JP2017531682A - 医薬製剤の粘度低下 - Google Patents
医薬製剤の粘度低下 Download PDFInfo
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Abstract
Description
本出願は、その全体が参照により本明細書に組み込まれる、2014年10月23日に出願された米国仮特許出願第62/067,637号の利益を主張する。
IgG2抗体調製物(140mg/ml)(抗体A)を、10mMグルタミン酸ナトリウム1%スクロースpH5.2に対して、Snakeskin(登録商標)プリーツ付き透析チューブ10,000MWCO(Thermo Fisher Scientific、マサチューセッツ州、ウォルサム)を使用して、透析した。120mg/mLの抗体Aを含む10mMグルタミン酸ナトリウム1%スクロースpH5.2を、3ccバイアル中に、各1mLの充填量で充填した。バイアルを、Virtis凍結乾燥機を使用して凍結乾燥した。バイアルを、450uLの様々な溶液(水−対照または200mM賦形剤溶液)で再構成した。再構成の後、抗体A濃度を、SOLO−VPE測定器を使用して190mg/mLであると決定した。粘度を、Aries ARG2レオメーターを使用して25℃で測定し、それらは以下の表1に記録されている。
IgG1抗体調製物(70mg/ml)(抗体B)及びIgG2抗体調製物(70mg/ml)(抗体C)を、それぞれ、20mM酢酸ナトリウムpH4.7及び4.9に対して、10,000MWCO透析チューブを使用して透析した。抗体試料を、30,000MWCO遠心フィルター及びAllegra X−12R遠心機を使用して濃縮した。抗体試料濃度を、Agilent紫外可視分光光度計を使用して決定した。賦形剤を含有する試料を、バルク濃縮液を予め秤量した固形賦形剤でスパイクすることによって調製した。粘性試料を、ポジティブディスプレイスメント式ピペットを使用して移した。粘度は、Brookfield RV−DVIII+プログラム可能レオメーターを使用して25℃で測定し、それらは以下の表2.1及び2.2に記録されている。
IgG2抗体調製物(140mg/ml)(抗体D)を、10mMグルタミン酸ナトリウム1%スクロースpH5.2に対して、Snakeskin(登録商標)プリーツ付き透析チューブ10,000MWCO(Thermo Fisher Scientific、マサチューセッツ州、ウォルサム)を使用して透析した。100mg/mLの抗体Dを含む10mMグルタミン酸ナトリウム1%スクロースpH5.2を、3ccバイアル中に、各1mLの充填量で充填した。バイアルを、Virtis凍結乾燥機を使用して凍結乾燥した。バイアルを、450uLの水(対照−賦形剤無し)または10mMグルタミン酸塩200mM n−アセチル−LアルギニンpH5.2のいずれかで再構成した。抗体D濃度を、SOLO−VPE測定器を使用して決定した。粘度は、Aries ARG2レオメーターを使用して25℃で測定し、それらは以下の表3.0に記録されている。
IgG2抗体調製物(140mg/ml)(抗体E)を、6ダイアフィルトレーション容量の緩衝液A(10mMグルタミン酸塩260mM n−アセチル−lアルギニンpH4.6)または緩衝液B(10mMグルタミン酸ナトリウムpH4.6)を用いて限外ろ過及びダイアフィルトレーションを使用して、200mg/mlまで濃縮した。UFDF試料の最終pHは、5.2であると決定された。抗体E濃度を、SOLO−VPE測定器を使用して決定した。粘度は、Aries ARG2レオメーターを使用して20℃で測定し、それらは以下の表4.0に記録した。
IgG2抗体調製物(140mg/ml)(抗体A)を、10mMグルタミン酸ナトリウム1%スクロースpH5.2に対して、Snakeskin(登録商標)プリーツ付き透析チューブ10,000MWCO(Thermo Fisher Scientific、マサチューセッツ州、ウォルサム)を使用して透析した。120mg/mLの抗体Aを含む10mMグルタミン酸ナトリウム1%スクロースpH5.2を、3ccバイアル中に、各1mLの充填量で充填した。バイアルを、Virtis凍結乾燥機を使用して凍結乾燥した。バイアルを、450uLの様々な溶液(水−対照または200mM賦形剤溶液)を用いて再構成した(以下の表5を参照されたい)。再構成の後、抗体A濃度を、SOLO−VPE測定器を使用して190mg/mLであると決定した。粘度を、Aries ARG2レオメーターを使用して25℃で測定し、それらは以下の表5に記録されている。
Claims (25)
- 治療用タンパク質を少なくとも70mg/mlの濃度で含む液体医薬製剤の粘度を低下させるための方法であって、粘度低下性濃度の、n−アセチルアルギニン、n−アセチルリジン、n−アセチルヒスチジン、n−アセチルプロリン及びそれらの混合物からなる群より選択される賦形剤と、前記治療用タンパク質とを組み合わせるステップを含む、前記方法。
- 前記賦形剤が、n−アセチルアルギニンである、請求項1に記載の方法。
- 前記賦形剤が、n−アセチルリジンである、請求項1に記載の方法。
- 前記賦形剤が、n−アセチルヒスチジンである、請求項1に記載の方法。
- 前記賦形剤が、n−アセチルプロリンである、請求項1に記載の方法。
- 前記製剤の粘度が少なくとも25%低下する、請求項1に記載の方法。
- 前記製剤の粘度が少なくとも50%低下する、請求項1に記載の方法。
- 前記製剤の粘度が少なくとも80%低下する、請求項1に記載の方法。
- 請求項1〜8のいずれかに記載の方法により生成された医薬製剤。
- 少なくとも70mg/mLの濃度の治療用タンパク質、ならびにn−アセチルアルギニン、n−アセチルリジン、n−アセチルヒスチジン、n−アセチルプロリン及びそれらの混合物からなる群より選択される賦形剤を含む、医薬組成物。
- 前記賦形剤が、n−アセチルアルギニンである、請求項10に記載の医薬組成物。
- 前記賦形剤が、n−アセチルリジンである、請求項10に記載の医薬組成物。
- 前記賦形剤が、n−アセチルヒスチジンである、請求項10に記載の医薬組成物。
- 前記賦形剤が、n−アセチルプロリンである、請求項10に記載の医薬組成物。
- 前記賦形剤の前記濃度が、約200mM未満である、請求項10に記載の医薬組成物。
- 約4.0から約8.0の間のpHを有する、請求項10〜15のいずれかに記載の医薬組成物。
- 約4.6〜約5.4のpHを有する、請求項16に記載の医薬組成物。
- 凍結乾燥粉末を調製する方法であって、請求項10〜17のいずれかに記載の医薬組成物を凍結乾燥するステップを含む、前記方法。
- 治療用タンパク質、ならびにn−アセチルアルギニン、n−アセチルリジン、n−アセチルヒスチジン、n−アセチルプロリン及びそれらの混合物からなる群より選択される賦形剤を含む凍結乾燥粉末であって、前記賦形剤が希釈剤を用いる再構成の際に粘度を低下させるのに有効な重量:重量濃度で存在する、前記凍結乾燥粉末。
- 前記賦形剤が、治療用タンパク質1mgあたり約100μgから治療用タンパク質1mgあたり約1mgの間の濃度で存在する、請求項19に記載の凍結乾燥粉末。
- 前記賦形剤が、治療用タンパク質1mgあたり約200μg〜約500μgから治療用タンパク質1mgあたり約1mgの間の濃度で存在する、請求項19に記載の凍結乾燥粉末。
- 滅菌水性希釈液を添加するステップを含む、請求項19〜21のいずれかに記載の凍結乾燥粉末を再構成するための方法。
- 前記治療用タンパク質が抗体である、請求項1〜8、18または22のいずれか一項に記載の方法。
- 前記治療用タンパク質が抗体である、請求項9〜17のいずれかに記載の医薬製剤または医薬組成物。
- 前記治療用タンパク質が抗体である、請求項19〜21のいずれかに記載の凍結乾燥粉末。
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