JP2015523356A - ジエチルアミノエチルメタクリレートコポリマーをベースにした活性成分含有固体分散体 - Google Patents
ジエチルアミノエチルメタクリレートコポリマーをベースにした活性成分含有固体分散体 Download PDFInfo
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- JP2015523356A JP2015523356A JP2015517670A JP2015517670A JP2015523356A JP 2015523356 A JP2015523356 A JP 2015523356A JP 2015517670 A JP2015517670 A JP 2015517670A JP 2015517670 A JP2015517670 A JP 2015517670A JP 2015523356 A JP2015523356 A JP 2015523356A
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Abstract
Description
部分中和度6mol: 6mol%の塩基性基がアジピン酸で部分中和。
一般手順
ポリマー/活性成分混合物を調製するために、物質の各量を50mlのペニシリン瓶に秤量した。
一般手順
ポリマー/活性成分混合物を調製するために、物質を適切な貯蔵容器に秤量した。対応する量の溶媒を加え、混合物をポリマーと活性成分が完全に溶解するまで撹拌した。フェノフィブラート調合物では、溶媒はアセトンであり、イトラコナゾール調合物では、溶媒はジクロロメタンであり、ナプロキセンを含む調合物では、アセトンを溶媒として使用した。噴霧溶液の固形物画分はすべての実験で20重量%であった。噴霧乾燥は実験室スケールで実施した。
一般手順
下記の実施例に記載される調合物を調製するために使用した二軸スクリュー押出機は、スクリュー直径16mm及び長さ40Dであった。押出機は、ノズルを含めて加熱可能な10個のゾーンからなるものであった。スクリュー配置は、ゾーン5及び7において、捏和エレメントを使用し、そうでない場合は輸送エレメントを使用するように選択した。ノズル (ゾーン10)を同様に加熱した。後述する押出の実施例について、使用するプロセスパラメーターを記載する。記載のゾーン温度はシリンダーの内部温度である。
固体分散体の特性評価を視覚的評価、XRD (X線回折)及びDSC (示差走査熱量測定)によって実施した。
XRD
装置:9管の試料交換器を備えたD 8 Advance回折計(Bruker/AXS社)
測定方法:反射におけるθ-θジオメトリー
角度範囲2θ:2〜40°
ステップ幅:0.02°
角度ステップあたりの測定時間:2.4秒
発散スリット:1.0mmの挿入されたアパーチャを備えたGobel鏡
散乱防止スリット: Sollerスリット
検出器:Sol-X検出器
温度:室温
発電機設定:40kV/50mA
DSC
装置:Q2000 (TA Instruments社、米国)
乾燥:試料を真空中40℃で終夜乾燥し、その後20バール圧密るつぼに秤量する
加熱速度: 20K/分。
押出プロセス及び噴霧乾燥により調製された固溶体を、手動又は半自動活性成分放出によって調査した。
活性成分放出を、USP装置(パドル法) 2に従って、700ml 0.08N HCl、37℃、50rpm(BTWS 600、Pharmatest社)で実施した。造粒機を使用して、ストランド状押出物のサイズを長さ3mmに低減し、この形で放出に供給した。いずれの場合にも、放出容器当たり活性成分(非シンク条件)100mgを使用した。放出された活性成分を、規定の時点後、10μmのフィルターに通して濾過した後、UV-VIS分光法(Agilent 8453 UV-VIS分光計、Agilent社)により手動で検出した。
活性成分放出を、USP装置(パドル法)2に従って、700ml 0.08N HCl、37℃、75rpm(BTWS 600、Pharmatest社)で実施した。造粒機を使用して、ストランド状押出物のサイズを長さ3mmに低減し、この形で放出に供給した。いずれの場合にも、放出容器当たり活性成分(非シンク条件)100mgを使用した。放出された活性成分を、規定の時点後、45μmのフィルターに通して濾過した後、UV-VIS分光法(Agilent 8453 UV-VIS分光計、Agilent社)により半自動で検出した。
活性成分放出を、USP装置(パドル法)2に従って、0.1% Tween(登録商標)80を含む700ml 0.08N HCl、37℃、100rpm(BTWS 600、Pharmatest社)で実施した。造粒機を使用して、ストランド状押出物のサイズを長さ3mmに低減した。サイズを低減したストランド状押出物をMF 10ベーシックミル(篩:0.5mm、IKA Werke社)を使用して粉砕し、この形で放出に供給した。いずれの場合にも、放出容器当たり活性成分(非シンク条件)100mgを使用した。放出された活性成分を、規定の時点後、45μmのフィルターに通して濾過した後、UV-VIS分光法(Agilent 8453 UV-VIS分光計、Agilent社)により半自動で検出した。
活性成分放出を、USP装置(パドル法)2に従って、700ml 0.08N HCl、37℃、75rpm(BTWS 600、Pharmatest社)で実施した。噴霧乾燥による生成物をゼラチンカプセル(サイズ: 0)に注ぎ込み、この形で放出に供給した。カプセルが浮かぶのを防止するために、白金線を使用してカプセルを重みで押し下げた。いずれの場合にも、放出容器当たり活性成分(非シンク条件)100mgを使用した。放出された活性成分を、規定の時点後、45μmのフィルターに通して濾過した後、UV-VIS分光法(Agilent 8453 UV-VIS分光計、Agilent社)により半自動で検出した。
Kollicoat(登録商標) Smartseal及び部分中和Kollicoat(登録商標) SmartsealとEudragit(登録商標) EPOとの、異なる活性成分についての配合能力の比較。本明細書で記載のフィルム中の濃度は、溶解している分子分散活性成分の配合能力を指す。すなわち、フィルム中で認められる活性成分の結晶はない。配合量が高くなるほど結晶性画分になる。
Kollicoat(登録商標) Smartseal(凍結乾燥)2925g及びブチルヒドロキシトルエン75gをTurbula混合容器に秤量し、Turbula混合器T10Bで10分間混合した。この混合物は、重量式計量ユニットDDW-MD2-DDSR20-10(Brabender Technologie社)を使用して、活性成分フェノフィブラートは、重量式計量ユニットMini Twin MT1 (Brabender Technologie社)を使用して、押出機に加えた。
・第1シリンダーのゾーン温度: 45℃;第2シリンダーのゾーン温度: 85℃
・第3シリンダーからのゾーン温度:150℃
・スクリュー速度:50rpm
・処理量: 500g/時
・ノズル直径:3mm
質量分率34%(w/w)のフェノフィブラートを含む製剤をXRDによって調査し、非晶質であることがわかった。
Kollicoat(登録商標) Smartseal(凍結乾燥)2925g及びブチルヒドロキシトルエン75gをTurbula混合容器に秤量し、Turbula混合器T10Bで10分間混合した。この混合物は、重量式計量ユニットDDW-MD2-DDSR20-10(Brabender Technologie社)を使用して押出機に加えた。Kollicoat(登録商標) Smartseal混合物(Kollicoat(登録商標) Smartsealとブチルヒドロキシトルエン)250g及びイトラコナゾール250gをTurbula混合容器に秤量し、Turbula混合器T2Cで10分間混合した。この活性成分混合物を第2の量式計量システムMini Twin MT1(Brabender Technologie社)により押出機に加えた。
・第1シリンダーのゾーン温度:50℃;第2シリンダーのゾーン温度: 100℃
・第3シリンダーから第10シリンダーまでのゾーン温度:160℃
・スクリュー速度:50rpm
・処理量:400g/時
・ノズル直径:3mm
固溶体をXRDによって調査し、最大で38%のイトラコナゾールが非晶質であることがわかった。0.08N HCl中において2時間後の活性成分の押出物からの放出(方法1)は89%であった(図1)。
対応する量の各ポリマー(Kollicoat(登録商標) Smartseal、8mol部分中和されたKollicoat(登録商標) Smartseal、Eudragit(登録商標) EPO)及び対応する活性成分カルバマゼピンをTurbula混合容器に秤量し(ポリマー+活性成分の全量はいずれの場合にも400gであった)、Turbula混合器T2Cで10分間混合した。この混合物は、重量式計量ユニットDDW-MD2-DDSR20-10 (Brabender Technologie社)を使用して押出機に加えた。
・第1シリンダーのゾーン温度:40℃;第2シリンダーのゾーン温度:80℃
・第3シリンダーから第10シリンダーまでのゾーン温度:160℃
・スクリュー速度:200rpm
・処理量:1000g/時
・ノズル直径:3mm
調製された製剤を、DSCを使用して調合物中の非晶質及び結晶質活性成分について分析した。
対応する量の特定ポリマー(Kollicoat(登録商標) Smartseal、6mol部分中和されたKollicoat(登録商標) Smartseal、Eudragit(登録商標) EPO)及び対応する活性成分イトラコナゾールをTurbula混合容器に秤量し(ポリマー+活性成分の全量はいずれの場合にも400gであった)、Turbula混合器T2Cで10分間混合した。この混合物は、重量式計量ユニットDDW-MD2-DDSR20-10 (Brabender Technologie社)を使用して押出機に加えた。
・第1シリンダーのゾーン温度:50℃;第2シリンダーのゾーン温度:90℃
・第3シリンダーから第9シリンダーまでのゾーン温度:160℃
・第10シリンダーのゾーン温度:150℃
・スクリュー速度:200rpm
・処理量:1000g/時
・ノズル直径:3mm
作製された調合物を視覚的に検査し、調合物中の非晶質(清澄な押出物)及び結晶質活性成分(曇りの始まり)の点から評価した。
対応する量の各ポリマー(Kollicoat(登録商標) Smartseal、Eudragit(登録商標) EPO)及び対応する活性成分ダナゾールをTurbula混合容器に秤量し(ポリマー+活性成分の全量はいずれの場合にも400gであった)、Turbula混合器T2Cで10分間混合した。この混合物は、重量式計量ユニットDDW-MD2-DDSR20-10 (Brabender Technologie社)を使用して押出機に加えた。
・第1シリンダーのゾーン温度:40℃;第2シリンダーのゾーン温度:80℃
・第3シリンダーから第10シリンダーまでのゾーン温度:180℃
・スクリュー速度:200rpm
・処理量:1000g/時
・ノズル直径:3mm
製剤を、XRDを使用して調合物中の非晶質及び結晶質活性成分について分析した。
噴霧乾燥における異なる活性成分についてのKollicoat(登録商標) Smartsealの配合能力。実験室スケールで実施された噴霧乾燥実験:
1.イトラコナゾール: 40 + 50% (w/w) イトラコナゾールを含むKollicoat(登録商標) Smartseal
2.フェノフィブラート: 40 + 50% (w/w) フェノフィブラートを含むKollicoat(登録商標) Smartseal
3.ナプロキセン: 40+50% (w/w)ナプロキセンを含むKollicoat(登録商標) Smartseal
実験条件:
Claims (16)
- 疎水性活性成分及びN,N-ジエチルアミノエチルメタクリレートとメチルメタクリレートとのモノマー重量比35:65〜55:45のカチオン性コポリマーの固体分散体。
- N,N-ジエチルアミノエチルメタクリレートとメチルメタクリレートとのモノマー重量比45:55のカチオン性コポリマーを含む、請求項1に記載の固体分散体。
- 10〜50重量%の疎水性活性成分を含む、請求項1又は2に記載の固体分散体。
- 20〜50重量%の疎水性活性成分を含む、請求項1〜3のいずれか1項に記載の固体分散体。
- 医薬品添加物をさらに含む、請求項1〜4のいずれか1項に記載の固体分散体。
- 可塑剤を含む、請求項1〜5のいずれか1項に記載の固体分散体。
- 酸化防止剤を含む、請求項1〜6のいずれか1項に記載の固体分散体。
- 請求項1〜7のいずれか1項に記載の疎水性活性成分及びN,N-ジエチルアミノエチルメタクリレートとメチルメタクリレートとのモノマー重量比35:65〜55:45のカチオン性コポリマーの固体分散体を調製する方法であって、疎水性活性成分及びカチオン性コポリマーを含む液体混合物を調製し、液体混合物を固形に変換する方法。
- 液体混合物が溶液又は溶融物の形態で存在する、請求項8に記載の方法。
- 液体混合物から固形への変換が噴霧乾燥によって行われる、請求項8に記載の方法。
- 液体混合物がスクリュー押出機中で加熱しながら調製され、押出後に冷却によって固化される、請求項8に記載の方法。
- 固形への変換が、液体混合物を成形してフィルムを生成し、これを固化することによって行われる、請求項8に記載の方法。
- カチオン性コポリマーが部分中和した形態で使用される、請求項8〜12のいずれか1項に記載の方法。
- 使用するカチオン性コポリマーがカチオン基に対して2〜15mol%まで部分中和されている、請求項8〜13のいずれか1項に記載の方法。
- 使用するカチオン性コポリマーがC3〜C10-ジカルボン酸で部分中和されている、請求項8〜13のいずれか1項に記載の方法。
- 医薬品、化粧品、農薬製剤、食事療法製剤又は栄養補助食品製剤としての、請求項1〜15のいずれか1項に記載の固体分散体の使用。
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PCT/EP2013/061972 WO2013189776A1 (de) | 2012-06-22 | 2013-06-11 | Wirkstoffhaltige festen dispersionen auf basis von diethylaminoethylmethacrylat-copolymeren |
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JP2020531446A (ja) * | 2017-08-17 | 2020-11-05 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | 塩基性又は中性の低分子量化合物のための新規な医薬組成物 |
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US9616029B2 (en) * | 2014-03-26 | 2017-04-11 | Sun Pharma Advanced Research Company Ltd. | Abuse deterrent immediate release coated reservoir solid dosage form |
WO2017098325A2 (en) | 2015-12-10 | 2017-06-15 | Adama Makhteshim Ltd. | Polyelectrolyte-layer forming block copolymers and compositions and used thereof |
WO2019063478A1 (en) * | 2017-09-26 | 2019-04-04 | Capsugel Belgium Nv | SUB-MICRONIC PARTICLE FORMULATIONS |
AR114185A1 (es) | 2018-01-23 | 2020-07-29 | Adama Makhteshim Ltd | Síntesis de 5-cloro-2-[(3,4,4-trifluoro-3-buten-1-il)tio]-tiazol |
EP3861989A1 (en) * | 2020-02-07 | 2021-08-11 | Bayer Aktiengesellschaft | Pharmaceutical composition containing regorafenib and a stabilizing agent |
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WO2012031934A1 (de) * | 2010-09-07 | 2012-03-15 | Basf Se | Verwendung von copolymeren auf basis von aminogruppenhaltigen polymeren als matrixbindemittel für die herstellung von wirkstoffhaltigen granulaten und darreichungsformen |
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DE19918435A1 (de) | 1998-07-23 | 2000-01-27 | Roehm Gmbh | Überzugs- und Bindemittel für orale oder dermale Arzneiformen |
ES2248291T3 (es) | 2001-02-27 | 2006-03-16 | ROHM GMBH & CO. KG | Agente de recubrimiento y aglutinante para formulaciones de medicamento con estabilidad al almcenamiento mejorada. |
DE10239999A1 (de) | 2002-08-27 | 2004-03-04 | Röhm GmbH & Co. KG | Granulat oder Pulver zur Herstellung von Überzugs- und Bindemitteln für Arzneiformen |
GB0607105D0 (en) * | 2006-04-10 | 2006-05-17 | Leuven K U Res & Dev | Enhancing solubility and dissolution rate of poorly soluble drugs |
EP2176301B1 (de) | 2007-08-02 | 2013-05-15 | Basf Se | Wässrige polymerdispersion auf basis von n, n-diethylaminoethylmethacrylat, deren herstellung und verwendung |
TW201008569A (en) * | 2008-08-08 | 2010-03-01 | Bayer Schering Pharma Ag | Progestin-containing drug delivery system |
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JP7291685B2 (ja) | 2017-08-17 | 2023-06-15 | エフ. ホフマン-ラ ロシュ アーゲー | 塩基性又は中性の低分子量化合物のための新規な医薬組成物 |
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CN104379174B (zh) | 2018-01-26 |
CN104379174A (zh) | 2015-02-25 |
WO2013189776A1 (de) | 2013-12-27 |
JP6189429B2 (ja) | 2017-08-30 |
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