JP6239657B2 - 抗体及び防腐剤を含む安定した多用量組成物 - Google Patents
抗体及び防腐剤を含む安定した多用量組成物 Download PDFInfo
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- JP6239657B2 JP6239657B2 JP2016022657A JP2016022657A JP6239657B2 JP 6239657 B2 JP6239657 B2 JP 6239657B2 JP 2016022657 A JP2016022657 A JP 2016022657A JP 2016022657 A JP2016022657 A JP 2016022657A JP 6239657 B2 JP6239657 B2 JP 6239657B2
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Classifications
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- 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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Description
(a)≧50mg/mlの抗体と、
(b)30mM以下の、塩化ナトリウム又は塩化マグネシウムなどの無機塩と、
(c)0〜25mMの、アルギニン又はグリシンなどのアミノ酸と、
(d)50mM以下の、ヒスチジン緩衝剤などの緩衝剤と、
(e)0.001〜0.005%の非イオン性界面活性剤と、
(f)0.001〜2%(w/v)の1つ又は複数の防腐剤と
を含む。
(a)100mg/mlの抗体と、
(b)25mMの塩化ナトリウムと、
(c)33mMのヒスチジン緩衝剤と、
(d)25mMのアルギニンと、
(e)0.001%のポリソルベート80と、
(f)0.001〜2%(w/v)の1つ又は複数の防腐剤と
を含む。
(a)100mg/mlの抗体と、
(b)25mMの塩化ナトリウムと、
(c)33mMのヒスチジン緩衝剤と、
(d)25mMのアルギニンと、
(e)0.001%のポリソルベート80と、
(f)1.5mg/mlのフェノール及び1.8mg/mlのm-クレゾールと
を含む。
(a)100mg/mlの抗体と、
(b)25mMの塩化ナトリウムと、
(c)33mMのヒスチジン緩衝剤と、
(d)25mMのアルギニンと、
(f)2〜6mg/mlのm-クレゾールと、
(f)85〜130mMのスクロースと
を含む。
(a)100mg/mlの抗体と、
(b)25mMの塩化ナトリウムと、
(c)33mMのヒスチジン緩衝剤と、
(d)25mMのアルギニンと、
(e)4mg/mlのm-クレゾールと、
(f)105mMのプロピレングリコールと
を含む。
一つの実施態様において、本発明の医薬組成物は、4週間を越える使用及び3年間を越える保存にわたって安定している。
一つの実施態様において、本発明の医薬組成物は、4週間を越える使用及び2年間を越える保存にわたって安定している。
一つの実施態様において、本発明の医薬組成物は、2週間を越える使用及び2年間を越える保存にわたって安定している。
一つの実施態様において、本発明の医薬組成物は、1週間を越える使用及び6か月間を越える保存にわたって安定している。
(実施例1)
抗IL-20の40℃での4週間安定性分析
12個の製剤を調製した(下記のTable 1(表1)を参照)。製剤を、約150mg/mlの抗IL-20抗体及び10Mmのヒスチジン緩衝剤を含有するpH6.5の貯蔵溶液から調製した。貯蔵溶液は従来のUF/DF/UFにより調製した。賦形剤の貯蔵溶液を調製し、正確な割合で混合した。最終製剤を、3mlのPenfill(登録商標)カートリッジ、1型ガラスに充填した。製剤を40℃で4週間保存し、次に化学的、薬学的及び生物物理学的に分析した。タンパク質凝集体の形成の増加(%HMWP)を、SEC-HPLCにより(上記に記載されているように)測定した。
抗IL-20の5℃及び40℃での3か月間安定性分析
この研究は、研究を5℃及び40℃で3か月間実施し、製剤がTable 4(表4)に記載されているスクロースを含有した以外は、実施例1の記載と同様の方法で実施した。
抗IL-20の改変防腐剤効能試験の結果
異なる防腐剤の効能を分析するため、防腐剤効能スクリーニング試験を実施した。防腐剤の効能は、改変USP /Ph Eur防腐剤効能試験を使用して測定した。改変試験では、製剤を黄色ブドウ球菌(Staphylococcus aureus)に対して試験した。接種した後、試料を室温で6及び24時間保存し、総細菌計数を、コロニー計数器を使用して測定した。対数減少値を、対数(初期計数/最終計数)として計算した。
抗TFPIの5℃及び40℃での3か月間安定性分析
この研究は、研究が抗IL-20抗体ではなく抗TFPI抗体で実施された以外は、実施例2の記載と同様に実施した。試験した製剤は、Table 13(表13)に記載されたとおりである。
実施態様1:抗体及び1つ又は複数の防腐剤を含む安定した多用量液体組成物。
実施態様2:防腐剤が0.001〜2%(w/v)の量で組成物内に存在する、実施態様1による組成物。
実施態様3:防腐剤が0.002〜1%(w/v)の量で組成物内に存在する、実施態様1又は2による組成物。
実施態様4:1つ又は複数の防腐剤が、フェノール、m-クレゾール、ベンジルアルコール、クロロブタノール、エタノール、フェノキシエタノール、p-クロル-m-クレゾール、メチルパラベン、プロピルパラベン、塩化ベンザルコニウム、チオメルサール又はこれらの任意の組み合わせから選択される、実施態様1〜3のいずれかによる組成物。
実施態様5:1つ又は複数の防腐剤が、フェノール、m-クレゾール、ベンジルアルコール及びクロロブタノールから選択される、実施態様1〜4のいずれかによる組成物。
実施態様6:組成物が単一の防腐剤を含む、実施態様1〜5のいずれかによる組成物。
実施態様7:組成物が、フェノール、m-クレゾール、ベンジルアルコール、クロロブタノール、エタノール、フェノキシエタノール、p-クロル-m-クレゾール、メチルパラベン、プロピルパラベン、塩化ベンザルコニウム及びチオメルサールから選択される単一の防腐剤を含む、実施態様1〜6のいずれかによる組成物。
実施態様8:単一の防腐剤としてフェノールを含み、前記フェノールが0.1〜1%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様9:単一の防腐剤としてフェノールを含み、前記フェノールが0.1〜0.5%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様10:単一の防腐剤としてフェノールを含み、前記フェノールが0.15又は0.5%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様11:単一の防腐剤としてフェノールを含み、前記フェノールが0.25〜0.5%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様12:単一の防腐剤としてm-クレゾールを含み、前記m-クレゾールが0.1〜1%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様13:単一の防腐剤としてm-クレゾールを含み、前記m-クレゾールが0.1〜0.5%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様14:単一の防腐剤としてm-クレゾールを含み、前記m-クレゾールが0.15又は0.35%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様15:単一の防腐剤としてm-クレゾールを含み、前記m-クレゾールがおよそ0.3%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様16:単一の防腐剤としてベンジルアルコールを含み、前記ベンジルアルコールが0.1〜2%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様17:単一の防腐剤としてベンジルアルコールを含み、前記ベンジルアルコールが0.1〜1.5%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様18:単一の防腐剤としてベンジルアルコールを含み、前記ベンジルアルコールが0.5又は1.1%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様19:単一の防腐剤としてベンジルアルコールを含み、前記ベンジルアルコールがおよそ1%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様20:単一の防腐剤としてクロロブタノールを含み、前記クロロブタノールが0.1〜1%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様21:単一の防腐剤としてクロロブタノールを含み、前記クロロブタノールが0.25〜0.75%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様22:単一の防腐剤としてクロロブタノールを含み、前記クロロブタノールが0.3又は0.6%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様23:単一の防腐剤としてクロロブタノールを含み、前記クロロブタノールが0.3〜0.5%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様24:単一の防腐剤としてメチルパラベンを含み、前記メチルパラベンが0.1〜0.5%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様25:単一の防腐剤としてメチルパラベンを含み、前記メチルパラベンがおよそ0.2%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様26:単一の防腐剤としてプロピルパラベンを含み、前記プロピルパラベンが0.1〜0.5%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様27:単一の防腐剤としてプロピルパラベンを含み、前記プロピルパラベンがおよそ0.2%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様28:単一の防腐剤としてフェノキシエタノールを含み、前記フェノキシエタノールが0.1〜2%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様29:単一の防腐剤としてフェノキシエタノールを含み、前記フェノキシエタノールがおよそ1%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様30:単一の防腐剤としてチオメルサールを含み、前記チオメルサールが0.002〜0.01%(w/v)の量で組成物内に存在する、実施態様1〜7のいずれかによる組成物。
実施態様31:フェノール、m-クレゾール、ベンジルアルコール及びクロロブタノールから選択される単一の防腐剤を含む、実施態様1〜7のいずれかによる組成物。
実施態様32:2つ以上の防腐剤を含む、実施態様1〜5のいずれかによる組成物。
実施態様33:2つの防腐剤を含む、実施態様32による組成物。
実施態様34:フェノール、m-クレゾール、ベンジルアルコール、クロロブタノール、エタノール、フェノキシエタノール、p-クロル-m-クレゾール、メチルパラベン、プロピルパラベン、塩化ベンザルコニウム及びチオメルサールから選択される2つの防腐剤を含む、実施態様32又は33による組成物。
実施態様35:フェノール、m-クレゾール、ベンジルアルコール及びクロロブタノールから選択される2つの防腐剤を含む、実施態様34による組成物。
実施態様36:前記2つの防腐剤がフェノール及びm-クレゾールである、実施態様32〜35のいずれかによる組成物。
実施態様37:フェノールが0.1〜0.75%(w/v)の量で組成物内に存在する、実施態様36による組成物。
実施態様38:フェノールが0.1〜0.5%(w/v)の量で組成物内に存在する、実施態様36又は37による組成物。
実施態様39:フェノールが0.15又は0.5%(w/v)の量で組成物内に存在する、実施態様36〜38のいずれかによる組成物。
実施態様40:m-クレゾールが0.1〜0.5%(w/v)の量で組成物内に存在する、実施態様36〜39のいずれかによる組成物。
実施態様41:m-クレゾールが0.15〜0.4%(w/v)の量で組成物内に存在する、実施態様36〜40のいずれかによる組成物。
実施態様42:m-クレゾールが0.18又は0.35%(w/v)の量で組成物内に存在する、実施態様36〜41のいずれかによる組成物。
実施態様43:前記2つの防腐剤がベンジルアルコール及びクロロブタノールである、実施態様32〜35のいずれかによる組成物。
実施態様44:ベンジルアルコールが0.25〜1%(w/v)の量で組成物内に存在する、実施態様43による組成物。
実施態様45:ベンジルアルコールが0.4〜0.9%(w/v)の量で組成物内に存在する、実施態様43又は44による組成物。
実施態様46:ベンジルアルコールが0.5又は0.8%(w/v)の量で組成物内に存在する、実施態様43〜45のいずれかによる組成物。
実施態様47:クロロブタノールが0.1〜0.5%(w/v)の量で組成物内に存在する、実施態様43〜46のいずれかによる組成物。
実施態様48:クロロブタノールが0.1〜0.4%(w/v)の量で組成物内に存在する、実施態様43〜47のいずれかによる組成物。
実施態様49:クロロブタノールが0.11又は0.3%(w/v)の量で組成物内に存在する、実施態様43〜48のいずれかによる組成物。
実施態様50:緩衝剤が存在し、緩衝剤が4〜8のpKaを有する、実施態様1〜49のいずれかによる組成物。
実施態様51:緩衝剤が5〜7のpKaを有する、実施態様50による組成物。
実施態様52:緩衝剤が存在し、緩衝剤が、酢酸ドナトリウム、炭酸ナトリウム、クエン酸塩、グリシルグリシン、ヒスチジン、グリシン、リシン、アルギニン、マレイン酸塩、コハク酸塩、リン酸二水素ナトリウム、リン酸水素二ナトリウム、リン酸ナトリウム若しくはトリス(ヒドロキシメチル)-アミノメタン又はこれらの混合物である、実施態様50又は51による組成物。
実施態様53:緩衝剤が、ヒスチジン、マレイン酸塩、コハク酸塩、リン酸塩又はトリス(ヒドロキシメチル)-アミノメタンである、実施態様52による組成物。
実施態様54:緩衝剤がヒスチジンである、実施態様53による組成物。
実施態様55:緩衝剤が、組成物の標的pHの±1pH単位のpKa値を有する、実施態様54による組成物。
実施態様56:塩が存在し、塩が、塩化ナトリウム、塩化マグネシウム、チオシアン酸ナトリウム、チオシアン酸アンモニウム、硫酸アンモニウム、塩化アンモニウム、塩化カルシウム、塩酸アルギニン、塩化亜鉛及び酢酸ナトリウム又はこれらの任意の組み合わせからなる群から選択される、実施態様1〜55のいずれかによる組成物。
実施態様57:塩が、塩化ナトリウム又は塩化マグネシウムである、実施態様56による組成物。
実施態様58:塩が塩化ナトリウムである、実施態様57による組成物。
実施態様59:塩がアルギニン-HClである、実施態様56による組成物。
実施態様60:5.0〜7.0のpHを有する、実施態様1〜59のいずれかによる組成物。
実施態様61:6.0〜7.0のpHを有する、実施態様60による組成物。
実施態様62:6.0又は6.5のpHを有する、実施態様61による組成物。
実施態様63:6.5のpHを有する、実施態様62による組成物。
実施態様64:追加的に界面活性剤を含む、実施態様1〜63のいずれかによる組成物。
実施態様65:界面活性剤がTween 80(すなわち、ポリソルベート80)である、実施態様64による組成物。
実施態様66:界面活性剤が0.01%未満の量で組成物内に存在する、実施態様64又は65による組成物。
実施態様67:界面活性剤が0.0075%未満の量で組成物内に存在する、実施態様64〜66のいずれかによる組成物。
実施態様68:界面活性剤が0.001%〜0.005%の量で組成物内に存在する、実施態様64〜67のいずれかによる組成物。
実施態様69:界面活性剤が0.001%の量で組成物内に存在する、実施態様64〜68のいずれかによる組成物。
実施態様70:界面活性剤が存在しない、実施態様1〜63のいずれかによる組成物。
実施態様71:追加的に張性調節剤を含む、実施態様1〜70のいずれかによる組成物。
実施態様72:張性調節剤が、スクロース又はプロピレングリコールである、実施態様71による組成物。
実施態様73:張性調節剤がスクロースである、実施態様72による組成物。
実施態様74:張性調節剤がプロピレングリコールである、実施態様72による組成物。
実施態様75:張性調節剤が50〜250mMの量で組成物内に存在する、実施態様71〜74のいずれかによる組成物。
実施態様76:張性調節剤が100〜200mMの量で組成物内に存在する、実施態様71〜75のいずれかによる組成物。
実施態様77:張性調節剤が100mMの量で存在する、実施態様71〜76のいずれかによる組成物。
実施態様78:組成物が薬学的に許容される、実施態様1〜77のいずれかによる組成物。
実施態様79:抗体が50mg/ml〜300mg/mlの濃度で組成物内に存在する、実施態様1〜78のいずれかによる安定した組成物。
実施態様80:抗体が75mg/ml〜300mg/mlの濃度で組成物内に存在する、実施態様79による安定した組成物。
実施態様81:抗体が100mg/ml〜300mg/mlの濃度で組成物内に存在する、実施態様80による安定した組成物。
実施態様82:抗体が50mg/ml〜200mg/mlの濃度で組成物内に存在する、実施態様81による安定した組成物。
実施態様83:抗体が、50、55、60、65、70、75、80、85、90、95、100、150、200、250又は300mg/mlの濃度で組成物内に存在する、実施態様82による安定した組成物。
実施態様84: 5〜7のpHに緩衝された、
(a)≧50mg/mlの抗体と、
(b)30mM以下の、塩化ナトリウム又は塩化マグネシウムなどの無機塩と、
(c)0〜25mMの、アルギニン又はグリシンなどのアミノ酸と、
(d)50mM以下の、ヒスチジン緩衝剤などの緩衝剤と、
(e)0.001〜0.005%の非イオン性界面活性剤と、
(f)0.001〜2%(w/v)の1つ又は複数の防腐剤と、
(g)100mMのスクロースと
を含む、実施態様1による組成物。
実施態様85: 6〜7のpHに緩衝された、
(a)100mg/mlの抗体と、
(b)25mMの塩化ナトリウムと、
(c)33mMのヒスチジン緩衝剤と、
(d)25mMのアルギニンと、
(e)0.001%のポリソルベート80と、
(f)0.001〜2%(w/v)の1つ又は複数の防腐剤と、
(g)100mMのスクロースと
を含む、実施態様1による組成物。
実施態様86: 6.5のpHに緩衝された、
(a)100mg/mlの抗体と、
(b)25mMの塩化ナトリウムと、
(c)33mMのヒスチジン緩衝剤と、
(d)25mMのアルギニンと、
(e)0.001%のポリソルベート80と、
(f)1.5mg/mlのフェノール及び1.8mg/mlのm-クレゾールと、
(g)120mMのスクロースと
を含む、実施態様1による組成物。
実施態様87: 5〜7のpHに緩衝された、
(a)100mg/mlの抗体と、
(b)25mMの塩化ナトリウムと、
(c)33mMのヒスチジン緩衝剤と、
(d)25mMのアルギニンと、
(e)0.01mg/mlのポリソルベート80と、
(f)1.5mg/mlのフェノール及び1.8mg/mlのm-クレゾールと、
(g)120mMのスクロースと
を含む、実施態様1による組成物。
実施態様88:
(a)100mg/mlの抗TFPIと、
(b)25mMの塩化ナトリウムと、
(c)33mMのヒスチジン緩衝剤と、
(d)25mMのアルギニンと、
(e)0.01mg/mlのポリソルベート80と、
(f)5mg/mlのフェノールと、
(g)100mMのスクロースと
を含む、実施態様1による組成物。
実施態様89:
(a)100mg/mlの抗体と、
(b)25mMの塩化ナトリウムと、
(c)33mMのヒスチジン緩衝剤と、
(d)25mMのアルギニンと、
(e)0.01mg/mlのポリソルベート80と、
(f)5mg/mlのフェノールと、
(g)95mMのプロピレングリコールと
を含む、実施態様1による組成物。
実施態様90:
(a)100mg/mlの抗IL-20と、
(b)25mMの塩化ナトリウムと、
(c)33mMのヒスチジン緩衝剤と、
(d)25mMのアルギニンと、
(e)0.01mg/mlのポリソルベート80と、
(f)4mg/mlのm-クレゾールと、
(g)105mMのプロピレングリコールと
を含む、実施態様1による組成物。
実施態様91:
(a)100mg/mlの抗IL-20と、
(b)25mMの塩化ナトリウムと、
(c)33mMのヒスチジン緩衝剤と、
(d)25mMのアルギニンと、
(e)2mg/mlのm-クレゾールと、
(f)129mMのスクロースと
を含む、実施態様1による組成物。
実施態様92:
(a)100mg/mlの抗IL-20と、
(b)25mMの塩化ナトリウムと、
(c)33mMのヒスチジン緩衝剤と、
(d)25mMのアルギニンと、
(e)4mg/mlのm-クレゾールと、
(f)109mMのスクロースと
を含む、実施態様1による組成物。
実施態様93:
(a)100mg/mlの抗IL-20と、
(b)25mMの塩化ナトリウムと、
(c)33mMのヒスチジン緩衝剤と、
(d)25mMのアルギニンと、
(e)6mg/mlのm-クレゾールと、
(f)88mMのスクロースと
を含む、実施態様1による組成物。
実施態様94:
(a)100mg/mlの抗IL-20と、
(b)25mMの塩化ナトリウムと、
(c)33mMのヒスチジン緩衝剤と、
(d)25mMのアルギニンと、
(e)4mg/mlのm-クレゾールと、
(f)105mMのプロピレングリコールと
を含む、実施態様1による組成物。
実施態様95:抗体がIgG4サブタイプのものである、実施態様1〜94の実施態様のいずれかによる組成物。
実施態様96:抗体がモノクローナル抗体である、実施態様1〜95のいずれかによる組成物。
実施態様97:モノクローナル抗体が抗IL-20モノクローナル抗体である、実施態様96による組成物。
実施態様98:モノクローナル抗体が、WO2010/000721に記載されている抗IL-20モノクローナル抗体である、実施態様96による組成物。
実施態様99:モノクローナル抗体が、WO2010/000721に記載されている抗IL-20モノクローナル抗体の15D2又は5B7である、実施態様96による組成物。
実施態様100:モノクローナル抗体が抗TFPIモノクローナル抗体である、実施態様96による組成物。
実施態様101:モノクローナル抗体が、PCT/EP2009/067598に記載されている抗TFPIモノクローナル抗体のHzTFPI4F36である、実施態様96による組成物。
実施態様102:治療に使用される、実施態様1〜101のいずれかによる安定した多用量液体組成物。
実施態様103:炎症性疾患を治療する方法であって、実施態様97〜99のいずれかによる組成物の治療有効量を患者に投与することを含む方法。
実施態様104:炎症性疾患の治療に使用される、実施態様97〜99のいずれかによる組成物。
実施態様105:炎症性疾患の治療のための薬剤の製造における、実施態様97〜99のいずれかによる組成物の使用。
実施態様106:炎症性疾患の治療に使用される、実施態様97〜99のいずれかによる抗IL-20組成物を含む医薬組成物。
実施態様107:凝血異常を治療する方法であって、実施態様100〜101のいずれかによる組成物の治療有効量を患者に投与することを含む方法。
実施態様108:凝血異常の治療に使用される、実施態様100〜101のいずれかによる組成物。
実施態様109:凝血異常の治療のための薬剤の製造における、実施態様100〜101のいずれかによる組成物の使用。
実施態様110:凝血異常の治療に使用される、実施態様100〜101のいずれかの抗TFPI組成物を含む医薬組成物。
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EP2575761A1 (en) | 2013-04-10 |
RU2012153786A (ru) | 2014-07-10 |
CA2800188A1 (en) | 2011-12-01 |
MX2012013586A (es) | 2013-01-24 |
EP2575761B1 (en) | 2024-08-14 |
US20130136733A1 (en) | 2013-05-30 |
KR20130086144A (ko) | 2013-07-31 |
AU2011257219B2 (en) | 2014-12-04 |
CN105055306A (zh) | 2015-11-18 |
JP6294075B2 (ja) | 2018-03-14 |
JP6568917B2 (ja) | 2019-08-28 |
JP2018030879A (ja) | 2018-03-01 |
CN102905692B (zh) | 2015-09-16 |
BR112012030139A2 (pt) | 2017-06-13 |
CN105055306B (zh) | 2019-10-01 |
CN102905692A (zh) | 2013-01-30 |
WO2011147921A1 (en) | 2011-12-01 |
US20180104335A1 (en) | 2018-04-19 |
US10835602B2 (en) | 2020-11-17 |
JP2013527189A (ja) | 2013-06-27 |
AU2011257219A1 (en) | 2012-11-22 |
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