JP7301043B2 - 粒子の形成を低減する方法及びそれにより形成される組成物 - Google Patents
粒子の形成を低減する方法及びそれにより形成される組成物 Download PDFInfo
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Description
本出願は、2017年9月19日に出願された、米国仮出願第62/560,365号の優先権の利益を主張する。当該仮出願の全体が参照することにより本明細書に組み込まれる。
場合によっては、親油性特性を有する特定のタンパク質に結合するように設計されたアフィニティークロマトグラフィーが、HICの代わりに、またはHICと組み合わせて使用される。一部のエステラーゼ、例えば、一般的にはリパーゼ、または具体的にはホスホリパーゼは、トリグリセリドまたはリン脂質に結合するため、それら脂質を模倣する分子を用いてエステラーゼを捕捉してもよい。例えば、「ミリストイル化ADPリボシル化因子1」(別名「myrARF1」)を用いてリパーゼを捕捉し、POIを未結合のままにしてフロースルーにすることができる。
いくつかの実施形態では、該FDSまたは医薬品は、温度約2~8℃で少なくとも6ヶ月保管される。他の実施形態では、該FDSまたは医薬品は、例えば、約5℃、15℃、22℃、24℃、または30~50℃、例えば、約35℃、40℃、45℃、もしくは50℃の温度で保管される。
共精製された宿主細胞タンパク質(HCP)リパーゼによるポリソルベートの分解に起因する遊離脂肪酸系の眼に見えない微粒子を生じやすいIgG4抗体医薬品の保存安定性を異なるDPサンプルで評価した。各DPサンプルは、体積2.136mLであり、同濃度のIgG4抗体(150mg/mL)、及びいくつかのロットのPS80のうちの1つを0.2%(w/v)含んでいた。PS80ロットの各ロットは、オレイン酸エステル含量の3つの異なる含量パーセンテージ(70%、87%、及び≧99%)のうちの1つを有した。以下の表は、各FDSサンプル中のPS80のオレイン酸エステル含量パーセンテージを要約している。
各サンプルDP(DP A~F)における各種の遊離脂肪酸の濃度(マイクログラム/mL)を、サンプルを5℃で18ヶ月間保存した後に評価した。サンプルDP A~Fを実施例1に記載の通りに調製した。遊離脂肪酸濃度を18ヶ月でLC-MSにより測定した。図4は、結果をグラフ形式で示す。示されるように、DP B及びC(この2つのDPサンプルは、オレイン酸エステル含量が≧99%のPS80を含む)は、最も高いオレイン酸濃度及び最も低い他のFFA濃度を示した。これは、DP B及びCにおけるFFA(すなわち、オレイン酸)の均一性を示している。
Claims (24)
- 医薬品において肉眼では見えない及び眼に見える粒子の形成を低減する方法であって、前記方法は、
前記医薬品に少なくとも100mg/mLのIgG抗体を含めることと、
前記医薬品にポリオキシエチレンソルビタンの脂肪酸エステルの混合物を含めることと、を含み、
前記ポリオキシエチレンソルビタンは、98%を超えるオレイン酸エステル含量を有する、方法。 - 前記医薬品を温度30℃~50℃で1~5ヶ月間保管することをさらに含み、
前記保管の後、フローイメージング顕微鏡法または膜顕微鏡法のうちの1つで検出して、直径10ミクロン以上を有する3000個未満の粒子が前記医薬品中で検出可能である、請求項1に記載の方法。 - 前記医薬品を温度2℃~8℃で18~36ヶ月間保管することをさらに含み、
前記保管の後、フローイメージング顕微鏡法または膜顕微鏡法のうちの1つで検出して、直径10ミクロン以上を有する3000個未満の粒子が前記医薬品中で検出可能である、請求項1に記載の方法。 - 前記IgG抗体がIgG4抗体である、請求項1に記載の方法。
- 前記IgG抗体が、リパーゼと共精製することが可能であり、前記医薬品が前記リパーゼを含む、請求項1に記載の方法。
- 前記IgG抗体が、前記医薬品への包含の前にアフィニティー精製のステップを用いて精製されている、請求項1に記載の方法。
- 前記医薬品に少なくとも100mg/mLの前記IgG抗体を含めることが、前記医薬品に少なくとも150mg/mLの前記IgG抗体を含めることを含む、請求項1に記載の方法。
- 前記IgG抗体が、前記医薬品への包含の前に疎水性相互作用クロマトグラフィー(HIC)を用いて精製されていない、請求項1に記載の方法。
- 前記IgG抗体がIgG4抗体であり、前記医薬品がホスホリパーゼB様2タンパク質を含む、請求項1に記載の方法。
- 前記医薬品に前記IgG抗体を含める前に、プロテインA精製ステップを用いて前記IgG抗体を精製することをさらに含む、請求項1に記載の方法。
- 前記ポリオキシエチレンソルビタン中の前記オレイン酸エステル含量が、少なくとも99%である、請求項1に記載の方法。
- 前記医薬品が、さらにエステラーゼを含む、請求項1に記載の方法。
- 前記混合物中の前記オレイン酸エステル含量が、ガス液体クロマトグラフィー、液体クロマトグラフィー、比色分析、または蛍光分析のうちの1つによって特定される、請求項1に記載の方法。
- 前記医薬品が、非経口投与用に構成される、請求項1に記載の方法。
- IgG抗体及びエステラーゼを含む医薬品において微粒子の形成を低減する方法であって、前記方法は、
前記医薬品にポリオキシエチレンソルビタンの脂肪酸エステルの混合物を含めることであって、前記ポリオキシエチレンソルビタンは、98%を超えるオレイン酸エステル含量を有する、前記医薬品に前記ポリオキシエチレンソルビタンの脂肪酸エステルの混合物を含めることを備え、
前記方法は、疎水性相互作用クロマトグラフィーを用いて前記IgG抗体を精製することを含まない、方法。 - 前記IgG抗体がIgG4抗体であり、前記エステラーゼがホスホリパーゼB様2タンパク質である、請求項15に記載の方法。
- 少なくとも100mg/mLのIgG抗体と、
ポリオキシエチレンソルビタンの脂肪酸エステルの混合物と、を含む製剤であって、
前記ポリオキシエチレンソルビタンが、98%を超えるオレイン酸エステル含量を有する、製剤。 - 少なくとも150mg/mLの前記IgG抗体を含む、請求項17に記載の製剤。
- 前記脂肪酸エステルの混合物がポリソルベート80である、請求項17に記載の製剤。
- 前記IgG抗体がIgG4抗体であり、前記製剤がホスホリパーゼB様2タンパク質を含む、請求項17に記載の製剤。
- 請求項17に記載の製剤を含む、医薬品。
- 前記医薬品が温度30℃~50℃で1~5ヶ月間保管された後、フローイメージング顕微鏡法または膜顕微鏡法のうちの1つによって、直径10ミクロン以上を有する3000個未満の粒子が前記医薬品中で検出可能である、請求項21に記載の医薬品。
- 前記医薬品が温度2℃~8℃で18~36ヶ月間保管された後、フローイメージング顕微鏡法または膜顕微鏡法のうちの1つによって、直径10ミクロン以上を有する3000個未満の粒子が前記医薬品中で検出可能である、請求項21に記載の医薬品。
- 前記医薬品を、温度30℃~50℃で3~5ヶ月間保管することをさらに含む、請求項1に記載の方法。
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