JP6426624B2 - ロフルミラストn−酸化物の吸入によって自己免疫、呼吸器性および炎症性の障害を処置する方法 - Google Patents
ロフルミラストn−酸化物の吸入によって自己免疫、呼吸器性および炎症性の障害を処置する方法 Download PDFInfo
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- JP6426624B2 JP6426624B2 JP2015554296A JP2015554296A JP6426624B2 JP 6426624 B2 JP6426624 B2 JP 6426624B2 JP 2015554296 A JP2015554296 A JP 2015554296A JP 2015554296 A JP2015554296 A JP 2015554296A JP 6426624 B2 JP6426624 B2 JP 6426624B2
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- roflumilast
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Description
本発明は、自己免疫、呼吸器性および/または炎症性の疾患または状態、例えば、喘息、COPD、ならびに肺の他のアレルギー性および/または炎症性の障害を、ロフルミラストN酸化物またはその薬学的に許容される塩の肺投与によって(例えば、吸入によって)処置する方法に関する。本発明はまた、この方法での使用のための薬学的組成物にも関する。
本発明は、自己免疫、呼吸器性および/または炎症性の疾患または状態を、有効量のロフルミラストN酸化物またはその薬学的に許容される塩の肺投与によって(例えば、吸入によって)処置する方法を提供する。なんら特定の理論に結び付けられるものではないが、本発明者らは、ロフルミラストN酸化物の肺投与が、ロフルミラストN酸化物およびロフルミラストの低い血漿レベルを生じ、従って、ロフルミラストの経口投与よりも副作用が少ないという理論を立てる。さらに、ロフルミラストN酸化物の肺送達は、ロフルミラストの経口送達よりも広い治療濃度域を有する。これによって、薬物をより低用量で投与すること、および/または有害事象が少なないままで薬物投与計画を長くさせることが可能になる。
本発明の方法は、少量の活性な化合物を用いて呼吸器性および炎症性の疾患および状態の処置を可能にする、ならびに/または呼吸器性および炎症性の疾患および状態の処置をより効率的な方式で長期間にわたって可能にする。本発明の方法はまた、ロフルミラストN酸化物の経口投与の際に期待されるよりもロフルミラストまたはロフルミラストN酸化物の全身的な副作用を低下することも可能にする。
本発明の一態様は、吸入可能なドライパウダーの形態でロフルミラストN酸化物を含んでいる薬学的処方物を提供し、ここでこの処方物は、活性成分としてロフルミラストN酸化物の微粉末化された粒子、および生理学的に許容される薬理学的に不活性な固体の担体の粒子を含む。本発明以前には、ロフルミラストN酸化物が吸入に適切な微粉末化された粒子として調製され得ることは公知ではなかった。
i)活性成分および担体を一緒に微粒子化する工程;ならびにii)得られた共微粒子化された混合物を凝集および球状化に供する工程。
i)活性成分および担体を別々に微粒子化する工程;ii)微粒子化された成分を混合する工程;ならびにiii)得られた混合物を凝集および球状化に供する工程。
1つの好ましい実施形態では、吸入によって投与されるロフルミラストN酸化物は、微粉末化される。微粉末化は、機械的な衝撃によって(例えば、ハンマーミル、ピンミルまたはビーズミリングのようなミルの使用によって)または液体エネルギーを介した衝撃によって(例えば、ジェットミリングまたはスパイラルジェットミルもしくは流動床ジェットミルの使用によって)行われてもよい。微粉末化および微粉末化過程の追加の詳細は、Spring 2005 Pharmaceutical Manufacturing and Packaging Sourcerarticle(J. M Larranによる),Journal of Pharmaceutical Processing,「Advances in Powder Micronization Technology in Pharmaceutical Industry by Hokosawa Micron Powder System」; 微粉末化についてのWikipedia項目;G.Gianola,「Micronization Systems−Innovative Equipment Design and Applications」(Advances in Pharmaceutical Processingに提示)(Somerset,NJ,2012)およびR.Smith,「Micronization of Active Pharmaceutical Ingredients to Nanometer Scale」、(Advances in Pharmaceutical Processingに提示)(Somerset,NJ,2012)に示される。
●15gmのロフルミラストN酸化物を秤量した。
●圧縮空気供給用のメインノブを開放した。
●ベンチャー(venture)圧力を6.0バールに、リング圧力を0.5バールに調節した。
●ロフルミラストN酸化物を約200mg/分の供給速度でホッパーを通じて手動的に添加した。
●微粉末化の完了後、メイン空気供給ノブをオフに回して、微粉末化されたロフルミラストN酸化物を収集した。
収率:約9.0g(約60%の収率)。D90の粒径分布(Particle Size Distribution)(PSD):3.021μm; D50:1.564μmおよびD10:0.777μm。
本発明はここで、以下の非限定的な実施例によってさらに例示される。
ラット、イヌおよびヒトの肺ミクロソームを用いて代謝安定性研究を行った。ラット、イヌおよびヒトの肺ミクロソームを用いる研究のためのプロトコール(Xenotech,USA由来)を下に示す。
気管内(IT)経路による肺動態
雄および雌のウイスターラットを秤量して、種々の時点で群に無作為化した。ロフルミラストN酸化物を、気管内投与のための適切なビヒクル中の懸濁物として調製した。気管内投薬のために、動物をケタミン(50mg/kg;i.p.)で麻酔して、ロフルミラストN酸化物をラット用Intratracheal Microsprayer(登録商標)Aerosolizerを介して0.5mlのガラスシリンジ(Model IA−1B−R−GL500)(Penn Century,US)を用いて投与した。0.5ml/kgの容積レベルを、ラットの気道系に1.0mg/kgの用量で単回用量のおよび複数回用量の研究のために投与した。動物を正常な規則的食餌条件下で維持して、ラットの咀嚼食餌はその研究全体にわたって自由に提供した。血液および肺のサンプル(全ての収集は各々の動物から各々150μl)をサンプリングスケジュールに従って収集した。血液サンプルを眼窩静脈叢から、抗凝固剤としてEDTA二カリウムを含有する微量遠心管中に収集した。血液サンプルを直ちに1000gの速度で4℃で10分間遠心分離して、分離した血漿サンプルを−80℃より下で凍結して分析まで保管した。全てのサンプル中のロフルミラストN酸化物の血漿および肺での濃度を、確立した方法のとおりLC−MS/MS(X−Calibur2.0.7ソフトウェアを用いる)によって分析した。定量下限(LOQ)未満のサンプルを、生データ中で定量限界未満(BLQ)(below level of quantification)と呼び、結果を適宜作表した。薬物動態学的パラメーターCmax、AUC0−t、AUC0−∞、Tmax、t1/2、Kel、VZおよびCLZを、WinNonlin(Phoenix6.1ソフトウェア)を用いて、上の濃度について推定して、結果を作表した。血漿の薬物動態パラメーターを、濃度データからng/mlとして算出した。CmaxおよびAUC値は、それぞれng/mlおよびng・h/mlとして報告した。肺の薬物動態学的パラメーターを、濃度データからng/gとして算出した。CmaxおよびAUC値は、それぞれng/gおよびng−h/gを単位として報告した。肺対血漿の濃度比を、1に等しい血漿密度を仮定することによって算出した。ロフルミラストN酸化物の時間−平均血漿濃度プロットを、Graph pad Prism 5.02ソフトウェアを用いて行った。表2は、単回および複数回用量の研究についての肺および血漿の動態を示す。
吸入研究のために、ロフルミラストN酸化物を懸濁物として投与する。ロフルミラストN酸化物(100mg)を乳鉢に入れて、重量測定希釈における適切な溶媒の添加後に粉砕して微細な懸濁液を得る。
MH−S(マウス肺胞マクロファージ)細胞におけるリポポリサッカライド(LPS)誘発性TNFα:
MH−Sとは、LPSによる誘発の際に大量のTNFαを分泌するマウスの肺胞マクロファージ細胞株である。細胞は1ウェルあたり150,000個の細胞で播種される。種々の濃度のロフルミラストN酸化物をLPSの添加の15分前に添加する。LPS(1μg/ml)を添加し、次いで4時間インキュベートする。上清をインキュベーション期間の終わりに収集して、TNFαを、ELISAキットを用いて推定する。阻害パーセントおよびIC50値を決定する。
A.雌のSprague−Dawleyラットモデルにおけるリポポリサッカライド(LPS)誘発性の肺好中球増加
好中球(neutrophila)の過大な補充およびその後の活性化は、重篤な喘息、慢性閉塞性肺疾患、嚢胞性線維症、および急性呼吸窮迫症候群のような気道および肺におけるいくつかの炎症性の疾患の発達および経過について重要であると考えられる。好中球増加(neutrophila)がこれらの疾患に寄与する機序は、好中球エラスターゼのようなタンパク質分解性酵素および遊離の活性酸素の放出を含み得る。放出された場合、これらの化合物は、気管支収縮、気管支の過敏性、過剰分泌、上皮の損傷、および気道の組織再構築を生じ得る。
ロフルミラストは経口投与の際に、0.3、1、3および10mg/kgで、コントロール群と比較して好中球浸潤において用量依存性の阻害を示した。結果を図1に示す。阻害パーセントは、それぞれ、7.89%、43.46%、68.02%、および92.21%であり、50%阻害(ED50)用量は1.8mg/kgであった。
ロフルミラストN酸化物は気管内投与の際に、10、30および100μg/kgで、コントロール群と比較して好中球浸潤において用量依存性の阻害を示した。結果を図3に示す。阻害パーセントは、それぞれ、37.52%、49.66%、および69.48%であって、50%阻害(ED50)用量は27μg/kgであった。
動物を実験の開始前に7日間順化させた。その動物を、その体重に基づいて種々の群に無作為に分布させた。ロフルミラストの経口投与のため、およびロフルミラストN酸化物の鼻腔内投与のため、ロフルミラストまたはロフルミラストN酸化物を適切なビヒクル中の懸濁物として調製した。1日目、マウスにロフルミラストN酸化物またはロフルミラストを投与し、1時間後、その動物を全身暴露ボックスに入れた。1日および2日目に、そのマウスを6本の煙草の主流煙に、そして3日目および4日目には8本の煙草の主流煙に曝した。各々の煙草の煙に対する暴露を10分間続けた(タバコは最初の2分で完全に燃え尽き、続いて動物のベンチレーターで気流に、次いで20分間新鮮な部屋の空気に曝された)。二本目の煙草の後ごとに、新鮮な部屋の空気への暴露を伴う追加の20分間の中断を行った。コントロールの動物を室温チャンバに曝した。1日目〜4日目に、動物にロフルミラストN酸化物またはロフルミラストを投与した。5日目に、最後の煙草の煙(cigarette smoke)(CS)暴露の24時間後、その動物を麻酔下で放血して、気管にカニューレを挿入し、肺をヘパリン化PBS(1単位/ml)の0.5mlのアリコートを用い気管カニューレを通じて4回洗浄した(総容積20ml)。収集した気管支肺胞液(BAL)を遠心分離して、総細胞および白血球数のためにアッセイするまで2〜8℃で保管した。BAL液を遠心分離(500×gで10分間)して、得られた細胞ペレットを0.5mlのヘパリン化生理食塩水中に再懸濁した。白血球の総数をBAL液中で決定して、1×106細胞/mlに調節した。種々の細胞数を手技的に、ディフクイック染色によって算出した。40マイクロリットルの細胞懸濁物を、サイトスピン3を用いて遠心分離して細胞スメアを調製した。この細胞スメアを、血液染色溶液を用いて鑑別のために染色し、顕微鏡で観察して、それらの形態学的特徴に従って細胞種を特定した。細胞スメアの300の白血球のうち各々の細胞種の数を決定してパーセンテージとして表し、各々のBAL液中の好中球およびマクロファージの数を算出した。
ロフルミラストは経口投与の際に、1、3および10mg/kgで、コントロール群と比較してマクロファージ浸潤において用量依存性の阻害を示した。阻害パーセントは、それぞれ、22.2%、51.00%、および69.11%であり、50%阻害(ED50)用量は3.5mg/kgであった。好中球浸潤における用量依存性の阻害を観察し、阻害パーセントはそれぞれ、70.85%、73.69%、および83.01%であり、50%阻害(ED50)用量は1.75mg/kgであった。マクロファージおよび好中球についての結果をそれぞれ、図4Aおよび図4Bに示す。
ロフルミラストN酸化物は鼻腔内投与の際に、0.003、0.03、0.3および3mg/kgで、コントロール群と比較してマクロファージ浸潤において用量依存性の阻害を示した。阻害パーセントは、それぞれ、50.68%、55.10%、62.79%および63.35%であって、50%阻害(ED50)用量は0.049mg/kgであった。好中球浸潤における用量依存性の阻害を観察し、阻害パーセントはそれぞれ、26.60%、59.28%、66.49%および72.08%であった。50%阻害(ED50)用量は0.038mg/kgであった。マクロファージおよび好中球についての結果をそれぞれ、図5Aおよび図5Bに示す。
気道炎症および過敏反応性(AHR)は、気管支喘息の顕著な特徴であって、識別性の特徴である。事前感作されたマウスの同じアレルゲンによる刺激は、優先的な好酸球浸潤を伴う気道炎症を誘発し、結果としてAHRを誘発する。気道音の神経制御の変化および気道上皮剥離に関連する肺の好酸球増加および気道の再構築は、喘息におけるAHRに寄与し得る。
経口投与によるロフルミラストに比較して吸入によるロフルミラストN酸化物の安全性を決定するために、7日および14日の反復用量の安全性研究を、下の表5に示されるプロトコールに従って行う。
Claims (20)
- 約5μg〜約2000μgの単回用量のロフルミラストN酸化物またはその薬学的に許容される塩の肺投与により、その必要な被験体において自己免疫、呼吸器性または炎症性の疾患または状態を処置するための組成物であって、ロフルミラストN酸化物またはその薬学的に許容される塩以外に薬学的活性成分を含まない組成物。
- 吸入によって肺投与するための、請求項1に記載の組成物。
- ドライパウダー、溶液または懸濁物としての吸入によって肺投与するための、請求項1に記載の組成物。
- ドライパウダーとして肺投与するための、請求項3に記載の組成物。
- 溶液または懸濁物として肺投与するための、請求項3に記載の組成物。
- 約20μg〜約1200μgの単回用量を含む、請求項1に記載の組成物。
- 約50μg〜約1000μgの単回用量を含む、請求項1に記載の組成物。
- 約100μg〜約800μgの単回用量を含む、請求項1に記載の組成物。
- 約100μg、約200μg、約400μg、または約600μgの単回用量を含む、請求項1に記載の組成物。
- 前記疾患または状態が喘息、COPD、慢性閉塞性細気管支炎、急性気管支炎、慢性気管支炎、肺気腫、アレルギー性鼻炎および非アレルギー性鼻炎から選択される、請求項1〜9のいずれか1項に記載の組成物。
- 前記疾患または状態が喘息である、請求項1〜10のいずれか1項に記載の組成物。
- 前記疾患または状態がCOPDである、請求項1〜10のいずれか1項に記載の組成物。
- 前記ロフルミラストN酸化物またはその薬学的に許容される塩が無水物、溶媒和物、または水和物である、請求項1〜12のいずれか1項に記載の組成物。
- 前記ロフルミラストN酸化物またはその薬学的に許容される塩が、約10ミクロン以下(例えば、約0.1〜約10ミクロン、例えば約0.5〜約5ミクロン)のd50またはd90を有している、請求項1〜13のいずれか1項に記載の組成物。
- 前記ロフルミラストN酸化物またはその薬学的に許容される塩が、(i)約10ミクロン以下、(ii)約6ミクロン未満、または(iii)約1ミクロンと約6ミクロンとの間のd 50 またはd 90 を有している、請求項14に記載の組成物。
- 定量吸入器(MDI)またはドライパウダー吸入器(DPI)に適した形態である、請求項1に記載の組成物。
- 唯一の活性成分としてのロフルミラストN酸化物またはその薬学的に許容される塩と生理学的に許容される薬理学的に不活性な固体の担体の粒子とを含んでいる吸入可能なドライパウダーの形態である、請求項1に記載の組成物。
- 唯一の活性成分としてのロフルミラストN酸化物またはその薬学的に許容される塩、噴霧剤ならびに、必要に応じて、1つ以上の共溶媒、薬学的に許容される担体および/または賦形剤を含んでいるエアロゾルの形態である、請求項1に記載の組成物。
- 前記ロフルミラストN酸化物またはその薬学的に許容される塩が前記噴霧剤中の粒子の懸濁物の形態である、請求項18に記載の組成物。
- 前記ロフルミラストN酸化物またはその薬学的に許容される塩のd50が約1ミクロンと約6ミクロンとの間である、請求項16〜19のいずれか1項に記載の組成物。
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PCT/IB2014/058617 WO2014115127A1 (en) | 2013-01-28 | 2014-01-28 | Methods of treating autoimmune, respiratory and inflammatory disorders by inhalation of roflumilast n-oxide |
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