JP2018528242A - 非プロトン性極性溶媒中の安定な治療用グルカゴン製剤を製造するための方法 - Google Patents
非プロトン性極性溶媒中の安定な治療用グルカゴン製剤を製造するための方法 Download PDFInfo
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Abstract
Description
本発明は、全般的に、非経口投与のための治療用製剤に関する。特に、本発明は、非プロトン性極性溶媒系において溶解させる前に緩衝化水溶液からペプチドを乾燥させる必要なく、非プロトン性極性溶媒系に治療剤(有効成分)を溶解させることにより安定な治療用製剤を調製するための非プロトン性極性溶媒の使用に関する。活性成分に加えて、製剤中に安定化賦形剤、特にイオン化安定化賦形剤も含めることができる。
非プロトン性極性溶媒に溶解されたペプチドは、水溶液に対して増強された安定性および溶解性を示し得る(US2014/0005135(特許文献1)およびUS8,697,644(特許文献2)参照)。しかしながら、非プロトン性極性溶媒中でのいくつかのペプチドの直接的な溶解は、しばしば、貯蔵安定性の欠如のために安定した治療用組成物を調製するための実行可能な方法ではない。1つの特定の例は、低血糖症の治療に使用される29アミノ酸残基ペプチドホルモンであるグルカゴンである。グルカゴンは約7.0の等電点を有し、その分子は中性pHで本質的に不溶性である。したがって、水溶液は、分子が治療的に関連する濃度で可溶化される前に、酸性またはアルカリ性のいずれかで作製されなければならない。しかしながら、酸性およびアルカリ性の溶液は、グルカゴン分解経路を促進し、グルカゴン分子は、希釈酸性溶液中でフィブリル化してゲル様凝集物を形成しやすいことがよく知られている。したがって、グルカゴン分子の不安定性のために、現在の利用可能な治療薬は、使用直前に希釈剤を用いて再構成しなければならない凍結乾燥粉末として販売されている。対照的に、グルカゴン分子は、非プロトン性極性溶媒、例えば、ジメチルスルホキシド(DMSO)において増強された安定性および溶解性を示し得る。
本明細書で使用される「溶解」という用語は、気体、固体、または液体状態の材料が、溶媒中の気体、液体、または固体の溶液を形成する、溶媒の溶質、溶解された成分となることを意味する。特定の態様では、治療剤または賦形剤、例えばイオン化安定化賦形剤は、その溶解限度までの量で存在するか、または完全に可溶化される。 「溶解する」という用語は、気体、液体、または固体が溶媒に組み込まれて溶液を形成することを意味する。
水性溶液として調製する場合、標準的な小分子、ペプチド、およびタンパク質分子は、複数の物理的および化学的な分解経路の影響を受けやすい。これらの治療用分子の多くでは、水を要求する分解経路(例えば、加水分解、ラセミ化、脱アミド化)を避けることができず、その結果、分子を適切に安定化することができない。従って、多くの治療剤は、非経口注射のための安定な溶液として調製することができず、代わりに、使用直前に再構成される粉末として調製される。
本発明の文脈における治療剤は、ペプチドまたはタンパク質化合物、小分子薬物、およびそれらの薬学的に許容可能な塩を包含する。治療剤が脱酸素化された非プロトン性極性溶媒中に存在する場合、治療剤の安定性は、未処理の非プロトン性極性溶媒中に存在する同じ治療剤と比較した場合にさらに増強され得る。増大した安定性は、少なくとも部分的には、治療剤の酸化的分解もしくは非プロトン性極性溶媒の酸化的分解の減少、またはそれら両方に起因し得る。当業者は、特定の疾患または状態を治療するために適した治療剤がどれであるかを承知しており、疾患または状態の治療のための本明細書に記載の製剤中の有効量の治療剤を投与することができるであろう。
本発明の製剤は、少なくとも1種のイオン化安定化賦形剤を含有する非プロトン性極性溶媒系中に存在する治療剤を含む。治療剤は、非プロトン性極性溶媒系に溶解(例えば、完全にまたは部分的に可溶化)または(完全にまたは部分的に)懸濁することができる。さらに、製剤は、単相溶液、ペーストもしくはスラリー、ゲル、エマルション、または懸濁液として構成することができる。
別の態様では、本発明は、疾患、状態、または障害を治療、軽減、または予防するために有効な量において、本明細書に記載の安定な製剤中の疾患、状態、または障害を治療するための治療剤を対象に投与することにより、疾患、状態、または障害を治療する方法を供する。
キットもまた、本発明の特定の態様において使用されると考えられる。例えば、本発明の製剤は、キット内に含めることができる。キットは容器を含むことができる。一態様では、例えば、製剤は、製剤を再構成または希釈する必要なく、対象に投与する準備ができている容器内に含まれ得る。すなわち、投与される製剤は、容器に保存され、必要に応じて直ちに使用され得る。容器は装置であり得る。装置は、シリンジ(例えば、予め充填されたシリンジ)、ペン注射装置、自動注射装置、製剤をポンプまたは投与することができる装置(例えば、自動または非自動外部ポンプ、埋め込み可能なポンプなど)、または灌流バッグであり得る。適切なペン/自動注射装置には、これらに限らないが、Becton-Dickenson, Swedish Healthcare Limited(SHL Group), YpsoMed Agなどにより製造されるこれらのペン/自動注射装置が含まれる。好適なポンプ装置には、これに限らないが、Tandem Diabetes Care, Inc., Delsys Pharmaceuticalsなどによって製造されたポンプ装置が含まれる。
本出願に開示される方法を用いて、また、先行技術に開示される方法(例えば、非プロトン性極性溶媒系におけるペプチドの直接的な溶解、および非プロトン性極性溶媒系に溶解する前の緩衝化水溶液からのペプチドの乾燥)も介して、多くのペプチドおよび小分子製剤を調製した。以下の実施例に示されるように、本発明の方法により調製された組成物は、非プロトン性極性溶媒系におけるペプチド粉末の直接的な溶解を介して観察される物理的および化学的安定性を超える物理的および化学的安定性を提供した。
この実施例では、グリシン塩酸塩(CAS No.6000-43-7)を5mM、10mM、および20mM濃度のDMSO(CAS No. 67-68-5)に直接溶解し、続いてグルカゴン粉末(MW = 3483g/mol; Bachem AG, product no. 4074733)を5mg/mLのペプチド濃度に溶解することによりグルカゴン溶液を調製した。調製した試料溶液を表1に示す。
この実施例では、グルカゴン粉末(Bachem AG, Product no. 4074733)を0.001M(1mM)〜0.01M(10mM)の範囲の異なる濃度の添加塩酸を含むDMSOに溶解することにより、グルカゴン溶液を5mg/mLの濃度で調製した。製剤に添加する水の量を最小にするために、DMSO溶液中に10mMおよび5.6mMのHClを調製するために5N HClを使用し、3.2mM、1.8mMおよび1.0mMの溶液を調製するために1N HClを使用した。一例として、DMSO溶液中の10mM HClは、20μLの5N HClを9.98mLのDMSO(ニート)に添加することにより調製し、DMSO溶液中の1.0mM HClは、10μLの1N HClを9.99mLのDMSO(ニート)に添加することにより調製した。各製剤のサンプルを2mLのCZバイアル(バイアルあたり0.5mLのサンプル)に保存し、40℃でインキュベートした。
種々の添加濃度のグリシン塩酸塩(CAS No. 6000-43-7)、ベタイン塩酸塩(CAS No. 590-46-5)、または塩酸(1N; CAS No.7647-01-0)を含むDMSOに5mg/mLの濃度までグルカゴン粉末(Bachem AG, Product No. 4074733)を溶解することにより試料溶液を調製した。試料製剤を調製するために用いた各イオン化安定化賦形剤の種々の濃度を表4に示す。各製剤の試料をCZバイアルに保存し、40℃でインキュベートした。28日間の保存の後、グルカゴンペプチドの化学的安定性をRP-HPLCにより評価し、純度を表4に報告した。この例は、添加されたイオン化安定化賦形剤のプロトン供与能(すなわちその「強さ」)が治療用分子を安定化させるのに要求される濃度に影響を与え得ることを証明する。グルカゴンは、分子が十分にプロトン化されていない場合にゲル化する(すなわち、不溶性凝集物を形成する)傾向があるため、モデルペプチドとして選択した。2mMまでの濃度のグリシン塩酸塩は、溶液中の不溶性凝集物の形成を防止するには不十分であったが、この濃度の塩酸ベタインおよび塩酸の両方は、40℃で28日間保存した後の不溶性凝集物の形成を防ぐのに十分であった。
以下の例は、添加した製剤成分(例えば、不活性剤、賦形剤)の存在下で本発明の方法に従って調製されたグルカゴン溶液の安定性を実証する。(1N HClのストック溶液からの)約3.2mMの添加HClを含有するDMSO中にグルカゴン粉末(Bachem AG, Product no. 4074733)を5mg/mLの濃度に溶解することにより試料溶液を調製した。これらの溶液に、種々の濃度の水分、ならびに5.5%(w/v)マンニトール(CAS No. 69-65-8)、および1%(v/v)ベンジルアルコール(CAS No. 100-51-6)を添加した。検査した実験試料を表5に列挙する。
以下の例は、製剤を安定化するのに要求されるイオン化安定化賦形剤の量に対するペプチド濃度の影響を実証する。
以下の例は、イオン化安定化賦形剤として硝酸、硫酸、リン酸、またはクエン酸を用いる本発明の方法にしたがって調製されたグルカゴン溶液の安定性を実証する。
5mMグリシン塩酸塩(CAS No. 6000-43-7)または5mMクエン酸無水物(CAS No. 77-92-9)の存在下でDMSO中に、プラムリンチドアセテート粉末(分子量=3949.4; CAS No. 196078-30-5; ChemPep、Inc., Wellington, FL)を溶解させることにより、アミリン類似体のプラムリンチドの製剤を1mg/mLの濃度で調製した。比較のため、酢酸プラムリンチド粉末を、同じ濃度で(ただし、賦形剤を添加せずに)DMSOに直接的に溶解した。各製剤の試料をCZバイアルに保存し、40℃でインキュベートした。研究期間中、試料溶液は透明であり(すなわち、不溶性凝集物がなく)、無色のままであった。14日間および28日間の保存の後、ペプチドの化学的安定性を、実施例1に記載の方法にしたがってRP-HPLCによって評価した。表11に示すように、5mMグリシンHClおよび5mMクエン酸の両方を含むことにより、プラムリンチドおよびDMSOのみを含む溶液と比較して、増加された安定性が供された。
プラムリンチドアセテート粉末をDMSOに(1mg/mLの濃度まで)溶解し、それに0.00001M(0.01mM)〜0.1M(100mM)の範囲の異なる濃度の塩酸を添加することにより、アミリン類似体のプラムリンチドの製剤を調製した。DMSO溶液中に100mMおよび10mMのHClを調製するために5NのHClを使用し、DMSO溶液中に1mM、0.1mM、および0.01mMのHClを調製するために1NのHClを使用した。一例として、DMSO溶液中の100mMのHClについて、10μLNの1N HClを9.99mLのDMSOに添加した。各製剤の試料をCZバイアルに保存し、40℃でインキュベートした。31日間の保存の後、ペプチドの化学的安定性を、実施例1に記載の方法に従ってRP-HPLCにより評価した。研究期間中、試料溶液は透明であり(すなわち不溶性物質を含まず)、無色のままであった。しかしながら、表12に示されるように、特定量のHCl(DMSO中1mM HCl)の添加は、他の試料製剤と比較して化学的分解を最小にし、ペプチド安定性を増強させた。
DMSO中のプラムリンチドの溶液を安定化することができる添加HClの範囲をさらに検査するため、0.00032(0.32mM)〜0.00316M(3.16mM)の範囲でDMSO溶液に添加される異なる濃度の塩酸の存在下において、DMSO中にプラムリンチドアセテート粉末を溶解することにより、5mg/mLの濃度でアミリン類似体であるプラムリンチドの製剤を調製した。研究したHCl濃度を表13に示す。0.5mL容量の溶液を2mLのCZバイアルに保存し、温度を40℃に設定したインキュベーターに入れた。研究期間中、試料製剤は透明なままであり(すなわち、不溶性物質がなく)、無色のままであった。31日間の保存の後の製剤中のペプチドの安定性(実施例1に記載の方法に従ってRP-HPLCにより評価)を以下の表13に示す。
所定のペプチドを安定化するのに必要なイオン化安定化賦形剤の濃度は、ペプチドのアミノ酸配列および溶液中のペプチドの濃度の両方を含む、様々な製剤パラメータに依存するであろう。本実施例では、DMSO中の酢酸プラムリンチドの溶液を、2つの異なる濃度:1mg/mLおよび5mg/mLで調製した。溶液に添加したイオン化安定化賦形剤は、HCl水溶液(5Nおよび1N濃度)であり、左側のカラムに特定される最終添加HCl濃度を得た。次に、サンプルを40℃で1ヶ月間、保存した。表14に示されているように、実施例1に記載の方法に従ってRP-HPLCにより評価したプラムリンチド分子の安定性は、薬物濃度を5倍に増加させると、分子を安定化するのに必要な添加HClの濃度のほぼ対応する増加を必要とすることを示す。これは、1mg/mLのプラムリンチド溶液は、1.00mMのHCl(または0.56mMと1.78mMの間のHCl)で最大の安定性を示したが、5mg/mLの溶液は、およそ3.16mMおよび5.62mMのHClで最大の安定性を示したからである。
*1mg/mLのプラムリンチド濃度の溶液については、HCl濃度が1.78mMから3.16mMに増加するにつれて製剤の安定性が低下したので、試料は5.62mMおよび10.0mMのHCl濃度で調製しなかった。
この例では、インスリン(組換えヒト)粉末(CAS No. 11061-68-0)をDMSO中に3.5mg/mLの濃度で溶解した。インスリン粉末の溶解の後、異なる濃度の塩酸を試料溶液に添加した。添加されたHClの濃度は0.010M(10mM)〜0.00032M(0.32mM)の範囲であった。研究したHCl濃度を表15に示す。試料インスリン溶液の0.5mLアリコートを2-mLのCZバイアルに保存し、温度を40℃に設定したインキュベーターに入れた。貯蔵後の溶液の目視観察は、それらがインキュベーション期間を通して透明で(すなわち、不溶性物質がない)、無色のままであることを明らかにした。製剤中のペプチドの化学的安定性を、14日間の保存後に実施例1に記載の方法に従ってRP-HPLCにより評価し、その結果(ペプチド純度として示す)を以下の表15に示す。
以下の例は、共製剤(同時処方物)の調製への本発明の適用性を実証する。インスリン(組換えヒト)粉末(CAS No. 11061-68-0)を、異なる濃度の塩酸が添加されているDMSO(ニート)中に3.5mg/mLの最終濃度まで溶解した。表16に示すように、HClの添加濃度は0.010M(10mM)〜0.00032M(0.32mM)の範囲であった。次にこれらの溶液に酢酸プラムリンチド粉末(CAS No. 196078-30-5)を1.0 mg/mLの濃度まで添加した。したがって、試料溶液のそれぞれは、特定濃度の添加HClを含むDMSOに溶解された3.5mg/mLのインスリン粉末および1.0mg/mLのプラムリンチド粉末を含んでいる。試料の共処方溶液の0.5mLアリコートを2-mLのCZバイアルに入れ、室温(22〜23℃)で保存した。製剤中のペプチドの安定性を、52日間の保存の後に(実施例1に記載の方法にしたがって)RP-HPLCにより評価し、その結果を表16に示す。単一のAPIを含む製剤に関する先の例のように、共処方物もまた、両方のペプチドに最適の安定性を提供する添加HCl濃度を示す。
以下の例は、小分子の安定な製剤の調製への本発明の適用性を実証する。(酒石酸水素塩由来の)エピネフリン粉末(CAS No. 51-42-3)を、(1Nストック溶液からの)異なる濃度の塩酸が添加されているDMSO(ニート)に10mg/mL(およそ55mM)のAPI濃度まで溶解した。HClの添加濃度は、表17に示すように、1mM〜100mMの範囲であった。エピネフリン溶液の0.5mLアリコートを2-mL(タイプ1)ガラスバイアルに保存し、温度40℃および相対湿度75%の安定チャンバに入れた。これらの試料は周囲環境で調製し、周囲雰囲気下でFluroTec(登録商標)でコーティングされたゴムストッパーで密封したバイアルに保存した(試料は不活性ガス(窒素、アルゴン)の下でも充填され得ることに留意されたい)。
以下の例は、不活性雰囲気下で試料バイアルを密封することと合わせた小分子の安定な製剤の調製への本発明の適用性を実証する。(重酒石酸塩由来の)エピネフリン粉末(CAS No. 51-42-3)を、(1Nストック溶液からの)異なる濃度の塩酸が添加されているDMSO(ニート)中に10mg/mL(約55mM)の最終API濃度まで溶解した。HClの添加濃度は、表18に示すように、1mM〜100mMの範囲であった。エピネフリン溶液の0.5mLアリコートを2-mL(タイプ1)ガラスバイアルに保存し、温度40℃および相対湿度75%の安定チャンバに入れた。これらの試料は周囲環境で調製したが、不活性ガス(アルゴン)下で密封した。これは、エピネフリンは酸化的分解反応に感受性であることがよく知られているからである。
以下の例は、小分子の安定な製剤の調製への本発明の適用性を実証する。(酒石酸水素塩由来の)エピネフリン粉末(CAS No. 51-42-3)を、(1Nストック溶液からの)異なる濃度の塩酸が添加されているDMSO(ニート)中にAPI濃度3mg/mL(およそ16mM)まで溶解した。HClの添加した濃度は、表19に示すように、0mM〜25mMの範囲であった。エピネフリン溶液の0.5mLアリコートを2-mL(タイプ1)ガラスバイアルに保存し、温度40℃および相対湿度75%の安定性チャンバに入れた。これらの試料を周囲環境で調製し、周囲雰囲気下でバイアル中に封入した(試料は不活性ガス(例えば、窒素、アルゴン)下に充填することもできることに留意のこと)。
Claims (20)
- 安定な製剤であって、
(a)グルカゴンペプチドまたはその塩と、
(b)イオン化安定化賦形剤と、
(c)非プロトン性極性溶媒と、
を含み、(i)前記グルカゴンペプチドまたはその塩が、前記非プロトン性溶媒に約0.1mg/mLから前記グルカゴンペプチドまたはその塩の溶解限度までの量で溶解され、かつ、(ii)前記イオン化安定化賦形剤が、前記グルカゴンペプチドまたはその塩のイオン化を安定化させる量で前記非プロトン性溶媒に溶解されている、製剤。 - 前記イオン化安定化賦形剤が、0.1mM〜100mM未満の濃度である、請求項1に記載の製剤。
- 前記イオン化安定化賦形剤が、鉱酸である、請求項1に記載の製剤。
- 前記鉱酸が、塩酸、硫酸、または硝酸から選択される、請求項3に記載の製剤。
- 前記非プロトン性溶媒がDMSOである、請求項1に記載の製剤。
- 前記非プロトン性溶媒が脱酸素化非プロトン性溶媒である、請求項1に記載の製剤。
- 前記脱酸素化非プロトン性溶媒が脱酸素化DMSOである、請求項6に記載の製剤。
- 前記イオン化安定化賦形剤が硫酸であり、前記非プロトン性溶媒がDMSOである、請求項1に記載の製剤。
- 含水量が10、5、または3%未満である、請求項1に記載の製剤。
- 10、5、または3%(w/v)未満の保存料をさらに含む、請求項1に記載の製剤。
- 前記保存料がベンジルアルコールである、請求項10に記載の製剤。
- 10、5、または3%(w/v)未満の二糖をさらに含む、請求項1に記載の製剤。
- 前記二糖がトレハロースである、請求項12に記載の製剤。
- 有効量の請求項1に記載の製剤をそれを必要とする対象に投与することにより低血糖症を治療する方法。
- 前記投与が、非経口注射によるものである、請求項14に記載の方法。
- 前記注射が皮内注射である、請求項15に記載の方法。
- グルカゴンペプチドを安定に製剤化する方法であって、
(a)非プロトン性極性溶媒系中のグルカゴンペプチドまたはその塩についての適切なイオン化プロファイルを決定する段階と、
(b)段階(a)で決定されたイオン化プロファイルを確立するために少なくとも1つのイオン化安定化賦形剤の適切な濃度を供するために、少なくとも1つのイオン化安定化賦形剤を非プロトン性溶媒と混合する段階と、
(c)室温で少なくとも1年間、グルカゴンペプチドまたはその塩を物理的および化学的に安定化させるために、グルカゴンペプチドまたはその塩を、適切なイオン化安定化賦形剤濃度を有する非プロトン性溶媒に溶解する段階と、
を含む方法。 - 前記イオン化安定化賦形剤が、塩酸、硝酸、硫酸、またはそれらの組み合わせである、請求項17に記載の方法。
- 前記イオン化安定化賦形剤濃度が0.1mM〜100mMである、請求項17に記載の方法。
- 前記非プロトン性溶媒がDMSOである、請求項17に記載の方法。
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BR112018005800A2 (pt) | 2018-10-16 |
JP6835831B2 (ja) | 2021-02-24 |
EA201890704A1 (ru) | 2018-10-31 |
CN108135980A (zh) | 2018-06-08 |
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CN108135980B (zh) | 2022-11-04 |
MX2018003705A (es) | 2018-06-06 |
EP4327804A2 (en) | 2024-02-28 |
KR20180054847A (ko) | 2018-05-24 |
CN115531523A (zh) | 2022-12-30 |
HK1250644A1 (zh) | 2019-01-11 |
US10485850B2 (en) | 2019-11-26 |
EP3352780A1 (en) | 2018-08-01 |
US20200215162A1 (en) | 2020-07-09 |
IL258298B (en) | 2021-06-30 |
DK3352780T3 (da) | 2024-02-19 |
ZA201904146B (en) | 2021-01-27 |
US20170312341A1 (en) | 2017-11-02 |
AU2016326749B2 (en) | 2022-06-16 |
US9649364B2 (en) | 2017-05-16 |
IL258298A (en) | 2018-05-31 |
KR20240056643A (ko) | 2024-04-30 |
AU2016326749A1 (en) | 2018-04-12 |
EP3352780B1 (en) | 2023-12-27 |
SA518391187B1 (ar) | 2022-12-19 |
CA3204984A1 (en) | 2017-03-30 |
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US20170087215A1 (en) | 2017-03-30 |
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