KR100504119B1 - Pharmaceutical composition useful for prevention or treatment of hepatitis - Google Patents
Pharmaceutical composition useful for prevention or treatment of hepatitis Download PDFInfo
- Publication number
- KR100504119B1 KR100504119B1 KR10-2002-0021352A KR20020021352A KR100504119B1 KR 100504119 B1 KR100504119 B1 KR 100504119B1 KR 20020021352 A KR20020021352 A KR 20020021352A KR 100504119 B1 KR100504119 B1 KR 100504119B1
- Authority
- KR
- South Korea
- Prior art keywords
- hepatitis
- formula
- virus
- catechin
- epicatechin
- Prior art date
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Classifications
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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
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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
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/38—Other non-alcoholic beverages
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- 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
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/324—Foods, ingredients or supplements having a functional effect on health having an effect on the immune system
-
- 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
- A23V2250/00—Food ingredients
- A23V2250/30—Other Organic compounds
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- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Nutrition Science (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Mycology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
본 발명은 하기 화학식 1의 구조를 가지는 카테킨 (catechin) 유도체 또는 하기 화학식 2의 구조를 가지는 에피카테킨 (epicatechin) 유도체를 B형 간염 예방 또는 치료에 사용하는 용도에 관한 것이다. 본 발명의 구체적으로 갈로카테킨갈레이트 (gallocatechingallate)를 포함하는 카테킨 유도체, 에피갈로카테킨갈레이트 (epigallocatechingallate)를 포함하는 에피카테킨 유도체 또는 그들의 약학적으로 허용 가능한 염은 바이러스성 간염을 만성 상태로 유지시키는 B형 간염 바이러스 e 항원의 분비를 억제하고, 세포 독성이 낮으므로 만성 및 급성 간염의 예방 및 치료에 유용하게 사용될 수 있다.The present invention relates to the use of a catechin derivative having a structure of Formula 1 or an epicatechin derivative having a structure of Formula 2 in the prevention or treatment of hepatitis B. Specifically, catechin derivatives including gallocatechingallate, epicatechin derivatives including epigallocatechingallate, or their pharmaceutically acceptable salts can be used to maintain viral hepatitis in a chronic state. Inhibiting the secretion of hepatitis B virus e antigen, and low cytotoxicity can be useful for the prevention and treatment of chronic and acute hepatitis.
<화학식 1><Formula 1>
<화학식 2><Formula 2>
상기 화학식 1 및 화학식 2에서 R1, R2, R3 및 R4는 독립적이며, H, OH 또는 기이다.In Formula 1 and Formula 2, R 1 , R 2 , R 3 and R 4 are independent, H, OH or Qi.
Description
본 발명은 하기 화학식 1의 구조를 가지는 카테킨 (catechin) 유도체 또는 하기 화학식 2의 구조를 가지는 에피카테킨 (epicatechin) 유도체를 B형 간염 예방 또는 치료에 사용하는 용도에 관한 것이다.The present invention relates to the use of a catechin derivative having a structure of Formula 1 or an epicatechin derivative having a structure of Formula 2 in the prevention or treatment of hepatitis B.
<화학식 1><Formula 1>
<화학식 2><Formula 2>
상기 화학식 1 및 화학식 2에서 R1, R2, R3 및 R4는 독립적이며, H, OH 또는 기이다.In Formula 1 and Formula 2, R 1 , R 2 , R 3 and R 4 are independent, H, OH or Qi.
사람의 B형 간염 바이러스 (HBV)는 급성 및 만성 간염을 유발하며, 자기제어성 급성 간염, 전격성 간염 또는 만성 활동성 간염 등의 병으로 진전될 수 있다. 만성 활동성 간염은 발전되어 간경변 및 간암 등을 유발하고, 간부전을 동반하는 심각한 급성으로 악화될 수 있다 (Brechot, C., J. Hepatol., 4, 269-279, 1987). 만성 간염에 감염되었을 때 대부분의 환자들은 지속성 또는 활동성 간염 증세를 보이는 반면 일부 환자들은 증세를 보이지 않는다. 상기 바이러스성 간염의 발병 기전이나 유발인자는 아직까지 명확히 밝혀지지 않은 실정이다. B형 간염 바이러스가 일으킨 간 손상은 숙주의 면역세포가 매개한다는 일부 증거가 제시된 이래 (Milich, D. R. et al., J. Immunol., 143, 3141-3147, 1989) 간세포 괴사를 유발하는 바이러스 항원과 특정 B 세포 및 T 세포의 면역 반응 및 바이러스 단백질의 직접적인 세포 발병 기전 또는 종양 발병 기전에 대한 연구가 집중적으로 이루어졌다 (R. Zschke, O. et al., Nature, 348, 252-254, 1990). 그러나 여전히 환자마다 다양하게 나타나는 임상 경로의 원인은 분명하지 않다.Human hepatitis B virus (HBV) causes acute and chronic hepatitis, and can develop into diseases such as self-controlling acute hepatitis, blunt hepatitis or chronic active hepatitis. Chronic active hepatitis develops, causes cirrhosis and liver cancer, and can be acutely acute with liver failure (Brechot, C., J. Hepatol. , 4, 269-279, 1987). When infected with chronic hepatitis, most patients show persistent or active hepatitis, while some do not. The pathogenesis or causative factors of the viral hepatitis are not clear yet. Since some evidence suggests that liver damage caused by the hepatitis B virus is mediated by the host's immune cells (Milich, DR et al., J. Immunol. , 143, 3141-3147, 1989), Intensive studies have been conducted on the immune response of specific B and T cells and the direct or pathogenic mechanisms of viral proteins (R. Zschke, O. et al., Nature , 348, 252-254, 1990). . However, the causes of the clinical pathways that still vary from patient to patient are not clear.
B형 간염은 그 증세의 심각성 때문에 그 치료에 많은 관심을 갖고 연구되어져 왔다. 현재 몇몇 약물과 백신이 개발되고 또한 임상 전실험과 임상 실험에서 좋은 평가를 받았으나 실제 치료제로 적용된 약은 거의 없는 상태로 지금까지 B형 간염 바이러스 (HBV)성 간염 환자에게 시행되는 유일한 치료법은 인체 면역 체계에 의존하는 것이다. HBV 에 대한 인체 면역 작용은 HBV 입자를 제거하지만 다른 한편으로는 간세포를 파괴하기 때문에 이러한 면역 작용의 부작용으로 치명적인 질환이 유발되기도 한다. 또한, 이러한 문제는 질병의 진행을 예측하기 어렵게 하므로 빠르고 효율적인 간염 치료를 위해서는 항바이러스 요법과 면역 치료법을 복합적으로 사용하는 것이 바람직하다. 즉, 바이러스성 간염의 치료시 감염된 간세포는 T 임파구 (cytotoxic T lymphocyte, CTL)에 의해 파괴되고, 파괴된 간세포에서 방출된 바이러스 입자는 바이러스에 대한 중화 항체를 제거하여 간세포로의 재감염도 막으면서 바이러스의 증식도 억제하여야 한다.Hepatitis B has been studied with great interest in its treatment because of its severity. Currently, several drugs and vaccines have been developed and have received good reviews in preclinical and clinical trials, but few drugs have been applied as a real treatment. To date, the only treatment for hepatitis B virus (HBV) hepatitis patients is human immunity. It depends on the system. Human immune action against HBV removes HBV particles, but on the other hand destroys hepatocytes, so side effects of these immune actions can lead to fatal diseases. In addition, since these problems make it difficult to predict disease progression, it is desirable to use a combination of antiviral therapy and immunotherapy for fast and efficient hepatitis treatment. In other words, during the treatment of viral hepatitis, infected hepatocytes are destroyed by cytotoxic T lymphocytes (CTLs), and virus particles released from the destroyed hepatocytes remove the neutralizing antibodies against the virus to prevent reinfection into the hepatocytes. Proliferation of should also be suppressed.
지금까지 B형 간염 바이러스를 치료하기 위하여 인터페론, 핵산 유도체 또는 면역 조절물질 등 여러 방법이 시도되었으나 인터페론-α만이 거의 유일하게 치료 효과가 있는 것으로 나타났으며 현재 인터페론-α만이 미국에서 간염 치료제로 사용되고 있다. 인터페론-α는 스컬레드 (Sculled) 등에 의하여 1970년대 중반 처음 만성 B형 간염 치료제로 시험되었는데 HBV 복제를 억제하는 효과가 있는 것으로 알려졌다. 그러나, 인터페론-α는 1주일에 3번씩 최소 3개월 동안 투여하였을 경우 평균 20 %의 환자에서 바이러스 증식이 억제되는 치료 효과를 나타낼 뿐 지속적인 억제 효과를 보이지는 못하며, 특히 동양 사람에게 많은 모자간의 수직 감염에 의한 환자 또는 어린이들은 인터페론-α에 내성을 나타내므로 그 치료 효과가 낮다. 또한, B형 간염 바이러스에 감염된 급성 및 만성 환자들 중 50% 이하만이 인터페론-α 치료법에 적합하다는 것이 최근 보고되었는데, 상기 환자들 중 바이러스에 대한 영향으로 간에서 생성되는 각종 효소들 (AST, SGOT, ALT, SGPT 등)의 양이 증가하는 경우에만 이 인터페론-α 치료법이 효과를 기대할 수 있다고 한다. 따라서 인터페론-α에 대해 내성을 가지는 환자들을 치료할 수 있는 B형 간염 바이러스 치료제의 개발이 시급한 실정이다. 특히 B형 간염 바이러스의 증식을 억제시키는 방법으로서 바이러스가 수용체에 부착하는 것을 저해하거나, 바이러스의 활성 단백질이나 중합효소를 특이적으로 저해하는 물질을 찾는 연구가 이루어지고 있다.Several methods have been tried to treat the hepatitis B virus, including interferon, nucleic acid derivatives or immunomodulators, but only interferon-α has been shown to be the only therapeutic effect. have. Interferon-α was first tested by Sculled et al. In the mid-1970s as a treatment for chronic hepatitis B. It has been shown to be effective in inhibiting HBV replication. However, interferon-α, when administered three times a week for at least three months, shows a therapeutic effect that inhibits virus growth in an average of 20% of patients, but does not show sustained inhibitory effects. Patients or children due to infection are resistant to interferon-α and therefore have a low therapeutic effect. In addition, it has recently been reported that only 50% or less of acute and chronic patients infected with the hepatitis B virus are suitable for the treatment of interferon-α, among which various enzymes (AST, Only if the amount of SGOT, ALT, SGPT, etc. is increased, the interferon-α treatment can be expected to be effective. Therefore, there is an urgent need to develop a hepatitis B virus therapeutic agent that can treat patients with resistance to interferon-α. In particular, as a method of inhibiting the proliferation of hepatitis B virus, research has been conducted to find a substance that inhibits the attachment of a virus to a receptor or specifically inhibits an active protein or a polymerase of a virus.
B형 간염 바이러스 복제시 3개 (c, s, e 항원)의 주요 항원이 만들어지는데 c (core) 항원은 구조적 항원 결정체이며 s (surface) 항원은 바이러스 표면 단백질에 의해 나타나는 항원 결정체이다. e 항원은 B형 간염 바이러스 감염 여부를 알아내는 혈액에서의 표시물질이다. e 항원은 B형 간염의 번식에 필수 조건은 아니며 B형 간염 바이러스의 생활사에서의 역할은 아직 확실히 밝혀져 있지 않다. 그러나, e 항원의 유전자가 유사 동물 바이러스에서 보존된 것으로 미루어 볼 때 상기 항원이 중요한 역할을 수행하리라는 것이 추측되고 있다. 따라서, e 항원은 바이러스를 제거하기 위한 면역학적인 목표물로서, 특히 숙주가 바이러스를 제거하는데 중요한 역할을 한다 (Pignatelli, M. et al., J. Hepal. 4, 15-16, 1987).Hepatitis B virus replication produces three major antigens (c, s, e antigens), the c (core) antigen is a structural antigen crystal and the s (surface) antigen is an antigenic crystal that is represented by viral surface proteins. The e antigen is a marker in the blood to detect hepatitis B virus infection. The e antigen is not a prerequisite for the propagation of hepatitis B and its role in the life history of the hepatitis B virus is not yet clear. However, it is speculated that the antigen plays an important role in view of the conserved gene of the e antigen. Thus, the e antigen is an immunological target for virus removal, in particular the host plays an important role in virus removal (Pignatelli, M. et al., J. Hepal. 4, 15-16, 1987).
용해성인 e 항원은 혈액상에서 순환되며 분비되는 성질을 가지고 있다. e 항원은 혈청에 분비되어 존재하며 태반을 통해 어머니에서 신생아에게 전달될 가능성은 있으나 s 항원이 전달될 가능성은 없다. e 항원이 순환계를 통해 흉선에 도달하면 T 도움세포 (helper cell)의 기능이 상실된다고 예상된다. 그러므로 양성 어머니로부터 태어난 신생아는 c 항원/e 항원-특정 T-도움세포의 무반응 (tolerance)이라는 면역적 결함을 가지고 있다 (Milich, D. R., et al., PNAS USA 87, 6599-6603, 1990). 이와 같은 T 도움세포의 무반응으로 e 항원 양성인 어머니로부터 태어난 신생아는 HBV에 감염되면 만성으로 가기가 쉽다.Soluble e antigens circulate and secrete in the blood. e antigens are present in the serum and may be transmitted from mother to newborn through the placenta, but not to s antigens. When e antigens reach the thymus through the circulatory system, it is expected that T helper cells will lose their function. Therefore, newborns born from positive mothers have an immunological defect called tolerance of c antigen / e antigen-specific T-helper cells (Milich, DR, et al., PNAS USA 87, 6599-6603, 1990). . Newborns born from e-positive mothers due to the non-response of T helper cells are more likely to go chronic when infected with HBV.
한편, 각종 채소 및 과일 중에 있는 페놀성 화합물이 항암, 항바이러스 및 지질산화 방지작용 및 순환기계 질환 예방 등 유익한 약리 활성이 있다고 보고된 바 있다 (조후종, 이춘자, 오성찬, 서연후 저, 식품이 약이 되는 증언들, 효일문화사, 1998).Meanwhile, various vegetables and phenolic compounds are anti-cancer, anti-viral and lipids has been reported that the anti-function and cardiovascular disease prevention such beneficial pharmacological activity oxidizing bar (johujong, yichunja, ohseongchan after seoyeon me, food in the fruit around Testimonies , Hyoil Cultural History, 1998).
이에, 본 발명자들은 천연물 중 항 B형 간염 바이러스 활성을 보이는 물질을 선별하여 간염 치료제로 개발하고자 연구한 결과, 식물에 광범위하게 존재하는 갈로카테킨갈레이트 등을 포함하는 카테킨 유도체 또는 에피갈로카테킨갈레이트 등을 포함하는 에피카테킨 유도체가 B형 간염 바이러스 e 항원의 분비를 강력히 억제하면서 세포 독성이 낮아 B형 급성 및 만성 간염의 예방 또는 치료에 유용하게 사용될 수 있음을 확인함으로써 본 발명을 완성하였다.Accordingly, the present inventors have selected a substance showing anti-hepatitis B virus activity from natural products and researched to develop it as a hepatitis therapeutic agent, catechin derivative or epigallocatechingal including gallocatechin gallate widely present in plants The present invention was completed by confirming that the epicatechin derivative including late rate and the like strongly inhibit the secretion of hepatitis B virus e antigen and can be usefully used for the prevention or treatment of acute and chronic hepatitis B due to its low cytotoxicity.
본 발명의 목적은 카테킨 또는 에피카테킨 유도체를 B형 간염 예방 또는 치료에 사용하는 용도를 제공하는 것이다. It is an object of the present invention to provide a use of a catechin or epicatechin derivative for the prevention or treatment of hepatitis B.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1의 카테킨 유도체,하기 화학식 2의 에피카테킨 유도체 또는 약학적으로 허용 가능한 그들의 염을 유효성분으로 함유하는 B형 간염 예방 또는 치료용 약학적 조성물을 제공한다. In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating hepatitis B containing as an active ingredient a catechin derivative of formula 1, epicatechin derivatives of formula 2 or pharmaceutically acceptable salts thereof. .
또한, 본 발명은 상기 카테킨 유도체, 에피카테킨 유도체 및 약학적으로 허용 가능한 그들의 염으로 구성된 군으로부터 선택되는 2 이상의 조합을 유효성분으로 함유하는 B형 간염 예방 또는 치료용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for hepatitis B prophylaxis or treatment containing two or more combinations selected from the group consisting of catechin derivatives, epicatechin derivatives and pharmaceutically acceptable salts thereof as an active ingredient.
또한, 본 발명은 상기 카테킨 유도체, 에피카테킨 유도체 또는 그들의 염을 유효성분으로 함유하는 B형 간염 예방 또는 치료용 식품 첨가물을 제공한다. 상기 식품 첨가물에는 음료 조성물 등이 포함된다.The present invention also provides a food additive for preventing or treating hepatitis B containing the catechin derivatives, epicatechin derivatives or salts thereof as an active ingredient. The food additives include beverage compositions and the like.
또한, 본 발명은 상기 카테킨 유도체 또는 에피카테킨 유도체를 유효성분으로 함유하는 면역증진제를 제공한다.The present invention also provides an immunostimulator containing the catechin derivative or epicatechin derivative as an active ingredient.
이하, 본 발명을 상세히 설명하면 다음과 같다. Hereinafter, the present invention will be described in detail.
본 발명은 하기 화학식 1의 구조를 가지는 카테킨 유도체, 화학식 2의 구조를 가지는 에피카테킨 유도체 또는 그들의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 B형 간염 예방 또는 치료용 약학적 조성물을 제공한다. The present invention provides a catechin derivative having a structure of Formula 1, an epicatechin derivative having a structure of Formula 2, or a pharmaceutical composition for hepatitis B prophylaxis or treatment containing a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 카테킨 유도체로는 하기 화학식 3의 갈로카테킨갈레이트 (gallocatechingallate) 등이 바람직하고, 에피카테킨 유도체로는 화학식 4의 에피갈로카테킨갈레이트 (epigallocatechingallate) 등이 바람직하다.As the catechin derivative of the present invention, gallocatechingallate of the following formula (3) is preferable, and epigallocatechinallate of the formula (4) is preferred as the epicatechin derivative.
또한, 본 발명의 B형 간염 예방 또는 치료용 약학적 조성물은 상기 카테킨 유도체, 에피카테킨 유도체 및 약학적으로 허용 가능한 그들의 염으로 구성된 군으로부터 선택되는 2 이상의 조합을 유효성분으로 함유할 수 있다.In addition, the hepatitis B preventive or therapeutic pharmaceutical composition of the present invention may contain a combination of two or more selected from the group consisting of the catechin derivatives, epicatechin derivatives and pharmaceutically acceptable salts thereof as an active ingredient.
상기 화학식 1 및 화학식 2에서 R1, R2, R3 및 R4는 독립적이며, H, OH 또는 기이다.In Formula 1 and Formula 2, R 1 , R 2 , R 3 and R 4 are independent, H, OH or Qi.
구체적으로, 본 발명은 상기 카테킨 유도체로 화학식 1에서 R1, R2, R3는 OH이고 R4는 인 하기 화학식 3의 갈로카테킨갈레이트 및 화학식 2에서 R1, R2, R3는 OH이고 R4는 인 하기 화학식 4의 에피갈로카테킨갈레이트 등을 포함한다.Specifically, in the present invention, the catechin derivative R 1 , R 2 , R 3 in Formula 1 is OH and R 4 is In the gallocatechin gallate of formula 3 and formula 2 R 1 , R 2 , R 3 is OH and R 4 is Epigallocatechin gallate of the formula (4), and the like.
상기 화학식 1 및 화학식 2로 표시되는 본 발명의 카테킨 및 에피카테킨 유도체는 약학적으로 허용 가능한 염의 형태로 사용될 수 있으며, 염으로는 약학적으로 허용 가능한 유리산 (free acid)에 의해 형성된 산부가염이 유용하다. 유리산으로는 무기산과 유기산을 사용할 수 있다. 무기산으로는 염산, 브롬산, 황산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 젖산, 주석산, 말레인산, 푸마린산, 글루콘산, 메탄술폰산, 글리콘산, 숙신산, 4-톨루엔술폰산, 글루투론산, 엠본산, 글루탐산, 또는 아스파르트산 등을 사용될 수 있다. 또한 화학식 1 및 2의 카테킨 및 에피카테킨 유도체는 염기로 인해 형성된 약학적으로 허용 가능한 금속염 특히 알칼리 금속염일 수도 있다. 이들의 예로는 나트륨염 및 칼륨염이 있다.The catechin and epicatechin derivatives of the present invention represented by Formula 1 and Formula 2 may be used in the form of a pharmaceutically acceptable salt, and acid addition salts formed by pharmaceutically acceptable free acid are useful as salts. Do. Inorganic acids and organic acids can be used as the free acid. Hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. may be used as the inorganic acid, and citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, 4-toluenesulfonic acid , Gluturonic acid, embonic acid, glutamic acid, aspartic acid and the like can be used. The catechin and epicatechin derivatives of Formulas 1 and 2 may also be pharmaceutically acceptable metal salts, in particular alkali metal salts, formed due to base. Examples of these are sodium salts and potassium salts.
본 발명은 상기 카테킨 유도체 및 에피카테킨 유도체의 B형 간염 바이러스에 대한 항바이러스 활성을 B형 간염 바이러스의 대표적인 표식물질인 HBeAg을 이용하여 효소면역 측정법 (EIA)으로 분석하여 보면, 카테킨 유도체 및 에피카테킨 유도체의 농도에 따라 HBeAg 양이 현저하게 감소되었다. 또한, 세포 외부로 분비되는 e 항원이 크게 억제되었으나 세포내의 e 항원 생산에는 영향을 미치지 않는 것으로 확인되었다 (도 1 및 도 2 참조). 한편 본 발명의 카테킨 유도체 및 에피카테킨 유도체는 B형 간염 바이러스 s 항원의 세포내 생산 및 세포 외부로의 분비에는 영향을 미치지 않는 것으로 나타났다 (도 3 및 도 4 참조).In the present invention, the antiviral activity of the catechin derivatives and epicatechin derivatives against hepatitis B virus is analyzed by enzyme immunoassay (EIA) using HBeAg, which is a representative marker of hepatitis B virus. The concentration of HBeAg was significantly reduced with concentration. In addition, it was confirmed that the e-antigen secreted to the outside of the cell was greatly suppressed but did not affect the e-gen production in the cell (see FIGS . 1 and 2 ). Meanwhile, the catechin derivatives and epicatechin derivatives of the present invention did not affect the intracellular production and secretion of hepatitis B virus s antigen into the cells (see FIGS . 3 and 4 ).
또한, 본 발명은 상기 카테킨 유도체 및 에피카테킨 유도체의 B형 간염 바이러스에 대한 항바이러스 활성을 조사하기 위하여, DNA 중합효소 활성의 변화를 측정한 결과, 카테킨 유도체 및 에피카테킨 유도체는 B형 간염 바이러스의 중합효소 활성에 영향을 미치지 않는 것으로 나타났다 (도 5 및 도 6 참조).In addition, the present invention, in order to investigate the antiviral activity of the catechin derivatives and epicatechin derivatives against hepatitis B virus, as a result of measuring the change of DNA polymerase activity, the catechin derivatives and epicatechin derivatives are polymerase of hepatitis B virus It did not appear to affect activity (see FIGS . 5 and 6 ).
따라서, 본 발명의 카테킨 유도체, 에피카테킨 유도체 또는 약학적으로 허용가능한 그들의 염을 유효성분으로 함유하는 약학적 조성물은 바이러스성 간염을 만성 상태로 유지시키는 B형 간염 바이러스 e 항원의 분비를 억제하여 만성 및 급성 간염의 예방 및 치료에 유용하게 사용될 수 있다.Therefore, the pharmaceutical composition containing the catechin derivatives, epicatechin derivatives or their pharmaceutically acceptable salts as an active ingredient of the present invention inhibits the secretion of hepatitis B virus e antigen which keeps viral hepatitis in a chronic state, thereby preventing chronic and It can be usefully used for the prevention and treatment of acute hepatitis.
본 발명에 의하면 B형 간염 바이러스 치료를 위하여 갈로카테킨갈레이트를 포함하는 카테킨 유도체 및 에피갈로카테킨갈레이트을 포함하는 에피카테킨 유도체 등을 유효성분으로 하고 이를 약제학적으로 허용되는 담체와 혼합하면 이들 질병의 예방 및 치료용 약학적 조성물을 제조할 수 있다. According to the present invention, the catechin derivative including gallocatechin gallate and the epicatechin derivative including epigallocatechin gallate are used as an active ingredient and mixed with a pharmaceutically acceptable carrier to treat the hepatitis B virus. Prophylactic and therapeutic pharmaceutical compositions can be prepared.
본 발명의 B형 간염 예방 및 치료용 약학 조성물은 통상적으로 사용되는 부형제, 붕해제, 감미제, 활택제, 향미제 등을 추가로 포함할 수 있으며, 통상적인 방법에 의해 정제, 캅셀제, 산제, 과립제, 현탁제, 유제, 시럽제, 기타 액제로 제형화될 수 있다.The pharmaceutical composition for preventing and treating hepatitis B of the present invention may further include excipients, disintegrants, sweeteners, lubricants, flavoring agents, etc. which are commonly used, tablets, capsules, powders, granules by conventional methods , Suspensions, emulsions, syrups, and other liquids.
구체적으로 본 발명의 약학적 조성물은 경구 투여용 제형, 예를 들면 정제, 트로치제 (troches), 로젠지 (lozenge), 수용성 또는 유성현탁액, 조제분말 또는 과립, 에멀젼, 하드 또는 소프트 캡슐, 시럽 또는 엘릭시르제 (elixirs)로 제제화된다. 정제 및 캡슐 등의 제형으로 제제하기 위해 락토오스, 사카로오스, 솔비톨, 만니톨, 전분, 아밀로펙틴, 셀룰로오스 또는 젤라틴과 같은 결합제; 디칼슘 포스페이트와 같은 부형제; 옥수수 전분 또는 고구마 전분과 같은 붕해제; 스테아르산 마그네슘, 스테아르산 칼슘, 스테아릴푸마르산 나트륨 또는 폴리에틸렌글리콜 왁스와 같은 윤활유가 함유된다. 캡슐제형의 경우는 상기에서 언급한 물질 이외에도 지방유와 같은 액체 담체를 함유한다.In particular, the pharmaceutical compositions of the present invention may be formulated for oral administration such as tablets, troches, lozenges, water-soluble or oily suspensions, prepared powders or granules, emulsions, hard or soft capsules, syrups or It is formulated with elixirs. Binders such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin for preparation in formulations such as tablets and capsules; Excipients such as dicalcium phosphate; Disintegrants such as corn starch or sweet potato starch; Lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate or polyethylene glycol wax. Capsules contain liquid carriers, such as fatty oils, in addition to the substances mentioned above.
또한, 본 발명의 약학적 조성물은 비경구로 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육내 주사 또는 흉부내 주사 주입방식에 의한다. 비경구 투여용 제형으로 제제화하기 위해서는 상기 화학식 1 또는 화학식 2의 유도체를 안정제 또는 완충제와 함께 물에서 혼합하여 용액 또는 현탁액으로 제조하고 이를 앰플 또는 바이알의 단위 투여형으로 제제한다. In addition, the pharmaceutical composition of the present invention can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection. To formulate into parenteral dosage forms, the derivatives of Formula 1 or Formula 2 are mixed in water with stabilizers or buffers to prepare solutions or suspensions and formulated in unit dosage forms of ampoules or vials.
독성실험 결과 본 발명의 카테킨 및 에피카테킨 유도체는 5 g/㎏의 용량으로 쥐에게 경구 투여하였을 때 독성이 거의 없는 것으로 밝혀졌고 간을 비롯한 장기의 기능에 어떠한 부작용도 나타내지 않음을 확인하였다.Toxicity test results showed that the catechin and epicatechin derivatives of the present invention showed little toxicity when administered orally to rats at a dose of 5 g / kg and showed no side effects on the function of organs, including liver.
또한, 상기 유도체는 간을 비롯한 장기의 기능에 어떠한 부작용도 나타내지 않는다고 알려져 있다 (Merck Index Vol. 11th edition. 1989). 본 발명에서는 세포독성 및 경구투여 급성독성 실험을 통하여, 이들 갈로카테킨갈레이트 등의 카테킨 유도체 및 에피갈로카테킨갈레이트 등의 에피카테킨 유도체가 안전함을 확인하였다. In addition, the derivatives are known to show no adverse effects on the function of organs, including liver (Merck Index Vol. 11th edition. 1989). In the present invention, it was confirmed that these catechin derivatives such as gallocatechin gallate and epicatechin derivatives such as epigallocatechin gallate were safe through cytotoxicity and acute toxicity experiments.
본 발명에 따른 유효성분의 투여량은 체내에서 활성성분의 흡수도, 불활성화율 및 배설속도, 환자의 연령, 성별 및 상태, 치료할 질병의 중증 정도에 따라 적절히 선택되나, 일반적으로 성인에게 1일에 체중 1 ㎏ 당 화학식 1 또는 화학식 2의 화합물을 0.1∼500 ㎎의 양으로 1회 내지 수회 나누어 투여할 수 있으며 바람직하기로는 0.1∼100 ㎎이다.The dosage of the active ingredient according to the present invention is appropriately selected depending on the absorption rate, inactivation rate and excretion rate of the active ingredient in the body, the age, sex and condition of the patient, and the severity of the disease to be treated, but generally in a day The compound of Formula 1 or Formula 2 may be administered once or several times in an amount of 0.1 to 500 mg per kg of body weight, preferably 0.1 to 100 mg.
또한, 본 발명은 상기 카테킨 유도체, 에피카테킨 유도체 또는 그들의 염을 유효성분으로 함유하는 B형 간염 예방 또는 치료용 식품 첨가물 또는 음료 조성물을 제공한다.The present invention also provides a food additive or beverage composition for hepatitis B prophylaxis or treatment containing the catechin derivative, epicatechin derivative or salt thereof as an active ingredient.
본 발명의 카테킨 유도체 또는 에피카테킨 유도체를 식품 첨가물로 사용할 경우, 상기 카테킨 유도체 또는 에피카테킨 유도체를 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용되고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효 성분의 혼합양은 그의 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 일반적으로, 카테킨 유도체 또는 에피카테킨 유도체를 식품 또는 음료의 제조시에 원료에 대하여 0.0001 내지 10 중량%, 바람직하게는 0.1 내지 5 중량%의 양으로 첨가될 수 있다. 그러나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 유효성분은 안전성 면에서 아무런 문제가 없기 때문에 상기 범위 이상의 양으로도 사용될 수 있음은 확실하다. 랫트에서 급성 독성실험을 행한 결과 5 g/㎏/일의 경구 투여량에서는 어떠한 죽음도 관찰되지 않음이 증명되었다.When the catechin derivative or epicatechin derivative of the present invention is used as a food additive, the catechin derivative or epicatechin derivative may be added as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method. The blending amount of the active ingredient can be suitably determined according to the purpose of its use (prevention, health or therapeutic treatment). In general, catechin derivatives or epicatechin derivatives may be added in amounts of 0.0001 to 10% by weight, preferably 0.1 to 5% by weight, based on the raw materials in the manufacture of food or beverage. However, in the case of long-term intake for health and hygiene or health control, the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety. Is sure. Acute toxicity testing in rats demonstrated no death was observed at the oral dose of 5 g / kg / day.
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있다.There is no particular limitation on the kind of food. Examples of the food to which the substance can be added include dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, drinks, Alcoholic beverages and vitamin complexes.
또한, 본 발명은 상기 카테킨 유도체, 에피카테킨 유도체 또는 그들의 약학적으로 허용 가능한 염을 유효성분으로 하는 면역증진제를 제공한다.In addition, the present invention provides an immunostimulator using the catechin derivatives, epicatechin derivatives or their pharmaceutically acceptable salts as an active ingredient.
바이러스 감염에 의하여 감염된 세포외로 분비되는 e-항원들이 순환계를 통하여 흉선에 도달할 경우 T-도움세포의 기능을 상실하게 하여 c 항원/e 항원-특정 T-도움세포의 무반응(tolerance)을 나타내게 된다. 갈로카테킨갈레이트(도 7a)와 에피갈로카테킨갈레이트(도 7b)를 아연(Zn) 투여에 의하여 e 항원 생산을 개시하도록 제작된 형질전환 마우스에서 T-도움세포를 활성화시켜서 바이러스 면역무반응을 해제하는 것으로 기대된다.When extracellularly secreted e-antigens, which are infected by viral infection, reach the thymus through the circulatory system, they lose the function of T-helper cells, resulting in tolerance of c antigen / e antigen-specific T-helper cells. do. Viral immunoreactivity by activating T-helper cells in transgenic mice prepared to initiate e antigen production by zinc (Zn) administration of gallocatechin gallate (FIG. 7 a) and epigallocatechin gallate (FIG. 7 b) It is expected to release it.
이하, 본 발명을 실시예에 의하여 상세히 설명한다.Hereinafter, the present invention will be described in detail by way of examples.
하기 실시예는 본 발명을 구체적으로 예시하는 것이며, 본 발명의 내용이 실시예에 의해 한정되는 것은 아니다.The following examples illustrate the present invention in detail, and the content of the present invention is not limited by the examples.
본 발명의 카테킨 및 에피카테킨 유도체를 유효성분으로 하는 약학적 조성물은 비경구 또는 경구로 투여될 수 있으며, 하기에 비경구용 제형으로 주사제, 경구용 제형으로 시럽제 및 정제로 제조하였다.Pharmaceutical compositions comprising the catechin and epicatechin derivatives of the present invention as an active ingredient can be administered parenterally or orally, and are prepared as parenteral formulations as injections, oral formulations as syrups and tablets.
<실시예 1> 주사액제의 제조방법Example 1 Preparation of Injection Solution
유효성분 10 ㎎을 함유하는 주사액제는 다음과 같은 방법으로 제조하였다. Injection solution containing 10 mg of the active ingredient was prepared by the following method.
갈로카테킨갈레이트 또는 에피갈로카테킨갈레이트 1 g, 염화나트륨 0.6 g 및 아스코르브산 0.1 g을 증류수에 용해시켜서 100 ㎖를 만들었다. 이 용액을 병에 넣고 20℃에서 30분간 가열하여 멸균시켰다.1 g of gallocatechin gallate or epigallocatechin gallate, 0.6 g of sodium chloride and 0.1 g of ascorbic acid were dissolved in distilled water to make 100 ml. The solution was bottled and sterilized by heating at 20 ° C. for 30 minutes.
상기 주사액제의 구성성분은 다음과 같다. The components of the injection solution are as follows.
갈로카테킨갈레이트 또는 에피갈로카테킨갈레이트 1 g1 g gallocatechin gallate or epigallocatechin gallate
염화나트륨 0.6 g0.6 g sodium chloride
아스코르브산 0.1 g0.1 g of ascorbic acid
증류수 정량Distilled Water Determination
<실시예 2> 시럽제의 제조방법Example 2 Preparation of Syrup
본 발명의 카테킨 및 에피카테킨 유도체의 산부가염 및 약학적으로 허용되는 그의 염을 유효성분 2% (중량/부피)로 함유하는 시럽은 다음과 같은 방법으로 제조한다. Syrups containing acid addition salts of catechin and epicatechin derivatives of the present invention and pharmaceutically acceptable salts thereof as an active ingredient of 2% (weight / volume) are prepared by the following method.
갈로카테킨갈레이트 또는 에피갈로카테킨갈레이트의 산부가염, 사카린, 당을 온수 80 g에 용해시켰다. 이 용액을 냉각시킨 후, 여기에 글리세린, 향미료, 에탄올, 소르브산 및 증류수로 이루어진 용액을 제조하여 혼합하였다. 이 혼합물에 물을 첨가하여 100 ㎖가 되게 하였다. Acid addition salts of gallocatechin gallate or epigallocatechin gallate, saccharin and sugar were dissolved in 80 g of warm water. After the solution was cooled, a solution consisting of glycerin, spices, ethanol, sorbic acid and distilled water was prepared and mixed therein. Water was added to this mixture to 100 ml.
상기 시럽제의 구성성분은 다음과 같다.The components of the syrup are as follows.
갈로카테킨갈레이트 또는 에피갈로카테킨갈레이트 2 g2 g gallocatechin gallate or epigallocatechin gallate
사카린 0.8 gSaccharin 0.8 g
당 25.4 g25.4 g per
글리세린 8.0 gGlycerin 8.0 g
향미료 0.04 g0.04 g of spices
에탄올 4.0 gEthanol 4.0 g
소르브산 0.4 g0.4 g of sorbic acid
증류수 정량Distilled Water Determination
<실시예 3> 정제의 제조방법Example 3 Preparation of Tablet
유효성분 15 ㎎이 함유된 정제는 다음과 같은 방법으로 제조한다.A tablet containing 15 mg of active ingredient is prepared by the following method.
갈로카테킨갈레이트 또는 에피갈로카테킨갈레이트 250 g, 락토오스 175.9 g, 감자전분 180 g 및 콜로이드성 규산 32 g과 혼합하였다. 이 혼합물에 10% 젤라틴 용액을 첨가시킨 후, 분쇄해서 14 메쉬체를 통과시켰다. 이것을 건조시키고 여기에 감자전분 160 g, 활석 50 g 및 스테아린산 마그네슘 5 g을 첨가해서 얻은 혼합물을 정제로 만들었다. 250 g of gallocatechin gallate or epigallocatechin gallate, 175.9 g lactose, 180 g potato starch and 32 g colloidal silicic acid were mixed. 10% gelatin solution was added to the mixture, which was then ground and passed through a 14 mesh sieve. It was dried and the mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate was made into a tablet.
상기 정제의 구성성분은 다음과 같다. The components of the tablet are as follows.
갈로카테킨갈레이트 또는 에피갈로카테킨갈레이트 250 g250 g gallocatechin gallate or epigallocatechin gallate
락토오스 175.9 gLactose 175.9 g
감자전분 180 g180 g potato starch
콜로이드성 규산 32 g32 g of colloidal silicic acid
10% 젤라틴 용액10% gelatin solution
감자전분 160 gPotato Starch 160 g
활석 50 g50 g of talc
스테아르산 마그네슘 5 g5 g of magnesium stearate
<실시예 4> 식품 및 음료의 제조방법Example 4 Preparation of Food and Beverage
본 발명자들은 카테킨 및 에피카테킨 유도체를 유효성분으로 함유하는 식품 또는 음료 조성물을 하기와 같이 제조하였다.The present inventors prepared a food or beverage composition containing catechin and epicatechin derivatives as active ingredients as follows.
<4-1> 츄잉껌의 제조<4-1> Preparation of Chewing Gum
껌베이스 20 %Gum base 20%
설탕 76.36 ∼ 76.76 %Sugar 76.36-76.76%
갈로카테킨갈레이트 또는 에피갈로카테킨갈레이트 0.24 ∼ 0.64 % Gallocatechin gallate or epigallocatechin gallate 0.24 to 0.64%
후르츠향 1 %1% fruit flavor
물 2 %Water 2%
상기 조성 및 함량으로 하여 통상적인 방법을 사용하여 츄잉껌을 제조하였다. Chewing gum was prepared using conventional methods using the above composition and content.
<4-2> 캔디의 제조<4-2> Preparation of Candy
설탕 50 ∼ 60 %50 to 60% sugar
물엿 39.26 ∼ 49.66 %Starch syrup 39.26-49.66%
갈로카테킨갈레이트 또는 에피갈로카테킨갈레이트 0.24 ∼ 0.64 % Gallocatechin gallate or epigallocatechin gallate 0.24 to 0.64%
오렌지향 0.1 %Orange flavor 0.1%
상기 조성 및 함량으로 하여 통상적인 방법을 사용하여 캔디를 제조하였다. Candy was prepared using conventional methods with the above composition and content.
<4-3> 비스켓의 제조<4-3> Preparation of Biscuits
박력1급 88 ㎏Force Class 1 88 kg
중력1급 76.4 ㎏Gravity First Class 76.4 ㎏
정백당 16.5 ㎏16.5 kg per white
식염 2.5 ㎏ 2.5 kg of salt
포도당 2.7 ㎏2.7 kg of glucose
팜쇼트닝 40.5 ㎏Palm shortening 40.5 kg
암모 5.3 ㎏5.3 kg of ammo
중조 0.6 ㎏Medium kg 0.6 kg
중아황산나트륨 0.55 ㎏0.55 kg sodium bisulfite
쌀가루 5.0 ㎏Rice flour 5.0 kg
비타민 B1 0.003 ㎏Vitamin B1 0.003 kg
비타민 B2 0.003 ㎏0.003 kg of vitamin B2
밀크향 0.16 ㎏Milk Flavor 0.16 ㎏
물 71.1 ㎏ 71.1 kg of water
전지분유 4 ㎏Whole milk powder 4 kg
대용분유 1 ㎏Substitute powder 1 kg
제일인산칼슘 0.1 ㎏0.1 kg of calcium phosphate
살포염 1 ㎏Spray salt 1 kg
분무유 25 ㎏ 25 kg of spray oil
갈로카테킨갈레이트 또는 에피갈로카테킨갈레이트 0.1 ∼ 0.5 ㎏Gallocatechin gallate or epigallocatechin gallate 0.1-0.5 kg
상기 조성 및 함량으로 하여 통상적인 방법을 사용하여 비스켓을 제조하였다. Biscuits were prepared using conventional methods with the above composition and content.
<4-4> 아이스크림의 제조<4-4> Preparation of Ice Cream
유지방 10.0 %Milkfat 10.0%
무지유고형분 10.8 %Non-fat solids 10.8%
설탕 12.0 %Sugar 12.0%
물엿 3.0 %Starch syrup 3.0%
유화안정제(스팬,span) 0.5 %Emulsifying stabilizer (span) 0.5%
향료(스트로베리) 0.15 %Spices (Strawberries) 0.15%
물 63.31 ∼ 62.91 % Water 63.31-62.91%
갈로카테킨갈레이트 또는 에피갈로카테킨갈레이트 0.24 ∼ 0.64 %Gallocatechin gallate or epigallocatechin gallate 0.24 to 0.64%
상기 조성 및 함량으로 하여 통상적인 방법을 사용하여 아이스크림을 제조하였다. Ice cream was prepared using conventional methods using the above composition and content.
<4-5> 음료의 제조<4-5> Preparation of Beverage
꿀 522 ㎎522 mg of honey
치옥토산아미드 5 ㎎Chioctosanamide 5 mg
니코틴산아미드 10 ㎎Nicotinamide 10 mg
염산리보플라빈나트륨 3 ㎎Riboflavin Sodium Hydrochloride 3 mg
염산피리독신 2 ㎎Pyridoxine hydrochloride 2 mg
이노시톨 30 ㎎Inositol 30 mg
오르트산 50 ㎎Orthoic acid 50 mg
갈로카테킨갈레이트 또는 에피갈로카테킨갈레이트 0.48 ∼ 1.28 ㎎ Gallocatechin gallate or epigallocatechin gallate 0.48-1.28 mg
물 200 ㎖200 ml of water
상기 조성 및 함량으로 하여 통상적인 방법을 사용하여 음료를 제조하였다. With the above composition and content, drinks were prepared using conventional methods.
<4-6> 소세지의 제조<4-6> Preparation of Sausage
돈육 63.6 %Pork 63.6%
계육 27.5 % Chicken 27.5%
전분 3.5 %Starch 3.5%
대두단백 1.7 %Soy Protein 1.7%
식염 1.62 %Saline 1.62%
포도당 0.5 %Glucose 0.5%
기타첨가물(글리세린) 0.94 ∼ 1.34 % Other additives (glycerine) 0.94-1.34%
갈로카테킨갈레이트 또는 에피갈로카테킨갈레이트 0.24 ∼ 0.64 %Gallocatechin gallate or epigallocatechin gallate 0.24 to 0.64%
상기 조성 및 함량으로 하여 통상적인 방법을 사용하여 소세지를 제조하였다. Sausages were prepared using conventional methods using the above composition and content.
<4-7> 쵸코렛의 제조<4-7> Preparation of Chocolate
설탕 34.36 ∼ 34.76 %Sugar 34.36-34.76%
코코아 버터 34 %Cocoa Butter 34%
코코아 매스 15 %Cocoa Mass 15%
코코아 파우다 15 %Cocoa Powder 15%
레시틴 0.5 %Lecithin 0.5%
바닐라향 0.5 %0.5% vanilla
갈로카테킨갈레이트 또는 에피갈로카테킨갈레이트 0.24 ∼ 0.64 %Gallocatechin gallate or epigallocatechin gallate 0.24 to 0.64%
상기 조성 및 함량으로 하여 통상적인 방법을 사용하여 초코렛을 제조하였다. With the above composition and content, chocolate was prepared using conventional methods.
<실험예 1> 카테킨 또는 에피카테킨 유도체의 항 간염 바이러스 활성 측정Experimental Example 1 Measurement of Anti-Hepatitis Virus Activity of Catechin or Epicatechin Derivatives
본 발명의 카테킨 및 에피카테킨 유도체가 B형 간염 바이러스에 대한 항 간염 바이러스 활성에 미치는 영향을 조사하기 위하여, 인간 간조직 유래의 동물세포에 농도별로 갈로카테킨갈레이트 및 에피갈로카테킨갈레이트를 처리한 후, e 항원 생성 억제효과를 살펴보았다. In order to investigate the effects of catechin and epicatechin derivatives of the present invention on anti-hepatitis virus activity against hepatitis B virus, animal cells derived from human liver tissue were treated with gallocatechin gallate and epigallocatechin gallate at different concentrations. Afterwards, the effects of e antigen generation were examined.
<1-1> 2.2.15. 세포의 배양<1-1> 2.2.15. Cell culture
상기 활성을 조사하기 위하여, 인간의 간 조직에서 유래된 HepG2 세포 (human hepatoblastoma cell)에 B형 간염 바이러스의 유전자가 삽입되어 있어 B형 간염 바이러스의 e 항원 (HBeAg)을 배지로 배출하는 2.2.15. 세포주 (Keui Ueda et al., Virology 169, 213-21, 1989)를 사용하였다. 2.2.15. 세포는 지름 10 cm 페트리디쉬에 4 ㎍/㎖ 겐타마이신 (Gm; Sigma)과 10%의 열처리된 소태아 혈청 (Fetal bovine serum, FBS; Gibco)이 첨가된 MEM 배지 (Gibco)를 사용하여 배양하는데, 37℃, 5% CO2 배양기에서 증식시켜 세포 단층이 형성되면 3∼4일 간격으로 트립신을 처리하여 계대하였다.In order to investigate the activity, the hep B2 gene (human hepatoblastoma cell) derived from human liver tissue is inserted into the hepatitis B virus gene and 2.2.15 which discharges the hepatitis B virus e antigen (HBeAg) into the medium. . Cell line (Keui Ueda et al., Virology 169, 213-21, 1989) was used. 2.2.15. Cells were cultured using MEM medium (Gibco) supplemented with 4 μg / ml gentamycin (Gm; Sigma) and 10% heat treated fetal bovine serum (FBS; Gibco) in 10 cm diameter Petri dishes. , 37 ° C, 5% CO 2 incubator was grown to form a cell monolayer, trypsin treatment at 3-4 days intervals were passaged.
<1-2> 카테킨 또는 에피카테킨 유도체의 B형 간염 바이러스 e 항원의 생성 저해 효과 측정<1-2> Inhibition of Hepatitis B Virus e Antigen Production by Catechin or Epicatechin Derivatives
B형 간염 바이러스 e 항원의 경우 B형 간염 항원 진단용 시약 (Enzygnost HBeAg monoclonal; Behring)을 이용하여 효소면역 측정법을 실시하였다. 상기 실험예 <1-1>에서 배양된 2.2.15. 세포를 24-웰 플레이트에 웰당 2 ×104 개의 농도로 FBS가 포함되지 않은 MEM 배지 배양액 100 ㎕와 함께 첨가하고 37℃, 5% CO2 배양기에서 24시간 동안 배양한 다음 농도별로 카테킨 유도체인 갈로카테킨갈레이트 또는 에피카테킨 유도체인 에피갈로카테킨갈레이트를 각각 처리하였다. 추출물을 처리한 지 48시간이 지난 다음 배양액만을 취하고 이 배양액을 1,500 rpm으로 5분 동안 원심분리하여 세포 분리물을 제거하였다. 이 때 얻은 상층 배양액만을 HBeAg에 대한 모노클로날 항체 (HBeAb)가 도말되어 있는 진단시약 플레이트에 일정량씩 분주한 다음 37℃ 배양기에 1시간 동안 방치하였다. 상기 진단시약 플레이트를 인산 완충용액으로 3회 세척한 후 퍼록시다아제 (peroxidase)가 표지되어 있는 HBeAb를 일정량씩 각 웰에 분주하고 37℃ 배양기에 1시간 동안 방치하여 HBeAg과의 2차 결합이 이루어지도록 하였다. 결합되지 않은 잉여분의 항체는 인산 완충용액으로 3회 세척하여 제거하였으며 퍼옥시다아제에 의해 발색반응을 일으키는 TMB (tetramethyl benzidine dihydrochloride) 기질이 포함된 용액을 일정량씩 분주하여 발색 반응을 유도하였다. 반응이 완료된 진단시약 플레이트는 450 nm에서의 흡광 정도를 읽어들여 e 항원의 변화를 평가하였다.In the case of hepatitis B virus e antigen, enzyme immunoassay was performed using a reagent for diagnosing hepatitis B antigen (Enzygnost HBeAg monoclonal; Behring). 2.2.15 cultured in Experimental Example <1-1>. Cells were added to a 24-well plate with 100 μl of MEM medium without FBS at a concentration of 2 × 10 4 per well, incubated for 24 hours in a 37 ° C., 5% CO 2 incubator and then gallo, a catechin derivative, by concentration. Epigallocatechin gallate, which is a catechin gallate or epicatechin derivative, was treated, respectively. After 48 hours of treatment with the extract, only the culture was taken and the culture was centrifuged at 1,500 rpm for 5 minutes to remove the cell isolate. Only the supernatant obtained at this time was dispensed in a predetermined amount onto a diagnostic reagent plate coated with a monoclonal antibody to HBeAg (HBeAb), and then left in a 37 ° C. incubator for 1 hour. The diagnostic reagent plate was washed three times with phosphate buffer solution, and then a predetermined amount of HBeAb labeled with peroxidase was dispensed into each well and left in a 37 ° C. incubator for 1 hour to prevent secondary binding with HBeAg. It was done. The excess unbound antibody was washed three times with phosphate buffer solution, and the color reaction was induced by dispensing a certain amount of solution containing TMB (tetramethyl benzidine dihydrochloride) substrate which causes color reaction by peroxidase. The diagnostic reagent plate that completed the reaction was evaluated for the change of e antigen by reading the degree of absorption at 450 nm.
상기의 방법으로 본 발명의 카테킨 및 에피카테킨 유도체가 간염 e 항원을 감소시키는 정도를 여러 가지 농도에서 측정하고 갈로카테킨갈레이트 및 에피갈로카테킨갈레이트에 의한 간염 항원 감소능을 나타내었다. In the above method, the catechin and epicatechin derivatives of the present invention were measured at various concentrations to reduce the hepatitis e antigen and exhibited the ability to reduce hepatitis antigen by gallocatechin gallate and epigallocatechin gallate.
그 결과, 갈로카테킨갈레이트 및 에피갈로카테킨갈레이트를 포함하는 카테킨 및 에피카테킨 유도체는 모두 1 ㎍/㎖의 농도만으로도 세포 외부로 분비되는 e 항원의 생성을 급격히 저하시킴으로써 항 간염 바이러스 활성을 나타냄을 알 수 있었으며(도 1), 이때 HepG2 2.2.15 세포에서 e 항원 생성을 50% 방해하는 약물농도(IC50)를 결정하여 하기 표 1에 나타내었다. 그러나 상기 유도체는 세포내의 B형 간염 바이러스 e 항원 생산에는 영향을 미치지 않았다(도 2).As a result, catechin and epicatechin derivatives including gallocatechin gallate and epigallocatechin gallate exhibited anti-hepatitis viral activity by rapidly decreasing the production of e antigen secreted outside the cell even at a concentration of 1 μg / ml. It was found ( FIG. 1 ), wherein the drug concentration (IC 50 ) that inhibits e antigen production 50% in HepG2 2.2.15 cells is determined and shown in Table 1 below. However, the derivatives did not affect the hepatitis B virus e antigen production in cells ( FIG. 2 ).
<1-3> 카테킨 또는 에피카테킨 유도체의 B형 간염 바이러스 s 항원에 대한 효과 분석<1-3> Effect of catechin or epicatechin derivative on hepatitis B virus s antigen
본 발명자들은 상기 실험예 <1-2>와 동일한 방법으로 카테킨 또는 에피카테킨 유도체에 의해 B형 간염 바이러스 s 항원의 생성에 영향을 미치는지 알아보았다.The present inventors examined whether the catechin or epicatechin derivative influences the production of hepatitis B virus s antigen in the same manner as in Experimental Example <1-2>.
그 결과, 갈로카테킨갈레이트 및 에피갈로카테킨갈레이트를 포함하는 카테킨 및 에피카테킨 유도체는 세포 내의 B형 간염 바이러스 s 항원 생산 및 세포 외부로 분비되는 s 항원의 생성에는 영향을 미치지 않았다(도 3 및 도 4).As a result, catechins and epicatechin derivatives, including gallocatechingallate and epigallocatechingallate, did not affect hepatitis B virus s antigen production in cells and the production of s antigens secreted out of the cells ( FIG. 3 and 4 ).
<실험예 2> 카테킨 또는 에피카테킨 유도체의 B형 간염 바이러스 DNA 중합효소 활동 억제 효과 측정Experimental Example 2 Inhibition of Hepatitis B Virus DNA Polymerase Activity of Catechin or Epicatechin Derivatives
B형 감염 바이러스를 중합효소완충액 (10 mM Tris HCl [pH 7.5], 200 mM의 dATP, dCTP 그리고 dGTP, 0.1% Triton X-100, 50 mM MgCl2)에 용해시키고 α-32P-dCTP와 본 발명의 유도체들과 16시간 반응시켰다. 상기 반응은 6 ㎕의 0.5 M EDTA로 중지시키고 와트만 DE81 여과지에 반점으로 찍은 후 0.5 M Na2HPO4로 4번, 증류수로 2번 95% 에탄올로 한번 세척 후 결합된 방사선의 양을 이미지 분석기 (image analyzer)로 측정하였다. 기존의 중합효소 활동 방해물질인 3TC를 양성 대조군으로 사용하였다.Hepatitis B virus was dissolved in polymerase buffer solution (10 mM Tris HCl [pH 7.5], 200 mM dATP, dCTP and dGTP, 0.1% Triton X-100, 50 mM MgCl 2 ) and treated with α- 32 P-dCTP. It was reacted with the derivatives of the invention for 16 hours. The reaction was stopped with 6 μl of 0.5 M EDTA, spotted on Whatman DE81 filter paper, washed four times with 0.5 M Na 2 HPO 4 , twice with distilled water and then with 95% ethanol to determine the amount of combined radiation. It measured by (image analyzer). 3TC, an existing polymerase activity blocker, was used as a positive control.
그 결과, 본 발명의 카테킨 및 에피카테킨 유도체들은 B형 간염 바이러스의 DNA 복제에는 영향이 없었으며(도 5), 중합효소 활성에도 영향을 미치지 않았다(도 6). 대조군으로 3TC를 처리하였을 때에는 10 μM 3TC (32%)와 20 μM 3TC (22%)에서 감소된 중합효소활동을 보여 주었다.As a result, the catechin and epicatechin derivatives of the present invention had no effect on DNA replication of hepatitis B virus ( FIG. 5 ) and did not affect polymerase activity ( FIG. 6 ). Treatment with 3TC as a control showed decreased polymerase activity at 10 μM 3TC (32%) and 20 μM 3TC (22%).
<실험예 3> 카테킨 또는 에피카테킨 유도체의 면역증진효과 분석Experimental Example 3 Analysis of Immune Enhancement Effect of Catechin or Epicatechin Derivatives
본 발명자들은 카테킨 또는 에피카테킨 유도체가 면역증진 효과를 나타내는지 알아보기 위하여, 카테킨 또는 에피카테킨 유도체를 정상 마우스와 아연(Zn) 투여에 의하여 e 항원 생산을 개시하도록 제작된 형질전환 마우스에 투여하여 B-세포 및 T-도움세포 생산 활성을 측정하였다.In order to determine whether catechin or epicatechin derivatives have an immunopromoting effect, the present inventors have administered catechin or epicatechin derivatives to normal mice and transgenic mice prepared to initiate e antigen production by zinc (Zn) administration to B-cells. And T-helper cell production activity was measured.
그 결과, 갈로카테킨갈레이트와 에피갈로카테킨갈레이트는 아연 투여에 의하여 e 항원 생산을 개시하도록 제작된 형질전환 마우스에서 T-도움세포 생산을 활성화시켰고(도 7), 이는 카테킨 또는 에피카테킨 유도체가 면역증진효과를 나타낸다는 것을 알 수 있다.As a result, gallocatechin gallate and epigallocatechin gallate activated T-helper cell production in transgenic mice designed to initiate e antigen production by zinc administration ( FIG. 7 ), which indicated that catechin or epicatechin derivatives were It can be seen that it shows an immune enhancing effect.
<실험예 4> 카테킨 또는 에피카테킨 유도체의 세포독성 검사Experimental Example 4 Cytotoxicity Test of Catechin or Epicatechin Derivative
상기 실험예들로부터 카테킨 및 에피카테킨 유도체들의 활성을 검증하여 세포에 미치는 독성을 확인하기 위하여 하기와 같이 갈로카테킨갈레이트 및 에피갈로카테킨갈레이트를 대상으로 CC50을 측정하였다.CC 50 was measured in gallocatechin gallate and epigallocatechin gallate as described below to verify toxic effects on cells by verifying the activity of catechin and epicatechin derivatives from the experimental examples.
공지의 방법 (Korba, B. E. et al., Use of a standardized cell culture assay to assess activities of nucleoside analogs against hepatitis B virus replication, Antiviral research, 19, 55-70, 1992)을 이용하여 갈로카테킨갈레이트 및 에피갈로카테킨갈레이트가 HepG2 세포 및 2.2.15. 세포에 대해 나타내는 세포 독성을 조사하였다. Gallocatechin gallate and epi using known methods (Korba, BE et al., Use of a standardized cell culture assay to assess activities of nucleoside analogs against hepatitis B virus replication, Antiviral research , 19, 55-70, 1992). Gallocatechin gallate was found in HepG2 cells and 2.2.15. The cytotoxicity expressed against the cells was investigated.
24-웰 플레이트에 웰 당 2 ×104 개의 세포를 100 ㎕ 부피로 첨가하고 37℃ 배양기에서 24시간 동안 배양한 다음 여러 가지 농도의 갈로카테킨갈레이트 및 에피갈로카테킨갈레이트 시료를 3일 동안 처리하였다. 배양액을 제거하고 20 ㎕의 염색 용액 (테트라졸리윰 화합물 (tetrazolium compound), 염 (inner salt) 및 페나진에톨설페이트 (phenazine ethosulfate)을 분주하고 1시간 동안 배양기에 두었고, 다음 인산 완충용액으로 2회 세척하여 여분의 염색 용액을 제거하고 20 ㎕의 정착 용액 (50% 에탄올, 1% 차가운 아세트산 [glacial acetic acid])을 가하여 30분 동안 교반시켰다. 510 nm에서의 흡광도를 스펙트로포토메터로 측정하였으며 추출물이 첨가되지 않은 세포의 흡광도와 비교하여 50%의 흡광도 감소를 유발하는 추출물의 농도를 CC50 (50% 세포독성 농도; cytotoxic concentration)으로 결정하였으며, 그 결과를 하기 표 2에 나타내었다.100 μl volume of 2 × 10 4 cells per well was added to a 24-well plate, incubated for 24 hours in a 37 ° C. incubator, and then various concentrations of gallocatechin gallate and epigallocatechin gallate samples were taken for 3 days. Treated. The culture solution was removed and 20 μl of staining solution (tetrazolium compound, inner salt and phenazine ethosulfate) were aliquoted and placed in the incubator for 1 hour, followed by 2 phosphate buffers. The excess dye solution was washed once to remove and 20 μl of fixation solution (50% ethanol, 1% cold acetic acid) was added and stirred for 30 minutes, the absorbance at 510 nm was measured by spectrophotometer. The concentration of the extract causing 50% absorbance reduction compared to the absorbance of the cells without the extract was determined as CC 50 (50% cytotoxic concentration), the results are shown in Table 2 below.
<실험예 5> 랫트에 대한 경구투여 급성 독성실험Experimental Example 5 Oral Acute Toxicity in Rats
본 발명의 카테킨 유도체인 갈로카테킨갈레이트 및 에피카테킨 유도체인 에피갈로카테킨갈레이트의 급성 독성을 알아보기 위하여, 하기와 같은 실험을 수행하였다.In order to determine the acute toxicity of the catechin derivative gallocatechin gallate and epicatechin derivative epigallocatechin gallate of the present invention, the following experiment was performed.
6주령의 특정병원부재 (SPF) SD계 랫트를 사용하여 급성독성실험을 실시하였다. 갈로카테킨갈레이트 및 에피갈로카테킨갈레이트을 각각 0.5% 메틸셀룰로오스 용액에 현탁하여 5 g/㎏/15 ㎖의 용량으로 단회 경구 투여하였다. 시험물질 투여후 동물의 폐사여부, 임상증상, 체중변화를 관찰하고 혈액학적 검사와 혈액생화학적검사를 실시하였으며, 부검하여 육안으로 복강장기와 흉강장기의 이상 여부를 관찰하였다. 시험 결과, 시험물질을 투여한 모든 동물에서 특기할 만한 임상증상이나 폐사된 동물은 없었으며, 체중변화, 혈액검사, 혈액생화학 검사, 부검소견 등에서도 독성 변화는 관찰되지 않았다. 이상의 결과 화학식 3의 갈로카테킨갈레이트 및 화학식 4의 에피갈로카테킨갈레이트는 랫트에서 5 g/㎏까지 독성 변화를 나타내지 않으며 경구 투여 최소 치사량 (LD50)은 5 g/㎏ 이상인 안전한 물질로 판단되었다.Acute toxicity test was performed using 6-week-old SPF SD rats. Gallocatechin gallate and epigallocatechin gallate were each suspended in 0.5% methylcellulose solution and administered once orally at a dose of 5 g / kg / 15 mL. After administration of the test substance, mortality, clinical symptoms, and changes in body weight were observed. Hematological and hematological examinations were performed. Necropsy was performed to observe abdominal and thoracic organ abnormalities. As a result, there were no clinical symptoms or deaths in all animals treated with the test substance, and no toxicity change was observed in weight change, blood test, blood biochemistry test, autopsy findings, etc. As a result, gallocatechin gallate of formula 3 and epigallocatechin gallate of formula 4 do not show toxicological changes in rats up to 5 g / kg, and the minimum lethal dose (LD 50 ) for oral administration is determined to be 5 g / kg or more. It became.
상기에서 살펴본 바와 같이, 본 발명의 갈로카테킨갈레이트 및 에피갈로카테킨갈레이트를 포함하는 카테킨 및 에피카테킨 유도체들은 간염을 만성상태로 유지시키는 e 항원의 생성을 강하게 억제시키며, 세포 독성이 낮아 B형 간염 환자, 특히 만성간염 환자를 치료하는데 유용하게 사용될 수 있다.As described above, the catechin and epicatechin derivatives including gallocatechin gallate and epigallocatechin gallate of the present invention strongly inhibit the production of e antigens that maintain hepatitis in a chronic state, and are low in cytotoxicity. It can be usefully used to treat hepatitis patients, especially chronic hepatitis patients.
도 1은 갈로카테킨갈레이트 (gallocatechingallate) 및 에피갈로카테킨갈레이트 (epigallocatechingallate)가 B형 간염 바이러스에 감염된 간세포에서 외부 (extracellular)로 B형 간염 바이러스 e 항원의 분비를 억제하는 것을 나타낸 그래프이고, 1 is a graph showing that gallocatechingallate and epigallocatechingallate inhibit the secretion of hepatitis B virus e antigen extracellularly in hepatocytes infected with hepatitis B virus,
도 2는 갈로카테킨갈레이트 및 에피갈로카테킨갈레이트가 B형 간염 바이러스에 감염된 간세포 내부 (intracellular)의 B형 간염 바이러스 e 항원의 생산에는 영향을 미치지 않는 것을 나타낸 그래프이고, FIG. 2 is a graph showing that gallocatechin gallate and epigallocatechin gallate do not affect the production of hepatitis B virus e antigen in intracellular infected with hepatitis B virus,
도 3은 갈로카테킨갈레이트 및 에피갈로카테킨갈레이트가 B형 간염 바이러스에 감염된 간세포에서 세포 내 (intracellular) B형 간염 바이러스 s 항원의 생산에는 영향을 미치지 않는 것을 나타낸 그래프이고, 3 is a graph showing that gallocatechin gallate and epigallocatechin gallate do not affect the production of intracellular hepatitis B virus s antigen in hepatocytes infected with hepatitis B virus,
도 4는 갈로카테킨갈레이트 및 에피갈로카테킨갈레이트가 B형 간염 바이러스에 감염된 간세포에서 세포 외 (extracellular) B형 간염 바이러스 s 항원의 생산에는 영향을 미치지 않는 것을 나타낸 그래프이고, 4 is a graph showing that gallocatechin gallate and epigallocatechin gallate do not affect the production of extracellular hepatitis B virus s antigen in hepatocytes infected with hepatitis B virus,
도 5는 갈로카테킨갈레이트와 에피갈로카테킨갈레이트가 B형 간염 바이러스 DNA 합성에 관여하지 않는다는 것을 나타낸 것이고, 5 shows that gallocatechin gallate and epigallocatechin gallate are not involved in hepatitis B virus DNA synthesis,
1: DMSO; 2: 1 μM DDC; 3: 0.1 μM (0.023 ㎍/㎖) 3TC;1: DMSO; 2: 1 μM DDC; 3: 0.1 μM (0.023 μg / mL) 3TC;
4: 1 μM (0.23 ㎍/㎖) 3TC; 5: 10 μM (2.3 ㎍/㎖) 3TC;4: 1 μM (0.23 μg / mL) 3TC; 5: 10 μM (2.3 μg / mL) 3TC;
6: 0.1 μM (㎍/㎖) 에피갈로카테킨갈레이트;6: 0.1 μM (μg / mL) epigallocatechingallate;
7: 1 μM (㎍/㎖) 에피갈로카테킨갈레이트; 7: 1 μM (μg / ml) epigallocatechingallate;
8: 10 μM (㎍/㎖) 에피갈로카테킨갈레이트;8: 10 μM (μg / mL) epigallocatechingallate;
9: 0.1 μM (㎍/㎖) 갈로카테킨갈레이트;9: 0.1 μM (μg / mL) gallocatechin gallate;
10: 1 μM (㎍/㎖) 갈로카테킨갈레이트;10: 1 μM (μg / ml) gallocatechin gallate;
11: 10 μM (㎍/㎖) 갈로카테킨갈레이트;11: 10 μΜ (μg / ml) gallocatechin gallate;
I : 세포 DNA;I: cellular DNA;
D2: 이중 가닥 직선 (double strand linear) DNA;D2: double strand linear DNA;
D1: 이중 가닥 원형 (double strand circular) DNA;D1: double strand circular DNA;
S: 단일 가닥 (single strand) DNAS: single strand DNA
도 6은 갈로카테킨갈레이트 및 에피갈로카테킨갈레이트가 B형 간염 바이러스의 중합효소 활성을 억제하는지 여부를 나타낸 그래프이다. 6 is a graph showing whether gallocatechin gallate and epigallocatechin gallate inhibit the polymerase activity of hepatitis B virus.
도 7a 및 7b는 갈로카테킨갈레이트와 에피갈로카테킨갈레이트가 e-항원 생산 형질전환 마우스의 T-도움세포의 생산을 활성화시키는 것을 나타낸 그래프이다. 7A and 7B are graphs showing that gallocatechin gallate and epigallocatechin gallate activate the production of T-helper cells in e-antigen producing transgenic mice.
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| KR1020050041985A KR20050053037A (en) | 2001-04-23 | 2005-05-19 | Food composition useful for prevention or inhibition of hepatitis |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020040117109A KR20050008606A (en) | 2001-04-23 | 2004-12-30 | Food composition useful for inhibition or prevention of hepatitis |
| KR1020050041985A KR20050053037A (en) | 2001-04-23 | 2005-05-19 | Food composition useful for prevention or inhibition of hepatitis |
Country Status (1)
| Country | Link |
|---|---|
| KR (3) | KR100504119B1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100792626B1 (en) * | 2006-05-30 | 2008-01-09 | 프로테온 주식회사 | Agent for preventing and treating infectious disease by influenza virus comprising cathechin derivative compounds |
| KR100853442B1 (en) * | 2007-08-21 | 2008-08-21 | 프로테온 주식회사 | The health food for preventing infectious disease by influenza virus comprising cathechin derivative compounds |
| IT202000007816A1 (en) * | 2020-04-14 | 2021-10-14 | Adamas Biotech S R L | CORONAVIRUS INHIBITOR MEDICAL DEVICE |
| US20240238242A1 (en) * | 2023-01-16 | 2024-07-18 | Hainan University | EGCG buccal tablet and use thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4166861A (en) * | 1976-03-23 | 1979-09-04 | Inverni Della Beffa S.P.A. | Pharmacologically active polyphenolic substances |
| JPH0248533A (en) * | 1988-08-09 | 1990-02-19 | Kissei Pharmaceut Co Ltd | Remedy for hepatopathy composed of extract of wild grape |
| JP2000060427A (en) * | 1998-08-19 | 2000-02-29 | Howaizu:Kk | Healthy black tea beverage |
-
2002
- 2002-04-18 KR KR10-2002-0021352A patent/KR100504119B1/en not_active IP Right Cessation
-
2004
- 2004-12-30 KR KR1020040117109A patent/KR20050008606A/en not_active Application Discontinuation
-
2005
- 2005-05-19 KR KR1020050041985A patent/KR20050053037A/en not_active Application Discontinuation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4166861A (en) * | 1976-03-23 | 1979-09-04 | Inverni Della Beffa S.P.A. | Pharmacologically active polyphenolic substances |
| JPH0248533A (en) * | 1988-08-09 | 1990-02-19 | Kissei Pharmaceut Co Ltd | Remedy for hepatopathy composed of extract of wild grape |
| JP2000060427A (en) * | 1998-08-19 | 2000-02-29 | Howaizu:Kk | Healthy black tea beverage |
Non-Patent Citations (5)
| Title |
|---|
| "건국대학교 동물자원 연구센터, ""간경화 및 간실질 세포에 작용하는 칡성분으로부터의 유효생리 활성물질의 응용에 관한 연구"", 한국음식문화연구원 논문집, 1997" * |
| Alan L. Miller, "Antioxidant flavonoids: structure, function and clinical usage", Alternative medicine review, 1996 * |
| Hasegawa R., et al., "Inhibitory effect of green tea infusion of hepatotoxicity", Kokuritsu lyakuhin shokuhin eisei kenkyusho hokoku, 1998 * |
| Methods Find Exp Clin Pharmacol, 8(3), 147-150(1986, 인용참증1) * |
| Tao P., "The inhibitory effects of catechin derivatives on the activities of human ...", Zhongguo Yi Xue Ke Xue Yuan Xue Bao, 1992 * |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20020082120A (en) | 2002-10-30 |
| KR20050053037A (en) | 2005-06-07 |
| KR20050008606A (en) | 2005-01-21 |
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