JP6334700B2 - Jak1阻害剤のための徐放性剤形 - Google Patents
Jak1阻害剤のための徐放性剤形 Download PDFInfo
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- JP6334700B2 JP6334700B2 JP2016533398A JP2016533398A JP6334700B2 JP 6334700 B2 JP6334700 B2 JP 6334700B2 JP 2016533398 A JP2016533398 A JP 2016533398A JP 2016533398 A JP2016533398 A JP 2016533398A JP 6334700 B2 JP6334700 B2 JP 6334700B2
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- isonicotinoyl
- pyrrolo
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- pyrazol
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- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
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- BICRTLVBTLFLRD-PTWUADNWSA-N voclosporin Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C=C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O BICRTLVBTLFLRD-PTWUADNWSA-N 0.000 description 1
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Description
癌におけるJAK/STATの活性化は、サイトカイン(例えば、IL−6またはGM−CSF)による刺激によって、またはSOCS(抑制因子またはサイトカインのシグナル伝達)またはPIAS(活性化STATのタンパク質阻害因子)などのJAKシグナル伝達の内在性抑制因子が減少することによって起こり得る(非特許文献3)。STATシグナル伝達、並びにJAKのその他の下流経路(例えばAkt)の活性化は、多くの癌型における予後不良に相関しているとされてきた(非特許文献4)。JAK/STATを通してシグナル伝達する循環サイトカインのレベルの上昇は、悪液質及び/または慢性疲労に因果的役割を担う。従って、JAK阻害は、潜在的な抗腫瘍活性以外にも及ぶために、癌患者にとって有益であり得る。
本出願は、自己免疫疾患、癌、骨髄増殖性疾患、炎症性疾患、骨吸収疾患、または臓器移植の拒絶反応の処置をそれを必要とする患者において行う方法であって、前記患者に本明細書に記載の1つまたは複数の徐放性剤形を経口投与することを含む、前記方法をさらに提供する。
例えば、化学療法剤、抗炎症剤、ステロイド、免疫抑制剤など、ならびに、例えば、その全体において参照により本明細書に組み込まれるWO2006/056399に記載されるものなどのBcr−Abl、Flt−3、RAF、及びFAKキナーゼ阻害剤、または他の薬剤などの1つまたは複数の追加の医薬品を、JAK関連疾患、障害、または状態の処置のために、本発明に記載の剤形と組み合わせて使用することができる。1つまたは複数の追加の医薬品は、患者に、同時にまたは連続して投与することができる。
徐放性錠剤を、以下の表に示す量である賦形剤と調製した。プロトコルAをSR1錠剤について用い、プロトコルBをSR2錠剤について用い、プロトコルCをSR3錠剤及び25mg SR錠剤について用い、プロトコルDをSR4錠剤について用いた。
ステップ1.式Iの化合物のアジピン酸塩、結晶セルロース、ヒプロメロース(Methocel K100 LV及びMethocel K4M)、及びラクトース一水和物を個別にスクリーニングする。
ステップ2.ステップ1で得たスクリーニングした物質を好適なブレンダーに移し、混合する。
ステップ3.ステップ2で得た混合物を好適な造粒機に移し、混合する。
ステップ4.混合中に精製水を加える。
ステップ5.ステップ4で得た顆粒を好適な乾燥機内へと移し、LODが3%未満になるまで乾燥する。
ステップ6.ステップ5で得た顆粒をスクリーニングする。
ステップ7.スクリーニングされたステアリン酸マグネシウムとステップ6の顆粒を好適なブレンダーにて混合する。
ステップ8.ステップ7の最終混合物を好適な回転式錠剤圧縮機上で圧縮する。
ステップ1.式Iの化合物のアジピン酸塩、結晶セルロース、ヒプロメロース及びα化澱粉を個別にスクリーニングする。
ステップ2.ステップ1で得たスクリーニングした物質を好適なブレンダーに移し、混合する。
ステップ3.ステップ2で得た混合物を好適な造粒機に移し、混合する。
ステップ4.混合中に精製水を加える。
ステップ5.ステップ4で得た顆粒を好適な乾燥機内へと移し、LODが3%未満になるまで乾燥する。
ステップ6.ステップ5で得た顆粒をスクリーニングする。
ステップ7.ポリオクス、ブチルヒドロキシトルエン及びコロイド状二酸化ケイ素を個別にスクリーニングした。
ステップ8.ステップ6で得た顆粒及びステップ7で得た物質を好適なブレンダーに移し、混合する。
ステップ9.スクリーニングしたステアリン酸マグネシウムをステップ8の物質に加え、ブレンドを継続する。
ステップ10.ステップ9の最終混合物を好適な回転式錠剤圧縮機上で圧縮する。
ステップ1.ラクトース一水和物、式Iの化合物のアジピン酸塩、結晶セルロース及びヒプロメロースを好適なふるいを通して個別にスクリーニングする。
ステップ2.ステップ1で得たスクリーニングした物質を好適なブレンダーに移し、混合する。
ステップ3.ステップ2で得た混合物を好適な造粒機に移し、混合する。
ステップ4.混合中に精製水を加える。
ステップ5.湿潤顆粒を好適なふるいを通してスクリーニングする。
ステップ6.ステップ5で得た顆粒を好適な乾燥機内へと移し、LODが3%未満になるまで乾燥する。
ステップ7.ステップ6で得た顆粒を粉砕する。
ステップ8.スクリーニングしたステアリン酸マグネシウムとステップ7の顆粒を好適なブレンダーにて混合する。
ステップ9.ステップ8の最終混合物を好適な回転式錠剤圧縮機上で圧縮する。
ステップ1.α化澱粉、式Iの化合物のアジピン酸塩、ヒプロメロース、及び必要な結晶セルロースの一部を好適なふるいを通して個別にスクリーニングする。
ステップ2.ステップ1で得たスクリーニングした物質を好適なブレンダーに移し、混合する。
ステップ3.ステップ2で得た混合物を好適な造粒機に移し、混合する。
ステップ4.混合中に精製水を加える。
ステップ5.湿潤顆粒を好適なふるいを通してスクリーニングする。
ステップ6.ステップ5で得た顆粒を好適な乾燥機内へと移し、LODが3%未満になるまで乾燥する。
ステップ7.ステップ6で得た顆粒を粉砕する。
ステップ8.結晶セルロースの残りの部分及び重炭酸ナトリウムの半分をスクリーニングする。
ステップ9.ステップ7で得た粉砕した顆粒及びステップ8で得たスクリーニングされた物質を好適なブレンダーに移し、混合する。
ステップ10.重炭酸ナトリウムの残りの部分をスクリーニングし、ステップ9の混合物と混合する。
ステップ11.ステアリン酸マグネシウムをスクリーニングし、ステップ10の混合物と混合する。
ステップ12.ステップ11の最終混合物を好適な回転式錠剤圧縮機上で圧縮する。
実施例3の試験にて使用されるIR製剤を、下記のプロトコルEに従い下記の表に示す組成を有する50mgカプセルとして調製した。
ステップ1.必要量の式Iの化合物のアジピン酸塩及びおおよそ等量のケイ化結晶セルロース(SMCC)を予混合する。
ステップ2.ステップ1の混合物を好適なふるい(例えば40メッシュ)に通す。
ステップ3.残りのSMCCをステップ2で使用したものと同一のスクリーンを通してスクリーニングする。
ステップ4.ステップ3で得たスクリーニングしたSMCCを、ステップ2で得た混合物と一緒に好適なブレンダーにて(例えばTurbulaブレンダー)おおよそ5分間混合する。
ステップ5.所望の充填重量まで該混合物をカプセルに充填する。
合計72人の健常成人対象が6つのコホートに登録され(1コホート当たり12対象)、ランダム化スケジュールに従い各コホート内で処置シーケンスに無作為化された。全ての処置は式Iの化合物の単回用量投与とした。処置期間と処置期間の間に7日間の休薬期間を設けた。
処置A:式Iの化合物の300mg(6×50mgカプセル)IR製剤を少なくとも10時間の一晩絶食後に経口投与した。
処置B:式Iの化合物の300mg(3×100mg錠剤)SR製剤を少なくとも10時間の一晩絶食後に経口投与した。
処置C:式Iの化合物の300mg(3×100mg錠剤)SR製剤を高脂肪食後に経口投与した。
処置A:300mg(式Iの化合物の3×100mg錠剤)SR3を少なくとも10時間の一晩絶食後に経口投与した。
処置B:300mg(式Iの化合物の3×100mg錠剤)SR3を中脂肪食後に経口投与した。
処置A:50mg(式Iの化合物の2×25mg錠剤(実施例1からの25mg SR錠剤))を少なくとも10時間の一晩絶食後に経口投与した。
処置B:50mg(式Iの化合物の2×25mg錠剤(実施例1からの25mg SR錠剤))を高脂肪食後に経口投与した。
処置C:100mg(1×100mg錠剤)SR3を少なくとも10時間の一晩絶食後に経口投与した。
中央値(90%信頼区間)が報告されるTmaxを除き、PKパラメータ値は平均±SD及び幾何平均である。
i)統計学的比較は用量標準化された。
中央値(90%信頼区間)が報告されるTmaxを除き、PKパラメータ値は平均±SD及び幾何平均である。
i)統計学的比較は用量標準化された。
試験の最初の28日間は、試験の第2部である3か月間の用量選択を導く、前向き用量を選択するために実施した。試験の第2部は、処置は84日間で、無作為化、二重盲検、プラセボ対照(治験依頼者非盲検)であった。第1部と同一の集団を用いて60人の対象を無作為化した:単一コホート、5つの並行処置群、各12対象:100mg SR3錠剤1日2回;300mg(3×100mg SR3錠剤)1日1回;200mg(2×100mg SR3錠剤)1日2回;600mg(6×100mg SR3錠剤)1日1回;及びプラセボ。中間データをACR(American College of Rheumatology)2013に提出した(84日間を終了したn=40対象)。3か月でのACRスコアを表6に示す。600mg 1日1回についてのACRスコアは、RAの処置に承認された他のJAK阻害剤と比較して前例がない。例えば、トファシチニブクエン酸塩(5mg 1日2回)について承認された製品は、3か月ではるかに低いACRスコアを示した:59%(ACR20)、31%(ACR50)、及び15%(ACR70)(表5のXELJANZ(登録商標)−トファシチニブクエン酸塩錠−標識)。
二重盲検(治験依頼者非盲検)、無作為化、プラセボ対照試験を28日間にわたって処置されたおおよそ48対象にて実施した。資格要件には以下を含む:スクリーニング時に少なくとも6カ月間活性な斑状乾癬;体表面積(BSA)の5%以上の斑状乾癬;5以上の乾癬の面積及び重症度指標(PASI)スコア;3以上の医師による静的総合評価指標(sPGA)スコア;局所療法に対する不十分な反応;保守的な安全性評価を伴う、用量間の急速な増加を可能にする革新的な設計。100mg 1日1回から200mg 1日1回、そこから200mg 1日2回へと、そこから600mg 1日1回へと漸増する各12対象(9活性剤及び3PBO)の4つの互い違いの用量群。一度4番目の対象(3活性剤1PBOの組)が28日間の投与をグレード3またはより高い有害事象なしに完了すると、12対象の次の群が次に高い用量で処置を開始した;この群の最初の4対象が28日間処置される間に、第1群を中程度から重度の乾癬を有する60対象とし、無作為化した。5つの処置群とした:プラセボ、100mg 1日1回、200mg 1日1回、200mg 1日2回及び600mg 1日1回。最低用量から最高用量まで増加し、それぞれ前の用量の最初の4対象が28日間完了した後である、順次漸増法を使用した、28日目での結果を表8に示す(PASI50は乾癬の面積及び重症度指標である)。600mg 1日1回用量について81.8%のこれらのPASI50スコアは、乾癬の処置のために開発中の他のJAK阻害剤と比較して前例がない。例えば、5mgトファシチニブ(タソシチニブとしても知られる)は、12週目で65.3%とより低いPASI50スコアを示した(http://press.pfizer.comに2010年10月7日に公開)。5mgトファシチニブ用量は、米国において安全性の理由のためにRA用に許可された投与量レベルである。
この試験では、18歳以上、原発性骨髄線維症(PMF)または真性多血症後MFまたは本態性血小板血症後MF(JAK2V617F陽性または陰性変異状態)の診断を受け、血小板数50×109/L以上、ヘモグロビンレベル8.0g/dL以上(これらのレベルを達成するための輸血可)、DIPSS規準で中間−1またはより高い、及び触知可能な脾臓または事前脾臓摘出された患者が登録された。3つの異なる用量コホートを評価した:(1)100mg SR3錠剤1日2回)(2)200mg(2×100mg SR3錠剤)1日2回;及び(3)600mg(6×100mg SR3錠剤)1日1回。図5(a)〜(b)は、ベースラインと比較して12週目で、各用量群における、Myelofibrosis Symptom Assessment Form(MFSAF)修正版v3.0電子日誌による総症状スコア(TSS)が50%以上低下した対象の割合に関する中間の結果を示す。(MFSAF修正版v3.0は、0(症状なし)から10(想像し得る最悪の症状)の尺度でMF関連症状を評価する19個の質問を含む)。図5(a)は、用量コホート単位(100mg 1日2回、200mg 1日2回、及び600mg 1日1回)で、12週目でのTSSが50%以上低下した患者の割合(%)を示す(12週目の来診より前に継続中止した患者は非応答者とみなした)。図5(b)は、用量コホート単位(100mg 1日2回、200mg 1日2回、及び600mg 1日1回)で、12週目でのベースラインからのTSSにおける変化割合(%)を示す(ベースラインと12週目のデータを有する患者のみ含んだ)。図6(a)は、用量コホート単位(100mg 1日2回、200mg 1日2回、及び600mg 1日1回)で、継時的な平均ヘモグロビンレベル(g/dL)を示す(全患者の試験の中間結果)。図6(b)は、用量コホート単位(100mg 1日2回、200mg 1日2回、及び600mg 1日1回)で、48週目での継時的な平均ヘモグロビンレベル(g/dL)を示す。図6(c)は、プラセボまたはルキソリチニブを投薬された(ルキソリチニブは、Jakafi(登録商標)のラベルに従って投与した)個体と比較して、用量コホート単位で、48週目での継時的な平均ヘモグロビンレベル(g/dL)を3つの用量コホートの平均として示す。データは、600mg 1日1回用量でヘモグロビンレベルの増加を示す。最後に、下記の表9は、各用量コホートについての中間血液検査結果(新規及び悪化)を示す。表9aは、長期曝露後の各用量コホートについての血液検査結果(新規及び悪化)を示す。
本明細書の式Iの化合物を、Parkら、Analytical Biochemistry 1999,269,94〜104に記載される、以下のインビトロアッセイに従って、JAK標的の阻害活性について試験した。N末端Hisタグを有するヒトJAK1(a.a.837〜1142)及びJAK2(a.a.828〜1132)の触媒ドメインを、昆虫細胞中のバキュロウイルスを使用して発現させ、精製した。JAK1及びJAK2の触媒活性をビオチン化ペプチドのリン酸化を測定することによってアッセイした。リン酸化されたペプチドをホモジニアス時間分解蛍光法(HTRF)によって検出した。化合物のIC50を、100mM NaCl、5mM DTT、及び0.1mg/mL(0.01%)BSAを含む50mMトリス(pH7.8)緩衝液中に酵素、ATP、及び500nMペプチドを含有する40μLの反応物中で各キナーゼについて測定した。1mMのIC50測定については、反応物中のATP濃度は、1mMであった。反応を室温で1時間実行し、次いでアッセイ緩衝剤(Perkin Elmer、マサチューセッツ州ボストン)中の20μLの45mM EDTA、300nM SA−APC、6nM Eu−Py20を用いて停止させた。ユーロピウム標識抗体に対する結合を、40分間行い、HTRFシグナルをFusionプレートリーダー(Perkin Elmer、マサチューセッツ州ボストン)上で測定した。式Iの化合物及びアジピン酸塩のJAK1でのIC50は、JAK2/JAK1の比が10超(1mMのATPで測定)で、5nM以下(1mMのATPで測定)であった。
成長のためにサイトカインに依存し故にJAK/STATシグナル変換に依存する癌細胞株は、RPMI1640、10%FBS、及び1nG/mLの適切なサイトカイン中、ウェル当たり6000個の細胞(96ウェルプレート形式)でプレートに蒔くことができる。化合物を、DMSO/培地(最終濃度0.2%DMSO)中の細胞に加え、37℃、5%CO2にて72時間インキュベートすることができる。細胞生存性に対する化合物の効果は、CellTiter−Glo蛍光細胞生存性分析(Promega)、続いて、TopCount(Perkin Elmer、マサチューセッツ州ボストン)定量法を使用して評価する。化合物の潜在的なオフターゲット効果を、同一のアッセイ計測値を有する非JAK駆動細胞株を使用して、並行して測定する。全ての実験は、通常、二重で行う。
本明細書の化合物は、免疫低下したマウスのヒト腫瘍異種移植モデルにおいて評価されることができる。例えば、INA−6形質細胞腫細胞株の腫瘍原生変異体を使用して、SCIDマウスに皮下的に播種することができる(Burger,Rら、Hematol J.2:42−53、2001)。腫瘍を有する動物は、次いで薬物処置群またはビヒクル処置群に無作為化され得、異なる用量の化合物を、経口、腹腔内、または埋め込みポンプを使用する連続注入を含む任意の数の通常の経路によって投与することができる。腫瘍成長は、キャリパーを使用して継時的に追跡する。さらに、腫瘍試料を上述の分析(実施例B)のために処置の開始後の任意の時点で採取して、JAK活性及び下流シグナル経路に与える化合物の効果を評価することができる。加えて、化合物(複数可)の選択性を、K562腫瘍モデルなどの他の周知のキナーゼ(例えば、Bcr−Abl)によって駆動される異種移植腫瘍モデルを使用して評価することができる。
本明細書の化合物を、T細胞駆動マウス遅延型過敏症試験モデルにおいてその(JAK標的を阻害する)効力について試験することもできる。マウス皮膚接触遅延型過敏症(DTH)応答を、臨床接触性皮膚炎及び他の皮膚のT−リンパ球媒介性免疫障害、例えば、乾癬の有効モデルと見なす(Immunol Today.1998 Jan;19(1):37−44)。マウスDTHは、乾癬と共通する特徴を複数有し、それには免疫浸潤物、炎症性サイトカインの随伴上昇、及びケラチノサイト過剰増殖が含まれる。さらに、臨床において乾癬の処置に有用な多種の薬剤は、マウスにおけるDTH応答の有効な阻害剤でもある(Agents Actions.1993 Jan;38(1−2):116−21)。
本明細書の化合物は、単一または複合的な炎症反応を再現するように設計した齧歯動物または非齧歯動物モデルにおいて評価することができる。例えば、関節炎の齧歯動物モデルを、予防的または治療的に投薬された化合物の治療可能性の評価に使用することができる。これらのモデルには、マウスまたはラットコラーゲン誘導性関節炎、ラットアジュバント誘導性関節炎、及びコラーゲン抗体誘導性関節炎が含まれるが、これらに限定されない。また、多発性硬化症、I型糖尿病、網膜ブドウ膜炎、甲状腺炎、重症筋無力症、免疫グロブリン腎症、心筋炎、気道感作(喘息)、狼瘡、または大腸炎を含むがこれらに限定されない自己免疫疾患も、本明細書の化合物の治療可能性の評価に使用することができる。これらのモデルは、研究コミュニティにおいて十分に確立され、当業者によく知られている(Current Protocols in Immunology,Vol 3.,Coligan,J.Eら、Wiley Press.;Methods in Molecular Biology:Vol.225,Inflammation Protocols.,Winyard,P.G.and Willoughby,D.A.,Humana Press,2003.)。
薬剤は、ウサギコンカナバリンA(ConA)涙腺モデル、スコポラミンマウスモデル(皮下または経皮)、ボツリヌスマウス涙腺モデル、または眼腺機能不全を生じる多くの自発性齧歯動物自己免疫モデルのうちのいずれか(例えば、NOD−SCID、MRL/lpr、またはNZB/NZW)(そのそれぞれがその全体において参照により本明細書に組み込まれる、Barabinoら、Experimental Eye Research2004,79,613−621及びSchraderら、Developmental Opthalmology,Karger2008,41,298〜312)を含むがこれらに限定されない、当業者に既知であるドライアイの1つまたは複数の前臨床モデルにおいて評価してもよい。これらのモデルにおける評価項目には、眼腺及び眼(角膜など)の組織病理と、場合により、涙液産生を測定する典型的なシルマー試験またはその修正版(Barabinoら)とが含まれ得る。活性は、測定可能な病気が存在する前または存在した後に開始し得る複数の投与経路(例えば、全身的または局所的)を介して投薬することによって評価され得る。
当業者に周知の骨減少症、骨粗鬆症、または骨吸収の様々な前臨床的モデルで化合物を評価してもよい。例えば、卵巣切除される齧歯動物を使用して、骨リモデリング及び/または骨密度のサイン及びマーカーに影響を与える化合物の能力を評価してもよい(その全体において参照により本明細書に組み込まれる、W.S.S.Jee and W.Yao,J Musculoskel.Nueron.Interact.,2001,1(3),193−207)。あるいは、治療(例えばグルココルチコイド)により骨減少症が誘発されたモデルにおいて、対照または化合物で処置された齧歯動物で、骨密度及び骨構造を評価してもよい(双方とも全体において参照により本明細書に組み込まれる、Yaoら、Arthritis and Rheumatism,2008,58(6),3485−3497;及び同上58(11)、1674−1686)。加えて、上(実施例E)に記載した関節炎の齧歯動物モデルにおいて、骨吸収及び骨密度に及ぼす化合物の効果が評価され得る。これらの全モデルに関する評価項目は様々あってもよいが、組織学的及び放射線学的評価、並びに免疫組織学及び骨リモデリングの適切な生化学的マーカーを含むことが多い。
Claims (42)
- {1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリル、またはその医薬的に許容され得る塩を含む徐放性製剤であって、1つまたは複数の該製剤が、{1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリル、またはその医薬的に許容され得る塩の遊離塩基基準で400mgから600mgの1日1回用量をそれを必要とする患者に経口投与するように用いられることを特徴とする、製剤。
- 1つまたは複数の製剤が、{1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリル、またはその医薬的に許容され得る塩の遊離塩基基準で600mgの1日1回用量をそれを必要とする患者に経口投与するように用いられることを特徴とする、請求項1に記載の製剤。
- {1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリル、またはその医薬的に許容され得る塩の遊離塩基基準で100mgをそれぞれ含む、6つの製剤が用いられることを特徴とする、請求項1または2に記載の製剤。
- {1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリル、またはその医薬的に許容され得る塩の遊離塩基基準で200mgをそれぞれ含む、3つの製剤が用いられることを特徴とする、請求項1または2に記載の製剤。
- {1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリル、またはその医薬的に許容され得る塩の遊離塩基基準で300mgをそれぞれ含む、2つの製剤が用いられることを特徴とする、請求項1または2に記載の製剤。
- {1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリル、またはその医薬的に許容され得る塩の遊離塩基基準で600mgを含む、1つの製剤が用いられることを特徴とする、請求項1または2に記載の製剤。
- 自己免疫疾患、癌、骨髄増殖性疾患、炎症性疾患、骨吸収疾患または臓器移植の拒絶反応を処置するための、請求項1から6のいずれか一項に記載の製剤。
- 自己免疫疾患が、皮膚障害、多発性硬化症、関節リウマチ、乾癬性関節炎、若年性関節炎、I型糖尿病、狼瘡、炎症性腸疾患、クローン病、重症筋無力症、免疫グロブリン腎症、心筋炎、自己免疫性甲状腺疾患、アトピー性皮膚炎、乾癬、皮膚感作、皮膚刺激、皮疹、接触性皮膚炎またはアレルギー性接触感作である、請求項7に記載の製剤。
- 自己免疫疾患が関節リウマチである、請求項7に記載の製剤。
- 患者のACR70スコアが40%を超える、請求項9に記載の製剤。
- 患者のACR70スコアが50%を超える、請求項9に記載の製剤。
- 自己免疫疾患が乾癬である、請求項7に記載の製剤。
- PASI50スコアが70%を超える、請求項12に記載の製剤。
- 癌が、前立腺がん、腎癌、肝癌、乳癌、肺癌、甲状腺癌、カポジ肉腫、キャッスルマン病、膵臓癌、リンパ腫、白血病、多発性骨髄腫、真性多血症(PV)、本態性血小板血症(ET)、骨髄様化生を伴う骨髄線維症(MMM)、原発性骨髄線維症(PMF)、慢性骨髄性白血病(CML)、慢性骨髄単球性白血病(CMML)、好酸球増加症候群(HES)、特発性骨髄線維症(IMF)、または全身性肥満細胞症(SMCD)である、請求項7に記載の製剤。
- 骨髄増殖性疾患が原発性骨髄線維症(PMF)である、請求項7に記載の製剤。
- 製剤が、ベースラインと比較して患者の総症状スコア(TSS)の低下をもたらす、請求項15に記載の製剤。
- 製剤が貧血症の減少をもたらす、請求項15に記載の製剤。
- 骨吸収疾患が、骨粗鬆症、骨関節炎、ホルモン失調に関連する骨吸収、ホルモン療法に伴う骨吸収、自己免疫疾患に伴う骨吸収、または癌に伴う骨吸収である、請求項7に記載の製剤。
- 絶食時個体への1つまたは複数の製剤の経口投与が提供する、{1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリルの平均最高血漿中濃度到達時間(Tmax)が、0.5時間から3時間である、請求項1から18のいずれか一項に記載の製剤。
- 絶食時個体への1つまたは複数の製剤の経口投与が提供する、{1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリルの平均最高血漿中濃度到達時間(Tmax)が、少なくとも0.5時間である、請求項1から18のいずれか一項に記載の製剤。
- 絶食時個体への1つまたは複数の製剤の経口投与が提供する、{1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリルの平均最高血漿中濃度(Cmax)の平均12時間血漿中濃度(C12h)に対する比率が、5から50である、請求項1から20のいずれか一項に記載の製剤。
- 絶食時個体への1つまたは複数の製剤の経口投与が提供する、{1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリルの平均最高血漿中濃度(Cmax)の平均12時間血漿中濃度(C12h)に対する比率が、9から40である、請求項1から20のいずれか一項に記載の製剤。
- 絶食時個体への1つまたは複数の製剤の経口投与が提供する、{1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリルの平均最高血漿中濃度(Cmax)の平均12時間血漿中濃度(C12h)に対する比率が、15から30である、請求項1から20のいずれか一項に記載の製剤。
- 絶食時個体への1つまたは複数の製剤の経口投与が提供する、{1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリルの平均半減期(t1/2)が、1時間から20時間である、請求項1から23のいずれか一項に記載の製剤。
- 高脂肪食後個体への1つまたは複数の製剤の経口投与が提供する、{1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリルの平均最高血漿中濃度到達時間(Tmax)が、1時間から9時間である、請求項1から18のいずれか一項に記載の製剤。
- 高脂肪食後個体への1つまたは複数の製剤の経口投与が提供する、{1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリルの平均最高血漿中濃度到達時間(Tmax)が、少なくとも1.5時間である、請求項1から18のいずれか一項に記載の製剤。
- 高脂肪食後個体への1つまたは複数の製剤の経口投与が提供する、{1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリルの平均最高血漿中濃度(Cmax)の平均12時間血漿中濃度(C12h)に対する比率が、10から70である、請求項1から18及び25から26のいずれか一項に記載の製剤。
- 高脂肪食後個体への1つまたは複数の製剤の経口投与が提供する、{1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリルの平均最高血漿中濃度(Cmax)の平均12時間血漿中濃度(C12h)に対する比率が、15から50である、請求項1から18及び25から26のいずれか一項に記載の製剤。
- 高脂肪食後個体への1つまたは複数の製剤の経口投与が提供する、{1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリルの平均最高血漿中濃度(Cmax)の平均12時間血漿中濃度(C12h)に対する比率が、25から45である、請求項1から18及び25から26のいずれか一項に記載の製剤。
- 高脂肪食後個体への1つまたは複数の製剤の経口投与が提供する、{1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリルの平均半減期(t1/2)が、1時間から7時間である、請求項1から18及び25から29のいずれか一項に記載の製剤。
- 高脂肪食後個体への1つまたは複数の製剤の経口投与が提供する、{1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリルの平均半減期(t1/2)が、2時間から5時間である、請求項1から18及び25から29のいずれか一項に記載の製剤。
- 1つまたは複数の製剤がそれぞれ錠剤である、請求項1から31のいずれか一項に記載の製剤。
- 1つまたは複数の製剤が、湿式造粒を含む製造方法によって製造される、請求項1から32のいずれか一項に記載の製剤。
- 1つまたは複数の製剤が、1つまたは複数のヒプロメロースをそれぞれ含む、請求項1から33のいずれか一項に記載の製剤。
- 1つまたは複数の製剤が、ヒプロメロース及び結晶セルロースから独立して選択された1つまたは複数の賦形剤をそれぞれ含む、請求項1から33のいずれか一項に記載の製剤。
- 1つまたは複数の製剤が、ヒプロメロース、結晶セルロース、ステアリン酸マグネシウム、ラクトース、及びラクトース一水和物から独立して選択された1つまたは複数の賦形剤をそれぞれ含む、請求項1から33のいずれか一項に記載の製剤。
- 1つまたは複数の製剤が、水中濃度2%で80cPから120cPの見掛け粘度を有することを特徴とする第一のヒプロメロース及び水中濃度2%で3000cPから5600cPの見掛け粘度を有することを特徴とする第二のヒプロメロースをそれぞれ含む、請求項1から33のいずれか一項に記載の製剤。
- 1つまたは複数の製剤が、10重量%から15重量%の1つまたは複数のヒプロメロースをそれぞれ含む、請求項1から33のいずれか一項に記載の製剤。
- 1つまたは複数の製剤が、16重量%から22重量%の結晶セルロースをそれぞれ含む、請求項1から33及び38のいずれか一項に記載の製剤。
- 1つまたは複数の製剤が、45重量%から55重量%のラクトース一水和物をそれぞれ含む、請求項1から33及び38から39のいずれか一項に記載の製剤。
- 1つまたは複数の製剤が、0.3重量%から0.7重量%のステアリン酸マグネシウムをそれぞれ含む、請求項1から18及び38から40のいずれか一項に記載の製剤。
- 塩が、{1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペリジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリルアジピン酸塩である、請求項1から41のいずれか一項に記載の製剤。
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