KR100319397B1 - Anti-Thrombotic and Anti-Hypercholestemic Composition Which Comprises Plant Extracts as an Active Ingredient - Google Patents
Anti-Thrombotic and Anti-Hypercholestemic Composition Which Comprises Plant Extracts as an Active Ingredient Download PDFInfo
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- KR100319397B1 KR100319397B1 KR1019990028024A KR19990028024A KR100319397B1 KR 100319397 B1 KR100319397 B1 KR 100319397B1 KR 1019990028024 A KR1019990028024 A KR 1019990028024A KR 19990028024 A KR19990028024 A KR 19990028024A KR 100319397 B1 KR100319397 B1 KR 100319397B1
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Classifications
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
- F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
- F16K11/00—Multiple-way valves, e.g. mixing valves; Pipe fittings incorporating such valves
- F16K11/10—Multiple-way valves, e.g. mixing valves; Pipe fittings incorporating such valves with two or more closure members not moving as a unit
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
- F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
- F16K17/00—Safety valves; Equalising valves, e.g. pressure relief valves
- F16K17/02—Safety valves; Equalising valves, e.g. pressure relief valves opening on surplus pressure on one side; closing on insufficient pressure on one side
- F16K17/04—Safety valves; Equalising valves, e.g. pressure relief valves opening on surplus pressure on one side; closing on insufficient pressure on one side spring-loaded
- F16K17/0473—Multiple-way safety valves
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
- F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
- F16K27/00—Construction of housing; Use of materials therefor
- F16K27/02—Construction of housing; Use of materials therefor of lift valves
- F16K27/0263—Construction of housing; Use of materials therefor of lift valves multiple way valves
Landscapes
- Engineering & Computer Science (AREA)
- General Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
본 발명은 전통 천연식물을 수집하여 열수 추출하고, 실험실적 조건에서 항혈전 활성 스크리닝을 통하여 활성이 강한 소재 8종을 선별하여, 활성이 극대화 될 수 있도록 효과적으로 배합한 천연식물소재 추출 혼합물을 유효성분으로 포함하는 항혈전 및 고지혈증 억제 조성물(Thrombo QTM)에 관한 것이다. 본 발명의 항혈전 및 고지혈증 억제 조성물은 실험실적 조건 및 생체내 조건에서 혈전용해, 혈소판 응집 활성 및 혈액응고 활성을 저하시킬 수 있음은 물론, 혈중 콜레스테롤 및 혈중 중성지방 억제 등의 활성을 지니고 있는 것으로 밝혀졌다. 본 발명의 천연식물소재 추출 혼합물을 이용한 항혈전 및 고지혈증 억제 조성물은 혈중 콜레스테롤의 감소, 혈소판 응집 활성 및 혈액응고 활성을 저하시킬 수 있을 뿐만 아니라, 심혈관계 질환을 효과적으로 예방할 수 있는 1차 예방제의 제조에도 널리 활용될 수 있을 것이다.The present invention collects traditional natural plants and extracts hot water, and selects eight kinds of highly active materials through anti-thrombotic activity screening under laboratory conditions, and effectively extracts the natural plant material extract mixture effectively mixed to maximize the activity It relates to an antithrombotic and hyperlipidemic composition (Thrombo Q ™ ) comprising a. The antithrombotic and hyperlipidemic inhibitory composition of the present invention is capable of lowering thrombolysis, platelet aggregation activity and blood coagulation activity under laboratory conditions and in vivo conditions, as well as having activities such as inhibiting blood cholesterol and triglyceride in blood. Turned out. Anti-thrombotic and hyperlipidemic inhibitory compositions using natural plant material extracts of the present invention can reduce blood cholesterol, reduce platelet aggregation and blood coagulation, as well as prepare a primary preventive agent that can effectively prevent cardiovascular diseases. It will also be widely used.
Description
본 발명은 천연식물소재 추출 혼합물을 이용한 항혈전 및 고지혈증 억제 조성물에 관한 것이다. 좀 더 구체적으로, 본 발명은 전통 천연식물을 수집하여 열수 추출하고, 실험실적 조건에서 항혈전 활성 스크리닝을 통하여 활성이 강한 소재 8종을 선별하여, 활성이 극대화 될 수 있도록 효과적으로 배합한 천연식물소재 추출 혼합물을 유효성분으로 포함하는 항혈전 및 고지혈증 억제 조성물에 관한 것이다.The present invention relates to antithrombotic and hyperlipidemic inhibitory compositions using natural plant material extract mixtures. More specifically, the present invention collects traditional natural plants, extracts hot water, and selects eight kinds of highly active materials through anti-thrombotic activity screening under laboratory conditions, and effectively combines natural plant materials to maximize the activity. It relates to an antithrombotic and hyperlipidemic composition comprising an extract mixture as an active ingredient.
우리나라의 경우 지난 20-30년간 급속한 경제성장과 함께, 식생활의 변화, 환경오염, 과도한 스트레스 등으로 질병의 발생율 및 사망원인도 크게 달라 지고 있다. 특히, 심근경색이나 뇌졸중으로 대표되는 심혈관계 질환에 의한 사망률이 악성종양보다도 높은 제1위를 나타내고 있다(참조: 사망원인 통계연보, 대한통계학회, 1994). 고지혈증, 동맥경화증, 심근경색증 및 뇌혈전증 등 심혈관계 질환의 발생 원인으로는, 식생활 양상의 변화에 따라 높은 지방함량과 식이섬유 함량이 적은 가공식품의 섭취, 유전적인 인자, 흡연, 음주, 고혈압, 당뇨, 비만, 운동부족, 과도한 스트레스 등이 관여한다고 널리 보고되고 있다(참조: Ernst N., et al., Circulation, 62:41, 1980; Goldstein J. L., et al., J. Clin. Invest., 52:1544,1973; Krombout D., American J. Clin. Nutr., 38:591, 1983; Norenz J. P., et al., J. Human Stress, 8:24, 1982; Harper A. E., et al., Dietary Fat and Health, 44:4965, 1983).In Korea, with the rapid economic growth over the last 20-30 years, the incidence of diseases and the causes of death are greatly changed due to changes in diet, environmental pollution, and excessive stress. In particular, the mortality rate due to cardiovascular disease, which is represented by myocardial infarction or stroke, is higher than malignant tumors (see Statistical Yearbook of Cause of Death, Korean Statistical Society, 1994). The causes of cardiovascular diseases, such as hyperlipidemia, arteriosclerosis, myocardial infarction and thrombosis, include the ingestion of processed foods with low fat and dietary fiber content according to changes in dietary habits, genetic factors, smoking, drinking, high blood pressure, and diabetes. , Obesity, lack of exercise, and excessive stress are widely reported (Ernst N., et al., Circulation, 62:41, 1980; Goldstein JL, et al., J. Clin. Invest., 52 Krombout D., American J. Clin. Nutr., 38: 591, 1983; Norenz JP, et al., J. Human Stress, 8:24, 1982; Harper AE, et al., Dietary Fat: and Health, 44: 4965, 1983).
생체 내에서 혈액은 응고와 용해작용이 항상 평형을 이루고 있어, 정상적인 상태에서는 출혈이나 혈전 등에 의해 흐름이 방해 받지 않는다. 그러나, 여러가지 요인으로 인하여, 이러한 평형상태가 깨지게 되면, 혈관의 흐름이 원활치 못하게 되고, 이로 인한 심혈관계 질환이 발생하게 된다(참조: Marks D., et al., Basic Medical Biochemistry, Baltimore, Williams & Wilkins, p107, 1996). 이러한 심혈관 질환 중 가장 대표적인 경우가 동맥경화증으로, 심장이나 뇌 등 중요장기에 허혈성 상태를 초래하여 심근경색이나 뇌경색을 일으키는 매우 위험한 질환으로 알려져 있다.In vivo, blood coagulates and dissolves at all times in equilibrium, and in normal conditions, flow is not disturbed by bleeding or blood clots. However, due to various factors, the breakdown of this equilibrium leads to poor flow of blood vessels, resulting in cardiovascular disease (Marks D., et al., Basic Medical Biochemistry, Baltimore, Williams & Wilkins, p 107, 1996). The most representative of these cardiovascular diseases is atherosclerosis, which is known to be a very dangerous disease causing myocardial infarction or cerebral infarction by causing ischemic conditions in important organs such as the heart and brain.
동맥경화의 발생원인에 관한 기초연구는 분자생물학적 관점에서 최근 활발히 진행되고 있다. 발생 초기에, 저밀도 지질단백질(LDL; low density lipoprotein) 등의 원인에 의하여 혈관내막세포의 기능이 저하되거나 손상되면, 세포부착분자(cell adhesion molecule)가 높은 수준으로 발현되고, 여기에 단구 (monocyte), T-임파구(T-lymphocyte) 및 혈소판 등이 부착하여, 혈관 내막세포 사이를 통하여 혈관벽 속으로 침윤하게 되는데, 이때, 혈액 속의 지질단백질도 함께 유입되게 된다. 혈관벽 내부로 유입된 단구들은 지질단백질을 탐식하여 대식세포(macrophage)로 변형되고, 이들로부터 분비된 증식인자에 의하여 혈관벽의 평활근 세포의 증식 및 활성화가 일어나 결체조직(extracelluar matrix)이 생성되며, 여기에 지방이 더욱 축적되어 동맥경화가 발생하게 된다. 이는 20세 이상의 성인에게서 20년 이상의 장기간에 걸쳐서 진행되는 만성적인 반응으로, 결국에는 동맥혈관을 협착(stenosis)시키는 것으로 알려지고 있다. 동맥경화가 발생하면, 혈관은 기능이 약화되고 유연성도 감소하여 약한 자극에도 쉽게 파열(rupture)될 수 있으며, 이때 혈관 내벽의 콜라겐(collagen)이 노출되면, 혈액 중의 혈소판이 점착됨으로써 혈액응고계를 활성화하여 급속한 혈전을 형성하게 된다(참조: Mustard J. F., et al., Pharmacol. Rev., 22:97, 1970; Longenecker G. L., The Platelet: Physiology and Pharmacology, part 17, Orlando, Academic Press INC., 1985). 이러한 현상은 심근경색에 의한 돌연사의 경우에 흔히 관찰되며, 사망한 환자의 관상동맥을 현미경 상에서 조사하면, 동맥경화에 의한 혈관의 협착과 혈전에 의해 완전히 폐쇄된 혈관을 볼 수 있다. 결국, 심장으로의 혈액공급이 순간적으로 차단되므로, 허혈성 상태를 지나 조직의 괴사를 일으키게 되는 것이다.Basic research on the causes of atherosclerosis has been actively conducted from the molecular biological point of view. In the early stages of development, when vascular endothelial cells are deteriorated or damaged due to low density lipoprotein (LDL) or the like, high levels of cell adhesion molecules are expressed, and monocytes are expressed here. ), T-lymphocyte (T-lymphocyte) and platelets are attached, and infiltrate into the vascular wall through the vascular endothelial cells, at this time, lipoproteins in the blood are also introduced. The monocytes introduced into the blood vessel wall are converted to macrophage by phagocytosis of lipoproteins and proliferation and secretion of smooth muscle cells of the vessel wall are produced by the growth factor secreted therefrom, resulting in an extracelluar matrix. Fat is further accumulated in the atherosclerosis. This is a chronic reaction that occurs over a 20-year period in adults over 20 years of age, eventually known to stenosis the arteries. When atherosclerosis occurs, blood vessels are weakened and their flexibility decreases, so they can be easily ruptured by weak stimuli.When collagen in the inner wall of blood vessels is exposed, platelets in the blood adhere to the blood coagulation system. Activation to form rapid thrombus (Musard JF, et al., Pharmacol. Rev., 22:97, 1970; Longenecker GL, The Platelet: Physiology and Pharmacology, part 17, Orlando, Academic Press INC., 1985 ). This phenomenon is often observed in the case of sudden death due to myocardial infarction. When the coronary artery of the deceased patient is examined under a microscope, the vessels completely closed by the narrowing of blood vessels due to atherosclerosis and blood clots can be seen. Eventually, the blood supply to the heart is momentarily blocked, causing tissue necrosis through the ischemic state.
따라서, 심혈관계 질환을 효과적으로 예방하기 위해서는, 혈중 콜레스테롤의 저하, 혈소판 응집 활성 및 혈액응고 활성의 억제, 혈관 평활근 세포의 증식억제 등이 요구된다. 현재 임상에서는 심혈관계 환자의 경우, 스타틴 계열의 콜레스테롤 저하제, 쿠마딘(coumadin)등의 항응고제, 아스피린 등의 항혈소판제를 장기복용하도록 처방하여 혈관협착을 억제하고 있다(참조: 정광회, 한국지혈혈전학회, 3:1-12, 1996). 유로키나제나 t-PA와 같은 혈전용해제는 이미 형성된 혈전을 용해시켜 혈액의 흐름을 돕는 효과적인 치료제로 사용되고 있다. 그러나, 항혈소판 제제로서 아스피린은 효능은 우수하지만 위장장애와 같은 부작용이 보고되고 있고(참조:Miwa K., et al., American Heart J., 105:262-273, 1983), 항응고제인 쿠마딘은 너무 강한 활성 때문에 출혈의 부작용이 나타나고 있는 등, 이들 모두 장기적인 1차 예방제로 사용하는데 한계가 있다. 또한, 고지혈증의 치료에 사용되는 스타틴 계열의 약제는 혈중 저밀도 지질단백질(LDL)을 낮추는데 매우 좋은 효과를 보이고 있으나, 가격이 너무 고가인 문제점이 있다. 결국, 이러한 유효한 약제들의 투여는 어디까지나 이미 심혈관 질환이 발생한 환자를 대상으로한 2차적 처방이며, 근원적인 예방을 위한 효과적인 1차 예방제는 아직 개발되지 못한 상황이다.Therefore, in order to effectively prevent cardiovascular diseases, lowering of blood cholesterol, suppressing platelet aggregation activity and blood coagulation activity, inhibiting proliferation of vascular smooth muscle cells, and the like are required. In the current clinical practice, cardiovascular patients are prescribed for long-term use of statin cholesterol lowering agents, anticoagulants such as coumadin, and antiplatelets such as aspirin. , 3: 1-12, 1996). Thrombolytic agents such as urokinase and t-PA are used as effective treatments to help the blood flow by dissolving the formed clots. However, aspirin is an effective antiplatelet agent, but side effects such as gastrointestinal disorders have been reported (Miwa K., et al., American Heart J., 105: 262-273, 1983). All of these have limitations for use as long-term primary preventive agents, such as the side effects of bleeding due to too strong activity. In addition, statin-based drugs used in the treatment of hyperlipidemia have shown a very good effect in lowering low-density lipoprotein (LDL) in the blood, but there is a problem that the price is too expensive. As a result, the administration of such effective drugs is a second-order prescription for patients who have already developed cardiovascular disease, and an effective first-preventive agent for the underlying prevention has not been developed yet.
최근, 이러한 1차 예방제의 개발을 위하여, 심혈관 질환의 증가와 식생활과의 연관성이 높다는 가정 하에, 일상적으로 섭취하고 있는 식품의 항혈전 및 항동맥경화 활성을 밝히기 위한 많은 연구들이 수행되고 있다(참조: Okuyama T., et al., J. Med. Pharm. Soc., WAKAN-YAKU, 5:167, 1988). 예를 들어, 프랑스의 경우, 적색포도주와 심혈관 질환의 상관관계(참조: Renauld A., et al., Lancet, 339:1523-1526, 1992), 에스키모인들의 동맥경화와 EPA 및 DHA의 상관관계(참조: Harris W. S., et al., Metabolism, 32:179, 1983)에 대한 연구가 진행 중이고, 일본의 경우, 전통발효식품인 납두와 혈전과의 상관관계(참조: Sumi H., et al., Experientia, 43:1110-1111, 1987), 녹차의 항혈전과 혈중 콜레스테롤 강하작용 및 항암효과(참조: Yamaguchi Y., et al., Nippon Yakurigaku Zasshi, 97:329-337, 1991; Muramatsu K., et al., J. Nutr. Sci. Vitaminol(Tokyo), 32:613-622, 1986; Stoner G. D., et al., J. Cell Biochem., 22:169-180, 1995)를 밝히고자 연구가 진행 중에 있다. 또한, 우리나라에서도 청국장(참조: 김용택 외, Korean J. Appl.Microbiol. Biotechnol., 23:1-5, 1995), 된장(참조: 최낙식 외, 한국지혈혈전학회지, 5:139-145, 1998), 젓갈(참조: Kim H. K., et al., J. Ferment. Biotech., 84:307-312, 1997), 김치(참조: 정영기 외, Korean J. Life Sci., 5:20-210, 1995) 등과 혈전과의 관계를 규명하기 위한 노력이 계속되어 왔다.Recently, for the development of such primary preventive agents, many studies have been conducted to identify the anti-thrombotic and anti-arteriosclerosis activity of foods ingested daily, assuming that the increase in cardiovascular disease is associated with diet. Okuyama T., et al., J. Med. Pharm. Soc., WAKAN-YAKU, 5: 167, 1988). For example, in France, the relationship between red wine and cardiovascular disease (Renauld A., et al., Lancet, 339: 1523-1526, 1992), the correlation between atherosclerosis of Eskimos and EPA and DHA (Research: Harris WS, et al., Metabolism, 32: 179, 1983), and in Japan, the relationship between naphtha and thrombi, a traditional fermented food (Sumi H., et al. , Experientia, 43: 1110-1111, 1987), antithrombotic and blood cholesterol lowering and anticancer effects of green tea (Yamaguchi Y., et al., Nippon Yakurigaku Zasshi, 97: 329-337, 1991; Muramatsu K. , et al., J. Nutr. Sci. Vitaminol (Tokyo), 32: 613-622, 1986; Stoner GD, et al., J. Cell Biochem., 22: 169-180, 1995). In progress. In addition, in Korea, Cheonggukjang (Ref .: Kim Yong-taek et al., Korean J. Appl.Microbiol. Biotechnol., 23: 1-5, 1995), Doenjang (Ref .: Nak-sik Choi et al. , Salted fish (Kim HK, et al., J. Ferment. Biotech., 84: 307-312, 1997), Kimchi (Jeong Young-ki et al., Korean J. Life Sci., 5: 20-210, 1995) Efforts have been made to determine the relationship between the back and blood clots.
따라서, 인체에 안전한 식품소재로부터 심혈관계와 관련된 유효성분들을 밝히고, 이를 섭취케 함으로써, 이들 질환에 대한 1차 예방과 더불어, 혈중 콜레스테롤의 감소, 혈소판 응집 활성 및 혈액응고 활성 저하 등의 치료효과가 기대되는 혼합물제제를 제조하는 기술을 개발할 필요성이 끊임없이 대두되었다.Therefore, by identifying the active ingredients related to the cardiovascular system from food materials that are safe for the human body and ingesting them, the primary prevention of these diseases, as well as the treatment effect such as reduction of blood cholesterol, platelet aggregation activity and blood coagulation activity There is a constant need to develop techniques for producing the expected mixture formulations.
이에, 본 발명자들은 혈중 콜레스테롤의 감소, 혈소판 응집 활성 및 혈액응고활성을 저하시킬 수 있는 천연식물소재 추출 혼합물을 이용한 항혈전 및 고지혈증 억제 조성물을 제조하고자 예의 노력한 결과, 전통 천연식물 소재를 수집하여 열수 추출하고, 실험실적 조건에서 항혈전 활성 스크리닝을 통하여 활성이 강한 소재 8종의 추출물을 선별하고, 효과적으로 배합한 천연식물소재 추출 혼합 조성물이 항혈전 및 고지혈증 억제 활성을 지니고 있음을 확인하고, 본 발명을 완성하게 되었다.Accordingly, the present inventors have made diligent efforts to produce anti-thrombotic and hyperlipidemic inhibitory compositions using natural plant material extract mixtures that can reduce blood cholesterol, platelet aggregation activity and blood coagulation activity, and collect hydrothermal water by collecting traditional natural plant materials. Extracted, selected from 8 kinds of extracts with strong activity through the anti-thrombotic activity screening under laboratory conditions, it was confirmed that the effective natural plant material extract mixed composition has anti-thrombotic and hyperlipidemic inhibitory activity, the present invention To complete.
결국, 본 발명의 주된 목적은 혈중 콜레스테롤의 감소, 혈소판 응집 활성 및 혈액응고활성을 저하시킬 수 있는 천연식물소재 추출 혼합물을 이용한 항혈전 및고지혈증 억제 조성물을 제공하는 것이다.After all, the main object of the present invention is to provide an antithrombotic and hyperlipidemic inhibitor composition using a natural plant material extract mixture that can lower blood cholesterol, platelet aggregation activity and blood coagulation activity.
도 1은 천연식물소재 추출 혼합 조성물(Thrombo-QTM) 투여 시, 혈소판 응집 억제활성의 변화를 보여주는 그래프이다.1 is a graph showing a change in platelet aggregation inhibitory activity when a natural plant extract mixture composition (Thrombo-Q ™ ) is administered.
도 2는 천연식물소재 추출 혼합 조성물(Thrombo-QTM) 투여 시, 전혈 응고시간의 변화를 나타내는 그래프이다.Figure 2 is a graph showing the change in whole blood coagulation time when the natural plant material extract mixture composition (Thrombo-Q TM ) administration.
도 3은 천연식물소재 추출 혼합 조성물(Thrombo-QTM) 투여 시, 혈장 응고시간의 변화를 나타내는 그래프이다.Figure 3 is a graph showing the change in plasma coagulation time upon administration of the natural plant material extract mixture composition (Thrombo-Q TM ).
도 4는 천연식물소재 추출 혼합 조성물(Thrombo-QTM) 투여 시, 출혈시간의 변화를 나타내는 그래프이다.Figure 4 is a graph showing the change in bleeding time when the natural plant material extract mixture composition (Thrombo-Q TM ) administration.
도 5는 천연식물소재 추출 혼합 조성물(Thrombo-QTM) 투여 시, 총 콜레스테롤, 유리 콜레스테롤 및 콜레스테롤 에스테르의 함량 변화를 수치로 나타낸 그래프이다.Figure 5 is a graph showing the numerical changes in the content of total cholesterol, free cholesterol and cholesterol esters when the natural plant extract mixture composition (Thrombo-Q TM ) administration.
도 6은 천연식물소재 추출 혼합 조성물(Thrombo-QTM) 투여 시, HDL-콜레스테롤 및 LDL-콜레스테롤의 함량변화를 수치로 나타낸 그래프이다.Figure 6 is a graph showing the numerical changes in the content of HDL-cholesterol and LDL-cholesterol when the natural plant extract mixture composition (Thrombo-Q TM ) administration.
도 7a는 천연식물소재 추출 혼합 조성물(Thrombo-QTM) 투여 시, HDL/LDL-콜레스테롤의 구성비를 수치로 나타낸 그래프이다.Figure 7a is a graph showing the numerical composition of the composition of the HDL / LDL-cholesterol when the natural plant extract mixture composition (Thrombo-Q TM ) administration.
도 7b는 천연식물소재 추출 혼합 조성물(Thrombo-QTM) 투여 시, 동맥경화지수를 수치로 나타낸 그래프이다.Figure 7b is a graph showing the arteriosclerosis index when the natural plant material extract mixture composition (Thrombo-Q TM ) administration.
도 8은 천연식물소재 추출 혼합 조성물(Thrombo-QTM) 투여 시, 중성지방인 트리글리세라이드의 함량변화를 수치로 나타낸 그래프이다.8 is a graph showing numerical values of triglyceride content as a triglyceride when the natural plant material extract mixture composition (Thrombo-Q ™ ) is administered.
본 발명자들은 전통 천연식물 소재 18종을 수집하여 유효성분을 열수 추출하고, 실험실적 조건에서 항혈전 활성 스크리닝을 통하여 활성이 강한 소재 8종을 선별하여, 활성이 극대화 될 수 있는 효과적인 배합 비율을 결정하여 천연식물소재 추출 혼합 조성물을 제조하고, 실험실적 조건 및 생체내 조건에서 혈전용해, 혈소판 응집 활성 및 혈액응고 활성을 저하시킬 수 있음은 물론, 혈중 콜레스테롤 및 혈중 중성지방 억제 등의 항혈전 및 고지혈증 억제 활성을 지니고 있음을 확인하였다.The present inventors collected 18 kinds of traditional natural plant material and extracted the active ingredient by hot water, and selected 8 kinds of highly active materials through anti-thrombotic activity screening under laboratory conditions to determine an effective compounding ratio to maximize the activity. It is possible to prepare a natural plant material extract mixed composition, and to reduce thrombolysis, platelet aggregation activity and blood coagulation activity under laboratory conditions and in vivo conditions, as well as antithrombosis and hyperlipidemia such as inhibition of blood cholesterol and triglyceride in blood It was confirmed that it has inhibitory activity.
이하, 본 발명을 구체적으로 설명하고자 한다.Hereinafter, the present invention will be described in detail.
본 발명자들은 심혈관질환의 발생을 예방할 수 있는 항혈전 및 고지혈증 억제 조성물을 개발하기 위하여, 전통식품소재 18종을 수집하고 유효성분을 열수 추출하여 실험실적 조건에서 항혈전 활성을 스크리닝한 다음, 활성이 강한 소재 8종을 선별하고, 이를 후술하는 표 2의 적절한 비율로 혼합한 물질을 '천연식물 소재 추출 혼합물'이라 하였다. 실험실적 조건에서의 항혈전활성의 측정을 위하여, 본 발명에서는 혈액응고 억제활성, 혈전 용해 활성 및 혈소판 응집 억제 활성을 측정하였으며, 전기의 실험결과와 함께 기보고된 자료 및 국가에서 공시한 식품공전을근거로 건강식품소재로 사용가능한 소재를 엄선하고, 혈전예방 및 고지혈증 예방을 위한 새로운 형태의 천연식물 소재 추출 혼합 조성물('Thrombo-QTM')을 제조하게 되었다.The present inventors collected 18 kinds of traditional food materials and extracted the active ingredient by hydrothermal extraction to screen antithrombotic activity under laboratory conditions in order to develop antithrombotic and hyperlipidemic inhibitory compositions that can prevent the development of cardiovascular disease. Eight strong materials were selected and the materials mixed in the appropriate proportions in Table 2 described below were called 'natural plant material extraction mixtures'. In order to measure antithrombotic activity under laboratory conditions, the present invention measured blood coagulation inhibitory activity, thrombolytic activity, and platelet aggregation inhibitory activity. Based on the selection of materials that can be used as a health food material, to prepare a new type of natural plant extract mixture composition ('Thrombo-Q TM ') for the prevention of thrombosis and hyperlipidemia.
또한, 천연식물 소재 추출 혼합 조성물(Thrombo-QTM)의 생체 내에서의 항혈전 및 고지혈증 억제활성을 통해 전기 조성물의 효과를 입증하고자, 실험동물에 경구투여하여 생체 내에서의 항혈전 및 동맥경화 유발인자들의 감소효과를 측정하였다. 혈소판 응집 활성을 조사한 결과, 천연식물소재 추출 혼합 조성물(Thrombo-QTM) 투여군에서 정상군에 비해 2.3배의 응집억제활성을 나타내었다. 이는 아스피린을 투여한 대조군의 2.53배 억제활성의 약 90에 해당하는 값으로, 천연식물 추출 혼합물로도 효과적인 혈소판 응집 활성을 억제할 수 있다는 가능성을 보여주고 있다. 전혈 응고시간 및 혈장 응고시간의 지연 효과를 조사한 결과, 천연식물 소재 추출 혼합 조성물(Thrombo-QTM)이 전기의 혈소판 응집억제 활성과 더불어 유의한 수준의 효과를 가지고 있음을 확인하였으며, 출혈시간의 변화에 있어서는, 정상군보다 대조군이 2.45배, 투여군이 2.33배의 연장 효과를 보여주었다.In addition, to demonstrate the effect of the electrical composition through the anti-thrombotic and hyperlipidemic inhibitory activity of the natural plant extract mixture composition (Thrombo-Q TM ) in vivo, antithrombotic and arteriosclerosis in vivo by oral administration to experimental animals The reducing effect of the triggers was measured. As a result of examining platelet aggregation activity, the natural plant extract mixture composition (Thrombo-Q ™ ) administered group showed 2.3 times the aggregation inhibitory activity compared to the normal group. This corresponds to about 90 of the 2.53-fold inhibitory activity of the control group administered with aspirin, demonstrating the potential of inhibiting effective platelet aggregation activity even with natural plant extract mixtures. As a result of investigating the delayed effects of whole blood coagulation time and plasma coagulation time, it was confirmed that the natural plant extract mixture composition (Thrombo-Q TM ) had a significant level of effect with the platelet aggregation inhibitory activity. In the change, the control group showed 2.45 times longer than the normal group and the administration group showed 2.33 times longer.
한편, Thrombo-QTM투여 시, 실험동물에서의 고지혈증 위험인자들의 변화를 확인한 결과, 총 콜레스테롤(cholesterol)과 유리 콜레스테롤(free cholesterol) 및 콜레스테롤 에스테르(cholesterol ester) 농도의 변화에 있어서, 총 콜레스테롤은 26의 감소효과를, 콜레스테롤 에스테르의 수치는 약 27의 감소효과를 나타내었다. 이는 Thrombo-QTM투여가 고콜레스테롤 억제에 효과적임을 보여주고 있다. 또한, LDL-콜레스테롤 수치는 약 25의 유의한 감소효과를 나타내었고, HDL/LDL 구성비에 있어서도, 약 1.7배의 증가를 나타내었다. 상기의 결과를 바탕으로 산출한 동맥경화 지수 또한 현저하게 낮춘다는 사실을 확인하였다. 트리글리세라이드 (triglyceride) 함량의 변화에 있어서도, 약 14정도 감소됨을 관찰하였는데, 이는 Thrombo-QTM투여가 콜레스테롤 대사뿐만 아니라, 중성지방의 대사에도 상당한 영향을 미친다는 것을 의미한다.On the other hand, as a result of confirming the change in the risk factors of hyperlipidemia in experimental animals when Thrombo-Q TM was administered, the total cholesterol in the change of the concentrations of total cholesterol, free cholesterol and cholesterol ester, 26 decreased the cholesterol ester level was about 27. This shows that Thrombo-Q ™ administration is effective in suppressing high cholesterol. In addition, LDL-cholesterol levels showed a significant reduction of about 25 and about 1.7-fold increase in HDL / LDL composition ratio. The atherosclerosis index calculated based on the above results was also found to be significantly lowered. The change in triglyceride content was observed to be reduced by about 14, which means that Thrombo-Q ™ administration has a significant effect on metabolism of triglycerides as well as cholesterol metabolism.
이하, 실시예를 통하여 본 발명을 보다 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 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 in more detail, it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. .
실시예 1: 항혈전활성을 가진 천연식물 소재 추출물의 선별 Example 1 Screening of Natural Plant Material Extracts with Antithrombotic Activity
실시예 1-1: 천연식물 소재로부터 유효성분의 추출 Example 1-1 Extraction of Active Ingredients from Natural Plant Materials
본 실험에 사용한 천연물 소재 중 유효성분 분석을 위하여, 16 종의 생약: 영지(Ganoderma lucidum), 은행잎(Ginkgonis folium), 산사자(Crataegus pinnatifida), 녹차(Camelliae sinensis: Green Tea),홍차(Theae sinensis: Black tea), 포도씨(Vitis vinifera), 빌베리(Vaccinium myrtillus), 마늘(Allium sativum), 양파(Allium cepa), 건칠(Rhus vernicifula), 목단피(Paeonica suffruticosa), 구기자(Lycium chinensis), 오미자(Schizandra chinensis), 인삼(Panax ginseng), 과채(Cumunis melo) 및 천궁(Cinidium officinale) 등을 열수 추출하였다. 즉, 상기의 모든 천연물소재 10g을 100ml의 증류수에 침지하여 90℃에서 2시간 동안 역류(reflux) 하에서 추출한 다음, 진공상태로 증발시켜 건조하였으며, 각각의 추출물 10mg을 1ml의 증류수에 다시 용해시킨 후 0.4mm여과지로 여과한 다음, PBS(phosphate buffered saline) 완충용액을 이용하여 5mg/ml의 농도가 되도록 하였다. 그 외 대두유래 플라보노이드(flavonoid) 및 대두발효추출물(fermented soybean extract, (주)풀무원, 한국)은 증류수에 용해되지 않으므로, 10%(v/v)의 에탄올에 1차 용해한 후, 다시 1%(v/v)의 에탄올로 연속희석하여 사용하였다.For the analysis of active ingredients among the natural materials used in this experiment, 16 kinds of herbal medicines: Ganoderma lucidum (Ganoderma lucidum), Ginkgo biloba (Ginkgonis folium), Mountain Lion (Crataegus pinnatifida), green tea(Camelliae sinensis: Green Tea),black tea(Theae sinensis: Black tea), grape seed (Vitis vinifera), Bilberry (Vaccinium myrtillus), garlic(Allium sativum), onion(Allium cepa), Dry (Rhus vernicifula), Neck skin (Paeonica suffruticosa), Wolfberry (Lycium chinensis), Schisandra(Schizandra chinensis), Ginseng(Panax ginseng), Fruit (Cumunis melo) And the skyCinidium officinale) And hot water extraction. That is 10 g of all natural materials were immersed in 100 ml of distilled water, extracted under reflux at 90 ° C. for 2 hours, and then evaporated to dryness in vacuo. After filtration, a concentration of 5 mg / ml was obtained using PBS (phosphate buffered saline) buffer. Soybean-derived flavonoids and fermented soybean extracts (Pulmuone, Korea) are not soluble in distilled water, so they are first dissolved in 10% (v / v) ethanol and then 1% ( v / v) was used by serial dilution with ethanol.
실시예 1-2: 실험실적 조건에서의 항혈전활성의 측정 Example 1-2 Determination of Antithrombotic Activity in Laboratory Conditions
실험실적 조건에서의 항혈전활성의 측정을 위하여, 유효성분 추출물의 혈액응고 억제활성, 혈전 용해 활성 및 혈소판 응집 억제 활성을 측정하였다: 실험실적 조건에서의 혈액응고 활성은 혈장 0.1ml에 동일부피의 50mM CaCl2를 첨가하여혈장이 응고될 때까지의 시간을 응집탱크(Coagulator, Behnk Elektronik Co., Germany)를 이용하여 측정하였고, 혈전 용해 활성을 측정하기 위해서는 피브리노겐(fibrinogen, (주)녹십자, 한국)을 기질로 하는 피브린 평판법(참조: Chung K. H., et al., Kor. Biochem. J., 25:696, 1992)을 응용하였다. 즉, 0.7(w/v) 사람의 피브리노겐 용액 10ml에 100NIH units/ml 농도의 사람 트롬빈(human thrombin, (주)녹십자, 한국) 용액 0.1ml을 잘 섞어 페트리디쉬(내경 10cm)에 부은 후, 실온에서 30분간 방치하여 피브린 평판(fibrin plate)를 제조한 다음, 시료를 10㎕씩 점적하여 37℃에서 하룻밤 반응하여 용해된 구획의 내경을 측정하여 용해활성을 측정하였다. 또한, 혈소판 응집 억제활성은 미리 예열된 실리콘 처리 응집탱크 유리 큐벳(coagulator glass cuvette)에 시료가 포함된 전혈(whole blood) 450㎕ 및 생리식염수 450㎕를 잘 혼합하여 37℃에서 3분간 가온시키고, 여기에 1mg/ml 농도의 콜라겐(collagen, Chrono-Log Co. U.S.A.) 5㎕를 첨가한 후, 혈소판 응집측정기(platelet aggregometer)를 이용한 전기전도도 측정방법(impedance method)법으로 혈소판응집 억제능을 측정하였다(참조: Nunez D., et al., Haemostas., 51:198, 1984).In order to measure the antithrombotic activity under laboratory conditions, the anticoagulant activity, thrombus lysis activity and platelet aggregation inhibitory activity of the active ingredient extracts were measured: The time until the coagulation of the plasma by adding 50 mM CaCl 2 was measured using a coagulation tank (Coagulator, Behnk Elektronik Co., Germany), and fibrinogen (Green Cross, Korea) was used to measure the thrombolytic activity. Fibrin plate method (see Chung KH, et al., Kor. Biochem. J., 25: 696, 1992) as a substrate. In other words, 10 ml of 0.7 (w / v) human fibrinogen solution is mixed with 0.1 ml of human thrombin (Green Cross, Korea) solution of 100NIH units / ml, and poured into Petri dish (10cm inside diameter). After leaving for 30 minutes to prepare a fibrin plate (fibrin plate) was prepared, and then 10 ㎕ each sample was reacted overnight at 37 ℃ to measure the dissolution activity by measuring the inner diameter of the dissolved compartment. In addition, the platelet aggregation inhibitory activity is warmed at 37 ° C. for 3 minutes by mixing well the preheated silicon treated coagulator glass cuvette with 450 μl of whole blood and 450 μl of saline solution. 5 μl of collagen (collagen, Chrono-Log Co. USA) at a concentration of 1 mg / ml was added thereto, and platelet aggregation inhibition was measured by an impedance method using a platelet aggregometer. (Nunez D., et al., Haemostas., 51: 198, 1984).
하기 표 1에서 보듯이, 혈액 응고 및 혈소판 응집을 억제하고 혈전용해 활성을 모두 나타내는 소재로는, 산사자, 녹차, 홍차, 포도씨, 빌베리 등 5종이 확인되었다. 이외에도, 3가지 활성을 모두 억제하지는 않았지만, 영지 추출물에서는 혈소판응집 억제활성이, 은행잎 추출물에서는 항응고작용이, 대두발효 추출물과 대두유래 플라보노이드는 혈전용해 활성이 우수하였다.As shown in Table 1 below, as a material that inhibits blood coagulation and platelet aggregation and exhibits thrombolytic activity, five species including mountain lion, green tea, black tea, grape seed, and bilberry were identified. In addition, all three activities were not inhibited, but platelet aggregation inhibitory activity in ganoderma lucidum extract, anticoagulant activity in ginkgo biloba extract, and soybean fermentation extract and soybean-derived flavonoids were excellent in thrombolytic activity.
*혈액응고 및 혈소판 응집에 관한 상대적 억제효과 정도는 다음과 같이 나타내었다: -, 비억제; +, 약한 억제; ++, 강한 억제; +++, 매우 강한 억제; n.d., 미확인(not detected) The relative degree of inhibitory effect on blood coagulation and platelet aggregation was expressed as follows:-, non-inhibition; +, Mild inhibition; ++, strong inhibition; +++, very strong inhibition; nd, not detected
a혈전 용해 활성에 대한 상대적 효과는 다음과 같이 나타내었다: -, 비활성; +, 약한 활성; ++, 강한 활성; +++, 매우 강한 활성 a Relative effect on thrombolytic activity is shown as follows:-, inactive; +, Weak activity; ++, strong activity; +++, very strong active
이러한 실험실적 조건의 실험 결과를 근거로 하여 항혈전소재를 선별하고, 건강보조식품의 제조규정인 식품공전(참조: 식품공전, 한국식품공업협회, 1997)의 기준에 따라 각 소재들의 함량을 결정하였다. 또한, 대두발효추출물과 대두유래 플라보노이드는 거의 활성이 유사하였고, 그 주원료가 동일한 대두로서, 원료수급 면에서 대두발효추출물이 유리하다고 판단되어, 대두발효추출물만을 선택하였다.Of these laboratory conditions Based on the experimental results, anti-thrombotic materials were selected, and the content of each material was determined according to the standards of the Food Code (Reference: Food Code, Korea Food Industry Association, 1997). In addition, the soybean fermented extract and soybean-derived flavonoids were almost similar in activity, and the soybean fermented extract was selected only because the soybean fermented extract was found to be advantageous in terms of raw material supply.
실시예 2: 천연식물소재 추출 혼합물을 이용한 항혈전 및 고지혈증 억제 조 Example 2 Antithrombotic and Hyperlipidemic Inhibition Tank Using Natural Plant Extract Mixtures
성물(Thrombo-QTM)의 제조Preparation of Relic (Thrombo-Q TM )
항혈전 및 고지혈증 활성을 지닌 천연식물 소재 추출 혼합 조성물(Thrombo-QTM)의 제조를 위하여, 실시예 1의 실험실적 조건에서의 항혈전활성 측정결과와 기보고된 자료 및 국가에서 공시한 식품공전(참조: 식품공전, 한국식품공업협회,1997)을 근거로 사용가능한 소재를 엄선하고, 적절한 함량비로 혼합하여 혈전예방 및 고지혈증 예방을 위한 새로운 형태의 혼합 조성물인 Thrombo-QTM를 제조하게 되었는 바, 각 천연식물소재 추출물들의 성분 및 성분비는 다음과 같다(참조: 표 2).In order to prepare a natural plant extract mixed composition (Thrombo-Q TM ) having antithrombotic and hyperlipidemic activity, the results of the measurement of antithrombotic activity under the laboratory conditions of Example 1, the reported data, and the national food disclosure (Reference: Korea Food Industry Association, Korea Food Industry Association, 1997) Based on the selection of available materials and mixing in an appropriate content ratio to produce Thrombo-Q TM , a new type of composition for preventing thrombus and hyperlipidemia. , Components and ratios of the extracts of each natural plant material are as follows (see Table 2).
본 발명의 천연식물 소재 추출물은 캡슐화하기 전의 혼합물 상태로서, 천연식물 소재 혼합 조성물(Thrombo-QTM)의 제조를 위해서는, 캡슐 제형화에 필요한 부형제로서, 천연식물 소재 추출 혼합물 전체 중량 100부에 대하여, 어유(fish oil) 또는 대두유(soybean oil) 100 내지 200부; 왁스 5 내지 20부; 비타민 P 0.5부 내지 2부; 및, 니아신(niacin) 0.5 내지 2부의 양이 추가로 함유되도록 한다. 생체내에서의 항혈전 및 고지혈증 억제활성을 통하여 상기 제조한 천연식물 소재 추출 혼합 조성물의 효과를 입증하고자, 실험동물에 경구투여하여 생체 내에서의 항혈전 및 동맥경화 유발인자들의 감소효과를 측정하였다.The natural plant extract of the present invention is a mixture state before encapsulation, and in order to prepare a natural plant mixture composition (Thrombo-Q ™ ), as an excipient required for capsule formulation, with respect to 100 parts by weight of the total natural plant extract mixture 100 to 200 parts of fish oil or soybean oil; 5 to 20 parts wax; 0.5 parts to 2 parts of vitamin P; And an amount of 0.5 to 2 parts of niacin. In order to demonstrate the effect of the natural plant extract mixture composition prepared by the anti-thrombotic and hyperlipidemic inhibitory activity in vivo, oral administration to experimental animals was measured the effect of reducing the antithrombotic and atherosclerosis inducing factors in vivo. .
실시예 3: Thrombo-QTM의 투여시, 실험동물에서의 항혈전활성의 변화 측정 Example 3 Measurement of Changes in Antithrombotic Activity in Experimental Animals Upon Administration of Thrombo-Q ™
실시예 3-1: 혈소판 응집 활성의 변화 측정 Example 3-1 Measurement of Change in Platelet Aggregation Activity
혈소판 응집 활성의 초기치 분석을 위하여, 혈소판 응집분석기(platelet aggregometer, Chrono-log Co., USA)를 이용하였는데, 이때, 전혈(whole blood)을 이용한 전기의 전기전도도 측정 방법(impedance method)을 사용하였다. 총 30마리의 SD 레트(Sprague-Dawley rat)를 에테르(ether)로 마취시킨 후, 개복하지 않은 상태에서 26 게이지의 바늘을 이용, 심장에서 직접 채혈(전혈 2ml)하여 콜라겐 유발 혈소판 응집 실험(collagen-induced platelet aggregation test)에 사용하였다. Thrombo-QTM투여 후, 후기치 분석은 SD 레트 30마리의 콜라겐-유발 혈소판 응집 결과를 근거로 그룹 간의 혈소판 응집 활성을 평균적으로 동일하게 선별한 다음, 각 군당 10마리씩을 할당하여 담체인 0.5의 카르복시메틸 셀룰로오스(carboxymethyl cellulose: CMC)만을 섭취하는 정상군, 아스피린(aspirin)을 섭취하는 대조군, Thrombo-QTM를 투여한 투여군 등 세그룹으로 나누어 실험을 수행하였다. 담체로서0.5의 CMC를 사용하여, 대조군은 100mg/kg의 아스피린을, 투여군은 100mg/kg의 Thrombo-QTM를 매일 1회 6일간 경구투여한 후, 12시간 동안 절식시키고, 7일째 되는 마지막 날 한번 더 경구투여를 하여, 1시간 후 에테르 마취하에 심장으로부터 혈액을 채취하여 후기치를 분석하였다(참조: 도 1).To analyze the initial value of platelet aggregation activity, a platelet aggregometer (Chrono-log Co., USA) was used, in which the electrical conductivity measurement method using whole blood was used. . A total of 30 Sprague-Dawley rats were anesthetized with ether, and then collected directly from the heart using a 26-gauge needle in an unopened state. -induced platelet aggregation test). After Thrombo-Q ™ administration, the post-treatment assay selected the same average platelet aggregation activity between groups based on the collagen-induced platelet aggregation results of 30 SD rats, and then assigned 10 animals in each group to provide a carrier of 0.5. The experiments were divided into three groups: normal group ingesting only carboxymethyl cellulose (CMC), control group ingesting aspirin, and administration group in which Thrombo-Q ™ was administered. Using 0.5 CMC as a carrier, the control group was orally administered 100 mg / kg of aspirin and 100 mg / kg of Thrombo-Q ™ once daily for 6 days, followed by fasting for 12 hours, and on the last day of day 7. Once again orally, blood was collected from the heart under ether anesthesia one hour later, and analyzed later (see FIG. 1).
도 1에서 보듯이, 혈소판 응집 활성을 조사한 결과 투여군에서 정상군에 비해 2.3배의 응집 억제 활성을 나타내었다. 이는 아스피린을 투여한 대조군의 2.53배 억제활성의 약 90에 해당하는 값으로, 천연식물 추출 혼합물로도 효과적인 혈소판 응집 활성을 억제할 수 있다는 가능성을 보여주고 있다.As shown in FIG. 1, the result of the investigation of platelet aggregation activity showed 2.3-fold aggregation inhibition activity in the administration group compared to the normal group. This corresponds to about 90 of the 2.53-fold inhibitory activity of the control group administered with aspirin, demonstrating the potential of inhibiting effective platelet aggregation activity even with natural plant extract mixtures.
실시예 3-2: 전혈(whole blood) 응고시간의 변화 측정 Example 3-2 Measurement of Changes in Whole Blood Coagulation Time
전혈(whole blood) 응고시간 측정을 위하여, 심장으로부터 채취한 전혈 0.25ml에 1.7CaCl20.05ml을 첨가한 후, 응집탱크(Coagulator, Behnk Elektronik Co., Germany)를 이용하여, 칼슘으로 유도되는 전혈의 응고시간을 각 군별로 살펴보았다(참조: 도 2). 도 2에서 보듯이, 정상군보다 대조군이 3.3배, 투여군이 3.1배 증가함을 나타내었다. 이는 Thrombo-QTM경구투여에 인한 전혈 응고시간이 아스피린보다는 못하지만, 역시 전혈응고시간 연장에 효과적으로 작용하고 있다는 사실을 보여주고 있다.In order to measure the whole blood clotting time, 0.05 ml of 1.7CaCl 2 was added to 0.25 ml of whole blood collected from the heart, and then calcium-induced whole blood using a coagulator tank (Coagulator, Behnk Elektronik Co., Germany). The coagulation time of was examined for each group (see Fig. 2). As shown in Figure 2, the control group was 3.3 times higher than the control group, the administration group showed an increase of 3.1 times. This suggests that the whole blood clotting time due to oral administration of Thrombo-Q ™ is less than that of aspirin, but it is also effective in prolonging whole blood clotting time.
실시예 3-3: 혈장 응고시간의 변화 측정 Example 3-3 Measurement of Change in Plasma Coagulation Time
혈장 응고시간의 변화를 측정하기 위하여, 채혈한 전혈을 4,500rpm, 10분간 원심분리하여 얻은 혈장 0.1ml에 50mM CaCl20.1ml을 첨가하여 각각의 혈장 응고시간을 측정하였다(참조: 도 3). 도 3에서 보듯이, 상기의 전혈 응고시간에서와 마찬가지로, 혈장응고시간을 각 군별로 측정해보았을 때, 대조군이 3.4배, 투여군이 2.33배 정도 정상군보다 혈장응고시간이 지연되었다. 이는 전혈 응고시간에서와 마찬가지로 역시 Thrombo-QTM투여군이 혈장응고시간에도 영향을 준다고 판단되었다.In order to measure the change in plasma coagulation time, the blood coagulation time was measured by adding 0.1 ml of 50 mM CaCl 2 to 0.1 ml of plasma obtained by centrifugation of 4,500 rpm for 10 minutes (see FIG. 3). As shown in Figure 3, as in the whole blood coagulation time, when the plasma coagulation time was measured for each group, the plasma coagulation time was delayed by 3.4 times in the control group, 2.33 times in the administration group. As in whole blood coagulation time, Thrombo-Q TM group also affected plasma coagulation time.
실시예 3-4: 출혈시간의 변화 측정 Example 3-4 Measurement of Change in Bleeding Time
출혈시간은 혼스트라(Hornstra) 등이 보고한 방법(참조: Hornstra G., et al., Prostagladins, 51:198, 1984)에 따라서 측정하였다. 실험은 3군으로 나누어 수행하였는데, 0.5CMC 담체만을 섭취한 정상군, 아스피린을 투여한 대조군, Thrombo-QTM를 투여한 군으로 각 군 당 10마리씩의 SD 레트를 이용하여 실시예 3-1에서 상술한 방법과 동일하게 실험을 수행하였다. 단, 7일째 되는 마지막 날 경구투여를 하고 1시간 후 졸레틸(Zoletil, Virbac Co, France)로 복강 마취하였으며, 꼬리 말단에서 5mm되는 부분을 절단하고 그 곳으로부터 5cm 정도 되는 곳까지 37℃생리식염수에 담구어, 혈액이 나오는 시점을 기준으로 혈액의 흐름이 멈춘 시점(loose & temporary platelet plug)까지를 출혈시간으로 측정하였다(참조: 도 4).Bleeding time was measured according to the method reported by Hornstra et al. (Honstra G., et al., Prostagladins, 51: 198, 1984). The experiment was divided into three groups, in which the normal group ingested with only 0.5CMC carrier, the control group administered with aspirin, and the group administered Thrombo-Q ™ were used in Example 3-1 using 10 SD rats in each group. The experiment was carried out in the same manner as described above. However, 1 hour after the last day of oral administration on the 7th day was intraperitoneally anesthetized with Zoletil (Zoletil, Virbac Co, France), and cut 5mm at the tail end and physiological saline at 37 ° C to about 5cm from there. After immersion, the blood flow was stopped from the point at which blood flow was stopped (loose & temporary platelet plug) was measured as a bleeding time (see FIG. 4).
도 4에서 보듯이, 출혈시간 변화를 조사한 결과 정상군보다 대조군이 2.45배, 투여군이 2.33배의 연장 효과를 보여주었다. 이러한 결과는 앞에서 보여준 혈소판 응집억제 활성, 전혈응고시간, 혈장응고 시간의 지연결과와 밀접한 관계가 있음을 나타내고 있다(참조: 표 3).As shown in Figure 4, as a result of examining the change in bleeding time, the control group showed a prolongation effect of 2.45 times, the administration group 2.33 times than the normal group. These results indicate that the platelet aggregation inhibitory activity, whole blood clotting time, and plasma coagulation time delay are shown to be closely related to each other (see Table 3).
..
실시예 4: Thrombo-QTM투여 시 실험동물에서의 고지혈증 위험인자들의 변 Example 4 Stool Changes in Hyperlipidemia Risk Factors in Experimental Animals Upon Thrombo-Q ™ Administration
화 조사Angry investigation
Thrombo-QTM투여 시, 총 콜레스테롤(cholesterol)과 유리 콜레스테롤(free cholesterol) 및 콜레스테롤 에스테르(cholesterol ester)의 농도 변화를 측정하기 위하여, 고지혈증 유발을 위한 합성식이를 다음, 하기 표 4와 같이 제조하여 정상군을 제외한 각군의 동물들에게 6주동안 섭취케 하였다. 체중과 식이섭취량은 일주일에 한번씩 측정하고, 물은 자유로이 섭취케 하였다.In order to measure the concentration change of total cholesterol, free cholesterol and cholesterol esters upon administration of Thrombo-Q ™ , a synthetic diet for hyperlipidemia was prepared as follows in Table 4 below. Animals of each group except normal group were ingested for 6 weeks. Body weight and dietary intake were measured once a week and water was taken freely.
실험은 정상군, 대조군, 투여군 등 세 군으로 나누어 수행하였는데, 정상군은 일반사료만을, 대조군은 고지혈증 유발식이를 섭취케 하였고, 투여군은 고지혈증 유발식이와 함께 매일 Thrombo-QTM(100mg/kg)를 경구투여시켰다. 혈액채취 전날 12시간 전부터 절식을 수행하여 식이에 대한 변화를 배제하였다. 혈액채취 시에는 에테르 마취 하에 개복한 후, 복부 대동맥으로부터 혈액을 항응고제가 함유된 시험관에 채취한 다음 3,000rpm에서 15분간 원심분리하여 혈장만을 채취하고 생화학적 분석시까지 냉동보관하였다.The experiment was divided into three groups: normal group, control group, and administration group. The normal group consumed only normal diet, the control group consumed hyperlipidemia-induced diet, and the administration group daily with Thrombo-Q TM (100mg / kg). Was administered orally. Fasting was performed 12 hours before the day of blood collection to exclude changes in diet. When blood collection was performed under ether anesthesia, blood was collected from the abdominal aorta into a test tube containing anticoagulant and centrifuged at 3,000 rpm for 15 minutes to collect only plasma and cryopreserved until biochemical analysis.
도 5 에서 보듯이, 6주간 콜레스테롤과 동물성 지방을 동시 섭취시킨 SD 레트에서 총 콜레스테롤 수치는 정상군(86.4mg/dl)보다 고지혈증 유발식이 섭취 대조군(205.6mg/dl)에서 2.13배, 콜레스테롤 에스테르 값은 22.4mg/dl에서 64mg/dl에서 182.4mg/dl로 약 2.9배의 증가치를 나타내었으나, 유리 콜레스테롤 값은 거의 변화가 없음을 관찰하였다. 이 결과로 고지혈증 유발식이에 의한 고지혈증 유발이 잘 수행되었다는 것을 확인하였다. Thrombo-QTM을 고지혈증 유발식이와 동시 투여한 투여군에서는, 총 콜레스테롤 수치가 151.5mg/dl로서 대조군의 값보다 약 26의 감소효과를, 콜레스테롤 에스테르의 수치는 182.4mg/dl에서 134mg/dl로 약 27의 감소효과를 나타내었다. 유리 콜레스테롤(free-cholesterol)의 측정치는 정상군, 대조군, 투여군 모두 큰 차이는 보이지 않았다. 이는 Thrombo-QTM투여가 고콜레스테롤 억제에 효과적임을 보여주고 있다. 도 5에서, ?는 총 콜레스테롤 수치를, ▨는 유리 콜레스테롤의 수치를, ▧는 콜레스테롤 에스테르의 수치를 나타낸다.As shown in Figure 5, the total cholesterol level in the SD rats fed with cholesterol and animal fat for 6 weeks was 2.13 times higher in cholesterol-induced diet intake control group (205.6 mg / dl) than in normal group (86.4 mg / dl), cholesterol ester value Showed a 2.9-fold increase from 22.4 mg / dl to 642.4 / dl to 182.4 mg / dl, but there was little change in free cholesterol. As a result, it was confirmed that the hyperlipidemia induced by the hyperlipidemia induced diet was well performed. In the co-administration group of Thrombo-Q ™ with a hyperlipidemic diet, the total cholesterol level was 151.5 mg / dl, which was about 26 times lower than that of the control group, and the cholesterol ester level was 182.4 mg / dl to 134 mg / dl. A reduction effect of 27 was shown. The measurement of free-cholesterol showed no significant difference in the normal, control and administration groups. This shows that Thrombo-Q ™ administration is effective in suppressing high cholesterol. In Fig. 5,? Denotes the total cholesterol level,? Represents the level of free cholesterol, and? Represents the level of the cholesterol ester.
혈중 지질변화의 측정에 있어서, 원심분리하여 얻어진 혈장 중의 중성지방은 부콜로(Bucolo) 방법(참조: Bucolo G., et al., Clin. Chem., 19:456, 1973)에 따라 진단시약을 사용하여 550nm에서의 흡광도 변화로 측정하였으며, 혈중 총-콜레스테롤은 효소법에 의한 방법을 사용하여 500nm에서 흡광도를 측정하여 비색정량하였다. 고밀도 지질단백질(HDL) 콜레스테롤의 측정은 혈장 내 HDL-콜레스테롤을 제외한 콜레스테롤을 침전시켜 제거한 후 상층액을 검체로 하여 혈중 총-콜레스테롤과 같은 방법으로 측정하였으며, 저밀도 지질단백질(LDL)-콜레스테롤은 분리시액으로 혈장내 LDL-콜레스테롤만을 침전시켜 역시 총-콜레스테롤과 같은 방법으로 측정하였다. 동맥경화지수는 총-콜레스테롤에 HDL-콜레스테롤을 뺀 값을 HDL-콜레스테롤로 나누어서 산출하였다(참조: 도 6, 도 7a 및 도 7b).In the measurement of lipid changes in blood, triglycerides obtained in the plasma were subjected to diagnostic reagents according to the Buccolo method (see Bucolo G., et al., Clin. Chem., 19: 456, 1973). The absorbance was measured at 550 nm, and blood total cholesterol was measured by colorimetric measurement at 500 nm using the enzymatic method. HDL cholesterol was measured by precipitating and removing cholesterol except for HDL-cholesterol in plasma. Precipitating only LDL-cholesterol in plasma with the test solution was also measured in the same way as total-cholesterol. Arteriosclerosis index was calculated by subtracting HDL-cholesterol from total-cholesterol divided by HDL-cholesterol (see FIGS. 6, 7A and 7B).
도 6에서 보듯이, HDL-콜레스테롤, LDL-콜레스테롤의 변화 측정을 위한 동물실험 결과, LDL-콜레스테롤은 정상군(15.1mg/dl)보다 고지혈증 유발 식이 섭취 대조군(72.2mg/dl)에서 약 4.8배의 증가율을 보여주었으나, HDL-콜레스테롤은 다소 감소한 결과를 보였는데, 이는 고지혈증 유발 식이가 혈중 내 LDL-콜레스테롤만을 급증시키며 HDL-콜레스테롤 함량에는 영향을 주지 않는다는 사실을 보여 주고 있다. 6주간의 Thrombo-QTM경구투여 후, HDL- 및 LDL-콜레스테롤 농도를 살펴본 결과, 역시 HDL-콜레스테롤은 거의 변화가 없었지만, LDL-콜레스테롤 수치는 고지혈증 유발식이 섭취 대조군(72.2mg/dl)보다 Thrombo-QTM을 고지혈증 유발식이와 동시 투여한 투여군(54.5mg/ml)에서 약 25의 유의한 감소효과를 나타내었다. 도 6에서, ?는 HDL-콜레스테롤의 함량을, ▧는 LDL-콜레스테롤의 함량을 나타낸다.As shown in Figure 6, the results of animal experiments for measuring the change of HDL-cholesterol, LDL-cholesterol, LDL-cholesterol was about 4.8 times higher in hyperlipidemia-induced dietary intake control group (72.2mg / dl) than normal group (15.1mg / dl). Although HDL-cholesterol increased slightly, it was shown that HDL-induced diet significantly increased LDL-cholesterol in the blood and did not affect HDL-cholesterol content. After six weeks of oral administration of Thrombo-Q ™ , HDL- and LDL-cholesterol levels showed little change in HDL-cholesterol, but LDL-cholesterol levels were higher than those of the hyperlipidemic dietary intake control group (72.2 mg / dl). In the group administered with -Q TM and the hyperlipidemia induced diet (54.5 mg / ml), a significant reduction of about 25 was shown. In Figure 6,? Indicates the content of HDL-cholesterol, ▧ indicates the content of LDL-cholesterol.
도 7a에서 보듯이, HDL/LDL 구성비 및 동맥경화 지수(atherogenic index)에대한 측정결과, HDL/LDL 구성비에 있어서도, 대조군은 0.128이었고, 투여군은 0.215로서 약 1.7배의 증가를 나타내었다(참조: 도 7a). 상기의 결과를 바탕으로 동맥경화 지수를 산출해본 결과, 대조군은 26.3인데 비해 투여군에서는 14.8로서, Thrombo-QTM의 투여가 동맥경화지수를 현저하게 낮춘다는 사실을 보여주고 있다(참조: 도 7b).As shown in FIG. 7A, as a result of the measurement of the HDL / LDL composition and the atherosclerotic index, the control group was 0.128 and the administration group showed an increase of about 1.7 times (0.215) in the HDL / LDL composition ratio. 7a). As a result of calculating the arteriosclerosis index based on the above results, the control group was 26.3, whereas the control group was 14.8, indicating that administration of Thrombo-Q TM significantly lowered the arteriosclerosis index (see FIG. 7B). .
Thrombo-QTM의 투여 시, 중성지방인 트리글리세라이드(triglyceride) 함량의 변화에 있어서는, 대조군보다 투여군에서의 트리글리세라이드의 농도가 74mg/dl에서 64mg/dl로 약 14정도 감소됨을 관찰하였다(참조: 도 8). 이는 Thrombo-QTM투여가 콜레스테롤 대사뿐만 아니라, 중성지방의 대사에도 상당한 영향을 준다고 볼 수 있다(참조: 표 5).In the case of administration of Thrombo-Q ™ , the triglyceride content, which is a triglyceride, decreased by about 14 from 74 mg / dl to 64 mg / dl in the administration group than the control group. 8). It can be seen that Thrombo-Q ™ administration significantly affects metabolism of triglycerides as well as cholesterol metabolism (Table 5).
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시태양일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.As described above in detail the specific parts of the present invention, for those skilled in the art, these specific descriptions are only preferred embodiments, which are not intended to limit the scope of the present invention. Will be obvious. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
이상에서 상세히 설명하고 입증하였듯이, 본 발명은 항혈전 활성 및 항고지혈 활성을 지닌 천연식물소재 추출 혼합 조성물(Thrombo-QTM)을 제공한다. 본 발명의 항혈전 및 고지혈증 억제 조성물은 실험실적 조건 및 생체내 조건에서 혈전용해, 혈소판 응집 활성 및 혈액응고 활성을 저하시킬 수 있음은 물론, 혈중 콜레스테롤 및 혈중 중성지방 억제 등의 활성을 지니고 있는 것으로 밝혀졌다. 본 발명의 천연식물소재 추출 혼합물을 이용한 항혈전 및 고지혈증 억제조성물은 혈중 콜레스테롤의 감소, 혈소판 응집 활성 및 혈액응고활성을 저하시킬 수 있을 뿐만 아니라, 심혈관계 질환을 효과적으로 예방할 수 예방할 수 있는 1차 예방제의 제조에도 널리 활용될 수 있을 것이다.As described and demonstrated in detail above, the present invention provides a natural plant material extract mixture composition (Thrombo-Q ™ ) having antithrombotic activity and antihyperlipidemic activity. The antithrombotic and hyperlipidemic inhibitory composition of the present invention is capable of lowering thrombolysis, platelet aggregation activity and blood coagulation activity under laboratory conditions and in vivo conditions, as well as having activities such as inhibiting blood cholesterol and triglyceride in blood. Turned out. Anti-thrombotic and hyperlipidemic inhibitor compositions using the natural plant material extract mixture of the present invention can not only reduce blood cholesterol, reduce platelet aggregation activity and blood coagulation activity, but can also prevent cardiovascular diseases effectively. It can also be widely used in the manufacture of.
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| KR100419451B1 (en) * | 2000-10-09 | 2004-03-11 | 드림바이오젠 주식회사 | Protein with thrombolytic activities extracted from natural product |
| US20030203854A1 (en) * | 2002-04-23 | 2003-10-30 | Ivo Pischel | Composition for effecting serum cholesterol levels |
| KR20040030376A (en) * | 2002-10-02 | 2004-04-09 | 천연제약 주식회사 | Pharmaceutical composition for treatment of thrombosis |
| PL2218342T3 (en) * | 2003-05-27 | 2019-01-31 | Dsm Ip Assets B.V. | Novel nutraceutical compositions and use thereof |
| ITMI20031313A1 (en) | 2003-06-27 | 2004-12-28 | Indena Spa | ASSOCIATIONS OF VASOPROTECTOR AGENTS AND FORMULATIONS CONTAINING THEM. |
| KR100733984B1 (en) * | 2004-07-19 | 2007-06-29 | 이동웅 | A pharmaceutical composition having effects of cure and prevention of obesity and hyperlipidemia by containing konjac and extract of medicinal herbs |
| KR100656241B1 (en) * | 2004-09-10 | 2006-12-11 | 롯데제과주식회사 | The extract of Korean fermented soybean with inhibitory effect on hyperlipemia and platelet aggregation, and their composition |
| KR101797993B1 (en) * | 2017-06-09 | 2017-12-12 | 조전호 | Composition comprising crude drug of willow variant for treating, preventing or improvingcardiovascular disease |
-
1999
- 1999-07-12 KR KR1019990028024A patent/KR100319397B1/en not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100496622B1 (en) * | 2002-04-29 | 2005-06-29 | (주) 김형민한약연구소 | Alcohol fermented food or pharmaceutical composition for prevention of obesity and process for preparation thereof |
| KR101575448B1 (en) | 2014-02-06 | 2015-12-09 | 건양대학교산학협력단 | Manufacturing Method of Black Tea Extract Having Anti-thrombus Effect |
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| Publication number | Publication date |
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| KR20010009590A (en) | 2001-02-05 |
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