JP2013209406A - 金属イオンとポリペプチドとの錯化 - Google Patents
金属イオンとポリペプチドとの錯化 Download PDFInfo
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- JP2013209406A JP2013209406A JP2013108953A JP2013108953A JP2013209406A JP 2013209406 A JP2013209406 A JP 2013209406A JP 2013108953 A JP2013108953 A JP 2013108953A JP 2013108953 A JP2013108953 A JP 2013108953A JP 2013209406 A JP2013209406 A JP 2013209406A
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Abstract
【解決手段】特定の観点では、非水性の生物適合性懸濁媒体に懸濁された金属イオンおよびポリペプチドの錯体を含んでなる調合物が提供される。生物適合性懸濁媒体が、ポリ乳酸(PLA)、ポリ乳酸グリコール酸、ポリビニルピロリドン、ポリオキシエチレンポリオキシプロピレンブロックコポリマー、およびポリ酢酸ビニルからなる群から選択されるポリマー、および溶媒としてのベンジルアルコールと安息香酸ベンジルの組み合わせを含み、水性媒質がそのような調合物に導入される時、個々のポリペプチド分子の凝集が低下し、ポリペプチドの安定化に役立つ。
【選択図】図1
Description
本出願は2005年6月23日に出願された特許文献1の利益を主張し、これは引用により全部、本明細書に編入する。
発明の分野
本発明の特定の観点は、非水性媒体(vehicle)に懸濁されたポリペプチドが、水性媒質(media)へ暴露された時の安定性を改善する調合物(formulations)および方法に関する。
タンパク質は疾患の防止、処置および診断のための薬剤(pharmaceuticals)としての用途を有する。タンパク質は水性環境で自然に活性であり、そして好適なタンパク質性調合物はこのような水溶液である。タンパク質は典型的には水溶液中でわずかに安定なだけであり、しかし水性の製薬学的調製物(pharmaceuticals
preparations)は周囲または生理学的温度で短い使用期限を現し、すなわちしばしば冷蔵を必要とする。さらに水溶液中の多くのタンパク質の溶解性は限られ、そして高濃度で水溶液に可溶性のタンパク質は凝集および沈殿し易い。さらに水が可塑剤として作用し、そしてタンパク質分子のアンフォールディング(unfolding)および不可逆的な分子凝集を促進する。非水性または実質的に非水性のタンパク質調合物は、このように一般に周囲または生理学的温度で時間を通してタンパク質の安定性を確実とすることが必要である。
特定の観点において本発明は、非水性の生物適合性懸濁媒体に懸濁された金属イオンと
ポリペプチドとの錯体を含んでなる調合物に関し、ここで調合物を水性媒質に暴露すると、ポリペプチドは実質的な程度まで凝集しない。他の態様では、本発明はポリペプチドと金属イオンとの錯体を形成することを含んでなる、非水性の生物適合性懸濁媒体に懸濁されたポリペプチドの、水性媒質への暴露時の安定性を改善する方法を対象とする。
本発明の特定の態様は、非水性の生物適合性懸濁媒体に懸濁されたポリペプチドの、水性媒質への暴露時の安定性を改善する調合物に関する。調合物は非水性懸濁物に懸濁されたポリペプチドと金属イオンとの錯体を含んでなる。水性媒質への暴露で、ポリペプチドは安定性を保持し、そして実質的な程度に凝集しない。本発明の他の観点は、ポリペプチドと金属イオンとの錯体を形成することを含んでなる、非水性の生物適合性懸濁媒体に懸濁されたポリペプチドの、水性媒質への暴露時の安定性を改善する方法に関する。ポリペプチド/金属イオン錯体は水性媒質への暴露に際して安定性を保持し、そしてポリペプチドは実質的な程度に凝集しない。
きない物質を指す。痕跡量もしくはわずかな量より多くの物質が水性媒質に溶解されれば、物質は「実質的程度に溶解される」。
のために、非水性の粘稠な媒体中の懸濁液として安定に調合されたポリペプチド/金属イオン錯体に関する。
安息香酸ベンジル(BB)(22.81g)およびベンジルアルコール(BA)(J.T.Bakerから得た)(2.55g)を窒素を充填したグローブボックス中のビーカー中で混合した。ポリビニルピロリドンC30(BASF、マウントオリーブ、ニュージャージー州)(9.96g)を、窒素を充填したグローブボックス中のガラス容器中のBB/BAの混合物(9.58g)に加えた。混合物はパチュラを用いて手で撹拌して、ポリマー粉末を完全に湿潤化した。混合物はさらに65℃で、オーバーヘッドミキサーに付いたスパチュラを用いて単相になるまで撹拌した。
ヒト成長ホルモン(hGH)、シュクロースおよびメチオニンの個々の溶液を、5.0
mM Trisバッファー、pH7.4に調製した。次いで3つの溶液を混合して、それぞれ100/200/100/9.1のhGH/シュクロース/メチオニン/Trisの重量比を有するhGH/シュクロース/メチオニン/Tris溶液を得た。この溶液を3500rpmで15分間、4℃で遠心し、そして上清を以下の条件を使用して噴霧乾燥した。
噴霧する空気圧 0.2MPa
空気流 0.43m3/分
入口温度 121−122℃
出口温度 87℃
噴霧乾燥器の排気湿度 4〜5%
噴霧乾燥器の排気温度 70℃
溶液流速 4ml/分
hGH粒子を得、その大部分は2〜20ミクロンのサイズ範囲にあった。
40mg/mLのhGH溶液および27.2mMの酢酸亜鉛溶液は、5mM TRISバッファー、pH7.0中に調製した。等しい部のhGHおよび酢酸亜鉛溶液を混合して、15:1の亜鉛 対 hGHのモル比を有する亜鉛/hGH溶液を得た。亜鉛/hGH溶液はおよそ1時間、4℃で錯化させた。hGH/Zn粒子は、以下の条件を使用して噴霧乾燥により調製した。
噴霧する空気圧 0.2MPa
空気流 0.43m3/分
入口温度 121−122℃
出口温度 87℃
噴霧乾燥器の排気湿度 4〜5%
噴霧乾燥器の排気温度 70℃
溶液流速 4ml/分
hGH/Zn粒子を得、その大部分は2〜20ミクロンのサイズ範囲にあった。
種々の媒質中のhGH/Zn粒子の溶解性を測定した。hGH/Zn粒子(4−8mg)は、1.0mlの脱イオン水(DI水)、リン酸ナトリウムバッファー(50mM、pH7.4、150mMのNaClを含有する)(PBS)、または20mMのエチレンジアミン四酢酸(EDTA)を含むPBSを含む1.5mlのエッペンドルフ試験管に加えた。エッペンドルフ試験管を室温で30分間、ゆっくりと両端にわたり回転し、そして次いで10,000rpmで1分間遠心した。上清中のhGH濃度は、UV吸収を測定することにより決定した。hGH/Znの溶解性は溶解したhGHの画分として表し、そして表2に示す。DI水中には本質的に不溶性であるが、hGH/Zn錯体はPBS中で可溶性である。また表2はhGH/Zn錯体の形成が錯化剤EDTAにより完全に可逆性であることを表す。
それぞれ実施例2および3に記載したように調製したhGHおよびZn/hGH粒子を、非水性の単相の粘稠媒体(実施例1に記載したように調製した調合物13)に装填した。調合物の組成は表3に示す。タンパク質粒子および非水性の単相の粘稠媒体を、窒素を充填したグローブボックス中のガラス容器に加えた。混合物はスパチュラを用いて手で撹拌して、タンパク質粒子を完全に湿潤化した。さらに混合物は65℃で、オーバーヘッドミキサーに付いたスパチュラを用いて均一な懸濁物になるまで撹拌した。
非水性媒体中のhGH粒子の安定性は、以下の手順に従い測定した。非水性媒体に懸濁したhGH粒子は、DI水または150mMのNaClを含有する50mMリン酸ナトリウムバッファー(PBS)、pH7.4のいずれかでスパイクした(表4)。懸濁物はDI水またはPBSが非水性媒体と均一に混合するまで穏やかに撹拌した。次いで懸濁物を37℃でインキュベーションした。hGHモノマー含量および総タンパク質回収(水溶性hGHの画分)は、サイズ排除クロマトグラフィー(SEC)を使用して測定した。
pH5.5の5mM酢酸バッファー、またはpH7.5、8.3もしくは9.6の5mM Trisバッファーのいずれかの溶液を調製した。酢酸亜鉛をバッファー溶液に加えて、5mM酢酸亜鉛の溶液を作成した。オメガ−IFNを別の容器中の同じバッファーに加えて、1mg/mLオメガ−IFNの溶液を作成した。亜鉛を含有する溶液を適当量のオメガ−IFN溶液に加えて、1:1〜50:1の範囲の亜鉛:オメガ−IFNモル比を有する混合物を作成した。
可溶性オメガ−IFNの画分を決定するために、亜鉛およびオメガ−IFNを最初に上記のように合わせた。生じた混合物を目で観察し、遠心し、そして透明な上清中の可溶性オメガ−IFNの量を測定した。混合物中のオメガ−IFNの総量および上清中のオメガ−IFNの量を比較することにより、可溶性オメガ−IFNの割合を決定した。得られた
データ(以下の表5)は、可溶性オメガ−IFNの画分がpHおよびオメガ−IFNに対する亜鉛の比率で変動することを示す。
マイクロ熱量実験は、亜鉛およびオメガ−IFNの混合物について5mMの酢酸バッファー、pH5.5中で行った。5mMの酢酸バッファー中、既知量の5mM酢酸亜鉛を1mg/mLのオメガ−IFN溶液(5mM酢酸バッファー中)を、一定温度で撹拌している5mM酢酸バッファー中の1mg/mLのオメガ−IFN溶液にゆっくりと加えた。オメガ−IFN溶液への亜鉛溶液の各注入後、発熱が1モルの注入物あたりkcalで記録された。得られたデータ(図3)は、熱が亜鉛をオメガ−IFN溶液に加えた時に吸収され、錯化が亜鉛イオンとオメガ−IFN分子との間で起こったことを示す。
Claims (8)
- 非水性の生物適合性懸濁媒体に懸濁された金属イオンとポリペプチドとの錯体を含んでなる調合物であって、
ポリペプチドが、骨形態形成タンパク質、インスリン、コルヒチン、グルカゴン、甲状腺刺激ホルモン、副甲状腺および下垂体ホルモン、カルシトニン、レニン、プロラクチン、コルチコトロピン、甲状腺刺激ホルモン、卵胞刺激ホルモン、絨毛性性腺刺激ホルモン、性腺刺激ホルモン放出ホルモン、ウシソマトトロピン、ブタソマトトロピン、オキシトシン、バソプレッシン、GRF、ソマトスタチン、リプレシン、パンクレオチミン、黄体形成ホルモン、LHRH、LHRHアゴニストおよびアンタゴニスト、ロイプロリド、インターフェロンアルファ−2a、インターフェロンアルファ−2b、インターフェロンタウ、インターフェロンオメガ、コンセンサスインターフェロン、インターロイキン、表皮増殖因子(EGF)、血小板由来増殖因子(PDGF)、繊維芽細胞増殖因子(FGF)、トランスフォーミング増殖因子−α(TGF−α)、トランスフォーミング増殖因子−β(TGF−β)、エリスロポエチン(EPO)、インスリン様成長因子−I(IGF−I)、インスリン様成長因子−II(IGF−II)、インターロイキン−1、インターロイキン−2、インターロイキン−6、インターロイキン−8、腫瘍壊死因子−α(TNF−α)、腫瘍壊死因子−β(TNF−β)、インターフェロン−β(INF−β)、インターフェロン−γ(INF−γ)、コロニー刺激因子(CGF)、血管細胞増殖因子(VEGF)、トロンボポイエチン(TPO)、間質細胞由来因子(SDF)、胎盤増殖因子(P1GF)、肝細胞増殖因子(HGF)、顆粒球マクロファージコロニー刺激因子(GM−CSF)、グリア−由来神経栄養因子(GDNF)、顆粒球コロニー刺激因子(G−CSF)、繊毛様神経栄養因子(CNTF)、骨形態形成タンパク質(BMP)、凝固因子、ヒト膵臓ホルモン放出因子、またはヒト成長ホルモンから選択され、
生物適合性懸濁媒体が、
ポリ乳酸(PLA)、ポリ乳酸グリコール酸、ポリビニルピロリドン、ポリオキシエチレンポリオキシプロピレンブロックコポリマー、およびポリ酢酸ビニルからなる群から選択されるポリマー、および
溶媒としてのベンジルアルコールと安息香酸ベンジルの組み合わせを含み、
ここで、
金属イオン/ポリペプチド錯体中の金属イオン対ポリペプチドのモル比は1:1〜100:1であり、
金属イオンは、亜鉛イオン、マグネシウムイオン、カルシウムイオン、ニッケルイオンまたは銅イオンであり、
金属イオン/ポリペプチド錯体粒子の直径は0.3〜50ミクロンである
調合物。 - 非水性の生物適合性懸濁媒体が更に表面活性剤を含んでなる請求項1に記載の調合物。
- 表面活性剤が多価アルコールのエステル、エトキシル化ヒマシ油、ポリソルベート、飽和アルコールのエステルもしくはエーテル、またはポリオキシエチレンポリオキシプロピレンブロックコポリマーである請求項2に記載の調合物。
- 多価アルコールのエステルがグリセロールモノラウレートであり、飽和アルコールのエステルまたはエーテルが乳酸ミリスチルである請求項3に記載の調合物。
- ポリペプチドと金属イオンとの錯体を形成することを含んでなる、非水性の生物適合性懸濁媒体に懸濁されたポリペプチドが水性媒質へ暴露された時の安定性を改善する方法であって、
ポリペプチドが、骨形態形成タンパク質、インスリン、コルヒチン、グルカゴン、甲状
腺刺激ホルモン、副甲状腺および下垂体ホルモン、カルシトニン、レニン、プロラクチン、コルチコトロピン、甲状腺刺激ホルモン、卵胞刺激ホルモン、絨毛性性腺刺激ホルモン、性腺刺激ホルモン放出ホルモン、ウシソマトトロピン、ブタソマトトロピン、オキシトシン、バソプレッシン、GRF、ソマトスタチン、リプレシン、パンクレオチミン、黄体形成ホルモン、LHRH、LHRHアゴニストおよびアンタゴニスト、ロイプロリド、インターフェロンアルファ−2a、インターフェロンアルファ−2b、インターフェロンタウ、インターフェロンオメガ、コンセンサスインターフェロン、インターロイキン、表皮増殖因子(EGF)、血小板由来増殖因子(PDGF)、繊維芽細胞増殖因子(FGF)、トランスフォーミング増殖因子−α(TGF−α)、トランスフォーミング増殖因子−β(TGF−β)、エリスロポエチン(EPO)、インスリン様成長因子−I(IGF−I)、インスリン様成長因子−II(IGF−II)、インターロイキン−1、インターロイキン−2、インターロイキン−6、インターロイキン−8、腫瘍壊死因子−α(TNF−α)、腫瘍壊死因子−β(TNF−β)、インターフェロン−β(INF−β)、インターフェロン−γ(INF−γ)、コロニー刺激因子(CGF)、血管細胞増殖因子(VEGF)、トロンボポイエチン(TPO)、間質細胞由来因子(SDF)、胎盤増殖因子(P1GF)、肝細胞増殖因子(HGF)、顆粒球マクロファージコロニー刺激因子(GM−CSF)、グリア−由来神経栄養因子(GDNF)、顆粒球コロニー刺激因子(G−CSF)、繊毛様神経栄養因子(CNTF)、骨形態形成タンパク質(BMP)、凝固因子、ヒト膵臓ホルモン放出因子、またはヒト成長ホルモンから選択され、
生物適合性懸濁媒体が、
ポリ乳酸(PLA)、ポリ乳酸グリコール酸、ポリビニルピロリドン、ポリオキシエチレンポリオキシプロピレンブロックコポリマー、およびポリ酢酸ビニルからなる群から選択されるポリマー、および
溶媒としてのベンジルアルコールと安息香酸ベンジルの組み合わせを含み、
ここで、
金属イオン/ポリペプチド錯体中の金属イオン対ポリペプチドのモル比は1:1〜100:1であり、
金属イオンは亜鉛イオン、マグネシウムイオン、カルシウムイオン、ニッケルイオンまたは銅イオンであり、
金属イオン/ポリペプチド錯体粒子の直径は0.3〜50ミクロンである
方法。 - 懸濁媒体が更に表面活性剤の少なくとも1つを含んでなる請求項5に記載の方法。
- 表面活性剤が多価アルコールのエステル、エトキシル化ヒマシ油、ポリソルベート、飽和アルコールのエステルもしくはエーテル、またはポリオキシエチレンポリオキシプロピレンブロックコポリマーである請求項6に記載の方法。
- 多価アルコールのエステルがグリセロールモノラウレートであり、飽和アルコールのエステルまたはエーテルが乳酸ミリスチルである請求項7に記載の方法。
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EP (2) | EP2363115A3 (ja) |
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CA2691531C (en) | 2007-06-22 | 2016-11-01 | Board Of Regents,The University Of Texas System | Formation of stable submicron peptide or protein particles by thin film freezing |
CA2743789C (en) | 2008-11-16 | 2017-10-31 | Board Of Regents, The Univesity Of Texas System | Low viscosity highly concentrated suspensions |
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JP6564369B2 (ja) | 2013-12-09 | 2019-08-21 | デュレクト コーポレイション | 薬学的活性剤複合体、ポリマー複合体、ならびにこれらを伴う組成物及び方法 |
CN109745566A (zh) * | 2019-02-21 | 2019-05-14 | 温州生物材料与工程研究所 | 基于组氨酸短肽的金属有机配位聚合物包裹生物大分子的方法 |
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EP1898883B1 (en) | 2012-10-17 |
WO2007002709A3 (en) | 2007-06-07 |
US20140088013A1 (en) | 2014-03-27 |
EP2363115A2 (en) | 2011-09-07 |
EP1898883A2 (en) | 2008-03-19 |
WO2007002709A2 (en) | 2007-01-04 |
TWI398270B (zh) | 2013-06-11 |
JP2008543950A (ja) | 2008-12-04 |
EP2363115A3 (en) | 2011-11-02 |
US20070015689A1 (en) | 2007-01-18 |
US20120122782A1 (en) | 2012-05-17 |
TW200711662A (en) | 2007-04-01 |
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