JP6937308B2 - キノリン誘導体またはその塩を含有する医薬組成物の製造方法 - Google Patents
キノリン誘導体またはその塩を含有する医薬組成物の製造方法 Download PDFInfo
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- JP6937308B2 JP6937308B2 JP2018534780A JP2018534780A JP6937308B2 JP 6937308 B2 JP6937308 B2 JP 6937308B2 JP 2018534780 A JP2018534780 A JP 2018534780A JP 2018534780 A JP2018534780 A JP 2018534780A JP 6937308 B2 JP6937308 B2 JP 6937308B2
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Description
1)2-20重量%の崩壊剤、該崩壊剤は架橋ポリビニルピロリドンである;
2)5-80重量%のフィラー、該フィラーは乳糖および結晶セルロースから成る群から選択される1つ以上である;
3)0.5-15重量%の結合剤、該結合剤はポリビニルピロリドン、ヒドロキシプロピルメチルセルロースおよびヒドロキシプロピルセルロースから成る群から選択される1つ以上である;および
4)0.5-5重量%の滑沢剤、該滑沢剤はステアリン酸マグネシウムおよびタルクから成る群から選択される1つ以上である;
を含有する。
各成分の含有率は、医薬組成物の全重量に基づく。
本発明を以下の実施例および試験例により更に詳細に説明する。これらの実施例および試験例は説明するためだけのものであり、本発明の範囲を限定するものではない。
実施例1〜5、比較例1
実施例1〜5および比較例1で得られた分けた顆粒100 gを、50メッシュと100メッシュのふるいを用いて振とうし、ふるい分けした。比較例1では湿潤剤として精製水が用いられたが、得られた顆粒中に多量の大粒子と微粉末があり、粒子径分布は望ましくない。エタノールを含む湿潤剤が実施例1〜5で用いられたが、得られた顆粒中には大粒子と微粉末は少なく、粒子径分布はより均一である。
ふるい分け結果を図1に示す。
実施例1〜5および比較例1の錠剤の溶出率を、中国薬局方(2010年版)の第II巻付録に記載された溶出率試験の第2法(パドル法)に従って測定した。溶出試験は37±0.5℃およびパドルスピード50 rpmで溶解培地として0.1 mol/L塩酸溶液900 mlを用いて行った。その結果、20重量%エタノール水溶液、50重量%エタノール水溶液、80重量%エタノール水溶液、93.75重量%エタノール水溶液および無水エタノールが実施例1〜5でそれぞれ湿潤剤として用いられたとき、得られた顆粒は望ましい粒子径分布を有し、化合物Aの溶出は迅速で完全であり;精製水が比較例1で湿潤剤として用いられたとき、得られた錠剤では化合物Aの溶出均一性が乏しいことは示された。エタノールを含む湿潤剤が実施例1〜5で湿潤剤として用いられたが、得られた錠剤では化合物Aの溶出均一性は良好である。
溶出プロフィールを図2〜7に示すが、図中に示したR1〜R6は試験したサンプル錠剤1〜錠剤6を表している。
実施例6〜11
実施例6〜11の錠剤の溶出率を、中国薬局方(2010年版)の第II巻付録に記載された溶出率試験の第2法(パドル法)に従って測定した。溶出試験は37±0.5℃およびパドルスピード50 rpmで溶解培地として0.1 mol/L塩酸溶液900 mlを用いて行った。その結果、実施例6〜9の異なる比率の崩壊剤を含有する錠剤および実施例10および11の異なる比率の化合物Aを含有する錠剤では、化合物Aの溶出が迅速で完全であることは示された。
溶出プロフィールを図8に示す。
Claims (21)
- 活性成分(R,E)-N-(4-(3-クロロ-4-(ピリジン-2-イルメトキシ)フェニルアミノ)-3-シアノ-7-エトキシキノリン-6-イル)-3-(1-メチルピロリジン-2-イル)-プロペンアミドまたはその薬理学的に許容される塩を湿潤剤と混合し、造粒する工程を含み、かつ得られた顆粒を乾燥させた後、それらを錠剤に打錠するか、またはカプセルに充填する工程も含み、該湿潤剤は、エタノールと水の混合溶媒であり、エタノールは、湿潤剤の総重量に対して50〜95重量%の量で存在する、ことを特徴とする、医薬組成物の製造方法。
- 活性成分が組成物の全重量に対して、5-70重量%の量で存在する、請求項1に記載の医薬組成物の製造方法。
- 活性成分が組成物の全重量に対して、10-50重量%の量で存在する、請求項2に記載の医薬組成物の製造方法。
- 活性成分が組成物の全重量に対して、20-40重量%の量で存在する、請求項2に記載の医薬組成物の製造方法。
- 薬理学的に許容される塩がマレイン酸塩である、請求項1に記載の医薬組成物の製造方法。
- 薬理学的に許容される塩がジマレイン酸塩である、請求項5に記載の医薬組成物の製造方法。
- 医薬組成物がフィラーを含有することを特徴とする、請求項1に記載の医薬組成物の製造方法。
- フィラーが、結晶セルロース、リン酸水素カルシウム、マンニトール、アルファ化デンプンおよび乳糖の1つ以上であることを特徴とする、請求項7に記載の医薬組成物の製造方法。
- フィラーが、組成物の全重量に対して、5-80重量%の量で存在していることを特徴とする、請求項7に記載の医薬組成物の製造方法。
- 医薬組成物が結合剤を含有することを特徴とする、請求項1に記載の医薬組成物の製造方法。
- 結合剤が、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、カルボキシメチルセルロースナトリウム、ポリビニルピロリドンおよびメチルセルロースの1つ以上であることを特徴とする、請求項10に記載の医薬組成物の製造方法。
- 結合剤が、組成物の全重量に対して、0.5-15重量%の量で存在していることを特徴とする、請求項10に記載の医薬組成物の製造方法。
- 医薬組成物が崩壊剤を含有することを特徴とする、請求項1に記載の医薬組成物の製造方法。
- 崩壊剤が、低置換度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、カルボキシメチルデンプンナトリウムおよび架橋ポリビニルピロリドンから成る群から選択される1つ以上であることを特徴とする、請求項13に記載の医薬組成物の製造方法。
- 崩壊剤は、組成物の全重量に対して、2-20重量%の量で存在していることを特徴とする、請求項13に記載の医薬組成物の製造方法。
- 崩壊剤は、組成物の全重量に対して、4-15重量%の量で存在していることを特徴とする、請求項13に記載の医薬組成物の製造方法。
- 崩壊剤は、組成物の全重量に対して、6-10重量%の量で存在していることを特徴とする、請求項13に記載の医薬組成物の製造方法。
- 医薬組成物が滑沢剤を含有することを特徴とする、請求項1に記載の医薬組成物の製造方法。
- 滑沢剤が、タルク、ステアリン酸マグネシウム、ステアリン酸亜鉛、ベヘン酸グリセリル、ラウリル硫酸ナトリウム、水素化植物油およびコロイド状二酸化ケイ素の1つ以上であることを特徴とする、請求項18に記載の医薬組成物の製造方法。
- 滑沢剤が、組成物の全重量に対して、約0.5-5重量%の量で存在していることを特徴とする、請求項18に記載の医薬組成物の製造方法。
- 活性成分(R,E)-N-(4-(3-クロロ-4-(ピリジン-2-イルメトキシ)フェニルアミノ)-3-シアノ-7-エトキシキノリン-6-イル)-3-(1-メチルピロリジン-2-イル)-プロペンアミドまたはその薬理学的に許容される塩を湿潤剤と混合し、造粒し、生成した顆粒を乾燥させ、錠剤に打錠するか、またはカプセルに充填する工程を含む医薬組成物の製造方法であって、該湿潤剤がエタノールと水との混合溶媒であり、エタノールが該湿潤剤の全重量に対して50〜80重量%の量で存在しており、該医薬組成物は、
1)2-20重量%の崩壊剤、該崩壊剤は架橋ポリビニルピロリドンである;
2)5-80重量%のフィラー、該フィラーは乳糖および結晶セルロースから成る群から選択される1つ以上である;
3)0.5-15重量%の結合剤、該結合剤はポリビニルピロリドン、ヒドロキシプロピルメチルセルロースおよびヒドロキシプロピルセルロースから成る群から選択される1つ以上である;および
4)0.5-5重量%の滑沢剤、該滑沢剤はステアリン酸マグネシウムおよびタルクから成る群から選択される1つ以上である;
を含有する、
製造方法。
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