WO2013070018A1 - Composition comprenant de l'acide carnosique ou un dérivé de celui-ci - Google Patents

Composition comprenant de l'acide carnosique ou un dérivé de celui-ci Download PDF

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Publication number
WO2013070018A1
WO2013070018A1 PCT/KR2012/009458 KR2012009458W WO2013070018A1 WO 2013070018 A1 WO2013070018 A1 WO 2013070018A1 KR 2012009458 W KR2012009458 W KR 2012009458W WO 2013070018 A1 WO2013070018 A1 WO 2013070018A1
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Prior art keywords
skin
carnosic acid
acid
formula
pharmaceutically acceptable
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PCT/KR2012/009458
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English (en)
Korean (ko)
Inventor
최수정
백흥수
주영협
전상훈
조영석
신송석
박영호
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(주)아모레퍼시픽
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Priority claimed from KR1020110117591A external-priority patent/KR20130052243A/ko
Priority claimed from KR1020110120662A external-priority patent/KR20130055114A/ko
Priority claimed from KR1020110146636A external-priority patent/KR20130077953A/ko
Application filed by (주)아모레퍼시픽 filed Critical (주)아모레퍼시픽
Publication of WO2013070018A1 publication Critical patent/WO2013070018A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/08—Ethers or acetals acyclic, e.g. paraformaldehyde
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • 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.
  • MMP matrix metalloproteinase
  • 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.
  • keratinocytes Keratinocytes
  • Langerhan's cells Langerhan's cells
  • cytokines cytokines
  • IL-6 interleukin-6
  • IL-8 interleukin-8
  • MCP-1 Monocyte chemotatic protein-1
  • 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.
  • cosmetics used to protect the skin or various transdermal absorbents applied to the skin
  • 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.
  • 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.
  • SLS sodium lauryl sulfate
  • an anionic surfactant mainly included in cosmetics such as soaps, toothpastes, and shampoos
  • cosmetics such as soaps, toothpastes, and shampoos
  • emulsifiers 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.
  • 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.
  • 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.
  • nerve growth factor nerve growth factor
  • 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.
  • 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.
  • 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').
  • 'SCF' stem cell factor
  • 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.
  • MITF microphthalmia-associated transcription factor
  • SCF / C-kit signal transduction plays an important role in the signal transduction process that promotes melanin synthesis by UV light.
  • 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.
  • 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.
  • 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. .
  • MMP matrix metalloproteinase
  • 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.
  • Tropoelastin a polypeptide
  • elastase which is an elastin degrading enzyme
  • Another object of the present invention to provide a matrix metalloproteinase (MMP) expression inhibitor.
  • MMP matrix metalloproteinase
  • an object of the present invention is to provide a composition for whitening or anti-aging.
  • 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,
  • 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.
  • MMP matrix metalloproteinase
  • 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 C 1 -C 6
  • 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.
  • IL-8 Interleukin-8
  • MCP-1 Monocyte Chemotactic Protein-1
  • IL-6 Interleukin-6
  • skin irritation by retinoids or surfactants can be alleviated.
  • 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 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.
  • 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.
  • 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.
  • 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”).
  • 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.
  • alcohol means a —ROH group, where R means an alkyl group as defined above.
  • R means an alkyl group as defined above.
  • alcohol includes, but is not limited to, methanol, ethanol, propanol, isopropanol, butanol or amyl alcohol.
  • 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.
  • 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.
  • 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-chlorobenzenes
  • an "active ingredient” means a component that can exhibit activity alone or with a carrier which does not exhibit the desired activity.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. .
  • carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof may be obtained by synthesis by conventional methods in the art.
  • 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.
  • IL-8 Interleukin-8
  • MCP-1 Monocyte Chemotactic Protein-1
  • 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.
  • IL-6 Interleukin-6
  • the skin irritation caused by the surfactant can be alleviated.
  • preparations comprising carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof can alleviate skin irritation.
  • Skin irritation relief agent may relieve skin irritation, dry skin, erythema, keratin abnormalities, itching or burning.
  • 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.
  • 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.
  • 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.
  • alkyl refers to a saturated aliphatic hydrocarbon group and includes straight or branched chains.
  • 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.
  • stem cell factor SCF
  • R 1 may be C 1 -C 3 alkyl and R 2 may be a C 1 -C 3 alkyl group.
  • R 1 is H or methyl group and R 2 may be a methyl group
  • the carnosic acid derivative is carnosic acid methyl ester or carnosic acid methyl alcohol May be, but is not limited thereto.
  • 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.
  • 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. .
  • 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.
  • carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof may be obtained by synthesis by conventional methods in the art.
  • 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.
  • the 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.
  • 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.
  • 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. .
  • R 3 may be a C 1 -C 3 alkyl group.
  • R 3 may be a methyl group, and specifically, may include carnoic acid methyl ester or carnosic methyl alcohol, but is not limited thereto.
  • 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.
  • 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. .
  • carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof may be obtained by synthesis by conventional methods in the art.
  • 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.
  • 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.
  • alkyl refers to a saturated aliphatic hydrocarbon group and includes straight or branched chains.
  • R 1 may be C 1 -C 3 alkyl and R 2 may be a C 1 -C 3 alkyl group.
  • 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.
  • the present invention is not limited thereto.
  • 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.
  • 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.
  • 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.
  • the elastase activity inhibitor of one aspect of the present invention can be used as a pharmaceutical composition or cosmetic composition.
  • 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.
  • MMP matrix metalloproteinase
  • R 1 may be C 1 -C 3 alkyl and R 2 may be a C 1 -C 3 alkyl group.
  • 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.
  • 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.
  • 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. .
  • 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.
  • carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof may be obtained by synthesis by conventional methods in the art.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • R 3 may be a C 1 -C 3 alkyl group.
  • R 3 may be a methyl group
  • the carnoic acid derivative may be carnoic acid methyl ester or carnosic acid methyl alcohol, but is not limited thereto.
  • 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 ).
  • 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.
  • 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.
  • 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.
  • 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 cleansing water
  • pack powder
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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 °C. 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.
  • Test cells keratinocytes (HaCaT, obtained from Dr. NE Fusenig, Liebes Krebsgeberstechnik, 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.
  • the cells were washed once with 200 ⁇ l of phosphate buffered saline (PBS), and 200 ⁇ l 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 ⁇ l 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).
  • PBS phosphate buffered saline
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • RTK receptor tyrosine kinase
  • Capture buffer including streptavidin-coated donor beads capable of binding to phosphorylated peptide substrates and receptor beads bound to antibodies P-Tyr-100
  • the degree of phosphorylation of the substrate is determined by measuring the alpha screen signal using a Fusion TM microplate analyzer.
  • the inhibitory effect was compared using Tyrphostin A51, which was previously known as a c-Kit activity inhibitor.
  • 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 12. Polyoxyethylene Hydrogenated Castor Oil 0.5 0.5 0.5 0.5 0.5 13. Preservative Quantity Quantity Quantity Quantity Quantity Quantity 14. Incense 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.
  • 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.
  • the degree of irritation to the skin of carnosic acid and carnosic acid derivatives was measured.
  • 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 ⁇ l.
  • 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.
  • ELISA enzyme immunoassay
  • UVA 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.
  • 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.
  • 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.
  • 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.
  • 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
  • Massage cream is prepared in a conventional manner according to the composition described in the table below.
  • Packs are prepared by conventional methods according to the compositions described in the table below.
  • 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 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.

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Abstract

La présente invention concerne un agent de réduction de l'irritation cutanée, comprenant de l'acide carnosique, un dérivé de celui-ci ou un sel pharmaceutiquement acceptable de celui-ci. La présente invention concerne un inhibiteur de l'activité C-kit comprenant de l'acide carnosique, un dérivé de celui-ci ou un sel pharmaceutiquement acceptable de celui-ci. La présente invention concerne un inhibiteur d'activité élastase ou un inhibiteur de l'expression de la métalloprotéinase de matrice (MPP) comprenant de l'acide carnosique, un dérivé de celui-ci ou un sel pharmaceutiquement acceptable de celui-ci. La présente invention concerne également une composition de blanchiment ou une composition anti-vieillissement comprenant un dérivé d'acide carnosique ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/KR2012/009458 2011-11-11 2012-11-09 Composition comprenant de l'acide carnosique ou un dérivé de celui-ci WO2013070018A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
KR10-2011-0117591 2011-11-11
KR1020110117591A KR20130052243A (ko) 2011-11-11 2011-11-11 카르노스산 또는 그 유도체를 포함하는 피부 자극 완화제
KR10-2011-0120662 2011-11-18
KR1020110120662A KR20130055114A (ko) 2011-11-18 2011-11-18 카르노스산 또는 그 유도체를 포함하는 씨-키트 활성 저해제
KR1020110146636A KR20130077953A (ko) 2011-12-30 2011-12-30 카르노스산 또는 그 유도체를 함유하는 엘라스테이즈 활성 저해제
KR10-2011-0146636 2011-12-30

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GR1009073B (el) * 2016-03-24 2017-07-07 Παναγιωτης Γεωργιου Καλλιμανης Εκχυλισματα δεντρολιβανου (rosmarinus officinalis l.) και φασκομηλου (salvia officinalis l. και salvia triloba l.), πλουσια σε διτερπενικες φαινολες, σε παθησεις του δερματος: συνθεσεις και μεθοδοι αντιμετωπισης
CN114796176A (zh) * 2022-06-09 2022-07-29 中南大学湘雅医院 一种用于治疗皮肤疾病的药物组合物及其制备方法

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JP2003192564A (ja) * 2001-12-27 2003-07-09 Nagase & Co Ltd メラニン生成抑制剤
KR20090089883A (ko) * 2006-11-24 2009-08-24 디에스엠 아이피 어셋츠 비.브이. 카르노스산 12-메틸에터를 포함하는 조성물

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POECKEL, D ET AL.: "Carnosic acid and carnosol potently inhibit human 5-lipoxygenase and suppress pro-inflammatory responses of stimulated human polymorphonuclear leukocytes", BIOCHEMICAL PHARMACOLOGY, vol. 76, 2008, pages 91 - 97, XP022757463, DOI: doi:10.1016/j.bcp.2008.04.013 *

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Publication number Priority date Publication date Assignee Title
GR1009073B (el) * 2016-03-24 2017-07-07 Παναγιωτης Γεωργιου Καλλιμανης Εκχυλισματα δεντρολιβανου (rosmarinus officinalis l.) και φασκομηλου (salvia officinalis l. και salvia triloba l.), πλουσια σε διτερπενικες φαινολες, σε παθησεις του δερματος: συνθεσεις και μεθοδοι αντιμετωπισης
CN114796176A (zh) * 2022-06-09 2022-07-29 中南大学湘雅医院 一种用于治疗皮肤疾病的药物组合物及其制备方法

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