JP5048871B2 - キノリン誘導体含有医薬組成物 - Google Patents
キノリン誘導体含有医薬組成物 Download PDFInfo
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- JP5048871B2 JP5048871B2 JP2011527665A JP2011527665A JP5048871B2 JP 5048871 B2 JP5048871 B2 JP 5048871B2 JP 2011527665 A JP2011527665 A JP 2011527665A JP 2011527665 A JP2011527665 A JP 2011527665A JP 5048871 B2 JP5048871 B2 JP 5048871B2
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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Description
すなわち、本発明は、以下の[1]〜[12]を提供する。
[1](1)下記式(I)で示される化合物もしくはその薬理学的に許容される塩またはそれらの溶媒和物、および(2)塩基性物質を含む医薬組成物。
[2]塩基性物質が炭酸塩である[1]に記載の組成物。
[3]塩がアルカリ土類金属塩である[2]に記載の組成物。
[4]アルカリ土類金属塩がマグネシウム塩またはカルシウム塩である[3]に記載の組成物。
[5]崩壊剤を含む[1]〜[4]のいずれか一項に記載の組成物。
[6]崩壊剤がカルメロースナトリウム、カルメロースカルシウム、カルボキシメチルスターチナトリウム、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロースまたはクロスポビドンである[5]に記載の組成物。
[7]R1が水素原子、メチル基、エチル基、n−プロピル基またはシクロプロピル基である[1]〜[6]のいずれか一項に記載の組成物。
[8]R1がシクロプロピル基である[1]〜[7]のいずれか一項に記載の組成物。
[9]R2が水素原子、メトキシ基またはエトキシ基である請求項1〜8のいずれか一項に記載の組成物。
[10]R2が水素原子である[1]〜[9]のいずれか一項に記載の組成物。
[11]薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、p−トルエンスルホン酸塩、硫酸塩、メタンスルホン酸塩またはエタンスルホン酸塩である[1]〜[10]のいずれか一項に記載の組成物。
[12]式(I)で示される化合物が4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキシアミドのメタンスルホン酸塩である[1]〜[11]のいずれか一項に記載の組成物。
4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミド、
4−(3−クロロ−4−(メチルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミド、
4−(3−クロロ−4−(エチルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミド、
N6−メトキシ−4−(3−クロロ−4−(((エチルアミノ)カルボニル)アミノ)フェノキシ)−7−メトキシ−6−キノリンカルボキサミド、
4−(3−クロロ−4−(1−プロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミド、
N6−メトキシ−4−(3−クロロ−4−(((シクロプロピルアミノ)カルボニル)アミノ)フェノキシ)−7−メトキシ−6−キノリンカルボキサミドおよび
N6−メトキシ−4−(3−クロロ−4−(((エチルアミノ)カルボニル)アミノ)フェノキシ)−7−メトキシ−6−キノリンカルボキサミド
からなる群から選ばれるキノリン誘導体、もしくはその薬理学的に許容される塩またはそれらの溶媒和物である。
4−(3−クロロ−4−(メチルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキシアミド、
4−(3−クロロ−4−(エチルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキシアミド、
4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキシアミド、
N6−メトキシ−4−(3−クロロ−4−(((シクロプロピルアミノ)カルボニル)アミノ)フェノキシ)−7−メトキシ−6−キノリンカルボキシアミド、および
N6−メトキシ−4−(3−クロロ−4−(((エチルアミノ)カルボニル)アミノ)フェノキシ)−7−メトキシ−6−キノリンカルボキシアミド
からなる群から選ばれるキノリン誘導体、もしくはその薬理学的に許容される塩またはそれらの溶媒和物である。
4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキシアミド、もしくはその薬理学的に許容される塩またはそれらの溶媒和物である。
4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキシアミドのメタンスルホン酸塩のC型結晶(以下、化合物Aと称する)、D−マンニトール(商品名:マンニトール、メルク)、沈降炭酸カルシウム(商品名:ホワイトンF、白石カルシウム)、ヒドロキシプロピルセルロース(HPC−L、日本曹達)、低置換度ヒドロキシプロピルセルロース(商品名:L−HPC(LH−21)、信越化学工業)および結晶セルロース(商品名:セオラスPH−101、旭化成)を表1の処方割合に従って、高速攪拌造粒装置(装置名:FM−VG−10、パウレック社製)を使用して、精製水を溶媒とする湿式造粒を実施した。さらに乾燥して、水分含有量2%未満とした顆粒を、粉砕整粒装置(装置名:パワーミルP−04S、昭和技研社製)を使用して、顆粒径1mm未満となるように整粒した。その後、整粒した顆粒に、表1の処方割合に従って、結晶セルロース(商品名:セオラスPH−102、旭化成)およびタルク(商品名:ハイフィラー17、岩井化学)を添加し、タンブラー型混合機(商品名:10L/20L交換型タンブラー混合機、東洋パッキング社製)を使用して十分に混合した。得られた顆粒100mgを4号のハードカプセルに充填し、化合物Aを含むカプセル剤を製造した。
化合物A、沈降炭酸カルシウム、低置換度ヒドロキシプロピルセルロース、D−マンニトールおよびタルクを表2および表3の処方割合に従って、乳鉢と乳棒を使用して十分に混合した。得られた混合物100mgを3号のハードカプセルに充填し、実施例4〜9のカプセル剤を製造した。また、同様の方法で、沈降炭酸カルシウムを含まない比較例1〜2のカプセル剤を製造した。
実施例4〜9および比較例1〜2のカプセル剤について、第十五改正日本薬局方に記載されている溶出試験法(パドル法、試験液:第1液)に従って、化合物Aの溶出性を検討した。その結果、炭酸カルシウムを配合しない比較例1〜2のカプセル剤では、化合物Aの溶出は不十分であった。一方、炭酸カルシウムを配合した実施例4〜9のカプセル剤では、化合物Aの溶出は良好であった(図1および図2)。
化合物A、炭酸マグネシウム(協和化学工業)、低置換度ヒドロキシプロピルセルロース、D−マンニトールおよびタルクを表4および表5の処方割合に従って、乳鉢と乳棒を使用して十分に混合した。得られた混合物100mgを3号のハードカプセルに充填し、実施例10〜15のカプセル剤を製造した。また、同様の方法で、炭酸マグネシウムを含まない比較例3〜4のカプセル剤を製造した。
試験例1と同様の方法で、実施例10〜15および比較例3〜4のカプセル剤について、化合物Aの溶出性を検討した。炭酸マグネシウムを配合しない比較例3〜4のカプセル剤では、化合物Aの溶出は不十分であった。一方、炭酸マグネシウムを配合した実施例10〜15のカプセル剤では、化合物Aの溶出は良好であった(図3および図4)。
化合物A、沈降炭酸カルシウムまたは炭酸マグネシウム、ヒドロキシプロピルセルロース、クロスカルメロースナトリウム(商品名:Ac−di−sol、旭化成)に精製水を加えて、乳鉢と乳棒を使用して造粒した後、乾燥した顆粒を顆粒径1mm未満となるように整粒した。その後、整粒した顆粒に、表6の処方割合に従って、結晶セルロース(商品名:セオラスPH−102、旭化成)、低置換度ヒドロキシプロピルセルロースおよびタルク(商品名:ハイフィラー17、岩井化学)を添加し、十分に混合した。得られた混合物100mgを4号のハードカプセルに充填し、実施例16〜17のカプセル剤を製造した。また、同様に表7の処方割合に従って、沈降炭酸カルシウムおよび炭酸マグネシウムを含まず、代わりにマンニトールまたはタルクを含む比較例5〜6のカプセル剤を製造した。
試験例1と同様の方法で、実施例16〜17および比較例5のカプセル剤について、化合物Aの溶出性を検討した。炭酸カルシウムおよび炭酸マグネシウムを配合しない比較例5のカプセル剤では、化合物Aの溶出は不十分であった。一方、炭酸カルシウムまたは炭酸マグネシウムを配合した実施例16〜17のカプセル剤では、化合物Aの溶出は良好であった(図5)。
実施例16〜17および比較例6のカプセル剤について、温度60℃、相対湿度75%の環境に開放系で1週間保存した後、分解物の生成を高速液体クロマトグラフで測定した。炭酸カルシウムおよび炭酸マグネシウムを配合しない比較例6のカプセル剤では、分解物が増加した。一方、炭酸カルシウムまたは炭酸マグネシウムを配合した実施例16〜17のカプセル剤では、分解物の増加は認められなかった(表8)。
実施例4〜9、比較例1〜2と同様の方法で、表9および10の処方に従って各成分を混合した。得られた混合物100mgを3号のハードカプセルに充填し、実施例18〜19、比較例7〜10のカプセル剤を製造した。
試験例1と同様の方法で、実施例18〜19、比較例7〜10のカプセル剤について、化合物Aの溶出性を検討した。その結果、酸化カルシウム、水酸化カルシウム、酸化マグネシウムまたは水酸化マグネシウムを配合した比較例7〜10のカプセルでは、化合物Aの溶出は不十分であった。一方、炭酸カルシウムまたは炭酸マグネシウムを配合した実施例18〜19のカプセルでは、化合物Aの溶出は良好であった(図6および図7)。
Claims (9)
- (1)下記式(I)で示される化合物もしくはその薬理学的に許容される塩またはそれらの溶媒和物、および(2)炭酸のアルカリ土類金属塩を含む医薬組成物。
- 炭酸のアルカリ土類金属塩が炭酸マグネシウムまたは炭酸カルシウムである請求項1に記載の組成物。
- 崩壊剤を含む請求項1または2に記載の組成物。
- 崩壊剤がカルメロースナトリウム、カルメロースカルシウム、カルボキシメチルスターチナトリウム、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロースまたはクロスポビドンである請求項3に記載の組成物。
- R1が水素原子、メチル基、エチル基、n−プロピル基またはシクロプロピル基である請求項1〜4のいずれか一項に記載の組成物。
- R1がシクロプロピル基である請求項1〜5のいずれか一項に記載の組成物。
- R2が水素原子である請求項1〜6のいずれか一項に記載の組成物。
- 薬理学的に許容される塩が、塩酸塩、臭化水素酸塩、p−トルエンスルホン酸塩、硫酸塩、メタンスルホン酸塩またはエタンスルホン酸塩である請求項1〜7のいずれか一項に記載の組成物。
- 式(I)で示される化合物が4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキシアミドのメタンスルホン酸塩である請求項1〜8のいずれか一項に記載の組成物。
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