, microemulsions, emulsions, and products with discrete phase separations. Emulsions include water-in-oil, oil-in-water emulsions, and multiple emulsions (e.g., water-in-oil-in-water or oil-in-water-in-oil). Products with discrete phase separations include two-phase or three-phase systems in which a separate aqueous phase or oil phase is clearly visible.

[0105] When the (cosmetic) composition is aqueous, it preferably comprises from 20% to 95% by weight of water. In a preferred embodiment, the aqueous composition comprises from 40% to 90% by weight of water. In a preferred embodiment, the aqueous composition comprises from 60% to 85% by weight of water. When the composition is non-aqueous, it preferably comprises from 0% to a maximum of 10% water, more particularly from 0.1% to 8%, most preferably from 0.5% to 5% water.

[0106] When the cosmetic composition is an emulsion, it includes an oil phase and an aqueous phase. The oil phase of the emulsion can be provided by any suitable oily component. Suitable oils for the oil phase can include, for example: a) hydrocarbon oils such as paraffin or mineral oil; b) waxes such as beeswax or paraffin; c) natural oils such as sunflower oil, almond oil, shea butter or jojoba oil; d) silicone oils such as dimethicone, silicone elastomer, cyclomethicone or cetyl dimethicone; e) fatty acid esters and ethers such as isopropyl palmitate or isopropyl myristate and polypropylene glycol-15 stearyl ether; f) fatty alcohols such as cetyl alcohol or stearyl alcohol; or g) mixtures thereof, for example, blends of waxes commercially available under the trade name Cutina (BASF).

[0107] The emulsion may comprise from 0.1% to 55% of the oil phase by weight of the emulsion. In one embodiment, the emulsion may comprise from 3% to 25% of the oil phase by weight of the emulsion, more preferably from 5% to 20% of the oil phase by weight of the emulsion. In alternative embodiments, the emulsion may comprise from 10% to 50% of the oil phase by weight of the emulsion, more preferably from 25-50% of the oil phase by weight of the emulsion.

[0108] The composition of the present invention may include an emulsifier. Suitable emulsifiers include all those emulsifiers suitable for this purpose and known to those skilled in the art for use in skin care products. Preferably, these emulsifiers have an HLB value of 14 or less, more preferably from 2 to 14, and even more preferably from 4 to 14.

[0109] In some embodiments, the composition further comprises one or more antioxidants selected from the group consisting of: a) ascorbic acid, its salts, esters, glucosides and glucosamines, in particular sodium ascorbyl phosphate, magnesium ascorbyl phosphate, ascorbyl palmitate and ethyl ascorbic acid, b) vitamin E (tocopherol) and its esters, in particular tocopheryl acetate, and dimethylmethoxychromanol, a synthetic analogue of gamma-tocopherol available from Lipotec SApolygon Industrial Camri Ral under the trade name Lipochroman-6, c) herbal extracts (excluding extracts of the species Annona, Panax and Trifolium), in particular Ginkgo biloba, such as that available from Univar PLC under the trade name "Gingko Biloba Leaf Powder", Morus alba, such as that available from Solabia under the trade name "Mulberry Concentrate", oregano (origanum vulgare), such as that available from S Black Ltd under the trade name "Pronalen Origanum". HSC", birch extracts such as those available under the trade names "Super Herbasol Extract Birch" and "HP Herbasol Betula" from Cosmetochem (UK) Ltd and "Phytelene of Birch" and "Aqueous Spray Dried Birch" from Blagden Chemicals, tea (camellia sinensis) such as that available under the trade name "Herbal Extract Green Tea 75% Solids" from Nichimen Europe, rosemary (rosmarinus officinalis) such as that available under the trade name "Pronalen Rosemary" from S. Black, acerola cherry powder such as that available as Acerola PE from Gee Lawson, emblica extract, available from Merck Specialty chemicals under the trade name Emblica TM Sold as well as grapeseed oil, such as that available from Chesham Chemicals Limited.

[0110] As will be understood by those skilled in the art, the amount of antioxidant used in the cosmetic composition is expressed on a dry weight basis. The total amount of antioxidant optionally present in the cosmetic composition may range from 0.005% to 10% by weight, preferably from 0.01% to 5%, and most preferably from 0.05% to 1.0% by weight, based on the total weight of the cosmetic composition.

[0111] The compositions of the present invention may optionally include a skin conditioning agent. The skin conditioning agent may preferably be selected from the group consisting of a humectant, an emollient, a moisturizer, or mixtures thereof. If present, they are preferably present at a level of 0.01% to 20%, more preferably 0.1% to 10%, and most preferably 0.5% to 7% by weight of the cosmetic composition.

[0112] Preferred skin conditioning agents are selected from the group consisting of guanidine, urea, glycolic acid and glycolate salts, salicylic acid, lactic acid and lactate salts, aloe vera, shea butter, polyhydroxy alcohols such as sorbitol, mannitol, xylitol, erythritol, glycerol, hexanetriol, butanetriol, (di)propylene glycol, butylene glycol, hexylene glycol, polyethylene glycol, sugars (e.g., fructose, glucose, xylose, honey, mannose, xylose), gluconolactone and starch and its derivatives, pyrrolidones, carboxylic acids, lactamide monoethanolamine, acetamide monoethanolamine, panthenol, allantoin, and mixtures thereof.

[0113] The composition can include a wetting agent that is a diol or triol. The composition can include a diol selected from the group consisting of pentanediol, caprylyl glycol, butylene glycol, dipropylene glycol (di-propylene glycol), ethylhexylglycerin, propylene glycol (propanediol), hexylene glycol (hexenediol), glycerol, butylene glycol, propylene glycol, isopentyl glycol, dipropylene glycol (dipropylene glycol), pentanediol, hexylene glycol (hexylene glycol), polypropylene glycol, butylene glycol, polyethylene glycol, sorbitol, glucitol, mannitol, hydroxypropyl sorbitol, erythritol, threitol, pentaerythritol, xylitol. The composition can include a triol selected from the group consisting of hexanetriol, glycerol, ethoxylated glycerol, propoxylated glycerol and mixtures thereof.

[0114] The composition may include propylene glycol, also known as propanediol (e.g., 0.3 to 2 wt% propylene glycol); butylene glycol (e.g., 0.1 to 0.5 butylene glycol); glycerin (e.g., 3 to 10% glycerin); panthenol (e.g., 0.1 to 0.9 wt% panthenol); and / or caprylyl glycol (e.g., 0.1 to 0.9%);

[0115] The compositions of the present invention may include one or more vitamins in addition to vitamin B / vitamin B derivatives. The compositions may include ascorbic acids, such as vitamin C, vitamin C derivatives, ascorbic acid, ascorbyl glucoside, ascorbyl palmitate, magnesium ascorbyl phosphate, sodium ascorbyl phosphate, and ethyl ascorbic acid.

[0116] In some embodiments, the cosmetic composition may include vitamin K, vitamin K derivatives, vitamin H, vitamin D, vitamin D derivatives, and mixtures thereof. In alternative embodiments of the present invention, the cosmetic composition includes vitamin E, vitamin E derivatives such as tocopherol and tocopheryl acetate, and provitamins thereof such as panthenol and mixtures thereof.

[0117] In another embodiment, the cosmetic composition of the present invention includes a retinoid compound, including retinoic acid, retinal, retinol, and derivatives thereof. In one embodiment, the cosmetic composition includes retinyl palmitate, retinyl acetate, retinyl retinoate, retinyl propionate, retinyl ascorbate, retinyl linoleate, retinyl retinoate, retinyl sunflower oleate, and mixtures thereof.

[0118] The vitamin compound can be included as the substantially pure material or as an extract obtained by suitable physical and / or chemical isolation from a natural (e.g., plant) source. In one embodiment, when the vitamin compound is present in the cosmetic composition of the present invention, the cosmetic composition comprises from about 0.0001% to 50%, more preferably 0.001% to 10%, still more preferably 0.01% to 8%, and still more preferably 0.1% to 5% of the vitamin compound by weight of the cosmetic composition.

[0119] The compositions of the present invention may optionally include a sunscreen component. Sunscreens may include organic or inorganic sun filters or a combination of both. Suitable inorganic filters include those selected from the group consisting of finely divided titanium dioxide, finely divided zinc oxide, boron nitride, and mixtures thereof. Suitable organic sunscreens include those selected from the group consisting of a) p-aminobenzoic acid, its esters and derivatives (e.g., 2-ethylhexyl p-dimethylaminobenzoate), b) methoxycinnamate (e.g., 2-ethylhexyl p-methoxycinnamate, 2-ethoxyethyl p-methoxycinnamate or a,p-di-(p-methoxycinnamoyl)-a'-(2-ethylhexanoyl)-glycerol), c) benzophenones (e.g., oxybenzone), d) dibenzoylmethanes such as 4-(tert-butyl)benzoate.

[0014] The preferred sunscreen ingredients include, for example, alkyl)-4'-methoxydibenzoylmethane, e) 2-phenylbenzimidazole-5'-sulfonic acid and its salts, f) alkyl-ss,ss-diphenylacrylates, for example, alkyl a-cyano-ss,ss-diphenylacrylates such as octocrylene, g) triazines such as 2,4,6-trianilino-(p-carbo-2-ethyl-hexyl-1-oxy)-1,3,5-triazine, h) camphor derivatives such as methylbenzylidenecamphor, and i) mixtures thereof. Other preferred sunscreen ingredients include those selected from the group consisting of homosalate, ethylhexyl salicylate, diethylhexyl butamido triazone, bis-ethylhexyloxyphenol methoxyphenyl triazine, diethylaminohydroxybenzoyl hexyl benzoate, butyl methoxydibenzoylmethane, methylene bis-benzotriazolyl tetramethylbutylphenol, polysilicone-15, and mixtures thereof. Sunscreens are optionally present in amounts of 0.1% to 10% by weight of the cosmetic composition.

[0120] The compositions of the present invention may also optionally include one or more of the following optional ingredients. The cosmetic compositions of the present invention may include preservatives such as 2-bromo-2-nitropropane-1,3-diol (bronopol, which is commercially available under the trade name Myacide R™), benzyl alcohol, bis(hydroxymethyl)imidazolidinyl urea, imidazolidinyl urea, methylparaben, phenoxyethanol, ethylparaben, propylparaben, sodium methylparaben, sodium dehydroacetate, polyhexamethylene biguanide hydrochloride, sodium benzoate, chlorhexidine digluconate, isothiazolones, and sodium propylparaben, suitably in an amount of 0.01% to 10% by weight of the cosmetic composition.

[0121] The compositions of the invention may include thickeners, viscosity modifiers and / or gelling agents, such as acrylic acid polymers, for example commercially available under the trade names Carbopol, Ultrez or Novethix (Lubrizol) or Sepigel, Sepiplus and Simulgel (Seppic). Modified celluloses, such as hydroxyethylcellulose (commercially available under the trade name Natrosol (Hercules)) or hydroxypropyl methylcellulose, amine oxides, block polymers of ethylene oxide and propylene oxide (for example, those available under the trade name "Pluronic" RTM from BASF Wyandotte), PVM, MA or decadiene crosspolymers (available under the trade name Stabilez 60), ethoxylated fatty alcohols, salts (magnesium chloride, sodium chloride), Aristoflex AVC (Clariant), phthalic acid amide, xanthan gum, sodium polyacrylate, polyvinyl alcohol, fatty alcohols and alkyl galactomannans (available under the trade name N-Hance from Hercules) may also be added, suitably in an amount of 0.1% to 10% by weight of the cosmetic composition.

[0122] Chelating agents such as ethylenediaminetetraacetic acid and its salts may be added to the cosmetic composition, suitably in an amount of 0.005% to 0.5% by weight of the cosmetic composition.

[0123] The composition may also include a wax, such as cocoa butter or shea butter, suitably in an amount of 1% to 99% (e.g. 3% to 10%) by weight of the cosmetic composition.

[0124] The cosmetic composition may also include a suitable, cosmetically acceptable diluent, carrier and / or propellant such as dimethyl ether.

[0125] The composition may also include a pearlising agent, such as stearic acid monoethanolamide and / or mica, suitably in an amount of 0.01% to 10% by weight of the cosmetic composition.

[0126] The composition may include fragrance. In some embodiments, fragrance is present in an amount of 0.01% to 2% by weight of the cosmetic composition. Water-soluble dyes such as tartrazine may also be present, suitably in an amount of trace amounts (such as 1 x 10-5%) to 0.1% by weight of the cosmetic composition.

[0127] The composition may also include a pH adjuster, such as sodium hydroxide, aminomethyl propanol, or triethanolamine, preferably in an amount of 0.01% to 10% by weight of the cosmetic composition. The cosmetic composition may be buffered by methods well known in the art, for example, by using a buffer system comprising succinic acid, citric acid, lactic acid, and acceptable salts thereof, phosphoric acid, monosodium phosphate or disodium phosphate, and sodium carbonate. Suitably, the cosmetic composition may have a pH between 3 and 10, preferably between 4 and 8, and more preferably between 4.5 and 6.

[0128] Exemplary Formulations

[0129] The composition of the present invention comprises (i) a monocyclic sesquiterpene alcohol, (ii) vitamin B or a derivative thereof, and (iii) an amide of formula (I). The composition may additionally comprise (iv) an extract of Annona fruit.

[0130] Component (i) - a monocyclic sesquiterpene alcohol (e.g., α-bisabolol or β-bisabolol) - may be present in the composition in an amount by weight less than component (ii) - vitamin B or its derivative (e.g., niacinamide). In particular, component (i) may be present in the composition in an amount of 3% to 30% by weight of component (ii).

[0131] Component (iii) - the amide of formula (I) (e.g., biphenylazepanyl ketone) may be present in the composition in an amount by weight less than component (i) - the monocyclic sesquiterpene alcohol (e.g., α-bisabolol or β-bisabolol). In particular, component (iii) may be present in the composition in an amount of 3% to 30% by weight of component (i).

[0132] Component (iii) - the amide of formula (I) (e.g., biphenylazepanyl ketone) may be present in the composition in an amount by weight less than component (ii) - vitamin B or its derivative (e.g., niacinamide). In particular, component (iii) may be present in the composition in an amount of 0.3% to 3% by weight of component (ii).

[0133] When present, component (iv) - Annona fruit extract (e.g., Annona chebula fruit extract) can be present in the composition in an amount by weight greater than each of components (i), (ii), and (iii). In particular, component (i) can be present in the composition in an amount of 3% to 30% by weight of the amount of component (iv); component (ii) can be present in the composition in an amount of 30% to 99% by weight of the amount of component (iv); and / or component (iii) can be present in the composition in an amount of 0.3% to 3% by weight of the amount of component (iv).

[0134] The composition may include bisabolol, niacinamide, and diphenyl azepanyl ketone. More preferably, the composition includes bisabolol, niacinamide, diphenyl azepanyl ketone, and Annona mume fruit extract. Specific examples of the amounts by weight (wt %) are listed in the table below.

[0135] Example A Example B Example C Bisabolol 0.03 to 0.3 0.05 to 0.15 0.01 to 0.1 Niacinamide 0.3 to 3.0 0.5 to 1.5 0.1 to 1.0 Biphenylazepanyl ketone 0.01 to 0.2 0.005 to 0.015 0.001 to 0.01 Annona chebula fruit extract 2.0 to 5.0 2.5 to 3.5 1.0 to 2.0

[0136] Skin cells affected by hormones

[0137] The method of the second aspect may be used to assess the effect of a test composition on hormone-influenced skin cells.

[0138] The skin cell may be a keratinocyte. The majority of cells in the epidermis (90-95%) are keratinocytes.

[0139] Skin cells can be cultured in a cell line, such as the HaCaT cell line. HaCaT is a cell line of spontaneously transformed aneuploid immortalized keratinocytes derived from adult human skin.

[0140] Skin cells can be grown in primary cell culture, which is the in vitro culture of cells freshly obtained from a multicellular organism, as distinguished from the culture of immortalized cell lines.

[0141] Applying a hormonal stimulus can include applying a hormone at a fixed concentration, or applying a hormone at a concentration that varies over time. For example, applying a hormonal stimulus can include applying a hormone and then reducing or stopping the hormone. This can be useful for simulating hormone fluctuations.

[0142] Applying hormonal stimulation can include applying steroid hormones or peptide hormones. Applying hormonal stimulation can include applying human hormones. Hormone can be glucocorticoid (for example cortisol, dexamethasone (dexamethasone)), mineralocorticoid, androgen (for example testosterone), estrogen (for example estradiol), progesterone (for example progesterone). Hormone can be peptide hormone (for example melanocyte stimulating hormone (MSH), glucagon, insulin, insulin-like growth factor 1 (IGF-1) or glycoprotein hormone (for example gonadotropin, such as luteinizing hormone (Luteinising hormone) (LH) or follicle stimulating hormone (FSH))) or thyroid hormone, such as thyroxine.

[0143] estrogen

[0144] Applying hormonal stimulation can include applying or withholding estrogen. Menopause represents a transitional period in which estrogen levels plummet. The skin exhibits the effects of estrogen deficiency, with reported dry skin, accelerated wrinkling, and loss of firmness being key patient and consumer concerns. These concerns correspond to changes in structure and architectural components (such as collagen abundance) and reduced sebum production. Interestingly, collagen levels in the skin are correlated with estrogen, and supplementation with systemic hormone replacement therapy has been shown to increase collagen synthesis. Estrogen is important for the normal functioning of many structures in the epidermis and dermis, including the vasculature, hair follicles, sebaceous / apocrine glands, exocrine glands, and melanocytes, acting through estrogen receptors, with beta receptors being more common in the skin. Keratinocytes have estrogen receptors, which are considered important regulators of differentiation, proliferation, and epithelialization. The changes in epidermal and stratum corneum thickness observed in postmenopausal skin were partially rescued in the HRT cohort, demonstrating the important role of estrogen in epidermal homeostasis. The inventors believe that these mechanisms are responsible for the visible changes in the appearance of skin observed during menopause: an impact on the skin's barrier function can lead to dryness; an impact on the epidermal renewal process can lead to a loss of skin radiance and brightness, as well as rougher skin.

[0145] cortisol

[0146] Applying the hormonal stimulus may include administering Cortisol.

[0147] Psychological stress is also known to exacerbate various skin diseases, including psoriasis, atopic dermatitis, and acne. Central to this increased inflammation are changes in cortisol levels, which can in turn affect sebum production in acne and skin barrier function in atopic dermatitis. In studies, the stress of final exams and job interviews has been shown to affect barrier function, the latter of which is associated with elevated plasma cortisol levels and upregulated inflammation. The skin is a target for cortisol; in fact, the skin is also capable of producing its own corticosteroids, with the corticosteroid (CR) receptors available in the skin mediating the biological effects.

[0148] Melanocyte-stimulating hormone (MSH)

[0149] Applying hormonal stimulation may include applying MSH. MSH is produced both locally in the skin and by the anterior pituitary gland. Increased expression during pregnancy is associated with a common associated increase in skin pigmentation.

[0150] Pharmaceutical composition

[0151] The compositions of the present invention can be used together with pharmaceutical compositions and thereby offset the side effects of pharmaceutical compositions. Typically, pharmaceutical compositions will be applied to the skin (topical application). However, pharmaceutical compositions can be delivered orally.

[0152] The pharmaceutical composition may include a retinoid, benzoyl peroxide, and / or azelaic acid (nonanedioic acid).The pharmaceutical composition may be described as "prescription strength."

[0153] Retinoids include first generation retinoids (e.g., retinol, retinal, tretinoin (retinoic acid), isotretinoin, and alitretinoin); second generation retinoids (e.g., etretinate and its metabolite acitretin); third generation retinoids (e.g., adapalene, bexarotene, and tazarotene); and fourth generation retinoids (e.g., trifarotene).

[0154] In particular, the pharmaceutical composition may include trans-retinoic acid (tretinoin), 13-cis retinoic acid (isotretinoin) and / or adapalene (differin) and tazarotene. The pharmaceutical composition may include at least 0.05 wt% retinoid, such as at least 0.05 wt% tretinoin.

[0155] The pharmaceutical composition may include benzoyl peroxide, such as at least 3 wt% or 5 wt% benzoyl peroxide.

[0156] The pharmaceutical composition may include azelaic acid, such as at least 10 wt%, 15 wt%, or 20 wt% azelaic acid.

[0157] The present invention is further described by the following examples and drawings, in which

[0158] Figure 1 is a schematic theoretical diagram illustrating the effect of the test composition on hormone-affected skin;

[0159] Figure 2 is a schematic theoretical diagram illustrating how skin sensitivity studies may be conducted; the test compositions were tested for their ability to inhibit inflammatory cytokines.

[0160] Exemplary Formulations

[0161] The following are examples of compositions according to the present invention. They are provided only as exemplary compositions and are not intended to limit the present invention.

[0162] Creamy Cleanser - Ingredients

[0163]

[0164]

[0165] Creamy Cleanser - Manufacturing Method

[0166] 1. In the main container, add Aqua (water), glycerin, and tetrasodium EDTA to make the aqueous phase.

[0167] 2. Weigh shea butter, isononyl isononanoate, glyceryl stearate, cetearyl alcohol, caprylic / capric triglyceride, and polyacrylate crosspolymer-6 separately to prepare an oil phase.

[0168] 3. Heat both phases to 70-80°C, add the oil phase to the water phase, and homogenize at 3500 rpm for 5 minutes.

[0169] 4. When the emulsion is below 35°C, add the following: bisabolol, diphenyl azepanyl ketone, saccharide isomers, cherimoya fruit extract, ceramide, niacinamide, sodium benzoate, and phenoxyethanol while stirring.

[0170] Gel Cleanser - Ingredients

[0171]

[0172]

[0173] Gel Cleanser - Manufacturing Method

[0174] 1. Add Aqua (Water), Glycerin, Panthenol, Tetrasodium EDTA, Sodium Hyaluronate, Phenoxyethanol, Cocamidopropyl Betaine, Sodium Cocoamphoacetate, Coco-Glucoside, Glyceryl Oleate, Disodium Laureth Sulfosuccinate, and Lauryl Glucoside to the main container. Mix until dissolved.

[0175] 2. Add the following to the main container: bisabolol, saccharide isomers, biphenylazepanyl ketone, cherimoya fruit extract, ceramides, niacinamide, ginseng root extract, and sodium benzoate. Mix until dissolved.

[0176] 3. Add PEG-7 Glyceryl Stearate to the main container. Stir until completely dissolved.

[0177] Rich Moisturizer - Ingredients

[0178]

[0179]

[0180] Rich Moisturizer-Manufacturing Method

[0181] 1. In the main container, add Aqua (Water), Glycerin, Tetrasodium EDTA and Sodium Hyaluronate to make the aqueous phase.

[0182] 2. Separately weigh: avocado oil, dimethicone, tocopheryl acetate, cetearyl alcohol, isononyl isononanoate, C12-15 alkyl benzoate, sodium polyacrylate, and bisabolol. Heat to 70-80°C with stirring until completely dispersed.

[0183] 3. Add the oil phase to the water phase and homogenize at 3500 rpm for 5 minutes.

[0184] 4. When the emulsion is below 35°C, add the following while stirring: phenoxyethanol, panthenol, diphenyl azepanyl ketone, saccharide isomers, cherimoya fruit extract, ceramide, niacinamide, and sodium benzoate.

[0185] Research

[0186] The inventors believe that inflammatory mechanisms at work in the skin are responsible for the varying manifestations of sensitivity. Psychological stress activates the hypothalamic-pituitary axis (HPA), leading to the release of cortisol and related hormones. These hormones influence gene expression in skin cells by, for example, binding to transcription factors such as activator protein-1 (AP-1) and NFK-β, downstream factors essential for inducing inflammation. Epidermal skin cells respond to cortisol by producing interleukin-6 and other proinflammatory cytokines. Other cells, such as sebaceous gland cells, which produce sebum, also respond to stress hormones by producing proinflammatory mediators. Similarly, other hormones, such as estrogen, play a role in regulating inflammation through epidermal receptors. Reduced or absent levels in postmenopausal skin lead to an increase in low-level inflammatory states, which may be associated with greater perception of skin sensitivity. The transient receptor potential vanilloid (TRYPV-1) "capsaicin receptor" ion channel is present on sensory nerve endings and other non-neuronal cells, such as keratinocytes and sebocytes, where it regulates calcium influx into cells. Its activation, particularly by histamine, is associated with itch. Furthermore, hormones such as estrogen are known to exert some of their effects through TRPV-1, so it is not surprising that hormone fluctuations can lead to skin sensitivity such as itching through this mechanism. Skin reactivity to capsaicin, a natural activator of TRPV1, has been shown to be correlated with sensitive skin.

[0187] Cell culture models

[0188] A skin cell culture model was developed to simulate the effects of hormones and hormone deficiency / fluctuations on skin cell behavior. Skin cells were cultured in a culture medium regulated with hormones such as estrogen and estradiol derivatives, cortisol, and corticosteroid derivatives. Biomarkers of cell health and performance were measured, including but not limited to proliferation rate, oxidative stress, inflammatory biomarkers, and cell viability.

[0189] A test composition (including a suspected active ingredient) is added to the culture medium and changes in cell behavior are measured. In particular, the ability of the active ingredient to mimic the effects of hormones and improve the resilience of skin cells to hormonal fluctuations can be assessed.

[0190] For example, the ability of a test composition to inhibit IL-6 or TRYPV-1 can be assessed.

[0191] IL-6 inhibition assay

[0192] Primary human keratinocytes, fibroblasts or immortalized keratinocytes (HaCAT) were seeded in 96-well plates at a density of 5,000 cells per well (according to the QPRO / 148 method for determining cell number) in cell growth medium with supplements and incubated at 37°C for 24 hours. After incubation, the cell growth medium was replaced with 100 μl of phosphate buffered saline (PBS) without calcium and magnesium and containing the desired active agent at the relevant concentration. Controls included untreated irradiated and non-irradiated samples, which required 100 μl of pure PBS without calcium and magnesium, or contained a maximum of 0.1% dimethyl sulfoxide (DMSO) if the active agent needed to be dissolved. 0.01% salicylic acid was used as a positive control. The cells were incubated with the active ingredient at 37°C for 30 min and then irradiated with 61,500 J / m 2 The cells were irradiated with a UV dose of 100 μl. After irradiation, the PBS and active ingredients were replaced with 100 μl of pre-warmed (37 ° C) medium without supplements and incubated at 37 ° C for 24 hours. The culture supernatant containing IL-6 expressed from the cells was then collected and transferred to a new 96-well plate and stored at -20 ° C until ELISA was performed. The IL-6 ELISA should be performed according to the manufacturer's protocol provided with the kit.

[0193] TRYPV-1 inhibition assay

[0194] After 24 h, the cell culture medium was replaced with DMEM containing 2 μM calcium fluorescent probe Fluo-3 and 0.04% Pluronic F127 (Beijing FanBo Biochemicals Co., Ltd.) and incubated for 30 min. Various concentrations of phenoxyethanol and capsaicin were added, 3 mM EGTA (ethylene glycol tetraacetic acid; Sigma, USA) was used as a negative control, and 0.01% Triton X-100 (Sigma, USA) was used as a positive control. 24 To confirm the role of TRPV1, 7.8 μg mL-1 ID1609 (trans-tert-butylcyclohexanol (TTBC) in pentanediol was also added as a SymSitive 1609 sales) with 250 μg mL-1 phenoxyethanol or 40 nM capsaicin (Symrise, Germany). Twenty minutes later, the cells were observed under a fluorescence microscope. ImageJ The software analyzed the fluorescence intensity of each image. Calcium influx was calculated using the following formula: [Ca++]i = Kd(F - Fmin) / (Fmax - F), where the Kd value for Fluo-3 is 400 nM, F is the mean fluorescence intensity for each culture condition, Fmin is the fluorescence intensity of the negative control, and Fmax is the fluorescence intensity of the positive control. Experiments were repeated at least three times for each culture condition.

[0195] The theoretical results are Figure 2 and are described in the following table.

[0196]

Claims

1. A composition comprising: (i) monocyclic sesquiterpene alcohols; (ii) vitamin B or its derivatives; as well as (iii) Amides of formula (I) Wherein X is CH or N, Y is CHR 8 or O, n is 0, 1 or 2, preferably 1 or 2, R 1 、R 2 and R 3 are independently selected from the group consisting of H, OH, a halogen atom, a carbamoyl group and a C1-C6 alkyl group, and R 4 、R 5 、R 6 、R 7 and R 8 are independently H or a C1-C6 alkyl group.

2. The composition according to claim 1, wherein (i) the monocyclic sesquiterpene alcohol is present in the composition in an amount of 0.001% to 2% by weight; and / or (ii) the vitamin B or its derivative is present in the composition in an amount of 0.01% to 5% by weight; and / or (iii) The amide of formula (I) is present in the composition in an amount of 0.001% to 1% by weight.

3. A composition according to claim 1 or claim 2, additionally comprising an Annona extract.

4. The composition according to claim 3, wherein The Annona extract is present in the composition in an amount of 0.1% to 5% by weight.

5. A composition according to any one of the preceding claims, wherein The monocyclic sesquiterpene alcohols include bisabolol.

6. A composition according to any one of the preceding claims, wherein The vitamin B or its derivative is a vitamin B3 compound having the following formula: wherein R is -CONH2 (nicotinamide), -COOH (nicotinic acid) or CH2OH (nicotinyl alcohol); or an ester or salt thereof.

7. A composition according to any one of the preceding claims, wherein The amide of formula (I) includes one or more of the following: (4-methylpiperidin-1-yl)(3-(6-methylpyridin-3-yl)phenyl)methanone, (4'-hydroxy-[1,1'-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone, (4'-fluoro-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone, (3'-fluoro-4'-methyl-[1,1-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone, (2'-chloro-[1,1'-biphenyl]-3-yl)(4-methyl 1,1'-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone, (4'-methyl-[1,1'-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone, (4'-chloro-[1,1'-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone, (3,3-dimethylpiperidin-1-yl)(3'-fluoro-4'-methyl-[1,1'-biphenyl]-3-yl)methanone, 3'-(4-methylpiperidin-1-carbonyl)-[1,1'-biphenyl]-4-carboxamide, (3'-hydroxy-[1,1'-biphenyl]-3-yl)(4-methylpiperidin-1-yl)methanone ketone, 3'-(4-methylpiperidine-1-carbonyl)-[1,1-biphenyl]-3-carboxamide, (2,2-dimethylmorpholino)(3'-fluoro-4'-methyl-[1,T-biphenyl]-3-yl)methanone, (2,6-dimethylmorpholino)(3'-fluoro-4'-methyl-[1,1-biphenyl]-3-yl)methanone, (2,6-dimethylmorpholino)(4'-methyl-[1,1-biphenyl]-3-yl)methanone, azepan-1-yl(3'-fluoro-4'-methyl-[1,1'-biphenyl]-3-yl)methanone, azacyclopentane-1-yl(3'-fluoro-4'-methyl-[1,1'-biphenyl]-3-yl)methanone, Heptane-1-yl(4'-chloro-[1,1'-biphenyl]-3-yl)methanone, azepan-1-yl(4'-methyl-[1,1'-biphenyl]-3-yl)methanone, azepan-1-yl(4'-hydroxy-[1,1'-biphenyl]-3-yl)methanone, azepan-1-yl(3-(6-methylpyridin-3-yl)phenyl)methanone, [1,1'-biphenyl]-3-yl(azepan-1-yl)methanone, or azepan-1-yl(3',4'-dimethyl-[1,1'-biphenyl]-3-yl)methanone.

8. A composition according to any one of the preceding claims, wherein (i) the monocyclic sesquiterpene alcohol includes α-bisabolol; (ii) the vitamin B or its derivative includes niacinamide; and / or (ii) The amide of formula (I) includes biphenylazepanyl ketone.

9. A composition according to any one of the preceding claims, wherein The composition includes Annona chebula fruit extract.

10. A composition according to any one of the preceding claims, wherein α-Bisabolol, niacinamide, biphenylazepanyl ketone and Annona chebula fruit extract are present in the composition in the amounts by weight shown in the table below. 。 11. A composition according to any preceding claim, additionally comprising a Panax species extract; at least one ceramide; a saccharide isomer; hyaluronic acid or a salt thereof; and / or a Trifolium species extract.

12. An in vitro method for evaluating the effect of a test composition on hormonally influenced skin, the method comprising: a) applying hormonal stimulation to skin cells in vitro to produce skin cells affected by hormones; b) applying a test composition to the skin cells affected by the hormone; as well as c) measuring changes in properties of the cells affected by the hormone.

13. A cosmetic method for preventing and / or treating skin sensitivity in a person in need thereof, said method comprising topically applying a composition as defined in any one of claims 1 to 11.

14. A kit comprising the composition according to any one of claims 1 to 11 and a pharmaceutical composition.

15. The kit according to claim 14, for use in a method for treating a skin disorder, wherein The composition of any one of claims 1 to 11 is applied to the skin of a person in need thereof before; simultaneously with; or after the pharmaceutical composition.

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