JP6442401B2 - プロバイオティクスを封入するための微粒子、この微粒子を得ることおよびその使用 - Google Patents
プロバイオティクスを封入するための微粒子、この微粒子を得ることおよびその使用 Download PDFInfo
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- JP6442401B2 JP6442401B2 JP2015519259A JP2015519259A JP6442401B2 JP 6442401 B2 JP6442401 B2 JP 6442401B2 JP 2015519259 A JP2015519259 A JP 2015519259A JP 2015519259 A JP2015519259 A JP 2015519259A JP 6442401 B2 JP6442401 B2 JP 6442401B2
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- microparticles
- chitosan
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- casein
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Description
健康な成人の腸内微生物叢は比較的安定しており、宿主の健康に重要な役割を果たすラクトバチルス種およびビフィドバクテリウム種から主に構成される種々の有益な細菌集合を含む。有益なコロニー状の微生物叢のバランスが崩れることは、様々な障害、例えば、胃腸管感染、便秘、過敏性腸症候群、炎症性腸疾患、アレルギー、心疾患および結腸癌の進行の原因となり得る。世界保健機関(WHO)は、これらのリスクを防ぐために有益な微生物またはプロバイオティクスの治療能力および予防能力の活用を推奨する。
・細菌の生存能力を損なわずに単純で経済的なプロセスによって得られること
・組み込まれる食品の官能特性の変化を防ぐのに適した粒径および特徴を有すること(100μmを超える粒径を有する粒子は、消費者によって意識される場合がある)
・プロバイオティクスを有害な環境条件(マトリックス、処理、保存など)から守ること
・プロバイオティクスを安定化し、上部胃腸管の条件から誘導されるストレスから守ること
・生きた細菌を腸内に放出すること。
従って、一態様において、本発明は、マトリックスとプロバイオティクス細菌とを含み、前記マトリックスが、カゼインおよびキトサンからなる微粒子(以下、「本発明の微粒子」)に関する。
−トリポリホスフェート(例えば、TPP)およびバニリン;
−トリポリホスフェート(例えば、TPP)およびゲニピン;
−トリポリホスフェート(例えば、TPP)および医薬または化粧品に許容され得るか、または、ヒトまたは動物の食品に使用するのに適した二価の金属カチオン、例えば、Ca2+、Mg2+、Zn2+、Fe2+およびこれらの組み合わせからなる群から選択される二価の金属カチオン;
−バニリンおよびゲニピン;
−バニリンおよび医薬または化粧品に許容され得るか、または、ヒトまたは動物の食品に使用するのに適した二価の金属カチオン、例えば、Ca2+、Mg2+、Zn2+、Fe2+およびこれらの組み合わせからなる群から選択される二価の金属カチオン;
−ゲニピンおよび医薬または化粧品に許容され得るか、または、ヒトまたは動物の食品に使用するのに適した二価の金属カチオン、例えば、Ca2+、Mg2+、Zn2+、Fe2+およびこれらの組み合わせからなる群から選択される二価の金属カチオン。
別の態様において、本発明は、カゼインまたはカゼイン源、プロバイオティクス細菌およびキトサンを混合することを含んでなる、マトリックスとプロバイオティクス細菌とを含み、前記マトリックスがカゼインおよびキトサンからなる微粒子(本発明の微粒子)を得るための方法(本明細書において以下「本発明の方法」)に関する。
本発明の微粒子は、プロバイオティクス細菌を封入し、処理中(カゼインおよびキトサンからなるマトリックスを含み、前記プロバイオティクス細菌が保持された微粒子を得る)および制御された条件または環境条件で長期間保存している間にプロバイオティクス細菌を保護し、さらに、摂取したときに胃腸管を取って移動する間に「酸性ペプシン」条件からプロバイオティクス細菌を保護する能力を有し、従って、異なる意図した製品(例えば、食品など)に組み込まれた後のプロバイオティクス細菌の不活性化が防がれるか、または実質的に低減する。
(i)本発明の複数の微粒子、または本発明の方法を用いることによって得ることができる複数の微粒子、または本発明の複数の微粒子と本発明の方法を用いることによって得ることができる微粒子とからなる組成物;および
(ii)本発明の少なくとも1つの微粒子、および/または本発明の方法を用いることによって得ることができる微粒子と、食品、機能性食品、化粧品または医薬品に許容され得る溶媒とを含む組成物
から選択される組成物(以下、「本発明の組成物」)に関する。
40〜60重量%のカゼイン、0.1〜3.5重量%のキトサン、109CFU/g〜5×1012CFU/gのプロバイオティクス細菌、0〜0.15重量%のトリポリリン酸ナトリウムおよび0〜60重量%の保護剤を含んでなり、重量比が組成物の合計重量基準である組成物A;
40〜60重量%のカゼイン、0.1〜3.5重量%のキトサン、109CFU/g〜5×1012CFU/gのプロバイオティクス細菌、0〜0.6重量%のバニリンおよび0〜60重量%の保護剤を含んでなり、重量比が組成物の合計重量基準である組成物B;
40〜60重量%のカゼイン、0.1〜3.5重量%のキトサン、109CFU/g〜5×1012CFU/gのプロバイオティクス細菌、0〜10重量%のCa2+および0〜60重量%の保護剤を含んでなり、重量比が組成物の合計重量基準である組成物C
から選択される。
−Th2応答が介在する移植拒絶反応、
−アレルギーおよびアレルギー関連疾患、
−免疫不全および前記免疫不全から誘導される病状、
−細胞内病原体によって引き起こされる感染、または
−粘膜感染
を予防および/または治療するための経口組成物である。
−植物花粉に対するアレルギー、例えば、Gramineaeの花粉(例えば、Lolium perenne、Poa pratense、Phleum pratense、Cynodon dactylon、Festuca pratensis、Dactylis glomerata、Secale cereale、Hordeum vulgare、Avena sativatriticum sativaなど)に対するアレルギー、他の草類の花粉(例えば、Artemisia vulgaris、Chenopodium album、Plantago lanceolata、Taraxacum vulgare、Parietaria judaica、Salsola kali、Urtica dioicaなど)に対するアレルギー、樹木の花粉(例えば、Olea Europea、Platanus sp.、Cupresus sp.など)に対するアレルギー;
−動物に対するアレルギー、動物(例えば、イヌ、ネコ、ウマ、鳥類など)の皮膚、鱗屑または羽根に対するアレルギー、昆虫に対するアレルギー、例えば、被検体において過敏反応を誘発する昆虫(例えば、ミツバチ、スズメバチ、蚊、ウマバエなど)の唾液、ハサミまたは針の中に存在する成分に対するアレルギー、ダニ、例えば、塵性ダニ(例えば、Dermatophagoides pteronyssimus、Dermatophagoides farinae、Acaros Siro、Blomia tropicalis、Euroglyphus maynei、Glyciphagus domesticus、Lepidoglyphus destructor、Tyrophagus putrescentiaeなど)に対するダニを含む;
−真菌(例えば、Alternaria alternata、Cladosporium herbarumなど)に対するアレルギー;
−食品または食品中に存在する食品成分、例えば、魚、果実(パイナップル、キウイなど)に対するアレルギー;
−金属(例えば、ニッケルなど)に対するアレルギー
がある。
I.空のカゼインおよびキトサンの微粒子を製造するための一般的方法
カゼインおよびキトサンの微粒子を製造するための方法は、カゼイン酸ナトリウム(ANVISA、マドリッド、スペイン)を水性媒体に溶解し、次いで、所定量のキトサン溶液と、場合により所定量の架橋剤を磁気攪拌条件、一定流量で加えることを含む。マンニトールのような保護剤を添加した後、この微粒子を含む懸濁物をスプレー乾燥機に通した後、生成した微粒子を乾燥させる。
微粒子の大きさは、Colorview Soft Imaging Systemsカメラを備えたOlympus CH40マイクロスコープを用いた光学顕微鏡によって決定した。
これらの実施例を実施するために使用したプロバイオティクス細菌は、それぞれ、コーンサイレージおよびチーズから単離したLactobacillus plantarum CECT 220およびLactobacillus casei CECT 475 Tであった。嫌気性チャンバ(MACS 500 AIRLOCK、AES Chemunex、スペイン)中、嫌気性雰囲気(85%窒素、10%水素、5%二酸化炭素)下、両微生物の凍結乾燥した製品を、MRSブロス(Merck、バルセロナ)中、37℃で再活性化した。使用するまで−85℃で冷凍保存したストック懸濁物の500μLアリコートを、これらの再活性化した培養物から調製した。
封入されたプロバイオティクス細菌を含有するカゼインおよびキトサンの微粒子を製造するための一般的な方法は、カゼイン酸ナトリウム(ANVISA、マドリッド、スペイン)を水性媒体に溶解し、次いで、上のIIIに記載した方法に従って得られた所定容積の細菌懸濁物を加え、遠心分離処理した後、磁気攪拌条件、一定流量で所定容積の2%スクロース溶液(w/v)に再び懸濁させることを含む。次いで、所定容積のキトサン溶液および場合により所定容積の架橋剤を加える。
細菌が微粒子内部に捕捉されること、すなわち、カゼインおよびキトサンからなるマトリックスが、プロバイオティクス細菌をコーティングすることを蛍光顕微鏡によって定性的に確認するために、この方法を行った。
封入された細菌を計測するために、1mLの1% NaOH(pH10)溶液を、既知の重量のマイクロカプセル(おおよそ500μg)に加え、5分間ボルテックスにより攪拌した後、対応する10倍希釈を0.1% BPWブロス(Merck、バルセロナ、スペイン)で行い、MRS寒天プレートに接種した。嫌気性条件下(MACS 500 Airlockチャンバ、AES Chemunex、スペイン)、37℃で24〜48時間インキュベーションした後、コロニーの計測を行った。
L.plantarumおよびL.caseiの胃腸での耐性をVinderolaら、2003に記載される方法に従って評価した。
−2g NaCl
−3.2g ペプシン(Sigma、バルセロナ、スペイン)
−7mL 37%HCl(v/v)
−6.8g 一塩基性リン酸カリウム(Panreac、マドリッド、スペイン)を250mLのI型の水に溶解し、これに、77mLの0.2N NaOHを加えた。
−500mLの水
−10gのパンクレアチン(Sigma、バルセロナ、スペイン)
保存期間中、室温(25℃)での細菌の生存能力を評価することによって、マイクロカプセル化された細菌の安定性試験を行った。
封入されたLactobacillus plantarum属のプロバイオティクス細菌を含有する、カゼインおよびキトサンの微粒子の調製および特性決定
細菌を含有する異なる種類の微粒子を調製し、すべての微粒子は、キトサンで修飾されたベースポリマーとしてカゼインを用いた。前記微粒子を調製するための方法は、架橋剤の存在または非存在、使用する架橋剤の種類によって変わった。
「一般的方法」のIIIに記載した細菌懸濁物(1.2×1012CFU/mL)1.5mLを、遠心分離処理し、2%スクロース溶液(w/v)に再懸濁させた後、カゼイン酸ナトリウムの10mg/mL水溶液25mLに加えた。次いで、400mgのキトサンを、攪拌しながら250mlの精製水に加え、0.1N HClでpHを調節することによって、pH5.5〜6の水性媒体中で調製した濃度1.6mg/mLのキトサン溶液10mLを、この混合物に加えた。
−空気投入口の温度:85℃
−空気出口の温度:40〜45℃
−空気圧:6bar(6×105Pa)
−サンプルの圧送速度:3.5mL/分
−吸引:100%
−空気の流れ:600L/h
バニリン水溶液(5mg/mL)0.5mLを、カゼイン酸ナトリウムの10mg/mL水溶液25mLに加えた。(少なくとも)15分インキュベーションした後、遠心分離処理し、2%スクロース溶液(w/v)に再懸濁させた後、「一般的方法」のIIIに記載した細菌懸濁物(4.7×1011CFU/mL)0.3mLをこの混合物に加えた。次いで、pH5.5〜6の水性媒体中で調製した濃度1.6mg/mLのキトサン溶液10mLを、この混合物に加えた。
遠心分離処理し、2%スクロース溶液(w/v)に再懸濁させた後、「一般的方法」のIIIに記載した細菌懸濁物(4.7×1011CFU/mL)1.5mLを、カゼイン酸ナトリウムの10mg/mL水溶液25mLに加えた。次いで、pH5.5〜6の水性媒体中で調製した濃度1.6mg/mLのキトサン溶液10mLを、この混合物に加えた。次いで、pH5.5〜6の水性媒体中で調製した濃度1.6mg/mLのキトサン溶液10mLを、この混合物に加えた。5分間インキュベーションした後、TPPの1mg/mL溶液0.8mLを加えた。
遠心分離処理し、2%スクロース溶液(w/v)に再懸濁させた後、「一般的方法」のIIIに記載した細菌懸濁物(1.2×1012CFU/mL)4mLを、カゼイン酸ナトリウムの10mg/mL水溶液25mLに加えた。次いで、pH5.5〜6の水性媒体中で調製した濃度1.6mg/mLのキトサン溶液2mLを、この混合物に加えた。5分間インキュベーションした後、2%(w/v)酢酸カルシウム溶液2mLおよび2%(w/v)塩化カルシウム溶液2mLを加えた。
環境条件で保存期間中、封入されたLactobacillus plantarumの安定性評価
実施例1に記載した製剤Ap、Bp、CpおよびDpを使用し、新しい懸濁物および凍結乾燥した製品を比較コントロールとして用い、環境条件(25℃)で長期間にわたる細菌の生存を評価した。図4は、得られた結果を示す。
疑似胃腸培地に対する、封入されたLactobacillus plantarum属のプロバイオティクス細菌の耐性の評価
実施例1に記載した製剤Ap、Bp、CpおよびDpを使用し、「一般的な方法」の第VII章に記載した方法に従って、疑似胃腸培地中、封入された細菌の耐性を評価した。図5は、プロセス全体の製剤について得られた結果と、封入されていない細菌について得られた耐性の結果を示す。遊離細菌(封入されておらず、凍結乾燥した細菌)の場合には、生存可能な計測数は、試験全体にわたって徐々に低下していき、最終的に平均で4対数単位消失した。製剤ApおよびDpにおいて、アッセイ全体にわたって計測数は実質的に一定に保たれ、胃模倣物のアッセイ終了時(2時間)および腸模倣物のアッセイ終了時(8時間)の両方で、凍結乾燥した製品よりも有意に高かった。製剤BpおよびCpにおいて、胃模倣物中に留まっている間に濃度の低下が観察され、2時間目の計測数は、凍結乾燥した製品と有意に同等であった。しかし、微粒子を腸模倣物に移すと、計測数の増加が観察され、アッセイ終了時(8時間)には、凍結乾燥した製品よりも有意に高かった。この最終的な計測数の増加は、ビフィズス菌を用いて行った試験において、別の著者らによってすでに記載されており、その著者らは、この現象は、低pHのストレス中によって細菌が受けた損傷は単に一時的なものであり、細菌を殺してしまわず、腸培地に移動したとき、細菌が回復することに起因すると結論づけている(LacroixおよびPicot、2004)。
封入されたLactobacillus casei属のプロバイオティクス細菌を含有する、カゼイン微粒子またはカゼインおよびキトサンの微粒子の調製および特性決定
細菌を含有する異なる種類の微粒子を調製し、すべての微粒子は、キトサンで修飾されたベースポリマーとしてカゼインを用いた。前記微粒子を調製するための方法は、使用する架橋剤の種類によって変わった。
「一般的方法」のIIIに記載した細菌懸濁物(2.2×1010CFU/mL)2mLを、遠心分離処理し、2%スクロース溶液(w/v)に再懸濁させた後、カゼイン酸ナトリウムの10mg/mL水溶液25mLに加えた。次いで、400mgのキトサンを、攪拌しながら250mlの精製水に加え、0.1N HClでpHを調節することによって、pH5.5〜6の水性媒体中で調製した濃度1.6mg/mLのキトサン溶液10mLを、この混合物に加えた。5分間インキュベーションした後、前述の混合物に100mgのマンニトールを加え、次いで、この製剤を、スプレー乾燥技術を用いて乾燥させた。処理条件は、以下のとおりであった。
−空気投入口の温度:85℃
−空気出口の温度:40〜45℃
−空気圧:6bar(6×105Pa)
−サンプルの圧送速度:3.5mL/分
−吸引:100%
−空気の流れ:600L/h
遠心分離処理し、2%スクロース溶液(w/v)に再懸濁させた後、「一般的方法」のIIIに記載した細菌懸濁物(9.4×1010CFU/mL)1.8mLを、カゼイン酸ナトリウムの10mg/mL水溶液150mLに加えた。次いで、pH5.5〜6の水性媒体中で調製した濃度1.6mg/mLのキトサン溶液25.5mLを、この混合物に加えた。この溶液に、カルシウム塩の混合物(12mlの2%酢酸カルシウム(w/v)および12mlの0.9%塩化カルシウムクロリド(w/v))を加えた。
−空気投入口の温度:75℃
−空気出口の温度:38℃
−空気圧:6bar(6×105Pa)
−サンプルの圧送速度:3.5mL/分
−吸引:100%
−空気の流れ:600L/h
バニリン水溶液(5mg/mL)0.5mLを、カゼイン酸ナトリウムの10mg/mL水溶液25mLに加えた。(少なくとも)15分インキュベーションした後、遠心分離処理し、2%スクロース溶液(w/v)に再懸濁させた後、「一般的方法」のIIIに記載した細菌懸濁物(1.2×109CFU/mL)3mLをこの混合物に加えた。次いで、pH5.5〜6の水性媒体中で調製した濃度1.6mg/mLのキトサン溶液10mLを、この混合物に加えた。
遠心分離処理し、2%スクロース溶液(w/v)に再懸濁させた後、「一般的方法」のIIIに記載した細菌懸濁物(9.4×1010CFU/mL)1.2mLを、カゼイン酸ナトリウムの10mg/mL水溶液100mLに加えた。次いで、pH5.5〜6の水性媒体中で調製した濃度1.6mg/mLのキトサン溶液20mLを、この混合物に加えた。これに、TPP(1mg/ml)1.6mLを加えた。
環境条件で保存期間中、封入されたLactobacillus caseiの安定性評価
実施例4に記載した製剤Ac、CcおよびDcを使用し、新しい懸濁物および凍結乾燥した製品を比較コントロールとして用い、環境条件で長期間にわたる細菌の生存を評価した。図7は、得られた結果をまとめている。
疑似胃腸培地に対する、封入されたLactobacillus casei属のプロバイオティクス細菌の耐性の評価
実施例4に記載した製剤Ac、CcおよびDcを使用し、「一般的方法」のVIIに記載した方法に従って、疑似胃腸培地中、封入された細菌の耐性を評価した。図8は、微粒子についての試験全体で得られた結果と、封入されておらず、凍結乾燥した細菌について得られた耐性の結果を示す。
L.plantarumに関連するカゼインバイオカプセルの免疫学的試験
この実施例を実施するために、実施例1に記載した、バニリン存在下、キトサンで修飾されたカゼイン微粒子(参照Bp)を使用した。そのため、バニリン(5mg/mL)0.5mLを、カゼイン酸ナトリウムの10mg/mL水溶液25mLに加えた。(少なくとも)15分インキュベーションした後、遠心分離処理し、2%スクロース溶液(w/v)に再懸濁させた後、「一般的方法」のIIIに記載した細菌懸濁物(4.6×1010CFU/mL)1mLをこの混合物に加えた。次いで、pH5.5〜6の水性媒体中で調製した濃度1.6mg/mLのキトサン溶液2mLを、この混合物に加えた。
−空気投入口の温度:85℃
−空気出口の温度:40〜45℃
−空気圧:6bar(6×105Pa)
−サンプルの圧送速度:3.5mL/分
−吸引:100%
−空気の流れ:600L/h
Claims (13)
- マトリックスとプロバイオティクス細菌とを含んでなり、前記マトリックスが、カゼインおよびキトサンからなり、キトサン:カゼインが、重量比で1:14〜40であることを特徴とする、微粒子。
- 架橋剤をさらに含んでなる、請求項1に記載の微粒子。
- 前記プロバイオティクス細菌が、Bifidobacterium属またはLactobacillus属の細菌である、請求項1または2に記載の微粒子。
- カゼインまたはカゼイン源、プロバイオティクス細菌、およびキトサンを混合することを含んでなる、請求項1〜3のいずれか一項に記載の微粒子を得るための方法。
- 架橋剤を加えることをさらに含んでなる、請求項4に記載の方法。
- 得られた微粒子を含有する懸濁物を乾燥させることをさらに含んでなる、請求項4または5に記載の方法。
- 請求項1〜3のいずれか一項に記載の複数の微粒子を含んでなる、組成物。
- 40〜60重量%のカゼイン、0.1〜3.5重量%のキトサン、109CFU/g〜5×1012CFU/gのプロバイオティクス細菌、0〜0.15重量%のトリポリリン酸ナトリウムおよび0重量%〜60重量%の保護剤を含んでなり、重量比が組成物の合計重量基準である組成物A;
40〜60重量%のカゼイン、0.1%〜3.5重量%のキトサン、109CFU/g〜5×1012CFU/gのプロバイオティクス細菌、0〜0.6重量%のバニリンおよび0〜60重量%の保護剤を含んでなり、重量比が組成物の合計重量基準である組成物B;
40%〜60重量%のカゼイン、0.1〜3.5重量%のキトサン、109CFU/g〜5×1012CFU/gのプロバイオティクス細菌、0〜10重量%のCa2+および0〜60重量%の保護剤を含んでなり、重量比が組成物の合計重量基準である組成物C
から選択される、請求項7に記載の組成物。 - 前記微粒子が乾燥粉末の形態である、請求項7または8に記載の組成物。
- 請求項1〜3のいずれか一項に記載の少なくとも1つの微粒子、または請求項7〜9のいずれか一項に記載の組成物を含んでなる、食品、医薬品、化粧品または機能性食品の製品。
- 請求項1〜3のいずれか一項に記載の微粒子、請求項7〜9のいずれか一項に記載の組成物、または請求項10に記載の製品を含んでなる、
−Th2が介在する移植拒絶反応、
−アレルギーおよびアレルギー関連疾患、
−免疫不全および前記免疫不全から誘導される病状、
−細胞内病原体によって引き起こされる感染、または
−粘膜感染
を予防および/または治療するための経口免疫系調整組成物。 - 粘膜感染を予防および/または治療するための経口組成物である、請求項11に記載の免疫系調整組成物。
- 免疫系調整組成物の製造のための、請求項1〜3のいずれか一項に記載の微粒子、請求項7〜9のいずれか一項に記載の組成物、または請求項10に記載の製品の使用。
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