KR20150099505A - Compositions for treatment, prevention or improvement of hepatotoxicity comprising taxifolin from seed of Hovenia dulcis - Google Patents
Compositions for treatment, prevention or improvement of hepatotoxicity comprising taxifolin from seed of Hovenia dulcis Download PDFInfo
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- KR20150099505A KR20150099505A KR1020150115458A KR20150115458A KR20150099505A KR 20150099505 A KR20150099505 A KR 20150099505A KR 1020150115458 A KR1020150115458 A KR 1020150115458A KR 20150115458 A KR20150115458 A KR 20150115458A KR 20150099505 A KR20150099505 A KR 20150099505A
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- Prior art keywords
- seed
- compound
- hepatotoxicity
- formula
- fraction
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- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
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- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
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- 235000019173 retinyl acetate Nutrition 0.000 description 1
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- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 235000013580 sausages Nutrition 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229940043175 silybin Drugs 0.000 description 1
- 235000014899 silybin Nutrition 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
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- 239000003381 stabilizer Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
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- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Images
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A23L1/30—
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- A23L1/3002—
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/72—Rhamnaceae (Buckthorn family), e.g. buckthorn, chewstick or umbrella-tree
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
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- Health & Medical Sciences (AREA)
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- Natural Medicines & Medicinal Plants (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Botany (AREA)
- Alternative & Traditional Medicine (AREA)
- Microbiology (AREA)
- Medical Informatics (AREA)
- Biotechnology (AREA)
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- Medicines Containing Plant Substances (AREA)
Abstract
Description
탁시폴린을 유효성분으로 하는 약학 조성물 또는 건강기능식품 조성물에 관한 것이다.
The present invention relates to a pharmaceutical composition or health functional food composition comprising texifolin as an active ingredient.
생체 내로 들어온 생체 외 물질은 일단 간을 통해 대사되므로 간은 영양소 이외에도 많은 독성물질에 노출될 위험이 다른 장기 보다 많아 그 만큼 손상될 확률도 매우 높다. 또한, 우리의 몸은 산업화에 따른 공해물질, 독성물질에 항상 노출되어 있어 우리의 간은 끊임없이 해독작용에 시달리고 있는데 간독성을 유발하는 물질 외에도 알코올, 흡연 등은 간 손상을 가중시켜 인체가 방어 해독 작용을 하지 못해 면역 체계에 이상을 가져와 다른 질병의 원인이 되기도 한다. Since in vivo substances entering the body are metabolized through the liver, the liver has a higher risk of being exposed to toxic substances than other organs in addition to nutrients. In addition, our body is always exposed to pollutants and toxic substances by industrialization, so our liver is constantly detoxified. In addition to substances that cause hepatotoxicity, alcohol and smoking add weight to liver damage, And it causes abnormalities in the immune system and causes other diseases.
간독성 질환은 병이 생기는 원인에 따라 약물독성 간질환, 알코올성 간질환등으로 구분할 수 있고, 간독성 질환을 비롯한 간질환은 초기에 자각증상이 없어 상당히 진행되어서야 발견되기 때문에, 우리나라뿐만 아니라 세계적으로도 사망원인의 수위를 차지하고 있으나, 효과적인 치료제 및 진단방법이 없는 실정이다. Hepatotoxic diseases can be classified into drug-toxic liver disease and alcoholic liver disease depending on the cause of the disease, and liver diseases including hepatotoxic diseases are not found until they have progressed considerably since there is no subjective symptoms at the beginning, It is the cause of the cause, but there is no effective treatment and diagnosis method.
현재까지 천연식물에서 추출되어 실제 임상에서 응용되고 있는 간 기능 보호제로서는 실리범 마리아넘(Silybum marianum)이라는 식물에서 추출된 실리빈(silybin), 실리디아민(silydiamine), 실리크리스틴(silycristine) 등의 이성체로 구성된 실리마린(silymarin) 제제가 있다. 이와 같이, 천연물로부터 간질환 치료제를 개발하려는 수많은 노력에도 불구하고 실제로 치료제로 현재 사용 중이거나 임상시험 중인 예는 소수에 불과하다.To date, hepatoprotective agents that have been extracted from natural plants and applied in clinical practice include isomers such as silybin, silydiamine, silycristine, etc. extracted from plants called Silybum marianum Lt; RTI ID = 0.0 > silymarin < / RTI > Thus, despite numerous efforts to develop a therapeutic agent for liver disease from natural products, only a small number of cases are currently being used as therapeutic agents or undergoing clinical trials.
이에, 본 발명자들은 간독성 질환을 나타내는 생체 외 물질로부터 간 보호 효과를 가지는 물질을 연구하던 중, 헛개나무 씨 추출물에서 간 보호 효과를 나타내는 분획을 확인하고, 그로부터 유효 화합물을 분리하여 화합물의 화학구조를 결정하고, 상기 화합물이 간독성 질환을 나타내는 생체 외 물질로부터 간 보호 효과를 가지는 물질로서 간독성 질환의 치료, 예방 또는 개선에 유용하게 사용될 수 있음을 확인함으로써 본 발명을 완성하였다. Accordingly, the inventors of the present invention have been studying a substance having hepatoprotective effect from an in vitro substance exhibiting hepatotoxic diseases, confirming the fraction showing hepatoprotective effect in the Hodgkin's seed extract, separating the effective compound from the fraction, And that the compound can be effectively used for the treatment, prevention or amelioration of hepatotoxic diseases as a substance having a liver protecting effect from an in vitro substance exhibiting hepatotoxic diseases.
헛개나무(Hovenia dulcis Thunb)는 갈매나무과 낙엽활엽교목으로 경기, 강원 이남의 표고 50-800m에 분포하고 있으며, 일본, 중국에도 분포하고 있다. 또한 한국과 일본에는 Hovenia dulcis Thunb(한국, 일본, 중국; 꽃은 연녹색, 잎에는 털이 없다)라는 기본종외에 그 변종들인 Hovenia dulcis var. latifolia Nakai.(일본특산 동북지방; Hovenia dulcis 에 비해 잎이 대단히 크다), Hovenia dulcis var. koreana Nakai(한국특산; 꽃은 백색이다) 그리고, Hovenia dulcis var. tomentella Makino(일본특산 본주, 사국; 잎에 털이 있다)가 분포하고 있다. 수고 10-15m, 흉고직경 30-40cm에 달하며 대경목으로는 수고 20m, 직경 80cm까지 자란다. 또한 내한성과 내음성, 맹아력이 강하다.
Hovenia dulcis Thunb is a deciduous broad-leaved arboreous tree, distributed at 50-800 m above sea level in Gyeonggi Province and south of Kangwon, and distributed in Japan and China. In Korea and Japan, there are Hovenia dulcis Thunb (Korea, Japan, China; flowers are pale green and leaves are hairless), as well as its variants Hovenia dulcis var. The leaves are very large compared to Hovenia dulcis, Hovenia dulcis var. koreana Nakai (Korean specialty; flowers are white) and Hovenia dulcis var. tomentella Makino (Japanese specialty, native country; with hair on the leaves). It is 10-15 meters long and 30-40 centimeters in diameter. It grows up to 20 meters in diameter and 80 centimeters in diameter. In addition, cold resistance, my voice, and strong vigor.
본 발명의 목적은 탁시폴린을 유효성분으로 하는 간독성 질환 치료 또는 예방용 약학 조성물을 제공하는 데에 있다. It is an object of the present invention to provide a pharmaceutical composition for the treatment or prevention of hepatotoxic diseases, which comprises taxifolin as an active ingredient.
본 발명의 또 다른 목적은 탁시폴린을 유효성분으로 하는 간독성 질환 예방 또는 개선용 건강기능식품 조성물을 제공하는 데에 있다.
It is still another object of the present invention to provide a health functional food composition for preventing or ameliorating hepatotoxic diseases using Taxifolin as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 다음 화학식 1로 표시되는 화합물을 유효성분으로 하는 간독성 질환 치료 또는 예방용 약학 조성물을 제공한다. In order to achieve the above object, the present invention provides a pharmaceutical composition for the treatment or prevention of hepatotoxic diseases, comprising a compound represented by the following formula (1) as an active ingredient.
또한 본 발명은 화학식 1로 표시되는 화합물을 유효성분으로 하는 간독성 질환 예방 또는 개선용 건강기능식품 조성물을 제공한다. The present invention also provides a health functional food composition for preventing or ameliorating hepatotoxicity, which comprises the compound represented by the general formula (1) as an active ingredient.
또한 본 발명은 헛개나무 씨를 물, 탄소수 1 내지 6의 알코올 또는 이들의 혼합 용매에 의한 추출하는 단계; 상기 단계의 추출물을 에틸아세테이트 또는 부탄올로 분획한 분획하는 단계; 및 상기 단계의 분획물을 실리카겔 크로마토그래피 방법 및 Sephadex LH-20 칼럼크로마토그래피를 수행하는 단계;를 포함하는 간독성 질환 치료 또는 예방 활성을 갖는 탁시폴린의 분리 방법을 제공한다.
The present invention also relates to a method for producing hovenochuel seeds, comprising the steps of: extracting hinoki seeds with water, an alcohol having 1 to 6 carbon atoms or a mixed solvent thereof; Fractionating the extract with ethyl acetate or butanol; And a step of performing a silica gel chromatography method and a Sephadex LH-20 column chromatography on the fractions of the step, and a method of separating tachesopholine having a therapeutic or preventive activity against hepatotoxicity.
탁시폴린은 간독성 유발물질인 사염화탄소로부터 유도된 간세포 손상을 보호하는 활성을 나타내므로, 간독성 질환의 치료 또는 예방용 약학 조성물, 또는 간독성 질환의 예방 또는 개선용 건강기능식품 조성물로 유용하게 사용될 수 있다.
Since texifolin exhibits an activity of protecting hepatocyte damage induced by carbon tetrachloride which is a hepatotoxicity inducing substance, it can be usefully used as a pharmaceutical composition for treating or preventing hepatotoxic diseases or a health functional food composition for preventing or improving hepatotoxic diseases.
도 1은 헛개나무 씨 추출물의 에틸아세테이트 분획물(HOV-seed-EA Fr.), 부탄올 분획물(HOV-seed-BuOH Fr.) 및 양성대조군(Silymarin)을 각각 농도를 달리하여, 사염화탄소 처리한 간 세포(primary mouse hepatoycytes)에 첨가하여, 사염화탄소만을 처리한 음성대조군(CCl4)의 ALT 활성을 100 %으로 할 때의 각각의 실험군의 상대 ALT 활성을 통해 간 세포 보호효과를 나타낸 그래프이다.
도 2는 헛개나무 씨 추출물의 에틸아세테이트 분획물(HOV-seed-EA Fr.)을 실리카겔 컬럼 크로마토그래피를 통해 얻은 8개의 2차 분획물을 실험군으로 각각 농도를 달리하여, 사염화탄소 처리한 간 세포(primary mouse hepatoycytes)에 첨가하여, 사염화탄소만을 처리한 음성대조군(CCl4)의 ALT 활성을 100 %으로 할 때의 각각의 실험군의 상대 ALT 활성을 통해 간 세포 보호효과를 나타낸 그래프이다.
도 3은 제조예 4의 4 번 2차 분획물(HOV-seed-EA Fr.4)을 Sephadex LH-20 컬럼 크로마토그래피로 용출시켜 얻은 7개의 3차 분획물을 실험군으로 각각 농도를 달리하여, 사염화탄소 처리한 간 세포(primary mouse hepatoycytes)에 첨가하여, 사염화탄소만을 처리한 음성대조군(CCl4)의 ALT 활성을 100 %으로 할 때의 각각의 실험군의 상대 ALT 활성을 통해 간 세포 보호효과를 나타낸 그래프이다.
도 4는 제조예 4의 4번 3차 분획물(HOV-seed-EA Fr.4-4)을 다시 실리카겔 컬럼 크로마토그래피를 통해 얻은 2개의 4차 분획물을 실험군으로 각각 농도를 달리하여, 사염화탄소 처리한 간 세포(primary mouse hepatoycytes)에 첨가하여, 사염화탄소만을 처리한 음성대조군(CCl4)의 ALT 활성을 100 %으로 할 때의 각각의 실험군의 상대 ALT 활성을 통해 간 세포 보호효과를 나타낸 그래프이다.FIG. 1 is a graph showing the results of a comparison between the concentrations of the ethyl acetate fraction (HOV-seed-EA Fr.), the butanol fraction (HOV-seed-BuOH Fr.) and the positive control group (Silymarin) (primary mouse hepatocytes), and the ALT activity of the negative control (CCl4) treated with carbon tetrachloride only was 100%.
FIG. 2 is a graph showing the results obtained by comparing 8 secondary fractions obtained from silica gel column chromatography of ethyl acetate fraction (HOV-seed-EA Fr.) of Hovenia dulcis Seed Extract with carbon tetrachloride-treated liver cells hepatocytes), and the ALT activity of the negative control (CCl4) treated with carbon tetrachloride only was 100%, respectively.
FIG. 3 is a graph showing the results of elution of 4th secondary fractions (HOV-seed-EA Fr.4) of Preparation Example 4 with Sephadex LH-20 column chromatography, (ALT) activity of each test group when the ALT activity of the negative control (CCl4) treated with carbon tetrachloride alone was added to the primary mouse hepatocytes.
FIG. 4 is a graph showing the results obtained by subjecting the 4th tertiary fraction (HOV-seed-EA Fr.4-4) obtained in Production Example 4 to silica gel column chromatography and then subjected to carbon tetrachloride treatment FIG. 3 is a graph showing the effect of hepatocyte protection on the relative ALT activity of each experimental group when the ALT activity of the negative control (CCl4) treated with carbon tetrachloride alone was added to the primary mouse hepatocytes.
본 발명은 헛개나무 씨 추출물 또는 그로부터 분리된 탁시폴린을 유효성분으로 하는 간독성 질환 치료 또는 예방용 약학 조성물을 제공한다. The present invention provides a pharmaceutical composition for the treatment or prevention of hepatotoxic diseases, which comprises as an active ingredient a Hodgkin's seed extract or tapsifolin isolated therefrom.
상기 헛개나무 씨 추출물은 헛개나무 씨를 물, 유기용매 또는 이들의 혼합물을 추출 용매로서 이용하여 헛개나무 씨 추출물을 제조할 수 있다. The hinoki seed extract can be prepared by using hinoki seed as an extraction solvent in water, an organic solvent or a mixture thereof.
예를 들어, 상기 유기용매는 저급 알코올, 헥산, 아세톤, 에틸 아세테이트, 클로로포름, 및 디에틸에테르로 이루어진 군으로부터 선택된 하나 이상의 용매일 수 있다. 상기 저급 알코올은 탄소수 1 내지 6의 알코올일 수 있다. 예를 들어, 저급 알코올로는 메탄올, 에탄올, 프로판올, 부탄올, 노말-프로판올, 이소-프로판올, 노말-부탄올, 1-펜탄올, 2-부톡시에탄올 또는 에틸렌글리콜 등을 이용할 수 있다. 유기용매는 이 외에도 아세트산, DMFO(dimethyl-formamide), DMSO(dimethyl sulfoxide) 등의 극성 용매, 아세토나이트릴, 에틸 아세테이트, 메틸 아세테이트, 플루오로알칸, 펜탄, 2,2,4-트리메틸펜탄, 데칸, 사이클로헥산, 사이클로펜탄, 디이소부틸렌, 1-펜텐, 1-클로로부탄, 1-클로로펜탄, o-자일렌, 디이소프로필 에테르, 2-클로로프로판, 톨루엔, 1-클로로프로판, 클로로벤젠, 벤젠, 디에틸 에테르, 디에틸 설파이드, 클로로포름, 디클로로메탄, 1,2-디클로로에탄, 어닐린, 디에틸아민, 에테르, 사염화탄소 및 THF(Tetrahydrofuran) 등의 비극성 용매를 사용할 수도 있다. For example, the organic solvent may be one or more solvents selected from the group consisting of lower alcohols, hexane, acetone, ethyl acetate, chloroform, and diethyl ether. The lower alcohol may be an alcohol having 1 to 6 carbon atoms. For example, as the lower alcohol, methanol, ethanol, propanol, butanol, n-propanol, iso-propanol, n-butanol, 1-pentanol, 2-butoxyethanol or ethylene glycol can be used. The organic solvent may be a polar solvent such as acetic acid, dimethyl-formamide (DMFO) or dimethyl sulfoxide (DMSO), acetonitrile, ethyl acetate, methyl acetate, fluoroalkane, pentane, 2,2,4-trimethylpentane, decane 1-pentene, 1-chlorobutane, 1-chloropentane, o-xylene, diisopropyl ether, 2-chloropropane, toluene, 1- chloropropane, chlorobenzene , Non-polar solvents such as benzene, diethyl ether, diethyl sulfide, chloroform, dichloromethane, 1,2-dichloroethane, aniline, diethylamine, ether, carbon tetrachloride and THF (tetrahydrofuran) may also be used.
본 발명의 바람직한 하나의 실시예로, 상기 헛개나무 씨 추출물은 물, 저급 알코올 또는 이들 혼합용매의 추출물일 수 있으며, 바람직하게는 헛개나무 씨 열수 추출물 또는 헛개나무 씨 에탄올 수용액 추출물, 예를 들어 헛개나무 씨 주정 추출물일 수 있다. In one preferred embodiment of the present invention, the Hovenuo seed extract may be water, a lower alcohol or an extract of a mixed solvent thereof, and is preferably a hydrolyzate extract of Hovenia dulcis or an aqueous solution of Hovenia cetonia ethanol, for example, It can be a wood seed extract.
본 명세서에서 사용되는 용어 '추출물'은 추출물을 추가적으로 분획(fractionation)한 분획물도 포함한다. 즉, 헛개나무 씨 추출물은 상술한 추출용매를 이용하여 얻은 것뿐만 아니라, 여기에 정제과정을 추가적으로 적용하여 얻은 것도 포함한다. 예를 들어, 상기 헛개나무 씨 추출물은 에틸아세테이트 및 부탄올을 사용하여 순차적으로 분획한 에틸아세테이트 분획물 또는 부탄올 분획물일 수 있다. As used herein, the term " extract " also includes fractions obtained by further fractionating the extract. That is, the Hovenuo seed extract is obtained not only by using the above-mentioned extraction solvent but also by additionally applying a purification process thereto. For example, the Houttuynia cordata extract may be an ethyl acetate fraction or a butanol fraction, which is sequentially fractionated using ethyl acetate and butanol.
또한 본 명세서에서 헛개나무 씨 추출물을 언급하면서 사용되는 용어 '추출물'은 헛개나무 씨에 추출 용매를 처리하여 얻은 조추출물뿐만 아니라 헛개나무 씨 추출물의 가공물도 포함한다. 예를 들어, 헛개나무 씨 추출물은 감압 증류 및 동결 건조 또는 분무 건조 등과 같은 추가적인 과정에 의해 분말 상태로 제조될 수 있다. The term " extract " used in reference to Hovenia dulcis extract in the present specification includes not only crude extract obtained by treating extract of Hovenia dulcis with an extraction solvent, but also a product of Hovenia dulcis seed extract. For example, hinoki seed extract can be prepared in powder form by further processes such as vacuum distillation and lyophilization or spray drying.
또한, 상기 추출물이나 분획물을 일정한 분자량 컷-오프 값을 갖는 한외 여과막을 통과시켜 얻은 분획, 다양한 크로마토그래피 (크기, 전하, 소수성 또는 친화성에 따른 분리를 위해 제작된 것)에 의한 분리 등, 추가적으로 실시된 다양한 정제 방법을 통해 화학식 1로 표시되는 화합물을 분리할 수 있다. Further, fractions obtained by passing the above extract or fractions through an ultrafiltration membrane having a constant molecular weight cut-off value, separation by various chromatography (manufactured for separation according to size, charge, hydrophobicity or affinity), and the like The compound represented by formula (1) can be isolated through various purification methods.
[화학식 1][Chemical Formula 1]
. .
이러한 분리 과정의 하나의 실시예로, 먼저 헛개나무 씨의 에탄올 추출물을 에틸아세테이트로 분획하여 분획물을 얻고, 실리카겔(silica gel) 컬럼 크로마토그래피로 8 분획 하고 다시 sephadex LH-20, ODS-A, diol, preparative MPLC, 또는 preparative HPLC 등의 다양한 크로마토그래피법을 이용하여 분리할 수 있다. As one example of this separation process, first, the ethanol extract of Hovenia dulcis was fractionated with ethyl acetate to obtain a fraction. The fractions were fractionated by silica gel column chromatography and then re-fractionated with sephadex LH-20, ODS-A, diol , preparative MPLC, or preparative HPLC.
본 발명의 간독성 질환 치료, 예방 또는 개선용 조성물의 유효 화합물은 상기 화학식 1의 화합물 뿐만 아니라, 이의 약학적으로 허용되는 염, 이로부터 제조될 수 있는 가능한 용매화물, 수화물, 라세미체, 또는 입체이성질체를 모두 포함한다. The effective compound of the composition for treating, preventing or ameliorating a hepatotoxic disease of the present invention is not limited to the compound of the above formula (1), but also its pharmaceutically acceptable salts, possible solvates, hydrates, racemates, Isomers.
본 발명의 상기 화학식 1의 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, 하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함한다. The compound of formula (I) of the present invention can be used in the form of a pharmaceutically acceptable salt. As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Sulfonate, methanesulfonate, propanesulfonate, naphthalene-1-sulphonate, naphthalene-1-sulphonate, , Naphthalene-2-sulfonate or mandelate.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 상기 화학식 1의 화합물을 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다.
The acid addition salt according to the present invention may be prepared by a conventional method, for example, by dissolving the compound of
동량의 상기 화학식 1의 화합물 및 산 수용액 또는 알코올을 가열하고, 이어서 이 혼합물을 증발시켜서 건조하거나 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다. By heating the same amount of the compound of formula (I) and the aqueous acid solution or alcohol, and then evaporating the mixture or drying the precipitated salt by suction filtration.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비 용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 은 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염(예, 질산은)과 반응시켜 얻는다. In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the salt of the undissolved compound, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).
또한 헛개나무 씨 에탄올 추출물의 에틸아세테이트 분획물, 부탄올 분획물은 사염화탄소에 의해 유도된 간 세포의 손상에 대하여 실리마린과 동등한 수준의 보호 효과를 나타내었고, 화학식 1의 화합물은 실리마린에 비해 현저히 뛰어난 활성을 나타냄을 확인하였다.
In addition, ethyl acetate fraction and butanol fraction of ethanol extract of Houttuynia cylindrica showed a protective effect equivalent to that of silymarin against the damage of liver cells induced by carbon tetrachloride, and the compound of formula (1) showed remarkably excellent activity compared to silymarin Respectively.
한편, 본 명세서에서 용어 '유효성분으로 포함하는'이란 본 발명의 헛개나무 씨 추출물 또는 화학식 1의 화합물을, 간 보호 효능 또는 활성을 달성하는 데 충분한 양을 포함하는 것을 의미한다. 본 발명의 간독성 질환 치료 또는 예방용 약학 조성물은, 조성물 총 중량에 대하여 헛개나무 씨 추출물 또는 화학식 1의 화합물을 0.1 내지 50 중량%로 포함하는 것이 바람직하나 이에 한정되지 않는다. As used herein, the term " comprising as an active ingredient " is meant to include a sufficient amount of the Hovenuo seed extract of the present invention or the compound of formula (I) to achieve liver protection efficacy or activity. The pharmaceutical composition for the treatment or prevention of hepatotoxic diseases according to the present invention preferably contains 0.1 to 50% by weight of the extract of Hovenia dulcis Thunb extract or the compound of formula (1) based on the total weight of the composition, but is not limited thereto.
본 발명의 조성물은 약제의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다. The compositions of the present invention may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of medicaments.
본 발명에 따른 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화 하여 사용될 수 있다. 본 발명의 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. The composition according to the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., oral preparations, suppositories and sterilized injection solutions according to a conventional method have. Examples of carriers, excipients and diluents that can be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
제제 화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 본 발명의 조성물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘(calcium carbonate), 슈크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤젤라틴 등이 사용될 수 있다. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may be formulated into the compositions of the present invention with at least one excipient such as starch, calcium carbonate, (sucrose), lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a suppository base, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol gelatin and the like can be used.
본 발명의 조성물은 경구 또는 비경구로 투여될 수 있으며, 비경구 투여법이라면 어느 것이나 사용 가능하고, 전신 투여 또는 국소 투여가 가능하나, 전신 투여가 더 바람직하며, 정맥 내 투여가 가장 바람직하다. The composition of the present invention may be administered orally or parenterally, and any parenteral administration method may be used, and systemic administration or topical administration is possible, but systemic administration is more preferable, and intravenous administration is most preferable.
본 발명의 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나 바람직한 효과를 위해서, 본 발명의 조성물은 1일 0.0001 내지 0.03 g/kg으로, 바람직하게는 0.001 내지 8 mg/kg으로 투여하는 것이 좋다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.
The preferred dosage of the composition of the present invention varies depending on the condition and the weight of the patient, the degree of disease, the type of drug, the route of administration and the period of time, but can be appropriately selected by those skilled in the art. However, for the desired effect, the composition of the present invention is preferably administered at 0.0001 to 0.03 g / kg per day, preferably 0.001 to 8 mg / kg per day. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way.
또한, 본 발명은 헛개나무 씨 추출물 또는 화학식 1의 화합물을 유효성분으로 함유하는 간독성 질환 예방 또는 개선용 건강기능식품 조성물을 제공한다. The present invention also provides a health functional food composition for preventing or ameliorating hepatotoxic diseases, which contains Hovenuo seed extract or the compound of formula (1) as an active ingredient.
상기 건강기능식품 조성물에서, 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 드링크제, 육류, 소시지, 빵, 비스킷, 떡, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 알코올 음료 및 비타민 복합제, 유제품 및 유가공 제품 등이 있으며, 통상적인 의미에서의 건강기능식품을 모두 포함한다. In the health functional food composition, the kind of the food is not particularly limited. Examples of the foods to which the above substances can be added include dairy products including dairy products, meat, sausage, bread, biscuits, rice cakes, chocolate, candies, snacks, confectionery, pizza, ramen and other noodles, gums, ice cream, Beverages, alcoholic beverages and vitamin complexes, dairy products, and dairy products, all of which include health functional foods in a conventional sense.
본 발명의 상기 헛개나무 씨 추출물 또는 화학식 1의 화합물은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효 성분의 혼합량은 그의 사용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강식품 중의 상기 화합물의 양은 전체 식품 중량의 0.1 내지 90 중량부로 가할 수 있다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다. The Hovenuo seed extract or the compound of formula (1) of the present invention can be added directly to the food or used together with other food or food ingredients, and can be suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (for prevention or improvement). Generally, the amount of the compound in the health food may be 0.1 to 90 parts by weight of the total food. However, in the case of long-term intake intended for health and hygiene purposes or for the purpose of controlling health, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.
음료를 제조하는 경우 지시된 비율로 필수 성분으로서 상기 헛개나무 씨 추출물 또는 화학식 1의 화합물을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다. There is no particular limitation on other components other than the above-mentioned Hovenuo Seed Extract or the compound of Formula (1) as an essential ingredient in the proportions indicated in the case of producing a drink, and various flavors or natural carbohydrates, ≪ / RTI > Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 of the composition of the present invention.
상기 외에 헛개나무 씨 추출물 또는 화학식 1의 화합물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 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 헛개나무 씨 추출물 또는 화학식 1의 화합물은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. In addition to the above, the Hovenuo seed extract or the compound of the formula (I) may be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and intermediates such as cheese and chocolate, Salts of alginic acid and its salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks and the like. Other hinoki seed extracts or compounds of formula (1) may contain flesh for the production of natural fruit juices and fruit juice drinks and vegetable drinks.
이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 헛개나무 씨 추출물 또는 화학식 1의 화합물 100 중량부 당 0.1 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.
These components may be used independently or in combination. The proportion of such additives is not so critical, but is generally selected in the range of 0.1 to about 20 parts by weight per 100 parts by weight of the Hovenuo seed extract or the compound of formula (1).
이하 본 발명을 실시예, 실험예 및 제조예에 의해 상세히 설명한다. 단, 하기 실시예, 실험예 및 제조예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예, 실험예 및 제조예에 한정되는 것은 아니다.
Hereinafter, the present invention will be described in detail with reference to Examples, Experimental Examples and Preparation Examples. However, the following Examples, Experimental Examples and Preparation Examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following Examples, Experimental Examples and Production Examples.
제조예 1: 헛개나무 씨 추출물의 제조Production Example 1: Preparation of Hovenia dulcis Seed Extract
헛개나무 씨 33.2kg을 에탄올을 사용하여 실온에서 3일간 추출하였으며, 추출액을 감압 농축하여 고형분 함량 266.668g을 얻었다.
33.2 kg of Houttuynia cylindrica was extracted with ethanol for 3 days at room temperature, and the extract was concentrated under reduced pressure to obtain a solid content of 266.668 g.
제조예 2 및 3: 헛개나무 씨 추출물의 분획물 제조Production Examples 2 and 3: Preparation of fractions of hinoki seed extract
상기 제조예 1의 헛개나무 씨 추출물 241.03g을 사용하여 에틸아세테이트, 부탄올을 사용하여 순차적으로 분획하였다. 각 분획물은 감압 농축하여 에틸아세테이트 분획물(제조예 2) 30.653g, 부탄올 분획물(제조예 3) 51.663g을 각각 얻었다.
241.03 g of the Houttuynia cordata extract of Preparation Example 1 was fractionated sequentially using ethyl acetate and butanol. Each fraction was concentrated under reduced pressure to obtain 30.653 g of ethyl acetate fraction (Preparation Example 2) and 51.663 g of butanol fraction (Preparation Example 3).
제조예 4: 헛개나무 씨 추출물로부터 유효 화합물의 분리Production Example 4: Isolation of Active Compound from Hovenia dulcis Seed Extract
상기 제조예 2의 에틸아세테이트 분획물을 분획물을 실리카겔 크로마토그래피 방법과 Sephadex LH-20(Pharmacia Fine Chemicals) 칼럼크로마토그래피를 사용하여 화학식 1의 화합물을 분리하였다. The ethyl acetate fraction of Preparation Example 2 was fractionated using silica gel chromatography and Sephadex LH-20 (Pharmacia Fine Chemicals) column chromatography.
먼저 제조예 2의 에틸아세테이트 분획물(26.369g)을 실리카겔로 충전시킨 open column에 용출 용매 클로로포름:메탄올(100:0 v/v)부터 클로로포름:메탄올(20:1 v/v), 클로로포름:메탄올(15:1 v/v), 클로로포름:메탄올(10:1 v/v), 클로로포름:메탄올(5:1 v/v), 클로로포름:메탄올(2:1 v/v), 클로로포름:메탄올(1:1 v/v)의 용매로 순차적으로 증가시키며 최종적으로 MeOH 100%을 사용하여 용출하였다. 상기 용출된 분취물들을 Agilent HPLC 1200 크로마토그래피를 통해 용출시킨 후 동일 시간대의 피크별로 나누어 8개의 2차 분획물로 모았다. First, an eluting solvent chloroform: methanol (100: 0 v / v) to chloroform: methanol (20: 1 v / v) was added to an open column packed with ethyl acetate fraction (26.369 g) 1: 1 v / v), chloroform: methanol (10: 1 v / v), chloroform: methanol 5: 1 v / v, chloroform: methanol 2: 1 v / v), and finally eluted with 100% MeOH. The eluted fractions were eluted through an Agilent HPLC 1200 chromatography and were then divided into 8 secondary fractions divided into peaks at the same time.
이중 4번 2차 분획물을 Sephadex LH-20(Pharmacia Fine Chemicals) 칼럼 크로마토그래피를 사용하고, 용출용매는 클로로포름:메탄올(1:1 v/v)을 이용하여 용출시켜 7개의 3차 분획물을 모았다. 이중 4번 3차 분획물을 실리카겔로 충진시킨open column에 용출 용매 클로로포름:메탄올(100:0 v/v), 클로로포름:메탄올(97:3 v/v), 메탄올100 %을 사용하여 최종 4-4-2 분획물에서 화합물(335mg)을 단리하였다.
Seven tertiary fractions were collected by eluting the eluted solvent using chloroform: methanol (1: 1 v / v) using Sephadex LH-20 (Pharmacia Fine Chemicals) column chromatography. A final column filled with silica gel was filled with silica gel. The eluate was eluted with chloroform: methanol (100: 0 v / v), chloroform: methanol (97: 3 v / v) The compound (335 mg) was isolated from the -2 fraction.
실험예 1: 헛개나무 씨 분획물의 간 세포 보호 효과EXPERIMENTAL EXAMPLE 1: Protective Effect of Hepatocyte Seed Fraction on Liver Cells
(1) 실험방법(1) Experimental method
간 세포는 Berry의 방법에 따라 collagenase perfusion방법으로 분리하여 배양하였다[Berry, M. N., Halls, H. J., and Gricell, M. B. (1995) Techniques for pharmacological and toxicological strudies with isolated hepatocyte suspensions. Life Sci. 51, 1-16]. 간세포를 얻기 위해 실험동물에 urethane(1g/kg body weight)을 복강주사 하여 마취시키고 70% ethanol로 복부를 소독하여 개복한 후, 37℃로 가온된 perfusion buffer Ⅰ(collagenase-free)을 24G IV catheter를 이용하여 간문맥에 관류시켜 간으로부터 혈액을 제거하였다. 2차적으로 perfusion buffer Ⅱ(collagenase)를 이용하여 간을 소화시킨 후, 간을 떼어내어 간세포를 유리시켰다. 유리시킨 간세포에 hepatocyte wash medium 40ml을 가하여 cell strainer(100um)로 여과시켰다. 여과액을 50g, 2분간 원심분리한 다음 상층액을 제거한 뒤, 동일한 방법을 3번 반복하였다. 10%FBS가 포함된 WME(Williams' Medium E) 배양액으로 세포를 현탁시켜 2X105cells/mL농도로 collagen type Ⅰ이 미리 도포된 24-well culture plate에 분주하였다.간세포를 CO2incubator에 넣고 37℃에서 16시간 부착시킨 후 대표적인 간독성 물질인 사염화탄소(carbon tetrachloride, CCl4)를 처리하여 인위적인 간손상을 유발시키면서 일정 농도의 제조예 2 의 헛개나무 씨 분획물(HOV-seed-EA Fr.) 및 제조예 3의 헛개나무 씨 분획물(HOV-seed-BuOH Fr.)을 4시간 동안 처리하였다. 4시간 후 배양액 내로 유리된 ALT의 활성을 측정하여 간세포 손상 정도를 확인하였다.
Hepatic cells were isolated by collagenase perfusion method according to Berry's method [Berry, MN, Halls, HJ, and Gricell, MB (1995) Techniques for pharmacological and toxicological straties with isolated hepatocyte suspensions. Life Sci. 51, 1-16]. To obtain hepatocytes, anesthetized by intraperitoneal injection of urethane (1 g / kg body weight) into the experimental animals, disinfected with 70% ethanol, and then perfused with 37 ˚C perfusion buffer Ⅰ (collagenase-free) Were used to remove blood from the liver by perfusion through the portal vein. Secondly, the liver was digested with perfusion buffer II (collagenase), and the liver was removed to liberate the hepatocytes. The hepatocyte wash medium (40 ml) was added to the liberated hepatocytes and filtered with a cell strainer (100 μl). The filtrate was centrifuged at 50 g for 2 minutes, and the supernatant was removed, and the same procedure was repeated 3 times. 10% by FBS suspending the cells in WME (Williams' Medium E) culture medium containing the was dispensed in 24-well culture plate with collagen type Ⅰ is previously applied to 2X10 5 cells / mL concentration. Insert the liver to CO 2 incubator 37 (HOV-seed-EA Fr.) and Preparation (2) of
(2) 실험결과(2) Experimental results
헛개나무 씨 분획물의 사염화탄소에 의해 유도된 간 독성 해소작용을 관찰하였을 때, 헛개나무 씨 에틸아세테이트 분획물과 부탄올 분획물은 농도별로 ALT 활성을 크게 감소시켰으며 양성 대조군인 실리마린(silymarin)과 유사한 간독성 해소효과를 나타내었다(도 1 참조).
When the hepatotolytic activity of hepatocyte seed fraction was investigated, hepatocyte ethyl acetate fraction and butanol fraction significantly decreased the ALT activity by the concentration, and hepatotoxicity resolved similar to the positive control silymarin (See Fig. 1).
실험예 2: 헛개나무 씨 2차 분획물의 간 세포 보호 효과Experimental Example 2: Protective Effect of the Second Fraction of Hovenia dulcis on Liver Cells
제조예 4에서, 제조예 2의 에틸아세테이트 분획물을 실리카겔 컬럼 크로마토그래피로 용출시켜, HPLC 검색하여 얻은 8개의 2차 분획물에 대하여 실험예 1과 동일한 방법으로 간 세포 보호 효과를 확인하였다. In Production Example 4, the ethyl acetate fraction of Preparative Example 2 was eluted by silica gel column chromatography, and the eight secondary fractions obtained by HPLC analysis were confirmed to have the hepatocyte protective effect in the same manner as in Experimental Example 1. [
헛개나무 씨 에틸아세테이트 분획물의 1, 2, 3번 2차 분획물은 효과가 없었고 4 내지 8번 2차 분획물에서 우수한 간보호 효과를 보였다. 특히 에틸아세테이트 분획물 중 4번 2차 분획물(HOV-seed-EA Fr4.)이 100μg/mL에서 가장 큰 효과를 보였다(도 2 참조).
The 1st, 2nd and 3rd secondary fractions of the Houttuyniae ethyl acetate fraction were ineffective and showed excellent liver protection in the fourth and eighth secondary fractions. In particular, the fourth fraction (HOV-seed-EA Fr4.) Of the ethyl acetate fraction showed the greatest effect at 100 μg / mL (see FIG. 2).
실험예 3: 헛개나무 씨 3차 분획물의 간 세포 보호 효과Experimental Example 3: Protective effect of hepatocyte seed fraction of Hovenia dulcis
제조예 4에서, 8개의 2차 분획물 중 가장 효과가 뛰어났던 4번 2차 분획물(HOV-seed-EA Fr4.)을 Sephadex LH-20(Pharmacia Fine Chemicals) 칼럼으로 용출시켜 얻은 7개의 3차 분획물에 대하여 실험예 1과 동일한 방법으로 간 세포 보호 효과를 확인하였다. In Production Example 4, seven tertiary fractions (HOV-seed-EA Fr4.), Which was the most effective of the eight secondary fractions, were eluted with a Sephadex LH-20 (Pharmacia Fine Chemicals) The protective effect of hepatocytes was confirmed in the same manner as in Experimental Example 1.
상기 3차 분획물 중에서 4-1, 4-2-1 및 4-2-2번 3차 분획물은 효과를 미미하게 보인 반면 4-3, 4-4 및 4-6번 3차 분획물에서 큰 효과를 나타내었고, 그중 4-4번 3차 분획물(HOV-seed-EA Fr.4-4)의 효과가 가장 우수하였다(도 3 참조).
Of the tertiary fractions, the tertiary fractions 4-1, 4-2-1 and 4-2-2 showed little effect, whereas the tertiary fractions 4-3, 4-4 and 4-6 showed a great effect , And the effect of the tertiary fraction 4-4 (HOV-seed-EA Fr.4-4) was the most excellent (see FIG. 3).
실험예 4: 헛개나무 씨 4차 분획물의 간 세포 보호 효과Experimental Example 4: Protective Effect of the Fourth Fractions of Hovenia dulcis on Liver Cells
제조예 4에서, 7개의 3차 분획물 중 가장 효과가 뛰어났던 4-4번 3차 분획물(HOV-seed-EA Fr.4-4)을 단일 화합물로 분리하기 위하여 다시 실리카겔 컬럼 크로마토그래피로 분리하여 2개의 4차 분획물을 얻은 다음, 실험예 1과 동일한 방법으로 간 세포 보호 효과를 확인하였다. In Production Example 4, the most effective fraction of the 7th tertiary fractions (HOV-seed-EA Fr.4-4) was isolated by silica gel column chromatography to separate into a single compound Two fourth fractions were obtained and then the protective effect of liver cells was confirmed in the same manner as in Experimental Example 1.
상기 4차 분획물 중에서 4-4-2번 4차 분획물(HOV-seed-EA Fr.4-4-2)은 4-4-1번 4차 분획물에 비하여 우수한 효과를 나타내어, 4-4번 3차 분획물 및 4번 2차 분획물의 효과는 4-4-2번 4차 분획물에 존재하는 화합물로 인한 것으로 판단하였다(도 4 참조).
4-4-2 fraction (HOV-seed-EA Fr.4-4-2) out of the 4th fraction exhibits a superior effect to the 4-4-1 fourth fraction, and 4-4-3 It was judged that the effect of the tea fraction and the fourth fraction was due to the compound present in the fourth fraction 4-4-2 (see FIG. 4).
실험예 5: 4-4-2 분획물에서 단리된 화합물의 구조 동정Experimental Example 5: Identification of isolated compounds from 4-4-2 fraction
상기 제조예 4의 4-4-2번 4차 분획물에 단리된 화합물의 구조동정을 위하여 성균관대학교 공동기기원에 의뢰하였으며, 질량분석은 LC/MS/MS를 측정하였고, 핵자기공명(NMR) 스펙트럼은 단리한 화합물을 CD3OD에 녹여 1H, 13C,DEPT,1H-1HCOSY,HMQC,HMBC를 측정하였다.The LC / MS / MS was measured by mass spectrometry, nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry were carried out in order to identify the structure of the compound isolated in the 4-4-2 fourth fraction of Production Example 4. [ spectra were measured for 1 H, 13 C, DEPT, 1 H- 1 HCOSY, HMQC, HMBC dissolving the isolated compound in CD 3 OD.
상기 LC/MS/MS m/z 는 302.9[M-H]- 이었고, 1H-NMR(500㎒, CD3OD)δ는 4.48(d,1H,J=11.5,H-3), 4.89(d,1H,J=11.5,H-2), 5.87(d,1H,J=2,H-8), 5.91(d,1H,J=2.5,H-6), 6.79(d,1H,J=8,H-5'), 6.83 (dd,1H,J=2,10.5,H-6'), 6.95 (d,1H,J=2,H-2')이었으며, 13C-NMR(500㎒, CD3OD)δ는 73.81(C-3), 85.27(C-2), 96.40(C-8), 97.43(C-8), 101.98(C-10), 116.01(C-2'), 116.20 (C-5'), 121.04 (C-6'), 129.99 (C-1'), 146.46 (C-3'). 147.28 (C-4'), 164.66 (C-9), 165.46 (C-5), 168.84 (C-7), 198.58 (C-4)을 나타내었다.The LC / MS / MS m / z was 302.9 [MH] - was, 1 H-NMR (500㎒,
상기 결과를 종합했을 때, 제조예 4의 4-4-2 분획물에 단리된 화합물은 화학식 1의 화합물로 구조 동정하였다. Based on the above results, the compound isolated in the 4-4-2 fraction of Preparation Example 4 was identified as the compound of Formula (1).
[화학식 1][Chemical Formula 1]
<제제예 1> 약학적 제제의 제조 ≪ Formulation Example 1 > Preparation of pharmaceutical preparation
1-1. 산제의 제조1-1. Manufacture of Powder
화학식 1의 화합물 500 ㎎500 mg of the compound of formula (1)
유당 100 ㎎
탈크 10 ㎎10 mg of talc
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.
The above components are mixed and filled in airtight bags to prepare powders.
1-2. 정제의 제조1-2. Manufacture of tablets
화학식 1의 화합물 500 ㎎500 mg of the compound of formula (1)
옥수수전분 100 ㎎
유당 100 ㎎
스테아린산 마그네슘 2 ㎎2 mg of magnesium stearate
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.
After mixing the above components, tablets are prepared by tableting according to the usual preparation method of tablets.
1-3. 캅셀제의 제조1-3. Manufacture of capsules
화학식 1의 화합물 500 ㎎500 mg of the compound of formula (1)
옥수수전분 100 ㎎
유당 100 ㎎
스테아린산 마그네슘 2 ㎎2 mg of magnesium stearate
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.
The above components are mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.
1-4. 주사제의 제조1-4. Injection preparation
화학식 1의 화합물 500 ㎎500 mg of the compound of formula (1)
주사용 멸균 증류수 적량Sterile sterilized water for injection
pH 조절제 적량pH adjuster
통상의 주사제의 제조방법에 따라 1 앰플당(2 ㎖) 상기의 성분 함량으로 제조한다.
(2 ml) per ampoule in accordance with the usual injection method.
1-5. 액제의 제조1-5. Manufacture of liquid agent
화학식 1의 화합물 100 ㎎100 mg of the compound of formula (1)
이성화당 10 g10 g per isomer
만니톨 5 g5 g mannitol
정제수 적량Purified water quantity
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬 향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100 ㎖로 조절한 후 갈색 병에 충진하여 멸균시켜 액체를 제조한다.
Each component was added to purified water in accordance with the usual liquid preparation method and dissolved, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed, and purified water was added thereto. The whole was adjusted to 100 ml with purified water, The liquid is prepared by sterilization.
제조예2: 건강기능식품(분말형)의 제조Production Example 2: Preparation of health functional food (powder type)
화학식 1의 화합물 1000 ㎎1000 mg of the compound of formula (1)
비타민 혼합물 적량Vitamin mixture quantity
비타민 A 아세테이트 70 ㎍70 [mu] g of vitamin A acetate
비타민 E 1.0 ㎎Vitamin E 1.0 mg
비타민 0.13 ㎎0.13 mg of vitamin
비타민 B2 0.15 ㎎0.15 mg of vitamin B 2
비타민 B6 0.5 ㎎0.5 mg of vitamin B 6
비타민 B12 0.2 ㎍Vitamin B 12 0.2 g
비타민 C 10 ㎎10 mg vitamin C
비오틴 10 ㎍Biotin 10 μg
니코틴산아미드 1.7 ㎎Nicotinic acid amide 1.7 mg
엽산 50 ㎎50 mg of folic acid
판토텐산 칼슘 0.5 ㎎Calcium pantothenate 0.5 mg
무기질 혼합물 적량Mineral mixture quantity
황산제1철 1.75 ㎎1.75 mg of ferrous sulfate
산화아연 0.82 ㎎0.82 mg of zinc oxide
탄산마그네슘 25.3 ㎎Magnesium carbonate 25.3 mg
제1인산칼륨 15 ㎎15 mg of potassium phosphate monobasic
제2인산칼슘 55 ㎎Secondary calcium phosphate 55 mg
구연산칼륨 90 ㎎Potassium citrate 90 mg
탄산칼슘 100 ㎎100 mg of calcium carbonate
염화마그네슘 24.8 ㎎24.8 mg of magnesium chloride
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다.
Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.
제조예 3: 건강기능식품(음료형)의 제조Production Example 3: Preparation of health functional foods (beverage type)
화학식 1의 화합물 1000 ㎎1000 mg of the compound of formula (1)
구연산 1000 ㎎Citric acid 1000 mg
올리고당 100 g100 g of oligosaccharide
매실농축액 2 gPlum concentrate 2 g
타우린 1 gTaurine 1 g
정제수를 가하여 전체 900 ㎖Purified water was added to a total of 900 ml
통상의 건강 음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간 동안 85에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2l 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 건강 음료 조성물 제조에 사용하였다. The above ingredients were mixed according to the usual health drink manufacturing method, and the mixture was stirred and heated at 85 for about 1 hour. The resulting solution was filtered to obtain a sterilized 2-liter container, which was sealed and sterilized, And used for manufacturing.
상기 조성비는 비교적 기호 음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호 도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.
Although the composition ratio is relatively mixed with the ingredient suitable for the favorite drink, it is also possible to arbitrarily modify the blending ratio according to the regional or national preference such as the demand class, demand country, use purpose, and the like.
제조예 4: 건강기능식품(츄잉검)의 제조Production Example 4: Preparation of health functional foods (chewing gum)
껌베이스 20 %Gum base 20%
설탕 76.36~76.76 %Sugar 76.36 ~ 76.76%
화학식 1의 화합물 0.24~0.64 %0.24 to 0.64%
후르츠향 1 %
물 2 %
상기 조성 및 함량으로 하여 통상적인 방법을 사용하여 츄잉껌을 제조하였다.
Chewing gum was prepared using the above-mentioned composition and content by a conventional method.
제조예 5: 건강기능식품(밀가루 식품)의 제조Preparation Example 5: Preparation of health functional foods (wheat flour foods)
화학식 1의 화합물 0.5 내지 5 중량부를 밀가루 100 중량부에 첨가하고, 이 혼합물을 이용하여 빵, 케이크, 쿠키, 크래커 및 면류를 제조하여 건강 증진용 식품을 제조하였다.
0.5 to 5 parts by weight of the compound of the formula (1) was added to 100 parts by weight of wheat flour, and bread, cake, cookies, crackers and noodles were prepared by using this mixture to prepare foods for health promotion.
제조예 6: 건강기능식품(유제품)의 제조Production Example 6: Preparation of health functional foods (dairy products)
화학식 1의 화합물 5 내지 10 중량부를 우유 100 중량부에 첨가하고, 상기 우유를 이용하여 버터 및 아이스크림과 같은 다양한 유제품을 제조하였다. 5 to 10 parts by weight of the compound of formula (1) were added to 100 parts by weight of milk, and various dairy products such as butter and ice cream were prepared using the milk.
Claims (6)
[화학식 1]
.
A pharmaceutical composition for the treatment or prevention of hepatotoxic diseases, which is a compound represented by the following formula (1):
[Chemical Formula 1]
.
The pharmaceutical composition for treating or preventing hepatotoxicity according to claim 1, wherein the compound of formula (1) is isolated from Hovenia dulcis.
The pharmaceutical composition for the treatment or prevention of hepatotoxic diseases according to claim 1, wherein the hepatotoxic disease is an alcoholic liver disease.
[화학식 1]
.
A health functional food composition for preventing or improving hepatotoxicity, which is a compound represented by the following formula (1):
[Chemical Formula 1]
.
The health functional food composition according to claim 4, wherein the hepatotoxic disease is an alcoholic liver disease.
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KR100403721B1 (en) | 2001-01-31 | 2003-11-05 | (주)생명의나무 | Lower alcohol insoluble extract and a polysaccharide therein isolated from hovenia dulcis var. koreana nakai having antihepatotoxic and anti-hangover activity and composition containing same |
KR100403720B1 (en) | 2002-01-17 | 2003-11-05 | (주)생명의나무 | Lower alcohol insoluble extract and a polysaccharide therein isolated from the young branches of hovenia dulcis thunb. having antihepatotoxic, anti-hangover and anti-fatigue activity and composition containing same |
CN101336978A (en) * | 2008-08-12 | 2009-01-07 | 西北农林科技大学 | Extraction method of total flavone of Hovenia dulcisThunb |
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KR100403720B1 (en) | 2002-01-17 | 2003-11-05 | (주)생명의나무 | Lower alcohol insoluble extract and a polysaccharide therein isolated from the young branches of hovenia dulcis thunb. having antihepatotoxic, anti-hangover and anti-fatigue activity and composition containing same |
CN101336978A (en) * | 2008-08-12 | 2009-01-07 | 西北农林科技大学 | Extraction method of total flavone of Hovenia dulcisThunb |
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