JP2017522335A - Mpges−1阻害剤を含むナノ粒子製剤 - Google Patents
Mpges−1阻害剤を含むナノ粒子製剤 Download PDFInfo
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- JP2017522335A JP2017522335A JP2017504408A JP2017504408A JP2017522335A JP 2017522335 A JP2017522335 A JP 2017522335A JP 2017504408 A JP2017504408 A JP 2017504408A JP 2017504408 A JP2017504408 A JP 2017504408A JP 2017522335 A JP2017522335 A JP 2017522335A
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Classifications
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
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Abstract
Description
本特許出願は、インド特許仮出願第2472/MUM/2014号(2014年8月1日に出願)の優先権を主張するものであり、その内容は参照により本明細書に組み込まれる。
a)mPGES−1阻害剤を、1つ以上の表面安定剤、水、及び任意に他の賦形剤と混合して、水性懸濁液を形成するステップと、
b)水性懸濁液の粒径を減少させる(例えば、ビーズミルまたは高圧湿式粉砕を用いて)ステップと、
c)水性懸濁液を噴霧乾燥させるステップと、を含む。
a)例えば、ビーズミルまたは高圧湿式粉砕を用いて、化合物Iまたはその薬学的に許容される塩の粒径を減少させるステップと、
b)化合物Iまたはその薬学的に許容される塩を、表面安定剤、水、及び任意に他の賦形剤と混合して、水性懸濁液を形成するステップと、
c)水性懸濁液を噴霧乾燥させるステップと、を含む。
1.ポリマー安定剤(コポビドン及びラウリル硫酸ナトリウムなど)を水(例えば、精製水)中に溶解するステップと、
2.界面活性剤(ポロキサマーなど)を水(例えば、精製水)中に溶解し、これをステップ1の溶液に添加するステップと、
3.mPGES−1阻害剤をステップ2の溶液に添加して、懸濁液(均一懸濁液)を形成するステップと、
4.ステップ3の懸濁液を粉砕して、所望の粒径を得るステップと、
5.ステップ4の粉砕された懸濁液を篩別するステップと、
6.ステップ5の粉砕された懸濁液を噴霧乾燥させて、顆粒を得るステップと、
7.ステップ6の顆粒を、袋(例えば、三重アルミニウム積層袋)に充填するか、または任意にカプセル剤に充填するか、または任意に錠剤に圧縮するステップと、を含む。
「活性成分」という用語(「活性物質(active)」または「活性物質(active substance)」または「薬物」と交換可能に使用される)は、本明細書で使用される場合、mPGES−1阻害剤を指す。好ましくは、mPGES−1阻害剤は、以下の構造式を有するN−(4−クロロ−3−(5−オキソ−1−(4−(トリフルオロメチル)フェニル)−4,5−ジヒドロ−1H−1,2,4−トリアゾル−3−イル)ベンジル)ピバル酸アミド(以下「化合物I」)、
好適なmPGES−1阻害剤は、参照によりその全体が本明細書に組み込まれる共譲渡された国際公開第WO 2013/186692号(「‘692出願」)に開示されるものを含むが、それらに限定されない。これらのmPGES−1阻害剤は、様々な病気及び病態における疼痛及び炎症の治療に有用である。‘692出願に記載される1つの好ましいmPGES−1阻害剤は、以下の構造式を有するN−(4−クロロ−3−(5−オキソ−1−(4−(トリフルオロメチル)フェニル)−4,5−ジヒドロ−1H−1,2,4−トリアゾル−3−イル)ベンジル)ピバル酸アミド(以後「化合物I」)、
表面安定剤は、1つ以上のポリマー、1つ以上の界面活性剤、またはそれらの組み合わせであり得る。好適なポリマーは、セルロース誘導体、例えば、ヒドロキシプロピルメチルセルロース(ヒプロメロース)、ヒドロキシプロピルセルロース、メチルセルロース、カルボキシメチルセルロースナトリウムもしくはカルシウム塩、ヒドロキシルエチルセルロース、ポリビニルピロリドン、コポビドン、カーボポール、ポリビニルピロリドンのコポリマー、ポリオキシエチレンアルキルエーテル、ポリエチレングリコール、エチレンオキシド及びプロピレンオキシドのコブロックポリマー(Poloxamer(登録商標)、Pluronic(登録商標))、ポリメタクリル酸誘導体、ポリビニルアルコール、ポリビニルアルコール誘導体、ならびにポリエチレングリコール誘導体、例えば、マクロゴールグリセロールステアリン酸、天然ガム、例えば、キサンタンガム、ローカストビーンガム、アルギン酸、カラギーナン、及びアルギン酸ナトリウムを含むが、それらに限定されない。好ましいポリマーは、ポリビニルピロリドン、コポビドン、ヒドロキシプロピルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルメチルセルロース、ポリエチレングリコール、ケイ酸アルミニウムマグネシウム、セルロース誘導体、及び天然ガムを含むが、それらに限定されない。
一実施形態は、化合物N−(4−クロロ−3−(5−オキソ−1−(4−(トリフルオロメチル)フェニル)−4,5−ジヒドロ−1H−1,2,4−トリアゾル−3−イル)ベンジル)ピバル酸アミド(化合物I)またはその薬学的に許容される塩などのmPGES−1阻害剤、及び1つ以上の表面安定剤を含むナノ粒子製剤である。
本発明は、経口、肺、直腸、眼、非経口、膣内、局部(local)、口腔、鼻、または局所(topical)経路を含むがこれらに限定されない適切な経路によって投与され得るナノ粒子製剤に関する。好ましくは、本ナノ粒子製剤は、経口投与に好適である。
本ナノ粒子製剤(または本ナノ粒子製剤を含む薬学的組成物)の調製は、粉砕、微粒子化、混合、均質化、篩別、噴霧、可溶化、分散、顆粒形成、潤滑化、圧縮、被覆、及び/または充填などの様々な単位操作を含み得る。これらのプロセスは、本発明のナノ粒子製剤及び薬学的組成物を調製するために使用され得る。粒径の低減は、乾燥もしくは湿潤粉砕、微粒子化、高圧均質化、逆溶剤を使用した制御沈殿、顕微溶液化、及び/または超臨界流体技術などの様々な技術を使用して達成され得る。
a)mPGES−1阻害剤またはその薬学的に許容される塩を1つ以上の表面安定剤、水、及び任意に他の賦形剤と混合して、水性懸濁液を形成するステップと、
b)ビーズミルまたは高圧湿式粉砕を用いて、水性懸濁液の粒径を減少させるステップと、
c)水性懸濁液を噴霧乾燥させるステップと、を含む。
a)ビーズミルまたは高圧湿式粉砕によってmPGES−1阻害剤の粒径を減少させるステップと、
b)mPGES−1阻害剤を表面安定剤及び他の賦形剤と混合するステップと、
c)ナノ懸濁液を噴霧乾燥させるステップと、を含む。
1.ポリマー安定剤(コポビドン及びラウリル硫酸ナトリウムなど)を水(例えば、精製水)中に溶解するステップと、
2.界面活性剤(ポロキサマーなど)を精製水中に溶解し、これをステップ1の溶液に添加するステップと、
3.mPGES−1阻害剤をステップ2の溶液に添加して、懸濁液、好ましくは均一懸濁液を形成するステップと、
4.ステップ3の懸濁液を粉砕して、所望の粒径を得るステップと、
5.ステップ4の粉砕された懸濁液を篩別するステップと、
6.ステップ5の粉砕された懸濁液を噴霧乾燥させて、顆粒を得るステップと、
7.ステップ6の顆粒を、袋、例えば、三重アルミニウム積層袋に充填するか、または任意にカプセル剤に充填するか、または任意に錠剤に圧縮するステップと、を含む。
本発明はまた、疼痛及び/もしくは炎症、または疼痛及び/もしくは炎症に関連する病気もしくは病態(例えば、mPGES−1が媒介する病気または病態など)を、本明細書に記載されるようなナノ粒子製剤(またはナノ粒子製剤を含む薬学的組成物)を対象に投与することによって治療する方法に関する。
1.コリドン、マンニトール、及びラウリル硫酸ナトリウムを、撹拌しながら水中に溶解して、透明溶液を得た。
2.ポロキサマー407及びGelucireを温水(50±10℃)中に溶解し、この溶液を撹拌しながらステップ1に添加して、透明溶液を得た。
3.化合物Iを撹拌しながらステップ2の溶液に添加して、均一懸濁液を形成した。
4.ステップ3の懸濁液をビーズミルを用いて粉砕して、所望の粒径分布(PSD)を得た。
5.ステップ4の粉砕された懸濁液を、150番(Pot Sieve)で篩別した。
6.ステップ5の粉砕された懸濁液を、噴霧乾燥器を用いて噴霧乾燥させて、顆粒を得た。
7.ステップ6の顆粒を三重アルミニウム積層袋に充填し、袋を密閉した
8.ステップ7の袋をキャニスタ―と併せてHDPE容器に詰めた。
9.顆粒は、カプセルに充填することができるか、または錠剤に圧縮することができる。
実施例1の顆粒の初期及び24時間の保管後の粒径データを以下に提供する。
1.実施例1の顆粒の標的正味充填重量(390mg)を硬ゼラチンカプセル1号に充填した。
2.このカプセル剤をHDPE容器またはブリスターパックに詰めた。
実施例2の安定性及び溶解データ:
1.微結晶性セルロースを、40番ふるいで篩別し、好適なブレンダー内で実施例1の顆粒と混合した。
2.コロイダルシリカ及びフマル酸ステアリルナトリウムを40番ふるいで篩別し、ステップ1の混合物に添加した。
3.標的正味充填重量(450mg)を好適なカプセル内に充填した。
4.このカプセル剤をHDPE容器またはブリスターパックに詰めた。
実施例3の安定性及び溶解データ:
1.HPMC、マンニトール、及びSLSを、それらが溶解するまで連続撹拌下で精製水に添加した
2.ポロキサマー407またはビタミンE TPGSを、それが溶解されるまで撹拌下で上の溶液に添加した
3.化合物Iをステップ2の溶液に添加し、45分間撹拌した。
懸濁液の粉砕
1.懸濁液をビーズミルまたは高圧湿式粉砕に装填した
2.懸濁液を、0.2/0.1mmのジルコニウムビーズを使用して、所望の粒径分布(PSD)が得られるまで粉砕した。
ナノ懸濁液の噴霧乾燥
1.懸濁液を、45〜65℃の製品温度で噴霧乾燥させて、流動性粉末を得た。
乾式圧縮造粒
1.Ceolous KG802、コロイダル二酸化ケイ素、及び噴霧乾燥させた顆粒を混合し、AST番号30で篩別した。
2.次いで上の顆粒を、乾式圧縮造粒機を使用して圧縮造粒し、ASTM番号30で篩別した。
圧縮造粒された顆粒の潤滑、及び圧縮
1.圧縮造粒された顆粒を、Ceolous KG802、SSF、Ac−di−sol混合物と10分間混合し、錠剤に圧縮した。
この錠剤を任意にフィルム被覆する。
ナノ粒子製剤を含む錠剤を押し砕いて、粉末塊を得る。粉末塊は、Yin et al.,Journal of Pharmaceutical Sciences Vol.94 No.7,July 2005に記載される高温光学顕微鏡技術にさらに供され得る。簡潔に言うと、粉末塊をスライドガラス上に載せ、それを制御した速度(例えば、10℃/分)で加熱する。DSC及び可変温度粉末X線回折により、高温で残留する粒子が結晶性薬物粒子であることを確認する。
Claims (35)
- 化合物N−(4−クロロ−3−(5−オキソ−1−(4−(トリフルオロメチル)フェニル)−4,5−ジヒドロ−1H−1,2,4−トリアゾル−3−イル)ベンジル)ピバル酸アミド(化合物I)、またはその薬学的に許容される塩、ならびにポリマー及び界面活性剤からなる群より選択される1つ以上の表面安定剤を含む、ナノ粒子製剤。
- 化合物IがmPGES1阻害剤として機能する、請求項1に記載の製剤。
- 該製剤が約20nm〜約1000nmの範囲の有効平均粒径を有する、請求項1に記載の製剤。
- 該ナノ粒子製剤が、1つ以上の薬学的に許容される賦形剤をさらに含む、請求項1に記載の製剤。
- 表面安定剤が、ポリビニルピロリドン、コポビドン、ヒドロキシプロピルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルメチルセルロース、ポリエチレングリコール、セルロース誘導体、天然ガム、及び/またはそれらの組み合わせのうちの1つ以上から選択されるポリマーである、請求項1に記載の製剤。
- 前記化合物Iまたはその薬学的に許容される塩対前記ポリマーの重量比が、約1:0.01〜約1:100の範囲にわたる、請求項1に記載の製剤。
- 前記化合物Iまたはその薬学的に許容される塩対前記ポリマーの重量比が、約1:0.1〜約1:50の範囲にわたる、請求項1に記載の製剤。
- 表面安定剤が、ポロキサマー、ポリオキシエチレンソルビタンエステル、ポリエトキシ化ひまし油、グリセロールモノステアレート、リン脂質、塩化ベンザルコニウム、トリエタノールアミン、ラウリル硫酸ナトリウム、ドクサートナトリウム、ビタミンE TPGS、及び大豆レシチンのうちの1つ以上から選択される界面活性剤である、請求項1に記載の製剤。
- 前記化合物Iまたはその薬学的に許容される塩対前記界面活性剤の重量比が、約1:0.01〜約1:100の範囲にわたる、請求項1に記載の製剤。
- 前記化合物Iまたはその薬学的に許容される塩対前記界面活性剤の重量比が、約1:0.1〜約1:50の範囲にわたる、請求項1に記載の製剤。
- mPGES1阻害剤としての化合物N−(4−クロロ−3−(5−オキソ−1−(4−(トリフルオロメチル)フェニル)−4,5−ジヒドロ−1H−1,2,4−トリアゾル−3−イル)ベンジル)ピバル酸アミド(「化合物I」)、またはその薬学的に許容される塩、ポリマー、及び界面活性剤を含み、約20nm〜約1000nmの範囲の有効平均粒径を有する、ナノ粒子製剤。
- 前記有効平均粒径が、約50nm〜約600nmの範囲内にある、請求項1〜11のいずれか一項に記載の製剤。
- 前記有効平均粒径が、約70nm〜約500nmの範囲内にある、請求項1〜12のいずれか一項に記載の製剤。
- 前記有効平均粒径が、約80nm〜約400nmの範囲内にある、請求項1〜13のいずれか一項に記載の製剤。
- 前記ポリマーが、ポリビニルピロリドン、コポビドン、ヒドロキシプロピルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルメチルセルロース、ポリエチレングリコール、及び天然ガムのうちの1つ以上から選択される、請求項11〜14のいずれか一項に記載の製剤。
- 前記化合物Iまたはその薬学的に許容される塩対前記ポリマーの重量比が、約1:0.01〜約1:50の範囲にわたる、請求項11に記載の製剤。
- 前記化合物Iまたはその薬学的に許容される塩対前記ポリマーの重量比が、約1:0.1〜約1:10の範囲にわたる、請求項11に記載の製剤。
- 前記界面活性剤が、ポロキサマー、ポリオキシエチレンソルビタンエステル、ポリエトキシ化ひまし油、グリセロールモノステアレート、リン脂質、塩化ベンザルコニウム、トリエタノールアミン、ラウリル硫酸ナトリウム、ドクサートナトリウム、ビタミンE TPGS、及び大豆レシチンのうちの1つ以上から選択される、請求項11〜14のいずれか一項に記載の製剤。
- 前記化合物Iまたはその薬学的に許容される塩対前記界面活性剤の重量比が、約1:0.01〜約1:50の範囲にわたる、請求項11に記載の製剤。
- 前記化合物Iまたはその薬学的に許容される塩対前記界面活性剤の重量比が、約1:0.1〜約1:10の範囲にわたる、請求項11に記載の製剤。
- 化合物N−(4−クロロ−3−(5−オキソ−1−(4−(トリフルオロメチル)フェニル)−4,5−ジヒドロ−1H−1,2,4−トリアゾル−3−イル)ベンジル)ピバル酸アミド(「化合物I」)もしくは薬学的に許容される塩、マンニトール、ラウリル硫酸ナトリウム、ヒドロキシプロピルメチルセルロース、ポロキサマー、またはビタミンETPGSを含み、約70nm〜約500nmの範囲内の有効平均粒径を有する、ナノ粒子製剤
- 前記有効平均粒径が、約80nm〜約400nmの範囲内にある、請求項21に記載のナノ粒子製剤。
- 前記製剤が、分散液、液体溶液、懸濁液、半固形剤、顆粒、粉末、錠剤、またはカプセル剤の形態にある、請求項1〜22のいずれか一項に記載のナノ粒子製剤。
- 請求項1〜23のいずれか一項に記載のナノ粒子製剤、及び薬学的に許容される賦形剤を含む、薬学的組成物。
- 前記組成物が、経口投与に好適な即時放出組成物である、請求項24に記載の薬学的組成物。
- 前記組成物が、経口投与に好適な持続放出または遅延放出組成物である、請求項24に記載の薬学的組成物。
- 対象における炎症及び/または疼痛の治療での使用のための請求項24〜26のいずれか一項に記載の薬学的組成物。
- 化合物N−(4−クロロ−3−(5−オキソ−1−(4−(トリフルオロメチル)フェニル)−4,5−ジヒドロ−1H−1,2,4−トリアゾル−3−イル)ベンジル)ピバル酸アミド(「化合物I」)、またはその薬学的に許容される塩、及び1つ以上の表面安定剤を含むナノ粒子製剤の調製のためのプロセスであって、
a)前記化合物Iまたはその薬学的に許容される塩を前記表面安定剤及び他の賦形剤と混合して、混合物を形成するステップと、
b)ビーズミルまたは高圧湿式粉砕によって前記混合物の粒径を減少させるステップと、
c)ナノ懸濁液を噴霧乾燥させるステップと、を含む、プロセス。 - N−(4−クロロ−3−(5−オキソ−1−(4−(トリフルオロメチル)フェニル)−4,5−ジヒドロ−1H−1,2,4−トリアゾル−3−イル)ベンジル)ピバル酸アミド(「化合物I」)、またはその薬学的に許容される塩、及び1つ以上の表面安定剤を含むナノ粒子製剤の調製のためのプロセスであって、
a)ビーズミルまたは高圧湿式粉砕によって前記化合物Iまたはその薬学的に許容される塩の粒径を減少させるステップと、
b)該化合物Iまたはその薬学的に許容される塩を前記表面安定剤及び他の賦形剤と混合するステップと、
c)ナノ懸濁液を噴霧乾燥させるステップと、を含む、プロセス。 - 対象における炎症及び/または疼痛の治療のためのナノ粒子製剤であって、化合物N−(4−クロロ−3−(5−オキソ−1−(4−(トリフルオロメチル)フェニル)−4,5−ジヒドロ−1H−1,2,4−トリアゾル−3−イル)ベンジル)ピバル酸アミド(「化合物I」)、またはその薬学的に許容される塩、及び1つ以上の表面安定剤を含み、約20nm〜約1000nmの範囲内の有効平均粒径を有する、ナノ粒子製剤。
- 前記ナノ粒子製剤が、約30nm〜約800nm、または好ましくは約50nm〜600nmの範囲内の有効平均粒径を有する、請求項30に記載の製剤。
- 前記ナノ粒子製剤が、約70nm〜約500nm、または好ましくは約80nm〜400nmの範囲内の有効平均粒径を有する、請求項30に記載の製剤。
- 前記該製剤が、対象に1日1回、1日2回、1日3回、または1日4回投与され得る、請求項30に記載の製剤。
- 化合物IがmPGES1阻害剤として機能する、請求項30に記載の製剤。
- 前記mPGES1阻害剤が、前記対象に10mg〜500mgの用量で投与される、請求項34に記載の製剤。
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