JP6431844B2 - Tnfr:fc融合プロテインの安定な医薬組成物 - Google Patents
Tnfr:fc融合プロテインの安定な医薬組成物 Download PDFInfo
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- JP6431844B2 JP6431844B2 JP2015538612A JP2015538612A JP6431844B2 JP 6431844 B2 JP6431844 B2 JP 6431844B2 JP 2015538612 A JP2015538612 A JP 2015538612A JP 2015538612 A JP2015538612 A JP 2015538612A JP 6431844 B2 JP6431844 B2 JP 6431844B2
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- etanercept
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- phosphate
- pharmaceutical composition
- tnfr
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Classifications
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- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
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- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
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Description
本発明は、また、該組成物の製造方法、投与方法および該組成物を含むキットを提供するものでもある。
組成物中で用いられるエタネルセプトの濃度は高いので、長期間保存中にプロテインが凝集する可能性があり得る。プロテインの安定性を改善するために、存在する添加剤の濃度を変えるか、または新しい添加剤を加えて組成物を改変するかのどちらかがあり得る。
本発明のその他の特徴、目的および利点は、発明の詳細な説明および特許請求の範囲の記載から明らかになるであろう。
より詳細には、この発明は、より低い劣化の可能性を発揮するリン酸塩−クエン酸塩バッファ中のエタネルセプトの安定な医薬組成物に関する。
この発明の一実施態様において、TNFR:Fc 融合プロテインはエタネルセプトである。
医薬組成物は、単回または連続注入により、皮下、筋肉内、静脈内、腹膜内、脳脊髄内、関節内、関節滑液内および/または包膜内のように、非経口投与され得る。
成人のリュウマチ関節炎の場合、25 mg のTNFR:Fcが1週間に2回、あるいは50 mg のTNFR:Fc が1週間に1回投与され得る。
強直性脊椎炎の場合、週2回25mg、あるいは週1回50mgのTNFR:Fc が投与され得る。
好ましい実施態様において、組成物は予め充填されるシリンジ中に含まれる。もう一つの好ましい実施態様において、組成物は予め充填されるバイアル中に含まれる。
上記のキットは、本発明の医薬組成物を含む一つ以上の単回投与剤形を含み得る。
上記のキットは、本発明による医薬組成物を自動注射器のような第2のもう一つのコンテナ中に含んでいてもよい。予め充填されたシリンジは水性の形態にある組成物を含んでいてもよい。記述されたシリンジは、自動注射器と共に供給されていてもよく、それはしばしば単回使用に対する使い捨て品であり、例えば0.1〜1mlの容量を有し得る。
本発明は、さらに予め充填されたシリンジ、バイアル、カートリッジまたはペンの形態にある安定な医薬組成物に関するものでもある。
組成物中のエタネルセプトの濃度は、10 mg/mL〜100 mg/mLである。本発明の好ましい実施態様において、組成物中のエタネルセプトの濃度は、10 mg/mL〜60 mg/mLである。本発明の最も好ましい実施態様において、組成物中のエタネルセプトの濃度は、20 mg/mL〜60 mg/mLである。
本発明のもう一つの実施態様において、該エタネルセプト組成物は、L−グリシン、ウレアおよびHPBCD から選択される抗凝集剤を含む。
本発明のもう一つの実施態様において、抗凝集剤がウレアであるとき、組成物中のウレアの濃度は20 mM〜50 mMである。
本発明のもう一つの実施態様において、抗凝集剤がHPBCDであるとき、HPBCDの濃度は10 mM〜100 mMである。
等張化剤は、塩化ナトリウム、塩化カリウム、塩化カルシウムのような塩、またはマンニトール、スクロース、グルコースのようなサッカライド、またはアルギニン、システイン、ヒスチジンのようなアミノ酸などの群から選択される。
好ましい等張化剤は塩化ナトリウムである。その濃度は0 mM〜150 mM の範囲で変動する。
安定化剤は、スクロース、トレハロース、ラクトース、マンニトールからなる群から選択される。好ましい安定化剤はスクロースである。
組成物中の安定化剤の濃度は、0.5 重量%〜10 重量%で変動する。本発明の最も好ましい実施態様において、組成物中の安定化剤の濃度は0.5重量% 〜1.5重量%である。
キレート剤は、EDTA、DTPA、HEDTA、NTAおよびTSPからなる群から選択される。好ましいキレート剤はEDTAである。本発明のより好ましい実施態様において、EDTAの濃度は0 mM〜10 mMである。
以下に記載された実施例のために用いられた活性成分、エタネルセプトは、組換えDNA技術によりCHO細胞中から導かれた。CHO細胞はフェッド−バッチプロセスで培養された。
エタネルセプトは、アフィニティ・クロマトグラフィならびにさらなるクロマトグラフィ工程および濾過工程を含む標準的な精製および濾過方法により、細胞を含まない培養物から精製された。以下の実施例、すなわち実施例2および実施例5で用いられた異なった製造バッチから導かれた。
エタネルセプトの医薬物質組成物を製造する方法は、2つのステップ、すなわち製剤バルクの調製および最終品の充填ステップを含む。
したがって、それはエタネルセプトの凝集および微細化を検知するのに有用である。
エタネルセプトの医薬物質組成物を製造する方法は、2つのステップ、すなわち製剤バルクの調製および最終品の充填ステップを含む、
表1は、抗凝集剤としてのL−グリシンを75 mM 濃度で用いて得られた組成物を記述している。
エタネルセプト組成物が、異なったバッファ中および異なった抗凝集剤を用いて試験された。
リン酸塩−クエン酸塩バッファを抗凝集剤としてのL−グリシンとともに含むエタネルセプト組成物の短期間試験が、リン酸塩バッファを抗凝集剤としてのL−グリシンとともに含むエタネルセプト組成物と並行して、その他の賦形剤は同じにして、SE-HPLCを用いて、5℃で6か月および40℃で2週間それぞれ行われた。その結果が表2に示されている。表2は、異なったエタネルセプト組成物の安定性試験を示している。
エタネルセプト医薬物質組成物の製造方法は、実施例1で説明されたのと同様であり、用いられた抗凝集剤はウレアである。表3に示された組成物は、抗凝集剤としてウレアを用いて調製された。
エタネルセプト医薬物質組成物の製造方法は、実施例1で説明されたのと同様であり、用いられた抗凝集剤はHPBCDである。表4に示された組成物は、抗凝集剤としてHPBCDを用いて調製された。
リン酸塩バッファおよび抗凝集剤としてのL-アルギニンを含むエタネルセプト組成物(組成物1)ならびにリン酸塩−クエン酸塩バッファおよび抗凝集剤としてのL−アルギニンを含むエタネルセプト組成物(組成物2)がPFS中に充填され、現在進行中の長期間安定性試験に付された。
これらの組成物の安定性が評価され、組成物1と2週間まで比較し得ることがわかった。
凍結乾燥試験のために用いられるエタネルセプトが製剤化され、表6に示される医薬組成物で広範に透析された。個々の製剤バルクが半栓されたバイアル中に充填されて、凍結乾燥に付された。
いくつかの実施態様および実施例が上記で詳細に記載されているが、それらの教示から離れることなく、該実施態様および実施例において、多くの修正が可能であることを、当業者は明らかに理解できるだろう。
Claims (2)
- エタネルセプト、リン酸塩−クエン酸塩バッファ、抗凝集剤としてのグリシン、等張化剤としての塩化ナトリウムおよび安定化剤としてのスクロースを含む安定な医薬組成物。
- 10 mg/ml 〜 100 mg/ml のエタネルセプト、約10 mM 〜 100 mM のリン酸塩−クエン酸塩バッファ、約10 mM 〜 300 mM のグリシン、約 1 mM 〜 150 mM の塩化ナトリウムおよび約 0.5 重量% 〜 10重量% のスクロースを含む、請求項1に記載の医薬組成物。
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