TWI816644B - 對於腸管之離子經細胞輸送體的作用劑、氯通道活化劑、腎疾患的預防或治療劑或排便促進劑 - Google Patents
對於腸管之離子經細胞輸送體的作用劑、氯通道活化劑、腎疾患的預防或治療劑或排便促進劑 Download PDFInfo
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- TWI816644B TWI816644B TW106135897A TW106135897A TWI816644B TW I816644 B TWI816644 B TW I816644B TW 106135897 A TW106135897 A TW 106135897A TW 106135897 A TW106135897 A TW 106135897A TW I816644 B TWI816644 B TW I816644B
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Abstract
本發明提供一種對於腸管之離子經細胞輸送體的作用劑,其含有比菲德氏菌屬(Bifidobacterium)、或乳桿菌屬(Lactobacillus)之菌或此等之處理物(但是,排除離子輸送體為氯通道且作用為抑制之情況、離子輸送體為Na+K+Cl-共輸送體(NKCC1)且作用為抑制之情況、菌為嬰兒型比菲德氏菌35624(Bifidobacterium infantis 35624)之情況、及菌為唾液乳桿菌UCC118(Lactobacillus salivarius UCC118)之情況)。本發明之劑在氯通道之活化、腎疾患之預防或治療及/或排便促進上有用,可作為醫藥、補品等使用。
Description
本發明係關於對於腸管之離子經細胞輸送體的作用劑、氯通道活化劑、腎疾患之預防或治療劑、或排便促進劑,此等含有特定菌或其處理物。
已知氯離子(Cl-)、鈣離子(Ca2+)、鈉離子(Na+)、鉀離子(K+)等不僅掌管水/電解質輸送、分泌、或細胞體積之調節等,而且在作為左右細胞反應的因子上扮演重要的角色。例如,氯通道為輸送氯離子的離子傳輸膜蛋白質。已報告各種類之離子經細胞輸送體存在於神經、肌肉、上皮等之細胞膜上,並參與各種生理功能或細胞防禦機構。
在腸管中,氯離子與下痢、便秘等病態關係密切,就氯離子平衡異常所造成之疾患而言,已知有難 治性便秘、肌肉緊張性萎縮症、腎結石等呈現高鈣尿症的疾患、不安、失眠症、囊胞性纖維症、癲癇、無感覺症、氣喘、支氣管炎、神經障礙等(專利文獻1)。
另一方面,已知加氏乳桿菌(Lactobacillus gasseri)之菌體、其菌體處理物、或此等之混合物,藉由抑制大腸氯通道而抑制水分分泌,其結果,具有使腸管之水分量減少的作用(專利文獻2)。但是,至目前為止,沒有關於可活化氯通道之菌等的報告。
[專利文獻1]日本特許第4786866號
[專利文獻2]日本特開第2014-101282號公報
本發明之目的為提供新穎的對於腸管之離子經細胞輸送體的作用劑、氯通道活化劑、腎疾患之預防或治療劑、或排便促進劑。再者,本發明之目的為提供具有對腸管之離子經細胞輸送體作用之能力、氯通道活化能力、腎疾患之預防或治療效果、或排便促進能力的新穎菌處理物及其製造方法。
本發明者為了解決上述課題而檢討,結果發現特定之菌或此等之處理物會對腸管之離子經細胞輸送 體作用,活化氯通道,在腎疾患之預防或治療上有效,或具有排便促進作用,進一步反覆檢討,得到各種新知識,而完成本發明。
亦即,本發明係關於以下之發明。
[1]一種對於腸管之離子經細胞輸送體的作用劑,其含有比菲德氏菌屬(Bifidobacterium)、或乳桿菌屬(Lactobacillus)之菌或此等之處理物(但是,排除離子輸送體為氯通道且作用為抑制的情況、離子輸送體為Na+K+Cl-共輸送體(NKCC1)且作用為抑制的情況、菌為嬰兒型比菲德氏菌35624(Bifidobacterium infantis 35624)的情況、以及菌為唾液乳桿菌UCC118(Lactobacillus salivarius UCC118)的情況)。
[2]如前述[1]記載之劑,其中,對於離子經細胞輸送體之作用為氯通道之活化。
[3]如前述[1]或[2]記載之劑,其為排便促進劑。
[4]一種腎疾患之預防或治療劑,其含有比菲德氏菌屬(Bifidobacterium)、或乳桿菌屬(Lactobacillus)之菌或此等之處理物,菌處理物為不含菌發酵代謝物之處理物,投予對象排除犬或貓。
[5]如前述[1]至[4]中任一項記載之劑,其中,比菲德氏菌屬(Bifidobacterium)之菌為長比菲德氏菌(Bifidobacterium longum)、雙歧比菲德氏菌(Bifidobacterium bifidum)、短比菲德氏菌(Bifidobacterium breve)、青春比菲德氏菌(Bifidobacterium adolescentis)、嬰兒型比菲德氏菌(Bifidobacterium infantis)、假長比菲德氏菌(Bifidobacterium pseudolongum)、或嗜熱比菲德氏菌(Bifidobacterium thermophilum)。
[6]如前述[1]至[5]中任一項記載之劑,其中,比菲德氏菌屬(Bifidobacterium)之菌為長比菲德氏菌CLA8013菌株(Bifidobacterium longum CLA8013,寄存編號:NITE BP-02352)或長比菲德氏菌MM-2菌株(Bifidobacterium longum MM-2,寄存編號:NITE BP-818)。
[7]如前述[1]至[6]中任一項記載之劑,其中,乳桿菌屬(Lactobacillus)之菌,為嗜酸乳桿菌(Lactobacillus acidophilus)、約氏乳桿菌(Lactobacillus johnsonii)、加氏乳桿菌(Lactobacillus gasseri)、乾酪乳桿菌(Lactobacillus casei)、植物乳桿菌(Lactobacillus plantarum)、德氏乳桿菌保加利亞亞種(Lactobacillus delbrueckii subsp.bulgaricus)、德氏乳桿菌乳亞種(Lactobacillus delbrueckii subsp.lactis)、發酵乳桿菌(Lactobacillus fermentum)、瑞士乳桿菌(Lactobacillus helveticus)、副乾酪乳桿菌副乾酪亞種(Lactobacillus paracasei subsp.paracasei)、洛德乳桿菌(Lactobacillus reuteri)、鼠李糖乳桿菌(Lactobacillus rhamnosus)、唾液乳桿菌(Lactobacillus salivarius)、或短乳桿菌(Lactobacillus brevis)。
[8]如前述[1]至[6]中任一項記載之劑,其中,乳桿菌屬(Lactobacillus)之菌為嗜酸乳桿菌JCM1132株(Lactobacillus acidophilus JCM1132)、約氏乳桿菌JCM2012
株(Lactobacillus johnsonii JCM2012)或加氏乳桿菌JCM5813株(Lactobacillus gasseri JCM5813)。
[9]一種菌株,其為長比菲德氏菌CLA8013菌株(Bifidobacterium longum CLA8013,寄存編號:NITE BP-02352)。
[10]一種菌處理物之製造方法,其為比菲德氏菌屬(Bifidobacterium)或乳桿菌屬(Lactobacillus)之菌處理物之製造方法,包含:將菌懸浮於不含糖之溶劑(但是,排除精製水及生理食鹽水)、或含DMEM(Dulbecco’s Modified Eagle Medium)及Ham’s F-12之溶劑中,得到菌懸浮液之步驟;將菌懸浮液於厭氧下放置之步驟;及將經放置之菌懸浮液的上清液用過濾器過濾,以得到之濾液作為處理物的步驟;該方法不含發酵步驟。
[11]一種上清液,其為含有比菲德氏菌屬(Bifidobacterium)或乳桿菌屬(Lactobacillus)之菌、及不含糖之溶劑(但是,排除精製水及生理食鹽水)、或含DMEM及Ham’s F-12之溶劑的懸浮液之上清液(但是,上清液不含比菲德氏菌屬(Bifidobacterium)或乳桿菌屬(Lactobacillus)之菌)。
本發明可提供新穎之對於腸管之離子經細胞輸送體的作用劑。本發明之劑在氯通道之活化、腎疾患之預防或治療之點、或具有排便促進作用之點上,具有特別顯著之效果。
第1圖表示藉由屬於比菲德氏菌屬(Bifidobacterium)之菌的處理物所致之腸管上皮細胞(T84)之短路電流變化圖。
第2圖表示藉由屬於乳桿菌屬(Lactobacillus)之菌的處理物所致之腸管上皮細胞(T84)之短路電流變化圖。
第3圖表示至血清BUN(尿素氮)測定為止之試驗時程的圖。
第4圖表示血清BUN值之測定結果的圖。
第5圖表示紅色糞便排出時間之測定結果的圖。
第6圖表示藉由各溶劑(精製水、生理食鹽水、DMEM/F-12、或PBS(-))處理後之8013E於腸管上皮細胞(T84)之短路電流變化圖。
第7圖表示血清BUN值之測定結果的圖。
本發明提供一種對於腸管之離子經細胞輸送體的作用劑,其含有屬於比菲德氏菌屬(Bifidobacterium)、或乳桿菌屬(Lactobacillus)之菌、或此等之處理物。具體而言,例如提供氯通道活化劑、腎疾患之預防或治療劑、或排便促進劑。本發明之劑,只要含有上述乳酸菌、或其處理物即可,亦可進一步含有其他成分。上述菌可單獨使用1種,亦可將2種以上混合使用。
本發明之劑含有屬於比菲德氏菌屬(Bifidobacterium)、或乳桿菌屬(Lactobacillus)之菌。就屬於比菲德氏菌屬(Bifidobacterium)之乳酸菌而言,以長比菲德氏菌(Bifidobacterium longum)、雙歧比菲德氏菌(Bifidobacterium bifidum)、短比菲德氏菌(Bifidobacterium breve)、青春比菲德氏菌(Bifidobacterium adolescentis)、嬰兒型比菲德氏菌(Bifidobacterium infantis)、假長比菲德氏菌(Bifidobacterium pseudolongum)、嗜熱比菲德氏菌(Bifidobacterium thermophilum)等為較佳,其中,以長比菲德氏菌(Bifidobacterium longum)、或雙歧比菲德氏菌(Bifidobacterium bifidum)為更佳。就長比菲德氏菌(Bifidobacterium longum)、或雙歧比菲德氏菌(Bifidobacterium bifidum)而言,以長比菲德氏菌CLA8013(Bifidobacterium longum CLA8013,寄存編號:NITE BP-02352)、長比菲德氏菌ID8009(Bifidobacterium longum ID8009)、長比菲德氏菌ID1163(Bifidobacterium longum ID1163)、長比菲德氏菌MM-2(Bifidobacterium longum MM-2:ID1001,寄存編號:NITE BP-818)、或雙歧比菲德氏菌ID8005(Bifidobacterium bifidum ID8005)為較佳,以長比菲德氏菌CLA8013(Bifidobacterium longum CLA8013,寄存編號:NITE BP-02352)、或長比菲德氏菌MM-2(Bifidobacterium longum MM-2:ID1001,寄存編號:NITE BP-818)為進一步更佳。就屬於乳桿菌(Lactobacillus)屬之乳酸菌而言,以嗜酸乳桿菌(Lactobacillus acidophilus)、約氏乳桿菌(Lactobacillus
johnsonii)、加氏乳桿菌(Lactobacillus gasseri)、乾酪乳桿菌(Lactobacillus casei)、植物乳桿菌(Lactobacillus plantarum)、德氏乳桿菌保加利亞亞種(Lactobacillus delbrueckii subsp.bulgaricus)、德氏乳桿菌乳亞種(Lactobacillus delbrueckii subsp.lactis)、發酵乳桿菌(Lactobacillus fermentum)、瑞士乳桿菌(Lactobacillus helveticus)、副乾酪乳桿菌副乾酪亞種(Lactobacillus paracasei subsp.paracasei)、洛德乳桿菌(Lactobacillus reuteri)、鼠李糖乳桿菌(Lactobacillus rhamnosus)、唾液乳桿菌(Lactobacillus salivarius)、短乳桿菌(Lactobacillus brevis)等為較佳,其中,以嗜酸乳桿菌(Lactobacillus acidophilus)、加氏乳桿菌(Lactobacillus gasseri)、或約氏乳桿菌(Lactobacillus johnsonii)為更佳。就嗜酸乳桿菌(Lactobacillus acidophilus)、加氏乳桿菌(Lactobacillus gasseri)、或約氏乳桿菌(Lactobacillus johnsonii)而言,以嗜酸乳桿菌JCM1132(Lactobacillus acidophilus JCM1132;ID2152T)、加氏乳桿菌JCM5813(Lactobacillus gasseri JCM5813;ID2145)、約氏乳桿菌JCM2012(Lactobacillus johnsonii JCM2012;ID2153T)為更佳,以嗜酸乳桿菌JCM1132(Lactobacillus acidophilus JCM1132;ID2152T)為進一步更佳。
此等菌體可容易地從例如ATCC或IFO等機構或財團法人日本比菲德氏菌中心等取得。此外,長比菲德氏菌CLA8013及長比菲德氏菌MM-2係以下述寄存編號寄存於
獨立行政法人製品評價技術基盤機構特許微生物寄託中心者(日本千葉縣木更津市上總鎌足2-5-8,122號室,郵遞區號292-0818)。又,亦可適當地使用市售者。
長比菲德氏菌CLA8013(寄存日:2016年9月21日,寄存編號:NITE BP-02352,顯示標識:Bifidobacterium longum CLA8013)
長比菲德氏菌MM-2(寄存日:2009年9月17日,寄存編號:NITE BP-818,顯示標識:Bifidobacterium longum MM-2)
本發明之劑不含嬰兒型比菲德氏菌35624(Bifidobacterium infantis 35624)、及唾液乳桿菌UCC118(Lactobacillus salivarius UCC118)。
在發揮本發明之效果的限制下,亦可含有上述乳酸菌以外之有用菌。可列舉:例如,枯草芽孢桿菌(Bacillus subtilis)129 BIO H(α)等枯草芽孢桿菌;馬鈴薯桿菌(Bacillus mesentericus)、多發酵芽孢桿菌(Bacillus polyfermenticus)等糖化菌;例如,凝結芽孢桿菌(Bacillus coagulans)等有孢子性乳酸菌;東洋芽孢桿菌(Bacillus toyoi)、地衣芽孢桿菌(Bacillus licheniformis)、丁酸梭菌(Clostridium butyricum)等酪酸菌;腸膜明串珠菌(Leuconostoc mesenteroides)等明串珠菌屬(Leuconostoc),乳酸乳球菌(Lactococcus lactis)、乳脂乳球菌(Lactococcus cremoris)等乳球菌屬(Lactococcus),嗜鹽四聯球菌(Tetragenococcus halophilus)等四聯球菌屬(Tetragenococcus),乳酸片球菌(Pediococcus acidilactici)、戊糖片球菌(Pediococcus pentosaceus)等片球菌屬(Pediococcus)。酒球菌(Oenococcus oeni)等酒球菌屬(Oenococcus)等乳酸球菌;其他有用菌。
此等菌體可從例如ATCC或IFO等機構容易地取得。又,亦可適當地使用市售者。
上述菌體可藉由周知之條件或以其為基準之條件培養而得到。例如,通常在含葡萄糖、酵母萃取物、蛋白腖等之液體培養基中,將1種或2種以上之上述乳酸菌,以通常約25至45℃左右,約4至72小時左右,進行好氧或厭氧培養,從培養液收集菌體,洗淨,可得到濕菌體。
在本發明中所用之菌,以活菌為較佳,然而即使為含乾燥物(菌體乾燥物)等之死菌亦可,亦可為混合有活菌與死菌者等。就菌體乾燥物而言,以單微米(single micron)之菌體乾燥物為較佳。菌體乾燥物通常意指經乾燥之各個菌體或經乾燥之菌體的集合物。又,單微米意指將小數第1位四捨五入之1至10μm。
在本發明中,菌之處理物意指對菌施加任何處理者,其處理並無特別限定。就菌之處理物而言,例如,可為該菌體與溶劑之混合液、其上清液或離心上清液等,亦可為將彼等藉由過濾器等過濾之濾液等。前述之菌體與溶劑之混合液,只要為將菌體與溶劑混合者即可,亦可為懸浮液。就菌體與溶劑之混合液而言,例如,只要使 用於約25至45℃左用,在好氧或厭氧條件下放置約30分鐘至3日左右者即可,亦可直接使用經混合者。又,菌之處理物亦可為從菌之處理物萃取之萃取物等。在本發明中,有時將此等簡記為萃取物。又,菌之處理物亦可為例如將濾液、萃取物或混合液依照周知技術進行濃縮、粉末化、凍結乾燥者。此外,本發明中之菌之處理物不含菌發酵代謝物。就溶劑而言,可列舉例如:包含磷酸緩衝液(PBS)等之不含糖溶劑、或DMEM/F-12等培養液等。磷酸緩衝液(PBS)可使用添加鈣鹽及鎂鹽之磷酸緩衝液(PBS(+)),亦可使用無添加鈣鹽及鎂鹽之磷酸緩衝液(PBS(-))。離心之條件無特別限定,然而離心力可為2,500至10,000×G。過濾器之孔眼大小,只要為能將菌過濾之孔眼大小即可,例如,可使用市售之0.1μm至1μm(例如0.22μm)的過濾器。DMEM/F-12等培養液可含糖,亦可不含糖。此外,本發明中之溶劑不包含精製水及生理食鹽水。
在本發明中,菌發酵代謝物意指例如將菌播種在含脫脂奶粉、乳糖、葡萄糖、蛋白腖、酵母萃取物等之菌增殖培養基中,於一定溫度(例如20℃至40℃)、一定時間(例如2至60小時)培養後的菌發酵代謝液等。
本發明中之菌之處理物,可含有菌,亦可不含有,以不含有為較佳。但是,在本發明的菌之處理物中含有不進行發酵之菌的情況不在前述之範圍內。
在本發明中,腸管意指例如:十二指腸、空腸、回腸等小腸;盲腸、上行結腸、橫結腸、下行結腸、 S狀結腸、直腸等大腸等。再者,在本發明中,腸管可為在體內之狀態,亦可將腸管切出至體外,或可為切開腹部將腸管之一部分從活體取出。
在本發明中,離子經細胞輸送體意指經由細胞中介之離子輸送體,有時亦以經細胞離子輸送體來表示。就離子輸送體而言,可列舉例如:離子通道、離子共輸送體、離子交換輸送體等。就離子通道而言,可列舉例如:氯通道、鈣通道、鈉通道、鉀通道、陽離子通道等。就氯通道而言,可列舉例如CFTR氯通道等。就離子共輸送體而言,可列舉例如Na+K+Cl-共輸送體(NKCC1)等。就離子交換輸送體而言,可列舉例如Cl-/HCO3 -交換輸送體(DRA)等。
在本發明中,對離子經細胞輸送體作用意指例如使離子經細胞輸送體之功能活化或抑制等,使其功能變化等。具體而言,例如:使氯通道活化、使鈣通道活化、使鈉通道活化、使鉀通道活化、使陽離子通道活化、使Na+K+Cl-共輸送體(NKCC1)活化、使Cl-/HCO3 -交換輸送體(DRA)活化等。又,具體而言,例如:使鈣通道抑制化、使鈉通道抑制化、使鉀通道抑制化、使陽離子通道抑制化、使Cl-/HCO3 -交換輸送體(DRA)抑制化等。
但是,在本發明中不包含:離子輸送體為氯通道且作用為抑制之情況、離子輸送體為Na+K+Cl-共輸送體(NKCC1)且作用為抑制之情況、菌為嬰兒型比菲德氏菌35624(Bifidobacterium infantis 35624)之情況、以及菌 為唾液乳桿菌UCC118(Lactobacillus salivarius UCC118)之情況。
以下關於本發明之對於腸管之離子經細胞輸送體的作用劑,針對每種態樣加以說明。具體而言,說明氯通道之活化劑、腎疾患之預防或治療劑、及排便促進劑。
就本發明之一態樣而言,可列舉例如氯通道之活化劑。在本發明中,將氯通道活化意指例如與本發明之劑投予前之狀態相比,離子之經細胞輸送能力變大等。離子之經細胞輸送能力,可藉由例如短路電流法(唐木晉一郎、桑原厚和,日藥理誌(Folia Pharmacol.Jpn.)123,211至218(2004),上皮膜之電解質輸送之電生理學測定法:短路電流法)來測定。
就本發明之一態樣而言,可列舉例如腎疾患之預防或治療劑。在本發明中,腎疾患之預防或治療劑在腎疾患之預防或治療上有用。在本發明中,腎疾患之「預防」意指例如對腸管之如離子通道的離子細胞經輸送體作用,阻止腎疾患之發病,腎疾患之「治療」,意指例如使腎疾患所導致之症狀緩解、或治癒。就腎疾患而言,可列舉例如:腎功能衰竭、尿毒症、糖尿病性腎症、慢性絲球體腎炎等。腎疾患可為例如慢性者,亦可為急性者。就慢性腎疾患而言,可列舉例如:慢性腎功能衰竭、慢性絲球體腎炎、糖尿病性腎症、腎病症候群等。就急性腎疾患而言,可列舉例如:急性絲球體腎炎、急性腎功能衰竭、溶血性 尿毒症症候群等。
在本發明中,判斷腎疾患經改善之方法,無特別限定,可藉由周知之方法等來判斷。就用於判斷藉由投予本發明之菌或其處理物、或本發明之劑,而使腎疾患經改善之方法而言,可列舉例如測定血清中BUN(尿素氮)之方法等。在使用測定血清中BUN之方法的情況,例如,藉由菌或菌處理物、或劑之投予,和投予此等之前相比,BUN值下降時,可判定為對腎疾患有改善效果等。
就本發明之一態樣而言,可列舉例如排便促進劑。此係由於本發明之劑具有氯通道活化作用,結果使腸管之水分量增加,而可得到排便促進作用等。
在本發明中,排便促進劑係例如可促進生理上之排便,或可使飲食至排便之時間縮短。
在本發明中,判斷排便促進效果之方法,無特別限定,可列舉例如,從排便次數、飲食至排便之時間、糞便所含之水分量等而判斷的方法。
本發明之劑可藉由將菌或其處理物單獨使用或將其與其他成分混合,而作為醫藥品、類醫藥產品(準醫藥品)、飲食品、食品添加物、飼料等之製造所使用的原料;或直接作為醫藥品、類醫藥產品、飲食品、食品添加物、飼料等態樣來使用。本發明之組成物可不含輔酶Q10。亦即,就本發明之一態樣而言,可列舉:醫藥品組成物、類醫藥產品(quasi-drug)組成物、飲食品組成物、食品添加物組成物、飼料組成物等。含此種本發明之劑的醫藥品組 成物,亦為本發明之較佳實施態樣之一。
本發明之醫藥品組成物之劑型,只要考慮各個成分之物理化學性質、生物學性質等,而製成適於投予的劑型即可。在適合經口投予方面,以內服劑為較佳。又,本發明之醫藥品組成物之劑型可為非經口劑。就內服劑之劑型而言,可列舉例如:錠劑(包含糖衣錠)、膠粒劑、細粒劑、散劑、顆粒劑、丸劑、咀嚼劑、片劑、膠囊劑等固形劑;水劑、懸浮劑、乳劑、糖漿劑、酏劑等液劑;果凍狀製劑等半固形劑等。其中,以錠劑、散劑、液劑或懸浮劑為較佳。再者,本發明之醫藥品組成物,除含有乳酸菌之外,亦可適當地含有:賦形劑(例如白糖、乳糖、澱粉、結晶纖維素、磷酸鈉、碳酸鎂、果膠、糖精、黃蓍膠等)、黏合劑(例如澱粉、明膠、羧甲基纖維素鈉、甲基纖維素、羥丙基甲基纖維素、羥丙基纖維素、聚乙烯基吡咯啶酮、果膠、黃蓍膠等)、崩散劑(例如澱粉、羧甲基纖維素鈉、黃蓍膠等)、潤滑劑(例如滑石粉、硬脂酸鎂、硬脂酸鈣、聚乙二醇(Macrogol)、蔗糖脂肪酸酯等)、安定劑(亞硫酸氫鈉、硫代硫酸鈉、乙底酸鈉(Sodium edetate)、檸檬酸鈉、抗壞血酸、二丁基羥基甲苯等)、增黏劑(鈉羧甲基纖維素等)、載劑(低熔點蠟、可可脂等)、著色劑、賦香劑(香料)、光澤劑、稀釋劑、緩衝劑、乳化劑、分散劑、懸浮化劑、防腐劑、吸收促進劑、矯味劑等所屬業界所使用之周知添加劑等。製劑中所含之菌或其處理物的合計量,通常,相對於最終製劑總量,可從約0.000001至99質量%之範圍 內適當地選擇而決定。其中,以含約0.05至約50質量%為較佳,以含約0.1至約25質量%為更佳。
在本發明中,以經口用之固形劑(錠劑(包含糖衣錠)、丸劑、膠囊劑、散劑、顆粒劑等)為較佳,將有效成分與例如賦形劑(乳糖、甘露醇、葡萄糖、微結晶纖維素、澱粉等)、黏合劑(羥丙基纖維素、聚乙烯基吡咯啶酮、偏矽酸鋁酸鎂等)、崩散劑(纖維素乙醇酸鈣等)、潤滑劑(硬脂酸鎂等)、安定劑、溶解輔助劑(麩胺酸、天冬胺酸等)等添加劑混合,依照常法製劑化。因應所需,可進一步以被覆劑(白糖、明膠、羥丙基纖維素、羥丙基甲基纖維素酞酸酯等)被覆,又,亦可以被覆2層以上。
在將本發明之劑以固形劑之形態使用的情況,依據乾燥方法,可只將粉末彼此混合,亦可將該粉末壓縮,製成顆粒,或製成錠劑。在藉由濕式法製造顆粒、錠劑之情況,可使用黏合劑之水溶液煉合、乾燥,形成目的之固形劑。再者,亦可將以此方式所得到之粉末或顆粒充填於膠囊,形成膠囊劑。
例如,在製造錠劑之情況,可使用周知之打錠機。就該打錠機而言,可列舉如單發式打錠機或旋轉型打錠機等。又,丸劑、咀嚼劑或片劑之製造方法,只要依照周知之方法進行即可,例如可與製造錠劑之相同手段製作。
為了將微量之有效成分(菌或其處理物)與大量之其他粉末混合,得到均勻之混合物,可採用所謂階 段式混合法。例如,將有效成分與其100至200體積倍之粉末混合,得到均勻之粉末,將其與殘餘之粉末混合,可得到均勻的經稀釋之粉末。
從含水物乾燥時,可採取噴霧乾燥、L-乾燥、凍結乾燥等手段。
在本發明中,經口用之液劑(水劑、懸浮劑、乳劑、糖漿劑、酏劑等)係將有效成分溶解於一般所用之稀釋劑(精製水、乙醇或彼等之混液等)中、進行懸浮或乳化而製劑化。再者,此液劑亦可含有濕潤劑、懸浮化劑、乳化劑、甜味劑、風味劑、芳香劑、防腐劑、緩衝劑等。
就非經口劑而言,可列舉:注射劑(例如,皮下注射劑、靜脈內注射劑、肌肉內注射劑、腹腔內注射劑)、點滴劑、外用劑(例如,經鼻投予製劑、經皮製劑、軟膏劑)、栓劑(例如,直腸栓劑、陰道栓劑)等。此等製劑可藉由該領域中通常施行之手法,使用前述藥學上容許的添加劑而製劑化。製劑中所含之菌或其處理物的合計量,通常可相對於最終製劑總量,從約0.000001至99質量%之範圍內適當地選擇而決定。其中,以含約0.05至約50質量%為較佳,以含約0.1至約25質量%為更佳。
在本發明中,就非經口劑而言,可列舉例如注射劑。注射劑包含溶液、懸浮液、乳濁液、及在使用時溶解或懸浮來使用的固形注射劑。注射劑係將有效成分於溶劑中溶解、懸浮或乳化而製劑化。就溶劑而言,可使用如注射用蒸餾水、生理食鹽水、植物油、丙二醇、聚乙 二醇、如乙醇之醇類等及彼等之組合。再者,此注射劑亦可含有安定劑、溶解輔助劑(麩胺酸、天冬胺酸、Polysorbate 80(註冊商標)等)、懸浮化劑、乳化劑、無痛化劑、緩衝劑、防腐劑等。此等係在最後步驟中藉由滅菌或無菌操作法而製造。又,注射劑亦可製造無菌之固形劑,例如凍結乾燥品,在其使用前溶解於無菌化或無菌之注射用蒸餾水或其他溶劑中而製造。
再者,就非經口劑而言,可列舉例如栓劑。此組成物可依照通常所使用之方法而製造。
本發明中所使用之菌,一般為厭氧性,由於乾燥狀態時對空氣或氧弱,又,於高溫及濕氣中弱,故組成物之製劑化時以盡可能在惰性氣體存在下或真空、低溫下處理為較佳。組成物之製劑化時之溫度,只要在發揮本發明之效果的限制下,則無特別限定,可依照周知之方法而決定。
在本發明中,對於包含人類之動物的菌之投予量,以約1×103至1×1011個/大人/次為較佳,以約1×106至1×1011個/大人/次為更佳,以約1×109至1×1011個/大人/次為進一步更佳。
在本發明中,對於包含人類之動物的菌處理物之投予量,以約1×103至1×1014個菌之處理物/大人/次為較佳,以約1×106至1×1014個菌之處理物/大人/次為更佳,以約1×109至1×1014個菌之處理物/大人/次為進一步更佳。
在本發明中,組成物之使用間隔,雖亦取決於對象(例如大鼠)、途徑(例如經口投予)、形式(例如液劑)等,然而例如可將本發明之組成物以1日1至5次使用,或以1週1至5次使用,或以1個月1至5次使用等。
在本發明中,組成物之使用期間,雖亦取決於對象(例如小鼠)、途徑(例如經口投予)、劑型(例如液劑)、使用間隔等,然而例如可為1日至6日,或為1週至4週,或為1個月至12個月。又,例如,亦可將組成物連續地使用等。
在本發明中,劑之投予對象,可針對例如動物(例如人類、大鼠、小鼠、兔子、綿羊、豬、牛、貓、犬、猴子等)投予。
在本發明中,腎疾患之預防或治療劑之投予對象,以排除犬及貓之動物(例如人類、大鼠、小鼠、兔子、綿羊、豬、牛、猴子等)為較佳。
就本發明之醫藥品組成物之適用疾患而言,可列舉:炎症性腸疾患、潰瘍性大腸炎、克隆氏病(Crohn's disease)、腸結核、感染性腸炎、非感染性腸炎、急性腸炎、急性胃腸炎、慢性腸炎、過敏性腸症候群(IBS)、大腸癌、腸閉塞、便秘、腎炎、腎功能衰竭、腎病症候群、糖尿病性腎症、絲球體腎炎、腎臟結石、多發性囊胞腎、腎性貧血、腎硬化症、水腎症等。
本發明之劑,就醫藥品組成物以外之其他組成物之原料而言,例如,可使用上述菌或其處理物,依 照周知之方法製造其他組成物。菌或其處理物相對於醫藥品組成物以外之其他組成物的含量,例如,可從相對於組成物總量,從約0.000001至99質量%之範圍中適當地選擇而決定。
在本發明中,就飲食品而言,可列舉例如:清涼飲料、乳性飲料、發酵乳、優格、乳酸菌飲料、補品等。
本發明包含菌處理物之製造方法,其為比菲德氏菌屬(Bifidobacterium)或乳桿菌屬(Lactobacillus)之菌處理物之製造方法,包含:將菌懸浮在不含糖之溶劑(但是,排除精製水及生理食鹽水)、或含DMEM及Ham’s F-12之溶劑中,得到菌懸浮液之步驟;將菌懸浮液放置於厭氧下之步驟;及將放置之菌懸浮液的上清液以過濾器過濾,以濾液作為處理物的步驟;但不包含發酵步驟。
在本發明中,就不含糖之溶劑而言,可列舉例如含磷酸之溶液、磷酸緩衝液(PBS)等,然而在本發明中,不含精製水及生理食鹽水。含磷酸之溶液只要至少含磷酸之溶液即可。磷酸緩衝液(PBS)可使用添加鈣鹽及鎂鹽之磷酸緩衝液(PBS(+)),亦可使用未添加鈣鹽及鎂鹽之磷酸緩衝液(PBS(-))。從離子經細胞輸送能力高之點而言,以使用PBS(-)為較佳。就糖而言,可列舉如乳糖、蔗糖、 寡糖、糖醇等。
在本發明中,DMEM可使用含有例如:甘胺酸、L-精胺酸鹽酸鹽、L-半胱胺酸二鹽酸鹽、L-麩醯胺酸、L-組胺酸鹽酸鹽一水合物、L-異白胺酸、L-白胺酸、L-離胺酸鹽酸鹽、L-甲硫胺酸、L-苯丙胺酸、L-絲胺酸、L-酥胺酸、L-色胺酸、L-酪胺酸二鈉水合物、L-纈胺酸、D-泛酸鈣、氯化膽鹼、葉酸、異肌醇、菸醯胺、吡哆醇鹽酸鹽、核黃素、硫胺素鹽酸鹽、無水氯化鈣、硝酸鐵九水合物、無水硫酸鎂、氯化鉀、氯化鈉、碳酸氫鈉、無水磷酸二氫鈉、D-葡萄糖、酚紅等者等。
在本發明中,Ham’s F-12亦可使用含有例如:甘胺酸、L-丙胺酸、L-精胺酸鹽酸鹽、L-天冬醯胺酸一水合物、L-天冬胺酸、L-半胱胺酸鹽酸鹽一水合物、L-麩胺酸、L-麩醯胺酸、L-組胺酸鹽酸鹽一水合物、L-異白胺酸、L-白胺酸、L-離胺酸鹽酸鹽、L-甲硫胺酸、L-苯丙胺酸、L-脯胺酸、L-絲胺酸、L-酥胺酸、L-色胺酸、L-酪胺酸二鈉水合物、L-纈胺酸、生物素、氯化膽鹼、D-泛酸鈣、葉酸、菸醯胺、吡哆醇鹽酸鹽、核黃素、硫胺素鹽酸鹽、維生素B12、異肌醇、無水氯化鈣、硫酸銅五水合物、硫酸鐵七水合物、氯化鉀、無水氯化鎂、氯化鈉、碳酸氫鈉、無水磷酸二氫鈉、硫酸鋅七水合物、D-葡萄糖、次黃嘌呤、亞油酸、硫辛酸、腐胺二鹽酸鹽、胸苷、酚紅、丙酮酸鈉等者等。
在本發明中,就含DMEM及Ham’s F-12之溶劑而言,可列舉例如:將DMEM與Ham’s F-12混合而 成之溶劑、含DMEM及Ham’s F-12之溶液、含DMEM及Ham’s F-12之培養基等。
在本發明中,含DMEM及Ham’s F-12之培養基,例如,可將市售品等混合而使用,可使用已混合之市售品等(DMEM/F-12培養基(Thermo Fishier Scientific公司製)),亦可使用不含糖之市售品等。
在本發明中所用之DMEM/F-12培養基,亦可使用將例如:市售品等所含之各個成分(L-麩醯胺酸、酚紅、丙酮酸鈉、無水氯化鈣、氯化鉀、無水氯化鎂、無水硫酸鎂、氯化鈉、碳酸氫鈉、無水磷酸氫二鈉、無水磷酸二氫鈉、硫酸銅五水合物、硝酸鐵九水合物、硫酸鐵七水合物、硫酸鋅七水合物、L-丙胺酸、L-精胺酸鹽酸鹽、L-天冬醯胺酸一水合物、L-天冬胺酸、L-半胱胺酸二鹽酸鹽、L-半胱胺酸鹽酸鹽一水合物、L-麩胺酸、L-麩醯胺酸、甘胺酸、L-組胺酸鹽酸鹽一水合物、L-異白胺酸、L-白胺酸、L-離胺酸鹽酸鹽、L-甲硫胺酸、L-苯丙胺酸、L-脯胺酸、L-絲胺酸、L-酥胺酸、L-色胺酸、L-酪胺酸二鈉水合物、L-纈胺酸、D-生物素、D-泛酸鈣、氯化膽鹼、葉酸、異肌醇、菸醯胺、吡哆醇鹽酸鹽、核黃素、硫胺素鹽酸鹽、維生素B12、D-葡萄糖、次黃嘌呤、亞油酸、硫辛酸、腐胺二鹽酸鹽、胸苷等)混合而製成者等。從簡便性之觀點,以使用市售品之DMEM/F-12為較佳。
在本發明中,於厭氧下放置,意指例如較佳進行氮置換,使頂上空間中之氧濃度成為零,或者在使 用培養槽之情況,放置於菌懸浮液中之D.O.值(溶氧濃度)為1.0ppm以下;就特佳方法而言,例如,將菌懸浮液藉由氮氣置換,使D.O.值(溶存氧濃度)調節至0.5ppm以下,於厭氧條件下放置之方法等,然而不以此等為限。
在本發明中,放置菌懸浮液,意指例如將菌及不含糖之溶劑(但是,排除精製水及生理食鹽水)或含DMEM及Ham’s F-12之溶劑混合後,對於菌懸浮液及/或加入菌懸浮液之容器不實施任何操作而予以靜置。靜置之時間無特別限定,然而可為例如30分鐘以上、1小時以上、6小時以上等,可為24小時以下、3日以下等。又,靜置菌懸浮液時之溫度,無特別限定,只要為例如菌能繁殖之溫度即可。將菌懸浮液靜置時之條件,可取決於菌之性質等,例如,可為好氧性條件下,亦可為厭氧性條件下等。
在本發明中,過濾器只要孔眼為能將菌過濾之大小的過濾器即可,例如,可使用市售之0.1μm至1μm(例如0.22μm)之過濾器。
在本發明中,亦可進一步包含例如將濾液之處理物進行濃縮、粉末化、凍結乾燥等的步驟。
在本發明中,不包含發酵步驟,意指例如不進行乳酸菌發酵,在進行製造方法中之全部步驟後所得到之處理物中,不含由乳酸菌發酵後之代謝物等。
在本發明中,判斷有無經由乳酸菌發酵之方法,無特別限定,例如,製作菌懸浮液,然後在放置菌懸浮液之步驟前後,測定菌懸浮液之pH,放置後之pH值與放置前之 pH值相比呈現下降(pH之值向酸性側變化)的情況,判斷為有發酵,為不包含於本發明中者。
本發明包含將比菲德氏菌屬(Bifidobacterium)、或乳桿菌屬(Lactobacillus)之菌或此等之處理物投予至動物,使氯通道活化的方法,預防或治療腎疾患之方法,或促進排便之方法。
又,本發明包含比菲德氏菌屬(Bifidobacterium)、或乳桿菌屬(Lactobacillus)之菌或此等之處理物的使用,其係用於氯通道之活化劑、腎疾患之預防或治療藥、或排便促進劑的製造。
再者,本發明包含用於氯通道之活化、腎疾患之預防或治療、或排便之促進的比菲德氏菌屬(Bifidobacterium)、或乳桿菌屬(Lactobacillus)之菌或此等之處理物。
又,本發明包含比菲德氏菌屬(Bifidobacterium)、或乳桿菌屬(Lactobacillus)之菌或此等之處理物的使用,其係用於動物中氯通道之活化、腎疾患之預防或治療、或排便之促進。
以下,藉由實施例詳述本發明,然而此等實施例僅為本發明之一例,本發明之技術範圍不受其等之限定,在本發明之技術思想內,所屬技術領域具有通常知識者可進行多種變化。
就比菲德氏菌屬(Bifidobacterium)或乳桿菌屬(Lactobacillus)所屬之菌而言,使用長比菲德氏菌(B.longum):ID1001(MM-2,寄存編號:NITE BP-818)、JCM1217(ID1100T)、ID1163、ID1164、ID1165、ID1166、ID1167、ID1168、ID1170、ID8009、CLA8013(寄存編號:NITE BP-02352)、雙歧比菲德氏菌(B.bifidum):ID1000、ID1077、ID1078、JCM1255(ID1079T)、ID1080、ID1127、ID1129、ID1130、ID1131、ID1188、ID1189、ID8005、ID8007、加氏乳桿菌(L.gasseri):ID2000、JCM1131(ID2151T)、ID2089、ID2092、ID2093、ID2100、ID2101、ID2124、ID2144、JCM5813(ID2145)、ID2146、約氏乳桿菌(L.johnsonii):JCM2012(ID2153T)、ID2091、ID2095、ID2096、ID2126、ID2142、ID2143、ID2154、嗜酸乳桿菌(L.acidophi1us):JCM1132(ID2152T)、ID2073、ID2107、ID2109、ID2110、副乾酪乳桿菌副乾酪亞種(L.paracasei subsp.paracasei):JCM8130(ID2148T)、ID2003、ID2004 ID2005、ID2012、ID2013、ID2014、ID2019、ID2031、ID2032、ID2033。其中B.longum JCM1217(ID1100T)、B.bifidum JCM1255(ID1079T)、L.gasseri JCM5813(ID2145)、L.gasseri JCM1131(ID2151T)、L.johnsonii JCM2012(ID2153T)、L.acidophilus JCM1132(ID2152T)、L.paracasei subsp.paracasei JCM8130(ID2148T)為各菌種之標準株。
將各菌株之凍結保存菌株(約1×106至1×108個)使用含有1%葡萄糖、0.1%Polysorbate 80之GAM(日水製藥股份有限公司)培養基,於37℃進行18至30小時厭氧培養。培養後,進行離心(3,000×G,10min.,R.T.),廢棄上清液,以PBS(-)洗淨後,再懸浮於10mL之DMEM/F-12(Thermo Fishier Scientific公司製)中,並於37℃,厭氧下放置24小時後,將離心上清液用過濾器(0.22μm)過濾,將濾液調製為菌處理物(Extract:以下有時簡稱為E)。
用含有10%FBS、青黴素/鏈黴素之DMEM/F-12來培養純株化人類結腸上皮細胞T84,以4×104個細胞/cm2之比率播種,每5至7日進行繼代培養。以5×105個細胞/孔之量播種於過濾器膜嵌套(snapwell)(corning,costar,1.13cm2),每3日交換培養基,將培養5至7日者用於試驗。
短路電流法係使用尤斯室系統(Ussing chamber system) (Physiologic Instruments公司製)測定。將成為單層(monolayer)之T84細胞依各個膜嵌套(snapwell)垂直地安裝於尤斯室(Ussing chamber),將T84細胞所接附之膜嵌套的左右,以5mL之被保溫於37℃之克雷布-林格液(Krebs-Ringer液)注滿,放置20分鐘以上,待經由T84細胞膜中介之電流之值(Isc)安定後,開始試驗。將100μL之菌處理物添加於T84細胞之黏膜側所對應的上側(相對於膜嵌套,為細胞接附之面的相反側),然後觀察Isc之變化(△Isc),比較經細胞離子分泌之變化。△Isc係檢體添加後,最大變化之Isc值與添加檢體時(0小時)之Isc值的差。
腸內之水分量對內容物之硬度、腸內移動造成影響,成為便秘或下痢的原因之一。由於腸管中之水之分泌吸收係與經由存在於腸管上皮之氯通道的氯離子之移動並行而發生,氯離子之移動成為水移動的指標。因此,使用腸管上皮細胞(T84細胞),並藉由使用尤斯室(Ussing chamber)之短路電流法檢討菌中之離子之經細胞輸送能力。藉由使用T84細胞之短路電流法,測定各菌處理物所造成離子之經細胞輸送能力的結果示於第1圖(比菲德氏菌)、第2圖(乳桿菌)。於長比菲德氏菌CLA8013之菌處理物顯示最大之△Isc。
又,將屬於氯通道抑制劑之CFTRinh172(Sigma C992-25MG)10mM(DMSO溶解),以成為5μL/5mL 克雷布-林格液液(終濃度10μM)之方式於T84細胞之黏膜側進行處置,2分鐘後,將100μL之長比菲德氏菌CLA8013之菌處理物添加於T84細胞之黏膜側。相對於未經CFTRinh172處置(DMSO處置)時之長比菲德氏菌LA8013之菌處理物的△Isc為11.38μA,經CFTRinh172處置時之長比菲德氏菌CLA8013之菌處理物的△Isc為3.50μA,藉由氯通道抑制劑,長比菲德氏菌CLA8013之菌處理物之作用降低。由此結果,顯示長比菲德氏菌CLA8013之菌處理物,於腸管中活化氯通道。因此,可知菌處理物由於具有氯通道活化作用,而具有經由促進水之分泌所致之排便促進作用。
將菌株長比菲德氏菌CLA8013之凍結保存菌株(約1×108個),使用10mL之含有1%葡萄糖、0.1%Polysorbate 80之GAM(日水製藥股份有限公司)培養基,於37℃進行30小時厭氧培養。培養後,進行離心(3,000×G,10分鐘,R.T.),廢棄上清液,以PBS(-)洗淨後,再懸浮於PBS(-)10mL中,於37℃,厭氧下放置24小時後,將離心上清液以過濾器(0.22μm)過濾,得到濾液作為菌(長比菲德氏菌CLA8013)處理物(8013E)。
將8013E用PBS(-)稀釋為吸光度260nm:33者作為8013E(10),以及用PBS(-)稀釋為吸光度260nm:3.3者作 為8013E(1)。
依照第3圖所示之時程實施試驗。將雄性之C57BL/6小鼠(日本CLEA股份有限公司),以通常飼料(CE-2,日本CLEA公司製)飼養至6週齡。在7週齡時,分開培養為以通常飼料飼養之通常飼料群(Normal),及以含0.2%腺嘌呤(和光公司製)之通常飼料(腺嘌呤食)飼養的腺嘌呤食飼料群。6週後,正常(Normal)群以0.2mL PBS(-)/隻,1日1次,藉由導管強制經口投予12日。
腺嘌呤食飼養群經6週之腺嘌呤食飼養後,回復通常飼料,分為PBS(-)投予群(RF)、菌(長比菲德氏菌CLA8013)處理物投予群(RF+8013E(1)、RF+8013E(10)),RF群分別用PBS(-)、RF+8013E(1)及RF+8013E(10)群分別用8013E(1)、8013E(10),以0.2mL/隻,各自以1日1次、藉由導管強制經口投予12日。
最終投予18小時後,進行解剖。
將各群之小鼠血清中BUN(尿素氮),使用DetectX尿素氮比色檢測套組(Urea Nitrogen Colorimetric Detection Kit)(ARBOR ASSAYS公司製)測定的結果示於第4圖。各群分別測定5隻或6隻。所得到之結果,以平均值±標準 偏差(mean±S.D.)表示(*:p<0.05vs正常群,#:p<0.05vs RF,Steel-Dwass法)。與正常群相比,可確認RF群中,屬於腎功能指標的血清BUN濃度上升。RF+8013E(1)及RF+8013E(10)群與RF群相比,血清BUN濃度降低,可確認8013E之用量依存性效果,並觀察到相對於RF群,RF+8013E(10)群有顯著差異。從此結果可知,8013E顯示改善腎功能。此外,試驗期間中的體重推論由於腺嘌呤食飼養而減少,而在受檢藥開始投予時藉由回復為通常飼料而回復體重,然而即使投予8013E亦未見對體重回復之影響,與RF群顯示相同之傾向。
將菌株長比菲德氏菌CLA8013之凍結保存菌株(約1×108個)使用10mL之含有1%葡萄糖、0.1%Polysorbate 80之GAM(日水製藥股份有限公司)培養基,於37℃進行30小時厭氧培養。培養後,進行離心(3,000×G,10min.,R.T.),廢棄上清液,藉由PBS(-)洗淨後,再懸浮於PBS(-)10mL中,於37℃,厭氧下放置24小時後,將離心上清液用過濾器(0.22μm)過濾,得到濾液作為菌(長比菲德氏菌CLA8013)處理物(8013E)。
將雄性之6週齡SD大鼠(日本SLC製)各別進行1週之預備飼養。預備飼養後,分為正常群及8013E群。正常群以PBS(-),8013E群以8013E,依照0.5mL/隻之用量,進行1次強制經口投予。投予終了後,將胭脂紅{(Carmine)(WAKO),3g/50mL,(0.5%羧甲基纖維素)}水溶液,以1mL/隻之用量,進行1次強制經口投予。
投予胭脂紅溶液後,各群8隻,分別測定染成紅色之糞便排出的時間(*:p<0.05 vs對照群(Mann-Whitney’s U test))。所得到之結果,以平均值±標準偏差表示。8013E群與正常群相比,紅色糞便排出時間顯著地縮短,可確認經由8013E所致之排便促進效果。
將菌株長比菲德氏菌CLA8013之凍結保存菌株使用10mL之含有1%葡萄糖、0.1%Polysorbate 80之GAM(日水製藥股份有限公司)培養基,於37℃進行30小時厭氧培養。培養後,進行離心(3,000×G,10min.,R.T.),廢棄上清液,藉由PBS(-)洗淨後,再懸浮於各溶劑(精製水、生理食鹽水、DMEM/F-12、或PBS(-))10mL中,於37℃,厭氧下放置24小時後,將離心上清液以過濾器(0.22μm)過濾,將濾液調製為菌(長比菲德氏菌CLA8013)處理物(8013E)。
將純株化人類結腸上皮細胞T84藉由含有10%FBS、青黴素/鏈黴素之DMEM/F-12培養,以4×104個細胞/cm2之量播種,每5至7日進行繼代培養。以5×105個細胞/孔之量播種於膜嵌套(snapwell)(costar,1.13cm2)中,每3日交換培養基,將培養5至7日者用於試驗。
依照與實施例1之短路電流法相同的方法求取△Isc。
將結果示於第6圖。製造菌處理物所用之溶劑為PBS(-)的情況,菌處理物之離子經細胞輸送能力最高,其次在DMEM/F-12之情況,菌處理物之離子經細胞輸送能力亦高。從此等結果,可確認藉由使菌體懸浮於PBS(-),可進行效果更高之處理物的調製。又,將菌體懸浮於DMEM/F-12,放置時,pH無變化。從此結果可知菌處理物所致之離子經細胞輸送能力增加顯然與菌體所致之發酵無關。
在懸浮於不含糖之DMEM/F-12的情況,亦可確認菌處理物之離子經細胞輸送能力變高。
依照與實施例2同樣之方法,將菌(長比菲德氏菌MM-2)進行12至18小時厭氧培養。隨後回收之菌體,使用PBS(-)調製成菌數5×109個/mL來使用。
藉由與實施例2同樣之時程及方法,將調製後之菌體以菌數1×109個/0.2mL/隻之用量投予至小鼠,最終投予之18小時後進行解剖。然後,藉由與實施例2記載之方法同樣的方法,對於各群分別測定5隻或10隻之血清BUN。將測定結果示於第7圖。所得到之結果,以平均值±標準偏差表示(**:p<0.01vs正常群,#:p<0.05vsRF)。與正常群相比,RF群中可確認到作為腎功能指標之血清BUN濃度上升。RF+MM-2群與RF群相比,血清BUN濃度降低。由此結果顯示MM-2菌體可改善腎功能。此外,試驗期間中之體重推論由於腺嘌呤食飼養而減少,在開始投予受檢藥時藉由將飼料改回通常飼料而回復,不過投予MM-2菌體未見到對體重回復之影響,而顯示與RF群相同之傾向。
在本發明中,推測例如,投予之菌或其處理物若具有長比菲德氏菌MM-2菌株所具有之程度的離子經細胞輸送能力,則藉由投予該菌或其處理物,有可改善腎功能的可能性。
在本發明中,暗示例如在使用無發酵之菌 的情況,即使投予含有菌之處理物,亦可改善腎功能。
以下,例示摻配本發明之對於腸管之離子經細胞輸送體的作用劑、氯通道活化劑、腎疾患之預防或治療劑、及/或排便促進劑的醫藥品、飲食品、及飼料之具體處方。各處方例之右端數值意指各含有成分之質量%。
本發明之劑,在氯通道之活化、腎疾患之預防或治療、及/或排便促進上有用,可作為醫藥、補品等使用。
1.日本國、獨立行政法人製品評價技術基盤機構 特許微生物寄託中心、2009年9月17日、NITE BP-818
2.日本國、獨立行政法人製品評價技術基盤機構 特許微生物寄託中心、2016年9月21日、NITE BP-02352
本發明之圖式皆為實驗數據圖,不足以代表本發明。
Claims (6)
- 一種對於腸管之離子經細胞輸送體的活化劑,其含有比菲德氏菌屬(Bifidobacterium)之菌或此之處理物,其中,前述比菲德氏菌屬(Bifidobacterium)之菌為長比菲德氏菌CLA8013(Bifidobacterium longum CLA8013,寄存編號:NITE BP-02352);前述處理物係前述菌與溶劑之混合液、其上清液、離心上清液、藉由過濾器過濾之濾液或萃取物。
- 如申請專利範圍第1項所述之活化劑,其中,離子經細胞輸送體為氯通道。
- 如申請專利範圍第1或2項所述之活化劑,其為排便促進劑。
- 一種菌株,其為長比菲德氏菌CLA8013菌株(Bifidobacterium longum CLA8013,寄存編號:NITE BP-02352)。
- 一種菌處理物之製造方法,其為比菲德氏菌屬(Bifidobacterium)之菌處理物之製造方法,包含:將菌懸浮在不含糖之溶劑、或含DMEM及Ham’s F-12之溶劑中,得到菌懸浮液之步驟,其中,該不含糖之溶劑排除精製水及生理食鹽水;將菌懸浮液於厭氧下放置之步驟;及將經放置之菌懸浮液的上清液以過濾器過濾,得到濾液作為處理物的步驟;該製造方法不包含發酵步驟;前述比菲德氏菌屬(Bifidobacterium)之菌為長比菲德 氏菌CLA8013(Bifidobacterium longum CLA8013,寄存編號:NITE BP-02352);前述處理物係前述菌與溶劑之混合液、其上清液、離心上清液、藉由過濾器過濾之濾液或萃取物。
- 一種懸浮液的上清液,該懸浮液含有(i)比菲德氏菌屬(Bifidobacterium)之菌、及(ii)不含糖之溶劑、或含DMEM及Ham’s F-12之溶劑,其中,該不含糖之溶劑排除精製水及生理食鹽水,其中,前述比菲德氏菌屬(Bifidobacterium)之菌為長比菲德氏菌CLA8013(Bifidobacterium longum CLA8013,寄存編號:NITE BP-02352)。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH092959A (ja) * | 1995-06-16 | 1997-01-07 | Yakult Honsha Co Ltd | IgE抗体産生抑制剤および抗アレルギー剤 |
WO2005032591A1 (en) * | 2003-09-30 | 2005-04-14 | Kibow Biotech, Inc. | Compositions and methods for augmenting kidney function |
WO2006045473A1 (en) * | 2004-10-22 | 2006-05-04 | Medinova Ag | Lactic acid bacteria strains useful against urogenital pathogens and compositions containing same |
WO2010126073A1 (ja) * | 2009-04-28 | 2010-11-04 | 協和発酵キリン株式会社 | ポリペプチドの分泌発現のための発現カセットおよびその使用 |
TW201311903A (zh) * | 2011-06-24 | 2013-03-16 | Calpis Co Ltd | 利用乳酸菌發酵之酪蛋白衍生胜肽之製造方法 |
WO2015112083A1 (en) * | 2014-01-23 | 2015-07-30 | Biogaia Ab | Selection of agents modulating gastrointestinal pain |
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CA2890507A1 (en) | 2012-11-16 | 2014-05-22 | Calpis Co., Ltd. | Agent for alleviating stress-induced bowel disorder containing specific lactobacillus gasseri strain or treated product threof |
JP6053466B2 (ja) | 2012-11-16 | 2016-12-27 | アサヒグループホールディングス株式会社 | ストレス性下痢の抑制剤 |
-
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH092959A (ja) * | 1995-06-16 | 1997-01-07 | Yakult Honsha Co Ltd | IgE抗体産生抑制剤および抗アレルギー剤 |
WO2005032591A1 (en) * | 2003-09-30 | 2005-04-14 | Kibow Biotech, Inc. | Compositions and methods for augmenting kidney function |
WO2006045473A1 (en) * | 2004-10-22 | 2006-05-04 | Medinova Ag | Lactic acid bacteria strains useful against urogenital pathogens and compositions containing same |
WO2010126073A1 (ja) * | 2009-04-28 | 2010-11-04 | 協和発酵キリン株式会社 | ポリペプチドの分泌発現のための発現カセットおよびその使用 |
TW201311903A (zh) * | 2011-06-24 | 2013-03-16 | Calpis Co Ltd | 利用乳酸菌發酵之酪蛋白衍生胜肽之製造方法 |
WO2015112083A1 (en) * | 2014-01-23 | 2015-07-30 | Biogaia Ab | Selection of agents modulating gastrointestinal pain |
Non-Patent Citations (1)
Title |
---|
期刊 Harunobu Amagase., "Current Marketplace for Probiotics: A Japanese Perspective". Clin Infect Dis. 2008 Feb 1;46 Suppl. 2:S73-S75. * |
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CN110267670A (zh) | 2019-09-20 |
JPWO2018074514A1 (ja) | 2019-09-05 |
US11376287B2 (en) | 2022-07-05 |
TW201818948A (zh) | 2018-06-01 |
US20190262408A1 (en) | 2019-08-29 |
JP6990660B2 (ja) | 2022-01-12 |
CN110267670B (zh) | 2023-08-15 |
WO2018074514A1 (ja) | 2018-04-26 |
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