JP2010533181A - TNFα阻害剤の肺投与のための方法及び組成物 - Google Patents
TNFα阻害剤の肺投与のための方法及び組成物 Download PDFInfo
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Abstract
Description
本願は、2007年7月13日提出の米国仮出願第60/959,426号(その全体において本明細書中に組み込まれる)に対する優先権を主張する。
「肺投与」又は「肺送達」という用語は、吸入による対象の肺を通じたTNFα阻害剤の投与を指す。
TNFα阻害剤、例えばTNFα抗体の肺投与により、薬物送達のより伝統的な手段、例えば皮下及び静脈内、に対して有利な代替法がもたらされる。疾患の治療のためにTNFα阻害剤を吸入することにより、対象は針を用いた注射に付随する疼痛を回避することができるが、それでもなおTNFα阻害剤の全身循環が達成され、その結果治療効果が得られる。
ある実施形態において、TNFα抗体又はその抗原結合部分を含むTNFα阻害剤は、ドライパウダー吸入器(DPI)を通じて対象に送達される。DPIは、ミストの代わりに肺へドライパウダーを送達するために対象の吸入を用いて、固体又は乾燥粉末形態のTNFα阻害剤などの薬剤を送達するために使用される。DPIは、直接対象の肺に行くようにTNFα阻害剤を吸い込む(吸入する)ために使用される。DPIは、噴射剤不含装置であり、この場合、送達用の薬剤は、当技術分野で公知の適切な担体と混合される。DPI装置で使用される薬剤の単位用量は、硬カプセルのドライパウダーブリスターディスクであることが多い。DPIは、噴霧乾燥、噴霧凍結乾燥及び微粒化造粒製剤を含む、吸入される、分散性の安定なドライパウダー製剤を生成させる。DPI装置は、インスリン、インターフェロン(IFN)及び成長ホルモン(GH)を含む巨大分子薬剤を送達するために使用されている。
カプセルから多孔性粉末を送達する小型の呼吸活性化システムを含むAIR(R)吸入器(Alkermes)(WO99/66903及びWO00/10541参照)を含む。多孔性粒子は、1から5μmの空気力学径を有し、噴霧乾燥により調製される。AIRTM吸入器は、アルブテロール、エピネフリン、インスリン及びhGHを送達するために使用されてきた。
ある実施形 態において、TNFα抗体又はその抗原結合部分を含むTNFα阻害剤は、定量吸入器(MDI)装置を通じて対象に送達される。MDI装置は、肺へ再現可能な計量薬物用量を送達するために噴射剤を使用し、薬物又は薬剤、噴射剤(例えばヒドロフルオロアルカン(HFA))、界面活性剤(例えばホスファチジルコリン、ホスファチジルエタノールアミン、ホスファチジルイノシトール、リソホスファチジルコリン、ホスファチジン酸、トリグリセリド、モノグリセリド、大豆レシチン、脂肪酸及びアルキル−ポリグリコシド)及び溶媒を含む。MDI装置は、キャニスター、絞り弁及びスペーサーを含む小型の加圧型ディスペンサーであることが多い。MDI装置により投与される用量は、一般にmg単位であり、約25から100mLの体積の範囲である。さらに、MDI装置は、それらに不正開封防止装置が付いている場合有利である。
ある実施形態において、TNFα抗体又はその抗原結合部分を含むTNFα阻害剤は、ネブライザー又は液体吸入器を用いて対象に送達される。一般に、ネブライザーは、吸入のための湿潤エアロゾル又はミストとして薬物を送達させるために圧縮空気を使用し、従って、薬物が水溶性であることが必要である。ネブライザー装置は、MDI又はDPI装置と比較して比較的大きい用量を送達させることができ、深部肺(末梢肺領域)への送達に特に有効である。ジェットネブライザー(エアジェットネブライザー及び液体ジェットネブライザー)及び超音波ネブライザーを含むネブライザーの場合噴射剤は必要ない。
本発明の方法での使用のための、抗体、抗体部分及びその他のTNFα阻害剤は、対象への肺投与に適切な医薬組成物へ組み込まれ得る。
本発明の方法及び組成物で使用されるTNFα阻害剤は、TNFα活性を妨害する何らかの薬剤を含む。好ましい実施形態において、TNFα阻害剤は、TNFα活性、特にクローン病、RA、PsA、JRA、AS及び乾癬及び関連合併症及び症候と関連する有害なTNFα活性を中和し得る。
a)表面プラズモン共鳴により計算された場合、1x10−3s−1以下のKoff速度定数でヒトTNFαから解離し;
b)配列番号3又は位置1、4、5、7もしくは8での1個のアラニン置換により又は位置1、3、4、6、7、8及び/又は9での1から5個の保存アミノ酸置換により配列番号3から修飾されたアミノ酸配列を含む軽鎖CDR3ドメインを有し;
c)配列番号4のアミノ酸配列又は位置2、3、4、5、6、8、9、10もしくは11での1個のアラニン置換により又は位置2、3、4、5、6、8、9、10、11及び/又は12での1から5個の保存的アミノ酸置換により配列番号4から修飾されたアミノ酸配列を含む重鎖CDR3ドメインを有する。
本明細書中で使用される場合、「TNFα活性が有害である疾患」という用語は、疾患に罹患している対象におけるTNFαの存在が、疾患の病態生理又は疾患の憎悪に関与する因子に関与するか又は関与することが疑われる、その疾病及びその他の疾患を含むものとする。従って、TNFα活性が有害である疾患は、TNFα活性の阻害により疾患の症候及び/又は進行が軽減されると予想される疾患である。このような疾患は、例えば上記のように抗TNFα抗体を使用することにより検出され得る、例えば、疾患に罹患している対象の体液中のTNFαの濃度の上昇(例えば、対象の、血清、血漿、滑液などの中の濃度の上昇)により証明され得る。以下に限定されないが、自己免疫疾患、例えば、関節リウマチ(RA)又は若年性関節リウマチ(JRA)、脊椎関節症、例えば強直性脊椎炎(AS)又は乾癬性関節炎(PsA)、腸管疾患、例えばクローン病、皮膚疾患、例えば乾癬及び肺疾患、例えばCOPD又は喘息を含め、TNFα活性が有害である疾患には多くの例がある。
ある実施形態において、本発明は、自己免疫疾患の治療を含む。アダリムマブなどのTNFα抗体は、自己免疫疾患を治療するために使用され得る。このような自己免疫状態の例には、関節リウマチ、リウマチ様脊椎炎、変形性関節症及び痛風性関節炎、アレルギー、多発性硬化症、自己免疫性糖尿病、自己免疫性ブドウ膜炎及びネフローゼ症候群が含まれる。自己免疫性状態のその他の例には、多臓器自己免疫疾患及び自己免疫性難聴が含まれる。自己免疫疾患のその他の例は、米国出願第10/622932号(本明細書中に参照により組み込まれる)に記載されている。
TNFαは、組織炎症を活性化し、関節リウマチにおける関節破壊を引き起こすことに関与している(例えば、Moeller、A.ら(1990)Cytokine 2:162−169;Moellerらに対する米国特許第5,231,024号;Moeller、A.らによる欧州特許公開260 610 B1;Tracey及びCerami、前出;Arend、W.P.及びDayer、J−M.(1995)Arth.Rheum.38:151−160;Fava、R.A.ら(1993)Clin.Exp.Immunol.94:261−266)。
腫瘍壊死因子は、若年性関節リウマチを含む若年性関節炎の病態生理に関与している(Gromら(1996)Arthritis Rheum.39:1703;Manggeら(1995)Arthritis Rheum.8:211)。ある実施形態において、本発明のTNFα抗体は、若年性関節リウマチを治療するために使用される。「若年性関節リウマチ」又は「JRA」という用語は、本明細書中で使用される場合、関節又は結合組織損傷を引き起こし得る16歳以前に起こる慢性の炎症性疾患を指す。JRAはまた、若年性慢性多発性関節炎及びスティル病とも呼ばれる。JRAは、16歳以下の小児における6週間を超える関節の炎症及び強張りを引き起こす。炎症は、関節において、発赤、腫脹、熱感及び痛みを引き起こす。あらゆる関節で起こり得、炎症により罹患関節の可動性が制限され得る。JRAのあるタイプはまた内臓にも影響を及ぼし得る。
ある実施形態において、本発明は、脊椎関節症の治療を含む。本明細書中で使用される場合、「脊椎関節症(spondyloarthropathy又はspondyloarthropathies)」という用語は、脊椎の関節を冒すいくつかの疾病の何れか1つを指すために使用され、このような疾病は、共通の臨床的、放射線学的及び組織学的特性を共有する。多くの脊椎関節症が遺伝子の特徴を共有し、即ちこれらはHLA−B27対立遺伝子に関連する。ある実施形態において、「脊椎関節症」という用語は、強直性脊椎炎を除く脊椎の関節が冒されるいくつかの疾患の何れか1つを指すために使用され、このような疾病は、共通の臨床的、放射線学的及び組織学的特性を共有する。脊椎関節症の例には、強直性脊椎炎、乾癬性関節炎/脊椎炎、腸疾患性関節炎、反応性関節炎又はロイター症候群及び未分化脊椎関節症が含まれる。脊椎関節症を研究するために使用される動物モデルの例には、ank/ankトランスジェニックマウス、HLA−B27トランスジェニックラット(Taurogら(1998)The Spondylarthritides.Oxford University Press参照)が含まれる。
ある実施形態において、本発明は、TNFα阻害剤、例えば、TNFα抗体又はその抗原結合部分を用いた強直性脊椎炎の治療を含む。腫瘍壊死因子は強直性脊椎炎の病態生理に関連している(Verjansら(1991)Arthritis Rheum.34:486;Verjansら(1994)Clin Exp Immunol.97:45;Kaijtzelら(1999)Hum Immunol.60:140参照)。強直性脊椎炎(AS)は、1以上の椎骨の炎症を含む炎症性疾患である。ASは、脊椎の対骨間の関節及び仙腸関節及び脊柱と骨盤との間の関節を含む、軸骨格及び/又は末梢関節が冒される慢性炎症性疾患である。ASにより、最終的に、罹患椎骨が融合するか又は1つになり得る。ASを含む脊椎関節症は、乾癬性関節炎(PsA)及び/又は潰瘍性大腸炎及びクローン病を含む炎症性腸疾患(IBD)に伴い得る。
ある実施形態において、本発明は、TNFα阻害剤、例えばTNFα抗体又はその抗原結合部位を使用した乾癬性関節炎の治療を含む。腫瘍壊死因子は、乾癬性関節炎(PsA)の病態生理に関与している(Partschら(1998)Ann Rheum Dis.57:691;Ritchlinら(1998)J Rheumatol.25:1544)。本明細書に記載のように、乾癬性TNFαは、組織炎症を活性化し、関節リウマチにおける関節破壊を引き起こすことに関与している(例えば、Moeller、A.ら(1990)Cytokine 2:162−169;Moellerらに対する米国特許第5,231,024号;Moeller、A.による欧州特許公開260 610 B1;Tracey及びCerami、上記;Arend、W.P及びDayer、J−M.(1995)Arth.Rheum.38:151−160;Fava、R.A.ら(1993)Clin.Exp.Immunol.94:261−266)。TNFαは、膵島細胞の死を促進すること、及び糖尿病におけるインスリン抵抗性を媒介することにも関与している(例えば、Tracey及びCerami、上記;PCT公開WO94/08609号参照)。TNFαは、乏突起膠細胞への細胞毒性の媒介及び多発性硬化症における炎症性斑の誘導にも関与している(例えば、Tracey及びCeram、上記参照)。キメラ及びヒト化マウス抗TNFα抗体は、関節リウマチの治療について、臨床試験が行われた(例えば、Elliott、M.J.ら(1994)Lancet 344:1125−1127;Elliot、M.J.ら(1994)Lancet 344:1105−1110;Rankin、E.C.ら(1995)Br.J.Rheumatol.34:334−342参照)。
ある実施形態において、本発明は、皮膚及び爪の疾患の治療を含む。本明細書中で使用される場合、「TNFα活性が有害である皮膚及び爪の疾患」という用語は、本疾患に罹患している対象でのTNFαの存在が、疾患(例えば乾癬)の病態生理に関与するか、又は疾患の悪化に寄与している因子の何れかであることが示されているか又は疑われている、皮膚及び/又は爪の疾患ならびにその他の疾患を含むものとする。したがって、TNFα活性が有害である皮膚及び爪の疾患は、TNFα活性の阻害が疾患の症候及び/又は進行を緩和することが予測される疾患である。特異的な皮膚及び爪の疾患の治療のための抗体、抗体部分及びその他のTNFα阻害剤の使用を以下でさらに述べる。ある種の実施形態において、本発明の抗体、抗体部分又はその他のTNFα阻害剤は、以下に記載されるように、別の治療剤と組み合わせて対象に投与される。ある実施形態において、TNFα抗体は、乾癬の治療のための別の治療剤と組み合わせて対象に投与される。
腫瘍壊死因子は、乾癬の病態生理に関与している(Takematsuら(1989)Arch Dermatol Res.281:398;Victor及びGottlieb、2002 J Drugs Dermatol.1(3):264)。乾癬は、皮膚における、発赤、かゆみ及び厚く乾燥した銀色の鱗屑の頻繁な発現を特徴とする皮膚の炎症(過敏及び発赤)として記載される。特に、表皮の増殖の一次及び二次的変化、皮膚の炎症性反応及びリンホカイン及び炎症性因子などの制御分子の発現を含む病変が形成される。乾癬性皮膚は、表皮細胞の代謝回転の増加、肥厚した表皮、異常な角質化、基底細胞周期の増加をもたらす、表皮中への炎症細胞の浸潤ならびに多形核白血球及びリンパ球の表皮層中への浸潤を形態学的特徴とする。乾癬は、爪において、陥凹、爪の分離、肥厚及び変色を呈することが多い。乾癬は、その他の炎症性疾患、例えば、関節リウマチ、炎症性腸疾患(IBD)及びクローン病を含む関節炎を伴うことが多い。
ある実施形態において、本発明は、対象へのTNFα阻害剤の肺送達を含む対象において肺疾患を治療する方法を提供するが、肺投与は、対象の肺へのTNFα阻害剤の局所送達を含む。本発明の局所送達法に従い治療され得る肺疾患の例には、以下に限定されないが、COPD及び喘息が含まれる。従って、「局所」という用語は、肺に関して本明細書中で使用される。
ある実施形態において、本発明のTNFα抗体は、特発性間質性肺疾患に罹患している対象を治療するために使用される。特発性間質性肺疾患は、3通りの様式で肺に影響を及ぼし;第一に、既知又は未知の様式で肺組織が損傷を受け;第二に、肺胞壁が炎症を起こし;最後に、間質(又は肺胞間の組織)において瘢痕化(又は線維化)が始まり;肺が硬化する。特発性間質性肺疾患の例を下記で示す。
腫瘍壊死因子は、特発性肺線維症(IPF)の病態生理に関連している(Piquetら(1989)J Exp Med.170:655;Whyte、M.ら(2000)Am J Respir Crit Care Med 162:755−8;Corbett ELら(2002)Am J Respir Crit Care Med.165:690−3参照)。例えば、IPF患者は、マクロファージ及びII型上皮細胞において、TNF発現レベルが増大することが見出された(Piquetら(1993)Am J Pathol 143:651;Nashら(1993)Histopathology 22:343;Zhangら(1993)J Immunol 150:4188)。ある種の遺伝的多型もTNF発現の増大と関連し、IPF及びケイ肺症においてある役割を果たすことに関連している(Whyteら、同上;Corbettら、同上)。
ある実施形態において、本発明のTNFα抗体を、慢性閉塞性気流障害に罹患している対象を治療するために使用する。これらの疾患において、気流閉塞は、慢性及び持続性又は偶発性及び再発性であり得る。気流閉塞は、通常、最大呼気中の経時吐出体積を記録する努力呼気肺活量測定によって判定される。気流が閉塞されていない対象においては、完全な努力呼気には通常3から4秒かかる。気流が閉塞した慢性閉塞性気流障害患者において、完全な努力呼気には、通常、最高15から20秒かかり、息こらえ時間によって限定され得る。正常な1秒量の努力呼気体積(FEV1)は容易に測定され、年齢、性別及び身長に基づいて正確に予測される。FEV1と努力肺活量の比(FEV1/FVC)は通常0.75を超える。強制呼気とそれに続く強制吸気中の容積に対する気流の記録(流量−容積ループ)も、主に下気道狭窄から上気道狭窄を区別するために有用である。慢性閉塞性気道疾患の例を以下で述べる。
腫瘍壊死因子は、喘息の病態生理に関連している(Anticevich SZら(1995)Eur J Pharmacol.284:221−5;Thomas PSら1995.Am J Respir Crit Care Med.152:76−80;Thomas PS、Heywood G.(2002)Thorax.57:774−8)。例えば、急性喘息発作は、肺好中球増加及びBAL TNFレベルの上昇と関連することが分かった(Ordonez CL.ら(2000)Am J Respir Crit Care Med 161:1185)。喘息症候の重症度は、ハウスダスト中の内毒素レベルと相関することが見出された。ラットでは、抗TNF抗体は、内毒素によって誘発される気道変化を抑制した(Kipsら(1992)Am Rev Respir Dis 145:332)。
腫瘍壊死因子は、慢性閉塞性肺疾患の病態生理に関係する(Keatings VM.(2000)Chest.118:971−5;Sakao S.ら(2001)Am J Respir Crit Care Med.163:420−22;Sakao S.ら(2002)Chest.122:416−20)。本明細書では交換可能に使用される場合、「慢性閉塞性肺疾患」又は「COPD」という用語は、肺胞膨大及び肺組織破壊の程度が様々である、不十分な気流を特徴とする肺疾患群を指す。COPDという用語は、慢性気管支炎(杯細胞粘膜下腺肥大を伴う粘液分泌過多)、慢性閉塞性気管支炎又は気腫(気道実質組織の破壊)又はこれらの状態の組み合わせを含む。気腫及び慢性気管支炎は、慢性閉塞性肺疾患の最も一般的な形態である。COPDは不可逆的気流閉塞によって規定される。
以下に限定されないが抗体又はその抗原結合部分などのTNFα阻害剤は、以下に限定されないが、RA、AS、PsA、JRA、乾癬及び喘息を含む、TNFα活性が有害である疾患に罹患している対象の急性管理において有効であることが知られているさらなる治療薬と組み合わせて肺送達を通じて投与され得る。
その他の好ましい組み合わせは、プレドニゾロンを含むコルチコステロイドであり;本発明の抗TNFα抗体と組み合わせて患者を治療する場合に必要とされるステロイド用量を次第に減少させることにより、ステロイド使用の周知の副作用を減少させるか又はさらに排除することができる。本発明の抗体又は抗体部分が組み合わせられ得る関節リウマチに対する治療剤の非限定例には、次のもの:サイトカイン抑制抗炎症剤(CSAID);その他のヒトサイトカイン又は成長因子に対する抗体又はアンタゴニスト、例えば、TNF、LT、IL−1、IL−2、IL−3、IL−4、IL−5、IL−6、IL−7、IL−8、IL−15、IL−16、IL−18、IL−21、IL−23、インターフェロン、EMAP−II、GM−CSF、FGF及びPDGFが含まれる。本発明の抗体又はその抗原結合部分は、CD2、CD3、CD4、CD8、CD25、CD28、CD30、CD40、CD45、CD69、CD80(B7.1)、CD86(B7.2)、CD90、CTLAなどの細胞表面分子又はCD154(gp39又はCD40L)を含むそれらのリガンドに対する抗体と組み合わせられ得る。
カニクイザルにおけるアダリムマブ(HUMIRA(R))の吸入薬物動態
次の実験は、カニクイザルを用いた、アダリムマブが吸入を介して治療的に所望の全身レベルを達成する可能性を述べる。この実験の主要な目的の1つは、肺手段を介して投与されるアダリムマブの薬物動態を調べることである。これには、2種類の異なる吸入方式で、10mg/kgで、麻酔され、気管挿管され、換気されたサルの肺にアダリムマブの霧状化エアロゾルを投与し、次いでアダリムマブの吸入薬物動態の特徴を血清アッセイにより調べることが含まれた。さらに、同様に投与された、フルオロフォア標識非吸入デキストラン(FD−150S)のマーカーエアロゾルを用いて吸入の各方式を介した肺の局所的分布を調べ、次いで様々な肺領域からそれを直接回収した。
本試験は、カニクイザルの非ヒト霊長類を使用し、中枢及び末梢気道をそれぞれ標的とした2種類の異なる(浅及び深)吸入方式後の血清アダリムマブ濃度プロファイル及び薬物動態を調べた。気管挿管の深さ及び霧状化エアロゾルの大きさと同時に、換気における吸入操作を適切に選択することによって、このような標的化が達成された。標的とする肺沈着用量は10mg/kgアダリムマブであり、その血清濃度を16日間測定した。同様に投与されたフルオレセインイソチオシアネート(FITC)標識したデキストラン(FD−150S)のマーカーエアロゾルによって、吸入の各方式後の肺局所分布を調べ、次いで各解剖領域における肺沈着を直接測定した。
全般的に、麻酔下でBird Mark 7A呼吸回路において、動物に気管挿管し、換気させた。その回路において直列のAernonebsによって4.6及び2.1μm溶液エアロゾルとしてHUMIRA(R)(50mg/mLアダリムマブ)を霧状化し、浅及び深呼吸操作でそれぞれ、10mg/kgの標的肺沈着用量で肺に投与した。次いで、有効なELISAにより、16日間、アダリムマブの血清濃度を調べ、静脈内注射プロファイルと比較して、吸入薬物動態の特徴を調べた。FITC標識デキストラン(FD150)のマーカーエアロゾルを用いて、中枢及び末梢肺領域でのその肺沈着を直接測定することにより、吸入のこれらの2種類の方法の肺局所分布を個々に調べた。
この試験において、アダリムマブ(D2E7;HUMIRA(R);50mg/mL)及び参照標準物質を使用した。各バイアルに緩衝液0.8mL中のアダリムマブ40mgを入れ、希釈なしで直接使用した。下記のような、各サルに対する肺沈着用量の10mg/kgを達成するために、2−4バイアルを合わせ、ネブライザー用の投与溶液を調製したことに注意すること。280nmでのUV検出及び特異的で感度の高いELISAとそれぞれ組み合わせたイオン交換HPLC(IE−HPLC)の有効な方法によって、非生体及び生体試料中の抗体を調べた。
この試験において、全部で7匹の雄カニクイザル(受領時体重2.6−3.0kg)を使用した。温度、湿度及び明暗サイクル時間に関して厳重に制御された部屋に各サルを1匹ずつ収容した。獣医及び動物看護士により行われる認可済みデイリーエンリッチメントプラン(daily enrichment plan)に従い、サルを慎重に維持し、馴化させた。薬物動態研究における覚醒状態下で血液試料採取が容易になるように、飼育ケージシステムから前肢又は後肢の何れか伸ばすように動物を訓練した。食餌又は水の制限はなかった。
吸入を介した肺へのアダリムマブ送達に対して、0.1mg/kg(0.4mg/mL;American Regent)の硫酸アトロピンの筋肉内注射、10.0mg/kgのケタミン塩酸塩(Ketaject(R);100mg/mL;Phoenix Pharmaceuticals)及び1.0mg/kgのキシラジン(Xyla−ject(R);20mg/mL;Phoenix Pharmaceuticals)の組合せで動物(体重3.0−3.8kg;INH−S及びINH−dに対してn=2;表1)を麻酔した。安定麻酔下で、カフ付き気管内(ET)チューブ(3.0mM I.D.及び4.2mM O.D.;Hudson Respiratory Care)を各動物に気管挿管し、空気圧で動くBird Mark 7A呼吸器(VIASYS Healthcare)で換気した。麻酔が妥当であること及び異常がないことを確認するために、この手順を通じて約10分ごとにそれらのバイタルサイン、例えば、心拍、血圧、体温及び酸素飽和度(SpO2)%ならびに眼瞼刺激に対する瞬目反応を監視した。異なる大きさのアダリムマブエアロゾルを生成させた2種類のタイプのAeroneb Labマイクロポンプネブライザー(AeroGen、Galway、Ireland)をMark 7A 呼吸器回路とともに直列で使用した。従って、表2で示されるように、次の、気管挿管の深度、呼吸器設定及び及びエアロゾルの選択を異なるように行うことによって、一方で10mg/kgの同様の肺用量を維持しながら、浅部及び深部の肺局所分布を標的化することができた。
上述の吸入薬物動態の実験と同じ方式で、動物(体重4.1及び3.6kg;IVに対してn=2;表1)に麻酔をかけ、気管挿管した。正常なバイタルサイン下で適切な麻酔を観察した後、3分以内に、側伏在静脈を通じて、50mg/mLアダリムマブ溶液それぞれ0.82及び0.72mLを静脈内注射し、10mg/kgの用量を達成した。0.5、1、2、4、6、12及び24時間、次いで2、4、6、8、10、12、14及び16日の様々な時間間隔で、注射後、静脈血試料(1.2mL)を採血し、分析前にそれらの血清を−70℃で保管した。使用した試料採取及び保管手順は、上述のものと同じであった。異常がないことを確認するために、毎日動物の観察を同様に行った。
図2及び3で示される各血清アダリムマブプロファイルは個々の各動物に相当し、次の薬物動態パラメーターを計算することができる:最大血清濃度(Cmax)及びデータ観察によるCmaxを達成するための時間(Tmax)、4から8日の間のプロファイルの自然対数線形回帰による、最終相速度定数(λ)及び半減期(T1/2=0.693/λ)、台形法による8日までの時間曲線に対する血清濃度下面積(AUC0−8日)及びAUC0−8日+外挿AUCからの無限大時間までの時間曲線に対する血清濃度下面積(AUC0−∞)、用量/AUC0−∞からの総全身クリアランス(CL)及び、CLに平均滞留時間(MRT)を掛けたものからの定常状態での見かけの分布容積(Vss)(後者は、血清アダリムマブプロファイルからのモーメント解析から計算される。)。
可能な相互作用及び/又は合併症を最小限に抑えるために約30日間の十分なウォッシュアウト期間後、実験を行った。上述の吸入薬物動態の実験と同じ方式で、動物(体重3.2−4.3kg;INH−S及びINH−Dに対してn=3;表1)に麻酔をかけ、気管挿管し、換気した(2種類の異なる(浅及び深)吸入方式を含む)(表2)。正常なバイタルサイン下での適切な麻酔の観察後、6−8分間乾燥するまで、呼吸器回路において、ネブライザーに入れた20mg/mL FD−150S溶液(PBS;pH7.4)2.0mLをエアロゾル化し、それにより、表2に記載の浅及び深吸入操作下で2.5mg/kgの標的用量で動物に投与した。呼吸器回路の出口でフィルターにより非沈着性呼気FD−150Sを回収した。投与終了時に、PBS 250mLを用いて、ネブライザー、呼吸器回路及び呼気フィルター中に残存するFD−150Sを回収し、次に有効な蛍光−GPCにより調べた。従って、ネブライザーカップに充填された最初の添加FD−150Sからそれを差し引くことによって、各実験における「実際の」FD−150Sの肺沈着用量を推測した(40mg;20mg/mLに2.0mLを掛ける)。
抗体のロバスト性が確認されたエアロゾルの大きさの特徴を調べるための次世代Pharmaceutical Impactorによって、呼吸器回路へと霧状化されたアダリムマブを回収することにより、感知可能な分解を引き起こすことなく、抗体がロバストであることが確認され、参照標準物質に対するものと変化がないことがそのIE−HPLCクロマトグラムにより明らかになった。全ての動物が、処置に関わらず、局所又は全身性の副作用の徴候なく、エアロゾルに良好な耐容性があった。投与のための麻酔中に監視された全てのバイタルサインは、麻酔での正常範囲内で安定であり、例えば、心拍90−125bpm、血圧115−180mmHg、体温36.0−37.6℃及びSpO283−99%であった。苦痛、合併症又は異常の徴候は全くなかった。肺局所分布の研究でのその切除時に各動物の肺を目視することにより、浮腫又は粘膜色の変化がないことから外見的に正常であると結論付けた。
2種類の異なる吸入方式後の時間に対する血清アダリムマブ濃度及び誘導される薬物動態パラメーターをそれぞれ図2及び表3で示す。推定肺沈着用量は、10.3−14.0mg/kg(表3)の範囲であり、10mg/kgの標的用量とよく一致した。全動物において、抗体は明らかに全身循環を達成し、一方、Cmaxは2.31−5.91mg/L(3.88±1.57mg/L;表3)の範囲であり、ヒトにおける所望の抗体レベル、即ち5mg/Lより僅かに低いか又は同等のままであった(アダリムマブ包装の挿入物の処方情報)。特に、Tmaxは遅いことがわかり、2−4日以降に現れ、これは、吸入方式にかかわらず、肺からのアダリムマブの吸収がかなり遅いことを意味した。一方で、サルにおけるエリスロポエチン(Epo)及び卵胞刺激ホルモン(FSH)の吸入Fc−融合タンパク質に対する同様の研究から、Tmaxが≦2日間より短いことが報告された。(Bitontiら(2004);Lowら(2005)Hum Reprod 20:1805−1813)。
この研究で使用される2種類の異なる吸入方式後の肺局所分布及びFD−150Sを表5及び図4で示す。6匹のマウスにおける肺沈着用量は2.18−3.82mg/kg(2.90±0.72mg/kg;表5)の範囲であり、合理的に、2.5mg/kgの標的用量と一致する。さらに、分析から、肺沈着用量に対する回収は≧90%(93.7±3.3%;表5)となり、このことから、発明者らの肺沈着用量推測法が有効であり、得られた肺局所分布データはアダリムマブに対する実際の分布に相当することが示唆された。結果として、挿管深度及びエアロゾルの大きさにおける操作と平行して浅及び深吸入操作(表2)は実際に、表5及び図4で示されるように、それぞれ大きな(〜60%)中枢及び末梢肺局所分布が得られた。
10mg/kgのアダリムマブ吸入によって、F%が1.0−4.2%と低いにもかかわらず、2−4日という比較的速いTmaxでその治療的に所望の血清レベル、即ち4mg/L、が得られた。上部気管支気道送達によって、おそらくFcRnが介在する機構により、アダリムマブの肺吸収が深部肺送達と同定度であったと思われた。サルでの上記の実験から、アダリムマブの肺送達により全身抗体レベル(2.31−5.91mg/L;表3)が達成されたが、同時に、2−4日という比較的速いTmaxで、ヒトにおいて皮下投薬計画で所望されるものと同等であり、その絶対的バイオアベイラビリティー(F%)が0.99−4.18%と低いままであることが明らかとなった。これは、本明細書中に記載のもの(肺からのFcRn−介在経細胞輸送性吸収が高親和性及び低容量系であり、それによってラットでのその速度が依然として≦100ng/時間であることを示唆する。)を含む、最近の知見と一致すると思われる(Kimら(2004)Am J Physiol 287:L616;Sakagamiら(2006)Pharm Res 23:270;及びSakagamiら(2006)Respiratory Drug Delivery X、1:57)。さらに、気道において、肺胞マクロファージは、おそらくアダリムマブを含め、IgG及びFc−分子を貪食し、肺吸収に対するデポーをさらに減少させ、それによってF%を低下させることが示された(Lonbryら(2004)Am J Physiol 286:L1002)。新たな証拠から、TNFαが喘息に対する有望な治療標的であり、その阻害によって患者における気道の過敏性及び肺機能が改善することが分かっている(Russoら(2005)Clin Sci(Lond)109:135;Howarthら(2005)Thorax 60:1012;Berryら(2005)Proc Am Thoracic Sco 2:A569)。この場合、より低い全身レベルで局所作用の持続時間を最大化するために有利であり得るのは、アダリムマブのみであった。
エアロゾル化アダリムマブ(HUMIRA(R))に対するL929抗原中和バイオアッセイ
次の実験は、L929抗原中和アッセイを用いた、吸入送達のための霧状化を介したアダリムマブのロバスト性を示す。この実験は、アダリムマブの生物活性が霧状化により減弱しないことを確認するために行われた。
本願を通じて引用され得る全ての引用参考文献の内容(参考文献、特許、特許出願及びウェブサイトを含む)は、そこで引用され参照物であるように、あらゆる目的のためにそれらの全体において参照により明らかに本明細書によって組み込まれる。本発明の実施は、別段の断りがない限り、当技術分野で周知である、免疫学、分子生物学及び細胞生物学の従来技術を使用する。
当業者は、本明細書に記載されている本発明の具体的な実施形態に対する多くの均等物を認識するか又は、定型的な実験操作のみを用いて均等物を究明することが可能である。このような均等物は、以下の特許請求の範囲によって包含されるものとする。本願を通じて引用される全ての参考文献、特許及び公開された特許出願の容は、参照により、本明細書に組み込まれる。
Claims (68)
- TNFαが有害である疾患が治療されるように、対象へTNFα阻害剤を肺送達することを含む、TNFα活性が有害である疾患に罹患している対象を治療する方法。
- TNFα阻害剤の全身循環が達成されるように、吸入を介して対象の中枢及び末梢肺領域にTNFα阻害剤を投与することを含む、対象においてTNFα阻害剤の全身循環を達成する方法。
- TNFα阻害剤の全身循環が達成されるように、吸入を介して対象の末梢肺領域にTNFα阻害剤を投与することを含む、対象においてTNFα阻害剤の全身循環を達成する方法。
- 吸入に適切な組成物中でTNFα阻害剤が処方される、請求項1から請求項3の何れか1項に記載の方法。
- 組成物が、吸入可能粉末、噴射剤含有エアロゾル及び噴射剤不含吸入溶液からなる群から選択される、請求項4に記載の方法。
- 吸入可能粉末がドライパウダー吸入器(DPI)を介して対象に投与される、請求項5に記載の方法。
- 噴射剤含有エアロゾルが定量吸入器(MDI)を介して対象に投与される、請求項5に記載の方法。
- 噴射剤不含吸入溶液がネブライザーを介して対象に投与される、請求項5に記載の方法。
- TNFα阻害剤に対して約4日以下のTmaxを達成することをさらに含む、請求項1から請求項8の何れか1項に記載の方法。
- 約0.3のP/C比が達成されるように、TNFα阻害剤が対象の中枢肺領域に分布する、請求項1から請求項8の何れか1項に記載の方法。
- 約1.3のP/C比が達成されるように、TNFα阻害剤が対象の末梢肺領域に分布する、請求項1から請求項8の何れか1項に記載の方法。
- TNFα阻害剤の少なくとも約2.3mg/Lの最大血清濃度(Cmax)が達成される、請求項1から請求項8の何れか1項に記載の方法。
- TNFα阻害剤の少なくとも約4.2mg/LのCmaxが達成される、請求項1から請求項8の何れか1項に記載の方法。
- TNFα阻害剤の少なくとも約5mg/LのCmaxが達成される、請求項1から請求項8の何れか1項に記載の方法。
- 約4日以下のTmax、少なくとも約0.99%の絶対的バイオアベイラビリティー(F%)及び少なくとも約2.3mg/LのCmaxからなる群から選択される少なくとも1つの薬物動態特性がTNFα阻害剤の投与後に達成される、請求項1から請求項8の何れか1項に記載の方法。
- TNFα阻害剤の投与後に約2から約4日のTmaxが達成される、請求項15に記載の方法。
- TNFα阻害剤の投与後に約2.3から約5.9mg/LのCmaxが達成される、請求項15に記載の方法。
- 対象がヒトである、請求項1から請求項17の何れか1項に記載の方法。
- 対象が、TNFα活性が有害である疾患に罹患している、請求項2から請求項17の何れか1項に記載の方法。
- TNFα活性が有害である疾患が、自己免疫疾患、脊椎関節症、腸管疾患、皮膚疾患及び肺疾患からなる群から選択される、請求項1又は19に記載の方法。
- 自己免疫疾患が関節リウマチ又は若年性関節リウマチである、請求項20に記載の方法。
- 脊椎関節症が強直性脊椎炎又は乾癬性関節炎である、請求項20に記載の方法。
- 腸管疾患がクローン病である、請求項20に記載の方法。
- 皮膚疾患が乾癬である、請求項20に記載の方法。
- 肺疾患が慢性閉塞性肺疾患又は喘息である、請求項20に記載の方法。
- TNFα阻害剤がTNFα抗体又はその抗原結合部分又は融合タンパク質である、請求項1から請求項25の何れか1項に記載の方法。
- 融合タンパク質がエタネルセプトである、請求項26に記載の方法。
- TNFα抗体又はその抗原結合部分が、インフリキシマブ、ゴリムマブ及びアダリムマブからなる群から選択される、請求項26に記載の方法。
- TNFα抗体又はその抗原結合部分が、ヒト化抗体、キメラ抗体、ヒト抗体及び多価抗体からなる群から選択される抗体である、請求項26に記載の方法。
- ヒトTNFα抗体又はその抗原結合部分が、1x10−8M以下のKd及び1x10−3s−1以下のKoff速度定数でヒトTNFαから解離し(両方とも、表面プラズモン共鳴により測定される)、1x10−7M以下のIC50で標準インビトロL929アッセイにおいてヒトTNFα細胞毒性を中和する、請求項29に記載の方法。
- ヒトTNFα抗体又はその抗原結合部分が、次の特性:
a)表面プラズモン共鳴により測定される場合に1x10−3s−1以下のKoff速度定数でヒトTNFαから解離すること;
b)配列番号3のアミノ酸配列又は位置1、4、5、7もしくは8での1個のアラニン置換により又は位置1、3、4、6、7、8及び/又は9での1から5個の保存的アミノ酸置換により配列番号3から修飾されたアミノ酸配列を含む軽鎖CDR3ドメインを有すること;
c)配列番号4のアミノ酸配列又は位置2、3、4、5、6、8、9、10もしくは11での1個のアラニン置換により又は位置2、3、4、5、6、8、9、10、11及び/又は12での1から5個の保存的アミノ酸置換により配列番号4から修飾されたアミノ酸配列を含む重鎖CDR3ドメインを有すること、
を有する、請求項29に記載の方法。 - ヒトTNFα抗体又はその抗原結合部分が、配列番号3のアミノ酸配列又は位置1、4、5、7もしくは8での1個のアラニン置換により配列番号3から修飾されたアミノ酸配列を含むCDR3ドメインを有する軽鎖可変領域(LCVR)を含み、配列番号4のアミノ酸配列又は位置2、3、4、5、6、8、9、10もしくは11での1個のアラニン置換により配列番号4から修飾されたアミノ酸配列を含むCDR3ドメインを有する重鎖可変領域(HCVR)を含む、請求項29に記載の方法。
- ヒトTNFα抗体又はその抗原結合部分が、配列番号1のアミノ酸配列を含む軽鎖可変領域(LCVR)及び配列番号2のアミノ酸配列を含む重鎖可変領域(HCVR)を含む、請求項29に記載の方法。
- 対象へのTNFα阻害剤の肺送達を含む、対象において肺疾患を治療する方法(肺投与は、対象の肺へのTNFα阻害剤の局所送達を含む)。
- 肺疾患が喘息又は慢性閉塞性肺疾患(COPD)である、請求項34に記載の方法。
- TNFα阻害剤がTNFα抗体又はその抗原結合部分又は融合タンパク質である、請求項34又は請求項35に記載の方法。
- 融合タンパク質がエタネルセプトである、請求項36に記載の方法。
- TNFα抗体又はその抗原結合部分が、インフリキシマブ、ゴリムマブ及びアダリムマブからなる群から選択される、請求項37に記載の方法。
- TNFα抗体又はその抗原結合部分が、ヒト化抗体、キメラ抗体、ヒト抗体及び多価抗体からなる群から選択される抗体である、請求項36に記載の方法。
- ヒトTNFα抗体又はその抗原結合部分が、1x10−8M以下のKdで及び1x10−3s−1以下のKoff速度定数で、ヒトTNFαから解離し(両方とも表面プラズモン共鳴により測定される)、1x10−7M以下のIC50で標準インビトロL929アッセイにおいてヒトTNFα細胞毒性を中和する、請求項39に記載の方法。
- ヒトTNFα抗体又はその抗原結合部分が、次の特性:
a)表面プラズモン共鳴により測定される場合に1x10−3s−1以下のKoff速度定数でヒトTNFαから解離すること;
b)配列番号3のアミノ酸配列又は位置1、4、5、7もしくは8で1個でのアラニン置換により又は位置1、3、4、6、7、8及び/又は9での1から5個の保存的アミノ酸置換により配列番号3から修飾されたアミノ酸配列を含む軽鎖CDR3ドメインを有すること;
c)配列番号4のアミノ酸配列又は位置2、3、4、5、6、8、9、10もしくは11での1個のアラニン置換により又は位置2、3、4、5、6、8、9、10、11及び/又は12での1から5個の保存的アミノ酸置換により配列番号4から修飾されたアミノ酸配列を含む重鎖CDR3ドメインを有すること、
を有する、請求項39に記載の方法。 - ヒトTNFα抗体又はその抗原結合部分が、配列番号3のアミノ酸配列又は位置1、4、5、7もしくは8での1個のアラニン置換により配列番号3から修飾されたアミノ酸配列を含むCDR3ドメインを有する軽鎖可変領域(LCVR)を含み、配列番号4のアミノ酸配列又は位置2、3、4、5、6、8、9、10もしくは11での1個のアラニン置換により配列番号4から修飾されたアミノ酸配列を含むCDR3ドメインを有する重鎖可変領域(HCVR)を含む、請求項39に記載の方法。
- ヒトTNFα抗体又はその抗原結合部分が、配列番号1のアミノ酸配列を含む軽鎖可変領域(LCVR)及び配列番号2のアミノ酸配列を含む重鎖可変領域(HCVR)を含む、請求項39に記載の方法。
- 医薬組成物が、対象による吸入に適切であり、吸入可能粉末又はドライパウダー組成物、噴射剤含有エアロゾル及び噴射剤不含吸入溶液又は懸濁液からなる群から選択される、TNFα抗体及び医薬的に許容可能な担体を含む医薬組成物。
- 医薬的に許容可能な担体がラクトース粉末又はグルコース粉末を含む、請求項44に記載の医薬組成物。
- TNFα抗体又はその抗原結合部分が、ヒト化抗体、キメラ抗体、ヒト抗体及び多価抗体からなる群から選択される抗体である、請求項44又は請求項45に記載の医薬組成物。
- TNFα抗体又はその抗原結合部分が、インフリキシマブ、ゴリムマブ及びアダリムマブからなる群から選択される、請求項44又は請求項45に記載の医薬組成物。
- ヒト抗TNFα抗体又はその抗原結合部分が、1x10−8M以下のKdで及び1x10−3s−1以下のKoff速度定数で、ヒトTNFαから解離し(両方とも表面プラズモン共鳴により測定される)、1x10−7M以下のIC50で標準インビトロL929アッセイにおいてヒトTNFα細胞毒性を中和する、請求項46に記載の医薬組成物。
- ヒトTNFα抗体又はその抗原結合部分が、次の特性:
a)表面プラズモン共鳴により測定される場合に1x10−3s−1以下のKoff速度定数でヒトTNFαから解離すること;
b)配列番号3のアミノ酸配列又は位置1、4、5、7もしくは8での1個のアラニン置換により又は位置1、3、4、6、7、8及び/又は9での1から5個の保存的アミノ酸置換により配列番号3から修飾されたアミノ酸配列を含む軽鎖CDR3ドメインを有すること;
c)配列番号4のアミノ酸配列又は位置2、3、4、5、6、8、9、10もしくは11での1個のアラニン置換により又は位置2、3、4、5、6、8、9、10、11及び/又は12での1から5個の保存的アミノ酸置換により配列番号4から修飾されたアミノ酸配列を含む重鎖CDR3ドメインを有すること、
を有する、請求項46に記載の医薬組成物。 - ヒトTNFα抗体又はその抗原結合部分が、配列番号3のアミノ酸配列又は位置1、4、5、7もしくは8での1個のアラニン置換により配列番号3から修飾されたアミノ酸配列を含むCDR3ドメインを有する軽鎖可変領域(LCVR)を含み、配列番号4のアミノ酸配列又は位置2、3、4、5、6、8、9、10もしくは11での1個のアラニン置換により配列番号4から修飾されたアミノ酸配列を含むCDR3ドメインを有する重鎖可変領域(HCVR)を含む、請求項46に記載の医薬組成物。
- ヒトTNFα抗体又はその抗原結合部分が、配列番号1のアミノ酸配列を含む軽鎖可変領域(LCVR)及び配列番号2のアミノ酸配列を含む重鎖可変領域(HCVR)を含む、請求項46に記載の医薬組成物。
- TNFα抗体又はその抗原結合部分の少なくとも約40mgを含む、請求項48から請求項51の何れか1項に記載の医薬組成物。
- TNFα抗体又はその抗原結合部分約40−160mgを含む、請求項48から請求項51の何れか1項に記載の医薬組成物。
- TNFα阻害剤を含む吸入可能粉末又はドライパウダー組成物を含む容器と、
吸入を介して吸入可能粉末又はドライパウダー組成物を対象に導入するための手段と、
を含む、対象へのTNFα阻害剤の肺投与のためのドライパウダー吸入器(DPI)装置。 - DPI装置が、単回投与又は複数回投与吸入器の何れかである、請求項54に記載のDPI装置。
- DPI装置が前計量型(pre−metered)又は装置計量型(device−metered)の何れかである、請求項54に記載のDPI装置。
- TNFα阻害剤を含むエアロゾル及び噴射剤を含む加圧キャニスターと、
吸入を介して対象にエアロゾルを導入するための手段と、を
含む、対象へのTNFα阻害剤の肺投与のための定量吸入器(MDI)装置。 - TNFα阻害剤を含む噴射剤不含吸入溶液又は懸濁液を含む容器と、対象へのTNFα阻害剤の肺投与のためのネブライザー装置と、を使用するための容器。
- TNFα阻害剤がTNFα抗体又はその抗原結合部分又は融合タンパク質である、請求項54から請求項58の何れか1項に記載の装置又は容器。
- 融合タンパク質がエタネルセプトである、請求項59に記載の装置又は容器。
- TNFα抗体又はその抗原結合部分が、ヒト化抗体、キメラ抗体、ヒト抗体及び多価抗体からなる群から選択される抗体である、請求項59に記載の装置又は容器。
- TNFα抗体又はその抗原結合部分が、インフリキシマブ、ゴリムマブ及びアダリムマブからなる群から選択される、請求項61に記載の装置又は容器。
- ヒトTNFα抗体又はその抗原結合部分が、1x10−8M以下のKdで及び1x10−3s−1以下のKoff速度定数で、ヒトTNFαから解離し(両方とも表面プラズモン共鳴により測定される)、1x10−7M以下のIC50で標準インビトロL929アッセイにおいてヒトTNFα細胞毒性を中和する、請求項61に記載の装置又は容器。
- ヒトTNFα抗体又はその抗原結合部分が、次の特性:
a)表面プラズモン共鳴により測定される場合に1x10−3s−1以下のKoff速度定数でヒトTNFαから解離すること;
b)配列番号3のアミノ酸配列又は位置1、4、5、7もしくは8での1個のアラニン置換により又は位置1、3、4、6、7、8及び/又は9での1から5個の保存的アミノ酸置換により配列番号3から修飾されたアミノ酸配列を含む軽鎖CDR3ドメインを有すること;
c)配列番号4のアミノ酸配列又は位置2、3、4、5、6、8、9、10もしくは11での1個のアラニン置換により又は位置2、3、4、5、6、8、9、10、11及び/又は12での1から5個の保存的アミノ酸置換により配列番号4から修飾されたアミノ酸配列を含む重鎖CDR3ドメインを有すること、
を有する、請求項61に記載の装置又は容器。 - ヒトTNFα抗体又はその抗原結合部分が、配列番号3のアミノ酸配列又は位置1、4、5、7もしくは8での1個のアラニン置換により配列番号3から修飾されたアミノ酸配列を含むCDR3ドメインを有する軽鎖可変領域(LCVR)を含み、配列番号4のアミノ酸配列又は位置2、3、4、5、6、8、9、10もしくは11での1個のアラニン置換により配列番号4から修飾されたアミノ酸配列を含むCDR3ドメインを有する重鎖可変領域(HCVR)を含む、請求項61に記載の装置又は容器。
- ヒトTNFα抗体又はその抗原結合部分が、配列番号1のアミノ酸配列を含む軽鎖可変領域(LCVR)及び配列番号2のアミノ酸配列を含む重鎖可変領域(HCVR)を含む、請求項61に記載の装置又は容器。
- TNFα抗体又はその抗原結合部分少なくとも約40mgを含む、請求項62から請求項66の何れか1項に記載の装置又は容器。
- TNFα抗体又はその抗原結合部分約40−160mgを含む、請求項62から請求項66の何れか1項に記載の装置又は容器。
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JP2015523395A (ja) * | 2012-07-24 | 2015-08-13 | ジェノア ファーマシューティカルズ,インク. | エアロゾルのピルフェニドン及びピリドンのアナログの化合物、及び、その使用 |
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JP2022078126A (ja) * | 2012-07-24 | 2022-05-24 | アヴァリン ファーマ インク. | エアロゾルのピルフェニドン及びピリドンのアナログの化合物、及び、その使用 |
JP7120984B2 (ja) | 2012-07-24 | 2022-08-17 | アヴァリン ファーマ インク. | エアロゾルのピルフェニドン及びピリドンのアナログの化合物、及び、その使用 |
Also Published As
Publication number | Publication date |
---|---|
WO2009011782A2 (en) | 2009-01-22 |
TW200922618A (en) | 2009-06-01 |
WO2009011782A3 (en) | 2009-03-26 |
US20090110679A1 (en) | 2009-04-30 |
JP2014062095A (ja) | 2014-04-10 |
CA2693771A1 (en) | 2009-01-22 |
EP2173380A4 (en) | 2011-08-31 |
CN101848733A (zh) | 2010-09-29 |
EP2173380A2 (en) | 2010-04-14 |
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