JP6633531B2 - 炎症性障害の治療のための医薬組成物 - Google Patents
炎症性障害の治療のための医薬組成物 Download PDFInfo
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- JP6633531B2 JP6633531B2 JP2016550646A JP2016550646A JP6633531B2 JP 6633531 B2 JP6633531 B2 JP 6633531B2 JP 2016550646 A JP2016550646 A JP 2016550646A JP 2016550646 A JP2016550646 A JP 2016550646A JP 6633531 B2 JP6633531 B2 JP 6633531B2
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- LZKAPHHZFJPLII-UHFFFAOYSA-N triazolo[4,5-b]pyridin-2-amine Chemical compound C1=CC=NC2=NN(N)N=C21 LZKAPHHZFJPLII-UHFFFAOYSA-N 0.000 description 1
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Description
本発明は、炎症性病態、自己免疫疾患、増殖性疾患、アレルギー、移植片拒絶、軟骨恒常性の低下及び/もしくは破壊を伴う疾患、先天性軟骨形成異常、及び/又はIL6もしくはインターフェロンの分泌過多に関連する疾患の予防並びに/又は治療に有用である、化合物シクロプロパンカルボン酸{5-[4-(1,1-ジオキソ-チオモルホリン-4-イルメチル)-フェニル]-[1,2,4]トリアゾロ[1,5-a]ピリジン-2-イル}-アミド(化合物1)の医薬として許容し得る塩を含む医薬組成物、並びにそのような組成物の調製方法に関する。本発明はまた、本発明の医薬組成物を投与することによる、炎症性病態、自己免疫疾患、増殖性疾患、アレルギー、移植片拒絶、軟骨恒常性の低下及び/もしくは破壊を伴う疾患、先天性軟骨形成異常、及び/又はIL6もしくはインターフェロンの分泌過多に関連する疾患を含む疾患の予防並びに/又は治療方法を提供する。
炎症性病態、自己免疫疾患、増殖性疾患、アレルギー、移植片拒絶、軟骨代謝回転の異常を伴う疾患、先天性軟骨形成異常、及び/又はIL6もしくはインターフェロンの分泌過多に関連する疾患、特に、関節リウマチを治療するための現在の治療は十分なものではなく、それらの治療に有用であり得る新しい治療剤を同定する必要性が依然として存在する。これらの病態は、長期治療、及び薬物の繰り返し摂取を必要とする慢性病態である。患者が薬物不耐性であるか、又は薬物不耐性になる可能性があり、さらには高投与量又は高投与頻度が不快な副作用及び/又は患者のコンプライアンスの低下をもたらし得、その場合、患者は時折、故意に又は偶然に用量を誤ることがあり得るので、長期治療は患者及び医師にも同様に重い負担となり得る。非遵守の影響は、慢性疾患により様々であり、最小のものから非常に重篤なものに及ぶ(Ingersoll及びCohenの文献、2008)。したがって、医師の戦略を強化する新しい薬剤、及び患者の生活を向上させる低頻度の投与レジメンを持つ化合物を特定する必要がある。
本発明は、炎症性病態、自己免疫疾患、増殖性疾患、アレルギー、移植片拒絶、軟骨恒常性の低下及び/もしくは破壊を伴う疾患、先天性軟骨形成異常、及び/又はIL6もしくはインターフェロンの分泌過多に関連する疾患の治療並びに/又は予防に有用である、化合物1の医薬として許容し得る塩、特に、塩酸塩もしくはその酸付加塩の溶媒和物もしくは水和物を含有する本発明の医薬組成物を提供する。特に、化合物1は、JAK、より特には、JAK1の阻害剤として作用し得る。本発明はまた、本発明のこれらの医薬組成物の製造方法、及び本発明の医薬組成物を投与することによる、炎症性病態、自己免疫疾患、増殖性疾患、アレルギー、移植片拒絶、軟骨恒常性の低下及び/もしくは破壊を伴う疾患、先天性軟骨形成異常、及び/又はIL6もしくはインターフェロンの分泌過多に関連する疾患の治療並びに/又は予防方法を提供する。
(i)化合物1の塩酸塩又はこの酸付加塩の溶媒和物もしくは水和物;
(ii)不活性固体希釈剤;及び
(iii)滑沢剤。
(i)化合物1の塩酸塩又はこの酸付加塩の溶媒和物もしくは水和物;
(ii)不活性固体希釈剤;
(iii)滑沢剤;及び
(iv)非イオン性崩壊剤。
(i)化合物1の塩酸塩又はこの酸付加塩の溶媒和物もしくは水和物;
(ii)不活性固体希釈剤;
(iii)滑沢剤;
(iv)非イオン性崩壊剤;及び
(v)流動促進剤。
(定義)
以下の用語は、それとともに以下に提示された意味を有することが意図され、本発明の説明及び意図される範囲を理解する際に有用である。
本発明は、炎症性病態、自己免疫疾患、増殖性疾患、アレルギー、移植片拒絶、軟骨恒常性の低下及び/もしくは破壊を伴う疾患、先天性軟骨形成異常、及び/又はIL6もしくはインターフェロンの分泌過多に関連する疾患の予防並びに/又は治療に有用である、化合物シクロプロパンカルボン酸{5-[4-(1,1-ジオキソ-チオモルホリン-4-イルメチル)-フェニル]-[1,2,4]トリアゾロ[1,5-a]ピリジン-2-イル}-アミド(化合物1)の医薬として許容し得る塩を含有する医薬組成物、並びにそのような組成物の調製方法に関する。特に、医薬組成物は、チロシンキナーゼファミリーのJAK、より特にはJAK1を阻害する。
(i)化合物1の塩酸塩又はこの酸付加塩の溶媒和物もしくは水和物;
(ii)不活性固体希釈剤;及び
(iii)滑沢剤。
(i)化合物1の塩酸塩又はこの酸付加塩の溶媒和物もしくは水和物;
(ii)不活性固体希釈剤;
(iii)滑沢剤;及び
(iv)非イオン性崩壊剤。
(i)化合物1の塩酸塩又はこの酸付加塩の溶媒和物もしくは水和物;
(ii)不活性固体希釈剤;
(iii)滑沢剤;
(iv)非イオン性崩壊剤;及び
(v)流動促進剤。
(i)1〜50重量%の1:1:3の[化合物1:HCl:H2O]付加物;及び
(ii)50〜99重量%の不活性固体希釈剤。
(i)1〜50重量%の1:1:3の[化合物1:HCl:H2O]付加物;
(ii)49.9〜94重量%の不活性固体希釈剤;及び
(iii)0.1〜5重量%の滑沢剤。
(i)1〜50重量%の1:1:3の[化合物1:HCl:H2O]付加物;
(ii)49.9〜94重量%の不活性固体希釈剤;
(iii)0.1〜5重量%の滑沢剤;
(iv)0.5〜5重量%の崩壊剤;及び
(v)0〜1重量%の流動促進剤;並びに必要に応じて
(vi)1種以上のさらなる医薬として許容し得る賦形剤。
(i)10〜40重量%の1:1:3の[化合物1:HCl:H2O]付加物;
(ii)55〜90重量%の不活性固体希釈剤;
(iii)1〜5重量%の滑沢剤;
(iv)1〜4重量%の崩壊剤;及び
(v)0.1〜1重量%の流動促進剤;並びに必要に応じて
(vi)1種以上のさらなる医薬として許容し得る賦形剤。
(i)15〜35重量%の1:1:3の[化合物1:HCl:H2O]付加物;
(ii)55〜85重量%の不活性固体希釈剤;
(iii)1.5〜5重量%の滑沢剤;
(iv)1.5〜3重量%の崩壊剤;及び
(v)0.2〜0.3重量%の流動促進剤;並びに必要に応じて
(vi)1種以上のさらなる医薬として許容し得る賦形剤。
(i)22〜35重量%の1:1:3の[化合物1:HCl:H2O]付加物;
(ii)57〜75重量%の微結晶セルロースを含む不活性固体希釈剤;
(iii)1.5〜5重量%の水素化植物油滑沢剤;
(iv)1.75〜2.25重量%の架橋ポリビニルピロリドンの崩壊剤の重量;及び
(v)0.2〜0.3重量%の流動促進剤としてのコロイド状二酸化ケイ素;並びに必要に応じて
(vi)1種以上のさらなる医薬として許容し得る賦形剤。
(i)約24.4重量%の1:1:3の[化合物1:HCl:H2O]付加物;
(ii)約71.35重量%の不活性固体希釈剤;
(iii)約2重量%の滑沢剤;
(iv)約2重量%の非イオン性崩壊剤;及び
(v)約0.25重量%の流動促進剤。
(i)約32.27重量%の1:1:3の[化合物1:HCl:H2O]付加物;
(ii)約60.48重量%の不活性固体希釈剤;
(iii)約5重量%の滑沢剤;
(iv)約2重量%の非イオン性崩壊剤;及び
(v)約0.25重量%の流動促進剤。
一実施態様において、本発明は、医薬において使用するための、本発明の医薬組成物を提供する。特定の実施態様において、本発明は、炎症性病態、自己免疫疾患、増殖性疾患、アレルギー、移植片拒絶、軟骨恒常性の低下及び/もしくは破壊を伴う疾患、先天性軟骨形成異常、及び/又はIL6もしくはインターフェロンの分泌過多に関連する疾患の予防並びに/又は治療において使用するための、本発明の医薬組成物を提供する。
(概要)
化合物1及びその塩酸塩は、以下の一般的方法及び手順を用いて容易に入手可能な出発材料から調製することができる。典型的な又は好ましいプロセス条件(すなわち、反応温度、時間、反応物のモル比、溶媒、圧力など)が与えられる場合、別途明記されない限り、他のプロセス条件も使用することができることが理解されるであろう。最適な反応条件は、使用される特定の反応物又は溶媒によって異なり得るが、そのような条件は、当業者によって、ルーチンの最適化手順により決定され得る。
表I.実験の節で使用される略語のリスト:
(実施例1.化合物1の調製)
(1.1.ルート1)
(1.1.1. 4-[4-(4,4,5,5-テトラメチル-[1,3,2]ジオキサボロラン-2-イル)-ベンジル]-チオモルホリン-1,1-ジオキシド)
5℃まで冷却したDCM(2.5L)中の2-アミノ-6-ブロモピリジン(1)(253.8g、1.467モル)溶液にエトキシカルボニルイソチオシアネート(173.0mL、1.467mol)を15分間かけて滴加する。次いで、反応混合物を室温(20℃)まで温め、16時間撹拌する。真空中で蒸発させて、固体を得、濾過により回収して、ガソリン(petrol)(3×600mL)で十分に洗浄し、風乾して、所望の生成物を得ることができる。このチオ尿素は、精製することなく次の工程にそのまま使用することができる。
EtOH/MeOH(1:1、900mL)中のヒドロキシルアミン塩酸塩(101.8g、1.465mol)の懸濁液に、N,N-ジイソプロピルエチルアミン(145.3mL、0.879mol)を添加し、該混合物を室温(20℃)で1時間撹拌する。次いで、1-(6-ブロモピリジン-2-イル)-3-カルボエトキシ-チオウレア(2)(89.0g、0.293mol)を添加し、該混合物をゆっくりと加熱還流する(注記:発生するH2Sをクエンチするためにブリーチスクラバーが必要である)。3時間還流後、該混合物を放冷し、濾過して、沈殿した固体を回収する。濾液を真空中で蒸発させ、H2O(250mL)を添加し、濾過して、さらなる生成物を回収する。合わせた固体を、連続的に、H2O(250mL)、EtOH/MeOH(1:1、250mL)、及びEt2O(250mL)で洗浄し、次いで、真空乾燥させ、トリアゾロピリジン誘導体(3)を固体として得る。該化合物を精製せずに次の工程でそのまま使用することができる。
前の工程で得られた、乾燥MeCN(150mL)中の2-アミノ-トリアゾロピリジン(7.10g、33.3mmol)の溶液に、5℃でEt3N(11.6mL,83.3mmol)、続いて、シクロプロパンカルボニルクロリド(83.3mmol)を添加する。次いで、反応混合物を周囲温度まで温め、全ての出発物質が消費されるまで撹拌する。必要であれば、さらなるEt3N(4.64mL、33.3mmol)及びシクロプロパンカルボニルクロリド(33.3mmol)を添加し、反応の完了を確実にする。真空中で溶媒蒸発させた後、得られた残渣を7Nメタノール性アンモニア溶液(50mL)で処理し、(1〜16時間)周囲温度で撹拌し、任意のビス-アシル化生成物を加水分解する。真空中で揮発性物質を除去し、続いて、Et2O(50mL)で粉砕することにより生成物の単離を行う。固体を濾過により回収し、H2O(2x50mL)、アセトン(50mL)及びEt2O(50mL)で洗浄し、次いで、真空乾燥させて、所望の化合物を得る。
(1.2.1.工程1:シクロプロパンカルボン酸[5-(4-ヒドロキシメチルフェニル)-[1,2,4]トリアゾロ[1,5-a]ピリジン-2-イル]-アミド)
HCl(THF中1M溶液)(655μl、0.65mmol、1.1当量)を、50℃で化合物1(252.6mg、0.59mmol、1当量)及びメタノール(5.05mL、20体積)の撹拌懸濁液に添加する。この混合物を1℃/分で25℃まで冷却し、25℃で22時間撹拌する。固体を真空濾過により単離し、吸引下で乾燥させる。XRPD分析により、4〜5%の水を含有し、測定された水溶解度が1.9mg/mLである安定な非吸湿性塩の形成を確認した。
(2.1.プロトコル1)
不活性雰囲気下で化合物1(45g、106mmol、1当量)に、DCM(675mL)及びメタノール(225mL)を添加する。得られた懸濁液を撹拌しながら35℃まで加熱し、水中の15%のトリメルカプトトリアジン三ナトリウム塩(22.5g、14mmol、0.13当量)を添加し、得られた溶液を5時間撹拌した後、この溶液を窒素圧下で0.45μm濾紙上で濾過する。
(2.2.1.工程1:化合物1.HCl.MeOH)
DCM(1.5L)に懸濁した化合物1(100g、235mmol、1当量)にMeOH(0.5L)を添加し、得られた溶液を35℃まで加熱する。水(42mL)中の85%トリメルカプトトリアジン三ナトリウム(8.7g、3mmol、0.13当量)を添加し、得られた混合物を35℃で少なくとも5時間撹拌する。次いで、溶液を窒素圧下で0.45μm濾紙上で濾過する。
水(36g、0.4当量)中のギ酸(200g、1.6当量)に、上記の工程1で得られた化合物1.HCl.MeOH(100g、1当量)を添加する。得られた混合物を攪拌しながら55℃まで加熱し、この溶液を0.45μmフィルターカートリッジを通して濾過する。85%水性ギ酸(200g)を添加し、混合物を穏やかに攪拌しながら28〜32℃まで冷却する。
化合物1.HCl.3H2Oをアセトン:水(1:1)から再結晶させる。結果を以下の表IVに開示する。
表IV.化合物1.HCl.3H2Oの単結晶構造
(3.1.イヌのバイオアベイラビリティの研究)
(3.1.1.実験セットアップ)
この実験の目的は、遊離塩基として又は2つの異なる強度のカプセル(25及び100mg)として製剤化した塩としての化合物1の単回経口投与後に、健康な雄ビーグル犬(1群あたり3匹のイヌ)におけるPKを比較することである。
表V. 25及び100mgのカプセル組成
必要に応じて、代表的な血漿アリコートを対照のイヌの血漿で希釈し、較正曲線の範囲内にその濃度が存在することを確実にし、内部標準として重水素化化合物1(150ng/mL)を含有する、酸性化した(0.1%ギ酸を用いて)2容量のアセトニトリルを用いてタンパク質沈殿によって抽出する。
(4.1.加速安定性試験)
(4.1.1.プロトコル)
[化合物1.HCl.3H2O]の試料を以下の表に記載される条件下で保存し、化学的安定性及び物理的安定性を評価する。
表VI.実験条件
上述のプロトコルに従って試験した場合、化合物1.HCl.3H2Oは、3カ月にわたってすべての条件下で安定であり、結晶性に変化は観察されない。
(5.1.本発明の医薬組成物の調製)
(5.1.1.カプセル剤)
(5.1.1.1.カプセル剤の形成)
以下のプログレッシブブレンド手順に従って、カプセル(ハードゼラチンカプセルスウェーデンオレンジOP.C307、サイズ0、Coni-Snap、Capsugel、ロット33234201)をTurbula ブレンダータイプT2A(Willy A. Bachofen社、basel、Switzerland)を使用して調製する。
- 充填剤の総量の半分:5分
- 化合物1の遊離塩基又は塩:20分
- 充填剤の総量の半分+崩壊剤:10分
- 滑沢剤:5分
表VII.カプセルA組成物(イオン性)
図4(カプセルA、イオン性賦形剤)に示すように、上記のプロトコルに従って試験した場合、安定性試験期間にわたって、約221℃での吸熱(endotherm)の形成を特徴とする継続的な劣化が示され、これは図5(カプセルB、非イオン性賦形剤)には存在しない。
(5.1.2.1.錠剤形成)
ブレンド前に、ステンレス製の篩を用いて化合物1.HCl.3H2Oをふるいにかけ(画分63〜250μm又は<250μm)、かつ賦形剤をふるいにかける(900μm)。次いで、化合物1.HCl.3H2O及び賦形剤を、以下の手順を用いてTurbulaタイプT2Aブレンダー(Willy A. Bachofen社、Switzerland)を用いてガラス瓶にブレンドする:
- 充填剤の半分を5分間ブレンドする
- 化合物1.HCl.3H2Oを添加し、20分間ブレンドする
- 充填剤の残り半分、崩壊剤及び流動促進剤を添加し、10分間ブレンドする
-滑沢剤を添加し、5分間ブレンドする。
破砕に対する錠剤の機械的完全性又は耐性を決定するために、錠剤の硬度又は破砕強度を測定する。Sotax社製H10硬度計(Sotax社、Allschwil、Switzerland)を使用する。楕円形の錠剤をそれらの長辺で試験する。10N/秒の一定の負荷速度モードを適用した。この装置で、錠剤の厚さ及び直径/長さも測定する。
液体媒体中に置かれたときに、錠剤が所定時間内に崩壊するか否かを決定するために、崩壊試験を行う。自動終点検出を有するSotax社製DT2崩壊テスター(Sotax社、Allschwil、Switzerland)を使用した。培地は、37℃の温度の精製水(Elix、Millipore社)であった。崩壊時間は、全試験錠剤が崩壊した時間である。
摩耗への暴露時の非被覆錠剤の物理的強度を決定するために、破砕性試験を行う。287mm及び38mmの内径を有するドラムを備えたSotax社製FT2摩損度試験機(Sotax社、Allschwil、Switzerland)を使用した。錠剤を秤量し、ドラム内に配置する。ドラムを25rpmで100回回転させ、錠剤を除去する。錠剤から出た埃又壊れた破片を除去する。錠剤がひび割れ、分割、又は破壊されていない場合には、錠剤を再び秤量し、破砕性を決定する(初期質量に対する失われた質量の割合)。
溶解試験を、パドル法を使用して、Evolution 4300自動溶解サンプラー(Distek社、New Brunswick、New Jersey、USA)と組み合わせてEvolution 6300溶解システム(Distek社、New Brunswick、New Jersey、USA)で行う。0.01N HClを溶解媒体として使用する。媒体(900mL)の温度を37±0.5℃に維持し、パドルの回転数を75rpmに設定する。5mlの(Distek社 45μmフィルターを用いてろ過した)試料を、5、10、15、20、30、45及び60分の時点で取り出し、HPLCにより分析する。
このプロトコルに供したとき、以下の表に記載されるように、錠剤Aの溶解速度は顕著により低くなり、特に、加速安定条件下では、溶解速度の急激な低下が示される。対照的に、錠剤Bの溶解は、長期保存条件及び加速安定条件の両方で影響されない。
表XII.錠剤A-長期貯蔵条件(図6)
錠剤A及び錠剤Bも、DSCサーモグラム(図10〜17)により安定性試験中に監視する。
溶解アッセイ及びDSCサーモグラム分析によって実証されるように、化合物1.HCl.3H2Oを含む医薬組成物は、周知の一般的に使用されるイオン性賦形剤の存在下で、分解を受ける。驚くべきことに、この問題は、特定の非イオン性賦形剤を使用することにより、本発明の医薬組成物において解決される。
前述の説明は例示的かつ説明的な性質のものであって、本発明及びその好ましい実施態様を説明することが意図されるものであることが当業者に理解されるであろう。ルーチンの実験を通じて、当業者は、本発明の精神を逸脱することなくなされ得る明白な修正及び変更を認識するであろう。添付の特許請求の範囲の範囲内に入る全てそのような修正は、その中に含まれることが意図される。したがって、本発明は、上記の説明によるだけでなく、以下の特許請求の範囲及びその等価物によっても定義されることが意図される。
(参考文献)
(構成1)
以下を含む医薬組成物:
(i)1〜50重量%の化合物1の塩酸塩;
(化1)
(ii)49.9〜94重量%の不活性固体希釈剤;及び
(iii)0.1〜5重量%の滑沢剤。
(構成2)
前記不活性固体希釈剤が、セルロース粉末、ケイ化微結晶セルロースアセテート、圧縮糖、粉砂糖、トウモロコシデンプン及びアルファ化デンプン、デキストレート、デキストリン、デキストロース、エリトリトール、エチルセルロース、フルクトース、フマル酸、パルミトステアリン酸グリセリル、吸入用乳糖、イソマルト、カオリン、ラクチトール、ラクトース、無水の、一水和物及びトウモロコシデンプン、噴霧乾燥一水和物及び微結晶性セルロース、マルトデキストリン、マルトース、マンニトール、中鎖トリグリセリド、微結晶性セルロース、ポリデキストロース、ポリメタクリレート、シメチコン、ソルビトール、アルファ化デンプン、滅菌トウモロコシ、スクロース、球状糖、スルホブチルエーテルβ-シクロデキストリン、タルク、トラガカント、トレハロース、及びキシリトールから選択される、構成1記載の医薬組成物。
(構成3)
前記不活性固体希釈剤が、微結晶セルロースである、構成1又は2記載の医薬組成物。
(構成4)
前記滑沢剤が非イオン性である、構成1〜3のいずれか一項記載の医薬組成物。
(構成5)
前記滑沢剤が、キャノーラ油、硬化ヒマシ油、綿実油、ベヘン酸グリセリル、モノステアリン酸グリセリル、パルミトステアリン酸グリセリル、中鎖トリグリセリド、鉱物油、軽油、オクチルドデカノール、ポロキサマー、ポリエチレングリコール、ポリオキシエチレンステアレート、ポリビニルアルコール、デンプン、及び水素化植物油から選択される、構成1〜4のいずれか一項記載の医薬用滑沢剤。
(構成6)
前記滑沢剤が、植物油、グリセロールジベヘネート、又はポリエチレングリコール10,000である、構成1〜4のいずれか一項記載の医薬用滑沢剤。
(構成7)
前記医薬組成物が、前記医薬組成物の重量で0.1〜5%を構成する非イオン性崩壊剤をさらに含む、構成1〜6のいずれか一項記載の医薬組成物。
(構成8)
前記崩壊剤が、アルギン酸、粉末セルロース、キトサン、コロイド状二酸化ケイ素、トウモロコシデンプン及びアルファ化デンプン、クロスポビドン、グリシン、グアーガム、低置換ヒドロキシプロピルセルロース、メチルセルロース、微結晶性セルロース、及びポビドンから選択される、構成7記載の医薬組成物。
(構成9)
前記崩壊剤が、ポリビニルポリピロリドン、アルファ化デンプン、又は微結晶性セルロースである、構成7記載の医薬組成物。
(構成10)
前記医薬組成物が、前記医薬組成物の重量で0.1〜0.5%を構成する流動促進剤をさらに含む、構成1〜9のいずれか一項記載の医薬組成物。
(構成11)
前記流動促進剤が、粉末セルロース、コロイド状二酸化ケイ素、疎水性コロイド状シリカ、二酸化ケイ素、及びタルクから選択される、構成10記載の医薬組成物。
(構成12)
前記化合物1の塩酸塩が1:1:3の[化合物1:HCl:H 2 O]付加物である、構成1〜11のいずれか一項記載の医薬組成物。
(構成13)
前記化合物1の塩酸塩が固体結晶形態にある、構成1〜12のいずれか一項記載の医薬組成物。
(構成14)
前記化合物1の塩酸塩が、少なくとも以下の位置: 7.3, 8.4, 8.8, 10.7, 12.0, 12.2, 13.2, 13.7, 14.5, 16.3, 16.7, 17.6, 19.3, 20.2, 20.6, 21.0, 21.4, 21.8, 22.8, 23.4, 23.9, 24.5, 25.2, 25.7, 25.9, 26.4, 27.2, 27.7, 28.3, 28.6, 28.9, 29.2, 29.6, 7及び32.7° 2θ±0.2° 2θのうちのすべてにある粉末X線回折ピークによって特徴付けられる、構成1〜13のいずれか一項記載の医薬組成物。
(構成15)
前記組成物の少なくとも90%が、溶解媒体として0.01NのHCl中、37±0.5℃、75rpmの速度でパドル法を用いて測定した場合、40℃/75%相対湿度で、開放受容器中で1カ月間貯蔵した後、約5分以内に溶解される、構成1〜14のいずれか一項記載の医薬組成物。
(構成16)
さらなる治療剤を含む、構成1〜15のいずれか一項記載の医薬組成物。
(構成17)
錠剤形態にある、構成1〜14のいずれか一項記載の医薬組成物。
(構成18)
カプセル形態にある、構成1〜14のいずれか一項記載の医薬組成物。
(構成19)
医薬に使用するための、構成1〜18のいずれか一項記載の医薬組成物。
(構成20)
炎症性病態、自己免疫疾患、増殖性疾患、アレルギー、移植片拒絶、軟骨恒常性の低下及び/もしくは破壊を伴う疾患、先天性軟骨形成異常、及び/又はIL6もしくはインターフェロンの分泌過多に関連する疾患の予防並びに/又は治療に使用するための、構成1〜18のいずれか一項記載の医薬組成物。
(構成21)
構成1〜18のいずれか一項記載の医薬組成物が、別の治療剤と組み合わせて投与される、構成19又は20記載の使用のための組成物。
(構成22)
前記さらなる治療剤が、炎症性病態、自己免疫疾患、増殖性疾患、アレルギー、移植片拒絶、軟骨恒常性の低下及び/もしくは破壊を伴う疾患、先天性軟骨形成異常、及び/又はIL6もしくはインターフェロンの分泌過多に関連する疾患の予防並びに/又は治療のための薬剤である、構成16記載の医薬組成物、又は構成21記載の使用。
Claims (14)
- 以下を含む医薬組成物:
(i)1〜50重量%の化合物1の塩酸塩;
(iii)キャノーラ油、硬化ヒマシ油、綿実油、ベヘン酸グリセリル、モノステアリン酸グリセリル、パルミトステアリン酸グリセリル、中鎖トリグリセリド、鉱物油、軽油、オクチルドデカノール、ポロキサマー、ポリエチレングリコール、ポリオキシエチレンステアレート、ポリビニルアルコール、デンプン、及び水素化植物油から選択される、0.1〜5重量%の非イオン性滑沢剤;
(iv)アルギン酸、粉末セルロース、キトサン、コロイド状二酸化ケイ素、トウモロコシデンプン及びアルファ化デンプン、クロスポビドン、グリシン、グアーガム、低置換ヒドロキシプロピルセルロース、メチルセルロース、微結晶性セルロース、及びポビドンから選択される、0.1〜5重量%の非イオン性崩壊剤;及び
(v)粉末セルロース、コロイド状二酸化ケイ素、疎水性コロイド状シリカ、二酸化ケイ素、及びタルクから選択される、0.1〜0.5重量%の流動促進剤。 - 前記不活性固体希釈剤が、微結晶性セルロースである、請求項1記載の医薬組成物。
- 前記滑沢剤が、植物油、グリセロールジベヘネート、又はポリエチレングリコール10,000である、請求項1記載の医薬組成物。
- 前記崩壊剤が、ポリビニルポリピロリドン、アルファ化デンプン、又は微結晶性セルロースである、請求項1記載の医薬組成物。
- 前記化合物1の塩酸塩が1:1:3の[化合物1:HCl:H2O]付加物である、請求項1〜4のいずれか一項記載の医薬組成物。
- 前記化合物1の塩酸塩が固体結晶形態にある、請求項1〜5のいずれか一項記載の医薬組成物。
- 前記化合物1の塩酸塩が、少なくとも以下の位置: 7.3, 8.4, 8.8, 10.7, 12.0, 12.2, 13.2, 13.7, 14.5, 16.3, 16.7, 17.6, 19.3, 20.2, 20.6, 21.0, 21.4, 21.8, 22.8, 23.4, 23.9, 24.5, 25.2, 25.7, 25.9, 26.4, 27.2, 27.7, 28.3, 28.6, 28.9, 29.2, 29.6, 7及び32.7° 2θ±0.2° 2θのうちのすべてにある粉末X線回折ピークによって特徴付けられる、請求項1〜6のいずれか一項記載の医薬組成物。
- さらなる治療剤を含む、請求項1〜7のいずれか一項記載の医薬組成物。
- 錠剤形態にある、請求項1〜7のいずれか一項記載の医薬組成物。
- カプセル形態にある、請求項1〜7のいずれか一項記載の医薬組成物。
- 医薬に使用するための、請求項1〜10のいずれか一項記載の医薬組成物。
- 炎症性病態、自己免疫疾患、増殖性疾患、アレルギー、移植片拒絶、軟骨恒常性の低下及び/もしくは破壊を伴う疾患、先天性軟骨形成異常、及び/又はIL6もしくはインターフェロンの分泌過多に関連する疾患の予防並びに/又は治療に使用するための、請求項1〜10のいずれか一項記載の医薬組成物。
- さらなる治療剤と組み合わせて投与される、請求項11又は12記載の医薬組成物。
- 前記さらなる治療剤が、炎症性病態、自己免疫疾患、増殖性疾患、アレルギー、移植片拒絶、軟骨恒常性の低下及び/もしくは破壊を伴う疾患、先天性軟骨形成異常、及び/又はIL6もしくはインターフェロンの分泌過多に関連する疾患の予防並びに/又は治療のための薬剤である、請求項8又は13記載の医薬組成物。
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CN105198879B (zh) * | 2015-09-18 | 2017-09-22 | 上海宣创生物科技有限公司 | 一种环丙烷甲酰胺衍生物c晶型及其制备方法 |
CN105198878B (zh) * | 2015-09-18 | 2017-07-25 | 上海宣创生物科技有限公司 | 一种环丙烷甲酰胺衍生物f晶型及其制备方法 |
CN105198877B (zh) * | 2015-09-18 | 2017-09-22 | 上海宣创生物科技有限公司 | 一种环丙烷甲酰胺衍生物g晶型及其制备方法 |
CN105198880B (zh) * | 2015-09-18 | 2017-07-25 | 上海宣创生物科技有限公司 | 一种环丙烷甲酰胺衍生物a晶型及其制备方法 |
CN105111206B (zh) * | 2015-09-18 | 2017-07-25 | 上海宣创生物科技有限公司 | 一种环丙烷甲酰胺衍生物e晶型及其制备方法 |
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CN105218539B (zh) * | 2015-09-18 | 2017-07-25 | 上海宣创生物科技有限公司 | 一种环丙烷甲酰胺衍生物b晶型及其制备方法 |
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US20150224199A1 (en) | 2015-08-13 |
AR099306A1 (es) | 2016-07-13 |
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AU2015215044A1 (en) | 2016-08-11 |
JP2017505330A (ja) | 2017-02-16 |
US10493158B2 (en) | 2019-12-03 |
CA2938217A1 (en) | 2015-08-13 |
TW201613601A (en) | 2016-04-16 |
TWI697330B (zh) | 2020-07-01 |
WO2015117980A1 (en) | 2015-08-13 |
EP3102213B1 (en) | 2020-04-01 |
HRP20200605T1 (hr) | 2020-07-10 |
UY35985A (es) | 2015-09-30 |
DK3102213T3 (da) | 2020-05-04 |
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