200906380 九、發明說明： 【發明所屬之技術領域】 本發明係關於新型抗病毒劑。更具體而言，係關於一種 以經基酷·醇（hydroxytyrosol)為有效成分之新型抗流行性感 冒病毒劑。 【先前技術】 流行性感冒係由流行性感冒病毒所引起之感染症，在曰 本於每年冬季流行。流行性感冒病毒係具有外膜之單股 RNA病毒，單股RNA於病毒粒子内部採取分節構造，8股 分段RNA與核蛋白質（NP)或聚合酶形成複合體。該複合體 藉由與支持病毒膜内側的基質蛋白1(M1)結合而變得穩 定。 流行性感冒病毒依NP及Ml的抗原性之差異，被分類為 A、B、C三種類型。進而，A型病毒依病毒膜上的蛋白質 即紅血球凝素素（HA)及神經胺酸酶（NA，neuraminidase)的 抗原性之差異，被分類為HA16種（H1〜H16)亞型、NA9種 (N1〜N9)亞型。又，A型病毒中存在人、水禽、豬、馬等 各動物所特有的病毒，但一般認為各動物的病毒不會感染 其他動物種，作為感染人之病毒已知有H1N1、H2N2、 H3N2之亞型。然而，於1997年在香港確認人會感染高病 原性禽流行性感冒病毒H5N1亞型，因而很有必要研究預 防該病毒感染之對策。 預防流行性感冒之基本方法係疫苗接種，但流行性感冒 疫苗防止發病的效果通常為70〜90%，對於高齡者則更 131591.doc 200906380 低。又’因抗原變異’故疫苗的效果亦會減弱。 另方面近年來亦開發出各種抗病毒劑，已知有金剛 烧胺（Amantadine)、神經胺酸酶抑制劑之紮那米韋 (Zanamivir)、奥司他韋（0seitamivir)等。抗病毒劑具有不 嗳流行性感冒病毒變異的影響之優點，其效果的程度視流 行性感冒的類型而異，又，亦存在發現有某種副作用等之 問題，因此業者正在尋求更安全且有效的抗病毒劑。 然而，曰本專利特開2002-20305號公報（專利文獻丨）中， 記載有一種包含橄欖科植物葉子成分的萃取物及芸香科植 物種子成分之組合物，可減少流行性感冒感染之死亡率。 關於橄欖葉或其萃取物之作用，曰本專利特開2〇〇4_ 161676號公報（專利文獻2)中記載有對軍團菌 (Legi〇nellales)等有抗菌作用。又，記載有撖欖中所含之 撖欖多酚（〇丨europein)及其衍生物對流行性感冒嗜血桿菌 (Haemophilus infiuenzae)及其他細菌顯示抗菌作用（非專利 文獻1)，曰本專利特開平8_1 19825號公報（專利文獻3)中記 載有作為橄欖多酚衍生物之羥基酪醇有抑制黑色素生成之 效果或抑制過氧化脂質生成之效果，且提出一種包含羥基 齡·醇之皮膚外用劑或浴用劑。 曰本專利特表2005-517033號公報（專利文獻4)中，記載 有一種愛滋病相關神經疾病、炎症、炎症相關疾病之處理 方法，其包含投與橄欖多酚與羥基酪醇的混合物（例如段 落〇〇36)。另一方面，日本專利特表別⑽巧。4“號公報（專 利文獻5)及日本專利特表2〇〇5·532398號公報（專利文獻幻 131591.doc 200906380 中所°己載之發明’係關於由撖欖植物液來製造富含羥基酪 醇之、、且口物的方法’該等文獻中有—行記載由橄欖所獲得 之經基路醇可作為抗病毒藥使用（分別於段落GG38、段落 0040)，但並未記載對何種病毒有效等具體内容。 專利文獻1 .日本專利特開2002_2〇3〇5號公報 專利文獻2 .曰本專利特開2〇〇4_161676號公報 專利文獻3 .日本專利特開平8_丨丨9825號公報 專利文獻4 ·日本專利特表2〇〇5_517〇33號公報 專利文獻5 .日本專利特表2004-523468號公報 專利文獻6 :日本專利特表2〇〇5·532398號公報 非專利文獻 1 : j〇urnal of Pharmacy and Phamac〇i〇gy,200906380 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a novel antiviral agent. More specifically, it relates to a novel anti-influenza virus agent which is based on hydroxytyrosol as an active ingredient. [Prior Art] Infectious influenza is an infection caused by the influenza virus, which is popular in winter every year. The influenza virus is a single-stranded RNA virus with an outer membrane. The single-stranded RNA adopts a segmented structure inside the virion, and the 8-stranded RNA forms a complex with a nuclear protein (NP) or a polymerase. This complex is stabilized by binding to matrix protein 1 (M1) supporting the inner side of the viral membrane. The influenza virus is classified into three types, A, B, and C, depending on the antigenicity of NP and Ml. Further, the type A virus is classified into HA16 species (H1 to H16) subtypes and NA9 species depending on the antigenicity of the proteins on the virus membrane, namely, hemagglutinin (HA) and neuraminidase (NA, neuraminidase). (N1 ~ N9) subtype. Further, in the type A virus, viruses specific to humans, waterfowl, pigs, horses, and the like are present, but it is generally considered that the virus of each animal does not infect other animal species, and H1N1, H2N2, and H3N2 are known as viruses for infecting humans. Subtype. However, it was confirmed in Hong Kong in 1997 that people infected with the highly pathogenic avian influenza virus H5N1 subtype, so it is necessary to study countermeasures against this virus infection. The basic method of preventing influenza is vaccination, but the effect of the influenza vaccine to prevent the onset is usually 70 to 90%, and for the elderly, it is 131591.doc 200906380. Moreover, the effect of the vaccine is also weakened due to antigenic variation. On the other hand, various antiviral agents have been developed in recent years, and Amantadine, a neuraminidase inhibitor, Zanamivir, and oseltamivir (0seitamivir) are known. Antiviral agents have the advantage of not affecting the variation of influenza virus, the degree of effect varies depending on the type of influenza, and there are also problems such as finding some side effects, so the operator is seeking safer and more effective. Antiviral agent. However, Japanese Patent Publication No. 2002-20305 (Patent Document No.) discloses a composition comprising an extract of a leaf component of an olive family plant and a seed component of a Rutaceae plant, which can reduce the mortality rate of influenza infection. . Regarding the action of the olive leaf or the extract thereof, the antibacterial action against Legionella (Legi〇nellales) and the like is described in Japanese Patent Laid-Open Publication No. Hei. No. 4-161676 (Patent Document 2). Further, it is described that eucalyptus polyphenol (P. europene) and its derivatives exhibit antibacterial activity against Haemophilus infiuenzae and other bacteria (Non-Patent Document 1). Japanese Patent Publication No. Hei 8-1 19825 (Patent Document 3) discloses that hydroxytyrosol as an olive polyphenol derivative has an effect of suppressing melanin production or an effect of suppressing generation of peroxidized lipid, and proposes a skin external application containing hydroxy-age alcohol. Agent or bath. Japanese Patent Laid-Open Publication No. 2005-517033 (Patent Document 4) discloses a treatment method for AIDS-related neurological diseases, inflammation, and inflammation-related diseases, which comprises administering a mixture of olive polyphenols and hydroxytyrosol (for example, paragraphs). 〇〇 36). On the other hand, the Japanese patent special (10) is clever. 4" (Patent Document 5) and Japanese Patent Laid-Open Publication No. H5-532398 (Patent Document No. 131591.doc 200906380, the invention of which is incorporated herein by reference) The method of tyrosol, and the oral substance, 'there is a record in the literature that the basal alcohol obtained from the olive can be used as an antiviral drug (in paragraph GG38, paragraph 0040, respectively), but it is not described Japanese Patent Laid-Open Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. Japanese Patent Laid-Open Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. 1 : j〇urnal of Pharmacy and Phamac〇i〇gy,
Volume 51，Number 8，1 August 1999, pp. 977-974(4) 【發明内容】 發明所欲解決之問題 本發明之目的在於提供一種安全性較高之新型抗流行性 感冒病毒劑。 解決問題之技術手段 本發明者們為了解決上述課題而反覆進行努力研究結 果發現於橄欖萃取物所含之成分中，羥基酪醇對流行性感 冒病毒有較高的失活效果，而且細胞毒性亦較低，從而最 終完成本發明。 即，本發明係關於： [1 ] 一種抗流行性感冒病毒劑’其含有羥基酪醇作為有效成 分； 131591.doc 200906380 [2] 如上述以]之抗流行性感冒病毒劑’其中上述流行性感 冒病毒係人或禽流行性感冒病毒； [3] 如上述[2]之抗流行性感冒病毒劑，其中上述禽流行性 感冒病毒係Η5Ν1亞型禽流行性感冒Α病毒； [4] 如請求項2之抗流行性感冒病毒劑，其中上述人流行性 感冒病毒係H1N1亞型或H3N2亞型人流行性感冒A病毒. 以及 fVolume 51, Number 8, 1 August 1999, pp. 977-974 (4) SUMMARY OF THE INVENTION Problems to be Solved by the Invention An object of the present invention is to provide a novel anti-epidemic cold virus agent having high safety. In order to solve the above problems, the inventors of the present invention have repeatedly conducted diligent research and found that among the components contained in the olive extract, hydroxytyrosol has a high deactivation effect on influenza virus, and cytotoxicity is also It is lower, thus finally completing the present invention. That is, the present invention relates to: [1] an anti-influenza virus agent which contains hydroxytyrosol as an active ingredient; 131591.doc 200906380 [2] Anti-influenza virus agent as described above] wherein the above epidemic A cold virus is a human or avian influenza virus; [3] an anti-influenza virus agent as described in [2] above, wherein the avian influenza virus system Η5Ν1 subtype avian influenza prion; [4] Item 2 of the anti-influenza virus agent, wherein the above-mentioned human influenza virus H1N1 subtype or H3N2 subtype human influenza A virus.
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[5] —種食品’其含有如上述⑴至[4]中任—項之抗流行性 感冒病毒劑。 發明之效果 對於經基路醇，本發明提供—種將其作為抗流行性感冒 病毒劑的有效成分之新的有用性及用⑨。經基路醇係撖： 的葉、果實、！、根等中所含之成分’因此對人或動物的 =性較^本發明之抗流行性感f病毒劑亦可作為食品 而攝取。 【實施方式】 效成 本發明之抗流行性感冒病毒劑含有羥基酪醇作 〇 ^ 源自橄欖葉萃取物等天然物之萃取物、將：萃可 者、或者經化學合成者中之任意者。將邊萃取物純 本發明之抗流行性感w 汉目病毒劑，可作 品、動物用飼料等使用1準的攝取量樂：健康 0.01〜500 mg/kg體重，較好 "、’’均每 杈好的疋(M〜300 mg/kg體重， 131591.doc 200906380 的是1〜200 mg/kg體重。 本發明之抗流行性感f病毒劑 冒病毒的對象作為目的而投予β可將治療感染流行性感 健康人攝取。 又’亦可作為預防劑而給 本發明之抗流行性感冒病 混合於食品、飼料、飲料中攝:。了直接攝取，亦可將其 加劑且藉由公知之方法f 又，亦可使用適當的添 可舉 糖漿 乳膏 點眼 黏合 出：錠劑、耀囊劑、顆粒劑。作為製劑化之例 劑、-劑、口含錠等二::膏Γ液劑 劑、貼繼之㈣；凝膠劑 劑、栓劑等。 舌下劑、吸入劑 作為上述添加劑，可舉屮. B、 .通吊所使用之賦形劑、那贫 诏、潤滑劑、崩散劑、著色 - m才丨 M緯味續臭劑、乳化劑、界 面活性劑、助溶劑、懸浮劑、 御^ ^ 剽專張化劑、緩衝劑，防腐 d、抗虱化劑、穩定劑、吸收促進劑等。 作為上述賦形劑，例如可與山. ^ j如了舉出.玉米澱粉、馬鈴薯澱 粕、α化澱粉、糊精、乳 Λ 4 裾白糖、阗萄糖、甘露醇、赤 鮮糖％、麥芽糖醇、山梨糖醇、海藻糖' 質無水石夕酸、石夕酸銘、㈣# 秒&鈣、偏矽酸鋁酸鎂' 磷酸氫 鈣、磷酸鈣、硫酸鈣等。 作為上述黏合劑，例如可舉出：聚乙烯醇、甲基纖維 素、乙基纖維素、經兩基纖維素、經丙基甲基纖維素、羥 丙基贏粕、聚乙烯吡咯啶酮、聚乙二醇、阿拉伯膠、黃蓍 膠、明膠、蟲膠等。 V 、 131591.doc 200906380 料上述潤滑劑，例如可舉出：硬賴鎂、硬脂酸的、 硬脂醯延胡索酸納、滑石等。 乍為上述朋政』’例如可舉出：結晶纖維素、瓊脂、明 ^碳㈣、碳酸氫納、檸檬_、糊精、果膠、低取代 度故丙基纖維素、交聯甲 來維酮、羧曱基纖維素、羧甲基纖 蝴、交聯缓甲基纖維素鈉、叛甲基殿粉納等。 作為上述著色劑，例如 — 化二鐵、洋紅、焦糖、二二鐵、黃色三氧 音紗舻如* Θ蘿匐素、氧化鈦、滑石、核黃 素^鈉、黃色铭色興（高waluminumlake)等。 2上=味料劑，例如可舉出：可可粉、薄荷油、 f醇、#橡油、龍腦、桂皮粉'抗壞血酸、酒石酸、蘋 果酸、阿斯巴甜、醋磺内，酉石“ 作為上述乳化劑或界面活性：me p°tassium)等。 乙醇胺、十二院基硫酸納::如可舉出：硬脂基三 單硬脂酸甘㈣、絲;Ί胺基丙酸、㈣脂、 作為上述助溶劑，例如:::::脂，等。 ””醋、乙醇、膽固醇…乙2乙一醇、丙二醇、苯 納、聚山梨酸賴、於驗酿胺等。.胺、碳酸鈉、檸檬酸 作為上述懸浮劑，除 出：聚乙乙^ 性劑以外，例如可舉 維素、羥乙基纖维f，、 卩基纖維素、羥f基纖 等。 纖、准素…纖維素等之親水性高分子 作為上述等張化劑，例如 露醇、山梨糖醇等。 準出.匍萄糖、氯化鈉、甘 I3159l.doc 200906380 為上述緩衝劑’例如可舉屮 鹽、檸檬酸鹽等之緩衝為丨竿出.磷酸鹽、醋酸鹽、碳酸 作為上述防腐劑，例如1 經基苯甲酸丙醋、氣丁舉出：對經基苯甲酸甲醋、對 (一一二醇、苯乙醇、去水醋酸 酸氧化劑’例—亞硫酸鹽、抗壞血 作：上述穩定劑’例如可舉出：抗壞血酸、四乙酸乙二 胺-納、異抗壞血酸、生育紛等。 古作為上述吸收促進劑’例如可舉出：十四酸異丙醋、生 月齡、名弓化醇。 =於成為本發明之抗流行性感冒劑的對象之流行性感冒 病毒並無特別限定’本發明之抗流行性感冒劑對人或禽流 行性感冒，尤其是H5N1亞型禽流行性感冒A病毒、mN1 亞型或H3N2亞型人流行性感冒八病毒具有較高的效果。 實施例 下面’利用實施例更詳細地說明本發明，但本發明並不 受s亥等實施例的任何限制。 <1·羥基酪醇對禽流行性感冒病毒之效果> 調查以下之羥基酪醇（1)及（2)對禽流行性感冒病毒（H5N1 亞型，A/chicken/Yamaguchi/7/04)感染之抗病毒效果。 (1) 11丁20群：羥基酪醇含量22.3% (2) HT100群：羥基酪醇含量98.3°/〇 將上述羥基酪醇分別以滅菌磷酸緩衝生理食鹽水（PBS) 131591.doc -12- 200906380 調製成濃度為2 mg/ml，再用孔徑Ο.22 μηι之薄膜過淚器進 行過滤·。 將禽流行性感冒病毒接種於10日齡之發育雞蛋的尿膜腔 内，於37.5 °C之條件下培養3日。其後，將尿臈腔液於 5 000 RPM、20分鐘之條件下離心分離，將上清液作為病 毒液。 將各群之羥基酪醇液及病毒液以等量加以混和（經基酷^ 醇之最終濃度為1 mg/ml)，於室溫下放置24小時。 將禽流行性感冒病毒以及各群之羥基酪醇混合液進行j 〇 倍系列稀釋（serial dilution)，再接種於以96孔微量盤所讲 養之MDCK細胞内。將各稀釋系列分別接種於4孔之細胞 内。 將病毒-羥基酪醇混合液接種於細胞内，培養5日後，用 顯微鏡觀察細胞之變性，算出病毒感染力價（50%組織培養 感染量，TCID50)。 禽流行性感冒病毒之實驗結果示於表1。表中之分數係 表示病毒增殖的孔數/接種孔數’例如「4/4」表示接種的4 個孔中均看到病毒的增殖。 [表1] 病毒稀釋系列(logio) 感染力價 萃取物 -1 -2 -3 -4 -5 -6 -7 TCID5〇(logi〇/0.1 ml) HT20 4/4 3/4 4/4 4/4 1/4 0/4 0/4 4.75 ^ HT100 0/4 0/4 0/4 0/4 0/4 0/4 0/4 <0.5 ~~~ 無 4/4 4/4 4/4 4/4 4/4 2/4 0/4 6.0 〜 於HT100群中，發現病毒感染力價顯著下降。又，於 131591.doc 13 200906380 HT20群中感染力價亦下降。 <2·經基路醇對禽流行性感冒病毒之效果> 將羥基酪醇（含量98.3%)以滅菌磷酸緩衝生理食鹽水調 製成濃度為 2、1、〇·5、〇 25及〇 125 mg/ml。 以與上述同樣之方式，使用H5N1亞型高病原性禽流行 性感冒病毒來製備病毒液。 將羥基酪醇液與病毒液以等量加以混和，於室溫下放置 24小時° 其後，將病毒-羥基酪醇混合液進行1〇倍系列稀釋，再 接種於MDCK細胞内。將各稀釋系列接種於細胞内，培養 5曰後，用顯微鏡觀察細胞之變性，算出每〇1 ml之病毒感 染力價（50%組織培養感染量，其實驗結果示於 表2。 [表2] 經基酷醇(mg/ml) TCID5〇(logi〇/0.1 ml) 失活 1.0 <1.5 >99.9 0.5 1.5 99.8 0.25 1.5 ~99ϋ~~ 0.125 3.5 80.0 0.0625 3.8 60.1 無 4.2 — 圓 <3 .羥基酪醇對人流行性感冒病毒之效果> 將羥基酪醇（含量98.3%)以滅菌磷酸緩衝生理食鹽水調 製成濃度為2 mg/ml。 以與上述同樣之方式，使用H1N1亞型（蘇聯型）及H3N2 亞型（香港型）流行性感冒病毒來製備病毒液。 將經基酷·醇液與病毒液以等量加以混和，於室溫下放置 131591.doc -14 - 200906380 24小時° 其後，將病毒-羥基酪醇混合液進行 接種於MDCK細胞内。將各稀釋 二:列稀釋，再 尔幻接種於細胞内，培養 5曰後，用顯微鏡觀察細胞之變性，算出每〇ι⑹之病毒感 力價（5 0 %細胞培着^咸达J署，Τ'Ρ'ΤΓΛ、 J+ 也。脣钬木里，TCIDso)。其實驗結果示於 表3。 [表3] --— 經基路醇(mg/mD TCIDso(logi〇/〇.l ml) 失活率(％) H1N1亞型 H3N2亞型 — 1 1.75 99.9 益 5.75 - —1 1.5 99.9 益 *、、、 4.75 - 由以上可明瞭，羥基酪醇對禽流行性感冒病毒濃度依賴 性地顯示較高的失活效果。又，對人流行性感冒病毒亦顯 示較高的失活效果。 131591.doc •15-[5] A food product comprising the anti-epidemic cold virus agent according to any one of the above (1) to [4]. EFFECTS OF THE INVENTION The present invention provides a novel usefulness and use as an active ingredient of an anti-influenza virus agent for a base alcohol. The ketone alcohol system: leaves, fruits, and! The component contained in the root or the like is therefore inferior to the human or animal. The anti-infective f virus agent of the present invention can also be ingested as a food. [Embodiment] The anti-influenza virus agent of the present invention contains hydroxytyrosol as an extract derived from a natural product such as an olive leaf extract, or any one of those obtained by chemical synthesis. The edge extract is pure in the anti-exposure sexy w Hanmu virus of the present invention, and can be used for works, animal feed, etc. 1 intake of meat: health 0.01~500 mg/kg body weight, preferably ", ''杈 疋 疋 M M 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 Ingestion of a healthy and healthy person. It can also be used as a prophylactic agent to mix the anti-influenza disease of the present invention in food, feed, or beverages: direct ingestion, or addition thereof, and by a known method f In addition, you can also use appropriate syrup cream to stick to the eye: tablets, sacs, granules. As a formulation, agent, mouth, etc. 2:: cream remedy Agents, pastes followed by (4); gel agents, suppositories, etc. Sublingual agents, inhalants as the above additives, 可. B, . Excipients used in hanging, that barren, lubricants, disintegrating agents , coloring - m 丨 M weiwei odorant, emulsifier, surfactant, cosolvent , suspending agent, ^ ^ 剽 剽 special agent, buffer, anti-corrosion d, anti-deuteration agent, stabilizer, absorption enhancer, etc. As the above excipients, for example, can be compared with mountains. ^ j. Corn starch, potato starch, alpha-starch, dextrin, milk thistle 4 裾 white sugar, glucosamine, mannitol, red sugar, maltitol, sorbitol, trehalose, anhydrous stone, acid, shi Acid, (4) #秒 & Calcium, magnesium bismuth succinate, calcium hydrogen phosphate, calcium phosphate, calcium sulfate, etc. As the above-mentioned binder, for example, polyvinyl alcohol, methyl cellulose, ethyl fiber , two-base cellulose, propylmethylcellulose, hydroxypropyl-win, polyvinylpyrrolidone, polyethylene glycol, gum arabic, tragacanth, gelatin, shellac, etc. V, 131591. Doc 200906380 The above-mentioned lubricants include, for example, hard magnesium, stearic acid, stearin, sodium sulphate, talc, etc. 乍 上述 上述 上述 上述 ' 结晶 结晶 结晶 结晶 结晶 结晶 结晶 结晶 结晶 结晶 结晶 结晶 结晶 结晶 结晶 结晶 结晶 结晶 结晶 结晶Carbon (tetra), sodium bicarbonate, lemon _, dextrin, pectin, low degree of substitution, propyl cellulose, cross-linking Levastatone, carboxymethyl cellulose, carboxymethyl fiber, cross-linked slow methyl cellulose sodium, methicillin powder, etc. As the above coloring agents, for example, bismuth, magenta, caramel, two Two iron, yellow nitrosonic yarns such as * lycopene, titanium oxide, talc, riboflavin, sodium, yellow luminescence, etc. 2 upper = flavoring agent, for example, cocoa Powder, peppermint oil, f alcohol, #橡油, borneol, cinnamon powder 'ascorbic acid, tartaric acid, malic acid, aspartame, vinegar, vermiculite" as the above emulsifier or interface activity: me p°tassium Etc. Ethanolamine, 12-sodium sulfate sodium:: exemplified by: stearyl tristearate (tetra), silk; guanylalanine, (iv) lipid, as the above-mentioned co-solvent, for example::::: Fat, etc. ""Vinegar, ethanol, cholesterol... Ethyl 2-propanol, propylene glycol, bena, polysorbate, and amines. Amine, sodium carbonate, and citric acid The suspending agent may be, for example, a vitamin, a hydroxyethyl group f, a mercapto cellulose or a hydroxy-f-based fiber. The hydrophilic polymer such as cellulose or cellulose is used as the above-mentioned isotonic agent, for example, sorbitol or sorbitol.匍 匍 、 、 、 、 、 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 063 For example, 1 propyl acetophenone propylene vinegar, gas condensate: for benzoic acid methyl vinegar, p-(mono diol, phenylethyl alcohol, dehydrated acetic acid oxidant 'example - sulfite, ascorbic: Examples of the stabilizers include ascorbic acid, ethylenediaminetetraacetate-nanoate, erythorbic acid, and fertility. The antibacterial agent of the above-mentioned absorption enhancer is exemplified by isopropyl vinegar, virgin vinegar, and a famous bow. The influenza virus which is the subject of the anti-influenza agent of the present invention is not particularly limited to the anti-influenza agent of the present invention for human or avian influenza, especially the H5N1 subtype avian prevalence. The cold A virus, the mN1 subtype or the H3N2 subtype human influenza VIII virus has a higher effect. EXAMPLES Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not subject to any of the examples of shai et al. Limit. <1·Hydroxytyrosol Effect of avian influenza virus> The following antiviral effects of hydroxytyrosol (1) and (2) on avian influenza virus (H5N1 subtype, A/chicken/Yamaguchi/7/04) infection were investigated. 1) 11 butyl group 20: hydroxytyrosol content 22.3% (2) HT100 group: hydroxytyrosol content 98.3 ° / 〇 The above hydroxy tyrosol is sterilized phosphate buffered saline (PBS) 131591.doc -12- 200906380 Prepared to a concentration of 2 mg/ml, and then filtered through a membrane tortoise with a pore size of 22.22 μηι. The avian influenza virus was inoculated into the urinary membrane cavity of a 10-day-old developing egg at 37.5 °C. The culture was carried out for 3 days. Thereafter, the urinary sputum cavity was centrifuged at 5,000 RPM for 20 minutes, and the supernatant was used as a virus solution. The hydroxytyrosol solution and the virus solution of each group were equally divided. Mixing (final concentration of 1 mg/ml via ketone) and allowing to stand at room temperature for 24 hours. Serial dilution of avian influenza virus and each group of hydroxytyrosol mixtures , and then inoculated into MDCK cells fed with 96-well microplates. The cells were seeded in 4 wells. The virus-hydroxytyrosol mixture was inoculated into the cells, and after 5 days of culture, the denaturation of the cells was observed with a microscope to calculate the viral infectious power (50% tissue culture infection amount, TCID50). The results of the experimental results of the influenza virus are shown in Table 1. The scores in the table indicate the number of wells for virus proliferation/the number of cells to be inoculated, for example, "4/4" indicates that virus proliferation was observed in the four wells inoculated. [Table 1 ] Virus dilution series (logio) Infectious price extract -1 -2 -3 -4 -5 -6 -7 TCID5〇(logi〇/0.1 ml) HT20 4/4 3/4 4/4 4/4 1/ 4 0/4 0/4 4.75 ^ HT100 0/4 0/4 0/4 0/4 0/4 0/4 0/4 <0.5 ~~~ No 4/4 4/4 4/4 4/4 4/4 2/4 0/4 6.0 ~ In the HT100 group, the viral infectious power price was found to be significantly reduced. Also, at 131591.doc 13 200906380, the price of infectious power in the HT20 group also decreased. <2. Effect of phenyl alcohol on avian influenza virus> Hydroxytyrosol (content 98.3%) was prepared in sterile phosphate buffered saline to a concentration of 2, 1, 〇·5, 〇25 and 〇 125 mg/ml. The virus solution was prepared in the same manner as above using the H5N1 subtype highly pathogenic avian influenza virus. The hydroxytyrosol solution and the virus solution were mixed in equal amounts and allowed to stand at room temperature for 24 hours. Thereafter, the virus-hydroxytyrosol mixture was serially diluted 1 〇 and inoculated into MDCK cells. Each dilution series was inoculated into the cells, and after culturing for 5 ,, the denaturation of the cells was observed with a microscope, and the viral infectivity (1% of the tissue culture infection amount per ml) was calculated, and the experimental results are shown in Table 2. [Table 2 ] 基基醇 (mg/ml) TCID5〇(logi〇/0.1 ml) Inactivation 1.0 <1.5 >99.9 0.5 1.5 99.8 0.25 1.5 ~99ϋ~~ 0.125 3.5 80.0 0.0625 3.8 60.1 None 4.2 — Round <3 Effect of hydroxytyrosol on human influenza virus> Hydroxytyrosol (content 98.3%) was prepared in sterile phosphate buffered saline to a concentration of 2 mg/ml. In the same manner as above, H1N1 subtype was used. (Soviet type) and H3N2 subtype (Hong Kong type) influenza virus to prepare virus solution. Mix the base alcohol solution and virus solution in equal amounts and place at room temperature. 131591.doc -14 - 200906380 24 After the hour, the virus-hydroxytyrosol mixture was inoculated into MDCK cells, and each dilution was diluted into two columns, and then inoculated into the cells. After 5 days of culture, the cells were observed by microscopy, and each was calculated. 〇ι(6) virus sensible price (50% cell culture ^ salty J Department, Τ 'Ρ' ΤΓΛ, J+ also. Lip 钬 wood, TCIDso). The experimental results are shown in Table 3. [Table 3] --- via base alcohol (mg / mD TCIDso (logi 〇 / 〇 .l ml) Inactivation rate (%) H1N1 subtype H3N2 subtype - 1 1.75 99.9 benefit 5.75 - -1 1.5 99.9 Benefits *, ,, 4.75 - It is clear from the above that hydroxytyrosol is dependent on avian influenza virus concentration Sexually shows a higher inactivation effect. Also, it shows a higher inactivation effect on human influenza virus. 131591.doc •15-