JP6475163B2 - 乳汁からラクトフェリンを精製するための改良されたプロセスおよびその製品 - Google Patents
乳汁からラクトフェリンを精製するための改良されたプロセスおよびその製品 Download PDFInfo
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- JP6475163B2 JP6475163B2 JP2015534883A JP2015534883A JP6475163B2 JP 6475163 B2 JP6475163 B2 JP 6475163B2 JP 2015534883 A JP2015534883 A JP 2015534883A JP 2015534883 A JP2015534883 A JP 2015534883A JP 6475163 B2 JP6475163 B2 JP 6475163B2
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- Prior art keywords
- lactoferrin
- milk
- membrane
- salt
- protein
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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Description
小分子を除去しラクトフェリン純度を増加させるためのラクトフェリンの限外ろ過
APVパイロット規模限外ろ過プラントに、1つの6インチ50kDa膜(シンダー(Synder))を装着し、次に、ベースライン圧力が3.2〜3.4バール、膜間差圧が1.2〜1.4バールになるように安定させた。ラクトフェリン溶液(2mg/mL)を各2Lの6ロットに分割した。導電率(0、20、40、60、80または100mS/cm)以外は同一である6つの実験において、2Lのラクトフェリン溶液をUF供給タンクに加え、170Lまで水をつぎ足し、塩化ナトリウム溶液を加えることによって指定の導電率に調節した。保持液は供給タンクに循環させ、透過液を収集した。取り除いた透過液は同じ導電率のダイアフィルトレーション溶液で置き換えた。純度はカチオン交換HPLCで評価した。
塩はラクトフェリンを脱凝集させる
ラクトフェリン(タンパク質の百分率として95%ラクトフェリン)を水に溶解して10mg/mLにした。HPLCにスーパーデックス(Superdex)200 10/300GLカラム(GEヘルスケア(GE Healthcare))を装着し、緩衝液A(トリスHCl(pH7、1g/L))により、0.5mL/分の流量で平衡化した。緩衝液Bは1M塩化ナトリウムを含有するトリスHCl(1g/L)(pH7)であり、注入した試料は100μLであった。緩衝液Bの量は、0分と50分の間は0%とし、50分と90分の間は100%緩衝液Bに増加させ、次に90分から150分までは16%緩衝液Bに増加させた。以後の実験のそれぞれでは、0分から50分までと、90分から150分までの塩を、16%Bずつ増加させた。
小分子を除去しラクトフェリン純度を増加させるためのラクトフェリンの限外ろ過
6つのビバセル250ユニット(ザルトリウス(Sartorius))に50kDa膜を装着した。それぞれに250mLラインまで1mg/mLラクトフェリン溶液を充填した。ただし、塩化ナトリウム濃度はそれぞれで異なっていた(0、1.5、3、4、5または6%NaCl)。セルを3バールまで加圧した。保持液および透過液の試料を収集し、カチオン交換HPLCで分析した。
小分子を除去しラクトフェリン純度を増加させるためのラクトフェリンの限外ろ過
限外ろ過プラントに1つの6インチ50kDa膜(シンダー)を装着し、次に、ベースライン圧力が3.2〜3.4バール、膜間差圧が1.2〜1.4バールになるように安定させた。ラクトフェリン溶液(2mg/mL)を各2Lの6ロットに分割した。導電率(0、20、40または60mS/cm)以外は同一である6つの実験において、2Lのラクトフェリン溶液をUF供給タンクに加え、170Lまで水をつぎ足し、塩化ナトリウム溶液を加えることによって指定の導電率に調節した。保持液は供給タンクに循環させ、透過液を収集した。取り除いた透過液は同じ導電率のダイアフィルトレーション溶液で置き換えた。純度はカチオン交換HPLCで評価した。
ラクトフェリン純度の増加を改善するための、限外ろ過を伴うまたは伴わない、二次カチオン交換クロマトグラフィーの使用
ストマッカーを使ってラクトフェリン粉末(40g、95.2%ラクトフェリン)を水(200mL)に溶解した。試料を収集し、カチオン交換HPLCで分析した。そのラクトフェリン溶液を、SPファストフロー(Fast Flow)樹脂(GEヘルスケア)を充填したカラム(50mmD×1000mmL)に適用した。結合したラクトフェリンを、0%塩化ナトリウムから5.8%(1M)塩化ナトリウムまでにわたる3Lの直線的勾配を使って、樹脂から溶出させた。主要ラクトフェリンピークを収集し、カチオン交換HPLCによって分析した。
ラクトフェリンの限外ろ過がラクトフェリン純度を十分に増加させることができるかどうかを決定するための最初の実験
ラクトフェリン粉末(1kg、純度96.3%タンパク質)を100Lの水に溶解した。そのラクトフェリン溶液を、1つのシンダー6.3インチ50kDa膜(BX−5XB−6338)を装着したAPV UFプラントに入れた。ラクトフェリン溶液とUFプラント中に存在する水の体積は合わせて180Lであり、塩化ナトリウムを加えたので導電率は58mS/cmであった。透過液(100L)を10分で取り出した。水(100L)および塩を加えて121mS/cmの導電率を得た。透過液(100L)を10分で取り出した。次に、水ダイアフィルトレーション(400Lの透過液)によって、ラクトフェリン保持液の導電率を1300μSに低下させた。次にラクトフェリン保持液を凍結乾燥した(48時間、1ミリバール、40℃)。液状試料はMGCにおいてカチオン交換HPLCで分析し、粉末試料は外部の試験所により、カチオン交換HPLCで分析された(粉末の形態で分析した試料の方が正確であると考えるべきである)。
膜性能に対する膜の分子量カットオフの効果
膜の分子量カットオフ(MWCO)は膜性能に対して最も重要な影響を及ぼす。膜の孔径が増加するに連れて、膜が通過を許すタンパク質は大きくなり(図11)、フラックスは増加する(図12)。膜には混合物中の構成要素を分離する能力があるが、それは、1つまたはいくつかの構成要素が膜のMWCOより小さく、かつ1つまたはいくつかの構成要素が膜のMWCOより大きい場合に限る。理想的な分離には、一般に、少なくとも2桁の分子量の差が必要である(すなわち28Daの水および58Daの塩化ナトリウムは78kDaのラクトフェリンからほぼ完全に分離することができる)が、それほど大きなサイズの差異が存在しなくても、ある程度の分離は可能である。目的がラクトフェリン溶液の純度を増加させることであるなら、50kDa膜が利用可能な最善の選択肢であると思われる(図13)。
限外ろ過膜
UF4
タイプ:スパイラル型ポリエーテルスルホン(PES) MWCO:30kDa
ブランド:シンダー 型番:MK2B−6338
1.カチオン交換カラムから溶出したラクトフェリンを濃縮し、かつ
2.ラクトフェリン溶出塩を、クロマトグラフィープロセスで再利用するために6%塩タンクに再循環した。
−塩化ナトリウム(バッチあたり2,000kg)は、ラクトフェリン製造プロセスでは、かなりのコスト(バッチあたり$1,200)であり、塩化ナトリウムを再循環させることができれば、生産コストが劇的に低減する。
−塩化ナトリウムを再循環させることによって環境の損壊が低減される。有機固形物を除去するためのレオンガタ(Leongatha)における3次処理後に、塩化ナトリウム含有流出液は海洋排水口を利用して処分され、生成する廃棄物の量を低減するためにあらゆる手段を講じなければならない。塩再循環プロセスにより、必要な塩の量は80%低減する。これは、環境に放出される塩化ナトリウムの量が、バッチあたり8,000kg低減すること(3分の2がUF4によるもの)を意味する。
−スパイラル膜は、大きな膜面積を得る比較的安価な方法であり、これにより、設置面積の小さなプラントでの高いフラックスが可能になる。
−PESは本質的に親水性の膜であり、迅速かつ完全に濡れて、優れた流速と高いスループットとを持つ迅速ろ過をもたらす。PES膜はタンパク質結合性も極めて低く、標的タンパク質結合の可能性を最小限にするが、それは、高い収量、安定した膜貫通フラックスおよび一貫した見かけの膜多孔度を意味する。
−30kDa膜は、収穫されたラクトフェリンをうまく保持し(膜を通るタンパク質の移行は、存在するタンパク質の0.6%である)、鍵となる夾雑物、特にRNアーゼが膜を通過することを許すことによって、純度を増加させる。
−塩化ナトリウム(58Da)が30kDa膜では保持されないのに対し、ラクトフェリン(80kDa)は保持される。そのため、低い濃度(0.1%タンパク質)でカラムから溶出するラクトフェリンを、相応の塩濃度増加やタンパク質の喪失を伴わずに、3%タンパク質まで濃縮することができる。
タイプ:スパイラル型ポリエーテルスルホン(PES) MWCO:5kDa
ブランド:シンダー 型番:MT2B−6338
1.カチオン交換カラムから溶出した非ラクトフェリンタンパク質を濃縮し、かつ
2.クロマトグラフィープロセスで再利用するために、2.5%塩を2.5%塩タンクに再循環した。
−塩化ナトリウム(バッチあたり2,000kg)は、ラクトフェリン製造プロセスでは、かなりのコスト(バッチあたり$1,200)であり、塩化ナトリウムを再循環させることができれば、生産コストが劇的に低減する。
−塩化ナトリウムを循環させることによって環境の損壊が低減される。有機固形物を除去するためのレオンガタにおける3次処理後に、塩化ナトリウム含有流出液は海洋排水口を利用して処分され、生成する廃棄物の量を低減するためにあらゆる手段を講じなければならない。塩再循環プロセスにより、必要な塩の量は80%低減する。これは、環境に放出される塩化ナトリウムの量が、バッチあたり8,000kg低減すること(3分の1がUF5によるもの)を意味する。
−スパイラル膜は、大きな膜面積を得る比較的安価な方法であり、これにより、設置面積の小さなプラントでの高いフラックスが可能になる。
−PESは本質的に親水性の膜であり、迅速かつ完全に濡れて、優れた流速と高いスループットとを持つ迅速ろ過をもたらす。PES膜はタンパク質結合性も極めて低く、標的タンパク質結合の可能性を最小限にするが、それは、高い収量、安定した膜貫通フラックスおよび一貫した見かけの膜多孔度を意味する。
−5kDa膜は非ラクトフェリン不純物を保持し、以後のラクトフェリン溶出中にそれらがクロマトグラフィープロセスに戻ってラクトフェリンに混入することを防止する。タンパク質混合物は、さらに小さいタンパク質を数多く含有するので(その多くは成長因子である)、さらに小さな膜が必要である。
−塩化ナトリウム(58Da)が5kDa膜では保持されないのに対し、ラクトペルオキシダーゼ(80kDa)、免疫グロブリン(150〜420kDa)および成長因子(5〜17kDa)は保持される。そのため、低い濃度(0.1%タンパク質)でカラムから溶出するタンパク質を、相応の塩濃度増加やタンパク質の喪失を伴わずに、3%タンパク質まで濃縮することができる。
タイプ:セラミックチューブ(アルミナ) MWCO:0.8μm
ブランド:ポール(Pall) 型番:メンブラロックス(Membralox)GP19
1.ラクトフェリン溶液中に存在する微生物の数を低減し、かつ
2.不溶物を除去した。
−セラミック膜は洗浄剤に対する耐性が高く、微生物の完全な除去を保証するために激しく洗浄することができる。これらは、夾雑物が膜を通過することを許しうる、裂けることがない非常に頑丈な膜でもある。
−不溶物の低減(清澄度の増加)および微生物汚染の低減
−本プラントは、タンパク質が妥当な体積および固形物濃度で膜を通過することを可能にするために、0.22μmではなく0.8μmである。主な原材料(脱脂乳)は事前に低温殺菌されているので、フィルターを完全な微生物除去ステップにしようとはしていない。
タイプ:スパイラル型ポリフッ化ビニリデン(PVDF) MWCO:50kDa
ブランド:シンダー 型番: BN4B−6338
1.非ラクトフェリンタンパク質を低減することによってラクトフェリン純度を増加させ、かつ
2.塩化ナトリウムおよび残存ラクトースを除去することによってタンパク質を>95%固形分に増加させた。
−フェリチンOB(Ferritin OB)製造向けのラクトフェリンは、標準ラクトフェリンより高いラクトフェリン純度を有する。その高純度は、歴史的に使用されてきた5kDa膜の代わりに50kDa膜を使用することによって得られる(図14)。
−スパイラル膜は大きな膜面積を得る比較的安価な方法であり、これにより、設置面積の小さなプラントでの高いフラックスと相対的に短いプロセス時間が可能になる。
−親水性ポリフッ化ビニリデン(PVDF)膜は膜貫通フラックスが高く、タンパク質に対するアフィニティが低い。これらの理由から、膜孔を詰まらせるタンパク質はほとんどないので、プロセスの継続期間中はフラックスが高く保たれ、収量が高く保たれる。
−50kDa膜は、ラクトフェリンを保持したまま非ラクトフェリンタンパク質(RNアーゼ、成長因子)の移行を改善することができるので、その使用は、これより小さな膜(歴史的には5kDa膜)より好ましい。非ラクトフェリンタンパク質の移行の増加は、ラクトフェリン純度の向上をもたらす(純度の平均増加量は1.8%タンパク質、P<0.001)。さらなる詳細は、「Increasing Lactoferrin Purity by Diafiltration with Salt Solution in an Ultrafiltration Plant Fitted with 50 kDa Membranes」(JR0010)から入手することができる。
−塩化ナトリウム(58Da)が50kDa膜では保持されないのに対し、ラクトフェリン(80kDa)は保持される。そのため、低い濃度(3%タンパク質)でカラムから溶出するラクトフェリンを、相応の塩濃度増加やタンパク質の喪失を伴わずに、>20%タンパク質まで濃縮することができる。
−水を除去することによって総固形分が増加し、それゆえに凍結乾燥器の固形分スループットが最大になる。
50kDa UFによってラクトフェリンの純度を増加させうることを確認するための完全に商業的規模での試行
この変更の有効性の比較が可能になるように、クロマトグラフィープロセスからのバッチを半分に分割した。半分に分けたうちの一方を、5kDa膜を装着したUF7により、塩ダイアフィルトレーションなしで処理し、他方を、50kDa膜を装着したUF7と塩ダイアフィルトレーションとによって処理した。
Claims (6)
- 乳汁または乳汁画分をMWCO30kDから50kDのフィルターを使ったろ過に付して、ラクトフェリンを含む保持液画分と、30kD未満の分子量を有する成長因子および/またはRNアーゼを含む透過液画分とに、前記乳汁または乳汁画分を分離することを含む、ラクトフェリンおよび30kD未満の分子量を有する成長因子またはRNアーゼを含む乳汁または乳汁画分からラクトフェリンを精製するためのプロセスであって、30kD未満の分子量を有する成長因子および/またはRNアーゼが前記透過液に流入するように、MWCO30kDから50kDのフィルターを使ったろ過中に、前記乳汁または乳汁画分を塩処理に付し、前記塩処理が、前記乳汁またはラクトフェリンを、MWCO30kDから50kDのフィルターを使ったろ過中は少なくとも0.2M NaClもしくはそれに相当する塩濃度または少なくとも20mS/cmの導電率に維持することを含み、前記ラクトフェリンを含む保持液画分が収集される、前記プロセス。
- 30kD未満の分子量を有する成長因子および/またはRNアーゼが前記透過液に流入するように、前記塩処理が、RNアーゼまたは成長因子のいかなる塊も脱凝集または脱会合させる、請求項1に記載のプロセス。
- 30kD未満の分子量を有する成長因子および/またはRNアーゼが前記透過液に流入するように、前記塩処理が、いかなるRNアーゼまたは成長因子もフィルターから分離させる、請求項1に記載のプロセス。
- フィルターが50kDのMWCOを有する、請求項1〜3のいずれか一項に記載のプロセス。
- 塩処理が少なくとも4時間は継続される、請求項1〜4のいずれか一項に記載のプロセス。
- ろ過が温度50〜70℃で行われる、請求項1〜5のいずれか一項に記載のプロセス。
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AU2012904391A AU2012904391A0 (en) | 2012-10-08 | Improved process for purifying milk proteins and products thereof | |
AU2012904391 | 2012-10-08 | ||
AU2013204858A AU2013204858B2 (en) | 2012-10-08 | 2013-04-12 | Improved process for purifying milk proteins and products thereof |
AU2013204858 | 2013-04-12 | ||
PCT/AU2013/001152 WO2014056025A1 (en) | 2012-10-08 | 2013-10-08 | Improved process for purifying lactoferrin from milk and products thereof |
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JP2015536905A JP2015536905A (ja) | 2015-12-24 |
JP2015536905A5 JP2015536905A5 (ja) | 2016-11-24 |
JP6475163B2 true JP6475163B2 (ja) | 2019-02-27 |
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US (1) | US10016487B2 (ja) |
EP (1) | EP2904006A4 (ja) |
JP (1) | JP6475163B2 (ja) |
KR (1) | KR20150068404A (ja) |
CN (1) | CN104768971B (ja) |
AU (1) | AU2013204858B2 (ja) |
BR (1) | BR112015007674A2 (ja) |
CA (1) | CA2886892A1 (ja) |
IN (1) | IN2015DN02971A (ja) |
NZ (1) | NZ631826A (ja) |
RU (1) | RU2683228C2 (ja) |
WO (1) | WO2014056025A1 (ja) |
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AU2013204858B2 (en) | 2012-10-08 | 2015-06-25 | Saputo Dairy Australia Pty Limited | Improved process for purifying milk proteins and products thereof |
CN106215174A (zh) * | 2016-08-04 | 2016-12-14 | 无锡科捷诺生物科技有限责任公司 | 一种人乳铁蛋白的制剂化制备方法 |
JP7370224B2 (ja) * | 2019-11-08 | 2023-10-27 | ライオン株式会社 | ラクトフェリン含有腸溶製剤 |
FR3115037A1 (fr) * | 2020-10-12 | 2022-04-15 | Compagnie Laitiere Europeenne | Procédé de purification de fraction de protéines cationiques et fraction ainsi obtenue |
CN113278063A (zh) * | 2021-05-13 | 2021-08-20 | 上海仁统生物科技中心 | 一种利用超滤法自初乳中获取乳铁蛋白的方法 |
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FR2584727B1 (fr) * | 1985-07-11 | 1988-06-17 | Roussel Uclaf | Procede d'extraction de proteines du lait, produits, application du procede, et compositions pharmaceutiques |
US5221734A (en) | 1987-10-01 | 1993-06-22 | Ciba-Geigy Corporation | Process for preparing a polypeptide growth factor for milk |
GB8729031D0 (en) * | 1987-12-11 | 1988-01-27 | Express Foods Group Ltd | Isolation of immunoglobulin rich fraction from whey |
JP2686831B2 (ja) | 1989-09-22 | 1997-12-08 | 雪印乳業株式会社 | 鉄結合性蛋白質を分離、精製し、採取する方法 |
ATE129125T1 (de) * | 1992-01-15 | 1995-11-15 | Campina Melkunie Bv | Verfahren zur isolierung von lactoferrin und lactoperoxidase aus milch und milchprodukten. |
JPH05202098A (ja) | 1992-01-29 | 1993-08-10 | Snow Brand Milk Prod Co Ltd | 乳質原料から生理活性物質の製造法 |
US5756680A (en) * | 1994-01-05 | 1998-05-26 | Sepragen Corporation | Sequential separation of whey proteins and formulations thereof |
ATE209862T1 (de) * | 1994-02-16 | 2001-12-15 | Pharming Intellectual Pty Bv | Isolierung von lactoferrin aus milch |
NL1005677C2 (nl) * | 1997-03-27 | 1998-09-29 | Campina Melkunie Bv | Werkwijze voor het winnen van groeifactoren, of een samenstelling die één of meer groeifactoren bevat, uit melk of een derivaat daarvan. |
US20040219225A1 (en) * | 2001-07-20 | 2004-11-04 | Kivits Marinus Gerardus Cornel | Process for obtaining growth factor (tgf-beta and igf-1), lactoperoxidase and immunoglobulins preparations from milk products having low mutual cross-contamination |
US6875459B2 (en) * | 2001-09-10 | 2005-04-05 | Henry B. Kopf | Method and apparatus for separation of milk, colostrum, and whey |
DK1480524T3 (da) * | 2002-03-07 | 2013-07-15 | Upfront Chromatography As | Fremgangsmåde til isolering af lactoferrin |
FR2841747B1 (fr) * | 2002-07-02 | 2004-08-20 | Cie Laitiere Europeenne | Isolat de proteines de lait et procede pour sa preparation |
GB0313892D0 (en) * | 2003-06-16 | 2003-07-23 | Hannah Res Inst | Control of lactation |
US20050208638A1 (en) * | 2004-03-22 | 2005-09-22 | Chao Wu | Process for preparing bioactive protein-enriched whey products |
US8252341B2 (en) | 2004-09-14 | 2012-08-28 | Paul Brazeau | Isolation of growth and differentiating factors from colostrum |
NZ566691A (en) * | 2005-09-09 | 2011-06-30 | Murray Goulburn Coop Co Ltd | Composition of whey growth factor extract for reducing muscle inflammation |
FR2901796A1 (fr) | 2006-05-31 | 2007-12-07 | Lab Francais Du Fractionnement | Procede d'extraction d'une ou de plusieurs proteines presentes dans du lait |
CN101626693B (zh) * | 2006-11-10 | 2014-05-14 | 墨累古尔本合作有限公司 | 用于制备血管生成素的方法 |
NZ589311A (en) * | 2008-05-14 | 2012-08-31 | Agriculture Victoria Serv Pty | Angiogenin-enriched milk fractions prepared by methods involving heating the milk to over 70 degrees celsius for at least one minute |
RU2579661C2 (ru) * | 2009-01-28 | 2016-04-10 | Жан-Поль ПЕРРОДЭН | Способ производства лактоферрина, фракция, содержащая лактоферрин, и ее применения |
AU2011283472B2 (en) | 2010-07-30 | 2014-02-13 | Morinaga Milk Industry Co., Ltd. | Antimicrobial activity enhancing agent |
AU2013204858B2 (en) | 2012-10-08 | 2015-06-25 | Saputo Dairy Australia Pty Limited | Improved process for purifying milk proteins and products thereof |
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US20150315264A1 (en) | 2015-11-05 |
US10016487B2 (en) | 2018-07-10 |
AU2013204858A1 (en) | 2014-04-24 |
WO2014056025A1 (en) | 2014-04-17 |
NZ631826A (en) | 2017-08-25 |
BR112015007674A2 (pt) | 2017-07-04 |
WO2014056025A8 (en) | 2015-05-14 |
AU2013204858B2 (en) | 2015-06-25 |
RU2015116933A (ru) | 2016-11-27 |
EP2904006A1 (en) | 2015-08-12 |
JP2015536905A (ja) | 2015-12-24 |
EP2904006A4 (en) | 2016-04-06 |
KR20150068404A (ko) | 2015-06-19 |
CN104768971A (zh) | 2015-07-08 |
RU2683228C2 (ru) | 2019-03-26 |
IN2015DN02971A (ja) | 2015-09-18 |
CN104768971B (zh) | 2017-12-05 |
CA2886892A1 (en) | 2014-04-17 |
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