JP6263169B2 - オレキシン受容体アンタゴニストの固形剤形 - Google Patents
オレキシン受容体アンタゴニストの固形剤形 Download PDFInfo
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- JP6263169B2 JP6263169B2 JP2015515118A JP2015515118A JP6263169B2 JP 6263169 B2 JP6263169 B2 JP 6263169B2 JP 2015515118 A JP2015515118 A JP 2015515118A JP 2015515118 A JP2015515118 A JP 2015515118A JP 6263169 B2 JP6263169 B2 JP 6263169B2
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- suvorexant
- polymer
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- AWIJRPNMLHPLNC-UHFFFAOYSA-N thiocarboxylic acid group Chemical group C(=S)O AWIJRPNMLHPLNC-UHFFFAOYSA-N 0.000 description 1
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Description
(1)スボレキサントまたは医薬的に許容可能なその塩と;
(2)スボレキサントのバイオアベイラビリティを向上させ、水溶性であるかまたは水中で容易に分散する、濃縮促進ポリマーと;
(3)場合によっては1以上の界面活性剤と
を含む医薬組成物を対象とする。
医薬処方物の調製の実施例を下記で与える。スボレキサントの試験処方物および/または他の処方物をビーグル犬に5mg/kgのスボレキサント用量で投与し、次いで時間の関数として血清または血液中のスボレキサントの量を測定することによって、バイオアベイラビリティをインビボで決定する。同量および同濃度のスボレキサントを含有する他の処方物、例えば従来の賦形剤を用いた固形処方物と比較を行う。本発明の処方物を用いた場合の溶解の改善を調べるために、本発明の処方物または、対照としての従来の賦形剤を用いた処方物を含む他の処方物を用いて、水または人工胃液中での処方物の溶解を観察し、測定して、液体中のスボレキサントの濃度および溶解速度を決定し得る。
噴霧乾燥処方物の調製
処方物1:
噴霧乾燥処方物は、スボレキサント(10から20%w/w);任意の界面活性剤、例えば(1)2から4%のSDS(ドデシル硫酸ナトリウム)、(2)2.5%ビタミンE TPGS、(3)2%Tween80、(4)2%Span80または(5)2%クレモフォアELまたはこれらの界面活性剤の2以上の混合物などを含み;バランスは、HPMCAS−L、HPMCAS−MまたはHPMCAS−H(信越化学からAQOATとして購入)の何れかである。溶媒系、例えばアセトン、メタノール、および水と有機溶媒の混合液(0.5から18%w/v固形物)などの中で構成成分を溶解させるか、または懸濁し、次いで下記のように噴霧乾燥させた。
スボレキサント、任意の界面活性剤およびポリマーを、アセトン、メタノールまたは、水と有機溶媒の混合液と次のように混合し、(構造性の懸濁液であり得る)溶液が得られた。薬物、界面活性剤およびポリマーを溶媒中で溶解させた。ポリマーはゆっくりと溶解し、インペラまたは磁石性撹拌バーおよび撹拌プレートを用いることなどによって激しく撹拌しながら長時間にわたりこれを溶媒に添加した。得られた溶液/懸濁液を噴霧乾燥前に少なくともさらに60分間撹拌した。
Niro SD Micro噴霧乾燥器で噴霧乾燥を遂行した。加熱乾燥窒素および処方物溶液を同時に二流体ノズルに供給し、次いでさらなる加熱ガスと一緒に、乾燥チャンバーにスプレーとして放出させ、その結果、急速蒸発が起こり、粒子が形成された。プロセッシングガスにより乾燥粒子をサイクロンに運び込み、次いで回収用のバッグフィルターチャンバーに運び込んだ。3つの処理速度を調節し、監視した:1)溶液供給速度、2)プロセッシング窒素流速および3)霧化窒素流速。外部蠕動ポンプによって溶液供給速度を調節したが、これは実験室スケールでは約5から20mL/分である。霧化窒素速度およびプロセッシング窒素速度は、霧化窒素に対して2から3kg/hrであり、プロセッシング窒素に対して20から30kg/hrであった。乾燥チャンバー排出口での目標プロセッシングガス温度は、溶媒系の沸点を僅かに下回ったが、30から70℃の範囲の温度は適正であることが明らかとなっており、(ノズルの排出口での)注入口チャンバー温度を調整して所望の排出口温度を得た。80から90℃の注入口温度設定点は標準的であった。生成物中の残存溶媒レベルは概して低かった(<1%w/w)。
処理の構成は、1mmオリフィスの二流体ノズルを備えたNiro PSD−1延長チャンバー噴霧乾燥器において噴霧乾燥を行ったことを除き、プロセス1と同様であった。次の処理条件を調節または監視した:処方物溶液供給速度(2から7.6kg/hr)、プロセッシングガス流速(35から38mmH2O)、霧化率(霧化ガス流速と供給速度との比)(0.9から2.8)、霧化圧力(0.25から1.5bar)、排出口ガス温度(43から70℃)および注入口ガス温度(61から134℃)。
より小さい処理スケールで、2つの領域、サイクロンおよびバッグフィルターチャンバーで物質回収を行った。噴霧乾燥プロセス1から得られた標準的な平均粒径の範囲は、1から30μmであり、サイクロン回収領域から試料採取した場合、個々の粒子は<1μmから>100μmの間で測定された。バッグフィルター中の粒子の大部分は1μm以下であったが、この粒子は非常に凝集していた。噴霧乾燥プロセス2の条件下で、サイクロン回収チャンバーのみから粒子を回収し、標準的な平均粒径はより大きいものであり得、標準的には5から70μmの間の範囲である。
ホットメルト押出成型処方物の調製
ホットメルト押出成型によって次の2種類の処方物を作製した。量は重量%で表す。KollidonVA64は、約1.2:1のコモノマー比を有するポリビニルピロリジノンおよびポリ酢酸ビニルのコポリマーである。これはコポビドンとしても知られる。このガラス転移温度(Tg)は約110℃である。
処方物1
2つの構成成分を混ぜ合わせ、次いで混合物をツインスクリュー押出機に供給することによって、処方物1を作製した。2Lのビンを備えるBohleビンブレンダ−中でKollidon VA64ポリマーおよびスボレキサントを室温で合わせることによって、混合物を作製した。
処方物1に対して使用したものと同じ手順を用いて処方物2を作製した。処方物1の押出成型と同じ全般的条件下で押出成型を行った。唯一の変更点は、ゾーン6から10の温度を140℃に設定し、ゾーン10を最初に150℃に設定し、その後140℃に戻したことであった。ダイス型から出たときの溶融押出成型物の温度は140℃であった。ダイス型圧力は低かった。処方物1に対して使用したものと同じ方法を用いて押出成型物を粉砕した。
Claims (10)
- (1)非晶質形態のスボレキサント;及び
(2)ポリビニルピロリジノンおよびポリビニルピロリジノン−ポリ酢酸ビニルコポリマーからなる群から選択される濃縮促進ポリマー、
を含む医薬組成物。 - 前記濃縮促進ポリマーが、ポリビニルピロリジノン−ポリ酢酸ビニルコポリマーである、請求項1に記載の医薬組成物。
- 前記濃縮促進ポリマーが、ポリビニルピロリジノンコポリマーである、請求項1に記載の医薬組成物。
- 陰イオン性界面活性剤および非イオン性界面活性剤からなる群から選択される1以上の界面活性剤を含んでいてもよい、請求項1に記載の医薬組成物。
- ドデシル硫酸ナトリウムおよび、(a)ソルビタン脂肪酸エステル、(b)ポリオキシエチレンソルビタン脂肪酸エステル、(c)ポリオキシエチレンヒマシ油、(d)ポリオキシエチレン水素化ヒマシ油および(e)ビタミンE TPGS;ならびにそれらの混合物から選択される1以上の非イオン性界面活性剤から選択される1以上の界面活性剤を含んでいてもよい、請求項4に記載の医薬組成物。
- スボレキサント、濃縮促進ポリマー及び任意の1以上の界面活性剤を含むホットメルト押出成型混合物、を含む、請求項1に記載の医薬組成物。
- スボレキサントが、スボレキサントの他の形態学的な形に対して少なくとも90重量%の非晶質形態で存在する、請求項1に記載の医薬組成物。
- スボレキサントが、スボレキサントの他の形態学的な形に対して少なくとも95重量%の非晶質形態で存在する、請求項1に記載の医薬組成物。
- スボレキサントが、スボレキサントの他の形態学的な形に対して少なくとも98重量%の非晶質形態で存在する、請求項1に記載の医薬組成物。
- スボレキサントが、スボレキサントの他の形態学的な形に対して少なくとも99重量%の非晶質形態で存在する、請求項1に記載の医薬組成物。
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US9969725B2 (en) | 2014-04-21 | 2018-05-15 | Merck Sharp & Dohme Corp. | Pharmaceutical salts of an orexin receptor antagonist |
CN105377840B (zh) * | 2014-05-28 | 2017-12-22 | 杭州普晒医药科技有限公司 | 一种二氮杂环庚烷化合物的盐及其晶型与无定型物 |
WO2016083315A1 (en) * | 2014-11-24 | 2016-06-02 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of ox1r antagonists for the treatment of inflammatory bowel diseases |
CZ201587A3 (cs) | 2015-02-10 | 2016-08-17 | Zentiva, K.S. | Amorfní pevná forma suvorexantu s kyselinou sírovou |
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KR102123130B1 (ko) | 2020-06-15 |
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