JP2001520993A - Acyl COA-cholesterol-O-acyltransferase inhibitors, inhibitors of macrophage-lipid complex accumulation on arterial walls and hesperidin and hesperetin as agents for preventing or treating liver diseases - Google Patents
Acyl COA-cholesterol-O-acyltransferase inhibitors, inhibitors of macrophage-lipid complex accumulation on arterial walls and hesperidin and hesperetin as agents for preventing or treating liver diseasesInfo
- Publication number
- JP2001520993A JP2001520993A JP2000517707A JP2000517707A JP2001520993A JP 2001520993 A JP2001520993 A JP 2001520993A JP 2000517707 A JP2000517707 A JP 2000517707A JP 2000517707 A JP2000517707 A JP 2000517707A JP 2001520993 A JP2001520993 A JP 2001520993A
- Authority
- JP
- Japan
- Prior art keywords
- hesperidin
- hesperetin
- composition
- use according
- food
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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Classifications
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- A—HUMAN NECESSITIES
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- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/52—Adding ingredients
- A23L2/56—Flavouring or bittering agents
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
(57)【要約】 本発明は、哺乳動物におけるアシルＣｏＡ−コレステロール−o−アシルトランスフェラーゼ抑制剤、動脈内皮上でのマクロファージ−脂質複合体形成の防止剤および肝疾患の予防または治療剤として有用なヘスペリジンまたはヘスペレチンの用途に関する。 (57) Abstract: The present invention is useful as an inhibitor of acyl-CoA-cholesterol-o-acyltransferase in mammals, an inhibitor of macrophage-lipid complex formation on arterial endothelium, and an agent for preventing or treating liver disease. It relates to the use of hesperidin or hesperetin.
Description
【０００１】発明の分野 本発明は、哺乳動物におけるアシルＣｏＡ−コレステロール−o−アシルトラ ンスフェラーゼ活性の抑制、動脈内皮上でのマクロファージ−脂質複合体蓄積の
抑制、および肝疾患予防または治療のためのヘスペリジンまたはヘスペレチンの
使用に関する。[0001] The present invention relates to a method for inhibiting acyl-CoA-cholesterol-o-acyltransferase activity in mammals, inhibiting macrophage-lipid complex accumulation on arterial endothelium, and preventing or treating liver diseases. It relates to the use of hesperidin or hesperetin.
【０００２】発明の背景 近来、動脈硬化および高コレステロール血症などのような冠状動脈性心臓血管
疾患が主要な死亡原因となっている。血中コレステロールの濃度が高いと、血管
壁に脂肪とともにマクロファージおよび泡沫細胞が沈着してプラークを形成して
動脈硬化症に至ると報告されている(Ross R., Nature, 362, 801-809(1993))。 血中コレステロールの量を減らす方法の一つは、コレステロールおよび脂肪の摂
取を減らす食餌療法である。他の方法は、コレステロールの吸収に係わる酵素を
抑制することによってコレステロールの吸収を阻止することによる。[0002] Background of the Invention Recently, coronary arterial cardiovascular disease, such as arteriosclerosis and hypercholesterolemia has become a major cause of death. It has been reported that high levels of blood cholesterol cause macrophages and foam cells to deposit with fat on blood vessel walls, form plaques, and lead to arteriosclerosis (Ross R., Nature, 362, 801-809 ( 1993)). One way to reduce the amount of blood cholesterol is a diet that reduces cholesterol and fat intake. Another method is by inhibiting cholesterol absorption by inhibiting enzymes involved in cholesterol absorption.
【０００３】 アシルＣｏＡ−コレステロール−o−アシルトランスフェラーゼ(Acyl CoA-cho
lesterol-o-acyltransferase、以下、ＡＣＡＴという)は、血中コレステロール のエステル化を促進する。泡沫細胞は、ＡＣＡＴ作用によって形成され、低密度
リポタンパク質によって運搬されるコレステロールエステルを多量含有している
。動脈血管壁上での泡沫細胞の形成は、ＡＣＡＴ活性に従って増進するため、Ａ
ＣＡＴ抑制剤は動脈硬化予防剤になり得る。また、ＬＤＬ-コレステロールの血 中濃度はＡＣＡＴ活性を抑制することによって低下すると報告されている(Witia
k, D. T. and D. R. Feller(eds), Antilipidemic Drugs : Medicinal, Chemica
l and Biochemical Aspects, Elsevier, pp159-195(1991))。[0003] Acyl CoA-cholesterol-o-acyltransferase (Acyl CoA-cho
lesterol-o-acyltransferase (ACAT) promotes the esterification of blood cholesterol. Foam cells are rich in cholesterol esters formed by ACAT action and carried by low density lipoproteins. The formation of foam cells on the arterial vessel wall is enhanced according to ACAT activity,
CAT inhibitors can be arteriosclerosis preventive agents. In addition, it has been reported that the blood concentration of LDL-cholesterol decreases by suppressing ACAT activity (Witia
k, DT and DR Feller (eds), Antilipidemic Drugs: Medicinal, Chemica
l and Biochemical Aspects, Elsevier, pp 159-195 (1991)).
【０００４】 一方、多量の脂肪を含有する食品またはアルコールの過度な摂取、あるいはＢ
型またはＣ型肝炎ウイルスの感染などによって肝機能が低下し、続いて、肝炎、
肝硬変または肝癌などに進行する。特に、脂肪含有食品および過度なアルコール
の摂取は脂肪肝の原因になり、多量の脂質が肝組織に蓄積し、血清ＧＯＴ(gluta
mate-oxaloacetate transaminase)、ＧＰＴ(glutamate-pyruvate transaminase)
、γ−ＧＴＰ(γ−glutamyl transpeptidase)などが増加することになる(T. Ban
ciu, et al., “The Hepatic Component in Alcoholic Encephalopathy”, Med.
Interne., 20, 69-71(1982);およびA. Par, et al., “Serum Gamma-Glutamyl
Transpeptidase : Its Clinical Significance”,Acta. Med. Acad. Sci. Hung.
, 33, 309-319(1976))。On the other hand, excessive consumption of food or alcohol containing a large amount of fat, or B
Liver function is reduced by infection with hepatitis C or hepatitis C virus, followed by hepatitis,
It progresses to cirrhosis or liver cancer. In particular, the consumption of fat-containing foods and excessive alcohol causes fatty liver, a large amount of lipids accumulate in liver tissue, and serum GOT (gluta).
mate-oxaloacetate transaminase), GPT (glutamate-pyruvate transaminase)
, Γ-GTP (γ-glutamyl transpeptidase) and the like (T. Ban
ciu, et al., “The Hepatic Component in Alcoholic Encephalopathy”, Med.
Interne., 20, 69-71 (1982); and A. Par, et al., “Serum Gamma-Glutamyl
Transpeptidase: Its Clinical Significance ”, Acta. Med. Acad. Sci. Hung.
, 33, 309-319 (1976)).
【０００５】 ＡＣＡＴ活性を抑制する薬物を開発するために多くの努力が払われ、その結果
、種々の微生物の培養液に由来する数々の化合物が報告された。このような化合
物の例としては、アスペルギルス・フミガツス培養液から分離したピリピロペネ
ン(S. Omura et al., J. Antibiotics, 46, 1168-1169(1993))およびシュドモナ
ス種から分離したアカテリン(S. Nagamura et al., J. Antibiotics, 45, 1216-
1221(1992))がある。Many efforts have been made to develop drugs that inhibit ACAT activity, resulting in the reporting of a number of compounds from cultures of various microorganisms. Examples of such compounds include pyripyropenene (S. Omura et al., J. Antibiotics, 46, 1168-1169 (1993)) isolated from Aspergillus fumigatus culture and acaterin (S. Nagamura) isolated from Pseudomonas species. et al., J. Antibiotics, 45, 1216-
1221 (1992)).
【０００６】 さらに、高コレステロール血症の治療剤としてロバスタチン(商標)と呼ばれる
ＨＭＧ−ＣｏＡ還元酵素抑制剤が米国のメルク社によって開発され市販されてい
る。しかし、この薬物は、肝臓のクレアチンキナーゼを増加させるという深刻な
副作用を誘発することが知られている。Further, an HMG-CoA reductase inhibitor called lovastatin (trademark) has been developed and marketed by Merck in the United States as a therapeutic agent for hypercholesterolemia. However, this drug is known to induce severe side effects of increasing creatine kinase in the liver.
【０００７】 したがって、毒性のない、ＡＣＡＴの抑制並びに動脈内皮上でのマクロファー
ジ−脂質複合体蓄積を抑制する阻害剤および肝疾患予防または治療剤の開発が求
めれている。[0007] Therefore, there is a need for the development of non-toxic inhibitors of ACAT and of macrophage-lipid complex accumulation on arterial endothelium and prophylactic or therapeutic agents for liver diseases.
【０００８】 本発明者らは、新規かつ活性の高いＡＣＡＴ抑制剤、マクロファージ−脂質複
合体蓄積抑制剤および肝疾患治療剤を天然物質中から発見することに鋭意努力し
、その結果、ヘスペリジンまたはヘスペレチンが強力なＡＣＡＴ抑制活性、マク
ロファージ−脂質複合体蓄積抑制活性および肝疾患予防または治療活性を有する
ことを発見した。[0008] The present inventors have made an intensive effort to discover a novel and highly active ACAT inhibitor, a macrophage-lipid complex accumulation inhibitor and a therapeutic agent for liver disease from natural substances, and as a result, hesperidin or hesperetin Have potent ACAT inhibitory activity, macrophage-lipid complex accumulation inhibitory activity and liver disease preventing or treating activity.
【０００９】 ヘスペリジン(Ｃ28Ｈ34Ｏ15, Ｍ.Ｗ.:６１０.５５)およびヘスペリジンのアグ
リコンであるヘスペレチン(Ｃ16Ｈ14Ｏ6,Ｍ.Ｗ.:３０２.２７)は、レモン、グレ
ープフルーツ、柑橘、シトロン、およびオレンジ(Citrus sinensis)から発見さ れるフラボノイドである(Horowitz, Gentili, Tetrahedron, 19, 773(1943))。Hesperidin (C 28 H 34 O 15 , MW: 610.55) and hesperetin (C 16 H 14 O 6 , MW: 302.27), which is an aglycone of hesperidin, are prepared from lemon and grapefruit. Is a flavonoid found in citrus, citron, and orange (Citrus sinensis) (Horowitz, Gentili, Tetrahedron, 19, 773 (1943)).
【００１０】 ヘスペリジンまたはヘスペレチンは、毛細血管強化、透過性減少、抗血小板凝
集、抗炎症、抗ウイルス、血圧降下およびコレステロール降下に有効であると報
告されている(Meyer, O. C., Angiology, 45, 579-584(1994); Struckmann, J.
R., et al., Angiol, 45, 419-428(1994); Matsubara, Y., et al., Japan Orga
nic Synthesis Chem. Association Journal., 52, 318−327(1994. Mar.)；Gala
ti, E. Ｍ., et al., Farmaco., 51(3), 219-221(1996, Mar.); Monforte, M. T
., et al., Farmaco., 50(9), 595-599(1995,Sep.);日本国特開平７−８６９２ ９号、日本国特開平７−８６９３０；Chung, M. I., et al., Chin. Pharm. J.(
Taipei)., 46, 429-437(1994,Nov.); Galati, E. M., et al., Farmaco., 40(11
), 709-712(1994, Nov.);およびEmim J. A., et al., J. Pharm. Pharmacol., 4
6(2),118-122(1994))。Hesperidin or hesperetin has been reported to be effective in enhancing capillaries, reducing permeability, antiplatelet aggregation, anti-inflammatory, antiviral, lowering blood pressure and lowering cholesterol (Meyer, OC, Angiology, 45, 579). -584 (1994); Struckmann, J.
R., et al., Angiol, 45, 419-428 (1994); Matsubara, Y., et al., Japan Orga
nic Synthesis Chem. Association Journal., 52, 318-327 (1994. Mar.); Gala
ti, E.M., et al., Farmaco., 51 (3), 219-221 (1996, Mar.); Monforte, M.T.
, et al., Farmaco., 50 (9), 595-599 (1995, Sep.); JP-A-7-86929; JP-A-7-86930; Chung, MI, et al., Chin. Pharm. J.
Taipei)., 46, 429-437 (1994, Nov.); Galati, EM, et al., Farmaco., 40 (11
), 709-712 (1994, Nov.); and Emim JA, et al., J. Pharm. Pharmacol., 4
6 (2), 118-122 (1994)).
【００１１】 さらに、ヘスペリジンは、脳貧血、網膜出血および紫斑病の予防および治療に
用いられてきた。In addition, hesperidin has been used in the prevention and treatment of cerebral anemia, retinal hemorrhage and purpura.
【００１２】 しかし、現在までヘスペリジンまたはヘスペレチンがＡＣＡＴを抑制する活性
、マクロファージ−脂質複合体蓄積を防止する活性および肝疾患予防または治療
活性を有するという報告はされていない。However, up to now, there has been no report that hesperidin or hesperetin has an activity of inhibiting ACAT, an activity of preventing accumulation of macrophage-lipid complex, and an activity of preventing or treating liver disease.
【００１３】発明の要約 したがって、本発明の主な目的は、哺乳動物のＡＣＡＴ活性を抑制するための
ヘスペリジンまたはヘスペレチンの新規用途を提供することである。[0013] SUMMARY OF THE INVENTION Accordingly, a primary object of the present invention is to provide a novel use of hesperidin or hesperetin for inhibiting the ACAT activity in mammals.
【００１４】 本発明の他の目的は、哺乳動物の動脈内皮壁上にマクロファージ−脂質複合体
が蓄積することを抑制するためのヘスペリジンまたはヘスペレチンの新規用途を
提供することである。[0014] Another object of the present invention is to provide a novel use of hesperidin or hesperetin for suppressing accumulation of macrophage-lipid complex on the arterial endothelial wall of mammals.
【００１５】 本発明のまた他の目的は、哺乳動物における肝疾患を予防または治療するため
のヘスペリジンまたはヘスペレチンの新規用途を提供することである。 本発明の前記および他の目的と特徴は添付の図面とともに下記本発明の説明か
ら明らかになる。Still another object of the present invention is to provide a novel use of hesperidin or hesperetin for preventing or treating liver disease in mammals. The above and other objects and features of the present invention will become apparent from the following description of the present invention, taken in conjunction with the accompanying drawings.
【００１６】 発明の詳細な説明 本発明の一実施態様によって、本発明は哺乳動物のアシルＣｏＡ−コレステロ
ール−o−アシルトランスフェラーゼ(ＡＣＡＴ)の活性を抑制するためのヘスペ リジンまたはヘスペレチンの用途を提供する。[0016] according to an embodiment of the DETAILED DESCRIPTION OF THE INVENTION The present invention provides a Hesupe lysine or hesperetin applications to inhibit the activity of mammalian acyl CoA- cholesterol -o- acyltransferase (ACAT) .
【００１７】 本発明の他の実施態様によって、本発明は哺乳動物の動脈内皮壁上にマクロフ
ァージ−脂質複合体が蓄積することを抑制するためのヘスペリジンまたはヘスペ
レチンの用途を提供する。According to another embodiment of the present invention, the present invention provides the use of hesperidin or hesperetin for inhibiting accumulation of macrophage-lipid complex on the arterial endothelial wall of a mammal.
【００１８】 本発明のまた他の実施態様によって、本発明は哺乳動物の肝疾患を予防または
治療するためのヘスペリジンまたはヘスペレチンの使用を提供する。According to yet another embodiment of the present invention, the present invention provides the use of hesperidin or hesperetin for preventing or treating liver disease in a mammal.
【００１９】 ヘスペリジンおよびヘスペレチンは、柑橘類の果皮から抽出されるか、ゼムプ
レン、ボグニャル、Ber., 75, 1043(1943)およびセカ、プロシェ、Monatsh., 69
, 284(1936)に記載の方法に従って合成され得る。また、ヘスペレチンはヘスペ リジンの加水分解によって製造され得る。Hesperidin and hesperetin are extracted from the citrus peel or from Zemprene, Bognal, Ber., 75, 1043 (1943) and Seca, Proche, Monatsh., 69
, 284 (1936). Hesperetin can also be produced by the hydrolysis of hesperidin.
【００２０】 ヘスペリジンまたはヘスペレチンは、０.１ｍｇ／ｋｇ／日以上の投与量でＡ ＣＡＴ活性抑制、動脈内皮壁上でのマクロファージ−脂質複合体蓄積の抑制、お
よび肝疾患予防または治療効果を有し、投与量が増加するにつれて当該効果が増
加する。Hesperidin or hesperetin has an effect of suppressing ACAT activity, suppressing accumulation of macrophage-lipid complex on arterial endothelial wall, and preventing or treating liver disease at a dose of 0.1 mg / kg / day or more. The effect increases as the dose increases.
【００２１】 さらに、このような有効性にも拘らず、ヘスペリジンまたはヘスペレチンはマ
ウスを用いた試験において毒性や有糸分裂(mitogenicity)をほどんど示さない。
さらに詳しくは、ヘスペリジンまたはヘスペレチンは５０ｋｇ体重のヒトに対し
て経口投与量３〜１０ｇ／ｋｇに該当する１００ｍｇ／ｋｇの量をマウスに経口
投与しても毒性を示さない。また、ヘスペリジンおよびヘスペレチンは肝機能に
対する副作用を惹起しない。In addition, despite its efficacy, hesperidin or hesperetin show little toxicity or mitogenicity in tests in mice.
More specifically, hesperidin or hesperetin does not show toxicity when administered orally to a 50 kg human body at a dose of 100 mg / kg corresponding to an oral dose of 3 to 10 g / kg to a mouse. Also, hesperidin and hesperetin do not cause side effects on liver function.
【００２２】 また、本発明は、活性成分としてヘスペリジンまたはヘスペレチンおよび薬剤
学的に許容可能な賦形剤、担体または希釈剤を含む、ＡＣＡＴ活性抑制、動脈壁
でのマクロファージ−脂質複合体蓄積抑制、および肝疾患予防または治療のため
の薬剤学的組成物を提供する。The present invention also provides a method for inhibiting ACAT activity, inhibiting macrophage-lipid complex accumulation on arterial walls, comprising hesperidin or hesperetin as an active ingredient and a pharmaceutically acceptable excipient, carrier or diluent. And a pharmaceutical composition for preventing or treating liver disease.
【００２３】 医薬剤形は、通常の方法に従って製造することができる。剤形の製造において
、活性成分を担体とともに混合または希釈するか、カプセル、におい袋(sachet)
またはその他容器形態の担体に封入することが好ましい。担体が希釈剤として働
く場合には、活性成分に対するビヒクル、賦形剤または媒質として作用する固体
、半固体または液状物質であり得る。したがって、剤形は、錠剤、丸剤、粉末、
におい袋、エリキシル、懸濁液、エマルジョン、溶液、シロップ、エーロゾル、
軟質または硬質ゼラチンカプセル、滅菌注射溶液、滅菌粉末などの形態であり得
る。Pharmaceutical dosage forms can be manufactured according to the usual methods. In the manufacture of dosage forms, the active ingredient may be mixed or diluted with a carrier, or capsules, sachets.
Alternatively, it is preferable to encapsulate in a carrier in the form of another container. When the carrier serves as a diluent, it can be a solid, semi-solid or liquid material that acts as a vehicle, excipient or medium for the active ingredient. Therefore, dosage forms include tablets, pills, powders,
Odor bags, elixirs, suspensions, emulsions, solutions, syrups, aerosols,
It can be in the form of soft or hard gelatin capsules, sterile injectable solution, sterile powder and the like.
【００２４】 適切な担体、賦形剤および希釈剤の例としては、ラクトース、デキストロース
、スクロース、ソルビトール、マンニトール、スターチ、アラビアゴム、アルギ
ン酸塩、ゼラチン、リン酸カルシウム、ケイ酸カルシウム、セルロース、メチル
セルロース、微晶質セルロース、ポリビニルピロリドン、水、ヒドロキシ安息香
酸メチル、ヒドロキシ安息香酸プロピル、タルク、ステアリン酸マグネシウムお
よびミネラル油などを挙げることができる。剤形は、充填剤、抗凝集剤、潤滑剤
、湿潤剤、香料、乳化剤、防腐剤などをさらに含むことができる。本発明の組成
物は、哺乳動物に投与された後、活性成分の迅速、遅速または遅延放出を提供す
るために当業界で公知の方法を用いて剤形化することができる。Examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline Cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil. The dosage form can further include fillers, anti-aggregants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, and the like. After administration to a mammal, the compositions of the present invention can be formulated using methods known in the art to provide rapid, slow or delayed release of the active ingredient.
【００２５】 本発明の薬剤学的組成物は、経口、経皮、静脈または筋肉内投与を含む種々の
経路を通じて投与され得る。ヒトの場合、ヘスペリジンまたはヘスペレチンの通
常の１日投与量は０.１〜１００ｍｇ／ｋｇ体重であり、好ましくは３〜１０ｍ ｇ/ｋｇ体重の範囲であり、１回または数回に分けて投与し得る。[0025] The pharmaceutical compositions of the present invention can be administered via a variety of routes, including oral, transdermal, intravenous or intramuscular administration. In the case of humans, the usual daily dose of hesperidin or hesperetin is 0.1 to 100 mg / kg body weight, preferably in the range of 3 to 10 mg / kg body weight, and is administered once or in several divided doses. obtain.
【００２６】 しかし、活性成分の実際投与量は処理条件、投与経路、患者の年齢、性別およ
び体重、および患者の症状を含む種々の関連因子を考慮して決定され、したがっ
て、前記投与量は本発明の範囲を制限しない。However, the actual dose of the active ingredient will be determined in consideration of various relevant factors including treatment conditions, administration route, age, sex and weight of the patient, and symptoms of the patient. It does not limit the scope of the invention.
【００２７】 また、本発明のヘスペリジンまたはヘスペレチンはＡＣＡＴ活性を抑制し、動
脈内皮上にマクロファージ−脂質複合体の蓄積を抑制するか、肝疾患を予防また
は治療する目的で食品または飲料に添加剤または食品補助剤として加え得る。前
記食品または飲料としては、各種肉類；野菜ジュース(たとえば、ニンジンジュ ース、トマトジュース)および果物ジュース(たとえば、オレンジジュース、ブド
ウジュース、パイナップルジュース、リンゴジュースおよびバナナジュース)； チョコレート；スナック類；お菓子類；ピザ；パン、ケーキ、クラッカー、クッ
キー、ビスケット、ヌードルなどのように穀物の粉末から作られる食品類；チュ
ーインガム類；牛乳、チーズ、ヨーグルトおよびアイスクリームのような乳製品
；スープ；肉汁；ペースト、ケチャップおよびソース；茶；アルコール飲料類；
コカ・コーラ(商標)およびペプシ・コーラ(商標)のような炭酸飲料；ビタミン複
合体；および様々な健康補助食品類などがある。Further, the hesperidin or hesperetin of the present invention suppresses ACAT activity, suppresses accumulation of macrophage-lipid complex on arterial endothelium, or is used as an additive or additive in foods or beverages for the purpose of preventing or treating liver disease. It can be added as a food supplement. The food or beverage includes various meats; vegetable juices (eg, carrot juice, tomato juice) and fruit juices (eg, orange juice, grape juice, pineapple juice, apple juice and banana juice); chocolate; snacks; Sweets; Pizza; Foods made from cereal powders, such as bread, cakes, crackers, cookies, biscuits, noodles, etc .; Chewing gums; Dairy products, such as milk, cheese, yogurt and ice cream; Soups; Pastes, ketchups and sauces; tea; alcoholic beverages;
Carbonated beverages such as Coca-Cola (TM) and Pepsi-Cola (TM); vitamin complexes; and various health supplements.
【００２８】 この場合、食品または飲料中のヘスペリジンまたはヘスペレチンの含量は０. ０１〜５重量％の範囲である。特に、本発明による飲料は飲料１,０００ｍｌ当 りヘスペリジンまたはヘスペレチン２００〜１０,０００ｍｇを含み得る。In this case, the content of hesperidin or hesperetin in the food or beverage is in the range of 0.01 to 5% by weight. In particular, the beverage according to the invention may comprise 200 to 10,000 mg of hesperidin or hesperetin per 1,000 ml of beverage.
【００２９】 前述のように、ヘスペリジンまたはヘスペレチンは有効で、かつ毒性のない、
ＡＣＡＴ活性抑制、動脈内皮上でのマクロファージ−脂質複合体の蓄積抑制、お
よび／または肝疾患予防または治療のための薬剤として用いられる。As mentioned above, hesperidin or hesperetin is effective and non-toxic,
It is used as an agent for inhibiting ACAT activity, inhibiting macrophage-lipid complex accumulation on arterial endothelium, and / or preventing or treating liver disease.
【００３０】 下記実施例は本発明をさらに詳細に説明するためのものであり、本発明の範囲
を制限しない。The following examples serve to illustrate the invention in more detail and do not limit the scope of the invention.
【００３１】 また、下記固体混合物中の固体、液体中の液体、および液体中の固体に対して
下記に与えられた百分率は、各々重量／重量、体積／体積および重量／体積に基
づいたものであり、別に言及しない限りすべての反応は室温で行われた。Also, the percentages given below for solids in solid mixtures, liquids in liquids, and solids in liquids are based on weight / weight, volume / volume and weight / volume, respectively. Yes, and unless stated otherwise, all reactions were performed at room temperature.
【００３２】 実施例１：柑橘類の果皮からヘスペリジン抽出 柑橘(済州島、韓国)、シトロン(全羅南道、韓国)およびオレンジ、グレープフ
ルーツおよびレモン(カリフォルニア、米国)の皮を室温で乾燥した後、粒径１０
０μｍ〜２００μｍ範囲の粒子サイズに粉末化した。この柑橘類果皮粉末５００
ｍｇずつにメタノール５０ｍｌずつを加えて５０℃で６時間水浴中で抽出した。
このように得られた抽出物を冷却し、濾過した後、濾液にメタノールを加えて５ ０ｍｌにした。Example 1: Hesperidin Extraction from Citrus Peel Peel Citrus (Jeju Island, Korea), Citron (Jeollanam-do, Korea) and Orange, Grapefruit and Lemon (California, USA) peels after drying at room temperature, particle size 10
Powdered to a particle size ranging from 0 μm to 200 μm. This citrus peel powder 500
50 mg of methanol was added to each mg, and the mixture was extracted in a water bath at 50 ° C. for 6 hours.
The extract thus obtained was cooled and filtered, and then the filtrate was made up to 50 ml with methanol.
【００３３】 前記のように得られた抽出物中のヘスペリジンの含量を確認するため、抽出液
５.０μｌを用いて、３７％メタノールで前もって平衡化したリクロソルブＲＰ −８カラム(５μｍ、４ｘ２５０ｍｍ)を３０℃で維持してＨＰＬＣを実施した。
抽出物は、３７％メタノールを用いて１.０ｍｌ／分の流速で溶出させた。ヘス ペリジン(Sigma Co., 米国)をメタノールに溶解して最終濃度が各々０.１、０. ２、０.３、０.４および０.５ｍｇ／ｍｌになるように標準溶液を調製し、前記 と同様な条件下でＨＰＬＣを行った。溶出物をＵＶ−ＶＩＳ分光光度計(spectro
photometer)を用いて２８０ｎｍで検出し、標準溶液と柑橘類果皮抽出物のＨＰ ＬＣプロファイル(profile)の面積比からヘスペリジンの含量を計算した。種々 の柑橘類の果皮抽出物からのヘスペリジンの含量を下記表１に示す。In order to confirm the content of hesperidin in the extract obtained as described above, 5.0 μl of the extract was applied to a Lichrosolve RP-8 column (5 μm, 4 × 250 mm) previously equilibrated with 37% methanol. HPLC was carried out at 30 ° C.
The extract was eluted with 37% methanol at a flow rate of 1.0 ml / min. Hesperidin (Sigma Co., USA) was dissolved in methanol to prepare standard solutions to give final concentrations of 0.1, 0.2, 0.3, 0.4 and 0.5 mg / ml, respectively. HPLC was performed under the same conditions as described above. The eluate was analyzed using a UV-VIS spectrophotometer (spectro
Detection was performed at 280 nm using a photometer, and the content of hesperidin was calculated from the area ratio of the HPLC profile between the standard solution and the citrus peel extract. The content of hesperidin from various citrus peel extracts is shown in Table 1 below.
【００３４】[0034]
【表１】 [Table 1]
【００３５】 実施例２：経口投与されたヘスペリジンまたはヘスペレチンの毒性実験 ７−８週齢の無菌ＩＣＲマウスであって、体重が２５〜２９ｇである雌マウス
(６匹)と体重が３４〜３８ｇである雄マウス(６匹)を温度２２±１℃、湿度５５
±５％、光周期１２Ｌ／１２Ｄの条件下で飼育した。実験動物用飼料(Cheiljeda
ng Co., マウスおよびラット用)および飲料水は滅菌した後摂取させた。Example 2 Toxicity Study of Orally Administered Hesperidin or Hesperetin 7-8 week old sterile ICR mice weighing 25-29 g
(6) and male mice (6) weighing 34-38 g at a temperature of 22 ± 1 ° C. and a humidity of 55
They were bred under the conditions of ± 5% and a light cycle of 12 L / 12 D. Laboratory animal feed (Cheiljeda
ng Co., for mice and rats) and drinking water were taken after sterilization.
【００３６】 ヘスペリジンまたはヘスペレチンを０.５％ツイーン８０に１００ｍｇ／ｍｌ の濃度で溶解した後、この溶液をマウスにマウス体重２０ｇ当り０.２ｍｌずつ 経口投与した。この溶液は、１回経口投与し、その後副作用または致死につく観
察を１、４、８、および１２時間後、そしてその後は１２時間ごとに１０日間行
った。ヘスペリジンまたはヘスペレチンの効果を調査するためにマウスの体重変
化を毎日記録した。また、投与１０日目にマウスを致死させた後、肉眼で内部臓
器を観察した。After dissolving hesperidin or hesperetin in 0.5% Tween 80 at a concentration of 100 mg / ml, the solution was orally administered to mice in an amount of 0.2 ml per 20 g of mouse body weight. The solution was administered orally once, followed by observations for side effects or lethality at 1, 4, 8, and 12 hours, and thereafter every 12 hours for 10 days. Mice's weight changes were recorded daily to investigate the effects of hesperidin or hesperetin. On the 10th day after the administration, the mice were sacrificed, and the internal organs were visually observed.
【００３７】 いずれのマウスも１０日目まで生存し、これはヘスペリジンまたはヘスペレチ
ンが１,０００ｍｇ／ｋｇの投与量では毒性を示さないことを示す。検体によっ てマウスに何ら病理的異常が発生しなかったことが確認され、１０日間の試験期
間中体重減少は観察されなかった。したがって、ヘスペリジンまたはヘスペレチ
ンは動物に経口投与する場合毒性がないと結論づけることができる。All mice survived up to day 10, indicating that hesperidin or hesperetin was not toxic at a dose of 1,000 mg / kg. The samples confirmed that no pathological abnormalities occurred in the mice, and no weight loss was observed during the 10-day test period. Therefore, it can be concluded that hesperidin or hesperetin is not toxic when administered orally to animals.
【００３８】 実施例３：ヘスペリジンまたはヘスペレチンの動物投与 体重９０〜１１０ｇの４週齢スプラグダウリーラット(テハン実験動物センタ ー、大韓民国)３０匹を無作為ブロックデザインに従って３つの食餌群に分けた 。３グループのラットに３種類の高コレステロール食餌、すなわち、１％コレス
テロールを含むＡＩＮ−７６実験動物食餌(ICN Biochemicals, Cleveland, OH,
U.S.A.)(対照群)、１％コレステロールと０.１％ヘスペリジンを含むＡＩＮ−７
６実験動物食餌(ヘスペリジン群)、および１％コレステロールと０.１％ヘスペ レチンを含むＡＩＮ−７６実験動物食餌(ヘスペレチン群)を各々摂取させた。３
群に摂取させた食餌組成は表２に示す。Example 3 Animal Administration of Hesperidin or Hesperetin Thirty 30 4-week-old Sprague-Dawley rats (Tehan Experimental Animal Center, Korea) weighing 90-110 g were divided into three diet groups according to a randomized block design. Three groups of rats were fed three high cholesterol diets, an AIN-76 experimental animal diet containing 1% cholesterol (ICN Biochemicals, Cleveland, OH,
(USA) (control group) AIN-7 containing 1% cholesterol and 0.1% hesperidin
Six experimental animal diets (hesperidin group) and an AIN-76 experimental animal diet containing 1% cholesterol and 0.1% hesperetin (hesperetin group) were each fed. Three
The dietary composition ingested by the groups is shown in Table 2.
【００３９】[0039]
【表２】 *は、テクラドプレミアー社(TEKLAD premier Co., Madison, WI, U. S. A.)から
購入した。[Table 2] * Was purchased from TEKLAD premier Co., Madison, WI, USA.
【００４０】 ラットに水とともに所定の食餌を６週間自由に摂取させ、摂取量を毎日記録し
、ラットの体重を７日ごとに測定した後飼育記録を分析した。すべてのラットは
正常な成長速度を示し、食餌摂取量と体重増加量においては３群間の差はほとん
どなかった。The rats were allowed to freely ingest a predetermined diet together with water for 6 weeks, the amount of intake was recorded every day, and the body weight of each rat was measured every 7 days, and the breeding record was analyzed. All rats showed normal growth rates, with little difference between the three groups in food intake and body weight gain.
【００４１】 実施例４：実験動物の血中総コレステロール、ＨＤＬ−コレステロールおよび中
性脂質含量の決定 ヘスペリジンまたはヘスペレチンの投与がラットの血中コレステロールと中性
脂質含量に及ぼす影響を次のように調査した。Example 4 Determination of Blood Total Cholesterol, HDL-Cholesterol, and Neutral Lipid Content of Experimental Animals The effects of administration of hesperidin or hesperetin on blood cholesterol and neutral lipid contents of rats were investigated as follows. did.
【００４２】 ３つの食餌群のラットから血液試料を採取し、これからデキストラン−硫酸塩
を含むＨＤＬ−コレステロール試薬(Sigma Chemical Co. Cat. No. 352-3)を用 いて血中ＨＤＬ分画を分離した。総コレステロールおよびＨＤＬ−コレステロー
ル濃度はシグマ社の診断キットカタログ番号352-100(Sigma Chemical Co., U. S
. A.)(Allain et al., Clin. Chem., 20, 470-475(1974))、中性脂質濃度はシグ
マ社の診断キットカタログ番号339-50(Bucolo, G. and David, H., Clin. Chem.
, 19, 476-482(1973))を各々用いて測定し、その結果を表３に示す。ここで、総
血中コレステロール濃度は、対照群の場合と比べるとき、ヘスペリジンを摂取し
たラット群においては１１％、ヘスペレチンを摂取したラット群においては１５
％減少した。Blood samples were collected from rats in the three diet groups, and blood HDL fractions were separated therefrom using an HDL-cholesterol reagent containing dextran-sulfate (Sigma Chemical Co. Cat. No. 352-3). did. Total cholesterol and HDL-cholesterol levels were determined by Sigma's diagnostic kit catalog number 352-100 (Sigma Chemical Co., U.S.
A.) (Allain et al., Clin. Chem., 20, 470-475 (1974)), neutral lipid levels are determined by Sigma's diagnostic kit catalog number 339-50 (Bucolo, G. and David, H. , Clin. Chem.
, 19, 476-482 (1973)), and the results are shown in Table 3. Here, the total blood cholesterol concentration was 11% in the rat group receiving hesperidin and 15% in the rat group receiving hesperetin, as compared with the control group.
%Diminished.
【００４３】[0043]
【表３】 [Table 3]
【００４４】 実施例５：ヘスペリジンおよびヘスペレチンによるＡＣＡＴ活性の抑制 (段階１)ミクロソームの製造 ラットに投与したヘスペリジンおよびヘスペレチンがＡＣＡＴ酵素活性に及ぼ
す影響を調査するために肝組織からミクロソームを分離して酵素源として用いた
。Example 5: Inhibition of ACAT activity by hesperidin and hesperetin (Step 1) Production of microsomes In order to investigate the effect of hesperidin and hesperetin administered to rats on ACAT enzyme activity, microsomes were isolated from liver tissue to investigate the effect of ACAT enzyme activity. Used as source.
【００４５】 まず、実施例３で製造した３群のラットを斬首して屠殺した後、肝を切り取っ
た。肝組織１ｇを均質化溶液５ｍｌ(０.１Ｍリン酸カリウム(ｐＨ７.４)、０.１
ｍＭ ＥＤＴＡおよび１０ｍＭ β−メルカプトエタノール)中で均質化した。 この均質液を４℃で３,０００ｘｇで１０分間遠心分離し、得られた上澄液を４ ℃で１５分間１５,０００ｘｇでさらに遠心分離して上澄液を得た。上澄液を超 遠心分離チューブ(ベックマン社)に入れ、４℃で１００,０００ｘｇで１時間遠 心分離してミクロソームペレットを得た後、これを均質化溶液３ｍｌに懸濁し、
４℃で１００,０００ｘｇで1時間遠心分離した。得られたペレットを前記均質化
溶液１ｍｌに懸濁した。懸濁液中のタンパク質濃度をローリ(Lowry)らの方法で 測定した後、タンパク質の濃度を４〜８ｍｇ／ｍｌに調節した。この懸濁液をデ
ィープフリーザー(Biofreezer, Forma Scientific Inc.)に保管した。First, the rats of the three groups produced in Example 3 were beheaded and sacrificed, and the liver was cut off. 1 g of liver tissue was mixed with 5 ml of a homogenized solution (0.1 M potassium phosphate (pH 7.4), 0.1 ml).
mM EDTA and 10 mM β-mercaptoethanol). This homogenate was centrifuged at 3,000 xg for 10 minutes at 4 ° C, and the resulting supernatant was further centrifuged at 15,000 xg for 15 minutes at 4 ° C to obtain a supernatant. The supernatant was placed in an ultracentrifuge tube (Beckman) and centrifuged at 100,000 xg for 1 hour at 4 ° C to obtain a microsome pellet, which was suspended in 3 ml of a homogenized solution.
Centrifuged at 100,000 xg for 1 hour at 4 ° C. The obtained pellet was suspended in 1 ml of the homogenized solution. After measuring the protein concentration in the suspension by the method of Lowry et al., The protein concentration was adjusted to 4-8 mg / ml. This suspension was stored in a deep freezer (Biofreezer, Forma Scientific Inc.).
【００４６】 (段階２)ＡＣＡＴ活性測定 アセトンに１ｍｇ／ｍｌの濃度で溶解したコレステロール溶液６.６７μｌを １０％トリトンＷＲ−１３３９(Sigma Co.)アセトン溶液６μｌと混合した後、 窒素ガスを用いてアセトンを蒸発させた。この混合物に蒸留水を加えてコレステ
ロールの濃度が３０ｍｇ／ｍｌになるように調節した。(Step 2) Measurement of ACAT activity 6.67 μl of a cholesterol solution dissolved in acetone at a concentration of 1 mg / ml was mixed with 6 μl of a 10% acetone solution of Triton WR-1339 (Sigma Co.), and then nitrogen gas was used. The acetone was evaporated. Distilled water was added to the mixture to adjust the concentration of cholesterol to 30 mg / ml.
【００４７】 前記コレステロール水溶液１０μｌに１Ｍリン酸カリウム１０μｌ(ｐＨ７.４
)、０.６ｍＭウシ血清アルブミン(ＢＳＡ)５μｌ、段階１で得られたミクロソー
ム溶液１０μｌおよび蒸留水５５μｌを加えた(総９０μｌ)。混合物を３７℃水
浴中で３０分間プレインキュベートした。10 μl of 1M potassium phosphate (pH 7.4) is added to 10 μl of the cholesterol aqueous solution.
), 5 μl of 0.6 mM bovine serum albumin (BSA), 10 μl of the microsomal solution obtained in step 1 and 55 μl of distilled water (total 90 μl). The mixture was pre-incubated for 30 minutes in a 37 ° C. water bath.
【００４８】 (１−14Ｃ)オレオイル−ＣｏＡ溶液１０μｌ(０.０５μＣｉ、最終濃度：１０
μＭ)をプレインキュベートした混合物に加え、生成した混合物を３７℃水浴中 で３０分間インキュベートした。これに、イソプロパノール：ヘプタン混合溶液
(４：１(ｖ／ｖ))５００μl、ヘプタン３００μlおよび０.１Ｍリン酸カリウム ２００μl(ｐＨ７.４)を加え、混合物をボルテックス(vortex)で激しく混合した
後、室温で２分間静置した。[0048] (1- 14 C) oleoyl -CoA solution 10 [mu] l (0.05 [mu] Ci, final concentration: 10
μM) was added to the pre-incubated mixture, and the resulting mixture was incubated for 30 minutes in a 37 ° C. water bath. To this, a mixed solution of isopropanol and heptane
500 μl (4: 1 (v / v)), 300 μl heptane and 200 μl 0.1 M potassium phosphate (pH 7.4) were added, the mixture was mixed vigorously with a vortex and allowed to stand at room temperature for 2 minutes.
【００４９】 上澄液２００μlをシンチレーション瓶に入れ、シンチレーション液(Lumac社)
４ｍｌを加えた。この混合物の放射線量を１４５０マイクロベータ液体シンチレ
ーション計数器(1450 Microbeta liquid scintillation counter, Wallacoy, Fi
nland)で測定した。ＡＣＡＴ酵素活性は、タンパク質１ｍｇ当り１分間合成した
オレイン酸コレステリルの量(ピコモル／分／ｍｇタンパク質)で計算した。その
結果を表４に示す。Put 200 μl of the supernatant in a scintillation bottle, and add a scintillation liquid (Lumac)
4 ml were added. The radiation dose of this mixture was measured using a 1450 Microbeta liquid scintillation counter, Wallacoy, Fi.
nland). ACAT enzyme activity was calculated as the amount of cholesteryl oleate synthesized per mg of protein for 1 minute (picomoles / min / mg protein). Table 4 shows the results.
【００５０】[0050]
【表４】 [Table 4]
【００５１】 表４から分かるように、ヘスペリジンおよびヘスペレチン投与群のＡＣＡＴ活
性度は対照群に比べて各々１９.２％および２３.５％減少した。As can be seen from Table 4, the ACAT activity of the group to which hesperidin and hesperetin were administered was reduced by 19.2% and 23.5%, respectively, as compared with the control group.
【００５２】 実施例６：ヘスペリジンおよびヘスペレチン投与群におけるマクロファージ−脂
質複合体によって誘導されたプラーク形成の抑制 (段階１)ヘスペリジンおよびヘスペレチンの動物投与 ２.５〜２.６ｋｇの３月齢ニュージーランド白ウサギ(大韓民国ヨンアム園芸 畜産大学)２４匹を温度２０±２℃、相対湿度５５±５％および光周期１２Ｌ／ １２Ｄの条件下で飼育した。ウサギを６匹ずつの群に分け、４群のウサギに４つ
の異なる食餌、すなわち、１％コレステロール(対照群)；１％コレステロールお
よび１ｍｇ／ｋｇロバスタチン(商標) (メルク社、米国)(比較群)；１％コレス テロールおよび０.１％ヘスペリジン；および１％コレステロールおよび０.１％
ヘスペレチンを各々含むＲＣ４食餌(Oriental Yeast Co.,日本)を摂取させた。 ＲＣ４食餌は７.６％水分、２２.８％粗タンパク質、２.８％粗脂肪、８.８％粗
灰粉、１４.４％粗セルロースおよび４３.６％無窒素溶解性物質を含む。ウサギ
は食餌と水を自由に摂取できるようにしながら６週間飼育した。Example 6: Inhibition of plaque formation induced by macrophage-lipid complex in hesperidin and hesperetin administration group (Step 1) Animal administration of hesperidin and hesperetin 2.5 to 2.6 kg of 3-month-old New Zealand white rabbit ( Twenty-four animals were raised under the conditions of a temperature of 20 ± 2 ° C., a relative humidity of 55 ± 5%, and a photoperiod of 12 L / 12 D. The rabbits were divided into groups of six and four groups of rabbits were given four different diets: 1% cholesterol (control group); 1% cholesterol and 1 mg / kg Lovastatin ™ (Merck, USA) (comparison group). ); 1% cholesterol and 0.1% hesperidin; and 1% cholesterol and 0.1%
An RC4 diet (Oriental Yeast Co., Japan) containing each of hesperetin was ingested. The RC4 diet contains 7.6% moisture, 22.8% crude protein, 2.8% crude fat, 8.8% crude ash flour, 14.4% crude cellulose and 43.6% nitrogen-free soluble substances. Rabbits were kept for 6 weeks with free access to food and water.
【００５３】 (段階２)大動脈の脂肪層(fatty streak)の分析 段階１で飼育したウサギを屠殺し、胸部を切開した。大動脈を大動脈弁の１ｃ
ｍ上方から下方に約５ｃｍ長さに切り取り、大動脈周辺の脂肪を除去した。大動
脈の中間を縦軸に沿って切開した後、皿上にピンで固定した。この湿った組織を
写真撮影した後エスパー(Esper E. et al.(J. Lab. Clin. Med., 121, 103-110(
1993))の方法に従って次のように脂肪層の染色を行った。(Step 2) Analysis of Fat Streak of Aorta The rabbit bred in Step 1 was sacrificed and the chest was incised. Aorta 1c of aortic valve
Approximately 5 cm in length was cut from above to below to remove fat around the aorta. After incising the middle of the aorta along the longitudinal axis, it was pinned on a dish. After photographing the wet tissue, Esper E. et al. (J. Lab.Clin. Med., 121, 103-110 (
1993)), the fat layer was stained as follows.
【００５４】 切開した大動脈の一部を無水プロピレングリコールで２分間隔で３回洗浄し、
プロピレングリコールに溶かしたオイルレッドオー(ORO, Sigma Co.)の飽和溶液
で３０分間染色した。次いで、動脈を８５％プロピレングリコールで３分間隔で
２回洗浄して残っている染色溶液を除去した後、生理食塩水で洗浄した。動脈を
写真撮影した後写真を透写した。染色された領域(脂肪層領域)の面積をイメージ
分析器(LEICA、Q-600、ドイツ)で測定し、大動脈の総面積に対する脂肪層の比率
(％)を計算した。A part of the incised aorta was washed with anhydrous propylene glycol three times at intervals of 2 minutes,
Stained with a saturated solution of Oil Red O (ORO, Sigma Co.) in propylene glycol for 30 minutes. The artery was then washed twice with 85% propylene glycol at 3 minute intervals to remove the remaining staining solution and then washed with saline. After photographing the artery, the photograph was translucent. The area of the stained area (fat layer area) was measured with an image analyzer (LEICA, Q-600, Germany), and the ratio of the fat layer to the total area of the aorta was measured.
(%) Was calculated.
【００５５】 一方、大動脈の他の部分は、ヘマトキシリン−エオシン(H&E)染色法およびマ ソーンの三色染色法(Masson's trichrome stain)に従って染色した後、光学顕微
鏡下で血管内膜(intima)、内部(internus)、弾性膜(elastic lamina)、中膜(med
ia)の各々にマクロファージ−脂質複合体が蓄積されているかを観察した。On the other hand, the other part of the aorta was stained according to the hematoxylin-eosin (H & E) staining method and Masson's trichrome stain, and then under an optical microscope, the intima, the inner lining, (internus), elastic membrane (elastic lamina), media (med
It was observed whether macrophage-lipid complexes had accumulated in each of ia).
【００５６】 さらに、ウサギから血液試料を採取し、実施例４と同様の方法で総コレステロ
ールおよび中性脂質濃度を測定した。 その結果を表５に示す。Further, a blood sample was collected from the rabbit, and the total cholesterol and neutral lipid concentrations were measured in the same manner as in Example 4. Table 5 shows the results.
【００５７】[0057]
【表５】 [Table 5]
【００５８】 表５から分かるように、１ｍｇ／ｋｇロバスタチン(商標)投与群、０.１％ヘ スペリジン投与群、および０.１％ヘスペレチン投与群においては、対照群に比 べて動脈内皮上に蓄積されたマクロファージ−脂質複合体の面積が著しく減少し
た。これから、ヘスペリジンおよびヘスペレチンは動脈内皮上にマクロファージ
−脂質複合体の蓄積を抑制することが確認された。特に、ヘスペリジンおよびヘ
スペレチンのマクロファージ−脂質複合体の蓄積抑制活性が正常のウサギの血中
コレステロール数値である約５０ｍｇ／ｄｌよりはるかに高い約１,１００ｍｇ ／ｄｌを示すことは注目すべきである。この結果は、ＨＭＧ−ＣｏＡ還元酵素抑
制剤によるコレステロール合成阻害、ＡＣＡＴ抑制剤によるコレステロール吸収
阻害、またはＣＥＴＰ抑制剤によるコレステロール転移阻害とは異なる新しい動
脈硬化症防止機構によるものであると思われる。As can be seen from Table 5, the 1 mg / kg Lovastatin ™ administration group, the 0.1% hesperidin administration group, and the 0.1% hesperetin administration group showed a higher level on the arterial endothelium than the control group. The area of accumulated macrophage-lipid complexes was significantly reduced. From this, it was confirmed that hesperidin and hesperetin suppressed the accumulation of macrophage-lipid complex on the arterial endothelium. In particular, it should be noted that the activity of hesperidin and hesperetin to suppress the accumulation of macrophage-lipid complex exhibits about 1,100 mg / dl, which is much higher than the blood cholesterol level of normal rabbits of about 50 mg / dl. This result seems to be due to a new mechanism of preventing arteriosclerosis different from inhibition of cholesterol synthesis by HMG-CoA reductase inhibitors, inhibition of cholesterol absorption by ACAT inhibitors, or inhibition of cholesterol transfer by CETP inhibitors.
【００５９】 図１Ａ、１Ｂおよび１Ｃは、各々１％コレステロール(対照群)；１％コレステ
ロールと１ｍｇ／ｋｇロバスタチン(商標) (比較群)；および１％コレステロー ルと０.１％ヘスペリジンを投与したウサギの動脈写真を示す。図１Ａ、１Ｂお よび１Ｃから分かるように、１％コレステロールを投与したウサギの動脈内皮上
にはマクロファージ−脂質複合体の厚い層が形成されるに反して、１％コレステ
ロールと１ｍｇ／ｋｇロバスタチン(商標)および１％コレステロールと０.１％ ヘスペリジンを投与したウサギの動脈内皮上にはマクロファージ−脂質複合体の
非常に薄い層が形成されるか、または層が形成されなかった。FIGS. 1A, 1B and 1C each show administration of 1% cholesterol (control group); 1% cholesterol and 1 mg / kg Lovastatin ™ (comparison group); and 1% cholesterol and 0.1% hesperidin. 2 shows an artery photograph of a rabbit. As can be seen from FIGS. 1A, 1B and 1C, a thick layer of macrophage-lipid complex was formed on the arterial endothelium of rabbits to which 1% cholesterol was administered, whereas 1% cholesterol and 1 mg / kg lovastatin ( A very thin layer or no layer of macrophage-lipid complex was formed on the arterial endothelium of rabbits that received 1% cholesterol and 0.1% hesperidin.
【００６０】 したがって、ヘスペリジンおよびヘスペレチンは動脈内皮上にマクロファージ
−脂質複合体の蓄積を強く抑制すると結論づけられる。Thus, it is concluded that hesperidin and hesperetin strongly inhibit macrophage-lipid complex accumulation on arterial endothelium.
【００６１】 実施例７：ヘスペリジンによる肝疾患の予防 (段階１)ヘスペリジンをラットに投与 体重９０〜１１０ｇの４週齢スプラグダウリーラット(テハン実験動物センタ ー、大韓民国)２０匹を無作為ブロックデザインに従って２つの食餌群に分けた 。この２群のラットに２種類の高コレステロール食餌、すなわち、１％コレステ
ロールを含むＡＩＮ−７６実験動物食餌(ICN Biochemicals, Cleveland, OH, U.
S.A.)(対照群)、および１％コレステロールと０.０４％ヘスペリジンを含むＡＩ
Ｎ−７６実験動物食餌(ヘスペリジン群)を各々摂取させた。２群に摂取させた食
餌組成を表６に示す。Example 7: Prevention of Liver Disease by Hesperidin (Step 1) Administration of Hesperidin to Rats Twenty four-week-old Sprague-Dawley rats (Tehan Experimental Animal Center, Korea) weighing 90-110 g according to a randomized block design They were divided into two diet groups. The two groups of rats were fed two high cholesterol diets, an AIN-76 laboratory animal diet containing 1% cholesterol (ICN Biochemicals, Cleveland, OH, U.S.A.).
SA) (control group) and AI containing 1% cholesterol and 0.04% hesperidin
N-76 experimental animal diet (hesperidin group) was ingested. Table 6 shows the dietary composition ingested by the two groups.
【００６２】[0062]
【表６】 *は、テクラドプレミアー社(TEKLAD premier Co., Madison, WI, U. S. A.)から
購入した。[Table 6] * Was purchased from TEKLAD premier Co., Madison, WI, USA.
【００６３】 ラットに水とともに所定の食餌を６週間自由に摂取させ、摂取量を毎日記録し
、ラットの体重を７日ごとに測定した後飼育記録を分析した。すべてのラットは
正常な゜成長速度を示し、食餌摂取量と体重増加量においては２群間の差はほと
んどなかった。The rats were allowed to freely ingest a predetermined diet together with water for 6 weeks, the amount of intake was recorded daily, the body weight of the rat was measured every 7 days, and the breeding record was analyzed. All rats showed a normal ゜ growth rate, with little difference between the two groups in food intake and body weight gain.
【００６４】 (段階２)血漿ＧＯＴおよびＧＰＴ濃度測定 ラットの肝機能に対するヘスペリジン投与の効果を次のように測定した。 ２つの食餌群のラットから血液試料を採取し、血漿ＧＯＴ(glutamate-oxaloac
etate transaminase)およびＧＰＴ(glutamate-pyruvate transaminase)濃度をレイトマンとフランケルの方法(Reitman, S. and J. S. F
rankel, Am. J. Clin. Pathol., 28, 56(1956))に従って測定した。ＧＯＴとＧ ＰＴは肝と心臓で合成される酵素であって、これらの組織が損傷すると血中に放
出される。従って、ＧＯＴとＧＰＴは肝機能検査の代表的な指標であり、高い血
漿ＧＯＴおよびＧＰＴ濃度は肝の損傷が重いことを示す。 実験結果、ヘスペリジン投与群のＧＯＴおよびＧＰＴ濃度は対照群のそれより
各々３０％および１０％低いことが観察された。(Step 2) Measurement of Plasma GOT and GPT Concentration The effect of hesperidin administration on rat liver function was measured as follows. Blood samples were collected from rats in the two diet groups and plasma GOT (glutamate-oxaloac)
etate transaminase) and GPT (glutamate-pyruvate transaminase) concentrations were determined by the method of Reitman and Frankel (Reitman, S. and JSF).
Rankel, Am. J. Clin. Pathol., 28, 56 (1956)). GOT and GPT are enzymes that are synthesized in the liver and heart and are released into the blood when these tissues are damaged. Thus, GOT and GPT are representative indicators of liver function tests, and high plasma GOT and GPT concentrations indicate severe liver damage. As a result of the experiment, it was observed that the GOT and GPT concentrations of the hesperidin-administered group were 30% and 10% lower than those of the control group, respectively.
【００６５】 (段階３)ウサギを用いた実験 ラットの代わりに２.５〜２.６ｋｇの３月齢ニュージーランド白ウサギ(大韓 民国ヨンアム園芸畜産大学)３０匹を用い、ウサギに３つの異なる高コレステロ ール食餌、すなわち、１％コレステロールを含むＲＣ４食餌(対照群)；１％コレ
ステロールと１ｍｇ／ｋｇロバスタチン(商標)を含む食餌(比較群)；および１％
コレステロールと０.１％ヘスペリジンを含む食餌を各々６週間摂取させること を除いては段階１と同様な手順を繰り返した。(Step 3) Experiment using rabbits Instead of rats, 30 2.5-2.6 kg 3-month-old New Zealand white rabbits (Yongam Horticultural and Livestock University of Korea) were used, and three different high cholesterols were used for the rabbits. 1% cholesterol and a diet containing 1% cholesterol and 1 mg / kg Lovastatin ™ (comparative group); and 1%
The same procedure as in step 1 was repeated, except that each diet containing cholesterol and 0.1% hesperidin was taken for 6 weeks.
【００６６】 次いで、ウサギから肝を分離し、次のように組織病理学的観察を行った。 ウサギをケタミン(７５ｍｇ／ｋｇ)の筋肉注射で麻酔した後、腹部を切開した
。肝の色調、硬化度を肉眼で観察し、ウサギから分離した肝を１０％中性緩衝ポ
ルマリン中で２４時間以上固定した。固定した肝を水で十分洗浄し、７０％、８
０％、９０％および１００％エタノールで段階的に脱水した後、パラフィン中に
固定した。固定した肝をミクロトーム(microtome)を用いて約４μｍ厚さに切り 、ヘマトキシリンとエオシンで染色した。染色した肝試料をキシレンで透明化し
、パーマウントに乗せた後、光学顕微鏡下で観察して病変の有無を調査した。Next, the liver was separated from the rabbit, and histopathological observation was performed as follows. The rabbit was anesthetized with an intramuscular injection of ketamine (75 mg / kg), and then the abdomen was opened. The color and stiffness of the liver were visually observed, and the liver separated from the rabbit was fixed in 10% neutral buffered porumarin for 24 hours or more. The fixed liver is thoroughly washed with water, and 70%, 8
After stepwise dehydration with 0%, 90% and 100% ethanol, they were fixed in paraffin. The fixed liver was cut into a thickness of about 4 μm using a microtome and stained with hematoxylin and eosin. The stained liver sample was clarified with xylene, mounted on a permount, and then observed under an optical microscope to examine the presence or absence of a lesion.
【００６７】 図２Ａ、２Ｂおよび２Ｃは、各々１％コレステロール投与群(対照群)；１％コ
レステロールと１ｍｇ／ｋｇロバスタチン(商標)投与群(比較群)；および１％コ
レステロールと０.１％ヘスペリジン投与群のウサギの肝の電子顕微鏡写真を示 す。図２Ａおよび２Ｂから分かるように、対照群および比較群の肝細胞は不規則
に配列し、かつ肥大化し、多量の脂肪が蓄積されている。反面、図２Ｃから分か
るように、ヘスペリジン投与群の肝細胞は正常であり、脂肪蓄積は観察されなか
った。この結果は、ヘスペリジンが肝細胞に副作用なしに脂肪肝の発生を強く抑
制することを示す。FIGS. 2A, 2B and 2C show 1% cholesterol administration group (control group); 1% cholesterol and 1 mg / kg Lovastatin ™ administration group (comparison group); and 1% cholesterol and 0.1% hesperidin. The electron micrograph of the liver of the rabbit of the administration group is shown. As can be seen from FIGS. 2A and 2B, the hepatocytes of the control group and the comparative group are irregularly arranged and enlarged, and a large amount of fat is accumulated. On the other hand, as can be seen from FIG. 2C, the hepatocytes in the hesperidin administration group were normal, and no fat accumulation was observed. This result indicates that hesperidin strongly suppresses the development of fatty liver without side effects on hepatocytes.
【００６８】 (段階４)ヒトを用いた実験 ヘスペリジンを５５歳の男性に毎日１０ｍｇ／ｋｇの投与量で６８日間経口投
与し、投与直前(０日)、投与後４５日(４５日)および６８日(６８日)に血漿ＧＯ
Ｔ、ＧＰＴおよびγＧＴＰ濃度を各々測定した。その結果、４５日と６８日に血
漿ＧＯＴ濃度が０日に比べて各々１７％減少した。４５日および６８日の血漿Ｇ
ＰＴの濃度は０日に比べて各々１５％および１９％減少した。また、４５日およ
び６８日に測定した血漿γＧＴＰ数値は０日に比べて各々２５％および５１％減
少した。驚くべきことに、６８日までの血漿γＧＰＴ濃度の減少は５０％以上で
あり、この結果はヘスペリジンまたはヘスペレチンが強力な肝保護活性および、
肝炎、脂肪肝およびアルコール性脂肪肝のような肝疾患に対する予防活性を有す
ることを示す。(Step 4) Experiment on Human Hesperidin was orally administered to a 55-year-old man at a dose of 10 mg / kg daily for 68 days, immediately before administration (day 0), 45 days after administration (day 45) and 68 days after administration. Plasma GO on the day (68th)
T, GPT and γGTP concentrations were measured respectively. As a result, the plasma GOT concentration was reduced by 17% on days 45 and 68, respectively, as compared to day 0. Plasma G on days 45 and 68
PT levels were reduced by 15% and 19%, respectively, compared to day 0. In addition, the plasma γGTP values measured on days 45 and 68 were reduced by 25% and 51%, respectively, compared to day 0. Surprisingly, the decrease in plasma γGPT concentration by day 68 was more than 50%, indicating that hesperidin or hesperetin had potent hepatoprotective activity and
It has prophylactic activity against liver diseases such as hepatitis, fatty liver and alcoholic fatty liver.
【００６９】 一方、毎日１００ｃｃのアルコール飲料を習慣的に飲む５６歳の男性にヘスペ
リジンを毎日６ｍｇ／ｋｇの量で３０日間経口投与し、血漿γＧＴＰ濃度を投与
直前(０日)と投与後３０日(３０日)に測定した。その結果、０日の初期血漿γＧ
ＴＰ濃度は１２９ ＩＵ／ｌである反面、３０日の場合には正常範疇内である６
９ ＩＵ／ｌに減少した。この結果は、ヘスペリジンまたはヘスペレチンがアル
コール性脂肪肝および肝硬変症に対して高い予防活性を有することを示す。On the other hand, hesperidin was orally administered at a dose of 6 mg / kg daily for 30 days to a 56-year-old man who regularly drinks 100 cc of alcoholic beverage every day, and the plasma γGTP concentration was immediately before administration (day 0) and 30 days after administration. (30 days). As a result, the initial plasma γG on day 0
The TP concentration is 129 IU / l, but is within the normal range in the case of 30 days 6
Reduced to 9 IU / l. This result indicates that hesperidin or hesperetin has high prophylactic activity against alcoholic fatty liver and cirrhosis.
【００７０】 実施例９：ヘスペリジンまたはヘスペレチンを含む食品 ヘスペリジンまたはヘスペレチンを含む食品は次のように製造した。 (１)トマトケチャップおよびソースの製造 ヘスペリジンまたはヘスペレチンをトマトケチャップまたはソースに０.０１ 〜５重量％の量で加えて健康増進用トマトケチャップまたはソースを得た。Example 9: Food containing hesperidin or hesperetin A food containing hesperidin or hesperetin was prepared as follows. (1) Production of tomato ketchup and sauce Hesperidin or hesperetin was added to tomato ketchup or sauce in an amount of 0.01 to 5% by weight to obtain tomato ketchup or sauce for promoting health.
【００７１】 (２)小麦粉食品の製造 ヘスペリジンまたはヘスペレチンを小麦粉に０.０１〜５重量％の量で加え、 この混合物を用いてパン、ケーキ、クッキー、クラッカーおよび麺類を製造して
健康増進用食品を得た。(2) Production of Flour Foods Hesperidin or hesperetin is added to flour in an amount of 0.01 to 5% by weight, and the mixture is used to produce breads, cakes, cookies, crackers and noodles, and foods for promoting health. I got
【００７２】 (３)スープおよび肉汁の製造 ヘスペリジンまたはヘスペレチンをスープおよび肉汁に０.０１〜５重量％の 量で加えて健康増進用スープおよび肉汁を得た。(3) Preparation of Soup and Gravy Hesperidin or hesperetin was added to the soup and gravy in an amount of 0.01 to 5% by weight to obtain a soup and gravy for promoting health.
【００７３】 (４)グラウンドビーフの製造 ヘスペリジンまたはヘスペレチンをグラウンドビーフに０.０１〜５重量％の 量で加えて健康増進用グラウンドビーフを得た。(4) Production of Ground Beef Hesperidin or hesperetin was added to ground beef in an amount of 0.01 to 5% by weight to obtain ground beef for health promotion.
【００７４】 (５)乳製品の製造 ヘスペリジンまたはヘスペレチンを牛乳に０.０１〜５重量％の量で加え、こ の牛乳を用いてバーターおよびアイスクリームのような種々の牛製品を製造した
。(5) Production of Dairy Products Hesperidin or hesperetin was added to milk in an amount of 0.01 to 5% by weight, and various milk products such as barter and ice cream were produced using the milk.
【００７５】 しかし、チーズの製造の際には、ヘスペリジンまたはヘスペレチンを凝固した
牛乳タンパク質に加え、ヨーグルトの製造の際には、ヘスペリジンまたはヘスペ
レチンを醗酵後に得られた凝固した牛乳タンパク質に加えた。However, in the production of cheese, hesperidin or hesperetin was added to the coagulated milk protein, and in the production of yogurt, hesperidin or hesperetin was added to the coagulated milk protein obtained after fermentation.
【００７６】 実施例１０：ヘスペリジンまたはヘスペレチンを含む飲料 (１)野菜ジュースの製造 ヘスペリジンまたはヘスペレチン２００〜１０,０００ｍｇをトマトまたはニ ンジンジュース１,０００ｍｌに加えて健康増進用野菜ジュースを得た。Example 10: Beverage containing hesperidin or hesperetin (1) Production of vegetable juice Hesperidin or hesperetin 200 to 10,000 mg was added to 1,000 ml of tomato or carrot juice to obtain a vegetable juice for promoting health.
【００７７】 (２)果物ジュースの製造 ヘスペリジンまたはヘスペレチン２００〜１０,０００ｍｇをリンゴまたはブ ドウジュース１,０００ｍｌに加えて健康増進用果物ジュースを得た。(2) Production of Fruit Juice 200 to 10,000 mg of hesperidin or hesperetin was added to 1,000 ml of apple or vinegar juice to obtain a fruit juice for promoting health.
【００７８】 (３)炭酸飲料の製造 ヘスペリジンまたはヘスペレチン２００〜１０,０００ｍｇをコカ・コーラ(商
標)またはペプシコーラ(商標)１,０００ｍｌに加えて健康増進用炭酸飲料を得た
。 本発明を具体的な実施態様と関連させて記述したが、添付した特許請求の範囲
によって定義される本発明の範囲内で、当該分野の熟練者が本発明を多様に変形
および変化させ得ると理解されなければならない。(3) Production of Carbonated Beverage Hesperidin or hesperetin (200 to 10,000 mg) was added to 1,000 ml of Coca-Cola (trademark) or Pepsi-Cola (trademark) to obtain a carbonated drink for promoting health. Although the present invention has been described in connection with specific embodiments, it is to be understood that, within the scope of the present invention, which is defined by the appended claims, those skilled in the art may make various modifications and variations to the present invention. Must be understood.
【図１】 図１Ａ、１Ｂおよび１Ｃは各々１％コレステロール、１％コレス
テロールと１ｍｇ／ｋｇロバスタチン(商標)、および１％コレステロールと０.１
％ヘスペリジンが投与されたウサギの動脈を示す写真である。1A, 1B and 1C show 1% cholesterol, 1% cholesterol and 1 mg / kg Lovastatin ™, and 1% cholesterol and 0.1% respectively.
5 is a photograph showing an artery of a rabbit to which% hesperidin was administered.
【図２】 図２Ａ、２Ｂおよび２Ｃは各々１％コレステロール、１％コレス
テロールと１ｍｇ／ｋｇロバスタチン(商標)、および１％コレステロールと０. １％ヘスペリジンが投与されたウサギの肝の電子顕微鏡写真である。FIGS. 2A, 2B and 2C are electron micrographs of the liver of a rabbit receiving 1% cholesterol, 1% cholesterol and 1 mg / kg Lovastatin ™, and 1% cholesterol and 0.1% hesperidin, respectively. is there.
【手続補正書】[Procedure amendment]
【提出日】平成１２年６月２８日（２０００．６．２８）[Submission date] June 28, 2000 (2000.6.28)
【手続補正１】[Procedure amendment 1]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】特許請求の範囲[Correction target item name] Claims
【補正方法】変更[Correction method] Change
【補正内容】[Correction contents]
【特許請求の範囲】[Claims]
【請求項５】 上記機能性食品が、肉類、チョコレート、スナック類、菓子
類、ピザ、穀物の粉末から作られる食品類、チューインガム類、乳製品、スープ、
肉汁、ペースト、ケチャップ、ソース、ビタミン複合体または健康食品類から選
ばれる食品である、請求項３記載の組成物。 5. The functional food is meat, chocolate, snacks, confectionery, pizza, food made from cereal powder, chewing gum, dairy product, soup,
The composition according to claim 3, which is a food selected from gravy, paste, ketchup, sauce, vitamin complex, and health foods.
【手続補正２】[Procedure amendment 2]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】００２２[Correction target item name] 0022
【補正方法】変更[Correction method] Change
【補正内容】[Correction contents]
【００２２】 また、本発明は、活性成分としてヘスペリジンまたはヘスペレチンおよび薬剤
学的に許容可能な賦形剤、担体または希釈剤を含む、ＡＣＡＴ活性抑制、動脈壁
でのマクロファージ−脂質複合体蓄積抑制、および肝疾患予防または治療のため
の薬剤学的組成物を提供する。 なお、(1)哺乳動物の動脈内皮上でのマクロファージ−脂質複合体の蓄積を抑 制するためのヘスペリジンまたはヘスペレチンを含む組成物および(1')哺乳動物
の肝疾患を予防または治療するためのヘスペリジンまたはヘスペレチンを含む組
成物の実施態様として、(2)上記哺乳動物がヒトである、(1)または(1')の組成物
；(3)哺乳動物のための医薬、または機能性食品に用いられる、(1)または(1')ま
たは(2)の組成物；(4)上記医薬に用いられるヘスペリジンまたはヘスペレチンの
量が０.１〜１００ｍｇ／ｋｇ体重／日の範囲である、(3)の組成物；(5)上記機 能性食品が、肉類、チョコレート、スナック類、菓子類、ピザ、穀物の粉末から 作られる食品類、チューインガム類、乳製品、スープ、肉汁、ペースト、ケチャ ップ、ソース、ビタミン複合体または健康食品類から選ばれる食品である、(3) の組成物；(6)上記穀物の粉末から作られる食品類が、パン、ケーキ、クラッカ ー、クッキー、ビスケットまたはヌードルである、(5)の組成物；(7)上記食品に
用いられるヘスペリジンまたはヘスペレチンの量が、０.０１〜５重量％の範囲 である、(5)または(6)の組成物；(8)上記機能性食品が、乳製品、野菜ジュース 、果物ジュース、茶、アルコール飲料類または炭酸飲料から選ばれる飲料である
、(3)の組成物；(9)上記飲料に用いられるヘスペリジンまたはヘスペレチンの量
が、飲料１,０００ｍｌ当り２００〜１０,０００ｍｇの範囲である、(8)の組成 物が含まれる。The present invention also provides a method for inhibiting ACAT activity, inhibiting macrophage-lipid complex accumulation on arterial walls, comprising hesperidin or hesperetin as an active ingredient and a pharmaceutically acceptable excipient, carrier or diluent. And a pharmaceutical composition for preventing or treating liver disease. In addition, (1) a composition containing hesperidin or hesperetin for suppressing accumulation of macrophage-lipid complex on the endothelial endothelium of a mammal and (1 ′) a composition for preventing or treating liver disease in a mammal. As an embodiment of the composition containing hesperidin or hesperetin, (2) the mammal is a human, (1) or (1 ′) composition; (3) a medicament for mammals, or functional foods (4) the composition of (1) or (1 ′) or (2) used; (4) the amount of hesperidin or hesperetin used in the medicament is in the range of 0.1 to 100 mg / kg body weight / day; (5) wherein the functional food is meat, chocolate, snacks, confectionery, pizza, food made from cereal powder, chewing gum, dairy products, soup, gravy, paste, ketchup; Pumps, sauces, vitamin complexes or The composition of (3), which is a food selected from health foods; (6) the foods made from the cereal powder are breads, cakes, crackers, cookies, biscuits, or noodles; (7) The composition of (5) or (6), wherein the amount of hesperidin or hesperetin used in the food is in the range of 0.01 to 5% by weight; The composition of (3), which is a beverage selected from dairy products, vegetable juices, fruit juices, teas, alcoholic beverages or carbonated beverages; (9) the amount of hesperidin or hesperetin used in the beverage is 1,000 ml of the beverage; The composition of (8), which is in the range of 200 to 10,000 mg per day.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ テーマコート゛(参考） Ａ２３Ｌ 1/30 Ａ２３Ｌ 1/30 Ｚ ４Ｂ０４２ 1/31 1/31 Ｚ ４Ｂ０４７ 2/52 Ａ６１Ｋ 31/7048 ４Ｃ０８６ Ａ６１Ｋ 31/7048 Ａ６１Ｐ 1/16 Ａ６１Ｐ 1/16 3/06 3/06 43/00 １１１ 43/00 １１１ Ｃ１２Ｇ 3/00 Ｃ１２Ｇ 3/00 Ａ２３Ｌ 2/00 Ｆ (31)優先権主張番号 １９９８／１２４１１ (32)優先日 平成10年４月８日(1998．4．8) (33)優先権主張国 韓国（ＫＲ） (31)優先権主張番号 １９９８／１３２８３ (32)優先日 平成10年４月14日(1998．4．14) (33)優先権主張国 韓国（ＫＲ） (81)指定国 ＥＰ(ＡＴ，ＢＥ，ＣＨ，ＣＹ， ＤＥ，ＤＫ，ＥＳ，ＦＩ，ＦＲ，ＧＢ，ＧＲ，ＩＥ，Ｉ Ｔ，ＬＵ，ＭＣ，ＮＬ，ＰＴ，ＳＥ)，ＣＡ，ＣＮ，Ｊ Ｐ，ＲＵ (72)発明者 ミュンソク・チョイ 大韓民国706−014テク、スソンク、ブメオ ４ドン、ガーデン・ハイツ・アパートメン ト102−203 (72)発明者 スルクシク・モン 大韓民国314−110チュンチョンナムド、ゴ ンジュシ、シンクワンドン、ナンバー５ 番、ゴムナル・アパートメント101−601 (72)発明者 ヨンコク・クウォン 大韓民国305−333テジョン、ユソンク、エ ウンドン、ナンバー99番、ハンビット・ア パートメント126−1307 (72)発明者 エウンソク・リー 大韓民国301−013テジョン、ジュンク、テ フン３ドン、ナンバー49−２番 (72)発明者 ビュンハ・ヒュン 大韓民国305−333テジョン、ユソンク、エ ウンドン、ナンバー99番、ハンビット・ア パートメント131−1401 (72)発明者 ヤンキュー・チョイ 大韓民国305−333テジョン、ユソンク、エ ウンドン、ナンバー99番、ハンビット・ア パートメント137−706 (72)発明者 チュルホー・リー 大韓民国302−171テジョン、ソーク、ガル マドン、ギュンソン・クンマエウル・アパ ートメント120−1307 (72)発明者 キファン・ベ 大韓民国302−200テジョン、ソーク、ゴイ ジョンドン、ナンバー113−12番 (72)発明者 ヨンボク・パク 大韓民国706−014テグ、スソンク、ブメオ ４ドン、ガーデン・ハイツ・アパートメン ト102−203 (72)発明者 ジュンソン・リー 大韓民国302−280テジョン、ソーク、ウォ ルピュンドン、ヌリ・アパートメント107 −102 (72)発明者 クワンヘー・ソン 大韓民国305−333テジョン、ユソンク、エ ウンドン、ナンバー99番、ハンビット・ア パートメント103−1702 (72)発明者 ビョンモグ・クウォン 大韓民国305−340テジョン、ドリョンド ン、ナンバー380−51番、ドリョン・ビラ 102 (72)発明者 ヨンコク・キム 大韓民国305−333テジョン、ユソンク、エ ウンドン、ナンバー99番、ハンビット・ア パートメント102−601 (72)発明者 ドイル・チョイ 大韓民国305−340テジョン、ユソンク、ド リョンドン、キスト・アパートメント２− 305 (72)発明者 ソンウク・キム 大韓民国305−333テジョン、ユソンク、エ ウンドン、ナンバー99番、ハンビット・ア パートメント110−405 (72)発明者 インギュ・ファン 大韓民国305−340テジョン、ユソンク、ド リョンドン、キスト・アパートメント２− 206 (72)発明者 ジュンアー・アーン 大韓民国300−092テジョン、ドンク、ガヤ ン２ドン、ナンバー162−40番 (72)発明者 ヨンベ・パク 大韓民国135−110ソウル、カンナムク、ア プグジョンドン、ヒュンダイ・アパートメ ント83−206 (72)発明者 ヒョーソー・キム 大韓民国135−110ソウル、カンナムク、ア プグジョンドン、ヒュンダイ・アパートメ ント85−1401 (72)発明者 ソーンチョーン・チョウ 大韓民国121−040ソウル、マポク、ドーワ ドン、マポ・サムソン・アパートメント 105−1204 Ｆターム(参考） 4B001 AC99 EC05 4B014 GB01 GB11 GK06 GL03 4B017 LC03 LG04 LG07 LK06 LK18 4B018 LB01 LB02 LB06 LB07 LB09 MD08 ME14 4B032 DB01 DB05 DB21 DB23 DK05 DL20 4B042 AC04 AH01 AK02 4B047 LG06 LG65 LG66 4C086 AA01 AA02 BA19 EA11 MA17 MA34 MA52 NA14 ZA45 ZA75 ZC20 ZC61 (54)【発明の名称】 アシルＣＯＡ−コレステロール−Ｏ−アシルトランスフェラーゼ抑制剤、動脈壁上でのマクロフ ァージ−脂質複合体蓄積の抑制剤および肝疾患予防または治療剤としてのヘスペリジンおよびヘ スペレチン──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 7 Identification code FI Theme coat ゛ (Reference) A23L 1/30 A23L 1/30 Z 4B042 1/31 1/31 Z 4B047 2/52 A61K 31/7048 4C086 A61K 31/7048 A61P 1/16 A61P 1/16 3/06 3/06 43/00 111 43/00 111 C12G 3/00 C12G 3/00 A23L 2/00 F (31) Priority claim number 1998/12411 (32 ) Priority date April 8, 1998 (1998.4.8) (33) Priority claiming country South Korea (KR) (31) Priority claim number 1998/13283 (32) Priority date April 14, 1998 (33 April 1998) (33) Countries claiming priority South Korea (KR) (81) Designated States EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC (NL, PT, SE), CA, CN, JP, RU (72) Inventor Mun-suk Choi Republic of Korea 706-014 Tech, Suseong, Bumeo 4Don, Garden Heights Apartment 102-203 (72) Inventor Suruksik Mon South Korea 314-110 Chungcheongnam-do, Gongjusi, Sinkwandong, No.5, Gonamal Apartment 101-601 (72) Inventor Yongkook Kwon South Korea 305-333 Daejeon, Yusongku, Eundong, No.99 Eunsuk Lee, Republic of Korea 301-013 Daejeon, Jungk, Taehung 3dong, No. 49-2, No. 49-2 (72) Inventor Byunha Hyun, Republic of Korea 305-333 Daejeon, Yusungk , Eun Dong, No. 99, Hanbit Apartment 131-1401 (72) Inventor Yankee Choi 305-333 Te, South Korea Eun-dong, Young-sung, Eun-dong, No. 99, Hanbit apartment 137-706 (72) Inventor Culho-lee South Korea 302-171 Daejeon, Sauk, Garmadon, Gyun-son kummaeul apartment 120-1307 (72) Inventor Kifang Bae Republic of Korea 302-200 Daejeon, Soak, Goi Jong-dong, No. 113-12 (72) Inventor Yeonbok Park Republic of Korea 706-014 Daegu, Susongk, Bumeo 4 Dong, Garden Heights Apartment 102 −203 (72) Inventor Junsung Lee Republic of Korea 302-280 Daejeon, Salk, Walpydon, Nuri Apartment 107−102 (72) Inventor Kwanghae Son Republic of Korea 305-333 Daejeon, Yusong, Eundong, No. 99, Hanbit Apartment 103-1702 (72) Inventor Byungmog Kwon 305-340 Daejeon, Korea Doryeong-dong, No. 380-51, Doryon Villa 102 (72) Inventor Yongkok Kim Republic of Korea 305-333 Daejeon, Yusung, Eun-dong, No. 99, Hanbit apartment 102-601 (72) Inventor Doyle・ Choy Korea 305-340 Daejeon, Yusung, Dong-dong, Kist Apartment 2-305 (72) Inventor Songwook Kim 305-333 Daejeon, Yusong, Korea, No.99, Hanbit Apartment 110-405 (72) Inventor Ingyu Hwang 305-340 Daejeon, Republic of Korea, Yusongku, Dryong-dong, Kist Apartment 2-206 (72) Inventor Jungah Aan 300-092 Daejeon, Republic of Korea No. 162-40, Daejeon, Dongk, Gayan 2-dong Number (72) Inventor Yongbe Park 135-110 South Korea, Gangnamuk, Apgujeongdong, Hyundai Apartment 83-206 (72) Inventor Hyo Seo Kim 135-110 South Korea, Gangnamuk, Apgujeong-dong, Hyundai Apartment 85-1401 (72) Inventor Thorn Chong Chou South Korea 121-040 Seoul, Mapok, Dowa Dong, Mapo Samson Apartment 105-1204 F-term (reference) 4B001 AC99 EC05 4B014 GB01 GB11 GK06 GL03 4B017 LC03 LG04 LG07 LK06 LK18 4B018 LB01 LB02 LB06 LB07 LB09 MD08 ME14 4B032 DB01 DB05 DB21 DB23 0405B04 A0420 LG06 LG65 LG66 4C086 AA01 AA02 BA19 EA11 MA17 MA34 MA52 NA14 ZA45 ZA75 ZC20 ZC61 (54) [Title of the Invention] Acyl COA-cholesterol-O-acyltransferase inhibitor, suppression of macrophage-lipid complex accumulation on arterial wall And hesperetin as drugs and liver disease prevention or treatment
Claims (27)
スペレチンの使用。1. Use of hesperidin or hesperetin for inhibiting the activity of acyl-CoA-cholesterol-o-acyltransferase (ACAT) in a mammal.
哺乳動物に投与され、該組成物が、薬剤学的組成物、食品組成物および飲料組成
物からなる群から選ばれる、請求項１記載の使用。3. The composition according to claim 1, wherein hesperidin or hesperetin is administered to the mammal in a form contained in the composition, wherein the composition is selected from the group consisting of a pharmaceutical composition, a food composition and a beverage composition. Use of the description.
チンの有効量が０.１〜１００ｍｇ／ｋｇ体重／日の範囲である、請求項３記載 の使用。4. The use according to claim 3, wherein the effective amount of hesperidin or hesperetin contained in the pharmaceutical composition ranges from 0.1 to 100 mg / kg body weight / day.
量が０.０１〜５重量％の範囲である、請求項３記載の使用。5. The use according to claim 3, wherein the content of hesperidin or hesperetin in the food composition is in the range of 0.01 to 5% by weight.
求項３記載の使用。6. The food product is prepared from meat, chocolate, snacks, confectionery, pizza, cereal powder, chewing gum, dairy product, soup, gravy, paste, ketchup, sauce, vitamin complex. 4. The use according to claim 3, which is a health food.
ッカー、クッキー、ビスケットまたはヌードルである、請求項６記載の使用。7. Use according to claim 6, wherein the food products made from the cereal powder are breads, cakes, crackers, cookies, biscuits or noodles.
茶、アルコール飲料類または炭酸飲料である、請求項３記載の使用。8. The beverage composition according to claim 1, wherein the dairy product, vegetable juice, fruit juice,
Use according to claim 3, which is a tea, an alcoholic beverage or a carbonated beverage.
量が、飲料１,０００ｍｌ当り２００〜１０,０００ｍｇの範囲である、請求項３
記載の使用。9. The beverage composition according to claim 3, wherein the content of hesperidin or hesperetin is in the range of 200 to 10,000 mg per 1,000 ml of the beverage.
Use of the description.
蓄積を抑制するためのヘスペリジンまたはヘスペレチンの使用。10. Use of hesperidin or hesperetin for inhibiting macrophage-lipid complex accumulation on mammalian arterial endothelium.
で哺乳動物に投与され、該組成物が、薬剤学的組成物、食品組成物および飲料組
成物からなる群から選ばれる、請求項１０記載の使用。12. The composition according to claim 10, wherein hesperidin or hesperetin is administered to the mammal in a form contained in the composition, wherein the composition is selected from the group consisting of a pharmaceutical composition, a food composition and a beverage composition. Use of the description.
レチンの有効量が０.１〜１００ｍｇ／ｋｇ体重／日の範囲である、請求項１２ 記載の使用。13. The use according to claim 12, wherein the effective amount of hesperidin or hesperetin contained in the pharmaceutical composition ranges from 0.1 to 100 mg / kg body weight / day.
有量が、０.０１〜５重量％の範囲である、請求項１２記載の使用。14. The use according to claim 12, wherein the content of hesperidin or hesperetin in the food composition is in the range of 0.01 to 5% by weight.
請求項１２記載の使用。15. The food, wherein the food is meat, chocolate, snacks, confectionery, pizza, food made from cereal powder, chewing gum, dairy product, soup, juice, paste, ketchup, sauce, vitamin complex. Or health foods,
13. Use according to claim 12.
ラッカー、クッキー、ビスケットまたはヌードルである、請求項１５記載の使用
。16. Use according to claim 15, wherein the food products made from the cereal powder are breads, cakes, crackers, cookies, biscuits or noodles.
、茶、アルコール飲料類または炭酸飲料である、請求項１２記載の使用。17. The use according to claim 12, wherein the beverage composition is a dairy product, vegetable juice, fruit juice, tea, alcoholic beverage or carbonated beverage.
有量が、飲料１,０００ｍｌ当り２００〜１０,０００ｍｇの範囲である、請求項
１２記載の使用。18. The use according to claim 12, wherein the content of hesperidin or hesperetin in the beverage composition ranges from 200 to 10,000 mg per 1,000 ml of beverage.
ンまたはヘスペレチンの使用。19. Use of hesperidin or hesperetin for preventing or treating liver disease in a mammal.
で哺乳動物に投与され、該組成物が、薬剤学的組成物、食品組成物および飲料組
成物からなる群から選ばれる、請求項１９記載の使用。21. The composition according to claim 19, wherein hesperidin or hesperetin is administered to the mammal in a form contained in the composition, wherein the composition is selected from the group consisting of a pharmaceutical composition, a food composition and a beverage composition. Use of the description.
レチンの有効量が、０.１〜１００ｍｇ／ｋｇ体重／日の範囲である、請求項２ １記載の使用。22. The use according to claim 21, wherein the effective amount of hesperidin or hesperetin contained in the pharmaceutical composition ranges from 0.1 to 100 mg / kg body weight / day.
量が０.０１〜５重量％の範囲である、請求項２１記載の使用。23. The use according to claim 21, wherein the content of hesperidin or hesperetin in the food composition ranges from 0.01 to 5% by weight.
請求項２１記載の使用。24. The food, wherein the food is meat, chocolate, snacks, confectionery, pizza, food made from cereal powder, chewing gum, dairy product, soup, juice, paste, ketchup, sauce, vitamin complex. Or health foods,
Use according to claim 21.
ラッカー、クッキー、ビスケットまたはヌードルである、請求項２４記載の使用
。25. The use according to claim 24, wherein the foods made from the cereal powder are breads, cakes, crackers, cookies, biscuits or noodles.
、茶、アルコール飲料類または炭酸飲料である、請求項２１記載の使用。26. The use according to claim 21, wherein the beverage composition is a dairy product, vegetable juice, fruit juice, tea, alcoholic beverage or carbonated beverage.
量が、飲料１,０００ｍｌ当り２００〜１０,０００ｍｇの範囲である、請求項２
１記載の使用。27. The content of hesperidin or hesperetin in the beverage composition ranges from 200 to 10,000 mg per 1,000 ml of beverage.
Use according to 1.
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019970055578A KR19990034089A (en) | 1997-10-28 | 1997-10-28 | Acylcoay: Cholesterol-Ortho-Acyltransferase Inhibitor Compositions Including Hesperidin or Hesperetin |
| KR1019980010888A KR19990076178A (en) | 1998-03-28 | 1998-03-28 | Composition for the prevention and treatment of liver disease, including hesperidin |
| KR1998/10888 | 1998-03-28 | ||
| KR1019980012411A KR19990079683A (en) | 1998-04-08 | 1998-04-08 | Functional health food containing citrus rind powder or rind extract |
| KR1998/12411 | 1998-04-08 | ||
| KR1997/55578 | 1998-04-14 | ||
| KR1019980013283A KR19990080214A (en) | 1998-04-14 | 1998-04-14 | Functional drink containing health extract of citrus peel |
| KR1998/13283 | 1998-04-14 | ||
| PCT/KR1998/000324 WO1999021549A1 (en) | 1997-10-28 | 1998-10-20 | Hesperidin and hesperetin as inhibitor of acyl coa-cholesterol-o-acyltransferase, inhibitor of macrophage-lipid complex accumulation on the arterial wall and preventive or treating agent for hepatic diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2001520993A true JP2001520993A (en) | 2001-11-06 |
Family
ID=27483239
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000517707A Pending JP2001520993A (en) | 1997-10-28 | 1998-10-20 | Acyl COA-cholesterol-O-acyltransferase inhibitors, inhibitors of macrophage-lipid complex accumulation on arterial walls and hesperidin and hesperetin as agents for preventing or treating liver diseases |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1063988A1 (en) |
| JP (1) | JP2001520993A (en) |
| CN (1) | CN1124133C (en) |
| CA (1) | CA2307890A1 (en) |
| WO (1) | WO1999021549A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006067925A1 (en) * | 2004-12-24 | 2006-06-29 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | Hepatic function remedial agent |
| JP2009007256A (en) * | 2007-06-26 | 2009-01-15 | Kao Corp | Nadh/nadph oxidase inhibitor |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020006953A1 (en) * | 1999-11-05 | 2002-01-17 | Carla R. McGill | Modification of cholesterol concentrations with citus phytochemicals |
| FR2841472B1 (en) * | 2002-06-28 | 2006-02-24 | Agronomique Inst Nat Rech | NUTRITIONAL OR THERAPEUTIC COMPOSITION CONTAINING THE HESPERIDINE COMPOUND OR ONE OF ITS DERIVATIVES |
| US8163319B2 (en) | 2004-07-23 | 2012-04-24 | Suntory Holdings Limited | Method of production of an alcohol-dipped food or drink |
| EP2368442B1 (en) | 2005-07-27 | 2014-12-17 | Symrise AG | Use of hesperetin for enhancing the sweet taste |
| CN101374424B (en) * | 2006-01-23 | 2013-03-27 | 三得利控股株式会社 | Food or drink and method of producing the same |
| JP2007112806A (en) * | 2006-11-27 | 2007-05-10 | Kao Corp | Agent for promoting body-fat burning |
| CN104688756A (en) * | 2013-12-09 | 2015-06-10 | 中国药科大学 | Pharmaceutical composition and its use in preparation of drug for treating alcoholic liver injury |
| TWI715172B (en) * | 2019-08-28 | 2021-01-01 | 健茂生物科技股份有限公司 | Composition in suppressing body fat accumulation |
| CN114832041A (en) * | 2021-02-01 | 2022-08-02 | 健茂生物科技股份有限公司 | Composition with liver protection effect and preparation method thereof |
| CN114832007A (en) * | 2021-02-01 | 2022-08-02 | 健茂生物科技股份有限公司 | Composition for reducing cholesterol and preparation method thereof |
| CN115607538A (en) * | 2022-09-26 | 2023-01-17 | 浙江工商大学 | Application of hesperetin in preparation of medicine for inhibiting and/or treating wheat allergy |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4150038A (en) * | 1977-05-16 | 1979-04-17 | Dynapol | Conversion of hesperidin into hesperetin |
| JPS54154569A (en) * | 1978-05-20 | 1979-12-05 | Lotte Co Ltd | Chewing gum for sports |
| DE3879688T2 (en) * | 1987-12-10 | 1993-07-01 | Tsumura & Co | ANTI-RETROVIRAL MEDICINAL PRODUCT. |
| EP0347864A3 (en) * | 1988-06-24 | 1992-04-01 | Andries Johannes Cornelus Strydom | Anti-atherogenic agents |
| JPH04295428A (en) * | 1991-03-22 | 1992-10-20 | Dai Ichi Seiyaku Co Ltd | Antiallergic agent |
| AU6666594A (en) * | 1993-04-20 | 1994-11-08 | Procter & Gamble Company, The | Methods of using hesperetin for sebum control and treatment of acne |
| JPH0725761A (en) * | 1993-07-09 | 1995-01-27 | Kureha Chem Ind Co Ltd | Agent for protecting cartilage |
| JP3557711B2 (en) * | 1995-04-12 | 2004-08-25 | 日本新薬株式会社 | Foods and manufacturing methods effective for improving lipid metabolism |
| JPH08283154A (en) * | 1995-04-12 | 1996-10-29 | Nippon Shinyaku Co Ltd | Lipid metabolism improver |
-
1998
- 1998-10-20 JP JP2000517707A patent/JP2001520993A/en active Pending
- 1998-10-20 CA CA002307890A patent/CA2307890A1/en not_active Abandoned
- 1998-10-20 EP EP98951777A patent/EP1063988A1/en not_active Withdrawn
- 1998-10-20 WO PCT/KR1998/000324 patent/WO1999021549A1/en not_active Application Discontinuation
- 1998-10-20 CN CN98810701A patent/CN1124133C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006067925A1 (en) * | 2004-12-24 | 2006-06-29 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | Hepatic function remedial agent |
| JP2013116918A (en) * | 2004-12-24 | 2013-06-13 | Hayashibara Co Ltd | Agent for ameliorating liver function |
| KR101356330B1 (en) | 2004-12-24 | 2014-01-27 | 가부시끼가이샤 하야시바라 세이부쓰 가가꾸 겐꾸조 | Hepatic function remedial agent |
| JP5694628B2 (en) * | 2004-12-24 | 2015-04-01 | 株式会社林原 | Liver function improving agent |
| JP2009007256A (en) * | 2007-06-26 | 2009-01-15 | Kao Corp | Nadh/nadph oxidase inhibitor |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1124133C (en) | 2003-10-15 |
| CA2307890A1 (en) | 1999-05-06 |
| CN1278170A (en) | 2000-12-27 |
| WO1999021549A1 (en) | 1999-05-06 |
| EP1063988A1 (en) | 2001-01-03 |
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