JP2022120156A - (S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミドの固体形態及び製剤 - Google Patents
(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミドの固体形態及び製剤 Download PDFInfo
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Abstract
Description
本出願は、2015年7月2日に提出された米国仮出願第62/188,468号、及び2015年12月28日に提出された米国仮出願第62/271,708号の利益を主張する国際出願である。尚、これら文献の各々は、その全体を参照により本明細書に組み込むものとする。
一部の実施形態では、本発明は、(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミドの結晶形態Iに関する。他の実施形態では、本発明は、胃酸抑制薬の作用を解消する医薬組成物をはじめとする、形態Iを含む医薬組成物、及びこれらの医薬組成物を被験者に投与することによって、癌又はその他の疾患を治療するための方法に関する。一部の実施形態では、本発明は、(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミドの結晶塩に関する。他の実施形態では、本発明は、胃酸抑制薬の作用を解消する医薬組成物をはじめとする、(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミドの結晶塩を含む医薬組成物、及びこれらの医薬組成物を被験者に投与することによって、癌又はその他の疾患を治療するための方法に関する。
ブルトン型チロシンキナーゼ(BTK)は、B細胞及び骨髄細胞で発現されるTecファミリー非受容体タンパク質キナーゼである。BTKは、プレスクトリン相同(PH)ドメイン、Tec相同(TH)ドメイン、Src相同3(SH3)ドメイン、Src相同2(SH2)ドメイン、及びチロシンキナーゼ又はSrc相同1(TK又はSH1)ドメインから構成される。成熟B細胞中のB細胞受容体(BCR)及び肥満細胞上のFCER1の結合によって活性化されるシグナル伝達経路中のBTKの機能は、十分に確立されている。ヒトのBTK中の機能性突然変異によって、プロB細胞期とプレB細胞期の間の遮断を伴うB細胞発生欠損を特徴とする原発性免疫不全症(X連鎖無ガンマグロブリン血症)が起こる。その結果、Bリンパ球がほぼ完全に存在しない状態となり、あらゆるクラスの血清イムノグロブリンの著しい減少を引き起こす。これらの知見は、自己免疫疾患の場合の自己抗体の産生の調節におけるBTKの重要な役割を支持するものである。
一実施形態では、本発明は、結晶性(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミド遊離塩基を含む組成物を提供する。
本発明の好ましい実施形態を本明細書に示し、説明するが、このような実施形態は、例としてのみ提供されるのであって、本発明の範囲を限定することを意図するものではない。本発明の実施に際して、記載される本発明の実施形態の様々な代替物が使用され得る。
別に定義されない限り、本明細書で使用される全ての技術及び科学用語は、本発明が属する技術分野の当業者により一般に理解されるものと同じ意味を有する。本明細書で参照される全ての特許及び刊行物は、その全体を本明細書に参照により組み込むものとする。
一実施形態では、本発明は、(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミド(式(1))の結晶固体形態を提供する。式(1)は、以下の化学構造を有する:
一実施形態では、本発明は、式(1)のBTK阻害剤の遊離塩基の結晶形態を含む医薬組成物を提供する。一実施形態では、本発明は、式(1)の遊離塩基の結晶性溶媒和物を含む医薬組成物を提供する。一実施形態では、本発明は、式(1)のBTK阻害剤の遊離塩基の結晶性水和物を含む医薬組成物を提供する。一実施形態では、本発明は、式(1)の結晶塩を含む医薬組成物を提供する。一実施形態では、本発明は、式(1)の遊離塩基の形態Iを含む医薬組成物を提供する。
投与される式(1)のBTK阻害剤の固体形態又は式(1)の遊離塩基の形態Iの量は、治療対象の哺乳動物、障害又は病状の重症度、投与速度、化合物の体内動態及び処方医師の判断に応じて変動し得る。しかし、有効投与量は、単回又は分割用量で、約0.001~約100mg/体重kg/日の範囲、例えば、約1~約35mg/kg/日である。70kgのヒトの場合、これは、約0.05~7g/日、例えば約0.05~2.5g/日の量となる。いくつかの事例では、前述の範囲の下限を下回る投与量が、適切な量を超える場合もあれば、別の事例では、例えば、より多量の用量を、終日投与のために複数の小用量に分割することによって、有害な副作用を引き起こすことなく使用される場合もある。
本明細書に記載される組成物及び方法を用いて、胃酸抑制薬の作用を解消することができる。胃酸抑制薬は、哺乳動物における弱酸性薬物(例えば、式(1)の遊離塩基)の曝露を大幅に制限することができる。Smelick, et al., Mol. Pharmaceutics 2013, 10, 4055-4065。胃酸抑制薬は、プロトンポンプ阻害剤、例えば、オメプラゾール、エソメプラゾール、ランソプラゾール、デキスランプラゾール、パントプラゾール、ラベプラゾール、及びイラプラゾールなど;H2受容体アンタゴニスト、例えば、シメチジン、ラニチジン、及びファモチジンなど;並びに制酸剤、例えば、重炭酸塩、炭酸塩、及びアルミニウム、カルシウム、マグネシウム、カリウム、及びナトリウムの水酸化物、並びに制酸剤と胃液分泌機構をターゲッティングする薬剤との混合物が挙げられる。胃酸抑制薬の影響の解消は、癌、炎症性疾患、免疫疾患、及び自己免疫疾患の患者が、一般に、その病状に伴うことが多い胃刺激症状のために胃酸抑制薬を同時投与されることから、そうした患者の治療において重要な課題である。胃酸抑制薬は、北米及び西欧において最も一般的に処方される。最近承認された経口癌治療薬は、pH依存性溶解度を有するため、胃酸抑制薬と薬物同士の相互作用を招き得る。癌患者の場合、全患者の20~33%が、何らかの形態の胃酸抑制薬を使用していると推定される。膵臓癌又は消化器癌などの特定の癌の場合、胃酸抑制薬の使用は、患者の60~80%と高い。Smelick, et al., Mol. Pharmaceutics 2013, 10, 4055-4062。
本明細書に記載される医薬組成物は、疾患を治療する方法に使用することができる。好ましい実施形態では、これらは、過剰増殖性疾患の治療に使用される。これらの組成物は、本明細書及び以下のパラグラフに記載されるような他の疾患を治療するのにも使用され得る。
実施例1.1.形態I結晶性無水物の調製
非晶質(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミドを入力として用いて、結晶化試験を実施した。このバッチの非晶質性は、PXRDによって確認した。冷却結晶化実験の場合、25mgの非晶質式(1)を300μLの溶媒に溶解させ、5℃/時間の速度で60℃に加熱し、その温度で1時間保持した後、同じ速度で5℃まで冷却した。スラリー実験の場合には、25mgの非晶質式(1)を150μLの溶媒に20℃で3日かけて懸濁させた。全ての固体をPXRD分析のために単離した。溶媒を真空下(200mバール)で蒸発させると、透明な溶液が得られた。結果を表1にまとめる。
以下:透過型PXRD(図1)、ラマン(図2)及びIR分光法(図3)、形態Iの溶解後の溶液NMR分光法、TG-FTIR、示差走査熱量測定(DSC)、半定量的溶解度試験、及び動的水蒸気吸収(Dynamic vapor sorption)(DVS:重力測定水蒸気吸収又はGVSとしても知られる)を含む様々な技術を用いて、メタノールの存在下のアセトンからの結晶化により生成した式(1)の遊離塩基の形態Iの特性決定を実施した(本明細書ではサンプルPP502-P1と呼ぶ)。
実施例2.1.形態II結晶性三水和物の調製
前述し、表1に記載する結晶化試験により、非常に限定された溶媒セットを用いて形態IIも得られた。
PXRD(図4)、光学顕微鏡検査、ラマン分光法(図5)、IR分光法、TG-FTIR、DSC、DVS、及び半定量溶解度試験を含む様々な技術を用いて、式(1)の遊離塩基の形態Iの特定決定を実施した。式IIに用いた方法の特性決定は、形態Iの特定決定について記載した通りに実施した。
実施例3.1.形態III結晶性二水和物の調製
形態I核を用いた種添加結晶化実験から形態(I)の遊離塩基の形態IIIを調製した。式(1)の飽和溶液は、60℃で調製した。溶液を冷却し、形態Iの種を添加した後、自発結晶化が起こった。結果を表4にまとめる。
34位置オートサンプラーを備えるMettler Toledo TGA/DSC1 STARe Systemを用いて、式(1)の遊離塩基の形態IIIの初期TGA、及びDSC特性決定を実施した。アルミニウムルツボ(40μL;有孔)を用いて、サンプルを調製した。典型的に、5~10mgのサンプルを予め計量したアルミニウムルツボに充填し、30℃で5分間維持した後、10℃/分で30℃から300℃まで加熱した。サンプルに対し、40mL/分の窒素パージを維持した。システム適合性チェックとして、インジウム及び亜鉛を参照として使用する。データ収集及び評価のために使用されるソフトウェアは、STARe Software v10.00 build 2480である。サーモグラムには補正を適用しない。形態IIIのさらなるDSC特性決定は、20℃/分の加熱速度及び開放パン構成を用いて、実施例1及び2に記載したように実施した。
約10%の典型的な含水率を有する三水和物である形態IIに加えて、形態IIのいくつかの他の誘導体も検査した。例えば、約20%相対湿度(RH)未満で形態IIを脱水させると、別の非溶媒和形態が得られる。この形態は、形態IVと称する。形態IVの特性決定を、PXRD及DSCなどの様々な技術を用いて実施したが、これらは、形態I及びIIの特性決定についてこれまで記載したように実施した。
非晶質(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミドは、米国特許出願公開第2014/0155385A1号及び国際特許出願公開番号:国際公開第2013/010868A1号の実施例6(その開示内容は、参照により本明細書に組み込む)に記載される手順をはじめとする、様々な方法によって調製することができる。ジクロロメタン中の溶液、又は共溶媒、例えば、アセトン若しくはアルコールとジクロロメタンの混合物中の溶液からの溶媒の高速蒸発を用いて、非晶形態を製造することができる。さらに、非晶形態は、遊離塩基形態Iを可溶化するために、少量の酸、例えば、ギ酸又は酢酸を含有する水溶液の凍結乾燥によって製造することもできる。
(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミド遊離塩基(サンプルPP502-P1、前述した通りに調製)についての塩スクリーニングは、以下:安息香酸、ベンゼンスルホン酸、クエン酸、フマル酸、塩酸、マレイン酸、ニコチン酸、リン酸、サッカリン、コハク酸、及びL-酒石酸をはじめとする、11の異なる酸を用いた結晶化実験を含んだ。これらのうち、クエン酸、フマル酸、マレイン酸、リン酸、コハク酸及びL-酒石酸を用いて、結晶性サンプルを取得した。
式(1)のフマル酸塩の結晶形態Aは、500mLのアセトンに16.294gのPP502-P1遊離塩基と4.065gのフマル酸を溶解させることにより調製した。続いて、混合物を50℃に加熱し、それにより50mLの水を添加した。水の添加により透明な溶液が得られ、この時点で、約300rpmで攪拌しながら、溶液を室温まで冷却させた。室温で、透明な溶液に約20mgのSP221-FUM-P5を種として添加し、約48時間後に、懸濁液を濾過して、固体を取得し、これを40℃で約24時間空気乾燥した。得られた固体の初期特性決定の結果、高性能液体クロマトグラフィー(HPLC)により測定して、純度約99.9%で、約13.6グラム(約64%)の収量が得られた。
結晶形態Aマレイン酸塩(サンプルSP221-MLE-P9)は、350mLのアセトンと35mLの水の混合物に16.296gのPP502-P1遊離塩基を溶解させることにより調製した。続いて、混合物を50℃に加熱し、それにより透明な溶液が得られた。その後、4.043gのマレイン酸を含有する20mLの水溶液を添加した。さらに、マレイン酸水溶液を保持する容器及びピペットを1.0mLの水で洗浄し、水溶液を混合物にも導入した。約300rpmで攪拌しながら、溶液を冷却させた。約45℃で、溶液に約20mgのSP221-MILE-8を種として添加した後、約20℃までさらに冷却させた。約24時間後、懸濁液を濾過して、固体を取得し、これを40℃で約20時間空気乾燥した。得られた固体の初期特性決定により、約14.1グラム(約66%)の収量が得られた。
式(1)のリン酸塩の結晶形態Aの調製は、次のようにして達成した。まず、350mLのアセトンと35mLの水を、16.2998グラム(35mmol)の式(1)遊離塩基PP502-P1に添加した。50℃に加熱すると、透明な溶液が得られた。この溶液に、2.5mLの85~90%リン酸(35mmol)をゆっくりと添加した。約300rpmで攪拌しながら、溶液を室温まで冷却させた。約38℃で、種添加なしで、結晶が観察された。約80時間後、懸濁液を濾過して、得られた固体を40℃で約24時間空気乾燥した。収量は、約20.48グラム(約97%)であった。リン酸塩は、微小な粒子として得られた。乾燥後、材料は塊状であり、極めて強度に凝集した粒子が観察された。タップ密度試験及び粒度分析のために、自由流動性粉末を取得する目的で、乾燥した材料を500μm篩で篩い分けた。乾燥後のサンプルをSP221-PO4-P5と称し、篩い分け後のサンプルは、SP221-PO4-P5aと称する。
式(1)L-酒石酸塩の結晶形態Aは、350mLのアセトンと35mLの水の混合物に16.298gのPP502-P1遊離塩基を溶解させることにより調製した。続いて、混合物を50℃に加熱し、それにより透明な溶液が得られた。次いで、この透明な溶液に、5.257gのL-酒石酸を含有する20mLの水溶液を添加した。約300rpmで攪拌しながら、溶液を約20℃まで冷却させた。約24時間後、懸濁液を濾過して、固体を取得し、これを40℃で約20時間空気乾燥した。得られた固体の初期特性決定の結果、HPLCにより測定して、純度約99.78%で、20.1グラム(約89%)の収量が得られた。
クエン酸は、分子式C6H8O7及び分子質量192.12g/molを有する。クエン酸中の3つのカルボン酸基のpKa値は、2.93、4.76及び6.40である。アセトン-水混合物からのクエン酸塩の結晶化によって、有意な量のアセトン及び幾分の水を含有するサンプルが得られたのに対し、1-プロパノールからの結晶化によって、多量の1-プロパノールを含有するサンプルが得られたが、これは、両方の相が、溶媒和物であり得ることを示している。
ゲンチジン酸は、2,5-ジヒドロキシ安息香酸、分子式C7H6O4、及び分子質量154.12g/molを有する。ゲンチジン酸のpKa値は、2.93である。まず、既述したスクリーンでゲンチジン酸塩を同定し(サンプルSP221-GEN-P1)、アセトン-水混合物からの結晶化により、アセトン半溶媒和物として再生した(SP221-GEN-P2)。アセトニトリル中のアセトン半溶媒和物の懸濁液平衡によって、残留有機溶媒を含有しない結晶性サンプルが得られた(サンプルSP221-GEN-P3)。TG-FTIRから、このサンプルが、約2.6%の水を含有することが判明した。この結果は、ゲンチジン酸一水和物の理論含水率2.8%と申し分なく一致した。
シュウ酸は、分子式C2H2O4を有し、分子質量が90.04g/molである。2つの酸基のpKa値は、1.27及び4.27である。まず、既述したスクリーンでシュウ酸を同定した。
式(1)の硫酸塩(サンプルSP221-SO4-P1)は、次のようにして調製した。アセトン-水中の式(1)遊離塩基の0.1M貯蔵液5.0mL(サンプルSL20150415FB、0.1M)に、濃縮硫酸の形態の1当量の硫酸(27.8μL)を添加し、これを50℃に加熱した後、室温まで冷却させた。結晶化が起こらなかったため、混合物に数mgの結晶性リン酸塩を種として添加した。室温で一晩攪拌した後、黄色/白色の懸濁液が得られ、この懸濁液から固体を濾過し、室温で空気乾燥した。
実施例7.1.遊離塩基の溶解度
pHに応じて式(1)遊離塩基の水溶解度を調べた。実験は、pH1、3、5、6.8、7.4、及び9のHCl水溶液及びバッファー溶液中で実施した。1及び3の低pHでは、平衡時間にわたって固体が完全に溶解し、当該系のpHは、いずれの実験においても約3に安定化することが判明した。約1のpHを有するHCl溶液中の溶解度は、少なくとも150mg/mLであることが判明した。3を超える様々なpH値での遊離塩基形態I(PP502-P1)の溶解度を表15に示す。
複数の試験を実施して、pHの関数としてのマレイン酸塩の水溶解度を決定した。pHが1、3、5、6.8、7.4及び9のHCl水溶液及びバッファー溶液中で実験を実施した。1及び3の低pHでは、平衡時間にわたって固体が完全に溶解し、当該系のpHは、いずれの実験においても約3で安定化することが判明した。同時に、純水中のフマル酸塩、マレイン酸塩、リン酸塩、及びL-酒石酸塩の水溶解度を示す。純水中のフマル酸塩、マレイン酸塩、リン酸塩、及びL-酒石酸塩の水溶解度を表16に記載するが、ここで、リン酸塩は、24時間後に最も高い全溶解度を示している。様々な水性媒体中のpHの関数としてのマレイン酸塩の溶解度データを表17に記載する。
式(1)遊離塩基I形態Iの最適化製造に向けた結晶化実験を実施した。結晶化実験のための出発材料は、再結晶化した式(1)形態Iであった。試験には、原油のサンプルからの遊離塩基の別の結晶化を追加した。結晶形態を調べるために、粉末X線回析(PXRD)又はラマン分光法を用いて、また、残留溶媒含量を調べるために、TG-FTIR若しくは1H NMR又はその両方により、得られた生成物を特性決定した。偏光顕微鏡画像を記録して、粒度を決定した。
様々な水-溶媒混合物及び非水性溶媒中で、再結晶化式(1)形態Iの溶解度を試験した。これらの及びその他の溶媒系について作成された完全な溶解度データを、以下の表19に表示する。
形態Iの結晶化の制御を証明するために、濁度計を備えるメトラー・トレドマルチマックス(Mettler-Toledo Multimax)結晶化過程最適化システムで準安定領域幅実験を実施した。
式(1)の遊離塩基の形態I及びIIについて、固有溶出速度(IDR)を測定した。パドルオーバー固定ディスクを備える溶出装置を用いてIDRを測定すると共に、標準に対する液体クロマトグラフィー分析を用いて、濃度を決定した。y切片で正規化した結果を、表示する傾き及び回帰係数と共に、図28に示す。形態Iは、人工胃液(SGF)(pH1.2)中で6.8mg/cm2/分のIDRを、またpH2.5のHCl/NaClバッファー中では0.44mg/cm2/分のIDRを有する。形態IIは、SGF中で5.4mg/cm2/分のIDRを、またpH2.5のHCl/NaClバッファー中では0.35mg/cm2/分のIDRを有する。従って、形態Iは、形態IIに対して、両方の条件で26%のIDR増加を示し、これは、有意に高い溶出速度をもたらし、有利である。
オメプラゾールなどの胃酸抑制薬は、既述した式(1)のpH溶解度プロフィールのために、哺乳動物における式(1)遊離塩基の曝露を制限し得る。このことは、癌、炎症性疾患、免疫疾患、及び自己免疫疾患の患者が、一般に、その病状に伴うことが多い胃刺激症状のために胃酸抑制薬を同時投与されることから、そうした患者の治療において重要な課題である。胃酸抑制薬は、北米及び西欧において最も一般的に処方される。最近承認された経口癌治療薬のうち、>50%がpH依存性溶解度を有するため、胃酸抑制薬と薬物同士の相互作用が起こり得る。癌患者の場合、全患者の20~33%が、何らかの形態の胃酸抑制薬を使用していると推定される。膵臓癌又は消化器癌などの特定の癌の場合、胃酸抑制薬の使用は、患者の60~80%と高い。Smelick, et al., Mol. Pharmaceutics 2013, 10, 4055-4062。
式(1)固体形態(塩及び遊離塩基形態I)の製剤を表20に示す通りに調製した。
式(1)遊離塩基の形態I及び形態IIの両方を、製剤F-2の製法及び組成(前述の通り)を用い、同様のパラメータの下で加工した。式(1)を上記成分とブレンドし、潤滑材を添加した後、個別の造粒ステップにて、トップフィードローラコンパクタでローラ圧縮した。次に、顆粒を潤滑化した。形態I及び形態IIから得られた顆粒をタップ密度及びゆるみ密度について特性決定した。形態II顆粒は、流動不良及び均質性不良に向かう一般的傾向を示した。
Claims (20)
- 結晶性(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミド遊離塩基を含む組成物。
- 前記結晶性(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミド遊離塩基が、6.4、8.6、10.5、11.6、及び15.7°2θ±0.2°2θにピークを含む透過型X線粉末回析パターンを特徴とする、請求項1に記載の組成物。
- 前記結晶性(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミド遊離塩基が、10.9、12.7、13.4、14.3、14.9、及び18.2°2θ±0.2°2θにピークをさらに含む透過型X線粉末回析パターンを特徴とする、請求項2に記載の組成物。
- 前記結晶性(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミド遊離塩基が、11.3、15.1、15.7、16.1、17.3、19.2、19.4、19.8、20.7、21.1、21.4、21.6、21.9、22.6、23.3、23.6、24.9、25.2、25.4、25.7、26.1、26.4、26.8、26.9、27.7、28.6、29.1、29.4、30.1、30.5、31.7、31.9、32.2、32.6、33.1、33.4、34.5、35.9、36.1、36.8、37.4、38.1、38.9、及び39.5°2θ±0.2°2θからなる群から選択される1つ又は複数のピークをさらに含む透過型X線粉末回析パターンを特徴とする、請求項2又は3のいずれか1項に記載の組成物。
- 前記結晶性(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミド遊離塩基が、図1に示す代表的なX線粉末回析パターンと実質的に同じ透過型X線粉末回析パターンを特徴とする、請求項1~4のいずれか1項に記載の組成物。
- 前記結晶性(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミド遊離塩基が、1620、1609、1547、1514及び1495cm-1±2cm-1にピークを含むラマンスペクトルを特徴とする、請求項1~5のいずれか1項に記載の組成物。
- 前記結晶性(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミド遊離塩基が、1680、1574、1454、1433、1351、1312、1255、1232、1187、1046、995、706、406、及び280cm-1±2cm-1からなる群から選択される1つ又は複数のピークをさらに含むラマンスペクトルを特徴とする、請求項6に記載の組成物。
- 前記結晶性(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミド遊離塩基が、図2に示す代表的なラマンスペクトルと実質的に同じラマンスペクトルを特徴とする請求項1~7のいずれか1項に記載の組成物。
- 前記結晶性(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミド遊離塩基が、1621、1608、1403、1303、及び764cm-1±4cm-1にピークを含む赤外(IR)スペクトルを特徴とする、請求項1~8のいずれか1項に記載の組成物。
- 前記結晶性(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミド遊離塩基が、3367、3089、2246、1682、1574、1514、1504、1454、1428、1345、1248、1194、1177、1149、1109、1049、1023、1003、947、900、858、842、816、734、729、701、689、665、623、及び612cm-1±4cm-1からなる群から選択される1つ又は複数のピークをさらに含むIRスペクトルを特徴とする、請求項9に記載の組成物。
- 前記結晶性(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミド遊離塩基が、図3に示す代表的なIRスペクトルと実質的に同じIRスペクトルを特徴とする、請求項1~10のいずれか1項に記載の組成物。
- 前記結晶性(S)-4-(8-アミノ-3-(1-(ブト-2-イノイル)ピロリジン-2-イル)イミダゾ[1,5-a]ピラジン-1-イル)-N-(ピリジン-2-イル)ベンザミド遊離塩基が、結晶構造中に水が存在しないことをさらに特徴とする、請求項2~11のいずれか1項に記載の組成物。
- 顆粒外在性(extragranular)酸味料をさらに含む、請求項1~12のいずれか1項に記載の組成物。
- 前記顆粒外在性酸味料が、フマル酸、コハク酸、D-酒石酸、L-酒石酸、ラセミ酒石酸、アスコルビン酸、イソアスコルビン酸(エリソルビン酸及びD-アラボアスコルビン酸としても知られる)、アルギン酸若しくはその塩、プロタシド(Protacid)F120NM、プロタシド(Protacid)AR1112(ケラシド(Kelacid)NFとしても知られる)、及びカルボポール(Carbopol)971P(カルボキシポリメチレン)、並びにこれらの組合せからなる群から選択される、請求項13に記載の組成物。
- 前記顆粒外在性酸味料が、約5重量%~約33重量%の濃度のアルギン酸、又はそのナトリウム若しくはカリウム塩である、請求項13に記載の組成物。
- 前記組成物が、少なくとも1種の薬学的に許容される賦形剤をさらに含む、請求項1~15のいずれか1項に記載の組成物。
- 過剰増殖性疾患を治療する方法であって、治療有効量の請求項16に記載の組成物を投与するステップを含み、ここで、前記過剰増殖性疾患が、以下:慢性リンパ球性白血病、非ホジキンリンパ腫、びまん性大細胞型B細胞リンパ腫、マントル細胞リンパ腫、濾胞性リンパ腫、B細胞リンパ増殖性疾患、B細胞急性リンパ芽球性白血病、ワルデンシュトレームマクログロブリン血症、バーキット白血病、ホジキン病、多発性骨髄腫、急性骨髄性白血病、若年性骨髄単球性白血病、有毛細胞白血病、肥満細胞性白血病、肥満細胞症、骨髄増殖性疾患(MPD)、骨髄増殖性腫瘍、真性赤血球増加症(PV)、本態性血小板血症(ET)、原発性骨髄線維症(PMF)、骨髄異形成症候群、慢性骨髄性白血病(BCR-ABL1陽性)、慢性好中球性白血病、慢性好酸球性白血病、原発性中枢神経系(CNS)リンパ腫、末梢神経系(PNS)の原発性多巣性リンパ腫、胸腺癌、脳腫瘍、神経膠芽腫、肺癌、扁平上皮癌、皮膚癌(例えば、黒色腫)、眼の癌、網膜芽細胞腫、眼内黒色腫、口腔及び口腔咽頭癌、膀胱癌、胃癌 (gastric cancer)、胃癌(stomach cancer)、膵臓癌、乳癌、子宮頸癌、頭部及び頸部癌、腎癌、腎臓癌、肝臓癌、卵巣癌、前立腺癌、大腸癌、骨癌(例えば、転移性骨癌)、食道癌、精巣癌、婦人科癌、甲状腺癌、類表皮癌、AIDS関連癌(例えば、リンパ腫)、ウイルス誘導性頸癌(ヒトパピローマウイルス(papillomavirus))、鼻咽頭癌(エプスタイン・バーウイルス(Epstein-Barr virus))、カポジ肉腫、原発性滲出性リンパ腫(カポジ肉腫ヘルペスウイルス(Kaposi’s sarcoma herpesvirus))、肝細胞癌(B型肝炎(hepatitis B)及びC型肝炎ウイルス(hepatitis C visuses))、T細胞白血病(ヒトT細胞白血病ウイルス-1(Human T-cell leukemia virus-1))、皮膚の良性過形成、再狭窄、良性前立腺肥大、腫瘍血管形成、慢性炎症性疾患、関節リウマチ、アテローム性動脈硬化、炎症性腸疾患、乾癬、湿疹、及び強皮症などの皮膚病、糖尿病、糖尿病性網膜症、未熟児網膜症、加齢黄斑変性、血管腫、潰瘍性大腸炎、アトピー性皮膚炎、回腸嚢炎、脊椎関節炎、ブドウ膜炎、ベーチェット病、リウマチ性多発筋痛症、巨細胞性動脈炎、サルコイドーシス、川崎病、若年性突発性関節炎、化膿性汗腺炎、シェーグレン症候群、乾癬性関節炎、若年性関節リウマチ、強直性脊椎炎、クローン病、狼瘡、並びにループス腎炎からなる群から選択される方法。
- 過剰増殖性疾患を治療する方法であって、治療有効量の請求項16に記載の組成物を投与するステップを含み、ここで、前記過剰増殖性疾患が、以下:慢性リンパ球性白血病、非ホジキンリンパ腫、びまん性大細胞型B細胞リンパ腫、マントル細胞リンパ腫、濾胞性リンパ腫、B細胞リンパ増殖性疾患、B細胞急性リンパ芽球性白血病、及びワルデンシュトレームマクログロブリン血症からなる群から選択される方法。
- 治療有効量の胃酸抑制薬を投与するステップをさらに含む、請求項17又は18のいずれか1項に記載の方法。
- 以下:
慢性リンパ球性白血病、非ホジキンリンパ腫、びまん性大細胞型B細胞リンパ腫、マントル細胞リンパ腫、濾胞性リンパ腫、B細胞リンパ増殖性疾患、B細胞急性リンパ芽球性白血病、ワルデンシュトレームマクログロブリン血症、バーキット白血病、ホジキン病、多発性骨髄腫、急性骨髄性白血病、若年性骨髄単球性白血病、有毛細胞白血病、肥満細胞性白血病、肥満細胞症、骨髄増殖性疾患(MPD)、骨髄増殖性腫瘍、真性赤血球増加症(PV)、本態性血小板血症(ET)、原発性骨髄線維症(PMF)、骨髄異形成症候群、慢性骨髄性白血病(BCR-ABL1陽性)、慢性好中球性白血病、慢性好酸球性白血病、原発性中枢神経系(CNS)リンパ腫、末梢神経系(PNS)の原発性多巣性リンパ腫、胸腺癌、脳腫瘍、神経膠芽腫、肺癌、扁平上皮癌、皮膚癌(例えば、黒色腫)、眼の癌、網膜芽細胞腫、眼内黒色腫、口腔及び口腔咽頭癌、膀胱癌、胃癌、胃癌、膵臓癌、乳癌、子宮頸癌、頭部及び頸部癌、腎癌、腎臓癌、肝臓癌、卵巣癌、前立腺癌、大腸癌、骨癌(例えば、転移性骨癌)、食道癌、精巣癌、婦人科癌、甲状腺癌、類表皮癌、AIDS関連癌(例えば、リンパ腫)、ウイルス誘導性頸癌(ヒトパピローマウイルス(papillomavirus))、鼻咽頭癌(エプスタイン・バーウイルス(Epstein-Barr virus))、カポジ肉腫、原発性滲出性リンパ腫(カポジ肉腫ヘルペスウイルス(Kaposi’s sarcoma herpesvirus))、肝細胞癌(B型肝炎(hepatitis B)及びC型肝炎ウイルス(hepatitis C visuses))、T細胞白血病(ヒトT細胞白血病ウイルス-1(Human T-cell leukemia virus-1))、皮膚の良性過形成、再狭窄、良性前立腺肥大、腫瘍血管形成、慢性炎症性疾患、関節リウマチ、アテローム性動脈硬化、炎症性腸疾患、乾癬、湿疹、及び強皮症などの皮膚病、糖尿病、糖尿病性網膜症、未熟児網膜症、加齢黄斑変性、血管腫、潰瘍性大腸炎、アトピー性皮膚炎、回腸嚢炎、脊椎関節炎、ブドウ膜炎、ベーチェット病、リウマチ性多発筋痛症、巨細胞性動脈炎、サルコイドーシス、川崎病、若年性突発性関節炎、化膿性汗腺炎、シェーグレン症候群、乾癬性関節炎、若年性関節リウマチ、強直性脊椎炎、クローン病、狼瘡、並びにループス腎炎からなる群から選択される過剰増殖性疾患の治療に使用するための請求項16に記載の組成物。
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