JP2011519347A - 安定化されたタンパク質組成物 - Google Patents
安定化されたタンパク質組成物 Download PDFInfo
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Abstract
Description
容器内にある、RANKLに対する特異的結合剤、TNFに対する特異的結合剤、および/またはIL-1R1に対する特異的結合剤の、安定化された組成物を提供する。そのような組成物の作製および使用の方法も同じく提供する。
ある種の治療用組成物は特異的結合剤を含む。ある場合には、治療用組成物は、例えば貯蔵および輸送のために、容器内に入れられる。ある場合には、そのような容器は、貯蔵条件および輸送条件のほか、例えば皮下、筋肉内または静脈内注射を非限定的に含む、投与の様式にも適合する。ある例示的な容器には、アンプル、プレフィリング(prefilling)に適した使い捨てシリンジを非限定的に含む使い捨てシリンジ、およびガラス製またはプラスチック製の多回使用バイアルが非限定的に含まれる。ある場合には、治療用組成物は、プレフィルドシリンジ内、例えば製造元が治療用組成物を中に入れたシリンジ内に含められる。
ある態様においては、特異的結合剤を含む組成物を含むプレフィルドシリンジ(prefilled syringe)であって、このプレフィルドシリンジに含まれる特異的結合剤が安定化されている、プレフィルドシリンジが提供される。
本明細書で用いる項目見出しは構成を目的としたものに過ぎず、記載される主題を限定するものとみなされるべきではない。特許、特許出願、論文、書籍および学術書を非限定的に含む、本出願において引用された文書または文書の部分はすべて、目的を問わず、その全体が参照により本明細書に明示的に組み入れられる。参照により組み入れられる文書または文書の部分のうち1つまたは複数が、ある用語を、本出願におけるその用語の定義と食い違って定義している場合には、本出願が支配的であるものとする。
本開示に従って利用される場合、以下の用語は、別に指定する場合を除き、以下の意味を有すると解釈されるものとする。
ある場合には、TNFは活性化されたマクロファージおよびT細胞から放出され、数多くの種類の細胞に対して多種多様な作用を誘導する。ある場合には、TNFは、正常な免疫応答の調節のほかに、さまざまな病的状態および疾患状態においても役割を果たす。そのようないくつかの病的状態および疾患状態には、敗血症に伴う全身毒性、AIDSの発病、ならびに、関節リウマチ、若年性関節リウマチ、強直性脊椎炎および尋常性乾癬を非限定的に含むさまざまな自己免疫疾患および炎症性疾患が非限定的に含まれる。
天然に存在する抗体の構造単位は、典型的にはテトラマーを含む。そのような各テトラマーは、典型的にはポリペプチド鎖の2つの同一な対で構成され、各対は、1つの完全長軽鎖(ある態様においては約25kDa)および1つの完全長重鎖(ある態様においては約50〜70kDa)を有する。
二重特異性または二機能性抗体は、典型的には、2つの異なる重鎖/軽鎖対および2つの異なる結合部位を有する人工的なハイブリッド抗体である。二重特異性抗体は、ハイブリドーマの融合、またはFab'断片の結び付けを非限定的に含む、種々の方法によって作製することができる。例えば、Songsivilai & Lachmann Clin. Exp. Immunol. 79: 315-321 (1990), Kostelny et al. J. Immunol. 148:1547-1553 (1992)を参照。
ある態様において、抗体は、ハイブリドーマ細胞系以外の細胞系において発現させることができる。ある態様においては、キメラ抗体を含む特定の抗体をコードする配列を、適した哺乳動物宿主細胞の形質転換のために用いることができる。ある態様によれば、形質転換は、例えば、ポリヌクレオチドをウイルス(またはウイルスベクター)中にパッケージングして、宿主細胞にそのウイルスによって形質導入すること、または米国特許第4,399,216号;第4,912,040号;第4,740,461号;および第4,959,455号に例示されているような、当技術分野において公知の手順を用いてベクターをトランスフェクトすることを含む、ポリヌクレオチドを宿主細胞に導入するための任意の公知の方法によって行うことができる。
ある態様において、ポリペプチド、例えばTNF-Rを非限定的に含むポリペプチドをコードするDNAを増幅または発現させるために、組換え発現ベクターを用いる。ある態様において、組換え発現ベクターは、哺乳動物TNF-Rまたは生物学的に同等な類似体をコードする合成性またはcDNA由来のDNA断片が、哺乳動物性、微生物性、ウイルス性または昆虫性遺伝子に由来する適した転写または調節制御エレメントと機能的に連結されたものを有する、複製可能なDNA構築物である。ポリペプチドをコードする合成性またはcDNA由来のDNA断片の発現のために適したさまざまな組換え発現ベクターが当業者に周知である。いくつかの例示的な組換え発現ベクターは、米国特許第5,945,397号に記載されている。
ある態様において、精製された哺乳動物TNF受容体または類似体は、TNF-R DNAの組換え翻訳産物を発現させるために適した宿主/ベクター系を培養し、続いてそれを培地または細胞抽出物から精製することによって調製される。
ある態様においては、少なくとも1種の特異的結合剤、少なくとも1種の安定化剤、および緩衝剤を含む組成物が提供される。そのようなある態様において、組成物はさらに、少なくとも1種の追加の薬学的薬剤を含む。ある態様において、特異的結合剤は、RANKLに対する特異的結合剤、TNFに対する特異的結合剤、および/またはIL-1R1に対する特異的結合剤である。ある態様において、特異的結合剤はRANKLに対する特異的結合剤であり、ここでRANKLに対する特異的結合剤はRANKLと特異的に結合する抗体である。ある態様において、抗体はαRANKL-1である。ある態様において、特異的結合剤はTNFに対する特異的結合剤であり、ここでTNFに対する特異的結合剤は可溶性TNF受容体である。ある態様において、可溶性TNF受容体はsTNFR:Fcである。ある態様において、特異的結合剤はIL-1R1に対する特異的結合剤であり、ここで特異的結合剤はIL-1R1と特異的に結合する抗体である。ある態様において、抗体は、米国特許出願公開第2004/0097712号に記載されたような15C4、26F5および27F2から選択される。
以下の実験は、ある条件下にて容器内で貯蔵した特異的結合剤組成物の安定性を評価するために行った。安定性を、静的貯蔵条件下および輸送後にモニターした。具体的には、ある条件下では組成物中の可視粒子の形成を招く、タンパク質凝集に影響を及ぼすパラメーターを同定するために、シリンジのいくつかの局面について調べた。プレフィルドシリンジの容器およびクロージャーのさまざまなシリコーンコーティング剤について調べた。以下の実験に用いた特異的結合剤はαRANKL-1であった。
以下の実験におけるαRANKL-1の濃度は、30mg/ml〜105mg/mlの幅とした。αRANKL-1は、10mM酢酸ナトリウム、5%ソルビトール、pH 5.2中にて製剤化した。バイアルを用いる実験に関しては、組成物を3ccバイアル内に最終容積1mlとして入れた。シリンジを用いる実験に関しては1mlシリンジを用いた。容器内にある組成物を、最長24ヶ月間にわたって貯蔵した。容器内にある組成物を、非変性SEC-HPLCまたは非還元変性SEC-HPLCによって、抗体モノマー、高分子種(凝集物)または低分子量種(例えば、クリッピングによって生成された分子)に関してモニターした。容器内にある組成物中の可視粒子は、以下に述べるように容器の目視検査によって検討評価した。
図1は、ガラスバイアル内で静的条件下で24ヶ月間貯蔵し、図中に表示したさまざまな時点で分析した、70mg/mlまたは105mg/mlのいずれかのタンパク濃度でのαRANKL-1組成物の非変性SEC-HPLC分析の結果を示している。3種類のロットを分析した(ロットA、BおよびC)。図1(A)は、主ピーク%(モノマー)を示し、図1(B)は凝集物%(プレピーク)を示している。これらの結果は、ガラスバイアル内で4℃で最長24ヶ月間にわたり静的条件下で貯蔵した場合に、αRANKL-1は凝集物形成をほとんど示さないことを指し示している。この図はまた、70mg/mlのタンパク質を含む製剤および105mg/mlタンパク質を含む製剤について、同様の結果が得られたことも示している。
図2は、ルアーロック付きガラス製プレフィルドシリンジまたはステーキ固定針付きガラス製プレフィルドシリンジ内で貯蔵して、図中に表示したさまざまな時点で分析した、さまざまなタンパク質濃度でのαRANKL-1組成物の非変性SEC-HPLCの結果を示している。これらの結果は、ルアーロック付きガラス製プレフィルドシリンジ内またはステーキ固定針付きガラス製プレフィルドシリンジ内のいずれかで4℃で最長24週間にわたり静的条件下で貯蔵した場合に、αRANKL-1がほとんど凝集物形成を示さないことを指し示している。この図はまた、70mg/mlのタンパク質を含む製剤、および105mg/mlタンパク質を含む製剤について同様の結果が得られたことも示している。
以上に論述した安定性の結果とは対照的に、αRANKL-1を60mg/mlタンパク質の濃度で含む、温度2℃〜8℃の間で1050マイルの距離を空路輸送したステーキ固定針付きガラス製プレフィルドシリンジは、目視検査による検討評価で、輸送後に可視粒子を示した(非提示データ)。
輸送後のプレフィルドシリンジ内での粒子形成に対する、さまざまなシリンジおよびプランジャー材料ならびにコーティング剤の効果を調べるために、以下の実験を行った。60mg/mlタンパク質のαRANKL-1組成物を、それぞれが表1および2に表示されたような異なるシリコーンコーティング剤および他のコーティング剤を有する、種々のタイプのクロージャーを有する種々のタイプの容器に入れた。これらの実験に用いた容器およびクロージャーの製造元およびカタログ番号は表1および2に提示されている。ガラス、環状オレフィンポリマー(「COP」;[Resin CZ(登録商標)])または環状オレフィンコポリマー(「COC」)のいずれかで構成される容器を試験した。3種類のシリコーンコーティング剤を試験した:焼き付けられた高粘度シリコーン、架橋されたシリコーンおよび吹き付けられたシリコーンオイル。いくつかの容器にはシリコーンコーティングを含めなかった。2種類のクロージャーコーティング剤を試験した:ポリテトラフルオロエチレン(PTFE)、Teflon(登録商標)およびエチレンテトラフルオロエチレン(ETFE)、Flurotec(登録商標)。
以下の実験では、αRANKL-1の濃度は60mg/mlまたは120mg/mlのいずれかとした。αRANKL-1は、10mM酢酸ナトリウム、5%ソルビトール、pH 5.2中にて製剤化した。この溶液を0.2μMセルロースフィルターに通すことによってαRANKL-1組成物を濾過滅菌した。続いて試料(1.0ml)を、1ml COP(Resin CZ(登録商標))プラスチック製シリンジ(表1参照)内に手作業で添加した。試料を内部に含むシリンジに、以下に述べる真空ストッパー配置法に従って、Flurotecコーティングしたプランジャー(表2参照)により、ストッパーで栓をした。
上記の実施例1において論述した結果は、ある種のプレフィルド容器の輸送中のプランジャーの動きがタンパク質凝集の一因となり、それが組成物中の可視粒子の形成を招く可能性があることを示唆する。このため、輸送中のプランジャーの動きの一因となるパラメーターについて検討した。そのようなパラメーターの1つはヘッドスペースである。ヘッドスペースが小さいほど、プランジャーの動きの量が小さくなるという仮説を立てたが、この仮説によれば、その結果として、輸送後の組成物中に観察される可視粒子は少なくなると考えられる。この仮説を検証するために、以下の実験を実施した。
以下の実験では、組成物中のsTNFR:Fcの濃度は50mg/mlとした。sTNFR:Fcは、25mMリン酸、25mMアルギニンHCl、100mM NaCl、1%スクロース、pH 6.3中にて製剤化した。αRANKL-1の濃度は60mg/mlとした。αRANKL-1は、10mM酢酸ナトリウム、5%ソルビトール、0.01%ポリソルベート-20、pH 5.2中にて製剤化した。
sTNFR:Fc組成物を含むプレフィルドシリンジに対して、可視粒子に関する容器の目視検査に加えて、Malvern Zetasizer装置(Malvern、Zetasizer Nano ZS、モデル番号ZEN3600)を用いた目では見えない粒子の分析をさまざまな条件下で行った。
(表6)
Claims (88)
- 特異的結合剤を含む組成物を含むプレフィルドシリンジ(prefilled syringe)であって、該プレフィルドシリンジに含まれる該特異的結合剤が安定化されている、プレフィルドシリンジ。
- 特異的結合剤が、RANKLに対する特異的結合剤、TNFに対する特異的結合剤、およびIL-1R1に対する特異的結合剤から選択される、請求項1記載のプレフィルドシリンジ。
- 特異的結合剤が、抗体、ポリクローナル抗体、モノクローナル抗体、重鎖および軽鎖が柔軟なリンカーによって接続された抗体、Fv分子、マキシボディ(maxibody)、抗原結合性断片、Fab断片、Fab'断片、F(ab')2分子、完全ヒト抗体、ヒト化抗体、ならびにキメラ抗体から選択される、請求項2記載のプレフィルドシリンジ。
- 特異的結合剤が、RANKLのRANKとの結合を実質的に阻害する抗体、TNFのTNF-Rとの結合を実質的に阻害する抗体、およびIL-1のIL-1R1との結合を実質的に阻害する抗体から選択される抗体である、請求項3記載のプレフィルドシリンジ。
- 抗体がRANKLのRANKとの結合を実質的に阻害する抗体であって、該抗体がαRANKL-1であり、αRANKL-1が重鎖および軽鎖を含み、該重鎖がSEQ ID NO:2に示されたアミノ酸配列またはその断片を含み、かつ該軽鎖がSEQ ID NO:4に示されたアミノ酸配列またはその断片を含む、請求項4記載のプレフィルドシリンジ。
- 抗体がIL-1のIL-1R1との結合を実質的に阻害する抗体である、請求項4記載のプレフィルドシリンジ。
- 組成物がさらに、少なくとも1種の追加の薬学的薬剤を含む、請求項1記載のプレフィルドシリンジ。
- 組成物がさらに、少なくとも1種の安定化剤および緩衝剤を含む、請求項1記載のプレフィルドシリンジ。
- 少なくとも1種の安定化剤が界面活性剤である、請求項8記載のプレフィルドシリンジ。
- 界面活性剤が、ポリソルベートおよびポリオキシプロピレン-ポリオキシエチレンエステル(Pluronic(登録商標))から選択される、請求項9記載のプレフィルドシリンジ。
- 界面活性剤がポリソルベートである、請求項10記載のプレフィルドシリンジ。
- ポリソルベートがポリソルベート20およびポリソルベート80から選択される、請求項11記載のプレフィルドシリンジ。
- 界面活性剤が0.001%〜1%の濃度で存在する、請求項9記載のプレフィルドシリンジ。
- 界面活性剤が0.002%〜0.5%の濃度で存在する、請求項13記載のプレフィルドシリンジ。
- 界面活性剤が0.004%の濃度で存在する、請求項14記載のプレフィルドシリンジ。
- 界面活性剤が0.01%の濃度で存在する、請求項14記載のプレフィルドシリンジ。
- 組成物のpHが6.6未満である、請求項8記載のプレフィルドシリンジ。
- 組成物のpHが5.5〜6.5の間である、請求項17記載のプレフィルドシリンジ。
- 組成物のpHが6.3である、請求項18記載のプレフィルドシリンジ。
- 組成物のpHが4.5〜5.5の間である、請求項17記載のプレフィルドシリンジ。
- 組成物のpHが5.2である、請求項20記載のプレフィルドシリンジ。
- シリコーンを含む材料を含み、該シリコーンが架橋されている、請求項1記載のプレフィルドシリンジ。
- シリコーンを含む材料を含み、該シリコーンが焼き付けられている、請求項1記載のプレフィルドシリンジ。
- シリコーンを含有せず、かつシリンジクロージャーがシリコーンを含有しない、請求項1記載のプレフィルドシリンジ。
- 高分子量プラスチック材料を含み、該高分子量プラスチック材料がシリコーンを含有しない、請求項1記載のプレフィルドシリンジ。
- 高分子量プラスチック材料が環状オレフィンポリマーを含む、請求項25記載のプレフィルドシリンジ。
- 高分子量プラスチック材料が環状オレフィンコポリマーを含む、請求項25記載のプレフィルドシリンジ。
- 特異的結合剤を含む組成物を含むプレフィルドシリンジであって、該組成物とシリンジクロージャーとの間のヘッドスペースが最小化されており、かつ該プレフィルドシリンジに含まれる該特異的結合剤が安定化されている、プレフィルドシリンジ。
- 最小化されたヘッドスペースが2.5mm〜3.0mmの間である、請求項28記載のプレフィルドシリンジ。
- 最小化されたヘッドスペースが2.0mm〜2.5mmの間である、請求項28記載のプレフィルドシリンジ。
- 最小化されたヘッドスペースが1.5mm〜2.0mmの間である、請求項28記載のプレフィルドシリンジ。
- 最小化されたヘッドスペースが1.0mm〜1.5mmの間である、請求項28記載のプレフィルドシリンジ。
- 特異的結合剤が、RANKLに対する特異的結合剤、TNFに対する特異的結合剤、およびIL-1R1に対する特異的結合剤から選択される、請求項28記載のプレフィルドシリンジ。
- 特異的結合剤が、抗体、ポリクローナル抗体、モノクローナル抗体、重鎖および軽鎖が柔軟なリンカーによって接続された抗体、Fv分子、マキシボディ、抗原結合性断片、Fab断片、Fab'断片、F(ab')2分子、完全ヒト抗体、ヒト化抗体、ならびにキメラ抗体から選択される、請求項33記載のプレフィルドシリンジ。
- 特異的結合剤が、RANKLのRANKとの結合を実質的に阻害する抗体、TNFのTNF-Rとの結合を実質的に阻害する抗体、およびIL-1のIL-1R1との結合を実質的に阻害する抗体から選択される抗体である、請求項34記載のプレフィルドシリンジ。
- 抗体がRANKLのRANKとの結合を実質的に阻害する抗体であって、該抗体がαRANKL-1であり、αRANKL-1が重鎖および軽鎖を含み、該重鎖がSEQ ID NO:2に示されたアミノ酸配列またはその断片を含み、かつ該軽鎖がSEQ ID NO:4に示されたアミノ酸配列またはその断片を含む、請求項35記載のプレフィルドシリンジ。
- 抗体がIL-1のIL-1R1との結合を実質的に阻害する抗体である、請求項35記載のプレフィルドシリンジ。
- 組成物がさらに、少なくとも1種の追加の薬学的薬剤を含む、請求項28記載のプレフィルドシリンジ。
- 組成物がさらに、少なくとも1種の安定化剤および緩衝剤を含む、請求項28記載のプレフィルドシリンジ。
- 少なくとも1種の安定化剤が界面活性剤である、請求項39記載のプレフィルドシリンジ。
- 界面活性剤が、ポリソルベートおよびポリオキシプロピレン-ポリオキシエチレンエステル(Pluronic(登録商標))から選択される、請求項40記載のプレフィルドシリンジ。
- 界面活性剤がポリソルベートである、請求項41記載のプレフィルドシリンジ。
- ポリソルベートがポリソルベート20およびポリソルベート80から選択される、請求項42記載のプレフィルドシリンジ。
- 界面活性剤が0.001%〜1%の濃度で存在する、請求項40記載のプレフィルドシリンジ。
- 界面活性剤が0.002%〜0.5%の濃度で存在する、請求項44記載のプレフィルドシリンジ。
- 界面活性剤が0.004%の濃度で存在する、請求項45記載のプレフィルドシリンジ。
- 界面活性剤が0.01%の濃度で存在する、請求項45記載のプレフィルドシリンジ。
- 組成物のpHが6.6未満である、請求項39記載のプレフィルドシリンジ。
- 組成物のpHが5.5〜6.5の間である、請求項48記載のプレフィルドシリンジ。
- 組成物のpHが6.3である、請求項49記載のプレフィルドシリンジ。
- 組成物のpHが4.5〜5.5の間である、請求項48記載のプレフィルドシリンジ。
- 組成物のpHが5.2である、請求項51記載のプレフィルドシリンジ。
- シリコーンを含む材料を含み、該シリコーンが架橋されている、請求項28記載のプレフィルドシリンジ。
- シリコーンを含む材料を含み、該シリコーンが焼き付けられている、請求項28記載のプレフィルドシリンジ。
- シリコーンを含有せず、かつシリンジクロージャーがシリコーンを含有しない、請求項28記載のプレフィルドシリンジ。
- 高分子量プラスチック材料を含み、該高分子量プラスチック材料がシリコーンを含有しない、請求項28記載のプレフィルドシリンジ。
- 高分子量プラスチック材料が環状オレフィンポリマーを含む、請求項56記載のプレフィルドシリンジ。
- 高分子量プラスチック材料が環状オレフィンコポリマーを含む、請求項56記載のプレフィルドシリンジ。
- 特異的結合剤を含む組成物を、該組成物とシリンジクロージャーとの間のヘッドスペースが最小化されるようにシリンジ内に導入する段階を含む、プレフィルドシリンジを調製する方法であって、該プレフィルドシリンジ内に含まれる該特異的結合剤が安定化されている、方法。
- 特異的結合剤が、RANKLに対する特異的結合剤、TNFに対する特異的結合剤、およびIL-1R1に対する特異的結合剤から選択される、請求項59記載の方法。
- 特異的結合剤が、抗体、ポリクローナル抗体、モノクローナル抗体、重鎖および軽鎖が柔軟なリンカーによって接続された抗体、Fv分子、マキシボディ、抗原結合性断片、Fab断片、Fab'断片、F(ab')2分子、完全ヒト抗体、ヒト化抗体、ならびにキメラ抗体から選択される、請求項60記載の方法。
- 特異的結合剤が、RANKLのRANKとの結合を実質的に阻害する抗体、TNFのTNF-Rとの結合を実質的に阻害する抗体、およびIL-1のIL-1R1との結合を実質的に阻害する抗体から選択される抗体である、請求項61記載の方法。
- 抗体がRANKLのRANKとの結合を実質的に阻害する抗体であって、該抗体がαRANKL-1であり、αRANKL-1が重鎖および軽鎖を含み、該重鎖がSEQ ID NO:2に示されたアミノ酸配列またはその断片を含み、かつ該軽鎖がSEQ ID NO:4に示されたアミノ酸配列またはその断片を含む、請求項62記載の方法。
- 抗体がIL-1のIL-1R1との結合を実質的に阻害する抗体である、請求項62記載の方法。
- 組成物がさらに、少なくとも1種の追加の薬学的薬剤を含む、請求項59記載の方法。
- 組成物がさらに、少なくとも1種の安定化剤および緩衝剤を含む、請求項59記載の方法。
- 少なくとも1種の安定化剤が界面活性剤である、請求項66記載の方法。
- 界面活性剤が、ポリソルベートおよびポリオキシプロピレン-ポリオキシエチレンエステル(Pluronic(登録商標))から選択される、請求項67記載の方法。
- 界面活性剤がポリソルベートである、請求項68記載の方法。
- ポリソルベートがポリソルベート20およびポリソルベート80から選択される、請求項69記載の方法。
- 界面活性剤が0.001%〜1%の濃度で存在する、請求項67記載の方法。
- 界面活性剤が0.002%〜0.5%の濃度で存在する、請求項71記載の方法。
- 界面活性剤が0.004%の濃度で存在する、請求項72記載の方法。
- 界面活性剤が0.01%の濃度で存在する、請求項72記載の方法。
- 組成物のpHが6.6未満である、請求項66記載の方法。
- 組成物のpHが5.5〜6.5の間である、請求項75記載の方法。
- 組成物のpHが6.3である、請求項76記載の方法。
- 組成物のpHが4.5〜5.5の間である、請求項75記載の方法。
- 組成物のpHが5.2である、請求項78記載の方法。
- シリンジがシリコーンを含む材料を含み、該シリコーンが架橋されている、請求項59記載の方法。
- シリンジがシリコーンを含む材料を含み、該シリコーンが焼き付けられている、請求項59記載の方法。
- シリンジがシリコーンを含有せず、かつシリンジクロージャーがシリコーンを含有しない、請求項59記載の方法。
- シリンジが高分子量プラスチック材料を含み、該高分子量プラスチック材料がシリコーンを含有しない、請求項59記載の方法。
- 高分子量プラスチック材料が環状オレフィンポリマーを含む、請求項83記載の方法。
- 高分子量プラスチック材料が環状オレフィンコポリマーを含む、請求項83記載の方法。
- 特異的結合剤が1mg/ml〜150mg/mlの濃度である、請求項1または請求項28記載のプレフィルドシリンジ。
- 特異的結合剤が1mg/ml〜150mg/mlの濃度である、請求項59記載の方法。
- 組成物中の特異的結合剤を安定化するための方法であって、該組成物がプレフィルドシリンジ内に含まれており、該プレフィルドシリンジ内の該組成物を、該組成物とシリンジクロージャーとの間のヘッドスペースが最小化されるように配置する段階を含み、かつ該プレフィルドシリンジ内に含まれる該特異的結合剤が安定化されている、方法。
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017515596A (ja) * | 2014-05-12 | 2017-06-15 | フォーマイコン アーゲーFormycon Ag | Vegf拮抗薬を収容したプレフィルドプラスチックシリンジ |
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Families Citing this family (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EA012801B1 (ru) | 2005-06-14 | 2009-12-30 | Эмджен Инк. | Самобуферирующиеся композиции белков |
EP2403873A1 (en) | 2009-03-05 | 2012-01-11 | Ablynx N.V. | Novel antigen binding dimer-complexes, methods of making/avoiding and uses thereof |
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JOP20200175A1 (ar) | 2012-07-03 | 2017-06-16 | Novartis Ag | حقنة |
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US9744303B2 (en) | 2013-07-10 | 2017-08-29 | Merit Medical Systems, Inc. | Pre-loaded syringes and methods related thereto |
WO2016040766A1 (en) * | 2014-09-12 | 2016-03-17 | Anthrogenesis Corporation | Methods for quantifying particulates in cell culture |
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US20170333641A1 (en) | 2014-10-30 | 2017-11-23 | Hoffmann-La Roche Inc. | Syringe and method of preparing syringe |
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JOP20190260A1 (ar) | 2017-05-02 | 2019-10-31 | Merck Sharp & Dohme | صيغ ثابتة لأجسام مضادة لمستقبل الموت المبرمج 1 (pd-1) وطرق استخدامها |
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WO2024049793A1 (en) * | 2022-08-30 | 2024-03-07 | Amgen Inc. | System and method of limiting subvisible particles in a syringe |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999018994A1 (fr) * | 1997-10-15 | 1999-04-22 | Asahi Kasei Kogyo Kabushiki Kaisha | Procede pour conserver la qualite d'une solution parenterale aqueuse de thrombomoduline pour l'entreposage ou la distribution |
WO2001017542A1 (fr) * | 1999-09-08 | 2001-03-15 | Chugai Seiyaku Kabushiki Kaisha | Preparation de solution de proteines et procede de stabilisation associe |
JP2005506963A (ja) * | 2001-06-26 | 2005-03-10 | アブジェニックス インコーポレイテッド | Opglへの抗体 |
JP2005527503A (ja) * | 2002-02-27 | 2005-09-15 | イミユネツクス・コーポレイシヨン | ポリペプチド製剤 |
JP2007502310A (ja) * | 2003-05-23 | 2007-02-08 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | 溶液中におけるタンパク質の安定化 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4652763A (en) * | 1985-03-29 | 1987-03-24 | Energy Sciences, Inc. | Electron-beam irradiation sterilization process |
US6146657A (en) * | 1989-12-22 | 2000-11-14 | Imarx Pharmaceutical Corp. | Gas-filled lipid spheres for use in diagnostic and therapeutic applications |
US5773024A (en) * | 1989-12-22 | 1998-06-30 | Imarx Pharmaceutical Corp. | Container with multi-phase composition for use in diagnostic and therapeutic applications |
US6551576B1 (en) * | 1989-12-22 | 2003-04-22 | Bristol-Myers Squibb Medical Imaging, Inc. | Container with multi-phase composition for use in diagnostic and therapeutic applications |
US5519984A (en) * | 1995-03-16 | 1996-05-28 | Mallinckrodt Medical, Inc. | Methods for packaging a pressure or vacuum sensitive product |
JP3329219B2 (ja) * | 1997-02-05 | 2002-09-30 | スズキ株式会社 | 船外機の電装部品設置構造 |
US6274169B1 (en) * | 1999-08-02 | 2001-08-14 | Abbott Laboratories | Low oxygen content compostions of 1α, 25-dihydroxycholecalciferol |
US6595961B2 (en) * | 2001-04-16 | 2003-07-22 | Becton, Dickinson And Company | Sterilizable transfer or storage device for medicaments, drugs and vaccines |
US20030104996A1 (en) * | 2001-08-30 | 2003-06-05 | Tiansheng Li | L-methionine as a stabilizer for NESP/EPO in HSA-free formulations |
BRPI0413197A (pt) * | 2003-08-01 | 2006-10-03 | Amgen Inc | cristal de eta wercept; método para fabricar um cristal de etanercept; composição; uso de um cristal de etanercept |
-
2009
- 2009-02-05 US US12/866,400 patent/US20110060290A1/en not_active Abandoned
- 2009-02-05 MX MX2010008696A patent/MX2010008696A/es not_active Application Discontinuation
- 2009-02-05 KR KR1020107019902A patent/KR20100138908A/ko not_active Application Discontinuation
- 2009-02-05 AU AU2009210741A patent/AU2009210741A1/en not_active Abandoned
- 2009-02-05 BR BRPI0908361 patent/BRPI0908361A2/pt not_active IP Right Cessation
- 2009-02-05 CA CA2714006A patent/CA2714006A1/en not_active Abandoned
- 2009-02-05 CN CN2009801125162A patent/CN102202643A/zh active Pending
- 2009-02-05 WO PCT/US2009/000759 patent/WO2009099641A2/en active Application Filing
- 2009-02-05 JP JP2010545880A patent/JP2011519347A/ja active Pending
- 2009-02-05 EP EP09708975A patent/EP2249801A2/en not_active Withdrawn
- 2009-02-05 EA EA201001223A patent/EA201001223A1/ru unknown
- 2009-02-05 CN CN201310467313.3A patent/CN103720587A/zh active Pending
- 2009-02-05 SG SG10201402265YA patent/SG10201402265YA/en unknown
-
2010
- 2010-08-02 IL IL207340A patent/IL207340A0/en unknown
- 2010-08-13 ZA ZA2010/05779A patent/ZA201005779B/en unknown
-
2011
- 2011-12-20 ZA ZA2011/09364A patent/ZA201109364B/en unknown
-
2014
- 2014-08-12 JP JP2014163998A patent/JP2015042638A/ja active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999018994A1 (fr) * | 1997-10-15 | 1999-04-22 | Asahi Kasei Kogyo Kabushiki Kaisha | Procede pour conserver la qualite d'une solution parenterale aqueuse de thrombomoduline pour l'entreposage ou la distribution |
WO2001017542A1 (fr) * | 1999-09-08 | 2001-03-15 | Chugai Seiyaku Kabushiki Kaisha | Preparation de solution de proteines et procede de stabilisation associe |
JP2005506963A (ja) * | 2001-06-26 | 2005-03-10 | アブジェニックス インコーポレイテッド | Opglへの抗体 |
JP2005527503A (ja) * | 2002-02-27 | 2005-09-15 | イミユネツクス・コーポレイシヨン | ポリペプチド製剤 |
JP2007502310A (ja) * | 2003-05-23 | 2007-02-08 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | 溶液中におけるタンパク質の安定化 |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2017515596A (ja) * | 2014-05-12 | 2017-06-15 | フォーマイコン アーゲーFormycon Ag | Vegf拮抗薬を収容したプレフィルドプラスチックシリンジ |
JP2022186793A (ja) * | 2014-05-12 | 2022-12-15 | フォーマイコン アーゲー | Vegf拮抗薬を収容したプレフィルドプラスチックシリンジ |
JP2018188430A (ja) * | 2017-04-28 | 2018-11-29 | アムジエン・インコーポレーテツド | ヒト抗rankl抗体の製剤及びその使用方法 |
JP2022062059A (ja) * | 2017-04-28 | 2022-04-19 | アムジエン・インコーポレーテツド | ヒト抗rankl抗体の製剤及びその使用方法 |
JP7190822B2 (ja) | 2017-04-28 | 2022-12-16 | アムジエン・インコーポレーテツド | ヒト抗rankl抗体の製剤及びその使用方法 |
JP7356525B2 (ja) | 2017-04-28 | 2023-10-04 | アムジエン・インコーポレーテツド | ヒト抗rankl抗体の製剤及びその使用方法 |
JP2019048091A (ja) * | 2018-10-23 | 2019-03-28 | ニプロ株式会社 | デクスメデトミジン注射液を充填したプレフィルドシリンジ |
US11739153B2 (en) | 2020-09-18 | 2023-08-29 | Chugai Seiyaku Kabushiki Kaisha | Anti-HLA-DQ2.5 antibody and its use for the treatment of celiac disease |
JP7220335B1 (ja) * | 2021-10-08 | 2023-02-09 | 中外製薬株式会社 | 抗hla-dq2.5抗体の製剤 |
WO2023058705A1 (ja) * | 2021-10-08 | 2023-04-13 | 中外製薬株式会社 | 抗hla-dq2.5抗体の製剤 |
WO2023058723A1 (ja) * | 2021-10-08 | 2023-04-13 | 中外製薬株式会社 | プレフィルドシリンジ製剤の調製方法 |
Also Published As
Publication number | Publication date |
---|---|
CA2714006A1 (en) | 2009-08-13 |
JP2015042638A (ja) | 2015-03-05 |
EP2249801A2 (en) | 2010-11-17 |
IL207340A0 (en) | 2010-12-30 |
SG10201402265YA (en) | 2014-08-28 |
KR20100138908A (ko) | 2010-12-31 |
CN103720587A (zh) | 2014-04-16 |
EA201001223A1 (ru) | 2011-06-30 |
ZA201005779B (en) | 2014-12-23 |
CN102202643A (zh) | 2011-09-28 |
US20110060290A1 (en) | 2011-03-10 |
ZA201109364B (en) | 2015-11-25 |
AU2009210741A1 (en) | 2009-08-13 |
BRPI0908361A2 (pt) | 2015-04-07 |
WO2009099641A2 (en) | 2009-08-13 |
MX2010008696A (es) | 2010-08-30 |
WO2009099641A3 (en) | 2011-02-24 |
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