JP2022507562A - Parpインヒビタを含む医薬組成物 - Google Patents
Parpインヒビタを含む医薬組成物 Download PDFInfo
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Abstract
Description
本開示は、医薬製剤の分野に属し、具体的には、PARPインヒビタを含む医薬組成物及びその調製方法に関する。
ポリアデノシン二リン酸リボシル化活性を特徴とするポリ(ADPリボース)ポリメラーゼ(PARPs)は、18の核及び細胞質酵素を含むスーパーファミリーを構成する。このポリアデノシン二リン酸リボシル化は、目的のタンパク質の触媒活性とタンパク質間相互作用を調節し、DNA修復、細胞死、ゲノム安定性など、多くの基本的な生物学的プロセスを制御する(D'Amours et al. Biochem, J. 1999, 342, 249(非特許文献1)を参照)。
本開示の目的は、式Iで表される化合物を含む固体分散体と、薬物の治療効果の改善のための医薬組成物を提供することにある。
General Notices, Volume II, Chinese Pharmacopoeia 2010に基づく試験に言及すると、微細な粉体へと粉砕された式Iで表される化合物を秤量し、特定量の溶媒(25℃±2℃)に移し、5分毎に30秒間、激しく振とうした。薬物の溶出を30分間以内に観察した。その後、溶液をろ過し、最初のろ液を捨て、それに続くろ液の濃度を試験した。溶解度を計算した。
加速条件下にける実施例2と3の二つの固体分散体の高温(40℃と60℃)、湿度(25℃、RH75±5%、25℃、RH90±5%)での物理的安定性と化学的安定性とを、それぞれ調べた。時計皿中において結晶形態の前記二つの固体分散体における外観と変化を比較した。更に、前記二つの固体分散体の残留触媒を試験した。
実施例5~7のカプセル剤の溶出、Dissolution Test Method 2(Paddle) Appendix, Volume II, Chinese Pharmacopoeia 2015に従って試験した。実施例5、6及び7のカプセル剤の溶出試験は、それぞれ、溶出媒体として0.5% Tween水溶液1000mLを使用して、37±0.5℃で、50rpmのパドルスピードで行った。溶出プロファイルを図1に示す。溶出の結果は、異なる強度のすべてのカプセル剤が急速かつ完全に溶出されたことを示した。
実施例2のサンプルを、12カ月間、長期条件(25℃/60%相対湿度)下で、そして、6カ月間、加速条件(4℃/75%相対湿度)下で、包装材料(乾燥剤とアルミホイルパウチを備える医薬的な低密度ポリエチレンバッグ中にシール)中で保存し、活性物質の含有率、不純物、見かけの溶解度(0.5%ポリソルベート80水溶液中での溶解度)、及び、結晶化を試験するべく、定期的にサンプルを採取した。その結果を以下の表に示す。
実施例7のカプセル剤を、固体医薬用の塩化ポリビニールシートと医薬包装用のアルミホイル中に入れ、ヒートシール後、医薬包装用の複合フィルムバッグで包装し、次いで、ヒートシール後、カートンに入れた。活性物質の含有率、不純物及び溶出を試験するために(45mmで、実施例8と同じ溶出試験方法で)、それぞれ、サンプルを40℃±2℃及びRH75%±5%で6カ月間の保存後に定期的に採取し、そして、サンプルを30℃±2℃及びRH65%±5%で6カ月間の保存後にサンプルを定期的に採取した。その結果を以下の表に示す。
Claims (15)
- 式Iで表される前記化合物は、アモルファス形である請求項1に記載の固体分散体。
- 前記固体分散体は、式Iで表される化合物と担体材料であるポリビニルピロリドンからなる請求項1に記載の固体分散体。
- 前記ポリビニルピロリドンに対する前記式Iで表される化合物の重量比は、1:0.1~1:10、好ましくは1:0.1~1:7、より好ましくは1:0.5~1:5そして、最も好ましくは1:3、である、請求項1~3のいずれか一項に記載の固体分散体。
- 請求項1~4のいずれか一項に記載の前記固体分散体と、単数又は複数の医薬的に許容可能な賦形剤とを含む医薬組成物。
- 式Iで表される前記化合物の含有量は、0.1mg~1000mg、好ましくは、1mg~500mg、より好ましくは、5mg~200mgである、請求項5に記載の医薬組成物。
- 式Iで表される前記化合物の含有率は、前記医薬組成物の総重量に基づいて0.01%~50%、好ましくは、1%~40%である、請求項5に記載の医薬組成物。
- 前記医薬組成物は、更に、充填剤、好ましくは、微結晶セルロース、リン酸水素カルシウム、マンニトール、アルファー化澱粉、ラクトースの単数又は複数を含み、前記充填剤の含有率は、前記医薬組成物の総重量に基づいて5%~90%である、請求項5に記載の医薬組成物。
- 前記医薬組成物は、更に、崩壊剤、好ましくは、クロスカルメロースナトリウム、澱粉、カルボキシメチル澱粉ナトリウム、クロスポビドンの単数又は複数を含み、前記崩壊剤の含有率は、前記医薬組成物の総重量に基づいて1%~20%である、請求項5に記載の医薬組成物。
- 前記医薬組成物は、更に、潤滑剤、好ましくは、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、硬化植物油、微粉シリカゲル、タルク、シリカの単数又は複数を含み、前記潤滑剤の含有率は、前記医薬組成物の総重量に基づいて0.5%~5%である、請求項5に記載の医薬組成物。
- 以下を有する医薬組成物であって、
ここで、前記医薬組成物の総重量に基づき、前記充填剤は、微結晶セルロース、リン酸水素カルシウム、マンニトール、アルファー化澱粉、及び、ラクトースの単数又は複数、好ましくは、ラクトースから選択され、前記崩壊剤は、クロスカルメロースナトリウム、澱粉、カルボキシメチル澱粉ナトリウム、及び、クロスポビドンの単数又は複数、好ましくは、カルボキシメチル澱粉ナトリウムから選択され、前記潤滑剤は、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、硬化植物油、微粉シリカゲル、タルク、及び、シリカの単数又は複数、好ましくは、ステアリン酸マグネシウム及び/又は二酸化ケイ素から選択される、医薬組成物。 - 請求項1~4のいずれか一項に記載の固体分散体を調製する方法であって、式Iで表される化合物と、ポリビニルピロリドン及び任意の賦形剤とを、溶融押出装置内で混合する工程と、混合物を加熱混合し、最終的に固体分散体製品を押出する工程とを含む方法(1)、又は、
式Iで表される化合物と、ポリビニルピロリドン及び溶媒とを混合する工程と、前記溶媒を除去する工程とを含む方法(2)、を含む方法。 - 前記溶媒の除去の方法は、ロータリー蒸発、噴霧乾燥、凍結乾燥、膜蒸発の単数又は複数から選択される請求項12に記載の方法。
- 請求項5~11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、請求項12又は13に記載の固体分散体を調製する工程と、前記固体分散体を単数又は複数の薬学的許容可能な賦形剤と混合する工程とを含む、方法。
- 請求項1~4のいずれか一項に記載の固体分散体又は請求項5~11のいずれか一項に記載の医薬組成物の、癌、好ましくは、乳癌、卵巣癌、すい臓癌、前立腺癌、肝臓癌、又は、結腸癌の治療用薬剤の製造における使用。
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