KR100370501B1 - Composition for treatment of hepatitis b, containing extract of lonicera japonica thunb - Google Patents
Composition for treatment of hepatitis b, containing extract of lonicera japonica thunb Download PDFInfo
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- KR100370501B1 KR100370501B1 KR1019940037732A KR19940037732A KR100370501B1 KR 100370501 B1 KR100370501 B1 KR 100370501B1 KR 1019940037732 A KR1019940037732 A KR 1019940037732A KR 19940037732 A KR19940037732 A KR 19940037732A KR 100370501 B1 KR100370501 B1 KR 100370501B1
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- 239000000284 extract Substances 0.000 title claims abstract description 20
- 239000000203 mixture Substances 0.000 title claims abstract description 12
- 244000167230 Lonicera japonica Species 0.000 title abstract 6
- 235000017617 Lonicera japonica Nutrition 0.000 title abstract 6
- 208000006454 hepatitis Diseases 0.000 title description 4
- 231100000283 hepatitis Toxicity 0.000 title 1
- 208000002672 hepatitis B Diseases 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims description 16
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 16
- 229910052709 silver Inorganic materials 0.000 claims description 16
- 239000004332 silver Substances 0.000 claims description 16
- 229910052737 gold Inorganic materials 0.000 claims description 15
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- 239000004480 active ingredient Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 241000700721 Hepatitis B virus Species 0.000 abstract description 20
- 238000010438 heat treatment Methods 0.000 abstract description 4
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- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 4
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- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 3
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- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
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- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 2
- 229960005314 suramin Drugs 0.000 description 2
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- YKBGVTZYEHREMT-KVQBGUIXSA-N 2'-deoxyguanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 YKBGVTZYEHREMT-KVQBGUIXSA-N 0.000 description 1
- WGNRJVBNOQRUFP-UHFFFAOYSA-N 2-amino-2-hydroxy-1H-purin-6-one Chemical compound OC1(NC(C2=NC=NC2=N1)=O)N WGNRJVBNOQRUFP-UHFFFAOYSA-N 0.000 description 1
- UZOVYGYOLBIAJR-UHFFFAOYSA-N 4-isocyanato-4'-methyldiphenylmethane Chemical compound C1=CC(C)=CC=C1CC1=CC=C(N=C=O)C=C1 UZOVYGYOLBIAJR-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010019755 Hepatitis chronic active Diseases 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 241000594163 Japonia Species 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
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- 241001465754 Metazoa Species 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 244000173207 Phyllanthus amarus Species 0.000 description 1
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- 206010047700 Vomiting Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- -1 anti-agglomerates Substances 0.000 description 1
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- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
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- 206010061428 decreased appetite Diseases 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
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- 239000012895 dilution Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
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- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229960005102 foscarnet Drugs 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 201000010284 hepatitis E Diseases 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
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- 208000017169 kidney disease Diseases 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/35—Caprifoliaceae (Honeysuckle family)
- A61K36/355—Lonicera (honeysuckle)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation or decoction
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- Health & Medical Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Alternative & Traditional Medicine (AREA)
- Biotechnology (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Medicinal Chemistry (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
Description
본 발명은 금은화 추출물을 포함하는 B형 간염 치료제에 관한 것으로, 보다 상세하게는 한방에서 청열 해독약으로 사용되는 금은화를 물중탕으로 가열하여 불용성 물질을 제거하여 얻은 추출물을 포함하는 B형 간염 치료용 약학 조성물에 관한 것이다.The present invention relates to a hepatitis B therapeutic agent comprising a gold silver extract, more specifically for treating hepatitis B comprising an extract obtained by heating a gold silver flower, which is used as a clearing antidote in herbal medicine, by removing the insoluble substance. It relates to a pharmaceutical composition.
B형 간염 바이러스(HBV)는 인체에 특이적으로 감염되는 헤파드나비리대(Hepadnavirdae) 계통의 바이러스로서, 세계적으로 약 2억 5천 만명의 인구가 HBV 에 감염되어 있다. B형 간염 바이러스는 전세계적으로 다양하게 분포하나 국가별 발병율은 큰차이를 보이는데, 미국은 0.5%, 일본은 1.5%, 유럽은 1% 등으로 낮고 한국은 8%, 중국은 15%. 아프리카는 7% 정도의 높은 발병율을 보인다. 현재까지 한국 국민의 B형 간염 바이러스 보유율은 8% 정도인데, 이중 15 내지 20% 가 간경변증까지 진행되고 간경변증 환자의 20% 정도에서 간암이 발생하는 것으로 알려져 있으며, 추후 더 이상의 보균자가 발생하지 않더라도 70만명의 간경변증 환자와 14 만명의 간암 환자가 발생할 것으로 추정된다(I. H. Hu et al.,월간약국 4월호, PP 54-59(1992)).Hepatitis B virus (HBV) is a virus of the Hepadnavirdae strain that specifically infects the human body, and an estimated 250 million people worldwide are infected with HBV. The hepatitis B virus is widely distributed in the world, but the incidence rate varies widely among countries. The US is 0.5%, Japan is 1.5%, Europe is 1%, and Korea is 8% and China is 15%. Africa has a high incidence of around 7%. To date, the Korean population has about 8% hepatitis B virus, of which 15-20% progress to cirrhosis and 20% of liver cirrhosis patients develop liver cancer, even if no further carriers occur. It is estimated that 10,000 patients with cirrhosis and 140,000 patients with liver cancer will develop (IH Hu et al., Monthly Pharmacy April , pp 54-59 (1992)).
B형 간염 바이러스의 잠복기는 60 내지 110 일 정도이며 다양한 정도의 임상기를 거쳐 90 내지 95%는 완전히 회복된다. 감염에서 회복되지 않는 환자의 경우에는, HBV DNA 가 사람 간세포의 게놈 DNA 에 동화되어 만성 활동성 간염, 간경병증, 간암 등으로 발전하게 된다. HBV 에 의한 만성간염은 다른 질환과 마찬가지로 만성 바이러스 감염증, 임파종 질환 및 만성 신장장애를 일으킨다. 따라서 만성간염은 더욱 강력한 형태의 질환으로 발전하여 결국 환자를 사망에 까지 이르게 하는 치사율이 매우 높은 질환이라 할 수 있다(Don Ganem et al.,Ann, Rev, Biochem, 56,651(1987): R.P. Beasley et al.,Lancet 2, 1129(1981): D. A. Shafritz et al.,New England J. Med. 305,1067(1981); S.N. Zaman et al., Lancet 1, 1357(1985)).The incubation period of the hepatitis B virus is about 60 to 110 days, and 90 to 95% of the hepatitis B virus recovers completely after various degrees of clinical trial. In patients who do not recover from infection, HBV DNA is assimilated into genomic DNA of human hepatocytes, leading to chronic active hepatitis, cirrhosis, liver cancer, and the like. Chronic hepatitis caused by HBV, like other diseases, causes chronic viral infections, lymphoma diseases and chronic kidney disorders. Therefore, chronic hepatitis is a disease with a high mortality rate that develops into a more powerful form of disease and eventually leads to death (Don Ganem et al., Ann, Rev, Biochem, 56, 651 (1987): RP Beasley et al., Lancet 2 , 1129 (1981): DA Shafritz et al., New England J. Med. 305, 1067 (1981); SN Zaman et al., Lancet 1, 1357 (1985)).
지금까지 HBV 감염을 예방하기 위한 많은 백신들이 개발되었다. 이들 백신들은 면역원(Immunogen)으로서 B형 표면항원(HBsAg)을 이용하는데, B형 표면항원은 B형 간염 바이러스에 감염된 보균자의 혈장으로부터 또는 유전공학 기법을 통해서 얻을 수 있다. 이러한 표면 항원계 백신은 개체 감염을 방지하는데는 일반적으로 효과적이라 할 수 있지만 백신이 투여된 모든 개체에서 보호 수준의 항체가 형성되는 것은 아니다. 이들 항체의 형성정도는 투여되는 을의 연령 및 면역시스템의 억제정도는 물론, 주사부위와 같은 요인들에 의해서 영향을 받으며, 또한 백신이 투여된 모든 사람은 과민반응을 일으킬 다소의 위험도 갖고 있다.To date, many vaccines have been developed to prevent HBV infection. These vaccines use type B surface antigen (HBsAg) as an immunogen, which can be obtained from the plasma of carriers infected with hepatitis B virus or through genetic engineering techniques. Such surface antigen-based vaccines are generally effective in preventing individual infections, but not all levels of protective antibodies are formed in all individuals to which the vaccine is administered. The degree of formation of these antibodies is influenced by factors such as the age of the group administered and the degree of suppression of the immune system, as well as the injection site, and all people who receive the vaccine have some risk of hypersensitivity.
일단 HBV 에 감염된 환자의 경우는 적절한 치료제의 공급이 요구된다. 현재까지 B형 간염 치료제로서 몇가지 약제가 개발되기는 하였으나 만족할만한 효능을지닌 것은 거의 없다. Ara-A가 지금까지 미국 FDA 로 부터 승인받은 유일한 약으로, 임상시험에서는 유의할 만한 결과를 보여 주었으나 약물 자체가 갖는 독성 때문에 사용이 극히 제한적이며 인터페론과 병용치료하는 방법으로 사용된다. Ara-A의 부작용으로는 오심, 식욕부진, 설사, 구토 및 혈소판 감소등에 의한 가역적 골수억제 등이 알려져 있다(J. A. Payne et al.,Disease a Month,March, pp. 117-159(1988)), 한편, 아사이클로비르(Acyclovir: 9-(2-히드록시 구아닌)나 인터페론의 경우, 투여시에는 B형 간염에 대해 다소의 치료효과를 보이기는 하지만 투여를 중지하면 투여전 상태로 다시 복귀하기 때문에 장기 투여를 하여야 하며, 이로 인해 심한 부작용을 초래한다는 문제점이 있다. 한편, 이외에도 포스포노포르메이트(Phosphono-formate, Foscarnet), 수라민(Suramin), 프로스타글란딘(Prostaglandin). 2-CDG(carbocyclic analogue of 2-deoxyguanosine), 팜사이크로비르(Famcicovir)등이 유망하다고 알려져 있기는 하지만 아직 많은 검증이 필요하다. 최근에 개발된 약제 가운데 약효 및 독성면에서 가장 유망하다고 알려진 FIAU(Fialuridine)의 경우 임상 II 단계에서 예상치 못한 사망으로 인해 임상시험이 중단된 예도 있다.Once a patient is infected with HBV, adequate treatment is required. To date, several drugs have been developed for the treatment of hepatitis B, but few have satisfactory efficacy. Ara-A is the only drug that has been approved by the US FDA so far, and clinical trials have shown significant results, but its use is extremely limited due to the toxicity of the drug itself, and is used in combination with interferon. Side effects of Ara-A include nausea, anorexia, diarrhea, vomiting and reversible bone marrow suppression due to platelet reduction (JA Payne et al., Disease a Month, March, pp. 117-159 (1988)), Acyclovir (9- (2-hydroxyguanine) or interferon, on the other hand, has some therapeutic effects on hepatitis B at the time of administration, but returns to the pre-administration state after discontinuation. Long-term administration is required, which causes severe side effects, in addition to phosphonoformate (Foscarnet), suramin (Suramin), and prostaglandin (2-CDG). Although 2-deoxyguanosine, Famcicovir, etc. are known to be promising, they still need a lot of validations.FiFiuridine (FIAU), which is the most promising in terms of efficacy and toxicity among the recently developed drugs, RHS II clinical death due to unexpected examples stage clinical trials are stopped.
지금까지 B형 간염 치료제로는 뉴클레오사이드 유사체들에 대한 연구가 주종을 이루었으나, 이들의 경우는 심한 부작용이 가장 큰 단점으로 지적되고 있다. 한편, 뉴클레오사이드 유사체가 아닌 천연약재로부터 B형 간염 치료제를 개발하고자 하는 연구도 보고되어 있다. 인디 안의 황달 치료제로 널리 알려진 필란써스 니루리(Phyllanthus niruri)와 필란써스 아마루스(Phyllanthus amarus)라는 약용식물의추출물이 동물실험에서 B형 간염 바이러스의 억제에 매우 효과적인 것으로 보고되었으며 현재 유효성분 분석과 임상시험중에 있다(P. S. Venkateswaren et al.,Proc. Natl. Acad. Sci. 84,274(1987); Blumberg et al.,Vaccine 8, 274(1990)).Until now, studies on nucleoside analogues have been mainly used as a treatment for hepatitis B, but the serious side effects are pointed out as the biggest disadvantage. On the other hand, studies have been reported to develop a hepatitis B therapeutic agent from natural medicine that is not a nucleoside analog. Pilran sseoseu you widely known as Jaundice drug in the indie Metalurgs (Phyllanthus niruri) and pilran sseoseu maybe Ruth was a medicinal plant extracts called (Phyllanthus amarus) reported to be highly effective in the inhibition of hepatitis B virus in animals currently active ingredient analysis, In clinical trials (PS Venkateswaren et al., Proc. Natl. Acad. Sci. 84, 274 (1987); Blumberg et al., Vaccine 8 , 274 (1990)).
한편, 금은화는 인동화, 은화 또는 이화 등의 여러가지로 호칭되기도 하는데, 인동과에 속하며 학명은 루니세라 자포니아 툰베르그(Lunicera japonia Thunberg)로 알려져 있다. 금은화는 오래전부터 민간요법이나 한방에서 청열해독약으로 널리 사용되어 왔으며, 이의 추출물 및 일부 유효성분들은 항인플루엔자 바이러스작용, 항균작용, 항진균 작용, 항염작용 및 해열작용 등의 여러가지 약리작용을 지니고 있어 각종 질병의 치료에 다양하게 응용되고 있다(한국 유용식물자원 연구 총람, 한국화학연구소, pp 201-204(1988);한방 임상응용, 성보사, pp 140-142(1982)). 물론, 상기의 여 러가지 보고들에 있어서 금은화와 B형 간염 바이러스와의 직접적인 관련성은 없으며, 또한 지금까지 전혀 연구된 바도 없다.On the other hand, gold and silver coins are also referred to as a variety of people , such as hwahwahwa , silver coins or hwahwa , belonging to the family of departments and the scientific name is known as Lunicera japonia Thunberg . Gold and silver has long been widely used in folk remedies and oriental medicine as a detoxification drug, and its extracts and some active ingredients have various pharmacological effects such as anti-influenza virus action, antibacterial action, antifungal action, anti-inflammatory action and antipyretic action. It is widely applied to the treatment of diseases ( Korean Institute of Plant Resources Research , Korea Research Institute of Chemical Technology, pp 201-204 (1988); Oriental Medical Clinical Application , Sungbosa, pp 140-142 (1982)). Of course, there are no direct links between the gold and silver hepatitis B viruses in these reports, and none have been studied so far.
본 발명자들은, 만성간염의 70 % 이상이 B형 간염 바이러스 에 기인한다는 사실에 기초하여, 독성의 가능성이 적은 천연약재로 부터 B형 간염 치료제를 개발하고자 노력하던 중, 한약재인 금은화의 수성 추출물이 B형 간염 바이러스의 생성을 강하게 억제한다는 사실을 발견하여 본 발명을 완성하게 되었다. 물론 금은화는 예로부터 한방에서 탕제로 사용되어 왔던 것이며 그 동안의 임상적 경험으로 보아, 그 수성추출물에 독성의 가능성은 없는 것으로 사료된다.Based on the fact that more than 70% of chronic hepatitis is caused by the hepatitis B virus, the present inventors have been trying to develop a hepatitis B therapeutic agent from natural drugs with low possibility of toxicity. The present invention was completed by discovering that the production of hepatitis B virus is strongly inhibited. Of course, gold and silver coins have been used as a herbal medicine for a long time. From the clinical experience, there is no possibility of toxicity in the aqueous extract.
즉, 본 발명의 목적은 금은화의 수성 추출물이 B형 간염 바이러스의 생성에 대하여 강한 억제효과가 있음을 밝히고, 이를 포함하는 B형 간염 치료에 유용한 약학 조성물을 제공하는 것이다.That is, it is an object of the present invention to find that the aqueous extract of gilding silver has a strong inhibitory effect on the production of hepatitis B virus, to provide a pharmaceutical composition useful for treating hepatitis B comprising the same.
상기 목적을 달성하기 위하여 본 발명에서는, 금은화의 수성 추출물을 포함하는 B형 간염 치료제 조성물이 제공된다.In order to achieve the above object, the present invention provides a hepatitis B therapeutic composition comprising an aqueous extract of sterling silver.
상기의 금은화 추출물은, 금은화를 물중탕하에 수성용매로 추출하여 얻어진 수성 추출물인 것을 특징으로 한다.Said gold and silver extract is an aqueous extract obtained by extracting gold and silver coins with an aqueous solvent in a water bath.
이하 본 발명을 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
먼저 금은화에 증류수를 넣고 물중탕으로 가열하여 추출한다. 이 때, 종류수중 금은화의 농도는 10 내지 40 % (w/v), 바람직하게는 20 % (w/v)이고 물중탕 가열은 비등하지 않을 정도의 온도, 즉 약 60 내지 90℃, 바람직하게는 80℃ 에서 12 내지 48 시간, 바람직하게는 24시간 동안 수행한다.First, distilled water is added to gold and silver coins and extracted by heating in a water bath. At this time, the concentration of gold and silver in the tangible water is 10 to 40% (w / v), preferably 20% (w / v) and the boiling water heating is not boiling, that is, about 60 to 90 ℃, preferably Is carried out at 80 ° C. for 12 to 48 hours, preferably 24 hours.
얻어진 금은화의 수성 추출액을 그대로 치료제에 응용할 수도 있으나, 여기에는 치료에 바람직하지 않은 성분과 많은 불순물이 포함되어 있으므로 원심분리 및 한외여과 등을 수행하여 보다 순수한 추출물로 만들 필요가 있다. 원심분리나 한외여과는 순수한 금은화 추출물을 얻기 위한 방법의 하나일 뿐, 본 발명의 조성물을 얻기 위한 방법이 이에 한정되는 것은 아니다. 이 때, 원심분리시의 회전속도(rpm)나 한외여과시의 막의 종류는 임의로 선택하여 사용할 수 있다.The aqueous extract of the gold and silver coins obtained may be applied as it is to a therapeutic agent, but since it contains components and many impurities which are undesirable for treatment, it is necessary to perform centrifugation and ultrafiltration to make a purer extract. Centrifugation or ultrafiltration is just one of the methods for obtaining pure sterling silver extract, but the method for obtaining the composition of the present invention is not limited thereto. At this time, the rotational speed (rpm) during centrifugation and the kind of membrane during ultrafiltration can be arbitrarily selected and used.
원심분리 또는 한외여과에 의하여 불순물이 제거된 수성 추출액을 감압하에 증발시켜 금은화의 수성 추출물을 얻는다.The aqueous extract from which impurities are removed by centrifugation or ultrafiltration is evaporated under reduced pressure to obtain an aqueous extract of sterling silver.
상기에서 얻은 순수한 금은화의 수성 추출물을 B형 간염 바이러스를 생성하는 세포주에 처리하여 일정 시간 배양한 후, 세포 배양액을 수집하여 B형 간염 표면항원의 생성에 대한 억제 정도를 정량 분석한다. 표면항원에 대한 억제 정도는, 예를 들어 상품화된 B형 간염 표면항원 검출키트(Auszyme R, Monoclonal, Abbott lab., #1980-24)를 이용하여 정량적으로 분석할 수 있다.The aqueous extract of pure sterling silver obtained above was treated with a cell line producing hepatitis B virus and incubated for a predetermined time, and then the cell cultures were collected to quantitatively analyze the degree of inhibition of the production of hepatitis B surface antigen. The degree of inhibition against surface antigen can be quantitatively analyzed using, for example, a commercialized hepatitis B surface antigen detection kit (Auszyme R, Monoclonal, Abbott lab., # 1980-24).
상기 실험 결과, 금은화의 수성 추출물이 B형 간염 표면항원 생성에 강한 억제효과를 갖는다는 것이 밝혀졌다. 따라서 금은화의 수성 추출물은 효과적인 B형 간염 치료제로서 사용될 수 있음을 알 수 있다.As a result of the experiment, it was found that the aqueous extract of sterling silver has a strong inhibitory effect on the production of hepatitis B surface antigen. Therefore, it can be seen that the aqueous extract of gold and silver coins can be used as an effective hepatitis B treatment.
본 발명의 B형 간염 치료제 조성물은, 금은화의 수성 추출물을 유효활성성분으로서 포함하며, 그 밖에 담체, 희석제, 충전제, 응집 방지제, 윤활제, 향미제 등 약제학적으로 허용되는 통상의 부형제를 첨가하여 공지의 방법에 따라 경구제, 피하 주사제, 정맥 주사제 등의 약제학적 제제로 제조될 수 있다. 상기 B형 간염 치료제는 경구적으로 또는 비경구적으로도 투여될 수 있으며, 일일 투여량은 수성 추출물로서 5 내지 25 mg/체중kg, 바람직하게는 10 mg/체중kg 의 양으로 사용할 수 있는데, 환자의 중상, 나이, 성별 등 여러가지 조건에 따라 조절 가능하다.The hepatitis B therapeutic composition of the present invention comprises an aqueous extract of sterling silver as an active ingredient, and other known pharmaceutically acceptable excipients such as carriers, diluents, fillers, anti-agglomerates, lubricants and flavors are added. It can be prepared by pharmaceutical preparations such as oral, subcutaneous, and intravenous. The hepatitis B therapeutic agent may be administered orally or parenterally, and the daily dose may be used as an aqueous extract in an amount of 5 to 25 mg / kg body weight, preferably 10 mg / kg body weight. It can be adjusted according to various conditions such as serious injury, age, sex.
이하 본 발명을 실시예에 의거하여 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail with reference to Examples.
하기 실시예는 단지 예시적인 목적으로 주어진 것이며 본 발명의 범위가 이로서 한정되는 것은 아니다.The following examples are given for illustrative purposes only and are not intended to limit the scope of the invention.
실시예Example
1. 금은화 추출물의 제조1. Preparation of Gold Coin Extract
한약재인 금은화 120g에 증류수 600㎖을 넣고 교반시키면서 물중탕으로 80 ℃에서 24 시간 동안 가열하였다. 이렇게 얻은 금은화 추출액을 8,500 rpm에서 30분간 원심분리하여 불용성 침전은 제거하고 상층액을 얻었다. 상기 상층액을 한외 여과막(whatman, No. 1)으로 여과하여 잔여 불용성 물질이 완전히 제거된 금은화의 수성 추출물을 얻었다.To 600 g of distilled water was added to 120 g of medicinal herb gold, and the mixture was heated with a water bath at 80 ° C. for 24 hours. The gold coin extract thus obtained was centrifuged at 8,500 rpm for 30 minutes to remove insoluble precipitate and to obtain a supernatant. The supernatant was filtered with an ultrafiltration membrane (whatman, No. 1) to obtain an aqueous extract of sterling silver from which residual insoluble matter was completely removed.
2. 세포 배양 및 금은화 추출물의 처리2. Cell Culture and Treatment of Gold Coin Extract
B형 간염 바이러스를 생성하는 세포주인 2. 2. 15(M. A. Shells et al.,Proc. Natl. Acad, Sci.,USA84, 1005(1987)) 세포를 T 75 플라스크에서 10 % FBS (Fetus Bovine Serum, GIBCO, # 16000-028), 1 %의 ABAM(Antibiotic-Antimycotic, GIBCO BRL, # 15240-013) 및 최종 농도 400 μg/ml의 제네티신(Geneticin, Sigma # G-9516)을 첨가한 IMDM(GIBCO, # 430-2200)로 5일 동안 배양한 후, 24공 마이크로플레이트의 각 공에 1.0 내지 1.5 X 105세포/ml 를 분주하여 5 % CO 배양기에서 1 내지 2 시간 정도 배양하였다. 세포가 바닥에 붙은 후에 동 배지로 10n씩 연속 희석한 금은화 추출물을 각 공당 0.1 ml 씩 처리하였다. 각 검체당 3회의 반복수를 유지하여 실험 오차를 최대로 줄이고자 하였다. 처리후 6 내지 8 일째에 배양액을 수집하여 B형 간염 바이러스에 대한 억제 정도를 분석하였다.2. Shell 15, a cell line producing hepatitis B virus (MA Shells et al., Proc. Natl. Acad, Sci., USA 84 , 1005 (1987)) was transferred to a 10% FBS (Fetus Bovine) flask in a T 75 flask. Serum, GIBCO, # 16000-028), 1% ABAM (Antibiotic-Antimycotic, GIBCO BRL, # 15240-013) and 400 μg / ml Geneticin (Geneticin, Sigma # G-9516) at a final concentration After 5 days of incubation with IMDM (GIBCO, # 430-2200), 1.0-1.5 × 10 5 cells / ml were dispensed into each ball of a 24-hole microplate and incubated for 1-2 hours in a 5% CO incubator. After the cells had adhered to the bottom, 0.1 ml of each gold-silver extract was serially diluted with copper medium for 10 n . We tried to reduce the experimental error to the maximum by maintaining three repetitions per sample. Six to eight days after the treatment, the cultures were collected and analyzed for the degree of inhibition against hepatitis B virus.
3. B형 간염 표면항원에 대한 억제정도 분석3. Analysis of the degree of inhibition of hepatitis B surface antigen
상기 2 로부터 얻은 금은화 추출물이 처리된 세포 배양액을 가지고 상품화된 B형 간염 표면항원 검출키트(Auszyme R, Monoclonal, Abbott lab., #1980-24)를 이용하여, 금은화 추출물의 B형 표면항원 생성에 대한 억제정도를 정량적으로 분석하였다.Using the hepatitis B surface antigen detection kit (Auszyme R, Monoclonal, Abbott lab., # 1980-24) commercialized with the cell culture solution treated with the sterling silver extract obtained from the above 2, the formation of the surface silver B antigen of the gold leaf extract The degree of inhibition was analyzed quantitatively.
세포 배양액을 인산염 완충 생리 식염수(pH 7.0)로 최종 흡광도가 1.0 내지 1.5 범위에 들도록 희석(대략 20 내지 50배 희석)한 후, 희석액 0.2 ㎖과 금은화 추출물이 처리되지 않은 대조군 용액 0.2 ㎖을 표면항원에 대한 1차 단일항체, HRP(Horse Radish Peroxidase)가 연결된 2차 단일항체가 이미 결합되어 있는 비드와 40℃에서 2시간 동안 각각 반응시킨 후, 비드를 증류수로 3회 세척하여 미결합 물질을 제거하였다. 다음에 과산화수소수가 함유된 0-페닐렌디아민(0-phenylene-diamine) 용액 30 ㎕을 가하고 30분 배양한 후 0.1N HCl 을 가하여 반응을 중지시켰다.After diluting the cell culture solution with phosphate buffered saline (pH 7.0) so that the final absorbance is in the range of 1.0 to 1.5 (approximately 20 to 50-fold dilution), 0.2 ml of the diluent and 0.2 ml of the control solution not treated with the sterling silver extract were surface antigen. After reacting the primary monoclonal antibody, HRP (Horse Radish Peroxidase) -connected secondary monoclonal antibody with beads already bound at 40 ° C. for 2 hours, the beads were washed three times with distilled water to remove unbound substances. It was. Next, 30 µl of a 0-phenylene-diamine solution containing hydrogen peroxide solution was added thereto, followed by incubation for 30 minutes, and then 0.1N HCl was added to stop the reaction.
대조군과 실험군의 흡광도를 492 nm에서 측정하고, 하기 식을 이용하여 B형 간염 표면항원 생성 억제 정도를 계산하였다.Absorbance of the control group and the experimental group was measured at 492 nm, and the degree of inhibition of hepatitis B surface antigen production was calculated using the following equation.
금은화 추출물을 처리하지 않은 대조군의 흡광도는 0.945 였으며, 금은화 추출물의 농도에 따른 흡광도 및 그로부터 계산된 B형 간염 표면항원 생성 억제정도를 아래 [표]에 나타내었다.Absorption of the control group was not 0.95, the absorbance according to the concentration of the gold and silver extract and the calculated hepatitis B surface antigen production inhibition is shown in the following table.
상기 표에서 보듯이, 금은화의 수성 추출물은 9.0 mg/ 의 농도에서 약 40 % 의 억제 효과를 나타냈으며, 0.09 mg/ 의 낮은 농도에서도 약 10 %의 억제율을 나타내고 있다. 즉, 금은화의 수성 추출물은 B형 간염 표면항원의 생성을 강하게 억제하는데, 따라서 E형 간염 치료제로서 유용하게 사용될 수 있음을 알 수 있다.As shown in the above table, the aqueous extract of sterling silver showed an inhibitory effect of about 40% at a concentration of 9.0 mg /, and an inhibition rate of about 10% even at a low concentration of 0.09 mg /. That is, it is understood that the aqueous extract of sterling silver strongly inhibits the production of hepatitis B surface antigen, and thus can be usefully used as a therapeutic agent for hepatitis E.
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| KR1019940037732A KR100370501B1 (en) | 1994-12-28 | 1994-12-28 | Composition for treatment of hepatitis b, containing extract of lonicera japonica thunb |
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