WO2013070018A1 - Composition comprising carnosic acid or derivative thereof - Google Patents

Abstract

The present invention relates to a skin irritation alleviation agent comprising carnosic acid, a derivative thereof or a pharmaceutically acceptable salt thereof. The present invention relates to a C-kit activity inhibitor comprising carnosic acid, a derivative thereof or a pharmaceutically acceptable salt thereof. The present invention relates to an elastase activity inhibitor or matrix metalloproteinase (MPP) expression inhibitor comprising carnosic acid, a derivative thereof or a pharmaceutically acceptable salt thereof. The present invention also relates to a whitening composition or anti-ageing composition comprising a carnosic acid derivative or a pharmaceutically acceptable salt thereof.

Description

Composition comprising carnosic acid or derivatives thereof

The present invention relates to a skin irritation reducing agent comprising carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof.

The present invention relates to C-kit activity inhibitors comprising carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof.

The present invention relates to an elastase activity inhibitor or matrix metalloproteinase (MMP) expression inhibitor comprising carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof.

The present invention also relates to a whitening composition or an anti-aging composition comprising a carnoic acid derivative or a pharmaceutically acceptable salt thereof.

Skin, which is directly exposed to the external environment and plays an important role in protecting the body from it, is directly exposed to various harmful environments such as synthetic compounds, ultraviolet rays, and microorganisms, and thus, skin is easily exposed to adverse reactions such as erythema, edema, itching, and inflammation. This adverse reaction is not only aesthetic problem, but it is known that the substances produced during the inflammatory reaction cause pigmentation of the skin and promote the collapse of skin elastic fibers to increase skin wrinkles.

In general, given stimulation from the outside, keratinocytes (Keratinocoyte) or Langerhan's cells (Langerhan's cells) make and release a variety of cytokines (Cytokine). These cytokines are essentially released during skin irritation and local inflammatory processes. In the case of irritant contact dermatitis, interleukin-6 (IL-6) and interleukin-8 (IL-8) ), MCP-1 (Monocyte chemotatic protein-1) is known to increase.

On the other hand, sensitive skin reacts more sensitively than normal skin to cosmetics used to protect the skin or various transdermal absorbents applied to the skin, such as dry skin, inflammation, erythema, keratin abnormalities, itching or burning, etc. Highly prone to symptoms For example, retinoids, which are used as the main active ingredients in cosmetics for improving wrinkles, promote the recovery of collagen and elastin to give elasticity to the skin and improve wrinkles. There are many side effects that cause local inflammatory reactions due to redness and peeling of the stratum corneum, making it difficult for those with sensitive skin to use. In addition, SLS (Sodium lauryl sulfate), an anionic surfactant mainly included in cosmetics, such as soaps, toothpastes, and shampoos, is added to cosmetic ingredients to inhibit cell metabolism and destroy cell membranes. It is known as a substance causing skin reactions. In addition, ingredients such as emulsifiers, chemical preservatives for long-term preservation of the product, backings, matrix reservoirs or adhesives, solubilizers, plasticizers, permeation enhancers, crosslinkers, which are commonly included in transdermal absorbents, It can act as the main causative agent of adverse reactions.

In order to prevent contact or allergic dermatitis caused by the above ingredients, only cosmetic products are manufactured in which the active ingredient that is likely to cause irritation is removed or the concentration is lowered. It can be said that it is not exhibited. Thus, if the cosmetics include a substance to relieve irritation may include more active ingredients, the effect may also be increased.

Carnosic acid is a major potent ingredient that can be separated from Rosmarinus officinalis or Sage ( Salvia officinalis) , and is known to have excellent antioxidant effects. In addition, carnosic acid and its derivatives are known to promote the synthesis of nerve growth factor (Nve growth factor), which is also effective in improving neurodegenerative diseases. However, there are no known uses for stimulating carnosic acid.

As the number of people enjoying outside activities increases due to the increase in the leisure population, melanin pigmentation due to ultraviolet rays is intensified, and hyperpigmentation is a serious mental burden in terms of skin beauty, which can interfere with normal social activities. In particular, women in the Asian region have long favored white and fine skin, and this has been an important criterion of beauty, and the desire for prevention and improvement of abnormal skin pigmentation and hyperpigmentation has been increasing, which prevents excessive production of melanin. The development of cosmetics and drugs for whitening for the purpose is actively progressing. Therefore, the research on melanin is conducted for the purpose of preventing and treating skin cancer as well as satisfying the beauty desire for clean and white skin.

Until now, the development of whitening agent has been focused on inhibiting tyrosinase. Typical inhibitors of tyrosinase activity include kojic acid and arbutin, and antioxidants that can reduce the produced melanin include tocopherol and vitamin-C. (L-Ascorbic acid) and derivatives thereof, but these whitening ingredients have poor stability in the prescription system, so they are degraded and colored, or their use is limited due to the occurrence of off-flavor, efficacy at the biological level, unclear effect and safety issues. It's happening. In addition, the effect is temporary and does not comprehensively care for skin health, which does not satisfy the needs of customers who want a fundamental whitening effect.

C-kit belongs to class III of receptor tyrosine kinase (RTK) and is known to be involved in the survival, proliferation and differentiation of melanocytes as one of the receptors on the cell surface of melanocytes. The ligand of the C-kit receptor is a stem cell factor (hereinafter referred to as 'SCF'). When SCF acts on the receptor, the SCF / C-kit interaction results in dimerization of the C-kit protein. It has the activity of phosphorylating itself. The intracellular signal transduction process induces Ras-Raf-MAP kinase activation and finally phosphorylates the microphthalmia-associated transcription factor (MITF), a helix-loop-helix and leucine zipper protein. By activating through to activate the transcription of melanogenesis enzymes such as tyrosinase (tyrosinase), TRP-2 and the like to induce melanin production in melanocytes.

SCF / C-kit signal transduction plays an important role in the signal transduction process that promotes melanin synthesis by UV light. Upon exposure to UV rays, SCF secreted by keratinocytes binds and interacts with C-kit to promote the differentiation of precursor melanocytes present in melanocytes into mature melanocytes and the transcription of enzymes involved in melanin synthesis. Thereby promoting the synthesis of melanin pigments.

Accordingly, the present inventors have tried to develop a new effective material that can overcome the disadvantages of the safety and whitening effect of the existing whitening material, the treatment of carnosic acid and its derivatives inhibits the activity of c-Kit whitening effect It was confirmed that bringing to complete the present invention.

The skin protects the body from external physical and chemical stimuli, and is responsible for various physiological functions such as the skin barrier function that prevents internal moisture and useful ingredients from leaking out, and the homeostasis function that keeps the body's humidity and body temperature constant. Is an important institution.

However, due to endogenous aging that occurs with age or photoaging caused by continuous exposure to external stimuli such as ultraviolet rays, the thickness of the epidermis, dermis, and subcutaneous tissue is thinned, which lowers the skin barrier function and decreases the moisture content. The skin loses its physiology, including drying out. The most prominent changes in the appearance of the skin accompanying the two aging phenomena are wrinkle formation and skin elasticity reduction. It is known that the reduction or modification of collagen and elastin, proteins in the dermis, is directly involved in wrinkle formation and decreased elasticity of the skin.

Collagen produced in the fibroblasts of the dermal layer of the skin is an important component of the extracellular matrix and plays an important role in securing the mechanical strength of the skin, inducing the resistance of connective tissues, supporting tissue binding and cell adhesion. . However, as aging progresses, the function of fibroblasts decreases, which reduces collagen production and promotes the reduction of collagen by promoting the expression of matrix metalloproteinase (MMP), an enzyme that degrades collagen.

Elastin is a factor in maintaining the elasticity of the skin and forms crosslinks with collagen to form a skin matrix. Elastin is synthesized in a cell into a polypeptide called Tropoelastin, and then has a second or three-dimensional elasticity through cross-linking between tropoelastin outside the cell. However, as aging progresses, the lack of elastin fibers and agglomeration or the activity of elastinase (elastase), which is an elastin degrading enzyme, increase rapidly, breaking the elastin's network structure, causing wrinkles on the skin and decreasing skin elasticity.

Currently, cosmetics containing collagen, elastin, anti-inflammatory agents, and / or antioxidants, etc. have been produced, but the effects are only temporary and are limited. In particular, although a retinoid is a representative skin aging inhibitor, its use is limited due to in vivo efficacy, unclear effect and safety issues.

It is an object of the present invention to provide a skin irritant.

It is an object of the present invention to provide a C-kit inhibitor that reduces melanogenesis.

It is also an object of the present invention to provide an inhibitor of elastase activity.

Another object of the present invention to provide a matrix metalloproteinase (MMP) expression inhibitor.

In addition, an object of the present invention is to provide a composition for whitening or anti-aging.

In order to achieve the above object, the present invention includes carnoic acid, a derivative thereof or a pharmaceutically acceptable salt thereof represented by the following Chemical Formula 1 as an active ingredient,

[Formula 1]

In Formula 1, R is -COOR ₁ , -CH ₂ OR ₁ , or -R ₂ OH, R ₁ is H or C ₁ -C ₆ alkyl group, R ₂ is a C ₁ -C ₆ alkyl group, Skin irritation inhibitors, C-kit activity inhibitors, elastase activity inhibitors or matrix metalloproteinase (MMP) expression inhibitors.

In the present invention, in Chemical Formula 1, R is -COOR ₁ , -CH ₂ OR ₁ , or -R ₂ OH, R ₁ is H or C ₁ -C ₆ alkyl group, and R ₂ is C ₁ -C ₆ Provided are a whitening composition or an antiaging composition comprising an alkyl group, a carnosic acid derivative, or a pharmaceutically acceptable salt thereof as an active ingredient.

The skin irritation reducing agent according to the present invention may include carnoic acid, its derivatives or pharmaceutically acceptable salts thereof as an active ingredient, thereby alleviating inflammation, skin drying, erythema, keratin abnormality, itching or burning due to skin irritation. have. In particular, by inhibiting the release of IL-8 (Interleukin-8), MCP-1 (Monocyte Chemotactic Protein-1) and IL-6 (Interleukin-6), skin irritation by retinoids or surfactants can be alleviated. In addition, the cosmetic composition according to the present invention by including the skin irritation mitigator, even those with sensitive skin can be used freely.

Carnosic acid, carnosic acid derivatives or pharmaceutically acceptable salts thereof of the present invention are useful because they can inhibit the activity of C-kit. By inhibiting the activity of C-kit, many biological responses mediated by C-kit can be suppressed. Carnosic acid derivatives or pharmaceutically acceptable salts thereof, on the other hand, can inhibit melanin production by inhibiting signal transduction of cells in melanocytes, thereby improving skin whitening. In particular, the present invention inhibits the activity of C-kit, inhibits pigmentation and brings about a blemish-improving effect, and is excellent in terms of skin safety because there is no side effect.

Carnosic acid, carnosic acid derivatives or pharmaceutically acceptable salts thereof of the present invention are useful because they can inhibit elastase activity or inhibit MMP expression. Inhibition of elastase activity or MMP expression can fundamentally inhibit many biological responses mediated by it. Carnosic acid derivatives or their pharmaceutically acceptable salts, on the other hand, may inhibit the activity of elastays or inhibit MMP expression, thereby promoting anti-aging by relieving skin wrinkles or improving elasticity and having no side effects. It is also excellent in terms of safety.

As used herein, the term "skin" refers to a tissue covering the body surface of an animal, and is a broad concept including not only tissues covering the body surface such as the face or body, but also the scalp and hair.

In addition, in the present specification, "sensitive skin" may be defined as skin that is prone to adverse reactions such as stinging, itching, burning, burning, redness, dryness, and inflammation due to low resistance to external stimuli. The causes of such sensitive skin include congenital skin characteristics, family history, medical history, misuse of cosmetics, living environment or stress.

As used herein, the term "extract" is a broad concept including all materials obtained by extracting the components of natural products, regardless of the extraction method, extraction solvent, extracted components or the form of the extract.

"Alkyl" as used herein means a monovalent saturated aliphatic hydrocarbon group. Hydrocarbon groups can be straight or branched. In one aspect of the invention “alkyl” may have 1 to 6 carbon atoms (“C ₁ to C ₆ alkyl”), specifically 1 to 3 carbon atoms (“C ₁ to C ₃ alkyl”) And more specifically 1 to 2 carbon atoms (“C ₁ to C ₂ alkyl”).

As used herein, "alkoxy" refers to an -OR group, where R refers to an alkyl group as defined above. Specifically "alkoxy" refers to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy or 1,2-dimethylbutoxy and the like. Including but not limited to.

As used herein, “alcohol” means a —ROH group, where R means an alkyl group as defined above. Specifically, "alcohol" includes, but is not limited to, methanol, ethanol, propanol, isopropanol, butanol or amyl alcohol.

As used herein, "alkoxyalkyl" refers to the group -ROR 'wherein R and R' mean an alkyl group as defined above and may be the same or different from one another.

As used herein, "pharmaceutically acceptable" means the approval of a government or equivalent regulatory body to use in animals, more specifically in humans, by avoiding significant toxic effects when used in conventional medicinal dosages. It can be received or approved, or listed in a pharmacopoeia or recognized as another general pharmacopeia.

As used herein, "pharmaceutically acceptable salts" means salts according to one aspect of the invention that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. The salt is formed from (1) an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like; Or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2,2,2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert Acid addition salts formed with organic acids such as butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid; Or (2) salts formed when the acidic protons present in the parent compound are substituted.

As used herein, an "active ingredient" means a component that can exhibit activity alone or with a carrier which does not exhibit the desired activity.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

In one aspect, the present invention includes carnoic acid of Formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, wherein R is -COOR ₁ , -CH ₂ OR ₁ , or -R ₂ OH, and R ₁ is H or a C ₁ -C ₆ alkyl group, and R ₂ is a C ₁ -C ₆ alkyl group.

[Formula 1]

Another aspect of the present invention provides a skin irritation reducing agent comprising carnosic acid (Formula 2), carnosic acid methyl ester (Formula 3), carnosic acid methyl alcohol (Formula 4), or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.

[Formula 2]

[Formula 3]

[Formula 4]

In one aspect of the present invention, carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof may be obtained by extracting and extracting from rosemary ( Rosmarinus officinalis ) or sage ( Salvia officinalis ) by conventional extraction methods in the art. In another aspect of the invention, carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof may be included in the hydrothermal or solvent extracts of rosemary or sage. The solvent includes at least one organic solvent, in particular one selected from the group consisting of alcohol, hexane, acetone, ethyl acetate, diethyl ether, ethyl methyl ketone, and chloroform, and more specifically includes C ₁ to C ₅ alcohols. .

In another aspect of the present invention, carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof may be obtained by synthesis by conventional methods in the art.

In one aspect of the invention, carnosic acid, derivatives thereof, or pharmaceutically acceptable salts thereof include IL-8 (Interleukin-8), which is an inflammatory mediator that is released during the inflammatory process caused by retinoids irritating the skin and By inhibiting the release of MCP-1 (Monocyte Chemotactic Protein-1), skin irritation caused by retinoids can be alleviated.

In another aspect of the invention, carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof inhibit the release of IL-6 (Interleukin-6), an inflammatory mediator that is released when the surfactant irritates the skin. The skin irritation caused by the surfactant can be alleviated. Thus, preparations comprising carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof can alleviate skin irritation.

Skin irritation relief agent according to an aspect of the present invention may relieve skin irritation, dry skin, erythema, keratin abnormalities, itching or burning. In another aspect of the present invention, skin irritation includes skin irritation by an external preparation for skin, in particular skin irritation by a retinoid or surfactant in the external preparation for skin. Skin irritation relaxing agent according to an aspect of the present invention can exhibit a particularly excellent effect in relieving skin irritation for sensitive skin.

Skin irritant according to an aspect of the present invention 0.01 to 20% by weight, specifically 0.1 to 10% by weight, more specifically 0.5 to 5% by weight based on the total weight of the skin irritant Acid, derivatives thereof, or pharmaceutically acceptable salts thereof. When included in the above range is not only suitable for showing the intended effect of the present invention, it can satisfy both the stability and safety of the composition, it may be appropriate to include in the above range in terms of cost-effectiveness. Specifically, when the carnos acid, its derivatives, or pharmaceutically acceptable salts thereof is less than 0.01% by weight, sufficient skin irritation-reducing effects may not be obtained, and when it exceeds 20% by weight, safety and formulation stability may be lowered.

The present invention relates to a C-kit activity inhibitor comprising, as another active ingredient, carnoic acid, a derivative thereof, or a pharmaceutically acceptable salt thereof represented by Chemical Formula 1, wherein, in Chemical Formula 1, R is -COOR ₁ , -CH ₂ OR ₁ , or -R ₂ OH, R ₁ is H or a C ₁ -C ₆ alkyl group, and R ₂ is a C ₁ -C ₆ alkyl group.

As used herein, "alkyl" refers to a saturated aliphatic hydrocarbon group and includes straight or branched chains.

The "C-kit activity inhibitor" of the present invention may be expressed as a "C-kit receptor antagonist", and stem cell factor (Stem cell factor (SCF)) as a ligand to the C-kit and subsequent neurotransmission mechanisms progress Means a material that interferes with the mechanism.

In the C-kit activity inhibitor of one aspect of the present invention, R ₁ may be C ₁ -C ₃ alkyl and R ₂ may be a C ₁ -C ₃ alkyl group.

In addition, in the C-kit activity inhibitor of one aspect of the present invention, wherein R ₁ is H or methyl group and R ₂ may be a methyl group, specifically the carnosic acid derivative is carnosic acid methyl ester or carnosic acid methyl alcohol May be, but is not limited thereto.

In the C-kit activity inhibitor of one aspect of the present invention, the carnosic acid, derivatives thereof, or a pharmaceutically acceptable salt thereof is derived from one or more plants selected from rosemary ( Rosmarinus officinalis ) or sage ( Salvia officinalis ), It can be obtained by extraction after extraction by conventional extraction methods in the art. In another aspect of the invention, carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof include hydrothermal or solvent extracts of rosemary or sage. The solvent includes at least one organic solvent, in particular one selected from the group consisting of alcohol, hexane, acetone, ethyl acetate, diethyl ether, ethyl methyl ketone, and chloroform, and more specifically includes C ₁ to C ₅ alcohols. . In addition, in one aspect of the present invention, carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof may be obtained by synthesis by conventional methods in the art.

In the C-kit activity inhibitor, which is an aspect of the present invention, the active ingredient is preferably contained in an amount of 0.0001 to 10% by weight based on the total weight of the inhibitor, but in a range in which c-Kit activity is inhibited and no toxicity appears. It may be used above or below the above range depending on the intended use. When the active ingredient is contained less than 0.0001% by weight, a slight C-kit activity inhibitory effect is observed slightly, when contained in more than 10% by weight, it was confirmed that the toxicity appears. In view of the above, the active ingredient of the present invention may be contained in 0.0005 to 8% by weight, 0.001 to 6% by weight or 0.01 to 4% by weight.

C-kit activity inhibitor of one aspect of the present invention can be used as a composition for the prevention or treatment of skin pigment disorders. The skin pigment abnormality disease may include a disease in which melanin is inherently or acquiredly lacking, and in particular, may include skin hypopigmentation, hyperpigmentation or lack of pigmentation, and more specifically, atopic skin, psoriasis, blemishes, moles, blemishes or surpluses. It may include, but is not limited to, blotch. In addition, the C-kit activity inhibitor of one aspect of the present invention can be used as a pharmaceutical composition.

The present invention relates to a composition for skin whitening comprising a carnosic acid derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient in another aspect, wherein in Formula 1, R is -COOR ₃ , -CH ₂ OR ₃ , or -R ₃ OH and R ₃ is a C ₁ -C ₆ alkyl group.

In the present specification, "skin whitening" is understood as a result of the inhibition of the production of melanin, specifically, means the prevention, delayed expression or treatment of symptoms caused by melanin production, such as blemishes, freckles, skin aging, etc. .

In the composition for skin whitening which is an aspect of the present invention, R ₃ may be a C ₁ -C ₃ alkyl group.

In addition, in the composition for skin whitening, which is an aspect of the present invention, R ₃ may be a methyl group, and specifically, may include carnoic acid methyl ester or carnosic methyl alcohol, but is not limited thereto.

In the composition for skin whitening, which is an aspect of the present invention, the carnosic acid derivative or pharmaceutically acceptable salt thereof is derived from one or more plants selected from rosemary ( Rosmarinus officinalis ) or sage ( Salvia officinalis ), It can be obtained by extraction after extraction by conventional extraction methods. In another aspect of the invention, the carnosic acid derivatives or their pharmaceutically acceptable salts include hydrothermal or solvent extracts of rosemary or sage. The solvent includes at least one organic solvent, in particular one selected from the group consisting of alcohol, hexane, acetone, ethyl acetate, diethyl ether, ethyl methyl ketone, and chloroform, and more specifically includes C ₁ to C ₅ alcohols. . In addition, in one aspect of the present invention, carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof may be obtained by synthesis by conventional methods in the art.

In a composition for skin whitening, which is an aspect of the present invention, the composition may further include one or more substances selected from the group consisting of ascorbyl glucoside, licorice extract, arbutin, ascorbic acid, and kojic acid.

In the composition for skin whitening which is an aspect of the present invention, the substance may be contained in 0.0001 to 10% by weight based on the total weight of the composition. If the substance is contained in less than 0.0001% by weight, it is difficult to show its efficacy by being absorbed by the skin, and when it is contained in an amount of more than 10% by weight, it is toxic to the skin or the skin stickiness is increased so that it is difficult to show its value as a cosmetic. Because. In view of the above, in the composition for skin whitening which is one aspect of the present invention, the substance may be contained in 0.001 to 9% by weight, 0.01 to 7% by weight or 0.5 to 5% by weight based on the total weight of the composition. .

The present invention relates to an elastase activity inhibitor comprising as an active ingredient carnoic acid, derivatives or pharmaceutically acceptable salts thereof represented by Chemical Formula 1 in another aspect, wherein in Chemical Formula 1, R Is —COOR ₁ , —CH ₂ OR ₁ , or —R ₂ OH, R ₁ is H or a C ₁ -C ₆ alkyl group, and R ₂ is a C ₁ -C ₆ alkyl group.

As used herein, "alkyl" refers to a saturated aliphatic hydrocarbon group and includes straight or branched chains.

In an elastase activity inhibitor of one aspect of the present invention, R ₁ may be C ₁ -C ₃ alkyl and R ₂ may be a C ₁ -C ₃ alkyl group.

In an elastase activity inhibitor of an aspect of the present invention, R ₁ may be H or a methyl group and R ₂ may be a methyl group, and specifically, the carnosic acid derivative may be carnosic acid methyl ester or carnosic acid methyl alcohol. However, the present invention is not limited thereto.

In the elastase activity inhibitor which is an aspect of the present invention, the active ingredient is preferably contained in 0.0001 to 20% by weight based on the total weight of the inhibitor, but in the range that has an effect of inhibiting the elastase activity and does not appear toxic It may be used above or below the above range depending on the intended use. When the active ingredient is contained at less than 0.0001% by weight, the effect of inhibiting elastase activity is slightly observed, and when contained in an amount exceeding 20% by weight, the stability of the inhibitor was confirmed to be low. In view of the above, the active ingredient of the present invention is 0.0005 to 18% by weight, 0.001 to 16% by weight, 0.005 to 14% by weight, 0.01 to 12% by weight, 0.05 to 10% by weight, 0.1 to 8% by weight, 0.5 to It may be contained in 6% by weight or 1 to 4% by weight.

Elastase activity inhibitor of one aspect of the present invention can be used as a composition for preventing or alleviating skin aging by reducing the degradation of elastin. In addition, the elastase activity inhibitor of one aspect of the present invention can be used as a pharmaceutical composition or cosmetic composition.

In another aspect, the present invention relates to an inhibitor of matrix metalloproteinase (MMP) expression, comprising carnoic acid represented by Formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, wherein in Formula 1, R is —COOR ₁ , —CH ₂ OR ₁ , or —R ₂ OH, R ₁ is H or a C ₁ -C ₆ alkyl group, and R ₂ is a C ₁ -C ₆ alkyl group.

In an MMP expression inhibitor of an aspect of the present invention, R ₁ may be C ₁ -C ₃ alkyl and R ₂ may be a C ₁ -C ₃ alkyl group.

In the MMP expression inhibitor of an aspect of the present invention, R ₁ is H or a methyl group and R ₂ may be a methyl group, specifically the carnosic acid derivative may be carnosic acid methyl ester or carnosic acid methyl alcohol, but It is not limited.

In an elastase activity inhibitor or MMP expression inhibitor which is an aspect of the present invention, the carnosic acid, derivatives thereof, or a pharmaceutically acceptable salt thereof is selected from one or more plants selected from rosemary ( Rosmarinus officinalis ) or sage ( Salvia officinalis ). As derived, it can be obtained by extraction after extraction by conventional extraction methods in the art. In another aspect of the invention, carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof include hydrothermal or solvent extracts of rosemary or sage. The solvent includes at least one organic solvent, in particular one selected from the group consisting of alcohol, hexane, acetone, ethyl acetate, diethyl ether, ethyl methyl ketone, and chloroform, and more specifically includes C ₁ to C ₅ alcohols. . In addition, in one aspect of the present invention, carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof may be obtained by synthesis by conventional methods in the art.

In the MMP expression inhibitor, which is an aspect of the present invention, the active ingredient is preferably contained in an amount of 0.0001 to 20% by weight based on the total weight of the inhibitor. Therefore, it can be used above or below the above range. When the active ingredient is contained less than 0.0001% by weight, the effect of suppressing MMP expression is slightly observed, and when contained in more than 20% by weight, the stability of the inhibitor was confirmed to be low. In view of the above, the active ingredient of the present invention is 0.0005 to 18% by weight, 0.001 to 16% by weight, 0.005 to 14% by weight, 0.01 to 12% by weight, 0.05 to 10% by weight, 0.1 to 8% by weight, 0.5 to It may be contained in 6% by weight or 1 to 4% by weight.

In an MMP expression inhibitor of one aspect of the present invention, the MMP includes, but is not limited to, MMP1, MMP8 or MMP13.

The present invention relates to a composition for anti-aging of skin comprising carnoic acid derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient in another aspect, wherein in Formula 1, R is -COOR ₃ ,- CH ₂ OR ₃ , or -R ₃ OH, wherein R ₃ is a C ₁ -C ₆ alkyl group.

As used herein, "anti-aging" includes, but is not limited to, the action of improving and preventing skin wrinkles, increasing and repairing skin elasticity, or increasing skin moisture content.

In a composition for anti-aging skin, which is an aspect of the present invention, R ₃ may be a C ₁ -C ₃ alkyl group.

In the anti-aging composition for skin of an aspect of the present invention, R ₃ may be a methyl group, and the carnoic acid derivative may be carnoic acid methyl ester or carnosic acid methyl alcohol, but is not limited thereto.

In the composition for skin anti-aging of an aspect of the present invention, the carnosic acid derivative or pharmaceutically acceptable salt thereof may be derived from one or more plants selected from rosemary ( Rosmarinus officinalis ) or sage ( Salvia officinalis ).

In the anti-aging composition for skin of an aspect of the present invention, the substance may be contained in 0.0001 to 20% by weight based on the total weight of the composition. The material is preferably contained in an amount of 0.0001 to 20% by weight based on the total weight of the composition, but may be used in the above or below the range according to the intended use in the range of suppressing MMP expression inhibition and no toxicity. When the substance is contained at less than 0.0001% by weight, the effect of inhibiting MMP expression is slightly observed, and when it is contained at more than 20% by weight, it is confirmed that the stability of the composition itself or the formulation of the composition is lowered. In view of the above, the material is 0.0005 to 18% by weight, 0.001 to 16% by weight, 0.005 to 14% by weight, 0.01 to 12% by weight, 0.05 to 10% by weight, 0.1 to 8% by weight, 0.5 to 6% by weight Or 1 to 4% by weight.

The composition is not particularly limited in formulation, and may be appropriately selected as desired. For example, softening cream (skin lotion and milk lotion), nourishing cream, essence, nourishing cream, massage cream, pack, gel, essence, eye cream, eye essence, cleansing cream, cleansing foam, cleansing water, pack, powder, It may be prepared in any one or more formulations selected from the group consisting of body lotion, body cream, body oil and body essence, but is not limited thereto. In addition, the cosmetic composition for skin whitening may include using in the form of an external preparation for skin in the form of ointments, patches, and the like.

In addition, the composition may include a pharmaceutical composition, and may include a cosmetic composition.

The pharmaceutical composition may include a pharmaceutical composition for inhibiting skin aging, skin whitening, skin wrinkle improvement, skin exfoliation, acne improvement, psoriasis improvement, or hair loss improvement, and specifically, a retinoid or a surfactant. Can be. In addition, the pharmaceutical composition may include a skin irritation-releasing agent comprising carnosic acid, a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient, so that those with sensitive skin may use it without hesitation.

Formulations of the pharmaceutical compositions according to the invention may be, but are not limited to, solutions, suspensions, emulsions, gels, drops, suppositories, patches or sprays. The formulations can be readily prepared according to conventional methods in the art, and include excipients, hydrating agents, emulsifying accelerators, suspending agents, salts or buffers for controlling osmotic pressure, colorants, spices, stabilizers, preservatives, preservatives or other compatible agents. Adjuvants may be used as appropriate.

The active ingredient of the pharmaceutical composition of the present invention will depend on the age, sex, weight, pathology and severity of the subject to be administered, the route of administration or the judgment of the prescriber. Dosage determination based on these factors is within the level of one skilled in the art and its daily dosage may be, for example, from 0.1 mg / kg / day to 100 mg / kg / day, more specifically from 5 mg / kg / day to 50 mg / kg. May be, but is not limited to.

The pharmaceutical composition of the present invention may be administered orally or transdermally, but is not limited thereto.

The cosmetic composition of the present invention includes a cosmetic composition for inhibiting skin aging, skin whitening, skin wrinkle improvement, skin exfoliation improvement, acne improvement, psoriasis improvement or hair loss improvement. Specifically, the cosmetic composition may be a composition including a retinoid or a surfactant, and may improve symptoms such as inflammation, skin drying, erythema, keratin abnormality, itching or burning due to the retinoid or the surfactant. In addition, the cosmetic composition does not deteriorate functions such as washing power, emulsifying power, dispersing power, osmotic power and bubble power of the surfactant. Sensitive skins, on the other hand, readily respond to irritation and therefore respond better to ingredients contained in cosmetic compositions such as retinoids or surfactants. The cosmetic composition according to one aspect of the present invention may be used by a person having sensitive skin by including a skin irritation reducing agent comprising carnosic acid, a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Cosmetic compositions according to the invention may be provided in all formulations suitable for topical application. For example, it may be provided in the form of a solution, an emulsion obtained by dispersing an oil phase in an aqueous phase, an emulsion obtained by dispersing an aqueous phase in an oil phase, a suspension, a solid, a gel, a powder, a paste, a foam, or an aerosol composition. Compositions of such formulations may be prepared according to conventional methods in the art.

The cosmetic composition according to the present invention may include other ingredients in addition to the above-mentioned substances within the range not impairing the main effect, preferably giving a synergistic effect to the main effect. In addition, the cosmetic composition according to the present invention may further include a moisturizer, an emulsifier, an ultraviolet absorber, a preservative, a fungicide, an antioxidant, a pH adjuster, organic and inorganic pigments, flavors, coolants, or limiting agents. The blending amount of the above components can be easily selected by those skilled in the art within the range that does not impair the object and effect of the present invention, the blending amount may be 0.01 to 5% by weight, specifically 0.01 to 3% by weight based on the total weight of the composition have.

Hereinafter, the configuration and effects of the present invention will be described in more detail with reference to Examples and Test Examples. However, the following examples and test examples are provided only for the purpose of illustration in order to help the understanding of the present invention, but the scope and scope of the present invention is not limited thereto.

Example 1 Obtaining Carnosic Acid

Carnosic acid can be obtained from rosemary ( Rosmarinus officinalis ) or Sage ( Salvia officinalis ) by conventional extraction methods in the art. Specifically, the leaves of rosemary or sage were heated and extracted with 70% (v / v) to 100% (v / v) ethanol for 2 days in an extractor equipped with a reflux condenser at 50 ° C. Then water within a range not exceeding 50% of the total ethanol volume was added to induce precipitation formation including carnosic acid from the extract. At this time, the precipitation formation temperature was maintained not to exceed 20 ℃. Three times or more in the same manner as described above to induce the formation of precipitates with ethanol and water to obtain carnosic acid.

Example 2 Preparation of Carnoic Acid Methyl Ester

1 g of carnosic acid obtained in Example 1 was dissolved in 30 ml of a mixed solvent of benzene and chloroform, and 1.5 ml of TMS-diazomethane was slowly added dropwise. After the reaction temperature was maintained at 0 ℃ stirred for 30 minutes. After the reaction was concentrated under reduced pressure, the compound was purified and separated by column chromatography (hexane: ethyl acetate = 7: 1) to obtain 680 mg of carnoic acid methyl ester. NMR data of the carnoic acid methyl ester obtained by the above method is as follows.

¹ H NMR (300 MHz, CDCl ₃ ) 7.47 (s, 1H), 6.54 (s, 1H), 5.78 (s, 1H), 3.7 (s, 3H), 3.31 (1H, dt), 3.20 (1H, m ), 2.82-2.70 (2H, m), 2.29 (1H, m), 1.86 (m, 1H), 1.68 (m, 1H), 1.61 (m, 1H), 1.56 (dd, 1H), 1.46 (dt, 1H), 1.31 (m, 1H), 1.24 (m, 1H), 1.22 (d, 3H), 1.20 (d, 3H), 1.00 (s, 3H), 0.80 (s, 3H).

Example 3 Preparation of Carnosic Acid Methyl Alcohol

100 mg of carnosic acid obtained in Example 1 was dissolved in 5 ml of THF solvent, and 1.5 ml of LAH was slowly added dropwise. Then, the reaction temperature is maintained at 80 ℃ and stirred for 5 hours. After completion of the reaction, the mixture was extracted with 5% aqueous hydrochloric acid solution and ethyl acetate, concentrated under reduced pressure, and then purified and separated by column chromatography (hexane: ethyl acetate = 10: 1) to obtain 32 mg of methyl carnosate alcohol. The NMR data of carnoic acid methyl alcohol obtained by this method is as follows.

¹ H NMR (300 MHz, CDCl ₃ ) ¹ H NMR (300 MHz, CDCl ₃ ) 8.6 (s, 1H), 6.53 (s, 1H), 4.51 (d, 1H), 3.98 (d, 1H), 3.21 ( m, 2H), 2.86 (m, 2H), 1.86 (m, 1H), 1.68 (m, 1H), 1.61 (m, 1H), 1.56 (dd, 1H), 1.46 (dt, 1H), 1.31 (m) , 1H), 1.24 (m, 1H), 1.22 (d, 3H), 1.20 (d, 3H), 1.00 (s, 3H), 0.80 (s, 3H).

Test Example 1 Confirmation of IL-8 and MCP-1 Free Inhibitory Efficacy

Test cells, keratinocytes (HaCaT, obtained from Dr. NE Fusenig, Deutsches Krebsforschungszentrum, Heidelberg, Germany) and 10% fetal bovine serum (Fetal bovine sereum, FBS, obtained from Gibco, USA) and 1 Using a DMEM (Dulbecco's Modified Eagle Medium, obtained from Lonza, USA) medium containing% Penicillin-Streptomycin (Gibco, USA), the drug was placed in a 48-well plate. After dispensing at a density of 2 × 10 ⁴ cells / well, the cells were incubated for 24 hours under 37 ° C. and 5% CO ₂ conditions. After the culture solution was removed, the cells were washed once with 200 μl of phosphate buffered saline (PBS), and 200 μl of DMEM medium containing fetal bovine serum was added and incubated for 24 hours. Then treated with Examples 1 to 3 and the positive control (hydrocortisone) for 10 minutes with DMEM containing 1% fetal calf serum, the retinoic acid of 100 ppm concentration: Sigma-Aldrich, USA) and incubated for 24 hours. 50 μl of the culture solution was taken, and the free inhibitory effect of these inflammatory mediators was evaluated by ELISA using IL-8, MCP-1 ELISA kit (available from BD pharmigen, USA). Specifically, a standard curve is calculated based on the absorbances of the reference materials rh IL-8 and rh MCP-1 (obtained by BD pharmigen, USA), and then the absorbances of the treated materials are substituted by applying the absorbances of the treated materials. The amount of inflammation mediators was obtained. Thereafter, the free inhibition rate (%) of IL-8 and MCP-1 was obtained according to the following formula, and the results are shown in the following table.

% Inhibition = 100 x [1- (Inflammation mediator secretion in substance treatment group / Inflammation mediator secretion in retinoic acid alone treatment group)]

Table 1

Test substance	Concentration (ppm)	IL-8		MCP-1
		% Inhibition	% Inhibition compared to hydrocortisone	Inhibition Rate (%)	% Inhibition compared to hydrocortisone
Retinoic acid	100	-	-	-	-
Carnosic Acid (Example 1)	One	20.4	22.0	79.6	96.6
	5	45.4	49.0	92.5	112.1
	10	84.9	91.6	93.4	113.3
Carnosic Acid Methyl Ester (Example 2)	One	30.1	32.5	85.1	103.1
	5	51.8	55.9	102	124
	10	92.4	99.7	105	127.7
Carnosic Acid Methyl Alcohol (Example 3)	One	25.8	27.9	82.1	99.5
	5	53.1	57.3	98.7	119.6
	10	93.4	100.8	102.3	124
Positive control (hydrocortisone)	One	92.6	-	82.5	-

As shown in Table 1, in the group treated with carnosic acid or derivatives thereof, the release of IL-8 and MCP-1 by retinoic acid was inhibited in a concentration-dependent manner. Especially with regard to MCP-1 free inhibition, it showed almost the same inhibition rate as hydrocortisone, a steroid known to cause side effects such as skin atrophy and vasodilation. As such, carnosic acid and its derivatives have excellent effects in relieving skin inflammation and skin irritation caused by retinoic acid. It may be an alternative skin irritant.

Test Example 2 Confirmation of IL-6 Free Inhibitory Effect

Except that 100 ppm of sodium lauryl sulfate was used as keratinocytes, the keratinocytes were treated in the same manner as in Test Example 1, and the cytokines IL- of the positive controls (hydrocortisone) of Examples 1 to 3 were used. The glass inhibitory effect of 6 was evaluated. Specifically, a standard curve was drawn based on the absorbance of rh IL-6 (obtained from BD pharmigen, USA) to obtain the reaction formula between the absorbance and the reference material, and then the absorbance of the treated material was substituted to obtain the amount of these cytokines. Thereafter, IL-6 free inhibition was calculated using the same formula as in Test Example 1, and the results are shown in the following table.

TABLE 2

Test substance	Concentration (ppm)	IL-6
		% Inhibition	% Inhibition compared to hydrocortisone
Sodium lauryl sulfate	100	-	-
Carnosic Acid (Example 1)	One	70.4	86.5
	5	78.6	96.6
	10	84.7	104.1
Carnosic Acid Methyl Ester (Example 2)	One	81.2	99.6
	5	89.7	110.1
	10	95.4	117.2
Carnosic Acid Methyl Alcohol (Example 3)	One	74.0	90.9
	5	81.2	99.7
	10	87.9	107.9
Positive control (hydrocortisone)	One	81.4	-

As can be seen from Table 2, in the group treated with carnosic acid or derivatives thereof, the release of IL-6 by the surfactant was inhibited in a concentration-dependent manner. It is estimated to have almost the same inhibitory activity as the steroid hydrocortisone. As such, carnoic acid and its derivatives have excellent effects in relieving skin irritation and skin irritation caused by surfactants, and therefore, steroids, which have been widely used because of their side effects, are effective in relieving skin inflammation and skin irritation. It may be an alternative skin irritant.

Test Example 3 Evaluation of Efficacy in Human Skin Erythema

Safety Evaluation of CTFA (The Cosmetic Toiletry and Fragrance Association) to evaluate the inhibitory effect of retinol on skin erythema induced by retinol of Examples 1 to 3 in healthy volunteers who had never taken steroid preparations and nonsteroidal anti-inflammatory drugs within one month before the start of the test Evaluation was conducted according to the Safety Testing Guideline (1981). Specifically, the composition formulated as Table 3 below was applied twice a day (50 μl / 1.5 × 1.5 cm 2) inside the forearm of 15 subjects, and wrapped for 3 hours in a wrap to assist absorption. . The test period was adjusted in consideration of the response level and skin condition of the subject, and was up to 3 weeks. The test was carried out daily before morning application, and the last test was carried out until 8 days after the application. Evaluation was continued after application to reflect the degree of recovery of stimulation, and no score was given when erythema completely disappeared and only pigmentation remained. At each test point, the degree of stimulation was evaluated according to the determination method shown in Table 4 below, and the results of calculating the stimulation inhibition rate (%) of Examples 1 to 3 based on the degree of stimulation of the comparative example are shown in Table 5 below.

TABLE 3

ingredient	Content (% by weight)
	Comparative example	Examples 1 to 3
Test substance	-	1.0
Retinol	3000 IU	3000 IU
Beeswax	4.00	4.00
Polysorbate	1.50	1.50
Sorbitan sesquioleate	0.70	0.70
Liquid paraffin	5.00	5.00
Caprylic / Caprictriglycerides	5.00	5.00
glycerin	3.00	3.00
Butylene glycol	3.00	3.00
Propylene glycol	3.00	3.00
Carboxy Vinyl Polymer	0.10	0.10
Triethanolamine	0.20	0.20
antiseptic	Quantity	Quantity
Pigment	Quantity	Quantity
Spices	Quantity	Quantity
Purified water	to 100	to 100

Table 4

Skin irritation	grade
Mild erythema	One
Severe erythema	2
Severe erythema with edema	3
Intense erythema with edema and vesicle with edema and blisters	4

Table 5

	Stimulation Relief (%)
Comparative Example 1	-
Example 1	42.3
Example 2	39.8
Example 3	33.5

As can be seen from the above results, carnoic acid or derivatives thereof of Examples 1 to 3 have an effect of inhibiting erythema induced by retinol in human skin. That is, it can be seen that carnoic acid or a derivative thereof has an excellent effect of alleviating skin irritation clinically.

Test Example 4 Measurement of C-kit Inhibition

In order to determine whether the compounds of Examples 1-3 had a C-kit activity inhibitory effect, RTK (receptor tyrosine kinase) efficacy search was performed. The compounds of Examples 1-3 were prepared to have respective final concentrations of 1 μM and 10 μM, and RTK C-kit 5 ng and ATP 100 μM (final concentration) were added to each well of a 384 well plate for 15 minutes at room temperature. Let the first reaction. As substrate, 5 nM (final concentration) of biotinylated poly [glutamine: tyrosine = 4: 1] was added to proceed with the secondary enzymatic reaction. Capture buffer including streptavidin-coated donor beads capable of binding to phosphorylated peptide substrates and receptor beads bound to antibodies (P-Tyr-100) ) To the third reaction. The degree of phosphorylation of the substrate is determined by measuring the alpha screen signal using a Fusion ^™ microplate analyzer. In addition, the inhibitory effect was compared using Tyrphostin A51, which was previously known as a c-Kit activity inhibitor.

C-Kit activity inhibition experiment was repeated three times for each sample. DMSO was added to the positive control instead of the sample, DMSO was added to the negative control and the buffer was added to the enzyme to obtain the c-Kit inhibition rate. The c-Kit activity inhibition rate from the sensed signal was calculated by the following equation and the results are summarized in Table 6.

Equation 1

Table 6

Test substance	Test concentration (μM)	% Inhibition
Tyrphostin a51	10	75
Formula 2 (Carnosic Acid)	One	71
	10	90
Chemical Formula 3 (Carnoic Acid Methyl Ester)	One	54
	10	78
Chemical Formula 4 (Methyl Alcohol)	One	60
	10	85

As can be seen from Table 6, carnosic acid and carnosic acid derivatives of Examples 1 to 3 was confirmed that the c-Kit inhibitory ability at a lower concentration than when compared to Tyrphostin A51 known as an inhibitor of c-Kit activity.

[Test Example 5] Pigmentation Inhibitory Effect Experiment

In order to verify the skin whitening effect of carnosic acid and carnosic acid derivatives according to the present invention, a pigmentation inhibitory effect experiment was conducted as follows. The aforementioned carnosic acid derivatives were evaluated using the compositions formulated with the ingredients and amounts listed in Table 7 below.

Twelve healthy men were placed with an opaque tape with six 1.5cm diameter holes on the upper forearm of the subject, followed by 1.5 ~ 2 times the UVB of Minimal Erythema Dose. Induced blackening of the skin by injecting, each of the Examples 1 to 3 in each morning and evening were corrected twice daily, two months later was measured using a color difference meter

TABLE 7

Ingredient (Unit: wt%)	Experimental Example 1	Experimental Example 2	Experimental Example 3	Comparative Example 1	Comparative Experiment 2
Kojic acid	-	-	-	-	1.0
2. Carnosic Acid (Example 1)	1.0	-	-	-	-
3. Carnosic Acid Methyl Ester (Example 2)	-	1.0	-	-	-
4. Carnosic Acid Methyl Alcohol (Example 3)	-	-	1.0	-	-
5. Purified water	To 100	To 100	To 100	To 100	To 100
6. Dipropylene Glycol	5.0	5.0	5.0	5.0	5.0
7. Butylene Glycol	5.0	5.0	5.0	5.0	5.0
8. Bio Sacrite Gum-1	4.0	4.0	4.0	4.0	4.0
9. Test substance	1.0	1.0	1.0	1.0	1.0
10. Ethanol	5.0	5.0	5.0	5.0	5.0
11.Phenyl Trimethicone	0.2	0.2	0.2	0.2	0.2
12. Polyoxyethylene Hydrogenated Castor Oil	0.5	0.5	0.5	0.5	0.5
13. Preservative	Quantity	Quantity	Quantity	Quantity	Quantity
14. Incense	Quantity	Quantity	Quantity	Quantity	Quantity

The determination of the effect was determined by measuring the degree of black and white of the skin using a color difference meter (Minolta CR2002). L, a, and b colorimeters are used to display the color. In the present invention, the "L" value representing the light and dark of the skin was obtained and analyzed (the non-burned Korean skin color generally shows a value of 50 to 70). The L value was calibrated with a standard whiteboard and the measurements were measured evenly by repeating the measurement at least 5 times in one site.

When the test substance is applied, the L value is gradually increased when the effect is applied, and the comparison between the test substances is calculated according to the following equation (2) of the difference in skin color (ΔL) at the start and the end of the application. The results are shown in Table 8.

Equation 2

Table 8

Test substance	Whitening effect (△ L)
Comparative Experimental Example 1	0.5
Comparative Experiment 2	1.80
Experimental Example 1	2.42
Experimental Example 2	2.04
Experimental Example 3	1.98

As can be seen in Table 8, Experimental Examples 1-3 showed a superior whitening effect than Comparative Experimental Example 1 and Comparative Experimental Example 2, no side effects were observed in the skin.

[Test Example 6] Experimental effect improvement

Ten healthy women with blemishes were selected and applied to Experimental Example 1 twice a day for 3 weeks on the blemish area of the face.

After the experiment was completed, the degree of pigment adherence by experts was visually determined, and the degree of improvement of blemishes was judged by subjective judgment of the test subjects, and evaluated whether or not the improvement of blemishes of Experimental Example 1 was effective or no effect. The results are shown in Table 9.

Table 9

	Effective (persons)	No difference (persons)
Expert judgment	7	3
Subjective Judgment	8	2

As can be seen from the results of Table 9, Experimental Example 1 containing carnosic acid showed a blemish-improving effect for at least seven of 10 subjects.

Test Example 7 Evaluation of Skin Stability

In order to evaluate the safety of the whitening cosmetic composition according to the present invention on the skin, the degree of irritation to the skin of carnosic acid and carnosic acid derivatives was measured.

Thirty-nine healthy adult women and one male with an average age of 37.3 years, the composition formulated on the back area as prescribed in Table 7 was closed for 24 hours, and the skin reaction was visually read for 30 minutes and 24 hours after removal. It was. The criteria for skin irritation were referred to CTFA guidelines (1981) and Frosch & Kligman's criteria. Reaction test readings are shown in Table 10 below.

Table 10

reaction	weight	Criteria of Judgment
-	0.0	No response
+	1.0	Faint erythema
++	2.0	Boundary but weak erythema, edema and papules
+++	3.0	Pronounced erythema, papules and blisters
++++	4.0	Cannon

It was confirmed that the numerical score of the skin average reactivity was 0 in all 40 patients who were subjected to Experimental Examples 1 to 3 of the present invention, so that no skin irritation was induced. In particular, since the skin average response score is determined to be very safe to 1 or less, the present invention was confirmed that the skin safety is very excellent.

Test Example 8 Measurement of Elastase Activity Inhibition

Retinol was used as a positive control to measure the activity of inhibiting the elastase activity of carnoic acid and its derivatives obtained in Examples 1-3.

MeOSuc-Ala-Ala-Pro-Val-pNA (final 0.7 mM) was used as the substrate and the activity of elastase (human leukocyte extraction, 0.2 mU) for each of Examples 1-3 at 37 ° C. The final volume of the reaction solution was 300 μl. After reacting for 10 minutes in kinetic mode, 405 nm using a Bio-tek powerwave x 340 microplate reader, the activity of the elastase was measured by obtaining the max slope. The effect of inhibiting elastase activity on each sample was calculated by the following equation, and the results are summarized in Table 11.

Equation 3

Table 11

Test substance	Test concentration (μM)	% Inhibition
Retinol	One	25
Formula 2 (Carnosic Acid)	One	67
	10	90
Chemical Formula 3 (Carnoic Acid Methyl Ester)	One	54
	10	79
Chemical Formula 4 (Methyl Alcohol)	One	60
	10	85

As can be seen in Table 11, it can be seen that the group treated with carnosic acid or a derivative thereof shows more potent inhibitory activity of elastase enzyme than retinol.

Test Example 9 Measurement of MMP-1 Expression Inhibition

In order to measure MMP-1 expression inhibition of carnosic acid and derivatives thereof of the present invention, enzyme immunoassay (ELISA) was performed.

Human dermal fibroblasts were irradiated with UVA at 5 J / cm ² using a UV chamber. The UV irradiation amount and incubation time as described above depend on the condition that the maximum amount of MMP-1 expression in fibroblasts is obtained through preliminary experiments. UVA emission was measured using a UV radiometer. The cells during the UVA irradiation were intact with the previously dispensed medium and irradiated with UVA and then exchanged with the medium containing the sample for 24 hours of incubation, and then the medium was recovered and coated on a 96-well plate. The primary antibody (MMP-1 (Ab-5) monoclonal antibody and MMP-2 (Ab-3) monoclonal antibody) was treated and reacted at 37 ° C. for 60 minutes. After reacting the secondary antibody anti-mouse Ig G (Whole mouse, alkaline phosphatase conjugated) again for about 60 minutes, the reaction with alkaline phosphate substrate solution (1 mg / ml p-nitrtophenyl phosphate in diethanolamine buffer) at room temperature for 30 minutes The absorbance was measured at 405 nm using a microplate reader (UVT-06685, Termo max, USA). At this time, the medium without the sample was used as a negative control, retinol as a comparison group. The results thus obtained are shown in Table 12.

Table 12

Test substance	Test concentration (μM)	% Inhibition
Retinol	3	70
Formula 2 (Carnosic Acid)	One	68
	3	81
Chemical Formula 3 (Carnoic Acid Methyl Ester)	One	62
	3	78
Chemical Formula 4 (Methyl Alcohol)	One	59
	3	71

As can be seen in Table 12, carnosic acid and its derivatives were found to show a superior MMP-1 expression inhibitory ability than the positive control retinol.

Test Example 10 Wrinkle Improvement Effect

In order to investigate the anti-wrinkle effect of the cosmetic composition containing carnoic acid and its derivatives of the present invention, it was formulated with the ingredients and contents shown in Table 13 below.

Table 13

Ingredient (Unit: wt%)	Experimental Example 4	Comparative Experiment 3
1.Carnosic acid	1.0	-
2. Purified water	To 100	To 100
3. Dipropylene Glycol	5.0	5.0
4. Butylene Glycol	5.0	5.0
5. Bio Sakarite Gum-1	4.0	4.0
6. Test substance	1.0	1.0
7. Ethanol	5.0	5.0
8. Phenyl Trimethicone	0.2	0.2
9. Polyoxyethylene Hydrogenated Castor Oil	0.5	0.5
10. Preservative	Quantity	Quantity
11. Incense	Quantity	Quantity

Experimental Example 4 on the left side of the subject's face, Comparative Experimental Example 3 on the right side were used twice a day, morning and evening, for three months after cleansing. The degree of wrinkle improvement was visually determined, and the wrinkle improvement effect of Experimental Example 1 was evaluated in four stages of "clear effect", "wrinkle improvement effect", "not sure", "none" compared to Comparative Experiment Example 1. And the results are shown in Table 14.

Table 14

Experimental substance	Has pronounced effect (persons)	Wrinkle improvement effect (persons)	I don't know (person)	None
Experimental Example 4	4	8	2	One

As shown in Table 14, the cosmetic composition containing carnoic acid prepared by the prescription of Experimental Example 4 showed a skin wrinkle improvement effect of at least 12 or more of the 15 subjects, did not show any side effects in the skin.

Test Example 11 Elasticity Improvement Effect

In order to examine the skin elasticity improvement effect of the cosmetic containing carnosic acid and its derivatives of the present invention was formulated with the ingredients and contents shown in Table 13.

In a constant temperature and humidity room at 22 ° C. and a relative humidity of 50%, Experimental Example 4 or Comparative Example 3 was applied to the neck of 35 healthy adults for 4 weeks, and then the elasticity before and after application was measured and compared.

Experimental Example 1 was applied to the left side of the subject's neck, and Comparative Example 1 was applied to the right side twice daily for four weeks (morning and evening) after washing. After 4 weeks, the degree of improvement of skin elasticity was measured using a skin elasticity measuring instrument (Cutometer, C + K, Germany). The degree of improvement used Ur / Uf as a parameter.

Table 15

	Elasticity improvement (%, n = 35)
Experimental Example 4	31.02
Comparative Experiment 3	2.49

As can be seen in Table 15, it was confirmed that the skin of the test subject treated with the cosmetics containing carnoic acid prepared by the formulation of Experimental Example 4 improves the elasticity.

Examples of the formulation of the composition according to one aspect of the present invention will be described below, but can be applied to various other formulations, which are intended to explain in detail only, not intended to limit the invention.

Formulation Example 1 Flexible Lotion

According to the composition described in the table below to prepare a flexible lotion in a conventional manner.

Table 16

Compounding ingredient	Content (% by weight)
Carnos acid	0.1
glycerin	3.0
Butylene glycol	2.0
Propylene glycol	2.0
Carboxy Vinyl Polymer	0.1
Fiji-12 nonylphenyl ether	0.2
Polysorbate 80	0.4
ethanol	10.0
Triethanolamine	0.1
Preservative, coloring, flavoring	Quantity
Purified water	Remaining amount

[Formulation Example 2] nutrition lotion

To prepare a nourishing lotion according to the composition described in the table below.

Table 17

Compounding ingredient	Content (% by weight)
Carnosic Acid Methyl Ester	0.5
glycerin	3.0
Butylene glycol	3.0
Propylene glycol	3.0
Carboxy Vinyl Polymer	0.1
Beeswax	4.0
Polysorbate 60	1.5
Caprylic / Capric Triglycerides	5.0
Squalane	5.0
Sorbitassquioleate	1.5
Liquid paraffin	0.5
Cetearyl Alcohol	1.0
Triethanolamine	0.2
Preservative, coloring, flavoring	Quantity
Purified water	Remaining amount

Formulation Example 3 Nutrition Cream

Nutritional creams are prepared by conventional methods according to the compositions set forth in the table below.

Table 18

Compounding ingredient	Content (% by weight)
Carnosic Acid Methyl Alcohol	1.0
glycerin	3.0
Butylene glycol	3.0
Liquid paraffin	7.0
Beta Glucan	7.0
Carbomer	0.1
Caprylic / Capric Triglycerides	3.0
Squalane	5.0
Cetearyl Glucoside	1.5
Sorbitan stearate	0.4
Polysorbate 60	1.2
Triethanolamine	0.1
Preservative, coloring, flavoring	Quantity
Purified water	Remaining amount

Formulation Example 4 Massage Cream

Massage cream is prepared in a conventional manner according to the composition described in the table below.

Table 19

Compounding ingredient	Content (% by weight)
Carnos acid	1.5
glycerin	8.0
Butylene glycol	4.0
Liquid paraffin	45.0
Beta Glucan	7.0
Carbomer	0.1
Caprylic / Capric Triglycerides	3.0
Beeswax	4.0
Cetearyl Glucoside	1.5
Sesqui oleic acid sorbitan	0.9
Vaseline	3.0
paraffin	1.5
Preservative, coloring, flavoring	Quantity
Purified water	Remaining amount

[Formulation Example 5] Pack

Packs are prepared by conventional methods according to the compositions described in the table below.

Table 20

Compounding ingredient	Content (% by weight)
Carnosic Acid Methyl Ester	0.1
glycerin	4.0
Polyvinyl alcohol	15.0
Hyaluronic acid extract	5.0
Beta Glucan	7.0
Allantoin	0.1
Nonyl Phenyl Ether	0.4
Polysorbate 60	1.2
ethanol	6.0
Preservative, coloring, flavoring	Quantity
Purified water	Remaining amount

Formulation Example 6 Ointment

Ointments are prepared by conventional methods according to the compositions described in the table below.

Table 21

Compounding ingredient	Content (% by weight)
Carnosic Acid Methyl Alcohol	0.1
glycerin	8.0
Butylene glycol	4.0
Liquid paraffin	15.0
Beta Glucan	7.0
Carbomer	0.1
Caprylic / Capric Triglycerides	3.0
Squalane	1.0
Cetearyl Glucoside	1.5
Sorbitan stearate	0.4
Cetearyl Alcohol	1.0
Beeswax	4.0
Preservative, coloring, flavoring	Quantity
Purified water	Remaining amount

The skin irritation reducing agent according to the present invention may include carnosic acid, its derivatives or pharmaceutically acceptable salts thereof as an active ingredient to alleviate inflammation, skin dryness, erythema, keratin abnormality, itching or burning due to skin irritation. have.

Carnosic acid, carnosic acid derivatives or pharmaceutically acceptable salts thereof of the present invention are useful because they can inhibit the activity of C-kit. By inhibiting the activity of C-kit, many biological responses mediated by C-kit can be suppressed. Carnosic acid derivatives or pharmaceutically acceptable salts thereof, on the other hand, can inhibit melanin production by inhibiting signal transduction of cells in melanocytes, thereby improving skin whitening. In particular, the present invention inhibits the activity of C-kit, inhibits pigmentation and brings about a blemish-improving effect, and is excellent in terms of skin safety because there is no side effect.

Carnosic acid, carnosic acid derivatives or pharmaceutically acceptable salts thereof of the present invention are useful because they can inhibit elastase activity or inhibit MMP expression. Inhibition of elastase activity or MMP expression can fundamentally inhibit many biological responses mediated by it. Carnosic acid derivatives or their pharmaceutically acceptable salts, on the other hand, may inhibit the activity of elastays or inhibit MMP expression, thereby promoting anti-aging by relieving skin wrinkles or improving elasticity and having no side effects. It is also excellent in terms of safety.

Claims (36)

1. Skin irritation reducing agent comprising as an active ingredient carnos acid, a derivative thereof or a pharmaceutically acceptable salt thereof represented by Formula 1 below:

   [Formula 1]

   

   In Formula 1, R is -COOR ₁ , -CH ₂ OR ₁ , or -R ₂ OH, R ₁ is H or C ₁ -C ₆ alkyl group, R ₂ is a C ₁ -C ₆ alkyl group.
2. The method of claim 1,

   R ₁ is a C ₁ -C ₃ alkyl group,

   R ₂ is a C ₁ -C ₃ alkyl group, skin irritant.
3. The method of claim 1,

   The skin irritation is one or more selected from the group consisting of inflammation, dry skin, erythema, keratin abnormalities, itching and burning, skin irritation.
4. The method of claim 1,

   The skin irritation includes a skin irritation agent including skin irritation by a skin external preparation.
5. The method of claim 4, wherein

   The skin irritation caused by the external preparation for skin is due to retinoids or surfactants in the external preparation for skin.
6. The method of claim 5,

   The retinoid is a skin irritant that includes at least one selected from the group consisting of retinol, retinal and retinoic acid.
7. The method of claim 1,

   The carnos acid, its derivatives or pharmaceutically acceptable salts thereof is derived from one or more plant extracts selected from rosemary or sage, skin irritant.
8. The method of claim 1,

   The emollient comprises 0.01 to 20% by weight of the active ingredient based on the total weight of the emollient, skin irritant.
9. Cosmetic composition containing a skin irritation reducing agent according to any one of claims 1 to 8.
10. The method of claim 9,

    The cosmetic composition for inhibiting skin aging, for skin whitening, for improving skin wrinkles, for improving skin exfoliation, for improving acne, for improving psoriasis or for improving hair loss.
11. The method of claim 9,

    The skin is sensitive skin, cosmetic composition.
12. C-kit activity inhibitor comprising as an active ingredient carnoic acid, a derivative thereof, or a pharmaceutically acceptable salt thereof represented by Formula 1 below:

    [Formula 1]

    

    In Formula 1, R is -COOR ₁ , -CH ₂ OR ₁ , or -R ₂ OH, R ₁ is H or C ₁ -C ₆ alkyl group, R ₂ is a C ₁ -C ₆ alkyl group.
13. The method of claim 12,

    R ₁ is C ₁ -C ₃ alkyl and R ₂ is a C ₁ -C ₃ alkyl group, C-kit activity inhibitor.
14. The method of claim 12,

    R ₁ is H or a methyl group and R ₂ is a methyl group, C-kit activity inhibitor.
15. The method of claim 12,

    The carnosic acid derivative is carnosic acid methyl ester or carnosic acid methyl alcohol, C-kit activity inhibitor.
16. The method of claim 12,

    The carnosic acid, its derivatives or pharmaceutically acceptable salts thereof is derived from at least one plant extract selected from rosemary or sage, C-kit activity inhibitor.
17. The method of claim 12,

    The inhibitor comprises the active ingredient in an amount of 0.0001 to 10% by weight based on the total weight of the inhibitor, C-kit activity inhibitor.
18. An elastase activity inhibitor comprising carnoic acid, a derivative thereof, or a pharmaceutically acceptable salt thereof represented by Formula 1 as an active ingredient.

    [Formula 1]

    

    In Formula 1, R is -COOR ₁ , -CH ₂ OR ₁ , or -R ₂ OH, R ₁ is H or C ₁ -C ₆ alkyl group, R ₂ is a C ₁ -C ₆ alkyl group.
19. The method of claim 18,

    Wherein R ₁ is C ₁ -C ₃ alkyl and R ₂ is a C ₁ -C ₃ alkyl group.
20. The method of claim 18,

    And R ₁ is H or a methyl group and R ₂ is a methyl group.
21. The method of claim 18,

    The carnosic acid derivative is carnosic acid methyl ester or carnosic acid methyl alcohol, elastase activity inhibitor.
22. The method of claim 18,

    Wherein the carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof are derived from one or more plant extracts selected from rosemary or sage.
23. The method of claim 18,

    Wherein the inhibitor contains 0.0001 to 20% by weight based on the total weight of the inhibitor, elastase activity inhibitor.
24. Carnotic acid represented by the following formula (1), derivatives thereof, or pharmaceutically acceptable salts thereof as an active ingredient, MMP (matrix metalloproteinase) expression inhibitor.

    [Formula 1]

    

    In Formula 1, R is -COOR ₁ , -CH ₂ OR ₁ , or -R ₂ OH, R ₁ is H or C ₁ -C ₆ alkyl group, R ₂ is a C ₁ -C ₆ alkyl group.
25. The method of claim 24,

    R ₁ is C ₁ -C ₃ alkyl and R ₂ is a C ₁ -C ₃ alkyl group, MMP expression inhibitor.
26. The method of claim 24,

    Wherein R ₁ is H or a methyl group and R ₂ is a methyl group.
27. The method of claim 24,

    The carnosic acid derivative is carnosic acid methyl ester or carnosic acid methyl alcohol, MMP expression inhibitor.
28. The method of claim 24,

    Carnosic acid, its derivatives or pharmaceutically acceptable salts thereof are derived from one or more plants selected from rosemary or sage.
29. The method of claim 24,

    The active ingredient is contained in 0.0001 to 20% by weight based on the total weight of the inhibitor, MMP expression inhibitor.
30. Carnosic acid derivatives represented by the following formula (1) or pharmaceutically acceptable salts thereof comprising a composition for skin whitening as an active ingredient.

    [Formula 1]

    

    In Chemical Formula 1, R is —COOR ₃ , —CH ₂ OR ₃ , or —R ₃ OH, and R ₃ is a C ₁ -C ₆ alkyl group.
31. Carnosic acid derivatives represented by the following formula (1) or a pharmaceutical composition for skin anti-aging comprising a pharmaceutically acceptable salt thereof as an active ingredient.

    [Formula 1]

    

    In Chemical Formula 1, R is —COOR ₃ , —CH ₂ OR ₃ , or —R ₃ OH, and R ₃ is a C ₁ -C ₆ alkyl group.
32. 32. The method of claim 30 or 31,

    R ₃ is a C ₁ -C ₃ alkyl group.
33. 32. The method of claim 30 or 31,

    R ₃ is a methyl group.
34. 32. The method of claim 30 or 31,

    The carnosic acid derivative is carnosic acid methyl ester or carnosic acid methyl alcohol.
35. 32. The method of claim 30 or 31,

    The carnosic acid derivative or pharmaceutically acceptable salt thereof is derived from at least one plant extract selected from rosemary or sage.
36. 32. The method of claim 30 or 31,

    The composition comprises 0.0001 to 20% by weight of the active ingredient relative to the total weight of the composition.