JP2023519583A - 医薬組成物、その調製方法及び使用方法 - Google Patents
医薬組成物、その調製方法及び使用方法 Download PDFInfo
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Abstract
Description
本出願の一態様は、加熱溶融押出用の押出混合物に関する。この押出混合物は、(a)式(I)
ある実施形態では、押出混合物は、成分として、質量部基準で、(a)式(I)の化合物1部と、(b)ガラス転移温度が90℃~130℃のコポビドン5~70部とを含む。
(a)式(I)の化合物1部と、
(b)ガラス転移温度が100℃~120℃のコポビドン15~45部と、
(c)1種以上の薬学的に許容される賦形剤0.1~3.0部と、を含み、この薬学的に許容される賦形剤は、不揮発性弱酸、中性及び弱酸性無機物、及び融点が80℃未満の薬学的に許容される賦形剤からなる群から選択される。
ある実施形態では、この押出混合物は、成分として、質量部基準で、(a)式(I)の化合物1部と、(b)ガラス転移温度が90℃~130℃のヒドロキシプロピルメチルセルロース3~40部とを含む。
(a)式(I)の化合物1部と、
(b)ガラス転移温度が100℃~120℃のヒドロキシプロピルメチルセルロース6~20部と、
(c)1種以上の薬学的に許容される賦形剤0.1~3.0部を含み、この薬学的に許容される賦形剤は、不揮発性弱酸、中性無機物、弱酸性無機物、及び融点が80℃未満の他の薬学的に許容される賦形剤からなる群から選択される。
本出願の別の態様は、本出願の押出混合物の押出物及び1種以上の薬学的に許容される担体を含む医薬組成物に関する。ある実施形態では、この医薬組成物は、脂肪性肝炎及び脂肪性肝炎に関連する疾患を治療するために使用することができる。
本出願の別の態様は、本出願の押出物を調製する方法に関する。この方法は、80℃~135℃の押出ダイヘッド又は押出出口温度(加熱溶融押出温度)で加熱溶融押出によって本出願の押出混合物を押し出して押出物を形成する工程を含む。ある実施形態では、加熱溶融押出温度は100℃~130℃である。ある実施形態では、加熱溶融押出温度は、80℃~130℃、80℃~120℃、80℃~110℃、80℃~100℃、80℃~90℃、90℃~130℃、90℃~120℃、90℃~110℃、90℃~100℃、100℃~130℃、100℃~120℃、100℃~110℃、110℃~130℃、110℃~120℃、又は120℃~130℃である。
本出願の別の態様は、被験者の脂肪性肝炎又は脂肪性肝炎関連疾患を治療するための方法に関する。この方法は、そのような治療を必要とする被験者に有効量の本出願の医薬組成物を投与する工程を含む。ある実施形態では、本出願の医薬組成物は経口投与される。ある実施形態では、本出願の医薬組成物は、錠剤又はカプセル剤の形態で経口投与される。ある実施形態では、本出願の医薬組成物は、1日2回、毎日、又は1日おきに投与される。
(1)本出願の医薬組成物は、式(I)の化合物の溶出率を大幅に向上させ、従来技術と同様の過飽和維持時間を達成することができる。
(2)本出願の医薬組成物は、冷蔵せずに室温(30℃以下)で長期間保存することができる。
1.API及び賦形剤の前処理:更なる調製の基準を満たすように、製剤技術の従来の手段によって、処方研究に使用されるAPI及び賦形剤を粉砕、ふるい分け、及び乾燥することにより、貯蔵中のケーキングを取り除き、吸湿性賦形剤の水分含有量を減少させた。
1.API及び賦形剤の前処理:更なる調製の基準を満たすように、製剤技術の従来の手段によって、処方研究に使用されるAPI及び賦形剤を粉砕、ふるい分け、及び乾燥することにより、貯蔵中のケーキングを取り除き、吸湿性賦形剤の水分含有量を減少させた。
表2のa2処方及び以下の調製プロセスに従って調製した。
1.API及び賦形剤の前処理:更なる調製の基準を満たすように、製剤技術の従来の手段によって、処方研究に使用されるAPI及び賦形剤を粉砕、ふるい分け、及び乾燥することにより、貯蔵中のケーキングを取り除き、吸湿性賦形剤の水分含有量を減少させた。
処方組成物:
1.API及び賦形剤の前処理:更なる調製の基準を満たすように、製剤技術の従来の手段によって、処方研究に使用されるAPI及び賦形剤を粉砕、ふるい分け、及び乾燥することにより、貯蔵中のケーキングを取り除き、吸湿性賦形剤の水分含有量を減少させた。
中国発明特許出願第202010105909.9号の実施例1のE1処方(以下の表5に示す)及び以下の調製プロセスに従って調製した。
1.ブランクマトリックスの調製:65℃の条件下で、ポリエチレングリコール1000、ポリエチレングリコール4000、ポリエチレングリコール6000、ポロキサマー188、及び無水クエン酸を順に加え、撹拌して完全に溶解させた。
〔比較実施例4〕
表6のe2及びf2処方及び以下の調製プロセスに従って調製した。
1.API及び賦形剤の前処理:更なる調製の基準を満たすように、製剤技術の従来の手段によって、処方研究に使用されるAPI及び賦形剤を粉砕、ふるい分け、及び乾燥することにより、貯蔵中のケーキングを取り除き、吸湿性賦形剤の水分含有量を減少させた。
表7のg2処方及び以下の調製プロセスに従って調製した。
1.API及び賦形剤の前処理:更なる調製の基準を満たすように、製剤技術の従来の手段によって、処方研究に使用されるAPI及び賦形剤を粉砕、ふるい分け、及び乾燥することにより、貯蔵中のケーキングを取り除き、吸湿性賦形剤の水分含有量を減少させた。
実施例1のA1~F1処方に従って加熱溶融押出して研磨して得られた顆粒を秤量し、比較実施例1のa2処方に従って湿式造粒及び乾燥した後の顆粒を研磨し、比較実施例2のb2及びc2処方に従って加熱溶融押出して研磨して得られた顆粒を研磨し、比較実施例3のd2処方に従ってカプセルを調製し、そして、それぞれ6つのサンプルについて水への溶出曲線を比較及び研究した。
I.表8及び図1に示すように、本発明の各実施形態の比率の処方により、式(I)で表される化合物は、最高で85%を超えて溶出することができ、これは、中国発明特許出願202010105909.9の半固体カプセルの結果と同様である(表9及び図2の比較実施例3のd2処方の結果と比較する)。
β‐シクロデキストリンによる可溶化方法などの可溶化手段を単純に適用することは、式(I)で表される化合物の溶出を増加させるのに適していない。ポリビニルカプロラクタム‐ポリ酢酸ビニル‐ポリエチレングリコールグラフト共重合体Soluplusなどの材料を選別せずに単に加熱溶融押出技術を適用することは、式(I)で表される化合物の溶出を増加させるのに適していない。コポビドンKollidon VA64などの賦形剤を式(I)で表される化合物に対して1:11の高比率で選択するだけでは、可溶化効果は理想的ではない。したがって、特定の可溶化物質を選択し、且つ適切な比率を維持することによってのみ、式(I)で表される化合物に対して十分な可溶化効果を達成することができる。
人間の消化管の消化液のpH値は増加している。経口投与後に高い過飽和度を維持することは、難溶性薬物が体循環に吸収されてその効果を発揮するための前提である。本実施例では、単純なインビトロ溶出試験設計(2時間+4時間溶出試験)を使用して、本発明の組成比及び調製プロセスを選択する理由を説明する。
I.表10及び図3に示すように、式(I)で表される化合物は、60%を超える最大溶出率に達し、6時間で30%を超える溶出率を維持することができる。
実施例2の結果は、特定の割合のコポビドン及び特定の加熱溶融押出調製プロセスによってのみ、より高い溶出率及びより長い過飽和維持時間を達成することができることを再度示す。
実施例1のB1処方に従って調製したカプセル及びE1処方に従って調製した錠剤を秤量し、それぞれ高密度ポリエチレン瓶に入れ、アルミフィルムで密封し、次に温度30℃±2℃、相対湿度65%±5%の条件下で加速試験を行った。比較実施例3のd2処方に従って調製したカプセルを秤量し、高密度ポリエチレン瓶に入れ、アルミフィルムで密封し、次に温度25℃±2℃、相対湿度60%±10%の条件下で加速試験を行った。加速1ヶ月の時点で、B1グループのカプセル、E1グループの錠剤及びd2グループのカプセルについて関連物質の測定を行った。
I.表13に示すように、実施例1の場合、B1及びE1処方に従って調製したカプセル及び錠剤を、温度30℃±2℃、相対湿度65%±5%の条件下で1ヶ月間加速試験にかけ、関連物質を測定した結果、式(I)で表される化合物のすべての既知の単一不純物(単一不純物、individual impurities)、未知の単一不純物、及び全不純物 (total impurities)にいずれも明らかな変化が見られず、特にGLC02‐Z6とGLC02‐Z7の合計はそれぞれ0.02%及び0.04%しか増加しなかった。生産バッチについては、表14に示すように、実施例1の場合、B1及びE1処方に従って調製したカプセル及び錠剤を、温度30℃±2℃、相対湿度65%±5%の条件下で6ヶ月間加速試験にかけ、関連物質を測定した結果、式(I)で表される化合物のすべての既知の単一不純物、未知の単一不純物、及び全不純物にいずれも明らかな変化が見られなかった。
加速結果は、実施例1の処方に従って調製した式(I)で表される化合物のカプセル又は錠剤を、温度30℃±2℃、相対湿度65%±5%の条件下で6ヶ月間加速安定性試験にかけた後、良好な結果が得られたことを示し、これは、室温で長期間保存できる見込みがあることを示す。
Claims (10)
- 成分(a)及び(b)は、混合されて80℃~135℃の範囲の温度で加熱溶融押出され、
好ましくは、コポビドン20~40部を含み、
さらに好ましくは、コポビドン22~33部を含む、請求項1に記載の医薬組成物。 - (c)1種又はそれ以上の薬学的に許容される賦形剤0.1~3.0部をさらに含み、前記薬学的に許容される賦形剤が、不揮発性弱酸、中性又は弱酸性無機物、及び融点が80℃未満の薬学的に許容される賦形剤からなる群から選択され、ここで、成分(a)、(b)及び(c)は混合されて80℃~135℃の範囲の温度で加熱溶融押出され、
好ましくは、前記医薬組成物は、1種又はそれ以上の薬学的に許容される賦形剤0.2~2.0部をさらに含む、請求項1に記載の医薬組成物。 - 前記1種又はそれ以上の薬学的に許容される賦形剤が、無水クエン酸、クエン酸一水和物又はそれらの混合物を含む、請求項3に記載の医薬組成物。
- 前記1種又はそれ以上の薬学的に許容される賦形剤が、1種又はそれ以上の中性又は弱酸性無機物を含み、前記中性又は弱酸性無機物が、マンニトール、ラクトース一水和物、無水ラクトース、ソルビトール、無水リン酸水素カルシウム及びコロイダルシリカからなる群から選択される、請求項3に記載の医薬組成物。
- 前記1種又はそれ以上の薬学的に許容される賦形剤が、1種又はそれ以上の賦形剤を含み、前記賦形剤が、ポリエチレングリコール4000、ポリエチレングリコール6000というポリエチレングリコール;クエン酸トリエチル、コハク酸ポリエチレングリコールという脂質材料;2,6‐ジ‐tert‐ブチル‐p‐クレゾール、ビタミンEという酸化防止剤、ポロキサマー188、ツイーン80という界面活性剤からなる群から選択される、請求項3に記載の医薬組成物。
- 前記医薬組成物が錠剤又はカプセル剤の形態で製剤化される、請求項1に記載の医薬組成物。
- 請求項1~7のいずれか一項に記載の医薬組成物を調製する方法であって、
80℃~135℃の加熱溶融押出温度で成分(a)及び(b)の混合物を加熱溶融押出により押出物を形成する工程と、
前記押出物を冷却する工程と、
冷却した押出物を切断、粉砕又は研磨によって顆粒、微粒子又は粉末に破砕する工程と、を含み、
好ましくは、破砕工程で得た顆粒、微粒子又は粉末を錠剤、カプセル剤に加工する工程をさらに含む、方法。 - 二軸加熱溶融押出装置を使用して成分(a)及び(b)の混合物を押し出し、ここで、前記二軸加熱溶融押出装置のスクリュー直径が8mm~50mmであり、押出速度が10rpm~300rpmであり、前記加熱溶融押出の滞留時間が30分未満である、請求項8に記載の方法。
- 脂肪性肝炎を治療するための医薬品の製造における、請求項1~7のいずれか一項に記載の医薬組成物の使用。
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