KR102456749B1 - Composition for preventing or treating swine influenza virus disease comprising Curcuma longa extract or sesquiterpenoids isolated therefrom as active ingredients - Google Patents
Composition for preventing or treating swine influenza virus disease comprising Curcuma longa extract or sesquiterpenoids isolated therefrom as active ingredients Download PDFInfo
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- KR102456749B1 KR102456749B1 KR1020200051446A KR20200051446A KR102456749B1 KR 102456749 B1 KR102456749 B1 KR 102456749B1 KR 1020200051446 A KR1020200051446 A KR 1020200051446A KR 20200051446 A KR20200051446 A KR 20200051446A KR 102456749 B1 KR102456749 B1 KR 102456749B1
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- compound
- influenza virus
- turmeric
- swine influenza
- extract
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Abstract
본 발명은 울금 (Curcuma longa) 추출물 또는 이로부터 분리한 세스퀴테르페노이드 (sesquiterpenoid) 계 화합물인 isoprocurcumenol (화합물 1), intermedin B (화합물 2), curcumadione (화합물 3), (-)-curcumenone (화합물 4) 및 (+)-turmeronol A (화합물 5)을 포함하는 돼지 인플루엔자 예방 및 치료용 조성물 에 관한 것이다.The present invention is turmeric ( Curcuma longa ) extract or sesquiterpenoid compounds isolated therefrom, isoprocurcumenol (Compound 1), intermedin B (Compound 2), curcumadione (Compound 3), (-)-curcumenone (Compound 4) and (+ )- It relates to a composition for preventing and treating swine influenza comprising turmeronol A (Compound 5).
Description
본 발명은 돼지인플루엔자 (H1N1) 바이러스에 대하여 세포병변 회복능을 보이는 울금 (Curcuma longa) 추출물과 분획물 또는 구성화합물 및 이를 유효성분으로 함유하는 돼지인플루엔자의 예방, 개선 또는 치료용 조성물에 관한 것으로, 더욱 상세하게는 울금 추출물로부터 얻은 세스퀴테르페노이드(sesquiterpenoid) 계열의 화합물 (isoprocurcumenol, intermedin B, curcumadione, (-)-curcumenone, (+)-turmeronol A) 중 어느 하나를 포함하는 돼지인플루엔자의 예방 및 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing, improving or treating swine influenza containing an extract and fractions or constituent compounds of Curcuma longa , which exhibits cell lesion recovery ability against swine influenza (H1N1) virus, and the same as an active ingredient, more In detail, the prevention of swine influenza, including any one of sesquiterpenoid-based compounds (isoprocurcumenol, intermedin B, curcumadione, (-)-curcumenone, (+)-turmeronol A) obtained from turmeric extract, and It relates to a therapeutic composition.
현재의 동물사육은 많은 사육 개체수를 밀집된 환경에서 사육하는 기업형 축산 시스템이 도입되어 대량생산에 적합한 유전적으로 우수한 개체를 선별하여 근친번식을 통하여 생산한 후 밀집하여 키워내고 있다. 그러나 유전적으로 다양하지 않은 개체의 대량 사육은 유전적 다양성이 낮아져 특정질환에 집중적으로 노출될 뿐만 아니라 밀집된 사육환경으로 인한 전염병이 창궐하여 사람에게 까지 영향을 주고 있는 실정이다. 또한 인간과 동물의 빈번한 접촉 및 교통기관의 발달에 따른 사회적 교류 관계의 증가는 인수공통질병 (사람동물 공통질병; Zoonotic diseases)의 빠른 확산을 가능하게 하였다. 즉, 교통기관이 발달되기 전까지 특정지역에서 발생한 질환은 이동의 제한에 따른 전파력의 확산저해로, 인간이 대비할 수 있는 최소한의 시간을 얻을 수 있었으나, 현재는 이러한 질병의 항시적인 대비를 통하여 특별한 인수공통성 질환의 발병가능성을 차단하는 통합적인 대비가 필요한 실정이다.In the current animal breeding, a corporate-type livestock system that breeds a large number of breeding individuals in a dense environment is introduced, and genetically excellent individuals suitable for mass production are selected, produced through inbreeding, and then clustered and raised. However, mass breeding of genetically non-diverse individuals is a situation that not only intensively exposes to specific diseases due to low genetic diversity, but also spreads infectious diseases due to the dense breeding environment, affecting even humans. In addition, frequent contact between humans and animals and the increase in social interaction due to the development of transportation systems enabled the rapid spread of zoonotic diseases. In other words, until the development of transportation systems, diseases that occurred in a specific area were prevented from spreading due to the restriction of movement, which allowed humans to prepare for a minimum amount of time. There is a need for an integrated preparation to block the possibility of developing common diseases.
인플루엔자 바이러스는 ‘올소믹소’과에 속하는 RNA 바이러스(Orthomyxovirus)로서 5개의 속 (genus) 중 A, B, C형으로 분류된다. A형은 사람에게 주로 감염이 확인되며 B, C형에 비하여 돼지, 기타 포유류 및 다양한 야생조류에서 감염이 확인되고 있는 바이러스이다. 최근, 전 세계적으로 문제가 되고 있는 조류 인플루엔자 (Avian influenza), 돼지 인플루엔자 (Swine influenza) 및 신종플루 (Novel flu) 등은 모두 A형 바이러스에 속한다. Influenza virus is an RNA virus (Orthomyxovirus) belonging to the ‘Orthomyxovirus’ and is classified into A, B, and C types among five genera. Type A is a virus that mainly infects humans, and is confirmed to be infected in pigs, other mammals, and various wild birds compared to types B and C. Recently, avian influenza, swine influenza, and novel flu, which have become a worldwide problem, all belong to type A viruses.
인플루엔자 바이러스의 표면에는 헤마글루티닌 (hemagglutinin, HA)과 뉴라미니데이즈 (neuraminidase, NA)라는 두 가지 당단백질이 존재하는데, HA는 16종이 있고 NA는 9종이 있으므로 16×9=144 종류의 인플루엔자 바이러스가 발생할 수 있다. 3종류의 헤마글루티닌 (H1, H2, H3)과 2가지 형태의 뉴라미니데이즈 (N1과 N2)만이 인간에서 인플루엔자 감염을 일으킨다고 알려져 있지만 최근 조류 인플루엔자의 바이러스가 유전자 재조합 과정을 거치지 않고 직접 사람에게 전파된 예도 발생하고 있다.There are two glycoproteins, hemagglutinin (HA) and neuraminidase (NA), on the surface of the influenza virus. There are 16 types of HA and 9 types of NA, so 16×9=144 types of influenza Viruses may occur. Only three types of hemagglutinin (H1, H2, H3) and two types of neuraminidase (N1 and N2) are known to cause influenza infection in humans. Cases of transmission to humans have also occurred.
돼지 인플루엔자 바이러스 (Swine influenza virus)는 1918년에 처음으로 보고되었으며 보통 돼지는 사람이 가지고 있는 인플루엔자 수용체 (N-acetylneuraminic acid α2,6 galactose)와 조류들이 갖고 있는 인플루엔자 수용체 (N-acetylneuraminic acid α2,3 galactose)를 동시에 가지고 있어 조류인플루엔자 바이러스가 돼지의 몸 안에서 재조합 (reassortment) 또는 적응 (adaptation)을 통하여 사람에게 감염될 수 있도록 바이러스 혼합용기 (mixing vessels)의 역할을 한다고 알려져 있다.Swine influenza virus was first reported in 1918, and usually pigs have human influenza receptors (N-acetylneuraminic acid α2,6 galactose) and birds have influenza receptors (N-acetylneuraminic acid α2,3). galactose), so that the avian influenza virus can infect humans through recombination or adaptation in the pig's body is known to act as virus mixing vessels.
2009년 멕시코에서 처음 발병하여 전 세계로 퍼져 수많은 사망자를 낸 신종플루 (Novel flu)는 돼지 인플루엔자 바이러스인 H1N1이 돼지에게 감염되어 인간에게 전염이 가능한 질환으로 변이된 것으로 확인되었다. 세계보건기구 (WHO)가 집계하는 신종플루의 감염자 수는 2009년 10월 초까지 그 수가 34만 3200명에 달하였고, 사망자는 4000명을 넘어섰으며, 세계보건기구는 그 당시 신종플루의 현황을 6단계인 대유행 상태로 격상하여 대응하였다. 신종플루는 일반 독감과 비슷하게 발열, 인후통, 기침, 콧물 또는 코막힘의 증상을 보이지만 더 나아가 일반독감보다 심한 치명적인 폐 손상을 유발하는 특징을 보이고 있으므로 신종플루의 예방 및 치료는 매우 중요한 문제라 할 수 있었다. 따라서 신종플루를 예방하기 위하여 백신의 확보가 필수적이며 신종플루가 급격하게 확대되기 전에 백신을 생산하여 국가적으로 접종할 필요가 있다. 그러나, 예방적 차원의 국가적 백신 대책으로는 매번 항원변이가 일어나는 RNA 바이러스를 모두 예방하는 백신을 만드는 것은 불가능에 가깝고 대량백신공급은 수개월의 시간이 걸리기 때문에 급박한 상황이 일어날 경우 이에 대한 대처가 쉽지 않은 것이 현실이다. 또한 조류 및 돼지 인플루엔자, 신종플루 또는 최악의 발병 가능성인 조류 인플루엔자와 신종플루가 섞인 킬러플루로의 변종 병원체 발생에 대비하기 위하여 이를 예방하고 치료할 수 있는 치료제의 개발은 필수적이다.H1N1, a swine influenza virus, was confirmed to have mutated into a disease that was contagious to humans by infecting pigs with the novel flu, which first broke out in Mexico in 2009 and spread to the world, causing numerous deaths. As of early October 2009, the number of infected people of the H1N1 flu, as compiled by the World Health Organization (WHO), reached 343,200 and the death toll exceeded 4,000. It responded by upgrading it to the 6th stage, the pandemic state. H1N1 flu has symptoms of fever, sore throat, cough, runny nose, or stuffy nose similar to the general flu, but furthermore, it causes more fatal lung damage than the general flu. there was. Therefore, it is essential to secure a vaccine to prevent H1N1 influenza, and it is necessary to produce and inoculate the vaccine nationally before H1N1 flu spreads rapidly. However, as a preventative national vaccine measure, it is almost impossible to make a vaccine that prevents all RNA viruses that cause antigenic mutations every time, and it takes several months to supply a mass vaccine. the reality is that it is not. In addition, in order to prepare for the occurrence of mutant pathogens such as avian and swine influenza, swine flu, or killer flu, which is a mixture of avian influenza and swine flu, which are the worst possible outbreaks, it is essential to develop a therapeutic agent that can prevent and treat them.
지금까지 인플루엔자 A 바이러스의 증식과 병리학적인 감염 기전에 근거한 다양한 목표점에 대한 치료제 개발이 시도되어 왔으며 현재 조류 및 돼지 인플루엔자, 신종플루 치료제로는 바이러스 기원의 뉴라미니데이즈에 선택적인 저해물질로 1996년에 개발되어 국내에는 2001년에 시판된 경구용 치료제 타미플루 (oseltamivir phosphate)와 동일하게 2001년에 시판된 흡입형인 리렌자 (zanamivir)가 있으며 최근 폴리머레이즈 억제제 (polymerase inhibitor)로서 2018년에 미국과 일본에서, 2019년에 국내 판매 승인을 받아 곧 출시 예정인 경구용 치료제 조플루자 (baloxabir) 등이 있다. 지난 20년간 독감치료제 시장을 독점해왔던 타미플루의 부작용으로는 오심, 구토, 신경계나 정신계의 이상이 보고되었으며, 일본의 경우 타미플루를 승인 후 확인된 소아환자의 사망예가 15건이 될 정도로 부작용을 갖고 있다. 또한, 타미플루에 대한 내성 바이러스의 출현이 보고되고 있으며, 타미플루 내성 바이러스의 인간 대 인간 전염조차도 발견되고 있는 실정이다. 따라서 조류 및 돼지 인플루엔자와 신종플루에 대한 바이러스 치료제의 개발은 인간의 보건안전에 필수적인 사항이며, 특히 한 번의 대유행을 경험한 인류에게 언제 다시 일어날지 모르는 조류 및 돼지 인플루엔자와 신종플루와의 전쟁에 있어서 더욱 필요하다.Until now, development of therapeutic agents for various target points based on influenza A virus proliferation and pathological infection mechanisms have been attempted. In Korea, there is an inhaled form of zanamivir that was developed and marketed in 2001 in the same way as the oral treatment Tamiflu (oseltamivir phosphate) marketed in 2001 in Korea. Others include Xofluza (baloxabir), an oral treatment that was approved for domestic sales in 2019 and is scheduled to be released soon. As side effects of Tamiflu, which has monopolized the flu treatment market for the past 20 years, nausea, vomiting, and nervous or mental disorders have been reported. . In addition, the appearance of a virus resistant to Tamiflu has been reported, and even human-to-human transmission of the Tamiflu-resistant virus has been found. Therefore, the development of a virus treatment for avian and swine influenza and swine flu is essential for human health and safety. need more
바이러스의 감염 및 증식과정을 살펴보면 바이러스는 세포에 감염 후 세포 내에서 새로운 바이러스를 만들고 다른 세포로 전파되기 위하여 세포 외부에 존재하는 시알릭산 (sialic acid)을 바이러스가 만든 뉴라미니데이즈를 이용하여 절단하는 것이 필요하다. 타미플루 내성 조류 인플루엔자 바이러스는 보통 타미플루가 결합하는 타미플루의 수용체 단백질의 아미노산을 변화시키는 3개의 유전적 변이(Arg292Lys, Asn274Ser, His295Tyr)를 통해 발생하는 것으로 알려지고 있다. 3곳의 유전적 변이 중 타미플루 내성 조류 인플루엔자 바이러스의 변종으로 가장 많이 발현하는 295의 His가 Tyr으로 변화한 바이러스의 경우는 타미플루의 소수성 잔기 (hydrophobic residue)가 타미플루 수용체에 결합하지 못하게 변이된 경우이다. 이는 미국과 유럽에서 2007~2008년 시즌에 10~25% 확률로 발견된 바이러스로서 향후의 신종플루에 대한 변이가능성에 대한 위험도를 증가시키고 있다. 따라서 이들 타미플루 내성 바이러스의 등장은 인간이 새로운 바이러스 치료제를 지속적으로 개발하여야 하는 당위성을 제공하고 있다.Looking at the process of infection and proliferation of viruses, viruses produce a new virus within the cell after infection, and in order to spread to other cells, sialic acid existing outside the cell is cut using neuraminidase made by the virus. something is needed Tamiflu-resistant avian influenza virus is known to occur through three genetic mutations (Arg292Lys, Asn274Ser, His295Tyr) that change the amino acid of the Tamiflu receptor protein to which Tamiflu binds. Among the three genetic mutations, in the case of the Tamiflu-resistant avian influenza virus, in which His at 295 is changed to Tyr, which is expressed the most, the hydrophobic residue of Tamiflu is mutated to prevent binding to the Tamiflu receptor. . This virus was discovered with a 10-25% probability in the 2007-2008 season in the United States and Europe, increasing the risk of mutagenicity to the H1N1 influenza in the future. Therefore, the emergence of these Tamiflu-resistant viruses provides justification for humans to continuously develop new viral therapeutics.
본 발명에서는 돼지 인플루엔자와 신종플루의 방어대책에 대한 시급성을 감안하여 효과가 확인되면 바로 적응이 가능한 식품 및 약용식물을 대상으로 하여 돼지 인플루엔자에 의한 세포병변을 회복시키는 물질을 탐색하였다. 일반적으로 새로운 성분의 약제를 개발하기 위해 기존 약제를 실험적으로 변형시키는 것보다는 전통 의학에서 사용되고 있는 천연물 약제들로부터 새로운 활성 성분을 찾는 것이 여러 가지 면에서 장점이 많다. 특히 이러한 활성 성분들은 오랫동안 사용되어 왔기 때문에 약물들에 의한 독성 염려가 적다. 이러한 사실은 신종플루 치료제로서 사용되는 타미플루도 출발물질은 중국의 토착식물인 '스타아니스' 열매를 주원료로 개발한 것에서 확인할 수 있다.In the present invention, in consideration of the urgency of the protective measures against swine influenza and swine flu, substances that recover cellular lesions caused by swine influenza were searched for food and medicinal plants that can be adapted immediately when the effect is confirmed. In general, there are many advantages to finding new active ingredients from natural drugs used in traditional medicine rather than experimentally modifying existing drugs to develop new drugs. In particular, since these active ingredients have been used for a long time, there is little concern about toxicity caused by drugs. This fact can be confirmed from the fact that the starting material for Tamiflu, which is used as a treatment for the H1N1 influenza, was developed from the fruit of 'Star Anis', a native plant in China, as the main raw material.
본 특허의 대상인 울금 (Curcuma longa)은 인도원산으로 인도로부터 동남아시아를 중심으로 열대 및 아열대 지방에서 넓게 재배되고 있는 다년생 초본이다. 울금은 최근 우리나라의 남쪽 지역에서 재배되고 있는 식물로 카레 등의 원료로 사용되고 있다. 울금에는 방향성 정유가 1~5% 포함되어 있으며, 황색색소인 커큐민(curcumine) 등을 0.3% 정도 함유하고 있어 방향성 건위제로 간장염, 담도염, 담석증, 카타르성 황달 등에 사용되었다.The subject of this patent, turmeric ( Curcuma longa ) is a perennial herb native to India and widely cultivated in tropical and subtropical regions from India to Southeast Asia. Turmeric is a plant that is recently cultivated in the southern regions of Korea and is used as a raw material for curry and the like. Turmeric contains 1 to 5% of aromatic essential oil and 0.3% of curcumin, a yellow pigment, so it has been used as a flavoring agent for hepatitis, cholangitis, cholelithiasis, and catarrhal jaundice.
본 발명자는 울금의 약리활성을 갖는 화합물을 연구하는 중 울금에서 분리한 세스퀴테르페노이드 계열의 화합물이 돼지 인플루엔자 바이러스에 의한 세포병변을 회복시키는 효과가 있음을 확인하고 본 발명을 완성하였다.The present inventors have completed the present invention by confirming that the sesquiterpenoid-type compound isolated from turmeric has the effect of restoring cell lesions caused by swine influenza virus while researching the compound having the pharmacological activity of turmeric.
한국등록특허 제1373219호에서는 관동화 꽃, 행인 종자, 황기 뿌리, 패장 식물체의 메탄올 추출 후 그 분획물이 인플루엔자 바이러스 H1N1에 대한 항바이러스 활성이 있음을 확인하였으며, 한국등록특허 제1317318호에는 마누카꿀, 프로폴리스, 자일리톨, 유향, 몰약, 행인, 도인, 삼릉, 봉출 및 비타민C를 유효성분으로 하는 항 인플루엔자 바이러스제를 기재하고 있으나, 본 발명의 울금에서 분리한 세스퀴테르페노이드 계열의 화합물을 포함하는 돼지 인플루엔자 바이러스 감염의 예방 또는 치료용 조성물과는 차이가 있다.In Korean Patent No. 1373219, it was confirmed that the fraction had antiviral activity against influenza virus H1N1 after methanol extraction of kandonghwa flower, passerine seed, astragalus root, and sage plant. Although the anti-influenza virus agent containing polis, xylitol, frankincense, myrrh, passerine, doin, samreung, bongchul and vitamin C as active ingredients is described, pig containing a sesquiterpenoid-type compound isolated from turmeric of the present invention It is different from the composition for preventing or treating influenza virus infection.
한국공개특허 제20030014556호는 커큐마 잔소리자 (Curcuma xanthorrhiza)로부터 잔소리졸 (xanthorrhizol)을 분리한 서 HIV 바이러스, 헤르페스Ⅱ 바이러스, 인플레인자 A 바이러스에 대하여 항바이러스 활성을 갖는 항바이러스제를 개시하고 있으나, 본 발명의 울금에서 분리한 세스퀴테르페노이드 계열의 화합물을 포함하는 돼지 인플루엔자 바이러스 감염의 예방 또는 치료용 조성물과는 차이가 있다.Korean Patent Application Laid-Open No. 20030014556 discloses Curcuma xanthorrhiza ) isolated from xanthorrhizol and disclosed an antiviral agent having antiviral activity against HIV virus, herpes II virus, and influenza A virus, but a sesquiterpenoid family isolated from turmeric of the present invention It is different from the composition for preventing or treating swine influenza virus infection comprising a compound of
한국등록특허 제1077920호는 커큐마 롱가 (Curcuma longa)로부터 분리한 커큐미노이드계의 3종 (커큐민, 데메톡시커큐민, 비스데메톡시커큐민)의 H1N1 인플루엔자 바이러스에 대한 활성을 개시하고 있으나, 이 역시, 본 발명의 울금에서 분리한 세스퀴테르페노이드 계열의 화합물을 포함하는 돼지 인플루엔자 바이러스 감염의 예방 또는 치료용 조성물과는 차이가 있다. 그 외에도 한국공개특허 제20070102487호는 생강으로부터 얻을 수 있는 제1 성분; 녹차로부터 얻을 수 있는 제2 성분; 강황 (tumeric)으로부터 얻을 수 있는 임의의 제3성분; 및 허용되는 담체를 갖는 조성물의 일정량을 포유동물 또는 새에게 투여하는 단계를 포함하는 질병 전염률을 감소시키는 조성물이 헤르페스 바이러스, HIV 바이러스, AIDS 바이러스, 인플루엔자 바이러스, H5N1 인플루엔자 바이러스, 코감기 바이러스, SARS 바이러스 및 호흡기 합포체 바이러스로 구성된 군으로부터 선택되는 바이러스에 효과가 있는 것이 기재되어 있으나, 본 발명의 울금에서 분리한 세스퀴테르페노이드 계열의 화합물을 포함하는 돼지 인플루엔자 바이러스 감염의 예방 또는 치료용 조성물과는 차이가 있다.Korean Patent No. 1077920 is Curcuma Longa longa ) discloses activity against H1N1 influenza virus of three types of curcuminoids (curcumin, demethoxycurcumin, bisdemethoxycurcumin) isolated from ), but this is also a sesquiterpe isolated from turmeric of the present invention It is different from the composition for preventing or treating swine influenza virus infection including a compound of the noid series. In addition, Korean Patent Application Laid-Open No. 20070102487 discloses a first ingredient obtainable from ginger; a second component obtainable from green tea; any third ingredient obtainable from turmeric; And a composition for reducing the transmission rate of a disease comprising administering to a mammal or a bird a certain amount of the composition having an acceptable carrier is a herpes virus, HIV virus, AIDS virus, influenza virus, H5N1 influenza virus, nasal cold virus, SARS Although it is described that it is effective against viruses selected from the group consisting of viruses and respiratory syncytial viruses, a composition for preventing or treating swine influenza virus infection comprising a sesquiterpenoid-type compound isolated from turmeric of the present invention is different from
본 발명의 목적은 울금 (Curcuma longa) 추출물 또는 이로부터 분리한 세스퀴테르페노이드계 화합물을 유효성분으로 포함하는 것을 특징으로 하는 돼지 인플루엔자 바이러스 감염의 예방 또는 치료용 조성물을 제공하는 데 있다.The object of the present invention is turmeric ( Curcuma longa ) to provide a composition for preventing or treating swine influenza virus infection, characterized in that it contains an extract or a sesquiterpenoid-based compound isolated therefrom as an active ingredient.
본 발명의 목적은 돼지 인플루엔자 바이러스에 의한 세포병변의 회복효과를 나타내는 울금으로부터 순수하게 분리 정제하여 얻은 세스퀴테르페노이드 계열의 화합물들을 유효성분으로 포함하는 돼지 인플루엔자 바이러스 감염의 예방 또는 치료용 약학 조성물을 제공하는 데 있다.An object of the present invention is a pharmaceutical composition for the prevention or treatment of swine influenza virus infection, comprising, as an active ingredient, sesquiterpenoid-type compounds obtained by pure separation and purification from turmeric, which has the effect of recovering cell lesions caused by the swine influenza virus. is to provide
본 발명의 또 다른 목적은 울금 (Curcuma longa) 추출물 또는 이로부터 분리한 세스퀴테르페노이드계 화합물을 유효성분으로 포함하는 돼지 인플루엔자 바이러스 감염의 예방 또는 개선용 건강기능식품을 제공하는 데 있다.Another object of the present invention is turmeric ( Curcuma longa ) extract or a sesquiterpenoid-based compound isolated therefrom as an active ingredient to provide a health functional food for preventing or improving swine influenza virus infection.
본 발명의 다른 목적은 울금 (Curcuma longa) 추출물 또는 이로부터 분리한 세스퀴테르페노이드계 화합물을 유효성분으로 포함하는 돼지 인플루엔자 바이러스 감염의 예방 또는 치료용 동물 약품을 제공하는 데 있다.Another object of the present invention is turmeric ( Curcuma longa ) extract or to provide an animal drug for the prevention or treatment of swine influenza virus infection comprising a sesquiterpenoid-based compound isolated therefrom as an active ingredient.
본 발명의 또 다른 목적은 울금 (Curcuma longa) 추출물 또는 이로부터 분리한 세스퀴테르페노이드계 화합물을 유효성분으로 포함하는 돼지 인플루엔자 바이러스 감염의 예방 또는 개선용 동물 사료 첨가제를 제공하는 데 있다.Another object of the present invention is turmeric ( Curcuma longa ) extract or to provide an animal feed additive for prevention or improvement of swine influenza virus infection comprising a sesquiterpenoid-based compound isolated therefrom as an active ingredient.
또한, 본 발명의 목적은 울금 (Curcuma longa) 추출물 또는 이로부터 분리한 세스퀴테르페노이드계 화합물을 유효성분으로 포함하는 돼지 인플루엔자 바이러스 감염의 예방용 천연소독제를 제공하는 데 있다.In addition, the object of the present invention is turmeric ( Curcuma longa ) extract or a sesquiterpenoid-based compound isolated therefrom to provide a natural disinfectant for preventing swine influenza virus infection as an active ingredient.
본 발명은 울금 (Curcuma longa) 추출물 또는 이로부터 분리한 세스퀴테르페노이드계 화합물을 유효성분으로 포함하는 것을 특징으로 하는 돼지 인플루엔자 바이러스 감염의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating swine influenza virus infection, comprising an extract of Curcuma longa or a sesquiterpenoid-based compound isolated therefrom as an active ingredient.
상기 울금 추출물은The turmeric extract is
(a) 울금을 40-90% (v/v) 에탄올로 추출하고 이를 감압농축하는 단계;(a) extracting turmeric with 40-90% (v/v) ethanol and concentrating it under reduced pressure;
(b) 상기 (a) 단계의 감압농축한 에탄올 추출물을 증류수에 현탁하는 단계; 및(b) suspending the ethanol extract concentrated under reduced pressure of step (a) in distilled water; and
(c) 상기 (b) 단계의 현탁액을 에틸아세테이트로 용매추출하는 단계;를 포함하는 울금 추출물 분리방법을 통해 수득한 울금의 40-90% (v/v) 에탄올-에틸아세테이트 분획물일 수 있다.(c) solvent-extracting the suspension of step (b) with ethyl acetate; 40-90% (v/v) ethanol-ethyl acetate fraction of turmeric obtained through a turmeric extract separation method comprising a.
상기 울금의 40-90% (v/v) 에탄올-에틸아세테이트 분획물은 세스퀴테르페노이드계 화합물이 50%-99% 함유된 것일 수 있다.The 40-90% (v/v) ethanol-ethyl acetate fraction of turmeric may contain 50%-99% of sesquiterpenoid compounds.
또한, 상기 세스퀴테르페노이드계 화합물은 하기 화학식 1의 이소프로컬큐메놀 (화합물 1), 인터메딘 B (화합물 2), 컬큐마디온 (화합물 3), (-)-컬큐메논 (화합물 4) 및 (+)-털메로놀 A (화합물 5)로 이루어진 군에서 선택되는 1종 이상의 화합물을 포함할 수 있다.In addition, the sesquiterpenoid-based compound is isoproculcumenol (Compound 1), intermedin B (Compound 2), curcumadione (Compound 3), (-)-curcumenone (Compound 4) of
[화학식 1][Formula 1]
또한, 본 발명은 상기 화학식 1의 이소프로컬큐메놀 (화합물 1), 인터메딘 B (화합물 2), 컬큐마디온 (화합물 3), (-)-컬큐메논 (화합물 4) 및 (+)-털메로놀 A (화합물 5)로 이루어진 군에서 선택되는 1종 이상의 화합물을 포함하는 울금 (Curcuma longa) 추출물을 유효성분으로 함유하는 돼지 인플루엔자 예방 또는 치료용 동물 약품에 관한 것이다.In addition, the present invention provides isoproculcumenol (Compound 1), Intermedin B (Compound 2), Curcumadione (Compound 3), (-)-Curcumenone (Compound 4) and (+)-hair of
상기 울금 추출물은 울금을 물, C1 내지 C4의 저급 알코올, 아세톤, 에틸아세테이트 및 헥산으로 이루어진 군에 서 선택되는 1종 이상의 용매로 추출한 추출물일 수 있으며, 상기 C1 내지 C4의 저급 알코올은 메탄올, 에탄올, 프로판올, 이소프란올, 부탄올 등일 수 있다. 바람직하게는 에탄올, 부탄올 및 아세톤이다. 가장 바람직하게는 에탄올 및 부탄올이다. 상기 용매는 울금 중량의 5배 내지 500배의 중량을 가할 수 있다. 또한, 상기 울금 추출물은 울금을 물, C1 내지 C4의 저급 알코올, 아세톤, 에틸아세테이트 및 헥산으로 이루어진 군에서 선택되는 1종 이상의 용매로 추출한 추출물을 농축하여 얻은 농축액을 희석한 희석액을 이온교환수지가 충전되어 있는 컬럼 크로마토그래피에 가하여 유기용매로 용출시켜 분획한 분획물일 수 있다. 상기 희석액은 울금 추출물의 농축액에 물을 가하여 만들 수 있으며, 농축액 중량의 10배 내지 50배의 중량을 가할 수 있다. 상기 이온교환수지는 디아이온 HP-20 (Diaion HP-20), SP825, AXT204, XAD1600T, MN200, SP70, SP710 등에서 선택하여 사용할 수 있다. 바람직하게는 디아이온 HP-20, SP825, AXT204, XAD1600T 및 MN2000이며, 가장 바람직하게는 디아이온 HP-20이다. 상기 유기용매는 C1 내지 C4의 저급 알코올 및 아세톤 일 수 있다. 상기 C1 내지 C4의 저급 알코올은 메탄올, 에탄올, 프로판올, 이소프란올, 부탄올 등 일 수 있다. 바람직하게는 에탄올 및 아세톤이며, 가장 바람직하게는 100% 에탄올이다.The turmeric extract may be an extract obtained by extracting turmeric with one or more solvents selected from the group consisting of water, C1 to C4 lower alcohol, acetone, ethyl acetate and hexane, and the C1 to C4 lower alcohol is methanol, ethanol , propanol, isopranol, butanol, and the like. Preferred are ethanol, butanol and acetone. Most preferred are ethanol and butanol. The solvent may be added by 5 times to 500 times the weight of turmeric. In addition, the turmeric extract is a diluted solution obtained by concentrating the extract obtained by extracting turmeric with one or more solvents selected from the group consisting of water, C1 to C4 lower alcohol, acetone, ethyl acetate and hexane. It may be a fraction fractionated by being added to the charged column chromatography and eluting with an organic solvent. The dilution may be made by adding water to the concentrate of the turmeric extract, and 10 to 50 times the weight of the concentrate may be added. The ion exchange resin may be selected from Diaion HP-20 (Diaion HP-20), SP825, AXT204, XAD1600T, MN200, SP70, SP710, and the like. Preferred are Diaion HP-20, SP825, AXT204, XAD1600T and MN2000, and most preferably Diaion HP-20. The organic solvent may be a C1 to C4 lower alcohol and acetone. The C1 to C4 lower alcohol may be methanol, ethanol, propanol, isopranol, butanol, or the like. Preferred are ethanol and acetone, most preferably 100% ethanol.
상기 울금으로부터 분리된 화학식 1의 이소프로컬큐메놀 (화합물 1), 인터메딘 B (화합물 2), 컬큐마디온 (화합물 3), (-)-컬큐메논 (화합물 4) 및 (+)-털메로놀 A (화합물 5) 화합물은 울금 추출물을 크로마토그래피로 분획하여 얻을 수 있으며, 상기 크로마토그래피 는 디아이온 HP-20 컬럼 크로마토그래피 (diaion HP-20 column chromatography), 실리카겔 컬럼 크로마토그래피 (silica gel column chromatography), RP-18 컬럼 크로마토그래피 (RP-18 column chromatography), LH-20 컬럼 크로마토그래피 (LH-20 column chromatography), 조제용 역상-고성능 액체 크로마토그래피 (preparative reversed-phase high performance chromatography), 중압 액체 크로마토그래피 (medium pressure liquid chromatography), 고성능 액체 크로마토그래피 (high-performance liquid chromatography) 등에서 선택하여 사용할 수 있다.Isoproculcumenol (Compound 1), Intermedin B (Compound 2), Curcumadione (Compound 3), (-)-Curcumenone (Compound 4) and (+)-Tulmero of
한편, 본 발명의 화합물은 당해 기술분야에서 통상적인 방법에 따라 합성될 수 있으며, 약학적으로 허용 가능한 염으로 제조될 수도 있다. Meanwhile, the compound of the present invention may be synthesized according to a conventional method in the art, and may be prepared as a pharmaceutically acceptable salt.
상기 울금 추출물 또는 이로부터 분리된 세스퀴테르페노이드계 화합물을 포함하는 약학 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 상기 약학 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, 셀룰로스, 메틸 셀룰로스, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화 할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함 되며, 이러한 고형제제는 본 발명의 울금 추출물 또는 이로부터 분리된 세스퀴테르페노이드계 화합물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로스 또는 락토즈, 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸 렌 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, 글리세로젤라틴 등이 사용 될 수 있다.The pharmaceutical composition comprising the turmeric extract or the sesquiterpenoid-based compound isolated therefrom, respectively, is a powder, granules, tablets, capsules, suspensions, emulsions, syrups, oral dosage forms, such as aerosols, according to a conventional method; It can be used in the form of external preparations, suppositories and sterile injection solutions. Carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, it is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient, e.g. For example, it is prepared by mixing starch, calcium carbonate, sucrose or lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. may be included. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, etc. may be used.
상기 약학 조성물의 투여량은 치료 받을 대상의 연령, 성별, 체중과, 치료할 특정 질환 또는 병리 상태, 질환 또는 병리 상태의 심각도, 투여경로 및 처방자의 판단에 따라 달라질 것이다. 이러한 인자에 기초한 투여량 결정은 당업자의 수준 내에 있으며, 일반적으로 투여량은 0.01 ㎎/㎏/일 내지 대략 2000 ㎎/㎏/일의 범위이다. 더 바람직한 투여량은 0.1 ㎎/㎏/일 내지 500 ㎎/㎏/일이다. 투여는 하루에 한 번 투여할 수도 있고, 수 회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 상기 약학 조성물은 쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상 될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 점막 또는 뇌혈관 내 주사에 의해 투여될 수 있다. 본 발명의 울금 추출물 또는 이로부터 분리된 세스퀴테르페노이드계 화합물은 독성 및 부작용이 거의 없으므로 예방 목적으로 장기간 복용시에도 안심하고 사용할 수 있는 약제이다.The dosage of the pharmaceutical composition will vary depending on the age, sex, and weight of the subject to be treated, the specific disease or pathological condition to be treated, the severity of the disease or pathological condition, the route of administration, and the judgment of the prescriber. Dosage determination based on these factors is within the level of one of ordinary skill in the art, and generally dosages range from 0.01 mg/kg/day to approximately 2000 mg/kg/day. A more preferred dosage is 0.1 mg/kg/day to 500 mg/kg/day. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way. The pharmaceutical composition may be administered to mammals such as mice, livestock, and humans by various routes. Any mode of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine mucosal or intracerebrovascular injection. The turmeric extract of the present invention or the sesquiterpenoid-based compound isolated therefrom has almost no toxicity and side effects, so it is a drug that can be safely used even when taken for a long period of time for prophylactic purposes.
또한, 본 발명은 상기 화학식 1의 이소프로컬큐메놀 (화합물 1), 인터메딘 B (화합물 2), 컬큐마디온 (화합물 3), (-)-컬큐메논 (화합물 4) 및 (+)-털메로놀 A (화합물 5)로 이루어진 군에서 선택되는 1종 이상의 화합물을 포함하는 울금 (Curcuma longa) 추출물을 유효성분으로 함유하는 돼지 인플루엔자 감염의 예방 또는 개선용 건강기능식품에 관한 것이다.In addition, the present invention provides isoproculcumenol (Compound 1), Intermedin B (Compound 2), Curcumadione (Compound 3), (-)-Curcumenone (Compound 4) and (+)-hair of
또한, 본 발명은 울금으로부터 분리된 상기 화학식 1의 이소프로컬큐메놀 (화합물 1), 인터메딘 B (화합물 2), 컬큐마디온 (화합물 3), (-)-컬큐메논 (화합물 4) 및 (+)-털메로놀 A (화합물 5)로 이루어진 군에서 선택되는 1종 이상의 화합물을 유효성분으로 함유하는 돼지 인플루엔자 바이러스 감염의 예방 또는 개선용 건강기능식품에 관한 것이다.In addition, the present invention is isoproculcumenol (Compound 1), intermedin B (Compound 2), curcumadione (Compound 3), (-)-curcumenone (Compound 4) and ( It relates to a health functional food for preventing or improving swine influenza virus infection containing at least one compound selected from the group consisting of +)-talmeronol A (compound 5) as an active ingredient.
본 발명은 울금 추출물 또는 이로부터 분리된 세스퀴테르페노이드계 화합물을 함유하는 식품학적으로 허용 가능한 식품보조 첨가제를 포함하는 건강기능식품을 제공한다. 본 발명의 건강기능식품은 정제, 캡슐제, 환제 또는 액제 등의 형태를 포함하며, 본 발명의 울금 추출물 또는 이로부터 분리된 세스퀴테르페노이드계 화합물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강기능성식품류 등이 있다. 상세하게는, 본 발명은 울금 추출물 또는 이로부터 분리된 세스퀴테르페노이드계 화합물을 함유하는 식품학적으로 허용 가능한 식품 보조 첨가제를 포함하는 인플루엔자 개선용 건강기능식품을 제공한다.The present invention provides a health functional food comprising a nutritively acceptable food supplement containing a turmeric extract or a sesquiterpenoid-based compound isolated therefrom. The health functional food of the present invention includes the form of tablets, capsules, pills or liquids, and the food to which the turmeric extract of the present invention or the sesquiterpenoid-based compound isolated therefrom can be added, for example, For example, there are various foods, beverages, gum, tea, vitamin complexes, health functional foods, and the like. In detail, the present invention provides a health functional food for improving influenza comprising a nutritively acceptable food supplement containing a turmeric extract or a sesquiterpenoid-based compound isolated therefrom.
또한, 본 발명은 울금으로부터 분리된 하기 화학식 1의 이소프로컬큐메놀 (화합물 1), 인터메딘 B (화합물 2), 컬큐마디온 (화합물 3), (-)-컬큐메논 (화합물 4) 및 (+)-털메로놀 A (화합물 5)로 이루어진 군에서 선택되는 1종 이상의 화합물을 유효성분으로 함유하는 돼지 인플루엔자 예방 또는 치료용 동물 약품에 관한 것이다.In addition, the present invention provides isoproculcumenol (compound 1), intermedin B (compound 2), curcumadione (compound 3), (-)-curcumenone (compound 4) and ( It relates to an animal drug for preventing or treating swine influenza containing at least one compound selected from the group consisting of +)-talmeronol A (Compound 5) as an active ingredient.
또한, 본 발명은 하기 화학식 1의 이소프로컬큐메놀 (화합물 1), 인터메딘 B (화합물 2), 컬큐마디온 (화합물 3), (-)-컬큐메논 (화합물 4) 및 (+)-털메로놀 A (화합물 5)로 이루어진 군에서 선택되는 1종 이상의 화합물을 포함하는 울금 (Curcuma longa) 추출물을 유효성분으로 함유하는 돼지 인플루엔자 개선용 동물 사료 첨가제에 관한 것이다.In addition, the present invention provides isoproculcumenol (Compound 1), Intermedin B (Compound 2), Curcumadione (Compound 3), (-)-Curcumenone (Compound 4) and (+)-hair of the following
본 발명의 울금 추출물 또는 이로부터 분리된 세스퀴테르페노이드계 화합물이 동물용 사료에 0.001중량% 내지 30중량%, 바람직하게는 0.001중량% 내지 10중량%, 가장 바람직하게는 0.001중량% 내지 5중량%로 첨가될 수 있다.The turmeric extract of the present invention or the sesquiterpenoid-based compound isolated therefrom is added to the animal feed in an amount of 0.001 wt% to 30 wt%, preferably 0.001 wt% to 10 wt%, most preferably 0.001 wt% to 5 wt% % by weight.
또한, 본 발명은 하기 화학식 1의 이소프로컬큐메놀 (화합물 1), 인터메딘 B (화합물 2), 컬큐마디온 (화합물 3), (-)-컬큐메논 (화합물 4) 및 (+)-털메로놀 A (화합물 5)로 이루어진 군에서 선택되는 1종 이상의 화합물을 포함하는 울금 (Curcuma longa) 추출물을 유효성분으로 함유하는 돼지 인플루엔자 예방용 천연소독제에 관한 것이다.In addition, the present invention provides isoproculcumenol (Compound 1), Intermedin B (Compound 2), Curcumadione (Compound 3), (-)-Curcumenone (Compound 4) and (+)-hair of the following
상기 천연소독제는 인플루엔자 바이러스의 소독용 조성물로, 액제, 정제, 과립제, 산제 등의 다양한 형태로의 제제로 제조가 가능하다.The natural disinfectant is a composition for disinfection of influenza virus, and can be prepared in various forms such as liquid, tablet, granule, and powder.
본 발명은 울금 (Curcuma longa) 추출물 또는 이로부터 분리한 세스퀴테르페노이드계 화합물을 유효성분으로 포함하는 돼지 인플루엔자의 예방 또는 치료용 조성물에 관한 것으로, 울금 추출물 또는 이로부터 분리한 세스퀴테르페노이드계 화합물인 이소프로컬큐메놀 (화합물 1), 인터메딘 B (화합물 2), 컬큐마디온 (화합물 3), (-)-컬큐메논 (화합물 4) 및 (+)-털메로놀 A (화합물 5) 화합물이 돼지 인플루엔자 바이러스에 대해 항바이러스 활성이 있음을 확인하였다. 이를 통해, 본 발명의 울금 추출물 또는 이로부터 분리한 이소프로컬큐메놀 (화합물 1), 인터메딘 B (화합물 2), 컬큐마디온 (화합물 3), (-)-컬큐메논 (화합물 4) 및 (+)-털메로놀 A (화합물 5) 화합물을 인플루엔자의 예방 또는 치료용 의약품, 건강기능식품, 동물 사료 첨가제 또는 천연소독제 등의 개발 시에 유용하게 이용할 수 있을 것으로 기대된다.The present invention is turmeric ( Curcuma longa ) It relates to a composition for preventing or treating swine influenza comprising an extract or a sesquiterpenoid-based compound isolated therefrom as an active ingredient, and isoprocal, a turmeric extract or a sesquiterpenoid-based compound isolated therefrom Cumenol (Compound 1), Intermedin B (Compound 2), Curcumadione (Compound 3), (-)-Curcumenone (Compound 4) and (+)-Turmeronol A (Compound 5) compounds are swine influenza It was confirmed that it had antiviral activity against the virus. Through this, the turmeric extract of the present invention or isoproculcumenol (compound 1), intermedin B (compound 2), curcumadione (compound 3), (-)-curcumenone (compound 4) and ( +)-Turmeronol A (Compound 5) compound is expected to be useful in the development of pharmaceuticals for the prevention or treatment of influenza, health functional foods, animal feed additives, or natural disinfectants.
도 1은 울금의 70% (v/v) 에탄올 추출물, 70% (v/v) 에탄올 추출물의 에틸아세테이트 용매추출한 분획물 및 70% (v/v) 에탄올 추출물의 물 용매추출한 분획물의 MDCK 세포에서의 세포독성을 나타낸 그래프이다.
도 2는 울금의 70% (v/v) 에탄올 추출물, 70% (v/v) 에탄올 추출물의 에틸아세테이트 용매추출한 분획물 및 70% (v/v) 에탄올 추출물의 물 용매추출한 분획물의 MDCK 세포에서의 H1N1 인플루엔자바이러스에 의한 세포병변을 회복시킨 것을 나타낸 그래프이다.
도 3은 울금의 에틸아세테이트 분획물의 각 소분획물의 MDCK 세포에서의 세포독성을 나타낸 그래프이다.
도 4는 울금의 에틸아세테이트 분획물의 각 소분획물이 MDCK 세포에서의 H1N1 인플루엔자바이러스에 의한 세포병변을 회복시킨 것을 나타낸 그래프이다.
도 5는 울금의 추출물의 에틸아세테이트 분획물을 순상 컬럼 크로마토그래피법을 사용하여 8종의 소분획으로 나누었을 때의 각 소분획물의 박층크로마토그래피의 패턴이다. 가장 왼쪽에서부터 UV 254 nm, UV 365 nm 및 황산발적을 통하여 확인한 모습이다.
도 6은 울금의 에틸아세테이트 분획물의 8종의 소분획물 중 대표적으로 F5와 F7의 주요 구성성분을 확인하여 비교한 크로마토그래프이다.1 is a 70% (v/v) ethanol extract of turmeric, an ethyl acetate solvent-extracted fraction of a 70% (v/v) ethanol extract, and a water-solvent-extracted fraction of 70% (v/v) ethanol extract in MDCK cells It is a graph showing cytotoxicity.
2 is a 70% (v/v) ethanol extract of turmeric, an ethyl acetate solvent-extracted fraction of a 70% (v/v) ethanol extract, and a water-solvent-extracted fraction of a 70% (v/v) ethanol extract in MDCK cells. It is a graph showing the recovery of cell lesions caused by the H1N1 influenza virus.
3 is a graph showing the cytotoxicity in MDCK cells of each small fraction of the ethyl acetate fraction of turmeric.
Figure 4 is a graph showing that each sub-fraction of the ethyl acetate fraction of turmeric recovered the cell lesion caused by the H1N1 influenza virus in MDCK cells.
5 is a thin layer chromatography pattern of each subfraction when the ethyl acetate fraction of the extract of turmeric was divided into 8 subfractions using normal phase column chromatography. From the far left, it was confirmed through
6 is a chromatograph comparing the main components of F5 and F7 representatively among the eight small fractions of the ethyl acetate fraction of turmeric.
본 발명자 그룹은 울금(Curcuma longa) 추출물의 돼지 인플루엔자 감염증에 미치는 영향을 연구하던 중, 울금의 대표적 추출성분인 커큐민(curcumin)의 함량이 낮은 추출분획에서 높은 항바이러스 활성이 나타나는 것을 관찰하고, 울금의 추출물로부터 항바이러스 활성이 높은 세스퀴테르페노이드계 물질을 분리하여 본 발명을 완성하였다.The present inventors group was studying the effect of turmeric ( Curcuma longa ) extract on swine influenza infection, observing that high antiviral activity appeared in an extract having a low content of curcumin, a representative extract component of turmeric, The present invention was completed by isolating a sesquiterpenoid-based material with high antiviral activity from the extract of
이하 본 발명의 바람직한 실시예를 상세히 설명하기로 한다. 그러나, 본 발명은 여기서 설명되는 실시예에 한정 되지 않고 다른 형태로 구체화될 수도 있다. 오히려, 여기서 소개되는 내용이 철저하고 완전해지고, 당업자에게 본 발명의 사상을 충분히 전달하기 위해 제공하는 것이다.Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, it is provided so that this disclosure will be thorough and complete, and will fully convey the spirit of the invention to those skilled in the art.
<실시예 1. 울금의 추출물 및 분획물의 제조 ><Example 1. Preparation of extracts and fractions of turmeric>
활성물질분리를 위한 대량추출에 앞서 소량의 울금을 대상으로 한 선행실험으로서 울금의 에탄올 추출물을 소량 취하여 speed vacuum을 활용하여 건조 후, 500 ㎕의 증류수에 현탁하였다. 이때 에탄올은 40-90% 에탄올을 사용하여 추출하였으며, 추출률은 크게 차이는 없었으나 추출률(mg/ml)이 가장 좋은 70% 에탄올을 이용한 추출물을 이후 실험에 사용하였다. 상기 증류수에 현탁된 울금의 에탄올 추출물을 헥산, 에틸아세테이트 및 부탄올 순서로 각기 용매추출하여 각각의 분획물 (500 ㎕ × 3회)을 획득하였다. 이 중 울금의 에탄올 추출물, 에탄올 추출물의 에틸아세테이트 분획물 및 물 분획물 소량을 취하여 건조 후, DMSO (dimethyl sulfoxide)에 녹여 50 ㎎/㎖의 stock solution을 만들었다.As a prior experiment for a small amount of turmeric prior to mass extraction for active material separation, a small amount of ethanol extract of turmeric was taken and dried using speed vacuum, and then suspended in 500 μl of distilled water. At this time, ethanol was extracted using 40-90% ethanol, and there was no significant difference in the extraction rate, but the extract using 70% ethanol with the best extraction rate (mg/ml) was used for subsequent experiments. The ethanol extract of turmeric suspended in the distilled water was solvent-extracted in the order of hexane, ethyl acetate and butanol to obtain each fraction (500 μl × 3 times). Among them, a small amount of an ethanol extract of turmeric, an ethyl acetate fraction and a water fraction of the ethanol extract were taken, dried, and dissolved in DMSO (dimethyl sulfoxide) to prepare a stock solution of 50 mg/ml.
<실시예 2. 울금 추출물 및 분획물의 MDCK 세포에 대한 세포독성 확인><Example 2. Confirmation of cytotoxicity of turmeric extracts and fractions on MDCK cells>
상기 실시예 1에서 제조한 울금의 에탄올 추출물, 에탄올 추출물의 에틸아세테이트 분획물 및 물 분획물을 대상으로 세포병변효과 회복 어세이를 수행하기 이전, 처리물질이 세포에 대해 독성을 나타내지 않는 농도를 확인하기 위해 세포 독성 실험을 진행하였다. 96웰 플레이트 (96 well plate)에 웰 당 5×103 개의 MDCK (Madin-Darby, canine kidney) 세포를 분주한 후 10% FBS (fetal bovine serum), 1% 페니실린/스트렙토마이신 (penicillin/streptomycin) 및 0.4% L-글루타민 (L-glutamine)이 포함된 DMEM (Dulbeco's Modified Eagle's Medium) 배지를 넣고 하루 동안 배양한 후, 배양액을 버리고 PBS (phosphate buffer saline)로 세척하였다. 이후 세포에 감염배지 (infection media, DMEM + 0.25% BSA (bovine serum albumin) + 1㎍/㎖ trypsin) 100 ㎕를 넣어 2시간 동안 감염시킨 후, PBS 용액으로 세척하였다. 중앙백신연구소로부터 제공받은 돼지 인플루엔자 바이러스를 50TCID50/100 ㎕/웰의 농도가 되도록 접종한 후, 상기 실시예 1에서 제조한 울금 추출물 및 분획물의 최종 농도가 0.2, 1.0 ㎍/㎖이 되도록 처리한 후 1일 동안 배양하였다. 이때, 세포에 아무것도 처리하지 않은 것을 정상 대조군으로 이용하였다.Before performing a cell lesion effect recovery assay for the ethanol extract of turmeric, the ethyl acetate fraction and the water fraction of turmeric prepared in Example 1, to determine the concentration of the treated material that does not show toxicity to cells A cytotoxicity test was performed. After dispensing 5×10 3 MDCK (Madin-Darby, canine kidney) cells per well in a 96-well plate, 10% FBS (fetal bovine serum), 1% penicillin/streptomycin And 0.4% L-glutamine (L-glutamine) containing DMEM (Dulbeco's Modified Eagle's Medium) medium and cultured for one day, the culture medium was discarded and washed with PBS (phosphate buffer saline). Thereafter, 100 μl of infection medium (infection media, DMEM + 0.25% bovine serum albumin (BSA) + 1 μg/ml trypsin) was added to the cells to infect for 2 hours, and then washed with PBS solution. After inoculating the swine influenza virus provided from the Central Vaccine Research Institute to a concentration of 50TCID50/100 μl/well, the final concentration of the turmeric extract and fractions prepared in Example 1 is 0.2, 1.0 μg/ml After treatment Cultured for 1 day. At this time, cells that were not treated with anything were used as normal controls.
1일 동안 배양한 세포를 이용하여 MTT (3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide) 어세이를 수행하였다. 배양한 세포에 MTT 용액을 넣고 37 ℃에서 반응시킨 후 배양액을 제거하고 100 ㎕의 DMSO를 넣었다. 잘 섞어 준 다음 10분 동안 방치한 후 570 ㎚에서 흡광도를 측정하여 세포의 생존율을 확인하였다. 이때, 정상 대조군의 세포생존율 100%를 기준으로 각 용매에 따른 추출물에 의한 세포생존율을 계산하였고, 그 결과를 도 1 에 나타내었다. 울금 추출물의 독성으로 인한 세포사멸 수준을 평가하였으므로, 추출물에 의한 세포생존율을 세포독성과 동일한 개념으로 사용하였다. 도 1에서 보여주듯이, 해당농도에서 세포독성을 나타내지 않았으므로 0.2, 1.0 ㎍/㎖를 세포병변효과 회복 어세이에서의 추출물 적용농도로 사용하였다.MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed using cells cultured for 1 day. MTT solution was added to the cultured cells and reacted at 37 °C, the culture medium was removed, and 100 μl of DMSO was added. After mixing well and leaving it for 10 minutes, the absorbance was measured at 570 nm to check the cell viability. At this time, the cell viability by the extracts according to each solvent was calculated based on 100% of the cell viability of the normal control group, and the results are shown in FIG. 1 . Since the level of apoptosis due to the toxicity of the turmeric extract was evaluated, the cell viability by the extract was used in the same concept as the cytotoxicity. As shown in FIG. 1, since it did not show cytotoxicity at the corresponding concentration, 0.2 and 1.0 μg/ml were used as the application concentration of the extract in the cytopathic effect recovery assay.
<실시예 3. 울금 추출물 및 분획물의 항바이러스 활성 확인><Example 3. Confirmation of antiviral activity of turmeric extract and fractions>
상기 실시예 1에서 제조한 울금의 에탄올 추출물, 에탄올 추출물의 에틸아세테이트 분획물 및 물 분획물을 대상으로 세포병변효과 회복 어세이를 통한 항바이러스 효능을 확인하기 위해 돼지 인플루엔자 바이러스 H1N1 (A/Sw/Kor/CAN1/04, KCTC11165BP)을 이용하였고, 바이러스 감염에 의한 세포의 생존율을 분석함으로써 항바이러스 활성을 확인하는 세포병변효과 회복 어세이 (cytopathic effect reduction assay, CPE reduction assay)를 수행하였다.Swine influenza virus H1N1 (A/Sw/Kor/ CAN1/04, KCTC11165BP) was used, and a cytopathic effect reduction assay (CPE reduction assay) was performed to confirm antiviral activity by analyzing the viability of cells caused by virus infection.
96웰 플레이트 (96 well plate)에 웰 당 5×103 개의 MDCK세포를 분주한 후 10% FBS, 1% 페니실린/스트렙토마이신 및 0.4% L-글루타민이 포함된 DMEM배지를 넣고 하루 동안 배양한 후, 배양액을 버리고 PBS로 세척하였다. 이후 세포에 감염배지 (infection media, DMEM + 0.25% BSA + 1 ㎍/㎖ trypsin) 100 ㎕를 넣어 2시간 동안 감염시킨 후, PBS 용액으로 세척하였다. 돼지 인플루엔자 바이러스를 50TCID50/100 ㎕/웰의 농도가 되도록 접종하고, 상기 실시예 1에서 제조한 울금 추출물 및 분획물의 최종 농도가 0.2, 1.0 ㎍/㎖이 되도록 처리한 후 2일 동안 배양하였다. 이때, 세포에 아무것도 처리하지 않은 것을 정상 대조군으로 이용하였고, 바이러스만을 처리한 것을 음성 대조군으로, 항바이러스제인 리바비린 (ribavirin) 10 μM을 처리한 것을 양성 대조군으로 이용하였다.After dispensing 5×10 3 MDCK cells per well in a 96-well plate, add DMEM medium containing 10% FBS, 1% penicillin/streptomycin and 0.4% L-glutamine, and incubate for one day. , the culture medium was discarded and washed with PBS. Thereafter, 100 μl of an infection medium (infection media, DMEM + 0.25% BSA + 1 μg/ml trypsin) was added to the cells to infect for 2 hours, and then washed with PBS solution. The swine influenza virus was inoculated to a concentration of 50TCID50/100 μl/well, and the final concentrations of the turmeric extract and fraction prepared in Example 1 were 0.2 and 1.0 μg/ml, and then cultured for 2 days. At this time, a cell untreated was used as a normal control, a virus treated only as a negative control, and an antiviral agent treated with 10 μM of ribavirin as a positive control.
2일 동안 배양한 세포를 이용하여 MTT 어세이를 수행하였다. 배양한 세포에 MTT 용액을 넣고 37 ℃에서 반응시킨 후 배양액을 제거하고 100 ㎕의 DMSO를 넣었다. 잘 섞어 준 다음 10분 동안 방치한 후 570 ㎚에서 흡광도를 측정하여 세포의 생존율을 확인하였다. 이때, 정상 대조군의 세포생존율 100%를 기준으로 각 용매에 따른 추출물에 의한 세포생존율을 계산하였고, 그 결과를 도 2 에 나타내었다. 울금 추출물 및 분획물의 항바이러스 활성은 인플루엔자 바이러스에 의한 세포사멸을 억제시키므로, 추출물에 의한 세포생존율을 항바이러스 활성과 동일한 개념으로 사용하였다.MTT assay was performed using cells cultured for 2 days. MTT solution was added to the cultured cells and reacted at 37 °C, the culture medium was removed, and 100 μl of DMSO was added. After mixing well and leaving it for 10 minutes, the absorbance was measured at 570 nm to check the cell viability. At this time, the cell viability by the extract according to each solvent was calculated based on 100% of the cell viability of the normal control group, and the results are shown in FIG. 2 . Since the antiviral activity of turmeric extract and fractions inhibits apoptosis by influenza virus, the cell viability by the extract was used in the same concept as the antiviral activity.
도 2에서 보여주듯이, 1 ㎍/㎖ 농도에서 울금의 70% 에탄올 추출물과 70% 에탄올 추출물의 에틸아세테이트 분획물 및 물 분획물 모두 항바이러스활성을 나타내었으며, 그 중 70% 에탄올로 추출한 추출물을 에틸아세테이트로 용매추출한 70% 에탄올-에틸아세테이트 분획물이 가장 좋았다. 특히 0.2 ㎍/㎖에서는 70% 에탄올로 추출한 추출물을 에틸아세테이트로 용매추출한 분획물 (70%EtOH-EA)이 가장 강한 효능을 나타내었으며 그에 반하여 물 분획물에서는 음성대조군 대비 활성이 전혀 없는 것으로 확인되었다. 이를 종합하여 보면, 70% 에탄올로 추출한 추출물을 에틸아세테이트로 용매추출한 분획물에 항바이러스물질이 함유되어 있음을 알 수 있었으며, 70% 에탄올로 추출한 추출물의 에틸아세테이트 용매추출 과정을 통해 항바이러스 물질이 보다 농축되어 분리된 것을 예상할 수 있었다.As shown in FIG. 2, both the 70% ethanol extract of turmeric, the ethyl acetate fraction and the water fraction of the 70% ethanol extract at a concentration of 1 μg/ml exhibited antiviral activity. The solvent-extracted 70% ethanol-ethyl acetate fraction was the best. In particular, at 0.2 μg/ml, the fraction extracted with 70% ethanol and solvent-extracted with ethyl acetate (70% EtOH-EA) showed the strongest efficacy, whereas the water fraction showed no activity compared to the negative control. Taken together, it was found that the fraction extracted with 70% ethanol and solvent-extracted with ethyl acetate contained antiviral substances. Concentration and separation could be expected.
<실시예 4. 울금의 소분획물의 제조 및 소분획물의 항바이러스 활성 확인><Example 4. Preparation of small fractions of turmeric and confirmation of antiviral activity of small fractions>
소량의 추출물을 대상으로 한 선행실험에서 70% 에탄올로 추출한 추출물의 에틸아세테이트 분획물에서 가장 강한 항바이러스 활성을 나타내었으므로 이 분획물에 활성물질이 함유되었다고 판단하여 대량 추출물을 대상으로 세부분획 및 물질분리를 진행하였다. 울금 390 g을 분쇄하여 70% (v/v) 에탄올로 2 ℓ 를 가한 후 하루 동안 3회에 걸쳐 초음파 추출하고, 이를 감압농축 하여, 70% 에탄올 추출물 83.8 g을 획득하였다. 획득한 추출물을 증류수 (1.5 ℓ)에 현탁하여 현탁액을 만들었다. 현탁액을 에틸아세테이트로 용매추출을 하여 에틸아세테이트 분획물 17.2 g을 얻었다.Ethyl acetate of the extract extracted with 70% ethanol in a previous experiment with a small amount of extract Since the fraction showed the strongest antiviral activity, it was judged that the fraction contained an active substance, and sub-fractionation and material separation were carried out for a large amount of extract. After grinding 390 g of turmeric, 2 ℓ of 70% (v/v) ethanol was added, followed by ultrasonic extraction three times during one day, and concentrated under reduced pressure to obtain 83.8 g of 70% ethanol extract. The obtained extract was suspended in distilled water (1.5 L) to make a suspension. The suspension was solvent-extracted with ethyl acetate to obtain 17.2 g of an ethyl acetate fraction.
이후 에틸아세테이트 분획물 (17.2 g)을 n-hexane/acetone 농도구배 (30:1 → 1:2 [v:v])의 조건으로 순상 컬럼 크로마토그래피 (입자크기:63-200 ㎛)를 실시하여 8개의 소분획물 (F1-8)을 얻었으며, 상기 실시예 2 및 3과 동일한 과정으로 각 소분획물에 대한 MTT 어세이 및 세포병변효과 회복 어세이를 수행하여 그 결과를 도 3 및 4에 나타내었다.Then, the ethyl acetate fraction (17.2 g) was subjected to normal phase column chromatography (particle size: 63-200 μm) under the condition of a gradient of n -hexane/acetone (30:1 → 1:2 [v:v]) to 8 Dog small fractions (F1-8) were obtained, and MTT assay and cytopathic effect recovery assay were performed for each small fraction in the same manner as in Examples 2 and 3, and the results are shown in FIGS. 3 and 4 .
도 3에서 보여주듯이, 0.2 및 1.0 ㎍/㎖의 농도에서 유의미한 세포독성은 관측되지 않았으며, 도 4에서 보여주듯이, 0.2 및 1.0 ㎍/㎖의 농도에서 소분획물 F4 내지 F8이 상대적으로 강한 활성을 나타내었다.As shown in FIG. 3, no significant cytotoxicity was observed at concentrations of 0.2 and 1.0 μg/ml, and as shown in FIG. 4, small fractions F4 to F8 at concentrations of 0.2 and 1.0 μg/ml showed relatively strong activity. indicated.
이와 동시에 활성물질의 분리를 위하여 박층크로마토그래피 (Thin layer chromatography, TLC) 분석을 수행하였다. 이를 위하여 표준물질 커큐민과 함께 8종의 소분획물을 순상고정상 (Normal phase)의 plate에 점적하여 n-hexane:acetone = 3:1의 용매조성으로 전개를 하였다. 이 후, UV 254 nm, 365 nm 및 황산발적을 통하여 각 물질의 극성패턴을 확인하였으며 그 결과는 도 5에 나타내었다.At the same time, thin layer chromatography (TLC) analysis was performed to separate the active material. To this end, 8 types of small fractions were added dropwise to a plate of a normal phase together with curcumin as a standard, and developed in a solvent composition of n-hexane:acetone = 3:1. Thereafter, the polarity pattern of each material was confirmed through
도 5에서 보여주듯이, 소분획물 F1 내지 F3은 가장 비극성의 물질로서 소분획물의 성상 또한 기름이었으므로 대부분 저분자량의 정유성분이 소분획물 F1 내지 F3을 구성함을 예상할 수 있었다. 또한 약리활성을 갖는 것으로 알려져 있는 커큐민은 소분획물 F6에서 용출되기 시작하여 F7 및 F8에 주로 함유되어 있음을 알 수 있었다.As shown in FIG. 5 , the small fractions F1 to F3 were the most non-polar substances, and since the properties of the small fractions were also oil, it could be expected that most of the low molecular weight essential oil components constitute the small fractions F1 to F3. In addition, curcumin, which is known to have pharmacological activity, started to elute from the small fraction F6, and it was found that it was mainly contained in F7 and F8.
이에 반하여 도 4에서 F7 정도의 항바이러스 활성을 나타낸 F4 내지 F5의 분획물은 페놀성 화합물인 컬큐미노이드 (curcuminoids, curcumin을 비롯한 이의 유도체를 총칭)가 대부분을 차지하는 F7 및 F8 보다는 비극성이면서, F1 내지 F3의 대부분을 차지하는 정유성분보다 높은 극성을 나타내는 물질로, 항바이러스 활성을 갖는 화합물이 포함되어 있을 것으로 예상되었다. 따라서, 이후 실험에서 F5 분획물에 포함된 화합물을 분리 분석하였다.In contrast, the fractions of F4 to F5, which showed antiviral activity of about F7 in FIG. 4, are non-polar than F7 and F8, in which most of the phenolic compounds, curcuminoids (curcuminoids, derivatives thereof including curcumin) occupy most, are non-polar, F1 to It is a material having a higher polarity than the essential oil component, which accounts for most of F3, and was expected to contain a compound having antiviral activity. Therefore, in subsequent experiments, the compounds included in the F5 fraction were separated and analyzed.
정확한 구성성분의 확인을 위하여 LC/MS 분석을 수행하였다. LC/MS 분석을 위하여 고성능 액체 크로마토그래피(high performance liquid chromatography, HPLC)는 Agilent 1260 Infinity system (Agilent Technologies, Inc., Santa clara, CA, USA)을, 컬럼은 INNO C18 (5 ㎛, 4.6×250.0 ㎜)를, 마지막으로 질량 분석기 (mass detector)는 Agilent 6130 Quadrupole mass spectrometer를 사용하였다. 분석 조건은, 액체크로마토그래피의 이동상은 0.1% [v/v] 포름산을 포함하는 증류수 (이동상 A)와 0.1% [v/v] 포름산을 포함하는 아세토니트릴 (이동상 B)을 사용하여 유속 0.6 ㎖/분으로 흘려주었고, 각 시료는 acetone을 사용하여 1 ㎎/㎖의 농도로 만들어 10 ㎕씩 주입하였다. 이동상의 조건은 다음과 같다. 분석 전 3분간 10% 이동상 B로 포화 후, 3.0~43.0분 10~90% 이동상 B 농도구배로, 43.1~50.0분 100% 이동상 B, 50.1~55.0분 10% 이동상 B로 흘려주었다. 이 중 대표적으로 F5와 F7의 크로마토그램의 비교결과를 도 6에 나타내었다.LC/MS analysis was performed to confirm the correct constituents. For LC/MS analysis, high performance liquid chromatography (HPLC) was performed using an Agilent 1260 Infinity system (Agilent Technologies, Inc., Santa clara, CA, USA), and the column was INNO C18 (5 μm, 4.6×250.0). mm), and finally, as a mass detector, an Agilent 6130 Quadrupole mass spectrometer was used. Analytical conditions, the mobile phase of liquid chromatography is distilled water containing 0.1% [v/v] formic acid (mobile phase A) and acetonitrile containing 0.1% [v/v] formic acid (mobile phase B), flow rate 0.6 ml It was flowed at /min, and each sample was made at a concentration of 1 mg/ml using acetone and injected by 10 μl. The conditions of the mobile phase are as follows. After saturation with 10% mobile phase B for 3 minutes before analysis, it was flowed with a gradient of 10 to 90% mobile phase B for 3.0 to 43.0 minutes, 100% mobile phase B for 43.1 to 50.0 minutes, and 10% mobile phase B for 50.1 to 55.0 minutes. Among them, the comparison results of the chromatograms of F5 and F7 are shown in FIG. 6 .
도 6을 통하여 표준물질과 함께 점적한 박층크로마토그래피의 결과에서 예측하였듯이, 소분획물 F7의 주요화합물이 커큐민이었음에 반하여, 소분획물 F5는 다수의 세스퀴테르페노이드계 화합물이 포함되어 있다는 것을 분자량과 UV 패턴을 통하여 확인할 수 있었다. 따라서 울금으로부터 분리한 추출물에 포함된 세스퀴테르페노이드계 화합물이 커큐민과 함께 항바이러스 활성을 나타내는 것을 확인하였다.As predicted from the results of thin layer chromatography instilled together with a standard material through FIG. 6, the main compound of the small fraction F7 was curcumin, whereas the small fraction F5 contained a large number of sesquiterpenoid compounds. and UV pattern. Therefore, it was confirmed that the sesquiterpenoid compound contained in the extract isolated from turmeric exhibits antiviral activity together with curcumin.
높은 수득률 (1.5 g)과 상기 도 4의 항바이러스 활성을 고려하여 F5를 대상으로 활성화합물을 분리를 위한 실험을 진행하였다.In consideration of the high yield (1.5 g) and the antiviral activity of FIG. 4, an experiment was performed for isolating the active compound from F5.
<실시예 5. 세스퀴테르페노이드계 화합물의 분리><Example 5. Separation of sesquiterpenoid compounds>
한국산 울금 390 g을 분쇄하여 70% (v/v) 에탄올로 2 ℓ를 가한 후 하루 동안 3회에 걸쳐 초음파 추출하고, 이를 감압농축 하여, 70% 에탄올 추출물 83.8 g을 획득하였다. 획득한 추출물을 증류수 (1.5 ℓ)에 현탁하여 현탁액을 만들었다. 현탁액을 에틸아세테이트로 용매추출을 하여 에틸아세테이트 분획물 17.2 g을 얻었다. 이후 에틸아세테이트 분획물 (17.2 g)을 n-hexane:acetone 농도구배(30:1 → 1:2 [v:v])의 조건으로 순상 컬럼 크로마토그래피 (입자크기: 63-200 μm)를 실시하여 TLC 패턴에 따라 8개의 소분획물 (F1-8)을 얻었다.After grinding 390 g of Korean turmeric, 2 ℓ of 70% (v/v) ethanol was added, followed by ultrasonic extraction three times a day, and concentrated under reduced pressure to obtain 83.8 g of a 70% ethanol extract. The obtained extract was suspended in distilled water (1.5 L) to make a suspension. The suspension was solvent-extracted with ethyl acetate to obtain 17.2 g of an ethyl acetate fraction. Then, the ethyl acetate fraction (17.2 g) was subjected to normal phase column chromatography (particle size: 63-200 μm ) under the condition of a gradient of n -hexane:acetone (30:1 → 1:2 [v:v]). Eight small fractions (F1-8) were obtained according to the TLC pattern.
상기 소분획 F5 (1.5 g)를 60% MeOH의 등용매조건으로 역상 컬럼크로마토그래피 (63 - 200 ㎛ particle size)를 실시하였다. 이를 수행하여 얻은 소분획 F5.2를 대상으로 등용매조건으로 (ACN in H2O, 0-85 min: 35%, ACN containing 0.1% formic acid, H2O containing 0.1% formic acid) 고성능 액체 크로마토그래피 (high performance liquid chromatography, HPLC) (컬럼종류: Luna 5 micro Phenyl-Hexyl, 컬럼크기: 250×10.0 mm, 입자크기: 5 ㎛, 유속: 2 ㎖/min, UV detection: 254 nm)를 사용하여 화합물 3 (1.1 ㎎, t R = 59.4 min)을 확보하였다. 소분획 F5 (1.5 g)을 대상으로 바로 HPLC (ACN in H2O, 0-120 min: 36%, flow rate 2 mL/min, ACN containing 0.1% formic acid, H2O containing 0.1% formic acid)를 실시하여 화합물 1 (2.8 ㎎, t R = 27.3 min), 화합물 2 (3.7 ㎎, t R = 48.7 min), 화합물 4 (2.0 ㎎, t R = 68.5 min) 그리고 화합물 5 (4.1 ㎎, t R = 90.3 min)를 확보하였다.The small fraction F5 (1.5 g) was subjected to reverse phase column chromatography (63 - 200 μm particle size) under isocratic conditions of 60% MeOH. High performance liquid chromatography on the small fraction F5.2 obtained by doing this under isocratic conditions (ACN in H 2 O, 0-85 min: 35%, ACN containing 0.1% formic acid, H 2 O containing 0.1% formic acid) Using high performance liquid chromatography (HPLC) (column type:
도 6의 결과를 토대로, 상기 소분획물 F5로부터 분리한 5종의 세스퀴테르페노이드계 화합물의 양을 확인하면, 70% 에탄올로 추출한 추출물을 에틸아세테이트로 용매추출한 분획물에는 상기 세스퀴테르페노이드계 화합물이 50% 이상(99% 미만)의 고농도로 함유된 것으로 확인되었다.Based on the results of FIG. 6 , when the amounts of five kinds of sesquiterpenoid-based compounds isolated from the small fraction F5 were confirmed, the sesquiterpenoids in the fraction extracted with 70% ethanol and solvent-extracted with ethyl acetate were It was confirmed that the system compound was contained in a high concentration of 50% or more (less than 99%).
<실시예 6. 울금으로부터 분리한 화합물의 물리 화학적 구조 확인><Example 6. Confirmation of the physical and chemical structure of the compound isolated from turmeric>
실시예 6-1. 이소프로컬큐메놀 (화합물 1) Example 6-1. Isoproculcumenol (Compound 1)
Isoprocurcumenol;Isoprocurcumenol;
갈색 수지;brown resin;
UV (메탄올) λmax nm (log ε) 254 (2.41);UV (methanol) λ max nm (log ε ) 254 (2.41);
ESIMS m/z 217.2 [M - H2O + H]+, 257.2 [M + Na]+;ESIMS m/z 217.2 [M - H 2 O + H] + , 257.2 [M + Na] + ;
1H-NMR (CDCl3, 600 MHz): δ H 3.22 (1H, d, J = 14.5 Hz, H-1), 1.25 (2H, m, H-2), 1.44 (2H, m, H-3), 1.41 (1H, s, H-5), 2.82 (2H, dd, J = 14.5, 1.3 Hz, H-6), 2.20 (1H, br s, H-9), 1.92 (3H, s, H-12), 1.82 (3H, H-13), 1.24 (1H, s, H-14), 4.91 (1H, m, H-15a), 4.90 (1H, m, H-15b). 1 H-NMR (CDCl 3 , 600 MHz): δ H 3.22 (1H, d, J = 14.5 Hz, H-1), 1.25 (2H, m, H-2), 1.44 (2H, m, H-3 ), 1.41 (1H, s, H-5), 2.82 (2H, dd, J = 14.5, 1.3 Hz, H-6), 2.20 (1H, br s, H-9), 1.92 (3H, s, H -12), 1.82 (3H, H-13), 1.24 (1H, s, H-14), 4.91 (1H, m, H-15a), 4.90 (1H, m, H-15b).
13C NMR (CDCl3, 150 MHz): δ C 51.1 (C-1), 24.7 (C-2), 28.1 (C-3), 79.8 (C-4), 58.8 (C-5), 39.7 (C-6), 134.4 (C-7), 203.3 (C-8), 53.7 (C-9), 141.7 (C-10), 143.8 (C-11), 21.8 (C-12), 22.8 (C-13), 24.3 (C-14), 111.5 (C-15). 13 C NMR (CDCl 3 , 150 MHz): δ C 51.1 (C-1), 24.7 (C-2), 28.1 (C-3), 79.8 (C-4), 58.8 (C-5), 39.7 ( C-6), 134.4 (C-7), 203.3 (C-8), 53.7 (C-9), 141.7 (C-10), 143.8 (C-11), 21.8 (C-12), 22.8 (C) -13), 24.3 (C-14), 111.5 (C-15).
실시예 6-2. 인터메딘 B (화합물 2) Example 6-2. Intermedin B (Compound 2)
Intermedin B;Intermedin B;
갈색 수지;brown resin;
UV (메탄올) λmax nm (log ε) 234 (3.15);UV (methanol) λ max nm (log ε ) 234 (3.15);
ESIMS m/z 217.2 [M - H2O + H]+, 257.2 [M + Na]+;ESIMS m/z 217.2 [M - H 2 O + H] + , 257.2 [M + Na] + ;
1H-NMR (CDCl3, 600 MHz): δ H 6.15 (1H, d, J = 10.0, 2.3 Hz, H-2), 5.77 (1H, d, J = 10.0 , H-3), 4.43 (1H, br s, H-5), 6.06 (1H, s, H-10), 1.88 (3H, s, H-12), 2.14 (3H, s, H-13), 0.90 (3H, d, J = 6.0, H-14), 4.97 (1H, s, H-15a), 5.07 (1H, s, H-15b). 1 H-NMR (CDCl 3 , 600 MHz): δ H 6.15 (1H, d, J = 10.0, 2.3 Hz, H-2), 5.77 (1H, d, J = 10.0 , H-3), 4.43 (1H , br s, H-5), 6.06 (1H, s, H-10), 1.88 (3H, s, H-12), 2.14 (3H, s, H-13), 0.90 (3H, d, J = 6.0, H-14), 4.97 (1H, s, H-15a), 5.07 (1H, s, H-15b).
13C NMR (CDCl3, 150 MHz): δ C 32.9 (C-1), 133.9 (C-2), 127.2 (C-3), 145.0 (C-4), 69.5 (C-5), 31.8 (C-6), 35.9 (C-7), 48.7 (C-8), 200.8 (C-9), 124.2 (C-10), 155.5 (C-11), 20.9 (C-12), 27.9 (C-13), 16.8 (C-14), 113.8 (C-15). 13 C NMR (CDCl 3 , 150 MHz): δ C 32.9 (C-1), 133.9 (C-2), 127.2 (C-3), 145.0 (C-4), 69.5 (C-5), 31.8 ( C-6), 35.9 (C-7), 48.7 (C-8), 200.8 (C-9), 124.2 (C-10), 155.5 (C-11), 20.9 (C-12), 27.9 (C) -13), 16.8 (C-14), 113.8 (C-15).
실시예 6-3. 컬큐마디온 (화합물 3) Example 6-3. Curcumadione (Compound 3)
Curcumadione;Curcumadione;
갈색 수지;brown resin;
UV (메탄올) λmax nm (log ε) 250 (2.23);UV (methanol) λ max nm (log ε ) 250 (2.23);
ESIMS m/z 235.2 [M + H]+, 257.2 [M + Na]+;ESIMS m/z 235.2 [M + H] + , 257.2 [M + Na] + ;
1H-NMR (CDCl3, 600 MHz): δ H 3.07 (1H, dd, J = 16.7, 7.1 Hz, H-2a), 2.51 (1H, dd, J = 16.7, 4.7 Hz, H-2b), 2.50-2.60 (2H, m, H-3), 5.50 (1H, t, J = 6.2, H-5), 2.24 (2H, m, H-6), 2.93 (1H, dd, J = 16.7, 7.1, H-9a), 2.59 (1H, m, H-9b), 2.45 (1H, m, H-10), 1.79 (3H, s, H-12), 1.99 (3H, s, H-13), 2.14 (3H, s, H-14), 1.07 (3H, d, J = 7.0, H-15). 1 H-NMR (CDCl 3 , 600 MHz): δ H 3.07 (1H, dd, J = 16.7, 7.1 Hz, H-2a), 2.51 (1H, dd, J = 16.7, 4.7 Hz, H-2b), 2.50-2.60 (2H, m, H-3), 5.50 (1H, t, J = 6.2, H-5), 2.24 (2H, m, H-6), 2.93 (1H, dd, J = 16.7, 7.1) , H-9a), 2.59 (1H, m, H-9b), 2.45 (1H, m, H-10), 1.79 (3H, s, H-12), 1.99 (3H, s, H-13), 2.14 (3H, s, H-14), 1.07 (3H, d, J = 7.0, H-15).
13C NMR (CDCl3, 150 MHz): δ C 140.9 (C-1), 28.0 (C-2), 42.9 (C-3), 208.5 (C-4), 121.4 (C-5), 30.4 (C-6), 134.9 (C-7), 205.5 (C-8), 48.8 (C-9), 35.2 (C-10), 143.9 (C-11), 22.5 (C-12), 22.8 (C-13), 30.2 (C-14), 19.3 (C-15) 13 C NMR (CDCl 3 , 150 MHz): δ C 140.9 (C-1), 28.0 (C-2), 42.9 (C-3), 208.5 (C-4), 121.4 (C-5), 30.4 ( C-6), 134.9 (C-7), 205.5 (C-8), 48.8 (C-9), 35.2 (C-10), 143.9 (C-11), 22.5 (C-12), 22.8 (C -13), 30.2 (C-14), 19.3 (C-15)
실시예 6-4. (-)-컬큐메논 (화합물 4) Example 6-4. (-)-curcumenone (compound 4)
(-)-Curcumenone;(-)-Curcumenone;
갈색 수지;brown resin;
UV (메탄올) λmax nm (log ε) 256 (3.03);UV (methanol) λ max nm (log ε ) 256 (3.03);
ESIMS m/z 235.2 [M + H]+, 257.2 [M + Na]+;ESIMS m/z 235.2 [M + H] + , 257.2 [M + Na] + ;
1H-NMR (CDCl3, 600 MHz): δ H 0.34 (1H, td, J = 7.2, 4.7 Hz, H-1), 1.49 (2H, m, H-2), 2.45 (2H, t, J = 6.9 Hz, H-3), 0.67 (1H, q, J = 3.9, H-5), 2.76 (2H, m, H-6), 2.54 (1H, d, J = 15.3, H-9a), 2.35 (1H, d, J = 15.3, H-9b), 2.00 (3H, s, H-12), 1.76 (3H, s, H-13), 2.06 (3H, s, H-14), 1.06 (3H, s, H-15). 1 H-NMR (CDCl 3 , 600 MHz): δ H 0.34 (1H, td, J = 7.2, 4.7 Hz, H-1), 1.49 (2H, m, H-2), 2.45 (2H, t, J ) = 6.9 Hz, H-3), 0.67 (1H, q, J = 3.9, H-5), 2.76 (2H, m, H-6), 2.54 (1H, d, J = 15.3, H-9a), 2.35 (1H, d, J = 15.3, H-9b), 2.00 (3H, s, H-12), 1.76 (3H, s, H-13), 2.06 (3H, s, H-14), 1.06 ( 3H, s, H-15).
13C NMR (CDCl3, 150 MHz): δ C 23.3 (C-1), 23.0 (C-2), 43.0 (C-3), 208.3 (C-4), 23.9 (C-5), 27.5 (C-6), 128.0 (C-7), 200.4 (C-8), 48.5 (C-9), 19.5 (C-10), 145.9 (C-11), 23.0 (C-12), 22.8 (C-13), 29.8 (C-14), 18.7 (C-15) 13 C NMR (CDCl 3 , 150 MHz): δ C 23.3 (C-1), 23.0 (C-2), 43.0 (C-3), 208.3 (C-4), 23.9 (C-5), 27.5 ( C-6), 128.0 (C-7), 200.4 (C-8), 48.5 (C-9), 19.5 (C-10), 145.9 (C-11), 23.0 (C-12), 22.8 (C) -13), 29.8 (C-14), 18.7 (C-15)
실시예 6-5. (+)-털메로놀 A (화합물 5) Example 6-5. (+)-Turmeronol A (Compound 5)
(+)-Turmeronol A;(+)-Turmeronol A;
갈색 수지;brown resin;
UV (메탄올) λmax nm (log ε) 224 (2.47), 282 (1.34);UV (methanol) λ max nm (log ε ) 224 (2.47), 282 (1.34);
ESIMS m/z 232.2 [M + H]+, 255.1 [M + Na]+;ESIMS m/z 232.2 [M + H] + , 255.1 [M + Na] + ;
1H-NMR (CDCl3, 600 MHz): δ H 6.64 (1H, d, J = 1.9 Hz, H-3), 6.70 (1H, dd, J = 7.9, 1.9 Hz, H-5), 7.01 (1H, d, H-6), 2.19 (3H, s, H-7), 3.23 (1H, m, H-8), 1.22 (3H, d, J = 6.9, H-9), 2.69 (1H, dd, J = 15.6, 6.4 Hz, H-10a), 2.58 (1H, dd, J = 15.8, 8.1 Hz, H-10b), 6.01 (1H, t, J = 1.4, H-12), 2.10 (3H, br s, H-14), 1.85 (3H, s, H-15). 1 H-NMR (CDCl 3 , 600 MHz): δ H 6.64 (1H, d, J = 1.9 Hz, H-3), 6.70 (1H, dd, J = 7.9, 1.9 Hz, H-5), 7.01 ( 1H, d, H-6), 2.19 (3H, s, H-7), 3.23 (1H, m, H-8), 1.22 (3H, d, J = 6.9, H-9), 2.69 (1H, dd, J = 15.6, 6.4 Hz, H-10a), 2.58 (1H, dd, J = 15.8, 8.1 Hz, H-10b), 6.01 (1H, t, J = 1.4, H-12), 2.10 (3H) , br s, H-14), 1.85 (3H, s, H-15).
13C NMR (CDCl3, 150 MHz): δ C 121.4 (C-1), 155.4 (C-2), 113.6 (C-3), 146.3 (C-4), 119.1 (C-5), 131.1 (C-6), 15.5 (C-7), 35.4 (C-8), 22.1 (C-9), 52.7 (C-10), 200.0 (C-11), 124.2 (C-12), 153.9 (C-13), 27.8 (C-14), 20.9 (C-15). 13 C NMR (CDCl 3 , 150 MHz): δ C 121.4 (C-1), 155.4 (C-2), 113.6 (C-3), 146.3 (C-4), 119.1 (C-5), 131.1 ( C-6), 15.5 (C-7), 35.4 (C-8), 22.1 (C-9), 52.7 (C-10), 200.0 (C-11), 124.2 (C-12), 153.9 (C) -13), 27.8 (C-14), 20.9 (C-15).
따라서, 상기 울금의 40-90% (v/v) 에탄올-에틸아세테이트 분획물로부터 항바이러스 활성이 있는 5종의 세스퀴테르페노이드계 화합물을 확인하였으며, 상기 세스퀴테르페노이드계 화합물은 이소프로컬큐메놀 (화합물 1), 인터메딘 B (화합물 2), 컬큐마디온 (화합물 3), (-)-컬큐메논 (화합물 4) 및 (+)-털메로놀 A (화합물 5)을 포함한다.Therefore, five types of sesquiterpenoid compounds having antiviral activity were identified from 40-90% (v/v) ethanol-ethyl acetate fractions of turmeric, and the sesquiterpenoid compounds were isoprocal Cumenol (Compound 1), Intermedin B (Compound 2), Curcumadione (Compound 3), (-)-Curcumenone (Compound 4) and (+)-Turmeronol A (Compound 5).
<실시예 7. 울금 추출물로부터 분리한 세스퀴테르페노이드계 화합물의 항바이러스 활성 (EC<Example 7. Antiviral activity of sesquiterpenoid compounds isolated from turmeric extract (EC 5050 ) 확인>) OK>
상기 실시예 5에서 분리한 화합물 1 내지 화합물 5 및 커큐민의 항바이러스 활성을 확인하였다. 이때, 각각의 화합물 및 커큐민의 농도는 2.5 μM 내지 500 μM로 하여 처리하였으며, 바이러스 및 화합물을 처리하지 않은 군을 정상 대조군으로, 바이러스만 처리한 군을 음성 대조군으로, 항바이러스제인 리바비린 (ribavirin)을 처리한 군을 양성 대조군으로 사용하였다. 그 결과를 표 1에 나타내었다.Antiviral activity of
삭제delete
상기 표 1에서 보는 바와 같이, MDCK 세포에 대하여 항바이러스제인 ribavirin의 EC50 (effective concentration) 값이 5.17 μM, 커큐민 (curcumin)의 EC50 값은 11.16 μM로 항바이러스활성을 나타내는 한편, 본 발명의 5가지 세스퀴테르페노이드계 화합물이 항바이러스 활성을 나타내는 것을 확인하였다. 특히 화합물 2는 커큐민보다 낮은 농도에서도 뛰어난 항바이러스 활성을 나타내었으며 (EC50 = 9.51 μM), 항바이러스제인 ribavirin의 항바이러스 활성에 육박하는 활성을 나타내었다. 그 이외의 화합물 1, 3, 4, 5는 커큐민보다는 높은 EC50 값을 나타내었으나, 역시 항바이러스 활성을 갖는 것을 확인하였다.As shown in Table 1 above, the EC 50 (effective concentration) value of ribavirin, an antiviral agent, is 5.17 μM , and the EC 50 value of curcumin is 11.16 μM for MDCK cells, indicating antiviral activity. It was confirmed that the five sesquiterpenoid compounds of the present invention exhibit antiviral activity. In particular,
<실시예 8. 울금 추출물로부터 분리한 세스퀴테르페노이드계 화합물의 세포독성 (CC<Example 8. Cytotoxicity of sesquiterpenoid compounds isolated from turmeric extract (CC 5050 ) 확인>) OK>
상기 실시예 5에서 분리한 화합물 1 내지 화합물 5에 의한 세포독성을 확인하기 위해 MTT 어세이를 진행하였다. 96웰 플레이트 (96 well plate)에 웰당 1×104 개의 MDCK 세포를 분주한 후 10% FBS, 1% 페니실린/스트렙토마이신 및 0.4% L-글루타민이 포함된 DMEM배지를 넣고 하루 동안 배양한 후, 배양액을 버리고 PBS 용액으로 세척하였다. 이후 세포에 새 배지를 넣고, 상기 실시예 5에서 분리한 화합물 1 내지 화합물 5를 2.5 μM ~ 160 μM이 되도록 처리한 후 3일 동안 배양하였다. 이때, 세포에 아무것도 처리하지 않은 것을 정상 대조군으로 이용하였고, 울금 추출물의 대표적인 지표화합물인 커큐민 (curcumin)과 항바이러스제인 리바비린(ribavirin)을 양성 대조군 1 및 2로 처리하였다. 3일 동안 배양한 세포를 이용하여 MTT 어세이를 수행하였다. 배양한 세포에 MTT용액을 넣고 37 ℃에서 반응시킨 후 배양액을 제거하고 200 ㎕의 DMSO를 넣었다. 피펫팅으로 잘 섞어 준 다음 10분 동안 방치한 후 550 ㎚에서 흡광도를 측정하여 세포의 생존율을 확인하였다. 이때, 정상 대조군의 세포생존율 대비 각각의 화합물에 의한 세포생존율을 백분율 (%)로 환산하였다. 각각 화합물의 세포독성을 확인한 결과를 표 2에 나타내었다. 표 2는 돼지 인플루엔자 바이러스에 대한 화합물의 CC50 (the half maximal cytotoxic concentration)값을 나타내고 있다.In order to confirm the cytotoxicity by the
표 2에서 보는 바와 같이, 50%의 세포독성 반응을 나타내는 CC50 값의 경우, MDCK 세포에 대하여 항바이러스제인 ribavirin의 CC50 값은 100 μM 이상이며, 커큐민 (curcumin)의 CC50 값은 42.06 μM 인 반면, 본 발명의 화합물 1 내지 화합물 5는 모두 500 μM 이상으로, 커큐민보다 높은 농도에서도 세포독성이 없는 것으로 확인하였다.As shown in Table 2, in the case of a CC 50 value indicating a cytotoxic response of 50%, the CC 50 value of ribavirin, an antiviral agent, against MDCK cells is 100 μM or more, and the CC 50 value of curcumin is 42.06 On the other hand, compounds 1 to 5 of the present invention were all 500 μM or more, and it was confirmed that there was no cytotoxicity even at a concentration higher than that of curcumin.
상기의 결과에서 보는 바와 같이, 본 발명의 화합물 1 내지 화합물 5는 고농도에서도 안전한 항바이러스제로 사용할 수 있음을 확인하였다.As can be seen from the above results, it was confirmed that
<제제예 1. 약학적 제제><Formulation Example 1. Pharmaceutical formulation>
제제예 1-1. 정제의 제조Formulation Example 1-1. manufacture of tablets
본 발명의 울금 추출물 20 g 또는 인터메딘 B (Intermedin B) (화합물 2) 200 ㎎ (또는 이소프로컬큐메놀 (화합물 1), 컬큐마디온 (화합물 3), (-)-컬큐메논 (화합물 4) 및 (+)-털메로놀 A (화합물 5)로 이루어진 군에서 선택되는 1종 이상 200 ㎎)을 각각 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.20 g of turmeric extract of the present invention or 200 mg of Intermedin B (Compound 2) (or isoproculcumenol (Compound 1), Curcumadion (Compound 3), (-)-Curcumenone (Compound 4) and (+)-talmeronol A (compound 5) at least one selected from the group consisting of 200 mg) were mixed with 175.9 g of lactose, 180 g of potato starch and 32 g of colloidal silicic acid, respectively. After adding a 10% gelatin solution to this mixture, it was ground and passed through a 14 mesh sieve. This was dried, and 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate were added thereto, and the resulting mixture was made into tablets.
제제예 1-2. 주사액제의 제조Formulation Example 1-2. Preparation of injectable solution
본 발명의 인터메딘 B (Intermedin B) (화합물 2) 100 ㎎ (또는 이소프로컬큐메놀 (화합물 1), 컬큐마디온 (화합물 3), (-)-컬큐메논 (화합물 4) 및 (+)-털메로놀 A (화합물 5)로 이루어진 군에서 선택되는 1종 이상 100 ㎎), 염화나트륨 0.6 g 및 아스코르브산 0.1 g을 증류수에 용해시켜서 100 ㎖를 만들었다. 이 용액을 병에 넣고 20 ℃에서 30분간 가열하여 멸균시켰다.Intermedin B (Compound 2) of the
<제제예 2. 식품 제조><Formulation Example 2. Food Manufacturing>
제제예 2-1. 조리용 양념의 제조Formulation Example 2-1. Preparation of cooking seasonings
본 발명의 울금 추출물 또는 인터메딘 B (Intermedin B) (화합물 2) (또는 이소프로컬큐메놀 (화합물 1), 컬큐마디온 (화합물 3), (-)-컬큐메논 (화합물 4) 및 (+)-털메로놀 A (화합물 5)로 이루어진 군에서 선택되는 1종 이상)를 각각 조리용 양념에 1중량%로 첨가하여 건강 증진용 조리용 양념을 제조하였다.Turmeric extract of the present invention or Intermedin B (Compound 2) (or isoproculcumenol (Compound 1), Curcumadion (Compound 3), (-)-Curcumenone (Compound 4) and (+) -Turmeronol A (at least one selected from the group consisting of compound 5) was added to each cooking seasoning in an amount of 1% by weight to prepare a cooking seasoning for health promotion.
제제예 2-2. 밀가루 식품의 제조Formulation Example 2-2. Flour food manufacturing
본 발명의 울금 추출물 또는 인터메딘 B (Intermedin B) (화합물 2) (또는 이소프로컬큐메놀 (화합물 1), 컬큐마디온 (화합물 3), (-)-컬큐메논 (화합물 4) 및 (+)-털메로놀 A (화합물 5)로 이루어진 군에서 선택되는 1종 이상) 을 각각 밀가루에 0.1중량% 로 첨가하고, 이 혼합물을 이용하여 빵, 케이크, 쿠키, 크래커 및 면류를 제조하여 건강 증진용 식품을 제조하였다.Turmeric extract of the present invention or Intermedin B (Compound 2) (or isoproculcumenol (Compound 1), Curcumadion (Compound 3), (-)-Curcumenone (Compound 4) and (+) -Turmeronol A (at least one selected from the group consisting of compound 5) is added in an amount of 0.1% by weight to flour, respectively, and the mixture is used to prepare bread, cakes, cookies, crackers and noodles for health promotion Food was prepared.
제제예 2-3. 스프 및 육즙 (gravies)의 제조Formulation Example 2-3. Preparation of soups and gravies
본 발명의 울금 추출물 또는 인터메딘 B (Intermedin B) (화합물 2) (또는 이소프로컬큐메놀 (화합물 1), 컬큐마디온 (화합물 3), (-)-컬큐메논 (화합물 4) 및 (+)-털메로놀 A (화합물 5)로 이루어진 군에서 선택되는 1종 이상)을 각각 육즙에 0.1중량%로 첨가하여 건강 증진용 수프 및 육즙을 제조하였다.Turmeric extract of the present invention or Intermedin B (Compound 2) (or isoproculcumenol (Compound 1), Curcumadion (Compound 3), (-)-Curcumenone (Compound 4) and (+) -Turmeronol A (at least one selected from the group consisting of compound 5) was added to the broth in an amount of 0.1% by weight, respectively, to prepare a health-improving soup and broth.
제제예 2-4. 유제품 (dairy products)의 제조Formulation Example 2-4. Manufacture of dairy products
본 발명의 울금 추출물 또는 인터메딘 B (Intermedin B) (화합물 2) (또는 이소프로컬큐메놀 (화합물 1), 컬큐마디온 (화합물 3), (-)-컬큐메논 (화합물 4) 및 (+)-털메로놀 A (화합물 5)로 이루어진 군에서 선택되는 1종 이상)을 각각 우유에 0.1중량%로 첨가하고, 상기 우유를 이용하여 버터 및 아이스크림과 같은 다양한 유제품을 제조하였다.Turmeric extract of the present invention or Intermedin B (Compound 2) (or isoproculcumenol (Compound 1), Curcumadion (Compound 3), (-)-Curcumenone (Compound 4) and (+) -Tulmeronol A (at least one selected from the group consisting of compound 5) was added in an amount of 0.1% by weight, respectively, to milk, and various dairy products such as butter and ice cream were prepared using the milk.
제제예 2-5. 야채주스 제조Formulation Example 2-5. vegetable juice production
본 발명의 울금 추출물 또는 인터메딘 B (Intermedin B) (화합물 2) (또는 이소프로컬큐메놀 (화합물 1), 컬큐마디온 (화합물 3), (-)-컬큐메논 (화합물 4) 및 (+)-털메로놀 A (화합물 5)로 이루어진 군에서 선택되는 1종 이상)을 각각 토마토주스 또는 당 근주스 1,000 ㎖에 가하여 건강 증진용 야채주스를 제조하였다.Turmeric extract of the present invention or Intermedin B (Compound 2) (or isoproculcumenol (Compound 1), Curcumadion (Compound 3), (-)-Curcumenone (Compound 4) and (+) -Turmeronol A (at least one selected from the group consisting of compound 5) was added to 1,000 ml of tomato juice or sugar root juice, respectively, to prepare vegetable juice for health promotion.
제제예 2-6. 과일주스 제조Formulation Example 2-6. fruit juice production
본 발명의 울금 추출물 또는 인터메딘 B (Intermedin B) (화합물 2) (또는 이소프로컬큐메놀 (화합물 1), 컬큐마디온 (화합물 3), (-)-컬큐메논 (화합물 4) 및 (+)-털메로놀 A (화합물 5)로 이루어진 군에서 선택되는 1종 이상)을 각각 0.1 g을 사과주스 또는 포도주스 1,000 ㎖에 가하여 건강 증진용 과일주스를 제조하였다.Turmeric extract of the present invention or Intermedin B (Compound 2) (or isoproculcumenol (Compound 1), Curcumadion (Compound 3), (-)-Curcumenone (Compound 4) and (+) -Tulmeronol A (at least one selected from the group consisting of compound 5) was added to 0.1 g each of apple juice or 1,000 ml of grape juice to prepare fruit juice for health promotion.
Claims (21)
[화학식 1]
A composition for preventing or treating swine influenza virus infection comprising a fraction obtained by suspending a 40-90% (v/v) ethanol extract concentrate of turmeric in water and then extracting it with ethyl acetate. Isoproculcumenol (Compound 1), Intermedin B (Compound 2), Curcumadione (Compound 3), (-)-Curcumenone (Compound 4) and (+)-Turmeronol of the following formula (1) without being included A composition for preventing or treating swine influenza virus infection, characterized in that 50 to 99% (w/w) of the sesquiterpenoid compound containing A (Compound 5) is contained in the ethanol-ethyl acetate extract fraction.
[Formula 1]
[화학식 1]
It is a health functional food for improving symptoms of swine influenza virus including a fraction obtained by suspending 40-90% (v/v) ethanol extract concentrate of turmeric in water and then extracting it with ethyl acetate. Curcumin is included as an effective active ingredient Isoproculcumenol (Compound 1), Intermedin B (Compound 2), Curcumadione (Compound 3), (-)-Curcumenone (Compound 4) and (+)-Turmeronol A of the following formula (1) A health functional food for improving symptoms of swine influenza virus, characterized in that 50 to 99% (w/w) of the sesquiterpenoid-based compound containing (Compound 5) is contained in the ethanol-ethyl acetate extract fraction.
[Formula 1]
[화학식 1]
An animal drug for preventing or treating swine influenza virus infection, comprising a fraction obtained by suspending a 40-90% (v/v) ethanol extract concentrate of turmeric in water and then extracting it with ethyl acetate. Isoproculcumenol (Compound 1), Intermedin B (Compound 2), Curcumadione (Compound 3), (-)-Curcumenone (Compound 4) and (+)-Tulmero of Formula 1 Animal for the prevention or treatment of swine influenza virus infection, characterized in that 50 to 99% (w/w) of the sesquiterpenoid compound containing Nol A (Compound 5) is contained in the ethanol-ethyl acetate extract fraction medicine.
[Formula 1]
[화학식 1]
It is an animal feed additive for improving symptoms of swine influenza virus including a fraction obtained by suspending 40-90% (v/v) ethanol extract concentrate of turmeric in water and then extracting it with ethyl acetate. Isoproculcumenol (Compound 1), Intermedin B (Compound 2), Curcumadione (Compound 3), (-)-Curcumenone (Compound 4) and (+)-Turmeronol A of the following formula (1) An animal feed additive for improving symptoms of swine influenza virus, characterized in that 50 to 99% (w/w) of the sesquiterpenoid compound containing (Compound 5) is contained in the ethanol-ethyl acetate extract fraction.
[Formula 1]
[화학식 1]
It is a natural disinfectant for preventing swine influenza virus infection comprising a fraction obtained by suspending 40-90% (v/v) ethanol extract concentrate of turmeric in water and then extracting it with ethyl acetate. Curcumin is not included as an effective active ingredient. Isoproculcumenol (Compound 1), Intermedin B (Compound 2), Curcumadione (Compound 3), (-)-Curcumenone (Compound 4) and (+)-Turmeronol A ( A natural disinfectant for preventing swine influenza virus infection, characterized in that 50 to 99% (w/w) of the sesquiterpenoid compound containing compound 5) is contained in the ethanol-ethyl acetate extract fraction.
[Formula 1]
[화학식 1]
A composition for the prevention or treatment of swine influenza virus infection, characterized in that it comprises a curcumadion (Compound 3) of Formula 1 below.
[Formula 1]
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Asian Pacific Journal of Tropical Medicine 2017 10(9) 871~876* |
Phytochemistry 85 (2013) 122~128* |
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