KR101976203B1 - Pharmaceutical composition comprising the extracts of mangosteen peduncle as an effective component for prevention or treatment of thrombosis and health functional food comprising the same - Google Patents
Pharmaceutical composition comprising the extracts of mangosteen peduncle as an effective component for prevention or treatment of thrombosis and health functional food comprising the same Download PDFInfo
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- KR101976203B1 KR101976203B1 KR1020170137515A KR20170137515A KR101976203B1 KR 101976203 B1 KR101976203 B1 KR 101976203B1 KR 1020170137515 A KR1020170137515 A KR 1020170137515A KR 20170137515 A KR20170137515 A KR 20170137515A KR 101976203 B1 KR101976203 B1 KR 101976203B1
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- Prior art keywords
- mangosteen
- extract
- thrombosis
- active ingredient
- treatment
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Abstract
본 발명은 망고스틴(Mangosteen, Garcinia mangostana L.)의 과경(Peduncle) 추출물을 유효성분으로 함유하는 항혈전 조성물에 관한 것으로서, 보다 상세하게는, 수세 정선된 망고스틴의 과경으로부터 수득되는 에탄올 추출물을 유효성분으로 함유하는 강력한 혈소판 응집 저해 및 혈액 응고 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 망고스틴 과경 추출물은, 본 명세서의 실시예를 통해 증명된 바와 같이, 혈소판 응집 저해, 혈전 생성 관련 효소 저해 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 혈전 생성 관련 효소 및 혈액 응고 인자 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 발명일 뿐만 아니라, 식용 후 폐기되는 과경을 이용하므로 불용 자원의 재이용 및 환경보존에 기여할 수 있는 장점이 있다.The present invention relates to a method of treating mangosteen (Mangosteen, Garcinia mangostana The present invention relates to an antithrombotic composition containing an extract of Peduncle of L., as an active ingredient, and more particularly, to an antithrombotic composition containing an extract of ethanol extract obtained from the moxibustion of washed mangosteen as an active ingredient, A pharmaceutical composition for preventing or treating / improving thrombosis through inhibition of blood clotting, and a health functional food. The pharmaceutical composition for the prevention or treatment of thrombosis according to the present invention and the mangosteen Thyme extract as an active ingredient of the health functional food can be used for the prevention and treatment of platelet aggregation inhibition, And exhibits a strong antithrombotic activity due to the inhibition of factors and exhibits no hemolytic activity against human erythrocytes and exhibits excellent thermal stability and can be used in an acidic condition of pH 2 and in a blood plasma for inhibiting thrombogenic enzymes and blood coagulation factors It is expected that it can be used for 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 extract, powder, ring, tablet, etc., Because of its excellent effect that can be prepared in this form, As well as products industrially very useful invention, there is an advantage that can contribute to the recycling and environmental conservation of resources, so insoluble using the fruit stalk that is discarded after cooking.
Description
본 발명은 망고스틴(Mangosteen, Garcinia mangostana L.)의 과경(Peduncle) 추출물을 유효성분으로 함유하는 항혈전 조성물에 관한 것으로서, 보다 상세하게는, 수세 정선된 망고스틴의 과경으로부터 수득되는 에탄올 추출물을 유효성분으로 함유하는 강력한 혈소판 응집 저해 및 혈액 응고 저해를 통한 혈전증의 예방 또는 치료/개선용 약학적 조성물 및 건강 기능 식품에 관한 것이다.The present invention relates to a method of treating mangosteen (Mangosteen, Garcinia mangostana The present invention relates to an antithrombotic composition containing an extract of Peduncle of L., as an active ingredient, and more particularly, to an antithrombotic composition containing an extract of ethanol extract obtained from the moxibustion of washed mangosteen as an active ingredient, A pharmaceutical composition for preventing or treating / improving thrombosis through inhibition of blood clotting, 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. The blood as a constituent of human body has various important functions such as oxygen and nutrients, the functions of carrying and buffering of waste products, maintenance of body temperature, control of osmotic pressure and maintenance of ion balance, maintenance of moisture, regulation of fluidity, maintenance and regulation of blood pressure, have. Normal blood circulation facilitates blood circulation by complementary regulation of the blood coagulation system and thrombolysis system in the body. Among them, the mechanism of the blood coagulation system is that the platelets adhere to the blood vessel walls and coagulate to form platelet thrombus , It is reported that the blood coagulation system is activated and fibrin thrombus is formed centering on the platelet aggregation mass.
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 저해 물질은 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, XII 인자, IX 인자, X 인자의 순차적 활성화에 이은 프로트롬빈의 활성화가 최종적으로 트롬빈을 활성화하는 것으로 알려져 상기의 혈액 응고 인자의 특이적 저해 역시 중요한 혈전성 질환 치료제의 개발 타겟이 되고 있으며, 외인성 혈전 생성 경로의 경우, II 인자(prothrombin), V 인자, VII 인자, X 인자의 활성화에 따른 혈전 생성이 알려져 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 production of fibrin thrombus is activated by thrombin involved in fibrin clotting through several steps of a number of blood coagulation factors to finally produce a fibrin monomer from fibrinogen. The fibrin monomers are polymerized by calcium, Cells to form a cross-linked fibrin polymer by factor XIII and produce a permanent thrombus. In addition, thrombin plays a pivotal role in thrombus formation by activating platelet, V factor, and Factor VII to promote blood coagulation. Therefore, the activity inhibitor of thrombin can be used as a prophylactic and therapeutic agent very useful for various thrombotic diseases caused by excessive blood coagulation. On the other hand, activation of prothrombin after sequential activation of factor XII, factor XI, factor XII, factor IX and factor X is finally known to activate thrombin in the endogenous thrombosis pathway, and the specific inhibition of blood clotting factor In the extrinsic thrombosis pathway, thrombogenesis is known to be caused by the activation of factor II (prothrombin), factor V, factor VII, and factor X. To date, various anticoagulants such as heparin, coumarin, aspirin, and europine have been used for the prevention and treatment of thrombotic diseases. However, these anticoagulants and thrombolytic agents are not only very expensive but also have hemorrhagic side effects, gastrointestinal disorders and hypersensitivity The use thereof is limited due to the reaction and the like.
한편, 인구의 증가로 과일 소비는 급격히 증가되고 있으며, 이에 따라 대량의 과피(과일껍질), 과경(열매꼭지) 및 씨앗이 쓰레기로 발생하고 있다. 따라서, 폐기되고 있는 미이용자원의 효율적인 재이용 연구가 절실하다(Cheok CY 등, 2016, Critical Reviews in Food Science and Nutrition, http://dx.doi.org/10.1080/ 10408398.2016.1176009). 망고스틴은 고추나무과의 열대 상록교목으로 학명은 Garcinia mangostana L.이며, 원산지는 동남아시아로, 특히 중국에서는 귀하게 여겨지는 약용식물이다. 나무의 높이는 약 10m, 지름 약 1m의 식물로 망고스틴의 열매는 피부 감염, 상처를 치료하고 근육 및 뼈 통증 완화, 식이장애, 설사 치료약으로 사용되어 왔다. 과일의 여왕이라 불리는 망고스틴의 열매는, 과육보다 과피의 부피가 더 큰 과일로 두껍고 단단한 진홍색 과피에 둘러싸여 있는 눈처럼 흰 다육질의 과육이 즙이 많고 결이 섬세하며 새콤하면서도 약간 떫은맛이 나는 특징이 있다. 망고스틴은 다소비 열대과일로 상당히 큰 과경을 가지고 있다. 과피 및 과육은 다류 및 생식으로 이용되고 있으나, 과경은 특이한 용도 없이 버려지고 있다. On the other hand, due to the increase in population, the consumption of fruits is rapidly increasing, resulting in a large amount of fruit husks, fruit stem and seeds as garbage. Therefore, there is an urgent need for research on the efficient reuse of disused resources (Cheok CY et al., 2016, Critical Reviews in Food Science and Nutrition, http://dx.doi.org/10.1080/ 10408398.2016.1176009). Mangosteen is a tropical evergreen tree of the red pepper tree. Scientific name is Garcinia mangostana L., and its origin is Southeast Asia. The tree is about 10 meters high and about 1 meter in diameter. The fruit of mangosteen has been used to treat skin infections, wounds, muscle and bone pain relief, dietary disorders, and diarrhea. The fruit of the mangosteen, called the queen of fruit, is a fruit with a larger volume than the flesh and is characterized by a juicy, fine-grained, sour, slightly pungent white fleshy flesh that is surrounded by thick, firm crimson horns have. Mangosteen is a consuming tropical fruit with a fairly large diameter. Peel and flesh are used for multipurpose and reproductive, but the gonads are discarded without any special use.
망고스틴의 과육 및 과피는 다양한 유용 성분을 다량 함유하고 있으며, 특히 과피의 주요성분인 α-, β-, γ-mangostin은 항산화(Ngawhirunpat T, 2010, Pharm Biol. 48: 55-62), 항당뇨, 항염증(Nakatani K, 2004, Mol Pharmacol. 66: 667-674), 간보호 활성(Jamila N 등, 2017. Afr J Tradit Complement Altern Med. 14: 374-382), 항균 활성(Mizushina Y 등, 2013, Food Chem Toxicol. 59: 793-800) 및 암세포 성장 억제활성(Chang HF 등, 2012, Molecules. 17: 8010-8021)이 보고되어 있으며, 아토피 및 알러지 완화에도 효과가 우수한 것으로 알려져 있다(Higuchi H 등, 2013, J Dermatol. 40: 786-796). 또한, 과피의 α-, 및 γ-mangostin은 혈소판 응집저해 활성으로 항혈전 활성에 기여하는 것으로 알려져 있다(Liu Y 등, 2015, Chem Biol Interact. 240: 240-248). 그러나, α-, 및 γ-mangostin은 메탄올 및 에탄올에 녹지만 물에는 녹지 않아 식품 사용에는 제한이 있는 것으로 알려져 있다.Mangosteen flesh and rind contains a large amount of various useful ingredients, and in particular, α-, β-, and γ-mangostin, the major components of the rind, are antioxidant (Ngawhirunpat T, 2010, Pharm Biol. 48: 55-62) Diabetes, anti-inflammation (Nakatani K, 2004, Mol Pharmacol. 66: 667-674), hepatoprotective activity (Jamila N et al., 2017. Afr J Tradit Complement Altern Med. 14: 374-382) , 2013, Food Chem Toxicol. 59: 793-800) and cancer cell growth inhibitory activity (Chang HF et al., 2012, Molecules. 17: 8010-8021) have been reported and have been shown to be effective against atopic and allergic relief Higuchi H et al., 2013, J Dermatol. 40: 786-796). In addition, perianal α- and γ-mangostin are known to contribute to antithrombotic activity by inhibiting platelet aggregation (Liu Y et al., 2015, Chem Biol Interact. 240: 240-248). However, α- and γ-mangostin are soluble in methanol and ethanol, but they are not soluble in water, so that there is a limit to the use of food.
또한, 현재까지 알려진 망고스틴과 관련된 특허로는 대한민국 특허 제10-1508294호에 [망고스틴 추출물 또는 감마, 알파 망고스틴을 유효성분으로 포함하는 C형 간염의 예방 또는 치료용 조성물]이, 특허 제10-1299013호에 [망고스틴 추출물을 포함하는 색소화 질환의 치료용 조성물]이, 특허 제10-1721917호에 [베타-망고스틴을 유효성분으로 함유하는 피부 미백용 조성물] 및 특허 제10-1618674호에 [망고스틴을 이용한 건강식품 및 그 제조방법]이 등록되어 있으며, 특허 제10-1658586호에는 [알파 또는 감마 망고스틴을 유효성분으로 함유하는 췌장암의 예방, 개선 또는 치료를 위한 조성물]이, 특허 제10-1671248호에는 [알파 망고스틴을 유효성분으로 함유하는 비알콜성 지방간 및 대사성 질환의 예방 또는 치료용 조성물]이 알려져 있다. 또한, 공개특허 제10-2016-0032801호에 [망고스틴 추출물 또는 알파, 감마 망고스틴을 유효성분으로 포함하는 치주질환 예방 또는 개선용 조성물]이, 공개특허 제10-2017-0065959호에 [망고스틴 추출물과 황금누에고치에서 추출한 세리신을 포함하는 마스크 팩용 화장료 조성물]이, 공개특허 제10-2014-0142871호에는 [감마 망고스틴을 유효성분으로 함유하는 퇴행성 뇌질환의 예방 또는 치료용 조성물]이 공개되어 있다. In addition, as a patent related to mangosteen known so far, Korean Patent No. 10-1508294 discloses a composition for preventing or treating hepatitis C comprising mangosteen extract or gamma, alpha mangosteen as an active ingredient, 10-1299013 discloses a composition for treating pigmentation diseases comprising mangosteen extract, a composition for skin whitening comprising beta-mangostin as an active ingredient, and Patent No. 10-1721917, 1618674 is registered [Patent No. 10-1658586] [Composition for prevention, improvement or treatment of pancreatic cancer containing alpha or gamma mangosteen as an active ingredient] Patent No. 10-1671248 discloses a composition for preventing or treating nonalcoholic fatty liver disease and metabolic disease containing alpha mangostin as an active ingredient. In addition, Japanese Patent Application Laid-Open No. 10-2016-0032801 discloses a composition for preventing or improving periodontal disease comprising mangosteen extract or alpha, gamma mangosteen as an active ingredient, in Japanese Patent Application Laid-Open No. 10-2017-0065959 A cosmetic composition for a mask pack comprising serine derived from a sunflower extract and a sericin extracted from a golden silkworm cocoa extract, and a composition for preventing or treating a degenerative brain disease containing gamma-mangosteen as an active ingredient is disclosed in JP-A 10-2014-0142871 It is public.
이와 같은 망고스틴과 관련된 다양한 연구 문헌 및 특허가 알려져 있으나, 현재까지 망고스틴의 혈액응고 저해와 관련된 항혈전 활성은 알려진 바 없으며, 특히 망고스틴 과경의 강력한 항혈전 활성은 전혀 알려진 바 없는 실정이다.Various studies and patents relating to mangosteen have been known. However, the antithrombotic activity related to inhibition of blood coagulation of mangosteen has not been known to date. In particular, there is no known strong antithrombotic activity of mangosteen.
본 발명은 상기와 같은 종래 기술의 문제점을 해결하기 위하여 안출된 것으로서, 본 발명에서 해결하고자 하는 과제는 폐기되고 있는 망고스틴 과경의 추출물을 유효성분으로 함유하는 항혈전성 조성물을 제공하고자 하는 것이다.Disclosure of Invention Technical Problem [8] Accordingly, the present invention has been made keeping in mind the above problems occurring in the prior art, and it is an object of the present invention to provide an antithrombogenic composition containing an extract of mangosteen root extract as an active ingredient.
상기와 같은 과제를 해결하기 위하여, 본 발명은 망고스틴의 과경 추출물을 유효성분으로 함유하는 혈전증의 예방 또는 치료용 약학적 조성물을 제공한다.In order to solve the above-mentioned problems, the present invention provides a pharmaceutical composition for preventing or treating thrombosis, which contains an extract of Mangosteen as a active ingredient.
상기 약학적 조성물의 유효성분인 망고스틴의 과경 추출물은 망고스틴의 과경 에탄올 추출물인 것이 바람직하다.Preferably, the hypercholesterolemia extract of mangosteen, which is an active ingredient of the pharmaceutical composition, is a high-molecular-weight ethanol extract of mangosteen.
또한, 본 발명은 망고스틴의 과경 추출물을 유효성분으로 함유하는 혈전증의 예방 또는 개선용 건강 기능 식품을 제공한다.Further, the present invention provides a health functional food for preventing or ameliorating thrombosis, which contains an extract of Mangosteen as an active ingredient.
상기 건강 기능 식품의 유효성분인 망고스틴의 과경 추출물은 망고스틴의 과경 에탄올 추출물인 것이 바람직하다.Preferably, the mangosteen extract of mangosteen, which is an active ingredient of the health functional food, is a high-molecular-weight ethanol extract of mangosteen.
본 발명의 혈전증의 예방 또는 치료용 약학적 조성물 및 건강 기능 식품의 유효성분으로서의 망고스틴 과경 추출물은, 본 명세서의 실시예를 통해 증명된 바와 같이, 혈소판 응집 저해, 혈전 생성 관련 효소 저해 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 혈전 생성 관련 효소 및 혈액 응고 인자 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 발명일 뿐만 아니라, 식용 후 폐기되는 과경을 이용하므로 불용 자원의 재이용 및 환경보존에 기여할 수 있는 장점이 있다.The pharmaceutical composition for the prevention or treatment of thrombosis according to the present invention and the mangosteen Thyme extract as an active ingredient of the health functional food can be used for the prevention and treatment of platelet aggregation inhibition, And exhibits a strong antithrombotic activity due to the inhibition of factors and exhibits no hemolytic activity against human erythrocytes and exhibits excellent thermal stability and can be used in an acidic condition of
도 1은 실험에 사용된 망고스틴 열매를 나타내고,
도 2는 망고스틴 열매 단면을 나타내고,
도 3은 망고스틴 열매의 과피를 나타내고,
도 4는 망고스틴 열매의 과육을 나타내고,
도 5는 망고스틴 열매의 과경을 나타내는 사진도이다.
도 6은 망고스틴 과경 에탄올 추출물의 인간 혈소판 응집저해 활성을 나타낸 것이다: 1: 용매 대조구(DMSO), 2: 아스피린(0.25mg/ml), 3: 아스피린(0.125mg/ml), 4: 망고스틴 과피의 에탄올 추출물(0.25mg/ml), 5: 망고스틴 과육의 에탄올 추출물(0.25mg/ml), 6: 망고스틴 과경의 에탄올 추출물(0.25mg/ml).Figure 1 shows mangosteen fruit used in the experiment,
2 shows a mangosteen fruit section,
Figure 3 shows the perianth of mangosteen fruit,
Figure 4 shows the flesh of mangosteen fruit,
5 is a photographic view showing the diameter of mangosteen fruit.
FIG. 6 shows human platelet aggregation inhibitory activity of mangosteen ethanol extracts: 1: solvent control (DMSO), 2: aspirin (0.25 mg / ml), 3: aspirin (0.125 mg / ml) (0.25 mg / ml), 5: ethanol extract of mangosteen pulp (0.25 mg / ml), and 6: ethanol extract of mangosteen tree root (0.25 mg / ml).
이하, 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 발명자들은 망고스틴 열매를 대상으로 항혈전 효능을 검정하기 위하여, 일정 방법으로 제조한 망고스틴 과피, 과육 및 과경의 추출물을 각각 조제하고, 상기 추출물의 항혈전 활성을 평가하여 망고스틴 과경 추출물을 신규한 항혈전 성분으로 회수하였으며, 상기 추출물은 인간 적혈구에 대해 용혈 활성은 전혀 나타내지 않으면서도, 열 안정성과 산 안정성이 우수한 특징을 가짐을 확인함으로써 상기 추출물을 혈전증의 예방 또는 치료/개선용 약학적 조성물 및 건강 기능 식품으로 활용하고자 하였다. The inventors of the present invention prepared extracts of mangosteen peel, flesh and root extract prepared by a certain method, and evaluated the antithrombotic activity of the extracts to examine antithrombogenic activity against mangosteen fruit, The extract was recovered as a novel anti-thrombogenic component. The extract was confirmed to have excellent heat stability and acid stability without showing hemolytic activity against human erythrocytes. Thus, the extract was used for preventing or treating / improving thrombosis As a pharmaceutical composition and a health functional food.
구체적으로, 본 발명자들은 민간에서 다양한 생리 활성이 있다고 알려진 망고스틴 열매를 이용하여 혈전증의 예방 또는 치료/개선용 약학적 조성물 및 건강 기능 식품을 개발하기 위하여, 망고스틴 열매의 과피, 과육 및 과경을 대상으로 에탄올 추출물을 각각 조제하고, 이들 추출물을 대상으로 항혈전 활성을 혈소판 응집 저해, 트롬빈 저해(Thrombin Time), 프로트롬빈 저해(Prothrombin Time) 및 혈액응고인자 저해(활성부분 트롬보플라스틴 타임, activated Partial Thromboplastin Time: aPTT)를 평가하여, 망고스틴 과경 추출물이 강력한 혈소판 응집 저해 및 트롬빈 저해의 의한 항혈전 활성이 우수함을 확인하였다. Specifically, the inventors of the present invention have found that, in order to develop a pharmaceutical composition and a health functional food for prevention or treatment / improvement of thrombosis using mangosteen fruit known to have various physiological activities in the private sector, Thrombin time, prothrombin time and blood coagulation factor inhibition (active partial thromboplastin time, activated (thrombin inhibition) time, thrombin time, prothrombin time and blood coagulation factor inhibition Partial Thromboplastin Time (aPTT) was evaluated, and it was confirmed that the mangosteen extract was superior in antithrombotic activity due to inhibition of strong platelet aggregation and thrombin inhibition.
망고스틴 과경은 전체 과일의 3~4%를 차지하며, 이의 에탄올 추출물은 망고스틴 과경 100g당 약 6g을 회수할 수 있어 상당히 경제적으로 항혈전제를 제조할 수 있다. 상기 에탄올 추출물은 5mg/ml 농도에서 무첨가구에 비해 15배 이상 연장된 트롬빈 타임, 1.21배 연장된 프로트롬빈 타임, 1.43배 연장된 aPTT를 나타내어 혈액 응고의 효율적 저해를 통한 혈전 생성을 억제하며, 특히, 트롬빈에 특이적으로 강한 저해 활성을 확인하였다. 또한, 망고스틴 과경의 에탄올 추출물은 기존에 혈소판 응집 저해 활성이 있는 것으로 보고된 바 있는 과피 추출물보다도 훨씬 강력한 혈소판 응집 저해 활성을 보였으며, 0.25mg/ml 농도에서 9.8%의 혈소판 응집을 나타내어 동일 농도의 아스피린의 혈소판 응집능 24.7%보다도 우수하였다. 또한, 망고스틴 과경 추출물은 2~4mg/ml 농도에서 인간 적혈구에 대한 용혈활성을 나타내지 않아 급성독성을 유발하지 않음을 확인하였다. The ethanol extract of mangosteen accounts for 3 to 4% of the whole fruit, and its ethanol extract can recover about 6 g per 100 g of mangosteen. Thus, the antithrombotic agent can be produced economically. The ethanol extract showed a prolonged thrombin time, an extended prothrombin time and a prolonged aPTT of 1.21 times or more, and inhibited thrombogenesis through efficient inhibition of blood coagulation at a concentration of 5 mg / ml, Specific inhibitory activity against thrombin was confirmed. In addition, the ethanol extract of mangosteen tuberculosis showed much more potent inhibitory activity against platelet aggregation than the perianthic extract which had been previously reported to have platelet aggregation inhibitory activity. At 0.25 mg / ml concentration, the platelet aggregation showed 9.8% Of aspirin was higher than that of platelet aggregation (24.7%). In addition, mangosteen extract showed no hemolytic activity against human erythrocytes at a concentration of 2 to 4 mg / ml and thus did not cause acute toxicity.
따라서, 본 발명은 망고스틴 과경 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 comprising an extract of mangosteen as a active ingredient.
상기 약학적 조성물의 유효성분인 망고스틴 과경 추출물은 열수 또는 에탄올 추출물인 것이 바람직하고, 에탄올 추출물인 것이 보다 바람직하다.The mangosteen extract of the mangosteen which is an effective ingredient of the pharmaceutical composition is preferably a hot water or ethanol extract, more preferably an ethanol extract.
또한, 본 발명은 망고스틴 과경 추출물을 유효성분으로 함유하는 혈전증의 예방 또는 개선용 건강 기능 식품을 제공한다.The present invention also provides a health functional food for preventing or ameliorating thrombosis, which contains mangosteen extract as an active ingredient.
상기 건강 기능 식품의 유효성분인 망고스틴 과경 추출물은 열수 또는 에탄올 추출물인 것이 바람직하고, 에탄올 추출물ㄴ 것이 보다 바람직하다.The mangosteen mangosteen extract, which is an effective ingredient of the health functional food, is preferably a hot water or ethanol extract, and more preferably an ethanol extract.
이하에서는, 본 발명의 망고스틴 과경 추출물의 제조 방법 및 효능 실험 등을 보다 구체적으로 설명한다.Hereinafter, the production method and efficacy test of the mangosteen extract of the present invention will be described in more detail.
본 발명의 발명자들은 본 발명의 목적을 달성하기 위하여, 정선, 세척된 망고스틴 열매로부터 과피, 과육 및 과경을 분리하는 단계; 분리된 과피, 과육 및 과경으로부터 추출물을 조제하는 단계; 상기 추출물의 항혈전 활성 평가 및 안정성 평가 단계의 실험들을 수행하였다.In order to achieve the object of the present invention, the inventors of the present invention have found that, in order to achieve the object of the present invention, Preparing an extract from the separated perilla, flesh, and perilla; Experiments were performed on the antithrombotic activity and stability evaluation of the extract.
본 발명의 조성물에 포함되는 "망고스틴 과경 추출물"은 망고스틴 열매로부터 과경을 회수하는 단계, 과경을 용매로 추출하는 단계 및 상기 추출액을 0.06mm 이하의 여과망을 사용하여 여과하고, 이를 감압농축하는 단계에 의해 수득될 수 있다.The " mangosteen extract of mangosteen " contained in the composition of the present invention is characterized by comprising a step of recovering the suspension from mangosteen fruit, a step of extracting the suspension with a solvent, a step of filtering the extract using a filter net of 0.06 mm or less, ≪ / RTI >
본 발명에서 사용되는 용매는 물(냉수, 열수), 주정, 탄소수 1~4의 무수 또는 함수 저급 알코올(메탄올, 에탄올, 주정, 프로판올, 부탄올 등), 상기 저급 알코올과 물과의 혼합용매 등을 이용할 수 있으며, 열수, 또는 95% 에탄올 추출이 가장 바람직하다. The solvent to be used in the present invention may be selected from the group consisting of water (cold water, hot water), alcohol, anhydrous or hydrous lower alcohol having 1 to 4 carbon atoms (methanol, ethanol, alcohol, propanol, butanol), a mixed solvent of the lower alcohol and water Most preferred is hot water, or 95% ethanol extraction.
바람직한 구체예로서, 본 발명의 망고스틴 과경 추출물은 망고스틴 과경을 열수 또는 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 수도 있다.As a preferred embodiment, the mangosteen extract of the present invention can be used by extracting mangosteen stem with hot water or ethanol. Here, the hydrothermal or ethanol extract may be sequentially or separately fractionated with an organic solvent of hexene, ethyl acetate and butanol to obtain a hexane fraction, an ethyl acetate fraction and a butanol fraction and a water residue, respectively.
본 발명에서는, 망고스틴 과경 추출물을 5mg/ml의 농도로 하여 트롬빈 타임, 프로트롬빈 타임, 에이피티 타임을 측정한 결과, 무첨가구에 비해 각각 15배 이상, 1.21배, 1.43배 연장된 시간을 나타내어 강력한 트롬빈 특이적 저해를 확인하였다. 이러한 저해는 농도 의존적으로 나타났으며, 7mg/ml 농도에서는 무첨가구에 비해 각각 15배 이상, 5.9배, 2.14배 연장된 트롬빈 타임, 프로트롬빈 타임, 에이피티 타임을 나타내었다. In the present invention, thrombin time, prothrombin time, and apitime time were measured at a concentration of 5 mg / ml of mangosteen thalidium manganese extract. As a result, the time was prolonged by 15 times, 1.21 times, and 1.43 times, respectively, Specific inhibition of thrombin. These inhibitions were concentration dependent. At 7mg / ml concentration, thrombin time, prothrombin time, and apathy time were increased by 15 times, 5.9 times and 2.14 times, respectively.
한편, 망고스틴 과경 에탄올 추출물의 인간 혈소판 응집 저해 활성을 평가한 결과, 기존에 항혈소판 활성이 있는 것으로 알려진 망고스틴 과피 및 과육 추출물은 물론, 현재 임상에서 혈소판 응집 저해제로 사용되고 있는 아스피린보다도 수배 강력한 혈소판 응집 저해 활성을 확인하였다. 이러한 결과는 망고스틴 과경의 에탄올 추출물은 강력한 트롬빈 저해 및 혈소판 응집 저해를 통해 위장 장애 등의 부작용 우려가 높은 아스피린을 대치할 수 있는 항혈전제로 개발 가능함을 제시하고 있다. As a result of evaluating human platelet aggregation inhibitory activity of mangosteen ethanol extract of mangosteen, it has been found that mangosteen peel and flesh extract, which have been known to have anti-platelet activity, as well as platelet aggregation inhibitor that is several times stronger than aspirin The activity of inhibiting aggregation was confirmed. These results suggest that the ethanol extract of mangosteen extract can be developed as an antithrombotic agent capable of replacing aspirin, which is highly likely to cause side effects such as gastrointestinal disorders through strong thrombin inhibition and inhibition of platelet aggregation.
본 발명의 망고스틴 과경 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 mangosteen extract of the present invention may be powdered by a conventional powdering process such as vacuum drying, freeze drying, spray drying and the like. They are not degraded by various degradation enzymes in the plasma, and 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 the prevention or treatment of various diseases associated with thrombosis. Such diseases include, for example, arterial thrombosis such as acute myocardial infarction, chest pain, dyspnea, loss of consciousness, ischemic stroke, hemorrhagic stroke, headache, dyskinesia, sensory abnormality, personality change, visual disturbance, epileptic seizure, , Deep vein thrombosis, lower limb edema, pain and acute peripheral artery occlusion. Vein thrombosis can include deep vein thrombosis, portal vein thrombosis, acute renal vein thrombosis, cerebral 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 containing the active ingredient of the present invention may be formulated into tablets, capsules, suspensions, emulsions, oral preparations such as syrups and aerosols, injections of sterilized injection solutions And may be administered by various routes including oral administration or 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.Such pharmaceutical compositions may further comprise carriers, excipients or diluents, and examples of suitable carriers, excipients or diluents that may be included include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, But are not limited to, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, amorphous cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, And the like. In addition, the pharmaceutical composition of the present invention may further include a filler, an anti-coagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, an antiseptic, 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, the solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient, for example starch, calcium carbonate, Sucrose, lactose, gelatin and the like are mixed and formulated. In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may also 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.Examples of the oral liquid preparation include suspensions, solutions, emulsions, syrups and the like. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, Perfumes, 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 preferable specific example, the preparation for parenteral administration includes sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-drying agents, suppositories, and the like. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester 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 the effective dose level will depend on the type of disease, severity, The sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal 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.As a preferable example, the effective amount of the active ingredient in the pharmaceutical composition of the present invention may vary depending on the age, sex, and body weight of the patient, and generally 1 to 5,000 mg, preferably 100 to 3,000 mg per kg of body weight per day Or every other day or one to three times a day. However, the dosage may not be limited in any way because it may be increased or decreased depending on route of administration, severity of disease, sex, weight, age, and the like.
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 may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections.
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 either oral or non-oral May be administered orally. The composition of the present invention may also be administered using any device capable of delivering an effective 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, the term " object " includes, but is not limited to, human, monkey, cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig , 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, 건강 보조 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 variously used for foods and beverages effective for prevention or improvement of thrombosis. Examples of foods containing the active ingredient of the present invention include various foods, beverages, gums, tea, vitamin complex, health supplement foods and the like, and they can be used in the form of powder, granule, tablet, capsule or beverage .
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 may generally be added in an amount of 0.01 to 15% by weight of the total food, and the health beverage composition may be added in a proportion of 0.02 to 10 g, preferably 0.3 to 1 g, based on 100 ml.
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. The health functional food of the present invention may contain, as an additional ingredient, a food-acceptable food-aid additive such as natural carbohydrates and various flavors, in addition to containing the above-mentioned compound as an essential ingredient in the indicated ratio.
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 sugar sugars such as glucose, monosaccharides such as fructose, disaccharides such as maltose and sucrose, 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.Examples of the flavoring agents include natural flavoring agents such as tautatin, rebaudioside A and stiglycerin such as glycyrrhizin, and synthetic flavoring agents such as saccharin and aspartame. 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 may contain various kinds of nutrients, vitamins, minerals, flavors such as synthetic flavors and natural flavors, colorants and heavy stabilizers, pectic acid and its salts, alginic acid and its salts, Thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like. In addition, the health functional food of the present invention may contain flesh for producing natural fruit juice, fruit juice drink, vegetable drink and the like. These components may be used independently or in combination. The ratio of such 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.
이하, 본 발명의 구체적인 방법을 실시예를 통하여 보다 상세하게 설명한다. 하기 실시예는 본 발명의 바람직한 하나의 구체예일뿐이며, 본 발명의 권리범위가 하기 실시예의 범위로 한정되는 것은 아니다.Hereinafter, the specific method of the present invention will be described in more detail by way of examples. The following examples are only a preferred embodiment of the present invention, and the scope of the present invention is not limited to the scope of the following examples.
[[ 실시예Example ]]
실시예Example 1: 망고스틴 1: Mangosteen 과경Hyperbolic 추출물의 조제 Preparation of extract
태국산 망고스틴 열매를 구입한 후 이물질을 제거하고, 과피, 과육 및 과경으로 각각 구분(도 1 ~ 도 5)하고, 이를 에탄올 추출물 제조에 사용하였다. 에탄올 추출물 조제시에는 각각의 시료에 대해 10배의 에탄올(95%, 덕산, 한국)을 가하고, 상온에서 1회 추출한 후 추출액을 모아 필터링한 후, 감압 농축하여 분말로 제조하였다. 에탄올 추출의 추출효율과 추출물의 성분 분석 결과는 표 1에 나타내었다. 조제된 추출물의 성분 분석으로 총 폴리페놀, 총 플라보노이드, 총 당 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 1N NaOH 40μl를 넣고 37℃에서 1시간 반응 후 420nm에서 흡광도를 측정하였다. 표준시약으로는 rutin을 사용하였다. 환원당은 DNS법으로, 총 당은 phenol-sulfuric acid법을 이용하여 정량하였다.After purchasing mangosteen fruit from Thailand, the foreign materials were removed and classified into pericarp, flesh, and perilla (Figs. 1 to 5), and they were used for the production of ethanol extract. Ethanol extracts were prepared by adding 10 times ethanol (95%, Duksan, Korea) to each sample and once extracting at room temperature. The extracts were collected by filtration and concentrated under reduced pressure to prepare powders. The extraction efficiency of the ethanol extract and the component analysis results of the extract are shown in Table 1. Total polyphenols, total flavonoids, total sugars and reducing sugar content were determined by analysis of the constituents of the prepared extracts. Total polyphenol content was determined by adding 50 μl of Folin-ciocalteau and 100 μl of saturated Na 2 CO 3 solution to 400 μl of the extract solution, leaving it at room temperature for 1 hour and measuring the absorbance at 725 nm. Tannic acid was used as a standard reagent. The total flavonoid content of each sample was measured by stirring for 18 hours in methanol. To the 400 μl of the filtered extract, 4 ml of 90% diethylene glycol was added and 40 μl of 1N NaOH was added. The reaction was carried out at 37 ° C. for 1 hour and then absorbance was measured at 420 nm. As a standard reagent, rutin was used. Reducing sugar was quantified by DNS method and total sugar was quantified by phenol-sulfuric acid method.
그 결과, 표 1에 나타낸 바와 같이, 망고스틴 열매의 부위별 추출효율은 과육이 11.9%로 가장 높았으며, 이후 과피 9.6%, 과경 6.0%의 수율을 나타내었다. 열매에서 과육:과피:과경의 무게비는 25:71:4의 비율로 확인되었다. 통상 과육을 먹고 난후 과피를 말려 차로 음용하는 과정 중, 망고스틴 과경은 특이 용도 없이 버려지게 되므로, 과경 추출물은 경제적으로 생산할 수 있을 것으로 판단된다. As a result, as shown in Table 1, the extraction efficiency of the fruit of mangosteen was the highest at 11.9% in the pulp, and then the yield was 9.6% and 6.0%, respectively. Fruits in fruit: Perilla: The weight ratio of perilla was confirmed at a ratio of 25: 71: 4. In general, during the process of drinking peaches after eating the pulp, the mangosteen root is discarded without any specific use, so it is thought that the root extract can be economically produced.
한편, 각각의 추출물의 총 폴리페놀 함량 분석 결과, 과피, 과경, 과육 순으로 나타났으며, 과피(255.8mg/g)는 과육보다 108배, 과경보다 2.15배 높은 함량을 나타내었다. 반면, 추출물들의 총 플라보노이드 함량 분석 결과, 과경, 과피, 과육 순으로 나타났으며, 과경(53.3mg/g)은 과육보다 38배, 과피보다 3.83배 높은 함량을 나타내었다. 총 당의 경우 과육, 과피, 과경의 순으로 나타났고, 환원당의 경우 예상과 달리, 과피가 과육 및 과경보다 1.6배 높은 함량을 나타내어 망고스틴 과피의 영양적 우수성을 확인하였으며, 과피를 분말화하여 식용으로 사용하는 근거를 알 수 있었다. On the other hand, total polyphenol contents of the extracts were in the order of perilla, perilla, and flesh. Perilla (255.8mg / g) was 108 times higher than pulp and 2.15 times higher than perilla. On the other hand, total flavonoid contents of extracts were in the order of periwinkle, perilla, and flesh, and the content of tuberculosis (53.3mg / g) was 38 times higher than that of pulp and 3.83 times higher than that of perilla. In the case of total sugar, flesh, peel, and stem were shown in the order. In case of reducing sugar, the content of peel was 1.6 times higher than that of flesh and thinning, confirming nutritional superiority of mangosteen peel. As well.
실시예Example 2: 망고스틴 열매의 2: Mangosteen fruit 과피pericarp , 과육 및 , Pulp and 과경Hyperbolic 추출물의 인간 혈소판 응집저해활성 평가 Evaluation of human platelet aggregation inhibitory activity of extract
실시예 1에서 제조된 망고스틴의 부위별 추출물을 대상으로 인간 혈소판 응집저해활성을 평가하여 그 결과를 표 2 및 도 6에 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, 혈관 내벽의 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 extract of each part of mangosteen prepared in Example 1 was evaluated and the results are shown in Table 2 and FIG. Platelets are cytoplasmic granules that contain various substances related to blood vessel damage protection and platelet aggregation at high concentration instead of nucleus, and circulating blood vessels together with various blood cells. It is an important cell that secretes factors and binds to collagen exposed by damage of endothelial cells to form a primary hemostatic plug to initiate thrombogenesis. Therefore, inhibition of platelet aggregation is a very important activity to prevent thrombogenesis. Platelet aggregation inhibitory activity was evaluated according to the following method.
혈소판 응집저해 활성(Platelet aggregation inhibition activity)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.Human platelets were used as platelets and 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, the cells were resuspended in a suspending buffer (138 mM NaCl, 2.7 mM KCl, 12 mM NaHCO 3 , 0.36 mM NaH 2 PO 4 , 5.5 mM Glucose, 0.49 mM MgCl 2 , 0.25% gelatin, pH 7.4) and incubated at 3,000 rpm for 10 minutes After centrifugation, the cells were resuspended in a suspending buffer and the platelet count was adjusted to 4 × 10 9 / ml. Then platelet aggregation was measured at 37 ° C using a whole-blood agarometer (Chrono-log, USA) after 2.5 μl of collagen was added to 1 ml of suspension and reacted for 5 minutes.
그 결과, 표 2 및 도 6에 나타낸 바와 같이, 용매대조구인 DMSO의 경우 혈소판은 콜라겐 첨가에 의해 빠르고 강하게 응집이 나타났으며, 혈소판 응집 저해제인 아스피린은 농도 의존적으로 혈소판 응집을 강력하게 저해하였다. 이때, 아스피린은 0.25mg/ml 농도에서 24.7%의 응집도, 0.125mg/ml 농도에서 38.1%의 응집도를 나타내어 임상에서 항혈전제로 사용되는 근거를 확인하였다. 한편, 망고스틴 열매의 과피, 과육 및 과경은 모두 우수한 혈소판 응집 저해 활성을 나타내었으며, 특히 과경 추출물은 가장 강력한 응집 저해 활성을 나타내었다. 실제 과경 추출물은 0.25mg/ml 농도에서 단지 9.8%의 혈소판 응집을 보여, 동일 농도의 아스피린이 24.7%의 응집도를 나타낸 것보다 매우 우수하였다. 현재까지 망고스틴 과육 및 과피에서 혈소판 응집 저해 활성이 보고(Liu Y 등, 2015, Chem Biol Interact. 240: 240-248)된 바 있으나, 본 실시예에 나타난 바와 같이, 과육 및 과피보다 강력한 과경의 혈소판 응집 저해 활성은 보고된 바 없다. As a result, as shown in Table 2 and FIG. 6, in the case of DMSO as a solvent control, platelets rapidly and strongly aggregated by the addition of collagen, and aspirin as a platelet aggregation inhibitor strongly inhibited platelet aggregation in a concentration-dependent manner. At this time, aspirin showed cohesion of 24.7% at a concentration of 0.25 mg / ml and coagulation degree of 38.1% at a concentration of 0.125 mg / ml. On the other hand, mangosteen fruit showed excellent platelet aggregation inhibitory activity, and especially Thunberg extract showed the strongest aggregation inhibitory activity. Actual Thymus extract showed only 9.8% platelet aggregation at 0.25mg / ml concentration, and the same concentration of aspirin was much better than 24.7% agglutination. (Liu Y et al., 2015, Chem Biol Interact. 240: 240-248) have been reported to date on platelet aggregation inhibitory activity in mangosteen flesh and rind. However, as shown in this Example, Platelet aggregation inhibitory activity has not been reported.
실시예Example 3: 망고스틴 열매의 3: Mangosteen fruit 과피pericarp , 과육 및 , Pulp and 과경Hyperbolic 추출물의 혈액응고 저해활성 평가 Evaluation of blood coagulation inhibitory activity of extract
실시예 1에서 제조된 망고스틴의 부위별 추출물의 혈액응고 저해활성을 평가하였으며, 기존에 보고된 방법(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)과 동일하게, 트롬빈 타임, 프로트롬빈 타임, 에이피티 타임을 측정하여 평가하였다. 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 coagulation inhibitory activity of the extract of mangosteen prepared in Example 1 was evaluated and compared with 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 apathy time were measured and evaluated. Plasma was measured using a commercially available control plasma (MD Pacific Technology Co., Ltd., Huayuan Industrial Area, China), and thrombin time, prothrombin time and apitime time were measured in the following manner.
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 30.5초의 응고시간을 나타내었다. 트롬빈 저해 효과는 3회 이상 반복한 실험의 평균치로 나타내었으며, 트롬빈 저해 활성은 시료 첨가시의 응고시간을 용매 대조구의 응고시간으로 나눈 값으로 나타내었다.50 μl of 0.5 U thrombin (Sigma Co., USA) and 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 at 37 ° C., After the addition, the time until the plasma coagulated was measured. As a control, aspirin (Sigma Co., USA) was used and DMSO was used as a solvent control instead of the sample. DMSO showed a solidification time of 30.5 sec. The thrombin inhibitory effect was expressed as the average value of the experiments repeated three or more times. The thrombin inhibitory activity was expressed by the value obtained by dividing the solidification time at the time of addition of the sample by the solidification 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 16.7초의 응고시간을 나타내었다. 프로트롬빈 저해활성은 시료 첨가시의 응고시간을 용매 대조구의 응고시간으로 나눈 값으로 나타내었다.Add 70 μl of standard plasma (MD Pacific Co., China) and 10 μl of various concentrations of sample solution to tubes of Amelung coagulometer KC-1A (Japan), heat at 37 ° C for 3 minutes, add 130 μl of PT reagent, The time from the start of the experiment to the start of the experiment was expressed as the average value of the experiments repeated three times. As a control, aspirin (Sigma Co., USA) was used and DMSO was used as a solvent control instead of the sample. DMSO showed a clotting time of 16.7 seconds. The prothrombin inhibitory activity was expressed as the value obtained by dividing the solidification time at the time of addition of the sample by the solidification time of the solvent control.
aPTT(activated Partial Thromboplastin Time) aPTT (activated Partial Thromboplastin 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 58.1초의 응고시간을 나타내었다. aPTT의 결과는 3회 반복한 실험의 평균치로 나타내었으며, 혈액응고인자 저해활성은 시료 첨가시의 aPTT를 용매 대조구의 aPTT로 나눈 값으로 나타내었다. Add 50 μl of aPTT reagent (Sigma, ALEXIN ™ ) to the tubes of Amelung coagulometer KC-1A (Japan) and incubate for 3 minutes at 37 ° C. Add 100 μl of plasma and 10 μl of various concentrations of sample extract Min. After the addition of 50 μl CaCl 2 (35 mM), the time until the plasma coagulated was measured. As the solvent control, DMSO was used instead of the sample. In this case, the solidification time was 58.1 seconds. The results of aPTT were expressed as the mean value of three repeated experiments. The activity of inhibiting blood coagulation factor was represented by aPTT divided by the aPTT of the solvent control when the sample was added.
그 결과, 표 3에 나타난 바와 같이, 망고스틴 과육의 경우, 항응고 활성이 나타나지 않았으나, 과피 추출물 및 과경 추출물은 우수한 항응고 활성을 나타내었다. 과피 추출물이 5mg/ml 농도에서 혈액 응고와 관련된 트롬빈, 프로트롬빈 및 혈액응고인자에 모두 강력한 저해를 나타낸 반면, 과경 추출물은 동일농도에서 트롬빈 타임만을 15배 이상 연장시켜 트롬빈에 우선적으로 작용하여 혈액응고 저해활성을 나타냄을 확인하였다. 과경 추출물은 농도의존적인 저해 활성을 나타내었으며, 7mg/ml 농도에서는 15배 이상 연장된 트롬빈 타임, 5.9배 연장된 프로트롬빈 타임, 2.14배 연장된 aPTT를 나타내어 강력한 항응고 활성을 나타내었다. 과경 추출물의 상기 표 2에 나타난 강력한 혈소판 응집 저해와 상기 표 3에 나타난 우수한 트롬빈 저해 활성을 고려할 때, 망고스틴 열매의 과경 추출물은 위장 장애를 나타내는 아스피린을 대치할 수 있는 강력한 항혈전제로 개발 가능함을 제시하고 있으며, 트롬빈에 높은 선택적 저해 활성으로 인해, 다양한 혈액응고인자들 저해에 따른 복합적 부작용 없이 혈전 생성을 효율적으로 저해하리라 판단된다. As a result, as shown in Table 3, mangosteen pulp did not exhibit anticoagulant activity, but peel extract and Thymus extract showed excellent anticoagulation activity. The extracts of cinnamon extracts strongly inhibited both thrombin, prothrombin and blood clotting factors associated with blood clotting at the concentration of 5 mg / ml, whereas Thyme extract had a prolonged thrombin time of only 15 times at the same concentration, Respectively. Thyroglobulin extract showed a concentration-dependent inhibitory activity. At the concentration of 7 mg / ml, prolonged thrombin time, 5.9-fold prothrombin time, and 2.14-fold extended aPTT showed strong anticoagulation activity. Considering the potent platelet aggregation inhibition shown in Table 2 above and the excellent thrombin inhibitory activity shown in Table 3 of the Thymus extract, the mangosteen extract of mangosteen fruit can be developed as a potent antithrombotic agent capable of replacing aspirin which is a gastrointestinal disorder And it is considered that thrombin is highly selective inhibitory activity, and therefore, thrombogenesis is effectively inhibited without complex side effects due to inhibition of various blood coagulation factors.
실시예Example 4: 망고스틴 열매의 4: Mangosteen fruit 과피pericarp , 과육 및 , Pulp and 과경Hyperbolic 추출물의 인간 적혈구 용혈 활성 평가 Evaluation of human erythrocyte hemolytic activity of extract
망고스틴 열매의 과육과 과피는 오래전부터 식용으로 사용하여 왔으며, 특히 과피는 말려서 차로 음용하고 있다. 과경의 경우, 그 기원세포가 꽃받침 또는 줄기의 세포로 열매와는 구조적으로 차이가 있으므로, 망고스틴 과경 추출물의 잠재적 급성 독성을 평가하기 위해 인간 적혈구 용혈 활성을 평가하였으며, 그 결과는 표 4에 나타내었다. 이때 용혈 활성은 기존의 보고(손호용, 2014년, Korean J. Microbiol. Biotechnol. 42: 285~292)에 준해 평가하였으며, 간단하게는 PBS로 3회 수세한 인간 적혈구 100μl를 96-well microplate에 가하고 다양한 농도의 시료용액 100μl를 가한 다음 37℃에서 30분간 반응시켰으며, 이후, 반응액을 10분간 원심분리(1,500rpm)하여 상등액 100μl를 새로운 microtiter plate로 옮긴 후 용혈에 따른 헤모글로빈 유출 정도를 414nm에서 측정하였다. 시료의 용매 대조구로는 DMSO(2%)를 사용하였으며, 적혈구 용혈을 위한 실험 대조구로는 Triton X-100(1mg/ml)를 사용하였다. 용혈 활성은 다음의 수식을 이용하여 계산하였다. Flesh and rind of mangosteen fruit have long been used for food, especially the skin is dried and is being drunk. In the case of tuberculosis, the hematopoietic activity of human erythrocytes was evaluated in order to evaluate the potential acute toxicity of mangosteen extract of the mangosteen, because the origin cells were structurally different from the calyx or stem cell and the fruit. The results are shown in Table 4 . The hemolytic activity was assessed in accordance with the existing report (Jung Ho Jeong, 2014, Korean J. Microbiol. Biotechnol. 42: 285-292). In brief, 100 μl of human erythrocytes washed three times with PBS was added to a 96-well microplate 100 μl of sample solution at various concentrations was added and reacted at 37 ° C for 30 minutes. Afterwards, 100 μl of the supernatant was transferred to a new microtiter plate by centrifugation (1,500 rpm) for 10 minutes and the degree of hemoglobin leaching from hemolysis was measured at 414 nm Respectively. Triton X-100 (1 mg / ml) was used as an experimental control for erythrocyte hemolysis. DMSO (2%) was used as a solvent control of the sample. Hemolytic activity was calculated using the following formula.
(( %% ) ) HemolysisHemolysis = [( = [( AbsAbs .S-.S- AbsAbs .C)/(.C) / ( AbsAbs .T-.T- AbsAbs .C)]×100. C)] x 100
Abs. S : 시료 첨가구의 흡광도,Abs. S: absorbance of sample added sphere,
Abs. C : DMSO 첨가구의 흡광도,Abs. C: absorbance of DMSO-added sphere,
AbsAbs . T : Triton X-100 . T: Triton X-100 첨가구의Additive 흡광도. Absorbance.
먼저, 대조구로 사용된 DMSO와 증류수는 적혈구 용혈 활성이 없었으며, Triton X-100은 1mg/ml 농도에서 적혈구를 100% 용혈시킴을 확인하였다. 한편, 망고스틴 열매의 과피, 과육 및 과경 추출물은 2mg/ml 및 4mg/ml 농도에서는 용혈활성이 나타나지 않았다. 그러나 흡광도의 변화는 크게 나타나, 적혈구 및 다양한 혈구세포의 형태적 변화 및 이화학적 변화는 유발시키는 것으로 확인되었다. 최종적으로 망고스틴 과경 추출물은 과육 및 과피와 동일하게 별도의 급성독성은 없으리라 판단되었다. First, DMSO and distilled water used as control did not have erythrocyte hemolytic activity, and Triton X-100 showed 100% hemolysis of red blood cells at a concentration of 1 mg / ml. On the other hand, hemolytic activity was not observed at the concentrations of 2 mg / ml and 4 mg / ml of mangosteen fruit. However, the change in absorbance was significant and it was confirmed that morphological changes and physico - chemical changes of red blood cells and various hemocytes were induced. Finally, it was concluded that the extract of Mangosteen mangosteen had no acute toxicity like the flesh and skin.
실시예Example 5: 망고스틴 5: Mangosteen 과경Hyperbolic 추출물의 혈장, 산 및 열 안정성 평가 Evaluation of Plasma, Acid and Thermal Stability of Extracts
상기 실시예 1에서 얻은 망고스틴 과경 추출물을 대상으로 항응고 활성에 대한 혈장 안정성, 열 안정성 및 산 안정성을 확인하였다. 상기 활성 분획물은 100℃에서 1시간 열 처리, pH 2(0.01M HCl)에서의 1시간 처리, 혈장에서 1시간 처리시에도 항응고 활성의 소실이 없이 우수한 활성을 유지하였다. 따라서, 실시예1의 성분 분석 결과와 실시예5의 결과를 고려할 때, 망고스틴 과경 추출물의 활성물질은 플라보노이드성 화합물, 또는 이의 배당체로 예상된다. 이상의 결과는 폐기되고 있는 망고스틴 과경으로부터 제조된 추출물이 항혈전제로 실제적 이용이 가능함을 제시하고 있으며, 위장 장애 등의 부작용이 보고된 아스피린을 보완, 대치할 수 있으리라 판단된다.The plasma stability, thermal stability and acid stability of the anticoagulant activity of the mangosteen extract obtained in Example 1 were confirmed. The active fractions retained excellent activity without heat treatment at 100 ° C for 1 hour, 1 hour treatment with pH 2 (0.01M HCl), and 1 hour treatment with plasma, without loss of anticoagulant activity. Therefore, considering the component analysis results of Example 1 and the results of Example 5, it is expected that the active substance of the mangosteen mangosteen extract is a flavonoid compound, or a glycoside thereof. These results suggest that the extract prepared from the discarded mangosteen root can be used as an antithrombotic agent and it may be possible to complement and replace the aspirin reported side effects such as gastrointestinal disorder.
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