JP2020059755A - 時限パルス放出システム - Google Patents
時限パルス放出システム Download PDFInfo
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- JP2020059755A JP2020059755A JP2019234192A JP2019234192A JP2020059755A JP 2020059755 A JP2020059755 A JP 2020059755A JP 2019234192 A JP2019234192 A JP 2019234192A JP 2019234192 A JP2019234192 A JP 2019234192A JP 2020059755 A JP2020059755 A JP 2020059755A
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Classifications
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Abstract
Description
本発明は、約5時間を超える所定の遅延(遅延時間)の後に薬物を放出する1種または複数種のアルカリ性医薬品の活性成分(actives)を含む時限パルス放出ビーズ集団(timed、pulsatile release bead populations)の開発に関し、さらに一日2回または1回の投与計画に適した目標PK(薬物動態、すなわち、血漿濃度−時間)プロファイルの経口薬物送達システムの提供に関するものであり、これによって、有害な副作用の潜在的な危険をできるだけなくし、患者のコンプライアンスおよび治療効果を向上させ、治療コストが削減される。
多くの治療薬は、一定の割合で吸収部位またはその付近に投与されるとき、最も効果的である。そのように投与された治療薬の吸収は、一般的に、最大の効能、及び、最小の有毒副作用を生じさせる所望の血漿濃度をもたらす。経口適用のための浸透デバイス(osmotic devices)などの精巧な薬物送達システムを開発することに多大の努力が注がれてきた。しかし、薬物の血中濃度を一定に保つことが望ましくない場合がある。例えば、心血管疾患の時間療法の主な目的は、最も必要とされるとき(例えば、早朝の時間)により高濃度の薬物を送達し、必要が少ないとき(例えば、深夜および早期の就寝時間)には濃度を低くすることである。適切に設計された薬物送達システムに加えて、投与の時間も同様に重要である。必要とされる特有の薬物動態プロファイルは、薬物動態パラメーター、薬物溶解度の知識、消化管からの吸収および排出半減期を用いて開発された模擬モデリングから計算することができる。
本発明は、酸性度/アルカリ性度、胃腸液への溶解度、およびその排出半減期に応じて、特定治療薬の経口投与による一日2回または一日1回の投与計画に適したパルス送達システムを提供する。このパルス送達システムは、即時放出(immediate release)(IR)ビーズおよび時限パルス放出(TPR)ビーズ集団などの1種または複数種のビーズ集団を含む。経口投与されると、所定の遅延時間(例えば、10時間以上が実現可能)の後に、各TPRビーズ集団は薬物を急速破裂または徐放性で放出する。IRビーズは、保護膜で被覆された単なる薬物コアであってよい(例えば、オパドライ・クリア(Opadry Clear)によるコーティング)。バリアコーティングを有するこうしたIRビーズを水不溶性高分子と腸溶性高分子の混合物の機能性膜で被覆し、可塑化高分子系は水性組成物または溶剤をベースとする組成物から施す。完成品の剤形は、一日1回または2回の投与計画に適した目標血漿濃度になるように、修飾放出(modified−release)(MR)カプセル、普通の(従来の)錠剤、または活性物質を含む被覆球状ビーズ集団を単独で含むかまたは2種以上の被覆ビーズ集団を含む口腔内崩壊錠(ODT)であってもよい。例えば、排出半減期が約7時間である活性成分の一日1回の剤形は、IRビーズ集団(即時放出が可能)、遅延時間の短い(約3〜4時間)第2のTPRビーズ集団(遅延「破裂」放出が可能)、および遅延時間の長い(約6〜9時間)第3のTPRビーズ集団(排出半減期が約7時間である活性成分の、遅延した(通常は)徐放プロファイルが可能)の混合物を含むことができ、これによって安全性、治療効果および患者のコンプライアンスが向上すると同時に、治療コストが削減される。達成可能な遅延時間は、バリアコーティングの組成と厚さ、遅延コーティングの組成と厚さ、ならびに治療薬の性質に依存する。遅延時間に影響する具体的な因子としては、治療薬のアルカリ性度/酸性度、溶解度、排出半減期、および投与計画(一日2回または一日1回)などがあるが、これらに限定されない。
活性薬剤成分(API)は、通常、精製水に懸濁させたときにわずかに酸性または塩基性のいずれかである(表1を参照)。酸性度またはアルカリ性度の程度は著しく異なる。例えば、pHは、塩酸プロプラノロールの場合のわずか5.7〜6.5からニザチジンの場合のpH6.5〜8.7、アテノロールの場合の7.9〜11.0ものpHまでの範囲に及びうる。固形分が2g/mLで水中に懸濁されたときに7.0以下のpHを示す活性薬剤成分は、本発明の開示においては酸性薬物と呼び、7.0以上のpHを示すAPIはアルカリ性薬物と呼ぶ。
1.1種または複数種の活性薬剤成分で不活性粒子(糖球またはセルロース球など)を高分子結合剤溶液/懸濁液からコーティングし、保護シールコートを施して、即時放出(IR)ビーズを形成することにより薬物含有コアを製造するステップと、
2.可塑化a)水不溶性高分子単独でまたは水溶性高分子と組み合わせて、あるいはb)腸溶性高分子を用いてIRビーズをコーティングして、膜厚が約1.5%〜20重量%のバリア被覆ビーズを形成するステップと、
3.水不溶性高分子と腸溶性高分子の可塑化混合物によってバリア被覆ビーズを約40〜60重量%の膜厚にコーティングして、最高約10時間以上の遅延時間を示すTPR(時限パルス放出)ビーズを形成するステップと、
4.2種以上のビーズ集団(IRビーズと1種または複数種のTPRビーズ集団(ここで、各TPRビーズ集団は異なった遅延時間を示し得る))を硬ゼラチンカプセルに充填するか、または圧縮して従来の錠剤または経口崩壊性錠剤にして、一日1回または一日2回のカプセル製剤を製造するステップと、
を含む時限パルス放出ビーズの製造方法も提供する。
A.ニザチジンのIRビーズ
ニザチジン(168kg)をクルーセル(Klucel)LFなどのヒドロキシプロピルセルロース(18.6kg)の水溶液にゆっくり添加し、よく混合した。#25−30メッシュの糖球(107.4kg)を、32インチの下部噴霧ウルスター(Wurster)インサートを装備したグラット(Glatt)流動床コーター(fluid bed coater)中で薬物懸濁液により被覆した。薬物含有粒子を乾燥させてから、オパドライ・クリア(Opadry Clear)のシールコート(2%(w/w))を最初に施し、過剰の表面水分を飛ばす予防手段としてグラット(Glatt)流動床装置で乾燥させた。薬物負荷は56%(w/w)であった。
上記のように製造されたIRビーズを、下部噴霧ウルスター(Wurster)インサートを装備したグラット(Glatt)GPCG 5を用いて、被覆ビーズの重量を基準にして10%だけ重量増加するように、アセトン/水(98/2)中に溶解したHPMCP(例えば、ヒプロメロース(hypromellose)フタル酸エステル、信越(Shin Etsu)から市販されているHP−55)および可塑剤としてクエン酸トリエチルを90/10の比率で被覆した。
上記のステップAからの薬物含有IRビーズに、アセトン/水(98/2)中の45.5/40/14.5のEC/HPMCP/TEC(エチルセルロース/HPMCP/クエン酸トリエチル)の溶液を流動床コーター中で、約20%、25%および30%だけ重量増加するように噴霧することにより外膜を設けた。被覆粒子は、10分間60℃で単位硬化(unit cured)してTPRビーズを製造した(バッチサイズ(batch size):4kg)。
上記のステップBからの腸溶性−被覆ビーズに、約20%、30%、および40%だけ重量増加するように、アセトン/水(98/2)中の45.5/40/14.5のEC/HPMCP/TECの溶液を流動床コーター中で噴霧することにより、外膜を設けた。被覆粒子は、10分間60℃で単位硬化してTPRビーズを製造した(バッチサイズ:4kg)。
上記(ステップA)のように製造されたIRビーズを、被覆ビーズの重量を基準にして5%だけ重量増加するように、下部噴霧ウルスター(Wurster)インサートを装備したグラット(Glatt)GPCG 5を用いて、アセトン/水中に溶解しTECで可塑化されたエチルセルロースおよびヒドロキシプロピルセルロース(例えば、アクアロン(Aqualon)から市販されているクルーセル(Klucel)LF)を、70/30の比率で被覆した。これらのバリア被覆ビーズに、約20%、30%および40%だけ重量増加するように、アセトン/水(98/2)中の45.5/40/14.5のEC/HPMCP/TECの溶液を流動床コーター中で噴霧することにより外膜を設けた。被覆粒子は、10分間60℃で単位硬化してTPRビーズを製造した(バッチサイズ:4kg)。
A.プロプラノロールHClのIRビーズ:
プロプラノロールHCl(168kg)を、ポリビニルピロリドン(8.8kgのポビドン(povidone)K−30)の水溶液中にゆっくり添加してよく混合した。25−30メッシュの糖球(117.2kg)を、32インチの下部噴霧ウルスター(Wurster)インサートを装備したグラット(Glatt)流動床造粒機を用いて、薬物溶液で被覆した。薬物含有ペレットを乾燥させてから、オパドライ・クリア(Opadry Clear)(6.0kg)のシールコートを最初に施し、過剰の表面水分を飛ばす予防手段としてグラット(Glatt)流動床装置で乾燥させた。薬物負荷は56%(w/w)であった。
上記のように製造したIRビーズを、被覆ビーズの重量を基準にして10%だけ重量増加するように、下部噴霧ウルスター(Wurster)インサートを装備したグラット(Glatt)GPCG 5を用いて、アセトン/水(98/2)中に溶解させたHPMCPおよびTECを90/10の比率で被覆した。
上記のステップAで製造されたIRビーズを、被覆ビーズの重量を基準にして20%、30%および40%だけ重量増加するように、グラット(Glatt)GPCG 5を用いて、アセトン/水(98/2)中に45.5/40/14.5の比率で溶かしたエチルセルロース、HPMCPおよびクエン酸トリエチルで被覆した。
ステップAで製造したIRビーズを、1.8重量%だけ重量増加するように、流動床装置(32インチの下部噴霧ウルスター(Wurster)インサートを装備したフルイド・エア(Fluid Air)FA0300)を用いて、エチルセルロースおよび可塑剤としてフタル酸ジエチル(DEP)を90/10の比率で被覆した。このコーティングの後、被覆ビーズの重量を基準にして15%だけ重量増加するように、アセトン/水(98/2)中に45.5/40/14.5の比率で溶かしたEC/HPMCP/DEPの遅延コーティングを施した。
薬物放出プロファイルは、US薬局方の方法(100rpmのバスケット付きの装置1および50rpmのパドル付きの装置2)に従った溶出試験で、700mLのpH1.2の緩衝液を2時間使用し、その後、残りの時点についてはpH6.8の900mLで試験することにより生成された。IRおよび腸溶性被覆ビーズは、900mLの0.1NのHCl中で1時間および1.5時間それぞれ試験した。別々の時点に抜き出したサンプルをHPLCで定量した。
被覆ビーズの安定性:
実施例1DのEC/HPMCPで40%だけ被覆されたニザチジンのTPRビーズをインダクションシール(induction−sealed)HDPEボトルにひとまとめに入れて、40℃/75%RHで安定状態に保ち、サンプルを1ヶ月、2ヶ月、3ヶ月および6ヶ月の時点で抜き出した。溶出試験は、上に詳述した手順に従って行った。加速安定条件(accelerated stability conditions)で保管されたTPRビーズは、少なくとも6ヶ月間は許容される安定性を示した。
完成品のカプセルは、所望の遅延時間を示す1種または複数種のTPRビーズ集団を含むか、または所望の比率でIRビーズも一緒に含むことができ、かつ目標インビトロ薬物放出プロファイルをもたらすのに十分な量だけ、それゆえに一日2回または一日1回の投与計画に適した目標薬物動態(PK)プロファイルをもたらすのに十分な量だけ、含むことができる。上記の溶出試験手順の後にインビトロ条件で試験すると、負荷投与量を与えるように設計されているIRビーズは、通常、1時間以内に、好ましくは最初の30分以内に薬物を実質的に全部放出する。時限パルス放出(TPR)ビーズは、最高で数時間(経口投与後の最小薬物放出(投与量の約10%未満)の期間)の遅延後に薬物放出を開始するよう設計されている。このパルスは、遅延コーティングおよび/またはバリアコートの厚さに応じて、急速破裂であるかまたは約2時間〜約20時間の範囲の期間にわたる拡散であってよい。
実施例1BのニザチジンIRビーズに施された腸溶性高分子コーティングは、1時間以内に多かれ少なかれ崩壊して、酸性緩衝液中に投与量のほとんどを放出したが、腸溶性高分子は溶解しないことになっていた。それに対して、実施例2Bの塩酸プロプラノロールの腸溶性被覆ビーズでは、pH1.2での1.5時間の溶出試験において放出されたのは投与量のせいぜい1%であり、予期された耐酸性を示した。理論に縛られることは望まないが、被覆ニザチジンビーズのコアに吸収された水分が一部のニザチジンを溶解してアルカリ性pH環境が生じ、その環境により、たとえ溶出溶媒が酸性であっても、腸溶性被覆IRビーズ上の腸溶性高分子膜が破壊される傾向があると思われる。
バリアコートなしのTPRビーズの薬物放出プロファイルを示している図1および2を比較すると、30重量%だけEC/HPMCPで被覆されたニザチジン(わずかにアルカリ性の薬物)被覆のTPRビーズは、遅延時間が3時間未満であることが明白である。それに対して、同じコーティング厚さの同じポリマーブレンドで被覆されたプロプラノロールHCl(わずかに酸性の薬物)のTPRビーズは、遅延時間が約5時間であることを示している。同じコーティング条件および組成物でのニザチジンとプロプラノロールHClのTPRビーズを観察して分かる遅延時間を比較すると、遅延時間を与える点で酸性度/アルカリ性度が重要な役割を果たしていることが明らかである(図3)。
Claims (23)
- 即時放出(IR)ビーズと時限パルス放出(TPR)ビーズとの混合物を含む医薬品多粒子剤形であって、前記TPRビーズが、
a)1種または複数種の塩基性の活性薬剤成分またはその薬学的に許容される塩を含むコア粒子と、
b)前記コア粒子を取り囲む内側バリアコーティングであって、i)腸溶性高分子またはii)水不溶性高分子を単独で、もしくは水溶性の造孔高分子と組み合わせて含む内側バリアコーティングと、
c)水不溶性高分子を腸溶性高分子と一緒に含む外側遅延コーティングであって、薬物放出の開始までに少なくとも約5時間の遅延時間をもたらす外側膜と
を含む、医薬品多粒子剤形。 - 前記活性薬剤成分が、鎮痛薬、抗痙攣薬、抗糖尿病剤、抗感染剤、抗悪性腫瘍薬、抗パーキンソン病薬、抗リウマチ剤、心血管薬、CNS(中枢神経系)刺激薬、ドーパミン受容体作動薬、制吐薬、胃腸薬、精神療法薬、オピオイド作動薬、オピオイド拮抗薬、抗てんかん剤、ヒスタミンH2拮抗薬、抗喘息薬および骨格筋弛緩剤からなる群から選択される、請求項1に記載の医薬品多粒子剤形。
- 一日1回または2回の投与計画に適した目標薬物動態プロファイルを与える2つ以上のビーズ集団を含み、USP装置1または2、および二段階溶出溶媒(最初に700mLの0.1NのHCl中に2時間、その後に900mL(pH6.8)中)を用いて溶出試験を行ったときに各集団が所定の(目標)薬物放出プロファイルを示す、請求項1に記載の医薬品多粒子剤形。
- 少なくとも1種のIRビーズ集団、第1TPRビーズ集団および第2TPRビーズ集団を含み、IRビーズと前記第1TPRビーズ集団と前記第2TPRビーズ集団との比率が、前記活性成分のアルカリ性度、pH依存性溶解度および/または排出半減期に応じてそれぞれ約10/20/70から約30/60/10まで変化する、請求項1に記載の医薬品多粒子剤形。
- 前記コア粒子が、
i)活性成分と高分子結合剤とで被覆された不活性粒子、あるいは
ii)ロートグラニュレーション、造粒−押出し−球状化または造粒−錠剤化によって製造された、前記活性成分、高分子結合剤および希釈剤/充填剤を含有するペレットまたはミニもしくはミクロ錠剤を含む、請求項1に記載の医薬品多粒子剤形。 - 前記高分子結合剤が、ポリビニルピロリドン、メチルセルロース、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、コーンスターチ、アルファ化でんぷんおよびそれらの混合物からなる群から選択される、請求項5に記載の医薬品多粒子剤形。
- 前記粒子バリアコーティングが、酢酸フタル酸セルロース、フタル酸ヒドロキシプロピルメチルセルロース、コハク酸ヒドロキシプロピルメチルセルロース、ポリ酢酸ビニルフタレート、pH感受性メタクリル酸−メタクリル酸メチル共重合体、シェラック、それらの誘導体、およびそれらの混合物からなる群から選択される腸溶性高分子を含む、請求項1に記載の医薬品多粒子剤形。
- 前記バリアコーティングが前記バリア被覆ビーズの約5〜20重量%を構成する、請求項7に記載の医薬品多粒子剤形。
- 粒子コアが、水不溶性高分子を単独で、または水溶性高分子と組み合わせて約9:1〜5:5の比率で含むバリアコーティングを備え、前記バリアコーティングは前記被覆ビーズの重量を基準にして約1.5〜15重量%だけ重量増加するように施される、請求項1に記載の医薬品多粒子剤形。
- 前記水溶性高分子が、メチルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、ポリビニルピロリドンおよびポリエチレングリコールならびにそれらの混合物などからなる群から選択される、請求項9に記載の医薬品剤形。
- 前記外側遅延コーティングが、前記TPRビーズの重量を基準にして約30〜60重量%だけ重量増加するように水不溶性高分子および腸溶性高分子をそれぞれ約10:1〜1:2の比率で含む、請求項1に記載の医薬品剤形。
- 前記水不溶性高分子が、エチルセルロース、酢酸セルロース、ポリ酢酸ビニル、メタクリル酸メチルエステルの重合体およびそれらの混合物からなる群から選択される、請求項11に記載の医薬品剤形。
- 前記内側バリアコーティングおよび前記外側遅延コーティングの少なくとも一方が、トリアセチン、クエン酸トリブチル、クエン酸トリエチル、アセチルクエン酸トリブチル、フタル酸ジエチル、セバシン酸ジブチル、ポリエチレングリコール、ポリプロピレングリコール、ヒマシ油、アセチル化モノグリセリドおよびジグリセリド、ならびにそれらの混合物からなる群から選択される可塑剤を含む、請求項1に記載の医薬品剤形。
- 前記遅延コーティングが、水不溶性高分子および腸溶性高分子をそれぞれ約3:1〜約1:1までさまざまな比率で含む、請求項1に記載の医薬品剤形。
- 前記剤形が、前記剤形の経口投与後の初めの1時間以内に前記IRビーズに含まれている前記活性成分の約90%以上を放出することにより負荷投与量を与える即時放出(IR)ビーズをさらに含む、請求項1に記載の医薬品剤形。
- 前記剤形が少なくとも2種類の時限パルス放出(TPR)ビーズ集団を含み、各TPRビーズ集団が前記剤形の経口投与時に所定の遅延時間に続いて異なる放出特性を示す、請求項1に記載の医薬品剤形。
- 前記遅延コーティングが、エチルセルロースおよびフタル酸ヒドロキシプロピルメチルセルロースを含む、請求項1に記載の医薬品剤形。
- a)1種または複数種の塩基性の活性薬剤成分またはその薬学的に許容される塩を含むIR(即時放出)ビーズを製造するステップと、
b)バリアコーティングを前記IRビーズに施すステップであって、前記バリアコーティングが前記被覆ビーズの乾燥重量を基準にして約1.5%〜20%だけ重量増加するように腸溶性高分子または水不溶性高分子を含むステップと、
c)前記被覆ビーズの乾燥重量を基準にして約30%〜60%だけ重量増加するように水不溶性高分子を腸溶性高分子と組み合わせてそれぞれ約10:1〜1:2の比率で含む外側遅延コーティングを施すことによって時限パルス放出(TPR)ビーズを形成するステップと、
d)適正量の1種または複数種のTPRビーズ集団をゼラチンカプセルに充填するかまたは従来の錠剤またはODT(口腔内崩壊錠)に圧縮して、そのような活性薬剤成分を必要とする患者において(一日1回または2回の投与計画に適した)目標PK(薬物動態)プロファイルを達成するステップと
を含む、多粒子剤形の製造方法。 - 前記外側遅延コーティングを薬学的に許容される溶媒系の溶液または水性分散液から施す、請求項18に記載の方法。
- 前記医薬品剤形が、硬ゼラチンカプセル、胃に入ると急速に崩壊して被覆ビーズになる従来の錠剤、または(頬側)口腔中で急速に崩壊して飲み込みやすい懸濁液を形成する経口崩壊性錠剤の形態である、請求項18に記載の方法。
- 前記医薬品剤形が、そのような治療を必要とする患者における目標PK放出プロファイルを与えるIRビーズをさらに含む、請求項18に記載の方法。
- 治療的に有効な量の1種または複数種の活性薬剤成分を含有する請求項1に記載の剤形を患者に経口投与することを含む方法。
- 請求項1に記載の剤形を患者に経口投与することを含む方法であって、前記剤形が治療的に有効な量の、1種または複数種の活性薬剤成分のIRビーズ集団および1種または複数種の多層被覆TPRビーズ集団を含み、各多層被覆TPRビーズ集団が少なくとも5時間の遅延時間に続いて異なる放出特性を示す方法。
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