JP7402195B2 - 医薬製剤及びその製造方法 - Google Patents
医薬製剤及びその製造方法 Download PDFInfo
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- JP7402195B2 JP7402195B2 JP2021080160A JP2021080160A JP7402195B2 JP 7402195 B2 JP7402195 B2 JP 7402195B2 JP 2021080160 A JP2021080160 A JP 2021080160A JP 2021080160 A JP2021080160 A JP 2021080160A JP 7402195 B2 JP7402195 B2 JP 7402195B2
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Description
本願は2016年10月21日に出願された米国仮特許出願第62/411,458号の利益を主張するものであり、その全体が参照により本明細書に組み込まれる。
下記の実施例は、製剤がpHを所望の範囲に維持することができるかどうかを、当業者がどのようにして決定することができるかを説明する。基本的には、医薬組成物は試験容器(ガラスバイアル、ガラスシリンジ、プラスチックシリンジ、ステンレス鋼製容器、又は医薬組成物に適した任意の様式の滅菌デバイスであり得る)中で製剤化して保存し、pHを時間0で評価し、その後、必要に応じて、示された時間で評価する。通常、試験条件は医薬組成物の貯蔵の必要性を予測し、それらの条件に重点を置くであろう。例えば、本発明の製剤は、制御された室温(CRT)下で、少なくとも2週間、少なくとも4週間、少なくとも8週間、少なくとも12週間、及び少なくとも24週間、所望のpHを維持することができる。CRTはUSPによって定義され、20℃~25℃(68°F~77°F)の通常の慣用の作業環境を包含し;25℃以下であると計算される平均動力学的温度をもたらし;かつ、薬局、病院、及び倉庫で経験される15℃~30℃(59°F~86°F)の間の偏位を許可する、サーモスタットで維持された温度を有する。
本発明はまた、緩衝液を除去し、かつpHを標的範囲に維持するための、エタネルセプト医薬組成物を製剤化する方法であって、標的範囲の緩衝製剤形態にエタネルセプトを製剤化する工程と、緩衝製剤を、その標的範囲内の、又は標的範囲のすぐ下の非緩衝製剤に交換する工程と、得られたエタネルセプトの医薬製剤を回収する工程とを含む方法を提供する。下に例示する好ましい実施形態では、本方法は、緩衝液を除去し、かつpHを6.0~6.6に維持するための、エタネルセプト医薬組成物を製剤化する方法であって、エタネルセプト製剤をpH6.0~6.6で緩衝製剤形態に製剤化する工程と、緩衝製剤をpH5.6~6.5の非緩衝製剤に交換する工程と、得られた医薬製剤を回収する工程とを含む方法を提供する。pHを6.1~6.5に維持するエタネルセプトの非緩衝組成物を得るには、出発の緩衝エタネルセプト製剤と非緩衝製剤の両方のpHの調整を確実に行うことが重要である。例えば、出発の緩衝エタネルセプト製剤がpH7.2である場合、それは、HClなどの強酸で6.1~6.5の範囲内に調整されるであろう。同様に、交換に使用される非緩衝製剤は、pH5.6~6.5に滴定されるべきである。交換用に使用される非緩衝製剤は、緩衝剤を有しないので、滴定の間、注意を払うべきである。
この実施例は50mg/mLのエタネルセプトに対するpH及び緩衝液の影響を実証し、リン酸緩衝液を添加しない高濃度(100mg/mL)溶液の安定性を評価する。以下の製剤を試験した。
この試験は、単施設、無作為化、一重盲検、クロスオーバーデザインであり、これには48人の健康な男性及び女性が6種の溶液の単回SC注射を受けた。
いくつかの新しい製剤候補中のエタネルセプトの安定性を観察するために、50mg/mLで長期研究を行った。4℃、25℃及び40℃で貯蔵した後、SE-HPLC、HIC HPLC、dSEC HPLC、及び粒子状物質(HIAC)を使用して、1mLのステークガラス針シリンジ(staked glass needle syringe)中の1mL充填物について安定性を評価した。重量オスモル濃度及びタンパク質濃度を時刻ゼロでのみ試験し、pHは、pHドリフトがないことを確認するために、時刻ゼロ及び12週間の貯蔵後に試験した。研究の結果、試験した製剤は、40℃の加速温度で12週後に、また2~8℃の推奨貯蔵及び25℃の加速温度で24週後に、現在の市販製剤との類似性を維持していることが示された。
3種の新しい製剤候補中のエタネルセプトの安定性を観察するために、50mg/mLで凍結/融解のサイクル研究を行った。現在市販の製剤PASS(25mMのリン酸緩衝液、25mMのL-アルギニン、100mMのNaCl、1%のスクロース)と比較した製剤は、SAST_100NaCl(25mMのL-アルギニン、100mMのNaCl、1%のスクロース、0.010%のポリソルベート20)、SAS_120NaCl(25mMのL-アルギニン、120mMのNaCl、1%のスクロース)、及びSAST_120NaCl(25 mMのL-アルギニン、120 mMのNaCl、1%のスクロース 0.010%のポリソルベート20)であった。55mLステンレス鋼製凍結容器中で、-30℃~4℃のサイクルを行った場合の凝集に対する安定性を、SE-HPLCを用いて凍結/融解サイクル5回まで評価した。
これらの実施例の目的は、TMS(トリス、マンニトール、スクロース)中のエタネルセプトの異なる調製物を試験製剤(L-アルギニン、スクロース、NaCl)中に透析し、最終pHを標的pHと比較することであった。
結果の要約を下記の表17に示す。
はじめに:この研究後に選択された製剤溶液は、SAS(120mMの塩化ナトリウム、25mMのL-アルギニン、1%のスクロース、pH6.3)と名付けられ、リン酸緩衝液は添加されていない。前の実施例で、pH7.56の試料中のエタネルセプトから出発する場合、透析するか、又はUF/DFを使用するかでは、標的pH6.3の達成は困難であると示されたことから、SAS製剤への交換の異なる方法が必要であった。異なる最終UF/DF出発材料を利用した以下の2つの方法を評価した:1)出発材料としてカラム3(AEX)中間体プール、及び2)出発材料としてPASS製剤緩衝液(PASS DS中間体プール)中のEnbrel原薬。それぞれの方法は以下に記載され、50g/LのSAS製剤化エタネルセプトを製造するための、最終UF/DF単位操作工程の開発を、SAS製剤溶液の調製、最終UF/DFの負荷調整及び処理を含めて要約する。
調整したAEX中間体プールは、制御された室温(CRT)で52.6時間まで保管することができる。保管中のプールのpHを図8に示す。
AEX中間体プールを出発材料として使用して生成された最終UF/DF SASプールは、CRTで96.3時間まで保管することができる。保管中のpH及び導電率を図9A及びBに示す。96.3時間の保管中、pH及び導電率は許容範囲内に留まる。
この中間体プールは既に目標pH(6.3)にあるので、SAS溶液によるUF/DF処理の前に、このPASSプールを調整する必要はない。プールの状態はEnbrel PASS DSから変えられなかったので、この中間体プールではプール保管研究を実施しなかった。プールは25℃で96時間まで保管することができる。
PASS DS中間体プールを出発材料として生成された、最終UF/DF SASプールは、CRTで96.3時間まで保管することができる。保管中のpH及び導電率を図9A及びBに示す。96.3時間の保管中、pH及び導電率は許容範囲内に留まる。
SAS製剤溶液は、CRTで28日間まで保管することができる。pH及び導電率を図10A及びBに示す。非常に小さなヘッドスペースを有する小規模ステンレス鋼製安定性チャンバ内で42日間保管した場合、SAS製剤溶液はpHを5.6~6.5内に維持することが示された。35日目及び42日目の時点で沈殿が観察された。21日目の時点の測定値5.09は、その後の時点では提案された許容基準内にあるという事実によって、外れ値のようである。
この実施例の目的は、40℃、75mg/mLでエタネルセプト安定性に対するアルギニン、スクロース又は塩化ナトリウムの増加した濃度が凝集に与える影響を決定することである。リン酸緩衝液を添加せずに、等張製剤を維持するために、これらの賦形剤の濃度をそれぞれ増加させた。さらに、ヒスチジンを、リン酸塩置換用緩衝液として評価した。試験した製剤を表22に要約する。
SAS製剤中、ポリソルベート20が、0、0.005、0.01及び0.015%の場合に、50mg/mLのエタネルセプトの安定性を観察するために長期研究を行った。さらに、100mg/mLの、エタネルセプトのSAST高濃度製剤を試験した。4℃、25℃及び40℃で貯蔵後、SE-HPLC、dSEC HPLC、及びの粒子状物質(HIAC)を使用して、1mLのステークガラス針シリンジ中の1mL充填物について安定性を評価した。時刻ゼロでのみ、重量オスモル濃度、pH、及びタンパク質濃度を試験した。試験の結果は、試験した50mg/mL製剤が、推奨される2~8℃、ならびに25℃及び40℃の加速温度で24週間後に、現在の市販製剤との類似性を維持したことが示された。100mg/mLのSAST製剤は、pH及びサブビジブル粒子に関して50mg/mL製剤と同等の挙動を示した;SECによる凝集レベルの差異はタンパク質濃度に起因すると考えられた。
COPプラスチック製の、シリコーン油を含まないプレフィルドシリンジシステム中における、50mg/mLエタネルセプトのPASS及びSAS製剤中のエタネルセプト安定性を、ガラス製のシリコーン処理したプレフィルドシリンジと比較して観察するために、長期研究を行った。4℃、25℃及び40℃で貯蔵後、SE-HPLC、pH、及びの粒子状物質(HIAC)を使用して、各種シリンジシステム中の1mL充填物について安定性を評価した。時刻ゼロでのみ、タンパク質濃度を試験した。
Claims (27)
- 2.0mM未満の全追加緩衝剤、75mM~150mMのNaCl、5mM~100mMのアルギニン、0.5%~2%(w/v)のスクロース、及び40mg/mL~100mg/mLのエタネルセプトを含み、6.1~6.5のpHを有するエタネルセプトの医薬組成物を製造する方法であって、前記方法は、追加緩衝剤を含まない溶液と、追加緩衝剤を含むエタネルセプト製剤を交換するステップを含み、
ここで、生じた組成物は40mg/mL~100mg/mLのエタネルセプトと、75mM~150mMのNaClとを含み、追加緩衝剤を含むエタネルセプト製剤、及び追加緩衝剤を含まない溶液は、それぞれ、6.1~6.5のpHを有する、方法。 - 交換するステップが透析ろ過である、請求項1に記載の方法。
- 追加緩衝剤を含まない溶液が等張である、請求項1に記載の方法。
- 追加緩衝剤を含まない溶液が、スクロース、アルギニン及びNaClを含む、請求項1に記載の方法。
- 追加緩衝剤を含まない溶液が、75mM~150mMのNaCl、5mM~100mMのアルギニン、及び0.5%~2%(w/v)のスクロースを含む、請求項4に記載の方法。
- 追加緩衝剤を含まない溶液が、約120mMのNaCl、約25mMのアルギニン、及び約1%のスクロース、及び水から本質的になる、請求項4に記載の方法。
- アルギニンが、L-アルギニンである、請求項4に記載の方法。
- 医薬組成物をろ過するステップをさらに含む、請求項1に記載の方法。
- 医薬組成物を薬剤製品形態へと等分するステップをさらに含む、請求項1に記載の方法。
- 追加緩衝剤を含むエタネルセプト製剤が、75mM~150mMのNaClを含み、追加緩衝剤を含まない溶液が、75mM~150mMのNaClを含み、医薬組成物が、75mM~150mMのNaClを含む、方法であって、NaCl除去ステップを含まない請求項1に記載の方法。
- 追加緩衝剤を含むエタネルセプト製剤が、約120mMのNaClを含み、追加緩衝剤を含まない溶液が、約120mMのNaClを含み、医薬組成物が、約120mMのNaClを含む、請求項10に記載の方法。
- 塩除去ステップを含まない、請求項1に記載の方法。
- 医薬組成物が、1.0mM未満の全追加緩衝剤を含む、請求項1に記載の方法。
- 医薬組成物が、0.5mM未満の全追加緩衝剤を含む、請求項1に記載の方法。
- 医薬組成物が、0.25mM未満の全追加緩衝剤を含む、請求項1に記載の方法。
- 医薬組成物が、約50mg/mLのエタネルセプト、約120mMのNaCl、約25mMのL-アルギニン塩酸塩、及び約1%(w/v)のスクロースを含む、請求項1に記載の方法。
- 医薬組成物が、約50mg/mLのエタネルセプト、約120mMのNaCl、約25mMのL-アルギニン塩酸塩、約1%(w/v)のスクロース、及び水から本質的になる、請求項16に記載の方法。
- 医薬組成物が、約50mg/mLのエタネルセプト、約120mMのNaCl、約25mMのL-アルギニン塩酸塩、約1%(w/v)のスクロース、及び水からなる、請求項16に記載の方法。
- エタネルセプトが、配列番号1のアミノ酸配列の二量体からなる、請求項1に記載の方法。
- 関節リウマチ、乾癬性関節炎、強直性脊椎炎、又は乾癬の治療のための医薬の製造のための医薬組成物の使用であって、医薬組成物は、75mM~150mMのNaCl、5mM~100mMアルギニン、0.5%~2%(w/v)のスクロース、40mg/mL~100mg/mLのエタネルセプト、及び2.0mM未満の全追加緩衝剤を含み、医薬組成物のpHは、6.1~6.5である、使用。
- 関節リウマチ、乾癬性関節炎、強直性脊椎炎、又は乾癬の治療のための医薬組成物であって、医薬組成物は、75mM~150mMのNaCl、5mM~100mMアルギニン、0.5%~2%(w/v)のスクロース、40mg/mL~100mg/mLのエタネルセプト、及び2.0mM未満の全追加緩衝剤を含み、医薬組成物のpHは、6.1~6.5である、医薬組成物。
- 医薬組成物が、
(a)1.0mM未満の全追加緩衝剤、
(b)0.5mM未満の全追加緩衝剤、
(c)0.25mM未満の全追加緩衝剤、又は
(d)0.1mM未満の全追加緩衝剤
を含む、請求項21に記載の医薬組成物。 - 医薬組成物が、
(a)約50mg/mLのエタネルセプト、約120mMのNaCl、約25mMのL-アルギニン塩酸塩、及び約1%(w/v)のスクロースを含む、又は
(b)約50mg/mLのエタネルセプト、約120mMのNaCl、約25mMのL-アルギニン塩酸塩、及び約1%(w/v)のスクロースから本質的になる、又は
(c)約50mg/mLのエタネルセプト、約120mMのNaCl、約25mMのL-アルギニン塩酸塩、約1%(w/v)のスクロース、及び水からなる
請求項21又は22に記載の医薬組成物。 - エタネルセプトが、配列番号1のアミノ酸配列の二量体からなる、請求項21~23のいずれか一項に記載の医薬組成物。
- 医薬組成物が、
(a)1.0mM未満の全追加緩衝剤、
(b)0.5mM未満の全追加緩衝剤、
(c)0.25mM未満の全追加緩衝剤、又は
(d)0.1mM未満の全追加緩衝剤
を含む、請求項20に記載の医薬組成物の使用。 - 医薬組成物が、
(a)約50mg/mLのエタネルセプト、約120mMのNaCl、約25mMのL-アルギニン塩酸塩、及び約1%(w/v)のスクロースを含む、又は
(b)約50mg/mLのエタネルセプト、約120mMのNaCl、約25mMのL-アルギニン塩酸塩、及び約1%(w/v)のスクロースから本質的になる、又は
(c)約50mg/mLのエタネルセプト、約120mMのNaCl、約25mMのL-アルギニン塩酸塩、約1%(w/v)のスクロース、及び水からなる、
請求項20又は25に記載の医薬組成物の使用。 - エタネルセプトが、配列番号1のアミノ酸配列の二量体からなる、請求項20、25又は26のいずれか一項に記載の医薬組成物の使用。
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US10307483B2 (en) | 2019-06-04 |
WO2018075818A1 (en) | 2018-04-26 |
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US20190022217A1 (en) | 2019-01-24 |
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