JP2016504390A - ロラゼパムの徐放性製剤 - Google Patents
ロラゼパムの徐放性製剤 Download PDFInfo
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- JP2016504390A JP2016504390A JP2015551869A JP2015551869A JP2016504390A JP 2016504390 A JP2016504390 A JP 2016504390A JP 2015551869 A JP2015551869 A JP 2015551869A JP 2015551869 A JP2015551869 A JP 2015551869A JP 2016504390 A JP2016504390 A JP 2016504390A
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- lorazepam
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Abstract
Description
本発明は、ロラゼパムの徐放性製剤と、1日1回用量のロラゼパムで患者を処置する方法とに関する。
本発明のその他の態様は、ロラゼパムで処置可能な患者の状態を処置する方法であって、その必要がある患者に上述の医薬組成物を、定常状態の状況にある間に24時間の治療効果をもたらすのに十分な用量で1日1回投与するステップを含む方法に関する。組成物は、(i)ロラゼパム徐放性ビーズと(ii)ロラゼパム遅延徐放性ビーズとを含んでいてもよく、前記組成物に含有されるロラゼパムの全量は0.5〜10mgである。典型的なロラゼパムで処置可能な状態には、全般性不安障害、および大うつ病に関連した不安症などの、不安障害が含まれるが、これらに限定するものではない。
徐放性ロラゼパムビーズは、2時間以内に好ましくはロラゼパムの20〜80%を放出し、典型的には20〜70%、より典型的には25〜60%、しばしば30〜50%を放出する。さらに、これらの好ましいビーズの放出プロファイルは、しばしば、4時間後(即ち、溶解試験の4時間の時点を超える)、より典型的には6時間後、いくつかの実施形態では8時間後に90%を実現することを含む。事実、いくつかの稀な実施形態では、溶解試験において90%の放出を実際には実現することができず;例えば溶解試験での最大放出は、例えばわずか85%になる可能性がある。そのような結果は、本発明の実施形態により、90%の放出が生じていないと考えられることまたは8時間前に実現されていないと考えられることを、意味すると考えられる。要するに、90%の放出が最終的に実現されたか否かに関わらず、指定された時点以前で90%は放出されない。いくつかの好ましい徐放性ロラゼパムビーズは非常に長持ちするので、10時間よりも前に、より好ましくは12時間よりも前に、いくつかの実施形態では13時間またはさらに14時間よりも前に、ロラゼパムの90%を放出しない。しかしほとんどの実施形態では、90%の放出は最終的には実現され、通常は、20時間よりも前に、一般には18時間までに、しばしば16時間までまたは16時間付近で生ずる。いくつかの実施形態では、90%の放出は、15時間よりも前にまたはさらに14時間よりも前に、例えば12または13時間までに生ずる。放出曲線は、放出の終わり近くで比較的平らになる可能性があるので、放出された薬物のパーセント量の小さい変化が生ずるのに何時間かを要する可能性がある。したがって、90%の放出を実現するための広い時間窓は、それにも関わらず比較的類似した放出曲線を含む可能性がある。90%の放出を実現するための典型的な時間枠は、8〜22時間、例えば8〜20時間または8〜18時間、より典型的には10〜18時間、時々12〜16時間を含む。しばしば溶解プロファイルは、6〜16時間、典型的には6〜14時間、より典型的には6〜12時間、時々7〜12時間の範囲内で、80%の放出の実現を含むことになる。いくつかの実施形態では、ロラゼパムの50%が1〜5時間以内に放出され、70%が4〜10時間以内に放出される。上記放出量−時間の関係のそれぞれは、個々に適用することができるが、本発明の好ましい徐放性ロラゼパムビーズは、上記関係の2つ以上の任意の組合せを満足させ;例えば放出曲線は、(i)2時間で20〜70%の関係、(ii)4〜10時間以内で70%の関係、および(iii)10〜19時間以内で90%の関係を満足させる。徐放性ロラゼパムビーズの定義とは異なって、徐放性ロラゼパムビーズに関する上述の好ましい放出関係のそれぞれは、USP I型装置(Basket)を使用する2媒体in vitro溶解試験を使用して決定/測定される。
下記の名目上の組成を有する徐放性ロラゼパムビーズを作製した。
遅延徐放性ロラゼパムビーズを、上記徐放性ロラゼパムビーズを使用することによって作製し、腸溶コーティングを付着させた。腸溶コーティングは、pH7以上で放出するように設計し、特にpH7.4で自由な放出がなされることを目的とした。得られた遅延徐放性ロラゼパムビーズは、下記の名目上の組成を有する。
徐放性ロラゼパムビーズおよび遅延徐放性ロラゼパムビーズを含有する医薬組成物を、カプセルに例1および2のビーズを充填することによって形成した。硬質ゼラチンカプセルに、下記の名目上の量の成分を充填して、2mgのロラゼパム経口剤形を形成した。
Claims (18)
- (i)ロラゼパム徐放性ビーズと(ii)ロラゼパム遅延徐放性ビーズとを含む医薬組成物であって、前記組成物に含有されるロラゼパムの全量が0.5〜10mgであり、典型的には1〜6mg、例えば1〜4mgである医薬組成物。
- 前記組成物が、患者に1日1回投与される場合、少なくとも24時間にわたり治療効果を維持する、請求項1に記載の医薬組成物。
- 前記組成物中のロラゼパムの少なくとも95%、好ましくは100%が、前記徐放性ビーズと前記遅延徐放性ビーズとの組合せに含有される、請求項1または2に記載の医薬組成物。
- 前記徐放性ビーズが、ロラゼパムの20〜70%、より典型的には25〜60%、しばしば30〜50%を2時間で放出するような2媒体in vitro溶解試験での溶解プロファイルを有し;前記2媒体in vitro溶解試験は、0.1N HClを含む媒体中で2時間にわたり実施され、次いでリン酸緩衝液を含みpHが7.4である媒体中で実施される、請求項1から3までのいずれかに記載の医薬組成物。
- 前記溶解プロファイルが、1〜5時間以内でロラゼパムの50%の放出および/または4〜10時間以内でロラゼパムの70%の放出をさらに含む、請求項4に記載の医薬組成物。
- 前記溶解プロファイルが、ロラゼパムの90%が10時間よりも前には放出されないことをさらに含む、請求項4または5に記載の医薬組成物。
- 前記ロラゼパム遅延徐放性ビーズが、6時間程度でありかつ/または末端回腸の高pHで開始される、in vivoでの放出の遅延を有する、請求項1から6までのいずれかに記載の医薬組成物。
- 前記ロラゼパム遅延徐放性ビーズが、ロラゼパムの90%の放出が10時間後に、典型的には12時間後に生ずるような2媒体in vitro溶解試験での溶解プロファイルを有し;前記2媒体in vitro溶解試験は、0.1N HClを含む媒体中で2時間にわたり実施され、次いでリン酸緩衝液を含みpHが7.4である媒体中で実施される、請求項1から7までのいずれかに記載の医薬組成物。
- 前記遅延徐放性ビーズが、pH依存性の遅延コーティングを含有し、前記遅延徐放性ビーズは、ロラゼパムの20〜80%、典型的には25〜50%が4時間で放出されるような2媒体in vitro溶解試験での溶解プロファイルを有し;前記2媒体in vitro溶解試験は、0.1N HClを含む媒体中で2時間にわたり実施され、次いでリン酸緩衝液を含みpHが7.4である媒体中で実施される、請求項1から8までのいずれかに記載の医薬組成物。
- 前記徐放性ビーズが、ポリマー母材中に分散されたロラゼパムを含み、前記遅延徐放性ビーズが、ポリマー母材中にロラゼパムが分散されている核と、前記核を取り囲む腸溶コーティングとを含む、請求項1から9までのいずれかに記載の医薬組成物。
- 徐放性ビーズ中および遅延徐放性ビーズ中の前記ポリマー母材がHPMCを含む、請求項10に記載の医薬組成物。
- 前記腸溶コーティングが、pH7以上で放出するように設計されている、請求項10または11に記載の医薬組成物。
- 前記組成物が、1日1回投薬された場合、ロラゼパム各1mgごとに10ng/ml+20%以下のロラゼパム血漿定常状態Cmax、および/またはロラゼパム各1mgごとに少なくとも5ng/mlのロラゼパム血漿定常状態Cminを提供する、請求項1から12までのいずれかに記載の医薬組成物。
- 前記組成物が、1日1回投与された場合、(1)b.i.d.で与えられかつ同じ全1日量のロラゼパムを有する即放性錠剤によって実現された対応するCmaxにほぼ等しいロラゼパム血漿定常状態Cmax、および/または(2)b.i.d.で与えられかつ同じ全1日量のロラゼパムを有する即放性錠剤によって実現された対応するCminにほぼ等しいロラゼパム血漿定常状態Cminを提供する、請求項1から13までのいずれかに記載の医薬組成物。
- 前記組成物が、単回用量薬物動態試験で決定される、20時間を超えて、好ましくは少なくとも24時間にわたり、より好ましくは少なくとも28時間にわたり、さらにより好ましくは少なくとも30時間にわたり、ロラゼパムの連続吸収を示す、請求項1から14までのいずれかに記載の医薬組成物。
- 徐放性ロラゼパム医薬組成物であって、単回用量薬物動態試験で、前記組成物が、4時間以上でTmaxを含みかつ20時間を超えて、好ましくは少なくとも24時間にわたり、より好ましくは少なくとも28時間にわたり、さらにより好ましくは少なくとも30時間にわたりロラゼパムの連続吸収を含む薬物動態プロファイルを有するように、十分な量および持続時間でロラゼパム長期放出ビーズを含み;前記組成物は、ロラゼパムを0.5〜10mg含有する経口剤形であり;前記組成物は、患者に1日1回投与された場合、少なくとも24時間にわたり治療効果を維持する医薬組成物。
- 前記薬物動態プロファイルが、0〜120時間での全AUCの40〜60%、しばしば45〜55%が0〜24時間で実現されることを含む、請求項16に記載の組成物。
- ロラゼパムで処置可能な患者の状態を処置するための、特に不安症を処置するための方法であって、その必要がある患者に、請求項1から17までのいずれかに記載の医薬組成物を、定常状態の条件下で24時間の治療効果がもたらされるように十分な用量で1日1回投与することを含む方法。
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JP7110366B2 (ja) | 2017-11-01 | 2022-08-01 | エッジモント・ファーマシューティカルズ・リミテッド・ライアビリティ・カンパニー・トラスト | ロラゼパムのアルコール耐性経口用医薬組成物 |
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