JP2012001545A - 心不全の処置における洞房結節If電流阻害剤およびアンギオテンシン変換酵素阻害剤の組み合わせの使用 - Google Patents
心不全の処置における洞房結節If電流阻害剤およびアンギオテンシン変換酵素阻害剤の組み合わせの使用 Download PDFInfo
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- JP2012001545A JP2012001545A JP2011132849A JP2011132849A JP2012001545A JP 2012001545 A JP2012001545 A JP 2012001545A JP 2011132849 A JP2011132849 A JP 2011132849A JP 2011132849 A JP2011132849 A JP 2011132849A JP 2012001545 A JP2012001545 A JP 2012001545A
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- perindopril
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- LZFZMUMEGBBDTC-QEJZJMRPSA-N enalaprilat (anhydrous) Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 LZFZMUMEGBBDTC-QEJZJMRPSA-N 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Abstract
【解決手段】選択的かつ特異的な洞房結節If電流阻害剤、さらに特定的にはイバブラジンまたはN−{[(7S)−3,4−ジメトキシビシクロ[4.2.0]オクタ−1,3,5−トリエン−7−イル]メチル}−3−(7,8−ジメトキシ−1,2,4,5−テトラヒドロ−3H−3−ベンゾアゼピン−3−イル)−N−メチル−3−オキソ−1−プロパンアミン、およびアンギオテンシン変換酵素を阻害する薬剤の組み合わせからなる医薬。
【選択図】なし
Description
− イバブラジン、すなわち式(I):
− 式(II)
より選択される。
− イバブラジン、および薬学的に許容されうる酸とのその付加塩、さらに特定的にはその塩酸塩、それらの水和物および結晶形態、
− N−{[(7S)−3,4−ジメトキシビシクロ[4.2.0]オクタ−1,3,5−トリエン−7−イル]メチル}−3−(7,8−ジメトキシ−1,2,4,5−テトラヒドロ−3H−3−ベンゾアゼピン−3−イル)−N−メチル−3−オキソ−1−プロパンアミン、および薬学的に許容されうる酸とのその付加塩、さらに特定的にはその塩酸塩およびそのフマル酸塩、それらの水和物および結晶形態
は、非常に有用な薬理学的および治療学的特性、特に陰性変時(心拍低下)特性を有し、そのことからそれらの化合物は、狭心症、心筋梗塞および関連する調律異常などの心筋虚血に関連する多様な心血管疾患の治療もしくは予防、または予後改善において、ならびにまた調律異常、特に上室調律異常を伴う様々な病態、および慢性心不全において有用となっている。
− イバブラジン、すなわち3−{3−[{[(7S)−3,4−ジメトキシビシクロ[4.2.0]オクタ−1,3,5−トリエン−7−イル]メチル}(メチル)アミノ]プロピル}−7,8−ジメトキシ−1,3,4,5−テトラヒドロ−2H−3−ベンゾアゼピン−2−オン、または
− N−{[(7S)−3,4−ジメトキシビシクロ[4.2.0]オクタ−1,3,5−トリエン−7−イル]メチル}−3−(7,8−ジメトキシ−1,2,4,5−テトラヒドロ−3H−3−ベンゾアゼピン−3−イル)−N−メチル−3−オキソ−1−プロパンアミン、
およびアンギオテンシン変換酵素を阻害する薬剤の組み合わせが、心不全、さらに特定的には収縮機能の保持された心不全の処置におけるその使用を可能にする有用な特性を有することを発見した。
− 塩酸塩の形態のイバブラジンまたはその水和物の形態もしくは結晶形態の一つ、および
− 塩酸塩もしくはフマル酸塩の形態のN−{[(7S)−3,4−ジメトキシビシクロ[4.2.0]オクタ−1,3,5−トリエン−7−イル]メチル}−3−(7,8−ジメトキシ−1,2,4,5−テトラヒドロ−3H−3−ベンゾアゼピン−3−イル)−N−メチル−3−オキソ−1−プロパンアミンまたはそれらの水和物もしくは結晶形態の一つ
より選択される。
− イバブラジン、もしくはその水和物、結晶形態、および薬学的に許容されうる酸との付加塩の一つ、さらに特定的にはその塩酸塩、またはN−{[(7S)−3,4−ジメトキシビシクロ[4.2.0]オクタ−1,3,5−トリエン−7−イル]メチル}−3−(7,8−ジメトキシ−1,2,4,5−テトラヒドロ−3H−3−ベンゾアゼピン−3−イル)−N−メチル−3−オキソ−1−プロパンアミンもしくはその薬学的に許容されうる酸との付加塩、さらに特定的にはその塩酸塩もしくはそのフマル酸塩、それらの水和物もしくは結晶形態の一つ、および
− ペリンドプリル、または薬学的に許容されうる塩基とのその付加塩、さらに特定的にはそのtert−ブチルアミン塩またはアルギニン塩、それらの水和物または結晶形態の一つ
を活性成分として含む、心不全、さらに特定的には収縮機能の保持された心不全の処置に使用するための薬学的組成物に関する。
・ 希釈剤として:ラクトース、デキストロース、スクロース、マンニトール、ソルビトール、セルロース、グリセロール、
・ 滑沢剤として:シリカ、タルク、ステアリン酸ならびにそのマグネシウムおよびカルシウム塩、ポリエチレングリコール、
・ 結合剤として:ケイ酸アルミニウムマグネシウム、デンプン、ゼラチン、トラガカント、メチルセルロース、カルボキシメチルセルロースナトリウムおよびポリビニルピロリドン、
・ 崩壊剤として:寒天、アルギン酸およびそのナトリウム塩、発泡性混合物
を挙げることができる。
dP/dtmax : 圧力最大上昇速度(毎秒)
dP/dtmin : 圧力最大減少速度(毎秒)
HF : 心不全
LVEDP : 左室拡張終末期圧
LVEDPVR : 左室拡張終末期圧容積関係
LVESP : 左室収縮終末期圧
LVESPVR : 左室収縮終末期圧容積関係
LV : 左心室
左冠動脈の結紮によりラットに心不全を誘導し(対照動物には手術を行ったが、結紮しなかった)、それにより、左心室壁の部分に虚血を引き起こす。動物を7日間回復させ、次に12週間それらの動物に3mg/kgの化合物A、または0.4mg/kgのペリンドプリル、またはペリンドプリルおよび化合物A(同時)のいずれかを投与する。
活性成分として7.5mgのイバブラジンおよび2mgのペリンドプリルtert−ブチルアミンをそれぞれ含有する錠剤1000錠を調製するための処方:
イバブラジン塩酸塩 8.085g
ペリンドプリルtert−ブチルアミン 2g
ラクトース一水和物 62g
ステアリン酸マグネシウム 1.3g
ポビドン 9g
コロイド状無水シリカ 0.3g
セルロースグリコール酸ナトリウム 30g
ステアリン酸 2.6g
化合物Aのフマル酸塩 12.48g
ペリンドプリルtert−ブチルアミン 2g
ラクトース一水和物 62g
ステアリン酸マグネシウム 1.3g
ポビドン 9g
コロイド状無水シリカ 0.3g
セルロースグリコール酸ナトリウム 30g
ステアリン酸 2.6g
Claims (16)
- 心不全の処置に使用するための選択的かつ特異的な洞房結節If電流阻害剤およびアンギオテンシン変換酵素を阻害する薬剤の組み合わせ。
- 処置される心不全が、収縮機能の保持された心不全であることを特徴とする、請求項1記載の組み合わせ。
- 選択的かつ特異的な洞房結節If電流阻害剤が:
− イバブラジン、すなわち3−{3−[{[(7S)−3,4−ジメトキシビシクロ[4.2.0]オクタ−1,3,5−トリエン−7−イル]メチル}(メチル)アミノ]プロピル}−7,8−ジメトキシ−1,3,4,5−テトラヒドロ−2H−3−ベンゾアゼピン−2−オン、もしくは薬学的に許容されうる酸とのその付加塩、それらの水和物および結晶形態の一つ、または
− N−{[(7S)−3,4−ジメトキシビシクロ[4.2.0]オクタ−1,3,5−トリエン−7−イル]メチル}−3−(7,8−ジメトキシ−1,2,4,5−テトラヒドロ−3H−3−ベンゾアゼピン−3−イル)−N−メチル−3−オキソ−1−プロパンアミン、もしくは薬学的に許容されうる酸とのその付加塩、それらの水和物および結晶形態の一つ
であることを特徴とする、請求項1または2の一項記載の組み合わせ。 - 選択的かつ特異的な洞房結節If電流阻害剤が、塩酸塩の形態のイバブラジン、またはその水和物もしくは結晶形態の一つであることを特徴とする、請求項1〜3の一項記載の組み合わせ。
- 選択的かつ特異的な洞房結節If電流阻害剤が、塩酸塩もしくはフマル酸塩の形態のN−{[(7S)−3,4−ジメトキシビシクロ[4.2.0]オクタ−1,3,5−トリエン−7−イル]メチル}−3−(7,8−ジメトキシ−1,2,4,5−テトラヒドロ−3H−3−ベンゾアゼピン−3−イル)−N−メチル−3−オキソ−1−プロパンアミン、またはそれらの水和物もしくは結晶形態の一つであることを特徴とする、請求項1〜3の一項記載の組み合わせ。
- アンギオテンシン変換酵素を阻害する薬剤が、ペリンドプリル、または薬学的に許容されうる塩基とのその付加塩、それらの水和物もしくは結晶形態の一つであることを特徴とする、請求項1〜5の一項記載の組み合わせ。
- ペリンドプリルが、tert−ブチルアミン塩もしくはアルギニン塩の形態またはそれらの水和物もしくは結晶形態の一つであることを特徴とする、請求項6記載の組み合わせ。
- 選択的かつ特異的な洞房結節If電流阻害剤が、塩酸塩の形態のイバブラジンまたはその水和物もしくは結晶形態の一つであり、アンギオテンシン変換酵素を阻害する薬剤が、tert−ブチルアミン塩もしくはアルギニン塩の形態のペリンドプリルまたはそれらの水和物もしくは結晶形態の一つであることを特徴とする、請求項1または2の一項記載の組み合わせ。
- 選択的かつ特異的な洞房結節If電流阻害剤が、塩酸塩もしくはフマル酸塩の形態のN−{[(7S)−3,4−ジメトキシビシクロ[4.2.0]オクタ−1,3,5−トリエン−7−イル]メチル}−3−(7,8−ジメトキシ−1,2,4,5−テトラヒドロ−3H−3−ベンゾアゼピン−3−イル)−N−メチル−3−オキソ−1−プロパンアミン、またはそれらの水和物もしくは結晶形態の一つであり、アンギオテンシン変換酵素を阻害する薬剤が、tert−ブチルアミン塩もしくはアルギニン塩の形態のペリンドプリルまたはそれらの水和物もしくは結晶形態の一つであることを特徴とする、請求項1または2の一項記載の組み合わせ。
- 活性成分として:
− 塩酸塩の形態のイバブラジン、またはその水和物もしくは結晶形態の一つ、および
− tert−ブチルアミン塩もしくはアルギニン塩の形態のペリンドプリルまたはそれらの水和物もしくは結晶形態の一つ
をそれら自身のみでまたは一つもしくは複数の薬学的に許容されうる賦形剤と組み合わせて含む、心不全の処置に使用するための薬学的組成物。 - 処置される心不全が、収縮機能の保持された心不全であることを特徴とする、請求項10記載の薬学的組成物。
- 活性成分として:
− 塩酸塩もしくはフマル酸塩の形態のN−{[(7S)−3,4−ジメトキシビシクロ[4.2.0]オクタ−1,3,5−トリエン−7−イル]メチル}−3−(7,8−ジメトキシ−1,2,4,5−テトラヒドロ−3H−3−ベンゾアゼピン−3−イル)−N−メチル−3−オキソ−1−プロパンアミン、またはそれらの水和物もしくは結晶形態の一つ、および
− tert−ブチルアミン塩もしくはアルギニン塩の形態のペリンドプリルまたはそれらの水和物もしくは結晶形態の一つ
をそれら自身のみでまたは一つもしくは複数の薬学的に許容されうる賦形剤と組み合わせて含む、薬学的組成物。 - 心不全の処置に使用するための、請求項12記載の薬学的組成物。
- 処置される心不全が、収縮機能の保持された心不全であることを特徴とする、請求項13記載の薬学的組成物。
- N−{[(7S)−3,4−ジメトキシビシクロ[4.2.0]オクタ−1,3,5−トリエン−7−イル]メチル}−3−(7,8−ジメトキシ−1,2,4,5−テトラヒドロ−3H−3−ベンゾアゼピン−3−イル)−N−メチル−3−オキソ−1−プロパンアミンまたは薬学的に許容されうる酸とのその付加塩、それらの水和物もしくは結晶形態の一つ、およびtert−ブチルアミン塩もしくはアルギニン塩の形態のペリンドプリル、またはそれらの水和物もしくは結晶形態の一つの組み合わせ。
- N−{[(7S)−3,4−ジメトキシビシクロ[4.2.0]オクタ−1,3,5−トリエン−7−イル]メチル}−3−(7,8−ジメトキシ−1,2,4,5−テトラヒドロ−3H−3−ベンゾアゼピン−3−イル)−N−メチル−3−オキソ−1−プロパンアミンが、塩酸塩もしくはフマル酸塩の形態またはそれらの水和物もしくは結晶形態の一つであることを特徴とする、請求項15記載の組み合わせ。
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FR3050380B1 (fr) | 2016-04-20 | 2020-07-10 | Les Laboratoires Servier | Composition pharmaceutique comprenant un betabloquant, un inhibiteur de l'enzyme de conversion et un antihypertenseur ou un ains. |
KR20190001340A (ko) * | 2017-06-27 | 2019-01-04 | 에리슨제약(주) | 이바브라딘을 포함하는 서방성 약제학적 조성물 및 이의 제조방법 |
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