KR100531643B1 - Composition comprising the extract of African Ganoderma mushroom for the treatment and protection of hepatitis B - Google Patents
Composition comprising the extract of African Ganoderma mushroom for the treatment and protection of hepatitis B Download PDFInfo
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- KR100531643B1 KR100531643B1 KR10-2003-0071684A KR20030071684A KR100531643B1 KR 100531643 B1 KR100531643 B1 KR 100531643B1 KR 20030071684 A KR20030071684 A KR 20030071684A KR 100531643 B1 KR100531643 B1 KR 100531643B1
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- KR
- South Korea
- Prior art keywords
- extract
- ganoderma lucidum
- african
- hepatitis
- hbv
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- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
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Abstract
본 발명은 B형 간염 바이러스(HBV) 억제능을 갖는 아프리카산 영지버섯(Ganoderma genus) 추출물을 함유하는 조성물에 관한 것으로, 본 발명의 아프리카산 영지버섯 추출물은 항바이러스 효과에 의해 B형 간염 바이러스의 증식을 억제하므로, B형 간염의 치료 및 예방을 위한 의약품 또는 건강기능식품에 유용하게 이용할 수 있다.The present invention relates to a composition containing an African Ganoderma genus extract having the ability to inhibit hepatitis B virus (HBV), the African Ganoderma genus extract of the present invention is proliferation of hepatitis B virus by the antiviral effect Since it inhibits, it can be usefully used in medicines or functional foods for the treatment and prevention of hepatitis B.
Description
본 발명은 B형 간염 바이러스 억제능을 갖는 아프리카산 영지버섯 추출물을 함유하는 B형 간염의 치료 및 예방을 위한 조성물에 관한 것이다.The present invention relates to a composition for the treatment and prevention of hepatitis B containing African Ganoderma lucidum extract with hepatitis B virus inhibitory ability.
B형 간염은 우리나라를 비롯하여 중국, 인도 및 동남아 등지에서 커다란 문제가 되고 있는 질환이다. B형 간염 바이러스(이하 HBV 바이러스라 함)는 헤파드나바이러스(hepadnaviruses)과에 속하며, 급성 간염뿐 아니라 간경변과 간암을 포함한 만성 간 질환을 유발하는 비세포병변(non-cytopathic) DNA 바이러스로 그 유전자(genome)는 약 3,200 bp의 불완전한 이중 나선 구조로서 이완된 원형을 유지하고 있다.Hepatitis B is a major problem in Korea, China, India and Southeast Asia. Hepatitis B virus (hereinafter referred to as HBV virus) belongs to the family hepadnaviruses and is a non-cytopathic DNA virus that causes not only acute hepatitis but also chronic liver disease including cirrhosis and liver cancer. The gene is an incomplete double helix structure of about 3,200 bp, maintaining a relaxed circle.
HBV 바이러스의 자기복제는 비리온(virion)이 간세포에 부착되면서 시작되는데, 간세포의 핵에서 HBV 바이러스 DNA의 플러스 사슬(plus strand)의 합성이 완료되면 바이러스 유전자는 공유결합의 닫힌 환형의 DNA(covalently closed circular DNA, cccDNA)로 전환된다. 이 cccDNA는 프리게놈 RNA(pregenomic RNA)의 주형(template)이 되고 이 프리게놈 RNA(pregenomic RNA)는 다시 HBV 바이러스 DNA의 마이너스 사슬(minus strand)로 역전사된다. 이 cccDNA는 두가지의 기원을 가지게 되는데, 즉 새로운 바이러스 단편(virus particle)이 간세포 내로 들어온 것이거나 또는 세포질 내의 미숙 뉴클레오캡사이드(immature nucleocapsid) 내에 있던 부분적으로 이중사슬화된 DNA(partially double stranded DNA)이다. 대부분의 항바이러스 제제는 이 cccDNA에는 거의 영향을 미치지 못하는 것으로 알려져 있는데 이것은 항바이러스 제제를 사용한 치료를 중단할 경우 재빨리 혈청 HBV 바이러스 DNA가 출현하는 이유로 생각된다.Self-replicating HBV virus begins with the attachment of virions to hepatocytes. Once the synthesis of the plus strand of HBV viral DNA is completed in the nucleus of the hepatocytes, the viral gene is covalently bound to the closed circular DNA (covalently). closed circular DNA, cccDNA). This cccDNA becomes a template of pregenomic RNA, which is then reverse transcribed into the minus strand of HBV viral DNA. This cccDNA has two origins: partly double-stranded DNA, either a new virus particle entering the hepatocyte or in an immature nucleocapsid in the cytoplasm. )to be. Most antiviral agents are known to have little effect on this cccDNA, which is thought to be the reason for the rapid emergence of serum HBV viral DNA when discontinued treatment with antiviral agents.
만성 B형 간염의 발병기전은 자세히 밝혀져 있지 않으나 결정적인 요인은 면역반응의 장애로 인하여 바이러스의 증식이 계속되고 불완전하게나마 이를 제어하려는 면역체계의 반응이 지속되기 때문으로 추정된다. 이와 같은 이론적인 배경 하에 만성 B형 간염의 치료를 위하여 면역능을 강화시키는 약제와 바이러스의 증식을 직접 억제할 수 있는 항바이러스제에 대한 많은 연구와 시도가 있어왔다. 만성 B형 간염 치료의 목적은 HBV 바이러스의 자기복제를 억제하고 간염의 완화(remission)를 유지하는 것이다. The pathogenesis of chronic hepatitis B has not been elucidated, but the decisive factor is presumably due to the impairment of the immune response, which continues the proliferation of the virus and the immune system's response to incomplete control. Under these theoretical backgrounds, many studies and attempts have been made on drugs that enhance immunity and antiviral agents that can directly inhibit the proliferation of viruses for the treatment of chronic hepatitis B. The purpose of chronic hepatitis B treatment is to inhibit self-replicated HBV virus and maintain remission of hepatitis.
현재 만성 B형 간염 치료제로는 인터페론(interferon, IFNs)과 라미부딘(lamivudine)이 주로 사용된다. 인터페론은 항바이러스 효과와 증식억제, 그리고 면역조절기능을 가지고 있는데 특히 IFN-α는 HBV 바이러스의 자기복제를 억제하고 간질환의 완화(remission)를 유도하는데 매우 효과적인 것으로 알려져 있다. 그러나 IFN-α의 효능은 아주 잘 선택된 소수의 환자에 대해서만 제한적으로 나타난다는 한계가 있다. 또한, 고가이며 부작용이 많고, 주로 출생 직후에 시작한 감염이 문제가 되는 아시아권 환자에서 그 효과가 떨어지는 것으로 알려져 있다.Currently, interferon (IFNs) and lamivudine are mainly used to treat chronic hepatitis B. Interferon has antiviral effects, proliferation suppression, and immunomodulatory functions. In particular, IFN-α is known to be very effective in inhibiting HBV virus self-replicating and inducing remission of liver disease. However, there is a limit that the efficacy of IFN-α is limited to only a few patients who are well selected. It is also known to be less effective in Asian patients, who are expensive and have many side effects, and whose infections that start shortly after birth are problematic.
라미부딘(상품명: 제픽스 Zeffix, glaxo사)은 2'-3'-디데옥시-3' 아시티딘(2'-3'dideoxy-3'-thiacytidine)의 (-) 거울상 이성질체(enantiomer)이다. 활성형의 트리포스페이트(triphosphate) (3TC-TP)로서 DNA 사슬에 결합하여 미숙 연쇄 종료(premature chain termination)를 초래해서 HBV 바이러스 DNA의 합성을 억제하며 HBV 바이러스 증식과정에서 RNA 프리게놈(pregenome)에서 마이너스 사슬 DNA(minus strand DNA)를 생성하는 역전사 과정을 방해하여 HBV 바이러스의 증식을 차단시키는 효과를 나타낸다. 그러나, HBsAg이나 HBeAg의 생산에는 영향을 미치지 못하는 것으로 알려져 있다. 또한 장기간 투약 시 라미부딘에 저항성인 변종(mutants; YMDD 변종(M204V/I))이 나타난다. 라미부딘은 YMDD 변종(motif) 근처에 가서 달라붙어 DNA 폴리머라제의 작용을 떨어뜨려 바이러스의 증식을 억제하게 된다. 그런데 YMDD 변종이 생긴 환자는 이 부분의 구조가 약간 변형되어 라미부딘이 달라붙을 때 완전하게 붙지 못하고 약간 틈이 생기기 때문에 효과가 떨어지게 된다.Lamivudine (trade name Zeffix, glaxo) is a negative enantiomer of 2'-3'-idedeoxy-3'-thiacytidine. Active triphosphate (3TC-TP), which binds to the DNA chain and leads to premature chain termination, inhibiting the synthesis of HBV viral DNA and inhibiting the synthesis of HBV virus DNA in the RNA pregenome during HBV virus propagation. Interfering with the reverse transcription process to produce minus strand DNA (HBV virus) has the effect of blocking the growth of HBV virus. However, it is known that it does not affect the production of HBsAg or HBeAg. In addition, mutations resistant to lamivudine (YMDD variant (M204V / I)) appear during long-term dosing. Lamivudine is bound to the YMDD variant (motif) and clings to reduce the action of the DNA polymerase to inhibit the growth of the virus. However, patients with the YMDD strain are slightly deformed because the structure of this part is slightly deformed when lamivudine sticks to it, and it becomes slightly cracked.
또한, B형 간염은 치료도 중요하지만 그것보다도 치료가 불가능한 간암으로 전환되는데 B형 간염 바이러스가 관여하는 것을 막는 것도 매우 중요하다. 이러한 HBV 바이러스의 증식은 대부분 간에서 일어나지만 일부는 비장, 신장, 췌장, 골수 등에서도 일어난다. 그러나 이러한 간 이외 장기에서의 증식은 조직 손상은 유발되지 않고 단지 HBV 바이러스만 증식된다. 이와 같이 만성 B형 간염은 전신 질환의 특성을 띄고 매우 복합적이고 복잡한 형태의 발병기전을 가지며 궁극적으로는 면역계의 장애가 중요한 발병 원인이 된다. 그러나 타 연구 분야에 비해 HBV 바이러스의 면역학적 병태생리 규명을 위한 실험실적 방법들이 충분히 개발되지 못하고 있어 현재까지도 여전히 B형 간염의 병태생리상 면역학적 기전의 규명은 매우 요원한 상태이며, 이미 HBV 바이러스에 감염되어 있는 환자들에게 도움이 될만한 치료법 역시 거의 없다.In addition, hepatitis B is important for treatment, but more important than that, it is also very important to prevent the hepatitis B virus involved in the conversion to liver cancer. Most of the growth of HBV virus occurs in the liver, but some occur in the spleen, kidney, pancreas and bone marrow. However, proliferation in these organs other than liver does not cause tissue damage, only HBV virus. As such, chronic hepatitis B is characterized by systemic diseases, has a very complex and complex pathogenesis, and ultimately, disorders of the immune system become important causes. However, laboratory methods for the immunological pathophysiology of HBV virus have not been fully developed in comparison with other research fields. Therefore, the pathophysiological mechanism of hepatitis B is still far from established. There are also few treatments that can help those who are infected.
현재의 치료제는 일시적으로 바이러스를 억제하지만 투약을 중단하면 다시 바이러스가 증식하며 내성이 생기는 문제점이 있는 것으로 보고되고 있다.Current treatments have been reported to temporarily inhibit the virus, but withdrawal of the virus causes the virus to multiply and develop resistance.
본 발명의 아프리카산 영지버섯(Ganoderma genus)은 불로초과(Ganodermataceae), 불로초속(Ganoderma)에 속하며, 아프리카 케냐의 고산 밀림지대에서 야생상태로 자생하는 활엽수 등에 기생하여 자라고 있는 버섯이다. 이곳의 생태적 특징은 적도부근의 열대지역임에도 불구하고 해발 5000 m급의 고산지대로서 버섯의 생육에 최적환경을 갖추고 있다. 목질이 강한 활엽수의 고사목과 그루터기에 자생하며 그루터기에 직각으로 자란다. 그 모양은 말발굽 모양으로써 원형이다. 표면은 매끈하고 콩팥형, 반원형의 형태를 가진다. 앞면은 처음에 황백색을 띠고 있으나 생장하면서 먼저 자란 부분부터 적갈색 내지 자갈색으로 변해간다. 뒷면은 황백색을 띠고 관공이 무수히 나 있다. 대는 갓의 표면과 같은 색으로 약간 굴곡이 생긴다. 가벼운 접촉에 의해 흰색의 관공 표면에 갈색반점이 나타나기 때문에 예술가의 모자(artist conk)라 불리어진다.African Reishi mushroom (Ganoderma genus) of the present invention is a mushroom growing to parasitic bulrochogwa (Ganodermataceae), it belongs to the genus bulrocho (Ganoderma), such as broad-leaved trees growing wild in the wild state in alpine jungle of Kenya. Although the ecological feature of this area is tropical near the equator, it is an alpine area of 5000m above sea level and has the optimal environment for mushroom growth. It grows on dead wood and stump of hardwood hardwood, and grows at right angle to stump. The shape is round in shape of a horseshoe. The surface is smooth and has the shape of a kidney, semicircle. The front is yellowish white at first, but grows from reddish brown to reddish brown. The back side is yellowish white and has a lot of bureaucracy. The stem is slightly curved with the same color as the surface of the lampshade. It is called an artist's hat because light spots show brown spots on the surface of white pores.
기억력 감소 방지, 노화억제, 생리활성, 세포활성, 항염, 항균작용, 혈압 강화작용, 항알레르기, 항히스타민, 항남성호르몬 작용 등에 유효한 것으로 알려져 있다. 그 외 항암효과를 나타내며, 추출물 역시 간암, 폐암 및 기타 여러 암들에 대한 우수한 치료 및 예방효과를 가짐이 임상실험에 의해 입증되었다. It is known to be effective in preventing memory loss, anti-aging, physiological activity, cellular activity, anti-inflammatory, antibacterial action, blood pressure strengthening action, anti allergy, antihistamine, anti-male hormone action. In addition, it has anti-cancer effects, and the extract has also been proved by clinical trials to have excellent therapeutic and preventive effects on liver cancer, lung cancer and many other cancers.
그러나, 지금까지 상기 아프리카산 영지버섯의 간염 치료효과에 대해서는 연구되어진 바 없다.However, the therapeutic effect of hepatitis of the African Ganoderma lucidum has not been studied until now.
본 발명자는 각종 바이러스 질환으로 고생하던 특정지역 주민들이 영지버섯의 끓인 물을 복용하던 중 탁월한 치료효과를 보인 것에 착안하여, 아프리카산 영지버섯 추출물 및 세부분획물의 HBV 억제능을 실험한 결과, 그 탁월한 효능을 확인하여 본 발명을 완성하였다.The present inventors focused on the excellent treatment effect of residents of a particular region suffering from various viral diseases while taking boiled water of Ganoderma lucidum mushroom, and tested the HBV inhibitory ability of African Ganoderma lucidum mushroom extracts and subfractions. It was confirmed to complete the present invention.
본 발명은 아프리카산 영지버섯 추출물을 함유하는 B형 간염의 예방 및 치료용 조성물로써 의약품 및 건강기능식품을 제공하는 것이다. The present invention is to provide a pharmaceutical and dietary supplement as a composition for the prevention and treatment of hepatitis B containing African Ganoderma lucidum extract.
상기 목적을 달성하기 위하여, 본 발명은 아프리카산 영지버섯(Ganoderma genus) 추출물을 함유하는 B형 간염의 예방 및 치료용 조성물을 제공한다.In order to achieve the above object, the present invention provides a composition for the prevention and treatment of hepatitis B containing African Ganoderma genus extract.
상기 영지버섯은 아프리카 케냐, 우간다, 탄자니아 등의 동남부 아프리카 지역, 바람직하게는 케냐에 자생하는 영지버섯을 포함한다. The ganoderma lucidum mushroom includes ganoderma lucidum native to Southeast Africa, preferably Kenya, such as Africa Kenya, Uganda and Tanzania.
상기 영지버섯 추출물은 조추출물 및 비극성 용매 가용성 추출물을 포함하며, 본 발명의 조추출물은 물, 에탄올, 메탄올, 부탄올과 같은 저급 알콜 또는 이들의 혼합용매, 바람직하게는 물 또는 메탄올에 가용한 추출물을 의미하며, 비극성 용매 가용추출물은 헥산, 디클로로메탄 또는 에틸 아세테이트와 같은 비극성 용매, 바람직하게는 헥산 또는 에틸 아세테이트에 가용한 추출물을 의미한다.The Ganoderma lucidum extract includes a crude extract and a non-polar solvent soluble extract, and the crude extract of the present invention comprises a lower alcohol such as water, ethanol, methanol, butanol, or a mixed solvent thereof, preferably an extract available in water or methanol. By nonpolar solvent soluble extract means an extract soluble in a nonpolar solvent such as hexane, dichloromethane or ethyl acetate, preferably hexane or ethyl acetate.
또한, 상기 아프리카산 영지버섯 추출물에는 고분자 다당체(분자량 12,000이상) 분획을 갖는 아프리카산 영지버섯 열수 추출물 및 고분자 단백질(분자량 12,000이상) 분획을 갖는 아프리카산 영지버섯 냉침 추출물을 포함한다. In addition, the African Ganoderma lucidum extract includes an African Ganoderma lucidum hydrothermal extract having a polymer polysaccharide (molecular weight 12,000 or more) fraction and an African Ganoderma lucidum mushroom extract having a macromolecular protein (molecular weight 12,000 or more) fraction.
이하, 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.
본 발명의 영지버섯 조추출물, 비극성용매 가용추출물, 고분자 다당체 분획을 갖는 열수 추출물 및 고분자 단백질 분획을 갖는 냉침 추출물은 하기와 같이 수득될 수 있다.The ganoderma lucidum extract of the present invention, a nonpolar solvent soluble extract, a hydrothermal extract having a polymer polysaccharide fraction, and a cold extract having a polymer protein fraction can be obtained as follows.
본 발명의 영지버섯을 채취하여 물로 깨끗이 수세하고 건조 후 균질기 등을 이용하여 마쇄하여 분말화 한 후, 영지버섯 건조중량의 약 2 내지 30 배, 바람직하게는 약 15 내지 30 배에 달하는 부피의 물, 메탄올, 에탄올 및 부탄올과 같은 저급 알콜 또는 이들의 약 1:0.1 내지 1:10의 혼합비를 갖는 혼합용매로, 바람직하게는 메탄올로 20 내지 100 ℃, 바람직하게는 50 내지 70 ℃의 추출 온도에서 약 0.5시간 내지 2일, 바람직하게는 1 시간 내지 1일 동안 열수 추출, 냉침 추출, 환류 냉각 추출 또는 초음파 추출 등의 추출방법, 바람직하게는 열수 추출로 1회 내지 5회, 바람직하게는 3회 연속 추출하여 감압 여과하고 여과추출물을 진공회전농축기로 20 내지 100 ℃, 바람직하게는 20 내지 70 ℃에서 감압 농축하여 물, 저급알콜 또는 이들의 혼합용매에, 바람직하게는 메탄올에 가용한 추출물로써 영지버섯 조추출물을 수득할 수 있다.After collecting the Ganoderma lucidum mushroom of the present invention, washed with water and dried, pulverized using a homogenizer and the like, and then powdered, Ganoderma lucidum mushroom has a volume of about 2 to 30 times the dry weight, preferably about 15 to 30 times Lower alcohols such as water, methanol, ethanol and butanol or mixed solvents having a mixing ratio of about 1: 0.1 to 1:10, preferably with an extraction temperature of 20 to 100 캜, preferably 50 to 70 캜 with methanol Extraction method such as hot water extraction, cold needle extraction, reflux cooling extraction or ultrasonic extraction for about 0.5 hours to 2 days, preferably 1 hour to 1 day, preferably 1 to 5 times, preferably 3 Continuous extraction and filtration under reduced pressure, and the filtrate was concentrated under reduced pressure at 20 to 100 ℃, preferably 20 to 70 ℃ with a vacuum rotary concentrator to water, lower alcohol or a mixed solvent thereof, preferably It can be obtained as a crude extract of Ganoderma lucidum extract available in coming.
본 발명의 비극성용매 가용 추출물은 상기 영지버섯 조추출물을 물에 현탁한 후, 헥산, 에틸아세테이트, 디클로로메탄, 클로로포름과 같은 비극성 용매를 이용하여 추출하여 본 발명의 영지버섯 비극성용매 가용 추출물을 수득할 수 있다. 좀 더 구체적으로는 영지버섯 조추출물, 바람직하게는 영지버섯 메탄올추출물에 영지버섯 건조중량의 약 2 내지 30 배, 바람직하게는 약 15 내지 30 배에 달하는 부피의 물을 넣고 잘 저으면서 녹인 후, 여기에 일정량의 헥산 또는 에틸 아세테이트를 혼합한 후, 3∼4 차례 반복, 분획하여 각각의 헥산 가용성 추출물 및 에틸아세테이트 가용성 추출물과 같은 비극성 용매 가용 추출물을 수득할 수 있다. The non-polar solvent soluble extract of the present invention is obtained by suspending the Ganoderma lucidum crude extract in water, followed by extraction using a non-polar solvent such as hexane, ethyl acetate, dichloromethane, and chloroform to obtain the Ganoderma lucidum non-polar solvent soluble extract of the present invention. Can be. More specifically, in the Ganoderma lucidum crude extract, preferably Ganoderma lucidum methanol extract, add about 2 to 30 times the dry weight of Ganoderma lucidum mushroom, preferably about 15 to 30 times the volume of water, and then stir well to dissolve it. After mixing a certain amount of hexane or ethyl acetate, and repeated three to four times, fractionation can be obtained to obtain a non-polar solvent soluble extract such as each hexane soluble extract and ethyl acetate soluble extract.
또한, 아프리카산 영지버섯 열수 추출물은 아프리카산 영지버섯을 물로 깨끗이 수세하고 건조시킨 다음, 건조상태의 영지버섯을 균질기를 이용하여 잘게 분쇄한 후, 영지버섯 건조 중량의 약 2 내지 30 배, 바람직하게는 약 3 내지 10 배에 달하는 부피의 물을 넣고 가열 멘틀을 이용하여 약 1 내지 24 시간, 바람직하게는 6 시간 동안 열수 추출한 후, 여지로 여과하여 수득한 열수 추출액에 약 1 내지 5 배, 바람직하게는 3 배의 저급알콜, 바람직하게는 냉(冷) 에탄올을 첨가하여 약 0 내지 10 ℃, 바람직하게는 4 ℃에서 약 12 내지 48 시간, 바람직하게는 24 시간 동안 침전시킨 다음, 상층액을 제거하고 원심분리하여 침전물을 모아 용매를 증발제거시킨 후, 약 50 내지 100 ℃, 바람직하게는 60 ℃에서 증류수로 펠렛(pallet)을 재용해시켜 원심분리하는 과정을 2 내지 5 회 반복수행하여 수득된 상층액을 약 0 내지 10 ℃, 바람직하게는 4 ℃에서, 약 12 내지 72 시간, 바람직하게는 48 시간 동안 증류수를 이용하여 투석한 후 동결건조하여 고분자 다당체(분자량 12,000이상) 분획을 갖는 본 발명의 아프리카산 영지버섯 열수 추출물을 수득할 수 있다.In addition, the African Ganoderma lucidum mushroom hydrothermal extract is washed with water and dried African Ganoderma lucidum with water, and then pulverized dried Ganoderma lucidum using a homogenizer, and then about 2 to 30 times the dry weight of Ganoderma lucidum mushroom, preferably Is about 3 to 10 times the volume of water and hot water extraction for about 1 to 24 hours, preferably 6 hours using a heating mantle, and then about 1 to 5 times, preferably in the hydrothermal extract obtained by filtration Preferably, three times lower alcohols, preferably cold ethanol, are added to precipitate for about 12 to 48 hours, preferably 24 hours at about 0 to 10 DEG C, preferably 4 DEG C, and then the supernatant is After removing and centrifuging to collect the precipitate to evaporate the solvent, the process of centrifugation by re-dissolving the pellet (pellet) with distilled water at about 50 to 100 ℃, preferably 60 ℃ The supernatant obtained by repeating five times was dialyzed with distilled water at about 0 to 10 ℃, preferably 4 ℃, for about 12 to 72 hours, preferably 48 hours, and then lyophilized to obtain a polymer polysaccharide (molecular weight: 12,000 Above) African Ganoderma lucidum hydrothermal extract of the present invention having a fraction can be obtained.
또한, 본 발명의 아프리카산 영지버섯 냉침 추출물은 아프리카산 영지버섯을 채취하여 물로 깨끗이 수세하고 건조시킨 다음, 건조상태의 영지버섯을 균질기를 이용하여 잘게 분쇄한 후, 완충용액을 가하고 약 0 내지 10 ℃, 바람직하게는 4 ℃에서 약 12 내지 24 시간 방치하여 냉침 추출한 후, 추출액을 여과하여 단백질 침전제로 에탄올, 아세톤 또는 황산암모늄(Ammonium sulfate)과 같은 염, 바람직하게는 황산암모늄을 가하고 포화상태로 한 후, 원심분리하여 상층액을 제거하고 수득한 침전물을 완충용액으로 재용해시킨 다음, 재용해된 추출물을 완충용액을 이용하여 약 0 내지 10 ℃, 바람직하게는 4 ℃에서, 약 50 내지 100 시간동안, 바람직하게는 74 시간 동안 투석한 후, 단백질 양을 정량하여 고분자 단백질(분자량 12,000이상) 분획을 갖는 아프리카산 영지버섯 냉침 추출물을 수득할 수 있다. In addition, the African Ganoderma lucidum mushroom cold sediment extract of the present invention, after collecting the African Ganoderma lucidum mushroom washed with water and dried, and then crushed the dried Ganoderma lucidum finely using a homogenizer, adding a buffer solution about 0 to 10 After cold extraction with standing at 12 DEG C., preferably at 4 DEG C for about 12 to 24 hours, the extract was filtered and added with a protein precipitant to a salt such as ethanol, acetone or ammonium sulfate, preferably ammonium sulfate, and saturated. After centrifugation, the supernatant was removed, and the precipitate obtained was redissolved with a buffer solution, and the redissolved extract was then buffered at about 0 to 10 ° C., preferably at 4 ° C., at about 50 to 100 ° C. African ganoderma lucidum having a high molecular weight protein (molecular weight of 12,000 or more) fraction by dialysis for a period of time, preferably 74 hours, Pop tall can be obtained naengchim extract.
본 발명은 상기 제조방법으로 얻어지는 B형 간염의 예방 및 치료에 효과적인 아프리카산 영지버섯 추출물을 제공한다.The present invention provides an African Ganoderma lucidum extract effective for the prevention and treatment of hepatitis B obtained by the above production method.
또한, 본 발명의 상기 아프리카산 영지버섯 추출물을 유효성분으로 함유하는 B형 간염의 예방 및 치료에 효과적인 조성물을 제공한다.In addition, the present invention provides an effective composition for the prevention and treatment of hepatitis B containing the African Ganoderma lucidum extract of the present invention as an active ingredient.
본 발명의 B형 간염의 예방 및 치료용 조성물은, 조성물 총 중량에 대하여 상기 추출물을 0.1 내지 80 중량 %, 바람직하게는 1.0 내지 50 중량 %를 포함한다.The composition for the prevention and treatment of hepatitis B of the present invention, the total weight of the composition comprises 0.1 to 80% by weight, preferably 1.0 to 50% by weight of the extract.
본 발명의 추출물의 약학적 투여 형태는 이들의 약학적 허용 가능한 염의 형태로도 사용될 수 있고, 또한 단독으로 또는 타 약학적 활성 분획물과 결합뿐만 아니라 적당한 집합으로 사용될 수 있다. Pharmaceutical dosage forms of the extracts of the present invention may be used in the form of their pharmaceutically acceptable salts, and may be used alone or in combination with other pharmaceutically active fractions, as well as in any suitable collection.
본 발명의 아프리카산 영지버섯 추출물을 포함하는 조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다. 추출물을 포함하는 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. The composition comprising the African Ganoderma lucidum extract of the present invention may further comprise a suitable carrier, excipient or diluent commonly used in the manufacture of pharmaceutical compositions. Carriers, excipients and diluents that may be included in the composition comprising the extract include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate , Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
본 발명에 따른 추출물을 포함하는 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 상세하게는, 제제화할 경우 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트 (calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Compositions comprising extracts according to the invention are each formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories or sterile injectable solutions according to conventional methods. Can be used. Specifically, it may be formulated using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. that are commonly used when formulated. Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and such solid preparations may include at least one excipient such as starch, calcium carbonate and sucrose in the extract. ) Or lactose, gelatin and the like can be mixed. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Oral liquid preparations include suspensions, solvents, emulsions, and syrups.In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
아프리카산 영지버섯 추출물의 사용량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으나, 일반적으로 0.01 내지 500 mg/㎏의 양, 바람직하게는 0.1 내지 100∼200 mg/㎏의 양을 일일 1회 내지 수회로 나누어 투여할 수 있다. 또한 추출물의 투여량은 투여경로, 질병의 종류 및 정도, 성별, 체중, 나이 등에 따라서 증감될 수 있다. 따라서, 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.The amount of African Ganoderma lucidum extract may vary depending on the age, sex, and weight of the patient, but in general, the amount of 0.01 to 500 mg / kg, preferably 0.1 to 100 to 200 mg / kg Can be administered in several divided doses. In addition, the dosage of the extract may be increased or decreased depending on the route of administration, the type and severity of the disease, sex, weight, age and the like. Therefore, the above dosage does not limit the scope of the present invention in any aspect.
본 발명의 조성물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내 (intracerebroventricular) 주사에 의해 투여될 수 있다. The composition of the present invention can be administered to mammals such as rats, mice, livestock, humans, etc. by various routes. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
본 발명의 아프리카산 영지버섯 추출물 자체는 독성 및 부작용이 거의 없으므로 예방 목적으로 장기간 복용 시에도 안심하고 사용할 수 있다. African Ganoderma lucidum extract itself of the present invention has little toxicity and side effects, so can be used with confidence even for prolonged administration for prophylactic purposes.
본 발명은 상기에 기재된 B형 간염의 예방 및 개선 효과를 나타내는 아프리카산 영지버섯 추출물 외에 식품학적으로 허용 가능한 식품보조 첨가제를 포함하는 건강기능식품을 제공한다.The present invention provides a health functional food comprising a food supplement acceptable food additives in addition to the African Ganoderma lucidum extract exhibiting the prevention and improvement effect of hepatitis B described above.
본 발명의 추출물들을 포함하는 조성물은 B형 간염의 예방 및 개선을 위한 식품 및 음료 등에 다양하게 이용될 수 있다. 본 발명의 아프리카산 영지버섯 추출물을 첨가할 수 있는 식품으로는, 각종 식품류, 예를 들어, 캔디, 초콜릿, 음료, 껌, 차, 비타민 복합제, 건강 기능 식품류 등이 있고, 분말, 과립, 정제, 캡슐 또는 음료인 형태로 사용할 수 있다.Compositions comprising the extracts of the present invention can be used in a variety of food and beverages for the prevention and improvement of hepatitis B. Foods to which the African Ganoderma lucidum extract of the present invention can be added include various foods, for example, candy, chocolate, beverages, gums, teas, vitamin complexes, health functional foods, and the like, powders, granules, tablets, It can be used in the form of a capsule or a beverage.
이때, 식품 또는 음료 중의 상기 추출물의 양은, 일반적으로 본 발명의 건강 기능 식품 조성물의 경우 전체 식품 중량의 0.01 내지 50 중량 %, 바람직하게는 0.1 내지 20 중량 %로 가할 수 있으며, 건강 기능 음료 조성물의 경우 100 ㎖를 기준으로 0.02 내지 10 g, 바람직하게는 0.3 내지 1 g의 비율로 가할 수 있다. At this time, the amount of the extract in the food or beverage, in the case of the health functional food composition of the present invention can generally be added to 0.01 to 50% by weight, preferably 0.1 to 20% by weight of the total food weight, In the case of 0.02 to 10 g, preferably 0.3 to 1 g, based on 100 ml.
본 발명의 건강 기능 음료 조성물은 지시된 비율로 필수 성분으로서 상기 추출물을 함유하는 외에는 액체성분에는 특별한 제한점은 없으며, 통상의 음료와 같이 여러가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등; 과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ㎖당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.The health functional beverage composition of the present invention is not particularly limited in the liquid component except for containing the extract as an essential ingredient in the indicated ratio, and may contain various flavors or natural carbohydrates, etc. as additional ingredients, as in general beverages. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; Polysaccharides such as dextrin, cyclodextrin and the like; Conventional sugars such as and sugar alcohols such as xylitol, sorbitol, erythritol. The proportion of such natural carbohydrates is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the composition of the present invention.
이 외 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어, 레바우디오시드 A, 글리시르히진 등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 또한, 본 발명의 조성물은 여러가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 조성물들은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그다지 중요하진 않지만 본 발명의 조성물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.Other flavors may be advantageously used natural flavors (tautin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.). The composition of the present invention is a variety of nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese, chocolate), pectic acid and salts thereof, alginic acid and salts thereof, Organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, etc. Other compositions of the present invention may be used in natural fruit juices and fruit juice beverages and vegetable beverages. The components may be used independently or in combination The ratio of such additives is not critical but is zero per 100 parts by weight of the composition of the present invention. It is generally selected from the range of about 20 parts by weight.
본 발명은 다음의 실시예 및 실험예에 의거하여 더욱 상세히 설명되나, 본 발명이 실시예 또는 실험예에 의해 제한되지는 않는다.The present invention is described in more detail based on the following examples and experimental examples, but the present invention is not limited to the examples or experimental examples.
실시예 1. 아프리카산 영지버섯 열수 추출물의 제조Example 1 Preparation of Hot Water Extract of African Ganoderma Lucidum Mushroom
아프리카산 영지버섯(아프리카 케냐에서 채집)을 10 kg을 채취하여 물로 깨끗이 수세하고 건조(차광된 음지에서 건조)시킨 다음, 건조상태의 영지버섯 20 g을 균질기(homogenizer)를 이용하여 잘게 분쇄한 후, 가열 멘틀(heating mantle)에 영지버섯 20 g 당 물 1 ℓ를 넣고 100 ℃에서 6 시간동안 열수 추출한 후, 여지(filter paper)로 여과(filtering)하여 수득한 열수 추출액 0.8 ℓ에 3배의 냉(cold) 95 % 에탄올을 첨가하여 4 ℃에서 24 시간동안 침전시킨 다음, 상층액을 제거하고 2800 rpm, 4 ℃, 20 분의 조건으로 원심분리하여 침전물만을 수집(harvesting)한 후, 침전물의 에탄올을 증발시킨 후, 60 ℃의 고온에서 증류수로 펠렛(pellet)을 재용해시켜 원심분리하는 과정을 3회 반복수행하여 수득된 상층액을 4 ℃에서 48 시간동안 증류수를 이용하여 투석(투석막 Mw 12,000이상)하고, 투석이 끝난 후 동결건조하여 고분자 다당체(분자량 12,000이상) 분획을 갖는 아프리카산 영지버섯 열수 추출물 1 g을 수득하였다.10 kg of African Ganoderma lucidum mushrooms (from Kenya, Africa) were taken, washed with water, dried (dried in shaded shade), and 20 g of Ganoderma lucidum dried finely ground using a homogenizer. Then, 1 liter of water per 20 g of Ganoderma lucidum was added to a heating mantle, followed by hot water extraction at 100 ° C. for 6 hours, followed by three times with 0.8 L of hot water extract obtained by filtering with filter paper. After adding cold 95% ethanol to precipitate for 24 hours at 4 ° C., the supernatant was removed, centrifuged at 2800 rpm, 4 ° C. for 20 minutes, and only the precipitate was collected. After evaporation of ethanol, the supernatant obtained by re-dissolving the pellet (pellet) with distilled water at a high temperature of 60 ° C. and repeating three times was dialyzed using distilled water at 4 ° C. for 48 hours (dialysis membrane Mw). More than 12,000) After lyophilization, 1 g of African Ganoderma lucidum hydrothermal extract having a polymer polysaccharide (molecular weight of 12,000 or more) fraction was obtained.
실시예 2. 아프리카산 영지버섯 냉침 추출물의 제조Example 2 Preparation of African Ganoderma Lucidum Mushroom Extract
아프리카산 영지버섯(아프리카 케냐에서 채집)을 10 ㎏을 채취하여 물로 깨끗이 수세하고 건조(차광된 음지에서 건조)시킨 다음, 건조 상태의 영지버섯 50 g을 균질기(homogenizer)를 이용하여 잘게 분쇄한 후, 영지버섯 20 g 당 50 mM 트리스-염산(Tris-HCl, pH 8.0) 완충용액 0.2 ℓ를 가하고 4 ℃에서 하룻밤동안 방치하여 냉침 추출한 후에, 추출액을 여과하여 황산암모늄(Ammonium Sulfate)을 가하고 100 % 포화상태로 한 후 원심분리(8000 g, 20 분)하여 상층액을 제거하고 수득한 침전물을 50 mM 트리스-염산(pH 8.0)과 50 mM 염화나트륨 완충용액으로 재용해 시킨 다음, 재용해된 추출물을 50 mM 트리스-염산(pH 8.0), 50 mM 염화나트륨 완충용액을 이용하여 4 ℃에서 72시간동안 투석(투석막 Mw 12,000 이상)하고, 투석이 끝난 후 단백질 양을 정량하여 고분자 단백질(분자량 12,000이상) 분획을 갖는 아프리카산 영지버섯 냉침 추출물 15 ㎖(농도 300 ㎍/㎖)를 수득하였다.Ten kilograms of African Ganoderma lucidum mushrooms (collected from Kenya, Africa) were collected, washed with water, dried (dried in shaded shades), and then 50 g of dried Ganoderma lucidum was ground finely using a homogenizer. After adding 0.2 L of 50 mM Tris-HCl (pH 8.0) buffer solution per 20 g of Ganoderma lucidum mushroom, it was allowed to stand overnight at 4 ° C, followed by cold extraction. The extract was filtered and added with ammonium sulfate (Ammonium Sulfate). After saturation, the supernatant was removed by centrifugation (8000 g, 20 minutes), and the obtained precipitate was redissolved with 50 mM tris-hydrochloric acid (pH 8.0) and 50 mM sodium chloride buffer, and then the redissolved extract. Dialysis (at dialysis membrane Mw 12,000 or more) for 72 hours using 50 mM tris-hydrochloric acid (pH 8.0) and 50 mM sodium chloride buffer solution, and after quantitative dialysis, the amount of protein was measured. minute The yield with the African Ganoderma lucidum extract naengchim 15 ㎖ (concentration 300 ㎍ / ㎖).
실시예 3. 아프리카산 영지버섯 조추출물의 제조Example 3. Preparation of Crude Mushroom Extracts from Africa
아프리카산 영지버섯(아프리카 케냐에서 채집)을 채취하여 물로 깨끗이 수세하고 건조(차광된 음지에서 건조)시킨 다음, 건조상태의 영지버섯 200 g을 균질기(homogenizer)를 이용하여 잘게 분쇄한 후, 가열 멘틀(heating mantle)에 넣고 메탄올 4 ℓ를 넣은 후, 79 ℃에서 일정시간(12 h) 간격으로 3회 반복 추출하여 얻은 추출액을 여지로 여과한 다음, 회전감압농축기(rotary vacuum evaporator)를 이용하여 감압 농축하여 영지버섯 조추출물 7 g을 수득하였다. Take an African Ganoderma lucidum mushroom (collected from Kenya, Africa), wash it with water, dry it (dried in shaded shade), and 200 g of dried Ganoderma lucidum using a homogenizer, and then heat it. Into a mantle (heating mantle) and 4 liters of methanol, the extract obtained by extracting three times at regular intervals (12 h) at 79 ℃ repeatedly filtered and then filtered using a rotary vacuum evaporator (rotary vacuum evaporator) Concentration under reduced pressure gave 7 g of ganoderma lucidum extract.
실시예 4. 아프리카산 영지버섯 헥산 가용성 분획물의 제조Example 4. Preparation of African Ganoderma lucidum hexane soluble fraction
상기 실시예 3에서 얻은 영지버섯 조추출물 즉, 영지버섯 메탄올 추출물 6.5 g을 300 ㎖ 3차 증류수에 넣고 1시간 가량 저으면서 녹인 후, 헥산 1.5 ℓ를 가하여 혼합하고 3차례 반복 분획하여 헥산 가용성 분획물을 얻은 후, 이 헥산 가용성 분획물을 여과 후 감압 농축시켜 영지버섯 헥산 가용성 추출물 0.5 g을 수득하였고, 4 ℃ 냉장고에 보관하면서 시료로 사용하였다.The Ganoderma lucidum crude extract obtained in Example 3, that is, 6.5 g of Ganoderma lucidum methanol extract was dissolved in 300 ml tertiary distilled water and stirred for about 1 hour, and then mixed with 1.5 L of hexane and repeatedly fractionated three times to obtain a hexane-soluble fraction. Then, this hexane soluble fraction was filtered and concentrated under reduced pressure to obtain 0.5 g of Ganoderma lucidum hexane soluble extract, which was used as a sample while being stored in a 4 ° C refrigerator.
실시예 5. 아프리카산 영지버섯 에틸아세테이트 가용성 분획물의 제조Example 5 Preparation of Ethyl Acetate Soluble Fraction of African Ganoderma Lucidum Mushroom
상기 실시예 3에서 얻은 영지버섯 조추출물 즉, 영지버섯 메탄올 추출물 6.5 g을 300 ㎖ 3차 증류수에 넣고 1시간 가량 저으면서 녹인 후, 에틸아세테이트 1.5 ℓ를 가하여 혼합한 후 3차례 반복, 분획하여 에틸아세테이트 가용성 분획물을 얻은 후, 이 에틸 아세테이트 가용성 분획물을 여과 후 감압 농축시켜 영지버섯 에틸 아세테이트 가용성 추출물 2.5 g을 수득하여 시료로 사용하였고, 4 ℃ 냉장고에 보관하면서 시료로 사용하였다. The Ganoderma lucidum crude extract obtained in Example 3, that is, 6.5 g of Ganoderma lucidum methanol extract was added to 300 ml of tertiary distilled water and stirred for 1 hour, and then dissolved by adding 1.5 L of ethyl acetate, followed by mixing three times, fractionating and ethyl acetate. After the soluble fraction was obtained, the ethyl acetate soluble fraction was concentrated under reduced pressure after filtration to obtain 2.5 g of Ganoderma lucidum ethyl acetate soluble extract, which was used as a sample, and used as a sample while being stored in a 4 ° C. refrigerator.
실험예 1. 아프리카산 영지버섯 추출물의 B형 간염 바이러스 억제 효과Experimental Example 1. Hepatitis B virus inhibitory effect of African Ganoderma lucidum extract
1-1. DNA 정량검사 방법1-1. DNA Quantitative Methods
추출물의 HBV 바이러스의 DNA에 대한 억제능을 측정하기 위하여, 마이크로플레이트상에서 화학발광법을 이용하여 혈청 내에 존재하는 B형 감염 바이러스의 DNA를 정량검사하였다. 이 실험은 혈청 내에 포함되어 있는 HBV 바이러스의 DNA와 결합할 수 있는 RNA 탐색자(RNA probe, ad & av stralms)를 이용하여 DNA: RNA 하이브리드를 만든 후, 이에 특이적인 항체가 포함되어 있는 마이크로플레이트에 포획(Capture)하고, 포획된 하이브리드를 알카린 포스파타제가 컨쥬게이션된 항체와 결합시킨 후 이를 화학발광물질을 사용하여 혈청 내에 존재하는 HBV 바이러스의 DNA 양을 빛의 세기로 측정하고 표준곡선(calibration curve)을 통해 그 농도를 결정하는 방법으로, 이 실험을 위하여 하이브리드 캡쳐기(hybrid capture technology, Digene사)를 사용하였다.In order to measure the inhibitory ability of the extract against the DNA of HBV virus, the DNA of hepatitis B virus present in the serum was quantitated by chemiluminescence on a microplate. This experiment was carried out using a RNA probe (ad & av stralms) capable of binding to the DNA of HBV virus contained in the serum to make a DNA: RNA hybrid, and then to a microplate containing specific antibodies. Capture and bind the captured hybrid to an antibody conjugated with alkaline phosphatase, and then measure the amount of HBV virus DNA in the serum using a chemiluminescent material as a light intensity and use a calibration curve. As a method of determining the concentration through), a hybrid capture technology (hybrid capture technology, Digene) was used for this experiment.
실험방법을 좀 더 구체적으로 설명하면, 먼저 마이크로플레이트 히터(microplate heater)에서 마이크로플레이트를 꺼낸 후 즉시 실러(sealer)를 제거하고, 칼리브레이터(Calibrators; Cal 1, Cal 2, Cal 3, Cal 4 및 Cal 5), 대조군(P3 및 P2), 실험군(실험군 S 및 실험군 A)을 각각 캡처 마이크로플레이트(Capture microplate ; 항-RNA:DNA 하이브리드 항체로 코팅된 마이크로플레이트)로 75 ㎕씩 옮겼다. 마이크로플레이트 실러를 이용하여 캡처 마이크로플레이트를 덮고 회전 교반기를 이용하여 1100 ±100 rpm, 18 내지 25 ℃에서 60 분간 배양시켰다. 캡처 마이크로플레이트의 여액을 피펫을 이용하여 제거한 후, 2~3회 깨끗한 흡수지에 두드려 여액을 완전히 제거하였다.In more detail, the test method is described in detail. First, the microplate heater is removed from the microplate heater, and then the sealer is immediately removed and the calibrator (Calibrators; Cal 1, Cal 2, Cal 3, Cal 4). And Cal 5), controls (P3 and P2), and experimental groups (Experimental Group S and Experimental Group A) were each transferred 75 μl into Capture microplates (microplates coated with anti-RNA: DNA hybrid antibody). The capture microplate was covered using a microplate sealer and incubated for 60 minutes at 1100 ± 100 rpm, 18-25 ° C. using a rotary stirrer. The filtrate of the capture microplate was removed using a pipette and then tapped on clean blotter paper 2-3 times to completely remove the filtrate.
소듐 아지드(sodium azide)를 포함하는 완충용액 중에서 RNA:DNA 하이브리드를 알카린 포스파타제(alkaline phosphatase)가 공액결합(conjugated)된 항체와 결합시킨 검출시약 75 ㎕를 각각의 캡처 마이크로플레이드 웰에 분주하고, 마이크로플레이트 실러를 이용하여 캡처 마이크로플레이트 웰을 덮고 20 ~ 25 ℃에서 30 분간 배양하였다. 이후 캡처 마이크로플레이트 웰의 여액을 완전히 제거한 후 캡처 마이크로플레이트 웰을 소듐아지드를 포함하는 희석 세척액으로 넘치도록 채운 후, 뒤집어서 버리는 방식으로 6회 세척하였다. 세척한 캡처 플레이트를 깨끗한 흡수지 위에서 10 내지 15분 정도 뒤집어 방치하여 남은 여액을 흡수시킨 후, 각각의 캡처 마이크로플레이트 웰에 화학발광물질(CDP-StarTM, Chemilumlnescent substrate)을 75 ㎕씩 분주하였다.In a buffer containing sodium azide, 75 μl of the detection reagent combining RNA: DNA hybrid with an antibody conjugated with alkaline phosphatase was dispensed into each capture microplate well. And, using a microplate sealer to cover the capture microplate well and incubated for 30 minutes at 20 ~ 25 ℃. After the filtrate of the capture microplate well was completely removed, the capture microplate well was flooded with dilution washing solution containing sodium azide, and then washed six times by turning it upside down. The washed capture plate was left inverted for 10-15 minutes on a clean blotter paper to absorb the remaining filtrate, and 75 μl of chemiluminescent material (CDP-Star ™ , Chemilumlnescent substrate) was dispensed into each capture microplate well.
마이크로플레이트 실러를 이용하여 캡처 마이크로플레이트 웰을 덮고 실온에서 15분 동안 직사광선을 피하여 배양하였다. 반응이 끝난 후 15분 이내에 DML 2000 루미노미터(Luminometer)를 이용하여 혈청내에 존재하는 HBV 바이러스의 DNA 양을 빛의 세기로 측정하였다. The microplate sealer was used to cover the capture microplate wells and incubated for 15 minutes at room temperature under direct sunlight. Within 15 minutes after the reaction was completed, the amount of DNA of the HBV virus present in the serum was measured by light intensity using a DML 2000 Luminometer.
실험에서, P3 및 P2는 양성대조군으로 감염성 HBV 바이러스 및 소듐 아지드를 포함한다. 칼리브레이터 1(Cal 1)은 HBV 음성의 인간 혈청내 운반체 DNA와 소듐 아지드를, 칼리브레이터 2(Cal 2)는 HBV 음성의 인간 혈청내 1.42 ×105 copies/㎖ (0.5 pg/㎖) HBV 바이러스 플라즈미드 DNA 와 운반체 DNA 및 소듐 아지드를, 칼리브레이터 3(Cal 3)는 HBV 음성의 인간 혈청내 2.83 ×107 copies/㎖ (100 pg/㎖) HBV 바이러스 플라즈미드 DNA 와 운반체 DNA 및 소듐 아지드를, 칼리브레이터 4(Cal 4)는 HBV 음성의 인간 혈청내 5.66 ×108 copies/㎖ (2000 pg/㎖) HBV 바이러스 플라즈미드 DNA 와 운반체 DNA 및 소듐 아지드를, 칼리브레이터 5(Ccal 5)는 HBV 음성의 인간 혈청내 1.70 ×109 copies/㎖ (100 pg/㎖) HBV 바이러스 플라즈미드 DNA 와 운반체 DNA 및 소듐 아지드를 포함한다.In the experiment, P3 and P2 were positive controls and included the infectious HBV virus and sodium azide. Calibrator 1 (Cal 1) is the carrier DNA and sodium azide in HBV negative human serum, Calibrator 2 (Cal 2) is 1.42 × 10 5 copies / mL (0.5 pg / ml) in HBV negative human serum. ) HBV virus plasmid DNA and carrier DNA and sodium azide, Calibrator 3 (Cal 3) is 2.83 × 10 7 copies / ml (100 pg / ml) HBV virus plasmid DNA and carrier DNA in HBV negative human serum. Sodium azide, Calibrate 4 (Cal 4), contains 5.66 × 10 8 copies / ml (2000 pg / ml) HBV virus plasmid DNA and carrier DNA and sodium azide in HBV negative human serum. (Ccal 5) comprises 1.70 × 10 9 copies / ml (100 pg / ml) HBV virus plasmid DNA in HBV negative human serum and carrier DNA and sodium azide.
대조약제인 제픽스는 분획물과 같이 100 ㎍/㎖의 농도로 맞추어 이중 10 ㎕를 1회 실험에 사용하였다.Gepix, the control drug, was used in one experiment, of which 10 μl was adjusted to a concentration of 100 μg / ml as fractions.
1-2. 아프리카산 영지버섯 열수 추출물의 HBV 억제능1-2. HBV Inhibitory Activity of Hot Water Extract of African Ganoderma Lucidum Mushroom
아프리카산 영지버섯의 HBV 억제능 측정을 위한 예비실험으로 HBV DNA 정량시험을 통하여 무작위로 HBV DNA를 함유하고 있는 혈청을 선별한 후, 선별된 환자 11명의 혈청을 HBV DNA를 적게 함유한 혈청부터 많이 함유한 혈청까지 정렬하고 각각의 혈청에 대하여 하기의 방법으로 아프리카산 영지버섯 열수 추출물의 HBV 억제 효과를 관찰하였다.As a preliminary experiment to measure HBV inhibition ability of African Ganoderma lucidum mushrooms, randomly selected serum containing HBV DNA was determined by HBV DNA quantitative test, and then the serum of 11 selected patients was included from serum containing less HBV DNA. One serum was sorted and the respective HBV inhibitory effects of the Ganoderma lucidum hydrothermal extracts were observed in the following manner.
먼저, 선별된 각각의 혈청 20 ㎕에 아프리카산 영지버섯 열수 추출물 10 ㎕를 처리하여 37 ℃에서 2시간동안 반응시킨 후 곧바로 혈청중의 HBV DNA양을 비교 측정함으로써 추출물의 HBV DNA억제효과를 관찰하고, 그 결과를 도 1에 나타내었다. 이 때, 실험군 S는 혈청 20 ㎕에 PBS 10 ㎕를 처리한 것이며 실험군 A는 혈청 20 ㎕에 추출물용액(농도: 50 g/1.5 ℓ) 10 ㎕를 처리한 것이다.First, 20 μl of each selected serum was treated with 10 μl of African Ganoderma lucidum hot water extract and reacted at 37 ° C. for 2 hours, and then the amount of HBV DNA inhibitory effect was observed by comparing and measuring the amount of HBV DNA in the serum. And the result is shown in FIG. At this time, experimental group S was treated with 10 μl of PBS in 20 μl of serum, and experimental group A was treated with 10 μl of extract solution (concentration: 50 g / 1.5 L) in 20 μl of serum.
그 결과, 도 1에서 볼 수 있는 것처럼, 아프리카산 영지버섯 열수 추출물은 HBV DNA를 억제할 뿐만 아니라, 시간이 경과할수록 지속적으로 바이러스 억제 효과를 보이는 것을 확인하였다.As a result, as shown in Figure 1, the African Ganoderma lucidum hydrothermal extract not only inhibited HBV DNA, but also confirmed that it continuously showed a virus inhibitory effect over time.
1-3. 아프리카산 영지버섯 각 추출물의 HBV 억제능1-3. HBV inhibitory activity of each extract of African Ganoderma lucidum
상기 실험예 1-2의 결과, 아프리카산 영지버섯의 HBV DNA 억제능이 확인되었으므로, 그 유효 추출물을 선별하기 위하여 각각의 추출물, 즉 열수 추출물, 냉침 추출물, 조추출물, 헥산 추출물, 에틸 아세테이트 추출물의 HBV DNA에 대한 억제능력을 관찰하기 위하여, 한 종류의 혈청에 대하여 각각의 추출물을 상기 실험예 1-1과 같은 방법으로 처리한 후, 37 ℃에서 각각 2시간, 8시간 동안 반응시킨 후 HBV DNA의 양을 측정(하기 실험예 1-3의 방법 사용)하였다. 이 때 대조군으로 제픽스(zeffix, glaxo 사)를 사용하였다. P3 및 P2는 양성대조군으로 감염성 HBV 바이러스 및 소듐 아지드를 포함한다.As a result of Experimental Example 1-2, HBV DNA inhibitory ability of African Ganoderma lucidum mushroom was confirmed, so that HBV of each extract, that is, hot water extract, cold extract, crude extract, hexane extract, ethyl acetate extract, was selected to select the effective extract. In order to observe the inhibitory ability against DNA, each extract was treated with one type of serum in the same manner as in Experimental Example 1-1, followed by reaction at 37 ° C. for 2 hours and 8 hours, respectively. The amount was measured (using the method of Experimental Example 1-3 below). At this time, zeffix (glaxo) was used as a control. P3 and P2 are positive controls and include infectious HBV virus and sodium azide.
그 결과, 하기 표 1에서 알 수 있는 것처럼, 2시간 후, 제픽스는 HBV DNA를 14.5 %억제하였고, 아프리카산 영지버섯 열수 추출물은 16.1 %, 냉침 추출물은 25.7 %, 조추출물은 12.9 %, 헥산 추출물은 15.4 %, 에틸 아세테이트 추출물은 0 % 억제하였다.As a result, as can be seen in Table 1, after 2 hours, Gepix suppressed 14.5% of HBV DNA, 16.1% of African Ganoderma lucidum extract, 15.7% of cold extract, 12.9% of crude extract, hexane extract 15.4% silver and 0% ethyl acetate extracts were inhibited.
또한, 하기 표 2에서 알 수 있는 것처럼, 8시간 후, 제픽스는 HBV DNA를 10.6 % 억제하였고, 아프리카산 영지버섯 열수 추출물은 14.5 %, 냉침 추출물은 20.4 %, 조추출물은 0 %, 헥산 추출물은 14.4 %, 에틸 아세테이트 추출물은 1.7 % 억제하였다(도 2a 및 2 b 참조). 즉, 아프리카산 영지버섯 각각의 추출물은 대체적으로 큰 차이없이 대조군과 비슷한 효과를 나타내었다.In addition, as can be seen in Table 2, after 8 hours, Gepix suppressed HBV DNA by 10.6%, African Ganoderma lucidum hot water extract 14.5%, cold extract 20.4%, crude extract 0%, hexane extract 14.4%, ethyl acetate extract was 1.7% inhibited (see FIGS. 2A and 2B). That is, the extracts of each of the African Ganoderma lucidum showed a similar effect to the control group without large differences.
실험예 2. 아프리카산 영지버섯 추출물의 독성 측정Experimental Example 2. Determination of Toxicity of African Ganoderma lucidum Extract
2-1. 아프리카산 영지버섯 추출물의 세포 독성2-1. Cytotoxicity of African Ganoderma Lucidum Extract
아프리카산 영지버섯 추출물의 세포 독성을 측정하기 위하여, 장내바이러스에 민감한 포유동물 유래의 세포주인 RD(Rabdomyosaarcoma, 6×104/세포)를 사용하여 실험실 내에서 아프리카산 영지버섯 각각의 추출물, 즉 열수 추출물, 조추출물, 헥산 추출물, 에틸 아세테이트 추출물의 세포독성을 MTT 분석법(MTT assay)으로 측정하였으며, 이때 각 추출물의 농도는 1 mg/㎖로 하였다.African to measure the cytotoxicity of the acid Ganoderma lucidum extract, a sensitive mammalian origin in enterovirus cell line RD (Rabdomyosaarcoma, 6 × 10 4 / cell) using the in the laboratory African Ganoderma each extract, that is, hot water Cytotoxicity of the extract, crude extract, hexane extract, ethyl acetate extract was measured by MTT assay (MTT assay), wherein the concentration of each extract was 1 mg / ㎖.
먼저, 세포 단분자층(6×104/세포)을 37 ℃에서 하룻밤 동안 배양한 후, 아프리카산 영지버섯 시료를 10 배 희석하고, 희석된 시료를 100 ㎕가한 다음, 37 ℃에서 3일 동안 배양한 후, MTT 염색약(MTT staining) 50 ㎕를 가하고, 37 ℃에서 2시간 동안 배양한 다음, 배지를 버리고 DMSO 150 ㎕를 가하고, 1 시간동안 휘저은 후 540 nm에서 흡광도를 측정하였다. 그리고 각 추출물의 세포 대조군(PBS) 평균에 대비한 OD 값을 비교하였으며, 세포 대조군의 평균을 일정한 선으로 나타내어 이를 기준으로 이 선보다 높은 것은 세포독성이 없고, 이 선보다 낮은 것은 세포독성이 있는 것으로 판정하였다.First, the cell monolayer (6 × 10 4 / cell) was incubated overnight at 37 ° C., and then the African Ganoderma lucidum sample was diluted 10-fold, 100 μl of the diluted sample was added, and then cultured at 37 ° C. for 3 days. Then, 50 μl of MTT staining (MTT staining) was added, incubated at 37 ° C. for 2 hours, and then the medium was discarded and 150 μl of DMSO was added, stirred for 1 hour, and the absorbance was measured at 540 nm. And the OD value compared to the average of the cell control (PBS) of each extract was compared, and the average of the cell control is represented by a constant line, based on which the higher than this line is not cytotoxic, the lower than this line is determined to be cytotoxic It was.
그 결과, 아프리카산 영지버섯의 열수 추출물에 대한 세포 독성을 나타낸 하기 표 3 및 그 외 조추출물, 헥산 추출물, 에틸 아세테이트 추출물에 대한 세포 독성을 나타낸 하기 표 4에서 알 수 있는 것처럼, 아프리카산 영지버섯 각각의 추출물들의 유의한 세포독성을 찾을 수 없었다(도 3 및 4 참조).As a result, as shown in Table 3 showing the cytotoxicity of the hydrothermal extract of African Ganoderma lucidum mushroom and Table 4 below showing the cytotoxicity of the crude extract, hexane extract, ethyl acetate extract, African Ganoderma lucidum No significant cytotoxicity of each extract was found (see Figures 3 and 4).
2-2. 아프리카산 영지버섯 추출물의 조직 독성2-2. Histotoxicity of African Ganoderma Lucidum Extract
아프리카산 영지버섯 추출물의 조직 독성을 측정하기 위하여, 수술시 적출되는 조직중 염색소견상 정상조직으로 판정된 포유동물 유래의 조직인 대장 조직(Nude mouse : normal colon)을 사용하여 아프리카산 영지버섯 조추출물, 헥산 추출물, 에틸 아세테이트 추출물의 조직 독성 실험을 측정하기 위하여 MTT 분석법을 실시하여, 여러 가지 오차를 고려하여 저해율이 30 % 이상인 경우만 그 추출물에 대하여 독성이 있다고 판단하였다. 저해율은 하기 수학식 1로 계산하였다.In order to measure the histotoxicity of African Ganoderma lucidum mushroom extract, crude Ganoderma lucidum extract of the Ganoderma lucidum extract using normal mouse (Nude mouse: normal colon), which was found to be normal tissue by staining of tissues extracted during surgery In order to measure the tissue toxicity experiments of the hexane extract and the ethyl acetate extract, MTT assay was performed, and it was determined that the extract was toxic only when the inhibition rate was 30% or more in consideration of various errors. Inhibition rate was calculated by the following equation (1).
그 결과, 아프리카산 영지버섯 조추출물의 조직 독성은 하기 표 5a 및 도 5a에, 헥산 추출물의 조직독성은 5b 및 도 5b에, 에틸 아세테이트 추출물의 조직독성은 5c 및 도 5c에 나타내었다. 이 때, 도에는 저해율(IR) 30 %일 때를 일정한 선으로 표시하여, 이 선 이상 막대가 올라간 추출물은 독성이 있다고 판정하였다. 하기 표 5a 내지 5 c(도 5a 내지 5c 참조)에서 볼 수 있는 것처럼, 아프리카산 영지버섯의 각각의 추출물들은 30 % 이상의 저해율을 나타낸 것이 없으므로 정상조직에서 독성이 없는 것으로 판단되었다.As a result, the histotoxicity of the crude extract of African Ganoderma lucidum is shown in Tables 5a and 5a, the histotoxicity of hexane extracts in 5b and 5b, and the histotoxicity of ethyl acetate extracts in 5c and 5c. In this case, the time when the inhibition rate (IR) is 30% is indicated by a constant line, and it was determined that the extract having the rod above this line was toxic. As can be seen in Tables 5a to 5c (see FIGS. 5a to 5c), the respective extracts of African Ganoderma lucidum mushrooms were not toxic in normal tissues because they showed no inhibition of more than 30%.
참조예 1. 아프리카산 영지버섯 동정REFERENCE EXAMPLE 1 Identification of African Ganoderma lucidum Mushroom
본 발명의 아프리카산 영지버섯의 종류를 동정하기 위하여, DNA 염기서열을 (주)마이크로 아이디에 의뢰하여 분석하였으며, ITS rDNA 염기서열분석(sequencing)으로 동정하였다. 이 때 먼저, % 유사성(similarity) 값을 구하고, 키무라스 투-파라메터 모델(Kimuras two-parameter model) (Kimura, M. A., J. Mol. Evol., 16, pp111-120, 1980)에 의하여 진화적인 거리(evolutionary distance)를 계산한 다음, 네이버-조이닝 방법(Neighbor-joining method) (Saitou, N. and Nei, M., Mol. Biol. Evol., 4, pp406-425, 1987)로 계통수(phylogenetic tree)를 작성하였다. 한 편, 계통수(Tree)의 스케일 바(scale bar)는 0.1 또는 0.01 각 위치 당 치환(substitution per site)을 의미하며, 계통수에서 각 가지(branch) 옆의 숫자는 부트스트랩 비율(bootstrap percentage)을 의미한다. 참고로 가노더마 속의 ITS 염기서열의 경우 ITS1과 ITS2가 독립적으로 데이터베이스에 등록된 경우가 많기 때문에 같은 균주에 대한 두개의 염기서열을 다운로드(download)하여 하나의 염기서열로 합하여 분석하였다. ITS1과 ITS2 사이에 존재하는 5.8S rDNA 염기서열은 분석에서 제외하였다.In order to identify the type of African Ganoderma lucidum mushroom of the present invention, DNA sequencing was analyzed by Micro ID Co., Ltd., and ITS rDNA sequencing was identified. In this case, first, the% similarity value is obtained, and the evolution is obtained by Kimuras two-parameter model (Kimura, MA, J. Mol. Evol., 16 , pp111-120, 1980). After calculating the evolutionary distance, the tree tree (Neighbor-joining method (Saitou, N. and Nei, M., Mol. Biol. Evol., 4 , pp406-425, 1987) phylogenetic tree). The tree's scale bar, on the other hand, represents 0.1 or 0.01 substitution per site, and the number next to each branch in the tree represents the bootstrap percentage. it means. For reference In the case of ITS nucleotide sequences in the genus ITS1 and ITS2 are frequently registered in a database independently, two nucleotide sequences of the same strain were downloaded and analyzed into a single nucleotide sequence. The 5.8S rDNA sequences present between ITS1 and ITS2 were excluded from the analysis.
그 결과, 결정된 염기서열의 개수는 567 bp로 그 염기서열은 도 6 및 서열번호 1에 나타내었다. 본 균주는 가노더마 속(Ganoderma genus)에 속하는 진균으로 판명되었다.As a result, the determined number of nucleotide sequences is 567 bp and the nucleotide sequences are shown in FIG. 6 and SEQ ID NO: 1. This strain is Ganoderma It was found to be a fungus belonging to the genus Ganoderma genus .
본 발명의 아프리카산 영지버섯 추출물은 아래와 같은 제형으로 투여할 수 있으며, 아래의 제제예는 본 발명을 예시하는 것일 뿐, 이에 의해 본 발명의 내용이 제한되는 것은 아니다. African Ganoderma lucidum extract of the present invention can be administered in the following formulations, the following formulation examples are merely to illustrate the present invention, thereby not limiting the contents of the present invention.
제제예 1. 주사제제의 제조Formulation Example 1 Preparation of Injection
실시예 3의 아프리카산 영지버섯 조추출물 100 ㎎100 mg of African Ganoderma lucidum extract of Example 3
소디움 메타비설파이트 3.0 ㎎Sodium Metabisulfite 3.0 mg
메틸파라벤 0.8 ㎎Methylparaben 0.8 mg
프로필파라벤 0.1 ㎎Propylparaben 0.1 mg
주사용 멸균증류수 적량Proper sterile distilled water for injection
상기의 성분을 혼합하고 통상의 방법으로 최종 부피가 2 ㎖이 되도록 제조한 후, 2 ㎖용량의 앰플에 충전하고 멸균하여 주사제를 제조한다.The above ingredients are mixed and prepared in a conventional manner to have a final volume of 2 ml, and then filled into 2 ml ampoules and sterilized to prepare an injection.
제제예 2. 정제의 제조Formulation Example 2 Preparation of Tablet
실시예 3의 아프리카산 영지버섯 조추출물 200 ㎎African Ganoderma lucidum extract of Example 3 200 mg
유당 100 ㎎Lactose 100 mg
전분 100 ㎎Starch 100 mg
스테아린산 마그네슘 적량Magnesium stearate proper amount
통상의 정제 제조방법에 따라 상기의 성분을 혼합하고 타정하여 정제를 제조한다.A tablet is prepared by mixing and tableting the above components according to a conventional tablet manufacturing method.
제제예 3. 캡슐제의 제조Formulation Example 3 Preparation of Capsule
실시예 3의 아프리카산 영지버섯 조추출물 100 ㎎100 mg of African Ganoderma lucidum extract of Example 3
유당 50 ㎎Lactose 50 mg
전분 50 ㎎Starch 50 mg
탈크 2 ㎎Talc 2 mg
스테아린산마그네슘 적량Magnesium stearate appropriate amount
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.According to a conventional capsule preparation method, the above ingredients were mixed and filled into gelatin capsules to prepare capsules.
제제예 4. 액제의 제조Formulation Example 4 Preparation of Liquid
실시예 3의 아프리카산 영지버섯 조추출물 1000 ㎎African Ganoderma lucidum extract of Example 3 1000 mg
설탕 20 g20 g of sugar
이성화당 20 g20 g of isomerized sugar
레몬향 적량Lemon flavor
정제수를 가하여 전체 1000 ㎖로 맞추었다. 통상의 액제의 제조방법에 따라 상기의 성분을 혼합한 다음, 갈색병에 충전하고 멸균시켜 액제를 제조하였다.Purified water was added to adjust the total volume to 1000 ml. According to the conventional method for preparing a liquid, the above components were mixed, and then filled into a brown bottle and sterilized to prepare a liquid.
제제예 5. 건강 식품의 제조Formulation Example 5 Preparation of Healthy Food
실시예 3의 아프리카산 영지버섯 조추출물 1000 ㎎African Ganoderma lucidum extract of Example 3 1000 mg
비타민 혼합물 적량Vitamin Mixture
비타민 A 아세테이트 70 ㎍70 μg of Vitamin A Acetate
비타민 E 1.0 ㎎Vitamin E 1.0 mg
비타민 B1 0.13 ㎎Vitamin B 1 0.13 mg
비타민 B2 0.15 ㎎Vitamin B 2 0.15 mg
비타민 B6 0.5 ㎎Vitamin B 6 0.5 mg
비타민 B12 0.2 ㎍0.2 μg of vitamin B 12
비타민 C 10 ㎎Vitamin C 10 mg
비오틴 10 ㎍10 μg biotin
니코틴산아미드 1.7 ㎎Nicotinic Acid 1.7 mg
엽산 50 ㎍Folate 50 ㎍
판토텐산 칼슘 0.5 ㎎Calcium Pantothenate 0.5mg
무기질 혼합물 적량Mineral mixture
황산제1철 1.75 ㎎Ferrous Sulfate 1.75 mg
산화아연 0.82 ㎎Zinc Oxide 0.82 mg
탄산마그네슘 25.3 ㎎Magnesium carbonate 25.3 mg
제1인산칼륨 15 ㎎Potassium monophosphate 15 mg
제2인산칼슘 55 ㎎Dibasic calcium phosphate 55 mg
구연산칼륨 90 ㎎Potassium Citrate 90 mg
탄산칼슘 100 ㎎Calcium Carbonate 100 mg
염화마그네슘 24.8 ㎎Magnesium chloride 24.8 mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다.Although the composition ratio of the above-mentioned vitamin and mineral mixtures is mixed with a component suitable for a health food in a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional health food manufacturing method. The granules may be prepared and used for preparing a health food composition according to a conventional method.
제제예 6. 건강 음료의 제조Formulation Example 6 Preparation of Healthy Drink
실시예 3의 아프리카산 영지버섯 조추출물 1000 ㎎African Ganoderma lucidum extract of Example 3 1000 mg
구연산 1000 ㎎Citric acid 1000 mg
올리고당 100 g100 g oligosaccharides
매실농축액 2 gPlum concentrate 2 g
타우린 1 g1 g of taurine
정제수를 가하여 전체 900 ㎖Add 900 ml of purified water
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간동안 85 ℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2 ℓ용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강음료 조성물 제조에 사용한다. After mixing the above components in accordance with the conventional healthy beverage production method, and stirred and heated at 85 ℃ for about 1 hour, the resulting solution is filtered and obtained in a sterilized 2 L container, sealed sterilized and stored in the refrigerator and then Used to prepare the healthy beverage composition of the invention.
본 발명의 영지버섯 추출물은 B형 간염 바이러스의 증식을 억제하는 효과를 가진다. 또한, 생체 내에서 부작용이 없고 약물 내성도 유발하지 않기 때문에 안전하게 장기간 투여할 수 있으므로, B형 간염의 치료 및 예방을 위한 약학조성물로서 유용하게 사용될 수 있다. Ganoderma lucidum extract of the present invention has the effect of inhibiting the proliferation of hepatitis B virus. In addition, since it can be safely administered for a long time because there are no side effects in vivo and does not cause drug resistance, it can be usefully used as a pharmaceutical composition for the treatment and prevention of hepatitis B.
도 1은 아프리카산 영지버섯 열수 추출물의 HBV 억제능을 관찰한 도이고,1 is a diagram observing the HBV inhibitory ability of the hot water extract of African Ganoderma lucidum extract,
도 2a 내지 2b는 아프리카산 영지버섯 각 용매 추출물의 HBV 억제능을 측정한 것으로, Figure 2a to 2b is to measure the HBV inhibitory ability of each solvent extract of African Ganoderma lucidum mushroom,
도 2a는 B형 간염 환자의 혈청과 각각의 추출물을 2시간 동안 반응시킨 결과도이며, Figure 2a is a result of the reaction of hepatitis B patients serum and each extract for 2 hours,
도 2b는 B형 간염 환자의 혈청과 각각의 추출물을 8시간 동안 반응시킨 결과도이고, Figure 2b is a result of the reaction of hepatitis B patients serum and each extract for 8 hours,
도 3은 아프리카산 영지버섯 열수 추출물의 세포독성을 측정한 도이며, 3 is a diagram measuring the cytotoxicity of the hydrothermal extract of African Ganoderma lucidum extract,
도 4는 아프리카산 영지버섯 각 용매 추출물의 세포독성을 측정한 도이고,4 is a diagram measuring the cytotoxicity of each solvent extract of African Ganoderma lucidum mushroom,
도 5a 내지 5c는 아프리카산 영지버섯 각 용매 추출물의 조직독성을 측정한 것으로, 5a to 5c are measured the histotoxicity of each solvent extract of the African Ganoderma lucidum mushroom,
도 5a는 조추출물의 조직독성을 측정한 도이고, Figure 5a is a diagram measuring the histotoxicity of crude extracts,
도 5b는 헥산 추출물의 조직독성을 측정한 도이며, Figure 5b is a diagram measuring the histotoxicity of the hexane extract,
도 5c는 에틸 아세테이트 추출물의 조직독성을 측정한 도이고, Figure 5c is a diagram measuring the histotoxicity of the ethyl acetate extract,
도6은 아프리카산 영지버섯의 염기서열을 나타낸 도이다.Figure 6 shows the nucleotide sequence of the African Ganoderma lucidum.
<110> KIM, JIN-DONG LEE, JONG-SUNG <120> Composition comprising the extract of African Ganoderma mushroom for the treatment and protection of hepatitis B <160> 1 <170> KopatentIn 1.71 <210> 1 <211> 567 <212> DNA <213> Ganoderma Genus <400> 1 gaaggatcat tatcgaattt ttgaccgggt tgtagctggc cttccgaggc atgtgcacgc 60 cctgctcaat ccactctaca cctgtgcact tactgtgggt gacggatcgc aaagcgggct 120 tcttgtccgt tataaagcgc atctgtggcc tgcgtttatc acaaactctt tgaaagtact 180 agaatgtaat attgggatat aatagatcta tatacaactt tcagcaacgg atctcttggc 240 tctcgcatcg atgaagaacg cagcgaaatg cgataagtaa tgtgaattgc agaattcagt 300 gaatcatcga atctttgaac gcaccttgcg ctccttggta ttccgaggag catgcctgtt 360 tgagtgtcat gaaatcttca acttgcaacc tctttgcgga gtttgtaggc ttggacttgg 420 agggcttgtc ggcctttaac ggtcggctcc tcttaaatgc attagcttga ttccttgcgg 480 atcggctgtc ggtgtgataa aatgtctacg ccgtgaccgt gaagcgtttg gatgagcttc 540 caaccgtctt gcttcaaaga caacttt 567<110> KIM, JIN-DONG LEE, JONG-SUNG <120> Composition comprising the extract of African Ganoderma mushroom for the treatment and protection of hepatitis B <160> 1 <170> KopatentIn 1.71 <210> 1 <211> 567 <212> DNA <213> Ganoderma Genus <400> 1 gaaggatcat tatcgaattt ttgaccgggt tgtagctggc cttccgaggc atgtgcacgc 60 cctgctcaat ccactctaca cctgtgcact tactgtgggt gacggatcgc aaagcgggct 120 tcttgtccgt tataaagcgc atctgtggcc tgcgtttatc acaaactctt tgaaagtact 180 agaatgtaat attgggatat aatagatcta tatacaactt tcagcaacgg atctcttggc 240 tctcgcatcg atgaagaacg cagcgaaatg cgataagtaa tgtgaattgc agaattcagt 300 gaatcatcga atctttgaac gcaccttgcg ctccttggta ttccgaggag catgcctgtt 360 tgagtgtcat gaaatcttca acttgcaacc tctttgcgga gtttgtaggc ttggacttgg 420 agggcttgtc ggcctttaac ggtcggctcc tcttaaatgc attagcttga ttccttgcgg 480 atcggctgtc ggtgtgataa aatgtctacg ccgtgaccgt gaagcgtttg gatgagcttc 540 caaccgtctt gcttcaaaga caacttt 567
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