Compositions suitable for use on sensitive skin and methods of using same

Abstract

Compositions and methods for treating sensitive skin with compositions containing compounds with retinol-like activity are provided. Methods for treating acne, wrinkles, and / or lightening skin in subjects with a reactive condition or a history of a reactive condition with compositions containing compounds with retinol-like activity are also provided.

Description

[Technical Field]

[0001] The present invention relates generally to compositions suitable for use on sensitive skin, and in particular to methods of using the compositions to treat skin. [Background technology]

[0002] Human skin undergoes certain aging processes, some of which are due to intrinsic processes (e.g., chronological aging) and some of which are due to extrinsic factors (e.g., photoaging). In addition, temporary or even permanent changes to the skin can occur, such as acne, oily or dry skin, keratosis, rosacea, photosensitivity, inflammatory, erythematous, and allergic or autoimmune reactions, such as dermatitis and photodermatosis.

[0003] The consequences of the aging process described above can include thinning of the skin, weakening of the epidermis and dermis intertwining, and a decrease in the number of cells and blood vessel supply. These consequences are often undesirable, and individuals suffering from these problems turn to topical treatments to address them.

[0004] Retinoids have been used to treat skin conditions caused by intrinsic aging, extrinsic factors, acne, or skin diseases.However, despite the beneficial effects of retinoid treatment, its benefits are limited due to the skin irritation caused by retinoids.These side effects limit the use of retinoids, especially for individuals with sensitive skin.

[0005] To date, the search for alternative compounds to replace retinoids, and particularly for individuals with sensitive skin, has met with some success in treating age-related skin conditions such as skin atrophy, acne, photoaging, and in reducing the appearance of wrinkles, fine lines, stretch marks, or cellulite. Summary of the Invention [Problem to be solved by the invention]

[0006] Therefore, there is a need for alternatives to traditional retinoids that are effective yet gentle enough for use on individuals with sensitive skin. [Means for solving the problem]

[0007] Accordingly, one aspect of the present invention relates to a method of treating sensitive skin, the method comprising administering to the sensitive skin a compound of formula I:

[0008] [ka] A compound of the formula During the ceremony, R1 is C1~C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 selected from the group consisting of alkynyl, and C3-C8 cycloalkyl or aryl; R2 is selected from the group consisting of hydrogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl or aryl, -OC1-C6 alkyl, -OC2-C6 alkenyl, -OC2-C6 alkynyl, -OC3-C8 cycloalkyl or aryl, thiol, -SC1-C6 alkyl, -SC2-C6 alkenyl, -SC2-C6 alkynyl, -SC3-C8 cycloalkyl or aryl, -NR4C1-C6 alkyl, -NR4C2-C6 alkenyl, -NR4C2-C6 alkynyl, and -NR4C3-C8 cycloalkyl or aryl; R3 is selected from -CO2H, -CO2R4, or an isosteric equivalent of a carboxy group, and R4 is C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, or aryl; Y is,

[0009] [ka] a compound of formula I, or applying a cosmetically acceptable salt thereof.

[0010] In one or more embodiments, R1 is a C5-C 16 Alkyl, C5-C 16 Alkenyl and C5-C 16 In some embodiments, R1 is selected from the group consisting of hydrogen, hydroxyl, -OC1-C6 alkyl, -OC2-C6 alkenyl, -OC2-C6 alkynyl, and -OC3-C8 cycloalkyl; R3 is selected from -CO2H, -CO2R4 where R4 is C1-C6 alkyl, or an isosteric equivalent of a carboxy group; and Y is -(CH2-CH2)- or -(CH=CH)-. In some embodiments, R1 is selected from the group consisting of C5-C6 alkyl, -OC2-C6 alkenyl, -OC2-C6 alkynyl, and -OC3-C8 cycloalkyl; R3 is selected from -CO2H, -CO2R4 where R4 is C1-C6 alkyl, or an isosteric equivalent of a carboxy group; and Y is -(CH2-CH2)- or -(CH=CH)-. 16alkenyl, and R2 is selected from the group consisting of hydrogen or -OC1-C3 alkyl. In one or more embodiments, the compound of Formula I is selected from the group consisting of 3-(4-farnesyloxyphenyl)-propionic acid, 3-(4-farnesyloxy-3-hydroxyphenyl)-propionic acid, 3-(4-farnesyloxy-3-methoxyphenyl)-propionic acid, ethyl esters thereof, and combinations of two or more thereof. In some embodiments, the compound of Formula I is 3-(4-farnesyloxyphenyl)-propionic acid. In one or more embodiments, the applying step comprises applying a compound of Formula I to sensitive skin, and the compound of Formula I is contained in a plant extract. In some embodiments, the plant extract is an extract of a plant of the genus Acronychia. In one or more embodiments, the plant extract is an extract of Acronychia acidula. In some embodiments, the extract is a polar extract. In one or more embodiments, the extract is present in an amount of about 0.1% to about 3% by weight, based on the total weight of the composition. In some embodiments, the extract is present in an amount of about 0.4% to about 1.5% by weight, based on the total weight of the composition. In one or more embodiments, sensitive skin includes the skin of a subject who, upon exposure to a retinoid, has a reaction condition or a history of a reaction condition selected from the group consisting of erythema, edema, burning, pain, itching, stinging, tingling, itching, tightness, dryness, scaling, roughness to the touch, peeling, flaky patches, and combinations thereof. In some embodiments, sensitive skin includes the skin of a subject who, upon exposure to a retinoid, has a condition or a history of a condition selected from the group consisting of atopic dermatitis, rosacea, seborrheic dermatitis, contact dermatitis, psoriasis, dry skin, and flaky skin. In one or more embodiments, the method of treating skin is a method of treating acne, wrinkles, and / or lightening skin in a subject with a condition or a history of a condition selected from the group consisting of atopic dermatitis, rosacea, seborrheic dermatitis, psoriasis, dry skin, and flaky skin.

[0011] Another aspect of the present invention relates to a method of treating acne, wrinkles, and / or lightening skin in a subject having or having a history of a reactive condition selected from the group consisting of erythema, edema, burning, pain, itching, stinging, tingling, itching, tightness, dryness, scaling, roughness to the touch, peeling skin, flaky patches, and combinations thereof, the method comprising applying 3-(4-farnesyloxyphenyl)-propionic acid to the skin.

[0012] In some embodiments, the applying step comprises applying to the sensitive skin a composition comprising a plant extract that is an extract of a plant of the genus Acronychia. In one or more embodiments, the plant extract is an extract of Acronychia acidula. In some embodiments, the extract is a polar extract. In one or more embodiments, the extract is present in an amount of about 0.1% to about 3% by weight, based on the total weight of the composition. In some embodiments, the extract is present in an amount of about 0.4% to about 1.5% by weight, based on the total weight of the composition. DETAILED DESCRIPTION OF THE INVENTION

[0013] It is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. The following specific embodiments are to be construed as merely illustrative, and not limitative of the following disclosure in any way.

[0014] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Furthermore, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference.

[0015] Unless otherwise specified, percentages used to express amounts of ingredients are weight percent (also referred to as "weight %, "wt %, "% by weight", or "%(W / W)"). Similarly, weight ratios used to express relative proportions of ingredients are also determined using weight percent (i.e., the weight ratio is calculated by dividing the weight percent of one ingredient by the weight percent of another ingredient). Unless otherwise specified, all ranges are inclusive of their endpoints; for example, "4 to 9" includes the endpoints 4 and 9.

[0016] As used herein, a composition that is "essentially free" of a component refers to a composition that has about 2% by weight or less of the component, based on the total weight of the composition. Preferably, a composition that is essentially free of a component has about 1% by weight or less of the component, more preferably about 0.5% by weight or less, more preferably about 0.1% by weight or less, more preferably about 0.05% by weight or less, and more preferably about 0.01% by weight or less of the component, based on the total weight of the composition. In certain more preferred embodiments, a composition that is essentially free of a component does not include the component, i.e., the component is not present in the composition.

[0017] As used herein, "cosmetically / dermatologically acceptable" means that the ingredient it describes is suitable for use in contact with tissue (e.g., skin or hair) without undue toxicity, incompatibility, instability, irritation, allergic reaction, etc. As will be recognized by those skilled in the art, cosmetically / dermatologically acceptable salts are acidic / anionic or basic / cationic salts.

[0018] As used herein, a "safe and effective amount" means an amount of an extract or composition that is sufficient to induce the desired effect, but small enough to avoid serious side effects. A safe and effective amount of a compound, extract, or composition will vary depending, for example, on the age, health, and environmental exposure 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 similar factors.

[0019] As used herein, the term "about" refers to within 5%, 4%, 3%, 2.5%, 2%, or 1% by weight of the disclosed value.

[0020] Generally, IUPAC nomenclature is used herein in accordance with the following definitions of terms.

[0021] The term "substituted" refers to a core molecule in which one or more hydrogen atoms have been replaced with a substituent, in the amount permitted by available valences. Substitution is not limited to the core molecule, but can also occur on substituent radicals, thereby rendering the radical a linking group.

[0022] The term "independently selected" refers to two or more substituents that may be selected from a substituent variable group, and the selected substituents may be the same or different.

[0023] The term "dependently selected" refers to one or more substituent variables that are specified in a specified combination for substitution within a core molecule (e.g., a variable that refers to a group of substituents listed in a table of compounds).

[0024] Acceptable salts derived from inorganic bases include, for example, sodium or potassium salts, etc. Acceptable salts derived from organic bases include, for example, salts formed with primary, secondary, or tertiary amines, etc.

[0025] One aspect of the present invention relates to a method of treating sensitive skin, the method comprising administering to the sensitive skin a compound of formula I:

[0026] [ka] A compound of the formula During the ceremony, R1 is C1~C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20selected from the group consisting of alkynyl, and C3-C8 cycloalkyl or aryl; R2 is selected from the group consisting of hydrogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl or aryl, -OC1-C6 alkyl, -OC2-C6 alkenyl, -OC2-C6 alkynyl, -OC3-C8 cycloalkyl or aryl, thiol, -SC1-C6 alkyl, -SC2-C6 alkenyl, -SC2-C6 alkynyl, -SC3-C8 cycloalkyl or aryl, -NR4C1-C6 alkyl, -NR4C2-C6 alkenyl, -NR4C2-C6 alkynyl, and -NR4C3-C8 cycloalkyl or aryl; R3 is selected from -CO2H, -CO2R4, or an isosteric equivalent of a carboxy group, and R4 is C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, or aryl; Y is,

[0027] [ka] a compound of formula I, or applying a cosmetically acceptable salt thereof.

[0028] Compounds of formula (I) In one or more embodiments, R1 is a C5-C 16 Alkyl, C5-C 16 Alkenyl and C5-C 16 In some embodiments, R1 is selected from the group consisting of hydrogen, hydroxyl, -OC1-C6 alkyl, -OC2-C6 alkenyl, -OC2-C6 alkynyl, and -OC3-C8 cycloalkyl; R3 is selected from -CO2H, -CO2R4 where R4 is C1-C6 alkyl, or an isosteric equivalent of a carboxy group; and Y is -(CH2-CH2)- or -(CH=CH)- (or a cosmetically acceptable salt thereof). In some embodiments, R1 is selected from the group consisting of C5-C6 alkyl, -OC2-C6 alkenyl, -OC2-C6 alkynyl, and -OC3-C8 cycloalkyl; R3 is selected from -CO2H, -CO2R4 where R4 is C1-C6 alkyl, or an isosteric equivalent of a carboxy group; and Y is -(CH2-CH2)- or -(CH=CH)- (or a cosmetically acceptable salt thereof). 16alkenyl, and R2 is selected from the group consisting of hydrogen or -OC1-C3 alkyl. In one or more embodiments, the compound of Formula I is selected from the group consisting of 3-(4-farnesyloxyphenyl)-propionic acid, 3-(4-farnesyloxy-3-hydroxyphenyl)-propionic acid, 3-(4-farnesyloxy-3-methoxyphenyl)-propionic acid, ethyl esters thereof, and combinations of two or more thereof. In one or more embodiments, the compound of Formula I is 3-(4-farnesyloxyphenyl)-propionic acid and / or its ethyl ester. In a preferred embodiment, the compound of Formula I is 3-(4-farnesyloxyphenyl)-propionic acid. 3-(4-farnesyloxyphenyl)-propionic acid and / or its ethyl ester can be synthesized using conventional organic synthesis processes.

[0029] The compound of formula I may be present in an amount ranging from about 0.00001% to 10%, or from about 0.0001 to about 10%, or from about 0.001 to about 5%, or from about 0.001% to about 1%, or from about 0.01% to about 3%, or from about 0.01% to about 1%, or from about 0.01% to about 0.5%, or from about 0.005% to about 1.5%, or from about 0.005% to about 0.06%, or from about 0.009% to about 0.06%, or from about 0.009% to about 0.03%, based on the total weight of the composition.

[0030] The compound according to formula I can also be obtained from natural sources. For example, the compound according to formula I can be found in a plant extract. Thus, the methods described herein can include applying a composition containing the plant extract to sensitive skin.

[0031] In one or more embodiments, the plant extract is an extract of a plant of the genus Acronychia. In further embodiments, the plant extract is an extract of Acronychia acidula (also known as lemon aspen). In one or more embodiments, at least one compound of Formula I above is present in the Acronychia extract at a concentration of about 0.01 to about 30%, or about 0.1 to about 30%, or about 0.1 to about 20%, or about 1 to about 20%, or about 1 to about 10%, or about 1.5 to about 9%, or about 3 to about 9% or more by weight of the Acronychia extract. In further embodiments, the Acronychia acidula extract contains 3-(4-farnesyloxyphenyl)-propionic acid at a concentration ranging from about 1% to about 10% based on the total weight of the extract.

[0032] Suitable extracts can be obtained using conventional methods including, but not limited to, grinding, maceration, pressing, squeezing, grinding, centrifugation, and / or cold irrigation, stirring / distillation, microwave-assisted extraction, supercritical / subcritical CO2 compressed gas extraction with or without polar modifiers, pressurized solvent extraction, accelerated solvent extraction, pressurized or regular hot water extraction, surfactant-assisted pressurized hot water extraction, oil extraction, membrane extraction, Soxhlet extraction, gold finger distillation / extraction, and / or direct extraction of material from biomass by, for example, the processes disclosed in U.S. Pat. Nos. 7,442,391, 7,473,435, and 7,537,791 (Integrated Botanical Technologies, LLC), which are incorporated herein by reference, or by other methods such as solvent extraction.

[0033] Any of a variety of solvents, including polar solvents, nonpolar solvents, or combinations of two or more thereof, may be used in methods involving solvent extraction. Suitable polar solvents include polar inorganic solvents such as water; polar organic solvents such as alcohols and corresponding organic acids, e.g., C1-C8 alcohols, including methanol, ethanol, propanol, butanol, and the like; organic acids, including acetic acid, formic acid, propanoic acid, and the like; polyols and glycols, including C1-C8 polyols / glycols, and the like; and combinations of two or more thereof. Suitable nonpolar solvents include nonpolar organic solvents, e.g., alkanes, including C1-C8 alkanes; cycloalkanes, including C1-C8 alkanes; alkyl ethers, including C1-C8 alkyl ethers; petroleum ether; ketones, including C1-C8 ketones; methylene chloride; ethyl acetate; xylene; toluene; chloroform; vegetable oil; mineral oil; and the like. In another embodiment, the extraction can be obtained by supercritical fluid extraction with or without the use of non-polar solvents as described above or polar modifiers such as C1-C8 alcohols, water, C1-C8 polyols / glycols, or C1-C8 organic acids.

[0034] In one or more embodiments, the extract comprises an extract of Acronychia acidula. In some embodiments, the extract of the present invention comprises a combination of polar and non-polar extracts of the fruit of Acronychia acidula. In other embodiments, the extract of the present invention comprises an alcoholic or glycolic extract of the fruit of Acronychia acidula.

[0035] In one or more embodiments, the extract is a polar extract. In further embodiments, the extract is prepared using a polar solvent including water, a C1-C8 alcohol, a C1-C8 polyol, or a C1-C8 glycol, or a combination of two or more thereof. In certain embodiments, the extract is extracted using one or more C1-C4 alcohols, C1-C4 polyols, and / or C1-C4 glycols. In one or more embodiments, the extract is prepared using a solvent including methanol, ethanol, or a combination thereof with or without water. In further embodiments, the extract is a polar extract extracted from the fruit of Acronychia acidula using a combination of alcohol and water.

[0036] In one or more embodiments, the extract is a non-polar extract prepared using a non-polar solvent comprising one or more C1-C8 alkanes, C1-C8 cycloalkanes, C1-C8 alkyl ethers, C1-C8 alkyl esters, and / or chloroform, more preferably one or more C1-C8 alkanes, C1-C8 alkyl esters, and / or chloroform. In further embodiments, the extract is a non-polar extract prepared using hexane, ethyl acetate, chloroform, or a mixture of two or more thereof. In yet further embodiments, the extract is a non-polar extract prepared using ethyl acetate.

[0037] For example, an extract using Acronychia acidula fruit can be prepared by homogenizing the fruit in a blender with an equal volume of denatured alcohol for 30 seconds. The pulp is then mixed and stirred for an additional 24 hours at ambient temperature (22-26°C). Additional denatured alcohol may be added as needed to keep the pulp well covered in alcohol. The mixture is then gravity filtered, and the resulting filter cake can be washed with additional amounts of denatured alcohol. The entire filtrate can then be dried under reduced pressure to remove the alcohol. The residue can then be freeze-dried to obtain a dry substance free of the extractant and water. The extraction can be repeated several times on the filter cake, with each extraction routinely yielding an extract yield of 5-7%.

[0038] Another example of the preparation of Acronychia acidula fruit extract is as follows: 500 gm of freeze-dried Acronychia acidula fruit can be sliced ​​into approximately 5 mm cubes and immersed in 5 L of ethanol at a 1:10 ratio (material to solvent) and stirred at room temperature for 12 hours. The suspension can then be filtered, and the resulting filtrate can be concentrated under low pressure to obtain a concentrate. The concentrate can then be further dried by freeze-drying to obtain 325 gm of residual material, referred to as the crude extract (65% yield). A 200 gm sample of the crude extract can then be dissolved in 1 L of ethanol and stirred overnight at room temperature. The mixture can then be filtered and dried under reduced pressure and low temperature to obtain the extract.

[0039] The extract may be present in an amount of about 0.00001, 0.0001, 0.001, 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.75, 1, 1.5, or 2 to about 0.00005, 0.0005, 0.005, 0.05, 0.5, 1, 1.5, 2, 2.5, 3, 4, or 5 wt.% based on the total weight of the composition. In one or more embodiments, the extract is present in an amount of about 0.01 wt.% to about 5 wt.% based on the total weight of the composition. In further embodiments, the extract is present in an amount of about 0.01 wt.% to about 3 wt.% based on the total weight of the composition. In one or more embodiments, the extract is present in an amount of about 0.1 wt.% to about 3 wt.% based on the total weight of the composition. In further embodiments, the extract is present in an amount of about 0.2 wt.% to about 2.5 wt.% based on the total weight of the composition. In one or more embodiments, the extract is present in an amount of about 0.5% to about 2% by weight, based on the total weight of the composition. In further embodiments, the extract is present in an amount of about 0.5% to about 1.5% by weight, based on the total weight of the composition.

[0040] sensitive skin As used herein, the term "sensitive skin" refers to an individual whose skin is more prone to unpleasant or undesirable sensations or reactions in response to stimuli that do not elicit such a response in most individuals. In one or more embodiments, the reaction of sensitive skin can be sensory, such as burning, pain, itching, stinging, prickling, itching, tightness, and / or dryness. In some embodiments, the reaction of sensitive skin can be visual, such as erythema (redness), edema (swelling), peeling, and / or flaky patches. In one or more embodiments, sensitive skin includes the skin of a subject who, when exposed to a retinoid, has a reactive state or a history of a reactive state selected from the group consisting of erythema (redness), edema (swelling), burning, pain, itching, stinging, prickling, itching, tightness, dryness, scaling, roughness to the touch, peeling, flaky patches, and combinations thereof. In one or more embodiments, sensitive skin includes skin of a subject having a condition or a history of a condition selected from the group consisting of atopic dermatitis, rosacea, seborrheic dermatitis, contact dermatitis, psoriasis, dry skin, and flaky skin.

[0041] use The compositions / compounds described herein may be used in skin treatments to treat acne, wrinkles, improve skin barrier function, and / or for skin lightening. In one or more embodiments, the treatment is for a subject with a condition or a history of a condition selected from the group consisting of atopic dermatitis, rosacea, seborrheic dermatitis, psoriasis, dry skin, and flaky skin.

[0042] As used herein, "treatment" or "treating" refers to the improvement, prevention, or amelioration of a condition, disease, or disorder, or at least one discernible symptom thereof. In one embodiment, "treatment" or "treating" refers to the improvement, prevention, or amelioration of at least one measurable physical parameter associated with the condition, disease, or disorder being treated, which is not necessarily discernible in or by the subject being treated. In another embodiment, "treatment" or "treating" refers to inhibiting or slowing the progression of the condition, disease, or disorder, either physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In another embodiment, "treatment" or "treating" refers to delaying the onset of the condition, disease, or disorder.

[0043] The compositions of the present invention are suitable for improving skin texture, or for improving skin firmness, or for improving any of the conditions / symptoms described below.

[0044] As used herein, "improving skin texture" means smoothing the surface of the skin to remove either bumps or crevices in the skin surface.

[0045] As used herein, "improving skin firmness" means enhancing skin firmness or elasticity, preventing loss of skin firmness or elasticity, or preventing or treating sagging, loose and lax skin.

[0046] As used herein, "loss of elasticity" includes loss of elasticity or structural integrity of skin or tissue, including, but not limited to, sagging, loose, and flaccid tissue. Loss of elasticity or structural integrity of tissue can be the result of many factors, including, but not limited to, disease, aging, hormonal changes, mechanical trauma, environmental damage, or the application of products, such as cosmetics or pharmaceuticals, to the tissue.

[0047] As used herein, "uneven skin" means a skin condition associated with diffuse or patchy pigmentation that can be classified as hyperpigmentation, such as post-inflammatory hyperpigmentation.

[0048] As used herein, "age spots" refers to a skin condition associated with redness or erythema.

[0049] As used herein, "age spots" refers to a skin condition associated with discrete pigmentation, such as small areas of darker pigmentation, which may occur on the face and hands.

[0050] Signs of skin aging also include a decrease in skin thickness and the presence of abnormal or decreased synthesis of glycoproteins, including collagen, glycosaminoglycans, proteoglycans, elastin, or fibronectin. In one embodiment, the sign of aging is selected from abnormal or decreased synthesis of glycoproteins, including collagen, glycosaminoglycans, proteoglycans, elastin, or fibronectin. In another embodiment, the sign of skin aging is decreased synthesis of collagen or elastin.

[0051] The example of skin aging that can be treated by topical use of the composition of the present invention includes, but is not limited to, skin wrinkles.As used herein, the term "wrinkles" includes fine lines, fine wrinkles, coarse wrinkles, cellulite, scars and stretch marks.Examples of wrinkles include, but are not limited to, the fine lines around the eyes (for example, "crow's feet"), wrinkles on the forehead and cheeks, wrinkles between the eyebrows, and age lines around the mouth.

[0052] As used herein, "topical use" or "topically applying" means to paint or spread directly onto the skin, hair, or nails, for example, by using an applicator such as the hand or a wipe.

[0053] The composition is also suitable for treating or preventing acne.As used herein, "acne" refers to a disorder that results from the action of hormones and other substances on sebaceous glands and hair follicles, and typically leads to the formation of clogged pores and inflammatory or non-inflammatory lesions on the skin.In particular, this relates to spots, lesions, or pimples, pre-emergent pimples, blackheads, and / or whiteheads.As used herein, "pre-emergent pimples" are inflammatory vesicles that are not visually apparent to the naked eye (e.g., as lesions) on the surface of the skin.

[0054] The compositions of the present invention are also suitable for treating or preventing rosacea. As used herein, "rosacea" means persistent erythema of the skin with or without papules, pustules, or nodules.

[0055] The compositions of the present invention are also suitable for reducing hyperkeratosis of the epidermis and may therefore be used to treat or prevent conditions characterized by hyperkeratosis, such as acne or warts.

[0056] The embodiments described herein may be combined in any suitable combination. For example, an exemplary embodiment relates to a method for treating acne, wrinkles, and / or whitening skin in a subject with or a history of a reactive condition selected from the group consisting of erythema, edema, burning, pain, itching, stinging, tingling, pruritus, tightness, dryness, scaling, roughness to the touch, peeling skin, flaky patches, and combinations thereof, the method comprising applying to the skin an extract of Acronychia acidula and / or 3-(4-farnesyloxyphenyl)-propionic acid. As discussed further below, 3-(4-farnesyloxyphenyl)-propionic acid can be chemically synthesized, naturally occurring in a plant extract, or chemically synthesized and added to a plant extract. In one or more embodiments, the applying step comprises applying to sensitive skin a composition comprising a plant extract that is an extract of a plant of the genus Acronychia. In a further embodiment, the plant extract is an extract of Acronychia acidula. In yet a further embodiment, the extract is a polar extract. In one or more embodiments, the extract is present in an amount of about 0.1% to about 3% by weight, based on the total weight of the composition. In a further embodiment, the extract is present in an amount of about 0.4% to about 1.5% by weight, based on the total weight of the composition.

[0057] The compositions described herein can be applied to any skin in need of treatment in the human body. For example, they can be applied to any one or more of the skin of the face, neck, chest, back, arms, armpits, hands, and / or feet. In certain preferred embodiments, the method comprises applying a compound of formula I to facial skin.

[0058] Any suitable method of applying the extract to skin in need can be used in accordance with the present invention.For example, the extract can be applied directly from the package to the skin in need, can be applied by hand to the skin in need, can be transferred from a substrate such as a wipe or mask, or can be a combination of two or more of these.In other embodiments, the extract can be applied via a dropper, tube, roller, spray, patch, or can be added to water that is to be bathed or otherwise applied to the skin.

[0059] In one or more embodiments, the method of the present invention further comprises the step of contacting the compound of Formula I with the skin for a period of time. For example, in certain preferred embodiments, the compound is contacted with the skin for about 15 minutes or more after application. In certain more preferred embodiments, the extract is contacted with the skin for about 20 minutes or more, more preferably about 1 hour or more.

[0060] In some embodiments, the methods of the invention comprise a regimen comprising applying to the skin multiple times over a selected period of time a compound of Formula I. For example, in certain embodiments, the invention provides a method of treating signs of aging comprising applying to skin in need of anti-aging a composition comprising a compound of Formula I once or twice daily for at least 12 weeks, preferably at least 8 weeks, and more preferably at least 2 weeks.

[0061] composition Any suitable carrier can be used in the compositions of the present invention. Preferably, in skin care compositions, the carrier is a cosmetically acceptable carrier. As will be recognized by those skilled in the art, a cosmetically acceptable carrier includes a carrier suitable for use in contact with the body, particularly the skin, for anti-aging applications without undue toxicity, incompatibility, instability, irritation, allergic reaction, etc. A safe and effective amount of 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%, and most preferably from about 99.8% to about 98% of the composition. The carrier may be in a wide variety of forms. For example, emulsion carriers are useful herein, 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 cover a wide range of viscosities, for example, from about 100 cP to about 200,000 cP. Examples of suitable cosmetically acceptable carriers include cosmetically acceptable solvents and materials for cosmetic solutions, suspensions, lotions, creams, serums, essences, gels, toners, sticks, sprays, ointments, cleansing solutions and bar soaps, shampoos, hair conditioners, pastes, foams, mousses, powders, shaving creams, wipes, patches, strips, powered patches, microneedle patches, bandages, hydrogels, film-forming products, facial and skin masks, makeup, liquid drops, etc. These product types may contain several types of cosmetically acceptable carriers, including, but not limited to, solutions, suspensions, emulsions such as microemulsions and nanoemulsions, gels, solids, liposomes, other encapsulation technologies, etc.

[0062] The following are non-limiting examples of such carriers. Other carriers can be formulated by those skilled in the art. In one embodiment, the carrier comprises water. In further embodiments, the carrier may further comprise one or more aqueous or organic solvents. Examples of organic solvents include, but are not limited to, dimethyl isosorbide; isopropyl myristate; cationic, anionic, and nonionic surfactants; vegetable oils; mineral oils; waxes; gums; synthetic and natural gelling agents; alkanols; glycols, and polyols. Examples of glycols include, but are not limited to, glycerin, propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, polyethylene glycol, polypropylene glycol, diethylene glycol, triethylene glycol, capryl glycol, glycerol, butanediol, and hexanetriol, as well as copolymers or mixtures thereof. Examples of alkanols include, but are not limited to, those having from about 2 carbon atoms to about 12 carbon atoms (e.g., from about 2 carbon atoms to about 4 carbon atoms), such as isopropanol and ethanol. Examples of polyols include, but are not limited to, those having from about 2 carbon atoms to about 15 carbon atoms (e.g., from about 2 carbon atoms to about 10 carbon atoms), such as propylene glycol. The organic solvent may be present in the carrier in an amount of from about 1% to about 99.99% (e.g., from about 20% to about 50%) based on the total weight of the carrier. Water may be present in the carrier in an amount of from about 5% to about 95% (e.g., from about 50% to about 90%) based on the total weight of the carrier (prior to use). The solution can contain any suitable amount of solvent, including from about 40% to about 99.99%. Particularly preferred solutions contain from about 50% to about 99.9%, about 60% to about 99%, about 70% to about 99%, about 80% to about 99%, or about 90% to about 99%.

[0063] A lotion can be made from such a solution. Lotions typically contain at least one emollient in addition to a solvent. A lotion may contain about 1% to about 20% (e.g., about 5% to about 10%) of an emollient and about 50% to about 90% (e.g., about 60% to about 80%) of water. As used herein, "emollient" refers to a material used to prevent or reduce dryness and to protect the skin or hair. Examples of emollients include, but are not limited to, those listed in the International Cosmetic Ingredient Dictionary and Handbook, eds. Wenninger and McEwen, pp. 1656-61, 1626, and 1654-55 (The Cosmetic, Toiletry, and Fragrance Assoc., Washington, DC, 7th Edition, 1997) (hereinafter, "ICI Handbook").

[0064] Another type of product that can be formulated from a solution is a cream, which typically contains about 5% to about 50% (e.g., about 10% to about 20%) emollient and about 45% to about 85% (e.g., about 50% to about 75%) water.

[0065] Yet another type of product that can be formulated from a solution is an ointment. Ointments can contain a simple base of animal, vegetable, or synthetic oils, or semi-solid hydrocarbons. Ointments can contain from about 2% to about 10% of an emollient and from about 0.1% to about 2% of a thickening agent.

[0066] The compositions useful in the present invention can also be formulated as emulsions. When the carrier is an emulsion, about 1% to about 10% (e.g., about 2% to about 5%) of the carrier contains an emulsifier. The emulsifier may be nonionic, anionic, or cationic. Examples of emulsifiers include, but are not limited to, those described on pages 1673 to 1686 of the ICI Handbook.

[0067] Lotions and creams can be formulated as emulsions. Such lotions typically contain 0.5% to about 5% emulsifier, and such creams typically contain about 1% to about 20% (e.g., about 5% to about 10%) emollient, about 20% to about 80% (e.g., about 30% to about 70%) water, and about 1% to about 10% (e.g., about 2% to about 5%) emulsifier.

[0068] Single-phase emulsion skin care formulations, such as lotions and creams, of the oil-in-water and water-in-oil types, are well known in the art and are useful in the present invention. Multiphase emulsion compositions, such as water-in-oil-in-water or oil-in-water-in-oil types, are also useful in the present invention. Generally, such single-phase or multiphase emulsions contain water, emollients, and emulsifiers as essential ingredients.

[0069] The compositions of the present invention can also be formulated as gels (e.g., aqueous, alcohol, alcohol / water, or oil gels using a suitable gelling agent). Suitable gelling agents for aqueous and / or alcoholic gels include, but are not limited to, natural gums, acrylic acid and acrylate polymers and copolymers, and cellulose derivatives (e.g., hydroxymethylcellulose and hydroxypropylcellulose). Suitable gelling agents for oils (such as mineral oil) include, but are not limited to, hydrogenated butylene / ethylene / styrene copolymers and hydrogenated ethylene / propylene / styrene copolymers. Such gels typically contain from about 0.1% to about 5% by weight of such gelling agents.

[0070] The compositions of the present invention can also be formulated into solid preparations (e.g., wax-based sticks, bar soap compositions, powders, or wipes). The compositions of the present invention can also be combined with solid, semi-solid, or soluble substrates (e.g., wipes, masks, pads, gloves, or strips).

[0071] The composition of the present invention may further comprise any of a variety of additional cosmetic active agents, which are preferably formulated for use on sensitive skin. Examples of suitable additional active agents include additional skin whitening agents, tanning agents, anti-acne agents, gloss regulators, antimicrobial agents (e.g., anti-yeast agents, anti-fungal agents, and anti-bacterial agents), anti-inflammatory agents, anti-parasitic agents, external analgesics, sunscreens, photoprotective agents, antioxidants, keratolytic agents, detergents / surfactants, moisturizers, nutrients, vitamins, energy enhancers, antiperspirants, skin astringents, deodorants, hair removal agents, hair growth enhancers, hair growth retardants, stabilizers, hydration enhancers, efficacy enhancers, anti-callus agents, skin conditioning agents, anti-cellulite agents, fluorides, tooth whitening agents, anti-tartar agents, and tartar dissolving agents, malodor inhibitors (e.g., malodor masking agents), or pH modifiers.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), bisdisulizole disodium (Neo Heliopan AP), diethylaminohydroxybenzoyl hexylbenzoate (Uvinul A Plus), ecamsule (Mexoryl SX), methyl anthranilate, 4-aminobenzoic acid (PABA), cinoxate, ethylhexyl triazone (Uvinul T150), homosalate, 4-methylbenzylidene camphor (Parsol 5000), octyl methoxycinnamate (octinoxate), octyl salicylate (octisalate), padimate O (Escalol 507), phenylbenzimidazole sulfonic acid (Ensulizole), polysilicone-15 (Parsol SLX), trolamine salicylate, bemotrizinol (Tinosorb S), benzophenone 1-12, dioxybenzone, drometrizole trisiloxane (Mexoryl XL), iscotrizinol (Uvasorb HEB), octocrylene, oxybenzone (Eusolex 4360), sulisobenzone, bisoctrizole (Tinosorb M), titanium dioxide, zinc oxide, carotenoids, free radical scavengers, spin traps, retinoids and retinoid precursors such as retinol, retinoic acid and retinyl palmitate, ceramides, polyunsaturated fatty acids, essential fatty acids, enzymes, enzyme inhibitors, minerals, hormones such as estrogen, 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 transporters such as NADH and FADH2, and other plant extracts such as oat, aloe vera, feverfew, soybean, and shiitake mushroom extracts, and derivatives and mixtures thereof.

[0072] In one embodiment, the composition of the present invention is a skin care composition comprising a compound of Formula I and at least one skin-lightening active 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), exfoliants, sunscreens, retinoids, antioxidants, tranexamic acid, skin whitening agents, allantoin, opacifiers, talc and silica, zinc salts, and other agents described in Solano et al. Pigment Cell Res. 2006, 19(550-571). Examples of suitable tyrosinase inhibitors include, but are not limited to, vitamin C and its derivatives, vitamin E and its derivatives, kojic acid, arbutin, resorcinol, hydroquinone, flavones (e.g., licorice flavanoids, licorice root extract, mulberry root extract, Dioscorea Coposita root extract, Saxifragaceae extract, etc.), ellagic acid, salicylate and derivatives, glucosamine and derivatives, fullerenes, hinokitiol, diacids, acetylglucosamine, magnolignans, combinations of two or more thereof, etc. Examples of vitamin C derivatives include, but are not limited to, ascorbic acid and its salts, ascorbic acid-2-glucoside, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, and vitamin C-rich natural extracts. Examples of vitamin E derivatives include, but are not limited to, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, and mixtures thereof, tocopherol acetate, tocopherol phosphate, and natural extracts enriched with vitamin E derivatives. Examples of resorcinol derivatives include, but are not limited to, resorcinol, 4-substituted resorcinols such as 4-butylresorcinol (rucinol), 4-hexylresorcinol, phenylethylresorcinol, 4-alkylresorcinols such as 1-(2,4-dihydroxyphenyl)-3-(2,4-dimethoxy-3-methylphenyl)-propane, and natural extracts enriched with resorcinol.Examples of salicylates include, but are not limited to, salicylic acid, acetylsalicylic acid, 4-methoxysalicylic acid, and salts thereof. In certain preferred embodiments, the tyrosinase inhibitor includes a 4-substituted resorcinol, a vitamin C derivative, or a vitamin E derivative. In more preferred embodiments, the tyrosinase inhibitor includes phenylethylresorcinol, 4-hexylresorcinol, or ascorbyl-2-glucoside.

[0073] Examples of suitable melanin degrading agents include, but are not limited to, peroxides and enzymes (e.g., peroxidase and ligninase). In certain preferred embodiments, melanin inhibitors include peroxides and ligninase.

[0074] Examples of suitable melanosome transfer inhibitors include PAR-2 ​​antagonists (e.g., soybean trypsin inhibitor or Bowman-Birk inhibitor), vitamin B3 and derivatives (e.g., niacinamide), essential soybean, whole soybean, soybean extract. In certain preferred embodiments, the melanosome transfer inhibitor includes soybean extract or niacinamide.

[0075] Examples of exfoliants include, but are not limited to, alpha-hydroxy acids (e.g., lactic acid, glycolic acid, malic acid, tartaric acid, citric acid, or any combination of any of the foregoing), beta-hydroxy acids (e.g., salicylic acid, polyhydroxy acids such as lactobionic acid and gluconic acid), and mechanical exfoliants (e.g., microdermabrasions). In certain preferred embodiments, the exfoliant includes glycolic acid or salicylic acid.

[0076] Examples of sunscreens include avobenzone (Parsol 1789), bisdisulizole disodium (Neo Heliopan AP), diethylaminohydroxybenzoyl hexylbenzoate (Uvinul A Plus), ecamsule (Mexoryl SX), methyl anthranilate, 4-aminobenzoic acid (PABA), cinoxate, ethylhexyl triazone (Uvinul T150), homosalate, 4-methylbenzylidene camphor (Parsol 5000), octyl methoxycinnamate (octinoxate), octyl salicylate (octisalate), padimate O (Escalol 507), phenylbenzimidazole sulfonic acid (ensulizole), polysilicone-15 (Parsol SLX), trolamine salicylate, and bemotrizinol (Tinosorb S), benzophenone 1-12, dioxybenzone, drometrizole trisiloxane (Mexoryl XL), iscotrizinol (Uvasorb HEB), octocrylene, oxybenzone (Eusolex 4360), sulisobenzone, bisoctrizole (Tinosorb M), titanium dioxide, zinc oxide, and the like.

[0077] Examples of retinoids include, but are not limited to, retinol, retinaldehyde, retinoic acid, retinyl palmitate, isotretinoin, tazarotene, bexarotene, and adapalene.In certain preferred embodiments, the retinoid is retinol.Nevertheless, in one or more embodiments, the composition is essentially free of retinoids or retinoid precursors, and in further embodiments, it is free of retinoids or retinoid precursors.

[0078] Examples of antioxidants include, but are not limited to, water-soluble antioxidants such as sulfhydryl compounds and their derivatives (e.g., sodium metabisulfite and N-acetylcysteine, glutathione), lipoic acid and dihydrolipoic acid, stilbenoids (e.g., resveratrol and derivatives), lactoferrin, and ascorbic acid and ascorbic acid derivatives (e.g., ascorbyl-2-glucoside, ascorbyl palmitate, and ascorbyl polypeptide). Oil-soluble antioxidants suitable for use in the compositions of the present invention include, but are not limited to, butylated hydroxytoluene, retinoids (e.g., retinol and retinyl palmitate), tocopherols (e.g., tocopherol acetate), tocotrienols, and ubiquinone. Natural extracts containing antioxidants suitable for use in the compositions of the present invention include, but are not limited to, extracts containing flavonoids and isoflavonoids, and their derivatives (e.g., genistein and daidzein), extracts containing resveratrol, etc. Examples of such natural extracts include grape seed, green tea, pine bark, feverfew, parthenolide-free feverfew, oat extract, grapefruit extract, wheat germ extract, hesperidin, grape extract, purslane extract, licochalcone, chalcone, 2,2'-dihydroxychalcone, primrose extract, propolis, and the like.

[0079] The additional cosmetic 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% by weight, such as from about 0.01% to about 5% by weight, etc. In certain preferred embodiments, the amount is from 0.1% to 5%, and in other preferred embodiments, from 1% to 2%.

[0080] Various other materials may also be present in the compositions of the present invention, including, for example, chelating agents, moisturizing agents, opacifiers, conditioners, preservatives, fragrances, etc. The compositions may also include surfactants, such as those selected from the group consisting of anionic, nonionic, amphoteric, cationic, or combinations of two or more thereof.

[0081] The compositions of the present invention may further contain chelating agents (e.g., EDTA) and preservatives (e.g., parabens). Examples of suitable preservatives and chelating agents are listed on pages 1626 and 1654-55 of the ICI Handbook. Additionally, the compositions useful herein may contain conventional cosmetic adjuvants such as colorants, including dyes and pigments, opacifiers (e.g., titanium dioxide), and fragrances.

[0082] In certain preferred embodiments, the present invention comprises applying the compound or composition of the present invention through a substrate comprising such a material. Any suitable substrate can be used in the present invention. Examples of suitable substrates and substrate materials are disclosed in, for example, U.S. Patent Application Publication Nos. 2005 / 022683 and 2009 / 0241242, the entire contents of which are incorporated herein by reference. In certain preferred embodiments, the substrate is a wipe or a facial mask.

[0083] Compositions and products containing such compositions of the present invention can be prepared using methods well known to those skilled in the art.

[0084] Example 1: Preparation of the composition Two compositions of the present invention (Examples 1-2) were prepared in the following manner using the amounts shown in Table 1 below. Examples 1-2 contained 0.5 and 1% by weight lemon aspen extract, respectively. Purified water was added to an appropriately sized beaker. Mixing began using a propeller mixing blade, and the water was heated to 75-80°C. Sepimax Zen™ was slowly added to the main batch and mixed until fully hydrated and no visible particles remained, increasing the mixing speed as necessary. The mixture was reheated to 75-80°C, and then chlorphenesin and emulsifier were added and mixed until uniform and no undissolved particles remained. The solution was then cooled to 60-65°C while adding glycerin and mixed until uniform. After the solution had cooled to 55-60°C, Sepiplus™ 400 and Acronychia acidula (lemon aspen) fruit extract (30% w / w in an aqueous carrier solution) were added and mixed until uniform. The Acronychia acidula fruit extract used in the examples typically contains approximately 1% to 10% 3-(4-farnesyloxyphenyl)-propionic acid; these samples contain 1.11% 3-(4-farnesyloxyphenyl)-propionic acid by weight of the extract in the carrier. The solution was allowed to cool to 40°C while mixing at a moderate speed. Dimethicone, phenoxyethanol, and ethylhexylglycerin were then added and mixed until uniform. Water was added and the pH was adjusted to pH 5. The solution was mixed until uniform.

[0085] [Table 1]

[0086] Example 2: Skin irritation model clinical trial Eight compositions were evaluated for inducing clinical irritation using a skin cumulative irritation patch test. Of the eight compositions, two were the inventive compositions Examples 1 and 2 described above. Examples 3-4 were two compositions that served as controls. Specifically, Example 3 was a positive control containing 0.5% sodium lauryl sulfate (SLS) in petrolatum. SLS served as the positive control because it is a known irritant (see, e.g., Zhai, H. et al., A bioengineering study on the efficacy of a skin protectant lotion in preventing SLS-induced dermatitis, Skin Research and Technology 2000:6:77-80, see page 77). Example 4 was a negative control consisting of petrolatum. Petrolatum is known for use as a negative control, as evidenced by Uliasz, MD, A. and Lebwohl, MD M., Evaluation of sensory irritation caused by topical medications using a novel technique, International Journal of Dermatology 2010, 49, 269-27 (see abstract). Examples 5-8 were commercially available compositions containing 0-0.5% by weight of retinol.

[0087] Sixty subjects were recruited for this study, with 54 completing the study. In this study, 0.2-0.3 grams of the test composition was applied to a designated area on each subject's back and held in place for 24 hours using a semi-occlusive patch (Professional Medical Products Patch). Each composition was applied in this manner three times per week for a total of nine applications. Forty-eight to 72 hours after each application, trained raters rated the test areas using the scale in Table 2 below.

[0088] [Table 2]

[0089] The cumulative irritation potential of a composition is the sum of the nine application scores (21 days) for each test site for each subject. The overall score for each composition was obtained by summing the 21-day totals for all subjects (maximum potential cumulative irritation score = 1944). The cumulative irritation mean score, standard deviation, minimum, median, and maximum are shown in Table 3 below. The skin cumulative irritation mean scores were then compared by calculating the level calculated from a mixed model using Tukey's HSD test for pairwise comparisons. The test hypothesis was that the mean change from baseline was equal between treatments. The resulting skin cumulative irritation scores and statistics are shown in Table 4 below.

[0090] [Table 3]

[0091] [Table 4]

[0092] This is surprising considering that the total concentration of Examples 1 and 2 of the present invention was comparable to that of the negative control, petrolatum, which is known as a very mild skin protectant. Even the sample with the lowest retinol concentration (0.04% in Example 5) was higher than the negative control. Furthermore, lemon aspen extract (containing the compound 3-(4-farnesyloxyphenyl)-propionic acid) has retinol-like activity, as evidenced by its mechanism of action via the retinol agonist receptor (RAR) pathway (see, e.g., U.S. Patent Publication No. 2020 / 0030226(A1)). Retinol and retinoids in general are typically not considered gentle on the skin and are, in fact, known to cause local skin irritation and erythema (see Kim, B. et al., "The mechanism of retinol-induced irritation and its application to anti-irritant development," Toxicology Letters 146 (2003), 65-73, Abstract). It is therefore surprising that the 0.5% and 1% w / w lemon aspen extract compositions were very gentle on the skin, even though the lemon aspen extract functions using the same mechanism of action.

[0093] Example 3: Clinical Tolerance Study in Subjects with Sensitive Skin Three compositions were evaluated for clinical tolerability in a single-center, 12-week, 3-cell, evaluator-blinded, full-face, randomized study. Two of the three compositions were inventive composition examples 1 and 2 described above. The third composition was a commercially available cream containing 0.1% retinol.

[0094] Subjects were screened and enrolled to ensure completion of at least 30 subjects in each of the three cells. The target population was female subjects aged 35 to 60 years with Fitzpatrick skin types I to IV, with moderate patchy hyperpigmentation, moderate fine lines / wrinkles, and moderate overall photodamage on the face. At least 50 percent of subjects in treatment groups Examples 1 and 2 had subjectively mild to moderately sensitive facial skin, using the scale in Table 5. For treatment with a commercially available cream containing 0.1% retinol, all subjects had subjectively normal skin (i.e., no sensitivity). Retinol was not tested on subjects with sensitive skin due to the known irritation and erythema it causes.

[0095] [Table 5]

[0096] Beginning at Visit 1, subjects washed their faces once in the morning and once in the evening using a specific commercial cleanser. Beginning at Visit 2, subjects used the assigned treatment once in the morning and once in the evening after using the provided cleanser. In addition, subjects applied a specific commercial sunscreen 5–10 minutes after applying facial moisturizer. Subjects were only permitted to use their usual cosmetic makeup products approved at Visit 1. On study visit days, subjects removed all leave-on products, including the provided cleanser, at least 30 minutes and a maximum of 2 hours before the visit. The study consisted of six visits over 12 weeks, including screening (Visit 1), baseline (Week 0; Visit 2), Week 1 (Visit 3), Week 2 (Visit 4), Week 4 (Visit 5), and Week 12 (Visit 6) scheduled visits. The over-the-counter cream treatment group containing 0.1% retinol was not evaluated at week 1.

[0097] The principal investigator (PI), an expert in clinical skin evaluation with 15 years of experience in this field, assessed each subject's facial skin for the tolerability parameters of erythema, edema, and dryness / scaling using a rating scale of 0 to 3 according to the rating scale in Table 6 (half points allowed).

[0098] [Table 6]

[0099] The PI also queried the subjects about the tolerability parameters of burning, stinging, itching, and tightness / dryness using a rating scale of 0 to 3 using the overall score according to the rating scale in Table 7 only.

[0100] [Table 7]

[0101] The above tolerability scores were evaluated using the Friedman test, along with a nonparametric repeated measures analysis of variance using Dunn's test as a post-hoc test to determine the level of significance from baseline at each time point. The mean change from baseline for each tolerability parameter is shown in Tables 8 and 9 below.

[0102] [Table 8]

[0103] [Table 9]

[0104] These data showed no statistically significant differences in the net change from baseline between cells at any time point for all endpoints, indicating that the treatment was non-irritating. As discussed above, lemon aspen extract (containing the compound 3-(4-farnesyloxyphenyl)-propionic acid) has retinol-like activity, as evidenced by its mechanism of action via the retinol agonist receptor (RAR) pathway, and retinoids are generally known to be poorly tolerated. Therefore, it is surprising that lemon aspen extract was very well tolerated in a population with self-perceived sensitive skin. As can be seen from the results, samples containing lemon aspen extract were non-irritating or less irritating in individuals with sensitive skin compared to retinol-containing compositions in individuals with normal skin.

[0105] Example 4: Instrumental Testing - Cutometer Three elasticity measurements were taken at each time point on the left cheek area of ​​the subjects in Example 3 using an elasticity property evaluation device sold under the trade name CUTOMETER MPA 580 (Courage+Khazaka electronic, Germany). The commercially available cream treatment group containing 0.1% retinol was not evaluated at week 1. The probe was repositioned for each measurement using 450 mbar pressure, a 2 mm diameter probe opening, 5 seconds of suction, and a 5 second relaxation time. Measurements of each check area were approximately 2 cm below the cheekbone, avoiding any blemishes or hyperpigmented spots.

[0106] The probe was placed perpendicularly on the skin in full contact with the skin, without applying a force large enough to deform the skin. The viscoelastic behavior of the skin was described by a deformation curve, with the skin deformation (amplitude in mm) measured as a function of time. The following absolute parameters (measured in mm) were calculated from the skin deformation curve: Ua / Uf(R2) - the ratio between the final contraction and the maximum deformation (i.e., the overall elasticity of the skin including viscous deformation) Ur / Uf (R7) - ratio of immediate contraction to total deformation (i.e., bioelasticity) Ur / Ue (R5) - ratio of immediate contraction to immediate deformation (i.e., net elasticity of the skin without viscous deformation)

[0107] Results were evaluated using repeated measures analysis of variance with Dunn's test as a post-hoc test to determine the level of significant change from baseline between treatments at each time point. The mean change from baseline for each skin elasticity parameter is shown in Table 10 below.

[0108] [Table 10]

[0109] Cutometer R2 values ​​showed an improvement in total elasticity (total recovery over total deformation) compared to baseline for all cells across all time points, with improvements continuing through week 12 for all cells.

[0110] Cutometer R5 values ​​show an improvement in net elasticity (immediate recovery to immediate deformation) compared to baseline for all cells, with little change from week 2 to week 12 for cells B and C, and a slight decrease in this improvement from week 2 to week 12 for cell A.

[0111] Cutometer R7 values ​​show improved elasticity (immediate recovery to total deformation) compared to baseline for all cells. The only statistically significant difference between cells was between Cell A and Cell B at week 1 (p<0.05).

[0112] The Cutometer values ​​of R2, R5, and R7 indicate improvements in gross elasticity (total recovery from total deformation), net elasticity (immediate recovery from immediate deformation), and elasticity (immediate recovery from total deformation), respectively, when compared to baseline for all treatments across all time points. Thus, the 0.5% and 0.1% lemon aspen compositions (Examples 1-2) demonstrate effectiveness in improving skin elasticity as indicated for treating signs of aging.

[0113] Furthermore, the results for three parameters, R2, R5, and R7, over 12 weeks for lemon aspen showed similar levels of improvement in sensitive skin as 0.1% retinol showed in normal skin, demonstrating the effectiveness of lemon aspen as a sufficiently gentle anti-aging treatment for sensitive skin and that its effectiveness is comparable to that of retinol in normal skin.

[0114] Example 5: Instrumental Testing - Erythema Index Erythema index measurements were obtained using a DSM II colorimeter (Cortex Technologies, Hadsund, Denmark) on the left cheek area and center of the forehead of the subjects in Examples 3-4.

[0115] Results were evaluated using repeated measures analysis of variance with Dunn's test as a post-hoc test to determine the level of significant change from baseline between treatments at each time point. The mean change from baseline for the erythema index from cheek measurements is shown in Table 11 below.

[0116] [Table 11]

[0117] The erythema index data show a small, gradual decrease in erythema for both lemon aspen compositions from week 2 to week 12. There were no statistically significant differences between treatments.

[0118] DSM II erythema index values ​​from the cheek show a small gradual decrease in erythema from week 2 to week 12 for both cells A and B. There were no statistically significant differences between the cells.

[0119] DSM II erythema index values ​​from the forehead show a small, gradual decrease in erythema from week 2 to week 12 for both cells A and B. There were no statistically significant differences between the cells.

[0120] There was no skin irritation manifested by redness of the skin as measured by the erythema index. These results confirm the observations in the patch test study above that the composition is non-irritating to sensitive skin.

[0121] Example 5: Instrumental Testing - Collagen Cross-Linking Three fluorescence measurements (i.e., three sets of scans) were performed on the left cheek area and center of the forehead of the subjects in Examples 3-5 using a SkinSkan spectrofluorometer (Horiba Jovin Yvon, Edison, NJ). Each SkinSkan measurement consisted of a set of three scans: two excitation scans (1: 270 nm to 320 nm, emission at 345 nm; 2: 290 nm to 360 nm, emission at 390 nm), followed by a synchronous scan (315 nm to 401 nm). Analysis of the fluorescence spectra provides information about skin fluorophores such as tryptophan and collagen crosslinks. The group treated with a commercial cream containing 0.1% retinol was not evaluated at week 1.

[0122] Results were evaluated using repeated measures analysis of variance with Dunn's test as a post-hoc test to determine the level of significant change from baseline between treatments at each time point. The mean change from baseline for fluorescence intensity from collagen crosslinks is shown in Table 12 below.

[0123] [Table 12]

[0124] Examples 1 and 2 each demonstrate a statistically significant improvement in collagen crosslinking at 12 weeks compared to baseline. Such an improvement in collagen crosslinking is indicated for treating signs of aging. Thus, the 0.5% and 0.1% lemon aspen compositions (Examples 1-2) demonstrate efficacy in treating signs of skin aging.

[0125] Furthermore, the results of Examples 1-2 showed similar levels of improvement in sensitive skin as 0.1% retinol did in normal skin, demonstrating the effectiveness of lemon aspen as an anti-aging treatment that is gentle enough for sensitive skin and that its effectiveness is comparable to that of retinol in normal skin.

[0126] [Embodiment] (1) A method of treating sensitive skin, said method comprising administering to said sensitive skin a compound of formula I: [ka] A compound of the formula During the ceremony, R1 is C1~C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 selected from the group consisting of alkynyl, and C3-C8 cycloalkyl or aryl; R2 is selected from the group consisting of hydrogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl or aryl, -OC1-C6 alkyl, -OC2-C6 alkenyl, -OC2-C6 alkynyl, -OC3-C8 cycloalkyl or aryl, thiol, -SC1-C6 alkyl, -SC2-C6 alkenyl, -SC2-C6 alkynyl, -SC3-C8 cycloalkyl or aryl, -NR4C1-C6 alkyl, -NR4C2-C6 alkenyl, -NR4C2-C6 alkynyl, and -NR4C3-C8 cycloalkyl or aryl; R3 is selected from -CO2H, -CO2R4, or an isosteric equivalent of a carboxy group, and R4 is C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, or aryl; Y is, [ka] a compound of formula I, or a cosmetically acceptable salt thereof. (2) R1 is C5~C 16Alkyl, C5-C 16 Alkenyl and C5-C 16 alkynyl; R2 is selected from the group consisting of hydrogen, hydroxyl, —O—C alkyl, —O—C alkenyl, —O—C alkynyl, —O—C cycloalkyl; R3 is selected from —COH, —COR where R4 is C—C alkyl, or an isosteric equivalent of a carboxy group; and Y is —(CH—CH)— or —(CH═CH)—. (3) R1 is C5~C 16 3. The method of embodiment 1 or 2, wherein R is selected from the group consisting of -C1-C3 alkyl and R2 is selected from the group consisting of -C1-C3 alkyl. (4) The method of any one of embodiments 1 to 3, wherein the compound of formula I is selected from the group consisting of 3-(4-farnesyloxyphenyl)-propionic acid, 3-(4-farnesyloxy-3-hydroxyphenyl)-propionic acid, 3-(4-farnesyloxy-3-methoxyphenyl)-propionic acid, its ethyl ester, and a combination of two or more thereof. (5) The method of any one of embodiments 1 to 4, wherein the compound of formula I is 3-(4-farnesyloxyphenyl)-propionic acid.

[0127] (6) The method of any one of embodiments 1 to 5, wherein the applying step comprises applying the compound of formula I to the sensitive skin, and the compound of formula I is contained in a plant extract. (7) The method according to any one of embodiments 1 to 6, wherein the plant extract is an extract of a plant of the genus Acronychia. (8) The method according to any one of the preceding claims, wherein the plant extract is an extract of Acronychia acidula. (9) The method according to any one of the preceding claims, wherein the extract is a polar extract. (10) The method according to any one of the preceding claims, wherein the extract is present in an amount of about 0.1% by weight to about 3% by weight based on the total weight of the composition.

[0128] (11) The method according to any one of embodiments 1 to 10, wherein the concentration of the compound of formula I is present in an amount ranging from about 0.0001% to about 1% by weight of the total composition. (12) The method of any one of embodiments 1 to 11, wherein the sensitive skin comprises skin of a subject having a reactive state or a history of a reactive state selected from the group consisting of erythema, edema, burning, pain, puritis, stinging, prickling, itching, tightness, dryness, scaling, roughness to the touch, peeling of the skin, flaky patches, and combinations thereof, when exposed to a retinoid. (13) The method of any one of embodiments 1 to 12, wherein the sensitive skin comprises skin of a subject having a condition or a history of a condition selected from the group consisting of atopic dermatitis, rosacea, seborrheic dermatitis, contact dermatitis, psoriasis, dry skin, and flaky skin. (14) The method of any one of embodiments 1 to 13, wherein the method of treating skin is a method of treating acne, wrinkles, and / or skin whitening in a subject having a condition or a history of a condition selected from the group consisting of atopic dermatitis, rosacea, seborrheic dermatitis, psoriasis, dry skin, and flaky skin. (15) A method for treating acne, wrinkles, and / or whitening skin in a subject having a reaction condition or a history of a reaction condition selected from the group consisting of erythema, edema, burning, pain, itching, stinging, tingling, itching, tightness, dryness, scaling, roughness to the touch, peeling skin, flaky patches, and combinations thereof, comprising applying 3-(4-farnesyloxyphenyl)-propionic acid to the skin.

[0129] 16. The method of claim 15, wherein the applying step comprises applying to the sensitive skin a composition comprising a plant extract, the plant extract being an extract of a plant of the genus Acronychia. (17) The method of any one of embodiments 15 to 16, wherein the plant extract is an extract of Acronichia acidula. (18) The method according to any one of embodiments 15 to 17, wherein the extract is a polar extract. (19) The method according to any one of embodiments 15 to 18, wherein the extract is present in an amount of about 0.1% by weight to about 3% by weight based on the total weight of the composition. (20) The method according to any one of embodiments 15 to 19, wherein the concentration of the compound of formula I is present in an amount ranging from about 0.0001% to about 1% by weight of the total composition.

Claims

1. 1. A method of treating sensitive skin, said method comprising administering to said sensitive skin a compound of formula I: 【Chemistry 1】 A compound of the formula During the ceremony, R １ But C １ ~C ２０ Alkyl, C ２ ~C ２０ Alkenyl, C ２ ~C ２０ Alkynyl, and C ３ ~C ８ selected from the group consisting of cycloalkyl or aryl; R ２ is hydrogen, hydroxyl, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ８ cycloalkyl or aryl, —OC １ ~C ６ Alkyl, —OC ２ ~C ６ Alkenyl, —OC ２ ~C ６ Alkynyl, —OC ３ ~C ８ Cycloalkyl or aryl, thiol, -SC １ ~C ６ Alkyl, -SC ２ ~C ６ Alkenyl, -SC ２ ~C ６ Alkynyl, -SC ３ ~C ８ cycloalkyl or aryl, —NR ４ C １ ~C ６ Alkyl, —NR ４ C ２ ~C ６ Alkenyl, —NR ４ C ２ ~C ６ Alkynyl, and —NR ４ C ３ ~C ８ selected from the group consisting of cycloalkyl or aryl; R ３ But -CO ２ H, -CO ２ R ４ or an isosteric equivalent of a carboxy group; R ４ But C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ３ ~C ８ cycloalkyl or aryl; Y is, 【Chemistry 2】 A compound of formula I, or a cosmetically acceptable salt thereof.

2. R １ But C ５ ~C １６ Alkyl, C ５ ~C １６ Alkenyl, and C ５ ~C １６ alkynyl; R ２ is hydrogen, hydroxyl, -OC １ ~C ６ Alkyl, —OC ２ ~C ６ Alkenyl, —OC ２ ~C ６ Alkynyl, —OC ３ ~C ８ cycloalkyl; R ３ But -CO ２ H, R ４ is C １ ~C ６ -CO, which is alkyl ２ R ４ or an isosteric equivalent of a carboxy group, and Y is selected from -(CH ２ -CH ２ 2. The method of claim 1, wherein the aryl group is -(CH═CH)- or -(CH═CH)-.

3. R １ But C ５ ~C １６ alkenyl; R ２ is hydrogen or -OC １ ~C ３ 3. The method of claim 1 or 2, wherein the alkyl is selected from the group consisting of alkyl.

4. 2. The method of claim 1, wherein the compound of Formula I is selected from the group consisting of 3-(4-farnesyloxyphenyl)-propionic acid, 3-(4-farnesyloxy-3-hydroxyphenyl)-propionic acid, 3-(4-farnesyloxy-3-methoxyphenyl)-propionic acid, its ethyl esters, and combinations of two or more thereof.

5. 2. The method of claim 1, wherein the compound of formula I is 3-(4-farnesyloxyphenyl)-propionic acid.

6. 10. The method of claim 1, wherein the applying step comprises applying the compound of formula I to the sensitive skin, and the compound of formula I is contained in a plant extract.

7. 2. The method of claim 1, wherein the plant extract is an extract of a plant of the genus Acronychia.

8. 2. The method of claim 1, wherein the plant extract is an extract of Acronychia acidula.

9. The method of claim 1 , wherein the extract is a polar extract.

10. 10. The method of claim 1, wherein the extract is present in an amount of about 0.1% to about 3% by weight, based on the total weight of the composition.

11. 10. The method of claim 1, wherein the concentration of the compound of formula I is present in an amount ranging from about 0.0001% to about 1% by weight of the total composition.

12. 10. The method of claim 1, wherein the sensitive skin comprises skin of a subject having a reactive condition or a history of a reactive condition selected from the group consisting of erythema, edema, burning, pain, itching, stinging, prickling, itching, tightness, dryness, scaling, roughness to the touch, peeling of the skin, flaky patches, and combinations thereof when exposed to a retinoid.

13. 10. The method of claim 1, wherein the sensitive skin comprises skin of a subject having a condition or a history of a condition selected from the group consisting of atopic dermatitis, rosacea, seborrheic dermatitis, contact dermatitis, psoriasis, dry skin, and flaky skin.

14. 10. The method of claim 1, wherein the method of treating skin is a method of treating acne, wrinkles, and / or whitening skin in a subject having a condition or a history of a condition selected from the group consisting of atopic dermatitis, rosacea, seborrheic dermatitis, psoriasis, dry skin, and flaky skin.

15. 1. A method of treating acne, wrinkles, and / or lightening the skin in a subject having or having a history of a reactive condition selected from the group consisting of erythema, edema, burning, pain, itching, stinging, tingling, itching, tightness, dryness, scaling, roughness to the touch, peeling skin, flaky patches, and combinations thereof, comprising applying 3-(4-farnesyloxyphenyl)-propionic acid to the skin.

16. 16. The method of claim 15, wherein the applying step comprises applying to the sensitive skin a composition comprising a plant extract that is an extract of a plant of the genus Acronychia.

17. 17. The method of claim 15 or 16, wherein the plant extract is an extract of Acronychia acidula.

18. 16. The method of claim 15, wherein the extract is a polar extract.

19. 16. The method of claim 15, wherein the extract is present in an amount of about 0.1% to about 3% by weight, based on the total weight of the composition.

20. 16. The method of claim 15, wherein the concentration of the compound of formula I is present in an amount ranging from about 0.0001% to about 1% by total weight of the composition.

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