JP6877472B2 - C1エステラーゼ抑制因子欠乏に関連する障害の予防及び治療のためのc1−inh組成物ならびに方法 - Google Patents
C1エステラーゼ抑制因子欠乏に関連する障害の予防及び治療のためのc1−inh組成物ならびに方法 Download PDFInfo
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- JP6877472B2 JP6877472B2 JP2019011084A JP2019011084A JP6877472B2 JP 6877472 B2 JP6877472 B2 JP 6877472B2 JP 2019011084 A JP2019011084 A JP 2019011084A JP 2019011084 A JP2019011084 A JP 2019011084A JP 6877472 B2 JP6877472 B2 JP 6877472B2
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Description
本発明の実施形態において、例えば以下の項目が提供される。
(項目1)
障害の治療、抑制、または予防を必要とする対象におけるC1エステラーゼ抑制因子の欠乏に関連する障害を治療、抑制、または予防するための方法であって、該方法が、少なくとも1つのC1エステラーゼ抑制因子を含む組成物を投与することを含み、該C1エステラーゼ抑制因子が、約400U/ml以上で存在する、前記方法。
(項目2)
該組成物が皮下投与される、項目1に記載の前記方法。
(項目3)
該組成物が静脈内投与される、項目1に記載の前記方法。
(項目4)
該障害が遺伝性血管性浮腫である、項目1に記載の前記方法。
(項目5)
該C1エステラーゼ抑制因子が、ヒトC1エステラーゼ抑制因子である、項目1に記載の前記方法。
(項目6)
該ヒトC1エステラーゼ抑制因子が、血漿から精製される、項目5に記載の前記方法。(項目7)
該組成物がクエン酸塩を含む、項目3に記載の前記方法。
(項目8)
該組成物がリン酸塩を含む、項目2に記載の前記方法。
(項目9)
該組成物が約6.5を超えるpHを有する、項目1に記載の前記方法。
(項目10)
少なくとも1つのC1エステラーゼを約400U/ml以上で含む、組成物。
(項目11)
少なくとも1つの薬学的に許容される担体をさらに含む、項目10に記載の前記組成物。
(項目13)
少なくとも1つの項目10に記載の組成物を含む、キット。
(項目14)
少なくとも1つのシリンジ及び/または再構成緩衝液をさらに含む、項目13に記載の前記キット。
(項目15)
該シリンジに該組成物が予め充填されている、項目14に記載の前記キット。
「1つの(a)」、「1つの(an)」、及び「その(the)」という単数形は、文脈が別途明確に指示しない限り、複数形の指示対象を含む。
タンパク質をスピン濃縮器に充填し、5〜10分間10,500rpmで回転させた。試料が回転を停止したとき、スピン濃縮器内の最終容積を記録し、それぞれのおおまかなタンパク質濃度を算定した。追加のタンパク質をスピン濃縮器に加え、所望のタンパク質濃度に達するまで回転させ、この時点でUV測定を行った。それぞれの標的タンパク質濃度において、UV及び粘度の測定を実施した。タンパク質の粘度が試料のさらなる濃縮を防止するまで、上記の手順を続けた。
ゲルを充填するピペット先端の所定の距離まで試料が引き込まれるのにかかった時間の量を測定することによって、粘度を判定した。試料粘度を算定するために、既知の粘度を有する一連の標準を使用して、標準曲線をまず調製した。スクロース(またはBrix)溶液が、かかる曲線を調製するために好適だが、規定の温度で既知の粘度を有するいかなる材料も適切であろう。
本実施例は、単一製剤(monoformulation)としての、より高濃度のC1 IΝΗの液体製剤を開発するための能力を判定した。初期研究は、スピン濃縮法を使用してC1 IΝΗの原液の濃度に着目した。溶液を、はじめにpHについて調節したが、他の賦形剤は添加しなかった。3つのpH値を調査した(pH5.9、6.9、及び7.9)。スピン濃縮すると、溶液のすべてが、試験したpH値すべてについて、最大約500U/ml(およそ100mg/ml)の濃度まで、澄んだままであった(表1)。これらの研究では可溶性限度に達しなかったが、濃度が300U/mlを超えると粘度に測定可能な上昇があった(図2)。すべてのpH値において、C1 INH濃度が400U/mlを超えると、粘度が顕著に上昇し始める。
Claims (11)
- 少なくとも1つのC1エステラーゼ抑制因子と、クエン酸塩またはクエン酸ナトリウムを含む緩衝液とを含む組成物であって、前記C1エステラーゼ抑制因子は400U/ml〜600U/mlで存在し、前記組成物は皮下投与のために製剤化されており、前記組成物は、6.5〜8.0の範囲のpHを有する、組成物。
- 前記組成物が、6.5〜8.0、例えば、6.5〜7.5、必要に応じて、6.5〜7.0の範囲のpHを有する、請求項1に記載の組成物。
- 前記クエン酸ナトリウムが、5mM〜50mMで、必要に応じて、10mM〜30mMで、または20mMで存在する、請求項1または2に記載の組成物。
- 前記C1エステラーゼ抑制因子が、図1の前記ヒトC1エステラーゼ抑制因子のアミノ酸配列と少なくとも90%、95%、98%、99%または100%同一であるアミノ酸配列を有する、請求項1〜3のいずれか一項に記載の組成物。
- 前記C1エステラーゼ抑制因子が、500U/mlで存在する、請求項1〜4のいずれか一項に記載の組成物。
- 前記C1エステラーゼ抑制因子が、ヒト血漿から単離または精製されているか、または組換え生産されており、ヒト血漿から精製されたC1エステラーゼ抑制因子は、必要に応じて、ナノ濾過または低温殺菌されている、請求項1〜5のいずれか一項に記載の組成物。
- 少なくとも1つのアミノ酸またはその塩を含む、請求項1〜6のいずれか一項に記載の組成物。
- 前記組成物が液体形態で調製されているか、または前記組成物が乾燥粉末形態から再構成されている、請求項1〜7のいずれか一項に記載の組成物。
- 前記組成物が、凍結乾燥形態から緩衝液中に再構成されている、請求項8に記載の組成物。
- 前記C1エステラーゼ抑制因子が、前記組成物中に100単位〜10,000単位、例えば、500単位〜5,000単位、必要に応じて、1,000単位〜3,500単位、または1,500単位〜2,500単位の範囲で存在する、請求項1〜9のいずれか一項に記載の組成物。
- 再構成緩衝液、皮下注射のためのシリンジ(例えば、使い捨て)、および説明材料のうちの少なくとも1つを必要に応じて含む、請求項1〜10のいずれか一項に記載の組成物を含むキット。
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