TWI812800B - 包含雌馬酚作為有效成分之針對腸內細菌之抗菌劑 - Google Patents
包含雌馬酚作為有效成分之針對腸內細菌之抗菌劑 Download PDFInfo
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- clostridium difficile
- intestinal bacteria
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Abstract
本發明提供一種對人類引起感染病之困難梭狀桿菌等腸內細菌之抗菌藥。
本發明係一種包含雌馬酚作為有效成分之針對腸內細菌之抗菌劑。
Description
本發明係關於一種針對腸內細菌、特別是困難梭狀桿菌之抗菌劑。
困難梭狀桿菌(C.difficile)係症狀為腹瀉或腹痛、且亦存在導致死亡之情況之困難梭狀桿菌感染病(CDI)之原因菌。困難梭狀桿菌感染病作為院內感染病而成為問題(參照非專利文獻1)。
針對困難梭狀桿菌(C.difficile)感染病,使用甲硝唑等抗原蟲藥或萬古黴素等抗生素作為抗菌藥,然而,於困難梭狀桿菌形成芽孢之情形時,該等抗菌藥之效果降低。
產氣莢膜梭菌(C.perfringens)係人類常駐菌,亦可於家畜或魚中檢測到。產氣莢膜梭菌耐熱,作為食物中毒之原因菌而為人所知。
脆弱類桿菌(B.fragilis)係人類常駐菌,亦存在毒素型之細菌。脆弱類桿菌亦可謂大腸癌之原因。
雌馬酚係大豆之代謝最終產物,藉由腸內細菌而由大豆異黃酮生物合成。雌馬酚之結構與作為女性激素之雌激素類似,因此已經確立了來自大豆之雌馬酚之製造方法(參照專利文獻1),雌馬酚被用作對強健骨骼等有用之補充品之有效成分(參照專利文獻2)。
[專利文獻1]日本專利特開2017-18120號公報
[專利文獻2]日本專利特開2013-184959號公報
[非專利文獻1]神谷茂、Modern Media、第56卷 第10號2010[話題之感染病]pp.233-241
本發明之目的在於提供一種對人類引起感染病之困難梭狀桿菌等腸內細菌之抗菌藥。
本發明者針對人類腸內所合成之雌馬酚,調查其對腸內細菌之影響。其結果,確認雌馬酚依存於濃度地阻礙困難梭狀桿菌等腸內細菌之生長,進而阻礙困難梭狀桿菌之芽孢形成,發現可使用雌馬酚作為困難梭狀桿菌等腸內細菌之抗菌劑,從而完成本發明。
即,本發明如下所示。
[1]一種抗菌劑,其係包含雌馬酚作為有效成分之針對腸內細菌之抗菌劑。
[2]如[1]之抗菌劑,其中腸內細菌選自由困難梭狀桿菌(Clostridioides difficile)、產氣莢膜梭菌(C.perfringens)及脆弱類桿菌(B.fragilis)所組成之群。
[3]如[1]或[2]之抗菌劑,其阻礙困難梭狀桿菌之生長、且阻礙困難梭狀桿菌之芽孢形成。
[4]一種困難梭狀桿菌感染病之預防或治療劑,其包含如[1]至[3]中
任一項之抗菌劑。
[5]一種整腸藥,其包含雌馬酚作為有效成分。
[6]如[5]之整腸藥,其緩解腸內細菌之腹瀉及/或腹痛之症狀。
[7]一種大腸癌預防及/或治療劑,其包含雌馬酚作為有效成分。
本說明書包含成為本案之優先權之基礎的日本專利申請號2018-203055號之揭示內容。
困難梭狀桿菌藉由形成芽孢而對抗菌藥呈現抗藥性,且藉由分泌毒素而引起感染病。又,困難梭狀桿菌引起院內感染。雌馬酚可依存於濃度地阻礙困難梭狀桿菌之生長,且阻礙困難梭狀桿菌之芽孢形成,因此,可用作困難梭狀桿菌之抗菌藥,亦可防止困難梭狀桿菌之院內感染。
圖1係示出雌馬酚對困難梭狀桿菌027株之生長阻礙效果之圖。
圖2係示出大豆異黃酮對困難梭狀桿菌之生長之影響之圖。
圖3係示出雌馬酚對困難梭狀桿菌4菌株之生長阻礙效果之圖。
圖4係示出雌馬酚對其他菌種之生長阻礙效果之圖。
圖5係示出雌馬酚對困難梭狀桿菌形態之影響之圖。
圖6係示出雌馬酚對困難梭狀桿菌之芽孢形成之阻礙效果之圖。
以下,對本發明進行詳細說明。
本發明係包含雌馬酚(Equol,4',7-異黃烷二酚)作為有效成
分之針對腸內細菌之抗菌劑。
於本發明中,「抗菌」並非指殺死細菌,而是指抑制或阻礙細菌之生長及增殖,其與「殺菌」或「除菌」不同。
雌馬酚係大豆之代謝最終產物,其藉由腸內細菌而由大豆異黃酮生物合成。雌馬酚之化學式為C15H14O3,結構式如下所示。
有人能於腸內合成雌馬酚,有人不能,此依存於腸內菌群之中是否具有雌馬酚產生菌。
雌馬酚對一部分腸內細菌具有抗菌活性。作為雌馬酚具有抗菌活性之腸內細菌,可列舉困難梭狀桿菌(C.difficile(Clostridioides difficile),CD)、產氣莢膜梭菌(C.perfringens(Clostridium perfringens))、脆弱類桿菌(B.fragilis(Bacteroides fragilis))等,其中,雌馬酚對困難梭狀桿菌有效。
已知困難梭狀桿菌引起作為代表性院內感染病之困難梭狀桿菌感染病(Clostridioides difficile infection,CDI)。困難梭狀桿菌感染病為消化道感染病,其引起腸炎,伴隨腹瀉或腹痛之症狀,且亦存在伴隨發熱或白血球增多之情況,於嚴重之情形時,亦存在導致死亡之情況。困難梭狀桿菌形成芽孢,若CDI患者之排泄物中含有困難梭狀桿菌或其芽孢、特別是芽孢(spore),則亦存在該等經由排泄物而殘存於盥洗室、床、地板等醫院內環境中,從而會引起院內感染之嚴重問題。針對困難梭狀桿菌,使用甲硝唑等抗原蟲藥或萬古黴素等抗生素作為抗菌藥,然而,於形
成芽孢之情形時,對抗菌藥呈現抗藥性,該等抗菌藥之效果降低。殘存之芽孢發芽而造成困難梭狀桿菌感染病復發。
產氣莢膜梭菌(C.perfringens(Clostridium perfringens))亦稱為產氣莢膜桿菌,存在於人類或家畜、魚等動物之腸內,釋放出毒素即腸毒素,從而引起食物中毒。產氣莢膜梭菌廣泛分佈於土壤、河川、海等中,因此容易混入至食品或烹飪器具,且於芽孢狀態下具有耐熱性,因此容易誘發食物中毒。進而,產氣莢膜梭菌被報告亦與老化或癌等有關。
脆弱類桿菌(B.fragilis(Bacteroides fragilis))係存在於人類之腸內的專性厭氧性革蘭氏陰性桿菌,不形成芽孢。其於侵入血管或腹腔內之情形時,存在引起感染病之情況。脆弱類桿菌被報告與大腸癌之發病有關。
雌馬酚依存於濃度地阻礙上述腸內細菌、特別是困難梭狀桿菌之生長,進而阻礙芽孢之形成。藉由阻礙腸內之困難梭狀桿菌之生長,可改善、預防困難梭狀桿菌感染病。又,藉由阻礙腸內之困難梭狀桿菌之生長,可防止困難梭狀桿菌感染病因院內感染等而擴張。進而,由於雌馬酚可阻礙腸內之困難梭狀桿菌之芽孢形成,故可預防困難梭狀桿菌感染病藉由芽孢而擴張。
雌馬酚對腸內菌群中不存在雌馬酚產生菌之受驗者、及存在雌馬酚產生菌之受驗者有用。
雌馬酚是否對腸內細菌具有抗菌活性可藉由如下方式調查:將腸內細菌培養至一定之菌量,於其培養基中添加各濃度之雌馬酚並繼續培養,確認雌馬酚對腸內細菌之生長之影響。培養例如可於厭氧性條件下、30~40℃下進行。
雌馬酚以大豆所含之大豆苷為起始物質,藉由腸內細菌之作用,依照大豆苷→大豆苷元→二氫大豆苷元→雌馬酚之路徑而合成。可使用與該等反應相關之細菌或自細菌提取之酵素而合成雌馬酚。雌馬酚之製造方法例如於日本專利特開2017-205117號公報、日本專利特開2017-18120號公報、日本專利特開2013-188220號公報、WO2009/084603等中有所記載,可依據該等記載而進行製造。
雌馬酚可為合成品,亦可為藉由醱酵所得之物質。作為藉由醱酵所得之物質,醱酵之素材只要為包含大豆苷元之素材即可,例如為來自大豆及/或大豆胚軸之素材,可列舉含雌馬酚之大豆胚軸醱酵物、含雌馬酚之大豆胚軸提取物醱酵物、含雌馬酚之大豆醱酵物、含雌馬酚之大豆提取物醱酵物等醱酵物中之雌馬酚。
藉由將本發明之包含雌馬酚作為有效成分之針對腸內細菌之抗菌劑應用於醫院內之設施或設備,可防止由困難梭狀桿菌、產氣莢膜梭菌或者脆弱類桿菌所導致之污染擴張,例如亦可針對困難梭狀桿菌阻礙其生長,防止困難梭狀桿菌感染病之擴張。於該情形時,該抗菌劑可製成包含10μg/mL~100g/mL之雌馬酚的水合劑、液劑、油劑、粉劑、粒劑、溶膠劑(懸浮劑)、凝膠劑等劑型而使用。
又,本發明之包含雌馬酚作為有效成分之針對腸內細菌之抗菌劑可作為醫藥組合物投予至感染困難梭狀桿菌、產氣莢膜梭菌或者脆弱類桿菌之受驗者而使用,例如,其為困難梭狀桿菌感染病之預防或治療劑。
又,包含雌馬酚作為有效成分之醫藥組合物可用作整腸藥。該整腸藥可用於緩解腸內細菌之腹瀉及/或腹痛之症狀。
進而,已知雌馬酚具有抗菌活性之腸內細菌與大腸癌之發病有關。因此,包含雌馬酚作為有效成分之醫藥組合物可用作大腸癌之預防及/或治療劑。
該等抗菌劑或預防或治療劑可包含生理學上可容許之載體或稀釋劑。作為載體,可列舉生理鹽水、磷酸鹽緩衝生理鹽水、葡萄糖溶液、緩衝生理鹽水等。對感染困難梭狀桿菌、產氣莢膜梭菌或者脆弱類桿菌之受驗者所使用之用於預防或治療感染病之醫藥組合物可以各種形態投予。例如,可以錠劑、膠囊劑、顆粒劑、散劑、糖漿劑等形態藉由經口投予,或者以注射劑、點滴劑、栓劑等形態藉由非經口投予而投予。投予量根據症狀、年齡、體重等而不同,通常情況下,於經口投予之情形時,針對成人,1日約0.01mg~1000mg,可將該等一次性或分數次投予。又,於非經口投予之情形時,可藉由皮下注射、肌肉注射或靜脈注射一次性投予約0.01mg~1000mg。
本發明亦包含含有雌馬酚之食品組合物。作為食品組合物,可列舉點心類(曲奇、餅乾、巧克力點心、薯片、蛋糕、口香糖、糖果、軟糖、饅頭、羊羹、布丁、果凍、酸乳酪、冰淇淋、雪酪等)、麵包、麵類、米飯類、系列食品、飲料(液劑、清涼飲料、碳酸飲料、營養飲料、粉末飲料、果實飲料、乳飲料、果凍飲料等)、湯(粉末、凍乾)、味噌湯(粉末、凍乾)等。
食品組合物不僅包含普通食品,亦包含具有功能之食品,例如包含健康食品、功能性表示食品、特定保健用食品、營養功能食品等。其中,特定保健用食品係指表示以下要旨之食品,即,於飲食生活中為了特定保健目的而攝入,藉由該攝入而可期待該保健之目的。作為該等
食品,例如亦可附有以下要旨之表示,即,用於調整腸胃或用於緩解腹瀉或腹痛。
於本發明之食品組合物中,雌馬酚於每1次攝入時,例如較佳為可攝入0.1mg~30mg,更佳為可攝入2mg~20mg,進而較佳為可攝入3mg~10mg。作為雌馬酚之1次攝入量之下限值之例,可列舉0.2mg、0.5mg、1mg、2mg、3mg、4mg、及5mg,作為上限值之例,可列舉30mg、20mg、10mg、6mg、5mg,雌馬酚之每1次之攝入量之較佳範圍可藉由該上限值與該下限值之組合而表示。
於本發明之食品組合物中,雌馬酚之每1日之攝入量較佳為,如上述為30mg以下。作為雌馬酚之每1日之攝入量,較佳為0.1mg~30mg,更佳為2mg~20mg,進而較佳為3mg~10mg。作為雌馬酚之每1日之攝入量之下限值之例,可列舉0.2mg、0.5mg、1mg、2mg、3mg、4mg、及5mg,作為上限值之例,可列舉30mg、20mg、10mg、6mg、5mg,雌馬酚之每1日之攝入量之較佳範圍可藉由該上限值與該下限值之組合而表示。每1日可攝入之雌馬酚可一次性攝入,或者可分複數次(例如2次、3次、4次、及5次)攝入。
藉由以下之實施例對本發明具體進行說明,但本發明並不受該等實施例限定。
將困難梭狀桿菌(NAP1/027株)添加於包含100μg/mL、75μg/mL、50μg/mL及25μg/mL之濃度之雌馬酚的培養基中(0小時),繼續進行培
養,確認直至培養開始後24小時為止之對生長之影響。培養條件全部於厭氧下、35℃下實施。
又,由於雌馬酚溶解於DMSO(dimethy sulphoxide,二甲基亞碸)中使用,故亦對僅添加DMSO者進行測定而作為對照。
細菌之生長係藉由對培養基之600nm之吸光度(OD600)進行測定而調查。
將結果示於圖1。如圖1所示,與對照相比而言,添加雌馬酚者之困難梭狀桿菌之生長更慢,認為被雌馬酚所阻礙。又,隨著雌馬酚之添加濃度變高,困難梭狀桿菌之生長速度變慢,因此阻礙依存於雌馬酚之濃度。
雌馬酚係藉由腸內細菌、自大豆苷(daizine)經歷大豆苷元(daidzein),二氫大豆苷元(dihydro daidzein)而生成之最終產物。藉由與實施例1相同之方法,測定雌馬酚(100μg/mL、50μg/mL)、大豆苷元(50μg/mL)及二氫大豆苷元(100μg/mL、50μg/mL)對困難梭狀桿菌之生長之阻礙。
將結果示於圖2。如圖2所示,於添加大豆苷元、二氫大豆苷元50μg/ml之培養基中,無法確認與對照之明確之差異,二氫大豆苷元(dihydrodaidzein)100μg/ml與雌馬酚50μg/ml同等程度地阻礙困難梭狀桿菌之生長,雌馬酚100μg/ml之阻礙之程度更大。
藉由與實施例1相同之方法而驗證除027株以外之困難梭狀桿菌之臨床分離株(TUM12745株、TUM12806株及TUM12855株)是否亦受到雌馬酚(100μg/mL)之生長阻礙。
將結果示於圖3。如圖3所示,於實驗所用之全部菌株中確認受到同樣之阻礙。
藉由與實施例1同樣之方法驗證雌馬酚(100μg/mL)是否亦對除困難梭狀桿菌以外之細菌產生阻礙。
將結果示於圖4。如圖4所示,大腸菌(大腸桿菌(E.coli或Escherichia coli)不受影響。產氣莢膜梭菌(C.perfringens(Clostridium perfringens))及脆弱類桿菌(B.fragilis(Bacteroides fragilis))可觀察到影響。特別是雖然脆弱類桿菌完全未確認增殖,但於試驗結束之52小時之時間點,將脆弱類桿菌移植到未添加雌馬酚之培養基中,其結果形成菌落,因此可知脆弱類桿菌僅生長受到阻礙,其未被殺死。
藉由與實施例1相同之方法,使雌馬酚(100μg/mL)作用,利用革蘭氏染色對困難梭狀桿菌進行染色,由此驗證雌馬酚對困難梭狀桿菌(NAP1/027株)之形態之影響。
將染色圖像示於圖5。圖5係培養第8日之革蘭氏染色之圖像。與對照之細胞相比而言,添加有100μg/ml雌馬酚之細胞呈現細長之形態。
為了驗證雌馬酚(100μg/mL)對困難梭狀桿菌之芽孢形成之影響,於困難梭狀桿菌生長至飽和狀態之培養基中添加雌馬酚,對所形成之芽孢之數量進行計數。
將結果示於圖6。如圖6所示,於自第2日開始之所有天數中,於對照中,芽孢較多,與此相對,於添加雌馬酚之培養基中,芽孢較少。
本發明之包含雌馬酚作為有效成分之抗菌劑對選自由困難梭狀桿菌、產氣莢膜梭菌及脆弱類桿菌所組成之群中之微生物具有抗菌作用,例如可預防或治療困難梭狀桿菌感染病,可防止由困難梭狀桿菌所導致之院內感染。
本說明書中引用之全部刊物、專利及專利申請係直接藉由引用而併入本說明書中。
Claims (5)
- 一種雌馬酚之用途,其係用於製造針對腸內細菌之抗菌劑,該腸內細菌係困難梭狀桿菌(Clostridioides difficile)或產氣莢膜梭菌(Clostridioides perfringens)。
- 如請求項1之用途,其中該抗菌劑係阻礙困難梭狀桿菌之生長、且阻礙困難梭狀桿菌之芽孢形成。
- 一種雌馬酚之用途,其係用於製造困難梭狀桿菌(Clostridioides difficile)或產氣莢膜梭菌(Clostridioides perfringens)感染病之預防或治療劑。
- 一種雌馬酚之用途,其係用於製造腸內細菌之腹瀉及/或腹痛之症狀的緩解藥,該腸內細菌係困難梭狀桿菌(Clostridioides difficile)或產氣莢膜梭菌(Clostridioides perfringens)。
- 一種雌馬酚之用途,其係用於製造阻礙困難梭狀桿菌之生長、且阻礙困難梭狀桿菌之芽孢形成的飲食品。
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JP7469778B2 (ja) | 2024-04-17 |
EP3875084A1 (en) | 2021-09-08 |
EP3875084A4 (en) | 2022-08-10 |
US20210379009A1 (en) | 2021-12-09 |
JP2024074853A (ja) | 2024-05-31 |
CA3117911A1 (en) | 2020-05-07 |
WO2020090789A1 (ja) | 2020-05-07 |
JPWO2020090789A1 (ja) | 2021-09-16 |
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