JP2017527629A - 乱用抵抗性医薬組成物 - Google Patents
乱用抵抗性医薬組成物 Download PDFInfo
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- JP2017527629A JP2017527629A JP2017534015A JP2017534015A JP2017527629A JP 2017527629 A JP2017527629 A JP 2017527629A JP 2017534015 A JP2017534015 A JP 2017534015A JP 2017534015 A JP2017534015 A JP 2017534015A JP 2017527629 A JP2017527629 A JP 2017527629A
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Abstract
Description
本発明は、2014年9月12日に出願された米国非仮特許出願第14/484,761号の利益を主張し、その全体を参照により本明細書に組み込む。
本発明は、乱用されやすいか、または乱用のおそれがある薬学的活性成分を含む組成物に関する。本発明の組成物は、このような乱用を低減または除去するために乱用抵抗性を有するように構成されている。
(i)糖球 25.0〜35.0%w/w
(ii)ポリエチレンオキシド 40.0〜50.0%w/w
(iii)ポビドン 2.5〜7.5%w/w
(iv)アンモニオメタクリレートコポリマー 5.0〜20.0%w/w
(v)二酸化ケイ素 1.0〜7.5%w/w
(vi)タルク 1.0〜7.5%w/w
からなることができる。
(i)酒石酸水素ヒドロコドン 5.0〜50.0mg/カプセル
(ii)糖球 65.0〜250.0mg/カプセル
(iii)ヒプロメロース 2.0〜15.0mg/カプセル
(iv)アンモニオメタクリレートコポリマー 7.5〜40.0mg/カプセル
(v)二酸化ケイ素 2.5〜25.0mg/カプセル
(vi)タルク 1.0〜7.5mg/カプセル
(vii)ポリエチレンオキシド 30.0〜100.0mg/カプセル
(vii)ポビドン 2.5〜12.5mg/カプセル
からなり、且つ20%の酒石酸水素ヒドロコドンが即効性ビーズ内に存在し、80%の酒石酸水素ヒドロコドンが放出制御ビーズ内に存在する。
a)ベンジルモルヒネ、ベジトラミド、ブプレノルフィン、ブトルファノール、カーフェンタニル、クロニタゼン、コデイン、デソモルヒネ、デキストロモルアミド、デゾシン、ジアセチルモルヒネ、ジアンプロマイド、ジアモルホンdiamorphine(diamorphone)、ジヒドロコデイン、ジヒドロモルヒネ、ジメノキサドール、ジメヘプタノール、ジメチルチアンブテン、ジフェノキシレート、ジオキサフェチルブチレート、ジプレノルフィン、ジピパノン、エプタゾシン、エトヘプタジン、エチルメチルチアンブテン、エチルモルヒネ、エトニタゼン、エトルフィン、ジヒドロエトルフィン、フェンタニール、ヒドロコドン、ヒドロモルホン、β−ヒドロキシ−3−メチルフェンタニール、ヒドロキシペチジン、イソメタドン、ケトベミドン、レボ−α−アセチルメタドール、レボルファノール、レボフェナシルモルファン、ロフェンタニル、メペリジン、メプタジノール、メタゾシン、メタドン、メトポン、モルヒネ、ミロフィン、ナルメフェン、ナルセイン、ニコモルヒネ、ノルレボルファノール、ノルメタドン、ナロルフィン、ナルブフェン(nalbuphene)、ノルモルヒネ、ノルピパノン、o−メチルナルトレキソン、アヘン、オキシコドン、オキシモルホン、パパベレタム、ペンタゾシン、ペチジン、フェナドキソン、フェノモルファン、フェナゾシン、フェノペリジン、ピミノジン、ピリトラミド、プロヘプタジン、プロメドール、プロペリジン、プロポキシフェン、レミフェンタニル、サフェンタニル、チリジン及びトラマドール、またはこれらの薬学的に許容される塩からなる群より選択されるオピオイドを含む溶液を独立して調製する工程、b)十分な量の工程(a)の溶液を、十分な量の糖球に施して前記オピオイドの即効性ビーズの集団を作製する工程、c)バインダをアルコールと水を含む溶剤混合物に溶解させることによりバインダ溶液を独立して形成する工程、d)前記バインダ溶液と十分な量のポリエチレンオキシド粉末を十分な量の糖球に施してポリエチレンオキシド層被覆糖球を作製する工程、e)透過性または半透過性のポリマーをアルコール、アセトン及び水を含む溶剤混合物に混合することにより被覆ポリマー混合物を独立して形成する工程、f)前記被覆ポリマー混合物を工程(e)のポリエチレンオキシド層被覆糖球に施してポリマーで被覆されたポリエチレンオキシド層被覆糖球を形成する工程、及びg)前記即効性ビーズと前記ポリマーで被覆されたポリエチレンオキシド層を有する糖球とを異なる割合で混合して剤形を形成する工程を含む。1つの実施形態において、工程(d)のバインダ溶液とポリエチレンオキシド粉末は適当なパラメータで糖球に施される。パラメータは、25〜42℃の範囲の空気温度;10〜30cfmの範囲の空気流;13〜56g/分の範囲のバインダ溶液噴霧速度;及び6〜48g/分の範囲の範囲のポリエチレンオキシド供給速度を含む。1つの実施形態において、工程(c)及び(e)のアルコールはイソプロピルアルコールである。工程(e)の溶剤混合物のアルコール、アセトン及び水の比は、それぞれ14.44:3.04:1であり得る。
(a)ゲル化剤(もしあれば、バインダと共に)を、流動床プロセッサーを用いてコアに施し、未被覆ゲル化剤ビーズを形成する;
(b)その後、被膜材料(もしあれば、流動促進剤及び他の添加剤と共に)を、流動床プロセッサーを用いて前工程の未被覆ゲル化剤ビーズに施し、所望の重量増加または厚さの被膜を有する被覆ゲル化剤ビーズを形成する;そして
(c)前工程で得られた被覆ビーズをその後乾燥し、一般に約12〜24時間の間、約30〜50℃の温度で乾燥し、完成ゲル化剤含有ビーズを形成する。
1.1ポリエチレンオキシドビーズ
本発明に従う組成物に使用される乱用抑制ビーズは下記の表1.1に示された材料を用いて製造した。
−イソプロピルアルコール及び水*(IPA中20重量%H2O)に溶解したポビドンを含むバインダ溶液を調製した。
−アンモニオメタクリレートコポリマーをイソプロピルアルコール、アセトン及び水の混合物(78.0重量%/16.6重量%/5.4重量%、即ち14.44:3.04:1のIPA:アセトン:水の比)に溶解し、5.5%w/wのポリマー溶液を形成した。
−流動促進剤ブレンドを二酸化ケイ素とタルクをバッグブレンドすることにより作製した。
−その後、バインダ溶液及びポリエチレンオキシド(粉末、約5,000,000の平均分子量を有する)を30/35メッシュ糖球にVector Granurex GX−40ロータープロセッサー(Freund−Vector Corp.−Marion,IA,USA)を用いて同時に施した。使用されるGranurexプロセスパラメータは以下の通りであった−スリット空気温度:25−42℃;スリット空気流:10−30cfm;ロータ速度:180−205rpm;バインダ溶液噴霧速度**:13−56g/min;PEO粉末供給速度**:6−48g/min。
−その後、被覆(被膜)懸濁液及び流動促進剤ブレンドを、Vector Granurex GX−40ロータープロセッサー(Freund−Vector Corp.−Marion,IA,USA)を用いてポリエチレンオキシド層が被覆された糖球に施し、乱用抑制ビーズを形成した。被膜を施すためのプロセスパラメータは以下の通りであった−スリット空気温度:42℃;スリット空気流:30cfm;ロータ速度:250rpm;被覆溶液噴霧速度;粉末供給速度:2.0g/min。
−乱用抑制ビーズは温度及び湿度が制御されたオーブン(平台トレーオーブン)で40℃/50%RH(相対湿度)で20時間乾燥し、残留溶剤を減少させ、水分含有量を安定化させた。
−乾燥後、ビーズをRussell Finex篩振とう機(Russell Finex Limited−Fletham,Middlesex,United Kingdom)を用いて集めて、スクリーニングし、もしあればプロセス中に形成された、大きすぎる材料(16−メッシュ篩で保持される)及び細かいもの(40−メッシュ篩を通過)を分離した。
(*上述の溶剤を、製造プロセス中及び/または乾燥中に追い出し、最終生成物にはかなりの程度までは取り込まれない。)
(**溶液噴霧速度及び粉末供給速度は、バッチの進行と共に増加した。)
表1.2に示された組成を有する酒石酸水素ヒドロコドン即効性(IR)ビーズは、以下に記載するように作製した。
−水に溶解した1.5%w/wのヒプロメロース及び6.0%w/wの酒石酸水素ヒドロコドン含有溶液を調製した。
−2.0%w/wの二酸化ケイ素を前工程で形成された溶液に添加し、混合して即効性被覆溶液を形成した。
−その後、IR被覆溶液を、30/50−メッシュ糖球にWurster insertを具備したGlatt(登録商標)GPCG流動床システム(Glatt air Techniques,Inc−Ramsey, NJ,USA)を用いて塗布した。
−糖球への活性成分の塗布後、得られたIRビーズを流動床で約10分間乾燥し、冷却後排出した。
−その後、排出されたRussell Finex篩振とう機を用いてスクリーニングし、もしあればプロセス中に形成された、大きすぎるもの(20−メッシュ篩で保持される)及び細かいもの(35−メッシュ篩を通過)を分離した。
以下に記載されるように、上述の酒石酸水素ヒドロコドンのIRビーズを、pH非依存性ポリマー被膜で被覆し、表1.3に示す組成を有する放出制御(CR)ビーズを製造した。
−アンモニオメタクリレートコポリマーType B(Eudragit(登録商標)RS)をイソプロピルアルコール、アセトン及び水(78.0:16.6:5.4)の混合物に溶解した。
−被覆中のビーズの凝集を防止するために、タルク及び二酸化ケイ素(いずれの場合も0.83%w/w)を、前工程で得られた溶液に抗粘着剤として添加した。
表1.4に示す組成を有する放出制御ビーズを製造した。
−メタクリル酸コポリマーType A(Eudragit(登録商標)L)(6.25%w/w)及びトリエチルシトレート(12.5%w/w)をイソプロピルアルコール、アセトン及び水(78.0:16.6:5.4)の混合物に溶解した。
−被覆中のビーズの凝集を防止するために、タルク及び二酸化ケイ素(いずれの場合も0.94%w/w)を、前工程で得られた溶液に抗粘着剤として添加した。
本発明の組成物、組成物1(以下の表2.1にまとめられている)は、セクション1.2に記載されたIRビーズ及びセクション1.3に記載されたCRビーズを、酒石酸水素ヒドロコドン含有量に基づいて20:80(IR:CR)の比でブレンドし、そして得られたブレンドを、セクション1.1に記載された75mgのPEOと共にサイズ0の硬質ゼラチンカプセルに充填し、20mg/カプセルの濃度を有する組成物を得ることにより作製した。
本発明の組成物、組成物3(以下の表3.1にまとめられている)を、セクション1.2に記載のIRビーズとセクション1.4に記載のCRビーズを、活性成分含有量に基づいて20:80(IR:CR)の比でブレンドし、得られたブレンドを、セクション1.1に記載のPEOビーズ75mgと共にサイズ0の硬質ゼラチンカプセルに充填して、20mg/カプセルの濃度を有する組成物を得ることにより調製した。
3.1イン・ビトロ放出プロファイル
図2は、組成物1及び3とそれぞれの比較(組成物2及び4)とのリン酸塩緩衝液(pH6.8)中の酒石酸水素ヒドロコドンのイン・ビトロ放出を示す。活性成分濃度は、以下の装置及び条件−USP Apparatus 1(40−メッシュバスケット);回転:100rpm;時点:1,2,4,6,8、及び12時間;媒体:500mLpH6.8リン酸塩緩衝液;温度:37.0±0.5℃を用いて、USP<711>に従って検証されたHPLC法により測定した。対照組成物/比較組成物は、同量の活性成分を含み、本発明に従うそれぞれの組成物と実質的に同じ速度でヒドロコドンを放出するように設計された。比較と本発明の組成物との主要な相違は、前者にはゲル化剤含有ビーズ集団が無く、ゲル化剤(PEO)ビーズは後者(本発明の組成物)の重要な特徴であることであった。図2は、4つ全ての組成物からの薬剤のイン・ビトロ放出が極めて類似していることを示している。組成物1及び3のPEOビーズの存在は活性成分の放出に影響を与えなかったことがこのデータから結論付けられる。
組成物1〜4が、ヒト薬物動態の研究において、単回投与で健常人に経口投与された。ヒドロコドンの血漿濃度は、投与後様々な時点で測定された。図3は、組成物1と比較組成物2の投与後の平均血漿濃度レベルを示す。図4は、組成物3と比較組成物4の投与後の平均血漿濃度レベルを示す。4つの組成物の種々のPKパラメータは下記の表3.1にまとめる。
[乱用軽減−小容量の水を用いた抽出の試み及びシリンジAPI]
本発明の組成物、組成物5及び6は、以下に記載するように調製した。
ポリエチレンオキシド粉末(重量平均分子量約5,000,000)を糖球コアにPVPバインダ溶液と共に塗布した。得られたPEOビーズは、アンモニオメタクリレートポリマー(10%ポリマー重量増加)を含む被膜で被覆された。バインダ溶液、ポリマー懸濁液及び最終PEOビーズの全含有量は、以下の表4.1〜4.3に、それぞれ示した。方法及びプロセスのパラメータは上記実施例1と実質的に同様であった。
20%IRビーズ/80%CRビーズ(活性成分含有量につき20:80)及び乱用抑制ビーズを含む酒石酸水素ヒドロコドン組成物は、PEO乱用抑制ビーズ(セクション4.1のように)、酒石酸水素ヒドロコドン即効性ビーズ(セクション1.2のように)及び酒石酸水素ヒドロコドン制御放出ビーズ(セクション1.3のように)をブレンドし、表4.4に示された量を与えることにより作製された。各ブレンドは硬質ゼラチンカプセルに充填された。
活性成分の注射可能形態を生み出す試みを抑制する本発明の組成物の能力は、組成物5(20mg酒石酸水素ヒドロコドン)及び組成物6(50mg酒石酸水素ヒドロコドン)のカプセルの内容物をいくつかの比較的小容量の水(それぞれ1,2及び5mL)に添加することにより調査された。使用された容量は、このタイプの組成物を乱用しようとする人により一般に使用され得る代表的な注射容量として選択された。サンプルは10分間振とうされ、常温条件及び沸騰水中に5分間置かれた後の両方で観察された。明確に視覚できる粘ちょう物が、いずれの場合も得られた、例えば図5A(組成物5;常温条件)を参照。調査された3つの容量のそれぞれでは、ゲル化剤が水の全量を吸収するように働き、粘ちょう物上に上澄み(浮遊物)は残らなかった。
この実施例は、本発明の組成物及び従来技術の比較組成物の、比較的大容量の水と混合した時の挙動を調査する。その目的は、各剤形から活性成分を抽出する試みをシミュレーションすることである。
−本発明に従う酒石酸水素ヒドロコドン(組成物5及び6)の単一のカプセル、または単一のオキシコドン錠剤(下記の注釈(1)参照)、水(100または200mL)及び磁気撹拌棒を、ねじ式の蓋を具備するガラスフラスコに入れた。
−活性成分の濃度を測定するためのplON,Spectra Rainbow Dynamicモデル・光ファイバープローブ(Pion,Inc−Billerica,MA,USA)を、蓋を通過させ、水と接触させた。酒石酸水素ヒドロコドン及びオキシコドンの場合、薬剤基材濃度を270−290nm(20mm路長、二次導関数)で測定した。
−撹拌棒を動かし、タイマーを始動させた。
−活性成分の濃度は様々な時点で測定した。
−フラスコ及び内容物の写真をt=0及びt=60分で撮影した。
([1]Oxycontin(登録商標)30mg及び80mgの錠剤からなるオキシコドンの比較。塩酸オキシコドンは別として、Oxycontin(登録商標)の添付文書によれば、各錠剤は下記の不活性成分を含む:アンモニオメタクリレートコポリマー、ヒプロメロース、ラクトース、ステアリン酸マグネシウム、ポリエチレングリコール400、ポビドン、水酸化ナトリウム、ソルビン酸、ステアリルアルコール、タルク、二酸化チタン及びトリアセチン。30mg錠剤もまた、ポリソルベート80、赤色酸化鉄、黄色酸化鉄、及び黒色酸化鉄を含む。80mg錠剤もまた、FD&C ブルーNo.2、ヒドロキシプロピルセルロース及び黄色酸化鉄を含む。(Oxycontin(登録商標)はPurdue Pharma LPの登録商標である))
本発明の組成物のゲル化剤成分は、組成物からの薬学的活性成分のイン・ビトロまたはイン・ビボ放出に悪影響は与えない(損傷を受けない、及びどのような改ざんも受けない)。特に、ゲル化剤含有ビーズの存在は活性成分の生体利用効率に、いかなる悪影響も与えない。
Claims (15)
- 第1のビーズの集団及び第2のビーズの集団を含む経口医薬組成物であって、
前記第1のビーズ集団は、ベンジルモルヒネ、ベジトラミド、ブプレノルフィン、ブトルファノール、カーフェンタニル、クロニタゼン、コデイン、デソモルヒネ、デキストロモルアミド、デゾシン、ジアセチルモルヒネ、ジアンプロマイド、ジアモルホン、ジヒドロコデイン、ジヒドロモルヒネ、ジメノキサドール、ジメヘプタノール、ジメチルチアンブテン、ジフェノキシレート、ジオキサフェチルブチレート、ジプレノルフィン、ジピパノン、エプタゾシン、エトヘプタジン、エチルメチルチアンブテン、エチルモルヒネ、エトニタゼン、エトルフィン、ジヒドロエトルフィン、フェンタニール、ヒドロコドン、ヒドロモルホン、β−ヒドロキシ−3−メチルフェンタニール、ヒドロキシペチジン、イソメタドン、ケトベミドン、レボ−α−アセチルメタドール、レボルファノール、レボフェナシルモルファン、ロフェンタニル、メペリジン、メプタジノール、メタゾシン、メタドン、メトポン、モルヒネ、ミロフィン、ナルメフェン、ナルセイン、ニコモルヒネ、ノルレボルファノール、ノルメタドン、ナロルフィン、ナルブフェン、ノルモルヒネ、ノルピパノン、o−メチルナルトレキソン、アヘン、オキシコドン、オキシモルホン、パパベレタム、ペンタゾシン、ペチジン、フェナドキソン、フェノモルファン、フェナゾシン、フェノペリジン、ピミノジン、ピリトラミド、プロヘプタジン、プロメドール、プロペリジン、プロポキシフェン、レミフェンタニル、サフェンタニル、チリジン及びトラマドール、またはこれらの薬学的に許容される塩からなる群より選択される薬学的活性成分を含み、且つ前記第1のビーズ集団がポリエチレンオキシドを実質的に含まず、そして
前記第2のビーズ集団は、ポリエチレンオキシドと、アンモニオメタクリレートコポリマー、メタクリル酸コポリマー及びこれらの混合物からなる群より選択される透過性または半透過性被膜とを含み、且つ前記第2のビーズ集団は薬学活性成分を実質的に含まない前記経口医薬組成物。 - 前記第2のビーズ集団がさらにポビドンを含む請求項1に記載の組成物。
- 前記活性成分が、コデイン、ジヒドロコデイン、ヒドロコドン、メタドン、モルヒネ及びオキシコドンからなる群より選択される請求項1または2に記載の組成物。
- 前記ポリエチレンオキシドが微粒子状で存在する請求項1〜4のいずれか1項に記載の組成物。
- 前記薬学的活性成分が酒石酸水素ヒドロコドンである請求項1〜4のいずれか1項に記載の組成物。
- 前記酒石酸水素ヒドロコドンが5〜250mgの量で存在する請求項1〜5のいずれか1項に記載の前記組成物。
- 前記第1のビーズ集団が即効性酒石酸水素ヒドロコドンビーズの部分と放出制御酒石酸水素ヒドロコドンビーズの部分とを含む請求項1に記載の経口医薬組成物。
- 前記即効性ビーズは、組成物中に酒石酸水素ヒドロコドン総量の1〜75%w/wを含有し、放出制御ビーズは、組成物中に酒石酸水素ヒドロコドン総量の25〜99%w/wを含有する請求項7に記載の組成物。
- カプセル形態またはタブレット形態で与えられる請求項1〜8のいずれか1項に記載の組成物を含む単位剤形。
- 前記単位剤形がカプセル当たり少なくとも約20mgのゲル化剤を含む、カプセル形態で与えられる請求項9に記載の単位剤形。
- 実質的にポリエチレンオキシドを含まない酒石酸水素ヒドロコドンビーズとゲル化剤含有ビーズとから作製された組成物を含む経口カプセルであって、前記ゲル化剤含有ビーズが、糖球、ポリエチレンオキシド、ポビドン、及びアンモニオメタクリレートコポリマー、メタクリル酸コポリマー及びこれらの組み合わせからなる群より選択されるポリマーを含む半透過性被膜から実質的になる前記経口カプセル。
- 前記ゲル化剤含有ビーズが、
(i)糖球 25.0〜35.0%w/w
(ii)ポリエチレンオキシド 40.0〜50.0%w/w
(iii)ポビドン 2.5〜7.5%w/w
(iv)アンモニオメタクリレートコポリマー 5.0〜20.0%w/w
(v)二酸化ケイ素 1.0〜7.5%w/w
(vi)タルク 1.0〜7.5%w/w
から実質的になる請求項11に記載の前記経口カプセル。 - 疼痛を処置するために使用される請求項1〜8のいずれか1項に記載の前記組成物であって、その使用が処置を必要とする被験者に前記組成物を投与することを含む前記組成物。
- 第1のビーズの集団及び第2のビーズの集団を含む組成物を、処置を必要とする被験者に投与することを含む疼痛の処置方法であって、
前記第1のビーズ集団が、実質的にポリエチレンオキシドを含まず、且つベンジルモルヒネ、ベジトラミド、ブプレノルフィン、ブトルファノール、カーフェンタニル、クロニタゼン、コデイン、デソモルヒネ、デキストロモルアミド、デゾシン、ジアセチルモルヒネ、ジアンプロマイド、ジアモルホン、ジヒドロコデイン、ジヒドロモルヒネ、ジメノキサドール、ジメヘプタノール、ジメチルチアンブテン、ジフェノキシレート、ジオキサフェチルブチレート、ジプレノルフィン、ジピパノン、エプタゾシン、エトヘプタジン、エチルメチルチアンブテン、エチルモルヒネ、エトニタゼン、エトルフィン、ジヒドロエトルフィン、フェンタニール、ヒドロコドン、ヒドロモルホン、β−ヒドロキシ−3−メチルフェンタニール、ヒドロキシペチジン、イソメタドン、ケトベミドン、レボ−α−アセチルメタドール、レボルファノール、レボフェナシルモルファン、ロフェンタニル、メペリジン、メプタジノール、メタゾシン、メタドン、メトポン、モルヒネ、ミロフィン、ナルメフェン、ナルセイン、ニコモルヒネ、ノルレボルファノール、ノルメタドン、ナロルフィン、ナルブフェン、ノルモルヒネ、ノルピパノン、o−メチルナルトレキソン、アヘン、オキシコドン、オキシモルホン、パパベレタム、ペンタゾシン、ペチジン、フェナドキソン、フェノモルファン、フェナゾシン、フェノペリジン、ピミノジン、ピリトラミド、プロヘプタジン、プロメドール、プロペリジン、プロポキシフェン、レミフェンタニル、サフェンタニル、チリジン及びトラマドール、またはこれらの薬学的に許容される塩からなる群より選択される活性成分を含み、そして
前記第2のビーズ集団が、薬学的活性成分を実質的に含まず、且つポリエチレンオキシドと、アンモニオメタクリレートコポリマー、メタクリル酸コポリマー及びこれらの混合物からなる群より選択される透過性または半透過性被膜とを含む前記疼痛の処置方法。 - オピオイドを含む即効性ビーズの集団とポリエチレンオキシド及び透過性または半透過性被膜ポリマーを含むゲル化剤含有ビーズの集団とを含む経口剤形を製造する方法であって、
下記の工程:
a)ベンジルモルヒネ、ベジトラミド、ブプレノルフィン、ブトルファノール、カーフェンタニル、クロニタゼン、コデイン、デソモルヒネ、デキストロモルアミド、デゾシン、ジアセチルモルヒネ、ジアンプロマイド、ジアモルホン、ジヒドロコデイン、ジヒドロモルヒネ、ジメノキサドール、ジメヘプタノール、ジメチルチアンブテン、ジフェノキシレート、ジオキサフェチルブチレート、ジプレノルフィン、ジピパノン、エプタゾシン、エトヘプタジン、エチルメチルチアンブテン、エチルモルヒネ、エトニタゼン、エトルフィン、ジヒドロエトルフィン、フェンタニール、ヒドロコドン、ヒドロモルホン、β−ヒドロキシ−3−メチルフェンタニール、ヒドロキシペチジン、イソメタドン、ケトベミドン、レボ−α−アセチルメタドール、レボルファノール、レボフェナシルモルファン、ロフェンタニル、メペリジン、メプタジノール、メタゾシン、メタドン、メトポン、モルヒネ、ミロフィン、ナルメフェン、ナルセイン、ニコモルヒネ、ノルレボルファノール、ノルメタドン、ナロルフィン、ナルブフェン、ノルモルヒネ、ノルピパノン、o−メチルナルトレキソン、アヘン、オキシコドン、オキシモルホン、パパベレタム、ペンタゾシン、ペチジン、フェナドキソン、フェノモルファン、フェナゾシン、フェノペリジン、ピミノジン、ピリトラミド、プロヘプタジン、プロメドール、プロペリジン、プロポキシフェン、レミフェンタニル、サフェンタニル、チリジン及びトラマドール、またはこれらの薬学的に許容される塩からなる群より選択されるオピオイドを含む溶液を独立して調製する工程、
b)十分な量の工程(a)の溶液を、十分な量の糖球に付与して前記オピオイドの即効性ビーズの集団を作製する工程、
c)バインダをアルコールと水を含む溶剤混合物に溶解させることによりバインダ溶液を独立して形成する工程、
d)前記バインダ溶液と十分な量のポリエチレンオキシド粉末を十分な量の糖球に施してポリエチレンオキシド層で被覆された糖球を作製する工程、
e)透過性または半透過性のポリマーをアルコール、アセトン及び水を含む溶剤混合物に混合することにより被覆ポリマー混合物を独立して形成する工程、
f)前記被覆ポリマー混合物を工程(e)のポリエチレンオキシド層被覆糖球に施してポリマーで被覆されたポリエチレンオキシド層被覆糖球を形成する工程、及び
g)前記即効性ビーズと前記ポリマーで被覆されたポリエチレンオキシド層被覆糖球とを異なる割合で混合して剤形を形成する工程
を含む前記方法。
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