JP6858716B2 - 心筋ミオシン活性化剤と洞房結節If電流阻害剤の併用療法 - Google Patents
心筋ミオシン活性化剤と洞房結節If電流阻害剤の併用療法 Download PDFInfo
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- JP6858716B2 JP6858716B2 JP2017566330A JP2017566330A JP6858716B2 JP 6858716 B2 JP6858716 B2 JP 6858716B2 JP 2017566330 A JP2017566330 A JP 2017566330A JP 2017566330 A JP2017566330 A JP 2017566330A JP 6858716 B2 JP6858716 B2 JP 6858716B2
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Images
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
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- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
を有するオメカムチブメカルビル(AMG 423、CK−1827452)、すなわち、メチル4−(2−フルオロ−3−(3−(6−メチルピリジン−3−イル)ウレイド)ベンジル)ピペラジン−1−カルボキシレート、またはその医薬的に許容される塩もしくは水和物、ならびに構造:
心不全の治療のための方法及び組成物を本明細書に提供する。企図される状態としては:急性(または非代償性)うっ血性心不全、慢性うっ血性心不全、及び収縮期心臓機能不全に関連する疾患が挙げられるがこれらに限定されない。
オメカムチブメカルビル、またはその医薬的に許容される塩もしくは水和物、及びイバブラジン、またはその医薬的に許容される塩もしくは水和物の、心不全の治療のための併用療法を本明細書に提供する。該2つの活性成分は、順次にまたは並行して投与することができる。並行の場合、該活性物質は、別々に投与または併せて製剤化することができる。
高及び低心拍数の麻酔イヌにおけるオメカムチブメカルビルの評価:ビーグル犬(雄;10〜12kg)を、モルヒネ(筋肉内1〜2mg/kg)及びアルファ−クロラロース(静脈内80〜120mg/kg;溶液強度:10mg/ml)による処置によって麻酔に誘導する。誘導直後から、一定のアルファ−クロラロース注入(静脈内35〜75mg/kg/時間)によって麻酔を試験期間中維持する(静注ポンプで供給を制御する)。イヌに気管内チューブを挿管し、直ちに陽圧呼吸により室内空気で通気し(Harvard Large Animal pump;速度:15ストローク/分;体積:100〜150ml/ストローク)、動脈血ガス測定によって評価する。サーモスタットで制御された加熱ブランケットを使用して、正常な中核体温(37℃)を維持する。静脈内輸液(生理食塩水:2〜5ml/kg/時間)を、本手順を通して注入し、尿流を確保するために膀胱内にフォーリーカテーテルを配置する。
本試験には、連続単極誘導心電図(ECG)、ならびに全身(動脈、AoP)及び左心室(LVP)圧力信号を与える無線遠隔測定装置を装備した健康な雄のビーグル犬(n=7)を用いた。スリングの順化後、これらの動物を、クロスオーバーデザインにて、10mL/kgの投与量で投与されるイバブラジン(IVA、5mg/kgで1日2回)または体積を合わせたプラセボ対照(滅菌水、CTRL)のいずれかの5日間反復経口(強制経口によって)処置を受けるように割り当てた。
+:SET:収縮期駆出時間;CT:収縮時間;FT:充満時間;RT:弛緩時間;S/D:収縮期対拡張期比(SET/RT+FT);n/u:単位なし。
*:対応のある両側スチューデントt検定(SigmaPlot 12.3;SysStat Software, Inc.)による。
(付記)
(付記1)
心不全の対象の治療方法であって、前記対象に対して、心筋ミオシン活性化剤及び洞房結節If電流阻害剤を投与することを含む、前記方法。
(付記2)
前記心筋ミオシン活性化剤が、オメカムチブメカルビル、またはその医薬的に許容される塩もしくは水和物である、付記1に記載の方法。
(付記3)
前記洞房結節If電流阻害剤が、イバブラジン、またはその医薬的に許容される塩もしくは水和物である、付記1または2に記載の方法。
(付記4)
前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物、及びイバブラジンまたはその医薬的に許容される塩もしくは水和物が、順次に投与される、付記3に記載の方法。
(付記5)
前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物の投与が、前記イバブラジンまたはその医薬的に許容される塩もしくは水和物の投与の前である、付記4に記載の方法。
(付記6)
前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物の投与が、前記イバブラジンまたはその医薬的に許容される塩もしくは水和物の投与の後である、付記4に記載の方法。
(付記7)
前記オメカムチブメカルビル、またはその医薬的に許容される塩もしくは水和物、及びイバブラジンまたはその医薬的に許容される塩もしくは水和物が、同時に投与される、付記3に記載の方法。
(付記8)
前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物、及びイバブラジンまたはその医薬的に許容される塩もしくは水和物が、同時に処方される、付記7に記載の方法。
(付記9)
前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物、イバブラジンまたはその医薬的に許容される塩もしくは水和物、またはその両方が、経口、静脈内、皮下、筋肉内、髄腔内、または吸入を介して投与される、付記3〜8のいずれか一項に記載の方法。
(付記10)
前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物が、経口投与される、付記2〜9のいずれか一項に記載の方法。
(付記11)
前記イバブラジンまたはその医薬的に許容される塩もしくは水和物が、経口投与される、付記3〜9のいずれか一項に記載の方法。
(付記12)
前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物が、1日の合計量10mg〜200mgで投与される、付記2〜11のいずれか一項に記載の方法。
(付記13)
前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物が、1日の合計量12.5mg〜75mgで投与される、付記12に記載の方法。
(付記14)
前記イバブラジンまたはその医薬的に許容される塩もしくは水和物が、1日の合計量2.5mg〜20mgで投与される、付記3〜13のいずれか一項に記載の方法。
(付記15)
前記対象が、うっ血性心不全に罹患している、付記1〜14のいずれか一項に記載の方法。
(付記16)
前記対象が、収縮期心不全に罹患している、付記1〜15のいずれか一項に記載の方法。
(付記17)
前記対象が、左心室駆出分画率の低下を伴う心不全に罹患している、付記1〜16のいずれか一項に記載の方法。
(付記18)
前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物、及びイバブラジンまたはその医薬的に許容される塩もしくは水和物の投与が、オメカムチブメカルビル単独の投与と比較して、虚血性イベントの減少をもたらす、付記3〜17のいずれか一項に記載の方法。
(付記19)
前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物、及びイバブラジンまたはその医薬的に許容される塩もしくは水和物の投与が、オメカムチブメカルビル単独の投与と比較して、収縮期対拡張期比の低下をもたらす、付記3〜18のいずれか一項に記載の方法。
(付記20)
前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物、及びイバブラジンまたはその医薬的に許容される塩もしくは水和物の投与が、オメカムチブメカルビル単独の投与と比較して、トロポニン値の低下をもたらす、付記3〜19のいずれか一項に記載の方法。
(付記21)
前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物、及びイバブラジンまたはその医薬的に許容される塩もしくは水和物の投与が、イバブラジン単独の投与と比較して、心収縮性の向上をもたらす、付記3〜18のいずれか一項に記載の方法。
(付記22)
心筋ミオシン活性化剤及び洞房結節If電流阻害剤を含む医薬組成物。
(付記23)
前記洞房結節If電流阻害剤が、イバブラジン、またはその医薬的に許容される塩もしくは水和物である、付記22に記載の組成物。
(付記24)
前記イバブラジンが、イバブラジン塩酸塩として存在する、付記23に記載の組成物。
(付記25)
前記心筋ミオシン活性化剤が、オメカムチブメカルビル、またはその医薬的に許容される塩もしくは水和物である、付記22〜24のいずれか一項に記載の組成物。
(付記26)
前記オメカムチブメカルビルが、オメカムチブメカルビル二塩酸塩水和物として存在する、付記25に記載の組成物。
(付記27)
錠剤の形態である、付記22〜26のいずれか一項に記載の組成物。
(付記28)
さらに、制御放出剤;pH調節剤;充填剤;及び滑沢剤を含む、付記27に記載の組成物。
(付記29)
前記制御放出剤が、メチルセルロース、ヒドロキシプロピルメチルセルロース、またはそれらの組合せを含む、付記28に記載の組成物。
(付記30)
前記pH調節剤がフマル酸を含む、付記28または29に記載の組成物。
(付記31)
前記充填剤が、微結晶性セルロース、ラクトース一水和物、またはそれらの組合せを含む、付記28〜30のいずれか一項に記載の組成物。
(付記32)
前記滑沢剤がステアリン酸マグネシウムを含む、付記28〜31のいずれか一項に記載の組成物。
(付記33)
心不全の治療のため、イバブラジンまたはその医薬的に許容される塩もしくは水和物との併用のためのオメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物。
(付記34)
心不全の治療のため、オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物との併用のためのイバブラジンまたはその医薬的に許容される塩もしくは水和物。
(付記35)
イバブラジン、またはその医薬的に許容される塩もしくは水和物、及びオメカムチブメカルビル、またはその医薬的に許容される塩もしくは水和物を、独立した存在として含む、経口投与用の併用治療薬。
(付記36)
前記心不全の治療における付記35に記載の併用治療薬の使用。
Claims (31)
- 心不全の対象の治療のための併用治療薬であって、イバブラジン、またはその医薬的に許容される塩もしくは水和物、及びオメカムチブメカルビル、またはその医薬的に許容される塩もしくは水和物を含む、併用治療薬。
- 前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物、及びイバブラジンまたはその医薬的に許容される塩もしくは水和物が、順次に投与される、請求項1に記載の併用治療薬。
- 前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物の投与が、前記イバブラジンまたはその医薬的に許容される塩もしくは水和物の投与の前である、請求項2に記載の併用治療薬。
- 前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物の投与が、前記イバブラジンまたはその医薬的に許容される塩もしくは水和物の投与の後である、請求項2に記載の併用治療薬。
- 前記オメカムチブメカルビル、またはその医薬的に許容される塩もしくは水和物、及びイバブラジンまたはその医薬的に許容される塩もしくは水和物が、同時に投与される、請求項1に記載の併用治療薬。
- 前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物、及びイバブラジンまたはその医薬的に許容される塩もしくは水和物が併せて製剤化されている、請求項5に記載の併用治療薬。
- 前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物、イバブラジンまたはその医薬的に許容される塩もしくは水和物、またはその両方が、経口、静脈内、皮下、筋肉内、髄腔内、または吸入を介して投与される、請求項1〜6のいずれか一項に記載の併用治療薬。
- 前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物が、経口投与される、請求項1〜7のいずれか一項に記載の併用治療薬。
- 前記イバブラジンまたはその医薬的に許容される塩もしくは水和物が、経口投与される、請求項1〜8のいずれか一項に記載の併用治療薬。
- 前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物が、1日の合計量10mg〜200mgで投与される、請求項1〜9のいずれか一項に記載の併用治療薬。
- 前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物が、1日の合計量12.5mg〜75mgで投与される、請求項10に記載の併用治療薬。
- 前記イバブラジンまたはその医薬的に許容される塩もしくは水和物が、1日の合計量2.5mg〜20mgで投与される、請求項1〜11のいずれか一項に記載の併用治療薬。
- 前記対象が、うっ血性心不全に罹患している、請求項1〜12のいずれか一項に記載の併用治療薬。
- 前記対象が、収縮期心不全に罹患している、請求項1〜13のいずれか一項に記載の併用治療薬。
- 前記対象が、左心室駆出分画率の低下を伴う心不全に罹患している、請求項1〜14のいずれか一項に記載の併用治療薬。
- 前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物、及びイバブラジンまたはその医薬的に許容される塩もしくは水和物の投与が、オメカムチブメカルビル単独の投与と比較して、虚血性イベントの減少をもたらす、請求項1〜15のいずれか一項に記載の併用治療薬。
- 前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物、及びイバブラジンまたはその医薬的に許容される塩もしくは水和物の投与が、オメカムチブメカルビル単独の投与と比較して、収縮期対拡張期比の低下をもたらす、請求項1〜16のいずれか一項に記載の併用治療薬。
- 前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物、及びイバブラジンまたはその医薬的に許容される塩もしくは水和物の投与が、オメカムチブメカルビル単独の投与と比較して、トロポニン値の低下をもたらす、請求項1〜17のいずれか一項に記載の併用治療薬。
- 前記オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物、及びイバブラジンまたはその医薬的に許容される塩もしくは水和物の投与が、イバブラジン単独の投与と比較して、心収縮性の向上をもたらす、請求項1〜16のいずれか一項に記載の併用治療薬。
- 心不全を治療するための医薬組成物であって、オメカムチブメカルビル、またはその医薬的に許容される塩もしくは水和物、及びイバブラジン、またはその医薬的に許容される塩もしくは水和物を含む、組成物。
- 前記イバブラジンが、イバブラジン塩酸塩として存在する、請求項20に記載の組成物。
- 前記オメカムチブメカルビルが、オメカムチブメカルビル二塩酸塩水和物として存在する、請求項21に記載の組成物。
- 錠剤の形態である、請求項20〜22のいずれか一項に記載の組成物。
- さらに、制御放出剤;pH調節剤;充填剤;及び滑沢剤を含む、請求項23に記載の組成物。
- 前記制御放出剤が、メチルセルロース、ヒドロキシプロピルメチルセルロース、またはそれらの組合せを含む、請求項24に記載の組成物。
- 前記pH調節剤がフマル酸を含む、請求項24または25に記載の組成物。
- 前記充填剤が、微結晶性セルロース、ラクトース一水和物、またはそれらの組合せを含む、請求項24〜26のいずれか一項に記載の組成物。
- 前記滑沢剤がステアリン酸マグネシウムを含む、請求項24〜27のいずれか一項に記載の組成物。
- 心不全の治療のための、イバブラジンまたはその医薬的に許容される塩もしくは水和物との併用のための、オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物を含む医薬組成物。
- 心不全の治療のための、オメカムチブメカルビルまたはその医薬的に許容される塩もしくは水和物との併用のための、イバブラジンまたはその医薬的に許容される塩もしくは水和物を含む医薬組成物。
- イバブラジン、またはその医薬的に許容される塩もしくは水和物、及びオメカムチブメカルビル、またはその医薬的に許容される塩もしくは水和物を含む、心不全の治療のための、経口投与用の併用治療薬。
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