KR101543998B1 - Composition for treating and improving fatty liver and hyperlipidemia comprising extract of olive as an active ingredient - Google Patents
Composition for treating and improving fatty liver and hyperlipidemia comprising extract of olive as an active ingredient Download PDFInfo
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- KR101543998B1 KR101543998B1 KR1020130162244A KR20130162244A KR101543998B1 KR 101543998 B1 KR101543998 B1 KR 101543998B1 KR 1020130162244 A KR1020130162244 A KR 1020130162244A KR 20130162244 A KR20130162244 A KR 20130162244A KR 101543998 B1 KR101543998 B1 KR 101543998B1
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- South Korea
- Prior art keywords
- cholesterol
- extract
- olive
- fatty liver
- composition
- Prior art date
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Abstract
본 발명은 감람나무 열매 추출물 및 이로부터 분리된 하이드록시타이로솔을 유효성분으로 함유하는 지방간 및 고지혈증 치료 및 개선을 위한 조성물에 관한 것이다.
본 발명의 감람나무 열매 추출물 및 이로부터 분리된 알칼로이드계 화합물은 고지질식이로 콜레스테롤과 저밀도 지단백의 수치가 증가한 랫트에서 혈중 콜레스테롤과 저밀도 지단백 농도를 감소시키고, 지방간 동물모델에서 중성지방과 콜레스테롤의 수치를 효과적으로 감소시킴으로써, 지방간, 특히 비알코올성 지방간에 대한 예방 또는 치료에 유용하게 사용될 수 있다.The present invention relates to a composition for the treatment and improvement of fatty liver and hyperlipidemia containing olive fruit extract and hydroxytorrosol separated therefrom as an active ingredient.
The olive fruit extract of the present invention and the alkaloid-based compounds isolated therefrom reduce blood cholesterol and low density lipoprotein levels in rats in which high lipid lipid cholesterol and low density lipoprotein levels are increased, and the levels of triglyceride and cholesterol Can be effectively used to prevent or treat fatty liver, especially nonalcoholic fatty liver.
Description
본 발명은 감람나무 열매 추출물을 유효성분으로 함유하는 지방간 및 고지혈증 치료 및 개선을 위한 약학 조성물 또는 식품 조성물에 관한 것이다. The present invention relates to a pharmaceutical composition or a food composition for the treatment and improvement of fatty liver and hyperlipidemia containing an olive extract as an active ingredient.
한국인의 혈장 콜레스테롤 농도는 서양인의 콜레스테롤 수준에 비하여 아직 낮은 범위이지만 최근 20～30년 사이에 10 ㎎/㎗ 이상 높아졌으며, 특히 낮은 연령층에서의 상승이 두드러지고 있다. The plasma cholesterol concentration in Koreans is still low compared to the cholesterol level of Westerners, but it has risen by more than 10 ㎎ / ㎗ in recent 20 to 30 years, especially in low age groups.
이로 인해 최근 수년간 고혈압, 뇌혈관 장애, 심질환의 환자 수는 해를 거듭할수록 증가하고 있으며, 심근경색 환자의 연령은 점차 낮아지고 있다. 이러한 변화는 동물성 지방과 단백질 섭취량이 현저히 증가한 한국인의 식생활 변화에서 그 원인을 찾을 수 있다.In recent years, the number of patients with hypertension, cerebrovascular disease, and cardiovascular disease has increased over the years, and the age of patients with myocardial infarction is gradually decreasing. These changes can be attributed to changes in dietary habits of Koreans whose animal fat and protein intake have increased significantly.
한편, 콜레스테롤은 탄소수 27개로 이루어진 불용성 스테로이드계 화합물로서, 동물세포의 필수적인 막 성분일 뿐만 아니라 프로게스틴(progestins), 코르티코스테로이드 (corticosteroids), 성호르몬인 앤드로겐(androgens)과 에스트로겐 (estrogens)의 전구체로 작용하며, 장으로부터 지방이나 지용성 비타민의 흡수에 필요한 담즙산(bile acids)의 형성, 간으로부터 지방을 말초조직으로 운반하기 위해 간에서 형성되는 초저밀도 지단백질(VLDL; very-low-density lipoprotein)의 형성에도 사용되어 진다.On the other hand, cholesterol is an insoluble steroid compound having 27 carbon atoms. It is not only an essential membrane component of animal cells, but also contains progestins, corticosteroids, precursors of the sex hormones androgens and estrogens And the formation of bile acids necessary for the absorption of fat and fat-soluble vitamins from the intestines and the formation of very low-density lipoprotein (VLDL), which forms in the liver to transport fat from the liver to the peripheral tissues .
콜레스테롤은 그의 축적이나 이용을 위해서 합성 또는 흡수된 조직으로부터 필요로 하는 조직까지 운반되어야 하고 트리글리세라이드(triglyceride)와 마찬가지로 혈장에서 지단백질 형태로 존재하면서 이동되고 대사된다.Cholesterol should be transported from the synthesized or absorbed tissue to the tissue it needs for its accumulation or utilization, and it is moved and metabolized in the form of lipoprotein in the plasma, like triglycerides.
또한, 간은 콜레스테롤과 트리글리세라이드를 분비할 때 주로 초저밀도 지단백질의 형태로 분비하며 이는 혈관벽의 지단백질 분해효소의 작용으로 트리글리세라이드가 제거되면서 중간밀도 지단백질(IDL; intermediate density lipoprotein)로 변하고 중간밀도 지단백질은 잔여 트리글리세라이드가 제거되어 저밀도 지단백질 (LDL;low-density lipoprotein)로 변하게 되는데, 저밀도 지단백질은 장기간 혈액 내에 체류하게 되며 혈장 콜레스테롤의 대부분 (60-70%)은 저밀도 지단백질의 형태로 존재하게 된다. 혈중 저밀도 지단백질은 간 및 말초조직에 의해 다시 섭취되고, 말단조직의 잉여 콜레스테롤은 역전이 시스템 (reverse cholesterol transport system)을 거쳐 다시 간으로 수송되어 담즙산염의 형태로 장으로 분비되어 배출된다.In addition, the liver secretes cholesterol and triglyceride mainly in the form of very low density lipoprotein, which is converted to intermediate density lipoprotein (IDL) by elimination of triglyceride by action of lipoproteinase in the blood vessel wall, (LDL; low-density lipoprotein). The low-density lipoprotein is retained in the blood for a long period of time. Most of the plasma cholesterol (60-70%) is present in the form of low-density lipoprotein. Low-density lipoprotein in the blood is taken up again by the liver and peripheral tissues, and excess cholesterol in the end tissues is transported back to the liver through the reverse cholesterol transport system and secreted into the intestines in the form of bile salts.
혈중 저밀도 지단백질(LDL)은 세포막의 LDL-수용체를 통해 세포 내로 이동되는데 세포 내 콜레스테롤의 농도가 높을 경우 LDL-수용체의 합성속도는 감소되며 혈액으로부터 콜레스테롤의 흡수가 느려진다. 혈중 콜레스테롤의 농도가 높을 경우에 심각한 병에 이를 수 있는데 생합성에 의한 콜레스테롤과 식품으로 섭취된 콜레스테롤의 양이 세포막, 담즙산, 스테로이드 호르몬의 합성에 필요한 양 이상일 경우에 혈관 내에 콜레스테롤의 축적이 일어나 혈관을 좁혀 혈류를 방해할 수도 있으며, 심할 경우에는 혈관의 폐색(관상 동맥경화)이 일어나 혈류를 정지시켜 조직이 사멸되기까지 한다. Low-density lipoprotein (LDL) in the blood is transported into the cell through the LDL-receptor of the cell membrane. When the intracellular cholesterol concentration is high, the rate of LDL-receptor synthesis decreases and cholesterol absorption from the blood slows down. High levels of blood cholesterol can lead to serious illness. Cholesterol accumulation occurs in the blood vessels when the amount of cholesterol and food cholesterol that is biosynthesized is greater than that required for cell membrane, bile acid, and steroid hormone synthesis. Narrowing may obstruct the blood flow, and in severe cases, occlusion of the blood vessel (coronary artery sclerosis) occurs and the blood flow is stopped and the tissue is also killed.
현재 이러한 심혈관 질환을 일으키는 주요 위험 요인으로 혈장 콜레스테롤 수준의 증가, 특히 LDL-콜레스테롤의 증가를 들고 있는데 따라서 이를 정상 수준으로 유지하는 것이 심혈관 질환을 방지하는 목적이 되고 있다. 사람의 경우 하루에 대략 300～500 ㎎의 콜레스테롤이 식이 중으로 섭취되며 700～900 ㎎ 정도가 체내에서 합성되는데 체내 총 콜레스테롤의 2/3 가량이 체내에서 직접 합성되기 때문에 콜레스테롤 생합성을 저해함으로써 LDL-수용체의 합성 속도를 증가시켜 혈장 콜레스테롤 수준을 낮추는 방법이 효과적인 것으로 여겨지고 있다.Currently, the major risk factor for cardiovascular disease is increased plasma cholesterol levels, especially LDL-cholesterol, and thus keeping it at normal levels is aimed at preventing cardiovascular disease. In humans, approximately 300 to 500 mg of cholesterol is ingested per day, and about 700 to 900 mg is synthesized in the body. Two-thirds of the total cholesterol in the body is directly synthesized in the body, thereby inhibiting cholesterol biosynthesis, The rate of synthesis of cholesterol by increasing the rate of plasma cholesterol is considered to be effective.
지금까지의 심혈관 질환의 치료제는 혈장 콜레스테롤을 낮추는 제제, 동맥 경화증상을 경감·완화시키는 제제, 심혈관 질환의 진전을 차단 또는 역전시키는 제제의 3가지로 구분될 수 있다. 이들 중에서 혈장 콜레스테롤을 낮추는 제제가 가장 광범위하게 사용되고 있으며 주로 혈중 LDL-콜레스테롤이나 총 콜레스테롤의 수준을 낮추는 작용을 한다. Up to now, therapeutic agents for cardiovascular diseases can be classified into three types: agents for lowering plasma cholesterol, agents for alleviating or alleviating the symptoms of arteriosclerosis, and agents for blocking or reversing the progress of cardiovascular diseases. Among these, agents that lower plasma cholesterol are the most widely used and mainly lower blood LDL-cholesterol and total cholesterol levels.
상기 제제는 작용 기작에 따라 세포 내 콜레스테롤의 이화작용을 촉진함으로써 혈장 콜레스테롤의 수준을 낮추는 제제, 예를 들면, 담즙산 격리제(bile acid sequestrant), 피브르산(fibric acid)의 유도체, 니코틴산(nicotinic acid)과 프로부콜 (probucol) 등이 있으며, 콜레스테롤 생합성 조절효소인 HMG-CoA 환원효소(3-hydroxy-methyl-glutaryl coenzyme A reductase)를 저해하여 LDL-수용체의 합성 속도를 증가시켜 혈장 콜레스테롤 수준을 낮추는 제제, 예를 들면, 컴팩틴(compactin) 유도체인 로바스타틴(lovastatin), 프로바스타틴(pravastatin), 심바스타틴(symvastatin)등이 있으며 콜레스테롤 전달효소인 ACAT (acyl-CoA: cholesterolacyltransferase)의 활성을 저해하여 콜레스테롤의 흡수를 억제함으로써 혈장 콜레스테롤의 수준을 낮추는 제제, 예를 들면, 일본에서 주로 개발된 퍼팩틴(purpactin), 에피코리퀴논(epicohliquinone), 아카테린Such agents may include agents that lower the level of plasma cholesterol by promoting catabolism of intracellular cholesterol according to the action mechanism, such as bile acid sequestrant, derivatives of fibric acid, nicotinic acid ) And probucol, which inhibit the cholesterol biosynthesis-regulating enzyme HMG-CoA reductase, thereby increasing the rate of LDL-receptor synthesis and lowering plasma cholesterol levels (Such as lovastatin, pravastatin, and symvastatin), which inhibit the activity of the cholesterol transporting enzyme ACAT (acyl-CoA: cholesterolacyltransferase) Agents that lower the level of plasma cholesterol by inhibiting absorption, for example, purpactin, which is mainly developed in Japan, Epicohliquinone, aceticin
(acaterin), 헬민토스포롤(helminthosporols), 락테리 (lacteritin), 짚세틴 (gypsetin), 엔니아틴(enniatins), 글리소프레닌(glisoprenins), 피리피로펜 (pyripyropenes), 터펜돌(terpendoles) 등으로 나눌 수 있다.helminthosporols, lacteritin, gypsetin, enniatins, glisoprenins, pyripyropenes, terpendoles, and the like. And so on.
이외에도, 고밀도 지단백질(HDL)에 있는 콜레스테롤을 저밀도 지단백질(LDL)로 전달하는 효소인 콜레스테롤 전이 단백질(cholesterolestertransfer protein, CETP)을 저해함으로써 고지혈증을 억제하여 동맥경화증을 예방하고자 하는 시도가 미국의 업존사 (UpjohnCo.), 머크사 (Merck Co.)를 비롯한 많은 제약회사에서 진행되고있다. 또한, 콜레스테롤 합성에 관여하는 중요한 효소인 스쿠알렌 합성효소 (SQS, squalene synthase)의 저해제를 탐색하는 연구가 최근에 새로이In addition, attempts to prevent hyperlipidemia and prevent arteriosclerosis by inhibiting cholesterol transfer protein (CETP), an enzyme that transfers cholesterol in high density lipoprotein (HDL) to low density lipoprotein (LDL) UpjohnCo.), Merck Co. (Merck Co.) and many other pharmaceutical companies. In addition, a search for an inhibitor of squalene synthase (SQS), an important enzyme involved in cholesterol synthesis,
시작되어 머크사의 자라고즈산(zaragozic acid) 및 글락소사 (Glaxo Co.)의 스쿠알레스타틴(squalestatin)등의 신물질을 미생물로부터 분리한 것이 보고되고 있다.It has been reported that a new material such as zaragozic acid and squalestatin from Glaxo Co. has been separated from microorganisms.
지방간에서 축적된 지방의 대부분은 중성지방(triglyceride)이며, 지방간은 크게 과음으로 인한 알코올성 지방간과 비만, 당뇨병, 고지혈증 또는 약물 등으로 인한 비알코올성 지방간으로 나눌 수 있다. 비알코올성 지방간은 비만, 인슐린 과민증, 당뇨병으로 앓고 있는 사람에게서 많이 발생하며 인슐린 저항성이나 과도한 지방 분해에 의해 혈액내 유리 지방산의 농도가 높아지는 것에 기인하여 나타난다.Most of the fat accumulated in the liver is triglyceride, and fatty liver can be divided into alcoholic fatty liver due to excessive drinking, non-alcoholic fatty liver due to obesity, diabetes, hyperlipidemia or drug. Nonalcoholic fatty liver disease occurs in people suffering from obesity, insulin hypersensitivity, and diabetes, and is caused by a rise in the concentration of free fatty acids in the blood due to insulin resistance or excessive fat breakdown.
현재 지방간을 약물학적으로 치료하는데 유용한 약제는 거의 없는 상태이며 운동과 식이요법만이 권장되고 있기 때문에 지방간 치료제 개발이 요구된다.Currently, few medications are available for the pharmacological treatment of fatty liver, and only exercise and diet are recommended.
한편 천연물질로부터 항 콜레스테롤 작용 또는 지방간 치료 효과를 갖는 유효물질을 찾고자 하는 연구가 다수 보고되었다. 예를 들어, 대한민국 특허등록 제 10-0640094호는 녹차씨유를 유효성분으로 함유하는 조성물에 관한 것으로, 녹차씨유가 혈장 콜레스테롤 농도를 저하시키며, 간의 지질과산화 정도를 유의적으로 감소시킴에 의해 고지방식이 섭취에 따른 산화적 스트레스를 방어하는 효과가 있으므로, 이를 포함하는 조성물은 고지혈증 또는 산화적 스트레스로 인한 질환의 예방 및 치료를 위한 약학 조성물 및 건강기능식품으로 유용하게 이용될 수 있다고 개시하고 있다. 또한 대한민국 특허공개 제 2013-0110929호는 감람나무 열매 추출물 및 이로부터 분리된 알칼로이드계 화합물은 생체 내 안정성을 가지고 있으며, ANT1 효소의 활성을 증가시키고, 지방간 동물모델의 간조직 내에서 지방산화를 촉진하고 이로 인해 지방축적 및 중성지방 생성을 효과적으로 억제함으로써, 지방간, 특히 비알코올성 지방간에 대한 예방 또는 치료에 유용하게 사용할 수 있다고 개시하고 있다. On the other hand, a number of studies have been reported to find an effective substance having an effect of treating cholesterol or fatty liver from natural substances. For example, Korean Patent Registration No. 10-0640094 relates to a composition containing green tea seed oil as an active ingredient, wherein the green tea seed oil lowers the plasma cholesterol concentration and significantly reduces the lipid peroxidation degree of the liver, Method has an effect of preventing oxidative stress due to ingestion, it has been disclosed that a composition containing the same can be effectively used as a pharmaceutical composition and a health functional food for the prevention and treatment of diseases caused by hyperlipidemia or oxidative stress . Korean Patent Laid-Open Publication No. 2013-0110929 discloses that the extract of olive tree and the alkaloid compounds separated therefrom have in vivo stability, increase the activity of ANT1 enzyme, promote lipid oxidation in liver tissue of liver animal model Thereby effectively inhibiting lipid accumulation and triglyceride production, thereby being useful for preventing or treating fatty liver, especially non-alcoholic fatty liver.
이에 본 발명자들은 천연물로부터 항 콜레스테롤 활성 또는 지방간 치료 효과를 갖는 신물질을 찾고자 예의 연구 노력한 결과, 감람나무 열매추출물에서 항 콜레스테롤 활성이 강한 분획을 추출하고 상기 분획이 혈중 콜레스테롤 농도를 효과적으로 저해하여 고지혈증, 고혈압, 뇌혈관 장애, 심질환, 비알코올성 지방간 등의 예방 및 치료용으로 유용하게 사용될 수 있음을 밝힘으로써 본 발명을 완성하였다.Accordingly, the present inventors have made intensive studies to find a new substance having an anticholesterol activity or a fatty liver therapeutic effect from a natural product. As a result, they have found that a fraction having a strong anticholesterol activity is extracted from an olive fruit extract and the fraction effectively inhibits the blood cholesterol concentration, , Cerebrovascular disorder, cardiovascular disease, nonalcoholic fatty liver, etc. The present invention has been completed based on this finding.
상기 목적을 달성하기 위해 본 발명은 In order to achieve the above object,
감람나무 열매 추출물을 유효성분으로 함유하는 지방간 및 고지혈증의 예방 및 치료용 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition for prevention and treatment of fatty liver and hyperlipidemia containing an olive fruit extract as an active ingredient.
또한 본 발명은 하기 화학식 1의 하이드록시타이로솔을 유효성분으로 함유하는 지방간 및 고지혈증의 예방 및 치료용 약학 조성물을 제공한다.The present invention also provides a pharmaceutical composition for the prevention and treatment of fatty liver and hyperlipemia, which comprises a hydroxythiazol as an active ingredient.
[화학식 1][Chemical Formula 1]
또한 본 발명은 감람나무 열매 추출물을 유효성분으로 함유하는 지방간 및 고지혈증의 개선용 식품 조성물을 제공한다.The present invention also provides a food composition for improving fatty liver and hyperlipidemia containing olive fruit extract as an active ingredient.
또한 본 발명은 상기 화학식 1의 하이드록시타이로솔을 유효성분으로 함유하는 지방간 및 고지혈증의 예방 및 치료용 개선용 식품 조성물을 제공한다.The present invention also provides a food composition for the prevention and treatment of fatty liver and hyperlipemia, which comprises the hydroxytorose of Formula 1 as an active ingredient.
본 발명의 감람나무 열매 추출물은 고지질식이로 콜레스테롤과 저밀도 지단백의 수치가 증가한 랫트에서 혈중 콜레스테롤과 저밀도 지단백 농도를 감소시키고, 지방간 동물모델에서 콜레스테롤과 중성지방의 수치 감소 효과가 우수하여 지방간 및 고지혈증의 예방 및 치료를 위한 약학적 조성물로 이용 가능할 뿐만 아니라, 지방간 및 고지혈증 예방 및 개선용 건강기능식품, 건강보조식품에 유용하게 이용될 수 있을 것으로 기대된다.The extract of olive tree of the present invention reduces blood cholesterol and low density lipoprotein levels in rats in which high cholesterol and low density lipoprotein levels are increased and has an excellent effect of reducing the cholesterol and triglyceride levels in an animal model of fatty liver, The present invention is expected to be useful not only as a pharmaceutical composition for the prevention and treatment of hyperlipemia, but also as a health functional food and a health supplement food for prevention and improvement of fatty liver and hyperlipidemia.
도 1은 감람나무 열매 추출물의 HPLC 분석 스펙트럼을 나타낸 도이다.
도 2는 본 발명에 따른 감람나무 열매 추출물의 H＆E 염색을 통한 지방간 개선 효과를 도시한 사진이다.
도 3은 고지질식이 투여로 인한 비만 랫트의 간기능을 나타내는 전이효소(AST, ALT)의 감람나무 열매 추출물 투여에 따른 변화를 측정한 그래프이다. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an HPLC analysis spectrum of olive fruit extract. FIG.
2 is a photograph showing the effect of the olive tree fruit extract according to the present invention on the improvement of fatty liver through H & E staining.
FIG. 3 is a graph showing changes in transit enzyme (AST, ALT) indicating liver function in obese rats due to administration of high fat diet according to administration of olive fruit extract.
본 발명은 감람나무 열매 추출물 및 이로부터 분리된 하기 화학식 1의 하이드록시타이로솔을 유효성분으로 포함하는 지방간 및 고지혈증의 예방 또는 치료용 조성물을 제공한다:The present invention provides a composition for prevention or treatment of fatty liver and hyperlipidemia comprising olive fruit extract and hydroxytorrosol of the following formula 1 as an active ingredient:
[화학식 1][Chemical Formula 1]
상기 조성물은 약학적 조성물 또는 식품 조성물을 포함한다.The composition comprises a pharmaceutical composition or a food composition.
본 발명의 감람나무(Olea europaea LINN) 열매 추출물은 하기와 같은 방법으로 얻을 수 있다. 감람나무 열매를 물로 세척하여 이물질을 제거한 후 그늘에서 건조하고 분쇄한다. 감람나무 열매는 재배한 것 또는 시판되는 것 등을 제한 없이 사용할 수 있다. 분쇄된 감람나무 열매에 적당한 양의 용매를 가하여 완전히 침지되도록 하여 감람나무 열매는 추출물을 수득한다. 추출 방법은 실온The olive tree extract ( Olea europaea LINN) of the present invention can be obtained by the following method. The olive fruit is washed with water to remove foreign matter, dried in the shade and crushed. The olive tree can be cultivated or marketed without restriction. The appropriate amount of solvent is added to the crushed olive fruit so as to be completely immersed so that the olive fruit extract is obtained. The extraction method was performed at room temperature
에서 함침 하거나 가온할 수 있다. 상기 추출 용매는 이에 제한되지 않으나, 물, 탄소수 1 내지 4의 알코올, 이들의 혼합용매로부터 선택된 1 종 이상의 용매를 이용할 수 있으며, 바람직하게는 메탄올 또는 에탄올이며, 더욱 바람직하게는 에탄올이다. 상기 감람나무 열매 추출물을 여과 및 농축한 후, 헥산, 클로르포름, 및 에틸아세테이트 순차적으로 분획하여 분획물을 얻는다. 상기 분획물 중 에틸아세테이트 분획물이 가장 우수한 항 콜레스테롤 활성 및 지방간 치료 효과를 나타내었다.Impregnated or warmed. The extraction solvent is not limited thereto, but at least one solvent selected from water, an alcohol having 1 to 4 carbon atoms, and a mixed solvent thereof may be used, preferably methanol or ethanol, more preferably ethanol. The olive fruit extract is filtered and concentrated, and then hexane, chloroform, and ethyl acetate are sequentially fractionated to obtain fractions. Among these fractions, the ethyl acetate fraction showed the best anticholesterol activity and fatty liver therapeutic effect.
상기 감람나무 열매 에틸아세테이트 분획물으로부터 액체 크로마토그래피를 이용하여 활성 물질을 분리하였으며, 활성물질이 하이드록시타이로솔임을 확인하였다.The active material was isolated from the olive ethyl acetate fraction using liquid chromatography to confirm that the active substance was hydroxytorosol.
본 발명에서 사용하는 크로마토그래피는 이에 제한되지 않으나, 실리카겔 칼럼 크로마토그래피(silica gel column chromatography), LH-20 칼럼 크로마토그래피(LH-20 column chromatography), 박층 크로마토그래피Chromatography used in the present invention is not limited to this, but silica gel column chromatography, LH-20 column chromatography, thin layer chromatography
(TLC; Thin layer chromatography) 또는 고성능 액체 크로마토그래피(high performance liqid chromatography)등이 이용될 수 있다.(TLC) or high performance liqid chromatography may be used.
본 발명에 따른 감람나무 열매 추출물 및 이로부터 분리된 하이드록시타이로솔은 고지질식이로 콜레스테롤과 저밀도 지단백의 수치가 증가한 랫트에서 혈중 콜레스테롤과 저밀도 지단백 농도를 감소시키고, 지방간 동물모델의 간 조직 내에서 콜레스테롤 및 중성지방의 생성을 효과적으로 억제한다.The extract of olive tree and the hydroxytorosol isolated therefrom according to the present invention reduce blood cholesterol and low density lipoprotein levels in rats having high levels of cholesterol and low density lipoprotein, Effectively inhibits the production of cholesterol and triglycerides.
따라서, 본 발명에 따른 감람나무 열매 추출물 및 이로부터 분리된 하이드록시타이로솔은 고지혈정, 지방간 특히 비알코올성 지방간의 예방 또는 치료에 유용한 의약품 또는 건강기능식품으로 사용될 수 있다.Therefore, the olive fruit extract according to the present invention and the hydroxytorrosol separated therefrom can be used as medicines or health functional foods useful for the prevention or treatment of high-fat diets, fatty acids, especially non-alcoholic fatty liver.
본 발명의 조성물은 감람나무 열매 추출물 및 이로부터 분리된 하이드록시타이로솔 단독으로 사용하거나 또는 다른 약학적 활성 화합물과의 결합체나 집합체의 형태로도 사용할 수 있다.The composition of the present invention can be used alone as an extract of olive tree and hydroxytolysol separated therefrom, or in the form of a combination or aggregate with other pharmaceutically active compounds.
본 발명의 조성물의 유효성분인 감람나무 열매 추출물 및 이로부터 분리된 하이드록시타이로솔은 다른 공지된 고지혈증, 지방간의 예방 또는 치료 약물과 혼합하여 복합제제 형태로 제형화하여 투여할 수 있다.The olive extract of the present invention, which is an active ingredient of the composition of the present invention, and the hydroxytorrosol isolated therefrom can be formulated in combination with other known drugs for preventing or treating hyperlipidemia and fatty liver and administered in the form of a combined preparation.
본 발명의 조성물은 고지혈증, 지방간의 예방 또는 치료를 위하여 단독으로, 또는 수술, 방사선 치료, 호르몬 치료, 화학 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다. The composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers for the prevention or treatment of hyperlipidemia and fatty liver.
본 발명의 약학 조성물는 조성물 총 중량에 대하여 상기 유효성분을 0.0001 내지 50 중량%로 포함할 수 있다. The pharmaceutical composition of the present invention may contain the active ingredient in an amount of 0.0001 to 50% by weight based on the total weight of the composition.
본 발명의 조성물은 투여를 위해서 상기 기재한 유효 성분 이외에 추가로 약제학적으로 허용 가능한 담체를 1종 이상 포함하여 약제학적 조성물로 바람직하게 제제화할 수 있다. 액상 용액으로 제제화되는 조성물에 있어서 허용 가능한 약제학적 담체로는, 멸균 및 생체에 적합한 것으로서, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사용액, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한, 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있으며, 표적 기관에 특이적으로 작용할 수 있도록 표적 기관 특이적 항체 또는 기타 리간드를 상기 담체와 결합시켜 사용할 수 있다. The composition of the present invention may be formulated into pharmaceutical compositions containing at least one pharmaceutically acceptable carrier in addition to the above-described active ingredients for administration. Acceptable pharmaceutical carriers for compositions that are formulated into a liquid solution include those suitable for sterilization and in vivo such as saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, One or more of these components may be mixed and used. If necessary, other conventional additives such as an antioxidant, a buffer, and a bacteriostatic agent may be added. In addition, it can be formulated into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like by additionally adding diluents, dispersants, surfactants, binders and lubricants, A target organ specific antibody or other ligand can be used in combination with the carrier.
본 발명의 조성물은 인간을 포함한 포유동물에 다양한 경로로 투여될 수 있다. 예를 들면, 정맥내, 동맥내, 복강내, 근육내, 복강내, 흉골내, 경피, 비측내, 흡입, 국소, 직장, 경구, 안구내 또는 피하내 경로를 통해 통상적인 방식이 가능하다. 이때, 투여방법은 특별히 이에 제한되는 것은 아니나, 비경구투여가 바람직하여, 피하내 투여가 더욱 바람직하다. The compositions of the present invention can be administered to mammals, including humans, by a variety of routes. For example, conventional routes are possible via intravenous, intraarterial, intraperitoneal, intramuscular, intraperitoneal, intrasternal, percutaneous, intranasal, inhalation, topical, rectal, intraoral or subcutaneous routes. At this time, the administration method is not particularly limited, but parenteral administration is preferable, and subcutaneous administration is more preferable.
본 발명에 따른 약학 조성물의 투여량은 질환의 종류, 질환의 중증도, 조성물에 함유된 유효 성분 및 다른 성분의 종류 및 함량, 제형의 종류 및 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율, 치료기간, 동시 사용되는 약물을 비롯한 다양한 인자에 따라 조절될 수 있다. 그러나, 바람직한 효과를 위해서, 본 발명의 조성물은 성인의 경우 감람나무 열매 추출물 및 이로부터 분리된 하이드록시타이로솔을 1일 1회 0.01㎍/kg/day~100㎍/kg/day, 바람직하게는 0.01㎍/kg/day~10㎍/kg/day의 용량으로 투여할 수 있다. 이때, 투여는 하루에 한번 투여할 수도 있고, 수회에 나누어 투여할 수 도 있다. The dosage of the pharmaceutical composition according to the present invention may vary depending on the kind of the disease, the severity of the disease, the kind and amount of the active ingredient and other ingredients contained in the composition, the type of the formulation and the age, body weight, The time of administration, the route of administration and the rate of administration of the composition, the duration of the treatment, the drugs used concurrently, and the like. However, in order to obtain the desired effects, the composition of the present invention is preferably applied to the adult in an amount of 0.01 / / kg / day to 100 / / kg / day once a day, preferably from the olive tree fruit extract and the hydroxy thyrosol separated therefrom Can be administered at a dose of 0.01 μg / kg / day to 10 μg / kg / day. In this case, the administration may be carried out once a day or divided into several times.
본 발명에서, 건강기능식품이란 질병의 예방 및 치료, 생체방어, 면역, 병후의 회복, 노화 억제 등 생체조절기능을 가지는 식품을 말하는 것으로, 장기적으로 복용하였을 때 인체에 무해하여야 한다.In the present invention, a health functional food refers to a food having a biological control function such as prevention and treatment of disease, bio-defense, immunity, recovery after disease, aging suppression, and should be harmless to human body when taken over a long period of time.
본 발명의 조성물은 고지혈증, 지방간의 예방 또는 개선을 목적으로 건강기능식품에 첨가될 수 있다. 본 발명의 조성물을 식품 첨가물로 사용할 경우, 상기 조성물을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 사용 목적 (예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 일반적으로, 식품 또는 음료의 제조 시에 본 발명의 조성물은 원료에 대하여 15중량 % 이하, 바람직하게는 10 중량 % 이하의 양으로 첨가된다. 그러나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.The composition of the present invention may be added to a health functional food for the purpose of prevention or improvement of hyperlipemia and fatty liver. When the composition of the present invention is used as a food additive, the composition can be added as it is or can be 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 (prevention, health or therapeutic treatment). In general, the composition of the present invention is added in an amount of not more than 15% by weight, preferably not more than 10% by weight based on the raw material, in the production of food or beverage. However, in the case of long-term intake for the purpose of health and hygiene 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.
또한, 지방간 및 고지혈증의 예방 및 개선을 위한 목적으로 산제, 과립제, 정제, 캡슐제, 환제, 현탁액, 에멀젼, 시럽 등의 약학투여형태 또는 건강음료 등의 형태인 건강기능식품 및 건강보조식품으로의 제조 및 가공이 가능하다.In addition, for the purpose of prevention and improvement of fatty liver and hyperlipemia, it is possible to use pharmaceutical dosage forms such as powders, granules, tablets, capsules, pills, suspensions, emulsions and syrups or health functional foods and health supplements in the form of health drinks Manufacturing and processing are possible.
본 발명의 기능성 건강음료 조성물은 지시된 비율로, 필수 성분으로서 상기 추출물을 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(포도당, 과당 등), 디사카라이드(말토스, 슈크로스 등), 및 폴리사카라이드(덱스트린, 시클로덱스트린 등)와 같은 통상적인 당과 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 100mL당 일반적으로 약 1~20g, 바람직하게는 약 5~12g이다.The functional health beverage composition of the present invention is not limited to any other components other than those containing the extract as an essential ingredient at the indicated ratios and may contain various flavors or natural carbohydrates as additional components such as ordinary beverages . Examples of the above-mentioned natural carbohydrates include conventional sugars such as monosaccharides (glucose, fructose, etc.), disaccharides (maltose, sucrose etc.) and polysaccharides (dextrin, cyclodextrin and the like), xylitol, sorbitol, And sugar alcohols such as erythritol. Natural flavors (tautatin, stevia extract, for example, 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 mL of the composition of the present invention.
상기 외에 본 발명의 조성물은 여러가지 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, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 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 aging agents (cheese, chocolate etc.), pectic 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.
또한 본 발명의 조성물들은 천연 과일 쥬스, 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있으며, 이에 한정되지 않는다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 제한이 없으나, 본 발명의 조성물 100 중량부 당 0 내지 20 중량부의 범위에서 선택되는 것이 일반적이다.The compositions of the present invention may also include, but are not limited to, flesh for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The ratio of such additives is not limited, but is generally selected in the range of 0 to 20 parts by weight per 100 parts by weight of the composition of the present invention.
또한, 본 발명의 감람나무 열매 추출물 및 이로부터 분리된 하이드록시타이로솔은 지방간 및 고지혈증의 예방 효과를 목적으로 식품 또는 음료에 첨가될 수 있다. 이때, 식품 또는 음료 중의 상기 추출물의 양은 전체 식품 중량의 0.01 내지 15 중량%로 가할 수 있으며, 건강 음료 조성물은 100mL를 기준으로 0.02 내지 5g, 바람직하게는 0.3 내지 1g의 비율로 가할 수 있다.
The olive fruit extract of the present invention and the hydroxytorrosol separated therefrom can be added to foods or beverages for the purpose of preventing fatty liver and hyperlipemia. At this time, the amount of the extract in the food or beverage may be 0.01 to 15% by weight of the total food, and the health drink composition may be added in a proportion of 0.02 to 5 g, preferably 0.3 to 1 g, based on 100 mL.
이하 본 발명의 바람직한 실시예를 기재한다. 하기 실시예는 본 발명을 보다 명확히 표현하기 위한 목적으로 기재될 뿐 본 발명의 내용이 하기 실시예에 한정되는 것은 아니다.
Hereinafter, preferred embodiments of the present invention will be described. The following examples are provided for the purpose of more clearly illustrating the present invention and are not intended to limit the scope of the present invention.
실시예Example 1: One: 감람나무 열매Olive 추출물 제조 Extract preparation
감람나무 열매 추출물을 얻기 위해서 아래와 추출공정을 진행하였다.In order to obtain the olive fruit extract, the following extraction process was carried out.
준비된 감람나무 열매 열매 시료경동시장에서 10 kg을 구입하였고, 그 중 1kg을 블렌더로 처리한 다음, 1 리터 병에 시료 100g을 넣었다. 75% 에탄올을 용기에 넣었다 (1L 기준-에탄올 750+ D.W 250). 3일 동안 37℃에서 shaking incubation한 다음, 3일 동안 incubation된 시료를 여과하였다(Vaccume 이용, filter paper size 2). 여과된 시료를 농축을 하였다(EYELA Rotary evaporator N-1000을 이용). 농축이 완료된 시료는 3~4일 동안 동결 건조를 하였다(-40℃ 이하, vaccum5~10 조건을 유지하는지 수시로 확인, 농축이 완료 된 후 바로 동결건조를 시키지 못하는 경우 시료를 4℃에서 보관). Prepared olive fruit fruit sample 10 kg was purchased in the market, 1 kg of which was treated with blender, and 100 g of sample was added to a 1 liter bottle. 75% ethanol was placed in a container (1 liter based on ethanol 750 + D.W 250). After shaking incubation at 37 ° C for 3 days, the samples incubated for 3 days were filtered (using Vaccume, filter paper size 2). The filtered sample was concentrated (using an EYELA Rotary evaporator N-1000). After concentration, the samples were lyophilized for 3 ~ 4 days (-40 ℃ or lower, vaccum 5-10). If samples were not freeze-dried immediately after concentration was completed, samples were stored at 4 ℃.
이 동결건조된 시료(180g)에 에탄올 수용액(10 v/v%)을 가하여 현탁하고, n-헥산, 클로로포름 및 에틸아세테이트 순으로 분획하여 n-헥산 가용추출물, 클로로포름 가용추출물, 에틸아세테이트 가용추출물 및 물 가용추출물을 수득하였다. 이때, 분별 추출은 분별 깔데기 등을 이용하여 추출하였다. n-헥산, 클로로포름 및 에틸아세테이트를 순서대로 이용하여 분별 추출하여 n-헥산 가용추출물(34.5 g/100 g), 클로로포름 가용추출물(4.5g/100 g), 에틸아세테이트 가용추출물 (55.6 g/100 g)을 수득하였다.To this lyophilized sample (180 g), an aqueous ethanol solution (10 v / v%) was added and suspended. The suspension was fractionated in the order of n-hexane, chloroform and ethyl acetate and extracted with n-hexane soluble extract, chloroform soluble extract, ethyl acetate soluble extract A water soluble extract was obtained. At this time, fractional extraction was performed using a fractionation funnel. (34.5 g / 100 g), chloroform-soluble extract (4.5 g / 100 g) and ethyl acetate-soluble extract (55.6 g / 100 g) were obtained by fractional extraction using n-hexane, chloroform and ethyl acetate, ).
상기에서 얻은 감람나무 열매의 추출물을 헥산으로 분획하여 비극성 부분을 분리하고, 남은 수층을 에틸아세테이트로 분획하여 감압 농축하였다. 이렇게 극성별로 나누어진 헥산층, 에틸아세테이트층, 물층의 분획들에서 에틸아세테이트분획을 실리카 겔로 세 분획 하고 다시 여러 컬럼 크로마토그래피를 이용하여 각각의 세 분획에서 계속하여 유효성분들을 분리하였다. 분획 및 물질의 분리는 실리카 겔뿐 아니라, sephadex LH-20, ODS-A, diol, preparative MPLC, 또는 preparative HPLC 등의 다양한 크로마토그래피법을 이용하여 시행하였다.The extract of the olive tree obtained above was fractionated with hexane to separate the non-polar portion, and the remaining aqueous layer was fractionated with ethyl acetate and concentrated under reduced pressure. The ethylacetate fractions in the hexane layer, the ethyl acetate layer, and the water layer were divided into three fractions by silica gel, and the fractions were separated from each other by various column chromatography. Separation of fractions and materials was carried out using various chromatographic methods such as sephadex LH-20, ODS-A, diol, preparative MPLC, or preparative HPLC as well as silica gel.
본 발명에 따른 감람나무 열매의 추출물을 극성에 따라 분획하고 각각의 분획에서 에틸아세테이트 분획 실리카 겔을 포함한 여러 가지 column을 사용하여 분리를 시도하여 1D NMR과 2D NMR 방법을 이용하여 구조를 동정하고 LC/MS, UV, IR과 같은 최신 기기를 사용하여 단일 물질의 구조 확인을 완료하였다. 상기의 절차에 의해 분획된 단일물질은 첨부된 화학식 1의 하이드록시타이로솔이 포함되어 있었다(도 1 참조).
The extracts of olive fruit according to the present invention were fractionated according to the polarity and the fractions were fractionated using various columns including ethyl acetate fraction silica gel in each fraction. The structure was identified using 1D NMR and 2D NMR, / MS, UV, and IR to complete structural verification of a single material. The single material fractionated by the above procedure contained the hydroxythiazole of the formula (1) (see FIG. 1).
실험예 1: 동물실험을 통한 고지혈증 예방및치료효과확인Experimental Example 1: Prevention and treatment effect of hyperlipidemia through animal experiment
실험동물은 8주령 웅성 SD계 랫트(~250g)를 4주 동안 고지혈증을 유도하기 위하여 5.5 wt% 옥수수유, 2 wt% 콜레스테롤, 1 wt% 콜산, 91.5 wt% 일반사료를 함유한 고지질 식이(western diet)를 실시하였다. Experimental animals were fed a high fat diet containing ~ 5.5 wt% corn oil, 2 wt% cholesterol, 1 wt% cholic acid, and 91.5 wt% general feed to induce hyperlipidemia in male SD rats (~ 250 g) western diet).
상기 실시예 1에서 얻은 감람나무 열매 추출물의 효과를 검증하기 위하여 1 군(일반식이+vehicle), 2 군(고지질 식이 diet+vehicle), 3 군(고지질 식이 +감람나무 열매추출물; 0.1g/kg), 4 군(고지질 식이 +감람나무 열매추출물; 0.3g/kg)로 총 4 군으로 구분하였다. 일반식이는 표준 랫트 사료로 단백질(~14 wt%), 지방(~10 wt%)과 탄수화물(~76 wt%)를 함유한다. In order to examine the effect of the olive fruit extract obtained in Example 1, Group 1 (general diet + vehicle), Group 2 (high diet diet + vehicle), Group 3 (high fat diet + olive fruit extract; / kg), group 4 (high fat diet + olive fruit extract; 0.3g / kg). The standard diet contains protein (~ 14 wt%), fat (~ 10 wt%) and carbohydrate (~ 76 wt%) as standard rat feed.
식이는 28일 동안 매일 오전에 물 또는 감람나무 열매 추출물(0.1g/kg 또는 0.3g/kg)을 경구투여(oral gavage) 하였다. 각 그룹의 랫트를 마취한 후 안와정맥혈을 통해 채혈한 후 혈장 분리를 위해 상온에서 30분간 인큐베이션 후 4℃에서 1500g로 15분간 원심분리를 2회 실시한 후 상층액을 획득한 다음 혈액생화학분석기(Hitachi)를 통해 총 콜레스테롤, LDL-콜레스테롤, HDL-콜레스테롤 및 중성지질(TG)를 분석하였다. 그 결과는 아래 표 1에 나타내었다. Diets were orally gavaged with water or olive extract (0.1 g / kg or 0.3 g / kg) daily in the morning for 28 days. Each rat was anesthetized and blood was collected through orbital venous blood. After the incubation at room temperature for 30 minutes, plasma was separated from the orbit by centrifugation at 1500g for 15 minutes for 15 minutes. After obtaining the supernatant, a blood biochemical analyzer ), Total cholesterol, LDL-cholesterol, HDL-cholesterol and triglyceride (TG) were analyzed. The results are shown in Table 1 below.
투여군Highland Choke
Administered group
상기 표 2의 결과에 나타낸 바와 같이, 고지질 식이에 의해 콜레스테롤과 저밀도 지단백의 수치가 증가하였지만, 감람나무 열매 추출물 투여에 의해 증가된 혈중 콜레스테롤과 저밀도 지단백 수치가 유의하게 감소되었다.
As shown in the results of Table 2 above, the high fat diet increased the levels of cholesterol and low density lipoprotein, but the increase in blood cholesterol and low density lipoprotein levels was significantly reduced by the administration of olive oil extract.
실험예 2: 동물실험을 통한 비알코올성지방간 예방및치료효과확인Experimental Example 2: Prevention and treatment effect of nonalcoholic fatty liver through animal experiment
지방간 모델에서 감람나무 열매의 지방간 억제 활성을 확인하기 위해 in vivo 지방간 모델을 유도하여 실험하였다. 5주령 웅성 SD계 랫트를 구입하여 일주일간 실험실 환경에서 순화시킨 뒤 4주간 고지방식이 실험에 사용하였다. 각 군의 실험식이 조성은 아래 표 1에 나타내었다. 16시간 절식 후 에테르 마취 하에 개복하여 복부 대동맥에서 채혈한 후 상온에서 30분간 방치한 후 1500rpm 10간 원심 분리한 다음 혈청을 분리하였다. 분리된 혈청에서 TG(Triglycerides), LDL(low-density lipoproteins)을 kit(아산제약)을 통해 측정하고, 혈청 내 AST, ALT, total cholesterol, ALP는 혈액분석기 Express PLUS(CHIRON, DIAGNOSTIC, USA)를 통해 AST, ALT를 측정하였다. 체중은 실험 시작 시점부터 매 2주간 측정하며, 최종투여 후 간을 적출하여 간의 무게를 측정하여 체중/간 의 비를 계산하였다(표 3). 간 조직내 총 지질(total lipid)과 콜레스테롤, 트리글리세라이드를 측정하기 위하여, 간조직을 균질화하여 얻은 샘플을 원심분리한 후 kit(아산제약)을 사용하여, 지방간 개선효과를 확인하였다(표 4). 분리된 혈청에서 TG(Triglycerides), AST, ALT, 총 콜레스테롤, ALP를 측정하였다. 또한, 간 조직내 지방을 확인하여, 단계별로 점수표를 작성하고 이를 통해 결과를 확인하였으며, 간 조직내 MDA(지질과산화 물)의 양을 측정하여, 지방간 개선효과를 확인하였다.To investigate the fatty liver inhibitory activity of olive fruit in the fatty liver model, in vivo fatty liver model was induced and tested. Five week old male SD rats were purchased and refined in a laboratory environment for one week, followed by 4 weeks of high fat diet. The composition of each experimental group is shown in Table 1 below. After abstinence for 16 hours, it was opened under ether anesthesia, and blood was collected from the abdominal aorta, left at room temperature for 30 minutes, centrifuged at 1500 rpm for 10 minutes, and serum was separated. Serum AST, ALT, total cholesterol, and ALP were measured using a blood analyzer, Express PLUS (CHIRON, DIAGNOSTIC, USA), and serum TG (Triglycerides) and low-density lipoproteins (LDL) AST and ALT were measured. Body weights were measured every 2 weeks from the beginning of the experiment, and after the final administration, the liver was weighed to determine the body weight / liver ratio (Table 3). In order to measure total lipid, cholesterol and triglyceride in liver tissues, samples obtained by homogenizing liver tissues were centrifuged and the fatty liver improvement effect was confirmed using kit (Asan Pharmaceutical Co., Ltd.) (Table 4) . TG (Triglycerides), AST, ALT, total cholesterol and ALP were measured in the separated serum. In addition, the fat in the liver tissues was identified, and a scoring table was created at each step. The results were confirmed, and the amount of MDA (lipid peroxide) in the liver tissue was measured to confirm the effect of improving the liver.
각 그룹의 마우스 간을 획득하였다. 각 그룹별로 획득된 마우스 간을 10% 포름알데하이드로 고정 후 파라핀 블록을 제작하고 마이크로 절편기로 잘라 조직절편을 획득하여 H＆E(Hematoxylin ＆ Eosin) 염색을 실시한 후 지방간 형성 및 개선 효과를 분석하였다. The mice of each group were obtained. Paraffin blocks were prepared with 10% formaldehyde in each mouse group, and cut with a micro - slicer to obtain histological sections. After hematoxylin & Eosin (H & E) staining, the formation and improvement of fatty liver were analyzed.
(5 wt% 옥수수유, 1 wt% 콜레스테롤, 0.5 wt% 콜산, 93.5 wt% 일반사료)Highland Choke
(5 wt% corn oil, 1 wt% cholesterol, 0.5 wt% cholic acid, 93.5 wt% general feed)
도 2는 본 발명에 따른 감람나무 열매 추출물의 H＆E 염색을 통한 지방간 개선 효과를 도시한 사진이다. 이때 A는 정상대조군, B는 대조군, C는 고지질식이와 함께 감람나무 열매 추출물 0.1g/kg 투여군, D는 고지질식이와 함께 감람나무 열매 추출물 0.3g/kg 투여군이다. 2 is a photograph showing the effect of the olive tree fruit extract according to the present invention on the improvement of fatty liver through H & E staining. At this time, A is a normal control group, B is a control group, C is a group of 0.1 g / kg of olive fruit extract together with a high fat diet group, and D is a group of 0.3 g / kg of olive fruit extract together with a high fat diet.
도 2를 참조하면, 고지질식이만 투여한 대조군(B)은 간조직에 약간의 지방층이 생겨 지방간이 유도된 것으로 사료되며, 고지질식이와 함께 감람나무 열매 추출물을 투여한 실험군(C, D)에서는 간조직에 지방층이 대조군(B)보다 덜 나타나는 것으로 보아 감람나무 열매 추출물의 투여로 지방간을 억제함을 알 수 있었다.2, the control group (B), which was administered with only high fat diet, was considered to have induced a fatty layer due to a slight fat layer in the liver tissue. In the experiment group (C, D ) Showed that fat layer was less in liver tissue than control group (B).
(mg/g)cholesterol
(mg / g)
(mg/g)TG
(mg / g)
(U/L)ALP
(U / L)
(umol/g liver)MDA
(umol / g liver)
도 3은 정상대조군, 대조군, 감람나무 열매 추출물 투여군의 AST(GOT), ALT(GPT) 수치를 측정한 결과를 나타낸 그래프이다. FIG. 3 is a graph showing the results of measurement of AST (GOT) and ALT (GPT) values of a normal control group, a control group and an olive fruit extract-administered group.
도 3의 결과에 나타난 바와 같이, 지방간의 유도로 인하여 AST(GOT), ALT(GPT) 큰 폭의 상승은 있지 않았으나 감람나무 열매 추출물의 투여로 유의성 있게 낮추어 주는 것으로 나타났다. 그러나 표 4를 참조하면, 콜레스테롤, 중성지방(Triglycerides), ALP, MDA 등은 대조군의 수치가 상승하였으며, 감람나무 열매 추출물의 투여로 유의성 있게 낮추어 줌을 나타내고 있다.
As shown in FIG. 3, there was no significant increase in AST (GOT) and ALT (GPT) due to the induction of fatty liver, but it was significantly lowered by the administration of olive fruit extract. However, referring to Table 4, the values of cholesterol, triglycerides, ALP, MDA and the like were increased in the control group and significantly lowered by the administration of the olive fruit extract.
<제제예 1: 약학적 제제예><Formulation Example 1: Example of pharmaceutical preparation>
1-1. 정제의 제조1-1. Manufacture of tablets
실시예 1의 감람나무 열매 추출물 60 mg60 mg of the olive fruit extract of Example 1
규산칼슘 20 mg
유당 130 mgLactose 130 mg
미결정셀룰로오스 100 mg
스테아린산마그네슘 적량Magnesium stearate qs
탈크 적량Talc quantity
코팅제 적량Coating agent amount
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.
1-2. 캅셀제의 제조1-2. Manufacture of capsules
실시예 1의 감람나무 열매 추출물 60 mg60 mg of the olive fruit extract of Example 1
유당 160 mgLactose 160 mg
전분 적량Starch content
통상의 캅셀제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캅셀제를 제조한다.
The above components are mixed in accordance with a conventional method for producing a capsule, and filled in a gelatin capsule to prepare a capsule.
1-3. 연질캅셀제의 제조1-3. Preparation of Soft Capsules
실시예 1의 감람나무 열매 추출물 60mg60 mg of the olive fruit extract of Example 1
트윈 80 175mg
PEG400 190mgPEG400 190 mg
프로필렌 카보네이트 100mg
프로필렌글리콜 적량Propylene glycol q.s.
폴록사머 407 적량Poloxamer 407 qs
통상의 연질캅셀제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캅셀제를 제조한다.
The above components are mixed according to a conventional method for preparing a soft capsule, and filled in a gelatin capsule to prepare a capsule.
<제제예 2 : 식품 제조예>≪ Formulation Example 2: Food preparation example >
2-1. 건강식품의 제조2-1. Manufacture of health food
실시예 1의 감람나무 열매 추출물 1000 ㎎1000 mg of the olive fruit extract of Example 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 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 ㎎
24.8 mg of magnesium chloride
2-1. 음료의 제조2-1. Manufacturing of beverages
꿀 0.26 중량%, 치옥토산아미드 0.0002 중량%, 니코틴산아미드 0.0004 중량%, 염산리보플라빈나트륨 0.0001 중량%, 염산피리독신 0.0001 중량%, 이노시톨 0.001 중량%, 오르트산 0.002 중량% 및 물 89.7362 중량%와 실시예 1의 감람나무 열매 추출물 10 중량%을 배합하여 통상의 방법으로 음료를 제조하였다.0.0001% by weight of niacinamide, 0.0001% by weight of sodium riboflavin hydrochloride, 0.0001% by weight of pyridoxine hydrochloride, 0.001% by weight of inositol, 0.002% by weight of orthoacetic acid and 89.7362% by weight of water, 1 < / RTI > of olive oil extract was added to prepare a beverage in a conventional manner.
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