KR102013312B1 - Pharmaceutical composition comprising the extract of apios americana medikus as an effective component for prevention or treatment of thrombosis and health functional food comprising the same - Google Patents
Pharmaceutical composition comprising the extract of apios americana medikus as an effective component for prevention or treatment of thrombosis and health functional food comprising the same Download PDFInfo
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- KR102013312B1 KR102013312B1 KR1020170105767A KR20170105767A KR102013312B1 KR 102013312 B1 KR102013312 B1 KR 102013312B1 KR 1020170105767 A KR1020170105767 A KR 1020170105767A KR 20170105767 A KR20170105767 A KR 20170105767A KR 102013312 B1 KR102013312 B1 KR 102013312B1
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- Prior art keywords
- extract
- thrombosis
- apios
- active ingredient
- pharmaceutical composition
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Abstract
본 발명은 아피오스(Apios americana Medikus) 추출물을 유효성분으로 함유하는 혈전증(thrombosis)의 예방 또는 치료용 약학적 조성물 및 건강 기능 식품에 관한 것으로서, 보다 구체적으로는, 아피오스 에탄올 추출물의 에틸아세테이트 분획물을 유효성분으로 하는 강력한 혈액 응고 저해 및 혈소판 응집 저해를 통한 혈전증의 예방 또는 치료/개선용 약학적 조성물 및 건강 기능 식품에 관한 것이다. 본 발명의 혈전증의 예방 및 치료 또는 개선용 약학적 조성물 및 건강 기능 식품의 유효성분으로서의 아피오스 추출물은 혈전 생성 관련 효소 및 혈액 응고 인자의 저해에 의한 강력한 항혈전 활성을 나타냄과 동시에, 인간 적혈구에 대한 용혈 활성을 전혀 나타내지 않고, 열 안정성이 우수하고, pH 2의 산성 조건 및 혈장 내에서도 혈액 응고 인자 저해 효과 및 혈전 생성 관련 효소 저해 효과의 손실이 나타나지 않으므로, 혈행 개선을 통해 허혈성 뇌졸중 및 출혈성 뇌졸중과 같은 혈전증의 예방 및 치료용으로 사용할 수 있을 것으로 기대되며, 상기 유효성분은 추출액, 분말, 환, 정 등의 다양한 형태로 가공되어 상시 복용이 가능한 형태로 조제할 수 있는 뛰어난 효과가 있으므로 제약 산업 및 식품 산업상 매우 유용한 발명인 것이다.The present invention relates to a pharmaceutical composition and a health functional food for preventing or treating thrombosis containing Apios americana Medikus extract as an active ingredient, and more specifically, ethyl acetate fraction of apius ethanol extract. The present invention relates to a pharmaceutical composition for the prevention or treatment / improvement of thrombosis through strong blood coagulation inhibition and platelet aggregation inhibition as an active ingredient, and a health functional food. Apiose extract as an active ingredient of the pharmaceutical composition for preventing and treating or improving thrombosis of the present invention and a health functional food exhibits strong antithrombotic activity by inhibition of a blood clotting enzyme and blood coagulation factor, It shows no hemolytic activity, no thermal hemolytic activity and no loss of blood coagulation factor and blood clotting enzyme-inhibiting effects in acidic conditions and plasma. It is expected to be used for the prevention and treatment of the same thrombosis, and the active ingredient is processed into various forms such as extract, powder, pills, tablets, etc., so that it can be prepared in a form that can be taken at all times in the pharmaceutical industry and It is a very useful invention in the food industry.
Description
본 발명은 아피오스(Apios americana Medikus) 추출물을 유효성분으로 함유하는 혈전증(thrombosis)의 예방 또는 치료용 약학적 조성물 및 건강 기능 식품에 관한 것으로서, 보다 구체적으로는, 아피오스 에탄올 추출물의 에틸아세테이트 분획물을 유효성분으로 하는 강력한 혈액 응고 저해 및 혈소판 응집 저해를 통한 혈전증의 예방 또는 치료/개선용 약학적 조성물 및 건강 기능 식품에 관한 것이다.The present invention relates to a pharmaceutical composition and a health functional food for preventing or treating thrombosis containing Apios americana Medikus extract as an active ingredient, and more specifically, ethyl acetate fraction of apius ethanol extract. The present invention relates to a pharmaceutical composition for the prevention or treatment / improvement of thrombosis through strong blood coagulation inhibition and platelet aggregation inhibition as an active ingredient, and a health functional food.
인체 구성 성분으로서의 혈액은 산소, 영양분, 노폐물의 운반 기능과 완충 작용, 체온 유지, 삼투압 조절 및 이온 평형 유지, 수분 일정 유지, 액성 조절 작용, 혈압의 유지 및 조절, 생체 방어 등 다양한 중요 기능들을 가지고 있다. 정상적인 혈액 순환은 체내에서의 혈액 응고 반응계와 혈전 용해 반응계가 상호 보완적으로 조절되면서 혈액 순환을 용이하게 하며, 이들 중 혈액 응고 반응계의 기작은 혈관벽에 혈소판이 점착, 응집하여 혈소판 혈전을 형성한 후, 혈액 응고계가 활성화되어 혈소판 응집괴를 중심으로 피브린 혈전이 형성되는 것으로 보고되어 있다. Blood as a human component has various important functions such as transporting and buffering oxygen, nutrients, and wastes, maintaining body temperature, controlling osmotic pressure and ion balance, maintaining moisture, controlling fluid, maintaining and regulating blood pressure, and defending the body. have. Normal blood circulation facilitates blood circulation as the blood coagulation reaction system and the thrombolytic reaction system in the body are complementarily regulated. Among them, the mechanism of the blood coagulation reaction system forms platelet thrombus due to the adhesion of platelets to the blood vessel walls and aggregation. In addition, it has been reported that the blood coagulation system is activated to form fibrin clots around platelet aggregates.
한편, 피브린 혈전의 생성은 수많은 혈액 응고 인자들의 여러 단계 반응을 거쳐 피브린 응고에 관여하는 트롬빈이 활성화되어, 최종적으로 피브리노겐으로부터 피브린 단량체를 생성하게 하며, 피브린 단량체들은 칼슘에 의해 중합되어, 혈소판과 내피세포에 결합하게 되며 XIII 인자에 의해 교차 결합된 피브린 폴리머를 형성하면서 영구적인 혈전을 생성하게 된다. 또한, 트롬빈은 혈소판, V 인자, VII 인자들을 활성화시켜 혈액 응고 반응을 촉진시키는 등 혈전 생성에 중추적 역할을 하게 된다. 따라서, 트롬빈의 활성 저해물질은 과다한 혈액 응고 이상으로 발생하는 다양한 혈전성 질환에 매우 유용한 예방 및 치료제로 사용될 수 있다. 한편, 내인성 혈전 생성 경로에는 XII 인자, XI 인자, IX 인자, X 인자의 순차적 활성화에 이은 프로트롬빈의 활성화가 최종적으로 트롬빈을 활성화하는 것으로 알려져 혈액 응고 인자의 특이적 저해 역시 중요한 혈전성 질환 치료제의 개발 타겟이 되고 있다. 현재까지 혈전성 질환의 예방과 치료에 헤파린, 쿠마린, 아스피린, 유로키네이즈 등의 다양한 항응고제, 항혈소판제, 혈전용해제 등이 사용되고 있으나, 이들은 가격이 매우 높을 뿐 아니라, 출혈성 부작용과 위장 장해 및 과민 반응 등으로 그 사용이 한정되고 있는 실정이다. On the other hand, the generation of fibrin thrombus is a multi-step reaction of numerous blood coagulation factors that activates thrombin, which is involved in fibrin coagulation, and finally generates fibrin monomers from fibrinogen, and the fibrin monomers are polymerized by calcium, thereby forming platelets and endothelial cells. It binds to cells and creates permanent thrombi, forming fibrin polymers cross-linked by factor XIII. In addition, thrombin plays a pivotal role in thrombus formation by activating platelets, factor V and factor VII to promote blood coagulation. Therefore, thrombin activity inhibitors can be used as a prophylactic and therapeutic agent that is very useful for various thrombotic diseases that occur due to excessive blood clotting. Meanwhile, in the endogenous thrombus generation pathway, sequential activation of XII, XI, IX and X factors is followed by the activation of prothrombin, which is known to activate thrombin. It is targeted. To date, various anticoagulants such as heparin, coumarin, aspirin, urokinase, antiplatelets, and thrombolytic agents have been used for the prevention and treatment of thrombotic diseases, but they are not only expensive but also have hemorrhagic side effects, gastrointestinal disorders and hypersensitivity reactions. Its use is limited to such circumstances.
아피오스(Apios americana Medikus)는 덩굴성의 다년생 콩과식물(Leguminosae)로 원산지는 북미 동부의 온대 및 아열대 지역이다. 아피오스는 big potato, indian potato, wild potato, wild bean, potato bean, groundnut, eathnut 등 다양한 이름으로 불리어 왔으며, 지하부에 염주상의 괴경을 형성하는데, 이는 단백질과 전분 함량이 높고, 미네랄 함량, 필수 아미노산, genistein, soyasaponin이 높아 오래 전부터 식용 및 강장용으로 이용하여 왔다(Ameny et al., 1994. Nutr, Res. 14, 1397-1406). 그러나, 지하부를 생으로 먹을 경우에는 구토, 설사가 나타나므로 반드시 찌거나 구워먹어야 한다고 알려져 있다. 최근에는 지하부 괴경을 구이, 튀김, 조리용으로 이용하기도 하며, 통조림, 이유식, 분말 등의 가공제품으로 개발되기도 하였다(강시용 외, 2005. Korean J. Plant Res. 18, 424-432). 국내에는 2000년 일본으로부터 제주도에 처음 도입되었으며, 현재까지 잘 알려져 있지 않은 상태로, 특유의 인삼향으로 인해 인삼감자로 더욱 잘 알려져 있다. Apios americana Medikus is a vine perennial legume (Leguminosae), native to temperate and subtropical regions of eastern North America. Apios has been called by various names such as big potato, indian potato, wild potato, wild bean, potato bean, groundnut, eathnut, and forms a tuber-shaped tuber in the basement, which has high protein and starch content, mineral content and essential amino acids. , genistein and soyasaponin have been used for food and tonic for a long time (Ameny et al., 1994. Nutr, Res. 14, 1397-1406). However, if you eat raw underground, vomiting, diarrhea appears, so you must steam or bake. Recently, underground tubers have been used for roasting, frying, and cooking, and have been developed as processed products such as canned food, baby food, and powder (Gang Si Yong et al., 2005. Korean J. Plant Res. 18, 424-432). It was first introduced to Jeju Island from Japan in 2000 and is not well known until now, and is known as ginseng potato due to its unique ginseng fragrance.
아피오스에 대한 연구로는, 아피오스의 재배에 관한 연구(강시용 외, 2005. Korean J. Plant Res. 18, 424-432)로 시작되어 아피오스의 특이한 전분 구조 특성 연구(박미혜 외, 2014, J. East Asian Soc Dietary Life, 24: 400-406; Kikuta C., 2012, J. Appl. Glycosic. 59: 21-30), 유용 성분, 유용 활성에 대한 연구로 주제가 변화되고 있다. 현재까지 알려진 아피오스의 유용 활성으로는 정장 작용, 아토피성 피부염, 요통 및 관절통 경감 효과(Krishnan 1998. Crop Sci. 38. 1052-1056; Mazur et al., 1998. J. Nutr. Biochem, 9, 193-200; Okubo 1994, Biosci. Biotechnol. Biochem. 58, 2248-2250; Wilson et al., 1986. J. Food Sci. 51, 1387-1388)가 있으며, 바이러스 또는 endotoxin에 의해 유도되는 폐손상, 염증을 완화하는 활성(Sohn SH 등, 2015. J. Microbiol. Biotechnol. 25: 2146-2152), 항산화 활성(Takashima M 등, 2013. Food Chem. 138: 298-305), 혈압 강하 및 혈중 지질 개선 효과(Iwai K., 2007, Nutr. Res. 27: 218-224) 등이 알려져 있다. 그러나, 현재까지 아피오스의 혈액응고효소 및 혈액응고인자 저해에 의한 강력한 항혈전 활성은 알려진 바 없다.The study of apios begins with a study on the cultivation of apios (Kang, Si-Yong et al., 2005. Korean J. Plant Res. 18, 424-432), and studies on the characteristic properties of apios starch structure (Mi-Hye Park et al., 2014, J. East Asian Soc Dietary Life, 24: 400-406; Kikuta C., 2012, J. Appl. Glycosic. 59: 21-30). Useful activities of apios known to date include intestinal action, atopic dermatitis, back pain and joint pain relief effects (Krishnan 1998. Crop Sci. 38. 1052-1056; Mazur et al., 1998. J. Nutr. Biochem, 9, 193-200; Okubo 1994, Biosci. Biotechnol. Biochem. 58, 2248-2250; Wilson et al., 1986. J. Food Sci. 51, 1387-1388), lung injury induced by virus or endotoxin, Inflammatory activity (Sohn SH et al., 2015. J. Microbiol. Biotechnol. 25: 2146-2152), antioxidant activity (Takashima M et al., 2013. Food Chem. 138: 298-305), lowering blood pressure and improving blood lipids Effects (Iwai K., 2007, Nutr. Res. 27: 218-224) and the like are known. However, there is no known strong antithrombotic activity by inhibiting coagulation factor and coagulation factor of apios.
한편, 아피오스와 관련된 특허로는 대한민국 등록특허 제10-1300664호에 아피오스를 습식분쇄하여 음료를 제조하는 [아피오스 음료의 제조방법], 등록특허 제10-1705548호에 [아피오스 추출물 또는 아피오스 발효 추출물을 유효성분으로 포함하는 면역증강용 조성물], 등록특허 제10-1453258호에는 [발효홍삼, 동과자 및 아피오스 추출물을 유효성분으로 포함하는 피부미용증진용 건강기능식품 조성물], 등록특허 제10-1227171호에는 아피오스의 다양한 부위 추출물을 화장품으로 이용하는 [아피오스를 이용한 화장료 조성물 및 이의 제조방법] 등이 알려져 있다. 또한, 대한민국 공개특허 제10-2011-0141395호에는 와송 추출물, 감초 추출물, 아피오스 추출물을 유효 성분으로 하는 [아토피 피부염 치료제 조성물], 제20-2008-0015177호에는 [아피오스 아메리카나 앙금 제조방법]이 공개되어 있다. 그러나, 현재까지 아피오스의 항혈전 활성과 관련된 특허는 알려진 바 없다.On the other hand, as a patent related to apis [Korean method for preparing apios beverages] to prepare a beverage by wet grinding apios in Korean Patent No. 10-1300664, Patent No. 10-1705548 [Apios extract or Immunity-enhancing composition comprising an apios fermented extract as an active ingredient], Registered Patent No. 10-1453258 [Registered health functional food composition for skin beauty enhancement comprising fermented red ginseng, dongja and apios extract as an active ingredient], Patent No. 10-1227171 discloses a cosmetic composition using apios and a method for preparing the same, which use various site extracts of apios as a cosmetic. In addition, the Republic of Korea Patent Publication No. 10-2011-0141395 [Which extract, licorice extract, apios extract] [Atopic dermatitis treatment composition] as an active ingredient, No. 20-2008-0015177 [Apios Americana sediment production method] Is open to the public. However, to date no patents relating to the antithrombotic activity of apios are known.
본 발명은 상기와 같은 종래 기술의 문제점을 해결하기 위하여 안출된 것으로서, 본 발명에서 해결하고자 하는 과제는 아피오스 추출물을 유효성분으로 함유하는 혈전성 질환의 예방 및 치료 또는 개선용 약학적 조성물 및 건강 기능 식품을 제공하고자 하는 것이다.The present invention has been made to solve the problems of the prior art as described above, the problem to be solved in the present invention is a pharmaceutical composition and health for the prevention and treatment or improvement of thrombotic disease containing apios extract as an active ingredient It is to provide a nutraceutical.
상기와 같은 과제를 해결하기 위하여, 본 발명은 아피오스(Apios americana Medikus) 추출물을 유효성분으로 함유하는 혈전증의 예방 또는 치료용 약학적 조성물을 제공한다.In order to solve the above problems, the present invention provides a pharmaceutical composition for the prevention or treatment of thrombosis containing Apios ( Apis americana Medikus) extract as an active ingredient.
상기 약학적 조성물의 유효성분으로서 아피오스 추출물은 아피오스 에탄올 추출물의 에틸아세테이트 분획물인 것이 바람직하다.As an active ingredient of the pharmaceutical composition, the apiose extract is preferably an ethyl acetate fraction of the apios ethanol extract.
또한, 본 발명은 아피오스(Apios americana Medikus) 추출물을 유효성분으로 함유하는 혈전증의 예방 또는 개선용 건강 기능 식품을 제공한다.The present invention also provides a dietary supplement for the prevention or improvement of thrombosis containing Apios ( Apis americana Medikus) extract as an active ingredient.
상기 건강 기능 식품의 유효성분으로서 아피오스 추출물은 아피오스 에탄올 추출물의 에틸아세테이트 분획물인 것이 바람직하다.As an active ingredient of the health functional food, the apios extract is preferably an ethyl acetate fraction of the apios ethanol extract.
본 발명의 혈전증의 예방 및 치료 또는 개선용 약학적 조성물 및 건강 기능 식품의 유효성분으로서의 아피오스 추출물은 혈전 생성 관련 효소 및 혈액 응고 인자의 저해에 의한 강력한 항혈전 활성을 나타냄과 동시에, 인간 적혈구에 대한 용혈 활성을 전혀 나타내지 않고, 열 안정성이 우수하고, pH 2의 산성 조건 및 혈장 내에서도 혈액 응고 인자 저해 효과 및 혈전 생성 관련 효소 저해 효과의 손실이 나타나지 않으므로, 혈행 개선을 통해 허혈성 뇌졸중 및 출혈성 뇌졸중과 같은 혈전증의 예방 및 치료용으로 사용할 수 있을 것으로 기대되며, 상기 유효성분은 추출액, 분말, 환, 정 등의 다양한 형태로 가공되어 상시 복용이 가능한 형태로 조제할 수 있는 뛰어난 효과가 있으므로 제약 산업 및 식품 산업상 매우 유용한 발명인 것이다.Apiose extract as an active ingredient of the pharmaceutical composition for preventing and treating or improving thrombosis of the present invention and a health functional food exhibits strong antithrombotic activity by inhibition of a blood clotting enzyme and blood coagulation factor, It shows no hemolytic activity, no thermal hemolytic activity and no loss of blood coagulation factor and blood clotting enzyme-inhibiting effects in acidic conditions and plasma. It is expected to be used for the prevention and treatment of the same thrombosis, and the active ingredient is processed into various forms such as extract, powder, pills, tablets, etc., so that it can be prepared in a form that can be taken at all times in the pharmaceutical industry and It is a very useful invention in the food industry.
도 1은 아피오스 지하부 마쇄물의 사진도이다.
도 2는 아피오스 에탄올 추출물 및 이의 순차적 유기용매 분획물의 인간 혈소판 응집저해 활성을 나타낸 것으로서, 여기에서, 1: 용매 대조구(DMSO), 2: 아스피린(0.125mg/ml), 3: 아스피린(0.25mg/ml), 4: 아스피린(0.5mg/ml), 5: 아피오스 에탄올 추출물(0.25mg/ml), 6: 아피오스 에탄올 추출물의 헥센 분획물(0.25mg/ml), 7: 아피오스 에탄올 추출물의 에틸아세테이트 분획물(0.25mg/ml), 8: 아피오스 에탄올 추출물의 부탄올 분획물(0.25mg/ml), 9: 아피오스 에탄올 추출물의 유기용매 분획 후의 물 잔류물(0.25mg/ml)을 각각 나타낸다.1 is a photographic view of an apios underground grinding material.
Figure 2 shows the human platelet aggregation inhibitory activity of the apiose ethanol extract and its sequential organic solvent fraction, where 1: solvent control (DMSO), 2: aspirin (0.125 mg / ml), 3: aspirin (0.25 mg / ml), 4: aspirin (0.5 mg / ml), 5: apiose ethanol extract (0.25 mg / ml), 6: hexene fraction of apios ethanol extract (0.25 mg / ml), 7: apis ethanol extract The ethyl acetate fraction (0.25 mg / ml), the butanol fraction of 8: apiose ethanol extract (0.25 mg / ml), and the water residue (0.25 mg / ml) after organic solvent fraction of 9: apios ethanol extract are shown, respectively.
이하, 본 발명을 상세하게 설명한다.EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.
본 발명의 발명자들은 항당뇨, 혈압 강하 효과가 우수한 아피오스를 대상으로 항혈전 효능을 검정하기 위하여, 아피오스 지하부 괴근의 추출물을 조제하고, 이후 추출물로부터 헥센 분획물, 에틸아세테이트 분획물, 부탄올 분획물 및 유기용매 분획 후의 물 잔류물을 회수하였으며, 추출물 및 분획물을 대상으로 인간 혈소판 응집저해 활성 및 혈액응고 저해 활성을 평가한 결과, 강력한 항혈전 활성을 나타내는 아피오스 지하부 에탄올 추출물의 에틸아세테이트 분획물을 확인하였으며, 이후 상기 활성 분획물은 열 안정성과 산 안정성이 우수한 특징을 가짐을 확인함으로써 상기 활성 분획물을 혈전증의 예방 또는 치료/개선용 약학적 조성물 및 건강 기능 식품으로 활용하고자 하였다. The inventors of the present invention to prepare the extract of the aphis underground muscle roots to assay the antithrombotic efficacy in apios excellent anti-diabetic, blood pressure-lowering effect, and then from the extract hexene fraction, ethyl acetate fraction, butanol fraction and organic Water residues after solvent fractionation were recovered, and the extracts and fractions were evaluated for human platelet aggregation inhibitory activity and blood coagulation inhibitory activity. As a result, ethylacetate fraction of apius underground ethanol extract showing strong antithrombotic activity was identified. Since the active fraction was confirmed to have excellent thermal stability and acid stability, the active fraction was intended to be utilized as a pharmaceutical composition and health functional food for the prevention or treatment / improvement of thrombosis.
구체적으로, 본 발명자들은 민간에서 항당뇨 및 혈압강하 효과가 우수하다고 알려진 아피오스를 이용하여 혈전증의 예방 또는 치료/개선용 약학적 조성물 및 건강 기능 식품을 개발하기 위하여, 아피오스 지하부 추출물을 조제하고, 이후 각각 헥센, 에틸아세테이트, 부탄올로 순차적 유기용매 분획하고, 마지막으로 분획 후 물 잔류물을 조제하였다. 아피오스 추출물과 분획물들의 항혈전 활성을 인간 혈장과 인간 트롬빈에 대한 트롬빈 직접 저해(Thrombin Time), 프로트롬빈 저해(Prothrombin Time) 및 활성부분 트롬보플라스틴 타임(activated Partial Thromboplastin Time: aPTT) 및 혈소판 응집저해 활성을 평가한 결과, 아피오스 에탄올 추출물의 에틸아세테이트 분획물에서 강력한 혈액응고저해 활성 및 양호한 혈소판 응집저해 활성을 확인하였다. 이러한 활성은 임상에서 항혈전제로 사용되고 있는 아스피린과 비교되는 강력한 항혈전 활성이었다. Specifically, the present inventors have prepared apios underground extract to develop pharmaceutical compositions and health functional foods for the prevention or treatment / improvement of thrombosis using apios which are known to have excellent anti-diabetic and blood pressure-lowering effects in the private sector. , And then sequentially fractionated organic solvents with hexene, ethyl acetate, and butanol, and finally water residue after fractionation. Antithrombotic Activity of Apis Extracts and Fractions on Thrombin Time, Prothrombin Time and Activated Partial Thromboplastin Time (aPTT) and Platelet Aggregation on Human Plasma and Human Thrombin As a result of evaluating the inhibitory activity, the ethyl acetate acetate fraction of the apiose ethanol extract confirmed the strong anticoagulant activity and good platelet aggregation inhibitory activity. This activity was a potent antithrombotic activity compared to aspirin, which is used as an antithrombotic in the clinic.
따라서, 본 발명은 본 발명은 아피오스 추출물을 유효성분으로 함유하는 혈전증의 예방 또는 치료용 약학적 조성물을 제공한다.Accordingly, the present invention provides a pharmaceutical composition for the prevention or treatment of thrombosis containing an apios extract as an active ingredient.
상기 약학적 조성물의 유효성분으로서 아피오스 추출물은 아피오스 에탄올 추출물의 에틸아세테이트 분획물인 것이 바람직하다.As an active ingredient of the pharmaceutical composition, the apiose extract is preferably an ethyl acetate fraction of the apios ethanol extract.
또한, 본 발명은 아피오스 추출물을 유효성분으로 함유하는 혈전증의 예방 또는 개선용 건강 기능 식품을 제공한다.The present invention also provides a health functional food for preventing or improving thrombosis containing an apios extract as an active ingredient.
상기 건강 기능 식품의 유효성분으로서 아피오스 추출물은 아피오스 에탄올 추출물의 에틸아세테이트 분획물인 것이 바람직하다.As an active ingredient of the health functional food, the apios extract is preferably an ethyl acetate fraction of the apios ethanol extract.
이하에서는, 본 발명의 아피오스 추출물의 활성 분획 물질의 제조 방법 및 효능 실험 등을 보다 구체적으로 설명한다.Hereinafter, the preparation method and efficacy test of the active fraction material of the apios extract of the present invention will be described in more detail.
본 발명은 아피오스 지하부(가식부)로부터의 추출물 및 이로부터 헥센, 에틸아세테이트, 부탄올의 순차적 유기용매 분획물 조제 및 이후 얻어지는 물 잔류물의 조제 단계; 다양한 추출물 및 분획물의 항혈전 활성 평가 단계; 강력한 항혈전 활성을 나타내는 아피오스 활성 분획물의 안정성 조사 단계를 포함한다.The present invention provides a step of preparing an extract from the apius subterranean (decoration part) and sequential organic solvent fractions of hexene, ethyl acetate, butanol, and water residues obtained thereafter; Evaluation of antithrombotic activity of various extracts and fractions; Stability investigation of the apiose active fractions exhibiting strong antithrombotic activity.
본 발명의 조성물에 포함되는 "아피오스 추출물"은 성숙된 아피오스의 지하부를 수확하는 단계; 수세하고 이물질을 제거한 아피오스를 마쇄하는 단계; 마쇄된 아피오스를 유기용매로 추출하는 단계 및 상기 추출액을 0.06mm 이하의 여과망을 사용하여 여과하고, 이를 감압농축 하는 단계에 의해 수득될 수 있다."Apiose extract" included in the composition of the present invention comprises the steps of harvesting the basement of mature apios; Crushing apios washed with water and debris removed; Extracting the ground apiose with an organic solvent and filtering the extract using a filter network of 0.06mm or less, it can be obtained by concentration under reduced pressure.
본 발명에서 사용되는 유기용매는 물(냉수, 열수), 주정, 탄소수 1~4의 무수 또는 함수 저급 알코올(메탄올, 에탄올, 주정, 프로판올, 부탄올 등), 상기 저급알코올과 물과의 혼합용매 등을 이용할 수 있으며, 바람직하게는, 열수 또는 95% 에탄올 추출, 가장 바람직하게는 95% 에탄올 추출이다.The organic solvent used in the present invention may be water (cold water, hot water), alcohol, anhydrous or hydrous lower alcohol having 1 to 4 carbon atoms (methanol, ethanol, alcohol, propanol, butanol, etc.), a mixed solvent of the lower alcohol and water, and the like. Can be used, preferably hot water or 95% ethanol extraction, most preferably 95% ethanol extraction.
바람직한 구체예로서, 본 발명의 아피오스 추출물은 아피오스를 열수 및 에탄올로 추출하여 사용할 수 있다. 여기에서, 상기 열수 또는 에탄올 추출물은 헥센, 에틸아세테이트 및 부탄올의 유기용매로 순차 또는 각각 분획하여 헥센 분획물, 에틸아세테이트 분획물 및 부탄올 분획물 및 물 잔류물을 추가적으로 수득할 수 있다.In a preferred embodiment, the apiose extract of the present invention can be used to extract the apiose with hot water and ethanol. Here, the hot water or ethanol extract may be sequentially or separately fractionated with an organic solvent of hexene, ethyl acetate and butanol to obtain an additional hexene fraction, ethyl acetate fraction and butanol fraction and water residue.
본 발명에서는, 아피오스 추출물과 이의 순차적 유기용매 분획물을 5mg/ml의 농도로 하여 트롬빈 타임, 프로트롬빈 타임 및 에이피티 타임을 측정한 결과, 에틸아세테이트 분획물에서만 15배 이상의 연장된 트롬빈 타임, 1.57배 연장된 프로트롬빈 타임, 2.18배 연장된 에이피티 타임을 나타내어 매우 강력한 혈액응고 저해효과를 확인하였다. 또한, 아피오스 추출물 및 이의 유기용매 순차적 분획물을 0.25mg/ml의 농도로 하여 인간 혈소판 응집저해 활성을 측정한 결과, 에탄올 추출물, 이의 부탄올 분획물, 물 잔류물에서는 강력한 혈소판 응집촉진을 나타내었으며, 에틸아세테이트 분획물에서는 약한 응집저해 효과를 나타내었다. 따라서, 아피오스의 에탄올 추출물의 에틸아세테이트 활성 분획물은, 위장장애와 같은 부작용 우려가 높은 아스피린을 대치할 수 있는 항응고제로 개발 가능함을 확인하였다. In the present invention, the thrombin time, prothrombin time and apititime was measured at the concentration of 5 mg / ml of the apios extract and its sequential organic solvent fractions. Prothrombin time, 2.18-fold extended epitaxial time was shown to be very potent anticoagulant effect. In addition, as a result of measuring human platelet aggregation inhibitory activity at the concentration of 0.25 mg / ml, the apios extract and the organic solvent sequential fraction showed strong platelet aggregation promotion in the ethanol extract, butanol fraction and water residue. The acetate fraction showed a weak coagulation inhibitory effect. Therefore, it was confirmed that the ethyl acetate active fraction of the ethanol extract of Apios can be developed as an anticoagulant that can replace aspirin, which has high side effects such as gastrointestinal disorders.
본 발명의 아피오스 추출물의 활성 분획 물질들은 감압건조 및 동결건조, 또는 분무건조 등과 같은 통상적인 분말화 과정을 거쳐 분말로 제조될 수 있다. 이들은 혈장 내의 다양한 분해효소에 분해되지 않으며, 100℃의 열처리와 pH 2의 인체 위 내의 pH에서도 활성을 유지한다.Active fraction materials of the apiose extract of the present invention can be prepared into a powder through a conventional powdering process such as vacuum drying and freeze drying, or spray drying. They are not degraded to various degrading enzymes in plasma and remain active at 100 ° C. heat treatment and pH 2 in the human stomach.
본 발명의 유효성분은 혈전증과 관련된 다양한 질환들의 예방 또는 치료용으로 사용될 수 있다. 상기 질환들은, 예를 들어, 동맥 혈전증으로서, 급성 심근 경색증, 가슴 통증, 호흡 곤란, 의식 소실, 허혈성 뇌졸중, 출혈성 뇌졸중, 두통, 운동 이상, 감각 이상, 성격 변화, 시력 저하, 간질 발작, 폐 혈전증, 심부정맥 혈전증, 하지 부종, 통증 및 급성 말초 동맥 폐쇄증 등을 들 수 있고, 정맥 혈전증으로서, 심부정맥 혈전증, 간문맥 혈전증, 급성 신장정맥 폐쇄증, 뇌 정맥동 혈전증 및 중심 망막정맥 폐쇄 등을 들 수 있다.The active ingredient of the present invention can be used for the prevention or treatment of various diseases associated with thrombosis. The diseases are, for example, arterial thrombosis, acute myocardial infarction, chest pain, shortness of breath, loss of consciousness, ischemic stroke, hemorrhagic stroke, headache, dyskinesia, paresthesia, personality changes, decreased vision, epileptic seizures, pulmonary thrombosis , Deep vein thrombosis, lower extremity edema, pain, and acute peripheral arterial obstruction. Examples of venous thrombosis include deep vein thrombosis, portal vein thrombosis, acute renal vein occlusion, cerebral venous thrombosis, and central retinal vein occlusion.
본 발명의 유효 성분을 포함하는 약학적 조성물은 각각의 사용 목적에 맞게 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁제, 에멀젼, 시럽, 에어로졸 등의 경구 제형, 멸균 주사용액의 주사제 등 다양한 형태로 제형화하여 사용할 수 있으며, 경구 투여하거나 정맥 내, 복강 내, 피하, 직장, 국소 투여 등을 포함한 다양한 경로를 통해 투여될 수 있다.The pharmaceutical composition comprising the active ingredient of the present invention may be orally formulated as a powder, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc. It may be formulated and used in various forms, and may be administered orally or through various routes including intravenous, intraperitoneal, subcutaneous, rectal, and topical administration.
이러한 약학적 조성물에는 추가적으로 담체, 부형제 또는 희석제 등이 더 포함될 수 있으며, 포함될 수 있는 적합한 담체, 부형제 또는 희석제의 예로는 락토오스, 덱스트로오스, 수크로오스, 솔비톨, 만니톨, 자일리톨, 에리쓰리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로스, 메틸 셀룰로스, 비정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 들 수 있다. 또한, 본 발명의 약학적 조성물은 충전제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 더 포함할 수도 있다.Such pharmaceutical compositions may further include carriers, excipients or diluents, and examples of suitable carriers, excipients or diluents that may be included include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, Starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, amorphous cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil Etc. can be mentioned. In addition, the pharmaceutical composition of the present invention may further include a filler, an anticoagulant, a lubricant, a humectant, a perfume, an emulsifier, a preservative, and the like.
바람직한 구체예로서, 경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 약학적 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로오스, 락토오스, 젤라틴 등을 혼합하여 제형화한다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 등과 같은 윤활제가 사용될 수도 있다.In a preferred embodiment, solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, which solid preparations comprise at least one excipient such as starch, calcium carbonate, Sucrose, lactose, gelatin and the like are mixed and formulated. In addition, lubricants such as magnesium stearate, talc and the like may also be used in addition to simple excipients.
바람직한 구체예로서, 경구용 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 예시될 수 있으며, 흔히 사용되는 단순 희석제인 물, 액체 파라핀 이외에 여러 가지 부형제, 예를 들면, 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.As a preferred embodiment, oral liquid preparations may be exemplified by suspensions, solvents, emulsions, syrups, and the like, and various excipients, for example, wetting agents, sweeteners, Fragrances, preservatives and the like.
바람직한 구체예로서, 비경구 투여를 위한 제제에는 멸균된 수용액제, 비수성용제, 현탁제, 유제, 동결건조제, 좌제 등을 예시할 수 있다. 비수성용제, 현탁제에는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 포함될 수 있다. 주사제에는 용해제, 등장화제, 현탁화제, 유화제, 안정화제, 방부제 등과 같은 종래의 첨가제가 포함될 수 있다.As a preferred embodiment, the preparation for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilizers, suppositories and the like. Non-aqueous solvents and suspending agents may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like. Injectables may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives, and the like.
본 발명의 유효 성분은 약제학적으로 유효한 양으로 투여한다. 본 발명에서, "약제학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The active ingredient of the present invention is administered in a pharmaceutically effective amount. In the present invention, “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level means the type, severity, activity of the drug, Sensitivity to drug, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent use of drugs, and other factors well known in the medical arts. The pharmaceutical compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered as single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.
바람직한 구체예로서, 본 발명의 약학적 조성물에서 유효성분의 유효량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 일반적으로는 체중 ㎏ 당 1 내지 5,000mg, 바람직하게는 100 내지 3,000mg을 매일 또는 격일 투여하거나 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나, 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.In a preferred embodiment, the effective amount of the active ingredient in the pharmaceutical composition of the present invention may vary depending on the age, sex, and weight of the patient, and generally 1 to 5,000 mg per kg of body weight, preferably 100 to 3,000 mg daily. Or every other day or divided into 1 to 3 times a day. However, the dosage may be increased or decreased depending on the route of administration, the severity of the disease, sex, weight, age, etc., and the above dosage does not limit the scope of the present invention in any way.
본 발명의 약학적 조성물은 다양한 경로를 통하여 대상에 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관 내(intracerebroventricular) 주사에 의해 투여될 수 있다.The pharmaceutical composition of the present invention can be administered to a subject through various routes. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
본 발명에서 "투여"는 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미하며, 본 발명의 약학적 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 일반적인 모든 경로를 통하여 경구 또는 비경구 투여될 수 있다. 또한, 본 발명의 조성물은 유효성분을 표적 세포로 전달할 수 있는 임의의 장치를 이용해 투여될 수도 있다.As used herein, "administration" means providing a patient with any substance by any suitable method, wherein the route of administration of the pharmaceutical composition of the present invention is oral or parenteral via all common routes as long as the target tissue can be reached. Oral administration. In addition, the composition of the present invention may be administered using any device capable of delivering an active ingredient to a target cell.
본 발명에서 "대상"은, 특별히 한정되는 것은 아니지만, 예를 들어, 인간, 원숭이, 소, 말, 양, 돼지, 닭, 칠면조, 메추라기, 고양이, 개, 마우스, 쥐, 토끼 또는 기니아 피그를 포함하고, 바람직하게는 포유류, 보다 바람직하게는 인간을 의미한다."Subject" in the present invention is not particularly limited, but includes, for example, humans, monkeys, cattle, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits or guinea pigs. And preferably mammals, and more preferably humans.
또한, 본 발명의 건강 기능 식품은 혈전증의 예방 또는 개선에 효과적인 식품 및 음료 등에 다양하게 이용될 수 있다. 본 발명의 유효성분을 포함하는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있고, 분말, 과립, 정제, 캡슐 또는 음료인 형태로 사용할 수 있다.In addition, the health functional food of the present invention can be used in a variety of foods and drinks effective for preventing or improving thrombosis. Examples of the food containing the active ingredient of the present invention include various foods, beverages, gums, teas, vitamin complexes, health supplements, and the like, and can be used in the form of powders, granules, tablets, capsules, or beverages. .
본 발명의 유효성분은 일반적으로 전체 식품 중량의 0.01 내지 15중량%로 가할 수 있으며, 건강음료 조성물은 100ml를 기준으로 0.02 내지 10g, 바람직하게는 0.3 내지 1g의 비율로 가할 수 있다.The active ingredient of the present invention can generally be added in 0.01 to 15% by weight of the total food weight, the health beverage composition may be added in a ratio of 0.02 to 10g, preferably 0.3 to 1g based on 100ml.
본 발명의 건강 기능 식품은 지시된 비율로 필수 성분으로서 상기 화합물을 함유하는 것 외에 식품학적으로 허용 가능한 식품보조 첨가제, 예컨대, 천연 탄수화물 및 다양한 향미제 등을 추가 성분으로서 함유할 수 있다. In addition to containing the compound as an essential ingredient in the indicated ratios, the health functional food of the present invention may contain food-acceptable food supplement additives such as natural carbohydrates and various flavoring agents as additional ingredients.
상기 천연 탄수화물의 예로는 포도당, 과당 등의 단당류, 말토오스, 수크로오스 등의 이당류 및 덱스트린, 시클로덱스트린 등의 다당류와 같은 통상적인 당 및 자일리톨, 소르비톨, 에리쓰리톨 등의 당알코올이 있다. Examples of the natural carbohydrates include conventional sugars such as monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
상기 향미제로는 타우마틴; 레바우디오시드 A 또는 글리시르히진과 같은 스테비아 등의 천연 향미제 및 사카린, 아스파르탐 등의 합성 향미제를 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 건강 기능 식품 100ml당 일반적으로 약 1 내지 20g, 바람직하게는 약 5 내지 12g을 사용한다. 상기 외에 본 발명의 건강 기능 식품은 여러 가지 영양제, 비타민, 광물, 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 건강 기능 식품은 천연 과일 주스 및 과일 주스 음료 및 야채 음료 등의 제조를 위한 과육을 함유할 수도 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 본 발명의 유효성분 100중량부 당 0.01 내지 약 20중량부의 범위에서 선택되는 것이 일반적이다.As the flavoring agent, taumartin; Natural flavors such as stevia such as rebaudioside A or glycyrzin and synthetic flavors such as saccharin and aspartame can be used. The ratio of the natural carbohydrate is generally used in the range of about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the health functional food of the present invention. In addition to the above, the health functional food of the present invention includes various nutrients, vitamins, minerals, synthetic flavors and natural flavoring agents, colorants and neutralizing agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloids Thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like. In addition, the health functional food of the present invention may contain a flesh for preparing natural fruit juice, fruit juice beverage, vegetable beverage and the like. These components can be used independently or in combination. The proportion of such additives is generally selected from 0.01 to about 20 parts by weight per 100 parts by weight of the active ingredient of the present invention.
이하에서는 실시예를 통하여 본 발명을 더욱 상세하게 설명한다. 하기 실시예는 본 발명의 바람직한 일 구체예일 뿐이며, 본 발명의 권리범위가 하기 실시예의 범위로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. The following examples are only preferred embodiments of the present invention, and the scope of the present invention is not limited to the following examples.
[[ 실시예Example ]]
실시예Example 1: One: 아피오스Apios 에탄올 추출물과 순차적 Ethanol Extracts and Sequential 유기용매Organic solvent 분획물의Fraction 제조 및 이들의 유용성분 분석 Preparation and Analysis of Useful Ingredients
2016년 경남 산청에서 재배, 수확한 아피오스 지하부를 구입하여, 이의 에탄올 추출물을 제조하였다. 흐르는 물로 이물질을 제거하고, 물기를 제거한 후, 식품용 마쇄기를 이용하여 마쇄한 후 용매 추출에 이용하였다. 마쇄물은 도 1에 나타내었다. 에탄올 추출물 조제시에는 아피오스 마쇄물에 대해 10배의 에탄올을 가하고, 상온에서 3회 반복 추출한 후 추출액을 모아 필터링한 후, 감압 농축하여 분말로 제조하여 에탄올 추출물을 제조하였다. 이후, 에탄올 추출물을 대상으로 헥센, 에틸아세테이트, 부탄올로 순차적 유기용매 분획하였으며, 최종적으로 물 잔류물을 회수하였다. 에탄올 추출의 추출 효율과 유기용매 분획 효율 및 추출물/분획물의 성분 분석 결과는 표 1에 나타내었다. 성분 분석으로 총 폴리페놀, 총 플라보노이드, 총당 및 환원당 함량을 측정하였다. 총 폴리페놀 함량은 추출 검액 400μl에 50μl의 Folin-ciocalteau, 100μl의 Na2CO3 포화용액을 넣고 실온에서 1시간 방치한 후 725nm에서 흡광도를 측정하였다. 표준시약으로는 tannic acid를 사용하였다. 총 플라보노이드 함량은 각각의 시료를 18시간 메탄올로 교반 추출하고, 여과한 추출 검액 400μl에 90% diethylene glycol 4ml를 첨가하고, 다시 1 N NaOH 40μl를 넣고, 37℃에서 1시간 반응 후 420nm에서 흡광도를 측정하였다. 표준시약으로는 rutin을 사용하였다. 환원당은 DNS법으로, 총 당은 phenol-sulfuric acid법을 이용하여 정량하였다.Purchasing and harvesting apios underground cultivated and harvested in Sancheong, Gyeongnam in 2016, to prepare an ethanol extract thereof. The foreign material was removed by running water, and after the water was removed, it was ground using a food grinder and used for solvent extraction. The grinding product is shown in FIG. 1. When preparing the ethanol extract, 10 times ethanol was added to the apiose grinding material, and extracted three times at room temperature, and the extract was collected, filtered, and concentrated under reduced pressure to prepare an ethanol extract. Thereafter, ethanol extract was subjected to sequential organic solvent fractionation with hexene, ethyl acetate, butanol, and finally, water residue was recovered. Extraction efficiency, organic solvent fractionation efficiency, and extract / fraction component analysis results of ethanol extraction are shown in Table 1. Component analysis determined total polyphenols, total flavonoids, total sugars and reducing sugars content. The total polyphenol content was added to 400μl of the extracted sample solution, 50μl of Folin-ciocalteau, 100μl of Na 2 CO 3 saturated solution, and left at room temperature for 1 hour and absorbance at 725nm. Tannic acid was used as the standard reagent. The total flavonoid content was extracted by stirring each sample with methanol for 18 hours, 4 ml of 90% diethylene glycol was added to 400 µl of the filtered extract sample, 40 µl of 1 N NaOH was added again, and the absorbance was measured at 420 nm after reaction for 1 hour at 37 ° C. Measured. Rutin was used as a standard reagent. Reducing sugar was determined by DNS method and total sugar was determined by phenol-sulfuric acid method.
[표 1] TABLE 1 아피오스Apios 에탄올 추출물 및 이의 순차적 Ethanol Extract and Its Sequential 분획물의Fraction 수율과 성분 분석 비교 Yield vs. Component Analysis
표 1에 나타낸 바와 같이, 아피오스 에탄올 추출물의 추출 효율은 2.8%로 나타났으며, 분획물은 부탄올 분획물(추출물의 73.2%)이 압도적으로 많았으며, 물 잔류물(20%), 에틸아세테이트 분획물(7.6%), 헥센 분획물(1.6%)로 나타났다. 따라서, 100g 아피오스로부터 부탄올 분획물은 약 2.05g, 에틸아세테이트 분획물은 약 0.22g 회수할 수 있음을 의미한다. 추출물 및 분획물의 성분 분석 결과, 총 폴리페놀 함량은 아피오스 추출물의 에틸아세테이트 분획물에서 가장 높은 125.4mg/g을 보였으며, 총 플라보노이드 함량 역시 에틸아세테이트 분획물에서 가장 높은 61.9mg/g을 보였다. 반면, 총 당 및 환원당 함량은 부탄올 분획물, 물 잔류물에서 가장 높은 함량을 나타내었다. 따라서, 아피오스 추출물 및 이의 에틸아세테이트 분획물의 경우 높은 유용성분 함량을 나타내어, 다양한 생리활성을 나타내리라 판단되었다. As shown in Table 1, the extraction efficiency of the apios ethanol extract was found to be 2.8%, and the fraction was predominantly the butanol fraction (73.2% of the extract), water residue (20%), ethyl acetate fraction ( 7.6%), hexene fraction (1.6%). Thus, about 2.05 g of butanol fraction and about 0.22 g of ethyl acetate fraction were recovered from 100 g of apiose. As a result of component analysis of the extract and fractions, the total polyphenol content was 125.4 mg / g, which was the highest in the ethyl acetate fraction of the apiose extract, and the total flavonoid content was the highest in the ethyl acetate fraction, which was 61.9 mg / g. On the other hand, the total sugar and reducing sugar contents showed the highest content in butanol fraction and water residue. Therefore, it was determined that the apiose extract and its ethyl acetate fraction showed high useful ingredient content, showing various physiological activities.
실시예Example 2: 2: 아피오스Apios 에탄올 추출물 및 이의 순차적 Ethanol Extract and Its Sequential 유기용매Organic solvent 분획물의Fraction 혈액응고 저해활성 Blood coagulation inhibitory activity
실시예 1의 추출물 및 분획물의 혈액응고 저해활성을 평가하여 그 결과를 표 2에 나타내었다. 이때, 혈액응고 저해활성 평가방법은 기존에 보고된 방법에 준해 평가하였으며(Sohn et al., 2004. Kor. J. Pharmacogn 35. 52-61; Kwon et al., 2004. J. Life Science, 14. 509-513; 류 등 2010. J. Life Science, 20. 922-928), 트롬빈 타임, 프로트롬빈 타임과 에이피티 타임을 측정하였다. 혈장은 시판 control plasma (MD Pacific Technology Co., Ltd, Huayuan Industrial Area, China)를 사용하였으며 트롬빈 타임, 프로트롬빈 타임과 에이피티 타임 측정법은 다음과 같은 과정으로 수행되었다.The anticoagulant inhibitory activity of the extracts and fractions of Example 1 was evaluated and the results are shown in Table 2. At this time, the blood coagulation inhibitory activity evaluation method was evaluated according to the previously reported method (Sohn et al., 2004. Kor. J. Pharmacogn 35. 52-61; Kwon et al., 2004. J. Life Science, 14 509-513; Ryu et al. 2010. J. Life Science, 20. 922-928), thrombin time, prothrombin time and episode time. Plasma was used as a commercial control plasma (MD Pacific Technology Co., Ltd, Huayuan Industrial Area, China), and thrombin time, prothrombin time and apiity time measurements were performed as follows.
트롬빈 타임(Thrombin Time)Thrombin Time
37℃에서 0.5U 트롬빈(Sigma Co., USA) 50μl와 20mM CaCl2 50μl, 다양한 농도의 시료 추출액 10μl를 Amelung coagulometer KC-1A(Japan)의 튜브에 혼합하여 2분간 반응시킨 후, 혈장 100μl를 첨가한 후 혈장이 응고될 때까지의 시간을 측정하였다. 대조로는 아스피린(Sigma Co., USA)을 사용하였으며, 용매 대조구로는 시료 대신 DMSO를 사용하였다. DMSO의 경우 24.2초의 응고시간을 나타내었다. 트롬빈 저해 효과는 3회 이상 반복한 실험의 평균치로 나타내었으며, 트롬빈 저해활성은 시료 첨가시의 응고시간을 용매 대조구의 응고시간으로 나눈 값으로 나타내었다.50 μl of 0.5 U thrombin (Sigma Co., USA), 50 μl of 20 mM CaCl 2 , and 10 μl of various concentrations of the sample extract were mixed in a tube of Amelung coagulometer KC-1A (Japan) for 2 minutes, and then 100 μl of plasma was added. After measuring the time until the coagulation of plasma. Aspirin (Sigma Co., USA) was used as a control, and DMSO was used instead of the sample as a solvent control. DMSO showed a solidification time of 24.2 seconds. The thrombin inhibitory effect was expressed as the average value of the experiment repeated three or more times, and the thrombin inhibitory activity was expressed as the solidification time of sample addition divided by the solidification time of the solvent control.
프로트롬빈 타임(Prothrombin Time prothrombinprothrombin time) time)
표준혈장(MD Pacific Co., China) 70μl와 다양한 농도의 시료액 10μl를 Amelung coagulometer KC-1A(Japan)의 튜브에 첨가하여 37℃에서 3분간 가온 후, 130μl의 PT reagent를 첨가하고 혈장이 응고될 때까지의 시간을 3회 반복한 실험의 평균치로 나타내었다. 대조로는 아스피린(Sigma Co., USA)을 사용하였으며, 용매 대조구로는 시료 대신 DMSO를 사용하였다. DMSO의 경우 16.8초의 응고시간을 나타내었다. 프로트롬빈 저해활성은 시료 첨가시의 응고시간을 용매 대조구의 응고시간으로 나눈 값으로 나타내었다.70 μl of standard plasma (MD Pacific Co., China) and 10 μl of various concentrations of sample solution were added to a tube of Amelung coagulometer KC-1A (Japan), warmed at 37 ° C. for 3 minutes, and then 130 μl of PT reagent was added and the plasma coagulated. The time until was expressed as the average value of the experiment repeated three times. Aspirin (Sigma Co., USA) was used as a control, and DMSO was used instead of the sample as a solvent control. DMSO showed a solidification time of 16.8 seconds. The prothrombin inhibitory activity was expressed as the coagulation time at the time of sample addition divided by the coagulation time at the solvent control.
aPTTaPTT (activated Partial (activated Partial ThromboplastinThromboplastin Time) Time)
혈장 100μl와 다양한 농도의 시료 추출액 10μl를 Amelung coagulometer KC-1A(Japan)의 튜브에 첨가하여 37℃에서 3분간 가온한 후, 50μl의 aPTT reagent(Sigma, ALEXINTM)를 첨가하고 다시 37℃에서 3분간 배양하였다. 이후, 50μl CaCl2(35mM)을 첨가한 후 혈장이 응고될 때까지의 시간을 측정하였다. 용매 대조구로는 시료 대신 DMSO를 사용하였으며, 이 경우 42.2초의 응고시간을 나타내었다. aPTT의 결과는 3회 반복한 실험의 평균치로 나타내었으며, 혈액응고인자 저해활성은 시료 첨가시의 aPTT를 용매 대조구의 aPTT로 나눈 값으로 나타내었다.100 μl of plasma and 10 μl of various concentrations of the sample extract were added to a tube of Amelung coagulometer KC-1A (Japan), warmed at 37 ° C. for 3 minutes, and then 50 μl of aPTT reagent (Sigma, ALEXIN TM ) was added again to 3 ° C. at 37 ° C. Incubate for minutes. Thereafter, 50 μl CaCl 2 (35 mM) was added and the time until the plasma coagulated was measured. DMSO was used instead of the sample as a solvent control, in which case it showed a solidification time of 42.2 seconds. The results of aPTT were shown as the average value of the experiment repeated three times, and the blood coagulation factor inhibitory activity was expressed as aPTT at the time of sample addition divided by aPTT of the solvent control.
[표 2] TABLE 2 아피오스Apios 에탄올 추출물 및 이의 순차적 Ethanol Extract and Its Sequential 유기용매Organic solvent 분획물의Fraction 혈액응고 저해활성 Blood coagulation inhibitory activity
표 2에 나타낸 바와 같이, 임상에서 사용되고 있는 항혈전제인 아스피린은 1.5mg/ml 농도에서 무첨가구에 비해, 각각 1.63배, 1.38배, 1.48배 연장된 트롬빈 타임, 프로트롬빈 타임, 에이피티 타임을 나타내어 우수한 항혈전 활성을 확인하였으며, 아피오스 추출물은 5mg/ml 농도에서 각각 1.12배, 1.12배, 0.86배 연장된 트롬빈 타임, 프로트롬빈 타임, 에이피티 타임을 나타내어 매우 미미한 혈액응고 저해활성을 나타내었다. 부탄올 분획물, 물 잔류물 역시 약한 혈액응고 저해활성이 나타난 반면, 에틸아세테이트 분획물은 5mg/ml 농도에서 무첨가구에 비해 트롬빈 타임, 프로트롬빈 타임, 에이피티 타임을 각각 15배 이상, 1.57배, 2.18배 연장시켜 강력한 혈액응고 저해 활성을 나타냄을 확인하였다. 에틸아세테이트 분획물을 7mg/ml 농도로 첨가한 경우에는 무첨가구에 비해 트롬빈 타임, 프로트롬빈 타임, 에이피티 타임을 각각 15배 이상, 2.2배, 4.78배 연장시켜 농도의존적인 혈액응고 저해 활성을 확인하였다. 이러한 결과는 아피오스 추출물의 에틸아세테이트 분획물은 상업적인 항혈전제로 개발 가능함을 제시하며, 위장장애 등의 부작용을 나타내는 기존의 항혈전제인 아스피린 등을 대치할 수 있을 것으로 판단된다. As shown in Table 2, aspirin, an antithrombotic agent used in the clinic, exhibited superior thrombin time, prothrombin time, and epitaxial time, respectively, 1.63 times, 1.38 times, and 1.48 times longer than the non-adult at 1.5 mg / ml. The antithrombotic activity was confirmed, and the apios extract showed 1.12 fold, 1.12 fold, 0.86 fold extended thrombin time, prothrombin time, and epitaxial time at 5 mg / ml concentrations, respectively, indicating a very small anticoagulant activity. Butanol fraction and water residue also showed weak coagulation inhibitory activity, while ethyl acetate fraction increased thrombin time, prothrombin time and apitime by 15 times, 1.57 times and 2.18 times, respectively, at 5 mg / ml. It was confirmed that it exhibits strong anticoagulant activity. When ethyl acetate fraction was added at a concentration of 7 mg / ml, thrombin time, prothrombin time, and apitime were extended by 15 times, 2.2 times, and 4.78 times, respectively, compared to the non-added groups to confirm the concentration-dependent blood coagulation inhibitory activity. These results suggest that the ethyl acetate fraction of apios extract can be developed as a commercial antithrombotic agent, and can be replaced with aspirin, which is an existing antithrombotic agent that shows side effects such as gastrointestinal disorders.
실시예Example 3: 3: 아피오스Apios 에탄올 추출물 및 이의 순차적 Ethanol Extract and Its Sequential 유기용매Organic solvent 분획물의Fraction 혈소판 응집저해 활성 Platelet aggregation inhibitory activity
실시예 1의 아피오스 에탄올 추출물 및 이의 순차적 유기용매 분획물의 인간 혈소판 응집저해 활성을 평가하고, 그 결과를 표 3 및 도 2에 나타내었다. 혈소판은 다양한 혈구세포와 함께 혈관을 순환하는 원반형의 작은 세포로서, 핵이 없는 대신 혈관손상보호 및 혈소판 응집과 관련된 다양한 물질을 고농도로 포함하는 cytoplasmic granule을 가지고 있으며, 혈관내벽의 손상이 나타나는 경우 응집인자들을 분비하고, 내피세포의 손상으로 노출된 collagen 등과 결합하여 1차 지혈 플러그(primary hemostatic plug)를 형성하여 혈전생성을 개시하는 중요한 세포이다. 따라서, 혈소판 응집저해는 혈전 생성을 방지하는 매우 중요한 활성이다. 혈소판 응집저해 활성은 다음의 방법에 준해 평가하였다. Human platelet aggregation inhibitory activity of the apiose ethanol extract of Example 1 and its sequential organic solvent fractions was evaluated, and the results are shown in Table 3 and FIG. 2. Platelets are discoid small cells that circulate blood vessels along with various blood cells. They have a cytoplasmic granule that contains high concentrations of various substances related to vascular damage protection and platelet aggregation instead of the nucleus. It is an important cell that secretes factors and binds collagen and the like exposed to damage of endothelial cells to form a primary hemostatic plug to initiate thrombus formation. Thus, platelet aggregation inhibition is a very important activity for preventing thrombus formation. Platelet aggregation inhibitory activity was evaluated according to the following method.
혈소판 응집저해 활성(Platelet aggregation inhibition activity)Platelet aggregation inhibition activity
혈소판은 인간 농축혈소판을 사용하였으며, 이를 washing buffer(138mM NaCl, 2.7mM KCl, 12mM NaHCO3, 0.36mM NaH2PO4, 5.5mM Glucose, 1mM EDTA, pH 6.5)로 1회 세척하였다. 이후, suspending buffer(138mM NaCl, 2.7mM KCl, 12mM NaHCO3, 0.36mM NaH2PO4, 5.5mM Glucose, 0.49mM MgCl2, 0.25% gelatin, pH 7.4)에 재 현탁한 후, 3,000rpm에서 10분간 원심분리한 후, 다시 suspending buffer에 재 현탁하였으며, 이때 혈소판 수는 4x109/ml이 되도록 조정하였다. 이후, 1ml 현탁액에 2.5μl collagen을 가해 5분간 반응시키고, whole-blood aggregometer(Chrono-log, USA)를 사용하여 37℃에서 혈소판 응집을 측정하였다.Platelets were human concentrated platelets, which were washed once with washing buffer (138 mM NaCl, 2.7 mM KCl, 12 mM NaHCO 3 , 0.36 mM NaH 2 PO 4 , 5.5 mM Glucose, 1 mM EDTA, pH 6.5). After resuspending in suspending buffer (138mM NaCl, 2.7mM KCl, 12mM NaHCO 3 , 0.36mM NaH 2 PO 4 , 5.5mM Glucose, 0.49mM MgCl 2 , 0.25% gelatin, pH 7.4), and then resuspended at 3,000 rpm for 10 minutes. After centrifugation, the suspension was resuspended in suspending buffer, and the platelet count was adjusted to 4 × 10 9 / ml. Thereafter, 2.5 μl collagen was added to the 1 ml suspension for 5 minutes, and platelet aggregation was measured at 37 ° C. using a whole-blood aggregometer (Chrono-log, USA).
[표 3] TABLE 3 아피오스Apios 에탄올 추출물 및 이의 순차적 Ethanol Extract and Its Sequential 유기용매Organic solvent 분획물의Fraction 혈소판 응집저해 활성 Platelet aggregation inhibitory activity
표 3 및 도 2에 나타낸 바와 같이, 먼저 아스피린은 0.125~0.5mg/ml 농도에서, 농도 의존적으로 강력한 혈소판 응집저해를 나타내어 임상에서 항혈전제로 사용되는 근거를 알 수 있었다. 특히, 아스피린은 0.25mg/ml 농도에서 혈소판 응집이 무첨가구의 39%를 나타내었다. 한편, 아피오스 에탄올 추출물, 이의 부탄올 분획물 및 물 잔류물은 0.25mg/ml 농도에서 오히려 인간 혈소판 응집을 강하게 촉진하여 지혈 효과를 나타내었다. 헥센 분획물은 미미한 응집촉진 효과를 나타내었으며, 에틸아세테이트 분획물은 0.25mg/ml 농도에서 무첨가구에 비해 83.4%의 혈소판 응집도를 나타내었다. 따라서, 아피오스 추출물의 에틸아세테이트 분획물은 혈소판 응집을 촉진하지 않으면서 혈액응고 효소 및 응고인자 등을 강력하게 저해하여 항혈전 효과를 나타낼 것으로 판단되었다. As shown in Table 3 and FIG. 2, first, aspirin showed strong platelet aggregation inhibition in a concentration-dependent manner at a concentration of 0.125 to 0.5 mg / ml, indicating the basis for use as an antithrombotic agent in the clinic. In particular, aspirin showed 39% of the platelet-free group at 0.25 mg / ml. On the other hand, the apiose ethanol extract, butanol fraction and water residues exhibited a hemostatic effect by strongly promoting human platelet aggregation at a concentration of 0.25 mg / ml. The hexene fraction showed a slight aggregation promoting effect, and the ethyl acetate fraction showed platelet aggregation of 83.4% compared to the no addition group at 0.25 mg / ml. Therefore, the ethyl acetate fraction of the apios extract was determined to exhibit antithrombotic effects by strongly inhibiting coagulation enzymes and coagulation factors without promoting platelet aggregation.
실시예Example 4: 4: 아피오스Apios 에탄올 추출물의 에틸아세테이트 Ethyl Acetate from Ethanol Extract 분획물의Fraction 혈장, 산 및 열 안정성 평가 Plasma, Acid and Thermal Stability Assessment
상기 실시예 1에서 얻은 아피오스 에탄올 추출물의 에틸아세테이트 분획물을 대상으로 항혈전 활성에 대한 혈장 안정성, 열 안정성 및 산 안정성을 확인하였다. 상기 시료들은 100℃에서 1시간 열 처리, pH 2(0.01M HCl)에서의 1시간 처리, 혈장에서 1시간 처리시에도 혈액 응고 저해 및 혈소판 응집 저해 활성의 심각한 감소가 나타나지 않아 높은 안정성을 나타내었다. 따라서, 상기의 활성 분획물은 소화 흡수과정 및 식품제조 과정 중, 우수한 항혈전 활성을 유지할 것으로 예상된다. 또한, 아피오스가 식품 원재료로 등록되어 있으며, 오랫동안 식용으로 사용하면서도 부작용이 보고되지 않은 점을 고려할 때, 별도의 안전성에 대한 문제도 야기하지 않을 것으로 판단된다.The ethyl acetate fraction of the apiose ethanol extract obtained in Example 1 was confirmed plasma stability, thermal stability and acid stability against antithrombotic activity. The samples showed high stability due to no significant decrease in blood coagulation inhibition and platelet aggregation inhibitory activity even when treated at 100 ° C. for 1 hour, 1 hour at pH 2 (0.01 M HCl), and 1 hour at plasma. . Therefore, the active fraction is expected to maintain excellent antithrombotic activity during digestion absorption and food preparation. In addition, apios is registered as a food raw material, and considering that no side effects have been reported even though it has been used for food for a long time, it would not cause any safety problems.
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