TW200815023A - Prevention and treatment of otitis media - Google Patents
Prevention and treatment of otitis media Download PDFInfo
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- TW200815023A TW200815023A TW096121359A TW96121359A TW200815023A TW 200815023 A TW200815023 A TW 200815023A TW 096121359 A TW096121359 A TW 096121359A TW 96121359 A TW96121359 A TW 96121359A TW 200815023 A TW200815023 A TW 200815023A
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- otitis media
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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Landscapes
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- Organic Chemistry (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
200815023 九、發明說明: 【發明所屬之技術領域】 本發明係關於令耳炎之預防及治療,尤其係對於嬰鬼及 幼兒。 【先前技徇"】 呼吸道感染極為常見,尤其在嬰兒及幼兒中。舉例而 言,嬰兒在出生後第一年中適常將經歷3至6次該等感染。 該等感染可為細菌性或病毒性起源。呼吸道病毒性感染之 實例包括普通感冒、流行性感冒及呼吸道融合病毒、呼级 道細ii性感染之實例包括肺炎及中耳炎。 頻繁之呼吸道感染通常與急性中耳炎相關。其為牛耳之 感染,其中經由口腔使中耳腔與外界環境相連接之耳咽管 (Eustachian tube)發炎,且接著受阻而無法截獲中耳中之 =菌。中耳腔亦發炎且伴以積液從而導致壓力升高,其使 得患者由於無法如健康受檢者般經由耳咽管來平衡中耳與 外界環境之間的壓力而感到疼痛。在嚴重㈣下,鼓^ 能於在Μ力下破裂使得感染之液體得以達到内耳。此係潛 在之危險狀況,若不進行治療則其可使得聽力永久受損。 50%之兒童在出生後f _年中將具有至少―次急性中耳 炎發作’且35。/^歲與3歲之間的兒童具有急性中耳炎之 復發。此又可導致形成稱為膠狀性中耳積液之病症,並中 流體在感染發作之間並不完全自中耳排出。若該病症得以 確立,則可能需要外科手術介入。 急性中耳炎似乎與常見於鼻咽腔之原生微生物中之病原 121853.doc 200815023 (1細菌之活性有.關。就數量上而言,最重.要之病原體為肺 k 鏈球 之情況)、無法歸 顯之/瓜感嗜血桿菌(//此所叩办以似ky^enzae)(3〇%之情況)及 黏臈 k 莫拉囷(Aforaxe//(2 1 0¾ 之情況)。由於 此原因,尤其對於嬰兒通常藉由投予抗生素來治療急性中 耳炎。確實,相較於任何其他嬰兒期之疾病而言,更經常 使用抗生素治療中耳炎。此不可避免地導致與中耳炎相關 之細菌菌株產生針對常用抗生素之抗性。舉例而言,認為 ^ 20/〇之肺戈鏈球菌菌株對盤尼西林(paiciuin)及頭抱 菌素(cephal〇sporin)具有抗性。類似地,至少3〇%之流感 嗜血桿菌菌株及大多數黏膜炎莫拉菌已產生出抗生素抗 I4生忒處方頻率至少部分係歸因於患有中耳炎之嬰兒及幼 兒所、、二又之疼痛,嬰兒及幼兒對於該疼痛表現為長期之哭 叫,其使家長及其他看護者非常憂慮難以放心。因此,明 』而要用於降低該痛苦及潛在嚴重病症在嬰兒及幼兒中之 發生率的替代方法。 已提出夕種替代療法。舉例而言,在WO 97/17089中提 出使用所明之免疫乳製劑來預防中耳炎。該製劑含有自牛 、彳又仔之IgG型抗耳炎免疫球蛋白,以補充被動免疫防 禦' 亦已提出夕種細菌菌株用於預防,治療中耳炎。在最近 之=床試驗中,將抑制性α溶灰性鍵球菌喷入患有急性中 )如鏈球菌(加epi0C0CCus及口腔鏠球菌 12lS53.doc 200815023 ora/Zs)。以此方‘式治療之兒童具有較少急 性中耳炎之發作(Roos等人,Effect of recolonisation with ^interfering alpha streptococci^ on recurrences of acute and secretory otitis media in children: randomised placebo controlled trial,BMJ 322:210-212)。然而,在該試驗中所 用之細菌菌株亦為牽涉於諸如心内膜炎及肺感染之病症中 的公認人類病原體。 WO 2004/072272提出使用唾液鏈球菌 M/z’var/M)之特定菌株預防及洽療中耳炎。據稱該菌株為 產生細菌素之非病原性菌株。其可經鼻投予、藉由吸入經 口腔投予或以含片或膠囊之形式投予。較佳地,在使用抗 生素或其他抗微生物劑之初始治療後投予該菌株。 WO 2006/007526描述關於81名芬籣嬰兒之研究,其中將 喂以嬰兒配方食品中鼠李糖乳酸桿菌 株之組合之嬰兒中的中耳炎發病率與未喂以任何益生菌之 對照組進行比較。發現補充以該兩種在人類食物產品中均 具有長久使用歷史之益生菌相較於未補充組而言可降低早 期急性中耳炎之風險。該效應係與補充組中感染數之總體 降低相關’且假定該效應係歸因於該等菌株之系統免疫刺 激效應。 自前述内容可見,仍需要用於預防及治療急性中耳炎之 有效方法,其不依賴於使用抗生素且其可便利且安全地投 予。 121853.doc 200815023 【發明内容】 本發明者意外地發現,共同投予具有 株在預防及治療令耳炎中尤其有效。 之細因医 因此’在第-態樣中,本㈣提供 ㈣ # ^ 、 夠強化系統免疫反應之非病;f性 細困因株.、能夠對於與形成令 關力^ 效應的非病原性細菌菌株w 扁原體施加抑菌 囷菌株及旎夠對於舆形成中耳炎 病原體施加殺菌效應的非病原性細菌菌株。 在第二態樣中,本發明以提供能夠強化系統免疫反應之 非病原性細菌菌株、能夠對於與形成中耳炎相: T加抑菌效應的非病原性細菌菌株及能夠對於與形成中耳 炎相關之病原體施加殺菌效應的非病原性細菌菌株在擎迭 預防或治療令耳炎之組合物中的用途。 、 本毛月進步擴展至用於預防或治療中耳炎之方法,盆 包含將治療量之能夠強化系統免疫反應之非病原性細菌菌 株、能夠對於與形成中耳炎相關之病原體施加抑菌效庫的 非病原性細菌菌株及能夠對.於與形成中耳炎相關之病原體 施加殺菌效應的非病原性細菌菌株投予有此需要之個體。丑 不希望受理論所限’本發明者認為如上所述之細菌菌株 在中耳炎之預防及治療中的功效可耜與疾病之病理學相 關。認為病原體肺炎鏈球菌、流感嗜血捍菌及黏膜炎莫拉 菌之單純存在將不會不可避免地導致急性中耳炎發生。、相 反’認為首先必須存在上呼吸道之最初病毒性感染,其以 某種並不完.全為人所瞭解但可能與系統免疫反應相關:方 12I853.doc 200815023 式擾亂鼻咽微生物,使得病原性細菌拓殖於黏膜且引起中 耳炎之發作。同時強化系統免疫反應及鼻咽腔中非病原性 抑囷及殺菌性細菌之數目可能有效地阻止與形成中耳炎相 關之病原性細菌在鼻咽黏膜上拓殖(colonisation)。 【實施方式】 在本說明書中,對以下詞語提供在閲讀及解释描述内 容、實例及申請專利範圍時必須考慮之定義。 x下疋義見於1991年5月14日之European C〇mmissi〇n Direct!ve 91 /321 /EEC關於嬰兒方食品及較大嬰兒配方食 品之條款1.2,且在本說明書中採用: ”嬰兒”:年齡在12個月以下之兒童; 要兒配方艮0口 ·針對嬰兒在出生後最初4至6個月期間 之特^養用途而設計且滿足此類人之營養需求的食品。 較大嬰兒配方食品” ··針對年齡在4個月以上之嬰兒之 特疋營養用途而設計且遽击仏夺5 , ^ Τ立構成此類人的逐漸多樣化之飲食中 之基本液體元素的食品。 ”成長乳”意謂適於幼兒之拉 1 ” 严兄之特疋營養需求的乳基飲料; ”非病原性細菌菌抶”音神 * 株心、明不為公認之人類病原體之細菌 中耳火之形成相關之病原體”意謂#炎鏈球菌、無 歸類之流感嗜血桿菌及黏臈炎莫拉菌中之一或多者。 ’’幼兒”意謂年齡為i歲與6歲之間的兒童。 除非另外指出,否則所右石\ 、斤有百分比均係以重量計。 應瞭解,本發明中所用 々^ 用之、、,田囷菌株在服用時必須.為 121853.doc 200815023 量 由於此原因.,根據菌落形成單位(cfu)來表示,菌株之 能夠強化系統免疫反應之細菌菌株較隹為鼠李糖乳酸桿 菌八1^€ 53103或鼠李糖乳酸桿菌(:(}1^(:(::1.3724。鼠李糖 乳酸桿® ATCC 53⑻可以LGG⑧之商標購自.芬蘭之Vaii〇 〇y ° 抑菌效應可由作為乳酸之有效產生者之菌株展現。當經 口投予該等細菌時,其產生足量之乳酸以在鼻咽黏膜附近 施加明顯之局部抑菌效應’因此阻止病原性細菌之拓殖。 該等細菌之一實例為嗜熱鏈球菌(加中則咖5 I,⑹㈣。嗜熱鏈球菌之合適菌株為以施商標由丹 麥之Christian Hansen銷售之菌株。 一些細㈣株能夠同時具有抑菌活性及殺菌活性。該等 菌株較佳用於本發明,此係因為其可同時充當能夠施加抑 ,菌效應之細諸株及能_加㈣效應之細耗株,因此 簡化製&複雜性。忒等菌株之實例包括易變微球菌 ⑽㈣⑽㈣··_)Μ(:ν8及唾液鏈球菌dsm測々及 D —5。唾液鏈球菌難13〇84可以Ku之名稱講自 新西蘭之BLIS Technologies Limited。 該等®株可使m錢予或按财投予。 組合物較佳為營養組合物,其作為液體服用且適於由嬰 兒及幼兒服用。該組合物可為在營養上完全之配方食品, 諸如嬰兒配方食品、齡 敉大要兒配方食品或成長乳。或者對 於嬰兒及幼兒之目標纟且,Φ i Μ 〜、、中年齡較大者而言,該組合物可為 121853.doc 200815023 (例如)果汁飲料或其他冷;束或存放穩定之飲料或湯。 —根據本發明之營養组合物較佳含有〗〇4至i〇,2 之各 菌株之Μ合物(乾重)。 根據本發明之營養組合物較佳進一步含有i少一種為 至6%之量的益菌助生質。i菌助生質為不可消化之 ^品成份,其,藉由選擇性刺激結腸中—種或有限數量之細 囷之生長與/或活性,而有益地影響宿主,且因此改良宿 主健康。該等成份為不可消化的,此表示其不會在胃或小 =分解或吸收’且因此得以完整傳遞至可由有益細菌選 酵之結腸。益菌助生質之實例包括特定募_,諸如 果养糖(FOS)及半乳寡糖(G〇s)。可使用益菌助生質之组 合’諸㈣⑽與10%短鏈果寡釀(諸如以商標 af_Se鎖售之產品)或與10%菊糖(諸如以商似祕此⑧ 品)°尤其較佳之益菌助生質之組合為鳩短鏈果 秦醣與30%菊糖。 不 現將藉助於實例來描述根據本發明之嬰兒配方食 般組合物。該配方食品含有蛋 6 π贫曰貝源。咸信蛋白質 對本發明並不重要,只要其可八' 、 要求且域保令人滿意之成長即可。 田 取低 , 此可使用以乳渣晷 二白及其混合物為主之蛋白質源 之蛋白貝源。就礼清蛋白而言,該蛋白質來 “'、 或甜乳清或其混合物為主,且可括' 以馱乳清 球蛋白及β-乳球蛋白。 _所要比例之心乳 該等蛋白質可為完整祕經轉的,或為終蛋白質與 I21853.doc 200815023 ι水解蛋白質之混合物。合 古^ ^ ^
症危險之嬰^言,可能需要提^部處=解生之牛蛋奶= (水解程度處於2%與20%之間)m經水解之.蛋白賊M ㈣水解過程可視需要依此項技術已知之方式進行。ς例 而言,可藉由一或多値步驟,^^ 不含乳糖,則可見該蛋白質在水解過程期間較不到 胺酸阻隔。此使得離胺酸阻隔程度能夠自約15重%她錐 胺酸降至約10重量%以下離胺酸;例如約7重量%離胺: 其顯著改良該蛋白質源之營養品質。 根據本發明之嬰兒配方食品含有碳水化合物源。⑽ 習知見於嬰兒配方食品中之任何碳水化合物源(諸如乳 糖、庶糖、麥芽糊精、澱粉及其混合物),但較佳俨 化合物源為乳糖。該等碳水化合物源較佳提供χ35=ζ 之間的配方食品總能量。 根據本發明之嬰兒配方食品含有脂 '質源。該脂質源可為 =適用於嬰兒配方食品之脂質或脂肪。較佳脂肪源包括 才示2精、高油酸葵花籽油及高油酸紅花子油。亦可添加 必而脂肪酸亞麻油酸及α-亞麻油鐵.,如同少量人有7人曰 預先形成之二十碳四烯酸及二十二碳六烯酸之油,::: 油或微生物油。總體而言,脂肪含量較佳為提供游。與 55%之間的配方食品總能量之含量。脂肪源較佳具有約5 1 至約…之η·6脂肪酸與η_3脂肪酸之比例;例如約1 10:1 〇 121853.doc -12· 200815023 女兒配方食品亦將合右 ^ ^ ,胃 有在日常飲食中視為必需且# 營養上大量之維生素及。已 2而且為 確定最低要求。放札所 ' 對特疋維生素及礦物質 _ " R貝、維生素及其他視情況存在於嬰兒 配方食品中之營養物包括 什任叫兒 、准生素A、維生素b 1、维生音 B2、維生素B6、維生素m 夺、素 C、雉决去TV、‘ 算生素E、維生素K、維生素 C 、准生素D、茶酸、肌 驗、每、碟、诚、鐵r 生物素、泛酸、膽 版 、鐵鎮、鋼、辞、錳、氯化物、鉀、
㈣二、牛磺酸及乙―肉驗。通常以鹽之形式添加 廣物貝。特疋礦物質及其他維生素之存在及量將視意向 兒群體而變化。 ^ 在必要時 大豆卵磷脂 物。 嬰。兒配方食品可含有乳化劑及穩定劑,諸如 早甘油酯及二甘油酯之檸檬酸酯及其類似 嬰兒配方食品可視情況含有可能具有有益效應之其他物 質:諸如乳鐵傳遞蛋白、核普酸、核芽及其類似物。 取終’配方食品將含有鼠李糖乳酸桿菌ATCC 53 103或 鼠李糖乳酸桿菌CGMCC〗.3724、唾液鏈球菌dsm」3〇84 及嗜熱鏈球菌TH4®,其各為104至10i2 cfu/g組合物(乾重) 及0.3%至6%之90% GOS與1 0%果寡醣之混合物的之間的 量。 可以任何合適方式製備該配方食品。舉例而言,其可藉 由將蛋白質、碳水.化合物源及脂肪源以合適比例掺合在一 起來製備。若使用此方式,則在此時可包括乳化劑。此時 可添加維生素及礦物質.,但通常稍後添加以避免熱降解。 121853.doc -13- 200815023 可將任何親脂性維生素、乳化劑乃1y ^ u w及其類似物溶解至脂肪源 中,隨後進行掺合。接著可混入士 ^^ 4奶入水(較佳為已經受逆滲透 之水)以形成液體混合物。水溫便利地為約5〇它至约8〇 °c,以有助於成份之分散。可使用市售液化器來形成液體 混合物。接著使該液體混合物均質化;例如以兩個階段。 接著(例如)藉由將該液體混合物加熱至約至約15〇 °C範圍内之溫度歷時約5秒至約5分鐘,可將該液體混合物 ㈣理崎低細菌負載量。此可藉由蒸氣注入、高壓爸或 熱交換器(例如板式熱交換器)來進行。 接著,可將該液體混合物冷卻至約崎至約价;例如 精由急速冷卻。接著可再次將該液體混合物均質化;例如 以兩個階段’其中第一階段中為約1〇胳至约3〇服,且 第二階段中為約2 ^至㈣略。接著可將經均質化之 混合物進—步冷卻,以添加任何熱敏組份;諸如維生素及 量… 將該均質化混合物轉務人$ 哭i? A嚀# P 口適乾燥裝置(諸如噴霧乾燥 态或冷凍乾燥器)中,且鯖 j 轉化為杨末。該粉末應具有小於 約5重1%之水分含量。 細菌菌株可根據任何合適方法來培養,且鄉 乾燥或喷霧乾燥而製 私 」以)冷凍 , 1 有以添加至乾燥嬰兒配方食品中。志 ’細困製劑可講自專門供應商,其已以適於添加至食: 嬰兒配方食品)之形式製備。藉由.乾燥混合二 囷固株添加至嬰兒配方食品中。 I21853.doc 14 200815023 若液體f品為較㈣,料將轉化混合物㈣,接著 將其在無菌條件下埴充 。。 …、充至。適谷益中’或可首先填充至容 且接著滅菌。接著獨立地提供細菌菌株,以備用於 在/肖耗%與液體混合。舉例而言,可提供封裝於獨立藥囊 中或含=體之包裝的獨立隔#中的細菌菌株。、 在另-實施财’組合物可為補充劑,其包括足以在個 體中達成所要效應之量的菌株。該投藥形式更適於目標年
齡組上端之兒童。么益辞彼 兄里、、、田囷囷株之母日劑量較佳在1〇4與1〇12 A之間。欲包括於補充劑中之細菌的量將相應地視投予 該補充劑之方式*選擇。舉例而言,若該補充劑欲每曰投 予兩次,則各補充劑將含有1〇2至1〇6 _之各細菌菌株。 補充劑可為例如錠劑、膠囊、片劑或液體之形式。補充劑 可進乂 έ有保濩性水膠體(諸如膠、蛋白質、改質殿 粉)、黏合劑、成膜劑、封裝劑/封裝材料、壁/殼材料、基 貝化α物、塗層、乳化劑、表面活性劑、助溶劑(油、脂 肪、蝶、_鱗脂等)、吸收劑、載劑、填充劑、複合化合 物、为政劑、濕潤劑、加工助劑(溶劑)、流化劑、味覺掩 敝劑、增重劑、膠凝劑及成膠劑。補充劑亦可含有習知醫 藥添加劑及佐劑、賦形劑及稀释劑,其包括(但不限於) 水、任何來源之明膠、植物膠、木質素磺酸鹽 (ligninsulfonate)、滑石粉、糖、澱粉、阿拉伯膠、植物 油、聚烷二醇、調味劑、防腐劑、穩定劑、乳化劑、緩衝 劑、潤滑劑、著色劑、濕潤劑、填充劑及其類似物。 另外’補充劑可含有根據政府部,門(諸如USRDA)推薦適 121853.doc > 15- 200815023 於經口或經腸投藥之有機或無機載劑物質以及維生素、 物質痕量元素及其他微量營養物。 實例1 以下提供關於本發明的嬰兒配方食品之組合物之一 例。該組合物係僅以說明之方式提供。
營養物 … . 每 1G0 kcal 每公升. 能量(kcal) . , 100 670 蛋白質(g) 1.83 12.3 脂肪㈤ 53 35.7 亞麻油酸(g) 0.79 53 α-亞麻油酸(mg) 101 675 乳糖(g) 11.2 74.7 益菌助生質(70%FOS,30%菊糖)(g) 0.64 43 礦物質(g) 0.37 2.5 Na(mg) 23 150 K(mg) 89 590 Cl(mg) 64 430 Ca(mg) 62 410 P(mg) 31 210 Mg(mg) 7 50 Mn(pg) 8 50 Se(pg) 2 13 維生素A〇igRE) 105 700 維生素D^g) 1.5 10 維生素E(mgTE) 0.8 5.4 維生素Kl(pg) 8 54 維生素C(mg) 10 67 維生素Bl(mg) 0.07 0.47 維生素B2(mg) 0.15 1.0 煙酸(mg) 1 6.7 維生素B6(mg) 0.075 0.50 葉酸(pg) 9 60 泛酸(mg) 0.45 3 維生素Β12(μ§) 0.3 2 生物素(pg) 2.2 15 膽驗(mg) 10 67 Ee(mg) .1.2 8 12I853.doc -16- 200815023 %g) ,' 15 100 Cu(mg) 0.06 0.4 Zn(mg) 0.75 5 鼠李糖乳酸桿菌ATCC 53103 2.1〇/ cfu/g粉末 唾液鏈球菌DSM 13084 cfb/g粉末 嗜熱鏈球菌TH4 Uo/cfu/g 粉末 :~ 實例2 該實例將根據本發明之組合物對於一些通常與中耳炎有 關之病原體,的抑制效應與單獨使用該組合物之組份的效應 進行比較。所測試之細菌菌株為單獨或組合之鼠李糖乳酸 桿菌八丁€^ 53103及唾液鏈球菌]^綱13〇料。對其細菌菌株 之抑制活性進行分析的病原性菌株為肺炎鏈球菌之三種不 同菌株及耳炎差異球菌姑爾以)之一種菌 株。如先丽所述(Tagg及Bannister 1979),藉由使用延缓拮 抗作用來確定測試菌株之抑制譜。簡而言之,將約i 從之測試菌株的劃線培養物接種於在營養上合適之壤脂 上。在培育後,使用破璃載片移除肉眼可見之細菌生長, 且藉由暴露於氯仿蒸氣30分鐘而殺死瓊脂表面上之殘餘細 胞。使填脂表面通風30分鐘。使用藥簽將病原性菌株之 T〇dd Hewitt肉湯(THB,Difc〇)培養物〇8小時,37。〇以合 適角度越過原始劃線培養物之線而接種。在37。〇下於空^ 中二氧化碳中培育24小時後,量測各病原性菌株:二 之^度。j下表=展示結果’由該表可見對於所有經測試 鏈::二:株而I’鼠李糖乳酸桿菌ATCC 531°3及唾液 任-者的抑制效應。 、“獨使用之菌株中 121S53.doc 200815023 表 病原體 〇靠 S β m f w 異 m Ό 00 s 赛 f 兴 m δ H—^ 愈 槔 m 5 v£? d專 9 ^ S溶 粦 Μ N τ s細 °° m 來源 R R R R R R 抑制劑 菌株 培養基 53103 BACA 0 0 0 0 0 13804 BACA 0 17 17 16 53103/13804 BACA 20 18 18 53103 CHOC 0 13804 CHOC 10 53103/13804 CHOC 15
BACA血液瓊脂及鈣瓊脂 CHOC巧克力血液瓊月旨 來源R=參照培養物 121853.doc -18·
Claims (1)
- 200815023 十、申請專利範爵< L 一種適用於預防或治療中耳炎之組合物,其包含能夠強 化系統免疫反應之非病原性細菌菌株、能夠對於與形成 中耳穴相關之病原體施加抑菌效應之非病原性細菌菌株 及此夠對於與形成中耳炎相關之病原體施加殺菌效應之 非病原性細菌菌株。 2·如睛求項!之組合,.物,其中該能夠強化系統免疫反應之 菌菌株為鼠李糖乳酸桿菌(Lact〇bacinus化咖⑽⑶“ 3·如請求項1或2之組合物,其中該等殺菌及抑菌效應係由 單一細菌菌株產生。 4·如明求項3之組合物,其中該單一細菌菌株為易變微球 (rococcus varians)MCV8 或唾液鍵球菌(strept〇coccus salivarius)DSM 13084 〇 5·如請求項4之組合物,其進一步包含嗜熱鏈球菌 (StreptOC〇ccus therm〇philus)。 心迷任一晴求項之組合物,其為營養組合物。 7·郭請求項6之組合物」其包含104至1〇12 cfu/g組合物(乾 重)之各菌株。 士明求項6或7之組合物,其進一步包含至少一種以該組 合物之重量計〇·3%至6%之量的益菌助生質。 9·如現求項6至8中任一項之組合物,其為嬰兒配方食品。 士 %求項6至8中任一項之組合物,其為較大嬰兒配方食 品0 121853.doc 200815023 士明求項6至8中.任一項之組合物,其為成長乳。 12.如明求項〗至5中任一項之組合物,其為補充劑且其每單 位劑量包含104至l〇12cfu之各菌株。 /、 13· 一種如請求項1至11中任一項之組合物在製造用於預防 或治療争耳炎之藥物或治療性營養組合物中的用途。 121853.doc 200815023 七、指定代表圖: (一) 本案指定代表圖為:(無) (二) 本代表圖之元件符號簡單說明: 八、本案若有化學式時,請揭示最能顯示發明特徵的化學式: (無) 121853.doc
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CA2652517A1 (en) | 2007-12-21 |
CN101460181A (zh) | 2009-06-17 |
RU2009100890A (ru) | 2010-07-20 |
EP2035023A1 (en) | 2009-03-18 |
CL2007001739A1 (es) | 2008-04-18 |
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MX2008015950A (es) | 2009-01-09 |
RU2445361C2 (ru) | 2012-03-20 |
BRPI0712844A2 (pt) | 2012-07-31 |
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