KR101027555B1 - Composition comprising the mixed herbal extract having hepatoprotective activity and preventing and treating hepatitis - Google Patents
Composition comprising the mixed herbal extract having hepatoprotective activity and preventing and treating hepatitis Download PDFInfo
- Publication number
- KR101027555B1 KR101027555B1 KR1020080133429A KR20080133429A KR101027555B1 KR 101027555 B1 KR101027555 B1 KR 101027555B1 KR 1020080133429 A KR1020080133429 A KR 1020080133429A KR 20080133429 A KR20080133429 A KR 20080133429A KR 101027555 B1 KR101027555 B1 KR 101027555B1
- Authority
- KR
- South Korea
- Prior art keywords
- extract
- shp
- rhubarb
- mixed herbal
- liver
- Prior art date
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Abstract
본 발명은 황금, 지실, 대황, 작약 및 시호의 혼합 생약 추출물을 유효성분으로 하는 간보호 및 간염의 예방 및 치료를 위한 조성물에 관한 것으로, 상세하게는 본 발명의 황금, 지실, 대황, 작약 및 시호의 혼합 생약 추출물은 사염화탄소 또는 D-갈락토사민(D-Galactosamine; GalN)에 의해 유도된 간질환 동물모델실험에서 알라닌 아미노전이효소(Alanine aminotransferase, ALT)활성 및 아스파테이트 아미노전이효소(Aspartate aminotransferase, AST)활성을 억제하고, 지질과산화 함량을 감소시키며, 글루타치온(Glutathione, GSH)함량의 고갈을 효과적으로 억제시킬 뿐만 아니라, 대식세포에서 리포폴리사카라이드(LPS)로 유도되는 프로스타글란딘 E2(PGE2)의 생성을 억제하는 효과를 확인함으로써, 상기 조성물은 간보호 및 간염의 예방 및 치료에 유용한 약학조성물 및 건강기능식품에 이용될 수 있다.The present invention relates to a composition for the prevention and treatment of hepatoprotection and hepatitis, which comprises a mixed herbal extract of golden, fruit, rhubarb, peony and shiho as an active ingredient, and specifically the golden, fruit, rhubarb, peony of the present invention and Shiho's mixed herbal extracts were characterized by alanine aminotransferase (ALT) activity and aspartate aminotransferase in animal models of liver disease induced by carbon tetrachloride or D-galactosamine (GalN). , Proteglandin E2 (PGE2) induced by lipopolysaccharide (LPS) in macrophages, as well as inhibiting AST) activity, reducing lipid peroxidation content, and effectively inhibiting depletion of glutathione (GSH) content By confirming the effect of inhibiting the production, the composition is useful in pharmaceutical compositions and health functional foods useful for liver protection and prevention and treatment of hepatitis. Can be used.
황금, 지실, 대황, 작약, 시호, 간보호, 간염 Golden, fruit, rhubarb, peony, shiho, liver protection, hepatitis
Description
본 발명은 황금, 지실, 대황, 작약 및 시호의 혼합 생약 추출물을 유효성분으로 하는 간보호 및 간염의 예방 및 치료를 위한 조성물에 관한 것이다.The present invention relates to a composition for the prevention and treatment of hepatoprotection and hepatitis, which comprises a mixed herbal extract of golden, fruit, rhubarb, peony and shiho.
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간은 인체에서 혈액 저장 및 순환, 혈액 양 조절과 방어해독작용을 하며 정신적 활동과도 밀접하게 관련되어 있다. 우리 몸은 산업화에 따른 각종 공해물질, 유독 물질에 항상 노출되어 간은 계속적인 해독작용에 시달리고 있으며, 정신적인 스트레스 또한 간손상을 일으키는 것으로 알려져 있다. 간 손상으로 인한 방어 해독 작용의 저하는 인체의 면역 체계에 이상을 가져와 다른 질병의 원인이 되기도 한다. 실험적으로 간독성을 일으키는 대표적인 물질로서 사염화탄소와 D-갈락토사민 등이 흔히 사용되어 지고 있다 (Bruckner et al., Fund. Appl. Toxicology, 6, pp.16-34, 1986; Butler, J. Pharmacol. Exp. Ther., 134, pp.311-319, 1961).The liver stores and circulates blood, regulates and regulates blood volume, and is closely related to mental activity. The body is constantly exposed to various pollutants and toxic substances due to industrialization, and the liver suffers from continuous detoxification. Mental stress is also known to cause liver damage. Degradation of the defenses caused by damage to the liver can cause abnormalities in the body's immune system and cause other diseases. Carbon tetrachloride and D-galactosamine are commonly used as examples of hepatotoxicity experimentally (Bruckner et al., Fund. Appl. Toxicology, 6 , pp. 16-34, 1986; Butler, J. Pharmacol. Exp. Ther., 134 , pp. 311-319, 1961).
담즙은 담즙산, 인지질, 빌리루빈, GSH 및 전해질 등의 성분을 가지며, 독성물질 및 지방분해 산물의 배설을 위한 통로일 뿐만 아니라, 지방의 소화 및 흡수에 관여하여 다양한 생리 기능을 수행하며, 빌리루빈(Bilirubin)과 같은 내인성 노폐물 및 약물과 여러 가지 독성물질을 배출하고, 장에서 정상적 지방 흡수를 증가시키며, 인체 콜레스테롤(cholesterol) 대사의 평형유지에 중추적 역할을 담당한다(Ballatori N et al., Am. J. Physiol, 263, pp.G617-G624, 1992). Bile has components such as bile acids, phospholipids, bilirubin, GSH and electrolytes, and is not only a pathway for the excretion of toxic substances and lipolytic products, but also performs various physiological functions by participating in the digestion and absorption of fat, and bilirubin (Bilirubin). It releases endogenous wastes and drugs, as well as various toxic substances, increases normal fat absorption in the intestines, and plays a pivotal role in balancing human cholesterol metabolism (Ballatori N et al., Am. J). Physiol , 263 , pp . G617-G624, 1992).
한편, 갈락토사민 / 리포폴리사카라이드 (Galactosamine / lipopoly saccharide)는 대표적인 담즙정체성 간질환 유발 모델 중의 하나로 널리 활용되고 있으며, 이 중 갈락토사민(Galactosamine)은 간 조직의 UTP와 UDP-글루커로닉 산(UDP-glucuronic acid)를 고갈시켜 단백질 생성을 억제함으로써 간 보호물질인 GSH(Glutathione)을 고갈시키고, 이물질 배설에 관여하는 글루커로니데이션(Glucuronidation)을 억제시켜 간독성을 유발하며, 실질조직의 세포괴사를 동반하여, 염증세포의 침윤도 관찰되는 것이 조직학적인 특징이다(Jonker AM et al., Hepatology, 11, pp.622-627, 1990). Meanwhile, galactosamine / lipopolysaccharide (Galactosamine / lipopolysaccharide) is widely used as one of the representative models of cholestatic liver disease, among which galactosamine (Galactosamine) as a liver tissue UTP and UDP-gluker By depleting nick acid (UDP-glucuronic acid) to inhibit protein production, it depletes GSH (glutathione), a liver protective substance, and inhibits glucuronidation, which is involved in the excretion of foreign substances, induces hepatotoxicity, and parenchyma tissue The infiltration of inflammatory cells, accompanied by cell necrosis, is a histological feature (Jonker AM et al., Hepatology, 11 , pp. 622-627, 1990).
또한, 리포폴리사카라이드(Lipopolysaccharide, 이하, LPS 라 함)는 LPS를 포함하는 장내 독소(Endotoxin)의 간 문맥 유입을 급속히 증가시켜 간내 염증세포의 활성화로 인한 TNF-α(Tumor Necrosis Factor-α)의 분비를 증가시켜 전격성 간염을 일으켜, 간에서의 급 만성 염증의 병리학적으로 간세포 운반단백질의 발현을 저하시키며, 이러한 운반단백질의 저하는 담즙배설의 장애로 이어져, 담즙정체성 간질환의 혈액학적 지표인 알카린 포스파타제(Alkaline phosphatase, 이하 ALP 라 함), γ-글루타밀 트랜스펩티다제(γ-glutamyl transpeptidase, 이하 γ-GT 라 함)등의 발현을 증가시킨다(Grun M et al., Acta Hepatogastroenterol (Stuttg), 24, pp.64-81, 1977). In addition, lipopolysaccharide (Lipopolysaccharide, hereinafter referred to as LPS) rapidly increases the hepatic portal influx of endotoxins containing LPS, resulting in activation of hepatic inflammatory cells (TNF-α). Increases the secretion of hepatic inflammatory hepatitis, reduces the expression of hepatocellular transporter proteins in the pathology of acute chronic inflammation in the liver, and the lowering of these transport proteins leads to impaired bile excretion and hematological of cholestatic liver disease Increasing expression of alkaline phosphatase (Alkaline phosphatase, ALP) and γ-glutamyl transpeptidase (γ-GT) (Grun M et al., Acta) Hepatogastroenterol (Stuttg), 24 , pp. 64-81, 1977).
간질환 진단을 위한 혈액의 화학적 검사 방법에서 가장 대표적인 측정항목 중 하나인 아미노전이효소(aminotransferase)는 간세포에 다량으로 포함되어 있다가 세포막 투과력이 항진되거나 간세포가 손상이 되었을 때, 그 손상된 정도에 비례하여 혈액 내로 방출되기 때문에, 혈액 내에서 이 효소의 활성 변화도를 측정하면 간세포의 손상 정도를 추정하는데 적합한 지표로 삼을 수 있다. 특히, 그 중에서도 알라닌 아미노전이효소 [alanine-aminotransferase(ALT) 또는 glutamate private transaminase (GPT)]는 아스파테이트 아미노전이효소 [aspartate aminotransferase(AST 또는 GOT)]와 함께 간질환 환자에서 그 효소활성이 정상인과 비교하여 매우 높아지며, 또한 대부분의 간질환에서 혈액 내 효소활성이 AST보다도 더 높게 나타나는 경향이 있기 때문에 간질환 진단에 있어서 매우 중요한 인자로 볼 수 있다. 알라닌 아미노전이효소 및 아스파테이트 아미노전이효소는 실제 간에서의 활성이 혈액 내의 효소활성보다 수천배 정도 더 높게 측정되는 것으로 알려져 있다(Rej R., Clin. Chem. 24, pp.1971-1979, 1978). 따라서 간 조직이 독성물질이나 바이러스의 감염, 알코올, 비만 등의 여러 가지 요인 등에 의하여 손상을 받게 되면 혈액 내로 방출되어 순환하기 때문에 혈액의 알라닌 아미노전이효소 및 아스파테이트 아미노전이효소 활성이 증가하게 된다. 그렇기 때문에 혈액 내의 이들의 활성을 측정하여 간질환의 진단 여부를 유추할 수 있다.One of the most representative measurement items in the blood test for diagnosing liver disease, aminotransferase, is contained in a large amount of hepatocytes and is proportional to the degree of damage when the cell membrane permeability is increased or the hepatocytes are damaged. Because it is released into the blood, measuring the change in the activity of this enzyme in the blood can be a good indicator for estimating the degree of damage to liver cells. In particular, alanine aminotransferase (ALT) or glutamate private transaminase (GPT), together with aspartate aminotransferase (AST or GOT), have normal enzyme activity in patients with liver disease. Compared to this, it is very high, and in most liver diseases, the enzyme activity in blood tends to be higher than that of AST. Alanine aminotransferase and aspartate aminotransferase are known to measure thousands of times higher activity in the liver than enzyme activity in blood (Rej R., Clin. Chem. 24 , pp.1971-1979, 1978 ). Therefore, when liver tissue is damaged by various factors such as toxic substance or virus infection, alcohol, obesity, etc., it is released into the blood and circulates, thereby increasing the activity of alanine aminotransferase and aspartate aminotransferase in blood. Therefore, it is possible to infer the diagnosis of liver disease by measuring their activity in the blood.
세포내의 각종 라디칼과 반응성 유해산소종은 간 보호효과를 하는 글루타치온과 결합함으로서 빠르게 글루타치온의 양이 줄어든다(Mitchell, J. R. et al. Drug Metab. Rev. 13, pp.539-553, 1982; Mitchell, J. R. et al. J. Pharmacol. Exp. Ther. 187, pp.211-217, 1973). 글루타치온과 결합하지 못한 각종 라디칼과 반응성 유해산소종은 세포 내 거대분자와 결합하게 되고, 세포막의 지질과산화를 일으키며, 또한 세포 내 칼슘의 조절을 방해하여 세포를 죽게 하는 결과를 초래한다(Mitchell, J. R. et al. J. Pharmacol. Exp. Ther. 187, pp.211-217, 1973; Vermeulen, N. P. E. Metab. Rev. 24, pp.367-407, 1992; Cohen, S. D. Drug Metab. Rev. 29, pp.59-77, 1997). 따라서 글루타치온과 지질과산화 정도를 측정함으로서 간손상 및 간보호 효과를 평가할 수 있다. Various radicals and reactive reactive oxygen species in cells rapidly reduce the amount of glutathione by binding to glutathione, which has a liver protective effect (Mitchell, JR et al. Drug Metab. Rev. 13 , pp. 539-553, 1982; Mitchell, JR et al. J. Pharmacol.Exp. Ther. 187 , pp. 211-217, 1973). Various radicals and reactive harmful oxygen species that do not bind to glutathione bind to macromolecules in the cell, cause lipid peroxidation of the cell membrane, and interfere with the regulation of intracellular calcium, resulting in cell death (Mitchell, JR). et al. J. Pharmacol.Exp. Ther. 187 , pp. 211-217, 1973; Vermeulen, NPE Metab. Rev. 24 , pp. 367-407, 1992; Cohen, SD Drug Metab. Rev. 29 , pp. 59-77, 1997). Therefore, liver damage and hepatoprotective effects can be evaluated by measuring the degree of glutathione and lipid peroxidation.
최근에는 간독성 및 간손상의 예방 또는 치료를 위해 식용 및 약용 식물 등의 천연물을 통한 유리기(free radical) 생성 억제 작용에 대한 실험들이 많이 보고되고 있다 (Caragy, Food Technology, 46, pp.65-68, 1992; Kim et al., Korean J. Food Sci. Technol., 27, pp.80-85, 1995; Middleton, E., Int. J. Pharmacognosy, 34, pp.344-348, 1996). 대표적인 간질환 치료제로는 실리마린(Silymarin)과 합성의약품 BDD (biphenyl dimethyl dicarboxylate)가 사용되고 있다. 실리마린은 국화과에 속하는 실리붐 마리아눔(Silybum marianum)의 열매에서 분리된 물질이며, BDD(biphenyl dimethyl dicarboxylate)는 오미자의 성분인 쉬잔드린(schizandrin)과 유사한 합성물질로써, 천연물 유래의 간질환 치료제로 개발되어 사용되고 있다. Recently, a lot of experiments have been reported on the inhibitory effect of free radical generation through natural products such as edible and medicinal plants for the prevention or treatment of liver toxicity and liver damage (Caragy, Food Technology, 46 , pp.65-68 , 1992; Kim et al., Korean J. Food Sci.Technol., 27 , pp. 80-85, 1995; Middleton, E., Int. J. Pharmacognosy, 34 , pp. 344-348, 1996). Representative agents for treating liver disease include silymarin (Silymarin) and synthetic drug BDD (biphenyl dimethyl dicarboxylate). Silymarin is a substance isolated from the fruit of Silybum marianum belonging to the Asteraceae family, and BDD (biphenyl dimethyl dicarboxylate) is a synthetic substance similar to schizandrin, which is a component of Schizandra chinensis. It is developed and used.
대식세포(macrophage)는 생체 내에 침입한 균을 제거하는데 있어서 주된 역할을 하는 효과기 세포(effector cell)이다. 감염된 대식세포는 IL-1, TNF-α와 IL-6과 같은 염증유발(pro-inflammatory) 사이토카인을 분비하여 면역계 시스템에서 다른 세포에 자극을 주는 방식으로 다른 대식세포를 활성화시키고 세포질 내 박테리아를 제거하는 역할을 하지만, 이러한 사이토카인들은 염증유발에 의한 조직 손상을 가져온다. 즉, 대식세포는 바이러스, 세균과 같은 외부의 자극에 의해 아라키돈산을 세포 내에서 생성하면서 염증반응을 시작하고, COX-1(cyclooxygenase-1), COX-2(cyclooxygenase-2)가 발현되어 아라키돈산의 대사에 관여함으로써 프로스타글란딘E2를 분비한다. 프로스타글란딘은 자궁내막에 자궁수축기능을 도와주는 물질 로 처음 알려졌지만, 현재는 세포손상 시 분비되는 염증전달 물질로서 주목을 받고 있고 프로스타글란딘 분비 시 통증이 증가하는 것으로 알려졌다. 이밖에도 염증반응과 관련하여 산화질소 및 TNF-α 등이 관여하는 것으로 알려져 있다. 일반적으로, 염증성 질환 치료제 및 진통제 개발에 있어서는 대식세포와 같은 면역세포를 리포폴리사카라이드 (lipopolysaccharide: LPS)와 같은 외부자극물질로 자극하여 세포 내에서 NO(산화질소), TNF-α, 프로스타글란딘E2 등이 생성되도록 하는 모델을 구축한 후, 염증질환 치료제 또는 진통제 후보물질의 투여가 이러한 모델에 있어서 NO(산화질소), TNF-α, 프로스타글란딘E2 등의 생성을 억제하는지 여부를 확인하여 상기 후보물질의 소염작용 또는 진통효과를 평가하는 방식을 채택하고 있다. 현재까지 소염제로서는 프로스타글란딘 합성을 저해하는 인도메타신, 아스피린과 같은 비스테로이드성 소염제(NSAID)가 주로 사용되고, 2차 처방으로는 덱사메타손과 같은 스테로이드제가 사용되어 왔다. 그러나 이러한 약제들은 다양한 부작용들이 있는데, 특히 위장장애, 간 및 신장 기능 장애의 부작용은 매우 잘 알려져 있다. Macrophage is an effector cell that plays a major role in eliminating invading bacteria in vivo. Infected macrophages secrete pro-inflammatory cytokines such as IL-1, TNF-α, and IL-6 to activate other macrophages and stimulate cytoplasmic bacteria by stimulating other cells in the immune system. These cytokines, however, are responsible for eliminating tissue damage caused by inflammation. In other words, macrophages initiate inflammatory reactions by generating arachidonic acid in cells by external stimuli such as viruses and bacteria, and expressing arachidone by expressing COX-1 (cyclooxygenase-1) and COX-2 (cyclooxygenase-2). Prostaglandin E2 is secreted by participating in acid metabolism. Prostaglandins were first known as substances that help the uterine contractile function in the endometrium, but are now attracting attention as an inflammation-transmitting agent secreted by cell damage and increased pain when secreted by prostaglandins. In addition, nitric oxide and TNF-α are known to be involved in inflammatory reactions. In general, in developing inflammatory diseases and analgesics, immune cells such as macrophages are stimulated with an external stimulus such as lipopolysaccharide (LPS), and NO (nitric oxide), TNF-α, and prostaglandin E2 in the cells. After constructing a model for generating a back light, and confirming whether administration of an inflammatory disease treatment agent or an analgesic candidate substance inhibits the production of NO (nitric oxide), TNF-α, prostaglandin E2, etc. in this model, The method of evaluating anti-inflammatory or analgesic effects is adopted. Until now, non-steroidal anti-inflammatory agents (NSAIDs), such as indomethacin and aspirin, which inhibit prostaglandin synthesis, are mainly used as anti-inflammatory agents, and steroids such as dexamethasone have been used as secondary prescriptions. However, these drugs have a variety of side effects, in particular the side effects of gastrointestinal disorders, liver and kidney dysfunction is very well known.
황금(Scutellariae Radix)은 꿀풀과(Labiatae)에 속한 다년생 본초인 황금(Scutellaria baicalensis)의 뿌리를 거피하여 건조한 것으로 제습열, 지혈, 안태(安胎)의 효능이 있어 임상에서 황련해독탕, 용담사간탕, 우황청심환 등 처방으로 고혈압, 유행성 뇌척수막염의 치료에 사용되어 온 한약재이다(김동찬 외., 方劑學, 서울, 영림사, pp.111-113, pp.263-264, p.338, 1990). 이에 대한 성분으로는 우고닌(wogonin), 바이칼린(baicalin), 바이칼레인(baicalein) 등의 플라보노이드 성분들이 대표적으로 알려져 있다. 지금까지 밝혀진 약리작용으로는 항균작용, 항염증작용(Kubo et al., Chem. Pharm. Bull., 32, pp.2724-2729, 1984), 항알레르기작용, 담즙분비촉진작용, 간 장애 예방작용, 이뇨작용, 고지혈증 개선작용, 장관운동억제작용, 항암작용 등이 보고되어 있다(국가중의학관리국: 중화본초, 상해, 상해과학기술출판사, pp.1682-1694, 1998). 또한 황금추출물의 발모촉진작용(대한민국 특허 등록 제 2007-0111765호), 치주질환 치료작용 (대한민국 특허 등록 제1994-0011006호) 및 신경 보호 작용이 (대한민국 특허 등록 제364383호) 특허로 출원 또는 등록된 바 있다. Scutellariae Radix is dried from the root of Scutellaria baicalensis , a perennial herb belonging to Labiatae, and has the effect of dehumidification fever, hemostasis, and anemia. It is a herbal medicine that has been used for the treatment of hypertension and epidemic meningitis by prescription such as Tang and Wu Hwang Cheong Shim Hwan (Kim Dong-chan et al., Methodology, Seoul, Yeonglimsa, pp.111-113, pp.263-264, p.338, 1990). Flavonoids such as wogonin, baicalin, and baicalein are known as components for this. Pharmacological actions that have been identified so far include antimicrobial action, anti-inflammatory action (Kubo et al., Chem. Pharm. Bull., 32 , pp.2724-2729, 1984), anti-allergic action, biliary secretion action, liver disorder prevention action , Diuresis, hyperlipidemia, intestinal motility suppression, anticancer activity have been reported (National Institute of Medicine: Chinese Herbal Medicine, Shanghai, Shanghai Science and Technology Press, pp.1682-1694, 1998). In addition, the hair extract promoting action (Korean Patent Registration No. 2007-0111765), periodontal disease treatment (Korea Patent Registration No. 194-0011006) and neuroprotective action (Korean Patent Registration No. 364383) are applied or registered as a patent It has been.
지실(Ponciri Fructus)은 탱자나무(Poncirius trifoliata)의 익지 않은 열매를 말린 것으로, 대부분 반구형이고, 바깥 면은 진한 녹색에서 갈색을 띠며 거칠고 유실(油室)에 의한 오목한 작은 점이 많다. 특이한 냄새가 있고 맛은 쓰며, 방향성 고미건위약에 쓰인다 (한약 규격집 주해서, 한국메디칼인덱스사, p.604, 1988). 또한 지실의 열수(熱水) 추출물은 전통적으로 위장질환, 염증, 알레르기의 치료에 사용된 것으로 알려져 있으며 (Chun and Sankawa, Shoyakugaku Zasshi, 43, pp.314-323, 1989; Takase et al., Jpn. J. Pharmacol., 66, pp.139-147, 1994), 지실 추출물 및 지실의 함유 성분 21α-methylmelianodiol과 21β-methylmelianodiol은 TNF-α 및 NF-κB의 활성을 억제함으로서 항염증 작용을 나타내는 것으로 보고되어있다(Zhou et al., Eur J Pharmacol., 572, pp.239-48, 2007; Shin et al., Toxicol In Vitro, 20, pp.1071-1076, 2006). 지실추출물을 유효성분으로 하는 수렴 화장료 조성물(대한민국 특허 제 2006-0008572호), 비만치료 및 예방용 조성물 (대한민국 특허 등록 제 0824704호) 및 치매 치료용 조성물(대한민국 특허 등록 제 378734호) 등이 특허 출원 또는 등록 된 바 있다. Ponciri Fructus is a dried fruit of the Poncirius trifoliata , mostly hemispherical, dark green to brown on the outside, with many rough and concave small spots. It has a peculiar smell and taste, and is used in fragrant high-density placebo (Medicine Herbal Standards, Korea Medical Index, p.604, 1988). In addition, hydrothermal extracts of fibromyalgia have been known to be traditionally used for the treatment of gastrointestinal diseases, inflammation, and allergies (Chun and Sankawa, Shoyakugaku Zasshi, 43 , pp.314-323, 1989; Takase et al., Jpn J. Pharmacol., 66 , pp. 139-147, 1994), Fruits Extracts and Their Containing Ingredients 21α-methylmelianodiol and 21β-methylmelianodiol have anti-inflammatory effects by inhibiting the activity of TNF-α and NF-κB. (Zhou et al., Eur J Pharmacol., 572 , pp.239-48, 2007; Shin et al., Toxicol In Vitro, 20 , pp. 1071-1076, 2006). Convergence cosmetic composition (Korean Patent No. 2006-0008572), obesity treatment and prevention composition (Korea Patent Registration No. 0824704) and dementia treatment composition (Korea Patent Registration No. 378734), etc. It has been filed or registered.
대황(Rhei Rhizoma)은 마디풀과에 속한 다년생 초본류인 장군풀, 동속 근연식물의 근 및 근경으로서 약 15종의 식물이 존재하는데, 이중에서도 우리나라에서는 장군풀(Rheum coreanum), 종대황(Rheum undulatum) 등의 건조한 근 및 근경을 기원식물로 하고 있으며, 중국에서는 장엽대황(Rheum palmatum), 당고특대황(Rheum tanguticum) 및 약용대황(Rheum offcinale) 등의 건조한 근 및 근경을 그 기원으로 삼고 있다. 대황은 주요 성분으로서 안트라퀴논(anthraquinone) 유도체로서 레인(rhein), 에모딘(emodin), 알로에-에모딘(aloe-emodin), 크리소파놀(chrysophanol), 피시온(physcion), 이들의 배당체 및 세노사이드(sennoside) A, B, C, D, E, F 등의 성분을 함유하는 것으로 알려져 있다. 예로부터 대황의 주된 약리작용은 사하작용이며, 이외에도 소화효소 분비 억제작용, 이담작용을 나타내며, 항균작용, 지혈작용, 항암작용, 이뇨작용, 간기능 보호, 혈청지질 강하작용, 면역조절작용 등의 약리작용을 나타내는 것으로 알려져 있다. 또한, 대황은 임상적으로 소화불량, 변비, 급성염증, 전염병, 기생충병, 출혈, 혈소판 감소증, 화상 및 피부병의 치료에 응용된다. Rheum Rhizoma is a perennial herbaceous genus, Rheum coreanum , Rheum coreanum and Rheum undulatum . The roots of dried roots and rhizomes are originated from China. The roots of the roots of the roots of the roots in China are Rheum palmatum , R heum tanguticum and Rheum offcinale . Rhubarb is the main component of anthraquinone derivatives as rhein, emodin, aloe-emodin, chrysophanol, physcion, glycosides thereof, and It is known to contain components, such as senoside A, B, C, D, E, F. Since the main pharmacological action of rhubarb is a hypothalamic action, in addition to the digestive enzymes secretion inhibitory effect, yidam effect, antibacterial action, hemostatic action, anti-cancer action, diuretic action, liver function protection, serum lipid lowering action, immunomodulatory action It is known to exhibit pharmacological action. In addition, rhubarb is clinically applied for the treatment of indigestion, constipation, acute inflammation, infectious diseases, parasitic diseases, bleeding, thrombocytopenia, burns and skin diseases.
작약(Paeoniae Radix)은 참작약(Paeonia albiflora var. trichocarpa)및 동속(同屬) 근록식물(近綠植物)의 뿌리를 지칭하며, 원식물의 잎은 어긋나고 잎자루는 길며 2회 삼출 겹잎으로 작은 잎은 알 모양이며, 톱니는 없다. 꽃은 줄기 끝에 한 개씩 나며, 5∼6월에 흰 꽃이 핀다. 과실은 골돌과로서 1∼3개이고 뿔 모양으로 홍색의 성숙치 않은 종자와 흑색의 성숙한 종자가 노출된다. 한방에서는 3월과 8월에 땅속줄기를 채취하여 햇볕에 말려 치조(治操), 양혈제(凉血劑), 보혈(補血), 익비(益脾), 지통(止痛)에 사용한다. 백작약은 진통효과가 강하고 복통, 신체수족의 동통 등에 사용하며 적작약은 이뇨, 산혈의 효과가 강하고 부인질환에 응용되고 있다. 페오니플로린, 아르비플로린, 안식향산, 탄닌 등의 주요성분으로 알려져 있다. Peony (Paeoniae Radix) is taken into account approximately (Paeonia albiflora var. Trichocarpa) and dongsok (同屬) geunrok refers to the roots of plants (近綠植物), the leaves of the plant source is offset from the petiole it is long and twice as small leaves exude gyeopip Is egg-shaped, without sawtooth; Flowers bloom one by one at the end of stem and white flowers bloom from May to June. Fruits are 1-3, with horn-shaped red mature seeds and black mature seeds. In oriental medicine, the underground stems are harvested in March and August and dried in the sun and used for alveolar, nourishing blood, blood, Ivy, and pain. Paekak medicine has a strong analgesic effect, abdominal pain, limb pain, etc. It is used for diuretic, acid blood and gynecological diseases. It is known as a major ingredient such as peonyflorin, arbiflorin, benzoic acid, tannin.
시호는(Bupleuri Radix) 미나리과(Umbelliferae)에 속하는 다년생 초본인 시호의(Bupleurum falcatum) 근경을 햇볕에 말려서 사용하며, 정유, 부플레루몰(bupleurumol), 올레익산(oleic acid), 리놀레익산(linoleic acid), 팔미틱산(palmitic acid), 스테아릭산(stearic acid), 리그노세릭산(lignoceric acid), 포도당 및 사포닌 등이 함유되어 있다. 시호에는 해열작용, 진정, 진통작용, 항염증작용, 항병원체작용 등의 효능이 있다(정보섭, 신민료, 도해 향약대사전, 영림사, pp.413-414, 1998).Shiho is a perennial herb, Bupleurum falcatum , which belongs to Bupleuri Radix, Umbelliferae, and is dried in the sun. acid), palmitic acid, stearic acid, lignoceric acid, glucose and saponin. Shiho has antipyretic, sedative, analgesic, anti-inflammatory and anti-pathogenic effects (Ji, Jung-seop, Shin Min-gyeo, Doha Herbal Medicine Dictionary, Younglimsa, pp.413-414, 1998).
본 발명자는 종래에 오랫동안 임상에서 사용해오며 독성이 적은 것으로 검증된 생약제인 황금, 지실, 대황, 작약 및 시호의 혼합 생약 추출물에 의한 간보호 및 간염의 예방 및 치료 효과에 대해 지속적으로 연구한 결과, 본 발명의 황금, 지실, 대황, 작약 및 시호의 혼합 생약 추출물이 사염화탄소 또는 D-갈락토사민(D-Galactosamine; GalN)에 의해 유도된 간질환 동물모델실험에서 알라닌 아미노전이효소(Alanine aminotransferase, ALT)활성 및 아스파테이트 아미노전이효소(Aspartate aminotransferase, AST)활성을 억제하고, 지질과산화 함량을 감소시 키며, 글루타치온(Glutathione, GSH)함량의 고갈을 효과적으로 억제시킬 뿐만 아니라, 대식세포에서 리포폴리사카라이드(LPS)로 유도되는 프로스타글란딘 E2(PGE2)의 생성을 억제하는 효과를 확인하여 본 발명을 완성하게 되었다.The present inventors have continuously studied the effect of preventing and treating hepatoprotection and hepatitis by the mixed herbal extracts of golden, fruit, rhubarb, rhubarb, peony and shiho, which have been used in clinical practice for a long time and proved to be low toxicity. Alanine aminotransferase (ALT) in a liver disease animal model experiment in which the mixed herbal extracts of golden, fruit, rhubarb, peony and peony of the present invention are induced by carbon tetrachloride or D-galactosamine (GalN) Inhibits the activity and aspartate aminotransferase (AST) activity, decreases lipid peroxidation content, and effectively inhibits the depletion of glutathione (GSH) content, as well as lipopolysaccharide in macrophages The present invention was completed by identifying the effect of inhibiting the production of prostaglandin E2 (PGE2) induced by (LPS).
상기 목적을 수행하기 위하여, 본 발명은 황금, 지실, 대황, 작약 및 시호의 혼합 생약 추출물을 유효성분으로 하는 간보호 및 간염의 예방 및 치료용 약학조성물을 제공한다.In order to carry out the above object, the present invention provides a pharmaceutical composition for the prevention and treatment of hepatoprotection and hepatitis, which comprises a mixed herbal extract of golden, fruit, rhubarb, peony and Shiho.
본원에서 정의되는 혼합 생약은 황금 : 지실 : 대황 : 작약 : 시호의 배합조성비가 16-21 : 16-21 : 1-4 : 16-21 : 33-51 중량%, 바람직하게는, 19.5 : 19.5 : 2.5 : 19.5 : 39 중량%로 배합된 조성물을 포함하며, 상기 혼합 생약 추출물은 조추출물, 극성용매 가용 추출물, 비극성 용매 가용 추출물을 포함한다.The mixed herbal medicine defined in the present invention may have a composition ratio of gold: fruit room: rhubarb: peony: peony: 16-21: 16-21: 1-4: 16-21: 33-51% by weight, preferably, 19.5: 19.5: 2.5: 19.5: 39% by weight of the composition, wherein the mixed herbal extract comprises a crude extract, polar solvent soluble extract, non-polar solvent soluble extract.
본원에서 정의되는 상기 조추출물은 물, C1 내지 C4의 저급 알콜 또는 이들의 혼합용매, 바람직하게는, 물, 에탄올 또는 이들의 혼합용매, 보다 바람직하게는 물에 가용한 추출물을 포함한다.The crude extract as defined herein comprises water, C 1 to C 4 lower alcohols or mixed solvents thereof, preferably water, ethanol or a mixed solvent thereof, more preferably extracts soluble in water.
본원에서 정의되는 상기 비극성 용매 가용 추출물은 상기 조추출물을 물에 현탁하고 이 현탁액을 헥산, 클로로포름, 메틸렌클로라이드 또는 에틸아세테이트 등의 비극성 용매, 바람직하게는 클로로포름 또는 메틸렌클로라이드, 보다 바람직 하게는 메틸렌클라이드로 추출 분획한 비극성 성분을 다량 함유한 추출물을 포함한다.The non-polar solvent soluble extract as defined herein may be prepared by suspending the crude extract in water and suspending the suspension with a non-polar solvent such as hexane, chloroform, methylene chloride or ethyl acetate, preferably chloroform or methylene chloride, more preferably methylene chloride. Extraction The extract contains an extract containing a large amount of nonpolar components.
본원에서 정의되는 상기 극성 용매 가용 추출물은 상기 조추출물로부터 비극성성분을 제거하고 극성 용매에 가용한 극성 성분을 다량 함유한 추출물로서, 물, C1 내지 C4의 저급 알콜 또는 이들의 혼합용매, 바람직하게는, 물, 부탄올 또는 이들의 혼합용매, 보다 바람직하게는 부탄올에 가용한 추출물을 포함한다.The polar solvent soluble extract as defined herein is an extract which removes the non-polar component from the crude extract and contains a large amount of the polar component soluble in the polar solvent, which is water, a lower alcohol of C 1 to C 4 or a mixed solvent thereof, preferably Preferably, extracts soluble in water, butanol or mixed solvents thereof, more preferably butanol.
또한, 본 발명의 호환적인 조성물은 상기 황금, 지실, 대황, 작약 및 시호 이외에 보조생약으로서 반하(Pinelliae Tuber), 생강 (Zingiberis Rhizoma), 인진쑥 (Artemisiae Capillaris Herba) 및 대추 (Zizpyphi Frucutus)중 하나의 보조생약을 추가적으로 약 16 중량부(%)의 양을 사용가능하다.In addition, the compatible composition of the present invention is a supplementary medicine (Pinelliae Tuber), ginger (Zingiberis Rhizoma), Artemisiae Capillaris Herba and Zizpyphi Frucutus as a supplemental medicine in addition to the golden, fruit, rhubarb, peony and shiho Supplementary herbal supplements may be used in an amount of about 16 parts by weight (%).
이하, 본 발명의 추출물을 수득하는 방법을 상세히 설명한다. Hereinafter, the method for obtaining the extract of the present invention will be described in detail.
본 발명의 황금, 지실, 대황, 작약 및 시호의 혼합 생약 추출물은 세절된 황금, 지실 및 작약을 각각 16 내지 21 중량%로, 대황을 1 내지 4 중량%로, 시호를 33 내지 51 중량%로 하여 혼합하는 제 1단계; 그 총 중량의 약 2배 내지 10배(v/w), 바람직하게는 약 3 내지 6배(v/w) 부피의 물, C1 내지 C4의 저급 알콜 또는 이들의 10:1 내지 1:10의 혼합비를 갖는 혼합용매, 바람직하게는 물로 80 내지 100℃, 바람직하게는 100℃에서 1시간 내지 5시간, 바람직하게는 3시간 동안 냉침 추출, 열수추출, 초음파 추출, 환류냉각 추출, 가열추출, 바람직하게는 가열추출의 추출방법으로 2회 반복하여 추출액을 수득하는 제 2단계; 0 내지 30℃, 바람직하게는 실온에서 빙냉하고, 여과하여 여과액을 회전감압농축기 또는 동결건조기로 감압 농축하는 제 3단계의 제조공정을 통하여 본 발명의 황금, 지실, 대황, 작약 및 시호의 혼합 생약 추출물을 수득할 수 있다.The mixed herbal extracts of golden, fruit, rhubarb, peony and shiho of the present invention are 16 to 21% by weight of shredded golden, fruit and peony, 1 to 4% by weight of rhubarb and 33 to 51% by weight of shiho Mixing the first step; About 2 to 10 times (v / w), preferably about 3 to 6 times (v / w) volume of water, C 1 to C 4 lower alcohols or 10: 1 to 1: Mixed solvent having a mixing ratio of 10, preferably cold water extraction, hot water extraction, ultrasonic extraction, reflux cooling extraction, heating extraction at 80 to 100 ° C., preferably at 100 ° C. for 1 hour to 5 hours, preferably 3 hours Preferably, the second step of obtaining an extract by repeating twice in the extraction method of the heating extraction; Mixing of the gold, fruit, rhubarb, peony and shiho of the present invention through a third step manufacturing process of ice-cooling at 0 to 30 ° C., preferably at room temperature, and filtering and concentrating the filtrate under reduced pressure with a rotary pressure reducer or a lyophilizer. A herbal extract can be obtained.
본 발명의 분획물은 상기에서 얻은 추출물 중량의 2 내지 10배, 바람직하게는 3 내지 6배 부피(v/w)의 물에 현탁시킨 후, 메틸렌클로라이드를 물과 동량 부피를 가하여 1 내지 4회, 바람직하게는 2 내지 3회 분획하여 수가용성층(Ⅰ)과 메틸렌클로라이드층으로 분리하는 제 1단계; 상기 분리된 메틸렌클로라이드층을 회전감압농축기로 감압 건조하여 본 발명의 메틸렌클로라이드 분획물을 수득하는 제 2단계; 상기 제 1단계의 수가용성층(Ⅰ)에 부탄올을 가하여 1 내지 5회, 바람직하게는 2 내지 4회 분획하여 수가용성층(Ⅱ)과 부탄올층으로 분리하는 제 3단계; 상기 분리된 부탄올층 및 수가용성층을 회전감압농축기로 감압 건조하는 제 4단계의 제조공정을 통하여 본 발명의 부탄올 분획물 및 수가용성 분획물을 수득할 수 있다. The fraction of the present invention is suspended in 2 to 10 times, preferably 3 to 6 times the volume (v / w) of water by weight of the extract obtained above, 1 to 4 times by adding an equal volume of water to methylene chloride, Preferably, the first step of fractionating 2-3 times to separate the water-soluble layer (I) and methylene chloride layer; A second step of obtaining the methylene chloride fraction of the present invention by drying the separated methylene chloride layer under reduced pressure with a rotary pressure reducer; A third step of adding butanol to the water-soluble layer (I) of the first step and fractionating 1 to 5 times, preferably 2 to 4 times, to separate the water-soluble layer (II) and the butanol layer; The butanol fraction and the water-soluble fraction of the present invention may be obtained through the fourth step of manufacturing the separated butanol layer and the water-soluble layer under reduced pressure with a rotary pressure reducer.
따라서, 본 발명은 상기 제조방법으로 제조된 황금, 지실, 대황, 작약 및 시호의 혼합 생약 추출물을 유효성분으로 하는 간보호 및 간염의 예방 및 치료용 약학조성물을 제공한다.Accordingly, the present invention provides a pharmaceutical composition for the prevention and treatment of hepatoprotection and hepatitis, which comprises the mixed herbal extract of gold, fruit, rhubarb, peony and shiho, prepared by the above method.
본 발명의 추출물을 유효성분으로 함유하는 약학조성물은 조성물 총 중량에 대하여 상기 추출물을 0.1 내지 50 중량%로 포함한다.The pharmaceutical composition containing the extract of the present invention as an active ingredient comprises 0.1 to 50% by weight of the extract, based on the total weight of the composition.
그러나 상기와 같은 조성은 반드시 이에 한정되는 것은 아니고, 환자의 상태 및 질환의 종류 및 진행 정도에 따라 변할 수 있다.However, the composition as described above is not necessarily limited thereto, and may vary according to the condition of the patient and the type and extent of the disease.
본 발명의 추출물 자체는 독성 및 부작용이 거의 없으므로 예방 목적으로 장기간 복용 시에도 안심하고 사용할 수 있는 약제이다. The extract of the present invention is a drug that can be used with confidence even when taken for a long time for the purpose of prevention because there is little toxicity and side effects.
본 발명의 조성물은 약학적 조성물의 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 pharmaceutical compositions.
본 발명의 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있으며, 추출물을 포함하는 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. 제제화할 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 상기 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상제제로는 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, 동결건조제제, 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, 글리세로제라틴 등이 사용될 수 있다.The compositions of the present invention can be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral formulations, external preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods. Carriers, excipients and diluents that may be included in the composition comprising the extract include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate , Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and the solid preparations may include at least one excipient such as starch, calcium carbonate, sucrose in the extract. ) Or lactose, gelatin and the like are mixed. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Oral liquid preparations include suspending agents, liquid solutions, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
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 추출물은 1일 0.01 mg/kg 내지 10 g/kg으로, 바람직하게는 1 mg/kg 내지 1 g/kg으로 투여하는 것이 좋다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수 있다. 따라서 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 extract of the present invention is preferably administered at 0.01 mg / kg to 10 g / kg, preferably 1 mg / kg to 1 g / kg per day. The administration may be carried out once a day or divided into several doses. Accordingly, the dosage is not limited in any way to the scope of the present invention.
본 발명의 조성물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내 (intracerebroventricular) 주사에 의해 투여될 수 있다.The composition of the present invention may be administered to mammals such as rats, mice, livestock, humans, and the like in various routes. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
또한, 본 발명은 황금, 지실, 대황, 작약 및 시호의 혼합 생약 추출물을 유효성분으로 하는 간보호 및 간염의 예방 및 개선용 건강기능식품을 제공한다.In addition, the present invention provides a health functional food for the prevention and improvement of hepatoprotection and hepatitis, which comprises a mixed herbal extract of golden, fruit, rhubarb, peony and Shiho.
본 발명의 추출물을 포함하는 조성물은 간보호 및 간염의 예방 및 개선을 위한 약제, 식품 및 음료 등에 다양하게 이용될 수 있다. 본 발명의 건조물 또는 그 추출물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있고, 분말, 과립, 정제, 캡슐 또는 음료인 형태로 사용할 수 있다.The composition comprising the extract of the present invention can be used in various ways, such as drugs, foods and drinks for the protection and prevention of hepatitis. Examples of the food to which the dried product or the extract of the present invention may be added include various foods, beverages, gums, teas, vitamin complexes, health supplements, and the like, and are powders, granules, tablets, capsules, or beverages. Can be used as
본 발명의 추출물은 간보호 및 간염의 예방 및 개선을 목적으로 식품 또는 음료에 첨가될 수 있다. 이 때, 식품 또는 음료 중의 상기 추출물 또는 화합물의 양은 일반적으로 본 발명의 건강식품 조성물은 전체 식품 중량의 0.01 내지 15 중량%로 가할 수 있으며, 건강 음료 조성물은 100 ㎖를 기준으로 0.02 내지 10 g, 바람직하게는 0.3 내지 1 g의 비율로 가할 수 있다. Extracts of the present invention may be added to food or beverages for the purpose of protecting the liver and preventing and improving hepatitis. At this time, the amount of the extract or compound in the food or beverage is generally added to the health food composition of the present invention 0.01 to 15% by weight of the total food weight, the health beverage composition is 0.02 to 10 g based on 100 ml, Preferably it can be added in the ratio of 0.3-1 g.
본 발명의 건강 음료 조성물은 지시된 비율로 필수 성분으로서 상기 추출물 또는 화합물을 함유하는 것 외에 액체성분에는 특별한 제한점은 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 등의 디사카라이드, 예를 들어 말토스, 슈크로스 등의 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, 글리시르히진 등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 mL당 일반적으로 약 1 내지 20g, 바람직하게는 약 5 내지 12g이 다.The health beverage composition of the present invention, in addition to containing the extract or compound as an essential ingredient in the indicated ratio, there is no particular limitation on the liquid component, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. have. Examples of the above-mentioned natural carbohydrates include monosaccharides such as disaccharides such as glucose and fructose such as maltose, sucrose and the like and polysaccharides such as dextrin, cyclodextrin and the like Sugar, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (tauumatin, stevia extract (e.g., Rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of natural carbohydrates is generally about 1 to 20 g, preferably about 5 to 12 g, per 100 mL of the composition of the present invention.
상기 외에 본 발명의 조성물은 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, 알콜, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 조성물들은 천연 과일 쥬스 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above-mentioned composition, the composition of the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and intermediates (cheese, chocolate etc.), pectic acid and its salts, Salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like. In addition, the compositions of the present invention may contain flesh for the production of natural fruit juices and vegetable beverages. These components can be used independently or in combination. The proportion of such additives is not so critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
본 발명의 황금, 지실, 대황, 작약 및 시호의 혼합 생약 추출물은 사염화탄소 또는 D-갈락토사민(D-Galactosamine; GalN)에 의해 유도된 간질환 동물모델실험에서 알라닌 아미노전이효소(Alanine aminotransferase, ALT)활성 및 아스파테이트 아미노전이효소(Aspartate aminotransferase, AST)활성을 억제하고, 지질과산화 함량을 감소시키며, 글루타치온(Glutathione, GSH)함량의 고갈을 효과적으로 억제시킬 뿐만 아니라, 대식세포에서 리포폴리사카라이드(LPS)로 유도되는 프로스타글란딘 E2(PGE2)의 생성을 억제하는 효과를 확인함으로써, 간보호 및 간염의 예방 및 치료에 유용한 약학조성물 및 건강기능식품에 이용될 수 있다.The mixed herbal extracts of gold, fruit, rhubarb, peony and shiho of the present invention are alanine aminotransferase (ALT) in liver disease animal model experiment induced by carbon tetrachloride or D-galactosamine (GalN). ) Inhibits the activity and aspartate aminotransferase (AST) activity, decreases lipid peroxidation content, and effectively inhibits the depletion of glutathione (GSH) content, as well as lipopolysaccharides in macrophages. By confirming the effect of inhibiting the production of prostaglandin E2 (PGE2) induced by LPS), it can be used in pharmaceutical compositions and health functional foods useful for liver protection and prevention and treatment of hepatitis.
이하, 본 발명을 참고예, 실시예 및 실험예에 의해 상세히 설명한다. Hereinafter, the present invention will be described in detail by reference examples, examples and experimental examples.
단, 하기 참고예, 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 참고예, 실시예 및 실험예에 한정되는 것은 아니다.However, the following Reference Examples, Examples, and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following Reference Examples, Examples, and Experimental Examples.
실시예 1. 황금, 지실, 대황, 작약 및 시호의 혼합 생약 추출물의 제조Example 1 Preparation of Mixed Herbal Extracts of Gold, Fruit, Rhubarb, Peony and Shiho
경동시장(서울, 한국)에서 구입한 세절된 황금, 지실 및 작약을 각각 120 g으로, 시호를 240 g, 대황을 15 g으로 하여 혼합한 후, 3 L의 물을 가하고 100℃에서 2시간 동안 가열하여 2회 반복 추출하였다. 실온에서 방냉하고 여과하여 여과액을 -70℃로 동결시킨 후, 동결건조기로 농축하여 황금, 지실, 대황, 작약 및 시호의 혼합 생약 추출물 20 g(수율: 3.25%)을 수득하여, 하기 실험예의 시료로 사용하였다(이하, “SHP-1”라 함).120 g of shredded gold, fruit and peony purchased from Gyeongdong market (Seoul, Korea) were mixed with 240 g of Siho and 15 g of rhubarb, and 3 L of water was added thereto at 100 ° C. for 2 hours. Heated extraction was repeated twice. After cooling to room temperature, filtered to freeze the filtrate to -70 ℃, and concentrated in a freeze dryer to obtain 20 g (yield: 3.25%) of the mixed herbal extracts of golden, fruit, rhubarb, peony and Shiho, yielding Used as a sample (hereinafter referred to as "SHP-1").
실시예 2. 황금, 지실, 대황, 작약 및 시호의 혼합 생약 분획물의 제조Example 2 Preparation of Mixed Herbal Fractions of Gold, Fruit, Rhubarb, Peony and Shiho
2-1. 메틸렌클로라이드 분획물의 제조2-1. Preparation of Methylene Chloride Fraction
상기 실시예 1에서 수득한 "SHP-1" 중 10 g을 1L의 물에 현탁시킨 후, 1L의 메틸렌클로라이드를 가하여 분획깔대기 상에서 물층과 메틸렌클로라이드층으로 분리하였으며, 이 과정을 2회 반복하였다. 메틸렌클로라이드층을 회전 감압농축기를 이용하여 30℃에서 감압 건조하여 메틸렌클로라이드 분획물 950mg(이하, “SHP-1(M)”라 함) 및 수용액을 수득하였고, 하기 실험예의 시료로 사용하였다. 10 g of "SHP-1" obtained in Example 1 was suspended in 1 L of water, and then 1 L of methylene chloride was added to separate the water layer and the methylene chloride layer on a separatory funnel, and the process was repeated twice. The methylene chloride layer was dried under reduced pressure at 30 ° C. using a rotary vacuum concentrator to obtain 950 mg of a methylene chloride fraction (hereinafter referred to as “SHP-1 (M)”) and an aqueous solution, which was used as a sample of the following experimental example.
2-2. 부탄올 분획물의 제조2-2. Preparation of Butanol Fraction
상기 실시예 2-1의 수용액에 수포화 부탄올 1L를 가하여 분획 깔대기 상에서 물층과 부탄올층으로 분리하였으며, 이 과정을 2회 반복하였다. 부탄올층 및 물층을 회전 감압농축기를 이용하여 50℃에서 감압 건조하여 부탄올 분획물 4.2g(이하, “SHP-1(B)”라 함) 및 수가용성 분획물 4.5g(이하, “SHP-1(W)”라 함)을 수득하였고, 하기 실험예의 시료로 사용하였다. 1 L of saturated butanol was added to the aqueous solution of Example 2-1 and separated into a water layer and a butanol layer on a fraction funnel, and the process was repeated twice. The butanol layer and the water layer were dried under reduced pressure at 50 ° C. using a rotary vacuum concentrator to produce 4.2 g of butanol fraction (hereinafter referred to as “SHP-1 (B)”) and 4.5 g of water-soluble fraction (hereinafter referred to as “SHP-1 (W). ) ”Was used as a sample of the following experimental example.
참고예 1. 실험동물의 준비Reference Example 1. Preparation of Laboratory Animals
실험동물은 (주) 현대바이오로부터 체중 200 g 내외의 SD계 웅성 흰쥐를, 대한 바이오링크로부터는 체중 20-25 g의 ICR계 생쥐를 각각 공급받아 온도 23 ± 1℃, 상대습도 55 ± 15% 및 300-500 Lux의 조도로 12시간 간격으로 명암이 조절되는 성균관대학교 약학대학 동물 사육실에서 7일 이상 순화시킨 후, 육안으로 증상을 관찰하여 정상적인 동물만을 실험에 사용하였으며, 실험동물용 고형사료((주)삼양사) 및 물은 자유롭게 섭취시켰다.The experimental animals were supplied with SD male rats weighing about 200 g from Hyundai Bio Co., Ltd. and ICR mice weighing 20-25 g from Daehan Biolink, respectively, at a temperature of 23 ± 1 ℃ and a relative humidity of 55 ± 15%. And purified at least 7 days in the animal breeding room of Sungkyunkwan University College of Pharmacy, where the contrast is controlled at 12-hour intervals with a light intensity of 300-500 Lux, and the symptoms were visually observed. Only normal animals were used for the experiment. Samyang Corp.) and water were freely ingested.
참고예 2. 통계학적 분석Reference Example 2 Statistical Analysis
각각의 실험결과에 대하여 평균 ± 표준오차로 나타내며, 이에 대한 통계학적인 분석은 일원배치분산분석(one-way analysis of variance, ANOVA)을 시행하여 p<0.05 및 p<0.01의 수준에서 유의성이 인정되는 경우, Dunnett's test로 시험군 간의 차이를 비교하였다.The mean ± standard error for each test result is statistically analyzed. One-way analysis of variance (ANOVA) is used to confirm the significance at the levels of p <0.05 and p <0.01. In the case of Dunnett's test, the differences between the test groups were compared.
참고예 3. ALT 활성, AST 활성, 지질과산화, GSH 함량 및 담즙 분비량 측정방법Reference Example 3. ALT activity, AST activity, lipid peroxidation, GSH content and bile secretion measurement method
알라닌 아미노트랜스페라제(ALT) 및 아스파테이트 아미노전이효소(AST) 활성은 IVD Lab kit(아이비디랩, 한국)를 사용하여, UV 분광기(UV-1601, Simadzu, 일본)로 측정하였다.Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity were measured by UV spectroscopy (UV-1601, Simadzu, Japan) using the IVD Lab kit (IVD Lab, Korea).
지질과산화 측정은 Ohkawa의 방법(Ohkawa et al., J. Med. Chem., 40, pp.559-573, 1997)에 준하여 치오바비투릭산 어세이법 (Thiobarbituric acid assay)를 이용하여 지질과산화의 최종산물인 말론디알데히드를 지표로 정량하였다. 즉, 간조직을 10배(v/w) 용량의 1.15% 염화칼륨 용액으로 균질화한 후, 균질액 0.2 ml, 8.1% SDS 0.2 ml, 20% 초산 (pH 3.5) 1.5 ml, 5% 부틸화 하이드록시톨루엔(Butylated hydroxytoluene) 0.5 ml 및 0.8% 치오바비투릭산 1.5 ml을 가하여 혼합하고, 100℃가 유지되는 항온조에서 60분간 반응시켜, 실온에서 1시간 동안 방치한 다음 3,000 rpm에서 10분간 원심분리하고 상층액을 취하여 532 nm에서의 UV 분광기로 흡광도를 측정하였다. Lipid peroxidation was measured using the Thiobarbituric acid assay according to Ohkawa's method (Ohkawa et al., J. Med. Chem., 40 , pp.559-573, 1997). The final product malondialdehyde was quantified as an indicator. That is, the liver tissue is homogenized with a 10-fold (v / w) dose of 1.15% potassium chloride solution, and then the homogenate 0.2 ml, 8.1% SDS 0.2 ml, 20% acetic acid (pH 3.5) 1.5 ml, 5% butylated hydroxy 0.5 ml of toluene (Butylated hydroxytoluene) and 1.5 ml of 0.8% chibabituric acid were added and mixed, the mixture was reacted for 60 minutes in a thermostat maintained at 100 ° C, and left at room temperature for 1 hour, followed by centrifugation at 3,000 rpm for 10 minutes, and the upper layer. The solution was taken and the absorbance measured by UV spectroscopy at 532 nm.
글루타치온(Glutathione, GSH) 함량은 문헌에 기재된 방법(Weiberg, J. M. J. et al. Clin. Invest. 80, pp.1446-1454, 1987)에 따라 하기와 같이 측정하였다. Glutathione (GSH) content was determined as follows according to the method described in the literature (Weiberg, JMJ et al. Clin. Invest. 80 , pp. 1446-1454, 1987).
간조직을 2배(v/w) 용량의 1% 피크릭산(Picric acid)으로 균질화한 후, 균질액 2ml을 500 × g에서 3분간 원심분리하여 상층액을 취하여 증류수로 50배(v/w) 희석하였다. 희석한 상층액 200㎕, 0.3mM NADPH 700ml 및 6mM 2-니트로-6-치오안식향산 100㎕를 가한 후, 30℃로 유지되는 항온조에 4분간 방치하고, 80 units GSH reductase/ml 용액 5㎕를 가하여, UV 분광기로 412nm에서 1분 동안 흡광도 증가를 측정하여 총 GSH 함량을 측정하였고, 위와 동일한 방법으로 2-비닐피리딘 2㎕와 0 units GSH reductase/ml 용액을 20 ㎕ 가한 후, 412nm에서 1분 동안 흡광도 증가를 측정하여 글루타치온 디설파이드(GSSG) 함량을 구하였다. GSH의 함량은 하기 수학식 1을 이용하여 구하였다.After homogenizing the liver tissue with 2% (v / w) 1% picric acid, 2 ml of homogenate was centrifuged at 500 × g for 3 minutes, and the supernatant was taken up to 50 times with distilled water (v / w). w) diluted. 200 µl of the diluted supernatant, 700 ml of 0.3 mM NADPH and 100 µl of 6 mM 2-nitro-6-thiobenzoic acid were added, and the mixture was left to stand at 30 ° C for 4 minutes, and 5 µl of 80 units GSH reductase / ml solution was added thereto. The total GSH content was measured by measuring the increase in absorbance at 412 nm for 1 minute with UV spectroscopy. In the same manner as above, 2 μl of 2-vinylpyridine and 20 μl of 0 units GSH reductase / ml solution were added, followed by 1 minute at 412 nm. The absorbance increase was measured to determine the glutathione disulfide (GSSG) content. The content of GSH was calculated using
담즙 분비량은 복부 정중선을 따라 개복하여 담관에 카테터를 삽입시켜 미리 무게를 측정해 놓은 마이크로관에 취하였으며, 이 양을 담즙 분비량으로 하였다.The bile secretion was opened along the midline of the abdomen, and the catheter was inserted into the bile duct. The bile was taken in a pre-weighed microtube.
실험예 1. 사염화탄소에 의해 유도된 간독성 동물모델실험Experimental Example 1. Animal model of hepatotoxicity induced by carbon tetrachloride
상기 실시예에서 수득한 혼합 추출물이 사염화탄소에 의해 유도된 간독성 동물모델실험에서 ALT 및 AST 활성, 지질과산화 함량 및 GSH 함량에 미치는 영향을 확인하기 위하여 문헌에 개시된 방법을 응용하여 하기와 같은 방법으로 실험을 실시하였다.In order to confirm the effect of the mixed extract obtained in the above example on ALT and AST activity, lipid peroxidation content and GSH content in carbon tetrachloride-induced hepatotoxicity animal model experiment, experiments were carried out as follows. Was carried out.
1-1. 검체 채취1-1. Sampling
12시간 절식시킨 상기 참고예 1의 생쥐에 사염화탄소-올리브오일 혼합액(0.5 : 9.5 (v/v))을 체중 10g 당 0.1ml씩 복강 내 투여하고, 24시간 후에 에테르로 마취시켜 복부 대정맥으로부터 혈액을 취한 후, 간조직을 채취하였다. 상기 실시예에서 수득한 혼합 생약 추출물(SHP-1)은 사염화탄소 투여 전 2시간 및 투여 후 2시간째에 체중 1kg 당 30, 100, 300 또는 600mg씩 경구 투여하였다. 양성대조약물로는 실리마린(Sigma, S0292-50G)을 사용하였으며, 그 용량은 300mg/kg으로 하였다.The mice of Reference Example 1 fasted for 12 hours were intraperitoneally administered with carbon tetrachloride-olive oil mixture (0.5: 9.5 (v / v)) at a rate of 0.1 ml per 10 g of body weight. After taking, liver tissue was collected. The mixed herbal extract (SHP-1) obtained in the above example was administered orally at 30, 100, 300 or 600 mg / kg body weight 2 hours before and 4 hours after carbon tetrachloride. Silymarin (Sigma, S0292-50G) was used as a positive control drug and the dose was 300 mg / kg.
1-2. ATL 및 AST 활성 측정1-2. ATL and AST activity measurement
상기 실험예 1-1의 혈액을 원심분리하여 취한 혈청으로부터 IVD Lab kit(아이비디랩, 한국)를 사용하여, UV 분광기(UV-1601, Simadzu, 일본)로 알라닌 아미노트랜스페라제(ALT) 및 아스파테이트 아미노트랜스페라제(AST) 활성을 측정하였다.Alanine aminotransferase (ALT) and UV spectroscopy (UV-1601, Simadzu, Japan) using an IVD Lab kit (IVD Lab, Korea) from serum taken by centrifugation of the blood of Experimental Example 1-1; Aspartate aminotransferase (AST) activity was measured.
1-3. 지질과산화 측정1-3. Lipid Peroxidation Measurement
문헌에 개시된 방법(Ohkawa et al., J. Med. Chem., 40, pp.559-573, 1997)을 응용하여 하기와 같은 치오바비투릭산 어세이법 (Thiobarbituric acid assay)로 지질과산화의 최종산물인 말론디알데히드를 지표로 정량하였다. Finalization of Lipid Peroxidation by Thiobarbituric Acid Assay by Application of the Method (Ohkawa et al., J. Med. Chem., 40 , pp.559-573, 1997) The product malondialdehyde was quantified as an indicator.
상기 실험예 1-1에서 취한 간조직을 10배(v/w) 용량의 1.15% 염화칼륨 용액으로 균질화한 후, 균질액 0.2 ml, 8.1% SDS 0.2 ml, 20% 초산 (pH 3.5) 1.5 ml, 5% 부틸화 하이드록시톨루엔(Butylated hydroxytoluene) 0.5 ml 및 0.8% 치오바비투릭산 1.5 ml을 가하여 혼합하고, 100℃가 유지되는 항온조에서 60분간 반응시켜, 실온에서 1시간 동안 방치한 다음 3,000 rpm에서 10분간 원심분리하고 상층액을 취하여 532 nm에서의 UV 분광기로 흡광도를 측정하였다. After homogenizing the liver tissue taken in Experimental Example 1-1 with 10 times (v / w) dose of 1.15% potassium chloride solution, the homogenate 0.2 ml, 8.1% SDS 0.2 ml, 20% acetic acid (pH 3.5) 1.5 ml, 0.5 ml of 5% butylated hydroxytoluene and 1.5 ml of 0.8% chiovabituric acid were added and mixed, reacted in a thermostat maintained at 100 ° C. for 60 minutes, allowed to stand at room temperature for 1 hour, and then at 3,000 rpm. Centrifuged for 10 minutes, the supernatant was taken and the absorbance was measured by UV spectroscopy at 532 nm.
1-4. 글루타치온 함량 측정1-4. Determination of Glutathione Content
글루타치온(Glutathione, GSH) 함량은 다음과 같은 방법(Weiberg, J. M. J. et al. Clin. Invest. 80, pp.1446-1454, 1987)으로 측정하였다. Glutathione (GSH) content was measured by the following method (Weiberg, JMJ et al. Clin. Invest. 80 , pp. 1446-1454, 1987).
상기 실험예 1-1에서 취한 간조직을 2배(v/w) 용량의 1% 피크릭산(Picric acid)으로 균질화한 후, 균질액 2ml을 500 × g에서 3분간 원심분리하여 상층액을 취하여 증류수로 50배(v/w) 희석하였다. 희석한 상측액 200㎕, 0.3mM NADPH 700ml 및 6mM 2-니트로-6-치오안식향산 100㎕를 가한 후, 30℃로 유지되는 항온조에 4분간 방치하고, 80 units GSH reductase/ml 용액 5㎕를 가하여, UV 분광기(UV-1601, Simadzu, 일본)로 412nm에서 1분 동안 흡광도 증가를 측정하여 총 GSH 함량을 측정하였고, 위와 동일한 방법으로 2-비닐피리딘 2㎕와 0 units GSH reductase/ml 용액을 20 ㎕ 가한 후, 412nm에서 1분 동안 흡광도 증가를 측정하여 글루타치온 디설파이드(GSSG) 함량을 구하였다. GSH의 함량은 상기 수학식 1을 이용하여 구하였다. After homogenizing the liver tissue taken in Experimental Example 1-1 with 2% (v / w) capacity of 1% picric acid, 2 ml of the homogenate was centrifuged at 500 x g for 3 minutes to remove the supernatant. Taken and diluted 50 times (v / w) with distilled water. 200 µl of diluted supernatant, 700 ml of 0.3 mM NADPH and 100 µl of 6 mM 2-nitro-6-thiobenzoic acid were added, and the mixture was left to stand at 30 ° C for 4 minutes, and 5 µl of 80 units GSH reductase / ml solution was added thereto. The total GSH content was measured by measuring the absorbance increase at 412 nm for 1 minute with a UV spectrometer (UV-1601, Simadzu, Japan). 2 μl of 2-vinylpyridine and 0 units of GSH reductase / ml solution were prepared in the same manner as above. After addition of μl, the absorbance increase was measured at 412 nm for 1 minute to obtain glutathione disulfide (GSSG) content. The content of GSH was calculated using
1-5. 조직학적 검사1-5. Histological examination
상기 실험예 1-1에서 취한 간조직의 일부를 10% 포름알데히드 용액에 고정시 킨 후, 헤마톡실린(Hematoxylin)과 에오신(eosin)으로 염색하여 광학현미경(Leica, DM1L)하에서 조직검사를 실시하였다. A part of the liver tissue taken in Experimental Example 1-1 was fixed in 10% formaldehyde solution, and then stained with hematoxylin and eosin to undergo histological examination under an optical microscope (Leica, DM1L). It was.
실험결과, 사염화탄소에 의해 유도된 간독성 동물모델실험에서 ALT 및 AST 활성에 대한 상기 실시예에서 수득한 SHP-1 30, 100, 300 및 600 mg/kg 투여군 및 실리마린 투여군(양성대조군, 이하, “Sily"라 함.)의 효과를 도 1에 나타내었다. 각 막대그래프는 실험군당 9 내지 11마리의 쥐에 대한 측정치+표준편차를 나타내며, **표시는 사염화탄소 무처치군 (Cont) 대비 유의성 있는 차이를 (P<0.01) 나타내고, ++표시는 사염화탄소 처치군 (CCl4) 대비 유의성 있는 차이를 (P<0.01) 나타낸다. 도 1에 나타난 바와 같이 SHP-1의 300mg/kg 투여군에서 실리마린 투여군보다도 ALT 활성을 유의성 있게 억제함을 확인할 수 있었으며, SHP-1의 300, 600mg/kg 투여군에서 실리마린 투여군보다도 AST 활성을 유의성 있게 억제함을 확인할 수 있었다. As a result, SHP-1 30, 100, 300 and 600 mg / kg administration group and silymarin administration group (positive control group, hereinafter referred to as “Sily” obtained in the above example for ALT and AST activity in hepatotoxic animal model experiment induced by carbon tetrachloride) The effect of "is shown in Figure 1. Each bar graph represents the measurement + standard deviation for 9 to 11 rats per experimental group, ** mark is a significant difference compared to the carbon tetrachloride untreated group (Cont) (P <0.01), and ++ indicates a significant difference (P <0.01) compared to the carbon tetrachloride treatment group (CCl 4 ) As shown in Fig. 1, ALT than the silymarin-administered group in the 300 mg / kg administration group of SHP-1. It was confirmed that the activity was significantly inhibited, and the 300, 600 mg / kg administration group of SHP-1 significantly inhibited the AST activity than the silymarin administration group.
또한, 사염화탄소에 의해 유도된 간독성 동물모델실험에서, 사염화탄소 무처치군(A), 사염화탄소(CCl4) 단독 처치군(B) 및 본 발명의 혼합 생약 추출물 (SHP-1) 300 mg/kg 투여군의 간조직 염색사진(현미경 배율: x100)을 도 2에 나타내었다. 도 2에 나타난 바와 같이, 정상적인 간조직(A)에 비하여, 간조직이 사염화탄소의 투여로 인하여 심하게 손상되었음을 확인할 수 있었으며(B), 본 발명의 혼합 생약 추출물 (SHP-1) 300 mg/kg 의 투여로 인하여 간조직이 현저하게 보호되었음(C)을 확인 할 수 있었다. In addition, in the hepatotoxic animal model experiment induced by carbon tetrachloride, the carbon tetrachloride untreated group (A), carbon tetrachloride (CCl 4 ) alone treatment group (B) and the mixed herbal extract (SHP-1) of the
또한, 사염화탄소에 의해 유도된 간독성 동물모델실험에서 말론디알데히드 수치 및 글루타치온 함량에 대한 본 발명의 혼합 생약 추출물 (SHP-1) 300 mg/kg 투여군 및 실리마린 투여군의 효과를 도 3에 나타내었다. 각 막대그래프는 실험군당 9 내지 11마리의 쥐에 대한 측정치+표준편차를 나타내며, * 및 **표시는 사염화탄소 무처치군 (Cont) 대비 유의성 있는 차이를 (P<0.05 및 P<0.01) 나타내며, +표시는 사염화탄소 처치군 (CCl4)대비 유의성있는 차이를 (P<0.05) 나타낸다. 도 3에 나타난 바와 같이 SHP-1의 300mg/kg 투여군에서 실리마린 투여군보다도 말론디알데히드 수치를 유의성 있게 감소시키고, 글루타치온 함량의 고갈을 효과적으로 억제시킴을 확인할 수 있었다.In addition, the effect of the 300 mg / kg administration group and the silymarin administration group of the mixed herbal extract (SHP-1) of the present invention on malondialdehyde levels and glutathione content in hepatotoxic animal model experiment induced by carbon tetrachloride is shown in FIG. Each bar graph represents the measurement + standard deviation for 9 to 11 rats per experimental group, and * and ** indicate significant differences (P <0.05 and P <0.01) compared to carbon tetrachloride-free group (Cont), Positive signs indicate a significant difference (P <0.05) compared to carbon tetrachloride treated group (CCl 4 ). As shown in FIG. 3, the 300 mg / kg administration group of SHP-1 significantly reduced malondialdehyde levels than the silymarin administration group and effectively inhibited the depletion of glutathione content.
실험예 2. D-갈락토사민에 의해 유도된 간염 동물모델실험Experimental Example 2 Hepatitis Animal Model Experiment Induced by D-galactosamine
상기 실시예에서 수득한 혼합 추출물이 D-갈락토사민에 의해 유도된 간염 동물모델실험에서 ALT 및 AST 활성, 지질과산화 함량 및 GSH 함량에 미치는 영향을 확인하기 위하여 문헌에 개시된 방법을 응용하여 하기와 같은 방법으로 실험을 실시하였다.In order to confirm the effect of the mixed extract obtained in the above example on ALT and AST activity, lipid peroxidation content and GSH content in hepatitis animal model experiment induced by D-galactosamine, The experiment was conducted in the same manner.
2-1. 검체 채취2-1. Sampling
18시간 절식시킨 상기 참고예 1의 흰쥐에 GalN (700mg/kg, PBS)을 복강 내 투여하고, 24시간 경과 후에 에테르로 마취시켜 복부 대정맥으로부터 혈액을 취한 후, 간조직을 채취하였다. 상기 실시예에서 수득한 혼합 생약 추출물은 GalN 투여 14일 전부터 1일 1회 동일한 시각에 체중 1kg 당 30, 100, 300 또는 600mg씩 경구 투여하였으며, GalN 투여 당일에는 GalN 투여 전 2시간 및 투여 후 2시간째에 체중 1kg 당 30, 100, 300 또는 600mg씩 경구 투여하였다. 양성대조약물로는 실리마린 300 mg/kg를 사용하였다.GalN (700 mg / kg, PBS) was intraperitoneally administered to the rat of Reference Example 1 fasted for 18 hours, anesthetized with ether 24 hours later, blood was taken from the abdominal vena cava, and liver tissue was collected. The mixed herbal extracts obtained in the above examples were administered orally at 30, 100, 300, or 600 mg / kg of body weight at the same time once a day from 14 days before GalN administration, and 2 hours before or after GalN administration on the day of GalN administration. At the time of administration, 30, 100, 300 or 600 mg / kg body weight was administered orally.
2-2. ATL 및 AST 활성 측정2-2. ATL and AST activity measurement
상기 실험예 2-1의 혈액을 사용하는 점만 제외하고, 실험예 1-2와 동일한 방법으로 알라닌 아미노트랜스페라제(ALT) 및 아스파테이트 아미노트랜스페라제(AST) 활성을 측정하였다.Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were measured in the same manner as in Experimental Example 1-2 except that the blood of Experimental Example 2-1 was used.
2-3. 지질과산화 측정2-3. Lipid Peroxidation Measurement
상기 실험예 2-1에서 채취한 간조직을 사용하는 점만 제외하고, 실험예 1-3과 동일한 방법으로 지질과산화의 최종산물인 말론디알데히드를 지표로 정량하였다. Except for using the liver tissue collected in Experimental Example 2-1, in the same manner as in Experimental Example 1-3, malondialdehyde, the final product of lipid peroxidation, was quantified as an indicator.
2-4. 글루타치온 함량 측정2-4. Determination of Glutathione Content
상기 실험예 2-1에서 채취한 간조직을 사용하는 점만 제외하고, 실험예 1-4와 동일한 방법으로 글루타치온(Glutathione, GSH) 함량을 측정하였다.Except for using the liver tissue collected in Experimental Example 2-1, glutathione (Glutathione, GSH) content was measured in the same manner as in Experimental Example 1-4.
2-5. 조직학적 검사2-5. Histological examination
상기 실험예 2-1에서 채취한 간조직을 사용하는 점만 제외하고, 실험예 1-5와 동일한 방법으로 조직검사를 실시하였다. Except for using the liver tissue collected in Experimental Example 2-1, a biopsy was performed in the same manner as in Experimental Example 1-5.
실험결과, D-갈락토사민(GalN)에 의해 유도된 간염 동물모델실험에서 ALT 및 AST 활성에 대한 상기 실시예에서 수득한 SHP-1 30, 100, 300 및 600 mg/kg 투여군 및 실리마린 투여군(양성대조군)의 효과를 도 4에 나타내었다. 각 막대그래프는 실험군당 7 내지 8마리의 쥐에 대한 측정치+표준편차를 나타내며, **표시는 GalN 무처치군 (Cont) 대비 유의성 있는 차이를 (P<0.01) 나타내며, + 및 ++표시는 GalN 처치군 대비 유의성있는 차이를 (P<0.05 및 P<0.01) 나타낸다. 도 4에 나타난 바와 같이 SHP-1의 300mg/kg 투여군에서 실리마린 투여군보다도 ALT 활성을 유의성 있게 억제함을 확인할 수 있었으며, SHP-1의 300, 600mg/kg 투여군에서 실리마린 투여군보다도 AST 활성을 유의성 있게 억제함을 확인할 수 있었다. As a result, in the hepatitis animal model experiment induced by D-galactosamine (GalN), the SHP-1 30, 100, 300 and 600 mg / kg administration group and silymarin administration group obtained in the above examples for ALT and AST activity ( Positive control) effect is shown in FIG. Each bar graph represents the measurement + standard deviation for 7 to 8 rats per experimental group, ** indicates significant difference (P <0.01) compared to GalN no treatment group (Cont), and + and ++ marks Significant differences (P <0.05 and P <0.01) are shown in the GalN treatment group. As shown in FIG. 4, it was confirmed that 300 mg / kg of SHP-1 significantly inhibited ALT activity than the silymarin-administered group, and significantly inhibited AST activity in the 300, 600 mg / kg-administered group of SHP-1 than silymarin. Could confirm.
또한, D-갈락토사민(GalN)에 의해 유도된 간염 동물모델실험에서, GalN 무처치군(A), D-갈락토사민(GalN) 단독 처치군(B) 및 본 발명의 혼합 생약 추출물 (SHP-1) 300 mg/kg 투여군의 간조직 염색사진(현미경 배율: x100)을 도 5에 나타내었다. 도 5에 나타난 바와 같이, 정상적인 간조직(A)에 비하여, 간조직이 D-갈락토사민의 투여로 인하여 심하게 염증이 발생되었음을 확인할 수 있었으며(B), 본 발명의 혼합 생약 추출물 (SHP-1) 300 mg/kg 의 투여로 인하여 간조직이 현저하게 보 호되었음(C)을 확인할 수 있었다. In addition, in the hepatitis animal model experiment induced by D-galactosamine (GalN), GalN untreated group (A), D-galactosamine (GalN) alone treatment group (B) and the mixed herbal extract of the present invention ( SHP-1) hepatic staining photograph (microscope magnification: x100) of the 300 mg / kg administration group is shown in FIG. 5. As shown in Figure 5, compared to normal liver tissue (A), it was confirmed that the liver tissue is severely inflamed due to the administration of D-galactosamine (B), the mixed herbal extract of the present invention (SHP-1 ) Hepatic tissue was significantly protected due to the administration of 300 mg / kg (C).
또한, D-갈락토사민(GalN)에 의해 유도된 간염 동물모델실험에서 말론디알데히드 수치 및 글루타치온 함량에 대한 본 발명의 혼합 생약 추출물 (SHP-1) 30, 100, 300 및 600 mg/kg 투여군 및 실리마린 투여군의 효과를 도 6에 나타내었다. 각 막대그래프는 실험군당 7-8마리의 쥐에 대한 측정치+표준편차를 나타내며, **표시는 GalN 무처치군 (Cont) 대비 유의성 있는 차이를 (P<0.01) 나타내며, + 및 ++ 표시는 GalN 처치군 대비 유의성 있는 차이를 (P<0.05 및 P<0.01) 나타낸다. 도 6에 나타난 바와 같이 SHP-1의 300mg/kg 투여군에서 실리마린 투여군보다도 말론디알데히드 수치를 유의성 있게 감소시킴을 확인할 수 있었다.In addition, the mixed herbal extract of the present invention (SHP-1) 30, 100, 300 and 600 mg / kg administration group on malondialdehyde level and glutathione content in hepatitis animal model experiment induced by D-galactosamine (GalN) And the effect of the silymarin administration group is shown in FIG. Each bar graph represents the measurement + standard deviation for 7-8 rats per experimental group, ** indicates significant difference (P <0.01) compared to GalN-treated group (Cont), and + and ++ marks Significant differences (P <0.05 and P <0.01) are shown as compared to the GalN treatment group. As shown in FIG. 6, it was confirmed that the malondialdehyde level was significantly reduced in the 300 mg / kg administration group of SHP-1 than the silymarin administration group.
실험예 3. 간장 허혈 및 재관류 유발 동물모델실험Experimental Example 3. Hepatic ischemia and reperfusion-induced animal model experiment
상기 실시예에서 수득한 혼합 추출물 또는 이로부터 분리한 화합물이 간장 허혈 및 재관류 유발 간염 동물모델실험에서 ALT 및 AST 활성, 지질과산화 함량 및 GSH 함량에 미치는 영향을 확인하기 위하여 문헌에 개시된 방법을 응용하여 하기와 같은 방법으로 실험을 실시하였다.Application of the method disclosed in the literature to determine the effect of the mixed extract obtained in the above example or a compound isolated therefrom on ALT and AST activity, lipid peroxidation content and GSH content in hepatic ischemia and reperfusion-induced hepatitis animal model experiment The experiment was carried out in the following manner.
3-1. 검체 채취3-1. Sampling
18시간동안 절식시킨 상기 참고예 1의 흰쥐에 케타민(60mg/kg)과 자일라진(Xylazine, 8mg/kg)을 복강 내 투여하여 마취시킨 후, 개복하여 간문맥의 왼쪽 분지와 간동맥 및 담관을 클램프(clamp)로 막아주어 허혈을 유발시켰다. 허혈 유발 60분 후에 클램프를 제거함으로써 재관류를 유발하였다. 재관류 5시간째에 복부의 정중선을 따라 개복하여 담관에 카테터를 삽입시켜 10분 동안 담즙을 채취한 후, 혈액 및 간조직을 채취하였다. 상기 실시예에서 수득한 혼합 생약 추출물은 허혈 및 재관류 유발 14일 전부터 1일 1회 동일한 시각에 체중 1kg 당 30, 100, 300 또는 600mg씩 경구 투여하였으며, 허혈 및 재관류 유발 당일에는 처치 후 2시간째에 체중 1kg 당 30, 100, 300 또는 600mg씩 경구 투여하였다. 양성대조약물로는 실리마린 300 mg/kg를 사용하였다. Ketamine (60mg / kg) and xylazine (Xylazine, 8mg / kg) were anesthetized intraperitoneally in the rats of Reference Example 1 fasted for 18 hours, and then opened to clamp the left branch of the portal vein and hepatic artery and bile duct. to prevent ischemia. Reperfusion was induced by removing the
3-2. ATL 및 AST 활성 측정3-2. ATL and AST activity measurement
상기 실험예 3-1의 혈액을 사용하는 점만 제외하고, 실험예 1-2와 동일한 방법으로 알라닌 아미노트랜스페라제(ALT) 및 아스파테이트 아미노트랜스페라제(AST) 활성을 측정하였다.Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were measured in the same manner as in Experimental Example 1-2 except that the blood of Experimental Example 3-1 was used.
3-3. 지질과산화 측정3-3. Lipid Peroxidation Measurement
상기 실험예 3-1에서 채취한 간조직을 사용하는 점만 제외하고, 실험예 1-3과 동일한 방법으로 지질과산화의 최종산물인 말론디알데히드를 지표로 정량하였다. Except for using the liver tissue collected in Experimental Example 3-1, malondialdehyde, the final product of lipid peroxidation, was quantified in the same manner as Experimental Example 1-3.
3-4. 글루타치온 함량 측정3-4. Determination of Glutathione Content
상기 실험예 3-1에서 채취한 간조직을 사용하는 점만 제외하고, 실험예 1-4 와 동일한 방법으로 글루타치온(Glutathione, GSH) 함량을 측정하였다.Except for using the liver tissue collected in Experimental Example 3-1, glutathione (Glutathione, GSH) content was measured in the same manner as in Experimental Example 1-4.
3-5. 조직학적 검사3-5. Histological examination
상기 실험예 3-1에서 채취한 간조직을 사용하는 점만 제외하고, 실험예 1-5와 동일한 방법으로 조직검사를 실시하였다. Except for using the liver tissue collected in Experimental Example 3-1, the histology was performed in the same manner as in Experimental Example 1-5.
실험결과, 간장 허혈 및 재관류(I/R) 유발 동물모델실험에서 ALT 및 AST 활성에 대한 상기 실시예에서 수득한 SHP-1 30, 100, 300 및 600 mg/kg 투여군 및 실리마린 투여군(양성대조군)의 효과를 도 7에 나타내었다. 각 막대그래프는 실험군당 7 내지 8마리의 쥐에 대한 측정치+표준편차를 나타내며, **표시는 I/R 무처치군 (Cont) 대비 유의성 있는 차이를 (P<0.01) 나타내며, + 및 ++표시는 I/R 처치군 대비 유의성있는 차이를 (P<0.05 및 P<0.01) 나타낸다. 도 7에 나타난 바와 같이 SHP-1의 300mg/kg 투여군에서 실리마린 투여군과 비슷한 수준으로 ALT 활성을 유의성 있게 억제함을 확인할 수 있었으며, SHP-1의 300, 600mg/kg 투여군에서 실리마린 투여군보다도 AST 활성을 효과적으로 억제함을 확인할 수 있었다. As a result, SHP-1 30, 100, 300 and 600 mg / kg administration group and silymarin administration group (positive control group) obtained in the above example for ALT and AST activity in hepatic ischemia and reperfusion (I / R) -induced animal model experiments The effect of is shown in FIG. Each bar graph represents the measurement + standard deviation for 7 to 8 rats per experimental group, ** indicates significant difference (P <0.01) compared to I / R untreated group (Cont), + and ++ Indications show significant differences (P <0.05 and P <0.01) compared to I / R treatment groups. As shown in FIG. 7, it was confirmed that 300 mg / kg of SHP-1 significantly inhibited ALT activity at a level similar to that of silymarin, and AST activity was higher than that of silymarin at 300 and 600 mg / kg of SHP-1. It was confirmed that the inhibition effectively.
또한, 간장 허혈 및 재관류(I/R) 유발 동물모델실험에서, 허혈 및 재관류(I/R)를 유발하지 않은 무처치군(A), 허혈 및 재관류(I/R)가 유발된 군(B) 및 본 발명의 혼합 생약 추출물 (SHP-1) 300 mg/kg 투여군의 간조직 염색사진(현미경 배율: x100)을 도 8에 나타내었다. 도 8에 나타난 바와 같이, 정상적인 간조직(A)에 비하여, 간장 허혈 및 재관류(I/R)로 인하여 간이 손상되었음을 확인할 수 있었으 며(B), 본 발명의 혼합 생약 추출물 (SHP-1) 300 mg/kg 의 투여로 인하여 간조직이 현저하게 보호되었음(C)을 확인할 수 있었다. In addition, in the hepatic ischemia and reperfusion (I / R) -induced animal model experiment, the untreated group (A) that did not cause ischemia and reperfusion (I / R), and the group in which ischemia and reperfusion (I / R) were induced (B) ) And liver tissue staining (microscope magnification: x100) of the mixed herbal extract (SHP-1) 300 mg / kg administration group of the present invention is shown in FIG. 8. As shown in Figure 8, compared to normal liver tissue (A), it was confirmed that the liver is damaged by hepatic ischemia and reperfusion (I / R) (B), the mixed herbal extract of the present invention (SHP-1) 300 Hepatic tissue was significantly protected by the administration of mg / kg (C) was confirmed.
또한, 간장 허혈 및 재관류(I/R) 유발 동물모델실험에서 말론디알데히드 수치 및 글루타치온 함량에 대한 본 발명의 혼합 생약 추출물 (SHP-1) 300 mg/kg 투여군 및 실리마린 투여군의 효과를 도 9에 나타내었다. 각 막대그래프는 실험군당 7-8마리의 쥐에 대한 측정치+표준편차를 나타내며, **표시는 I/R 무처치군 (Cont) 대비 유의성 있는 차이를 (P<0.01) 나타내며, + 표시는 I/R 처치군 대비 유의성있는 차이를 (P<0.05) 나타낸다. 도 9에 나타난 바와 같이 SHP-1의 300mg/kg 투여군에서 실리마린 투여군보다도 말론디알데히드 수치를 유의성 있게 감소시키고, 글루타치온 함량의 고갈을 실리마린 투여군과 비슷한 수준으로 유의성 있게 억제시킴을 확인할 수 있었다.In addition, the effects of the 300 mg / kg administration group of the mixed herbal extract (SHP-1) of the present invention and the silymarin administration group on malondialdehyde levels and glutathione content in hepatic ischemia and reperfusion (I / R) -induced animal model experiment Indicated. Each bar graph represents the measurement + standard deviation for 7-8 rats per experimental group, ** indicates significant difference (P <0.01) compared to I / R untreated group (Cont), + indicates I A significant difference (P <0.05) is shown in the / R treatment group. As shown in FIG. 9, 300 mg / kg of the SHP-1 group significantly reduced malondialdehyde levels than the silymarin-administered group and significantly inhibited the depletion of glutathione content to a level similar to that of the silymarin-administered group.
또한, 간장 허혈 및 재관류(I/R) 유발 동물모델실험에서 담즙 분비에 대한 본 발명의 혼합 생약 추출물 (SHP-1) 30, 100, 300 및 600 mg/kg 투여군 및 실리마린 투여군의 효과를 도 10에 나타내었다. 각 막대그래프는 실험군당 7 내지 8마리의 쥐에 대한 측정치+표준편차를 나타내며, **표시는 I/R 무처치군 (Cont) 대비 유의성 있는 차이를 (P<0.01) 나타내며, + 표시는 I/R 처치군 대비 유의성있는 차이를 (P<0.05) 나타낸다. 도 10에 나타난 바와 같이 SHP-1의 300mg/kg 투여군에서 실리마린 투여군보다도 담즙 분비량을 유의성 있게 증가시킴을 확인할 수 있었다.In addition, the effects of the mixed herbal extract (SHP-1) 30, 100, 300 and 600 mg / kg administration group and silymarin administration group of the present invention on bile secretion in hepatic ischemia and reperfusion (I / R) -induced animal model experiment Shown in Each bar graph represents the measurement + standard deviation for 7 to 8 rats per experimental group, ** indicates significant difference (P <0.01) compared to I / R untreated group (Cont), and + indicates I A significant difference (P <0.05) is shown in the / R treatment group. As shown in FIG. 10, the bile secretion was significantly increased in the 300 mg / kg administration group of SHP-1 than in the silymarin administration group.
실험예 4. 리포폴리사카라이드로 유도되는 프로스타글란딘 E2의 생성 억제 효과Experimental Example 4 Inhibition Effect of Prostaglandin E2 Induced by Lipopolysaccharide
프로스타글란딘(PGE2)의 생성 억제 효과를 측정하기 위하여 ParameterTM PGE2 assay kit(R&D Systems)를 사용하였다. Parameter TM PGE 2 assay kit (R & D Systems) was used to measure the inhibitory effect of prostaglandin (PGE2) production.
Raw264.7 cell(ATCC, 1×105 cells)에 리포폴리사카라이드(LPS; lipopolysaccharide)를 1 ㎍/㎕ 농도로 처리하여 염증반응을 유도하였다. 상기 실시예에서 수득한 혼합 생약 추출물 및 분획물을 각각 20 ㎍/ml로 처리하고 24시간 동안 반응 시킨 후, 80㎕의 상층액을 취하여 160㎕의 희석 버퍼(diluent buffer)로 희석시키고, goat anti-mouse 다클론 항체(polyclonal antibody)가 코팅되어있는 웰에 PGE2 conjugate와 같이 경쟁적 반응을 시켰다. 상기 ParameterTM PGE2 assay kit내의 포함되어 있는 PGE2에 대한 항체를 첨가하여 24시간 동안 항원-항체 반응시킨 후, 450nm에서 발색정도를 측정하여 비교 정량하였다. 대조군으로서는 LPS 비처리군, LPS 처리군 및 인도메타신 (7 ㎍/ml 농도) 처리군을 사용하였다.Inflammatory responses were induced by treating lipopolysaccharide (LPS; lipopolysaccharide) at a concentration of 1 μg / μl in Raw264.7 cells (ATCC, 1 × 10 5 cells). The mixed herbal extracts and fractions obtained in the above examples were treated with 20 ㎍ / ml each and reacted for 24 hours, followed by 80 ul of supernatant, diluted with 160 ul of diluent buffer, and goat anti- Competitive reactions with PGE 2 conjugate were performed on wells coated with mouse polyclonal antibody. Antibody-antibody reaction was performed for 24 hours by adding an antibody to PGE 2 contained in the Parameter TM PGE 2 assay kit, followed by comparative quantitation by measuring the color development at 450 nm. As a control group, an LPS untreated group, an LPS treated group, and an indomethacin (7 μg / ml concentration) treated group were used.
실험결과, Raw264.7 세포에서 리포폴리사카라이드(LPS)로 프로스타글란딘 E2(PGE2)의 생성을 유도한 실험 모델에서, 상기 실시예에서 수득한 SHP-1(M), SHP-1(B) 및 SHP-1(W) 20 ㎍/ml 투여군, LPS 단독처리군(LPS+), 음성대조군(LPS-) 및 인도메타신 처리군(Ind)의 프로스타그란딘 E2 (PGE2) 생성 억제 효과를 도 11에 나타내었다. 도 11에 나타난 바와 같이 SHP-1(M), SHP-1(B) 및 인도메타신(Ind)의 7 ㎍/ml 처리군에서 음성대조군(LPS 비처리군)과 비슷한 수준으로 프로스타그란딘 E2 (PGE2) 생성을 유의성 있게 억제하는 효과를 확인할 수 있었다. Experimental results showed that prostaglandin E2 (PGE2) was induced with lipopolysaccharide (LPS) in Raw264.7 cells. In the experimental model induced production, SHP-1 (M), SHP-1 (B) and SHP-1 (W) 20 ㎍ / ml administration group, LPS monotherapy (LPS +), negative control group obtained in the above example The inhibitory effect of (LPS-) and indomethacin treated group (Ind) on the production of prostaglandin E2 (PGE2) is shown in FIG. 11. As shown in FIG. 11, the prostaglandin E2 (PGE2) at 7 ug / ml treated group of SHP-1 (M), SHP-1 (B) and indomethacin (Ind) was similar to the negative control group (LPS untreated group). ) Significantly inhibit the production.
하기에 본 발명의 황금, 지실, 대황, 작약 및 시호의 혼합 생약 추출물을 유효성분으로 하는 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.Hereinafter, an example of the formulation of a composition comprising the mixed herbal extracts of gold, fruit, rhubarb, peony and shiho of the present invention as an active ingredient will be described, but the present invention is not intended to limit the present invention but only to be described in detail.
제제예 1. 산제의 제조Formulation Example 1 Preparation of Powder
SHP-1 20 mgSHP-1 20 mg
유당 100 mg
탈크 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.The above ingredients are mixed and filled in an airtight cloth to prepare a powder.
제제예 2. 정제의 제조Formulation Example 2 Preparation of Tablet
SHP-1(M) 10 mgSHP-1 (M) 10 mg
옥수수전분 100 mg
유당 100 mg
스테아린산 마그네슘 2 mg2 mg 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 a conventional method for preparing tablets.
제제예 3. 캅셀제의 제조 Formulation Example 3 Preparation of Capsule
SHP-1(B) 10 mgSHP-1 (B) 10 mg
결정성 셀룰로오스 3 mg3 mg of crystalline cellulose
락토오스 14.8 mgLactose 14.8 mg
마그네슘 스테아레이트 0.2 mgMagnesium Stearate 0.2 mg
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare capsules.
제제예 4. 주사제의 제조Formulation Example 4 Preparation of Injection
SHP-1(W) 10 mgSHP-1 (W) 10 mg
만니톨 180 mg180 mg mannitol
주사용 멸균 증류수 2974 mgSterile sterilized water for injection 2974 mg
Na2HPO4,12H2O 26 mgNa2HPO4,12H2O 26 mg
통상의 주사제의 제조방법에 따라 1 앰플당(2㎖) 상기의 성분 함량으로 제조한다.According to the conventional method for preparing an injection, the amount of the above ingredient is prepared per ampoule (2 ml).
제제예 5. 액제의 제조Formulation Example 5 Preparation of Liquid
SHP-1 20 mg SHP-1 20 mg
이성화당 10 g10 g of isomerized sugar
만니톨 5 g5 g of mannitol
정제수 적량Purified water
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100㎖로 조절한 후 갈색병에 충진하여 멸균시켜 액제를 제조한다.After dissolving each component in purified water according to the usual method of preparing a liquid solution, adding lemon flavor appropriately, mixing the above components, adding purified water, adjusting the whole to 100 ml by adding purified water, and then filling into a brown bottle. The solution is prepared by sterilization.
제제예 6. 건강 식품의 제조Formulation Example 6 Preparation of Healthy Food
SHP-1(M) 1000 ㎎SHP-1 (M) 1000 mg
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 B1 0.13 ㎎0.13 mg vitamin B1
비타민 B2 0.15 ㎎0.15 mg of vitamin B2
비타민 B6 0.5 ㎎0.5 mg vitamin B6
비타민 B12 0.2 ㎍0.2 [mu] g vitamin B12
비타민 C 10 ㎎10 mg vitamin C
비오틴 10 ㎍Biotin 10 μg
니코틴산아미드 1.7 ㎎Nicotinic acid amide 1.7 mg
엽산 50 ㎍50 ㎍ 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 ㎎Magnesium chloride 24.8 mg
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.
제제예 7. 건강 음료의 제조Formulation Example 7 Preparation of Healthy Drink
SHP-1(B) 1000 ㎎SHP-1 (B) 1000 mg
구연산 1000 ㎎
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 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2ℓ 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강음료 조성물 제조에 사용한다. The above components were mixed according to a conventional health drink manufacturing method, and the mixture was heated at 85 DEG C for about 1 hour with stirring, and the solution thus prepared was filtered to obtain a sterilized 2-liter container, which was sealed and sterilized, ≪ / RTI >
상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 수요계층, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.Although the composition ratio is a mixture of the components suitable for the preferred beverage as a preferred embodiment, the blending ratio may be arbitrarily varied according to the regional and national preferences such as the demand level, the demanding country, and the intended use.
도 1은 사염화탄소 간독성 동물모델실험에서 ALT 및 AST 활성에 대한 혼합 생약 추출물(SHP-1) 및 실리마린 투여군의 효과를 나타낸 도이고,1 is a diagram showing the effect of the mixed herbal extract (SHP-1) and silymarin administration group on ALT and AST activity in carbon tetrachloride hepatotoxicity animal model experiments,
도 2는 사염화탄소 간독성 동물모델실험에서 음성대조군(A), 사염화탄소 단독 처치군(B) 및 혼합 생약 추출물(SHP-1) 300 mg/kg 투여군(C)의 간조직 염색 도이며,Figure 2 is a liver tissue staining of the negative control group (A), carbon tetrachloride alone treatment group (B) and mixed herbal extract (SHP-1) 300 mg / kg administration group (C) in the carbon tetrachloride liver toxicity animal model experiment,
도 3은 사염화탄소 간독성 동물모델실험에서 말론디알데히드 수치 및 글루타치온 함량에 대한 혼합 생약 추출물(SHP-1) 300 mg/kg 투여군 및 실리마린 투여군의 효과를 나타낸 도이고,3 is a diagram showing the effect of 300 mg / kg mixed group herbal extract (SHP-1) administration and silymarin administration group on malondialdehyde levels and glutathione content in carbon tetrachloride hepatotoxicity animal model experiments,
도 4는 GalN를 처치한 쥐의 간염 모델실험에서 ALT 및 AST 활성에 대한 황금, 지실, 대황, 작약 및 시호의 혼합 생약 추출물(SHP-1) 및 실리마린 투여군의 효과를 나타낸 도이며,Figure 4 is a diagram showing the effect of the mixed herbal extract (SHP-1) and silymarin administration of gold, fruit, rhubarb, peony and Siho on ALT and AST activity in the hepatitis model experiment of rats treated with GalN,
도 5는 GalN를 처치한 쥐의 간염 모델실험에서 음성대조군(A), 갈락토사민 단독 처치군(B) 및 혼합 생약 추출물(SHP-1) 300 mg/kg 투여군(C)의 간조직 염색 도이고,Figure 5 is a liver tissue staining of the negative control group (A), galactosamine alone treatment group (B) and mixed herbal extract (SHP-1) 300 mg / kg administration group (C) in the hepatitis model experiment of galN-treated rats ego,
도 6은 GalN를 처치한 쥐의 간염 모델실험에서 말론디알데히드 수치 및 글루타치온 함량에 대한 혼합 생약 추출물(SHP-1) 투여군 및 실리마린 투여군의 효과를 나타낸 도이며,Figure 6 is a diagram showing the effect of the mixed herbal extract (SHP-1) administration group and silymarin administration group on malondialdehyde levels and glutathione content in hepatitis model experiment of rats treated with GalN,
도 7은 쥐의 간에서 허혈 및 재관류를 수행한 모델실험에서 ALT 및 AST 활성에 대한 황금, 지실, 대황, 작약 및 시호의 혼합 생약 추출물(SHP-1) 및 실리마린 투여군의 효과를 나타낸 도이고,7 is a diagram showing the effect of the mixed herbal extract (SHP-1) and silymarin administration group of golden, fruit, rhubarb, peony and Shiho on ALT and AST activity in a model experiment in which ischemia and reperfusion were performed in the liver of rats,
도 8은 쥐의 간에서 허혈 및 재관류를 수행한 모델실험에서 음성대조군(A), 허혈 및 재관류가 유발된 군(B) 및 혼합 생약 추출물(SHP-1) 300 mg/kg 투여군(C)의 간조직 염색 도이며,FIG. 8 shows negative control group (A), ischemia and reperfusion-induced group (B) and mixed herbal extract (SHP-1) 300 mg / kg administration group (C) in a model experiment in which ischemia and reperfusion were performed in rat liver. Liver tissue staining degree,
도 9는 쥐의 간에서 허혈 및 재관류를 수행한 모델실험에서 말론디알데히드 수치 및 글루타치온 함량에 대한 혼합 생약 추출물(SHP-1) 투여군 및 실리마린 투여군의 효과를 나타낸 도이고,9 is a diagram showing the effect of the mixed herbal extract (SHP-1) administration group and silymarin administration group on malondialdehyde levels and glutathione content in a model experiment that ischemia and reperfusion in the liver of rats,
도 10은 쥐의 간에서 허혈 및 재관류를 수행한 모델실험에서 담즙 분비에 대한 혼합 생약 추출물(SHP-1) 투여군 및 실리마린 투여군의 효과를 나타낸 도이며,10 is a diagram showing the effect of the mixed herbal extract (SHP-1) administration group and silymarin administration group on bile secretion in a model experiment that ischemia and reperfusion in the liver of the rat,
도 11은 Raw264.7 세포에 리포폴리사카라이드(LPS)를 처리하여 프로스타그란딘 E2(PGE2) 생성을 유도한 모델실험에서 혼합 생약 추출물(SHP-1)의 분획물인 메틸렌클로라이드 분획물, 부탄올 분획물 및 수가용성 분획물의 프로스타그란딘 E2(PGE2) 생성 억제 작용을 나타낸 도이다.11 is a methylene chloride fraction, butanol fraction and water soluble fraction of mixed herbal extract (SHP-1) in a model experiment in which Raw264.7 cells were treated with lipopolysaccharide (LPS) to induce prostaglandin E2 (PGE2) production. Figure showing the inhibitory effect of the production of prostaglandin E2 (PGE2).
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