JP2014511393A - イソインドリン化合物を用いた疾患の治療方法 - Google Patents
イソインドリン化合物を用いた疾患の治療方法 Download PDFInfo
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Abstract
【選択図】 図1
Description
本出願は、その全体が引用により本明細書中に組み込まれている、2011年3月7日に出願された米国仮出願第61/449,716号の恩典を主張する。
本明細書で提供されるのは、皮膚筋炎、結節性痒疹、壊疽性膿皮症、円形脱毛症、化膿性汗腺炎、酒さ、扁平苔癬、巨細胞性動脈炎、シェーグレン症候群、痛風、慢性前立腺炎、後部ブドウ膜炎、外陰痛、及び間質性膀胱炎から選択される疾患を、(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオン、シクロプロピル{2-[(1S)-1-(3-エトキシ-4-メトキシフェニル)-2-(メチルスルホニル)エチル]-3-オキソイソインドリン-4-イル}カルボキシアミド、又はこれらの組合せの投与によって治療、予防、及び/又は管理する方法である。
腫瘍壊死因子アルファ(TNF-α)は、主に、免疫賦活剤に応答した単核貪食細胞によって放出されるサイトカインである。TNF-αは、分化、動員、増殖、及びタンパク質分解などのほとんどの細胞プロセスを増強することができる。低レベルでは、TNF-αは、感染体、腫瘍、及び組織損傷に対する防御を与えることができる。しかしながら、TNF-αは、多くの疾患において役割を果たすこともできる。例えば、哺乳動物又はヒトに投与されたとき、TNF-αは、炎症、発熱、心血管作用、出血、凝固、並びに急性感染及びショック状態において見られるのと同様の急性期応答を引き起こすか、又はこれらを悪化させる。
一態様において、本明細書で提供されるのは、ヒトの炎症性疾患、自己免疫疾患、及び他の関連疾患、例えば、皮膚疾患及びリウマチ性疾患から選択される疾患を治療、予防、及び/又は管理する方法である。いくつかの実施態様において、本明細書で提供されるのは、ヒトの皮膚疾患、リウマチ性疾患、及び炎症性疾患から選択される疾患を、TNF-α阻害剤、PDE4阻害剤、又はこれらの組合せによって治療、予防、及び/又は管理する方法である。
一態様において、本明細書で提供されるのは、皮膚筋炎、結節性痒疹、壊疽性膿皮症、円形脱毛症、化膿性汗腺炎、酒さ、扁平苔癬、巨細胞性動脈炎、シェーグレン症候群、痛風、慢性前立腺炎、後部ブドウ膜炎、外陰痛、間質性膀胱炎、及びこれらの組合せから選択される疾患を治療、管理、及び/又は予防する方法であって、該疾患を有する患者に、治療的又は予防的有効量の(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオン、又はその医薬として許容し得る塩もしくは溶媒和物を投与することを含む、方法である。いくつかの実施態様において、該化合物は、その(-)-エナンチオマーを実質的に含まない。
本明細書で使用される場合、別途示されない限り、用語「本発明の化合物」は、(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオン、シクロプロピル{2-[(1S)-1-(3-エトキシ-4-メトキシフェニル)-2-(メチルスルホニル)エチル]-3-オキソイソインドリン-4-イル}カルボキシアミド、これらの医薬として許容し得るプロドラッグ、代謝体、多形、塩、溶媒和物、立体異性体、及び包摂化合物、並びにこれらの組合せを含むが、これらに限定されない。
((+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオン)
本明細書で提供されるのは、皮膚筋炎、結節性痒疹、壊疽性膿皮症、円形脱毛症、化膿性汗腺炎、酒さ、扁平苔癬、巨細胞性動脈炎、シェーグレン症候群、痛風、慢性前立腺炎、後部ブドウ膜炎、外陰痛、間質性膀胱炎、及びこれらの組合せから選択される疾患を治療、管理、又は予防する方法であって、そのような治療、管理、又は予防を必要としている患者に、治療的又は予防的有効量の(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオン(アプレミラストとしても知られている)の(+)-エナンチオマーを投与することを含む、方法である。
本明細書で提供されるのは、皮膚筋炎、結節性痒疹、壊疽性膿皮症、円形脱毛症、化膿性汗腺炎、酒さ、扁平苔癬、巨細胞性動脈炎、シェーグレン症候群、痛風、慢性前立腺炎、後部ブドウ膜炎、外陰痛、間質性膀胱炎、及びこれらの組合せから選択される疾患を治療、管理、又は予防する方法であって、そのような治療、管理、又は予防を必要としている患者に、治療的又は予防的有効量のシクロプロピル{2-[(1S)-1-(3-エトキシ-4-メトキシフェニル)-2-(メチルスルホニル)エチル]-3-オキソイソインドリン-4-イル}カルボキシアミド又はN-[2-[(1S)-1-(3-エトキシ-4-メトキシフェニル)-2-(メチルスルホニル)エチル]-2,3-ジヒドロ-3-オキソ-1H-イソインドール-4-イル]-シクロプロパンカルボキサミドを投与することを含む、方法である。
本明細書で提供されるのは、皮膚筋炎、結節性痒疹、壊疽性膿皮症、円形脱毛症、化膿性汗腺炎、酒さ、扁平苔癬、巨細胞性動脈炎、シェーグレン症候群、痛風、慢性前立腺炎、後部ブドウ膜炎、外陰痛、及び間質性膀胱炎から選択される疾患を、本発明の化合物の1つ又は複数を、該疾患を有する患者に投与することによって、治療、予防、及び/又は管理する方法である。
本実施態様によって包含される特定の方法において、本発明の化合物は、本明細書に開示される1以上の疾患を治療、管理、及び/又は予防する方法において、別の薬物(「第二の活性剤」)と組み合わせて投与される。第二の活性剤としては、抗炎症剤、例えば、非ステロイド剤及びコルチコステロイド、抗マラリア薬、免疫抑制薬、抗生物質、抗ウイルス薬、免疫増強薬、ホルモン剤、PGE2、並びにこれらの組合せが挙げられるが、これらに限定されない。本発明の化合物の投与と組み合わせて使用することができる方法又は療法の非限定的な例としては、抗体の注射又は注入、及び幹細胞移植が挙げられる。
いくつかの実施態様において、本発明の化合物は、本明細書に開示される疾患を有する患者に周期的に投与することができる。周期的療法は、一定期間の本発明の化合物の投与、その後の一定期間の休止、及びこの連続的投与の反復を含む。周期的療法は、1以上の療法に対する抵抗性の発生を低下させ、該療法のうちの1つの副作用を回避もしくは軽減し、及び/又は治療の効力を向上させることができる。
一実施態様において、(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンは、経口的に、かつ1日1回の単回投与として、好ましくは、1日を通じた分割用量として与えられる、1日当たり約1mg〜約1000mgの量の単回又は分割1日用量で投与することができる。より具体的には、(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンの1日用量は、1日に2回、等分割用量で投与される。具体的には、(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンの1日用量範囲は、1日当たり約5mg〜約500mg、より具体的には、1日当たり約10mg〜約200mgであることができる。具体的には、(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンの1日用量は、5mg、10mg、15mg、20mg、25mg、30mg、50mg、又は100mg剤形で投与することができる。患者を管理する際に、療法は、より低い用量、おそらくは、約1mg〜約30mgで開始し、必要であれば、患者の全体的な応答に応じて、単回用量又は分割用量のいずれかとして、1日当たり最大約200mg〜約1000mgまで増加させるべきである。具体的には、(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンは、1日当たり2回、10mg、20mg、及び30mgで投与することができる。或いは、(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオンは、1日当たり1回、40mgで投与することができる。或いは、1日用量は、0.01mg/kg〜100mg/kgである。
医薬組成物を、個別的な、単一単位剤形の調製において使用することができる。本明細書に開示される医薬組成物及び剤形は、本発明の化合物、又はその医薬として許容し得る塩、溶媒和物、もしくは立体異性体、及び任意に第二の活性剤を含むことができる。任意の第二の活性剤の例は、本明細書に開示されている(例えば、第6.3.1節を参照されたい)。本明細書に開示される医薬組成物及び剤形は、1以上の担体、賦形剤、又は希釈剤をさらに含むことができる。
経口投与に好適である本明細書に開示される医薬組成物は、個別剤形、例えば、限定されないが、錠剤(例えば、チュアブル錠)、カプレット剤、カプセル剤、及び液体(例えば、フレーバーシロップ)として提示することができる。そのような剤形は、所定量の活性成分を含有しており、当業者に周知の薬学の方法によって調製することができる。一般に、レミントンの医薬科学(Remington's Pharmaceutical Sciences), 第18版, Mack Publishing社, Easton PA(1990)を参照されたい。
本発明の活性成分は、制御放出手段によるか、又は当業者に周知である送達装置によって投与することができる。制御放出手段又は送達装置の非限定的な例としては、その各々が引用により本明細書中に組み込まれている、米国特許第:3,845,770号;第3,916,899号;第3,536,809号;第3,598,123号;第4,008,719号;並びに第5,674,533号、第5,059,595号、第5,591,767号、第5,120,548号、第5,073,543号、第5,639,476号、第5,354,556号、及び第5,733,566号に記載されているものが挙げられる。そのような剤形を用いて、例えば、所望の放出プロファイルを提供するためにヒドロプロピルメチルセルロース、他のポリマーマトリックス、ゲル、透過膜、浸透圧系、多層コーティング、微粒子、リポソーム、ミクロスフェア、又はこれらの組合せを様々な割合で用いて、1以上の活性成分の低速又は制御放出を提供することができる。本明細書に記載されているものを含む、当業者に公知の好適な制御放出製剤は、本発明の活性成分とともに使用するために容易に選択することができる。したがって、本発明は、経口投与に好適な単一単位剤形、例えば、限定されないが、制御放出に適している錠剤、カプセル剤、ゲルキャップ剤、及びカプレット剤を包含する。
非経口剤形は、限定されないが、皮下、静脈内(ボーラス注射を含む)、筋肉内、及び動脈内を含む、様々な経路によって患者に投与することができる。その投与は、通常、汚染物質に対する患者の自然防御を回避するので、非経口剤形は、滅菌されているか、又は患者に投与する前に滅菌することができることが好ましい。非経口剤形の非限定的な例としては、注射にそのまま利用可能な溶液、注射のための医薬として許容し得るビヒクルにすぐに溶解又は懸濁させることができる乾燥品、注射にそのまま利用可能な懸濁剤、及び乳剤が挙げられる。
薬物は、皮膚及びその付属器に、又は種々の粘膜に局所的に適用することができる。使用することができる経路としては、局所、経皮、舌下、鼻腔、膣、嚢胞、直腸、包皮、眼球、口腔、又は耳が挙げられる。多くの剤形は、活性成分を適用部位に送達し、局所的効果をもたらすように開発されている。本発明の経皮、局所、及び粘膜剤形としては、点眼液、スプレー剤、エアゾール剤、クリーム剤、ローション剤、軟膏剤、ゲル剤、液剤、乳剤、懸濁剤、又は当業者に公知の他の形態が挙げられるが、これらに限定されない。例えば、レミントンの医薬科学(Remington's Pharmaceutical Sciences), 第16版及び第18版, Mack Publishing社, Easton PA(1980 & 1990);及び医薬剤形入門(Introduction to Pharmaceutical Dosage Forms), 第4版, Lea & Febiger社, Philadelphia(1985)を参照されたい。口腔内の粘膜組織を治療するのに好適な剤形は、マウスウォッシュとしてか又はオーラルゲルとして製剤化することができる。さらに、経皮剤形としては、「リザーバ型」又は「マトリックス型」パッチが挙げられ、これらは、皮膚に適用し、特定の時間装着して、所望量の活性成分の透過を可能にすることができる。
いくつかの実施態様を以下の非限定的な実施例によって例証する。これらの実施例は、その範囲の限定とみなされるべきではない。本発明の範囲は、添付の特許請求の範囲によってのみ定義される。
(3-アミノフタル酸の調製)
10%Pd/C(2.5g)と3-ニトロフタル酸(75.0g、355mmol)とエタノール(1.5L)の混合物を窒素下の2.5LのParr水素化装置に仕込んだ後、水素を該反応容器に55psi(379kPa)まで仕込んだ。水素圧を50psi(245kPa)〜55psi(379kPa)で維持しながら、該混合物を13時間振盪させた。水素を放出させ、該混合物を窒素で3回パージした。懸濁液をセライト床に通して濾過し、メタノールですすいだ。濾液を真空中で濃縮すると、固体が得られた。該固体をエーテルに懸濁させ、真空濾過により単離した。該固体を真空中で一定重量まで乾燥させると、54g(84%収率)の3-アミノフタル酸が黄色の生成物として得られた。DMSO-d6中の該生成物は、以下の化学シフト(δ、単位ppm): 3.17(s, 2H), 6.67(d, 1H), 6.82(d, 1H), 7.17(t, 1H), 8-10(brs, 2H)を示す1H NMRスペクトルを特徴とした。DMSO-d6中の該生成物は、以下の化学シフト(δ、単位ppm): 112.00, 115.32, 118.20, 131.28, 135.86, 148.82, 169.15, 170.09を示す13C-NMRスペクトルを特徴とした。
3-アミノフタル酸(108g、596mmol)と無水酢酸(550mL)の混合物を、機械撹拌器、温度計、及び冷却器を装備した1Lの3つ口丸底フラスコに仕込んだ。反応混合物を3時間還流させ、周囲温度に冷却し、0〜5℃でさらに1時間保持した。結晶性固体を真空濾過により収集し、エーテルで洗浄した。固体生成物を真空中で周囲温度で一定重量まで乾燥させると、75g(61%収率)の3-アセトアミドフタル酸無水物が白色の生成物として得られた。CDCl3中の該生成物は、以下の化学シフト(δ、単位ppm): 2.21(s, 3H), 7.76(d, 1H), 7.94(t, 1H), 8.42(d, 1H), 9.84(s, 1H)を示す1H NMRスペクトルを特徴とした。
2-(3-エトキシ-4-メトキシフェニル)-1-(メチルスルホニル)-エト-2-イルアミン(137.0g、500mmol)とN-アセチル-L-ロイシン(52g、300mmol)とメタノール(1.0L)の混合物を、機械撹拌器、温度計、及び冷却器を装備した3Lの3つ口丸底フラスコに仕込んだ。反応混合物を1時間還流させた後、該混合物を周囲温度に冷却させておき、その後、周囲温度でさらに3時間撹拌した。スラリーを濾過し、メタノール(250L)で洗浄した。固体を風乾させ、その後、真空中で周囲温度で一定重量まで乾燥させると、109.5g(98%収率)の粗生成物(85.8%ee)が得られた。粗固体(55.0g)及びメタノール(440mL)を1時間還流させ、室温に冷却し、周囲温度でさらに3時間撹拌した。スラリーを濾過し、濾過ケーキをメタノール(200mL)で洗浄した。固体を風乾させ、その後、真空中で30℃で一定重量まで乾燥させると、49.6g(90%回収)の(S)-2-(3-エトキシ-4-メトキシフェニル)-1-(メチルスルホニル)-エト-2-イルアミン-N-アセチル-L-ロイシン塩(98.4%ee)が得られた。キラルHPLC(1/99 EtOH/20mM KH2PO4 @pH7.0、Agilent Technologies社製のUltron Chiral ES-OVS、150mm×4.6mm、0.5mL/分、@240nm):18.4分(S-異性体、99.2%)、25.5分(R-異性体、0.8%)。
500mLの3つ口丸底フラスコに、機械撹拌器、温度計、及び冷却器を装備した。該反応容器に、(S)-2-(3-エトキシ-4-メトキシフェニル)-1-(メチルスルホニル)-エト-2-イルアミンN-アセチル-L-ロイシン塩(25g、56mmol、98%ee)、3-アセトアミドフタル酸無水物(12.1g、58.8mmol)、及び氷酢酸(250mL)を仕込んだ。混合物を一晩還流させ、その後、<50℃に冷却した。溶媒を真空中で除去し、残渣を酢酸エチルに溶解させた。得られた溶液を水(250mL×2)、飽和水性NaHCO3(250mL×2)、及びブライン(250mL×2)で洗浄し、その後、無水硫酸ナトリウム上で乾燥させた。溶媒を真空中で蒸発させ、残渣を、エタノール(150mL)とアセトン(75mL)の混合物を含む二成分溶媒から再結晶化させた。固体を真空濾過により単離し、エタノール(100mL×2)で洗浄した。生成物を真空中で60℃で一定重量まで乾燥させると、19.4g(75%収率)のS-{2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-イノイソインドリン-1,3-ジオンが98%eeで得られた。キラルHPLC(15/85 EtOH/20mM KH2PO4 @pH5、Agilent Technology社製のUltron Chiral ES-OVS、150mm×4.6mm、0.4mL/分、@240nm):25.4分(S-異性体、98.7%)、29.5分(R-異性体、1.2%)。CDCl3中の該生成物は、以下の化学シフト(δ、単位ppm):
シクロプロピル{2-[(1S)-1-(3-エトキシ-4-メトキシフェニル)-2-(メチルスルホニル)エチル]-3-オキソイソインドリン-4-イル}カルボキサミドを、米国特許第6,667,316号の実施例57についての調製手順に従って調製した。テトラヒドロフラン(10mL)中の7-アミノ-2-[(1S)-1-(3-エトキシ-4-メトキシフェニル)-2-(メチルスルホニル)エチル]イソインドリン-1-オン(1.7g、4.2mmol)とシクロプロパンカルボニルクロリド(0.46mL、5.1mmol)の撹拌混合物を15分間加熱還流させた。該混合物に、メタノール(4mL)を室温で添加し、該混合物を10分間撹拌した。溶媒を真空中で除去すると、油状物が得られた。該油状物をエタノール(20mL)から再結晶化させると、化合物(II)が白色の固体(1.4g、71%収率)として得られた;m.p.172〜174℃;
(A)材料)
(A)材料)
(A)材料)
(CpG-A刺激されたヒトPBMCにおけるIFN-α産生)
(CpG-A刺激されたhPBMCにおけるIFN-αの産生の阻害に対する化合物の効果)
(A)材料)
Claims (40)
- ヒトの皮膚筋炎、結節性痒疹、壊疽性膿皮症、円形脱毛症、化膿性汗腺炎、酒さ、扁平苔癬、巨細胞性動脈炎、シェーグレン症候群、痛風、慢性前立腺炎、後部ブドウ膜炎、外陰痛、及び間質性膀胱炎から選択される疾患を治療する方法であって、該疾患を有する患者に、その(-)-エナンチオマーを実質的に含まない、治療的有効量の(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオン、又はその医薬として許容し得る塩もしくは溶媒和物を投与することを含む、前記方法。
- ヒトの皮膚筋炎、結節性痒疹、壊疽性膿皮症、円形脱毛症、化膿性汗腺炎、酒さ、扁平苔癬、巨細胞性動脈炎、シェーグレン症候群、痛風、慢性前立腺炎、後部ブドウ膜炎、外陰痛、及び間質性膀胱炎から選択される疾患を治療する方法であって、該疾患を有する患者に、その(R)-エナンチオマーを実質的に含まない、治療的有効量のシクロプロピル{2-[(1S)-1-(3-エトキシ-4-メトキシフェニル)-2-(メチルスルホニル)エチル]-3-オキソイソインドリン-4-イル}カルボキシアミド、又はその医薬として許容し得る塩もしくは溶媒和物を投与することを含む、前記方法。
- ヒトの皮膚筋炎、結節性痒疹、壊疽性膿皮症、円形脱毛症、化膿性汗腺炎、酒さ、扁平苔癬、巨細胞性動脈炎、シェーグレン症候群、痛風、慢性前立腺炎、後部ブドウ膜炎、外陰痛、及び間質性膀胱炎から選択される疾患を治療する方法であって、該疾患を有する患者に、その(-)-エナンチオマーを実質的に含まない、治療的有効量の(+)-2-[1-(3-エトキシ-4-メトキシフェニル)-2-メチルスルホニルエチル]-4-アセチルアミノイソインドリン-1,3-ジオン、又はその医薬として許容し得る塩もしくは溶媒和物を含む医薬組成物を投与することを含む、前記方法。
- ヒトの皮膚筋炎、結節性痒疹、壊疽性膿皮症、円形脱毛症、化膿性汗腺炎、酒さ、扁平苔癬、巨細胞性動脈炎、シェーグレン症候群、痛風、慢性前立腺炎、後部ブドウ膜炎、外陰痛、及び間質性膀胱炎から選択される疾患を治療する方法であって、該疾患を有する患者に、その(R)-エナンチオマーを実質的に含まない、治療的有効量のシクロプロピル{2-[(1S)-1-(3-エトキシ-4-メトキシフェニル)-2-(メチルスルホニル)エチル]-3-オキソイソインドリン-4-イル}カルボキシアミド、又はその医薬として許容し得る塩もしくは溶媒和物を含む医薬組成物を投与することを含む、前記方法。
- 前記医薬組成物が、治療的有効量の第二の活性剤をさらに含む、請求項3又は4記載の方法。
- 前記医薬組成物が、1以上の賦形剤、希釈剤、又は担体をさらに含む、請求項3、4、又は5記載の方法。
- 前記疾患が皮膚筋炎である、請求項1〜6のいずれか一項記載の方法。
- 前記疾患が結節性痒疹である、請求項1〜6のいずれか一項記載の方法。
- 前記疾患が壊疽性膿皮症である、請求項1〜6のいずれか一項記載の方法。
- 前記疾患が円形脱毛症である、請求項1〜6のいずれか一項記載の方法。
- 前記疾患が化膿性汗腺炎である、請求項1〜6のいずれか一項記載の方法。
- 前記疾患が酒さである、請求項1〜6のいずれか一項記載の方法。
- 前記疾患が扁平苔癬である、請求項1〜6のいずれか一項記載の方法。
- 前記疾患が巨細胞性動脈炎である、請求項1〜6のいずれか一項記載の方法。
- 前記疾患がシェーグレン症候群である、請求項1〜6のいずれか一項記載の方法。
- 前記疾患が痛風である、請求項1〜6のいずれか一項記載の方法。
- 前記疾患が慢性前立腺炎である、請求項1〜6のいずれか一項記載の方法。
- 前記疾患が後部ブドウ膜炎である、請求項1〜6のいずれか一項記載の方法。
- 前記疾患が外陰痛である、請求項1〜6のいずれか一項記載の方法。
- 前記疾患が間質性膀胱炎である、請求項1〜6のいずれか一項記載の方法。
- 前記化合物が、医薬として許容し得る塩として投与される、請求項1〜20のいずれか一項記載の方法。
- 前記化合物が、医薬として許容し得る溶媒和物として投与される、請求項1〜20のいずれか一項記載の方法。
- 前記溶媒和物が水和物である、請求項22記載の方法。
- 前記患者に、治療的有効量の第二の活性剤を投与することをさらに含む、請求項1〜23のいずれか一項記載の方法。
- 前記第二の活性剤が、抗炎症薬、免疫調節化合物、抗マラリア薬、免疫抑制薬、抗生物質、抗ウイルス薬、免疫グロブリン、免疫増強薬、ホルモン剤、PGE2、又はこれらの組合せである、請求項24記載の方法。
- 前記第二の活性剤がPGE2である、請求項25記載の方法。
- 前記医薬組成物又は前記化合物、もしくはその医薬として許容し得る塩もしくは溶媒和物が経口投与される、請求項1〜26のいずれか一項記載の方法。
- 前記医薬組成物又は前記化合物、もしくはその医薬として許容し得る塩もしくは溶媒和物が非経口投与される、請求項1〜26のいずれか一項記載の方法。
- 前記医薬組成物又は前記化合物、もしくはその医薬として許容し得る塩もしくは溶媒和物が局所投与される、請求項1〜26のいずれか一項記載の方法。
- 前記医薬組成物又は前記化合物、もしくはその医薬として許容し得る塩もしくは溶媒和物が、軟膏剤、クリーム剤、ゲル剤、ペースト剤、散布剤、ローション剤、スプレー剤、リニメント剤、湿布剤、エアゾール剤、液剤、乳剤、又は懸濁剤の剤形で局所投与される、請求項29記載の方法。
- 前記医薬組成物又は前記化合物、もしくはその医薬として許容し得る塩もしくは溶媒和物が、錠剤又はカプセル剤の剤形で経口投与される、請求項1〜26のいずれか一項記載の方法。
- 前記医薬組成物又は前記化合物、もしくはその医薬として許容し得る塩もしくは溶媒和物が、5mg、10mg、15mg、20mg、又は25mgの錠剤又はカプセル剤で経口投与される、請求項31記載の方法。
- 前記治療的有効量が、1日当たり約1mg〜約1000mgである、請求項1〜26のいずれか一項記載の方法。
- 前記治療的有効量が、1日当たり約5mg〜約500mgである、請求項33記載の方法。
- 前記治療的有効量が、1日当たり約10mg〜約200mgである、請求項34記載の方法。
- 前記治療的有効量が、1日当たり2回、20mgである、請求項1〜26のいずれか一項記載の方法。
- 前記治療的有効量が、1日当たり2回、30mgである、請求項1〜26のいずれか一項記載の方法。
- 前記治療的有効量が、1日当たり1回、40mgである、請求項1〜26のいずれか一項記載の方法。
- 前記医薬組成物又は前記化合物、もしくはその医薬として許容し得る塩もしくは溶媒和物が、1日当たり1回又は2回投与される、請求項1〜26のいずれか一項記載の方法。
- 前記医薬組成物又は前記化合物、もしくはその医薬として許容し得る塩もしくは溶媒和物が周期的に投与される、請求項1〜26のいずれか一項記載の方法。
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WO2023120466A1 (ja) * | 2021-12-23 | 2023-06-29 | 沢井製薬株式会社 | アプレミラスト水和物含有製剤 |
Also Published As
Publication number | Publication date |
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EP3320902A1 (en) | 2018-05-16 |
EP2683376B1 (en) | 2018-11-28 |
WO2012121988A3 (en) | 2013-01-10 |
ES2868231T3 (es) | 2021-10-21 |
ES2711100T3 (es) | 2019-04-30 |
US20140187599A1 (en) | 2014-07-03 |
EP3320902B1 (en) | 2021-02-17 |
EP2683376A2 (en) | 2014-01-15 |
WO2012121988A2 (en) | 2012-09-13 |
US9387195B2 (en) | 2016-07-12 |
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