JP2016503411A - 医薬コアシェル複合粉末、及びそれを作成するための方法 - Google Patents
医薬コアシェル複合粉末、及びそれを作成するための方法 Download PDFInfo
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- JP2016503411A JP2016503411A JP2015541920A JP2015541920A JP2016503411A JP 2016503411 A JP2016503411 A JP 2016503411A JP 2015541920 A JP2015541920 A JP 2015541920A JP 2015541920 A JP2015541920 A JP 2015541920A JP 2016503411 A JP2016503411 A JP 2016503411A
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Abstract
Description
本発明は、水溶性が乏しい物質の経口送達のための送達組成物に関する。とくに、本発明は、ナノサイズの薬剤または活性物質を経口剤形で送達するための、微細な担体粒子を使用した個別の非凝集複合粒子から構成される粒子状組成物、及びそれらを作成するための方法を対象とする。
水中で可溶性が乏しい医薬有効成分は低いバイオアベイラビリティを有し、この結果として、患者への投与後、その医薬品のごく小さな一部分しか標的組織に利用可能とならない。乏しいバイオアベイラビリティは、医薬組成物の開発において直面する顕著な問題である。水溶性が乏しい医薬品、例えば約10mg/mlより低い水溶性を有するものは、循環血へと吸収される前に胃腸管から排除される傾向にある。
例証の目的で、本発明の原理が様々な代表的な実施形態を参照することにより開示される。本明細書においては本発明のいくらかの実施形態が特に開示されるが、当業者は、同じ原理が他のシステム及び方法に対して同等に応用可能であり、かつ用いられうることを容易に認識するだろう。本発明の開示される実施形態を詳細に説明する前に、本発明はその応用において、示されるいかなる特定の実施形態の詳細にも限定されないことが理解されるべきである。さらに、本明細書において使用される用語は、限定ではなく開示の目的である。さらに、いくつかの方法は、本明細書において一定の順序で示される工程を参照しながら開示されるが、多くの場合、これらの工程は当業者により認識されうるいかなる順で実施されてもよい。従って、この新規の方法は、本明細書で開示される工程の特定の順序に限定されない。
攪拌溶媒ミル:L−89:30%FNB、10%HPMC、5%SDS、50%マンニトール、〜160nm
LASP:L−94:14.8%FNB、19.2%HPMC、7.7%SDS、50%マンニトール、d50〜3μm
生じたFNB複合粒子の溶出特性が、図34に示される。本溶出結果は、LASP(l−94、3mm)法で生成されたフェノフィブラート粒子は攪拌溶媒粉砕(l−88/l−89、0.16mm)により生成されたものよりずっと大きいにもかかわらず、なおもフェノフィブラートの85%が5分より短い時間で溶出することを示す。本溶出結果は、LASPにおいて必要となる高いポリマー濃度がフェノフィブラートの溶出を制限することを示唆する。
配合組成2:14.8%FNB、19.2%HPMC、7.7%SDS、50%マンニトール、d50〜3μm
本API複合粒子の溶出特性は、図35に示される。P−68の使用は著しくより小さい粒子を生じるにもかかわらず、このポリマー界面活性剤は、API複合粒子におけるフェノフィブラートの溶出を著しく遅延させる。
Claims (35)
- コア、及び
摂取可能な物質のナノ粒子と、少なくとも1つのマトリクス形成性物質とを有する外層
を有する、複合粒子。 - 請求項1記載の複合粒子において、前記コアが、約20μMから約200μMの範囲にある粒子サイズ中央値を有する粒子である、複合粒子。
- 請求項1記載の複合粒子において、前記コアが、デンプン、ラクトース、スクロース、セルロース、セルロースエーテル、及びこれらの混合物から選択される物質を有する、複合粒子。
- 請求項1記載の複合粒子であって、さらに、前記コアと前記外層との間に位置する流動化用物質層を有する、複合粒子。
- 請求項4記載の複合粒子において、前記流動化用物質が、シリカ、アルミナ、チタニア、カーボンブラック、ケイ酸アルミニウムカルシウム、ケイ酸カルシウム、ケイ酸マグネシウム、ケイ酸カリウム、ケイ酸ナトリウム、アルミノケイ酸ナトリウム、アルミノケイ酸ナトリウムカルシウム、ケイ酸三カルシウム、シリカエアロゲル、タルク、酸化鉄、他の金属酸化物、及びこれらの組み合わせから選択される、複合粒子。
- 請求項4記載の複合粒子において、前記流動化用物質が、60mJ/m2より小さい分散表面エネルギー、及び5nm〜100nmの粒子サイズ中央値を有する、複合粒子。
- 請求項6記載の複合粒子において、前記流動化用物質がシリカナノ粒子を有する、複合粒子。
- 請求項1記載の複合粒子において、前記摂取可能な物質が、0.01〜50重量%の範囲にある少なくとも1つの医薬品有効成分を有する、複合粒子。
- 請求項9記載の複合粒子において、前記摂取可能な物質の粒子が、約10nm〜約1000nmの範囲にあるサイズを有する、複合粒子。
- 請求項9記載の複合粒子において、前記摂取可能な物質の粒子が、約10nm〜約200nmの範囲にあるサイズを有する、複合粒子。
- 請求項1記載の複合粒子において、前記マトリクス形成性物質が少なくとも1つのポリマーを有する、複合粒子。
- 請求項12記載の医薬複合粒子において、少なくとも1つのポリマーが、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリ(ビニルアルコール)、ポリ(ビニルピロリドン)、アンモニオメタクリル酸共重合体、エチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、メチルセルロース、カルボキシメチルセルロースナトリウム塩、アカシアゴム、及びこれらの組み合わせからなる群から選択される、医薬複合粒子。
- 請求項12記載の複合粒子において、少なくとも1つの界面活性剤が、硫酸ドデシルナトリウム、ジオクチルスルホコハク酸、エチレンオキシド/プロピレンオキシド共重合体、臭化セチルトリメチルアンモニウム、ポリエチレンソルビトールエステル、アルギン酸ナトリウム、レシチン、ラウリル硫酸ナトリウム、モノオレイン酸、モノラウリン酸、モノステアリン酸、ステアリルアルコール、セトステアリルアルコール、チロキサポール、ポリエトキシル化ヒマシ油、及びこれらの組み合わせからなる群から選択される、複合粒子。
- 複合粒子を調製する方法であって、
摂取可能な物質のナノ粒子と少なくとも1つのマトリクス形成性物質との懸濁液を調製する工程と、
前記懸濁液を担体粒子上に流動層塗布する工程と
を有する、方法。 - 請求項14記載の方法において、前記担体粒子が、約20μM〜約200μMの範囲にある粒子サイズ中央値を有する、方法。
- 請求項15記載の方法において、前記担体粒子が、デンプン、ラクトース、スクロース、セルロース、セルロース誘導体、及びこれらの混合物から選択される物質を有する、方法。
- 請求項15記載の方法において、前記ナノ粒子が、5nm〜100nmの範囲にある粒子サイズ中央値を有する、方法。
- 請求項15記載の方法において、前記ナノ粒子物質が、シリカ、アルミナ、チタニア、カーボンブラック、ケイ酸アルミニウムカルシウム、ケイ酸カルシウム、ケイ酸マグネシウム、ケイ酸カリウム、ケイ酸ナトリウム、アルミノケイ酸ナトリウム、アルミノケイ酸ナトリウムカルシウム、ケイ酸三カルシウム、シリカエアロゲル、タルク、酸化鉄、他の金属酸化物、及びこれらの組み合わせからなる群から選択される、方法。
- 請求項15記載の方法であって、さらに、前記流動層塗布する工程の前に、前記担体物質を流動化用物質で乾式被覆する工程を有する、方法。
- 請求項19記載の方法において、前記乾式被覆する工程が、前記担体物質の表面積被覆率が35%〜約100%となるのを達成するのに十分な時間をかけて実施される、方法。
- 請求項20記載の方法において、前記流動化用物質が、前記流動化用物質と担体物質との合計重量の0.1%〜10%を有する、方法。
- 請求項15記載の方法において、前記摂取可能な物質が少なくとも1つの医薬品有効成分を有する、方法。
- 請求項22記載の方法において、前記医薬品有効成分が、前記懸濁液の合計重量の5重量/体積%〜50重量/体積%を有する、方法。
- 請求項22記載の方法において、前記医薬品有効成分を含有する粒子が、約10nm〜約1000nmの範囲にあるサイズを有する、方法。
- 請求項22記載の方法において、前記懸濁液に使用される溶剤が、第三ブチルアルコール(TBA)、テトラヒドロフラン(THF)、ジメチルスルホキシド(DMSO)、ジクロロメタン、ジメチルホルムアミド(DMF)、メタノール、及びこれらの混合物から選択される、方法。
- 請求項22記載の方法において、前記懸濁液に使用される溶剤が水を有する、方法。
- 請求項26記載の方法において、前記懸濁液が、少なくとも1つのマトリクス形成性物質と界面活性剤とを有する、方法。
- 請求項22記載の方法において、前記少なくとも1つのマトリクス形成性物質がポリマーを有する、方法。
- 請求項28記載の方法において、前記ポリマーが、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリ(ビニルアルコール)、ポリ(ビニルピロリドン)、ポリ(ビニルピロリドン)−K360、ポリ(ビニルピロリドン)−K30、アンモニオメタクリル酸共重合体、エチルセルロース、及びこれらの組み合わせからなる群から選択される、方法。
- 請求項28記載の方法において、前記懸濁液がさらに非イオン性界面活性剤を有する、方法。
- 請求項28記載の方法において、前記界面活性剤が、硫酸ドデシルナトリウム、ジオクチルスルホコハク酸、ポロキサマー188、臭化セチルトリメチルアンモニウム、ポロキサマー407、ポリエチレンソルビトールエステル、アルギン酸ナトリウムからなる群から選択される、方法。
- 請求項22記載の方法において、前記少なくとも1つのマトリクス形成性物質が、前記ナノ懸濁液の5重量/体積%〜50重量/体積%を有する、方法。
- 請求項15記載の方法において、前記流動層塗布する工程が、1cm/秒〜10cm/秒の範囲にある流動化速度を使用する、方法。
- 請求項15記載の方法において、前記流動層塗布する工程が、0.1cfm〜5cfmの範囲にある流動化用流速を使用する、方法。
- 請求項15記載の方法において、前記懸濁液を微粒子化するために、前記流動層塗布する工程が、5psig〜35psigの範囲にある微粒子化圧を使用する、方法。
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