KR102453857B1 - Pharmaceutical composition comprising the ethanol extract of cirsium japonicum var ussuriense as an effective component for prevention or treatment of thrombosis and health functional food comprising the same - Google Patents
Pharmaceutical composition comprising the ethanol extract of cirsium japonicum var ussuriense as an effective component for prevention or treatment of thrombosis and health functional food comprising the same Download PDFInfo
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- KR102453857B1 KR102453857B1 KR1020200084996A KR20200084996A KR102453857B1 KR 102453857 B1 KR102453857 B1 KR 102453857B1 KR 1020200084996 A KR1020200084996 A KR 1020200084996A KR 20200084996 A KR20200084996 A KR 20200084996A KR 102453857 B1 KR102453857 B1 KR 102453857B1
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- Prior art keywords
- thistle
- extract
- thrombosis
- active ingredient
- ethanol extract
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Abstract
본 발명은 엉겅퀴(Cirsium japonicum var. ussuriense) 에탄올 추출물을 유효성분으로 함유하는 혈전증(thrombosis)의 예방 또는 치료용 약학적 조성물 및 건강 기능 식품에 관한 것으로서, 보다 구체적으로는, 엉겅퀴 잎 또는 뿌리의 에탄올 추출물을 유효성분으로 함유하는 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 또는 치료용 약학적 조성물 및 건강 기능 식품의 유효성분으로서의 엉겅퀴 에탄올 추출물은 혈전 생성 관련 효소 및 혈액 응고 인자의 저해와 함께 혈전 생성의 개시 역할을 수행하는 혈소판의 응집 저해 효과에 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 for preventing or treating thrombosis and a health functional food containing an ethanol extract of thistle ( Cirsium japonicum var. ussuriense) as an active ingredient. It relates to a pharmaceutical composition and health functional food for preventing or treating/improving thrombosis through inhibition of blood clotting and platelet aggregation containing the extract as an active ingredient. The ethanol extract of milk thistle as an active ingredient of the pharmaceutical composition for the prevention or treatment of thrombosis of the present invention and as an active ingredient of a health functional food is effective in inhibiting platelet aggregation, which plays a role in initiating thrombus formation along with inhibition of thrombus formation-related enzymes and blood coagulation factors. It exhibits strong antithrombotic activity by Therefore, it is expected that it can be used for the prevention and treatment of thrombosis such as ischemic stroke and hemorrhagic stroke through improvement of blood circulation, and the active ingredient is processed into various forms such as extracts, powders, pills, tablets, etc. It is a very useful invention in the pharmaceutical industry and food industry because it has an excellent effect that it can be formulated in a form.
Description
본 발명은 엉겅퀴(Cirsium japonicum var. ussuriense) 에탄올 추출물을 유효성분으로 함유하는 혈전증(thrombosis)의 예방 또는 치료용 약학적 조성물 및 건강 기능 식품에 관한 것으로서, 보다 구체적으로는, 엉겅퀴 잎 또는 뿌리의 에탄올 추출물을 유효성분으로 함유하는 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 for preventing or treating thrombosis and a health functional food containing an ethanol extract of thistle ( Cirsium japonicum var. ussuriense) as an active ingredient. It relates to a pharmaceutical composition and health functional food for preventing or treating/improving thrombosis through inhibition of blood clotting and platelet aggregation containing the extract as an active ingredient.
인체 구성성분으로 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. As a component of the human body, blood has a variety of important functions, such as transporting oxygen, nutrients, and waste products and buffering, maintaining body temperature, osmotic pressure control and ion balance maintenance, water constant maintenance, fluid control, blood pressure maintenance and control, and biological defense. have. Normal blood circulation facilitates blood circulation as the blood coagulation and thrombolytic systems in the body are controlled complementary to each other. , it has been reported that the blood coagulation system is activated to form a fibrin clot centered on platelet agglomerates.
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 activated by thrombin involved in fibrin coagulation through a multi-step reaction of numerous blood coagulation factors, and finally produces fibrin monomers from fibrinogen. It binds to cells and forms a fibrin polymer cross-linked by factor XIII, forming a permanent thrombus. In addition, thrombin plays a pivotal role in thrombus formation, such as activating platelets, factor V, and factor VII to promote a blood coagulation reaction. Therefore, the thrombin activity inhibitor can be used as a very useful prophylactic and therapeutic agent for various thrombotic diseases caused by excessive blood clotting abnormalities. On the other hand, it is known that the activation of prothrombin following the sequential activation of factor XII, factor XI, factor IX, and factor X in the endogenous thrombus formation pathway ultimately activates thrombin. being targeted To date, various anticoagulants such as heparin, coumarin, aspirin, and urokinase have been used for the prevention and treatment of thrombotic diseases. As such, its use is limited.
한편, 엉겅퀴는 초롱꽃목 국화과 여러해살이 풀로 한국, 일본, 중국 등지에서 서식한다. 엉겅퀴는 전체적으로 거미줄 같은 흰 털이 많으며, 잎은 어긋나며(互生), 우상(羽狀)으로 양면에 털이 있고, 가장자리에 결각상(缺刻狀) 톱니가 있으며, 날카로운 가시도 있다. 국내에서는 가시나물이라고도 불린다. 꽃은 6~8월에 적색 또는 자주색으로 피며, 가지와 원줄기 끝에 1개씩 두화(頭花)가 달리며, 모두 관상화(冠狀花)다. 암술이 성장하기 전에 수술이 먼저 성장해 꽃가루를 방출한다. 열매는 여윈열매(瘦果)로 백색 깃털(冠毛)이 있으며, 바람에 의해 풍산포(風散布)한다.On the other hand, thistle is a perennial grass of the Asteraceae family of the order Asteraceae, and it inhabits Korea, Japan, and China. Thistle has a lot of white hairs like a spider's web as a whole, and the leaves are alternate phyllotaxis, and there are hairs on both sides as an idol. In Korea, it is also called thorn namul. Flowers bloom in red or purple in June-August, and two flowers hang one by one at the end of branches and main stems, and they are all ornamental flowers. Before the pistil grows, the stamen grows first and releases pollen. The fruits are skinny berries, with white feathers, and are dispersed by the wind.
엉겅퀴는 전초를 나물로 요리해 식용하고 있으며, 특히 봄에 채취하는 어린순은 반찬으로 먹기도 하며, 말려서 약재로 사용한다. 또한, 끓여서 차로 마시거나, 식혜를 만들거나 술로 담그기도 한다. 엉겅퀴 잎의 영양 성분 분석 결과, 건조물 100g 당, 단백질 22.4g, 지방 1.6g, 탄수화물 55.6g, 회분 11.8g을 포함하여 총 229kcal/100g의 열량을 나타내며, 칼륨(1,120mg), 칼슘(435mg), 인(290mg)을 다량 함유하고 있으며, 지용성 비타민인 베타카로틴 함량도 226μg을 함유하고 있어 영양적으로 매우 우수한 식품 원재료이다. Thistle is cooked and eaten with herbs, and young shoots harvested in spring are sometimes eaten as a side dish, or dried and used as medicine. In addition, it is boiled and drunk as a tea, made sikhye or made into alcohol. As a result of analysis of the nutritional content of milk thistle leaves, per 100 g of dry matter, protein 22.4 g, fat 1.6 g, carbohydrate 55.6 g, and ash 11.8 g, showing total calories of 229 kcal/100 g, potassium (1,120 mg), calcium (435 mg), It contains a large amount of phosphorus (290mg) and contains 226μg of beta-carotene, a fat-soluble vitamin, so it is a nutritionally excellent raw material for food.
[표 1] 엉겅퀴 건조물과 숙건의 영양성분 분석[Table 1] Nutrient analysis of dried thistle and suk-gun
또한, 중국과 일본에서는 엉겅퀴의 뿌리를 귀계, 또는 대계로 부르며 약재로 이용하여 왔으며, 국내에서도 늦가을에 수확하는 엉겅퀴 뿌리를 대계근, 엉겅퀴 지상부를 대계초라 하여 약용으로 사용하여 왔다. 민간에서는 암을 치료하고, 혈액 순환 개선, 어혈 제거 및 지혈 작용이 잘 알려져 있으며, 특히 뿌리는 고혈압, 당뇨, 간염 치료에 사용하여 왔다. 동의보감에 의하면 엉겅퀴는 성질은 평(平)하고, 맛은 쓰며[苦] 독이 없으며, 어혈이 풀리게 하고, 코피를 흘리는 것을 멎게 하며, 옹종과 옴과 버짐을 낫게 할 뿐만 아니라 여자의 적·백대하를 낫게 하고 정(精)을 보태 주며 혈을 보한다고 기록되어 있다.In addition, in China and Japan, the root of thistle is called guigye or daegye, and has been used as a medicine. In folklore, it is well known for treating cancer, improving blood circulation, removing stasis and hemostasis, and especially the root has been used to treat high blood pressure, diabetes, and hepatitis. According to Donguibogam, thistle has a flat nature, is bitter in taste, is non-toxic, relieves blood clots, stops bleeding nosebleeds, cures swelling, scabies, and ringworm, as well as cures red and white scabies in women. It is recorded that it heals people, adds soul, and purifies blood.
현재까지 엉겅퀴에 대한 연구는 국내외 약 230 여편이 알려져 있으며, 효능으로는 강력한 항산화 활성 및 항비만 활성이 보고되어 있으며, 남성 갱년기 개선효과, 항당뇨 활성, 피부 미백 효과, 간세포 암화 억제 활성, 항염증 활성, 항돌연변이 활성, 항균 활성 및 관절염 억제 효과 등이 알려져 있다. 활성 물질로는 실리마린(silymarin)이 잘 알려져 있으며, 이는 국화과에 속하는 엉겅퀴(milk thistle, Silybum marianum Gaertn.)의 열매에서 추출한 플라보리그난(flavolignan) 계열 화합물들의 복합체이다. 엉겅퀴 추출물에는 실리빈(silybin)을 비롯하여 이소실리빈(isosilybin), 실리크리스틴(silychristin), 실리디아닌(silydianin) 등 다양한 플라보리그난 화합물이 존재하며, 이들을 총칭하여 실리마린(silymarin)이라 칭한다. 실리마린(Silymarin)은 간기능 회복 효과, 항산화 효과 등을 나타내는 것으로 알려져 있고, 특히 피부암을 예방하고 피부 염증에도 관여하는 등 피부 세포를 보호하는 효과를 나타낸다. So far, about 230 studies on milk thistle are known at home and abroad, and powerful antioxidant activity and anti-obesity activity have been reported as efficacy. Activity, anti-mutagenic activity, antibacterial activity, and arthritis inhibitory effect are known. A well-known active substance is silymarin, which is a complex of flavolignan compounds extracted from the fruit of milk thistle (Silybum marianum Gaertn.) belonging to the Asteraceae. In the milk thistle extract, various flavolignan compounds such as silybin, isosilybin, silychristin, and silydianin exist, and these are collectively referred to as silymarin. Silymarin is known to exhibit liver function recovery effects and antioxidant effects, and in particular, it exhibits an effect of protecting skin cells, such as preventing skin cancer and participating in skin inflammation.
한편, 엉겅퀴의 항혈전 활성과 관련한 연구로는, 엉겅퀴 잎의 열수 추출물이 염증인자 TNF-α 및 부착인자 ICAM 생성을 강력히 저해하여 항혈전 활성을 나타냄이 보고된 바 있다(강현주 외, 2013, Ferric Chloride로 유도된 렛트 경동맥 손상 및 혈전에 대한 수용성 엉겅퀴 잎 추출물의 혈행 개선 효과. Kor. J. Pharmacogn. 44, 131-137; 김상희, 2015, 선문대학교 통합의학대학원 석사논문 67p. 선문대학교 통합의학대학원). 그러나, 현재까지 엉겅퀴 에탄올 추출물에 의한 혈액 응고 관련 효소 저해 및 혈소판 응집 저해를 통한 강력한 항혈전 활성에 대한 보고는 알려진 바 없다. On the other hand, as a study related to the antithrombotic activity of milk thistle, it has been reported that hot water extract of milk thistle leaf exhibits antithrombotic activity by strongly inhibiting the production of the inflammatory factor TNF-α and the adhesion factor ICAM (Hyeonju Kang et al., 2013, Ferric) Improving blood circulation of water-soluble milk thistle leaf extract on chloride-induced rat carotid artery injury and thrombus Kor J. Pharmacogn. 44, 131-137; ). However, there have been no reports of strong antithrombotic activity through inhibition of blood clotting-related enzymes and platelet aggregation by milk thistle ethanol extract to date.
한편, 엉겅퀴와 관련된 국내 특허는 약 180 여건이 있으며, 임실생약영농조합법인(8건), 바이오스펙트럼 주식회사(5건), 부경대학교(4건) 및 삼진제약(4건)에서 다수의 특허를 출원하였다. 개인으로는 정세헌(4건)씨가 다수 특허 출원하였다. 연도별로는 2016~2017년 매년 20건의 특허가 출원되었으며, 2018년에는 4건만이 출원되었다. 통상 제품화가 이루어지기 2~3년전에 특허출원 및 등록을 진행하는 것을 고려한다면, 엉겅퀴 관련 제품은 2018년, 2019년 이후에 다수의 제품이 출시될 것으로 판단된다. 현재 엉겅퀴를 이용한 식품제조와 관련한 대한민국 등록특허로는, 제10-1961356호 [엉겅퀴 엑기스 조성물 및 그 제조방법], 제10-1925386호 [엉겅퀴 추출물을 첨가한 발효유 및 그의 제조 방법], 제10-1784870호 [숙취 해소용 음료 조성물 및 그 제조방법], 제10-1466490호 [고구마와 엉겅퀴 추출액을 함유한 건강식 탕수육의 제조 방법], 제10-1736079호 [엉겅퀴가 함유된 삼양주를 이용한 식초 제조방법], 제10-1911746호 [엉겅퀴 추출액을 이용한 국수제조방법], 제10-1568925호 [엉겅 퀴 된장의 제조 방법 및 상기 방법으로 제조된 엉겅퀴 된장], 제10-1019812호 [엉겅퀴 또는 약용 식물을 맥반석 혼합하여 덖음차 제조방법], 제10-1884294호 [민들레와 엉겅퀴 뿌리를 이용한 액상 차 조성물 및 그 제조방법] 등이 개시되어 있으며, 제10-1917822호에는 [Lactobacillus plantarum KCCM 11322 균주를 이용한 cirsimaritin이 강화된 엉겅퀴농축액의 제조방법]도 알려져 있다. 한편, 엉겅퀴의 생리 활성과 관련하여, 제10-1902932호 [엉겅퀴 및 흰민들레의 꽃과 뿌리를 제거한 전초 추출물을 함유하는 알코올성 위염의 예방, 개선 또는 치료용 조성물], 제10-1446743호 [실리마린을 유효성분으로 포함하는 알콜성 위궤양 예방 및 치료용 조성물], 제10-2039623호 [간세포 보호용 엉겅퀴 과립 조성물 및 이의 제조방법], 제10-1438717호 [간세포 보호작용을 갖는 민들레 복합식물 발효추출 조성물], 제10-1373120호 [엉겅퀴 추출물을 함유하는 간성상세포 활성 억제용 조성물], 제10-1989407호 [엉겅퀴 추출물을 유효성분으로 포함하는 멜라닌 생성 촉진용 조성물], 제10-1969475호 [엉겅퀴를 포함하는 복합 식물의 추출물을 유효성분으로 포함하는 피부개선용 화장료 조성물], 제10-1920859호 [엉겅퀴 꽃 발효식초를 함유하는 두피 및 모발용 조성물 및 이의 제조방법], 제10-1898262호 [엉겅퀴 씨껍질 추출물을 유효성분으로 포함하는 염증성 질환을 예방 또는 치료하기 위한 약학적 조성물], 제10-1862568호 [미생물에 의한 생약 발효물을 포함하는 아토피 피부염의 예방 또는 개선용 조성물], 제10-1841959호 [Nrf-2 활성 증진 엉겅퀴 전초 추출물의 제조방법 및 이를 함유하는 화장료 조성물], 제10-1764639호 [월경전 증후군 예방 및 개선용 조성물], 제10-1756740호 [치주조직 재생 촉진용 조성물], 제10-1563577호 [갱년기 여성의 에스트로겐 저하증의 개선 및 예방용 기능성 조성물], 제10-1318055호 [엉겅퀴 추출물과 이소플라본을 유효성분으로 하는 골다공증 치료 및 예방용 조성물], 제10-1315888호 [엉겅퀴 추출물 또는 이로부터 분리된 아피제닌을 유효성분으로 하는 불면증 개선 및 치료용 약학 조성물], 제10-1281710호 [엉겅퀴 추출물 또는 이로부터 분리된 화합물을 유효성분으로 함유하는 비만 치료 및 예방용 조성물] 등의 다양한 유용 생리활성이 보고되어 있다. 한편, 엉겅퀴의 항혈전 활성과 관련한 특허로는 제10-1352591호 [엉겅퀴 추출물을 함유하는 혈행 개선용 조성물]이 개시되어 있으나, 이는 엉겅퀴 잎 열수 추출물이 염증인자 TNF-α 및 부착인자 ICAM 생성을 강력히 저해하여 항혈전 활성을 나타냄을 개시하고 있으며, 대한민국 공개특허 제10-2014-0119934호에 [엉겅퀴 추출물을 함유하는 허혈성 뇌졸중 개선용 조성물]이 공개되어 있으나, 이는 로즈벵갈 염료를 정맥주사하여 광섬유로 유도한 광화학적 뇌경색 모델에서, 엉겅퀴 추출물 투여시 뇌경색의 크기 감소 확인을 공개하고 있다. 그러나, 현재까지 엉겅퀴 에탄올 추출물에 의한 혈액 응고 관련 효소 저해 및 혈소판 응집 저해를 통한 강력한 항혈전 활성에 대한 특허는 알려진 바 없다.On the other hand, there are about 180 domestic patents related to milk thistle, and a number of patents were obtained from Imsil Herbal Medicine Agricultural Cooperative Corporation (8 cases), Biospectrum Co., Ltd. (5 cases), Pukyong National University (4 cases) and Samjin Pharmaceutical (4 cases). applied. As an individual, Jeong Se-heon (4 cases) has applied for a number of patents. By year, 20 patents were applied every year from 2016 to 2017, and only 4 were filed in 2018. Considering that patent applications and registrations are usually made 2-3 years before commercialization, it is judged that a number of products related to milk thistle will be released after 2018 and 2019. Currently, the Republic of Korea registered patents related to food production using milk thistle include No. 10-1961356 [Milk thistle extract composition and manufacturing method thereof], No. 10-1925386 [Fermented milk with milk thistle extract and manufacturing method thereof], No. 10- No. 1784870 [Beverage composition for relieving hangover and its manufacturing method], No. 10-1466490 [Method for producing healthy sweet and sour pork containing sweet potato and thistle extract], No. 10-1736079 [Production of vinegar using Samyangju containing milk thistle] Method], Nos. 10-1911746 [Method for making noodles using milk thistle extract], No. 10-1568925 [Method for preparing milk thistle miso and milk thistle miso prepared by the above method], No. 10-1019812 [Method for preparing milk thistle or medicinal plants] [Method for preparing black tea by mixing elvan stone], No. 10-1884294 [Liquid tea composition using dandelion and thistle root and method for manufacturing the same], etc. are disclosed, and No. 10-1917822 [cirsimaritin using Lactobacillus plantarum KCCM 11322 strain] A method for preparing this fortified milk thistle concentrate] is also known. On the other hand, with respect to the physiological activity of milk thistle, No. 10-1902932 [Composition for the prevention, improvement or treatment of alcoholic gastritis containing a herbal extract from which flowers and roots of milk thistle and white dandelion have been removed], No. 10-1446743 [Silymarin] Composition for the prevention and treatment of alcoholic gastric ulcer containing as an active ingredient], No. 10-2039623 [Milk thistle granule composition for hepatocellular protection and manufacturing method thereof], No. 10-1438717 [Composition with fermented extract of dandelion complex with hepatocellular protection action] ], No. 10-1373120 [Composition for inhibiting hepatic stellate cell activity containing milk thistle extract], No. 10-1989407 [Composition for promoting melanin production containing milk thistle extract as an active ingredient], No. 10-1969475 [Milk thistle Cosmetic composition for skin improvement comprising extract of a complex plant as an active ingredient, including Pharmaceutical composition for preventing or treating inflammatory diseases comprising seed bark extract as an active ingredient], No. 10-1862568 [Composition for preventing or improving atopic dermatitis comprising fermented herbal medicines caused by microorganisms], No. 10- No. 1841959 [Method for preparing Nrf-2 activity-enhancing milk thistle extract and cosmetic composition containing same], No. 10-1764639 [Composition for the prevention and improvement of premenstrual syndrome], No. 10-1756740 [Composition for promoting periodontal tissue regeneration] ], No. 10-1563577 [Functional composition for improvement and prevention of hypoestrogenism in menopausal women], No. 10-1318055 [Composition for treatment and prevention of osteoporosis using milk thistle extract and isoflavones as active ingredients], No. 10-1315888 No. [Pharmaceutical composition for improving and treating insomnia using milk thistle extract or apigenin isolated therefrom as an active ingredient], No. 10-1281710 [For the treatment and prevention of obesity containing milk thistle extract or a compound isolated therefrom as an active ingredient] composition] reported various useful physiological activities such as has been On the other hand, as a patent related to the antithrombotic activity of milk thistle, No. 10-1352591 [composition for improving blood circulation containing milk thistle extract] is disclosed. Discloses that it exhibits antithrombotic activity by strongly inhibiting it, and Korean Patent Application Laid-Open No. 10-2014-0119934 [Composition for improving ischemic stroke containing milk thistle extract] is disclosed, but this is an optical fiber by intravenous injection of Rose Bengal dye. In a photochemical cerebral infarction model induced by . However, to date, there has been no patent for a potent antithrombotic activity through inhibition of blood clotting-related enzymes and platelet aggregation by milk thistle ethanol extract.
본 발명은 상기와 같은 종래 기술의 문제점을 해결하기 위하여 안출된 것으로서, 본 발명에서 해결하고자 하는 과제는 엉겅퀴 에탄올 추출물을 유효성분으로 함유하는 혈전성 질환의 예방 또는 치료용 약학적 조성물 및 건강 기능 식품을 제공하고자 하는 것이다.The present invention has been devised to solve the problems of the prior art as described above, and the problem to be solved in the present invention is a pharmaceutical composition for the prevention or treatment of thrombotic diseases and a health functional food containing milk thistle ethanol extract as an active ingredient. is intended to provide.
상기와 같은 과제를 해결하기 위하여, 본 발명은 엉겅퀴(Cirsium japonicum var. ussuriense) 에탄올 추출물을 유효성분으로 함유하는 혈전증 예방 또는 치료용 약학적 조성물을 제공한다.In order to solve the above problems, the present invention provides a pharmaceutical composition for preventing or treating thrombosis containing an ethanol extract of Cirsium japonicum var. ussuriense as an active ingredient.
상기 엉겅퀴는 엉겅퀴의 잎 또는 뿌리인 것이 바람직하다.The thistle is preferably a leaf or root of thistle.
또한, 본 발명은 엉겅퀴(Cirsium japonicum var. ussuriense) 에탄올 추출물을 유효성분으로 함유하는 혈전증 예방 또는 개선용 건강 기능 식품을 제공한다.In addition, the present invention provides a health functional food for preventing or improving thrombosis containing an ethanol extract of thistle ( Cirsium japonicum var. ussuriense) as an active ingredient.
상기 엉겅퀴는 엉겅퀴의 잎 또는 뿌리인 것이 바람직하다.The thistle is preferably a leaf or root of thistle.
또한, 본 발명은 엉겅퀴(Cirsium japonicum var. ussuriense) 에탄올 추출물을 유효성분으로 함유하는 항혈소판제를 제공한다.In addition, the present invention provides an antiplatelet agent containing an ethanol extract of thistle ( Cirsium japonicum var. ussuriense ) as an active ingredient.
상기 엉겅퀴는 엉겅퀴의 잎 또는 뿌리인 것이 바람직하다.The thistle is preferably a leaf or root of thistle.
본 발명의 혈전증의 예방 또는 치료용 약학적 조성물 및 건강 기능 식품의 유효성분으로서의 엉겅퀴 에탄올 추출물은 혈전 생성 관련 효소 및 혈액 응고 인자의 저해와 함께 혈전 생성의 개시 역할을 수행하는 혈소판의 응집 저해 효과에 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 ethanol extract of milk thistle as an active ingredient of the pharmaceutical composition for the prevention or treatment of thrombosis of the present invention and as an active ingredient of a health functional food is effective in inhibiting platelet aggregation, which plays a role in initiating thrombus formation along with inhibition of thrombus formation-related enzymes and blood coagulation factors. It exhibits strong antithrombotic activity by Therefore, it is expected that it can be used for the prevention and treatment of thrombosis such as ischemic stroke and hemorrhagic stroke through improvement of blood circulation, and the active ingredient is processed into various forms such as extracts, powders, pills, tablets, etc. It is a very useful invention in the pharmaceutical industry and the food industry because it has an excellent effect that it can be formulated in a form.
도 1은 엉겅퀴의 지상부 및 지하부의 사진도를 나타낸 것이다.
도 2는 엉겅퀴 잎 에탄올 추출물의 인간 혈소판 응집 저해 활성을 나타낸 것이다: 1: 용매 대조구(DMSO), 2: 용매 대조구(물), 3: 아스피린(0.25mg/ml), 4: 엉겅퀴 잎의 열수 추출물(0.25mg/ml), 5: 엉겅퀴 잎의 에탄올 추출물(0.25mg/ml).
도 3은 엉겅퀴 뿌리 에탄올 추출물의 인간 혈소판 응집 저해 활성을 나타낸 것이다: 1: 용매 대조구(DMSO), 2: 용매 대조구(물), 3: 아스피린(0.25mg/ml), 4: 엉겅퀴 뿌리의 열수 추출물(0.25mg/ml), 5: 엉겅퀴 뿌리의 에탄올 추출물(0.25mg/ml). 1 is a photograph showing an above-ground part and an underground part of a thistle.
Figure 2 shows the human platelet aggregation inhibitory activity of ethanol extract of thistle leaf: 1: solvent control (DMSO), 2: solvent control (water), 3: aspirin (0.25 mg/ml), 4: hot water extract of thistle leaf. (0.25 mg/ml), 5: Ethanol extract of thistle leaf (0.25 mg/ml).
3 shows the human platelet aggregation inhibitory activity of ethanol extract of thistle root: 1: solvent control (DMSO), 2: solvent control (water), 3: aspirin (0.25 mg/ml), 4: hot water extract of thistle root. (0.25 mg/ml), 5: Ethanol extract of thistle root (0.25 mg/ml).
이하, 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 발명자들은 엉겅퀴를 대상으로 항혈전 효능을 검정하기 위하여, 일정 방법으로 성숙한 엉겅퀴 지상부 잎과 지하부 뿌리를 회수하고, 이의 열수 및 에탄올 추출물을 조제하고 항혈전 활성을 평가한 결과, 엉겅퀴 지상부 잎과 지하부 뿌리의 에탄올 추출물을 활성 성분으로 회수하였으며, 상기 추출물은 인간 적혈구에 대한 용혈 활성은 전혀 나타내지 않으면서도, 열 안정성과 산 안정성이 우수한 특징을 가짐을 확인함으로서 상기 추출물을 혈전증의 예방 또는 치료/개선용 약학적 조성물 및 건강 기능 식품으로 활용하고자 하였다. In order to test the antithrombotic efficacy of milk thistle, the inventors of the present invention collected mature thistle leaves and underground roots by a certain method, prepared hot water and ethanol extracts thereof, and evaluated the antithrombotic activity. The ethanol extract of the root and subterranean root was recovered as an active ingredient, and the extract showed no hemolytic activity against human red blood cells, but showed excellent thermal stability and acid stability. It was intended to be utilized as a pharmaceutical composition for improvement and as a health functional food.
구체적으로, 본 발명자들은 민간에서 간 보호, 항염증, 항비만, 간염, 피부병 치료 등 다양한 질환에 효과가 있다고 알려진 엉겅퀴를 이용하여 혈전증의 예방 또는 치료/개선용 약학적 조성물 및 건강 기능 식품을 개발하기 위하여, 엉겅퀴의 지상부 잎 및 지하부 뿌리를 회수하고 각각의 열수 및 에탄올 추출물을 조제하고, 이들의 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)을 평가하여, 엉겅퀴 지상부 잎과 지하부 뿌리의 에탄올 추출물에서 우수한 항응고 활성과 함께 강력한 혈소판 응집 저해를 확인하였다. Specifically, the present inventors developed a pharmaceutical composition and health functional food for preventing or treating/improving thrombosis using milk thistle, which is known to be effective in various diseases such as liver protection, anti-inflammatory, anti-obesity, hepatitis, and skin disease treatment in the private sector. In order to do this, the above-ground leaves and underground roots of thistle were recovered, hot water and ethanol extracts were prepared, and their antithrombotic activity was directly inhibited by thrombin on human plasma and human thrombin (Thrombin Time) and prothrombin inhibition (Prothrombin Time). And by evaluating activated Partial Thromboplastin Time (aPTT), it was confirmed that strong platelet aggregation inhibition with excellent anticoagulant activity was obtained from the ethanol extract of the above-ground part of thistle leaf and the root of the underground part.
따라서, 본 발명은 엉겅퀴(Cirsium japonicum var. ussuriense) 잎의 에탄올 추출물을 유효성분으로 함유하는 혈전증 예방 또는 치료용 약학적 조성물을 제공한다.Accordingly, the present invention provides a pharmaceutical composition for preventing or treating thrombosis containing an ethanol extract of the leaf of thistle ( Cirsium japonicum var. ussuriense) as an active ingredient.
또한, 본 발명은 엉겅퀴(Cirsium japonicum var. ussuriense) 에탄올 추출물을 유효성분으로 함유하는 혈전증 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating thrombosis containing an ethanol extract of thistle ( Cirsium japonicum var. ussuriense) as an active ingredient.
상기 엉겅퀴는 엉겅퀴의 잎 또는 뿌리인 것이 바람직하다.The thistle is preferably a leaf or root of thistle.
또한, 본 발명은 엉겅퀴(Cirsium japonicum var. ussuriense) 에탄올 추출물을 유효성분으로 함유하는 혈전증 예방 또는 개선용 건강 기능 식품을 제공한다.In addition, the present invention provides a health functional food for preventing or improving thrombosis containing an ethanol extract of thistle ( Cirsium japonicum var. ussuriense) as an active ingredient.
상기 엉겅퀴는 엉겅퀴의 잎 또는 뿌리인 것이 바람직하다.The thistle is preferably a leaf or root of thistle.
또한, 본 발명은 엉겅퀴(Cirsium japonicum var. ussuriense) 에탄올 추출물을 유효성분으로 함유하는 항혈소판제를 제공한다.In addition, the present invention provides an antiplatelet agent containing an ethanol extract of thistle ( Cirsium japonicum var. ussuriense ) as an active ingredient.
상기 엉겅퀴는 엉겅퀴의 잎 또는 뿌리인 것이 바람직하다.The thistle is preferably a leaf or root of thistle.
이하에서는, 본 발명의 엉겅퀴 에탄올 추출물의 제조 방법 및 효능 실험 등을 보다 구체적으로 설명한다.Hereinafter, the method for preparing the ethanol extract of milk thistle of the present invention and the efficacy experiment will be described in more detail.
본 발명은 엉겅퀴 지상부 잎 및 지하부 뿌리로부터 열수 및 에탄올 추출물을 조제하는 단계; 상기 추출물의 항혈전 활성 평가 단계; 및 활성 물질의 안정성 조사 단계를 포함한다.The present invention comprises the steps of preparing an extract of hot water and ethanol from the above-ground part of thistle leaf and the root of the underground part; evaluating the antithrombotic activity of the extract; and a step of examining the stability of the active substance.
본 발명의 조성물에 포함되는 "엉겅퀴 에탄올 추출물"은 엉컹퀴 지상부 잎 또는 지하부 뿌리를 음건하는 단계, 음건 지상부 또는 지하부를 95% 에탄올로 추출하는 단계 및 상기 추출액을 0.06mm 이하의 여과망을 사용하여 여과하고, 이를 감압농축하는 단계에 의해 수득될 수 있다.The "thistle ethanol extract" contained in the composition of the present invention includes the steps of drying the above-ground leaves or the roots of the underground part in the shade, extracting the above-ground part or underground part in the shade with 95% ethanol, and filtering the extract using a filtration network of 0.06 mm or less. , it can be obtained by concentrating it under reduced pressure.
또한, 본 발명의 엉겅퀴 에탄올 추출물은 헥센, 에틸아세테이트 및 부탄올의 유기용매로 순차 또는 각각 분획하여 헥센 분획물, 에틸아세테이트 분획물 및 부탄올 분획물 및 물 잔류물을 추가적으로 수득할 수도 있다.In addition, the milk thistle ethanol extract of the present invention may be fractionated sequentially or separately with an organic solvent of hexene, ethyl acetate and butanol to additionally obtain a hexene fraction, an ethyl acetate fraction, a butanol fraction, and a water residue.
본 발명에서는, 엉겅퀴 잎의 에탄올 추출물을 5mg/ml의 농도로 하여 트롬빈 타임, 프로트롬빈 타임, 에이피티 타임을 측정한 결과, 무첨가구에 비해 각각 1.79배, 1.18배, 1.39배 연장된 우수한 항응고 활성을 나타내었다. 이러한 활성은 항혈전제로 알려진 아스피린(1.5mg/ml)과 유사한 활성이었다. 반면, 엉겅퀴 잎의 열수 추출물은 5mg/ml의 농도로 하여 트롬빈 타임, 프로트롬빈 타임, 에이피티 타임을 측정한 결과, 무첨가구에 비해 각각 1.14배, 1.20배, 1.32배 연장된 항응고 활성을 나타내어 에탄올 추출물보다 미약하였다. 또한, 엉겅퀴 뿌리의 에탄올 추출물을 5mg/ml의 농도로 하여 트롬빈 타임, 프로트롬빈 타임, 에이피티 타임을 측정한 결과, 무첨가구에 비해 각각 1.30배, 1.09배, 1.34배 연장된 항응고 활성을 나타내으며, 엉겅퀴 뿌리의 열수 추출물은 5mg/ml의 농도로 하여 트롬빈 타임, 프로트롬빈 타임, 에이피티 타임을 측정한 결과, 무첨가구에 비해 각각 1.37배, 1.06배, 0.88배 연장된 항응고 활성을 나타내었다. 따라서, 엉겅퀴 잎의 에탄올 추출물이 가장 우수한 항응고 활성을 나타냄을 확인하였다. 또한, 엉겅퀴 잎의 에탄올 추출물을 0.25mg/ml 농도로 조정한 후 혈소판 응집저해 활성을 확인한 결과, 무첨가구에 비해 45.4%의 응집도를 나타내었으며, 엉겅퀴 잎의 열수 추출물은 동일 농도에서 116.0%의 응집도를 나타내어 혈소판 응집에 거의 영향을 미치지 않았다. 이러한 결과는 엉겅퀴 잎과 뿌리의 에탄올 추출물이 매우 강력한 항혈전 활성을 나타냄을 의미하며, 기존의 부작용 우려가 높은 아스피린과 같은 항응고제를 대치할 수 있음을 제시한다. In the present invention, as a result of measuring thrombin time, prothrombin time, and AP time using the ethanol extract of thistle leaf at a concentration of 5 mg/ml, the excellent anticoagulant activity was extended 1.79 times, 1.18 times, and 1.39 times, respectively, compared to the non-additive group. was shown. This activity was similar to that of aspirin (1.5 mg/ml), which is known as an antithrombotic agent. On the other hand, as a result of measuring thrombin time, prothrombin time, and AP time at a concentration of 5 mg/ml, the hot water extract of thistle leaf showed 1.14 times, 1.20 times, and 1.32 times longer anticoagulant activity, respectively, compared to the non-additive group. It was weaker than the extract. In addition, as a result of measuring thrombin time, prothrombin time, and AP time using the ethanol extract of thistle root at a concentration of 5 mg/ml, the anticoagulant activity was extended by 1.30 times, 1.09 times, and 1.34 times, respectively, compared to the non-additive group. , The hot water extract of thistle root was measured at a concentration of 5 mg/ml and the thrombin time, prothrombin time, and AP time were measured. As a result, the anticoagulant activity was extended by 1.37 times, 1.06 times, and 0.88 times, respectively, compared to the non-additive group. Therefore, it was confirmed that the ethanol extract of thistle leaf exhibited the best anticoagulant activity. In addition, after adjusting the ethanol extract of thistle leaf to a concentration of 0.25 mg/ml, platelet aggregation inhibitory activity was confirmed. As a result, the aggregation degree was 45.4% compared to the unadded group, and the hot water extract of thistle leaf had an aggregation degree of 116.0% at the same concentration. showed little effect on platelet aggregation. These results indicate that the ethanol extract of thistle leaf and root exhibits very strong antithrombotic activity, suggesting that it can replace the existing anticoagulant such as aspirin, which has a high concern about side effects.
또한, 엉겅퀴 잎의 에탄올 추출물을 0.25mg/ml 농도로 조정한 후 혈소판 응집저해 활성을 확인한 결과, 무첨가구에 비해 45.4%의 응집도를 나타내었으며, 엉겅퀴 잎의 열수 추출물은 동일 농도에서 99.8%의 응집도를 나타내어 혈소판 응집에 거의 영향을 미치지 않았다. 엉겅퀴 뿌리의 경우, 에탄올 추출물을 0.25mg/ml 농도로 조정한 후 혈소판 응집저해 활성을 확인한 결과, 무첨가구에 비해 19.3%의 응집도를 나타내었으며, 엉겅퀴 뿌리의 열수 추출물은 동일 농도에서 80.3%의 응집도를 나타내어 미미한 혈소판 응집저해 효과를 나타내었다. 이러한 결과는 엉겅퀴 잎 및 뿌리의 에탄올 추출물이 매우 강력한 항혈전 활성을 나타냄을 의미하며, 기존의 부작용 우려가 높은 아스피린과 같은 항혈소판제를 대치할 수 있음을 제시한다.In addition, after adjusting the ethanol extract of thistle leaf to a concentration of 0.25 mg/ml, the platelet aggregation inhibitory activity was confirmed. As a result, the aggregation degree was 45.4% compared to the unadded group, and the hot water extract of thistle leaf had a degree of aggregation of 99.8% at the same concentration. showed little effect on platelet aggregation. In the case of thistle root, after adjusting the ethanol extract to a concentration of 0.25 mg/ml, platelet aggregation inhibitory activity was confirmed. As a result, the aggregation level was 19.3% compared to that of the no-addition group. and showed a slight platelet aggregation inhibitory effect. These results indicate that the ethanol extract of thistle leaf and root exhibits very strong antithrombotic activity, suggesting that it can replace the existing antiplatelet agents, such as aspirin, which have high concerns about side effects.
본 발명의 엉겅퀴 에탄올 추출물은 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.The milk thistle ethanol extract of the present invention may be prepared as a powder through a conventional powdering process such as drying under reduced pressure, freeze drying, or spray drying. They are not degraded by various degrading enzymes in plasma, and they maintain their activity even at 100°C heat treatment and
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 preventing or treating various diseases related to thrombosis. These diseases include, for example, arterial thrombosis, acute myocardial infarction, chest pain, shortness of breath, loss of consciousness, ischemic stroke, hemorrhagic stroke, headache, dyskinesia, paresthesia, personality changes, blurred vision, epileptic seizures, pulmonary thrombosis , deep vein thrombosis, lower extremity edema, pain and acute peripheral arterial occlusion, and the like, and examples of venous thrombosis include deep vein thrombosis, portal vein thrombosis, acute renal vein occlusion, cerebral vein sinus 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 can be prepared according to a conventional method for each purpose of use, oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., and injections of sterile injection solutions. It can be formulated and used in various forms, such as oral administration, or administered through various routes including intravenous, intraperitoneal, subcutaneous, rectal, topical administration, and the like.
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.The pharmaceutical composition may further include a carrier, excipient or diluent, and the like, and examples of suitable carriers, excipients or diluents that may be included include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, Starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, amorphous cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. and the like. In addition, the pharmaceutical composition of the present invention may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a fragrance, 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, and such solid preparations include at least one excipient in the pharmaceutical composition, for example, starch, calcium carbonate, It is formulated by mixing sucrose, lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate, talc and the like may be used.
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, the liquid formulation for oral use may be exemplified by suspensions, internal solutions, emulsions, syrups, etc., and various excipients, for example, wetting agents, sweetening agents, in addition to commonly used simple diluents water and liquid paraffin, Perfumes, preservatives, and the like may be included.
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, sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-drying agents, suppositories, etc. can be exemplified as preparations for parenteral administration. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Injections may contain conventional additives such as solubilizing agents, isotonic agents, suspending agents, emulsifying agents, stabilizing agents, and preservatives.
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 with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type, severity, activity of the drug, and the type of disease in the patient; Sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, factors including concomitant drugs, and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with 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 is generally 1 to 5,000 mg per kg of body weight, preferably 100 to 3,000 mg daily. Alternatively, it may be administered every other day or divided into 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, disease severity, sex, weight, age, etc., the dosage is not intended to 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 may be administered to a subject through various routes. Any mode of administration can be envisaged, 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.In the present invention, "administration" means providing a predetermined substance to a patient by any suitable method, and the administration route of the pharmaceutical composition of the present invention is oral or parenteral through all general routes as long as it can reach the target tissue. It can be administered orally. 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.In the present invention, "subject" 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 a mammal, more preferably a human.
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 various ways, such as food and beverage effective for preventing or improving thrombosis. Foods containing the active ingredient of the present invention include, for example, various foods, beverages, gums, tea, vitamin complexes, health supplements, and the like, and may be used in powder, granule, tablet, capsule or beverage form. .
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.In general, the active ingredient of the present invention may be added in an amount of 0.01 to 15% by weight of the total food weight, and the health drink 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 above compound as an essential ingredient in the proportion indicated, the health functional food of the present invention may contain food pharmaceutically 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 carbohydrate include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and common sugars such as 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.The flavoring agent includes: thaumatin; A natural flavoring agent such as stevia, such as rebaudioside A or glycyrrhizin, and a synthetic flavoring agent such as saccharin or aspartame may be used. The ratio of the natural carbohydrate is generally 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, flavoring agents such as synthetic and natural flavoring agents, colorants and thickeners, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloids It may contain thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated beverages, and the like. In addition, the health functional food of the present invention may contain natural fruit juice, fruit juice for the production of fruit juice drinks, vegetable drinks, and the like. These components may be used independently or in combination. The ratio of these additives is generally selected in the range of 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 through examples. The following examples are only preferred embodiments of the present invention, and the scope of the present invention is not limited to the scope of the following examples.
[실시예][Example]
실시예 1: 엉겅퀴 추출물 제조 및 이들의 유용성분 분석 Example 1: Preparation of milk thistle extract and analysis of useful components thereof
2018년 경북 안동의 엉겅퀴 재배농장으로부터 엉겅퀴 전초를 구입한 후, 이를 1주일간 음건한 후 열수 추출물 및 에탄올 추출물 제조에 사용하였다. 구체적으로는 11월에 수확한 엉겅퀴 전초(도 1)를 지상부 잎, 지하부 뿌리로 구분한 후 1주일간 실온에서 음건하였으며, 각각의 시료에 대해 10배의 에탄올을 가하고, 상온에서 2회 반복 추출한 후 추출액을 모아 필터링한 후, 감압 농축하여 분말로 제조하여 에탄올 추출물을 제조하였으며, 열수 추출물의 경우에는 시료 무게에 비해 20배의 증류수를 가한 후 100℃에서 1시간 추출한 후 상기와 동일하게 여과, 감압농축하여 분말로 조제하였다. After purchasing thistle outpost from a thistle farm in Andong, Gyeongbuk in 2018, it was dried in the shade for 1 week and then used to prepare hot water extract and ethanol extract. Specifically, thistle outpost harvested in November (FIG. 1) was divided into above-ground leaves and underground roots, dried in the shade at room temperature for 1 week, and 10 times of ethanol was added to each sample, followed by extraction twice at room temperature. After collecting and filtering the extract, it was concentrated under reduced pressure to prepare a powder to prepare an ethanol extract. In the case of a hot water extract, distilled
엉겅퀴 추출물의 성분 분석으로 총폴리페놀, 총플라보노이드, 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 메탄올 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, 총당은 phenol-sulfuric acid법을 이용하여 정량하였다. The contents of total polyphenols, total flavonoids, total sugars and reducing sugars were measured by component analysis of the milk thistle extract. For the total polyphenol content, 50 μl of Folin-ciocalteau and 100 μl of Na 2 CO 3 saturated solution were added to 400 μl of the extraction sample, left at room temperature for 1 hour, and absorbance was measured at 725 nm. As a standard reagent, tannic acid was used. For the total flavonoid content, each sample was extracted with methanol for 18 hours, and 4 ml of 90% diethylene glycol was added to 400 μl of the filtered extraction sample, 40 μl of 1 N NaOH was added, and the absorbance was measured at 420 nm after reaction at 37° C. for 1 hour. As a standard reagent, rutin was used. Reducing sugar was quantified by DNS method and total sugar was quantified by phenol-sulfuric acid method.
[표 2] 엉겅퀴 부위별 추출물의 추출효율 및 유용성분 분석[Table 2] Extraction efficiency and useful component analysis of extracts by part of milk thistle
표 2에 나타낸 바와 같이, 엉겅퀴 지상부 잎의 열수 추출 효율은 7%인데 비해 지하부 뿌리의 경우 열수 추출 효율은 56.1%로 상당량의 수용성 성분을 포함하고 있었다. 반면, 엉겅퀴 지상부 잎 및 지하부 뿌리의 에탄올 추출효율은 2.8% 및 0.6%로 매우 낮았다. 엉겅퀴 추출물의 총 폴리페놀 함량 분석 결과, 지상부 잎에서는 매우 높은 48.6~49.4mg/g의 함량을 보인 반면, 지하부 뿌리에서는 3.2~8.8mg/g의 상대적으로 낮은 함량을 보였다. 또한, 플라보노이드 함량 분석 결과 엉겅퀴 지상부 잎 추출물에서는 33.4~42.3mg/g의 높은 함량을 보였다. 반면, 총당 함량은 엉겅퀴 지하부 뿌리에서 지상부 잎 추출물보다 약 3.8~5.8배 높게 나타났다. 따라서, 엉겅퀴 지상부 잎에서는 다양한 phytochemical 성분을 고농도로 함유하고 있으며, 지하부 뿌리에서는 상당량의 (다)당류를 포함하고 있음을 알 수 있었다. 실제 항산화 활성 평가 결과에서 엉겅퀴 지상부 잎이 지하부 뿌리 추출물보다 매우 강력한 활성을 나타내었다. As shown in Table 2, the hot water extraction efficiency of the above-ground leaf of thistle was 7%, whereas the hot water extraction efficiency of the underground root was 56.1%, which contained a significant amount of water-soluble components. On the other hand, the ethanol extraction efficiencies of the above-ground leaf and underground root of thistle were very low at 2.8% and 0.6%. As a result of analysis of the total polyphenol content of milk thistle extract, the above-ground leaves showed a very high content of 48.6-49.4 mg/g, while the underground roots showed a relatively low content of 3.2-8.8 mg/g. In addition, as a result of the flavonoid content analysis, it was found that the high content of thistle leaf extract was 33.4-42.3 mg/g. On the other hand, the total sugar content was about 3.8 to 5.8 times higher in the underground root of thistle than in the above-ground leaf extract. Therefore, it was found that the above-ground leaf of thistle contains various phytochemical components at high concentrations, and that the root of the underground part contains a significant amount of (poly)saccharides. In the actual antioxidant activity evaluation results, the above-ground thistle leaf showed a much stronger activity than the underground root extract.
실시예 2: 엉겅퀴 추출물의 혈액응고 저해활성 평가 Example 2: Evaluation of blood clotting inhibitory activity of milk thistle extract
실시예 1의 엉겅퀴 추출물들의 혈액응고 저해활성을 평가하여 그 결과를 표 3 및 표 4에 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 blood clotting inhibitory activity of the milk thistle extracts of Example 1 was evaluated, and the results are shown in Tables 3 and 4. 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 AP time were measured. For plasma, commercially available control plasma (MD Pacific Technology Co., Ltd, Huayuan Industrial Area, China) was used, and thrombin time, prothrombin time, and AP time were measured as follows.
트롬빈 타임(Thrombin Time)Thrombin Time
37℃에서 0.5U 트롬빈(Sigma Co., USA) 50μl와 20 mM 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 32.1초의 응고시간을 나타내었다. 트롬빈 저해 효과는 3회 이상 반복한 실험의 평균치로 나타내었으며, 트롬빈 저해활성은 시료 첨가시의 응고시간을 용매 대조구의 응고시간으로 나눈 값으로 나타내었다.At 37°C, 50 μl of 0.5U thrombin (Sigma Co., USA), 50 μl of 20 mM CaCl 2 , and 10 μl of sample extracts of various concentrations were mixed in a tube of Amelung coagulometer KC-1A (Japan) and reacted for 2 minutes, and then 100 μl of plasma was collected. After addition, the time until plasma coagulation was measured. Aspirin (Sigma Co., USA) was used as a control, and DMSO was used instead of the sample as a solvent control. DMSO showed a coagulation time of 32.1 seconds. The thrombin inhibitory effect was expressed as an average of three or more repeated experiments, and the thrombin inhibitory activity was expressed as the value obtained by dividing the coagulation time at the time of sample addition by the coagulation time of the solvent control.
프로트롬빈 타임(prothrombin time)prothrombin 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 18.1초의 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 sample solutions of various concentrations were added to the tube of Amelung coagulometer KC-1A (Japan), heated at 37° C. for 3 minutes, 130 μl of PT reagent was added, and plasma was coagulated. The time until completion 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. In the case of DMSO, the clotting time was 18.1 seconds. The prothrombin inhibitory activity was expressed as the value obtained by dividing the coagulation time at the time of sample addition by the coagulation time of the solvent control.
aPTT(activated Partial Thromboplastin Time) Activated Partial Thromboplastin Time (aPTT)
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 55.1초의 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 sample extracts of various concentrations were added to the tube of Amelung coagulometer KC-1A (Japan) and heated at 37° C. for 3 minutes. Then, 50 μl of aPTT reagent (Sigma, ALEXIN TM ) was added, and then 3 Incubated for minutes. Then, after adding 50 μl CaCl 2 (35 mM), the time until plasma coagulation was measured. As a solvent control, DMSO was used instead of the sample, and in this case, the coagulation time was 55.1 seconds. The results of aPTT were expressed as the average value of the experiment repeated three times, and the blood coagulation factor inhibitory activity was expressed as the value obtained by dividing the aPTT at the time of sample addition by the aPTT of the solvent control.
[표 3] 엉겅퀴 부위별 열수 추출물의 혈액응고 저해활성[Table 3] Blood coagulation inhibitory activity of hot water extract by each part of milk thistle
[표 4] 엉겅퀴 부위별 에탄올 추출물의 혈액응고 저해활성[Table 4] Blood clotting inhibitory activity of ethanol extracts for each part of milk thistle
표 3 및 표 4에 나타낸 바와 같이, 엉겅퀴 지상부 잎의 에탄올 추출물을 5mg/ml의 농도로 하여 트롬빈 타임, 프로트롬빈 타임, 에이피티 타임을 측정한 결과, 무첨가구에 비해 각각 1.79배, 1.18배, 1.39배 연장된 우수한 항응고 활성을 나타내었다. 이러한 활성은 항혈전제로 알려진 아스피린(1.5mg/ml)과 유사한 활성이었다. 반면, 엉겅퀴 지상부 잎의 열수 추출물은 5mg/ml의 농도로 하여 트롬빈 타임, 프로트롬빈 타임, 에이피티 타임을 측정한 결과, 무첨가구에 비해 각각 1.14배, 1.20배, 1.32배 연장된 항응고 활성을 나타내어 에탄올 추출물보다 미약하였다. 또한, 엉겅퀴 지하부 뿌리의 에탄올 추출물을 5mg/ml의 농도로 하여 트롬빈 타임, 프로트롬빈 타임, 에이피티 타임을 측정한 결과, 무첨가구에 비해 각각 1.30배, 1.09배, 1.34배 연장된 항응고 활성을 나타내으며, 엉겅퀴 지하부 뿌리의 열수 추출물은 5mg/ml의 농도로 하여 트롬빈 타임, 프로트롬빈 타임, 에이피티 타임을 측정한 결과, 무첨가구에 비해 각각 1.37배, 1.06배, 0.88배 연장된 항응고 활성을 나타내었다. 따라서, 엉겅퀴 지상부 잎의 에탄올 추출물에서 가장 우수한 항응고 활성을 확인하였다.As shown in Tables 3 and 4, thrombin time, prothrombin time, and AP time were measured with the ethanol extract of the above-ground thistle leaf at a concentration of 5 mg/ml. It exhibited excellent anticoagulant activity with fold extension. This activity was similar to that of aspirin (1.5 mg/ml), which is known as an antithrombotic agent. On the other hand, as a result of measuring thrombin time, prothrombin time, and AP time at a concentration of 5 mg/ml, the hot water extract of the above-ground thistle leaf showed 1.14, 1.20, and 1.32 times prolonged anticoagulant activity, respectively, compared to the non-additive group. It was weaker than the ethanol extract. In addition, as a result of measuring thrombin time, prothrombin time, and AP time using the ethanol extract of the underground root of thistle at a concentration of 5 mg/ml, the anticoagulant activity was increased by 1.30 times, 1.09 times, and 1.34 times, respectively, compared to the non-additive group. In addition, as a result of measuring thrombin time, prothrombin time, and AP time at a concentration of 5 mg/ml, the hot water extract of the underground root of thistle showed 1.37 times, 1.06 times, and 0.88 times longer anticoagulant activity, respectively, compared to the non-additive group. It was. Therefore, the best anticoagulant activity was confirmed in the ethanol extract of the above-ground leaf of thistle.
실시예 3: 엉겅퀴 추출물의 혈소판 응집저해 활성Example 3: Platelet aggregation inhibitory activity of milk thistle extract
실시예 1의 엉겅퀴 지상부 잎과 지하부 뿌리 추출물의 인간 혈소판 응집저해 활성을 평가하여 그 결과를 표 5, 표 6, 도 2 및 도 3에 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. The human platelet aggregation inhibitory activity of the above-ground thistle leaf and underground root extract of Example 1 was evaluated, and the results are shown in Tables 5, 6, 2 and 3 . Platelets are disk-shaped small cells that circulate blood vessels together with various blood cells. Instead of having a nucleus, they have cytoplasmic granules containing various substances related to vascular damage protection and platelet aggregation in high concentrations. It is an important cell that secretes factors and initiates thrombus formation by forming a primary hemostatic plug by binding to collagen exposed due to endothelial cell damage. to be. The 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). Thereafter, re-suspended 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 at 3,000 rpm for 10 minutes After centrifugation, it was resuspended in suspending buffer, and the platelet count was adjusted to be 4x10 9 /ml. Then, 2.5 μl collagen was added to 1 ml suspension and reacted for 5 minutes, and platelet aggregation was measured at 37° C. using a whole-blood aggregometer (Chrono-log, USA).
[표 5] 엉겅퀴 지상부 잎 추출물의 혈소판 응집저해 활성[Table 5] Platelet aggregation inhibitory activity of thistle leaf extract
표 5 및 도 2에 나타낸 바와 같이, 먼저 아스피린은 0.25mg/ml 농도에서 48.8%의 응집을 나타내어 강력한 혈소판 응집저해 활성을 확인하였으며, 임상에서 항혈전제로 사용되는 근거를 알 수 있었다. 한편, 엉겅퀴 잎의 열수 추출물은 혈소판 응집 저해 활성이 인정되지 않았으나, 에탄올 추출물은 0.25mg/ml에서 45.4%의 응집율을 보여, 아스피린 0.25mg/ml에서의 응집도와 유사하였다. 상기의 결과는 엉겅퀴 잎의 에탄올 추출물이 항응고 및 혈소판 응집저해 활성이 모두 우수하여 항혈전제로 실제적인 이용이 가능함을 제시하고 있다. As shown in Table 5 and FIG. 2, first, aspirin exhibited 48.8% aggregation at a concentration of 0.25 mg/ml, confirming strong platelet aggregation inhibitory activity, and the evidence for its use as an antithrombotic agent in clinical practice was found. On the other hand, the hot water extract of thistle leaf was not recognized for platelet aggregation inhibitory activity, but the ethanol extract showed an aggregation rate of 45.4% at 0.25 mg/ml, which was similar to the aggregation rate at 0.25 mg/ml aspirin. The above results suggest that the ethanol extract of thistle leaf has excellent anticoagulant and platelet aggregation inhibitory activity, and thus can be practically used as an antithrombotic agent.
[표 6] 엉겅퀴 지하부 뿌리 추출물의 혈소판 응집저해 활성[Table 6] Platelet aggregation inhibitory activity of thistle root extract
한편, 표 6 및 도 3에 나타낸 바와 같이, 엉겅퀴 뿌리의 열수 추출물은 미약한 혈소판 응집 저해 활성이 나타났으나, 에탄올 추출물은 0.25mg/ml에서 19.3%의 응집율을 보여, 아스피린 0.25mg/ml에서의 응집도보다 매우 강력한 응집저해 효과를 나타내었다. 상기의 결과는 엉겅퀴 뿌리의 에탄올 추출물이 항응고 및 혈소판 응집저해 활성이 모두 우수하여 항혈전제로 실제적인 이용이 가능함을 제시하고 있다.On the other hand, as shown in Table 6 and Figure 3, the hot water extract of thistle root showed weak platelet aggregation inhibitory activity, but the ethanol extract showed an aggregation rate of 19.3% at 0.25 mg/ml, aspirin 0.25 mg/ml showed a much stronger anti-aggregation effect than the degree of aggregation in The above results suggest that the ethanol extract of thistle root has excellent anticoagulant and platelet aggregation inhibitory activity, so that it can be practically used as an antithrombotic agent.
실시예 4: 엉겅퀴 추출물의 혈장, 산 및 열 안정성 평가 Example 4: Evaluation of Plasma, Acid and Thermal Stability of Milk Thistle Extract
상기 실시예 1에서 얻은 엉겅퀴 잎과 뿌리의 에탄올 추출물을 대상으로 항혈전 활성에 대한 혈장 안정성, 열 안정성 및 산 안정성을 확인하였다. 엉겅퀴 잎과 뿌리의 추출물은 100℃에서 1시간 열 처리, pH 2(0.01M HCl)에서의 1시간 처리, 혈장에서 1시간 처리시에도 혈액 응고 저해 및 혈소판 응집 저해 활성의 감소가 나타나지 않았다. 따라서, 엉겅퀴 잎과 뿌리의 에탄올 추출물은 내산성, 내열성을 가진 항혈전 활성 물질을 포함하고 있을 것으로 예상된다.Plasma stability, thermal stability and acid stability with respect to antithrombotic activity were confirmed for the ethanol extract of thistle leaf and root obtained in Example 1 above. The extracts of thistle leaf and root did not show any decrease in blood coagulation inhibition and platelet aggregation inhibitory activity even after 1 hour heat treatment at 100° C., 1 hour treatment at pH 2 (0.01 M HCl), and 1 hour treatment in plasma. Therefore, it is expected that the ethanol extract of thistle leaf and root contains antithrombotic active substances with acid resistance and heat resistance.
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