Compositions suitable for use on sensitive skin and methods of use thereof

Abstract

Compositions and methods for treating sensitive skin with a composition comprising a compound having retinol-like activity are provided. Also provided are methods of treating acne, wrinkles, and / or lightening skin in a subject having a response disorder or a history of response disorder with a composition comprising a compound having retinol-like activity.

Description

Technical Field

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

[0002] Human skin undergoes certain aging processes, which are partly attributable to intrinsic processes (e.g., chronological aging) and partly to extrinsic factors (e.g., photoaging). In addition, the skin may undergo transient or even persistent changes such as acne, oily or dry skin, keratosis, rosacea, photosensitivity, inflammation, erythema nodosum, and allergic or autoimmune reactions, such as dermatoses and photodermatoses.

[0003] Consequences of the aforementioned aging process may include thinning of the skin, weakening of the interweaving of the epidermis and dermis, and a decrease in the number of cells and blood vessels supplying the skin. These consequences are generally undesirable, and individuals suffering from these problems will seek topical treatments to address them.

[0004] Retinoids have been used to treat skin conditions caused by intrinsic aging, external factors, acne, or skin diseases. However, while retinoid treatment has beneficial effects, their benefits are limited by the fact that retinoids can cause skin irritation. These side effects can limit the use of retinoids, particularly for individuals with sensitive skin.

[0005] To date, the search for alternative compounds to retinoids, and particularly for individuals with sensitive skin, has had limited success in treating skin conditions associated with aging (such as skin atrophy, acne, photoaging) and in reducing the appearance of wrinkles, fine lines, stretch marks or cellulite.

[0006] Therefore, there is a need for alternatives to traditional retinoids that are effective yet mild enough for use in individuals with sensitive skin. Summary of the Invention

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

[0008]

[0009] in:

[0010] R1 is selected from the group consisting of: C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl and C3-C8 cycloalkyl or aryl;

[0011] R2 is selected from the group consisting of hydrogen, hydroxy, 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;

[0012] R3 is selected from -CO2H, -CO2R4 or an isosteric equivalent of a carboxyl group, wherein R4 is C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or aryl; and

[0013] Y is -(CH2-CH2)-, -(CH=CH)- or -(C ＝ C)-;

[0014] or a cosmetically acceptable salt thereof.

[0015] In one or more embodiments, R1 is selected from the group consisting of: C5-C 16 Alkyl, C5-C 16 Alkenyl and C5-C 16 alkynyl; R2 is selected from the group consisting of hydrogen, hydroxyl, -OC1-C6 alkyl, -OC2-C6 alkenyl, -OC2-C6 alkynyl, -OC3-C8 cycloalkyl; R3 is selected from -CO2H, -CO2R4, wherein R4 is a C1-C6 alkyl, or an isosteric equivalent of a carboxyl group; and Y is -(CH2-CH2)- or -(CH=CH)-. In some embodiments, R1 is selected from the group consisting of C5-C 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, their ethyl esters, 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 the compound of Formula I to the sensitive skin, and the compound of Formula I is contained in a plant extract. In some embodiments, the plant extract is an extract of an Acronychia plant. 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% by weight to about 1.5% by weight based on the total weight of the composition. In one or more embodiments, the sensitive skin includes the skin of a subject having a reaction condition or a history of a reaction condition when exposed to a retinoid selected from the group consisting of erythema, edema, burning, pain, itching, stinging, tingling, itching, tightness, dryness, peeling, tactile roughness, peeling skin, flaky patches, and combinations thereof. In some embodiments, the sensitive skin includes the 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, flaky skin. In one or more embodiments, the method for treating skin is a method for treating acne, wrinkles, and / or skin lightening 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, flaky skin.

[0016] Another aspect of the invention relates to a method of treating acne, wrinkles and / or skin lightening in 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, tingling, itching, tightness, dryness, scaling, roughness to the touch, peeling skin, flaky patches, and combinations thereof, the method comprising applying to the skin 3-(4-farnesyloxyphenyl)-propionic acid.

[0017] In some embodiments, the applying step comprises applying a composition comprising a plant extract from a plant of the genus Citrus to sensitive skin. In one or more embodiments, the plant extract is an extract of Citrus aurantium. In some embodiments, the extract is a polar extract. In one or more embodiments, the extract is present in an amount from 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 from about 0.4% to about 1.5% by weight, based on the total weight of the composition. DETAILED DESCRIPTION

[0018] 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 remainder of the disclosure in any way whatsoever.

[0019] 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 the invention belongs. In addition, all publications, patent applications, patents and other references mentioned herein are incorporated by reference.

[0020] Unless otherwise indicated, percentages used to express the amount of an ingredient are weight percentages (referred to as "weight %," "wt %," "weight %," or "% (W / W)"). Similarly, weight ratios used to express the relative proportions of ingredients are also determined using weight percentages (i.e., the weight ratio is calculated by dividing the weight percentage of one ingredient by the weight percentage of another ingredient). Unless otherwise indicated, all ranges are inclusive, e.g., "4 to 9" includes the values ​​4 and 9.

[0021] As used herein, a composition that is "substantially free" of an ingredient refers to a composition that has about 2% by weight or less of the ingredient (based on the total weight of the composition). Preferably, a composition that is substantially free of an ingredient has about 1% by weight or less, 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 ingredient (based on the total weight of the composition). In certain more preferred embodiments, a composition that is substantially free of an ingredient does not contain the ingredient, that is, the composition is completely free of the ingredient.

[0022] As used herein, "cosmetically / dermatologically acceptable" means that the ingredients described in the term are suitable for use in contact with tissue (e.g., skin or hair) without undue toxicity, incompatibility, instability, irritation, allergic response, etc. As will be appreciated by those skilled in the art, cosmetically / dermatologically acceptable salts are either acidic / anionic or basic / cationic salts.

[0023] As used herein, the term "safe and effective amount" refers to an amount of an extract or composition that is sufficient to produce the desired effect but insufficient to avoid serious side effects. The safe and effective amount of a compound, extract, or composition will vary depending on factors such as the age, health, and environmental exposures of the end user, the duration and nature of the treatment, the specific extract, ingredient, or composition employed, and the specific pharmaceutically acceptable carrier employed.

[0024] As used herein, the term "about" means within 5 weight percent, within 4 weight percent, within 3 weight percent, within 2.5 weight percent, within 2 weight percent, or within 1 weight percent of the disclosed value.

[0025] In general, IUPAC nomenclature is used herein and the following terms are defined.

[0026] The term "substituted" means that one or more hydrogen atoms on the core molecule have been replaced by a substituent group in an amount permitted by the available valence. Substitution is not limited to the core molecule but can also be carried out on a substituent group so that the group becomes a linking group.

[0027] The term "independently selected" refers to two or more substituents that can be selected from a variable group of substituents, wherein the selected substituents may be the same or different.

[0028] The term "dependently selected" refers to one or more substituent variables being designated for substitution in the core molecule in the indicated combination (eg, variables involving groups of substituents appearing in a tabular listing of a compound).

[0029] 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, tertiary amines, etc.

[0030] One aspect of the present invention relates to a method for treating sensitive skin, comprising administering to the sensitive skin a compound of formula I:

[0031]

[0032] in:

[0033] R1 is selected from the group consisting of: C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl and C3-C8 cycloalkyl or aryl;

[0034] R2 is selected from the group consisting of hydrogen, hydroxy, 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;

[0035] R3 is selected from the group consisting of: -CO2H, -CO2R4 or an isosteric equivalent of a carboxyl group, wherein R4 is C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or aryl; and

[0036] Y is -(CH2-CH2)-, -(CH=CH)- or -(C ＝ C)-;

[0037] or a cosmetically acceptable salt thereof.

[0038] Compounds of formula I

[0039] In one or more embodiments, R1 is selected from the group consisting of: C5-C 16 Alkyl, C5-C 16 Alkenyl and C5-C 16 Alkynyl; R2 is selected from the group consisting of hydrogen, hydroxyl, -OC1-C6 alkyl, -OC2-C6 alkenyl, -OC2-C6 alkynyl, -OC3-C8 cycloalkyl; R3 is selected from -CO2H, -CO2R4, wherein R4 is a C1-C6 alkyl, or an isosteric equivalent of a carboxyl 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-C 16 alkenyl; 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, their ethyl esters, and combinations of two or more thereof. In one or more embodiments, the compound of Formula I above is 3-(4-farnesyloxyphenyl)-propionic acid and / or its ethyl ester. In a preferred embodiment, the compound of Formula I comprises 3-(4-farnesyloxyphenyl)-propionic acid. 3-(4-farnesyloxyphenyl)-propionic acid and / or its ethyl ester can be synthesized using conventional organic synthesis processes.

[0040] The compound of Formula I can 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%, from about 0.01% to about 1%, 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.

[0041] The compounds according to Formula I can also be obtained from natural sources. For example, the compounds according to Formula I can be present in plant extracts. Thus, the methods described herein can comprise applying a composition comprising a plant extract to sensitive skin.

[0042] In one or more embodiments, the plant extract is an extract of a plant of the genus Citrus. In another embodiment, the plant extract is an extract of Citrus aurantium (also known as lemon aspen). In one or more embodiments, at least one compound of Formula I described above is present in the Citrus aurantium extract at a concentration equal to or greater than 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%, based on the weight of the Citrus aurantium extract. In another embodiment, the Citrus aurantium extract comprises 3-(4-farnesyloxyphenyl)-propionic acid at a concentration ranging from about 1% to about 10%, based on the total weight of the extract.

[0043] Suitable extracts can be obtained using conventional methods including, but not limited to, direct extraction of the material from the biomass by grinding, maceration, pressing, squeezing, mashing, centrifugation, and / or processes such as cold percolation, stirring / distillation, microwave-assisted extraction, supercritical / subcritical CO2 compressed gas extraction with or without polar modifiers, pressurized solvent extraction, accelerated solvent extraction, pressurized or normal hot water extraction, surfactant-assisted pressurized hot water extraction, oil extraction, membrane extraction, Soxhlet extraction, Gold Finger distillation / extraction, and / or the processes disclosed in, for example, U.S. Patent Nos. 7,442,391, 7,473,435, and 7,537,791 to Integrated Botanical Technologies, LLC (each incorporated herein by reference), or by other methods such as solvent extraction.

[0044] Any of a variety of solvents including polar solvents, non-polar solvents, or a combination of two or more thereof can be used in methods including solvent extraction. Suitable polar solvents include polar inorganic solvents such as water, polar organic solvents such as alcohols and corresponding organic acids, for example, C1-C8 alcohols including methanol, ethanol, propanol, butanol, organic acids including acetic acid, formic acid, propionic acid, polyols and glycols including C1-C8 polyols / glycols, and combinations of two or more thereof. Suitable non-polar solvents include non-polar organic solvents such as alkanes (including C1-C8 alkanes), cycloalkanes (including C1-C8 alkanes), alkyl ethers (including C1-C8 alkyl ethers), petroleum ether, ketones (including C1-C8 ketones), dichloromethane, ethyl acetate, xylene, toluene, chloroform, vegetable oils, mineral oils, and the like. In another embodiment, extraction can be obtained by non-polar solvent or supercritical fluid extraction as described above with or without polar modifiers such as C1-C8 alcohols, water, C1-C8 polyols / diols, or C1-C8 organic acids.

[0045] In one or more embodiments, the extract comprises an extract of Citrus aurantium. In some embodiments, the extract of the present invention comprises a combination of polar and non-polar extracts of Citrus aurantium fruit. In another embodiment, the extract of the present invention comprises an alcoholic or glycolic acid extract of Citrus aurantium fruit.

[0046] In one or more embodiments, the extract is a polar extract. In another embodiment, the extract is a polar extract prepared using a polar solvent comprising water, a C1-C8 alcohol, a C1-C8 polyol, or a C1-C8 diol, 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 diols. In one or more embodiments, the extract is prepared using a solvent comprising methanol, ethanol, or a combination thereof, with or without water. In another embodiment, the extract is a polar extract extracted from the fruit of the citrus aurantium using a combination of alcohol and water.

[0047] 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 other embodiments, the extract is a non-polar extract prepared using hexane, ethyl acetate, chloroform, or a mixture of two or more thereof. In yet other embodiments, the extract is a non-polar extract prepared using ethyl acetate.

[0048] For example, an extract using the fruit of Citrus aurantium can be prepared by homogenizing the fruit in a blender with an amount of denatured alcohol equal to the amount of fruit for 30 seconds. The pulp is then mixed and stirred at ambient temperature (22°C to 26°C) for an additional 24 hours. Additional denatured alcohol may be added as needed to keep the pulp well coated in the alcohol. The mixture is then gravity filtered, and the resulting filter cake is washed with additional amounts of denatured alcohol. The total 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 extraction solvent and water. The extraction can be repeated several times on the filter cake, with a regular extract yield of 5% to 7% being obtained from each extraction.

[0049] Another example of preparing an extract of the fruit of Citrus amygdalus is as follows: 500 g of freeze-dried Citrus amygdalus fruit is cut into approximately 5 mm cubes and soaked with 5 L of ethanol at a ratio of 1:10 (raw material to solvent) and stirred at room temperature for 12 hours. The suspension can then be filtered, and the resulting filtrate is concentrated under low pressure to obtain a concentrate. The concentrate can then be further dried by a freeze-drying method to obtain 325 g of residual material referred to as a crude extract (65% yield). A 200 g sample of the crude extract is then dissolved in 1 L of ethanol and stirred at room temperature overnight. The mixture can then be filtered and dried under reduced pressure and low temperature to provide an extract.

[0050] Extract can exist with the amount of about 0.00001 % by weight, 0.0001 % by weight, 0.001 % by weight, 0.01 % by weight, 0.1 % by weight, 0.2 % by weight, 0.3 % by weight, 0.4 % by weight, 0.5 % by weight, 0.75 % by weight, 1 % by weight, 1.5 % by weight or 2 % by weight to about 0.00005 % by weight, 0.0005 % by weight, 0.005 % by weight, 0.05 % by weight, 0.5 % by weight, 1 % by weight, 1.5 % by weight, 2 % by weight, 2.5 % by weight, 3 % by weight, 4 % by weight or 5 % by weight of the gross weight of said composition. In one or more embodiments, this extract exists with the amount of about 0.01 % by weight to about 5 % by weight of the gross weight of said composition. In other embodiments, this extract exists with the amount of about 0.01 % by weight to about 3 % by weight of the gross weight of said composition. 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 further embodiments, the extract is present in an amount of about 0.2% to about 2.5% by weight 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.

[0051] sensitive skin

[0052] As used herein, the term "sensitive skin" refers to an individual whose skin is more prone to producing an unpleasant or undesirable sensation or reaction in response to a stimulus that would not cause such a reaction in most individuals. In one or more embodiments, the reaction of sensitive skin can be sensory, such as burning, pain, itching, stinging, tingling, itching, tightness and / or dryness. In some embodiments, the reaction of sensitive skin can be visual, such as erythema (redness), edema (swelling), peeling of the skin and / or flaky patches. In one or more embodiments, sensitive skin includes the skin of a subject who has a reaction condition or a history of a reaction condition when exposed to retinoids and is selected from the group consisting of erythema (redness), edema (swelling), burning, pain, itching, stinging, tingling, itching, tightness, dryness, peeling, tactile roughness, peeling of the skin, flaky patches, and combinations thereof. In one or more embodiments, the sensitive skin comprises the 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, flaky skin.

[0053] use

[0054] The compositions / compounds described herein can be used to treat skin for the treatment of acne, wrinkles, improving skin barrier function, and / or lightening of the skin. In one or more embodiments, the treatment is for 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.

[0055] As used herein, "treating" means improving, preventing or reversing a condition, disease or disorder, or at least one identifiable symptom thereof. In one embodiment, "treating" refers to improving, preventing or reversing at least one measurable physical parameter associated with the condition, disease or disorder being treated, which is not necessarily identifiable in or by the subject being treated. In another embodiment, "treating" refers to inhibiting or slowing the progression of a condition, disease or disorder, which may be physical (e.g., stabilizing an identifiable symptom), physiological (e.g., stabilizing a physical parameter), or both. In another embodiment, "treating" refers to delaying the onset of a condition, disease or disorder.

[0056] The compositions of the present invention are useful for improving the texture of the skin or improving the firmness of the skin, or any of the following conditions / symptoms.

[0057] As used herein, "improving the texture of the skin" means smoothing the surface of the skin to remove bumps or fissures on the surface of the skin.

[0058] As used herein, "improving the firmness of skin" means enhancing the firmness or elasticity of skin, preventing loss of firmness or elasticity of skin, or preventing or treating sagging, loose, and loose skin.

[0059] As used herein, "loss of elasticity" includes loss of elasticity or structural integrity of the skin or tissue, including but not limited to sagging, loose, and loose tissue. Loss of elasticity or tissue structural integrity can be caused by a variety of factors, including but not limited to disease, aging, hormonal changes, mechanical trauma, environmental damage, or as a result of applying products such as cosmetics or medications to the tissue.

[0060] As used herein, "uneven skin tone" refers to a skin condition associated with diffuse or patchy pigmentation, which may be categorized as hyperpigmentation, such as post-inflammatory hyperpigmentation.

[0061] As used herein, "scarring" means a skin condition that is associated with redness or erythema.

[0062] As used herein, "age spots" means a skin condition associated with discrete pigmentation, such as small areas of darker pigmentation that can develop on the face and hands.

[0063] Signs of skin aging also include decreased skin thickness and the presence of abnormal or reduced synthesis of collagen, glycosaminoglycans, proteoglycans, elastin, or glycoproteins including fibronectin. In one embodiment, the signs of aging are selected from abnormal or reduced synthesis of collagen, glycosaminoglycans, proteoglycans, elastin, or glycoproteins (including fibronectin). In another embodiment, the sign of skin aging is reduced synthesis of collagen or elastin.

[0064] Examples of skin aging that can be treated by topical application of the compositions of the present invention include, but are not limited to, wrinkles on the skin. As used herein, the term "wrinkles" includes fine lines, microwrinkles, coarse wrinkles, cellulite, scars, and stretch marks. Examples of wrinkles include, but are not limited to, fine lines around the eyes (e.g., "crow's feet"), forehead and cheek wrinkles, frown lines, and laugh lines around the mouth.

[0065] As used herein, "topical use" and "topical application" mean application or spreading directly to the skin, hair, or nails, for example, by using the hands or an applicator such as a wipe.

[0066] The composition is also suitable for treating or preventing acne. As used herein, "acne" refers to a disorder caused by the action of hormones and other substances on the sebaceous glands and hair follicles, generally resulting in the blockage of pores and the formation of inflammatory or non-inflammatory lesions on the skin. Specifically, it relates to blemishes, lesions or papules, pre-emergent papules, blackheads and / or whiteheads. As used herein, "pre-emergent papules" are inflamed hair follicles that are not visible to the naked eye (e.g., as lesions) on the surface of the skin.

[0067] 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.

[0068] The composition of the present invention is also suitable for reducing epidermal hyperkeratosis.Thus, the composition can be used to treat or prevent conditions characterized by hyperkeratosis, such as acne or warts.

[0069] The embodiments described herein can be combined in any suitable combination. For example, exemplary embodiments relate to methods for treating acne, wrinkles and / or skin lightening in subjects with 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, peeling, tactile roughness, skin peeling, flaky patches and combinations thereof, the method comprising applying an extract of citrus aurantium and / or 3-(4-farnesyloxyphenyl)-propionic acid to the skin. As will be 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 a composition comprising a plant extract to sensitive skin, the plant extract being an extract of a plant of the genus Citrus. In another embodiment, the plant extract is an extract of citrus aurantium. In yet another 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 other 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.

[0070] The compositions described herein can be applied to any part of the human body where treatment is desired. For example, the compositions can be applied to any one or more of the skin on the face, neck, chest, back, arms, axillae, hands, and / or legs. In certain preferred embodiments, the method comprises applying a compound of Formula I to the skin of the face.

[0071] Any method suitable for applying the extract to the skin in need thereof can be used in accordance with the present invention. For example, the extract can be applied directly to the skin in need thereof from the packaging, applied by hand to the skin in need thereof, or transferred via a substrate such as a wipe or mask, or a combination of two or more thereof. In other embodiments, the extract can be applied via a dropper, tube, roller, spray, patch, or added to a tub or otherwise added to water for application to the skin, etc.

[0072] In one or more embodiments, the methods of the present invention further comprise 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 allowed to contact the skin for about 15 minutes or longer after application. In certain more preferred embodiments, the extract is allowed to contact the skin for about 20 minutes or longer, more preferably about 1 hour or longer.

[0073] In some embodiments, the methods of the present invention comprise a course of treatment comprising applying to the skin multiple times over a selected period of time a compound of Formula I. For example, in certain embodiments, the present invention provides a method of treating signs of aging comprising applying a composition comprising a compound of Formula I to skin in need of anti-aging treatment once or twice daily for at least 12 weeks, preferably at least 8 weeks, and more preferably at least 2 weeks.

[0074] Composition

[0075] Any suitable carrier may be used in the compositions of the present invention. Preferably, for skin care compositions, the carrier is a cosmetically acceptable carrier. As will be appreciated by those skilled in the art, cosmetically acceptable carriers include carriers suitable for use in contact with the body, particularly the skin, for anti-aging applications without causing undue toxicity, incompatibility, instability, irritation, allergic reactions, and the like. A safe and effective amount of carrier comprises 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 present in a wide variety of forms. For example, emulsion carriers including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and oil-in-water-in-silicone emulsions may be used herein. These emulsions may encompass a range of viscosities, for example, from about 100 centipoise to about 200,000 centipoise. Examples of suitable cosmetically acceptable carriers include cosmetically acceptable solvents and materials used in cosmetic solutions, suspensions, lotions, creams, serums, essences, gels, toners, sticks, sprays, ointments, washes and bars, shampoos, hair conditioners, pastes, foams, mousses, powders, shaving creams, wipes, patches, strips, super patches, microneedle patches, bandages, hydrogels, film-forming products, facial and skin masks, foundations, 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, and the like.

[0076] The following are non-limiting examples of such carriers. Other carriers can be formulated by one of ordinary skill in the art. In one embodiment, the carrier comprises water. In another embodiment, the carrier may further comprise one or more aqueous solvents or organic solvents. Examples of organic solvents include, but are not limited to, dimethyl isosorbide; isopropyl myristate; surfactants of cationic, anionic, and nonionic nature; vegetable oils; mineral oils; waxes; gums; synthetic and natural gelling agents; alkanols; glycols; and polyols. Examples of glycols include, but are not limited to, glycerol, propylene glycol, butylene glycol, pentanediol, hexylene glycol, polyethylene glycol, polypropylene glycol, diethylene glycol, triethylene glycol, octanediol, glycerol, butylene glycol, and hexanetriol, and copolymers or mixtures thereof. Examples of alkanols include, but are not limited to, alkanols 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 isopropyl alcohol and ethanol. The example of polyol includes but is not limited to polyols with about 2 carbon atoms to about 15 carbon atoms (for example, about 2 carbon atoms to about 10 carbon atoms), such as propylene glycol. Based on the gross weight of the carrier, the organic solvent can be present in the carrier in an amount of about 1% to about 99.99% (for example, about 20% to about 50%). Based on the gross weight of the carrier, water can be present in the carrier (before use) in an amount of about 5% to about 95% (for example, about 50% to about 90%). The solution can include any suitable amount of solvent, including about 40% to about 99.99%. Some preferred solutions include 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 99%.

[0077] Lotions can be prepared by this type of solution. In addition to solvents, lotions typically include at least one emollient. Lotions can include about 1% to about 20% (e.g., about 5% to about 10%) of emollient and about 50% to about 90% (e.g., about 60% to about 80%) of water. As used herein, "emollient" refers to a material for preventing or alleviating dryness and for protecting skin or hair. Examples of emollients include, but are not limited to, those listed in the International Cosmetic Ingredient Dictionary and Handbook edited by Wenninger and McEwen, pages 1656 to 61, 1626, and 1654 to 55 (U.S. Cosmetic and Fragrance Association, Washington, DC, 7th edition, 1997) (hereinafter, "ICI Handbook").

[0078] Another type of product that can be formulated from a solution is a cream. Creams typically contain from about 5% to about 50% (e.g., from about 10% to about 20%) of an emollient and from about 45% to about 85% (e.g., from about 50% to about 75%) of water.

[0079] Another type of product that can also be formulated from a solution is an ointment. Ointments can contain a simple base of animal, vegetable, or synthetic oils or semisolid 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.

[0080] The compositions useful in the present invention can also be formulated as emulsions. If the carrier is an emulsion, about 1% to about 10% (e.g., about 2% to about 5%) of the carrier comprises an emulsifier. The emulsifier can be nonionic, anionic, or cationic. Examples of emulsifiers include, but are not limited to, those listed in the ICI Handbook, pages 1673 to 1686.

[0081] Lotions and creams can be formulated as emulsions. Typically such lotions contain 0.5% to about 5% emulsifier, while such creams will typically contain about 1% to about 20% (e.g., about 5% to about 10%) of an emollient; about 20% to about 80% (e.g., 30% to about 70%) of water; and about 1% to about 10% (e.g., about 2% to about 5%) of an emulsifier.

[0082] Oil-in-water and water-in-oil single-phase emulsion skin care formulations (such as lotions and creams) are well known in the art and can be used in the present invention. Multiphase emulsion compositions (such as water-in-oil-in-water or oil-in-water-in-oil) can also be used in the present invention. Generally speaking, such single or multiphase emulsions contain water, an emollient, and an emulsifier as the main ingredients.

[0083] The compositions of the present invention may also be formulated as gels (e.g., aqueous gels, alcohol gels, alcohol / hydrogels, or oleogels, using a suitable gelling agent). Suitable gelling agents for aqueous and / or alcohol gels include, but are not limited to, natural gums, acrylic acid and acrylate polymers and copolymers, and cellulose derivatives (e.g., hydroxymethyl cellulose and hydroxypropyl cellulose). 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 5% by weight of such a gelling agent.

[0084] The compositions of the present invention may also be formulated as solid formulations (e.g., wax-based sticks, soap bar compositions, powders, or wipes). The compositions of the present invention may also be combined with solid, semisolid, or dissolvable substrates (e.g., wipes, masks, pads, gloves, or strips).

[0085] The compositions of the present invention may also contain any of a variety of additional cosmetic active agents, but they are preferably formulated for use on sensitive skin. Examples of suitable additional active agents include additional skin lightening agents, darkening agents, anti-acne agents, shine control agents, antimicrobial agents such as anti-yeast agents, anti-fungal agents and anti-bacterial agents, anti-inflammatory agents, anti-parasitic agents, topical analgesics, sunscreens, photoprotectants, antioxidants, keratolytics, detergents / surfactants, moisturizers, nutrients, vitamins, energy enhancers, antiperspirants, astringents, deodorants, depilatories, hair growth promoters, hair growth retardants, firming agents, hydrating agents, synergists, anti-sclerosis agents, skin conditioning agents, anti-cellulite agents, fluoride, tooth whitening agents, anti-plaque agents, as well as plaque dissolving agents, odor control agents (such as odor masking agents) or pH adjusters, etc.Examples of various suitable additional cosmetically acceptable actives include hydroxy acids, benzoyl peroxide, D-panthenol, UV filters such as, but not limited to, avobenzone (Parsol 1789), bisdisulizoledisodium (Neo Heliopan AP), diethylaminohydroxybenzoyl hexyl benzoate (Uvinul A Plus), ecamsule (Mexoryl SX), methyl anthranilate, 4-aminobenzoic acid (PABA), cinoxate, ethylhexyl triazone (Uvinul T 150), homosalate, 4-methylbenzylidene camphor (Parsol 5000), octyl methoxycinnamate (Octinoxate), octyl salicylate (Octisalate), padimate O (Escalol 507), phenylbenzimidazole sulfonic acid (Ensulizole), polysilicone-15 (Parsol SLX), triethanolamine salicylate, bis-ethylethoxyphenol methoxyphenyl triazine (Tinosorb S), benzophenone 1-12, dihydroxybenzone, drometrizole trisiloxane (Mexoryl XL), diethylhexyl butamido triazone (Uvasorb HEB), octocrylene, oxybenzone (Eusolex 4360), sulisophenone, methylene dibenzotriazole tetramethylbutylphenol (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 estrogens, steroids such as hydrocortisone, 2-dimethylaminoethanol, copper salts such as copper chloride, copper-containing peptides such as Cu:Gly-His-Lys, coenzyme Q10, amino acids such as proline, vitamins, lactobionic acid, acetyl-CoA, niacin, riboflavin, thiamine, ribose, electron transporters such as NADH and FADH2, and other plant extracts (such as oat, aloe, feverfew, soybean, shiitake mushroom extract), and derivatives and mixtures thereof.

[0086] 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, melanin transfer inhibitors (including PAR-2 ​​antagonists), exfoliants, sunscreens, retinoids, antioxidants, tranexamic acid, skin bleaching agents, allantoin, sunscreens, talc and silica, zinc salts, and the like, as well as other agents as described by Solano et al. in 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, flavonoids (e.g., total flavonoids from licorice, licorice root extract, mulberry root extract, Dioscorea zingiberensis root extract, Saxifraga officinalis extract, etc.), ellagic acid, salicylates and derivatives, glucosamine and derivatives, fullerenes, hinokitiol, dioic acid, acetylglucosamine, magnolia officinalis lignans, and combinations of two or more thereof. Examples of vitamin C derivatives include, but are not limited to, ascorbic acid and salts, ascorbic acid-2-glucoside, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, and natural extracts rich in vitamin C. 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 rich in vitamin E derivatives. Examples of resorcinol derivatives include, but are not limited to, resorcinol, 4-substituted resorcinols, such as 4-alkylresorcinols (such as 4-n-butylresorcinol (rucinol), 4-hexylresorcinol), phenylethylresorcinol, 1-(2,4-dihydroxyphenyl)-3-(2,4-dimethoxy-3-methylphenyl)-propane, and natural extracts rich in 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 comprises a 4-substituted resorcinol, a vitamin C derivative, or a vitamin E derivative. In a more preferred embodiment, the tyrosinase inhibitor comprises phenylethylresorcinol, 4-hexylresorcinol, or ascorbic acid-2-glucoside.

[0087] Examples of suitable melanin degrading agents include, but are not limited to, peroxides and enzymes, such as peroxidases and ligninases. In certain preferred embodiments, the melanin inhibitor comprises a peroxide or a ligninase.

[0088] Examples of suitable melanosome transfer inhibitors include PAR-2 ​​antagonists, such as soybean trypsin inhibitor or Bowman-Birk inhibitor, vitamin B3 and derivatives such as nicotinamide, soy essence, whole soybean, soy extract. In certain preferred embodiments, the melanosome transfer inhibitor includes soy extract or nicotinamide.

[0089] Examples of exfoliants include, but are not limited to, alpha-hydroxy acids (such as lactic acid, glycolic acid, malic acid, tartaric acid, citric acid, or any combination of any of the foregoing), beta-hydroxy acids (such as salicylic acid, polyhydroxy acids such as lactobionic acid and gluconic acid), and mechanical exfoliation, such as microdermabrasion. In certain preferred embodiments, the exfoliant comprises glycolic acid or salicylic acid.

[0090] Examples of sunscreens include, but are not limited to, avobenzone (Parsol 1789), disodium phenyldibenzimidazole tetrasulfonate (Neo Heliopan AP), diethylamino hydroxybenzoyl hexyl benzoate (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), triethanolamine salicylate, bis-ethylhexyloxyphenol methoxyphenyl triazine (Tinosorb S), dibenzophenone 1–12, dihydroxybenzone, drometrizole trialkoxyane (Mexoryl XL), diethylhexyl butamido triazone (UvasorbHEB), octocrylene, oxybenzone (Eusolex 4360), sulibenzone, methylene dibenzotriazole tetramethylbutylphenol (Tinosorb M), titanium dioxide, zinc oxide, etc.

[0091] Examples of retinoids include, but are not limited to, retinol, retinal, retinoic acid, retinyl palmitate, isotretinoin, tazarotene, bexarotene, and adapalene. In certain preferred embodiments, the retinoid is retinol. However, in one or more embodiments, the composition is substantially free of a retinoid or a retinoid precursor; and in further embodiments, free of a retinoid or a retinoid precursor.

[0092] 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, stilbenes such as resveratrol and derivatives, lactoferrin, and ascorbic acid and ascorbic acid derivatives (e.g., ascorbyl-2-glucoside, ascorbyl palmitate, and ascorbic acid 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., tocopheryl 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 isoflavones and their derivatives (e.g., genistein and diadzein), extracts containing resveratrol, and the like. Examples of such natural extracts include grape seed, green tea, pine bark, feverfew, feverfew without parthenol, oat extract, grapefruit extract, malt extract, hesperidin, grape extract, purslane extract, licorice chalcone, chalcone, 2,2'-dihydroxy chalcone, primrose extract, propolis, and the like.

[0093] The additional cosmetic active agent may be present in the composition in any suitable amount, for example, in an amount from about 0.0001% to about 20%, for example from about 0.001% to about 10%, such as from about 0.01% to about 5%, by weight of the composition. In certain preferred embodiments, the amount is from 0.1% to 5%, while in other preferred embodiments, the amount is from 1% to 2%.

[0094] Many other substances may also be present in the compositions of the present invention. These include, for example, chelating agents, humectants, sunscreens, conditioners, preservatives, fragrances, and the like. The compositions may contain surfactants, such as those selected from the group consisting of anionic, nonionic, zwitterionic, cationic, or a combination of two or more thereof.

[0095] The compositions of the present invention may also contain chelating agents (e.g., EDTA) and preservatives (e.g., parabens). Examples of suitable preservatives and chelating agents are listed on pages 1626 and 1654-1655 of the ICI Handbook. In addition, the compositions useful herein may contain conventional cosmetic adjuvants, such as colorants such as dyes and pigments, sunscreens (e.g., titanium dioxide), and fragrances.

[0096] In certain preferred embodiments, the present invention includes applying the compound or composition of the present invention via a substrate comprising such material. Any suitable substrate can be used in the present invention. For example, examples of suitable substrates and substrate materials are disclosed in U.S. published patent applications No. 2005 / 022683 and No. 2009 / 0241242, which are incorporated herein by reference in their entirety. In certain preferred embodiments, the substrate is a wipe or a facial mask.

[0097] Compositions and products comprising such compositions of the present invention can be prepared using methods well known to those of ordinary skill in the art.

[0098] Example 1: Preparation of composition

[0099] Two compositions of the present invention (Examples 1 and 2) were prepared in the following manner using the amounts shown in Table 1 below. Examples 1 and 2 contained 0.5% and 1% by weight of Populus tremula extract, respectively. Purified water was added to a suitably sized beaker. Mixing was initiated using a propeller mixing blade and the water was heated to 75°C to 80°C. Sepimax Zen TM Slowly add to the main batch and mix until fully hydrated and free of visible particles, increasing the mixing speed as needed. Reheat the mixture to 75°C to 80°C, then add chlorphenesin and emulsifier and mix until homogenous and free of undissolved particles. Next, allow the solution to cool to 60°C to 65°C, add glycerin, and mix until homogenous. Once the solution has cooled to 55°C to 60°C, add Sepiplus TM 400 and Citrus aurantifolia (Populus tremuloides) fruit extract (30% weight / weight in a carrier aqueous solution) were added and mixed until homogeneous. The Citrus aurantifolia fruit extract used in the Examples typically contains between approximately 1% and 10% 3-(4-farnesyloxyphenyl)-propionic acid; these samples contained 1.11% 3-(4-farnesyloxyphenyl)-propionic acid by weight of the extract in carrier. Cooling to 40°C was continued while mixing the solution at a moderate speed. Dimethicone, phenoxyethanol, and ethylhexylglycerin were then added and mixed until homogeneous. Water was added q.s. and the pH was adjusted to pH 5. The solution was mixed until homogeneous.

[0100] Table 1: Examples of the present invention

[0101]

[0102] Example 2: Clinical study of skin irritation model

[0103] Eight compositions were evaluated for clinical irritation induction using a skin cumulative irritation patch test. Of the eight compositions, two were Examples 1 and 2 of the present invention described above. Examples 3 and 4 are two compositions used as controls. Specifically, Example 3 is a positive control containing a 0.5% sodium lauryl sulfate (SLS) solution in petrolatum. SLS is used as a positive control because it is a known irritant (see, for example, 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 is a negative control consisting of petrolatum. Petrolatum is known to be used as a negative control, as demonstrated in Uliasz, MD, A. and Lebwohl, MD M., Evaluation of sensory irritation caused by topical medication using a novel technique, International Journal of Dermatology 2010, 49, 269-27, see abstract. Examples 5 to 8 are commercially available compositions containing between 0% and 0.5% by weight retinol.

[0104] Recruit 60 subjects to carry out this study, wherein 54 subjects complete this study. In this study, 0.2 gram to 0.3 gram test composition is applied to the designated area on each subject's back, and is fixed in place using a semi-closed patch (professional medical product patch) and continues for 24 hours. In this way, each composition is applied three times per week, and a total of nine times are applied. After 48 hours to 72 hours at each application, a trained grader uses the score sheet in the following table 2 to assess the test area.

[0105] Table 2: Grading Scores

[0106]

[0107] The cumulative irritation potential of the composition is the sum of the nine application scores (21 days) for each test site of each subject. The grand total score for each composition is obtained by adding the 21-day sums for all subjects (maximum potential cumulative irritation score = 1944). The cumulative irritation mean scores, standard deviations, minimums, medians, and maximums are shown in Table 3 below. The skin cumulative irritation mean scores are then compared by calculating levels, which are calculated by a mixed model with Tukey's HSD test for pairwise comparisons. The test hypothesis is that the mean changes from baseline are equal between treatments. The resulting skin cumulative irritation scores and statistics are shown in Table 4 below.

[0108] Table 3: Descriptive statistics of cumulative skin irritation scores

[0109]

[0110]

[0111] Table 4: Treatment comparisons of cumulative skin irritation scores

[0112]

[0113] The results of Examples 1 to 2 of the present invention are surprising because the sum is comparable to the negative control vaseline, which is a well-known very mild skin protectant. Even the sample with the lowest retinol concentration (0.04% in Example 5) is higher than the negative control. In addition, the extract of lemon bergamot (containing the compound 3-(4-farnesyloxyphenyl)-propionic acid) has retinol-like activity, as demonstrated by its mechanism of action through the retinol agonist receptor (RAR) pathway (see, for example, U.S. Patent Publication No. 20200030226A1). In general, retinol and retinoids are not generally considered to be mild to the skin and are in fact known to cause local irritation and erythema of the skin (Kim, B. et al., The mechanism of retinol-induced irritation and its application to anti-irritant development, Toxicology Letters 146 (2003), 65-73, see abstract). It is therefore surprising that the 0.5% w / w and 1% w / w Populus tremuloides extract compositions are so mild to the skin, even though the Populus tremuloides extracts work using the same mechanism of action.

[0114] Example 3: Tolerability clinical study in subjects with sensitive skin

[0115] The clinical tolerability of three compositions was evaluated in a single-center, 12-week, 3-group, assessor-blind, comprehensive, randomized study. Of the three compositions, two were compositions of the present invention from Examples 1 and 2 above. The third composition was a commercial cream containing 0.1% retinol.

[0116] Subjects were screened and enrolled to ensure that at least 30 subjects were completed in each of the three (3) groups. The target population was female subjects aged 35 to 60 years with Fitzpatrick skin types I-IV who had moderate mottled hyperpigmentation, moderate fine lines / wrinkles, and moderate overall photodamage of their facial skin. Using the scores in Table 5, at least 50% of the subjects in treatment groups Examples 1 and 2 had self-perceived mild to moderately sensitive facial skin. All subjects had self-perceived normal skin (i.e., not sensitive at all) for treatment with a commercial cream containing 0.1% retinol. Retinol was not tested on subjects with sensitive skin because it is known to cause irritation and erythema.

[0117] Table 5: Self-perceived sensitivity rating scores

[0118] Score grade 5 Extremely sensitive 4 Very sensitive 3 Moderately sensitive 2 Mildly sensitive 1 Completely insensitive

[0119] Starting at Visit 1, subjects washed their faces once in the morning and once in the evening using a specific commercially available cleanser. Starting at Visit 2, subjects applied the prescribed treatment once in the morning and once in the evening after using the provided cleanser. In addition, subjects applied a specific commercially available sunscreen 5 to 10 minutes after applying their facial moisturizer. Subjects were only allowed to use their normal cosmetic products approved at Visit 1. On study visit days, subjects removed all residual product using the provided cleanser at least 30 minutes before the visit and up to 2 hours before the visit. The study consisted of 6 visits over 12 weeks, with visits scheduled at 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). The commercial cream treatment group containing 0.1% retinol was not evaluated at Week 1.

[0120] The principal investigator (PI), a skin clinical grading expert with 15 years of experience in this field, assessed the tolerability parameters of erythema, edema, and dryness / peeling of the facial skin of each subject using a 0-3 grading scale (allowing half a score) according to the grading scale in Table 6.

[0121] Table 6: Grading scores for tolerability parameters (clinical)

[0122]

[0123] The PI also asked the subjects about tolerability parameters of burning, stinging, itching, and tightness / dryness using a 0 to 3 scale (using whole points only) according to the scale in Table 7.

[0124] Table 7: Grading scores for tolerability parameters (subjective) .

[0125]

[0126]

[0127] The above tolerance scores were evaluated using the Freidman test, and nonparametric repeated measures analysis of variance and Dunn's post hoc test were used to determine the significance level of each time point from baseline. The mean change from baseline for each tolerance parameter is shown in Tables 8 and 9 below.

[0128] Table 8: Mean Changes from Baseline in Tolerability Parameters over 12 Weeks .

[0129]

[0130] Table 9: Mean Changes from Baseline in Subjective Tolerability Parameters over 12 Weeks .

[0131]

[0132] These data show that there were no statistically significant differences in the net change from baseline between the groups for all endpoints at any time point, indicating that the treatment was non-irritating. As described above, the Populus tremuloides extract (comprising the compound 3-(4-farnesyloxyphenyl)-propionic acid) has retinol-like activity, as demonstrated by its mechanism of action through the retinol agonist receptor (RAR) pathway, and retinoids are generally known to be not well tolerated. Therefore, it is surprising that the Populus tremuloides extract is very well tolerated in a population with self-perceived sensitive skin. It can also be seen from the results that the samples containing the Populus tremuloides extract were non-irritating or less irritating in individuals with sensitive skin than the composition containing retinol in individuals with normal skin.

[0133] Example 4: Instrument Test - Skin Tester

[0134] At each time point, three (3) elasticity measurements were taken on the left cheek area of ​​the subject from Example 3 using an elasticity characterization instrument sold under the trade name CUTOMETER MPA 580 (Courage+Khazakaelectronic, Germany). The commercial cream treatment group containing 0.1% retinol was not evaluated at week 1. The probe was repositioned for each measurement using a pressure of 450 mbar, a 2 mm diameter probe hole, 5 seconds of suction, and a 5 second relaxation time. Each examination area was measured approximately 2 cm below the zygomatic bone, avoiding any blemishes or hyperpigmented spots.

[0135] The probe is placed vertically on the skin, making full contact with it without applying too much force that would deform the skin. The viscoelastic behavior of the skin is described by a deformation curve, where the skin deformation (amplitude, in mm) is measured over time. The following absolute parameters (measured in mm) are calculated from the skin deformation curve:

[0136] Ua / Uf(R2) - ratio between final retraction and maximum deformation (i.e., total elasticity of the skin, including viscous deformation)

[0137] Ur / Uf (R7) - ratio of immediate recoil to total deformation (i.e., bioelasticity)

[0138] Ur / Ue(R5) - ratio of immediate retraction to immediate deformation (i.e., net elasticity of the skin without viscous deformation)

[0139] Results were evaluated using repeated measures ANOVA with Dunn's 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.

[0140] Table 10: Mean Change from Baseline for Skin Testers (R7, R5, and R2) over 12 Weeks

[0141]

[0142] For all groups, at all times, the skin tester R2 values ​​showed an improvement in total elasticity (total recovery relative to total deformation) compared to baseline, with improvements continuing through week 12 for all groups.

[0143] For all groups, the skin tester R5 values ​​showed an improvement in net elasticity (immediate recovery relative to immediate deformation) compared to baseline, with Group B and Group C showing almost no change from Week 2 to Week 12, and Group A showing a small decrease in this improvement from Week 2 to Week 12.

[0144] For all groups, the skin tester R7 values ​​showed an improvement in elasticity (immediate recovery relative to total deformation) compared to baseline. The only statistically significant difference between the groups was the difference between Group A and Group B at Week 1 (p<0.05).

[0145] The skin tester values ​​of R2, R5, and R7 show that total elasticity (total recovery relative to total deformation), net elasticity (immediate recovery relative to immediate deformation), and elasticity (immediate recovery relative to total deformation) were improved, respectively, when compared to the baseline for all treatments at all time points. Therefore, the 0.5% and 0.1% citronella compositions (Examples 1-2) show efficacy in improving skin elasticity, which is suitable for treating signs of aging.

[0146] Additionally, over 12 weeks, the results for the three parameters, R2, R5, and R7, for Asparagus lemon showed similar levels of improvement in sensitive skin as 0.1% retinol in normal skin. This demonstrates the efficacy of Asparagus lemon as an anti-aging treatment that is gentle enough for sensitive skin and comparable to the efficacy of retinol in normal skin.

[0147] Example 5: Instrumental Test - Erythema Index

[0148] Erythema index measurements were obtained using a DSMII colorimeter (Cortex Technologies, Hadsund, Denmark).In Examples 3 to 4, measurements were taken on the left cheek area and the center of the forehead of the subjects.

[0149] Results were evaluated using repeated measures ANOVA with Dunn's post hoc test to determine the level of significant change from baseline between treatments at each time point.The mean change from baseline in erythema index from cheek measurements is shown in Table 11 below.

[0150] Table 11: Mean Change from Baseline in Erythema Index Measurements over 12 Weeks

[0151]

[0152] The erythema index data showed a small incremental reduction in erythema for both Aspen Lemon compositions from Week 2 to Week 12. There were no statistically significant differences between the treatments.

[0153] The DSMII erythema index values ​​from the cheeks showed a small incremental reduction in erythema from week 2 to week 12 for both Group A and Group B. There were no statistically significant differences between the groups.

[0154] The DSMII erythema index values ​​from the forehead showed a small incremental reduction in erythema from week 2 to week 12 for both Group A and Group B. There were no statistically significant differences between the groups.

[0155] There was no skin irritation as evidenced by skin redness as measured by the erythema index. These results confirm the observations made in the patch test studies above that the composition was non-irritating to sensitive skin.

[0156] Example 5: Instrumental Testing - Collagen Cross-linking

[0157] Three (3) fluorescence measurements (i.e., three (3) sets of scans) were performed on the left cheek area and the center of the forehead of the subjects in Examples 3 to 5 using a SkinSkan fluorescence spectrophotometer (Horiba Jovin YVON, Edison, NJ). A SkinSkan measurement is a set of three scans - two excitation scans (1: 270 nm - 320 nm, emission at 345 nm, 2: 290 nm - 360 nm, emission at 390 nm) followed by a synchronous scan (315 nm - 401 nm). Analysis of the fluorescence spectrum provides information about skin fluorophores (such as tryptophan), collagen cross-linking. The commercial cream treatment group containing 0.1% retinol was not evaluated at week 1.

[0158] Results were evaluated using repeated measures ANOVA with Dunn's post hoc test to determine the level of significant change from baseline between treatments at each time point.The mean change from baseline in fluorescence intensity from collagen cross-linking is shown in Table 12 below.

[0159] Table 12: Mean Change from Baseline in Collagen Cross-linking Fluorescence over 12 Weeks

[0160]

[0161] Examples 1 and 2 each showed statistically significant improvements in collagen cross-linking compared to baseline at week 12. Such improvements in collagen cross-linking are useful for treating signs of aging. Thus, the 0.5% and 0.1% bergamot compositions (Examples 1-2) showed efficacy in treating signs of skin aging.

[0162] In addition, the results of Examples 1 and 2 showed a similar level of improvement in sensitive skin as that achieved with 0.1% retinol in normal skin. This demonstrates the efficacy of bergamot as an anti-aging treatment that is gentle enough for sensitive skin and comparable to the efficacy of retinol in normal skin.

Claims

1. A method for treating sensitive skin, comprising applying to the sensitive skin a compound of formula I: in: R1 is selected from the group consisting of: C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl and C3-C8 cycloalkyl or aryl; R2 is selected from the group consisting of hydrogen, hydroxy, 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 the group consisting of: -CO2H, -CO2R4 or an isosteric equivalent of a carboxyl group, wherein R4 is C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or aryl; and Y is -(CH2-CH2)-, -(CH=CH)- or -(C=C)-; or a cosmetically acceptable salt thereof.

2. The method according to claim 1, wherein R1 is selected from the group consisting of: C5-C 16 Alkyl, C5-C 16 Alkenyl and C5-C 16 Alkynyl; R2 is selected from the group consisting of hydrogen, hydroxy, -OC1-C6 alkyl, -OC2-C6 alkenyl, -OC2-C6 alkynyl, -OC3-C8 cycloalkyl; R3 is selected from -CO2H, -CO2R4, wherein R4 is a C1-C6 alkyl, or an isosteric equivalent of a carboxyl group; and Y is -(CH2-CH2)- or -(CH=CH)-.

3. The method according to claim 1 or 2, wherein R1 is selected from the group consisting of: C5-C 16 alkenyl; and R2 is selected from the group consisting of: hydrogen or -OC1-C3 alkyl.

4. The method according to any one of claims 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, ethyl esters thereof, and combinations of two or more thereof.

5. The method according to any one of claims 1 to 4, wherein the compound of formula I is 3-(4-farnesyloxyphenyl)-propionic acid.

6. The method according to any one of claims 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 claims 1 to 6, wherein the plant extract is an extract of a plant of the genus Citrus.

8. The method according to any one of claims 1 to 7, wherein the plant extract is an extract of Citrus aurantium.

9. The method according to any one of claims 1 to 8, wherein the extract is a polar extract.

10. The method of any one of claims 1 to 9, wherein the extract is present in an amount of about 0.1 wt% to about 3 wt% based on the total weight of the composition.

11. The method of any one of claims 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 according to any one of claims 1 to 11, wherein The sensitive skin includes the skin of a subject having a reaction condition or a history of a reaction condition when exposed to a retinoid 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.

13. The method according to any one of claims 1 to 12, wherein The sensitive skin includes the 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, flaky skin.

14. The method of any one of claims 1 to 13, wherein the method of treating skin is a method of treating acne, wrinkles and / or skin lightening 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, flaky skin.

15. A method of treating acne, wrinkles and / or skin lightening in 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, 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. The method of claim 15, wherein the applying step comprises applying a composition comprising a plant extract of the genus Citrus to the sensitive skin.

17. The method according to claim 15 or 16, wherein the plant extract is an extract of Citrus aurantium.

18. The method according to any one of claims 15 to 17, wherein the extract is a polar extract.

19. The method of any one of claims 15 to 18, wherein the extract is present in an amount of about 0.1 wt% to about 3 wt% based on the total weight of the composition.

20. The method of any one of claims 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.

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