JP7445315B2 - 弱酸性薬物の医薬組成物および投与方法 - Google Patents
弱酸性薬物の医薬組成物および投与方法 Download PDFInfo
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- JP7445315B2 JP7445315B2 JP2021567850A JP2021567850A JP7445315B2 JP 7445315 B2 JP7445315 B2 JP 7445315B2 JP 2021567850 A JP2021567850 A JP 2021567850A JP 2021567850 A JP2021567850 A JP 2021567850A JP 7445315 B2 JP7445315 B2 JP 7445315B2
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- phospholipid
- treprostinil
- weakly acidic
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Description
本出願は、2019年5月14日に出願された米国出願第62/847,337号の利益を主張し、その開示全体は、参照により本明細書に組み込まれる。
半減期が2時間未満の弱酸性薬物をカプセル化する少なくとも1つのリポソームを含み、1~100のピーク対トラフ薬物血漿濃度比(peak to trough drug plasma concentration ratio)(P/T比)(すなわち、より平坦な血漿プロファイル)を生じる、および/または遊離の弱酸性薬物の効力と比較してカプセル化された弱酸性薬物の効力を増加させるように製剤化された医薬組成物が、本明細書に開示される。
平均肺動脈圧(PAP)が安静時に25mmHgを超えるまたは運動中に30mmHgを超えることと定義される、肺高血圧症(PH)は、しばしば肺血管抵抗の漸進的かつ持続的な増加を特徴とする。最終的には右室不全に至ることもあり、治療しなければ生命を脅かす状態となりうる。世界保健機構(WHO)は、病態生理、臨床所見、および治療の選択肢に基づいてPHを5群に分けている[J Am Coll Cardiol. 2009; 54(1 Suppl):S43-54]。
本発明は、リポソームが外部媒体中に懸濁されてなる医薬組成物であって、前記リポソームが、(a)少なくとも1の小胞形成リン脂質を含む、外部脂質二重層;ならびに(b)内部水性媒体であって、2時間未満の半減期を有する弱酸性薬物および前記内部水性媒体と前記外部媒体との間にpH勾配を提供する塩を含む、内部水性媒体を含み、少なくとも6時間毎に前記医薬組成物の投与後、約1~約100のピーク対トラフ薬物血漿濃度比(peak to trough drug plasma concentration ratio)(P/T比)を生じる、医薬組成物を提供する。
本明細書で使用される、冠詞「a」及び「an」は、冠詞の文法的対象の1つまたは複数(すなわち、少なくとも1つ)を指す。例として、「要素(an element)」とは、1つの要素または複数の要素を意味する。
PAP減少を増大させ、弱酸性薬物の効力を高める。医薬組成物の効力は、遊離弱酸性薬物の効力よりも2、3、4、5、6、7、8、9、10、11、12、13、14または15倍高い。いかなる特定の理論にも拘束されないが、弱酸性薬物(例えば、プロスタサイクリンおよび/またはその類似体)の初期スパイク血漿レベル(initial spiked plasma level)および/または高いP/T比が異なるプロスタノイド受容体サブタイプの活性化を介して、血管収縮および血管拡張の両方を媒介すると考えられる。したがって、高いP/T比を有する弱酸性薬物は、血漿中のピーク薬物濃度が高くなり、これにより肺血管系を収縮させる血管収縮受容体(例えば、DP1、IP、EP2およびEP4)の活性化によるPAP減少が少なくなる。他方、より低いP/T比(例えば、100未満)を有する弱酸性薬物は、薬物血漿濃度の初期のスパイクを防ぎ(すなわち、より平坦な血漿プロファイル)、ゆえに肺血管系を拡張する血管拡張受容体(例えば、EP3、EP1およびFP)のみの活性化によりPAP減少を大きくし、薬効を増加させる。
本明細書で使用される「リポソーム」という用語は、内部水性媒体を封入する1以上の脂質二重層で構成される微視的な(microscopic)小胞(vesicles)または粒子(particles)を指す。リポソームを形成するには、少なくとも1つの「小胞形成脂質(vesicle-forming lipid)」の存在が必要であり、これは脂質二重層を形成するまたは脂質二重層に組み込まれることができる両親媒性脂質である。適切な小胞形成脂質を使用して、リポソームを構成する脂質二重層を形成することができる。小胞形成脂質としては、以下に限定されないが、ホスファチジルコリン(PC)、ホスファチジルグリセロール(PG)、ホスファチジルイノシトール(PI)、ホスファチジン酸(PA)、ホスファチジルエタノールアミン(PE)またはホスファチジルセリン(PS)などのリン脂質、および正に帯電した脂質または負に帯電した脂質などの荷電脂質(charged lipids)などがある。
リポソームトレプロスチニル組成物
リポソームコロイド懸濁液を、以下のようにエタノール注入技術を用いて調製した。
リポソームコロイド懸濁液を、以下のようにエタノール注入技術を用いて調製した。
遊離トレプロスチニル溶液は、6.52mg/mLの塩化ナトリウム、6.31mg/mLのクエン酸ナトリウムおよび0.2mg/mLの水酸化ナトリウムを含有する10mL溶液に0.6mgのトレプロスチニルを溶解することによって調製した。溶液のpHを、1N塩酸を用いて6.0~7.2に調節した。
遊離イロプロスト溶液は、1.62mg/mLのエタノール、0.242mg/mLのトロメタミンおよび9.0mg/mLの塩化ナトリウムを含有する10mLの溶液に0.02mgのイロプロストを溶解することによって調製した。
PDA検出器を備えたWaters HPLCシステムを用いて、リポソームトレプロスチニル組成物または遊離トレプロスチニル溶液中のトレプロスチニル濃度の分析を行った。試料溶液20μLのアリコートを、50:50の容積比のアセトニトリルおよびリン酸緩衝液(pH 2.5)の混合物を移動相として用いて1.0mL/分の流速でHPLCシステムに直接注入した。分離を、45℃でC18カラム、4.6mm×7.5cm、3.5μmで行い、ピークを220nmで検出した。
PDA検出器を備えたWaters HPLCシステムを用いて、リポソームイロプロスト組成物または遊離イロプロスト溶液中のイロプロスト濃度の分析を行った。試料溶液30μLのアリコートを、36:17:47の容積比のアセトニトリル、メタノールおよびリン酸緩衝液(pH 2.5)の混合物を移動相として用いて1.0mL/分の流速でHPLCシステムに直接注入した。分離を、25℃で3.9mm×15.0cm、5.0μmで行い、ピークを205nmで検出した。
試験物質(トレプロスチニルまたはイロプロストを含むリポソーム組成物、遊離トレプロスチニル溶液またはイロプロスト溶液)を、高圧シリンジ(PennCentury)に取り付けたマイクロスプレーエアロゾル装置(MicroSprayer, PennCentury, Philadelphia, PA)によって研究動物に投与した。各Sprague Dawleyラット(>250g)をイソフルランで麻酔し、上歯によって45°~50°の角度でしっかりと配置した。マイクロスプレーエアロゾルチップを気管分岐部に挿入し、0.5mL/kgの試験物質を投与した。
リポソームトレプロスチニル組成物を、マイクロネブライザー(Micro nebulizers)(Philips Health Care, Chichester, UK)を使用して健常ヒト対象(放出用量(emitted dose) 51μg;n=6)に投与した。吸入後の所定の時点で、トレプロスチニル血漿濃度を評価した。液体/液体抽出によりトレプロスチニルを単離し、上清を窒素気流下で蒸発させ、残りの残渣を再構成した。最終抽出物をUPLCおよびMS/MS検出により分析した(表3)。
ラットにおける急性PHの誘導
体重約300~350gの雄のSprague Dawleyラットをこの研究に使用した。圧力カテーテルの一端をラットの肺動脈(PA)に挿入し、圧力を測定した。カテーテルの他端を首のうなじに露出させ、圧力トランスデューサーに接続した。翌日、ラットを低酸素チャンバーに移した(酸素濃度は10%/FiO2=0.1)。遷延性PH(persistent PH)を誘導するために、ラットを低酸素チャンバー中に一晩放置した。一旦PHが確立されると、マイクロスプレーヤーを使用して、気管分岐部のすぐ上に試験物質を送達した。各所定の時点で、PAPを30秒間連続的に測定し(平均PAPを計算するため)、血液サンプルを集めた。
シミュレートされた血漿プロファイルは、特定の期間後(すなわち、吸入してから8、10および12時間後)のラットまたはヒトにおける測定された薬物血漿レベルに基づいて、線形内部法(linear internalmethod)を使用して計算された。
図1A~1Dは、異なる投薬頻度でのラットにおけるリポソームトレプロスチニル組成物の測定されたおよびシミュレートされたPKプロファイルを示す。トレプロスチニル血漿レベルは、48μg/kgのリポソームトレプロスチニル組成物を気管内投与してから、8時間までは2.0~3.0ng/mLであり、12時間後に0.3ng/mLまで低下した(図1A~1Dの測定データ参照)。したがって、本発明のリポソームトレプロスチニル組成物は、トレプロスチニルの治療血漿レベルを維持しながら、1日2回(BID、8、10または12時間毎)または1日3回(TID、8時間毎)送達することができる(図1A~1Dのシミュレートされたプロファイルを参照のこと)。
リポソームイロプロスト組成物(60μg/kg)の気管内投与後、イロプロスト血漿濃度は投与の5分以内にピークCmax(8.10ng/mL)に達し、投与の8時間後には0.32ng/mL、投与の12時間後には0.17ng/mLにまで徐々に減少した(図2A~2D、測定データ)。したがって、リポソームイロプロスト組成物は、イロプロストの治療血漿レベルを維持しながら、1日2回(BID、6~8時間毎)または1日3回(TID、6~8時間毎)送達することができる(図2A~2Dのシミュレートされたプロファイルを参照のこと)。
吸入リポソームトレプロスチニル組成物(102μg放出用量)のヒトPKプロファイルは、血漿トレプロスチニル濃度が投与後8時間0.12~0.26ng/mLの間に維持され、投与後12時間で0.02ng/mLに徐々に減少したことを示す(図3A~3D、測定データ)。したがって、本発明のリポソーム組成物は、トレプロスチニルの治療的血漿レベルを維持しながら、1日2回(BID、8、10および12時間毎)または1日3回(TID、8時間毎)で投与され得る(図3A~3D、シミュレートされたプロファイル)。
リポソームトレプロスチニル組成物のPKおよびPDプロファイルを、急性PHを有する意識のあるラットで評価した。ラットにおける低酸素誘発性PHの信頼性を確認するために、生理食塩水対照群を含めた。生理食塩水対照群のラットのPAPは、12時間まで上昇したままであった。
遊離イロプロスト溶液(2.5μg/kg)を投与したPHラットは、PAPの軽度の低下を示した。最大効果(PAPがベースラインの低酸素値の76%に低下)は投与0.75時間後にみられ、イロプロスト血漿濃度は0.1ng/mL(LLOQ)未満であった(図5A参照)。
Claims (11)
- リポソームが外部媒体中に懸濁されてなる医薬組成物であって、前記リポソームが、
(a)ホスファチジルコリン(PC)、ホスファチジルグリセロール(PG)、ホスファチジルイノシトール(PI)、ホスファチジン酸(PA)、ホスファチジルエタノールアミン(PE)、ホスファチジルセリン(PS)およびそれらの任意の組み合わせからなる群から選択される第1のリン脂質と、PEG修飾リン脂質である第2のリン脂質、または正に荷電したもしくは負に荷電したリン脂質と、コレステロール、ヘキサコハク酸コレステロール、エルゴステロール、ラノステロール、およびそれらの組み合わせからなる群から選択されるステロールと、の混合物を含む、外部脂質二重層;ならびに
(b)内部水性媒体であって、イロプロストである弱酸性薬物および前記内部水性媒体と前記外部媒体との間にpH勾配を提供する約50mM~約600mMの濃度である重炭酸塩を含む、内部水性媒体
を含み、
少なくとも6時間毎に、前記医薬組成物の投与後、約1~約100のピーク対トラフ薬物血漿濃度比(P/T比)を生じ、前記第1のリン脂質:前記第2のリン脂質:前記ステロールのモル比は、75~99:0.1~25:0~14.9である、医薬組成物。 - 前記P/T比が約5~約40である、請求項1に記載の医薬組成物。
- 前記第1のリン脂質がHSPC、DSPC、DPPC、DMPC、またはそれらの組み合わせから選択され、前記第2のリン脂質がDSPG、DPPG、DMPG、PEG-DSPE、またはそれらの組み合わせから選択される、請求項1に記載の医薬組成物。
- 前記医薬組成物中の前記弱酸性薬物の効力が、遊離弱酸性薬物の効力の少なくとも2倍である、請求項1に記載の医薬組成物。
- 前記弱酸性薬物が実質的に担体を含まない、請求項1に記載の医薬組成物。
- 肺高血圧症を治療するために用いられる、請求項1に記載の医薬組成物であって、前記医薬組成物は、少なくとも6時間毎に投与される、医薬組成物。
- 前記医薬組成物が、1日に1回、2回、または3回投与される、請求項6に記載の医薬組成物。
- 前記医薬組成物が吸入によって投与される、請求項6に記載の医薬組成物。
- 前記弱酸性薬物の治療効果が、前記医薬組成物の投与後少なくとも6時間維持される、請求項8に記載の医薬組成物。
- 約1~約40のピーク対トラフ薬物血漿濃度比(P/T比)が、前記医薬組成物の投与後約1時間~約12時間維持される、請求項8に記載の医薬組成物。
- 肺高血圧症を治療するのに有効な少なくとも1つの他の薬剤と組み合わせて投与される、請求項6に記載の医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201962847337P | 2019-05-14 | 2019-05-14 | |
US62/847,337 | 2019-05-14 | ||
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WO1996032930A1 (en) | 1995-04-18 | 1996-10-24 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Liposome drug-loading method and composition |
WO2003000227A2 (en) | 2001-06-25 | 2003-01-03 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | A method for preparation of vesicles loaded with biological material and different uses thereof |
US7666876B2 (en) * | 2002-03-19 | 2010-02-23 | Vernalis (R&D) Limited | Buprenorphine formulations for intranasal delivery |
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US8119156B2 (en) * | 2006-10-24 | 2012-02-21 | Aradigm Corporation | Dual action, inhaled formulations providing both an immediate and sustained release profile |
US9114081B2 (en) | 2007-05-07 | 2015-08-25 | Insmed Incorporated | Methods of treating pulmonary disorders with liposomal amikacin formulations |
US20110104052A1 (en) * | 2007-12-03 | 2011-05-05 | The Johns Hopkins University | Methods of synthesis and use of chemospheres |
CA2752296C (en) * | 2009-02-18 | 2018-09-11 | Aradigm Corporation | Ph-modulated formulations for pulmonary delivery |
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US9233089B2 (en) * | 2012-03-23 | 2016-01-12 | The Board Of Trustees Of The Leland Stanford Junior University | Treatment of pulmonary hypertension with leukotriene inhibitors |
US9445993B2 (en) * | 2012-04-16 | 2016-09-20 | Rutgers, The State University Of New Jersey | Nanotechnology approach for inhalation therapies |
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US9693968B2 (en) * | 2013-03-14 | 2017-07-04 | Jerome J. Schentag | Cholestosome vesicles for incorporation of molecules into chylomicrons |
WO2015138423A1 (en) * | 2014-03-11 | 2015-09-17 | Insmed Incorporated | Prostacylin compositions and methods for using the same |
US20170246175A1 (en) * | 2014-09-24 | 2017-08-31 | Nanyang Technological University | Sustained timolol maleate delivery from liposomes for glaucoma therapy and occular hypertension |
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