JP2019506181A - Lactobacillus plantarumの新規プロバイオティクス細菌株ならびにそれらの組成物及び炎症の治療における使用 - Google Patents
Lactobacillus plantarumの新規プロバイオティクス細菌株ならびにそれらの組成物及び炎症の治療における使用 Download PDFInfo
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- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229960003500 triclosan Drugs 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 238000009966 trimming Methods 0.000 description 1
- VXYADVIJALMOEQ-UHFFFAOYSA-K tris(lactato)aluminium Chemical compound CC(O)C(=O)O[Al](OC(=O)C(C)O)OC(=O)C(C)O VXYADVIJALMOEQ-UHFFFAOYSA-K 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- WGIWBXUNRXCYRA-UHFFFAOYSA-H trizinc;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O WGIWBXUNRXCYRA-UHFFFAOYSA-H 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 229920006163 vinyl copolymer Polymers 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 239000011746 zinc citrate Substances 0.000 description 1
- 235000006076 zinc citrate Nutrition 0.000 description 1
- 229940068475 zinc citrate Drugs 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
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Abstract
【選択図】図1A
Description
本発明の株は、Bacillus subtilis、Bifidobacterium animalis、Bifidobacterium bifidum、Bifdobacterium longum、Bifidobacterium breve、Bifidobacterium lactis、Lactobacillus acidophilus、Lactobacillus casei、Lactobacillus LAFTI、Lactobacillus plantarum、Lactobacillus reuteri、Lactobacillus rhamnosus、Lactobacillus paracasei、Lactobacillus bulgaricus、Lactobacillus gasseri、Lactobacillus fermentum、Lactobacillus brevis、Lactobacillus cellobiosus、Lactobacillus salivarius、Streptococcus thermophilus、及びLactococcus lactisの株を含む50を超える候補プロバイオティクス株の中から選択された。
凍結した(−80℃)プロバイオティクス株を一晩かけて4℃で解凍し、翌朝、6mlの無菌9%NaCl溶液を1.2mlの細菌に添加した。試料を遠心分離(5分、5000rpm)し、上澄みを捨て、ペレットを8mlの9%NaClで洗浄し、再び5分間、5000rpmで遠心分離した。その後、ペレットを1.2mlの9%NaCl中に再懸濁し、1mlの試料を50mlの37℃の温かい培地(MRSブイヨン、Carl Roth KG、Karlsruhe)に添加し、37℃でインキュベートした。50mlの無菌ポリプロピレン管(Greiner)内でインキュベーションを実施し、増殖曲線を評価するために異なる時点で探針を取り入れた。
ODの判定のために、500μlの細菌懸濁液を除去し、1.5ml−PS−キュベット(Brand)内で1mlのMRSブイヨンで希釈した。600nm(ThermoScientific、Helios Epsilon)でOD判定を実施した。1.5mlのMRSブイヨンをブランクとして使用した。
CFUの判定のために、細菌を希釈し(1:10.000.000、1:50.000.000、及び1:100.000.000)、MRS寒天プレート(MRS寒天、X924、Carl Roth)上に蒔き、2日間37℃でインキュベートした。その後、増殖したコロニーを数え、CFUを計算した。
新規プロバイオティクス株による単球細胞培養物の刺激を、粉末として得られた株を使用することによって確立した。まず、増殖した細菌(対数期から採取)、増殖した細菌培養物の上澄み、溶解した粉末の直接適用、及び粉末の上澄みを使用するようないくつかの適用形態を試験した。結果に従って、対数期の終わりの細菌で、2バッチの凍結された株を用いてこれを試験した。上澄みを使用する代わりに、それら2つの株の熱失活を確立し、不活性化された細菌を活性化された細菌と比較した。
ヒト初代単球を、健康なヒト血液提供者の軟膜から単離した。細胞をELISA実験用の24ウェルプレートに播種した。細胞をLPSと共に24時間インキュベートした。LPS処理の30分前にプロバイオティクス(5投与量)を添加した。24時間後、上澄みを取り出し、遠心分離し、製造者のプロトコルを使用してEIA(PGE2、AssayDesignから、イソプロスタン、Caymanから)またはELISA(全サイトカイン、Immunotools、MMP−9、GE Healthcare)中のIL−1ベータ、TNFアルファ、IL−6、IL−8、MMP−9、イソプロスタン−8、及びPGE2濃度を調査した。各投与量を、2人の異なる提供者からの2つの軟膜内で2〜3度調査した。
熱失活の確立
熱失活は2バッチで確立された。細菌の増殖対数期の終わりで、細菌懸濁液のアリコートを取り出し、未使用の50ml管に添加し、水浴中にて80℃で5分間インキュベートした。80℃での5分間が、細菌を不活性化し、このように細菌の増殖を止めた。
様々なプロバイオティクス株を、それらの活性化されたもの及び不活性化されたもの(熱失活形態)において、LPS誘発ヒト初代単球に関してスクリーニングした(IL−1ベータ、IL−6、IL−8、TNFアルファ、PGE2、8−イソプロスタン、及びMMP−9を判定する)。
本発明の選択された株を、ヒト歯肉線維芽細胞に適用した。製造者のプロトコルに説明されるように、線維芽細胞培養物を維持した。刺激の前に、ELISA実験用の24ウェルプレートに細胞を播種する。細胞をIL−1ベータ無し(非刺激対照群)で、またはそれと共に24時間インキュベートした。IL−1処理の30分前にプロバイオティクス(5投与量、スクリーニング分析の結果による)を添加する。24時間後、上澄みを取り出し、遠心分離し、製造者のプロトコルを使用してEIA(PGE2、AssayDesignから、Caymanからのイソプロスタン)またはELISA(IL−6、IL−8、Immunotools)中のIL−6、IL−8、イソプロスタン、及びPGE2濃度を調査した。各投与量を少なくとも2〜3度調査した。株は、いくつかのIL−6阻害効果を示した。
●構成成分1及び6を真空コンパートメント乾燥機中で50℃及び最大10mbarの圧力で16時間乾燥する。
●全ての構成成分を正確に測る。
構成成分1、2、3、4、及び5を組み合わせて、完全に混合する(ブロックA)。グラム当たり約105〜1012コロニー形成単位(CFU)の活性を有する凍結乾燥形態でプロバイオティクス物質を適用する。
●続いて、ブロックAを構成成分6に添加し、5分間完全に混合する。
●粉末混合物を、錠剤プレスEK0(Korsch AG、Berlin)中で15〜20kNの調整圧力で錠剤にプレス加工する。
目標指標:
○錠剤直径:20mm
○錠剤重量:2.0g
●密封されたアルミニウム小袋内で室温にて保管する。5トローチ剤当たり1gの乾燥剤を除湿に使用する(真空コンパートメント乾燥機内で、105℃で3時間保管することによって活性化される)。
●構成成分7を真空コンパートメント乾燥機中で50℃及び最大10mbarの圧力で16時間乾燥する。
●全ての構成成分を正確に測る。
●構成成分1、2、3、及び4を組み合わせて、共に完全に混合する(ブロックA)。
●構成成分5及び6を、必要な場合は、組み合わせて、完全に混合する(ブロックB)。グラム当たり約105〜1012コロニー形成単位(CFU)の活性を有する凍結乾燥形態でプロバイオティクス物質を適用する。
●続いて、ブロックA及びBを組み合わせて、共に完全に混合する
●混合物を構成成分7に添加し、5分間完全に混合する。
●密封されたアルミニウム小袋内で、粉末混合物は、分量当たり1gの乾燥剤(真空コンパートメント乾燥機内で、105℃で3時間保管することによって活性化される)と共に室温での保管量当たり0.5gの分量に作り上げられる。
●構成成分6、9及び10を真空コンパートメント乾燥機中で50℃及び最大10mbarの圧力で16時間乾燥する。
●全ての構成成分を正確に測る。
●構成成分1、2、3、4、5、及び6を組み合わせて、共に完全に混合する(ブロックA)。
●構成成分7及び8を組み合わせて、共に完全に混合する(ブロックB)。グラム当たり約105〜1012コロニー形成単位(CFU)の活性を有する凍結乾燥形態でプロバイオティクス物質を適用する。
●続いて、ブロックA及びBを組み合わせて、共に完全に混合する
●構成成分9及び10を組み合わせて、共に完全に混合する(ブロックC)。
●2つの混合物(ブロックA/B及びブロックC)を組み合わせ、5分間完全に混合する。
●粉末混合物を、錠剤プレスEK0(Korsch AG、Berlin)中で15〜20kNの調整圧力で錠剤にプレス加工する。
目標指標
○錠剤直径:9mm
○錠剤重量:0.3g
●密封されたアルミニウム小袋内で室温にて保管する。3錠剤当たり1gの乾燥剤を除湿に使用する(真空コンパートメント乾燥機内で、105℃で3時間保管することによって活性化される)。
●構成成分2を真空コンパートメント乾燥機中で50℃及び最大10mbarの圧力で16時間乾燥する。
●全ての構成成分を正確に測る。
●構成成分1を、チューインガムラボ混練機内で45〜59℃に調節し、均質の塊が得られるまで加熱と共に混練する。加熱は、全混合プロセスの間で行われる。
●続いて、構成成分2、3、及び4を添加し、混合物が均質で、粉末がもう見えなくなるまで混練する。
●処方により、構成成分6を、構成成分5(ブロックC)または構成成分7(ブロックD)のいずれかに組み入れる。グラム当たり約105〜1012コロニー形成単位(CFU)の活性を有する凍結乾燥形態でプロバイオティクス物質を適用する。構成成分を、均一な懸濁液が得られるまで混合する。
●まず、ブロックCをチューインガムの塊に添加し、均質の塊が得られるまで再び混練する。
●最後に、ブロックDをそれに従って処理する。添加の後、均一なチューインガムの塊が得られるまで、構成成分を混練しなければならない。
●ミキサーから塊を取り出し、エンボスセット「slabs」を使用し、エンボスローラにより小さな棒に形成する。
●密封されたアルミニウム小袋内で室温にて保管する。7つのチューインガム当たり1gの乾燥剤を除湿に使用する(真空コンパートメント乾燥機内で、105℃で3時間保管することによって活性化される)。
アルジネートビードレットの沈殿物のための塩化カルシウム浴の製造:
●2%の塩化カルシウム溶液を蒸留水及び塩化カルシウムから製造する。CaCl2を完全に溶解するように注意を払わなければならない。
アルジネート溶液の製造(アルジネートの代わりに、また、ペクチンまたはゲランガムを使用し得る):
●反応槽内で、攪拌機を用いて、バッチサイズに好適である水を提供する。
●攪拌機を作動し、高レベルでの攪拌の間、任意に必要なゲランガムと並んで、アルジネート、アラビアガム、小麦繊維、及びプロバイオティクスのそれぞれの量を、添加する。
●攪拌しながら混合物を80℃に加熱し、この温度で5分間保持し、この手順の間、構成成分を形成しているジェルを溶解する。
●その後、加熱を止め、ダマがなくなるまで少なくとも30分間熱いジェル溶液をさらに攪拌する。
●続いて、溶液を攪拌しながら冷蔵によって39〜43℃に冷却する。
●さらなる槽内で、必要な場合、芳香及び染料を提供し、完全に混合する。芳香が使用されない場合、染料はグリセロールと混合する。
●染料分散液を均質に混合した場合、バッチ槽にアルジネート溶液と添加する。混合槽を水を使用し分散液に添加される約10%の量のアルジネート溶液で何度か洗浄する。
●アルジネート分散液を、少なくとも5分間さらに攪拌する。
●続いて、低速でさらに少なくとも15分間バッチを攪拌し、存在する可能性のある空気を除去する。
●アルジネート分散液を、2つの排水口を有する厳封可能圧力安定反応槽に移動する。1つの排水口で、加圧空気を適用する。第2の排水口は、管を介して滴下ユニットのノズルにつながる。
●アルジネート溶液が約45℃に到達するように、反応槽を加熱プレート上で調節する。溶液を磁力攪拌機で少し攪拌する。
●反応槽への圧力の適用後、アルジネート溶液をノズルに押し込み、発振器によって発振を始める。圧力の適応及び発振器の振動数によって、ノズルの先端で結果として得られる滴のサイズを調整することができる。
●ノズルの先端で形成するアルジネート溶液の滴は、最初に調製された塩化カルシウム溶液が流れる漏斗の形態で収集槽内に落ちる。
●硬化されたアルジネートビードレットを、塩化カルシウム溶液と漏斗を通過し、篩で収集溶液され、収集された塩化カルシウムを滴下ユニットの下で漏斗内に送り戻し、このように再循環する。
45℃の排気温度に到達するまで、80℃の供給空気温度で、Aeromatic流体ベッド乾燥機内でビードレットを乾燥する。
Claims (15)
- 微生物の単離された調製物であって、前記微生物が、Lactobacillus plantarum GOS 42(DSM 32131)を含む、またはそれからなる、調製物。
- 前記微生物が、栄養細胞及び/または胞子として存在する、請求項1に記載の調製物。
- 前記微生物が、弱毒化されているか、または死滅している、請求項1または2に記載の調製物。
- 請求項1〜3のいずれかに記載の微生物を、担体、賦形剤、及び/または希釈剤と共に含む、組成物。
- 前記組成物が、薬学的組成物である、請求項4に記載の組成物。
- 前記微生物の総量が、各々の場合において前記組成物の総量に対して、0.01〜100%の範囲内にあり、より好ましくは、0.1〜50%の範囲内にあり、最も好ましくは、1〜10%の範囲内にあり、かつ/または前記微生物の総量が、1×103〜1×1011コロニー形成単位(CFU)の範囲内にあり、より好ましくは、1×105〜1×1010CFUの範囲内にある、請求項1〜5のいずれか一項に記載の組成物。
- 前記微生物の総量が、前記組成物の総量に対して0.1〜50%の範囲内にあり、かつ/または前記微生物の総量が、1×105〜1×1010CFUの範囲内にある、請求項6に記載の組成物。
- 前記微生物の総量が、前記組成物の総量に対して1〜10%の範囲内にあり、かつ/または前記微生物の総量が、1×108〜1×109CFUの範囲内にある、請求項7に記載の組成物。
- 前記組成物が、コーティングまたはカプセル化されている、請求項4〜8のいずれか一項に記載の組成物。
- 前記組成物が、溶液、懸濁液、乳剤、錠剤、顆粒、粉末、またはカプセルの形態である、請求項4〜9のいずれか一項に記載の組成物または製品。
- 前記組成物または製品が、練り歯磨き粉、歯磨きジェル、歯磨き粉、歯洗浄液、歯洗浄フォーム、口内洗浄液、口内スプレー、糸ようじ、チューインガム、及びトローチ剤からなる群から選択される、請求項4〜10のいずれか一項に記載の組成物または製品。
- 前記組成物が、動物用食品及び/または飲料構成成分を含む、請求項1〜11のいずれか一項に記載の組成物。
- 医薬における使用のための請求項1〜12のいずれか一項に記載の単離された調製物または組成物。
- 前記医薬における使用が、炎症の治療及び/または予防におけるものである、請求項13に記載の単離された調製物または組成物。
- 前記医薬における使用が、インターロイキン1(IL−1)、インターロイキン6(IL−6)、インターロイキン8(IL−8)、腫瘍壊死因子(TNF)、プロスタグランジンE2(PGE2)、イソプロスタン、マトリックスメタロペプチダーゼ9(MMP9)、及びNF−κBからなる群から選択される1つ以上の炎症因子の放出を低減及び/または阻害するためのものである、請求項13または14に記載の単離された調製物または組成物。
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PCT/EP2017/051003 WO2017125446A1 (en) | 2016-01-19 | 2017-01-18 | Novel probiotic bacterial strain of lactobacillus plantarum and compositions and uses thereof in the treatment of inflammation |
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EP3858368B1 (en) * | 2018-09-25 | 2023-11-29 | National Cerebral and Cardiovascular Center | Antitumor effect potentiator |
CN111996137B (zh) * | 2020-08-07 | 2022-08-05 | 华东理工大学 | 一株植物乳杆菌 |
CN113234639B (zh) * | 2021-06-16 | 2022-08-30 | 广东海天创新技术有限公司 | 一株植物乳杆菌zf632及其应用 |
US20230131140A1 (en) * | 2021-10-26 | 2023-04-27 | University Of South Florida | Human origin probiotic lactobacilius rhamnosus hl-200 to reduce leaky gut by metabolizing ethanolamine |
CN114672480A (zh) * | 2022-04-29 | 2022-06-28 | 浙江工商大学 | 植物乳杆菌凝胶珠及其制备方法 |
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