WO2018160021A1 - Composition, containing oxya chinensis sinuosa extract or compound isolated therefrom as active ingredient, for prevention, relief, or treatment of skin wrinkles - Google Patents

Composition, containing oxya chinensis sinuosa extract or compound isolated therefrom as active ingredient, for prevention, relief, or treatment of skin wrinkles Download PDF

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Publication number
WO2018160021A1
WO2018160021A1 PCT/KR2018/002501 KR2018002501W WO2018160021A1 WO 2018160021 A1 WO2018160021 A1 WO 2018160021A1 KR 2018002501 W KR2018002501 W KR 2018002501W WO 2018160021 A1 WO2018160021 A1 WO 2018160021A1
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Prior art keywords
formula
compound
extract
acceptable salt
skin wrinkles
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PCT/KR2018/002501
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French (fr)
Korean (ko)
Inventor
채성욱
임아랑
나민균
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한국 한의학 연구원
충남대학교산학협력단
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Publication of WO2018160021A1 publication Critical patent/WO2018160021A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/63—Arthropods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/98—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/98—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin
    • A61K8/987—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin of species other than mammals or birds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/318—Foods, ingredients or supplements having a functional effect on health having an effect on skin health and hair or coat
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/20—Natural extracts
    • A23V2250/204—Animal extracts

Definitions

  • the present invention is rice locust chinensis sinuosa ) relates to a composition for preventing, improving or treating skin wrinkles containing an extract or a compound separated therefrom as an active ingredient.
  • the skin protects the organs of the body from stimulation of the external environment and plays an important role in maintaining homeostasis such as temperature control.
  • the skin is aging due to various internal and external factors, and is classified into endogenous aging due to genetic causes and exogenous aging due to environmental causes.
  • photoaging means aging by ultraviolet (UV).
  • UV ultraviolet
  • ozone layer destruction due to environmental pollution has increased the amount of ultraviolet rays, and thus research on photoaging has been focused.
  • cosmetic features such as roughness, loss of elasticity, wrinkles and irregular pigmentation are observed.
  • the main research field of photo-aging is about the change of skin wrinkles.
  • MMPs collagen degrading enzymes
  • rice locusts are 30 ⁇ 38cm in length, yellowish green in color, but yellowish brown in head and chest. Compound eyes are oval, glossy greyish brown. There are three narrow grooves on the pronotum and brown vertical lines on both sides. The wings are yellowish brown and longer than the tip of the belly but do not fly very much. Inhabits grasses near rice fields or farmland. Occurs once a year, wintering in the ground. The pellets are wrapped in a gelatinous membrane. The mature nymph has a fourth scab, and its length is about 30mm. The number of pesticides used as a major pest of rice has decreased, but gradually increased. It occurred on the Yellow Sea in 1930 and bought eggs from the government. It is distributed in Korea, Japan, and China.
  • Korean Patent No. 1648612 discloses a method for producing a diet food composition comprising a rice locust component
  • Korean Patent Publication No. 2010-0002661 discloses a functional complex including hyaluronic acid and a method for preparing the same, There is no disclosure related to the prevention, improvement or treatment of skin wrinkles containing the rice locust extract of the invention or a compound isolated therefrom as an active ingredient.
  • the present invention has been made in accordance with the above requirements, and the present invention provides a compound of formula 1 or an acceptable salt thereof; A compound of formula 2 or an acceptable salt thereof; A compound of formula 3 or an acceptable salt thereof; Or byeomettugi (Oxya comprising at least one compound selected from compounds of formula 1-3 chinensis sinuosa ) relates to a composition for preventing, improving or treating skin wrinkles containing the extract as an active ingredient, wherein the compounds of the formulas 1 to 3 and rice locust extracts have no cytotoxicity and have increased expression of MMP-1 by UV irradiation.
  • the present invention has been completed by confirming that it significantly reduces.
  • the present invention is a compound of Formula 1 or an acceptable salt thereof; A compound of formula 2 or an acceptable salt thereof; A compound of formula 3 or an acceptable salt thereof; Or byeomettugi (Oxya comprising at least one compound selected from compounds of formula 1-3 chinensis sinuosa ) provides a health functional food composition for the prevention or improvement of skin wrinkles containing the extract as an active ingredient.
  • the present invention provides a compound of formula 1 or an acceptable salt thereof; A compound of formula 2 or an acceptable salt thereof; A compound of formula 3 or an acceptable salt thereof; Or byeomettugi (Oxya comprising at least one compound selected from compounds of formula 1-3 chinensis sinuosa ) provides a pharmaceutical composition for preventing or treating skin wrinkles containing the extract as an active ingredient.
  • the present invention provides a compound of Formula 1 or an acceptable salt thereof; A compound of formula 2 or an acceptable salt thereof; A compound of formula 3 or an acceptable salt thereof; Or as the active ingredient for the prevention, improvement or treatment composition for the skin wrinkles containing byeomettugi (Oxya chinensis sinuosa) extract comprising one or more compounds selected from compounds of formula 1-3 as an active ingredient it has no cytotoxicity Since the effect of inhibiting the expression of MMP-1 is remarkable, it can be usefully used for health functional food or medicine for preventing, improving or treating skin wrinkles.
  • byeomettugi Oxya chinensis sinuosa
  • Figure 2 is a result of confirming the cell survival rate (%) after treating the compound derived from the rice locust extract of the present invention (Compound A (Formula 1), Compound B (Formula 2) and Compound C (Formula 3)) by concentration.
  • Figure 3 is the result of confirming the expression change of MMP-1 after treating the rice locust extract of the present invention by concentration.
  • A is the result of H & E staining
  • B is the result of Masson's trichome staining.
  • the present invention is a compound of Formula 1 or an acceptable salt thereof; A compound of Formula 2 or an acceptable salt thereof; A compound of formula 3 or an acceptable salt thereof; Or rice grasshopper containing one or more compounds selected from compounds of the formula 1 to 3 ( Oxya chinensis sinuosa ) relates to a health functional food composition for preventing or improving skin wrinkles containing the extract as an active ingredient.
  • the compounds of Formulas 1 to 3 are preferably extracted from rice locust, but are not limited thereto, and may be extracted or synthesized from other natural products.
  • the rice locust extract may be prepared by a method comprising the following steps, but is not limited thereto:
  • the extraction solvent in the step (1) is preferably selected from water, lower alcohols of C 1 ⁇ C 4 or mixtures thereof, more preferably ethanol, even more preferably 70% (v / v) ethanol It is not limited to this.
  • the extraction method may use all conventional methods known in the art, such as filtration, hot water extraction, immersion extraction, reflux cooling extraction and ultrasonic extraction.
  • the extraction solvent is preferably extracted by adding 1 to 20 times the weight of the dried rice locust, more preferably 5 to 15 times.
  • Extraction temperature is preferably 4 to 50 °C but is not limited thereto.
  • the extraction time is preferably 0.5 to 10 hours, more preferably 0.5 to 5 hours, most preferably 1 hour, but is not limited thereto.
  • the vacuum concentration in step (3) is preferably used as a vacuum vacuum concentrator or a vacuum rotary evaporator, but not always limited thereto.
  • the drying is preferably reduced pressure drying, vacuum drying, boiling drying, spray drying or freeze drying, but is not limited thereto.
  • the dietary supplement composition is characterized by inhibiting the expression of MMP-1 or MMP-9.
  • the health functional food composition may be prepared in any one formulation selected from powder, granules, pills, tablets, capsules, candy, syrups and beverages, but is not limited thereto.
  • the health functional food composition of the present invention may be prepared by adding one or more selected from the compounds of the formula (1-3) derived from rice locust extract or rice locust extract as it is or mixing with other food or food ingredients, and according to a conventional method as appropriate Can be prepared.
  • foods to which one or more selected from the compounds of Formulas 1 to 3 derived from the rice locust extract may be added include caramel, meat, sausage, bread, chocolate, candy, snacks, confectionary, pizza, ramen, other noodles, gum, ice cream Dairy products, including various kinds of soups, beverages, tea, drinks, alcoholic beverages and vitamin complexes can be any one of the forms selected, including all the health functional foods in the ordinary sense. That is, the kind of food is not particularly limited.
  • the dietary supplement composition includes various nutrients, vitamins, minerals (electrolytes), synthetic and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pectic acid and salts thereof, alkonic acid and salts thereof, organic acids, protective colloids. Thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like. It may also contain pulp for the production of natural fruit juices and vegetable drinks. The above components can be used independently or in combination.
  • the health functional food composition of the present invention may contain various flavors or natural carbohydrates, etc.
  • the natural carbohydrate is glucose, monosaccharides such as fructose, disaccharides such as maltose, sucrose, and dextrin, Polysaccharides such as cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • the ratio of the said natural carbohydrate is not important, it is preferable that it is 0.01-0.04g with respect to 100g of the composition of this invention, More preferably, it contains 0.02-0.03g, but it is not limited to this.
  • the sweetening agent natural sweetening agents such as tautin and stevia extract, synthetic sweetening agents such as saccharin and aspartame, and the like can be used.
  • the present invention provides a compound of Formula 1 or an acceptable salt thereof; A compound of formula 2 or an acceptable salt thereof; A compound of formula 3 or an acceptable salt thereof; Or byeomettugi (Oxya comprising at least one compound selected from compounds of formula 1-3 chinensis sinuosa ) relates to a pharmaceutical composition for preventing or treating skin wrinkles containing the extract as an active ingredient.
  • the pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier, excipient or diluent.
  • Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are conventionally used in the preparation, saline solution, sterile water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, lactose, dex Straw, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, syrups, methyl cellulose, methylhydroxybenzoate, propyl Hydroxybenzoate, talc, magnesium stearate and mineral oil, and the like.
  • composition of the present invention may be administered orally or parenterally, and the parenteral administration may be administered by injection or application to the skin.
  • suitable dosages of the pharmaceutical compositions of the present invention may be prescribed in various ways depending on factors such as the formulation method, mode of administration, age, weight, sex, morbidity, condition of food, time of administration, route of administration, rate of excretion and response to response of the patient. Can be.
  • Rice locust (4.87 kg) was extracted with ethanol containing 1% (v / v) acetic acid, and then distilled under reduced pressure to obtain 421.8 g of brown locust ethanol extract.
  • Ethanol extract (421.8 g) was extracted using hexane / ethyl acetate 100: 0 (6 L), 80:20 (6 L), 60:40 (6 L), 40:60 (6 L) and 20: using VLC (vacuum liquid chromatography). 80 (6 L) (v: v); Chloroform / methanol 100: 0 (6 L), 80:20 (6 L), 60:40 (6 L), 40:60 (6 L) and 20:80 (6 L) (v: v) gradient gradient elution conditions and methanol washing Six small fractions were obtained through the conditions (A to F).
  • the D fraction (35.7 g) was purified by hexane / ethyl acetate 100: 0 (6 L), 85:15 (6 L), 75:25 (6 L) and 50:50 (6 L) using VLC (vacuum liquid chromatography). v); 7 small fractions with chloroform / methanol concentration gradient elution conditions of 85:15 (6 L), 80:20 (6 L), 67:33 (6 L) and 50:50 (6 L) (v: v) was obtained (D-1 to D-7).
  • the D-5 fraction (18.3 g) was subjected to concentration gradient elution conditions of acetonitrile / water (10: 90-60: 40, 8160 mL) using MPLC (medium pressure liquid chromatography), and acetonitrile washing conditions. Small fractions were obtained (D-5-1 to D-5-6).
  • MMP-1 Cell viability and expression level of MMP-1 were analyzed using HaCaT cells. It was incubated in a medium containing mycin (penicillin-streptomycin; PS, Gibco) at 37 °C, 5% CO 2 conditions.
  • mycin penicillin-streptomycin; PS, Gibco
  • the hairless mice were used after 6 weeks old male hairless mice (male HR-1, hairless mice, Japan SLC, Inc.) were purchased from a central laboratory animal and adapted for 1 week. Healthy animals were used for testing by observing general conditions during the adaptation period.
  • the breeding environment was maintained at a temperature of 23 ⁇ 3 °C, a humidity of 50 ⁇ 5% and a contrast cycle of 12 hours (07: 00-19: 00 / lighting time).
  • 6 animals per group were kept in polycarbonate cages (200 ⁇ 320 ⁇ 145 mm, Three-shine Co., Daejeon, Korea), and the feed was free of 5L79 (Charles river, USA).
  • Sample administration was conducted in three groups: control group, UV-treated group (UV-vehicle), rice locust extract (BMG) administration group. Sample administration was performed by oral administration using a mouse zone. The administration period was a total of 12 weeks for 5 days a week.
  • UV irradiation was carried out three times a week for 12 weeks in the experimental group, except for the control group, the UVB lamp (Mineralight UV Display lamp, UVP, USA) was used. UV irradiation dose is 60 mJ / cm 2 for 1-4 weeks, 90 mJ / cm 2 for 5-8 weeks 9-12 weeks were examined at 120 mJ / cm 2 for 12 weeks. The amount of ultraviolet radiation was controlled by the irradiation time after measuring the amount of light using a photometer (Delta OHM, Italy).
  • the cultured HaCaT cells were treated by diluting each sample by concentration for 24 hours, and treated with MTS assay (CellTiter Aqueous One Solution Cell proliferation assay kit, 3- (4,5-dimethylthiazol-2-yl) -5- ( Microcarboxy reader at 490 nm with 3-carboxymethoxyphenyl) -2- (4-sulfophynyl) -2H-tetrazolium, inner salt; MTS, Promega Co. Madison, WI, USA) technique (Molecular Devices, Sunnyvale, CA, USA) Was measured.
  • MTS assay CellTiter Aqueous One Solution Cell proliferation assay kit, 3- (4,5-dimethylthiazol-2-yl) -5- ( Microcarboxy reader at 490 nm with 3-carboxymethoxyphenyl) -2- (4-sulfophynyl) -2H-tetrazolium, inner salt; MTS, Promega Co. Madison, WI, USA) technique (Molecular Device
  • the cell survival rate in the UVB irradiation group was lower than in the control group without any treatment, and after the UVB irradiation, the relative cell survival rate when the sample of the present invention (rice locust extract and the compound of Formulas 1 to 3) was treated.
  • the relative cell survival rate when the sample of the present invention (rice locust extract and the compound of Formulas 1 to 3) was treated.
  • the rice locust extract of the present invention and the compound of Formulas 1 to 3 were found to have little cytotoxicity.
  • the rice locust extract of the present invention and the compounds of Formulas 1 to 3 were each treated by concentration. Thereafter, ultraviolet (UV) irradiation, the culture supernatant was collected and centrifuged for 5 minutes at 13,000 rpm. Then, the supernatant was taken and subjected to fluorescence assay using an ELISA kit to quantitatively analyze the expression level of MMP-1.
  • UV ultraviolet
  • the epidermal thickness was measured by using a microscope equipped with a thickness from the keratin layer of the tissue subjected to H & E staining to the epidermal cell basement membrane.
  • the UV irradiation group had a stratum corneum as compared with the control group, and the epidermal thickness was also increased.
  • the rice locust extract (BMG) administration group had a stratum corneum as compared to the UV irradiation group. It was alleviated and the epidermal thickness was also decreased.
  • MMPs Collagen degrading enzymes

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Abstract

The present invention relates to a composition for prevention, relief, or treatment of skin wrinkles, the composition containing, as an active ingredient, an Oxya chinensis sinuosa extract comprising a compound of chemical formula 1 or an acceptable salt thereof, a compound of chemical formula 2 or an acceptable salt thereof, a compound of chemical formula 3 or an acceptable salt thereof, or at least one compound selected from the compounds of chemical formulas 1 to 3. The composition suppresses cell damage caused by ultraviolet irradiation and remarkably inhibits MMP-1 expression, and thus can be utilized as a health functional food or medicinal product for prevention, relief, or treatment of skin wrinkles.

Description

벼메뚜기 추출물 또는 이로부터 분리한 화합물을 유효성분으로 함유하는 피부주름의 예방, 개선 또는 치료용 조성물Composition for the prevention, improvement or treatment of skin wrinkles containing rice locust extract or a compound isolated therefrom as an active ingredient
본 발명은 벼메뚜기(Oxya chinensis sinuosa) 추출물 또는 이로부터 분리한 화합물을 유효성분으로 함유하는 피부주름의 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention is rice locust chinensis sinuosa ) relates to a composition for preventing, improving or treating skin wrinkles containing an extract or a compound separated therefrom as an active ingredient.
피부는 외부환경의 자극으로부터 체내의 기관들을 보호해주며, 체온조절 등의 생체 항상성 유지에 중요한 역할을 한다. 이러한 피부는 여러 가지 내외적 요인에 의해서 노화가 발생되며, 크게 유전적 원인에 의한 내인성 노화와 환경적 원인에 의한 외인성 노화로 구분된다. 이 중, 광노화는 자외선(ultraviolet; UV)에 의한 노화를 의미한다. 최근 환경오염으로 인한 오존층 파괴는 자외선의 양을 증가시켰고 이에 따라 광노화에 대한 연구가 주목되고 있다. 광노화 된 피부에서는 거칠어짐, 탄력 손실, 주름 발생 및 불규칙한 색소 침착 등과 같은 외관상의 특징이 관찰되며, 이 중 광노화의 주된 연구 분야는 피부 주름의 변화에 대한 것이다. 상기 광노화에 의한 피부 주름 형성에 관해 피부의 주요 구성성분인 콜라겐(collagen)의 합성, 분해 및 수분 함유량 등의 기초적인 생리 대사 변화에 대한 연구 결과가 다수 보고되고있다. 특히 자외선에 의해 활성 산소종(reactive oxygen species) 생성이 증가되고 피부의 효소적, 비효소적 항산화 방어체계가 붕괴되어 콜라겐의 분해 증가 및 생합성을 감소시켜 진피층 내의 콜라겐이 현저하게 감소된다. 상기 콜라겐 감소에 중요한 영향을 미치는 것은 콜라겐 분해 효소(MMPs; matrix metalloproteinases)로, 이는 세포외기질(extracellular matrix)과 기저막(basement membrane)의 분해에 관여한다. 상기 효소는 자외선에 의해 활성이 증가되며 이를 억제함으로써 자외선에 의해 유도되는 피부 두께 증가 및 주름 형성이 감소된다는 연구 결과들이 보고되어 있다. 따라서 광노화의 예방 및 치료를 위해서는 MMPs를 조절하는 것이 효과적인 방법으로 알려져 있다. The skin protects the organs of the body from stimulation of the external environment and plays an important role in maintaining homeostasis such as temperature control. The skin is aging due to various internal and external factors, and is classified into endogenous aging due to genetic causes and exogenous aging due to environmental causes. Among these, photoaging means aging by ultraviolet (UV). Recently, ozone layer destruction due to environmental pollution has increased the amount of ultraviolet rays, and thus research on photoaging has been focused. In photo-aged skin, cosmetic features such as roughness, loss of elasticity, wrinkles and irregular pigmentation are observed. Among them, the main research field of photo-aging is about the change of skin wrinkles. Many studies have been reported on basic physiological metabolic changes, such as the synthesis, degradation, and water content of collagen, which is a major component of skin, on skin wrinkle formation caused by photoaging. In particular, UV radiation increases the production of reactive oxygen species and disrupts the enzymatic and non-enzymatic antioxidant defenses of the skin, leading to increased collagen degradation and biosynthesis, thereby significantly reducing collagen in the dermis. Significant effects on collagen reduction are collagen degrading enzymes (MMPs), which are involved in the degradation of extracellular matrix and basement membrane. It has been reported that the enzyme increases the activity by ultraviolet light and thereby inhibits the increase of skin thickness and wrinkle formation induced by ultraviolet light. Therefore, it is known to control MMPs for the prevention and treatment of photoaging.
한편, 벼메뚜기는 몸길이 30~38cm으로, 몸빛깔은 황록색이나 머리와 가슴은 황갈색이다. 겹눈은 달걀 모양이고 광택이 있는 회갈색이다. 앞가슴등판에 가느다란 3개의 가로홈이 있고 양쪽에 갈색의 세로줄이 있다. 날개는 황갈색이고 배끝보다 길지만 별로 날아다니지 않는다. 논이나 경작지 근처의 풀밭에 서식한다. 연 1회 발생하며, 땅 속에서 알무더기로 월동한다. 알무더기는 아교질의 엷은 막으로 싸여 있다. 다 자란 약충은 날개딱지가 제4배마디에 이르며 몸길이는 약 30mm이다. 벼의 주요 해충으로 농약을 사용하면서 그 수가 줄어들었으나 차차 늘어나고 있다. 1930년 황해도에서 발생해 알덩어리를 정부에서 사들인 일도 있다. 한국·일본·중국 등지에 분포한다. On the other hand, rice locusts are 30 ~ 38cm in length, yellowish green in color, but yellowish brown in head and chest. Compound eyes are oval, glossy greyish brown. There are three narrow grooves on the pronotum and brown vertical lines on both sides. The wings are yellowish brown and longer than the tip of the belly but do not fly very much. Inhabits grasses near rice fields or farmland. Occurs once a year, wintering in the ground. The pellets are wrapped in a gelatinous membrane. The mature nymph has a fourth scab, and its length is about 30mm. The number of pesticides used as a major pest of rice has decreased, but gradually increased. It occurred on the Yellow Sea in 1930 and bought eggs from the government. It is distributed in Korea, Japan, and China.
한국등록특허 제1648812호에 벼메뚜기 성분을 포함하는 다이어트 식품 조성물 제조 방법에 관하여 개시되어 있고, 한국공개특허 제2010-0002661호에 히알루론산을 포함하는 기능성 복합체 및 그 제조방법에 관하여 개시되어 있으나, 본 발명의 벼메뚜기 추출물 또는 이로부터 분리한 화합물을 유효성분으로 함유하는 피부주름의 예방, 개선 또는 치료 관련 기술은 개시된 바 없다.Korean Patent No. 1648612 discloses a method for producing a diet food composition comprising a rice locust component, and Korean Patent Publication No. 2010-0002661 discloses a functional complex including hyaluronic acid and a method for preparing the same, There is no disclosure related to the prevention, improvement or treatment of skin wrinkles containing the rice locust extract of the invention or a compound isolated therefrom as an active ingredient.
본 발명은 상기와 같은 요구에 의해 도출된 것으로서, 본 발명은 화학식 1의 화합물 또는 이의 허용가능한 염; 화학식 2의 화합물 또는 이의 허용가능한 염; 화학식 3의 화합물 또는 이의 허용가능한 염; 또는 화학식 1~3의 화합물 중에서 선택된 하나 이상의 화합물을 포함하는 벼메뚜기(Oxya chinensis sinuosa) 추출물을 유효성분으로 함유하는 피부주름의 예방, 개선 또는 치료용 조성물에 관한 것으로, 화학식 1~3의 화합물 및 벼메뚜기 추출물이 세포 독성이 없으며, UV 조사에 의해 증가된 MMP-1의 발현량을 현저하게 감소시킨다는 것을 확인함으로써, 본 발명을 완성하였다.The present invention has been made in accordance with the above requirements, and the present invention provides a compound of formula 1 or an acceptable salt thereof; A compound of formula 2 or an acceptable salt thereof; A compound of formula 3 or an acceptable salt thereof; Or byeomettugi (Oxya comprising at least one compound selected from compounds of formula 1-3 chinensis sinuosa ) relates to a composition for preventing, improving or treating skin wrinkles containing the extract as an active ingredient, wherein the compounds of the formulas 1 to 3 and rice locust extracts have no cytotoxicity and have increased expression of MMP-1 by UV irradiation. The present invention has been completed by confirming that it significantly reduces.
상기 목적을 달성하기 위하여, 본 발명은 화학식 1의 화합물 또는 이의 허용가능한 염; 화학식 2의 화합물 또는 이의 허용가능한 염; 화학식 3의 화합물 또는 이의 허용가능한 염; 또는 화학식 1~3의 화합물 중에서 선택된 하나 이상의 화합물을 포함하는 벼메뚜기(Oxya chinensis sinuosa) 추출물을 유효성분으로 함유하는 피부주름의 예방 또는 개선용 건강기능식품 조성물을 제공한다.In order to achieve the above object, the present invention is a compound of Formula 1 or an acceptable salt thereof; A compound of formula 2 or an acceptable salt thereof; A compound of formula 3 or an acceptable salt thereof; Or byeomettugi (Oxya comprising at least one compound selected from compounds of formula 1-3 chinensis sinuosa ) provides a health functional food composition for the prevention or improvement of skin wrinkles containing the extract as an active ingredient.
또한, 본 발명은 본 발명은 화학식 1의 화합물 또는 이의 허용가능한 염; 화학식 2의 화합물 또는 이의 허용가능한 염; 화학식 3의 화합물 또는 이의 허용가능한 염; 또는 화학식 1~3의 화합물 중에서 선택된 하나 이상의 화합물을 포함하는 벼메뚜기(Oxya chinensis sinuosa) 추출물을 유효성분으로 함유하는 피부주름의 예방 또는 치료용 약학 조성물을 제공한다.In addition, the present invention provides a compound of formula 1 or an acceptable salt thereof; A compound of formula 2 or an acceptable salt thereof; A compound of formula 3 or an acceptable salt thereof; Or byeomettugi (Oxya comprising at least one compound selected from compounds of formula 1-3 chinensis sinuosa ) provides a pharmaceutical composition for preventing or treating skin wrinkles containing the extract as an active ingredient.
본 발명은 화학식 1의 화합물 또는 이의 허용가능한 염; 화학식 2의 화합물 또는 이의 허용가능한 염; 화학식 3의 화합물 또는 이의 허용가능한 염; 또는 화학식 1~3의 화합물 중에서 선택된 하나 이상의 화합물을 포함하는 벼메뚜기(Oxya chinensis sinuosa) 추출물을 유효성분으로 함유하는 피부주름의 예방, 개선 또는 치료용 조성물에 관한 것으로, 상기 유효성분은 세포독성이 없고, MMP-1의 발현을 억제하는 효과가 현저하므로, 피부주름의 예방, 개선 또는 치료용 건강기능성식품 또는 의약품에 유용하게 사용할 수 있다.The present invention provides a compound of Formula 1 or an acceptable salt thereof; A compound of formula 2 or an acceptable salt thereof; A compound of formula 3 or an acceptable salt thereof; Or as the active ingredient for the prevention, improvement or treatment composition for the skin wrinkles containing byeomettugi (Oxya chinensis sinuosa) extract comprising one or more compounds selected from compounds of formula 1-3 as an active ingredient it has no cytotoxicity Since the effect of inhibiting the expression of MMP-1 is remarkable, it can be usefully used for health functional food or medicine for preventing, improving or treating skin wrinkles.
도 1은 본 발명의 벼메뚜기 추출물을 농도별로 처리한 후 세포 생존률(%)을 확인한 결과이다. 1 is a result of confirming the cell survival rate (%) after treating the rice locust extract of the present invention by concentration.
도 2는 본 발명의 벼메뚜기 추출물 유래의 화합물(화합물 A(화학식 1), 화합물 B(화학식 2) 및 화합물 C(화학식 3))을 농도별로 처리한 후 세포 생존률(%)을 확인한 결과이다.Figure 2 is a result of confirming the cell survival rate (%) after treating the compound derived from the rice locust extract of the present invention (Compound A (Formula 1), Compound B (Formula 2) and Compound C (Formula 3)) by concentration.
도 3은 본 발명의 벼메뚜기 추출물을 농도별로 처리한 후 MMP-1의 발현량 변화를 확인한 결과이다. Figure 3 is the result of confirming the expression change of MMP-1 after treating the rice locust extract of the present invention by concentration.
도 4는 본 발명의 벼메뚜기 추출물 유래의 화합물(화합물 A(화학식 1), 화합물 B(화학식 2) 및 화합물 C(화학식 3))을 농도별로 처리한 후 MMP-1의 발현량 변화를 확인한 결과이다. 4 is a result of confirming the expression change of MMP-1 after treating the compound derived from the rice locust extract of the present invention (Compound A (Formula 1), Compound B (Formula 2) and Compound C (Formula 3)) for each concentration .
도 5는 UV 조사에 의해 증가한 표피 두께가 본 발명의 벼메뚜기 추출물을 투여하여 감소한 것을 확인한 결과이다. ####은 정상군에 비해 자외선 조사군의 표피 두께가 증가하였다는 것이고, p<0.0001이다. ****는 자외선 조사군에 비해 본 발명의 벼메뚜기 추출물을 처리한 군의 표피 두께가 감소하였다는 것으로 p<0.0001이다. 5 is a result confirming that the epidermal thickness increased by UV irradiation was reduced by administering the rice locust extract of the present invention. #### indicates that the epidermal thickness of the UV irradiation group was increased compared to the normal group, and p <0.0001. **** is p <0.0001 that the epidermal thickness of the group treated with the rice locust extract of the present invention was reduced compared to the ultraviolet irradiation group.
도 6은 UV 조사에 의해 증가한 표피 두께와 감소한 콜라겐의 함량을 확인한 후, 본 발명의 벼메뚜기 추출물을 투여하여 표피 두께의 감소 및 콜라겐 함량의 증가를 확인한 결과이다. A는 H&E 염색 결과이고, B는 Masson's trichome 염색 결과이다.6 is a result of confirming the decrease in epidermal thickness and the increase in collagen content by administering the rice locust extract of the present invention after confirming the increased epidermal thickness and reduced collagen content by UV irradiation. A is the result of H & E staining, B is the result of Masson's trichome staining.
도 7은 본 발명의 벼메뚜기 추출물의 투여에 따른 피부의 주름에 관여하는 MMP-1과 MMP-9의 발현량의 변화를 분석한 결과이다. ###, ####은 정상군에 비해 자외선 조사군의 MMP-1과 MMP-9의 발현량이 유의미하게 증가하였다는 것이고, ###은 p<0.001이고, ####은 p<0.0001이다. **, ***는 자외선 조사군에 비해 본 발명의 벼메뚜기 추출물을 처리한 군의 MMP-1과 MMP-9의 발현량이 유의하게 감소하였다는 것으로 **는 p<0.01이고, ***는p<0.001이다. 7 is a result of analyzing the change in the expression level of MMP-1 and MMP-9 involved in the wrinkles of the skin according to the administration of the rice locust extract of the present invention. ###, #### is a significant increase in the amount of MMP-1 and MMP-9 expression in the UV irradiation group compared to the normal group, ### is p <0.001, #### is p < 0.0001. ** and *** are significantly reduced expression levels of MMP-1 and MMP-9 in the group treated with the rice locust extract of the present invention compared to the ultraviolet irradiation group ** is p <0.01, *** p <0.001.
본 발명은 하기 화학식 1의 화합물 또는 이의 허용가능한 염; 하기 화학식 2의 화합물 또는 이의 허용가능한 염; 하기 화학식 3의 화합물 또는 이의 허용가능한 염; 또는 하기 화학식 1~3의 화합물 중에서 선택된 하나 이상의 화합물을 포함하는 벼메뚜기(Oxya chinensis sinuosa) 추출물을 유효성분으로 함유하는 피부주름의 예방 또는 개선용 건강기능식품 조성물에 관한 것이다.The present invention is a compound of Formula 1 or an acceptable salt thereof; A compound of Formula 2 or an acceptable salt thereof; A compound of formula 3 or an acceptable salt thereof; Or rice grasshopper containing one or more compounds selected from compounds of the formula 1 to 3 ( Oxya chinensis sinuosa ) relates to a health functional food composition for preventing or improving skin wrinkles containing the extract as an active ingredient.
Figure PCTKR2018002501-appb-C000001
Figure PCTKR2018002501-appb-C000001
Figure PCTKR2018002501-appb-C000002
Figure PCTKR2018002501-appb-C000002
Figure PCTKR2018002501-appb-C000003
Figure PCTKR2018002501-appb-C000003
상기 화학식 1~3의 화합물은 벼메뚜기로부터 추출한 것이 바람직하지만 이에 제한하는 것은 아니며, 다른 천연물로부터 추출하거나 합성하는 것이 얼마든지 가능하다.The compounds of Formulas 1 to 3 are preferably extracted from rice locust, but are not limited thereto, and may be extracted or synthesized from other natural products.
상기 벼메뚜기 추출물은 하기의 단계를 포함하는 방법에 의해 제조되는 것일 수 있으나, 이에 한정하지 않는다:The rice locust extract may be prepared by a method comprising the following steps, but is not limited thereto:
(1) 벼메뚜기에 추출용매를 가하여 추출하는 단계;(1) extracting by adding an extraction solvent to the rice grasshopper;
(2) 단계 (1)의 추출물을 여과하는 단계; 및 (2) filtering the extract of step (1); And
(3) 단계 (2)의 여과한 추출물을 감압 농축하고 건조하여 추출물을 제조하는 단계. (3) concentration of the filtered extract of step (2) under reduced pressure and drying to prepare an extract.
상기 단계 (1)에서 추출용매는 물, C1~C4의 저급 알코올 또는 이들의 혼합물 중에서 선택하는 것이 바람직하며, 더 바람직하게는 에탄올이고, 더욱더 바람직하게는 70%(v/v) 에탄올이지만 이에 한정하지 않는다.The extraction solvent in the step (1) is preferably selected from water, lower alcohols of C 1 ~ C 4 or mixtures thereof, more preferably ethanol, even more preferably 70% (v / v) ethanol It is not limited to this.
상기 제조방법에 있어서, 추출방법은 여과법, 열수 추출, 침지 추출, 환류 냉각 추출 및 초음파 추출 등의 당 업계에 공지된 모든 통상적인 방법을 이용할 수 있다. 상기 추출용매는 건조된 벼메뚜기 중량의 1~20배 첨가하여 추출하는 것이 바람직하며, 더 바람직하게는 5~15배 첨가하는 것이다. 추출온도는 4 내지 50℃인 것이 바람직하나 이에 한정하지 않는다. 또한, 추출시간은 0.5~10시간인 것이 바람직하며, 0.5~5시간이 더욱 바람직하고, 1 시간이 가장 바람직하나 이에 한정하지 않는다. 상기 방법에 있어서, 단계 (3)의 감압농축은 진공 감압 농축기 또는 진공회전증발기를 이용하는 것이 바람직하나 이에 한정하지 않는다. 또한, 건조는 감압건조, 진공건조, 비등건조, 분무 건조 또는 동결 건조하는 것이 바람직하나 이에 한정하지 않는다.In the above production method, the extraction method may use all conventional methods known in the art, such as filtration, hot water extraction, immersion extraction, reflux cooling extraction and ultrasonic extraction. The extraction solvent is preferably extracted by adding 1 to 20 times the weight of the dried rice locust, more preferably 5 to 15 times. Extraction temperature is preferably 4 to 50 ℃ but is not limited thereto. In addition, the extraction time is preferably 0.5 to 10 hours, more preferably 0.5 to 5 hours, most preferably 1 hour, but is not limited thereto. In the above method, the vacuum concentration in step (3) is preferably used as a vacuum vacuum concentrator or a vacuum rotary evaporator, but not always limited thereto. In addition, the drying is preferably reduced pressure drying, vacuum drying, boiling drying, spray drying or freeze drying, but is not limited thereto.
상기 건강기능식품 조성물은 MMP-1 또는 MMP-9의 발현을 저해하는 것이 특징이다. The dietary supplement composition is characterized by inhibiting the expression of MMP-1 or MMP-9.
상기 건강기능식품 조성물은 분말, 과립, 환, 정제, 캡슐, 캔디, 시럽 및 음료 중에서 선택된 어느 하나의 제형으로 제조될 수 있으나, 이에 한정하는 것은 아니다.The health functional food composition may be prepared in any one formulation selected from powder, granules, pills, tablets, capsules, candy, syrups and beverages, but is not limited thereto.
본 발명의 건강기능식품 조성물은 벼메뚜기 추출물 또는 벼메뚜기 추출물 유래의 화학식 1~3의 화합물 중에서 선택된 하나 이상을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 혼합하여 제조될 수 있고, 통상적인 방법에 따라 적절하게 제조될 수 있다. 상기 벼메뚜기 추출물 유래의 화학식 1~3의 화합물 중에서 선택된 하나 이상을 첨가할 수 있는 식품의 예로는 카라멜, 육류, 소시지, 빵, 초콜릿, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 수프, 음료수, 차, 드링크제, 알코올 음료 및 비타민 복합제 중에서 선택된 어느 하나의 형태일 수 있으며, 통상적인 의미에서의 건강기능식품을 모두 포함한다. 즉, 상기 식품의 종류에는 특별한 제한은 없다. 상기 건강기능식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 및 천연 풍미제, 착색제 및 증진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알킨산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 또한, 천연 과일 주스 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 상기의 성분은 독립적으로 또는 조합하여 사용할 수 있다. 또한, 본 발명의 건강기능식품 조성물은 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있으며, 상기 천연 탄수화물은 포도당, 과당과 같은 단당류, 말토스, 슈크로스와 같은 이당류, 및 덱스트린, 사이클로덱스트린과 같은 다당류, 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상기 천연 탄수화물의 비율은 크게 중요하지 않지만, 본 발명의 조성물 100g에 대하여, 0.01~0.04g 인 것이 바람직하고, 더욱 바람직하게는 0.02 내지 0.03g을 포함하는 것이지만 이에 한정하지 않는다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. The health functional food composition of the present invention may be prepared by adding one or more selected from the compounds of the formula (1-3) derived from rice locust extract or rice locust extract as it is or mixing with other food or food ingredients, and according to a conventional method as appropriate Can be prepared. Examples of foods to which one or more selected from the compounds of Formulas 1 to 3 derived from the rice locust extract may be added include caramel, meat, sausage, bread, chocolate, candy, snacks, confectionary, pizza, ramen, other noodles, gum, ice cream Dairy products, including various kinds of soups, beverages, tea, drinks, alcoholic beverages and vitamin complexes can be any one of the forms selected, including all the health functional foods in the ordinary sense. That is, the kind of food is not particularly limited. The dietary supplement composition includes various nutrients, vitamins, minerals (electrolytes), synthetic and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pectic acid and salts thereof, alkonic acid and salts thereof, organic acids, protective colloids. Thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like. It may also contain pulp for the production of natural fruit juices and vegetable drinks. The above components can be used independently or in combination. In addition, the health functional food composition of the present invention may contain various flavors or natural carbohydrates, etc. as additional components, the natural carbohydrate is glucose, monosaccharides such as fructose, disaccharides such as maltose, sucrose, and dextrin, Polysaccharides such as cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. Although the ratio of the said natural carbohydrate is not important, it is preferable that it is 0.01-0.04g with respect to 100g of the composition of this invention, More preferably, it contains 0.02-0.03g, but it is not limited to this. As the sweetening agent, natural sweetening agents such as tautin and stevia extract, synthetic sweetening agents such as saccharin and aspartame, and the like can be used.
또한, 본 발명은 화학식 1의 화합물 또는 이의 허용가능한 염; 화학식 2의 화합물 또는 이의 허용가능한 염; 화학식 3의 화합물 또는 이의 허용가능한 염; 또는 화학식 1~3의 화합물 중에서 선택된 하나 이상의 화합물을 포함하는 벼메뚜기(Oxya chinensis sinuosa) 추출물을 유효성분으로 함유하는 피부주름의 예방 또는 치료용 약학 조성물에 관한 것이다.In addition, the present invention provides a compound of Formula 1 or an acceptable salt thereof; A compound of formula 2 or an acceptable salt thereof; A compound of formula 3 or an acceptable salt thereof; Or byeomettugi (Oxya comprising at least one compound selected from compounds of formula 1-3 chinensis sinuosa ) relates to a pharmaceutical composition for preventing or treating skin wrinkles containing the extract as an active ingredient.
[화학식 1][Formula 1]
Figure PCTKR2018002501-appb-I000001
Figure PCTKR2018002501-appb-I000001
[화학식 2][Formula 2]
Figure PCTKR2018002501-appb-I000002
Figure PCTKR2018002501-appb-I000002
[화학식 3][Formula 3]
Figure PCTKR2018002501-appb-I000003
Figure PCTKR2018002501-appb-I000003
본 발명의 약학 조성물은 약학적으로 허용되는 담체, 부형제 또는 희석제를 추가로 포함할 수 있다. 본 발명의 약학 조성물에 포함되는 약학적으로 허용되는 담체는 제제 시에 통상적으로 이용되는 것으로서, 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로즈 용액, 말토덱스트린 용액, 글리세롤, 에탄올, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 또한 상기 성분들 이외에 항산화제, 완충액, 정균제, 희석제, 계면활성제, 결합제, 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제 또는 보존제 등을 추가로 포함할 수 있다. 본 발명의 약학 조성물은 경구 또는 비경구 투여할 수 있으며, 비경구 투여는 주사 또는 피부에 도포하는 방법으로 투여할 수 있는 것이다. 본 발명의 약학 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier, excipient or diluent. Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are conventionally used in the preparation, saline solution, sterile water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, lactose, dex Straw, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, syrups, methyl cellulose, methylhydroxybenzoate, propyl Hydroxybenzoate, talc, magnesium stearate and mineral oil, and the like. In addition to the above components, it may further include antioxidants, buffers, bacteriostatic agents, diluents, surfactants, binders, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents or preservatives. The pharmaceutical composition of the present invention may be administered orally or parenterally, and the parenteral administration may be administered by injection or application to the skin. Suitable dosages of the pharmaceutical compositions of the present invention may be prescribed in various ways depending on factors such as the formulation method, mode of administration, age, weight, sex, morbidity, condition of food, time of administration, route of administration, rate of excretion and response to response of the patient. Can be.
이하, 실시예를 이용하여 본 발명을 더욱 상세하게 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로 본 발명의 범위가 이들에 의해 제한되지 않는다는 것은 당해 기술분야에서 통상의 지식을 가진 자에게 있어 자명한 것이다. Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for explaining the present invention in more detail, it is obvious to those skilled in the art that the scope of the present invention is not limited by them.
[재료 및 방법] [ Materials and methods]
1. 벼메뚜기 추출물의 제조1. Preparation of Rice Locust Extract
벼메뚜기(4.87kg)를 1%(v/v) 아세트산이 포함된 에탄올로 추출한 후, 감압증류하여 갈색을 띠는 벼메뚜기 에탄올 추출물 421.8g을 획득하였다.Rice locust (4.87 kg) was extracted with ethanol containing 1% (v / v) acetic acid, and then distilled under reduced pressure to obtain 421.8 g of brown locust ethanol extract.
2. 화학식 1~3의 화합물의 분리 및 구조 결정2. Isolation and Structure Determination of the Compounds of Formulas 1 to 3
에탄올 추출물(421.8g)을 VLC(vacuum liquid chromatography)를 이용하여 헥산/에틸아세테이트 100:0(6ℓ), 80:20(6ℓ), 60:40(6ℓ), 40:60(6ℓ) 및 20:80(6ℓ)(v:v); 클로로포름/메탄올 100:0(6ℓ), 80:20(6ℓ), 60:40(6ℓ), 40:60(6ℓ) 및 20:80(6ℓ)(v:v)의 농도구배 용리 조건 및 메탄올 세척조건을 통해 6개의 소분획물을 얻었다(A~F).Ethanol extract (421.8 g) was extracted using hexane / ethyl acetate 100: 0 (6 L), 80:20 (6 L), 60:40 (6 L), 40:60 (6 L) and 20: using VLC (vacuum liquid chromatography). 80 (6 L) (v: v); Chloroform / methanol 100: 0 (6 L), 80:20 (6 L), 60:40 (6 L), 40:60 (6 L) and 20:80 (6 L) (v: v) gradient gradient elution conditions and methanol washing Six small fractions were obtained through the conditions (A to F).
D 분획물(35.7g)을 VLC(vacuum liquid chromatography)를 이용하여 헥산/에틸아세테이트 100:0(6ℓ), 85:15(6ℓ), 75:25(6ℓ) 및 50:50(6ℓ)(v:v); 클로로포름/메탄올 85:15(6ℓ), 80:20(6ℓ), 67:33(6ℓ) 및 50:50(6ℓ)(v:v)의 농도구배 용리 조건 및 메탄올 세척조건을 통해 7개의 소분획물을 얻었다(D-1~D-7).The D fraction (35.7 g) was purified by hexane / ethyl acetate 100: 0 (6 L), 85:15 (6 L), 75:25 (6 L) and 50:50 (6 L) using VLC (vacuum liquid chromatography). v); 7 small fractions with chloroform / methanol concentration gradient elution conditions of 85:15 (6 L), 80:20 (6 L), 67:33 (6 L) and 50:50 (6 L) (v: v) Was obtained (D-1 to D-7).
D-5 분획물(18.3g)을 MPLC(medium pressure liquid chromatography)를 이용하여 아세토나이트릴/물(10:90~60:40, 8160㎖)의 농도구배 용리 조건 및 아세토나이트릴 세척 조건을 통해 6개의 소분획물을 얻었다(D-5-1~D-5-6).The D-5 fraction (18.3 g) was subjected to concentration gradient elution conditions of acetonitrile / water (10: 90-60: 40, 8160 mL) using MPLC (medium pressure liquid chromatography), and acetonitrile washing conditions. Small fractions were obtained (D-5-1 to D-5-6).
D-5-2 분획물(1.9g)에 대하여 prep HPLC(Phenomenex Kinetex C18 250×21mm, 5μm, Kinetex Biphenyl 250×21mm, 5μm)를 진행하여 화합물 A(t R 52분: 331.2mg), 화합물 B(t R, 47분: 389.2mg), 화합물 C(t R 64분: 37.2mg)를 획득하였다. Preparative HPLC (Phenomenex Kinetex C 18 250 × 21mm, 5μm, Kinetex Biphenyl 250 × 21mm, 5μm) was performed on the D-5-2 fraction (1.9g) to obtain Compound A ( t R 52min: 331.2mg), Compound B. ( t R , 47 min: 389.2 mg), Compound C ( t R 64 min: 37.2 mg) was obtained.
3. 세포배양3. Cell Culture
세포 생존율 및 MMP-1의 발현량 분석은 HaCaT 세포를 이용하였으며, HaCaT 세포는 Dulbecco's Modified Eagle Medium (DMEM, Gibco)에 10% 소태아 혈청(Fetal bovine serum;FBS, Gibco)과 1% 페니실린-스트렙토마이신(penicillin-streptomycin;PS, Gibco)이 함유된 배지에서 37℃, 5% CO2 조건에서 배양하였다.Cell viability and expression level of MMP-1 were analyzed using HaCaT cells. It was incubated in a medium containing mycin (penicillin-streptomycin; PS, Gibco) at 37 ℃, 5% CO 2 conditions.
4. 실험동물 및 시료투여4. Administration of experimental animals and samples
무모생쥐는 6주령의 수컷 무모쥐(male HR-1, hairless mice, Japan SLC, Inc.)를 중앙실험동물로부터 구입하여 1주 동안 적응시킨 후 사용하였다. 적응기간 중 일반 상태를 관찰하여 건강한 상태의 동물을 시험에 사용하였다. 사육환경은 온도 23±3℃, 습도 50±5%, 명암주기 12시간 (07:00-19:00/조명시간)으로 유지하였다. 시험기간 중 실험동물은 polycarbonate 케이지 (200×320×145 mm, Three-shine Co., Daejeon, Korea)에 군당 6마리로 사육하였고 사료는 마우스 전용사료 5L79 (Charles river, USA)를 자유급이 하였으며, 음수는 자외선으로 소독한 상수도수를 자유 급이하였다. The hairless mice were used after 6 weeks old male hairless mice (male HR-1, hairless mice, Japan SLC, Inc.) were purchased from a central laboratory animal and adapted for 1 week. Healthy animals were used for testing by observing general conditions during the adaptation period. The breeding environment was maintained at a temperature of 23 ± 3 ℃, a humidity of 50 ± 5% and a contrast cycle of 12 hours (07: 00-19: 00 / lighting time). During the test period, 6 animals per group were kept in polycarbonate cages (200 × 320 × 145 mm, Three-shine Co., Daejeon, Korea), and the feed was free of 5L79 (Charles river, USA). , Negative water freely supplied tap water sterilized with ultraviolet rays.
시료투여는 대조군(control), 자외선 처리군(UV-vehicle), 벼메뚜기 추출물(BMG) 투여군으로 총 3개 군으로 나누어 실험을 하였다. 시료투여는 마우스 존대를 이용하여 경구투여를 실시하였다. 투여기간은 총 12주로 주 5일 동안 투여하였다.Sample administration was conducted in three groups: control group, UV-treated group (UV-vehicle), rice locust extract (BMG) administration group. Sample administration was performed by oral administration using a mouse zone. The administration period was a total of 12 weeks for 5 days a week.
5. 자외선조사5. UV irradiation
자외선조사는 대조군을 제외한 실험군에 12주 동안 주 3회 실시하였고, 자외선은 UVB 램프 (Mineralight UV Display lamp, UVP, USA)를 사용하였다. 자외선 조사량은 1-4주간은 60 mJ/cm2, 5-8주는 90 mJ/cm2, 9-12주는 120 mJ/cm2로 12주 동안 조사하였다. 자외선 조사량은 광측정기(Delta OHM, Italy)를 이용하여 광량을 측정한 후 조사시간으로 조절하였다.Ultraviolet irradiation was carried out three times a week for 12 weeks in the experimental group, except for the control group, the UVB lamp (Mineralight UV Display lamp, UVP, USA) was used. UV irradiation dose is 60 mJ / cm 2 for 1-4 weeks, 90 mJ / cm 2 for 5-8 weeks 9-12 weeks were examined at 120 mJ / cm 2 for 12 weeks. The amount of ultraviolet radiation was controlled by the irradiation time after measuring the amount of light using a photometer (Delta OHM, Italy).
6. 피부의 조직학적 분석6. Histological Analysis of Skin
주름억제 효능을 확인하기 위하여, 각 실험군의 피부조직을 적출하여 10% 중성 포르말린 용액에 고정한 후 수세, 탈수, 투명, 침투 과정을 거친 다음 파라핀으로 포매하고 4μM 두께로 절편을 만든 후 Hematoxylin & Eosin (H&E) 염색 및 Masson's trichome 염색을 실시하였다. H&E 염색을 실시한 조직의 케라틴층에서 표피세포 기저막(epidermal basement membrane)까지의 두께를 현미경에 장착된 자를 이용하여 측정하였다. In order to confirm the antiwrinkle effect, skin tissues of each experimental group were extracted, fixed in 10% neutral formalin solution, washed, dehydrated, cleared, and infiltrated, embedded with paraffin, sections were made into 4μM thickness, and then hematoxylin & Eosin ( H & E) staining and Masson's trichome staining were performed. The thickness from the keratin layer of the tissue subjected to H & E staining to the epidermal basement membrane was measured using a microscope mounted on a microscope.
실시예Example 1.  One. 세포생존률Cell survival rate 분석 analysis
상기 배양한 HaCaT 세포에 24시간 동안 각각의 시료를 농도별로 희석하여 처리하고, MTS 어세이(CellTiter Aqueous One Solution Cell proliferation assay kit, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophynyl)-2H-tetrazolium, inner salt; MTS, Promega Co. Madison, WI, USA) 기법으로 세포 생존률을 490nm에서 마이크로플레이트 리더(Molecular Devices, Sunnyvale, CA, USA)로 측정하였다. The cultured HaCaT cells were treated by diluting each sample by concentration for 24 hours, and treated with MTS assay (CellTiter Aqueous One Solution Cell proliferation assay kit, 3- (4,5-dimethylthiazol-2-yl) -5- ( Microcarboxy reader at 490 nm with 3-carboxymethoxyphenyl) -2- (4-sulfophynyl) -2H-tetrazolium, inner salt; MTS, Promega Co. Madison, WI, USA) technique (Molecular Devices, Sunnyvale, CA, USA) Was measured.
그 결과, 아무것도 처리하지 않은 Control군 대비 UVB 조사군에서의 세포생존률이 낮아졌으며, UVB 조사 후, 본 발명의 시료(벼메뚜기 추출물 및 화학식 1~3의 화합물)를 처리하였을 때의 상대적 세포생존률(%)이 다소 증가하였거나 유지했다는 것을 도 1 및 2에 나타내었다. 따라서, 본 발명의 벼메뚜기 추출물 및 화학식 1~3의 화합물은 세포 독성이 거의 없다는 것을 알 수 있었다.As a result, the cell survival rate in the UVB irradiation group was lower than in the control group without any treatment, and after the UVB irradiation, the relative cell survival rate when the sample of the present invention (rice locust extract and the compound of Formulas 1 to 3) was treated. Are increased or maintained somewhat in FIGS. 1 and 2. Therefore, the rice locust extract of the present invention and the compound of Formulas 1 to 3 were found to have little cytotoxicity.
실시예Example 2.  2. MMPMMP -1의 발현량 분석Expression Analysis of -1
HaCaT 세포에 24시간 동안 각각의 시료를 처리하고 자외선(UV Crosslinker, Ultra Lum)을 20mJ/cm2로 조사한 후, MMP-1 ELISA kit(R&D Systems, Inc., Minneapolis, MN, USA)를 이용하여 MMP-1의 발현량을 측정하였다. Each sample was treated with HaCaT cells for 24 hours and irradiated with UV crosslinker (Ultra Lum) at 20 mJ / cm 2 , followed by MMP-1 ELISA kit (R & D Systems, Inc., Minneapolis, MN, USA). The expression level of MMP-1 was measured.
상세하게는 96웰 플레이트에 HaCaT 세포를 도말한 후, 본 발명의 벼메뚜기 추출물 및 화학식 1~3의 화합물을 각각 농도별로 처리하였다. 이후, 자외선(UV) 조사하고, 배양물의 상등액을 수집하고 13,000rpm으로 5분 동안 원심분리하였다. 이후 상등액을 취해 ELISA 키트를 이용한 형광 어세이를 수행하여 MMP-1의 발현량을 정량분석하였다.Specifically, after the HaCaT cells were plated in 96-well plates, the rice locust extract of the present invention and the compounds of Formulas 1 to 3 were each treated by concentration. Thereafter, ultraviolet (UV) irradiation, the culture supernatant was collected and centrifuged for 5 minutes at 13,000 rpm. Then, the supernatant was taken and subjected to fluorescence assay using an ELISA kit to quantitatively analyze the expression level of MMP-1.
그 결과, 도 3 및 4에 개시한 바와 같이 자외선을 조사하지 않은 음성대조군에 비해, 자외선을 조사한 군에서 현저하게 MMP-1의 발현량이 증가한다는 것을 확인하였고, 본 발명의 시료(벼메뚜기 추출물 및 화학식 1~3의 화합물)의 MMP-1의 발현량이 자외선 조사군에 비해 현저하게 감소한다는 것을 확인하였다.As a result, as shown in FIGS. 3 and 4, it was confirmed that the expression level of MMP-1 increased significantly in the group irradiated with ultraviolet rays, compared to the negative control group not irradiated with ultraviolet rays, and the sample of the present invention (rice locust extract and chemical formula). It was confirmed that the expression level of MMP-1 of the compounds 1 to 3 was significantly reduced compared to the ultraviolet irradiation group.
실시예Example 3. 동물 모델의 표피두께 변화에 의한 효능평가 3. Efficacy evaluation by epidermal thickness change of animal model
주름억제 효능을 표피두께 변화측정을 통해서도 확인하였다. 표피두께는 H&E염색을 실시한 조직의 케라틴층에서 표피세포 기저막까지의 두께를 현미경에 장착된 자를 이용하여 두께를 측정하였다. Wrinkle inhibition effect was also confirmed through the measurement of epidermal thickness change. The epidermal thickness was measured by using a microscope equipped with a thickness from the keratin layer of the tissue subjected to H & E staining to the epidermal cell basement membrane.
그 결과 도 5에 개시한 바와 같이, 자외선 조사 시 표피두께가 증가되었다는 것을 확인할 수 있었고, 벼메뚜기 추출물(BMG) 투여군에 의해서 표피두께가 감소하였다는 것을 확인할 수 있었다. As a result, as shown in FIG. 5, it was confirmed that the epidermal thickness was increased during ultraviolet irradiation, and that the epidermal thickness was decreased by the rice locust extract (BMG) administration group.
실시예Example 4. 동물모델의 조직염색에 의한 효능평가 (H&E 염색) 4. Efficacy evaluation by tissue staining of animal model (H & E staining)
자외선으로 유발된 주름억제 효능을 확인하기 위해 무모생쥐의 피부조직을 떼어낸 후 조직염색을 통해서도 확인하였다.In order to confirm the anti-wrinkle effect caused by UV light, skin tissues of hairless mice were removed and confirmed through tissue staining.
그 결과 도 6(A)에 개시한 바와 같이, 자외선 조사군은 대조군에 비해서 각질층이 일어났으며, 표피두께 또한 증가된 것을 확인할 수 있었으나, 벼메뚜기 추출물(BMG) 투여군은 자외선 조사군에 비해서 각질층이 완화되었고, 표피두께 또한 감소함을 확인할 수 있었다. As a result, as shown in FIG. 6 (A), the UV irradiation group had a stratum corneum as compared with the control group, and the epidermal thickness was also increased. However, the rice locust extract (BMG) administration group had a stratum corneum as compared to the UV irradiation group. It was alleviated and the epidermal thickness was also decreased.
실시예Example 5. 조직염색에 의한 효능평가 ( 5. Efficacy evaluation by tissue staining ( Masson'sMasson's trichometrichome 염색)  dyeing)
자외선으로 유발된 주름억제 효능을 확인하기 위해 무모생쥐의 피부조직을 떼어낸 후 콜라겐 조직염색을 통해서도 확인하였다. In order to confirm the anti-wrinkle effect caused by UV light, skin tissues of hairless mice were removed and confirmed through collagen tissue staining.
그 결과 도 6(B)에 개시한 바와 같이, 자외선에 의해서 콜라겐이 감소하였고 본 발명의 벼메뚜기 추출물 처리군에서는 콜라겐의 양이 회복되었다는 것을 확인하였다. As a result, as shown in FIG. 6 (B), collagen was decreased by ultraviolet rays, and the amount of collagen was recovered in the rice locust extract treatment group of the present invention.
실시예Example 6.  6. MMPMMP -1 및 -1 and MMPMMP -9의 발현량 분석Expression Analysis of -9
콜라겐 분해 효소(MMP; matrix metalloproteinases)는 세포외 기질과 기저막의 분해에 관여함으로써, 콜라겐 감소에 영향을 미치는 효소이다. 피부의 주름에 관여하는 MMP-1과 MMP-9의 발현량의 변화를 분석하여 시료가 주름개선 효과가 있는지 여부를 확인하였다. Collagen degrading enzymes (MMPs) are enzymes that affect collagen reduction by participating in the degradation of extracellular matrix and basement membrane. Changes in the expression levels of MMP-1 and MMP-9 involved in skin wrinkles were analyzed to determine whether the sample had an antiwrinkle effect.
그 결과 도 7에 개시한 바와 같이, 자외선 조사에 의해 MMP-1과 MMP-9의 발현량 모두 자외선을 조사하지 않은 세포에 비해 증가하였으며 본 발명의 벼메뚜기 추출물을 처리한 경우 발현량이 감소하는 것을 확인하였다. As a result, as shown in Figure 7, the expression of MMP-1 and MMP-9 by ultraviolet irradiation was increased compared to the cells not irradiated with ultraviolet rays, and the expression level was reduced when the rice locust extract of the present invention treated It was.

Claims (6)

  1. 하기 화학식 1의 화합물 또는 이의 허용가능한 염; 하기 화학식 2의 화합물 또는 이의 허용가능한 염; 하기 화학식 3의 화합물 또는 이의 허용가능한 염; 또는 하기 화학식 1~3의 화합물 중에서 선택된 하나 이상의 화합물을 포함하는 벼메뚜기(Oxya chinensis sinuosa) 추출물을 유효성분으로 함유하는 피부주름의 예방 또는 개선용 건강기능식품 조성물.A compound of Formula 1 or an acceptable salt thereof; A compound of Formula 2 or an acceptable salt thereof; A compound of formula 3 or an acceptable salt thereof; Or rice grasshopper containing one or more compounds selected from compounds of the formula 1 to 3 ( Oxya chinensis sinuosa ) Health functional food composition for the prevention or improvement of skin wrinkles containing the extract as an active ingredient.
    [화학식 1][Formula 1]
    Figure PCTKR2018002501-appb-I000004
    Figure PCTKR2018002501-appb-I000004
    [화학식 2][Formula 2]
    Figure PCTKR2018002501-appb-I000005
    Figure PCTKR2018002501-appb-I000005
    [화학식 3][Formula 3]
    Figure PCTKR2018002501-appb-I000006
    Figure PCTKR2018002501-appb-I000006
  2. 제1항에 있어서, 상기 벼메뚜기 추출물은 물, C1~C4의 저급 알코올 및 이들의 혼합물 중에서 선택된 하나 이상의 용매를 이용하여 추출한 것을 특징으로 하는 피부주름의 예방 또는 개선용 건강기능식품 조성물.[Claim 2] The health functional food composition for preventing or improving skin wrinkles of claim 1, wherein the rice locust extract is extracted using at least one solvent selected from water, C 1 -C 4 lower alcohols, and mixtures thereof.
  3. 제1항에 있어서, 상기 조성물은 MMP-1 또는 MMP-9의 발현을 저해하는 것을 특징으로 하는 피부주름의 예방 또는 개선용 건강기능식품 조성물.The health functional food composition for preventing or improving skin wrinkles according to claim 1, wherein the composition inhibits the expression of MMP-1 or MMP-9.
  4. 제1항에 있어서, 상기 조성물은 분말, 과립, 환, 정제, 캡슐, 캔디, 시럽 및 음료 중에서 선택된 어느 하나의 제형으로 제조되는 것을 특징으로 하는 피부주름의 예방 또는 개선용 건강기능식품 조성물.According to claim 1, wherein the composition is powder, granules, pills, tablets, capsules, candy, syrups and beverages, characterized in that the health functional food composition for preventing or improving skin wrinkles, characterized in that it is prepared.
  5. 하기 화학식 1의 화합물 또는 이의 허용가능한 염; 하기 화학식 2의 화합물 또는 이의 허용가능한 염; 하기 화학식 3의 화합물 또는 이의 허용가능한 염; 또는 하기 화학식 1~3의 화합물 중에서 선택된 하나 이상의 화합물을 포함하는 벼메뚜기(Oxya chinensis sinuosa) 추출물을 유효성분으로 함유하는 피부주름의 예방 또는 치료용 약학 조성물.A compound of Formula 1 or an acceptable salt thereof; A compound of Formula 2 or an acceptable salt thereof; A compound of formula 3 or an acceptable salt thereof; Or rice grasshopper containing one or more compounds selected from compounds of the formula 1 to 3 ( Oxya chinensis sinuosa ) A pharmaceutical composition for preventing or treating skin wrinkles containing the extract as an active ingredient.
    [화학식 1][Formula 1]
    Figure PCTKR2018002501-appb-I000007
    Figure PCTKR2018002501-appb-I000007
    [화학식 2][Formula 2]
    Figure PCTKR2018002501-appb-I000008
    Figure PCTKR2018002501-appb-I000008
    [화학식 3][Formula 3]
    Figure PCTKR2018002501-appb-I000009
    Figure PCTKR2018002501-appb-I000009
  6. 제5항에 있어서, 상기 유효성분 이외에 약학적으로 허용되는 담체, 부형제 또는 희석제를 추가로 포함하는 것을 특징으로 하는 피부주름의 예방 또는 치료용 약학 조성물.6. The pharmaceutical composition for preventing or treating skin wrinkles according to claim 5, further comprising a pharmaceutically acceptable carrier, excipient or diluent in addition to the active ingredient.
PCT/KR2018/002501 2017-02-28 2018-02-28 Composition, containing oxya chinensis sinuosa extract or compound isolated therefrom as active ingredient, for prevention, relief, or treatment of skin wrinkles WO2018160021A1 (en)

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