JP5419866B2 - 新たな医薬組成物 - Google Patents
新たな医薬組成物 Download PDFInfo
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- JP5419866B2 JP5419866B2 JP2010507380A JP2010507380A JP5419866B2 JP 5419866 B2 JP5419866 B2 JP 5419866B2 JP 2010507380 A JP2010507380 A JP 2010507380A JP 2010507380 A JP2010507380 A JP 2010507380A JP 5419866 B2 JP5419866 B2 JP 5419866B2
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- pharmaceutical
- diluent
- microns
- pharmaceutical tablet
- disintegrant
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Description
賦形剤の特定の型および量、ならびに錠剤化技術の選択は、エルトロンボパグオールアミンおよび賦形剤のさらなる特性、例えば、圧縮率、流動性、粒径、適合性および密度に依存する。錠剤は、直接圧縮、乾式造粒、流動層造粒および湿式造粒を含む当該分野にて公知の方法に従って調製され得、そのため、使用される賦形剤の方は変動するだろう。湿式造粒は、強度が高く、破損が少ない、比較的高濃度のエルトロンボパグオールアミン(例えば、約40%またはそれ以上)を含む錠剤を、適切な商業製造規模で提供することに特に適切であることが知られている。本発明の適切な湿式造粒錠剤は、エルトロンボパグオールアミンおよび1つまたは複数の充填剤、結合剤および崩壊剤を含む顆粒を含み、顆粒は、さらなる充填剤、結合剤、崩壊剤および/または潤滑剤と混合されて、錠剤を形成するために圧縮される圧縮混合物を形成する。
(i)約2%〜約65%のエルトロンボパグオールアミン;
(ii)約25%〜約89%の希釈剤;
(iii)約8%まで、適切には約5%まで、適切には約4%までの結合剤;
(iv)約2%まで、適切には約1.5%まで、適切には約1%までの潤滑剤;および
(v)4%〜約12%、適切には6%〜10%、適切には7%〜9%の崩壊剤
を含む。
(i)約2%〜約88%のエルトロンボパグオールアミン;
(ii)約10%〜約96%の希釈剤;
(iii)約2%〜約5%の結合剤;および
(iv)所望により、0%〜約4%の崩壊剤
を含み、外部賦形剤は、錠剤の重量で、
(i)0%〜約70%の希釈剤;
(ii)約0.25%〜約2%、適切には0.25%〜約1.25%の潤滑剤;および
(iii)約4%〜約10%の崩壊剤
を含む。
(i)セルロースフィルム形成ポリマー;および
(ii)可塑剤。
湿式造粒される本発明の医薬錠剤は、以下の工程を含む方法によって調製され得る:
I)以下のことを含む、顆粒を調製する工程:
a)材料を均質にすることに十分な時間、エルトロンボパグオールアミン、希釈剤、結合剤、および、所望により、崩壊剤を一緒に混合すること;
b)好ましくは、混合しながら、造粒液を乾燥した材料の混合物に添加すること;
c)湿った顆粒を形成するために、乾燥した材料を全体的に均一に濡らすために十分な造粒の時間、乾燥した材料の混合物と造粒液を混合すること;
d)湿った顆粒をよく製粉すること;
e)よく製粉した顆粒を乾燥させて、乾燥した顆粒を形成すること;ならびに
f)乾燥した顆粒を乾式破砕して、所望の大きさの顆粒を形成すること;
II)以下のことを含み、錠剤を調製する工程;
a)顆粒および外側の賦形剤を均質にするために十分な時間、充填剤、潤滑剤および崩壊剤を含む外側の賦形剤と、工程I)にて調製した顆粒を混合する工程;ならびに
b)顆粒および外側の賦形剤のを含む混合物を圧縮して、錠剤を形成すること。
湿式造粒された顆粒を調製する際、乾燥した材料は、当該分野にて知られている適切な機器(例えば、Niro−Fielder Blender/Granulator、Bear Varimixer、Key High Shear Mixer/Granulator)を用いて、材料を均質にするために十分な時間(例えば、約3分間)混合され得る。
賦形剤の特定の型および量、ならびに用いるカプセル化技術の選択は、エルトロンボパグオールアミンおよび賦形剤のさらなる特性(例えば、圧縮率、流動性、粒径、適合性および密度)に依存する。カプセルは、当該分野にて知られている方法(適切には、商業生産に適したスケールで、適切には、2つの標準的な硬ゼラチンカプセルに賦形剤と混合したエルトロンボパグオールアミンを充填すること、適切には、2つの標準的な硬ゼラチンカプセルに本発明によって調製した顆粒を充填すること)に従って調製され得る。本発明の適切なカプセルは、エルトロンボパグオールアミン、および1つまたは複数の充填剤、結合剤および崩壊剤を含む顆粒を含み、顆粒は、さらなる充填剤、結合剤、崩壊剤および/または潤滑剤と混合されて、カプセルに充填された顆粒混合物を形成する。
本発明はまた、本発明の固体経口医薬剤形の製造における、エルトロンボパグオールアミンの使用を提供する。
本発明はまた、血小板減少症を処置することにおける使用のための、本発明の固体経口医薬剤形の製造における、エルトロンボパグオールアミンの使用を提供する。
本発明はまた、本発明のエルトロンボパグオールアミンおよび医薬上許容される担体を含む、血小板減少症の処置における使用のための固体経口医薬剤形を提供する。
本発明はまた、配位金属を実質的に含まず、および/または還元糖を実質的に含まない1つまたは複数の希釈剤を含む、固体経口医薬剤形を製造するための方法を提供し、方法は、エルトロンボパグオールアミンを1つまたは複数の希釈剤と一緒にする工程を含む。
当業者であれば、さらに詳述することなしに、上の記載を使用して、本発明を完全に用いることができる。したがって、以下の実施例は、単に例示であって、本発明の範囲を限定することなく構成される。
本明細書にて用いられる全ての賦形剤は、当業者に知られている多くの製造者から入手可能な、標準的な医薬グレードの賦形剤である。
エルトロンボパグオールアミンおよび表1の成分を含む、湿式造粒の錠剤を調製した。
リン酸カルシウム二塩基酸アンヒドロ亜酸配位金属を含む希釈剤を含むエルトロンボパグオールアミン錠剤を、上記と同様のやり方で製造した。錠剤の配位金属希釈剤のための錠剤組成物を、表2にて提供する。
図2は、エルトロンボパグオールアミンの溶解に対するAPI粒径分布の効果を示す。エルトロンボパグオールアミン75mgの錠剤を、実施例5にて記載するやり方で、異なる粒径を使用して一般に調製した。粒径は、処方物にて使用した薬物の顆粒の粒径をいう。
Claims (45)
- 3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸ビス−(モノエタノールアミン)を含む医薬錠剤であって、配位金属を含まず、および還元糖を含まない1つまたは複数の希釈剤を使用する湿式造粒プロセスによって製造される医薬錠剤。
- 3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸ビス−(モノエタノールアミン)を含む医薬錠剤であって、配位金属を含まず、および還元糖を含まない1つまたは複数の希釈剤を使用する湿式造粒プロセスによって、商業規模で製造される医薬錠剤。
- 90%の薬物粒子が10ミクロンより大きいが90ミクロンより小さい粒径を有する、請求項1記載の医薬錠剤。
- 90%の薬物粒子が10ミクロンより大きいが90ミクロンより小さい粒径を有する、請求項2記載の医薬錠剤。
- 90%の薬物粒子が20ミクロンより大きいが50ミクロンより小さい粒径を有する、請求項2記載の医薬錠剤。
- 50%の薬物粒子が5ミクロンより大きいが50ミクロンより小さい粒径を有する、請求項2記載の医薬錠剤。
- 50%の薬物粒子が5ミクロンより大きいが20ミクロンより小さい粒径を有する、請求項2記載の医薬錠剤。
- a)2%〜65%のエルトロンボパグオールアミン;
b)25%〜89%の希釈剤;
c)8%までの結合剤;
d)2%までの潤滑剤;および
e)4%〜12%の崩壊剤
を含む、請求項1記載の医薬錠剤。 - a)2%〜65%のエルトロンボパグオールアミン;
b)25%〜89%の希釈剤;
c)8%までの結合剤;
d)2%までの潤滑剤;および
e)6%〜10%の崩壊剤
を含む、請求項1記載の医薬錠剤。 - a)2%〜65%のエルトロンボパグオールアミン;
b)25%〜89%の希釈剤;
c)8%までの結合剤;
d)2%までの潤滑剤;および
e)7%〜9%の崩壊剤
を含む、請求項1記載の医薬錠剤。 - a)2%〜65%のエルトロンボパグオールアミン;
b)25%〜89%の希釈剤;
c)8%までの結合剤;
d)2%までの潤滑剤;および
e)4%〜12%の崩壊剤
を含む、請求項2、4または5のいずれか1項記載の医薬錠剤。 - a)2%〜65%のエルトロンボパグオールアミン;
b)25%〜89%の希釈剤;
c)8%までの結合剤;
d)2%までの潤滑剤;および
e)6%〜10%の崩壊剤
を含む、請求項2、4または5のいずれか1項記載の医薬錠剤。 - a)2%〜65%のエルトロンボパグオールアミン;
b)25%〜89%の希釈剤;
c)8%までの結合剤;
d)2%までの潤滑剤;および
e)7%〜9%の崩壊剤
を含む、請求項2、4または5のいずれか1項記載の医薬錠剤。 - a)2%〜65%のエルトロンボパグオールアミン;
b)25%〜89%の希釈剤;
c)8%までの結合剤;
d)2%までの潤滑剤;および
e)4%〜12%の崩壊剤
を含む、請求項6または7記載の医薬錠剤。 - a)2%〜65%のエルトロンボパグオールアミン;
b)25%〜89%の希釈剤;
c)8%までの結合剤;
d)2%までの潤滑剤;および
e)6%〜10%の崩壊剤
を含む、請求項6または7記載の医薬錠剤。 - a)2%〜65%のエルトロンボパグオールアミン;
b)25%〜89%の希釈剤;
c)8%までの結合剤;
d)2%までの潤滑剤;および
e)7%〜9%の崩壊剤
を含む、請求項6または7記載の医薬錠剤。 - 希釈剤成分が非還元糖および結晶セルロースを含む、請求項8記載の医薬錠剤。
- 非還元糖がマンニトールであり、結合剤がポリビニルピロリドンであり、崩壊剤がデンプングリコール酸ナトリウムであり、かつ潤滑剤がステアリン酸マグネシウムである、請求項17記載の医薬錠剤。
- 希釈剤成分が非還元糖および結晶セルロースを含む、請求項11記載の医薬錠剤。
- 非還元糖がマンニトールであり、結合剤がポリビニルピロリドンであり、崩壊剤がデンプングリコール酸ナトリウムであり、かつ潤滑剤がステアリン酸マグネシウムである、請求項19記載の医薬錠剤。
- 希釈剤成分が非還元糖および結晶セルロースを含む、請求項14記載の医薬錠剤。
- 非還元糖がマンニトールであり、結合剤がポリビニルピロリドンであり、崩壊剤がデンプングリコール酸ナトリウムであり、かつ潤滑剤がステアリン酸マグネシウムである、請求項21記載の医薬錠剤。
- 商業規模で製造される、請求項18記載の医薬錠剤。
- 請求項1〜23のいずれか1項記載の医薬錠剤であって、血小板減少症の処置のための医薬錠剤。
- 請求項1〜23のいずれか1項記載の医薬錠剤であって、TPO受容体を刺激するための医薬錠剤。
- コロニー刺激因子、サイトカイン、ケモカイン、インターロイキンまたはサイトカイン受容体アゴニストもしくはアンタゴニスト、可溶性受容体、受容体アゴニストもしくはアンタゴニスト抗体、あるいは該薬剤の1つまたは複数と同じ機序によって作用する低分子またはペプチドからなる群より選択され、同時に投与される薬剤をさらに含む、請求項24記載の医薬錠剤。
- 3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸ビス−(モノエタノールアミン)を含む固体経口医薬剤形であって、配位金属を含まず、および還元糖を含まない1つまたは複数の希釈剤を使用する湿式造粒プロセスによって製造される固体経口医薬剤形。
- 3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸ビス−(モノエタノールアミン)を含む固体経口医薬剤形であって、配位金属を含まず、および還元糖を含まない1つまたは複数の希釈剤を使用する湿式造粒プロセスによって、商業規模で製造される固体経口医薬剤形。
- 90%の薬物粒子が10ミクロンより大きいが90ミクロンより小さい粒径を有する、請求項27記載の固体経口医薬剤形。
- a)2%〜65%のエルトロンボパグオールアミン;
b)25%〜89%の希釈剤;
c)8%までの結合剤;
d)2%までの潤滑剤;および
e)4%〜12%の崩壊剤
を含む、請求項27記載の固体経口医薬剤形。 - 商業規模で製造される、請求項30記載の固体経口医薬剤形。
- 請求項27〜31のいずれか1項記載の固体経口医薬剤形であって、血小板減少症の処置のための固体経口医薬剤形。
- 請求項27〜31のいずれか1項記載の固体経口医薬剤形であって、TPO受容体を刺激するための固体経口医薬剤形。
- コロニー刺激因子、サイトカイン、ケモカイン、インターロイキンまたはサイトカイン受容体アゴニストもしくはアンタゴニスト、可溶性受容体、受容体アゴニストもしくはアンタゴニスト抗体、あるいは該薬剤の1つまたは複数と同じ機序によって作用する低分子またはペプチドからなる群より選択され、同時に投与される薬剤をさらに含む、請求項32記載の固体経口医薬剤形。
- 3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸ビス−(モノエタノールアミン)を含む医薬カプセルであって、配位金属を含まず、および還元糖を含まない1つまたは複数の希釈剤を使用する湿式造粒プロセスによって製造される医薬カプセル。
- 3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸ビス−(モノエタノールアミン)を含む医薬カプセルであって、配位金属を含まず、および還元糖を含まない1つまたは複数の希釈剤を使用する湿式造粒プロセスによって、商業規模で製造される医薬カプセル。
- 90%の薬物粒子が10ミクロンより大きいが90ミクロンより小さい粒径を有する、請求項35記載の医薬カプセル。
- a)2%〜65%のエルトロンボパグオールアミン;
b)25%〜89%の希釈剤;
c)8%までの結合剤;
d)2%までの潤滑剤;および
e)4%〜12%の崩壊剤
を含む、請求項35記載の医薬カプセル。 - 商業規模で製造される、請求項38記載の医薬カプセル。
- 請求項35〜39のいずれか1項記載の医薬カプセルであって、血小板減少症の処置のための医薬カプセル。
- 請求項35〜39のいずれか1項記載の医薬カプセルであって、TPO受容体を刺激するための医薬カプセル。
- コロニー刺激因子、サイトカイン、ケモカイン、インターロイキンまたはサイトカイン受容体アゴニストもしくはアンタゴニスト、可溶性受容体、受容体アゴニストもしくはアンタゴニスト抗体、あるいは該薬剤の1つまたは複数と同じ機序によって作用する低分子またはペプチドからなる群より選択され、同時に投与される薬剤をさらに含む、請求項40記載の医薬カプセル。
- 3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸ビス−(モノエタノールアミン)を含む医薬顆粒であって、配位金属を含まず、および還元糖を含まない1つまたは複数の希釈剤を使用する湿式造粒プロセスによって製造される医薬顆粒。
- 3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸ビス−(モノエタノールアミン)を含む医薬顆粒であって、配位金属を含まず、および還元糖を含まない1つまたは複数の希釈剤を使用する湿式造粒プロセスによって、商業規模で製造される医薬顆粒。
- 請求項1に記載の3’−[(2Z)−[1−(3,4−ジメチルフェニル)−1,5−ジヒドロ−3−メチル−5−オキソ−4H−ピラゾール−4−イリデン]ヒドラジノ]−2’−ヒドロキシ−[1,1’−ビフェニル]−3−カルボン酸ビス−(モノエタノールアミン)の治療有効量、ならびに配位金属を含まず、および還元糖を含まない1つまたは複数の希釈剤を含む固体経口治療剤形の湿式造粒プロセスによる製造方法であって、請求項1に記載の化合物を1つまたは複数の希釈剤と一緒にする工程を包含する製造方法。
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