JP5122823B2 - 微粒子 - Google Patents
微粒子 Download PDFInfo
- Publication number
- JP5122823B2 JP5122823B2 JP2006552696A JP2006552696A JP5122823B2 JP 5122823 B2 JP5122823 B2 JP 5122823B2 JP 2006552696 A JP2006552696 A JP 2006552696A JP 2006552696 A JP2006552696 A JP 2006552696A JP 5122823 B2 JP5122823 B2 JP 5122823B2
- Authority
- JP
- Japan
- Prior art keywords
- formulation
- oxycodone
- hours
- release
- minutes
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
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- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
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- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 238000010947 wet-dispersion method Methods 0.000 description 1
Images
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Description
水中室温で15分間の振盪:10%未満の有効成分の放出、好ましくは7.5%未満の有効成分の放出、より好ましくは5%未満の有効成分の放出、例えば1.5〜4%の有効成分の放出。
水中50℃で5分間静置した後に同じ温度で15分間の振盪:20%未満の有効成分の放出、好ましくは15%未満の有効成分の放出、より好ましくは12%未満の有効成分の放出、例えば4〜12%の有効成分の放出。
75℃で5分間静置した後に同じ温度で15分間の振盪:25%未満の有効成分の放出、好ましくは20%未満の有効成分の放出、より好ましくは15%未満の有効成分の放出、例えば10〜15%の有効成分の放出。
100℃で5分間静置した後に同じ温度で15分間の振盪:30%未満の有効成分の放出、好ましくは25%未満の有効成分の放出、より好ましくは20%未満の有効成分の放出、例えば12〜20%の有効成分の放出。
40%エタノール中室温で15分間の振盪:35%未満の有効成分の放出、好ましくは30%未満の有効成分の放出、より好ましくは25%未満の有効成分の放出、例えば15〜25%の有効成分の放出。
a)顆粒化、好ましくは湿式顆粒化;
b)任意に顆粒の押出;
c)好ましくは流動層乾燥機による顆粒又は押出顆粒の乾燥;
d)任意に段階c)からの乾燥顆粒又は乾燥押出顆粒のスクリーニング及び/又は微粉砕;並びに
e)段階c)又はd)からの生産物の溶融押出.
a)顆粒化;
b)任意に顆粒の押出;
c)好ましくは流動層乾燥機による顆粒又は押出顆粒の乾燥;
d)任意に段階c)からの生産物のスクリーニング及び/又は微粉砕;並びに
e)段階c)又はd)からの乾燥顆粒又はスクリーニングもしくは微粉砕した生産物の溶融押出.
多微粒子の三つのバッチ(実施例)を同様な手順の後に作製した。
ステップ1.最初に、下記の品目を、40℃に予熱したグラール10高せん断ミキサー中に配置し、高速で2分間乾燥ブレンドした。
オキシコドン塩酸塩
オイドラギットRS PO
ステアリルアルコール
ステアリン酸
ステップ2.オイドラギットNE 40 D分散液を350ミクロンメッシュに通して選別し、凝集体を除去して、適当な大きさの容器に移した。
ステップ3.選別されたオイドラギットNE 40 D分散液を、混合ボウル中、混合/細断しながらステップ1の乾燥ブレンドした物質上に低噴霧圧で吹き付けた。
ステップ4.オイドラギットNE 40 Dの適用を顆粒生成が起こるまで続けた。
ステップ5.オイドラギットNE 40 Dの適用を定期的に中断し、混合ボウルの側面をこすった。
ステップ6.全てのオイドラギットNE 40 Dを適用した後に、顆粒を同一の温度条件下、低減した混合/細断速度で乾燥した。
ステップ7.その後、顆粒を、コンベヤーとペレタイザーとが備わっているライストリッツマイクロ18押出機に制御された速度で供給した。該押出機は、1.5mmのダイプレートと、下記の熱ステーション;90℃〜100℃のステーション3〜8、100℃のステーション9及び10とを有する。供給速度は2.0〜2.6kg/hrであって、スクリュー速度が100〜141rpmで、50〜60%/40〜50barのトルク/溶融圧力を有する。
この実施例では、代替の切断手順を使用した。押出物は、ライストリッツマイクロ18押出機のダイヘッドの12個のオリフィスから出てくる。二枚の刃を有するロータリーカッターを使用し、圧力を受け、更にダイプレートのオリフィスから溶融されて出てくる押出混合物を切断する。該刃は、ダイヘッドの表面を一掃し、オリフィスを通過する。切断された押出物の粒子を膨張及び冷却するにつれて、それらは丸みをつけた表面を形成する傾向がある。
多微粒子の二つのバッチを、可塑剤としてクエン酸トリブチル(およそ43%w/wの薬物量)を用いて計画した。含有量の百分率、w/wは、下記のとおりである。
ステップ1.クエン酸トリブチルをグラール10高せん断ミキサー中のエチルセルロースに緩徐に添加し、ブレンドした。
ステップ2.オキシコドンをグラール10高せん断ミキサー中のステップ1の配合物に添加し、5分間ブレンドした。
ステップ3.オイドラギットNE 40 D分散液を350ミクロンメッシュに通して選別し、凝集体を除去して、適当な大きさの容器に移した。次に、選別されたオイドラギットNE 40 D分散液を、38℃に予熱したグラール10混合ボウル中、混合/細断しながらステップ2のブレンドした物質上に蠕動ポンプで緩徐に添加した。
ステップ4.オイドラギットNE 40 Dの適用を、顆粒生成が起こり、全てのオイドラギットNE 40 Dを添加するまで続けた。
ステップ5.オイドラギットNE 40 Dの適用を定期的に中断し、混合ボウルの側面をこすることができた。
ステップ6.全てのオイドラギットNE 40 Dを添加した後に、湿式顆粒を通常の押出機に通して押出し、流動層乾燥機において約42℃で乾燥した。
ステップ7.乾燥顆粒を室温まで冷却し、収集した。
ステップ8.その後、顆粒を、実施例1と同じ条件下、1.0mmのダイプレートと、コンベヤー及びペレタイザーとが備わっているライストリッツマイクロ18押出機に制御された速度で供給した。押出ストランドをダイヘッドからコンベヤー上に運搬し、シリンダー形の多微粒子に切断した。
・ステップ1において可塑剤(クエン酸トリブチル)を添加しなかった。その代わりに、ステップ1を除外し、ステップ2がグラール10高せん断ミキサーによるオキシコドン塩酸塩とエチルセルロースとの混合からなった。
・顆粒を篩にかけ(1.5mmメッシュ)、大き過ぎる顆粒を微粉砕し(1.0mmメッシュ)、他の顆粒と再結合した。
・潤滑剤(グリセロールジベヘネート)を、ステップ7の終わりで押出機に供給する直前に、乾燥顆粒に添加した。
・押出機は、1.5mmのオリフィス付きのダイプレートを有した。
100〜120℃の範囲の温度、240rpm以下のスクリュー速度、並びに直径1.5mm(実施例7及び8)及び1.0mm(実施例9)のダイプレートの寸法以外は、これまでの実施例に関して同一の手順及び押出条件を使用し、下記の配合処方により加工し、多微粒子を作製した。
これまでの実施例のものと同様な手順を用いて、多微粒子を下記の配合処方で作製した。
a)水10ml中、室温で15分間の振盪
b)水10ml中、50℃で5分間加熱した後、15分間の振盪
c)水10ml中、75℃で5分間加熱した後、15分間の振盪
d)水10ml中、100℃で5分間加熱した後、15分間の振盪
e)40%エタノール10ml中、室温で15分間の振盪
Claims (26)
- 溶融押出マルチ粒子を含み、前記マルチ粒子は、中性ポリ(エチルアクリレート,メチルメタクリレート)共重合体と、放出を加減するために他の重合体としてアルキルセルロースまたは水不溶性メタクリル酸アンモニウム共重合体と、活性薬剤としてオピオイドとを含有するゴム状マトリクスを構成する、耐改ざん性(耐タンパー性)の放出制御された製剤処方物であって、前記処方物は、400mgのマルチ粒子を、乳鉢および乳棒における24回転の乳棒による粉砕、および水900ml中37℃で45分間の放置にかけることを含む試験方法によって試験した場合に、10%未満の活性薬剤しか放出しない、処方物。
- 前記処方物は、アペックスヘルスケアプロダクツ社製のピル微粉砕機で一投与量を破砕した後、スプーン上で加熱して沸騰させた水2mlで抽出し、ろ過することを含む試験方法によって試験した場合に、15%未満の活性薬剤しか放出しない、請求項1に記載の処方物。
- 前記活性薬剤はオキシコドンである、請求項1または2に記載の処方物。
- 前記他の重合体はエチルセルロースである、請求項1に記載の処方物。
- 前記エチルセルロースの量は処方物の10〜50重量%である、請求項4に記載の処方物。
- 60%w/w以下の前記活性薬剤、15〜50%w/wの中性ポリ(エチルアクリレート,メチルメタクリレート)共重合体、5〜60%w/wのエチルセルロース、および7.5〜20%の可塑剤を含む、請求項1に記載の処方物。
- さらに5〜60%の不溶性メタクリル酸アンモニウム共重合体を含む、請求項7に記載の処方物。
- 35〜50%の低透過性の不溶性メタクリル酸アンモニウム共重合体および/または5〜30%の高透過性メタクリル酸アンモニウム共重合体を含む、請求項8に記載の処方物。
- 増量剤を含む、請求項1に記載の処方物。
- オピオイドおよびオピオイドアンタゴニストを含む、請求項1に記載の処方物。
- 120〜300mgのオキシコドンマルチ粒子および125〜175mgのオキシコドンアンタゴニストマルチ粒子を含む、請求項11に記載の処方物。
- オキシコドンおよびナルトレキソンを含む、請求項1に記載の処方物。
- ガラスフラスコ中の液体10mlを用いて一投与量のマルチ粒子を混合すること、スチュアートサイエンティフィック振盪機SF1型を用いて毎分500〜600の振動で15分間振盪することを含む試験方法により試験した場合に、下記の特徴(a)〜(e)のうちの少なくとも一つを示す、請求項1に記載の処方物:
a.水中室温で15分間の振盪:7.5%未満の活性薬剤の放出、
b.水中50℃で5分間静置した後に同じ温度で15分間の振盪:15%未満の活性薬剤の放出、
c.75℃で5分間静置した後に同じ温度で15分間の振盪:20%未満の活性薬剤の放出、
d.100℃で5分間静置した後に同じ温度で15分間の振盪:25%未満の活性薬剤の放出、25%未満の活性薬剤の放出、
e.40%エタノール中室温で15分間の振盪:25%未満の活性薬剤の放出。 - 5mg、10mg、20mg、30mg、40mg、60mg、80mg、120mgまたは160mgのオキシコドンからなる群から選択される量のオキシコドンを含む、請求項1に記載の処方物を含む単位用量形態。
- 一日に一回の投与に適した、請求項15に記載の単位用量形態。
- 37℃でpH1.6〜7.2の水性緩衝液900ml中、100rpmでUSPバスケット法により測定した場合に、1時間で0%から40%まで、4時間で8%から70%まで、8時間で20%から80%まで、12時間で30%から95%まで、18時間で35%から95%まで、および24時間で50%より大きい、生体外でのオキシコドン溶解率を有する、請求項16に記載の単位用量形態。
- 生体内で得られたオキシコドンの最高血漿中濃度は投与形態の投与後2時間〜17時間で発現する、請求項17に記載の単位用量形態。
- 37A単位用量形態でpH1.2の水性緩衝液(酵素なしでの模擬胃液)900ml中、100rpmでUSPバスケット法<<7 11>>装置1を用い、波長206nmでのUVを使うHPLCによる検出によって測定した場合に、1時間で10から30%まで、2時間で20から35%まで、8時間で35から75%まで、および16時間で50%より大きい、生体外でのオキシコドン溶解率を有する、請求項16に記載の単位用量形態。
- 一日に二回の投与に適した、請求項15に記載の単位用量形態。
- 37℃で水性緩衝液(pH1.6〜7.2)900ml中、100rpmでUSPパドル法(米国薬局方XXII 1990参照)により測定した場合に、1時間後に放出されたオキシコドン12.5および42.5(重量)%の間、2時間後に放出されたオキシコドン25および56(重量)%の間、4時間後に放出されたオキシコドン45および75(重量)%の間および6時間後に放出されたオキシコドン55および85(重量)%の間の生体外でのオキシコドン溶解率を有する、請求項20に記載の単位用量形態。
- 37℃でpH1.2の水性緩衝液(酵素なしでの模擬胃液)900ml中、100rpmでUSPバスケット法<<7 11>>装置1を用い、波長206nmでのUVを使うHPLCによる検出よって測定した場合に、1時間で0から40%まで、2時間で20から70%まで、3時間で40から80%まで、4時間で60から95%まで、および5時間で70%より大きい、生体外でのオキシコドン溶解率を有する、請求項20に記載の単位用量形態。
- 生体内で得られたオキシコドンの最高血漿中濃度は投与形態の投与後2および4.5時間の間で発現する、請求項22に記載の単位用量形態。
- 請求項1に記載の耐改ざん性の放出制御された製剤処方物の調製方法であって、中性ポリ(エチルアクリレート,メチルメタクリレート)共重合体、他の重合体としてアルキルセルロースまたは水不溶性メタクリル酸アンモニウム共重合体、および活性薬剤としてオピオイドを含有する混合物の溶融押出を含む、方法。
- 改ざん(タンパー)に対する耐性を提供するためのオピオイドを含む薬の製造における請求項1に記載の耐改ざん性の放出制御された製剤処方物の使用。
- 前記他の重合体は水不溶性メタクリル酸アンモニウム共重合体である、請求項1に記載の処方物。
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NZ548962A (en) | 2010-08-27 |
CA2555423C (en) | 2018-07-24 |
US20120141583A1 (en) | 2012-06-07 |
PE20091898A1 (es) | 2009-12-31 |
JP2007522196A (ja) | 2007-08-09 |
UY28744A1 (es) | 2005-08-31 |
US20170079923A1 (en) | 2017-03-23 |
AU2005215239B2 (en) | 2011-03-24 |
JP2012193186A (ja) | 2012-10-11 |
IL177313A (en) | 2014-11-30 |
NO20064094L (no) | 2006-11-10 |
TW200529888A (en) | 2005-09-16 |
BRPI0507683A8 (pt) | 2018-12-26 |
JP5746664B2 (ja) | 2015-07-08 |
EA200601468A1 (ru) | 2007-02-27 |
KR101189038B1 (ko) | 2012-10-08 |
KR20070029673A (ko) | 2007-03-14 |
BRPI0507683A (pt) | 2007-07-17 |
AU2005215239A1 (en) | 2005-09-01 |
US20150148366A1 (en) | 2015-05-28 |
WO2005079760A1 (en) | 2005-09-01 |
EP1729731A1 (en) | 2006-12-13 |
CA2555423A1 (en) | 2005-09-01 |
PE20050775A1 (es) | 2005-11-28 |
IL177313A0 (en) | 2006-12-10 |
US20180153812A1 (en) | 2018-06-07 |
US20070298103A1 (en) | 2007-12-27 |
US8920836B2 (en) | 2014-12-30 |
AR047540A1 (es) | 2006-01-25 |
TWI350762B (en) | 2011-10-21 |
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