JP6314188B2 - トファシチニブの経口持続放出剤形 - Google Patents
トファシチニブの経口持続放出剤形 Download PDFInfo
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- JP6314188B2 JP6314188B2 JP2016174293A JP2016174293A JP6314188B2 JP 6314188 B2 JP6314188 B2 JP 6314188B2 JP 2016174293 A JP2016174293 A JP 2016174293A JP 2016174293 A JP2016174293 A JP 2016174293A JP 6314188 B2 JP6314188 B2 JP 6314188B2
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- Prior art keywords
- tofacitinib
- coating
- dosage form
- water
- core
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- 239000002700 tablet coating Substances 0.000 description 1
- 229940039887 tofacitinib 5 mg Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 229940074410 trehalose Drugs 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 229940001496 tribasic sodium phosphate Drugs 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
- 235000019801 trisodium phosphate Nutrition 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 239000003232 water-soluble binding agent Substances 0.000 description 1
- 239000004207 white and yellow bees wax Substances 0.000 description 1
- 235000008939 whole milk Nutrition 0.000 description 1
- 229940039916 xeljanz Drugs 0.000 description 1
Classifications
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Description
a)制御放出成分のみ
b)遅延放出および制御放出成分
c)遅延放出および即時放出成分
一実施形態では、トファシチニブは、浸食性または非浸食性のポリマー性マトリックス錠剤に組み込まれる。浸食性マトリックスとは、純水中で浸食性または膨潤性または溶解性のいずれかである、またはポリマー性マトリックスが、浸食または溶解を引き起こすのに十分なだけイオン化するのに、酸または塩基の存在が必要になるという意味の、水性浸食性または水膨潤性または水性溶解性という意味である。水性の使用環境と接触させたとき、浸食性ポリマー性マトリックスは、吸水し、トファシチニブを閉じ込める含水膨潤ゲルまたは「マトリックス」を形成する。含水膨潤したマトリックスは、使用環境中で徐々に浸食、膨潤、崩壊、分散または溶解し、それによって、トファシチニブの使用環境への放出が制御される。そのような剤形の例は、当業界でよく知られている。たとえば、Remington:The Science and Practice of Pharmacy、第20版、2000を参照されたい。
別の実施形態では、マトリックス多粒子は、複数のトファシチニブ含有粒子を含み、各粒子は、トファシチニブと、トファシチニブの水性媒質への溶解速度を制限しうるマトリックスが形成されるように選択された1種または複数の賦形剤との混合物を含む。この実施形態に有用なマトリックス材料は、一般に、蝋、セルロース、他の水不溶性ポリマーなどの、水に不溶性の材料である。必要となれば、マトリックス材料に、結合剤または透過性改変剤として使用することのできる水溶性材料を場合により配合してもよい。こうした剤形の製造に有用なマトリックス材料としては、ヒドロキシプロピルメチルセルロースなどの結合剤が加えられているグレードの微結晶性セルロースを含めて、Avicel(FMC Corp.(ペンシルヴェニア州フィラデルフィア)の登録商標)などの微結晶性セルロース、パラフィン、変性植物油、カルナウバ蝋、硬化ヒマシ油、蜜蝋などの蝋、ならびにポリ(塩化ビニル)、ポリ(酢酸ビニル)、酢酸ビニルとエチレンのコポリマー、ポリスチレンなどの合成ポリマーが挙げられる。マトリックスに場合により配合することのできる水溶性結合剤または放出調整剤としては、水溶性ポリマー、たとえば、ヒドロキシプロピルセルロース(HPC)、ヒドロキシプロピルメチルセルロース(HPMC)、メチルセルロース、ポリ(N−ビニル−2−ピロリジノン)(PVP)、ポリ(エチレンオキシド)(PEO)、ポリ(ビニルアルコール)(PVA)、キサンタンガム、カラゲナン、ならびに他のそうした天然および合成材料が挙げられる。加えて、放出調整剤として機能する材料として、糖や塩などの水溶性材料も挙げられる。好ましい水溶性材料としては、ラクトース、スクロース、グルコース、およびマンニトール、ならびにHPC、HPMC、およびPVPが挙げられる。
別の実施形態では、トファシチニブは、浸透圧送達デバイス、または当業界で知られているとおりの「浸透圧ポンプ」に組み込まれる。浸透圧ポンプは、半透膜に取り囲まれた浸透圧的に有効な組成物を含有するコアを含む。用語「半透性」とは、この文脈では、水は、膜を介して容易に拡散しうるが、水に溶解した溶質は、水が膜を介して拡散する速度の割に、通常は膜を介して容易に拡散できないことを意味する。使用の際、水性環境に置かれたとき、デバイスは、コア組成物の浸透圧活性により、吸水する。取り囲んでいる膜が半透性の性質であるために、デバイスの中身(トファシチニブおよび任意の賦形剤を含む)は、膜の多孔質でない領域を通過することができず、浸透圧によって、剤形に予め作り込まれ、または別法として、コーティングに意図的に組み込まれた弱点が浸透圧の影響下で破裂するようなことにより胃腸管においてその場で形成された開口部または通路を通して、デバイスから押し出される。浸透圧的に有効な組成物としては、コロイド浸透圧を生じさせる水溶性の種、および水膨潤性ポリマーが挙げられる。このような剤形の例は、当業界でよく知られている。たとえば、参照として本明細書に援用される、Remington:The Science and Practice of Pharmacy、第21版、2006、第47章、950〜1頁を参照されたい。
コアは、まず、トファシチニブ含有組成物の混合物を錠剤成形機に入れ、次いで、混合物を緩やかな圧縮によって均展することにより調製する。次いで、トファシチニブ含有組成物の上部に水膨潤性組成物を載せ、圧縮して、コアの形成を完了する。別法として、錠剤成形機に最初に水膨潤性組成物を入れてから、トファシチニブ含有組成物を入れることもできる。
コアの形成に続いて、半透性コーティングを適用する。コーティングは、高い透水性および高い強度を備えながら、同時に製作および適用が容易であるべきである。高い透水性は、水を十分な体積でコアに浸入させるのに必要となる。高い強度は、コアが吸水するにつれて膨張したとき、コーティングが破裂して、コアの中身が制御されずに送達されることがないよう徹底するために必要となる。最後に、コーティングは、再現性および収率が高くなければならない。
a.実質的に水に不溶性の1種または複数のポリマーと、
b.40℃/75パーセントRHで12週間貯蔵した後、約0.01パーセントw:wより多い量の過酸化水素またはホルムアルデヒドを含有しない、1種または複数の固体水溶性ポリマー材料と
を含む、剤形を提供する。
コアは、まずトファシチニブ含有組成物の混合物を錠剤成形機に入れ、圧縮して、コアの形成を完了することにより調製する。錠剤の形状には、当業者に知られているどんな錠剤形状も含めることができる。好ましい錠剤形状として、SRC(標準丸凹形)、楕円、変形楕円、カプセル、カプレット、およびアーモンドが挙げられる。より好ましい錠剤形状として、楕円、変形楕円、カプレット、およびカプセルが挙げられる。
コアの形成に続いて、半透性コーティングを適用する。コーティングは、高い透水性および高い強度を備えながら、同時に製作および適用が容易であるべきである。高い透水性は、水を十分な体積でコアに浸入させるのに必要となる。高い強度は、コアが吸水するにつれて膨張したとき、コーティングが破裂して、コアの中身が制御されずに送達されることがないよう徹底するために必要となる。最後に、コーティングは、再現性および収率が高くなければならない。
別のクラスの本発明のトファシチニブ持続放出剤形として、膜調節またはレザバー系が挙げられる。このクラスにおいて、トファシチニブのレザバーは、律速膜に取り囲まれている。トファシチニブは、限定はしないが、膜に溶解した後、膜の向こう側へ拡散するもの、または膜内の、液体で満たされた細孔を通して拡散するものを含めて、当業界でよく知られている物質輸送機序によって膜を横断する。こうした個々のレザバー系剤形は、単一の大きなレザバーを含有する錠剤の場合でのように大きくてもよいし、または、それぞれが個々に膜でコーティングされている複数のレザバー粒子を含有するカプセル剤の場合でのように多粒子でもよい。コーティングは、多孔質ではないが、トファシチニブに対して透過性であるものでもよく(たとえば、トファシチニブは、膜から直接拡散してもよい)、または多孔質のものでもよい。本発明の他の実施形態でのように、特定の輸送機序が肝要であるとは考えられていない。
別のクラスの剤形として、トファシチニブの制御放出が始まる前に遅れが組み込まれている形態が挙げられる。一実施形態は、トファシチニブの制御放出に有用なタイプのポリマー材料からなる第一のコーティングと、剤形が摂取されたときに薬物の放出を遅らせるのに有用なタイプの第二のコーティングでコーティングされたトファシチニブを含有するコアを含む錠剤を実例として挙げることができる。第一のコーティングは、錠剤を覆って適用され、錠剤を取り囲む。第二のコーティングは、第一のコーティングを覆って適用され、これを取り囲む。
さらなる一実施形態(「破裂浸透圧コアデバイス」)では、トファシチニブが、トファシチニブと、場合により1種または複数のオスマジェントとを含有する錠剤コアまたはビーズコアを含む浸透圧破裂デバイスに組み込まれている。このタイプのデバイスは、参照により本明細書に援用される、Bakerの米国特許第3,952,741号で一般に開示されている。オスマジェントの例は、グルコース、スクロース、マンニトール、ラクトースなどの糖、塩化ナトリウム、塩化カリウム、炭酸ナトリウムなどの塩、酒石酸やフマル酸などの水溶性の酸である。トファシチニブを含有する錠剤コアまたはビーズコアは、半透膜、すなわち、水に対しては透過性であるが、トファシチニブに対しては実質的に不透過性である膜を形成するポリマーでコーティングされている。半透膜となるポリマーの例は、酢酸セルロース、酢酸酪酸セルロース、およびエチルセルロースであり、好ましくは酢酸セルロースである。別法として、半透性コーティング膜は、1種または複数の蝋、たとえば、蜜蝋などの昆虫および動物蝋、ならびにカルナウバ蝋や硬化植物油などの植物蝋から構成されたものでもよい。イソニアジド錠剤についてYoshinoが記載しているように(Capsugel Symposia Series、Current Status on Targeted Drug Delivery to the Gastrointestinal Tract、1993、185〜190頁)、ポリエチレングリコール、たとえばポリエチレングリコール−6000と、硬化油、たとえば硬化ヒマシ油の溶融混合物を、コーティングとして使用してもよい。一部の好ましい半透性コーティング材料は、セルロースエステルおよびセルロースエーテル、ポリアクリレートやポリアクリル酸エステルなどのポリアクリル酸誘導体、ならびにエチレンビニルアルコールコポリマーなどのポリビニルアルコールとポリアルケンである。他の半透性コーティング材料は、酢酸セルロースおよび酢酸酪酸セルロースである。
22mg錠剤コア
1回分量の半分のソルビトール2663.01グラム(以下の表1も参照のこと)を、28L容器に加えた。次いで、28L容器に、1回分量のコポビドン420.00グラムを加えた。次いで、28L容器に、1回分量のトファシチニブ623.98gを加えた。次いで、28L容器に、1回分量のヒドロキシセルロース560.00グラムを加えた。28L容器に、残りの1回分量の半分のソルビトール2663.01グラムを加えた。成分すべてを、容器において12+/−1RPMで15分間混和した。
1回分量の半分のソルビトール2819.01グラム(以下の表2も参照のこと)を、28L容器に加えた。次いで、28L容器に、1回分量のコポビドン420.00グラムを加えた。次いで、28L容器に、1回分量のトファシチニブ311.99gを加えた。次いで、28L容器に、1回分量のヒドロキシセルロース560.00グラムを加えた。28L容器に、残りの1回分量の半分のソルビトール2819.0グラムを加えた。成分すべてを、容器において12+/−1RPMで15分間混和した。
4.049キログラムのコーティング溶液を、次のステップに従って調製した。最初に、全396.0グラムの水(以下の表3も参照のこと)および1464.0グラムのアセトンを、5リットル容器に加え、5分間混合した。混合物に、32.4グラムのヒドロキシプロピルセルロースを加え、5分間混合した。混合物に、48.6グラムの酢酸セルロースを加え、5分間混合した。混合物に、残りの2108グラムのアセトンを加え、3時間混合した。この手順によって、2%固体(w/w)溶液が生じた。
11mg錠剤コア
1回分量の半分のソルビトール38.014キログラム(以下の表5も参照のこと)を、300L容器に加えた。次いで、300L容器に、1回分量のコポビドン6.00キログラムを加えた。次いで、300L容器に、1回分量のトファシチニブ8.914キログラムを加えた。次いで、300L容器に、1回分量のヒドロキシセルロース8.00キログラムを加えた。300L容器に、残りの1回分量の半分のソルビトール38.014キログラムを加えた。材料はすべて、真空移送システムによって加え、0.032”スクリーン、およびおよそ1400RPMで回転する丸刃インペラを備え付けたComil回転ミルに通した。成分すべてを、容器において12+/−1RPMで20分間混和する。
1回分量の半分のソルビトール33.086キログラム(以下の表6も参照のこと)を、300L容器に加えた。次いで、300L容器に、1回分量のコロイド状二酸化ケイ素1.00kgを加えた。次いで、300L容器に、1回分量のコポビドン6.00キログラムを加えた。次いで、300L容器に、1回分量のトファシチニブ8.914キログラムを加えた。次いで、300L容器に、1回分量のヒドロキシセルロース8.00キログラムを加えた。300L容器に、残りの1回分量の半分のソルビトール33.086キログラムを加えた。材料はすべて、真空移送システムによって加え、0.032”スクリーン、およびおよそ1400RPMで回転する丸刃インペラを備え付けたComil回転ミルに通した。成分すべてを、容器において12+/−1RPMで20分間混和した。
11mgおよび22mgのトファシチニブ持続放出錠剤コアを、実施例2に記載のとおりに調製した。
1回分量(以下の表11も参照のこと)1484.85gのLactose Fast Flo 316を加え、12+/−1RPMで2分間混和することにより、10L容器の金属表面を予めコーティングした。10L容器に、1回分量のトファシチニブ171.15gを加え、ラクトース一水和物中に混ぜ込んだ。トファシチニブ容器を、10L容器からのラクトース一水和物の一部ですすいだ。10L容器に、1回分量のヒプロメロース720gを加えた。成分すべてを、容器において12+/−1RPMで10分間混和した。
1回分量のトファシチニブおよびポリエチレンオキシドN80(表13も参照のこと)を、30メッシュスクリーンに通し、500cc褐色びんに加えた。混和物をTurbulaボトルブレンダーで10分間混合した。0.2グラムのステアリン酸マグネシウムを30メッシュスクリーンに通し、活性混和物のびんに加え、3分間混合した。
1回分量のポリエチレンオキシドN80(活性層)(表16も参照のこと)を30メッシュスクリーンに通した。スクリーンに残った大きい粒子を廃棄した。ポリエチレンオキシドを500cc褐色びんに加え、手作業で混和して、びんの内側をコーティングした。1回分量のトファシチニブを加え、Turbulaボトルブレンダーで10分間混合した。活性混和物のびんに1.0グラムのステアリン酸マグネシウムを加え、3分間混合した。
実施例7の製剤は、次のとおりに作製した(表19も参照のこと)。ポリエチレンオキシドN80を30メッシュスクリーンに通した。スクリーンに残った大きいポリエチレンオキシドN80粒子を廃棄した。別途、メタ重亜硫酸ナトリウムおよびブチルヒドロキシアニソールの一次粒径を、乳鉢と乳棒を使用して小さくした。4分の1回分量のポリエチレンオキシドを、1回分量のメタ重亜硫酸ナトリウムおよびブチルヒドロキシアニソールと合わせ、950cc褐色ガラスびんに加え、Turbulaボトルブレンダーで5分間混合した。950cc褐色ガラスびんに、残りのポリエチレンオキシドN80および1回分量のトファシチニブクエン酸塩を加え、Turbulaボトルブレンダーで10分間混合した。混和物を、0.8mmスクリーンサイズを使用してmini Co−milに通して、成分の混合および分布を強化した。次いで、混和物をTurbulaボトルブレンダーでさらに10分間混合した。次いで、950cc褐色ガラスびんに入った先の混合物に、1回分量のステアリン酸マグネシウムを加え、Turbulaボトルブレンダーで3分間混合した。
実施例8の製剤は、次のとおりに作製した(表22も参照のこと)。1回分量のポリエチレンオキシドN80を30メッシュスクリーンに通した。スクリーンに残った大きい粒子を廃棄した。ポリエチレンオキシドN80を500cc褐色びんに加え、手作業で混和して、びんの内側をコーティングした。1回分量のトファシチニブを加え、Turbulaボトルブレンダーで10分間混合した。活性混和物のびんに1.0グラムのステアリン酸マグネシウムを加え、3分間混合した。
実施例9は、次のように製剤する(表25も参照のこと)。1回分量のトファシチニブ、マンニトール、微結晶性セルロース、およびリン酸水素カルシウムを、30メッシュスクリーンに通し、500cc褐色びんに加える。混和物をTurbulaボトルブレンダーで10分間混合する。0.3グラムのステアリン酸マグネシウムを30メッシュスクリーンに通し、活性混和物のびんに加え、3分間混合する。
プレミックス
98.94グラムのポリエチレンオキシド(Polyox WSR N80 LEO)および1.06グラムのステアリン酸マグネシウムを、30メッシュ篩に通し、250ml褐色びんに加えた。49サイクル/分で動作するTurbulaミキサー(モデルT2F)を使用して、混和物を2分間混合した。
283.71mgのプレミックスを1ドラムガラスバイアルに加え、手作業で振盪して、ガラスバイアルの内側を予めコーティングした。32.57mgのトファシチニブクエン酸塩を20または30メッシュ篩に通し、1ドラムガラスバイアルに加えた。次いで、1ドラムガラスバイアルに、追加の283.71mgのプレミックスを加えた。次いで、ガラスバイアルの中身を、49サイクル/分で動作するTurbulaミキサー(モデルT2F)を使用して5分間混和した。次いで、混和物をNatoli単一ステーション液圧錠剤成形機に移し、5.500”B型0.3051”Modified Ball Upper Punchと4.755”B型0.3051”Flat Face Bevel Edge Lower Punchを使用して、目標厚さ15.6mmに圧縮した。
実施例10の製剤のための膨潤剤層を、次のとおりに作製した(表27も参照のこと)。1回分量のポリエチレンオキシド凝固剤グレード、青色レーキ染料、塩化ナトリウム、および微結晶性セルロースを、20または30メッシュスクリーンに通し、10リットルビンブレンダーにこの順序で加えた。ブレンダーの中身を12rpmで10分間混合した。次いで、混和物を、丸インペラおよび0.055”丸スクリーンを備えた、1000rpmで動作するComil 197Sに通した。ビンブレンダー中のほぐした混和物の中央に、1回分量のステアリン酸マグネシウムを加えた。ブレンダーの中身を12rpmで5分間混合した。次いで、混和物をKilian T−100回転錠剤成形機に移し、5.500”B型0.3051”Modified Ball Upper Punchと4.755”B型0.3051”Flat Face Bevel Edge Lower Punchを使用して、目標重量300mg、目標厚さ6.65mmに圧縮した。
25グラムのポリソルベート80を2475グラムのアセトンと合わせ、10分間または溶解するまで混合して1%(w/w)溶液を得ることにより、2.5kgのプレコーティング溶液を調製した。
活性層を、予め孔が開けられたカプセル殻の片方に挿入した。同じ方のカプセル殻に、膨潤剤層を平らな側面から挿入して、激しく膨らんで活性層にぶつかるようにした。これらの構成要素を、カプセル殻のもう片方に挿入して、カプセルを閉じた。このようにして調製し、合体させたとき、これらの構成要素では、溶解試験1に基づき、pH6.8の媒質、50rpmのパドルにおいて、以下の放出が実現された(表29)。
プレミックス
98.94グラムのポリエチレンオキシド(Polyox WSR N80 LEO)および1.06グラムのステアリン酸マグネシウムを30メッシュ篩に通し、250ml褐色びんに加えた。49サイクル/分で動作するTurbulaミキサー(モデルT2F)を使用して、混和物を2分間混合した。
283.71mgのプレミックスを1ドラムガラスバイアルに加え、手作業で振盪して、ガラスバイアルの内側を予めコーティングした。32.57mgのトファシチニブクエン酸塩を20または30メッシュ篩に通し、1ドラムガラスバイアルに加えた。次いで、1ドラムガラスバイアルに、283.71mgのプレミックスを加えた。次いで、ガラスバイアルの中身を、49サイクル/分で動作するTurbulaミキサー(モデルT2F)を使用して5分間混和した。次いで、混和物をNatoli単一ステーション液圧錠剤成形機に移し、5.500”B型0.3051”Modified Ball Upper Punchと4.755”B型0.3051”Flat Face Bevel Edge Lower Punchを使用して、目標厚さ15.6mmに圧縮した。
実施例11の製剤のための膨潤剤層を、次のとおりに作製した(表30も参照のこと)。1回分量のポリエチレンオキシド凝固剤グレード、青色レーキ染料、塩化ナトリウム、および微結晶性セルロースを、20または30メッシュスクリーンに通し、10リットルビンブレンダーにこの順序で加えた。ブレンダーの中身を12rpmで10分間混合した。次いで、混和物を、丸インペラおよび0.055”丸スクリーンを備えた、1000rpmで動作するComil 197Sに通した。ビンブレンダー中のほぐした混和物の中央に、1回分量のステアリン酸マグネシウムを加えた。ブレンダーの中身を12rpmで5分間混合した。次いで、混和物をKilian T−100回転錠剤成形機に移し、5.500”B型0.3051”Modified Ball Upper Punchと4.755”B型0.3051”Flat Face Bevel Edge Lower Punchを使用して、目標重量300mg、目標厚さ6.65mmに圧縮した。
25グラムのポリソルベート80を2475グラムのアセトンと合わせ、10分間または溶解するまで混合して1%(w/w)溶液を得ることにより、2.5kgのプレコーティング溶液を調製した。
活性層を、予め孔が開けられたカプセル殻の片方に挿入する。同じ方のカプセル殻に、膨潤剤層を平らな側面から挿入して、激しく膨らんで活性層にぶつかるようにする。これらの構成要素を、カプセル殻のもう片方に、カプセルが閉じるまで挿入する。このようにして調製し、合体させたとき、これらの構成要素では、溶解試験1に基づき、pH6.8の媒質、50rpmのパドルにおいて、以下の放出が実現される(表32)。
1回分量(以下の表33も参照のこと)963gのLactose Fast Flo 316を加え、12+/−1RPMで2分間混和することにより、10L容器の金属表面を予めコーティングした。10L容器に、1回分量のトファシチニブ164gを加え、ラクトース一水和物中に混ぜ込んだ。トファシチニブ容器を、10L容器からのラクトース一水和物の一部ですすいだ。10L容器に、1回分量のヒプロメロース1150gを加えた。成分すべてを、容器において12+/−1RPMで10分間混和した。
20mgトファシチニブの異なる2種の経口持続放出製剤の単一用量の、10mgトファシチニブ即時放出(IR)錠剤の単一用量を基準とした相対的生物学的利用能を実施し、トファシチニブについて、次の終点:Cmax、Tmax、AUCinf、AUClastを求めた。各持続放出製剤に関するトファシチニブの相対的生物学的利用能(%RBA)について、追加の終点を、IR製剤を基準として求めた。
トファシチニブ10mg即時放出対照錠剤(参照):実施例13で調製したもの
トファシチニブ20mg二層浸透圧カプセル剤:実施例10で調製したもの
トファシチニブ20mg二層浸透圧カプセル剤:実施例11で調製したもの
22mgトファシチニブの異なる3種の経口持続放出製剤の、10mgトファシチニブ即時放出(IR)錠剤の単一用量を基準とした相対的生物学的利用能を実施し、トファシチニブについて、次の終点:Cmax、Tmax、AUCinf、AUClastを求めた。各持続放出製剤に関するトファシチニブの相対的生物学的利用能(%RBA)について、追加の終点を、IR製剤を基準として求めた。
トファシチニブ5mg即時放出錠剤(参照):上記実施例14で調製したもの
トファシチニブ22mg押出性コア系錠剤:上記実施例1で調製したもの
トファシチニブ22mgマトリックス錠剤:上記実施例4および12で調製したもの
11mgトファシチニブの経口持続放出製剤の単一用量の、22mgトファシチニブ持続放出錠剤の単一用量を基準とした相対的生物学的利用能を実施し、トファシチニブについて、次の終点:Cmax、Tmax、AUCinf、AUClastを求める。11mg持続放出製剤に関するトファシチニブの用量正規化相対的生物学的利用能(%RBA)について、追加の終点を、22mg持続放出製剤を基準として求めた。
トファシチニブ22mg持続放出剤形:上記実施例1で調製したもの
トファシチニブ11mg持続放出剤形:上記実施例1で調製したもの
11mgトファシチニブ持続放出錠剤の、2個の5mgトファシチニブ即時放出(IR)錠剤の単一用量を基準とした相対的生物学的利用能を実施し、トファシチニブについて、次の終点:Cmax、Tmax、AUCinf、AUClastを求めた。各持続放出製剤に関するトファシチニブの相対的生物学的利用能(%RBA)について、追加の終点を、IR製剤を基準として求めた。
トファシチニブ5mg即時放出錠剤(参照):上記のとおり調製したもの
トファシチニブ11mg持続放出剤形:上記のとおり調製したもの
Claims (16)
- 11mgのトファシチニブまたは同量のトファシチニブを含む薬学的に許容できるその塩、およびオスマゲンを含有するコア、
およびコアを囲む半透膜コーティングを含む、前記コーティングが水不溶性ポリマーを含む、前記水不溶性ポリマーがセルロース誘導体である、
標準のUSP回転パドル装置において37℃で、0.05MのpH6.8リン酸カリウム緩衝液900mLを含む試験媒質に加え、パドルを50rpmで回転させたとき、
1時間でトファシチニブまたは薬学的に許容できるその塩の30%以下、
2.5時間でトファシチニブまたは薬学的に許容できるその塩の35%以上かつ75%以下、
5時間でトファシチニブまたは薬学的に許容できるその塩の75%以上が溶解する、
1日1回の持続放出医薬剤形。 - 前記剤形の送達系が、押出性コア系、膨潤性コア系、および非対称膜技術からなる群から選択される、請求項1に記載の医薬剤形。
- 前記セルロース誘導体が酢酸セルロースである、請求項1〜2のいずれか一項に記載の医薬剤形。
- コーティングが、平均分子量が2000〜100,000ダルトンの間である水溶性ポリマーをさらに含む、請求項1〜3のいずれか一項に記載の医薬剤形。
- 前記水溶性ポリマーが、水溶性セルロース誘導体、アカシア、デキストリン、グアーガム、マルトデキストリン、アルギン酸ナトリウム、デンプン、ポリアクリレート、およびポリビニルアルコールからなる群から選択される、請求項4に記載の医薬剤形。
- 前記水溶性セルロース誘導体が、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、またはヒドロキシエチルセルロースを含む、請求項5に記載の医薬剤形。
- オスマゲンが糖である、請求項1〜5のいずれか一項に記載の医薬剤形。
- 糖がソルビトールである、請求項7に記載の医薬剤形。
- 22mgのトファシチニブまたは同量のトファシチニブを含む薬学的に許容できるその塩、およびオスマゲンを含有するコア、
およびコアを囲む半透膜コーティングを含む、前記コーティングが水不溶性ポリマーを含む、前記水不溶性ポリマーがセルロース誘導体である、
標準のUSP回転パドル装置において37℃で、0.05MのpH6.8リン酸カリウム緩衝液900mLを含む試験媒質に加え、パドルを50rpmで回転させたとき、
1時間でトファシチニブまたは薬学的に許容できるその塩の30%以下、
2.5時間でトファシチニブまたは薬学的に許容できるその塩の35%以上かつ75%以下、
5時間でトファシチニブまたは薬学的に許容できるその塩の75%以上が溶解する、
1日1回の持続放出医薬剤形。 - 前記剤形の送達系が、押出性コア系、膨潤性コア系、および非対称膜技術からなる群から選択される、請求項9に記載の医薬剤形。
- 前記セルロース誘導体が酢酸セルロースである、請求項9〜10のいずれか一項に記載の医薬剤形。
- コーティングが、平均分子量が2000〜100,000ダルトンの間である水溶性ポリマーをさらに含む、請求項9〜11のいずれか一項に記載の医薬剤形。
- 前記水溶性ポリマーが、水溶性セルロース誘導体、アカシア、デキストリン、グアーガム、マルトデキストリン、アルギン酸ナトリウム、デンプン、ポリアクリレート、およびポリビニルアルコールからなる群から選択される、請求項12に記載の医薬剤形。
- 前記水溶性セルロース誘導体が、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、またはヒドロキシエチルセルロースを含む、請求項13に記載の医薬剤形。
- オスマゲンが糖である、請求項9〜13のいずれか一項に記載の医薬剤形。
- 糖がソルビトールである、請求項15に記載の医薬剤形。
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