JP6791929B2 - タンパク質含有製剤の安定化に有用な組成物及び方法 - Google Patents
タンパク質含有製剤の安定化に有用な組成物及び方法 Download PDFInfo
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Description
本出願は、35USC 119(e)に基づき2010年3月22日に出願された仮出願第61/316326号の優先権を主張する、37CFR 1.53(b)(1)に基づき出願する非仮出願であり、その内容を出典明記により本明細書中に援用する。
本発明は、タンパク質含有製剤の安定化のための、及びこのような製剤中におけるタンパク質の凝集の防止のための、例えばポリオキシエチレン(POE)ソルビタン及びポリエチレングリコール(PEG)を含む非界面活性化合物の使用に関する。
本発明は、以下の特定の実施態様の詳細な説明及びそこに含まれる実施例を参照することによって、より容易に理解されるだろう。
ここでa+b+c+dが好ましくは約6〜約80、より好ましくは約8〜約60、更により好ましくは約10〜約40、更により好ましくは約10〜約20である。上記に関して、当分野では、ここに記載されるPOEソルビタン等の化合物の化学合成は、完全に均一な調製物というより、いくらか不均一な化合物の混合物となることが理解される。このように、a+b+c+dが例えば好ましくは約6〜80であるとここで記載される場合、該定義は、その化学合成から生じる不均一な混合物の大部分の要素を指すことが理解される。
ここで、nは約5〜約240であり、場合によってはある程度の不飽和を含みうる。本発明における使用に対して包含されるPEGは、分岐又は線状であり得、好ましくは線状である。上記に関して、当分野では、ここに記載されるPEG等の化合物の化学合成は、完全に均一な調製物というより、いくらか不均一な化合物の混合物となることが理解される。このように、nが好ましくは約5〜240であるとここで記載される場合、該定義は、その化学合成から生じる不均一な混合物の大部分の要素を指すことが理解される。
この実施例は、ポリソルベート、脂肪酸及びPOEソルビタンが、水溶液中におけるタンパク質凝集にどのように作用するかを示す。
(i) 添加物無し、コントロール;
(ii) ラウリン酸(29ppm);
(iii) ラウリン酸(29ppm)及びポリソルベート20(24ppm);
(iv) POEソルビタン20”(a+b+c+d=20)”(150ppm);
(v) POEソルビタン20”(a+b+c+d=20)”(150ppm)及びポリソルベート20(24ppm);
(vi) POEソルビタン20”(a+b+c+d=20)”(150ppm)及びラウリン酸(29ppm);
(vii) POEソルビタン20”(a+b+c+d=20)”(150ppm)、ラウリン酸(29ppm)、及びポリソルベート20(24ppm);
(viii) ポリソルベート20(24ppm)。
この実施例は、タンパク質の凝集を防止又は低減するための、安定剤としてのPOEソルビタン及びPEGの使用を説明する。
(i) 添加物無し、コントロール;
(ii) 200ppmの濃度でのPOEソルビタン20”(a+b+c+d=20)”
(iii) 1000ppmの濃度でのPOEソルビタン20”(a+b+c+d=20)”
(iv) 5000ppmの濃度でのPOEソルビタン20”(a+b+c+d=20)”
(v) 200ppmの濃度でのPEG1000;
(vi) 1000ppmの濃度でのPEG1000;
(vii) 5000ppmの濃度でのPEG1000;
(viii) 200ppmの濃度でのPEG6000;
(ix) 1000ppmの濃度でのPEG6000;
(x) 5000ppmの濃度でのPEG6000。
上記のように振とうさせた後直ちに、タンパク質含有溶液をタンパク質凝集を除去するために濾過し、次いで濾液中のタンパク質濃度を紫外分光法により決定した。タンパク質濃度データを0.5又は1cm光路長セル及びAgilent 8453紫外分光計を使用して25oCで測定した。278nmで1.45及び1.60mLmg−1cm−1の消衰係数Εを使用し、0.2μmシリンジフィルターを通した濾過後の抗体濃度を決定した。散乱効果に対し320nmでの吸光度値を278nmでの吸光度値から減算した。これに関して、タンパク質含有溶液中のタンパク質の濃度が、UV吸光分析を使用して定量的に測定されうることが当分野でよく知られている(例えば、Liu等, J. Pharm. Sci., 94(9):1928-1940 (2005)を参照)。抗IL13抗体及び抗IgE抗体に関して得たデータの結果を、図2及び3にそれぞれ示す。
上記のように、340−360nmでの紫外分光法は溶液中に存在するタンパク質凝集の量を定量的に決定するための効果的な手段を提供し、ここで濁度は存在する凝集タンパク質の量に直接相関する。抗IL13抗体及び抗IgE抗体の濁度分析から得た結果を、図4及び5にそれぞれ示す。
また、上記の抗体含有水溶液を、そこに含まれるタンパク質の粒子サイズ分布を決定するために分析した。具体的に、2〜50μmの不溶性粒子の数及びサイズを、HIAC/Royco 3000A液体シリンジサンプラーに取り付けられたHIAC/Royco 9703液体粒子カウンター、HRLD-150センサーを使用して室温で測定し、PacificSpec Version 2.0ソフトウェアを使用して解析した。検出の上限は〜18000粒子/mlであり、この閾値を超えるサンプルは測定に対して適切に希釈した。各サンプルを注入あたり1.0mLの容積で4回測定した。最初の注入は処分し、平均値を最後の3回の注入から得た。各サンプルの分析間に、装置の2μm粒子カウントが<10となるまで注入用水を用いてシステムを洗浄した。≧2、5、10、15、25、35、及び50μmのSub-visible粒子はmlあたりの累積カウントとして表される。
Claims (2)
- 水溶液中における抗体の凝集を防止又は低減させる方法であって、前記抗体をポリエチレングリコールと混合することを含み、ここで前記ポリエチレングリコールが約20ppm〜約10,000ppmの間の濃度で存在し水溶液中における前記抗体の凝集を防止又は低減させ、前記抗体が、抗IL13抗体又は抗IgE抗体であり、ポリエチレングリコールが、PEG1000及びPEG6000から成る群から選択される、方法。
- 前記抗体がモノクローナル抗体である、請求項1に記載の方法。
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