JP5513380B2 - 肝細胞増殖因子に対する特異的結合剤の組成物 - Google Patents
肝細胞増殖因子に対する特異的結合剤の組成物 Download PDFInfo
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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Description
非極性アミノ酸および肝細胞増殖因子(HGF)への特異的結合剤を含む組成物を提供する。そのような組成物を作製し、使用する方法も提供する。
肝細胞増殖因子(HGF)は、ある場合において、肝細胞の強力なマイトジェンである。HGFは、ある場合において、上皮細胞の運動性を誘発する線維芽細胞、および平滑筋の分泌タンパク質でもある。抗体を含むがこれに限定されない、HGFへの特定の特異的結合剤が説明されている。例えば、あらゆる目的のために参照することにより本出願に組み込まれる、2005年6月2日に公開された、米国特許第2005/0118643号(特許文献1)を参照されたい。
特定の実施形態では、HGFへの特異的結合剤、少なくとも1つの安定化剤、および緩衝剤を含む組成物が提供され、少なくとも1つの安定化剤は、少なくとも1つの非極性アミノ酸であり、組成物のpHは、5.4を上回る。特定の実施形態では、特異的結合剤は、抗体、ポリクローナル抗体、モノクローナル抗体、重鎖および軽鎖が柔軟なリンカーにより連結される抗体、Fv分子、マキシボディ、免疫学的に機能的な免疫グロブリン断片、Fab断片、Fab′断片、F(ab′)2分子、完全ヒト抗体、ヒト化抗体、キメラ抗体、およびHGFのc−Met受容体への結合を実質的に抑制する抗体から選択される。特定の実施形態では、特異的結合剤は、完全ヒト抗体であり、完全ヒト抗体は、2.12.1である。特定の実施形態では、HGFへの特異的結合剤は、0.5mg/ml〜200mg/mlの濃度である。特定の実施形態では、HGFへの特異的結合剤は、30mg/mlの濃度である。
[本発明101]
HGFへの特異的結合剤、少なくとも1つの安定化剤、および緩衝剤を含む組成物であって、前記少なくとも1つの安定化剤が、少なくとも1つの非極性アミノ酸であり、かつ前記組成物のpHが、5.4を上回る、組成物。
[本発明102]
前記特異的結合剤が、抗体、ポリクローナル抗体、モノクローナル抗体、重鎖および軽鎖が柔軟なリンカーで連結される抗体、Fv分子、マキシボディ、免疫学的に機能的免疫グロブリン断片、Fab断片、Fab′断片、F(ab′) 2 分子、完全ヒト抗体、ヒト化抗体、キメラ抗体、およびHGFの、c-Met受容体への結合を実質的に抑制する抗体から選択される、本発明101に記載の組成物。
[本発明103]
前記特異的結合剤が、完全ヒト抗体であり、前記完全ヒト抗体が、2.12.1である、本発明102に記載の組成物。
[本発明104]
少なくとも1つの付加的薬学的剤をさらに含む、本発明101に記載の組成物。
[本発明105]
前記少なくとも1つの非極性アミノ酸が、グリシン、アラニン、バリン、ロイシン、イソロイシン、プロリン、メチオニン、フェニルアラニン、およびトリプトファンから選択される、本発明101に記載の組成物。
[本発明106]
前記少なくとも1つの非極性アミノ酸が、アラニンであり、アラニンが、少なくとも0.02Mの濃度で存在する、本発明105に記載の組成物。
[本発明107]
アラニンが、0.02Mの濃度で存在する、本発明106に記載の組成物。
[本発明108]
アラニンが、0.2Mの濃度で存在する、本発明106に記載の組成物。
[本発明109]
前記少なくとも1つの非極性アミノ酸が、ロイシンであり、ロイシンが、少なくとも0.02Mの濃度で存在する、本発明105に記載の組成物。
[本発明110]
ロイシンが、0.02Mの濃度で存在する、本発明109に記載の組成物。
[本発明111]
ロイシンが、0.075Mの濃度で存在する、本発明109に記載の組成物。
[本発明112]
前記少なくとも1つの非極性アミノ酸が、第1の非極性アミノ酸および第2の非極性アミノ酸である、本発明101に記載の組成物。
[本発明113]
前記第1の非極性アミノ酸が、アラニンであり、かつ前記第2の非極性アミノ酸が、ロイシンである、本発明112に記載の組成物。
[本発明114]
アラニンが、少なくとも0.02Mの濃度で存在し、かつロイシンが、少なくとも0.02Mの濃度で存在する、本発明113に記載の組成物。
[本発明115]
アラニンが、0.02の濃度で存在し、かつロイシンが、0.02Mの濃度で存在する、本発明114に記載の組成物。
[本発明116]
アラニンが、0.2Mの濃度で存在し、かつロイシンが、0.075Mの濃度で存在する、本発明114に記載の組成物。
[本発明117]
少なくとも1つの非極性アミノ酸が、メチオニンであり、かつ前記組成物の変色が、低減される、本発明105に記載の組成物。
[本発明118]
メチオニンが、少なくとも、0.001Mの濃度で存在する、本発明117に記載の組成物。
[本発明119]
メチオニンが、0.01Mの濃度で存在する、本発明117に記載の組成物。
[本発明120]
前記少なくとも1つの非極性アミノ酸が、第1の非極性アミノ酸、第2の非極性アミノ酸、および第3の非極性アミノ酸である、本発明101に記載の組成物。
[本発明121]
前記第1の非極性アミノ酸が、アラニンであり、前記第2の非極性アミノ酸が、ロイシンであり、前記第3の非極性アミノ酸が、メチオニンであり、かつ前記組成物の変色が、低減される、本発明120に記載の組成物。
[本発明122]
アラニンが、少なくとも、0.02Mの濃度で存在し、ロイシンが、少なくとも、0.02Mの濃度で存在し、かつメチオニンが、少なくとも、0.001Mの濃度で存在する、本発明121に記載の組成物。
[本発明123]
アラニンが、0.02Mの濃度で存在し、ロイシンが、0.02Mの濃度で存在し、かつメチオニンが、0.01Mの濃度で存在する、本発明122に記載の組成物。
[本発明124]
アラニンが、0.2Mの濃度で存在し、ロイシンが、0.075Mの濃度で存在し、かつメチオニンが、0.01Mの濃度で存在する、本発明122に記載の組成物。
[本発明125]
前記緩衝剤が、ヒスチジン、プロピオン酸塩、および酢酸塩から選択される、本発明101に記載の組成物。
[本発明126]
pHが、5.7である、本発明125に記載の組成物。
[本発明127]
pHが、5.6である、本発明125に記載の組成物。
[本発明128]
前記緩衝剤が、少なくとも、0.01Mの濃度で存在する、本発明125に記載の組成物。
[本発明129]
前記緩衝剤が、0.01Mの濃度で存在する、本発明128に記載の組成物。
[本発明130]
糖をさらに含む、本発明101に記載の組成物。
[本発明131]
前記糖が、ソルビトールである、本発明130に記載の組成物。
[本発明132]
ソルビトールが、少なくとも、5%の濃度で存在する、本発明131に記載の組成物。
[本発明133]
ソルビトールが、5%の濃度で存在する、本発明132に記載の組成物。
[本発明134]
界面活性剤をさらに含む、本発明101または本発明130に記載の組成物。
[本発明135]
前記界面活性剤が、ポリソルベート20である、本発明134に記載の組成物。
[本発明136]
ポリソルベート20が、少なくとも0.004%の濃度で存在する、本発明135に記載の組成物。
[本発明137]
ポリソルベート20が、0.004%の濃度で存在する、本発明136に記載の組成物。
[本発明138]
前記HGFへの特異的結合剤が、0.5mg/ml〜200mg/mlの濃度である、本発明102に記載の組成物。
[本発明139]
前記HGFへの特異的結合剤が、30mg/mlの濃度である、本発明138に記載の組成物。
[本発明140]
前記少なくとも1つの安定化剤が、少なくとも1つの非極性アミノ酸および少なくとも1つの抗凍結剤である、本発明101に記載の組成物。
[本発明141]
前記少なくとも1つの非極性アミノ酸が、アラニンである、本発明140に記載の組成物。
[本発明142]
アラニンが、少なくとも、0.02Mの濃度で存在する、本発明141に記載の組成物。
[本発明143]
アラニンが、0.02Mの濃度で存在する、本発明142に記載の組成物。
[本発明144]
アラニンが、0.2Mの濃度で存在する、本発明142に記載の組成物。
[本発明145]
前記少なくとも1つの非極性アミノ酸が、ロイシンである、本発明140に記載の組成物。
[本発明146]
ロイシンが、少なくとも、0.02Mの濃度で存在する、本発明145に記載の組成物。
[本発明147]
ロイシンが、0.02Mの濃度で存在する、本発明146に記載の組成物。
[本発明148]
ロイシンが、0.2Mの濃度で存在する、本発明146に記載の組成物。
[本発明149]
前記少なくとも1つの非極性アミノ酸が、第1の非極性アミノ酸および第2の非極性アミノ酸である、本発明140に記載の組成物。
[本発明150]
前記第1の非極性アミノ酸が、アラニンであり、かつ第2の非極性アミノ酸が、ロイシンである、本発明149に記載の組成物。
[本発明151]
アラニンが、少なくとも、0.02Mの濃度で存在し、かつロイシンが、少なくとも、0.02Mの濃度で存在する、本発明150に記載の組成物。
[本発明152]
アラニンが、0.02Mの濃度で存在し、かつロイシンが、0.02Mの濃度で存在する、本発明151に記載の組成物。
[本発明153]
アラニンが、0.2Mの濃度で存在し、かつロイシンが、0.075Mの濃度で存在する、本発明151に記載の組成物。
[本発明154]
前記少なくとも1つの抗凍結剤が、親水性ポリマー、アルコール、糖、および塩基性アミノ酸から選択される、本発明140に記載の組成物。
[本発明155]
前記少なくとも1つの抗凍結剤が、少なくとも1つの親水性ポリマーである、本発明154に記載の組成物。
[本発明156]
前記少なくとも1つの親水性ポリマーが、ポリビニルピロリドンK15、ポリエチレングリコール200、ポリエチレングリコール400、ポリエチレングリコール600、ポリエチレングリコール4000およびポリエチレングリコール30,000から選択される、本発明155に記載の組成物。
[本発明157]
前記少なくとも1つの抗凍結剤が、少なくとも1つのアルコールである、本発明154に記載の組成物。
[本発明158]
前記少なくとも1つのアルコールが、エタノール、2-プロパノール、プロピレングリコール、ヘキサンジオール、L-(+)-2、3-ブタンジオール、および(±)2-メチル-2、4-ペンタンジオールから選択される、本発明157に記載の組成物。
[本発明159]
前記少なくとも1つの抗凍結剤が、少なくとも1つの糖である、本発明154に記載の組成物。
[本発明160]
前記少なくとも1つの糖が、グルコース、マンノース、スクロース、ラクトース、マンニトール、キシリトール、エリトリトール、トレイトール、ソルビトール、イノシトール、グリセロール、L-グルコネート、トレハロース、およびラフィノースから選択される、本発明159に記載の組成物。
[本発明161]
前記少なくとも1つの抗凍結剤が、少なくとも1つの塩基性アミノ酸である、本発明154に記載の組成物。
[本発明162]
前記少なくとも1つの塩基性アミノ酸が、アルギニンおよびヒスチジンから選択される、本発明161に記載の組成物。
[本発明163]
前記少なくとも1つの抗凍結剤が、0.1Mの濃度で存在する、本発明140または本発明153に記載の組成物。
[本発明164]
HGFへの特異的結合剤と、少なくとも1つの安定化剤と、緩衝剤とを含む組成物を保持する容器を含む製品。
[本発明165]
組成物内のHGFへの特異的結合剤を調製するための方法であって、前記HGFへの特異的結合剤と、少なくとも1つの安定化剤と、緩衝剤とを混合する工程を含む、方法。
本明細書に使用される項の見出しは、整理目的のみであり、記載する主題を制限するものであると解釈されない。特許、特許出願書、記事、書籍、および論文を含むが、これらに限定されない、本出願に引用するすべての文書、または文書の一部は、任意の目的のために、参照することにより全体として本出願に明示的に組み込まれる。参照することにより組み込まれた文書または文書の一部の1つ以上が、本出願内の用語の定義と相反するように用語を定義する場合には、本出願が優先する。
本開示によって使用する以下の用語は、特定の指示がない限り、以下の意味を有するものと理解されたい。
特定の実施例では、HGFは、Met受容体を結合して、Metリン酸化を誘発する。特定の実施例では、正常なHGF誘発Metリン酸化は、様々な細胞過程を調節する。特定の実施例では、異常なMet−HGF活性は、多くのヒトの病状と相関する。例えば、特定の実施例では、過剰のHGF活性は、特定の癌と相関する。したがって、特定の実施例では、HGF活性を調節することは、治療的に有用であり得る。特定の実施形態では、HGFへの特異的結合剤を使用して、異常に高いレベルからHGF活性量を減少させる。特定の実施形態では、異常に高いレベルからHGF活性量を減少させることは、腫瘍活性を減少させ、癌の重症度を低減させる。特定の実施形態によると、HGFへの特異的結合剤を使用して、癌を治療する。特定の実施形態では、HGFへの特異的結合剤を使用して、癌を予防する。
自然発生する抗体構造単位は、概して、四量体を成す。それぞれのそのような四量体は、典型的に、2つの同一の対のポリペプチド鎖から成り、それぞれの対は、1つの完全長軽鎖(特定の実施形態では、約25kDa)および1つの完全長重鎖(特定の実施形態では、約50−70kDa)を有する。
二重特異性または二機能性抗体は、典型的に、2つの異なる重鎖/軽鎖の対および2つの異なる結合部位を有する人工ハイブリッド抗体である。二重特異性抗体は、ハイブリドーマの融合またはFab′断片の連結を含むが、これらに限定されない、様々な方法によって産生され得る。例えば、Sougsivilai & Lachmann Clin. Exp. Immunol.. 79:315−321 (1990)、Kostelny et al. J. Immunol. 148:1547−1553 (1992)を参照されたい。
特定の実施形態では、抗体は、ハイブリドーマ細胞株以外の細胞株に発現し得る。特定の実施形態では、キメラ抗体を含む特定の抗体をコード化する配列は、適切な哺乳類の宿主細胞の形質転換に使用することができる。特定の実施形態によれば、形質転換は、米国特許第4,399,216号、第4,912,040号、第4,740,461号、および第4,959,455号に例示するとおり、例えば、ウイルス内に(またはウイルスベクターに)ポリヌクレオチドを凝縮するステップ、および当該技術において周知の手順を使用して、宿主細胞をウイルスで形質導入する、またはベクターをトランスフェクトすることによって形質導入するステップを含む、ポリヌクレオチドを細胞に導入する周知の方法のいずれかによって行うことができる。
特定の実施形態では、HGFへの特異的結合剤、少なくとも1つの安定化剤、および緩衝剤を含む組成物を提供する。特定のそのような実施形態では、組成物は、少なくとも1つの付加的な薬学的剤をさらに含む。
実施例1
HGFへの特異的結合剤に対する異なる組成物の効果を評価するために、HGFに対する完全ヒトIgG2モノクローナル抗体である2.12.1の組成物を下の表1に示す6つの異なる製剤に製剤化した。製剤すべてにおける2.12.1の濃度は、30mg/mlであった。全製剤のpHは、5.7であった。組成物を3ccのバイアルに1mlの最終容量まで充填した。組成物を0週間、4週間、8週間、または12週間、37℃でインキュベートした。各組成物に対して、各時間点で、未変性SEC−HPLCによる抗体モノマーのモニタのために試料を各バイアルから取り出した。
HGFへの特異的結合剤に対する異なる組成物の効果を評価するために、2.12.1の組成物を下の表2に示す21の異なる製剤に製剤化した。製剤すべてにおける2.12.1の濃度は、30mg/mlであった。組成物を3ccのバイアルに1mlの最終容量まで充填した。以下に詳細に説明するとおり、一定期間、組成物を37℃または45℃で、インキュベートした。実験の開始時に表2に示す製剤のpHを測定した。pHは、45℃で、少なくとも8週間、安定であった。いくつかの場合、pHは、45℃で8週間後、開始時のpHと変わらなかった。いくつかの場合には、pHは、45℃で8週間後、開始時のpHより0.1〜0.2pH単位高かった。抗体モノマーに対して、いくつかの組成物を未変性SEC−HPLCでモニタした(図2〜6)。また、抗体凝集および/または切り出し(clip)に対して、いくつかの組成物を非還元変性SEC−HPLCでモニタした(図7)。
HGFへの特異的結合剤を含む組成物における遊離L−メチオニン(「Met」)の効果を評価するために、Metを含む、またはMetを含まないいずれかの2.12.1の組成物を様々な時間、様々な波長および強度の光に曝した。組成物における2.12.1の濃度は、29〜30mg/mlで、10mMの酢酸ナトリウム、5%ソルビトール、pH5.2に製剤化された。Metの濃度は、組成物に存在する時、10mMであった。組成物を3ccのガラスバイアルに1mlの最終容量に充填した。試験をした各光の条件において、製剤の視覚的な鮮明度および混濁度を、以下に詳細に説明するとおり、眼および/または紫外/可視(UV/Vis)分光光度測定により検査した。
HGFへの特異的結合剤に対する異なる組成物の効果を評価するために、2.12.1の組成物を下の表4に示す17の異なる製剤に製剤化した。製剤すべてにおける2.12.1の濃度は、30mg/mlであった。組成物を3ccのバイアルに1mlの最終容量まで充填した。以下に詳細を説明するとおり、組成物を29℃、37℃または45℃で、一定期間、インキュベートした。実験の開始時に表4に示す製剤のpHを測定した。pHは、45℃で、少なくとも8週間、安定であった。いくつかの場合には、pHは、45℃で8週間後、開始時のpHと変わらなかった。いくつかの場合には、pHは、45℃で8週間後、開始時のpHより0.1〜0.2pH単位高かった。抗体モノマーに対して、いくつかの組成物を未変性SEC−HPLCでモニタした(データ示さず)。
HGFへの特異的結合剤に対する異なる組成物の効果を評価するために、2.12.1の組成物を下の表6に示す15の異なる製剤に製剤化した。製剤すべてにおける2.12.1の濃度は、30mg/mlであった。組成物を3ccのバイアルに2mlの最終容量まで充填した。組成物を12週間、37℃でインキュベートした。
HGFへの特異的結合剤に対する異なる組成物の効果を評価するために、2.12.1の組成物を下の表7に示す7つの異なる製剤に製剤化した。製剤すべてにおける2.12.1の濃度は、30mg/mlであった。組成物を5ccのバイアルに2mlの最終容量まで充填した。組成物を0、1、2、または3ヶ月間、37℃でインキュベートした。
HGFへの特異的結合剤に対する異なる組成物の効果を評価するために、2.12.1の組成物を下の表8に示す4つの異なる製剤に製剤化した。製剤すべてにおける2.12.1の濃度は、30mg/mlであった。組成物を5ccのバイアルに2mlの最終容量まで充填した。組成物を2年間、4℃でインキュベートした。
HGFへの特異的結合剤に対する異なる組成物の効果を評価するために、2.12.1の組成物を下の表9に示す6つの異なる製剤に製剤化した。製剤すべてにおける2.12.1の濃度は、30mg/mlであった。組成物を3ccのバイアルに0.5mlの最終容量まで充填した。組成物を37℃で0週間、1週間、2週間、4週間、または3ヶ月間、もしくは−30℃で0週間、4週間、または3ヶ月間インキュベートした。
HGFへの特異的結合剤に対する、1回以上の凍結/融解サイクルに供された組成物の異なる剤の効果を評価するために、2.12.1の組成物を下の表9に示す3つの異なる製剤:A56L、A56L PEG200およびA56Sに製剤化した。製剤すべてにおける2.12.1の濃度は、30mg/mlであった。すべての製剤は、10mMの酢酸ナトリウムを含み、pH5.6であった。組成物を3ccのバイアルに0.5mlの最終容量まで充填した。
HGFへの特異的結合剤に対する異なる組成物の効果を評価するために、2.12.1の組成物を下の表10に示す8つの異なる製剤に製剤化した。製剤すべてにおける2.12.1の濃度は、30mg/mlであった。組成物を3ccのバイアルに0.25mlの最終容量まで充填した。組成物を37℃で4週間、インキュベートした。
HGFへの特異的結合剤に対する異なる組成物の効果を評価するために、2.12.1の組成物を20の異なる製剤に製剤化した。5つの異なる安定化剤を試験した:5%ソルビトール、50mMのL−アラニン、100mMのL−アラニン、200mMのL−アラニン、および300mMのL−アラニン。各製剤において、4つの異なる2.12.1の濃度を試験した:10、30、70、および100mg/ml。各製剤は、緩衝剤として10mMの酢酸ナトリウムを含み、pH5.2であった。組成物を3ccのバイアルに0.25mlの最終容量まで充填した。組成物を3ヶ月間、4℃でインキュベートした。
HGFへの特異的結合剤に対する、1回以上の凍結/融解サイクルに供された組成物の異なる剤の効果を評価するために、2.12.1の組成物をソルビトール(「A52S」)、またはL−アラニンおよびPEG200(「A52Ala PEG200」)に製剤化した。各製剤の2.12.1の濃度は、30mg/mlであった。各製剤は、10mMの酢酸ナトリウム、pH5.2を含んだ。A52Sは、5%(w/v)ソルビトールを含んだ。A52Ala PEG200は、100mMのL−アラニンおよび200mMのPEG200を含んだ。組成物を3ccのバイアルに0.5mlの最終容量まで充填した。
HGFへの特異的結合剤に対する、1回以上の凍結/融解サイクルに供された組成物の異なる剤の効果を評価するために、2.12.1の組成物をソルビトール(「A56S」)、またはL−アラニンおよびPEG200(「A56AlaP」)に製剤化した。各製剤の2.12.1の濃度は、30mg/mlであった。各製剤は、10mMの酢酸ナトリウムを含み、pH5.6であった。A56Sは、5%(w/v)ソルビトールを含んだ。A56AlaPは、100mMのL−アラニンおよび200mMのPEG200を含んだ。組成物を3ccのバイアルに0.5mlの最終容量まで充填した。
Claims (6)
- 肝細胞増殖因子への特異的結合剤、少なくとも1つの安定化剤、および緩衝剤を含む組成物であって、前記特異的結合剤が、抗体、ポリクローナル抗体、モノクローナル抗体、重鎖および軽鎖が柔軟なリンカーで連結された抗体、Fv分子、マキシボディ、免疫学的に機能的な免疫グロブリン断片、Fab断片、Fab′断片、F(ab′) 2 分子、完全ヒト抗体、ヒト化抗体、キメラ抗体、および肝細胞増殖因子のc−Met受容体への結合を実質的に抑制する抗体から選択され、前記少なくとも1つの安定化剤が、アラニンおよびロイシンを含み、かつ前記組成物のpHが、5.4を上回る、組成物。
- 前記特異的結合剤が、完全ヒト抗体であり、前記完全ヒト抗体が、2.12.1である、請求項1に記載の組成物。
- 少なくとも1つの付加的薬学的剤をさらに含む、請求項1に記載の組成物。
- 前記少なくとも1つの安定化剤がメチオニンをさらに含み、かつ前記組成物の変色が、低減される、請求項1に記載の組成物。
- 前記少なくとも1つの安定化剤が、少なくとも1つの抗凍結剤をさらに含む、請求項1に記載の組成物。
- 前記少なくとも1つの抗凍結剤が、ポリビニルピロリドンK15、ポリエチレングリコール200、ポリエチレングリコール400、ポリエチレングリコール600、ポリエチレングリコール4000およびポリエチレングリコール30,000から選択される、請求項5に記載の組成物。
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