KR102075482B1 - A composition for preventing or treating vasculitis comprising lignans from extract of Forsythia koreana flower - Google Patents
A composition for preventing or treating vasculitis comprising lignans from extract of Forsythia koreana flower Download PDFInfo
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- KR102075482B1 KR102075482B1 KR1020180128368A KR20180128368A KR102075482B1 KR 102075482 B1 KR102075482 B1 KR 102075482B1 KR 1020180128368 A KR1020180128368 A KR 1020180128368A KR 20180128368 A KR20180128368 A KR 20180128368A KR 102075482 B1 KR102075482 B1 KR 102075482B1
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- koreanaside
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Abstract
Description
본 발명은 개나리 꽃 추출물 유래 리그난을 포함하는 혈관 염증 질환 예방 또는 치료용 조성물에 관한 것으로, 구체적으로 코리아나사이드 A를 포함하는 혈관 염증 질환 예방 또는 치료용 약학 조성물; 혈관 염증 질환 예방 또는 개선용 건강기능식품 및 코리아나사이드 A를 인간을 제외한 개체에 투여하는 단계를 포함하는 혈관 염증 질환 예방 또는 치료방법에 관한 것이다.The present invention relates to a composition for preventing or treating vascular inflammatory diseases, including lignan from forsythia flower extract, specifically, a pharmaceutical composition for preventing or treating vascular inflammatory diseases, including koreanaside A; The present invention relates to a method for preventing or treating vascular inflammatory disease, and the step of administering Coreanaside A to an individual except a human.
동맥경화와 같은 혈관질환의 초기병변은 주로 혈관내피세포의 염증반응이 원인이 되고 있다(Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999 Jan 14;340(2):115-26). 정상 혈관내피세포들은 염증세포와 상호작용이 일어나지 않고 혈류를 따라 흘러갈 뿐이므로 혈관벽과의 접촉이 거의 일어나지 않는 반면, 혈관내피세포에 염증이 일어나면, 염증세포와 상호작용이 일어나 염증세포가 혈관벽에 달라붙어 염증반응이 일어나게 된다. 초기 동맥 염증 과정에서, 병원체(pathogen), 산화 지질 또는 종양괴사인자(TNF)-α, 인터루킨(IL)-1/3 및 IL-6와 같은 사이토카인을 비롯한 다양한 자극에 의해 내피세포가 활성화되며, 이후 연속적으로 순환하는 단핵구가 플라그-형성 병소(foci)로 되는 것을 증가시키는 특정 부착 수용체인 VCAM-1(Vascular cell adhesion protein-1) 단백질의 발현을 유도한다. 염증이 생긴 혈관내피세포에서 롤링(rolling) 및 부착된 단핵구는 연속적으로 전이되어, 결과적으로 혈관벽을 통해 삼출(diapedesis)된다. 이러한 혈관염증반응에서의 주요 매개체로 알려진 VCAM-1의 발현을 억제하는 물질은 염증으로 인한 혈관질환의 치료물질로 활용되고 있다(Preiss DJ, Sattar N. Vascular cell adhesion molecule-1: a viable therapeutic target for atherosclerosis; Int J Clin Pract. 2007 Apr;61(4):697-701). 혈관염증에 의해 야기되는 혈관염증질환으로는 동맥경화증, 고혈압, 협심증, 심근경색, 허혈성 심장질환, 심부전, 경혈관 동맥 성형술 후 발생하는 합병증, 뇌경색, 뇌출혈 및 뇌졸중을 예로 들 수 있다.Early lesions of atherosclerosis, such as arteriosclerosis, are mainly caused by the inflammatory response of vascular endothelial cells (Ross R. Atherosclerosis--an inflammatory disease.N Engl J Med. 1999 Jan 14; 340 (2): 115-26 ). Normal vascular endothelial cells do not interact with the inflammatory cells and flow along the bloodstream, so there is little contact with the vascular wall. Inflammation of the vascular endothelial cells causes interaction with the inflammatory cells, causing the inflammatory cells to interact with the vascular wall. It will stick and cause an inflammatory reaction. During early arterial inflammation, endothelial cells are activated by various stimuli, including cytokines such as pathogens, oxidized lipids or tumor necrosis factor (TNF) -α, interleukin (IL) -1/3, and IL-6. Induced expression of Vascular Cell Adhesion Protein-1 (VCAM-1) protein, a specific adhesion receptor that then increases the successive circulating monocytes into plaque-forming foci. In inflamed vascular endothelial cells, rolling and adhered monocytes are metastasized continuously, resulting in diapedesis through the vascular wall. A substance that inhibits the expression of VCAM-1, which is known as a major mediator in this inflammatory response, has been used as a therapeutic agent for vascular diseases caused by inflammation (Preiss DJ, Sattar N. Vascular cell adhesion molecule-1: a viable therapeutic target for atherosclerosis; Int J Clin Pract. 2007 Apr; 61 (4): 697-701). Vascular inflammatory diseases caused by vasculitis include atherosclerosis, hypertension, angina pectoris, myocardial infarction, ischemic heart disease, heart failure, complications after cerebral angioplasty, cerebral infarction, cerebral hemorrhage and stroke.
한편, 개나리(Forsythia koreana)는 쌍떡잎식물 용담목 물푸레나무과의 낙엽 관목으로, 이의 뿌리, 줄기, 잎, 열매 등이 약용으로 사용되고 있다. 특히, 개나리 열매는 연교로 불리며 한방에서는 한열, 발열, 화농성질환, 림프선염, 소변불리, 종기, 신장염, 습진 등에 처방되고 있으며, 다양한 약용 성분이 포함되어 있다고 알려져 있다. 다만, 약리 활성 규명에 대한 대부분의 연구가 연교에 집중되어 있어, 개나리의 다른 부위에 대한 활발한 연구가 필요한 실정이다.On the other hand, Forsythia koreana is a deciduous shrub of the dicotyledonous genus Aureaceae , whose roots, stems, leaves, and fruits are used for medicinal purposes. In particular, forsythia fruit is called Yeon-kyo and is prescribed in cold, fever, purulent diseases, lymphadenitis, urinary tract, boil, nephritis, eczema, and is known to contain various medicinal ingredients. However, most of the research on pharmacological activity has been concentrated in the Fellowship, and active research on other parts of forsythia is necessary.
이러한 배경하에, 본 발명자들은 혈관 염증 질환을 치료하기 위한 조성물을 개발하기 위해 연구한 결과, 개나리 꽃 추출물 유래 리그난, 특히 코리아나사이드 A가 혈관 염증 질환에 관여하는 인자인 VCAM-1에 대한 발현 억제 효과가 우수함을 확인함으로써, 본 발명을 완성하였다.Against this background, the present inventors have studied to develop a composition for treating vascular inflammatory diseases. As a result, the lignans from forsythia flower extract, especially Koreanaside A, have an inhibitory effect on expression of VCAM-1, a factor involved in vascular inflammatory diseases. By confirming the superiority, the present invention was completed.
본 발명의 하나의 목적은 코리아나사이드 A를 포함하는 혈관 염증 예방 또는 치료용 약학 조성물을 제공하는 것이다.One object of the present invention is to provide a pharmaceutical composition for preventing or treating vascular inflammation comprising Coreanaside A.
본 발명의 다른 하나의 목적은 코리아나사이드 A를 포함하는 혈관 염증 예방 또는 개선용 건강기능식품을 제공하는 것이다.It is another object of the present invention to provide a health functional food for preventing or improving vascular inflammation, including Koreanaside A.
본 발명의 또 다른 하나의 목적은 코리아나사이드 A를 인간을 제외한 개체에 투여하는 단계를 포함하는 혈관 염증 예방 또는 치료방법을 제공하는 것이다.Yet another object of the present invention is to provide a method for preventing or treating vascular inflammation, comprising administering Koreanaside A to a subject other than a human.
상기 목적을 달성하기 위해, 본 발명의 하나의 양태는 코리아나사이드 A를 포함하는 혈관 염증 예방 또는 치료용 약학 조성물을 제공한다.In order to achieve the above object, one embodiment of the present invention provides a pharmaceutical composition for preventing or treating vascular inflammation, including the corenaside A.
본 발명에서 용어, "코리아나사이드 A(koreanaside A)"는 하기 화학식 1로 표시되는 것일 수 있다. 코리아나사이드 A는 기존에 공지되지 않은 신규한 화합물로서, 그 구조는 물론 개나리 꽃에 존재하는 것 또한 본 발명자들에 의해 처음으로 규명되었다.In the present invention, the term "Koreanaside A (koreanaside A)" may be represented by the following formula (1). Coreanaside A is a novel compound that has not been previously known, and its structure as well as what is present in forsythia flowers has also been first identified by the present inventors.
[화학식 1][Formula 1]
본 발명에 따른 상기 코리아나사이드 A는 개나리 꽃 추출물 유래 리그난일 수 있다.The Koreanaside A according to the present invention may be a lignan derived from forsythia flower extract.
본 발명에서 용어, "개나리 꽃"은 개나리(Forsythia koreana)의 꽃을 의미한다. 상기 개나리 꽃의 추출물이 항산화 효과가 있음은 공지된 바 있으나, 혈관 염증 치료 효과에 대해서는 공지된 바 없으며, 본 발명자들에 의해 최초로 규명되었다.In the present invention, the term "forsythia flower" means a flower of forsythia ( Forsythia koreana ). Although it is known that the extract of the forsythia flower has an antioxidant effect, it is not known about the vascular inflammation treatment effect, it was first identified by the present inventors.
상기 개나리 꽃은 상업적으로 판매되는 것을 구입하거나, 자연에서 채취 또는 재배된 것을 사용할 수 있다.The forsythia flowers may be purchased commercially, or may be used for harvested or grown in nature.
본 발명에서 용어, "추출물"은 상기 개나리 꽃을 추출 처리하여 얻어지는 추출액, 상기 추출액의 희석액이나 농축액, 상기 추출액을 건조하여 얻어지는 건조물, 상기 추출액의 조정제물이나 정제물, 또는 이들의 혼합물 등, 추출액 자체 및 추출액을 이용하여 형성 가능한 모든 제형의 추출물을 포함한다.As used herein, the term "extract" refers to an extract obtained by extracting the forsythia flower, a diluent or concentrate of the extract, a dried product obtained by drying the extract, a crude or purified product of the extract, or a mixture thereof. Extracts of all formulations that can be formed using itself and extracts.
상기 개나리 꽃을 추출하는 방법은 특별히 제한되지 않으며, 당해 기술 분야에서 통상적으로 사용하는 방법에 따라 추출할 수 있다. 상기 추출 방법의 비제한적인 예로는, 열수 추출법, 초음파 추출법, 여과법, 환류 추출법 등을 들 수 있으며, 이들은 단독으로 수행되거나 2종 이상의 방법을 병용하여 수행될 수 있다.The method of extracting the forsythia flower is not particularly limited and may be extracted according to a method commonly used in the art. Non-limiting examples of the extraction method, hot water extraction method, ultrasonic extraction method, filtration method, reflux extraction method and the like, these may be performed alone or in combination of two or more methods.
또한, 상기 개나리 꽃을 추출하는데 사용되는 추출 용매의 종류는 특별히 제한되지 않으며, 당해 기술 분야에서 공지된 임의의 용매를 사용할 수 있다. 상기 추출 용매의 비제한적인 예로는 물, 탄소수 1 내지 4의 알코올 또는 이들의 혼합 용매 등을 들 수 있으며, 이들은 단독으로 사용되거나 1종 이상 혼합하여 사용될 수 있다. 구체적으로, 메탄올 또는 에탄올 수용액이 사용될 수 있으며, 상기 메탄올 또는 에탄올 수용액은 70 내지 90%(v/v), 더욱 구체적으로 75 내지 85%(v/v), 가장 구체적으로 80%(v/v) 메탄올 또는 에탄올일 수 있지만, 이에 제한되지 않는다.In addition, the type of extraction solvent used to extract the forsythia flower is not particularly limited, and any solvent known in the art may be used. Non-limiting examples of the extraction solvent may include water, alcohols having 1 to 4 carbon atoms or mixed solvents thereof, and these may be used alone or in combination of one or more thereof. Specifically, methanol or ethanol aqueous solution may be used, the methanol or ethanol aqueous solution is 70 to 90% (v / v), more specifically 75 to 85% (v / v), most specifically 80% (v / v ) Methanol or ethanol, but is not limited thereto.
상기 리그난은 개나리 꽃 추출물을 물, 탄소수 1 내지 4의 알코올 등의 극성 용매; 헥산(Hexane), 에틸 아세테이트(Ethyl acetate) 등의 비극성 용매; 또는 이들의 혼합용매로 분획하여 수득한 분획물일 수 있다.The lignan is forsythia flower extract water, a polar solvent such as alcohol having 1 to 4 carbon atoms; Nonpolar solvents such as hexane (Hexane) and ethyl acetate; Or a fraction obtained by fractionation with a mixed solvent thereof.
본 발명에서 용어, "분획물"은 여러 다양한 구성 성분들을 포함하는 혼합물로부터 특정 성분 또는 특정 성분 그룹을 분리하기 위하여 분획을 수행하여 얻어진 결과물을 의미한다.As used herein, the term "fraction" refers to the result obtained by performing the fractionation to separate a specific component or a specific component group from a mixture comprising various various components.
상기 분획물을 얻는 분획 방법은 특별히 제한되지 않으며, 당해 기술 분야에서 통상적으로 사용하는 방법에 따라 수행될 수 있다. 상기 분획 방법의 비제한적인 예로는, 다양한 용매를 처리하여 수행하는 용매 분획법, 일정한 분자량 컷-오프 값을 갖는 한외 여과막을 통과시켜 수행하는 한외여과 분획법, 다양한 크로마토그래피(크기, 전하, 소수성 또는 친화성에 따른 분리를 위해 제작된 것)를 수행하는 크로마토그래피 분획법, 및 이들의 조합 등이 있다. The fractionation method of obtaining the fractions is not particularly limited and may be performed according to a method commonly used in the art. Non-limiting examples of the fractionation method include a solvent fractionation method performed by treating various solvents, an ultrafiltration fractionation method performed through an ultrafiltration membrane having a constant molecular weight cut-off value, and various chromatography (size, charge, hydrophobicity). Or a chromatographic fractionation method for performing separation according to affinity), and combinations thereof.
또한, 상기 분획물을 얻는데 사용되는 분획 용매의 종류는 당해 기술 분야에서 공지된 임의의 용매를 사용할 수 있다. 상기 분획 용매의 비제한적인 예로는 물, 탄소수 1 내지 4의 알코올 등의 극성 용매; 헥산(Hexane), 에틸 아세테이트(Ethyl acetate) 등의 비극성 용매; 또는 이들의 혼합용매 등을 들 수 있다. 이들은 단독으로 사용되거나 1종 이상 혼합하여 사용될 수 있지만, 이에 제한되지 않는다. 구체적으로, 물, 메탄올, 부탄올, 헥산, 에틸아세테이트 또는 이들의 혼합용매가 사용될 수 있다.In addition, as the type of fractionation solvent used to obtain the fraction, any solvent known in the art may be used. Non-limiting examples of the fractionation solvents include polar solvents such as water and alcohols having 1 to 4 carbon atoms; Nonpolar solvents such as hexane (Hexane) and ethyl acetate; Or these mixed solvents etc. are mentioned. These may be used alone or in combination of one or more, but are not limited thereto. Specifically, water, methanol, butanol, hexane, ethyl acetate or a mixed solvent thereof may be used.
구체적으로 상기 분획물은 개나리 꽃 추출물을 부탄올을 포함하는 용매로 제1분획하고, 물을 포함하는 용매로 제2분획한 후, 메탄올을 포함하는 용매로 제3분획, 아세톤을 포함하는 용매로 제4분획을 수행한 후, 물을 포함하는 용매로 제5분획하여 수득할 수 있다. 또한, 상기 제1분획 내지 제5분획은 3회 내지 5회, 구체적으로 4회 반복 수행될 수 있다.Specifically, the fraction is the first fraction of the forsythia flower extract with a solvent containing butanol, the second fraction with a solvent containing water, and then the third fraction with a solvent containing methanol, the fourth fraction as a solvent containing acetone After fractionation may be carried out by a fifth fraction with a solvent comprising water. In addition, the first to fifth fractions may be repeated three to five times, specifically four times.
이때, 상기 제1분획은 부탄올 분획물일 수 있고, 상기 제2분획은 클로로포름, 메탄올 및 물로 구성된 용매로 분획 후 에틸아세테이트, 부탄올 및 물로 구성된 용매로 재분획하여 수득된 물 분획물일 수 있으며, 상기 제3분획은 클로로포름, 메탄올 및 물로 구성된 용매로 분획하여 수득된 메탄올 분획물일 수 있고, 상기 제4분획은 아세톤 및 물로 구성된 용매로 분획하여 수득된 아세톤 분획물일 수 있으며, 상기 제5분획은 아세톤, 메탄올 및 물로 구성된 용매로 분획하여 수득된 물 분획물일 수 있다.In this case, the first fraction may be a butanol fraction, the second fraction may be a water fraction obtained by fractionation with a solvent consisting of chloroform, methanol and water and then re-fractionation with a solvent consisting of ethyl acetate, butanol and water. The third fraction may be a methanol fraction obtained by fractionation with a solvent consisting of chloroform, methanol and water, and the fourth fraction may be an acetone fraction obtained by fractionation with a solvent consisting of acetone and water, and the fifth fraction is acetone, methanol And it may be a water fraction obtained by fractionation with a solvent consisting of water.
본 발명의 일 실시예에서는, 건조한 개나리 꽃을 80% 메탄올을 이용하여 개나리 꽃 추출물을 수득하였고, 상기 추출물을 부탄올로 분획하여 부탄올 분획물인 제1분획을 수득하였으며, 상기 제1분획을 클로로포름, 메탄올 및 물로 구성된 용매로 분획 후 에틸아세테이트, 부탄올 및 물로 구성된 용매로 재분획하여 제2분획을 수득하였다. 또한, 상기 제2분획을 클로로포름, 메탄올 및 물로 구성된 용매로 분획하여 제3분획을 수득하였고, 상기 제3분획을 아세톤 및 물로 구성된 용매로 분획하여 제4분획을 수득한 후, 상기 제4분획을 아세톤, 메탄올 및 물로 구성된 용매로 분획하여 제5분획을 수득하였다.In an embodiment of the present invention, the forsythia flower extract was obtained using 80% methanol of dried forsythia flowers, and the extract was fractionated with butanol to obtain a first fraction, a butanol fraction, wherein the first fraction was chloroform and methanol. And fractionated with a solvent consisting of water and then repartitioned with a solvent consisting of ethyl acetate, butanol and water to obtain a second fraction. In addition, the second fraction was partitioned with a solvent consisting of chloroform, methanol, and water to obtain a third fraction, and the third fraction was fractionated with a solvent consisting of acetone and water to obtain a fourth fraction, and then, the fourth fraction was separated. Fractionation with a solvent consisting of acetone, methanol and water gave a fifth fraction.
본 발명에서 용어, "리그난(lignan)"은 식물에서 발견되는 폴리페놀(polyphenol)의 일부로서, 에스트로겐과 유사한 화학구조로 콜레스테롤에서 합성되는 스테로이드 화합물이다. 55개 이상의 식물군에 존재하며 항생제와 병원균 및 박테리아에 대한 방어 분자로 작용한다. 리그난은 피토에스트로겐(phytoestrogen)의 일종으로, 에스트로겐과 유사한 역할을 하는 식물성 에스트로겐이다. 리그난은 섬유층 밑에 있는 단일 세포층으로 섬유소와 단단히 결합되어 있는 과실의 껍질에 풍부하다. 인체에서 역학 및 생리학 연구 결과에 따르면 리그난은 제II형 당뇨병과 암 예방에 긍정적인 효과를 나타낼 수 있고 에스트로겐 관련된 암을 발생률을 감소시킬 수 있다. 또한 인체의 골다공증을 감소하거나 예방할 수 있다. 리그난의 종류에는 엔트리리그난 (enterlignan), 엔테디올(enterodiol)과 엔테로락톤(enterolactone)이 있다.As used herein, the term "lignan" is a part of polyphenols found in plants and is a steroid compound synthesized in cholesterol with a chemical structure similar to estrogen. It is found in over 55 plant groups and acts as a defense molecule against antibiotics, pathogens and bacteria. Lignan is a type of phytoestrogen, a phytoestrogen that plays a role similar to estrogen. Lignan is a single cell layer underneath the fibrous layer that is abundant in the skin of the fruit, tightly bound to fibrin. Epidemiological and physiological studies in the human body show that lignans can have a positive effect on the prevention of type II diabetes and cancer and reduce the incidence of estrogen-related cancers. It can also reduce or prevent osteoporosis in the human body. Types of lignans include enterlignan, enterodiol and enterolactone.
본 발명에서 용어, "혈관 염증 질환"은 혈관벽의 염증과 이에 따른 조직 손상을 특징으로 하는 질환을 의미한다. 혈관벽에 염증이 발생하면 이 혈관을 통해 영양 공급을 받던 조직에도 허혈이 일어나 결국 조직 손상이 발생된다. 신체 내 모든 형태의 혈관과 모든 장기의 혈관이 침범될 수 있으므로 침범된 혈관의 위치와 특성에 따라 증상 및 증후가 매우 다양하게 나타난다. 기저 질환 없이 원발성으로 발생하는 경우도 있고 류마티스 관절염이나 전신 홍반 루프스 같은 류마티스 질환과 동반되어 이차적으로 발생할 수도 있다.As used herein, the term "vascular inflammatory disease" means a disease characterized by inflammation of the blood vessel wall and thus tissue damage. Inflammation of the vessel wall causes ischemia in tissues that have been fed through the vessels, resulting in tissue damage. Since all types of blood vessels and blood vessels of all organs can be invaded, the symptoms and symptoms vary according to the location and characteristics of the involved vessels. It may occur primary without underlying disease, or secondary with rheumatic arthritis such as rheumatoid arthritis or systemic lupus erythematosus.
상기 혈관 염증 질환은 이에 제한되지 않으나, 동맥경화증, 고혈압, 협심증, 심근경색, 허혈성 심장질환, 심부전, 경혈관 동맥 성형술 후 발생하는 합병증, 뇌경색, 뇌출혈 및 뇌졸중일 수 있다.The vascular inflammatory disease is not limited thereto, but may be atherosclerosis, hypertension, angina pectoris, myocardial infarction, ischemic heart disease, heart failure, complications arising after angioplasty, angioplasty, cerebral infarction, cerebral hemorrhage and stroke.
상기 혈관 염증 예방 또는 치료는 VCAM-1의 발현을 억제함으로써 달성되는 것일 수 있다.The prevention or treatment of vascular inflammation may be achieved by inhibiting the expression of VCAM-1.
본 발명의 구체적인 일 실시예에서는, 마우스 혈관 평활근 (MOVAS) 세포주에 개나리 꽃 추출물 유래 리그난을 처리한 후, TNF-α에 의해 유도된 혈관 세포 부착 분자-1 (VCAM-1) 발현에 대한 억제 효과를 확인한 결과, 코리아나사이드 A가 VCAM-1의 발현을 효과적으로 억제함을 확인하였다 (도 3).In one specific embodiment of the present invention, after treatment of forsythia flower extract-derived lignan to mouse vascular smooth muscle (MOVAS) cell line, the inhibitory effect on the expression of vascular cell adhesion molecule-1 (VCAM-1) induced by TNF-α As a result, it was confirmed that Koreanaside A effectively inhibited the expression of VCAM-1 (FIG. 3).
본 발명에서 용어, "예방"은 본 발명에 따른 개나리 꽃 추출물 유래 리그난을 포함하는 조성물의 투여로 혈관 염증의 증상을 억제 또는 지연시키는 모든 행위를 말한다.As used herein, the term "prevention" refers to any action that inhibits or delays the symptoms of vascular inflammation by administration of a composition comprising lignans derived from forsythia flower extract according to the present invention.
본 발명에서 용어, "치료"는 본 발명에 따른 개나리 꽃 추출물 유래 리그난을 포함하는 조성물의 투여로 상기 혈관 염증의 증상이 호전되거나 이롭게 변경되는 모든 행위를 말한다.As used herein, the term "treatment" refers to any action in which a symptom of vascular inflammation is improved or beneficially changed by administration of a composition comprising forsythia flower extract-derived lignans.
본 발명에서 사용된 용어 "약학 조성물"이란, 질병의 예방 또는 치료를 목적으로 제조된 것을 의미하며, 각각의 통상의 방법에 따라 다양한 형태로 제형화하여 사용될 수 있다. 예컨대, 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽 등의 제형으로 제형화할 수 있고, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 구체적으로, 점안투여하기 적합한 형태, 예를 들어, 점안제, 크림제, 연고제, 겔제 또는 로션제로 제형화하여 사용될 수 있다.As used herein, the term "pharmaceutical composition" means that is prepared for the purpose of preventing or treating a disease, and can be used by formulating in various forms according to each conventional method. For example, it may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, and the like, and may be used in the form of external preparations, suppositories, and sterile injectable solutions. In particular, it may be used in a form suitable for topical administration, for example, eye drops, creams, ointments, gels or lotions.
본 발명의 용어, "약학적으로 허용가능한 염"은 양이온과 음이온이 정전기적 인력에 의해 결합하고 있는 물질인 염 중에서도 약제학적으로 사용될 수 있는 형태의 염을 의미하며, 통상적으로 금속염, 유기염기와의 염, 무기산과의 염, 유기산과의 염, 염기성 또는 산성 아미노산과의 염 등이 될 수 있다. 예를 들어, 금속염으로는 알칼리 금속염(나트륨염, 칼륨염 등), 알칼리 토금속염(칼슘염, 마그네슘염, 바륨염 등), 알루미늄염 등이 될 수 있고; 유기염기와의 염으로는 트리에틸아민, 피리딘, 피콜린, 2,6-루티딘, 에탄올아민, 디에탄올아민, 트리에탄올아민, 시클로헥실아민, 디시클로헥실아민, N,N-디벤질에틸렌디아민 등과의 염이 될 수 있으며; 무기산과의 염으로는 염산, 브롬화수소산, 질산, 황산, 인산 등과의 염이 될 수 있고; 유기산과의 염으로는 포름산, 아세트산, 트리플루오로아세트산, 프탈산, 푸마르산, 옥살산, 타르타르산, 말레인산, 시트르산, 숙신산, 메탄술폰산, 벤젠술폰산, p-톨루엔술폰산 등과의 염이 될 수 있으며; 염기성 아미노산과의 염으로는 아르기닌, 라이신, 오르니틴 등과의 염이 될 수 있고; 산성 아미노산과의 염으로는 아스파르트산, 글루탐산 등과의 염이 될 수 있다.As used herein, the term “pharmaceutically acceptable salts” refers to salts that can be used pharmaceutically, even among salts in which cations and anions are bonded by electrostatic attraction. Salts, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. For example, the metal salt may be an alkali metal salt (sodium salt, potassium salt, etc.), alkaline earth metal salt (calcium salt, magnesium salt, barium salt, etc.), aluminum salt, or the like; Salts with organic bases include triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N-dibenzylethylenediamine Salts and the like; Salts with inorganic acids may be salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like; Salts with organic acids can be salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like; Salts with basic amino acids can be salts with arginine, lysine, ornithine and the like; Salts with acidic amino acids can be salts with aspartic acid, glutamic acid and the like.
본 발명의 약학 조성물은 조성물 총 중량에 대하여 코리아나사이드 A 또는 이의 약학적으로 허용가능한 염을 0.01 내지 80%, 구체적으로 0.01 내지 70%, 더욱 구체적으로 0.01 내지 60 중량%로 포함할 수 있으나, 치매 예방 또는 치료 효과를 나타내는 한, 이에 제한되지 않는다.The pharmaceutical composition of the present invention may include Koreannaside A or a pharmaceutically acceptable salt thereof in an amount of 0.01 to 80%, specifically 0.01 to 70%, and more specifically 0.01 to 60% by weight, based on the total weight of the composition. As long as it shows a prophylactic or therapeutic effect, it is not limited to this.
상기 본 발명의 조성물은, 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 또는 희석제를 추가로 포함하는 창상 예방 또는 치료용 약학 조성물의 형태로 제조될 수 있는데, 상기 담체는 비자연적 담체(non-naturally occuring carrier)를 포함할 수 있다. The composition of the present invention may be prepared in the form of a pharmaceutical composition for preventing or treating wounds further comprising a suitable carrier, excipient or diluent commonly used in the manufacture of the pharmaceutical composition, wherein the carrier is an unnatural carrier ( non-naturally occuring carriers).
본 발명에서, 상기 약학 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.In the present invention, carriers, excipients and diluents which may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, Calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 상엽 추출물과 이의 분획물들에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는 데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and the solid preparations include at least one excipient such as starch, calcium carbonate, and the like in the above extracts and fractions thereof. , Sucrose or lactose, gelatin and the like are mixed and prepared. In addition to simple excipients, lubricants such as magnesium styrate and talc are also used. Liquid preparations for oral use may include various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used to include suspensions, solutions, emulsions, and syrups. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
본 발명의 약학 조성물은 목적하는 방법에 따라 경구, 비경구, 직장, 국소, 경피, 정맥 내, 근육 내, 복강 내, 피하 등으로 투여할 수 있으며, 약학 조성물의 유효성분은 투여받을 대상의 연령, 성별, 체중, 병리 상태 및 그 심각도, 투여 경로 또는 처방자의 판단에 따라 달라질 것이다. 이러한 인자에 기초한 적용량 결정은 당업자의 수준 내에 있으며, 이의 1일 투여 용량은 예를 들어 0.1 mg/g/일 내지 100 mg/g/일, 보다 구체적으로는 5 mg/g/일 내지 50 mg/g/일이 될 수 있고, 본 발명의 조성물의 투여빈도는 특별히 이에 제한되지 않으나, 1일 1회 투여하거나 또는 용량을 분할하여 수회 투여할 수 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.The pharmaceutical composition of the present invention may be administered orally, parenterally, rectally, topically, transdermally, intravenously, intramuscularly, intraperitoneally, subcutaneously, etc. according to the desired method, and the active ingredient of the pharmaceutical composition may be administered to the age of the subject to be administered. , Sex, weight, pathology and severity, route of administration or prescriber's judgment. Dosage determination based on these factors is within the level of one of skill in the art and its daily dosage may be, for example, from 0.1 mg / g / day to 100 mg / g / day, more specifically from 5 mg / g / day to 50 mg / day. g / day, and the frequency of administration of the composition of the present invention is not particularly limited, but may be administered once a day or several times in divided doses. The dosage does not limit the scope of the invention in any aspect.
본 발명의 다른 하나의 양태는, 개나리 꽃 추출물 유래 리그난을 포함하는 혈관 염증 예방 또는 개선용 건강기능식품을 제공한다.Another aspect of the present invention provides a dietary supplement for preventing or improving vascular inflammation, including lignans from forsythia flower extract.
본 발명에서 용어, "개나리 꽃", "추출물", "리그난", "혈관 염증"은 상기에서 설명한 바와 같다.In the present invention, the terms "forsythia flower", "extract", "lignan", "vascular inflammation" are as described above.
건강기능식품 (functional food)이란, 특정보건용 식품 (food for special health use, FoSHU)과 동일한 용어로, 영양 공급 외에도 생체조절기능이 효율적으로 나타나도록 가공된 의학, 의료효과가 높은 식품을 의미하는데, 상기 식품은 암 전이 억제에 유용한 효과를 얻기 위하여 정제, 캡슐, 분말, 과립, 액상, 환 등의 다양한 형태로 제조될 수 있다.Functional food is the same term as food for special health use (FOSHU), and refers to foods with high medical and medical effects that are processed to show efficient bioregulatory functions in addition to nutrition. In addition, the food may be prepared in various forms such as tablets, capsules, powders, granules, liquids, pills, etc. in order to obtain useful effects in inhibiting cancer metastasis.
본 발명의 건강기능식품은 식품학적으로 허용가능한 담체를 추가로 포함하는 것일 수 있다.The dietary supplement of the present invention may further comprise a food acceptable carrier.
본 발명의 개나리 꽃 추출물 유래 리그난을 포함하는 조성물을 첨가할 수 있는 식품의 종류에는 별다른 제한이 없으며, 예를 들어 각종 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있다. 상기 식품 조성물에는 혈관 염증 치료 효과에 방해가 되지 않는 다른 성분을 추가할 수 있으며, 그 종류는 특별히 제한되지 않는다. 예를 들어, 통상의 식품과 같이 여러 가지 생약 추출물, 식품학적으로 허용가능한 식품보조첨가제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다.There is no restriction | limiting in particular in the kind of food which can add the composition containing the lignan derived from forsythia flower extract of this invention, For example, there are various beverages, gum, tea, a vitamin complex, a health supplement, etc. The food composition may be added to other ingredients that do not interfere with the vascular inflammation treatment effect, the kind is not particularly limited. For example, various herbal extracts, food acceptable additives, natural carbohydrates, and the like may be contained as additional ingredients, such as conventional foods.
상기 식품보조첨가제는 각 제형의 건강기능식품을 제조하는데 첨가되는 것으로서 당업자가 적절히 선택하여 사용할 수 있다. 예를 들어 여러 가지 영양제, 비타민, 광물 (전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등이 포함되지만, 상기 예들에 의해 그 종류가 제한되는 것은 아니다.The food supplement additive is added to prepare the health functional food of each formulation can be used by those skilled in the art as appropriate. For example, various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic and natural flavors, colorants and fillers, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters , Stabilizers, preservatives, glycerin, alcohols, carbonation agents used in the carbonated beverage, and the like, but the kind is not limited by the above examples.
이때, 상기 식품에 포함되는 추출물의 함량은 특별히 이에 제한되지 않으나, 식품 조성물의 총 중량에 대하여 0.01 내지 100 중량%, 보다 바람직하게는 1 내지 80 중량%로 포함될 수 있다. At this time, the content of the extract contained in the food is not particularly limited, but may be included in 0.01 to 100% by weight, more preferably 1 to 80% by weight relative to the total weight of the food composition.
식품이 음료인 경우에는 100 ㎖를 기준으로 1 내지 30 g, 바람직하게는 3 내지 20 g의 비율로 포함될 수 있다. 또한, 상기 조성물은 식품 조성물에 통상 사용되어 냄새, 맛, 시각 등을 향상시킬 수 있는 추가 성분을 포함할 수 있다. 예를 들어, 비타민 A, C, D, E, B1, B2, B6, B12, 니아신 (niacin), 비오틴 (biotin), 폴레이트 (folate), 판토텐산 (panthotenic acid) 등을 포함할 수 있다. 또한, 아연 (Zn), 철 (Fe), 칼슘 (Ca), 크롬 (Cr), 마그네슘 (Mg), 망간 (Mn), 구리 (Cu) 등의 미네랄을 포함할 수 있다. 또한, 라이신, 트립토판, 시스테인, 발린 등의 아미노산을 포함할 수 있다. 또한, 방부제 (소르빈산 칼륨, 벤조산나트륨, 살리실산, 데히드로초산나트륨 등), 살균제 (표백분과 고도 표백분, 차아염소산나트륨 등), 산화방지제 (부틸히드록시아니졸 (BHA), 부틸히드록시톨류엔 (BHT) 등), 착색제 (타르색소 등), 발색제 (아질산 나트륨, 아초산 나트륨 등), 표백제 (아황산나트륨), 조미료 (MSG 글루타민산나트륨 등), 감미료 (둘신, 사이클레메이트, 사카린, 나트륨 등), 향료 (바닐린, 락톤류 등), 팽창제 (명반, D-주석산수소칼륨 등), 강화제, 유화제, 증점제 (호료), 피막제, 검기초제, 거품억제제, 용제, 개량제 등의 식품 첨가물 (food additives)을 첨가할 수 있다. 상기 첨가물은 식품의 종류에 따라 선별되고 적절한 양으로 사용된다.When the food is a beverage, it may be included in a ratio of 1 to 30 g, preferably 3 to 20 g based on 100 ml. In addition, the composition may include additional ingredients that are commonly used in food compositions to improve the smell, taste, time and the like. For example, it may include vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid, and the like. Also, minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn) and copper (Cu) may be included. It may also contain amino acids such as lysine, tryptophan, cysteine, valine and the like. Also, preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetic acid, etc.), fungicides (bleaching powder and highly bleaching powder, sodium hypochlorite, etc.), antioxidants (butylhydroxyanisol (BHA), butylhydroxytoluene ( BHT), etc.), colorants (such as tar pigment), colorants (such as sodium nitrite, sodium nitrite), bleach (sodium sulfite), seasonings (such as MSG glutamate), sweeteners (ducin, cyclate, saccharin, sodium, etc.) , Food additives such as flavorings (vanillin, lactones, etc.), swelling agents (alum, potassium D-tartrate, etc.), reinforcing agents, emulsifiers, thickeners (pigments), coatings, gum herbicides, foam inhibitors, solvents, improvers, etc. ) Can be added. The additive is selected according to the type of food and used in an appropriate amount.
본 발명의 건강기능식품은 당업계에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조 시에는 당업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어날 수 있다.The health functional food of the present invention can be prepared by a method commonly used in the art, and the preparation can be prepared by adding raw materials and ingredients commonly added in the art. In addition, unlike the general medicine has the advantage that there is no side effect that can occur when taking a long-term use of the drug as a raw material, and can be excellent in portability.
본 발명의 또 다른 하나의 양태는, 개나리 꽃 추출물 유래 리그난을 인간을 제외한 개체에 투여하는 단계를 포함하는 혈관 염증 예방 또는 치료방법을 제공한다.Yet another aspect of the present invention provides a method for preventing or treating vascular inflammation, comprising administering a forsythia flower extract-derived lignan to an individual except a human.
본 발명에서 용어, "개나리 꽃", "추출물", "리그난", "혈관 염증"은 상기에서 설명한 바와 같다.In the present invention, the terms "forsythia flower", "extract", "lignan", "vascular inflammation" are as described above.
본 발명에서 사용되는 용어, "개체"란, 혈관 염증이 발병되었거나 발병할 가능성이 있는 인간을 포함한 모든 동물을 의미할 수 있다. 상기 동물은 인간뿐만 아니라 이와 유사한 증상의 치료를 필요로 하는 소, 말, 양, 돼지, 염소, 낙타, 영양, 개, 고양이 등의 포유동물일 수 있으나, 이에 제한되지는 않는다.As used herein, the term "individual" may mean any animal, including humans, which have or are likely to develop vascular inflammation. The animal may be a mammal such as, but not limited to, a human, a cow, a horse, a sheep, a pig, a goat, a camel, a antelope, a dog, a cat, and the like, which require treatment of similar symptoms.
본 발명의 상기 예방 또는 치료 방법은 구체적으로, 혈관 염증이 발병하였거나 발병할 위험이 있는 개체에 상기 조성물을 약학적으로 유효한 양으로 투여하는 단계를 포함할 수 있다.The prophylactic or therapeutic method of the present invention may specifically include administering the composition to a subject having or at risk of developing vascular inflammation in a pharmaceutically effective amount.
본 발명에서 사용된 용어, "투여"는 어떠한 적절한 방법으로 환자에게 본 발명의 약학적 조성물을 도입하는 것을 의미하며, 본 발명의 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있다.As used herein, the term "administration" refers to introducing the pharmaceutical composition of the present invention to a patient in any suitable manner, wherein the route of administration of the composition of the present invention is oral or parenteral as long as the target tissue can be reached. Administration can be via a variety of routes.
본 발명에 따른 개나리 꽃 추출물 유래 리그난인 코리아나사이드 A는 우수한 항산화 활성을 가지며, VCAM-1의 발현을 억제하는 효과를 가지므로 혈관 염증 예방 또는 치료용 조성물로 용이하게 사용될 수 있다.Foranax A, a lignan from a forsythia flower extract, according to the present invention has excellent antioxidant activity and has an effect of inhibiting the expression of VCAM-1, and thus can be easily used as a composition for preventing or treating vascular inflammation.
도 1은 개나리 꽃 추출물 유래 6종 리그난의 분자구조를 나타낸 도면이다; 1, 코리아나사이드 A; 2, 코리아나사이드 B; 3, 필리게닌; 4, 에피피노레시놀; 5, 피노레시놀; 6, 타이노스포사이드 A.
도 2는 개나리 꽃 추출물 유래 6종 리그난의 ORAC 수치을 라디칼 소거제인 트롤록스에 비례하여 나타낸 그래프이다; 트롤록스 ORAC 수치 = 1.
도 3은 TNF-α에 의해 유도된 VCAM-1(vascular cell adhesion molecule-1) 발현에 대한 개나리 꽃 추출물 유래 리그난의 효과를 나타낸 그래프이다; (A) 웨스턴 블롯 분석을 통해 MOVAS에서 확인한 VCAM-1 단백질의 발현 수준, β-액틴 단백질 발현 수준은 대조군으로 사용되었다; (B) β-액틴으로 정량화한 VCAM-1 발현 수준; 1, 코리아나사이드 A; 2, 코리아나사이드 B.1 is a diagram showing the molecular structure of six lignans derived from forsythia flower extract; 1, Koreanaside A; 2, Koreanaside B; 3, piligenin; 4, epipinoresinol; 5, pinoresinol; 6, Tynosposide A.
FIG. 2 is a graph showing ORAC values of six lignans derived from forsythia flower extracts in proportion to trolox, a radical scavenger; Trolox ORAC readings = 1.
3 is a graph showing the effect of forsythia flower extract derived lignans on vascular cell adhesion molecule-1 (VCAM-1) expression induced by TNF-α; (A) The expression level of VCAM-1 protein, β-actin protein expression level identified in MOVAS through Western blot analysis was used as a control; (B) VCAM-1 expression levels quantified by β-actin; 1, Koreanaside A; 2, Koreana B.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as being limited by these examples.
실시예 1. 개나리 꽃 추출물 유래 화합물의 분리Example 1. Isolation of Forsythia Flower Extract-Derived Compound
건조된 개나리 꽃 (962g)을 80% 메탄올 (MeOH, 33LХ2)을 이용하여 실온에서 24시간 동안 추출하였고, 이를 여과 및 농축시켰다. 이후, 수득한 메탄올 추출물에 물(500 ㎖)을 연속적으로 부었고, n-부탄올(n-BuOH, 450 ㎖Х2) 및 에틸 아세테이트(EtOAc, 500 ㎖Х2)를 이용하여 추출하였다. 상기 추출물들을 농축시켜 EtOAc 분획물(FKE, 45g), n-BuOH 분획물(FKB, 110g) 및 물 분획물(FKW, 395g)의 잔류물을 얻었다.The dried forsythia flower (962 g) was extracted with 80% methanol (MeOH, 33 LХ2) for 24 hours at room temperature, which was filtered and concentrated. Thereafter, water (500 mL) was continuously poured into the obtained methanol extract, and extracted with n-butanol (n-BuOH, 450 mLH 2) and ethyl acetate (EtOAc, 500 mLH 2). The extracts were concentrated to give a residue of EtOAc fraction (FKE, 45g), n-BuOH fraction (FKB, 110g) and water fraction (FKW, 395g).
분획물의 수득 후 컬럼 크로마토그래피를 이용하여 화합물을 분리하였다.After obtaining of the fractions the compounds were separated using column chromatography.
구체적으로, 상기 EtOAc 분획물을 SiO2 c.c.(SiO2 Column chromatography, φ 12Х17 cm)을 이용하여 n-헥산-EtOAc(10:1→2:1→1:1, 각각 14 ℓ) → CHCl3-MeOH-물(30:3:1→20:3:1→10:3:1→65:35:10, 각각 15 ℓ)로 용출하였고, 12개의 분획물(FKE-1 ~ FKE-12)을 얻었다.Specifically, the EtOAc fraction was n -hexane-EtOAc (10: 1 → 2: 1 → 1: 1, 14 L each) using SiO 2 cc (SiO 2 Column chromatography, φ 12Х17 cm) → CHCl 3 -MeOH Eluted with water (30: 3: 1 → 20: 3: 1 → 10: 3: 1 → 65: 35: 10, 15 L each) to obtain 12 fractions (FKE-1 to FKE-12).
상기 12개의 분획물 중에서, FKE-10 분획물[1.9 g, 용리액/총 부피(Ve/Vt) 0.072-0.088]을 SiO2 c.c.(φ 4.5Х15 cm)을 이용하여 CHCl3-EtOAc(10:1→3:1, 각각 5.6 ℓ)로 용출하였고, 19개 분획물(FKE-10-1 ~ FKE-10-19)의 분획물을 얻었다.Of the 12 fractions, FKE-10 fraction [1.9 g, eluent / total volume (Ve / Vt) 0.072-0.088] was converted to CHCl 3 -EtOAc (10: 1 → 3) using SiO 2 cc (φ 4.5Х15 cm). : 1, 5.6 L each), and 19 fractions (FKE-10-1 to FKE-10-19) were obtained.
상기 19개의 분획물 중에서, FKE-10-12 분획물[78.1 mg, Ve/Vt 0.055-0.070]을 ODS c.c. (Φ 2 x 5 cm)을 이용하여 아세톤-물(1:1, 480 ㎖)로 용출하였고, 7개의 분획물(FKE-10-12-1 ~ FKE-10-12-7)을 얻었다. 이후, 상기 7개의 분획물 중 FKE-10-12-4 분획물에서 필리게닌(phylligenin)[23.2 mg, Ve/Vt 0.500-0.667, TLC (SiO2) 0.45, CHCl3-EtOAc (6:2), TLC (ODS) 0.51, 아세톤-물 (2:1 → 4:2)]을 분리하였다.Of the 19 fractions, FKE-10-12 fraction [78.1 mg, Ve / Vt 0.055-0.070] was eluted with acetone-water (1: 1, 480 mL) using ODS cc (Φ 2 × 5 cm). , Seven fractions (FKE-10-12-1 to FKE-10-12-7) were obtained. Then, phylligenin [23.2 mg, Ve / Vt 0.500-0.667, TLC (SiO 2 ) 0.45, CHCl 3 -EtOAc (6: 2), TLC in the FKE-10-12-4 fraction of the seven fractions (ODS) 0.51, acetone-water (2: 1-> 4: 2)].
또한, 상기 19개의 분획물 중에서, FKE-10-14 분획물[220.0mg, Ve/Vt 0.736-0.780]을 ODS c.c.(φ 2.5Х5 cm)를 이용하여 아세톤-물(2:1→1:1, 각각 2.2 ℓ)로 용출하였고, 8개의 분획물(FKE-10-14-1 ~ FKE-10-14-8)을 얻었으며, 상기 8개의 분획물 중 FKE-10-14-2 분획물[69.0 mg, Ve/Vt 0.736-0.780]을 SiO2 (φ 2Х10 cm) 컬럼을 이용하여 CHCl3-EtOAc(5:1, 500 ㎖)로 용출하였고, 3개의 분획물(FKE-10-14-2-1 ~ FKE-10-14-2-3)을 얻었다. 이후, 상기 3개의 분획물 중 FKE-10-14-2-1 분획물에서 에피피노레시놀(epipinoresinol)[27.6 mg, Ve/Vt 0.000-0.275, TLC (SiO2) 0.50, CHCl3-EtOAc (6:2), TLC (ODS) 0.53, 아세톤-물 (4:2)]을 분리하였다.In addition, among the 19 fractions, FKE-10-14 fraction [220.0 mg, Ve / Vt 0.736-0.780] was converted to acetone-water (2: 1 → 1: 1, respectively) using ODS cc (φ 2.5Х5 cm). 2.2 L), eleven fractions (FKE-10-14-1 to FKE-10-14-8) were obtained, and FKE-10-14-2 fraction [69.0 mg, Ve / Vt 0.736-0.780] was eluted with CHCl 3 -EtOAc (5: 1, 500 mL) using an SiO 2 (φ 2Х10 cm) column and three fractions (FKE-10-14-2-1 to FKE-10). -14-2-3). Thereafter, in the FKE-10-14-2-1 fraction of the three fractions, epipinoresinol [27.6 mg, Ve / Vt 0.000-0.275, TLC (SiO 2 ) 0.50, CHCl 3 -EtOAc (6: 2), TLC (ODS) 0.53, acetone-water (4: 2)].
또한, 상기 19개의 분획물 중에서, FKE-10-15 분획물[450.0 mg, Ve/Vt 0.780-0.860]을 ODS c.c.(φ 3Х5 cm)를 이용하여 아세톤-물(3:1→2:1→1:1, 각각 350 mL)로 용출하였고, 5개의 분획물(FKE-10-15-1 ~ FKE-10-15-5)을 얻었으며, 상기 5개의 분획물 중 FKE-10-15-1 분획물[42.0 mg, Ve/Vt 0.000-0.017]을 SiO2 c.c.(φ 3Х30 cm)를 이용하여 n-hexane-EtOAc (1:3, 550 mL)로 용출하였고, 7개의 분획물(FKE-10-15-1-1 ~ FKE-10-15-1-7)을 얻었다. 이후, 상기 7개의 분획물 중 FKE-10-15-1-4 분획물에서 피노레시놀(pinoresinol)[FKE-10-15-1-4, 11.1 mg, Ve/Vt 0.855-0.909, TLC (SiO2) 0.35, CHCl3-EtOAc (6:4), TLC (ODS) 0.42, 아세톤-물 (2:2)]을 분리하였다.In addition, among the 19 fractions, FKE-10-15 fraction [450.0 mg, Ve / Vt 0.780-0.860] was converted to acetone-water (3: 1 → 2: 1 → 1 :) using ODS cc (φ 3Х5 cm). 1, 350 mL each), and five fractions (FKE-10-15-1 to FKE-10-15-5) were obtained, and FKE-10-15-1 fraction [42.0 mg] out of the five fractions. , Ve / Vt 0.000-0.017] was eluted with n -hexane-EtOAc (1: 3, 550 mL) using SiO 2 cc (φ 3Х30 cm), and 7 fractions (FKE-10-15-1-1) FKE-10-15-1-7) was obtained. Then, pinoresinol [FKE-10-15-1-4, 11.1 mg, Ve / Vt 0.855-0.909, TLC (SiO 2 ) in the FKE-10-15-1-4 fraction of the seven fractions. 0.35, CHCl 3 -EtOAc (6: 4), TLC (ODS) 0.42, acetone-water (2: 2)].
또한, 상기 n-BuOH 분획물을 SiO2 c.c.(Φ 11Х15 cm)를 이용하여 CHCl3-MeOH-H2O (30:3:1→20:3:1→10:3:1, 각각 43 L) → EtOAc-n-BuOH-H2O (4:5:1, 45 L)로 용출하였고, 15개의 분획물(FKB-1 ~ FKB-15)을 얻었으며, 상기 15개의 분획물 중 FKB-4 분획물[11.5 g, Ve/Vt 0.154-0.363]을 SiO2 c.c.(φ 5.5Х15 cm)를 이용하여 CHCl3-MeOH-H2O (25:3:1, 7.7 L)로 용출하였고, 10개의 분획물(FKB-4-1 ~ FKB-4-10)을 얻었다.In addition, the n-BuOH fraction was purified using CH 2 3 -MeOH-H 2 O (30: 3: 1 → 20: 3: 1 → 10: 3: 1, 43 L each) using SiO 2 cc (Φ 11Х15 cm). → eluted with EtOAc- n- BuOH-H 2 O (4: 5: 1, 45 L), and 15 fractions (FKB-1 to FKB-15) were obtained, the FKB-4 fraction of which 15 fractions [ 11.5 g, Ve / Vt 0.154-0.363] was eluted with CHCl 3 -MeOH-H 2 O (25: 3: 1, 7.7 L) using SiO 2 cc (φ 5.5Х15 cm) and 10 fractions (FKB) -4-1 to FKB-4-10).
상기 10개의 분획물 중 FKB-4-6 분획물[4.9 g, Ve/Vt 0.316-0.411]을 ODS c.c. (Φ 5Х6 cm)를 이용하여 아세톤-물 (1:2, 2 L)로 용출하였고, 4개의 분획물(FKB-4-6-1 ~ FKB-4-6-4)을 얻었으며, 상기 4개의 분획물 중 FKB-4-6-1 분획물[2.2 g, Ve/Vt 0.000-0.571]을 ODS c.c. (Φ 4Х6 cm)를 이용하여 아세톤-MeOH-물 (1:1:4, 2.6 L)로 용출하였고, 7개의 분획물(FKB-4-6-1-1 ~ FKB-4-6-1-7)을 얻었다. 이후, 상기 7개의 분획물 중 FKB-4-6-1-4 분획물에서 코리아나사이드 A(koreanaside A)[219.8 mg, Ve/Vt 0.712-0.731, TLC (SiO2) 0.51, CHCl3-MeOH-H2O (16:6:2), TLC (ODS) 0.20, 아세톤-MeOH-물 (2:2:8)]를 분리하였다.FKB-4-6 fraction [4.9 g, Ve / Vt 0.316-0.411] of the 10 fractions was eluted with acetone-water (1: 2, 2 L) using ODS cc (Φ 5Х6 cm) and 4 Fractions (FKB-4-6-1 to FKB-4-6-4) were obtained, and FKB-4-6-1 fraction [2.2 g, Ve / Vt 0.000-0.571] of the four fractions was obtained by ODS cc ( Eluted with acetone-MeOH-water (1: 1: 4, 2.6 L) using Φ 4Х6 cm) and seven fractions (FKB-4-6-1-1 to FKB-4-6-1-7) Got. Then, Koreanaside A (koreanaside A) [219.8 mg, Ve / Vt 0.712-0.731, TLC (SiO 2 ) 0.51, CHCl 3 -MeOH-H 2 in the FKB-4-6-1-4 fraction of the seven fractions. 0 (16: 6: 2), TLC (ODS) 0.20, acetone-MeOH-water (2: 2: 8)].
또한, 상기 10개의 분획물 중 FKB-4-7 분획물[1.2 g, Ve/Vt 0.413-0.531]을 SiO2 c.c. (Φ 4Х15 cm)를 이용하여 CHCl3-MeOH-H2O (25:3:1, 3.5 L)로 용출하였고, 6개의 분획물(FKB-4-7-1 ~ FKB-4-7-6)을 얻었다. 이후, 상기 6개의 분획물 중 FKB-4-7-6 분획물에서 타이노스포사이드 A(tinosposide A)[FKB-4-7-6, 242.4 mg, Ve/Vt 1.000, TLC (SiO2) 0.45, CHCl3-MeOH-H2O (14:6:2), TLC (ODS) 0.55, 아세톤-물 (4:6)]를 분리하였다.Also, FKB-4-7 fractions of the 10 fractions [1.2 g, Ve / Vt 0.413-0.531 ] a SiO 2 cc using a (Φ 4Х15 cm) CHCl 3 -MeOH -H 2 O (25: 3: 1 , 3.5 L), and 6 fractions (FKB-4-7-1 to FKB-4-7-6) were obtained. Thereafter, tinosposide A (FKB-4-7-6, 242.4 mg, Ve / Vt 1.000, TLC (SiO 2 ) 0.45, CHCl 3 in the FKB-4-7-6 fraction of the six fractions. -MeOH-H 2 0 (14: 6: 2), TLC (ODS) 0.55, acetone-water (4: 6)].
또한, 상기 12개의 분획물 중에서, FKB-8 분획물[2.9 g, Ve/Vt 0.594-0.693]을 ODS c.c. (Φ 6Х20 cm)를 이용하여 아세톤-물 (1:1, 1.2 L)로 용출하였고, 8개의 분획물(FKB-8-1 ~ FKB-8-8)을 얻었으며, 상기 8개의 분획물 중 FKB-8-1 분획물[2.0 g, Ve/Vt 0.000-0.203]을 SiO2 c.c. (Φ 3.5Х17 cm)를 이용하여 EtOAc-n-BuOH-H2O (40:3:1 → 35:3:1 → 30:3:1 → 25:3:1 → 20:3:1, 각각 1 L)로 용출하였고, 12개의 분획물(FKB-8-1-1 ~ FKB-8-1-12)을 얻었다.In addition, among the 12 fractions, FKB-8 fraction [2.9 g, Ve / Vt 0.594-0.693] was eluted with acetone-water (1: 1, 1.2 L) using ODS cc (Φ 6Х20 cm), 8 Fractions (FKB-8-1 to FKB-8-8) were obtained, and the FKB-8-1 fraction [2.0 g, Ve / Vt 0.000-0.203] of the eight fractions was converted into SiO 2 cc (Φ 3.5Х17 cm). Elution with EtOAc- n- BuOH-H 2 O (40: 3: 1 → 35: 3: 1 → 30: 3: 1 → 25: 3: 1 → 20: 3: 1, 1 L each) Twelve fractions (FKB-8-1-1 to FKB-8-1-12) were obtained.
상기 12개의 분획물 중 FKB-8-1-11 분획물[762.5 mg, Ve/Vt 0.145-0.363]을 SiO2 c.c. (Φ 3.5Х16 cm)를 이용하여 EtOAc-n-BuOH-H2O (11:3:1, 3.2 L)로 용출하였고, 10개의 분획물(FKB-8-1-11-1 ~ FKB-8-1-11-10)을 얻었으며, 상기 10개의 분획물 중 FKB-8-1-11-5 분획물에서 코리아나사이드 B(koreanaside B) [FKB-8-1-11-5, 55.6 mg, Ve/Vt 0.380-0.473, TLC (SiO2) 0.45, EtOAc-n-BuOH-H2O (16:6:2), TLC (ODS) 0.82, 아세톤-MeOH (4:2)]를 분리하였다.FKB-8-1-11 fraction [762.5 mg, Ve / Vt 0.145-0.363] of the 12 fractions was purified using EtOAc 2 cc (Φ 3.5Х16 cm) in EtOAc- n- BuOH-H 2 O (11: 3). : 1, 3.2 L), eleven fractions (FKB-8-1-11-1 to FKB-8-1-11-10) were obtained, and FKB-8-1-11 of the ten fractions was obtained. Koreanaside B [FKB-8-1-11-5, 55.6 mg, Ve / Vt 0.380-0.473, TLC (SiO 2 ) 0.45, EtOAc- n- BuOH-H 2 O (16) : 6: 2), TLC (ODS) 0.82, acetone-MeOH (4: 2)].
종합하면, 개나리 꽃 80% 메탄올 추출물의 에틸아세테이트 또는 부탄올 분획물로부터 코리아나사이드 A, 코리아나사이드 B, 필리게닌, 에피피노레시놀, 피노레시놀 및 타이노스포사이드 A의 총 6종 화합물을 수득할 수 있었다. 상기 6종 화합물의 구조는 도 1에 나타내었다.Taken together, a total of six compounds were obtained from ethylacetate or butanol fractions of 80% methanol extract of forsythia flowers, including Coreanaside A, Coreanaside B, Piligenin, Epipinoresinol, Pinoresinol and Tynosposide A. . The structures of the six compounds are shown in FIG. 1.
또한, 표 1에 나타낸 바와 같이, 코리아나사이드 A 및 코리아나사이드 B에 대하여 1H-NMR, 13C-NMR, gHMBC, CD 또는 HR-FAB-MS의 분석을 수행한 결과, 상기 2종의 화합물은 기존에 보고되지 않은 신규한 리그난임을 확인하였다.In addition, as shown in Table 1, the analysis of 1 H-NMR, 13 C-NMR, gHMBC, CD or HR-FAB-MS for Coreanaside A and Coreanaside B, the two compounds are We have confirmed that this is a new lignan that has not been reported previously.
실시예 2. 개나리 꽃 추출물 유래 신규 리그난의 항산화 활성 분석Example 2 Analysis of Antioxidant Activity of Novel Lignans Derived from Forsythia Flower Extract
활성산소종(reactive oxygen species, ROS)이 염증 과정에 기여하고 항산화 제 활성을 가진 화합물이 iNOS, COX-2, p-p65 및 VCAM-1과 같은 염증 인자를 억제한다고 보고되어 있으므로(Lee, Ah Young, et al., 2016; Thi, Nhan Nguyen, et al., 2017), 상기 실시예 1을 통해 분리한 6종 리그난의 항산화 활성을 확인하였다.Because reactive oxygen species (ROS) contribute to the inflammatory process and compounds with antioxidant activity have been reported to inhibit inflammatory factors such as iNOS, COX-2, p-p65 and VCAM-1 (Lee, Ah) Young, et al., 2016; Thi, Nhan Nguyen, et al., 2017), the antioxidant activity of the six lignans isolated through Example 1 was confirmed.
상기 6종 화합물의 항산화 활성은 매우 보편적이며 표준화된 화학적 항산화 시험인 산소 라디칼 흡광도 (oxygen radical absorbance capacity, ORAC) 분석을 통해 수행되었다. ORAC은 잘 알려진 라디칼 소거제인 트롤록스(Trolox)와 비교하여 활성 수준을 확인하였다. Antioxidant activity of the six compounds was carried out through oxygen radical absorbance capacity (ORAC) analysis, a very common and standardized chemical antioxidant test. ORAC confirmed the activity level compared to Trolox, a well known radical scavenger.
그 결과, 도 2에 나타낸 바와 같이, 타이노스포사이드 A를 제외한 5종의 화합물은 높은 항산화 효과를 보였고, 5종 화합물의 ORAC는 0.88 ± 0.13 내지 1.02 ± 0.01로 나타났다. 이러한 결과는 타이노스포사이드 A가 벤젠 고리에 수산기를 갖지 않는 반면, 이를 제외한 5종의 화합물은 벤젠 고리에 하나 이상의 하이드록시기를 가져 항산화 효과를 나타내기 때문으로 판단된다.As a result, as shown in Figure 2, five compounds except the tynosposide A showed a high antioxidant effect, the ORAC of the five compounds was found to be 0.88 ± 0.13 to 1.02 ± 0.01. These results indicate that the tynosposide A does not have a hydroxyl group in the benzene ring, but five other compounds have an antioxidant effect by having at least one hydroxyl group in the benzene ring.
실시예 3. 개나리 꽃 추출물 유래 신규 리그난의 VCAM-1 발현 억제 효과 분석Example 3. Analysis of the inhibitory effect of VCAM-1 expression of forsythia flower extract-derived novel lignans
혈관 염증에 대한 신규 리그난의 효과를 확인하기 위해, 상기 실시예 2을 통해 수득한 개나리 꽃 유래 화합물 중 신규한 리그난인 코리아나사이드 A 및 B의 마우스 혈관 평활근 (MOVAS) 세포주에서 TNF-α에 의해 유도된 혈관 세포 부착 분자-1 (VCAM-1) 발현에 대한 억제 효과를 평가하였다. In order to confirm the effect of novel lignans on vascular inflammation, induced by TNF-α in mouse vascular smooth muscle (MOVAS) cell lines of novel lignans Koreanaside A and B of forsythia flower derived compounds obtained through Example 2 above The inhibitory effect on vascular cell adhesion molecule-1 (VCAM-1) expression was assessed.
마우스 혈관 평활근 세포를 각각 코리아나사이드 A 또는 B(25mg/mL)로 2시간 동안 전처리 한 다음 TNF-α (10ng/mL)로 24시간 동안 자극하고 VCAM-1의 발현을 측정하였다.Mouse vascular smooth muscle cells were pretreated with Coreanaside A or B (25 mg / mL) for 2 hours, and then stimulated with TNF-α (10ng / mL) for 24 hours and the expression of VCAM-1 was measured.
그 결과, 도 3에 나타낸 바와 같이, 코리아나사이드 B는 MOVAS에서 TNF-α에 의해 유도된 VCAM-1의 발현을 유의적으로 억제하지 못한 반면, 코리아나사이드 A 는 VCAM-1의 발현을 효과적으로 억제하였다.As a result, as shown in Fig. 3, Koreana B did not significantly inhibit the expression of VCAM-1 induced by TNF-α in MOVAS, while Koreana A effectively inhibited the expression of VCAM-1. .
종합하면, 본 발명에 따른 개나리 꽃 유래 신규 리그난인 코리아나사이드 A는 우수한 항산화 활성을 갖는 동시에 TNF-α에 의해 유도된 VCAM-1의 발현을 억제하므로, 혈관 염증 치료 효과를 가지는 것으로 판단할 수 있다.Taken together, Koreanaside A, a novel lignan derived from forsythia flowers according to the present invention, has excellent antioxidant activity and inhibits the expression of VCAM-1 induced by TNF-α, and thus can be judged to have a therapeutic effect on vascular inflammation. .
본 명세서는 본 발명의 기술 분야에서 통상의 지식을 가진 자이면 충분히 인식하고 유추할 수 있는 내용은 그 상세한 기재를 생략하였으며, 본 명세서에 기재된 구체적인 예시들 이외에 본 발명의 기술적 사상이나 필수적 구성을 변경하지 않는 범위 내에서 보다 다양한 변형이 가능하다. 따라서 본 발명은 본 명세서에서 구체적으로 설명하고 예시한 것과 다른 방식으로 실시될 수 있으며, 이는 본 발명의 기술 분야에 통상의 지식을 가진 자이면 이해할 수 있는 사항이다.In the present specification, those skilled in the art of the present disclosure can fully recognize and infer the details thereof, and the detailed descriptions thereof have been omitted, and the technical spirit or essential configuration of the present invention may be changed in addition to the specific examples described herein. More variations are possible within the scope of not doing so. Accordingly, the present invention may be practiced in a manner different from that specifically described and illustrated herein, which will be understood by those of ordinary skill in the art.
Claims (5)
[화학식 1]
.
Pharmaceutical composition for preventing or treating vascular inflammatory disease comprising Koreanaside A represented by Formula 1;
[Formula 1]
.
상기 코리아나사이드 A는 개나리 꽃 추출물을 물, 탄소수 1 내지 4의 알코올 등의 극성 용매; 헥산(Hexane), 에틸 아세테이트(Ethyl acetate) 등의 비극성 용매; 또는 이들의 혼합용매로 분획하여 수득한 것인, 약학 조성물.
The method of claim 1,
The Koreanaside A is a forsythia flower extract water, a polar solvent such as alcohol having 1 to 4 carbon atoms; Nonpolar solvents such as hexane (Hexane) and ethyl acetate; Or obtained by fractionation with a mixed solvent thereof.
상기 혈관 염증 예방 또는 치료는 VCAM-1의 발현을 억제함으로써 달성되는 것인, 약학 조성물.
The method of claim 1,
The prevention or treatment of vascular inflammation is achieved by inhibiting the expression of VCAM-1, pharmaceutical composition.
Health functional foods for preventing or improving vascular inflammatory diseases, including Koreanaside A.
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