KR20230146695A - Composition for inhibiting influenza virus - Google Patents
Composition for inhibiting influenza virus Download PDFInfo
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- KR20230146695A KR20230146695A KR1020220045169A KR20220045169A KR20230146695A KR 20230146695 A KR20230146695 A KR 20230146695A KR 1020220045169 A KR1020220045169 A KR 1020220045169A KR 20220045169 A KR20220045169 A KR 20220045169A KR 20230146695 A KR20230146695 A KR 20230146695A
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- influenza virus
- pharmaceutical composition
- extract
- maple
- antiviral
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Classifications
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/20—Aceraceae (Maple family)
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- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/324—Foods, ingredients or supplements having a functional effect on health having an effect on the immune system
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Abstract
본 발명은 단풍나무 추출물을 유효성분으로 포함하는 항바이러스용 약학 조성물; 단풍나무 추출물을 유효성분으로 포함하는 인플루엔자 바이러스 감염질환의 예방 또는 치료용 약학 조성물; 상기 약학 조성물을 인플루엔자 바이러스 감염질환 증상이 나타나거나 또는 나타날 우려가 있는 인간을 제외한 개체에 투여하는 단계를 포함하는 인플루엔자 바이러스 감염질환의 예방 또는 치료 방법; 단풍나무 추출물을 유효성분으로 포함하는 항바이러스용 건강기능식품 조성물, 의약외품 조성물, 사료조성물에 관한 것으로,
단풍나무 잎 추출물은 인플루엔자 바이러스의 감염을 억제하는 효과를 나타내므로, 인플루엔자 바이러스에 의한 감염증의 예방 또는 치료를 위한 항바이러스제 개발에 이용될 수 있다.The present invention provides an antiviral pharmaceutical composition containing maple tree extract as an active ingredient; A pharmaceutical composition for preventing or treating influenza virus infectious diseases containing maple tree extract as an active ingredient; A method for preventing or treating an influenza virus infectious disease, comprising administering the pharmaceutical composition to an entity other than a human that is exhibiting or at risk of exhibiting symptoms of the influenza virus infectious disease; It relates to antiviral health functional food compositions, quasi-drug compositions, and feed compositions containing maple tree extract as an active ingredient,
Maple leaf extract has an effect of suppressing influenza virus infection, so it can be used to develop antiviral agents for preventing or treating infections caused by influenza viruses.
Description
본 발명은 단풍나무 추출물을 유효성분으로 포함하는 항바이러스용 약학 조성물; 단풍나무 추출물을 유효성분으로 포함하는 인플루엔자 바이러스 감염질환의 예방 또는 치료용 약학 조성물; 상기 약학 조성물을 인플루엔자 바이러스 감염질환 증상이 나타나거나 또는 나타날 우려가 있는 인간을 제외한 개체에 투여하는 단계를 포함하는 인플루엔자 바이러스 감염질환의 예방 또는 치료 방법; 단풍나무 추출물을 유효성분으로 포함하는 항바이러스용 건강기능식품 조성물, 의약외품 조성물, 사료조성물에 관한 것이다.The present invention provides an antiviral pharmaceutical composition containing maple tree extract as an active ingredient; A pharmaceutical composition for preventing or treating influenza virus infectious diseases containing maple tree extract as an active ingredient; A method for preventing or treating an influenza virus infectious disease, comprising administering the pharmaceutical composition to an entity other than a human that is exhibiting or at risk of exhibiting symptoms of the influenza virus infectious disease; It relates to an antiviral health functional food composition, quasi-drug composition, and feed composition containing maple tree extract as an active ingredient.
바이러스(virus)는 라틴어로 독성물질을 의미하며, 세균여과지(0.22㎛)를 통과하는 일군의 감염형 병원성 입자이다. 바이러스는 숙주세포의 종류에 따라 박테리오파지, 식물 바이러스, 동물 바이러스로 분류하기도 하며, 핵산의 종류에 따라 DNA 바이러스, RNA 바이러스로 분류할 수 있다. 최근 신종플루, AI 및 구제역 등 다양한 바이러스 질병이 사회적으로 큰 문제를 일으켰으며, 이에 따라 바이러스 질병의 효과적인 대책에 대한 고민이 사회적으로 큰 관심을 불러일으키고 있다.Virus means toxic substance in Latin and is a group of infectious pathogenic particles that pass through bacterial filter paper (0.22㎛). Viruses can be classified into bacteriophages, plant viruses, and animal viruses depending on the type of host cell, and into DNA viruses and RNA viruses depending on the type of nucleic acid. Recently, various viral diseases such as swine flu, AI, and foot-and-mouth disease have caused major social problems, and as a result, concerns about effective countermeasures against viral diseases are attracting great social interest.
현재 바이러스성 질병을 예방하기 위한 가장 좋은 방법은 백신접종이지만, 바이러스에 의한 질병의 경우, 대체로 많은 바이러스 혈청형(아형) 생성 등에 따른 백신의 효율성 문제가 중요하게 제기되고 있다. 이러한 백신의 문제점을 보완해 줄 수 있는 바이러스 예방용 억제제의 개발 및 보급은 중요한 사항이며, 이를 위해 특히 바이러스에 대한 초기 방어시스템인 생체 내 선천적 면역시스템을 자극하여 개체 동물의 면역력을 높여주는 예방제제의 발굴 및 개발은 중요한 제제 개발 방법이 될 수 있다.Currently, the best way to prevent viral diseases is vaccination, but in the case of diseases caused by viruses, there is an important issue raised about the effectiveness of vaccines due to the generation of many virus serotypes (subtypes). It is important to develop and distribute inhibitors for preventing viruses that can compensate for the problems of these vaccines, and for this purpose, preventive agents that increase the immunity of individual animals by stimulating the innate immune system in vivo, which is the initial defense system against viruses, The discovery and development of can be an important agent development method.
한편, 교통수단의 발달과 도시화에 따른 인구의 집중으로 인하여, 공기 중으로 전파되는 인플루엔자, 폐렴균 등에 의한 호흡기 감염성 질병이 공공에 심각한 위협이 되고 있다.Meanwhile, due to the development of transportation and concentration of population due to urbanization, respiratory infectious diseases caused by airborne influenza, pneumoniae, etc. are posing a serious threat to the public.
인플루엔자 바이러스(Influenza virus)는 오르소믹소 계통(Family Orthomyxoviridae)에 속하는 RNA 바이러스로서 혈청형은 A형, B형, C형 등 3가지로 구분된다. 인플루엔자바이러스의 증식을 억제하는 대표적인 항바이러스 제제로는 아만타딘(amantadine)과 리만타딘(rimantadine)이 있으나, 이들 두 가지 항바이러스 제제들은 혈청형 A형 인플루엔자바이러스에만 효과적이며, M2 단백질이 없는 혈청형 B형 인플루엔자바이러스에는 효과가 없는 것으로 확인되었다. 또한, 아만타딘과 리만타딘은 사용 시 인플루엔자바이러스 M2 단백질의 이온채널기능에 영향을 미치지 못하는 변이 바이러스의 출현이 매우 쉽게 일어나는 단점이 있는 것으로 확인되고 있다. 이러한 단점을 보완하기 위하여 16종의 모든 혈청형 A형 인플루엔자바이러스와 혈청형 B형 인플루엔자바이러스에 효과적인 항바이러스 제제로 자나미비르(zanamivir)와 오셀타미비르(oseltamivir)가 개발되었다. 그러나 자나미비르는 흡입 및 정맥 투여해야 하는 단점이 있으며, 오셀타미비르는 경구투여가 가능하나, 최근 내성 바이러스의 출현 보고와 경구투여 시 구토와 현기증 등의 부작용이 있어 단점으로 지적되고 있다.Influenza virus is an RNA virus belonging to the Orthomyxoviridae family and is divided into three serotypes: type A, type B, and type C. Representative antiviral agents that inhibit the proliferation of influenza viruses include amantadine and rimantadine, but these two antiviral agents are only effective against serotype A influenza viruses and serotype B viruses that do not have the M2 protein. It was confirmed to be ineffective against influenza viruses. In addition, it has been confirmed that amantadine and rimantadine have the disadvantage of very easily causing the emergence of mutant viruses that do not affect the ion channel function of the influenza virus M2 protein when used. To compensate for these shortcomings, zanamivir and oseltamivir were developed as antiviral agents effective against all 16 types of serotype A influenza virus and serotype B influenza virus. However, zanamivir has the disadvantage of having to be administered by inhalation and intravenous administration, and oseltamivir can be administered orally, but recent reports of the emergence of resistant viruses and side effects such as vomiting and dizziness during oral administration have been pointed out as disadvantages.
이러한 상황에서, 최근 해외 및 국내에서 기존의 항바이러스 제제의 단점을 극복하고자 하는 많은 노력들이 이루어지고 있으며, 그 중의 하나로 국내에서는 생약 추출물 및 식물 추출물을 대상으로 항바이러스 효능에 대한 연구가 진행중이기는 하지만, 아직까지는 미비한 실정이므로, 기존의 항바이러스 제제의 단점을 극복하여 독성 및 부작용이 거의 없이 우수한 선천면역 증진 효과 및 항바이러스 활성을 발휘할 수 있는 조성물의 개발이 필요한 실정이다.In this situation, many efforts have been made recently to overcome the shortcomings of existing antiviral agents both overseas and domestically, and as one of them, research on the antiviral efficacy of herbal medicine extracts and plant extracts is in progress in Korea. , Since it is still insufficient, there is a need to develop a composition that can overcome the shortcomings of existing antiviral agents and exhibit excellent innate immunity-enhancing effects and antiviral activity with little toxicity and side effects.
한편, 단풍나무(Acer palmatum Thunb.)는 낙엽 활목 교목으로, 한방에서는 단풍나무의 뿌리껍질과 가지를 해독 효과의 약재로 사용하고, 무릎관절염으로 통증이 심할 때 물에 넣고 달여서 복용하며, 골절상을 입었을 때 오가피를 배합해서 사용한다. 단풍나무의 치주질환 (KR 10-2021-0098887 A) 또는 전립선암 (KR 10-2021-0151509 A)에 대하여는 알려져 있으나, 항바이러스 활성에 관해 보고된 바 없다. Meanwhile, maple tree (Acer palmatum Thunb.) is a deciduous tree. In oriental medicine, the root bark and branches of maple tree are used as medicine for detoxification. When pain is severe due to knee arthritis, it is boiled in water and taken to treat fractures. When worn, it is used in combination with apricot ginseng. Maple trees are known to treat periodontal disease (KR 10-2021-0098887 A) or prostate cancer (KR 10-2021-0151509 A), but there has been no report on their antiviral activity.
이러한 배경 하에 본 발명자들은 신규한 인플루엔자 바이러스 치료제를 개발하기 위한 노력을 계속한 결과, 안정성이 보장된 단풍나무 추출물이 인플루엔자 바이러스 증식을 억제하는 우수한 효과가 있음을 확인함으로써, 본 발명을 완성하였다. Against this background, the present inventors continued their efforts to develop a novel influenza virus treatment agent and completed the present invention by confirming that a maple tree extract with guaranteed stability has an excellent effect in inhibiting the proliferation of influenza virus.
본 발명의 목적은 단풍나무 추출물을 유효성분으로 포함하는 항바이러스용 약학 조성물을 제공하는 것이다. The purpose of the present invention is to provide an antiviral pharmaceutical composition containing maple tree extract as an active ingredient.
본 발명의 다른 목적은 단풍나무 추출물을 유효성분으로 포함하는 인플루엔자 바이러스 감염질환의 예방 또는 치료용 약학 조성물을 제공하는 것이다. Another object of the present invention is to provide a pharmaceutical composition for preventing or treating influenza virus infectious diseases containing maple tree extract as an active ingredient.
본 발명의 또 다른 목적은 상기 약학 조성물을 인플루엔자 바이러스 감염질환 증상이 나타나거나 또는 나타날 우려가 있는 인간을 제외한 개체에 투여하는 단계를 포함하는 인플루엔자 바이러스 감염질환의 예방 또는 치료 방법을 제공하는 것이다.Another object of the present invention is to provide a method for preventing or treating influenza virus infectious disease, which includes the step of administering the pharmaceutical composition to an individual other than a human who is showing or is at risk of showing symptoms of an influenza virus infectious disease.
본 발명의 또 다른 목적은 단풍나무 추출물을 유효성분으로 포함하는 항바이러스용 건강기능식품 조성물을 제공하는 것이다.Another object of the present invention is to provide an antiviral health functional food composition containing maple tree extract as an active ingredient.
본 발명의 또 다른 목적은 단풍나무 추출물을 유효성분으로 포함하는 항바이러스용 의약외품 조성물을 제공하는 것이다. Another object of the present invention is to provide an antiviral quasi-drug composition containing maple tree extract as an active ingredient.
본 발명의 또 다른 목적은 단풍나무 추출물을 유효성분으로 포함하는 항바이러스용 사료 조성물을 제공하는 것이다.Another object of the present invention is to provide an antiviral feed composition containing maple tree extract as an active ingredient.
이를 구체적으로 설명하면 다음과 같다. 한편, 본 발명에서 개시된 각각의 설명 및 실시형태는 각각의 다른 설명 및 실시 형태에도 적용될 수 있다. 즉, 본 발명에서 개시된 다양한 요소들의 모든 조합이 본 발명의 범주에 속한다. 또한, 하기 기술된 구체적인 서술에 의하여 본 발명의 범주가 제한된다고 볼 수 없다.This is explained in detail as follows. Meanwhile, each description and embodiment disclosed in the present invention may also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Additionally, the scope of the present invention cannot be considered limited by the specific description described below.
또한, 당해 기술분야의 통상의 지식을 가진 자는 통상의 실험만을 사용하여 본 발명에 기재된 본 발명의 특정 양태에 대한 다수의 등가물을 인지하거나 확인할 수 있다. 또한, 이러한 등가물은 본 발명에 포함되는 것으로 의도된다.Additionally, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Additionally, such equivalents are intended to be encompassed by this invention.
본 발명의 하나의 양태는 단풍나무 추출물을 유효성분으로 포함하는 항바이러스용 약학 조성물을 제공한다.One aspect of the present invention provides an antiviral pharmaceutical composition containing maple tree extract as an active ingredient.
본 발명의 용어, "단풍나무"는 Acer palmatum Thunb.의 학명을 갖는 낙엽 활목 교목을 의미한다. 본 발명에서, 상기 단풍나무의 뿌리, 줄기, 잎, 열매, 꽃 등이 항바이러스용으로 사용될 수 있으며, 더욱 구체적으로 잎이 사용될 수 있으나, 항바이러스 효과를 갖는 한, 특별히 이에 제한되지 않는다. 또한, 상기 단풍나무는 상업적으로 판매되는 것을 구입하거나, 자연에서 채취 또는 재배된 것을 사용할 수 있다.As used herein, the term “maple tree” refers to a deciduous tree with the scientific name Acer palmatum Thunb. In the present invention, the roots, stems, leaves, fruits, flowers, etc. of the maple tree can be used for antiviral purposes, and more specifically, the leaves can be used, but there is no particular limitation thereto as long as it has an antiviral effect. Additionally, the maple tree can be purchased commercially, or collected or cultivated from nature.
본 발명의 용어, "항바이러스"는 바이러스 감역을 억제하는 성질을 말하며, 상기 "바이러스"란 동물, 식물, 세균 등 살아 있는 세포에 기생하고, 세포 안에서만 증식이 가능한 미생물을 의미한다. 본 발명에서 바이러스는 인플루엔자 바이러스일 수 있으나, 이에 제한되지 않는다. The term "antiviral" in the present invention refers to the property of suppressing viral immunity, and the "virus" refers to a microorganism that parasitizes living cells such as animals, plants, and bacteria and can proliferate only within the cells. In the present invention, the virus may be an influenza virus, but is not limited thereto.
본 발명에서, "인플루엔자 바이러스"는 오르소믹소 계통(Family Orthomyxoviridae)에 속하는 RNA 바이러스로서 혈청형은 A형, B형, C형 등 3가지로 구분된다. A형 인플루엔자 바이러스의 혈청형은 바이러스 표면의 두 가지 단백질인 해마글루티닌(Hemagglutinin: HA), 뉴라미니다제(Neuraminidase: NA)의 종류에 따라 구분되며, 혈청형에 따라 144종류(HA형 16종과 NA형 9종)로 분류할 수 있다. B, C형 바이러스의 경우 A형만큼 변이가 빠르게 일어나지 않기 때문에 이러한 구분수단을 따로 사용하지 않는다. 인플루엔자 바이러스는 독감, 감기, 인후염, 기관지염, 폐렴을 일으킬 수 있으며, 특히 조류독감, 돼지독감 또는 염소독감 등을 야기시킬 수 있다.In the present invention, “influenza virus” is an RNA virus belonging to the Orthomyxoviridae family, and its serotypes are divided into three types: type A, type B, and type C. The serotypes of influenza A virus are classified according to the types of two proteins on the surface of the virus, Hemagglutinin (HA) and Neuraminidase (NA), and there are 144 types (HA type) depending on the serotype. It can be classified into 16 types and 9 NA types. In the case of type B and C viruses, mutations do not occur as quickly as type A, so this means of classification is not used separately. Influenza viruses can cause flu, colds, sore throat, bronchitis, and pneumonia, and especially bird flu, swine flu, or goat flu.
본 발명에서 인플루엔자 바이러스는 인플루엔자 A타입 또는 인플루엔자 B 타입일 수 있으며, 구체적으로, H1N1, H2N2, H3N2, H3N8, H5N1, H5N6, H7N2, H7N3, H7N7, H7N9 또는 인플루엔자 바이러스 B일 수 있으나, 이에 제한되지 않는다. In the present invention, the influenza virus may be influenza A type or influenza B type, and specifically may be H1N1, H2N2, H3N2, H3N8, H5N1, H5N6, H7N2, H7N3, H7N7, H7N9, or influenza virus B, but is not limited thereto. No.
본 발명의 일 구현예에서, 단풍나무 잎 추출물과 인플루엔자 바이러스를 동시 감염시킨 후 관찰한 결과, 단풍나무 잎 추출물을 처리한 경우 바이러스 증식에 의한 형광 발현 정도가 대조군 대비 감소하였고 (도 4), 인플루엔자 바이러스 단백질 발현을 억제시키는 것을 확인하였다 (도 5). 뿐만 아니라, 단풍나무 잎 추출물은 세포사멸 효과를 감소시켜 Raw 264.7 세포생존률이 현저히 증가함을 확인하였다. 이를 통해, 단풍나무 잎 추출물이 인플루엔자 바이러스 감염 억제 효과가 우수함을 확인하였다.In one embodiment of the present invention, as a result of observation after co-infection with maple leaf extract and influenza virus, when treated with maple leaf extract, the degree of fluorescence expression due to virus proliferation decreased compared to the control group (FIG. 4), and influenza virus It was confirmed that viral protein expression was suppressed (Figure 5). In addition, it was confirmed that maple leaf extract reduced the cell death effect and significantly increased Raw 264.7 cell survival rate. Through this, it was confirmed that maple leaf extract has an excellent effect in suppressing influenza virus infection.
본 발명의 용어, "추출물"은 상기 단풍나무를 추출 처리하여 얻어지는 추출액, 상기 추출액의 희석액이나 농축액, 상기 추출액을 건조하여 얻어지는 건조물, 상기 추출액의 조정제물이나 정제물, 또는 이들의 혼합물 등, 추출액 자체 및 추출액을 이용하여 형성 가능한 모든 제형의 추출물을 포함한다.As used herein, the term "extract" refers to an extract obtained by extracting and processing the maple tree, a diluted or concentrated liquid of the extract, a dried product obtained by drying the extract, a crude product or purified product of the extract, or a mixture thereof, etc. It includes extracts of all formulations that can be formed on their own and using extracts.
상기 단풍나무를 추출하는 방법은 특별히 제한되지 않으며, 당해 기술 분야에서 통상적으로 사용하는 방법에 따라 추출할 수 있다. 상기 추출 방법의 비제한적인 예로는, 열수 추출법, 초음파 추출법, 상온 추출법, 냉침 추출법, 여과법, 환류 추출법, 증기 추출법 등을 들 수 있으며, 이들은 단독으로 수행되거나 2종 이상의 방법을 병용하여 수행될 수 있다.The method for extracting the maple tree is not particularly limited, and may be extracted according to a method commonly used in the art. Non-limiting examples of the extraction method include hot water extraction, ultrasonic extraction, room temperature extraction, cold needle extraction, filtration, reflux extraction, steam extraction, etc., which can be performed alone or by combining two or more methods. there is.
본 발명에서 상기 단풍나무를 추출하는데 사용되는 추출 용매의 종류는 특별히 제한되지 않으며, 당해 기술 분야에서 공지된 임의의 용매를 사용할 수 있다. 상기 추출 용매의 비제한적인 예로는 물, 탄소수 1 내지 4의 알코올 또는 이들의 혼합 용매 등을 들 수 있으며, 이들은 단독으로 사용되거나 1종 이상 혼합하여 사용될 수 있다. 구체적으로 물 또는 에탄올이 사용될 수 있지만, 이에 제한되는 것은 아니며, 상기 에탄올은 10 내지 99%, 더욱 구체적으로 20 내지 50% 에탄올일 수 있지만, 이에 제한되는 것은 아니다.In the present invention, the type of extraction solvent used to extract the maple tree is not particularly limited, and any solvent known in the art can be used. Non-limiting examples of the extraction solvent include water, alcohols having 1 to 4 carbon atoms, or mixed solvents thereof, and these may be used alone or in combination of one or more types. Specifically, water or ethanol may be used, but is not limited thereto, and the ethanol may be 10 to 99% ethanol, more specifically 20 to 50% ethanol, but is not limited thereto.
본 발명에서, 상기 단풍나무 추출물은 단풍나무 알코올 또는 열수 추출물인 것일 수 있고, 더욱 구체적으로 에탄올 추출물일 수 있으나, 항바이러스 효과를 나타내는 한, 이에 제한되지 않는다.In the present invention, the maple extract may be a maple alcohol or hot water extract, and more specifically may be an ethanol extract, but is not limited thereto as long as it exhibits an antiviral effect.
본 발명의 일 구현예에서는, 단풍나무 추출물을 제조하기 위하여, 단풍나무 잎 분쇄물을 에탄올에 넣고 실온 침적하여 추출한 뒤, 상기 추출물을 감압농축하고 동결건조하여 단풍나무 잎 에탄올 추출물을 제조하였으며, 마우스 대식 세포주 RAW 264.7 세포에 대하여 세포 독성이 없음을 확인하였다 (도 1).In one embodiment of the present invention, in order to prepare a maple extract, crushed maple leaves were placed in ethanol and extracted by immersion at room temperature, and then the extract was concentrated under reduced pressure and freeze-dried to prepare an ethanol extract of maple leaves. Mouse It was confirmed that there was no cytotoxicity against the macrophage cell line RAW 264.7 cells (Figure 1).
본 발명의 용어, "약학 조성물"은 총 조성물의 중량 대비 상기 단풍나무 추출물을 0.000001 내지 80 중량%로 포함할 수 있으며, 구체적으로 0.00001 중량% 내지 40 중량%로 포함할 수 있으나, 이에 제한되는 것은 아니다.The term "pharmaceutical composition" of the present invention may include 0.000001 to 80% by weight of the maple extract relative to the weight of the total composition, and may specifically include 0.00001 to 40% by weight, but is limited thereto. no.
상기 약학 조성물은 약학 조성물의 제조에 통상적으로 사용하는 약학적으로 허용가능한 담체, 부형제 또는 희석제를 추가로 포함할 수 있고, 상기 담체는 비자연적 담체(non-naturally occuring carrier)를 포함할 수 있다. The pharmaceutical composition may further include a pharmaceutically acceptable carrier, excipient, or diluent commonly used in the preparation of the pharmaceutical composition, and the carrier may include a non-naturally occurring carrier.
상기 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.The pharmaceutical composition can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injection solutions according to conventional methods.
상기 "약학적으로 허용가능한"은 상기 조성물에 노출되는 세포나 인간에게 독성이 없는 특성을 나타내는 것을 의미한다.The term “pharmaceutically acceptable” means that the composition exhibits non-toxic properties to cells or humans exposed to the composition.
구체적으로, 상기 담체의 종류는 특별히 제한되지 않으며, 당해 기술 분야에서 통상적으로 사용되고 약학적으로 허용되는 담체라면 어느 것이든 사용할 수 있다. 상기 담체의 비제한적인 예로, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사 용액, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 등을 들 수 있다. 이들은 단독으로 사용되거나 2종 이상을 혼합하여 사용될 수 있다. 또한, 필요한 경우 항산화제, 완충액 및/또는 정균제 등 다른 통상의 첨가제를 첨가하여 사용할 수 있으며, 희석제, 분산제, 계면 활성제, 결합제, 윤활제 등을 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제 등으로 제제화하여 사용할 수 있다.Specifically, the type of the carrier is not particularly limited, and any carrier commonly used in the art and pharmaceutically acceptable can be used. Non-limiting examples of the carrier include saline solution, sterile water, Ringer's solution, buffered saline solution, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, etc. These may be used alone or in combination of two or more types. In addition, if necessary, other common additives such as antioxidants, buffers, and/or bacteriostatic agents can be added and used, and diluents, dispersants, surfactants, binders, lubricants, etc. can be additionally added to form solutions such as aqueous solutions, suspensions, emulsions, etc. It can be formulated and used in dosage form, pills, capsules, granules, or tablets.
본 발명에 따른 항바이러스용 약학 조성물의 투여 방식은 특별히 제한되지 않으며, 당해 기술 분야에서 통상적으로 사용하는 방식에 따를 수 있다. 상기 투여 방식의 비제한적인 예로, 조성물을 경구 투여 또는 비경구 투여 방식으로 투여할 수 있다. 또한, 본 발명의 인플루엔자 바이러스 감염질환의 예방, 개선 또는 치료용 조성물은 목적하는 투여 방식에 따라 다양한 제형으로 제조될 수 있다.The administration method of the antiviral pharmaceutical composition according to the present invention is not particularly limited and may follow a method commonly used in the art. As a non-limiting example of the administration method, the composition may be administered by oral administration or parenteral administration. Additionally, the composition for preventing, improving, or treating influenza virus infectious diseases of the present invention may be prepared in various formulations depending on the desired administration method.
본 발명의 다른 하나의 양태는 단풍나무 추출물을 유효성분으로 포함하는 인플루엔자 바이러스 감염질환의 예방 또는 치료용 약학 조성물을 제공한다. Another aspect of the present invention provides a pharmaceutical composition for preventing or treating influenza virus infectious diseases containing maple tree extract as an active ingredient.
상기 "단풍나무", "항바이러스", "인플루엔자 바이러스", "추출물" 및 "약학 조성물"은 전술한 바와 같다. The “maple tree”, “antiviral”, “influenza virus”, “extract” and “pharmaceutical composition” are as described above.
본 발명의 용어, "감염질환"은 감염에 의해 발병되는 질환을 의미한다.As used herein, the term “infectious disease” refers to a disease caused by infection.
본 발명에서 "감염"은 병원성 미생물이 숙주가 되는 생물체의 체내에 침입하여, 발육ㆍ증식한 상태를 의미한다.In the present invention, “infection” refers to a state in which pathogenic microorganisms invade the body of a host organism and grow and proliferate.
본 발명의 용어, "예방"은 단풍나무 추출물을 포함하는 본 발명의 약학 조성물의 투여에 의해 바이러스 감염질환을 억제시키거나 또는 지연시키는 모든 행위를 의미한다.The term "prevention" of the present invention refers to all actions that suppress or delay viral infectious diseases by administering the pharmaceutical composition of the present invention containing maple tree extract.
본 발명의 용어, "치료"는 상기 약학 조성물의 투여에 의해 바이러스 감염질환이 호전되거나 이롭게 변경되는 모든 행위를 의미한다.As used herein, the term “treatment” refers to any action in which a viral infectious disease is improved or beneficially altered by administration of the pharmaceutical composition.
본 발명의 다른 하나의 양태는, 상기 약학 조성물을 인플루엔자 바이러스 감염질환 증상이 나타나거나 또는 나타날 우려가 있는 인간을 제외한 개체에 투여하는 단계를 포함하는 인플루엔자 바이러스 감염질환의 예방 또는 치료 방법을 제공한다. Another aspect of the present invention provides a method for preventing or treating an influenza virus infection disease, including the step of administering the pharmaceutical composition to an entity other than a human that is showing or is at risk of showing symptoms of an influenza virus infection disease.
상기 "단풍나무", "항바이러스", "인플루엔자 바이러스", "추출물", "약학 조성물", "감염질환", "예방" 및 "치료"는 전술한 바와 같다. The terms “maple tree,” “antivirus,” “influenza virus,” “extract,” “pharmaceutical composition,” “infectious disease,” “prevention,” and “treatment” are as described above.
본 발명의 용어, "투여"는 적절한 방법으로 개체에게 소정의 물질을 도입하는 것을 의미한다. As used herein, the term “administration” means introducing a given substance into a subject by an appropriate method.
본 발명의 용어, "개체"는 인플루엔자 바이러스 감염질환이 발병하였거나, 발병할 수 있는 인간을 포함한 쥐, 생쥐, 가축 등의 모든 동물을 의미한다. 구체적인 예로, 인간을 포함한 포유동물일 수 있다.As used herein, the term “individual” refers to all animals, including rats, mice, and livestock, including humans, that have or may develop an influenza virus infectious disease. As a specific example, it may be a mammal, including humans.
구체적으로, 본 발명의 인플루엔자 바이러스 감염질환의 예방 또는 치료 방법은 인간을 제외한 개체에 단풍나무 추출물을 포함하는 약학 조성물을 약학적으로 유효한 양으로 투여하는 단계를 포함할 수 있다.Specifically, the method for preventing or treating an influenza virus infectious disease of the present invention may include administering a pharmaceutical composition containing a maple tree extract in a pharmaceutically effective amount to an entity other than a human.
본 발명의 용어, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효 용량 수준은 환자의 성별, 연령, 체중, 건강상태, 질병의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로, 및 배출 비율, 치료 기간, 배합 또는 동시에 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 당업자에 의해 용이하게 결정될 수 있다.As used herein, the term "pharmaceutically effective amount" refers to an amount that is sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment and does not cause side effects, and the effective dose level is determined by the patient's gender, Factors including age, weight, health status, type and severity of the disease, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration, and excretion rate, duration of treatment, drugs combined or used simultaneously, and other medical factors. It can be easily determined by a person skilled in the art according to factors well known in the art.
본 발명의 약학 조성물은 고형분을 기준으로 1일 0.000001 내지 100 mg/체중 kg으로, 더욱 구체적으로 0.0001 내지 100 mg/체중 kg으로 투여할 수 있다. 투여는 상기 권장 투여량을 하루에 한 번 투여할 수도 있고, 수회 나누어 투여할 수도 있다.The pharmaceutical composition of the present invention can be administered at 0.000001 to 100 mg/kg of body weight per day, more specifically 0.0001 to 100 mg/kg of body weight, based on solid content. The recommended dosage may be administered once a day, or it may be administered several times.
본 발명의 약학 조성물은 개별 치료제로 투여되거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다. 또한, 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용을 유발하지 않으면서 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. Additionally, it can be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve maximum effect with the minimum amount without causing side effects, and this can be easily determined by a person skilled in the art.
본 발명의 인플루엔자 바이러스 감염질환의 예방 또는 치료 방법에서, 상기 조성물을 투여하는 투여 경로 및 투여 방식은 특별히 제한되지 않으며, 목적하는 해당 부위에 상기 조성물을 포함하는 조성물이 도달할 수 있는 한 임의의 투여 경로 및 투여 방식에 따를 수 있다. 구체적으로, 상기 조성물은 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있으며, 그 투여 경로의 비제한적인 예로는, 구강, 직장, 국소, 정맥내, 복강내, 근육내, 동맥내, 경피, 비측내 또는 흡입 등을 통하여 투여되는 것을 들 수 있다. 본 발명의 단풍나무 추출물이 인플루엔자 바이러스 감염질환의 예방 또는 치료에 효과가 있는 특성상, 조성물의 투여 경로는 경구를 통하여 투여될 수 있다.In the method for preventing or treating influenza virus infectious diseases of the present invention, the administration route and method of administering the composition are not particularly limited, and any administration may be performed as long as the composition containing the composition can reach the target site. It may depend on the route and method of administration. Specifically, the composition may be administered through various oral or parenteral routes, and non-limiting examples of the administration route include oral, rectal, topical, intravenous, intraperitoneal, intramuscular, intraarterial, transdermal, and nasal. It may be administered intralaterally or through inhalation. Because the maple extract of the present invention is effective in preventing or treating influenza virus infectious diseases, the composition may be administered orally.
본 발명의 다른 하나의 양태는 단풍나무 추출물을 유효성분으로 포함하는 항바이러스용 건강기능식품 조성물을 제공한다. Another aspect of the present invention provides an antiviral health functional food composition containing maple tree extract as an active ingredient.
상기 "단풍나무", "항바이러스", "인플루엔자 바이러스" 및 "추출물"은 전술한 바와 같다. The “maple tree”, “antiviral”, “influenza virus” and “extract” are as described above.
본 발명의 용어, "건강기능식품"(functional food)은 특정보건용 식품(food for special health use, FoSHU)과 동일한 용어로, 영양 공급 외에도 생체조절기능이 효율적으로 나타나도록 가공된 의학, 의료효과가 높은 식품을 의미한다. 본 발명에서, 상기 건강기능식품은 건강식품 또는 건강보조식품과 호용된다.The term "functional food" of the present invention is the same as food for special health use (FoSHU), and is a medicine processed to efficiently exhibit bioregulatory functions in addition to nutritional supply, and medical effects. refers to foods with high . In the present invention, the health functional food is compatible with health food or health supplement food.
본 발명의 건강기능식품 조성물은 일상적으로 섭취하는 것이 가능하기 때문에 높은 인플루엔자 바이러스 감염질환 개선 효과를 기대할 수 있으므로, 건강 증진 목적으로 매우 유용하게 사용될 수 있다.Since the health functional food composition of the present invention can be consumed on a daily basis, it can be expected to have a high effect on improving influenza virus infectious diseases, so it can be very useful for health promotion purposes.
이때, 상기 건강기능식품 조성물에 포함되는 추출물의 함량은 특별히 이에 제한되지 않으나, 건강기능식품 조성물의 총 중량에 대하여 0.01 내지 100 중량%, 보다 바람직하게는 1 내지 80 중량%로 포함될 수 있다.At this time, the content of the extract included in the health functional food composition is not particularly limited, but may be included in 0.01 to 100% by weight, more preferably 1 to 80% by weight, based on the total weight of the health functional food composition.
상기 건강기능식품은 인플루엔자 바이러스 감염질환의 예방 또는 개선에 유용한 효과를 얻기 위하여 환제, 분말, 과립, 침제, 정제, 캡슐 및 음료 형태로 이루어지는 군에서 선택되는 것으로 제형화된 것으로 제조될 수 있다. 본 발명의 단풍나무 추출물을 포함하는 조성물을 첨가할 수 있는 식품의 종류에는 별다른 제한이 없으며, 예를 들어 각종 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있다. The health functional food may be manufactured in a form selected from the group consisting of pills, powders, granules, precipitates, tablets, capsules and beverages in order to obtain useful effects in preventing or improving influenza virus infectious diseases. There is no particular limitation on the type of food to which the composition containing the maple extract of the present invention can be added, for example, various beverages, gum, tea, vitamin complexes, health supplements, etc.
상기 건강기능식품 조성물에는 건강기능식품의 예방 또는 개선 효과에 방해가 되지 않는 다른 성분을 추가할 수 있으며, 그 종류는 특별히 제한되지 않는다. 예를 들어, 통상의 식품과 같이 여러 가지 생약 추출물, 식품학적으로 허용 가능한 식품보조첨가제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다.Other ingredients that do not interfere with the preventive or improving effect of the health functional food may be added to the health functional food composition, and their types are not particularly limited. For example, like regular foods, it may contain various herbal extracts, foodologically acceptable food additives, or natural carbohydrates as additional ingredients.
또한, 상기 건강기능식품 조성물은 식품학적으로 허용가능한 담체를 추가로 포함할 수 있으며, 이는 당업자가 적절히 선택하여 사용할 수 있다. 예를 들어 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등이 포함되지만, 상기 예들에 의해 그 종류가 제한되는 것은 아니다.In addition, the health functional food composition may further include a foodologically acceptable carrier, which can be appropriately selected and used by a person skilled in the art. For example, various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavors, colorants and fillers, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters. , stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated drinks, etc., but the types are not limited to the above examples.
또한, 상기 건강기능식품 조성물은 식품 조성물에 통상 사용되어 냄새, 맛, 시각 등을 향상시킬 수 있는 추가 성분을 포함할 수 있다. 예를 들어, 비타민 A, C, D, E, B1, B2, B6, B12, 니아신(niacin), 비오틴(biotin), 폴레이트(folate), 판토텐산(panthotenic acid) 등을 포함할 수 있다. 또한, 아연(Zn), 철(Fe), 칼슘(Ca), 크롬(Cr), 마그네슘(Mg), 망간(Mn), 구리(Cu) 등의 미네랄을 포함할 수 있다. 또한, 라이신, 트립토판, 시스테인, 발린 등의 아미노산을 포함할 수 있다. In addition, the health functional food composition may include additional ingredients that are commonly used in food compositions to improve smell, taste, vision, etc. For example, it may include vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, pantothenic acid, etc. Additionally, it may contain minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), and copper (Cu). Additionally, it may contain amino acids such as lysine, tryptophan, cysteine, and valine.
또한, 방부제(소르빈산 칼륨, 벤조산나트륨, 살리실산, 데히드로초산나트륨 등), 살균제(표백분과 고도 표백분, 차아염소산나트륨 등), 산화방지제(부틸히드록시아니졸(BHA), 부틸히드록시톨류엔(BHT) 등), 착색제(타르색소 등), 발색제(아질산 나트륨, 아초산 나트륨 등), 표백제(아황산나트륨), 조미료(MSG 글루타민산나트륨 등), 감미료(둘신, 사이클레메이트, 사카린, 나트륨 등), 향료(바닐린, 락톤류 등), 팽창제(명반, D-주석산수소칼륨 등), 강화제, 유화제, 증점제(호료), 피막제, 검기초제, 거품억제제, 용제, 개량제 등의 식품 첨가물(food additives)을 첨가할 수 있다.In addition, preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), disinfectants (bleaching powder, high bleaching powder, sodium hypochlorite, etc.), antioxidants (butylhydroxyanisole (BHA), butylhydroxytoluene ( BHT), etc.), colorants (tar color, etc.), coloring agents (sodium nitrite, sodium nitrite, etc.), bleaching agents (sodium sulfite), seasonings (MSG monosodium glutamate, etc.), sweeteners (dulcine, cyclemate, saccharin, sodium, etc.) , food additives such as flavorings (vanillin, lactones, etc.), leavening agents (alum, D-potassium hydrogen tartrate, etc.), strengthening agents, emulsifiers, thickeners (grease), coating agents, gum base agents, anti-foam agents, solvents, improvers, etc. ) can be added.
본 발명의 다른 하나의 양태는 단풍나무 추출물을 유효성분으로 포함하는 항바이러스용 의약외품 조성물을 제공한다.Another aspect of the present invention provides an antiviral quasi-drug composition containing maple tree extract as an active ingredient.
상기 "단풍나무", "항바이러스", "인플루엔자 바이러스" 및 "추출물"은 전술한 바와 같다.The “maple tree”, “antiviral”, “influenza virus” and “extract” are as described above.
본 발명의 용어, "의약외품"은 사람이나 동물의 질병을 진단, 치료, 개선, 경감, 처치 또는 예방할 목적으로 사용되는 물품들 중 의약품보다 작용이 경미한 물품들을 의미한다. 예를 들어, 약사법에 따른 의약외품은 의약품의 용도로 사용되는 물품을 제외한 것으로, 사람/동물의 질병 치료나 예방에 쓰이는 제품, 인체에 대한 작용이 경미하거나 직접 작용하지 않는 제품 등이 포함된다.The term "quasi-drug" in the present invention refers to products that have a milder effect than pharmaceuticals among products used for the purpose of diagnosing, treating, improving, alleviating, treating, or preventing diseases in humans or animals. For example, quasi-drugs under the Pharmaceutical Affairs Act exclude products used for pharmaceutical purposes and include products used to treat or prevent diseases in humans and animals, and products that have a mild or no direct effect on the human body.
본 발명에 따른 단풍나무 추출물을 의약외품 첨가물로 사용할 경우, 상기 조성물을 그대로 첨가하거나 다른 의약외품 또는 의약외품 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 유효성분의 혼합량은 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다.When using the maple extract according to the present invention as a quasi-drug additive, the composition can be added as is or used together with other quasi-drugs or quasi-drug ingredients, and can be used appropriately according to conventional methods. The mixing amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment).
상기 의약외품 조성물은 특별히 이에 제한되지 않으나, 개인위생용품, 소독청결제 또는 연고제를 포함한다. 상기 개인위생용품에는 특별히 이에 제한되지 않으나, 구체적으로 치약, 가글, 세정 겔 또는 틀니 등의 보철제에 대한 보관제가 포함될 수 있다. 또한, 상기 의약외품 조성물은 특별히 이에 제한되지 않으나, 구체적으로 연고제, 로션제, 스프레이제, 패취제, 크림제, 산제, 현탁제, 겔제 또는 젤의 형태로 제조되어 사용될 수 있다.The quasi-drug composition is not particularly limited thereto, but includes personal hygiene products, disinfectant cleaners, or ointments. The personal hygiene products are not particularly limited thereto, but may specifically include toothpaste, gargles, cleaning gels, or preservatives for prosthetics such as dentures. In addition, the quasi-drug composition is not particularly limited thereto, but may be specifically manufactured and used in the form of ointment, lotion, spray, patch, cream, powder, suspension, gel, or gel.
본 발명의 다른 하나의 양태는 단풍나무 추출물을 유효성분으로 포함하는 항바이러스용 사료 조성물을 제공한다.Another aspect of the present invention provides an antiviral feed composition containing maple tree extract as an active ingredient.
상기 "단풍나무", "항바이러스", "인플루엔자 바이러스" 및 "추출물"은 전술한 바와 같다.The “maple tree”, “antiviral”, “influenza virus” and “extract” are as described above.
본 발명의 용어, "사료"는 동물이 먹고, 섭취하며, 소화시키기 위한 또는 이에 적당한 임의의 천연 또는 인공 규정식, 한끼식 등 또는 상기 한끼식의 성분을 의미한다.As used herein, the term "feed" means any natural or artificial diet, meal, etc., or a component of the meal, for or suitable for eating, ingestion, and digestion by animals.
상기 사료의 종류는 특별히 제한되지 아니하며, 당해 기술 분야에서 통상적으로 사용되는 사료를 사용할 수 있다. 상기 사료의 비제한적인 예로는, 곡물류, 근과류, 식품 가공 부산물류, 조류, 섬유질류, 제약 부산물류, 유지류, 전분류, 박류 또는 곡물 부산물류 등과 같은 식물성 사료; 단백질류, 무기물류, 유지류, 광물성류, 유지류, 단세포 단백질류, 동물성 플랑크톤류 또는 음식물 등과 같은 동물성 사료를 들 수 있다. 이들은 단독으로 사용되거나 2종 이상을 복합하여 사용될 수 있다.The type of feed is not particularly limited, and feed commonly used in the art can be used. Non-limiting examples of the feed include plant feeds such as grains, roots and fruits, food processing by-products, algae, fiber, pharmaceutical by-products, oils and fats, starches, cucurbits or grain by-products; Examples include animal feeds such as proteins, inorganic substances, fats and oils, minerals, oils and fats, single-cell proteins, zooplanktons or foods. These may be used singly or in combination of two or more types.
본 발명에 따른 단풍나무 추출물은 세포에 독성이 없으며, 인플루엔자 바이러스의 감염을 억제하는 효과를 나타내므로, 인플루엔자 바이러스에 의한 감염증의 예방 또는 치료를 위한 항바이러스제 개발에 이용될 수 있다.The maple extract according to the present invention is not toxic to cells and has an effect of inhibiting influenza virus infection, so it can be used to develop an antiviral agent for preventing or treating infections caused by influenza virus.
도 1은 단풍나무 잎 추출물의 마우스 대식 세포 RAW 264.7 세포에 대한 농도별 독성을 CCK 시약을 처리하여 확인한 결과를 나타낸 그래프이다.
도 2는 단풍나무 잎 추출물의 인플루엔자 바이러스(PR8-GFP)에 대한 억제 효능을 확인한 형광현미경으로 사진이다.
도 3는 도 2에서 형광현미경으로 관찰한 각 세포를 유세포분석기를 사용하여 GFP 발현 정도를 분석한 결과를 나타낸 그래프이다.
도 4는 도 3의 GFP 단백질의 형광값을 수치화하여 비교 분석한 그래프이다.
도 5은 바이러스 단백질 M2, NP, HA, NA 발현 면역형광염색법으로 확인 결과를 나타낸 사진이다.
도 7은 단풍나무 잎 추출물을 인플루엔자 H1N1, H3N2, 인플루엔자 바이러스 B (IBV)에 대한 억제 효능을 나타낸 그래프이다.Figure 1 is a graph showing the results of confirming the toxicity of maple leaf extract to mouse macrophage RAW 264.7 cells by treatment with CCK reagent.
Figure 2 is a fluorescence microscope photograph confirming the inhibitory effect of maple leaf extract on influenza virus (PR8-GFP).
Figure 3 is a graph showing the results of analyzing the level of GFP expression in each cell observed with a fluorescence microscope in Figure 2 using a flow cytometer.
Figure 4 is a graph comparing and analyzing the numerical fluorescence values of the GFP protein of Figure 3.
Figure 5 is a photograph showing the results confirmed by immunofluorescence staining for the expression of viral proteins M2, NP, HA, and NA.
Figure 7 is a graph showing the inhibitory efficacy of maple leaf extract against influenza H1N1, H3N2, and influenza virus B (IBV).
이하 본 발명을 실시예 및 실험예를 통하여 보다 상세하게 설명한다. 그러나 이들 실시예 및 실험예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예 및 실험예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples and experimental examples. However, these examples and experimental examples are for illustrative purposes only and the scope of the present invention is not limited to these examples and experimental examples.
실험예 1. 단풍나무 잎 추출물 제조Experimental Example 1. Preparation of maple leaf extract
단풍나무 잎 분쇄물 1700g을 17L의 25% 에탄올에 넣고 24시간 실온 침적하여 추출하였다. 그 후, 상기 추출물을 감압농축하고 동결건조하여 단풍나무 잎 25% 에탄올 추출물(이하, 'KIOM-2015E'로 명명함) 78.57g을 수득하였다.1700 g of maple leaf pulverization was added to 17 L of 25% ethanol and soaked at room temperature for 24 hours for extraction. Afterwards, the extract was concentrated under reduced pressure and freeze-dried to obtain 78.57g of maple leaf 25% ethanol extract (hereinafter referred to as 'KIOM-2015E').
실시예 1: RAW 264.7 세포 배양Example 1: RAW 264.7 cell culture
본 발명의 단풍나무 잎 추출물의 항 바이러스 효능 실험을 위해, 마우스 대식 세포주 RAW 264.7 세포를 준비하여 10% 소 태아 혈청 (Fetal bovine serum, FBS), 100 U/ml 페니실린 (penicillin) 및 100 μg/ml 스트렙토마이신 (streptomycin)이 포함된 RPMI-1640 배지 (Hyclone)를 사용하여 배양하였다. 상기 세포는 37℃, 95% 습도, 5% CO2 조건의 배양기에서 배양하였으며 2 내지 3일마다 새로운 배양액으로 계대 배양하였다.To test the antiviral efficacy of the maple leaf extract of the present invention, mouse macrophage cell line RAW 264.7 cells were prepared and added with 10% fetal bovine serum (FBS), 100 U/ml penicillin, and 100 μg/ml. Culture was performed using RPMI-1640 medium (Hyclone) containing streptomycin. The cells were cultured in an incubator at 37°C, 95% humidity, and 5% CO2, and subcultured with new culture medium every 2 to 3 days.
실시예 2: 단풍나무 잎 추출물의 세포 독성 분석Example 2: Cytotoxicity analysis of maple leaf extract
단풍나무 잎 추출물의 세포 독성이 없는 농도를 확인하기 위하여, RAW 264.7 세포를 96 well 세포 플레이트 seeding하였고 (1 x 105/ well), 단풍나무 잎 추출물을 1 μg/ml, 10 μg/ml, 50 μg/ml, 100 μg/ml, 200 μg/ml, 500 μg/ml, 1000 μg/ml 농도로 24시간 처리하였다. 24시간 배양 후, CCK-8 시약을 10 μl 넣고 2시간 반응시킨 후 450nm 파장에서 흡광도를 측정하였다 (도 1). To confirm the non -cytotoxic concentration of maple leaf extract, RAW 264.7 cells were seeded in a 96 well cell plate (1 It was treated at concentrations of μg/ml, 100 μg/ml, 200 μg/ml, 500 μg/ml, and 1000 μg/ml for 24 hours. After 24 hours of incubation, 10 μl of CCK-8 reagent was added, reacted for 2 hours, and absorbance was measured at a wavelength of 450 nm (Figure 1).
그 결과, 1 μg/ml 내지 500 μg/ml 농도에서 세포독성이 없음을 확인하였다. 본 발명의 단풍나무 추출물은 인플루엔자 바이러스 억제함에 있어 독성 없이 안전하게 사용될 수 있음을 알 수 있었다. As a result, it was confirmed that there was no cytotoxicity at a concentration of 1 μg/ml to 500 μg/ml. It was found that the maple extract of the present invention can be used safely without toxicity in suppressing influenza viruses.
실시예 3: 단풍나무 잎 추출물의 항바이러스 효능 확인Example 3: Confirmation of antiviral efficacy of maple leaf extract
단풍나무 잎 추출물의 인플루엔자 바이러스 감염에 억제 효능을 확인하기 위해 형광 현미경을 이용하여 확인하였으며, 구체적인 실험 방법은 하기와 같다.In order to confirm the inhibitory effect of maple leaf extract on influenza virus infection, it was confirmed using a fluorescence microscope, and the specific experimental method is as follows.
12-well 플레이트에 Raw 264.7 세포(5X105 cell/well)를 배양한 후, 상기 실험예 1에서 제조한 단풍나무 잎 추출물 10 μg/ml, 50 μg/ml, 또는 100 μg/ml와 형광 단백질 (green fluorescence protein; gfp)를 부착한 인플루엔자 바이러스 (PR8-GFP)를 동시 감염시키고, 24시간 후 바이러스의 복제(replication)를 gfp 형광 발현을 통해 관찰하였다 (도 2). After culturing Raw 264.7 cells ( 5 Influenza virus (PR8-GFP) attached with green fluorescent protein (gfp) was co-infected, and 24 hours later, virus replication was observed through gfp fluorescence expression (Figure 2).
이어서, 상기 세포를 원심분리하여 모아서 4% 파라포름알데하이드 용액으로 고정한 후, PBS (Phosphate buffered saline) 용액에 재현탁하여 유세포분석기 (FACS, Fluorescence activated cell sorter)를 활용하여 형광의 발현 정도를 분석하였으며 (도 3), 상기 유세포분석기로 얻은 형광값을 수치화하여 PR8-GFP 바이러스에 의한 형광값을 1로 기준으로 하여 상대적으로 비교 분석하였다 (도 4).Next, the cells were collected by centrifugation, fixed with 4% paraformaldehyde solution, resuspended in PBS (Phosphate buffered saline) solution, and the level of fluorescence was analyzed using a flow cytometer (FACS, Fluorescence activated cell sorter). (FIG. 3), the fluorescence values obtained by the flow cytometer were quantified and compared and analyzed relative to the fluorescence value caused by the PR8-GFP virus as 1 (FIG. 4).
Mock은 음성 대조군, PR8-GFP는 인플루엔자 바이러스 감염군, PR8-GFP/단풍나무 잎 10 μg/ml은 바이러스와 단풍나무 잎 10 μg/ml 동시처리군, PR8-GFP/단풍나무 잎 50 μg/ml은 바이러스와 단풍나무 잎 50 μg/ml 동시처리군, PR8-GFP/단풍나무 잎 100 μg/ml은 바이러스와 단풍나무 잎 100 μg/ml 동시처리군을 나타낸다. Mock is the negative control group, PR8-GFP is the influenza virus infection group, PR8-GFP/maple leaf 10 μg/ml is the virus and maple leaf 10 μg/ml co-treatment group, PR8-GFP/maple leaf 50 μg/ml represents a group co-treated with virus and maple leaf 50 μg/ml, and PR8-GFP/maple leaf 100 μg/ml represents a group co-treated with virus and maple leaf 100 μg/ml.
그 결과, 단풍나무 잎 추출물과 인플루엔자 바이러스를 동시에 감염시킨 경우, 농도의존적으로 바이러스 증식에 의한 형광이 감소되는 것을 확인하였으며, 특히 단풍나무 잎 추출물 50 μg/ml 농도 이상에서 인플루엔자 바이러스에 의한 GFP 형광값이 현저히 감소함을 확인하였다. 따라서 본 발명의 단풍나무 잎 추출물이 효과적으로 인플루엔자 바이러스의 감염률을 억제하는 효능이 있음을 확인하였다. As a result, it was confirmed that when the maple leaf extract and the influenza virus were simultaneously infected, the fluorescence due to virus proliferation decreased in a concentration-dependent manner. In particular, the GFP fluorescence value caused by the influenza virus increased at a concentration of 50 μg/ml or higher of the maple leaf extract. It was confirmed that this significantly decreased. Therefore, it was confirmed that the maple leaf extract of the present invention has the effect of effectively suppressing the infection rate of influenza virus.
실시예 4: 형광면역분석법 (Immuno fluorescence technique)을 통한 인플루엔자 바이러스 단백질 발현 억제 효능 확인Example 4: Confirmation of efficacy of suppressing influenza virus protein expression through fluorescence immunoassay (Immuno fluorescence technique)
단풍나무 잎 추출물의 인플루엔자 바이러스에 대한 항바이러스의 효능이 확인됨에 따라 단풍나무 잎 추출물이 바이러스 단백질 발현에도 영향을 미치는지 여부를 형광면역분석법을 이용하여 확인하였으며, 구체적인 실험 방법은 하기와 같다. As the antiviral efficacy of maple leaf extract against influenza virus was confirmed, it was confirmed using fluorescence immunoassay whether maple leaf extract also affects viral protein expression, and the specific experimental method is as follows.
12-well 플레이트에 Raw 264.7 세포(5X105 cell/well)를 배양한 후, 상기 실험예 1에서 제조한 단풍나무 잎 추출물 100 μg/ml와 인플루엔자 바이러스 (PR8-GFP)를 Raw 264.7 세포에 동시에 처리하여 24시간 감염시킨 후 세포를 PBS로 세척하였다. 그 후, 100% 차가운 메탄올 용액에 5분, 3.7% 포르말린 용액에 10분간 고정하였다. 1% BSA와 0.05% tween-20이 함유된 PBS 용액에서 1시간 blocking, 바이러스 단백질 M2 (Matrix protein 2), NP (Nucleoprotein), HA (Hemagglutinin), NA (Neuraminidase))에 대한 1차 항체에 실온에서 1시간 반응시킨 후 PBS로 3번 세척한 후 Alexa594가 결합된 2차 항체와 1시간 반응하였다 (Red 형광). PBS로 3번 세척한 후 hoechst 33342 용액을 첨가하여 핵을 염색한 후 (blue 형광), 형광현미경으로 merge하여 두 가지 색의 형광을 겹쳐서 확인하였다 (도 5). After culturing Raw 264.7 cells ( 5 After infection for 24 hours, the cells were washed with PBS. Afterwards, it was fixed in a 100% cold methanol solution for 5 minutes and in a 3.7% formalin solution for 10 minutes. Blocked for 1 hour in a PBS solution containing 1% BSA and 0.05% tween-20, incubated with primary antibodies against viral proteins M2 (Matrix protein 2), NP (Nucleoprotein), HA (Hemagglutinin), and NA (Neuraminidase) at room temperature. After reacting for 1 hour, the reaction mixture was washed three times with PBS and then reacted with Alexa594-conjugated secondary antibody for 1 hour (Red fluorescence). After washing three times with PBS, hoechst 33342 solution was added to stain the nuclei (blue fluorescence), and then merged under a fluorescence microscope to confirm the two colors of fluorescence overlapping (Figure 5).
Hoechst 33342는 세포의 핵을 염색하며, Merge는 핵과 바이러스 단백질의 위치를 동시에 표시한 것이고, Brightfield는 일반현미경으로 세포를 확인한 결과이다. Medium은 음성 대조군, PR8-GFP은 인플루엔자 바이러스 감염군, PR8-GFP/단풍나무 잎은 바이러스와 단풍나무 잎 200 μg/ml을 동시에 처리한 군을 나타낸다.Hoechst 33342 stains the nucleus of a cell, Merge simultaneously marks the location of the nucleus and viral proteins, and Brightfield is the result of checking the cell under a general microscope. Medium represents the negative control group, PR8-GFP represents the influenza virus infection group, and PR8-GFP/maple leaf represents the group simultaneously treated with the virus and 200 μg/ml of maple leaf.
그 결과, 단풍나무 잎 추출물과 인플루엔자 바이러스를 동시에 감염시킨 경우, 바이러스 단백질 M2, NP, HA, NA 모두 현저히 감소되었음을 알 수 있는바, 단풍나무 잎 추출물에 의해 바이러스 단백질의 발현이 억제됨을 확인하였다. 본 발명의 단풍나무 잎 추출물이 효과적으로 바이러스 단백질의 발현을 억제함으로 항바이러스 효능이 있음을 확인하였다. As a result, when the maple leaf extract and the influenza virus were simultaneously infected, the viral proteins M2, NP, HA, and NA were all significantly reduced, confirming that the expression of the viral protein was suppressed by the maple leaf extract. It was confirmed that the maple leaf extract of the present invention has antiviral efficacy by effectively inhibiting the expression of viral proteins.
실시예 5: 인플루엔자 A 타입의 H1N1, H3N2와 인플루엔자 B에 의한 세포살상효과 (CPE, cytopathic effect) 억제 효능 확인Example 5: Confirmation of efficacy in suppressing cytopathic effect (CPE) caused by influenza A type H1N1, H3N2 and influenza B
바이러스에 감염된 세포가 죽으면서 나타나는 형태적 변화를 세포살상 현상 (CPE)이라 하고, 단풍나무 잎 추출물이 인플루엔자 바이러스에 의한 CPE가 억제되어 세포 생존률이 증가하는지 확인하기 위하여 CCK-8 어세이를 진행하였는바, 구체적인 실험 방법은 하기와 같다. The morphological change that occurs when virus-infected cells die is called cell killing phenomenon (CPE), and a CCK-8 assay was performed to determine whether maple leaf extract increases cell survival rate by inhibiting CPE caused by influenza virus. Well, the specific experimental method is as follows.
12-well 플레이트에 Raw 264.7 세포(5X105cell/well)를 배양한 후, 단풍나무 잎 추출물 0, 10 μg/ml, 50 μg/ml, 100 μg/ml, 또는 200 μg/ml와 인플루엔자 바이러스A의 H1N1 야생형 바이러스, H3N2 타입, 또는 인플루엔자 바이러스 B (IBV)와 동시 감염시켰다. 그 후, 24시간 배양한 세포에 CCK-8 용액을 넣어서 2시간 반응시킨 후, 450nm 파장에서 흡광도를 측정하였으며, 세포의 생존률을 배지에 대한 백분율로 나타내었다 (도 6). After culturing Raw 264.7 cells ( 5 were co-infected with H1N1 wild-type virus, H3N2 type, or influenza virus B (IBV). Afterwards, the CCK-8 solution was added to the cells cultured for 24 hours and reacted for 2 hours. The absorbance was measured at a wavelength of 450 nm, and the survival rate of the cells was expressed as a percentage of the medium (Figure 6).
Mock는 음성 대조군, H1N1, H3N2, IBV는 인플루엔자 바이러스 감염군, H1N1, H3N2, IBV/단풍나무 잎 10 μg/ml는 단풍나무 잎 10 μg/ml 처리군, H1N1, H3N2, IBV/단풍나무 잎 50 μg/ml는 단풍나무 잎 50 μg/ml 처리군, H1N1, H3N2, IBV/단풍나무 잎 100 μg/ml는 단풍나무 잎 100 μg/ml 처리군, H1N1, H3N2, IBV /단풍나무 잎 200 μg/ml는 단풍나무 잎 200 μg/ml 처리군을 나타낸다.Mock is the negative control group, H1N1, H3N2, IBV is the influenza virus infection group, H1N1, H3N2, IBV/maple leaf 10 μg/ml is the maple leaf 10 μg/ml treatment group, H1N1, H3N2, IBV/maple leaf 50 μg/ml is maple leaf 50 μg/ml treatment group, H1N1, H3N2, IBV/maple leaf 100 μg/ml is maple leaf 100 μg/ml treatment group, H1N1, H3N2, IBV/maple leaf 200 μg/ ml represents the maple leaf 200 μg/ml treatment group.
그 결과, 단풍나무 잎 추출물과 H1N1, H3N2, IBV 인플루엔자 바이러스를 동시에 감염시킨 경우, CPE를 농도의존적으로 억제하여 세포 생존률이 증가하는 것을 확인하였다.As a result, it was confirmed that when maple leaf extract and H1N1, H3N2, and IBV influenza viruses were simultaneously infected, CPE was inhibited in a concentration-dependent manner and cell survival rate increased.
본 발명의 단풍나무 잎 추출물을 처리한 후 H1N1, H3N2 및 인플루엔자 B 바이러스에 의한 CPE를 농도의존적으로 억제하여 세포 생존률을 증가시키는 것을 확인하였으며, 특히 단풍나무 잎 추출물 50 μg/ml 농도 이상에서 세포 생존률이 현저히 증가함을 확인하였다. 본 발명의 단풍나무 잎 추출물이 바이러스의 복제에 의한 CPE를 억제함으로 인플루엔자 바이러스 A 뿐만 아니라, 인플루엔자 바이러스 B에서도 항바이러스 효능이 있음을 확인하였다.After treatment with the maple leaf extract of the present invention, it was confirmed that CPE caused by H1N1, H3N2, and influenza B viruses was inhibited in a concentration-dependent manner, thereby increasing cell survival rate. In particular, cell survival rate increased at a concentration of 50 μg/ml or higher of the maple leaf extract. It was confirmed that this significantly increased. It was confirmed that the maple leaf extract of the present invention has antiviral efficacy not only against influenza virus A but also against influenza virus B by inhibiting CPE caused by virus replication.
이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, those skilled in the art to which the present invention pertains will understand that the present invention can be implemented in other specific forms without changing its technical idea or essential features. In this regard, the embodiments described above should be understood in all respects as illustrative and not restrictive. The scope of the present invention should be construed as including the meaning and scope of the patent claims described below rather than the detailed description above, and all changes or modified forms derived from the equivalent concept thereof are included in the scope of the present invention.
Claims (10)
An antiviral pharmaceutical composition containing maple tree extract as an active ingredient.
The pharmaceutical composition according to claim 1, wherein the maple tree extract is a maple leaf extract.
The pharmaceutical composition according to claim 1, wherein the virus is an influenza virus.
The pharmaceutical composition according to claim 1, wherein the maple tree extract is prepared by extraction with a solvent selected from the group consisting of water, alcohols having 1 to 4 carbon atoms, and mixed solvents thereof.
The pharmaceutical composition according to claim 2, wherein the extraction is hot water extraction, ultrasonic extraction, room temperature extraction, cold needle extraction, reflux cooling extraction, or steam extraction.
A pharmaceutical composition for preventing or treating influenza virus infectious diseases containing maple tree extract as an active ingredient.
A method for preventing or treating an influenza virus infectious disease, comprising the step of administering the pharmaceutical composition of any one of claims 1 to 6 to an entity other than a human that is showing or is likely to show symptoms of an influenza virus infectious disease.
An antiviral health functional food composition containing maple tree extract as an active ingredient.
An antiviral quasi-drug composition containing maple tree extract as an active ingredient.
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