JP2017505306A - Cgrp活性化合物の錠剤製剤 - Google Patents
Cgrp活性化合物の錠剤製剤 Download PDFInfo
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- JP2017505306A JP2017505306A JP2016548023A JP2016548023A JP2017505306A JP 2017505306 A JP2017505306 A JP 2017505306A JP 2016548023 A JP2016548023 A JP 2016548023A JP 2016548023 A JP2016548023 A JP 2016548023A JP 2017505306 A JP2017505306 A JP 2017505306A
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Classifications
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Abstract
Description
(式中、「Ra」は様々な置換基である(例えば、式中、「Ra」は水素:(S)−N−((3S,5S,6R)−6−メチル−2−オキソ−5−フェニル−1−(2,2,2−トリフルオロエチル)ピペリジン−3−イル)−2’−オキソ−1’,2’,5,7−テトラヒドロスピロ[シクロペンタ[b]ピリジン−6,3’−ピロロ[2,3−b]ピリジン]−3−カルボキサミドであり、例えば、式中、「Ra」の3つはフッ素:(S)−N−((3S,5S,6R)−6−メチル−2−オキソ−1−(2,2,2−トリフルオロエチル)−5−(2,3,6−トリフルオロフェニル)ピペリジン−3−イル)−2’−オキソ−1’,2’,5,7−テトラヒドロスピロ[シクロペンタ[b]ピリジン−6,3’−ピロロ[2,3−b]ピリジン]−3−カルボキサミドとなるように選択される)。これらの化合物は、副作用および代謝性合併症の可能性が低い、忍容性が良好な強力なCGRPアンタゴニストとして有望である。しかし、これらの化合物は可溶性が低く、一般的に、安定な医薬製剤の調製に適した塩を形成しない。
押出物と、
(b)崩壊系と
を含む錠剤であって、
ここで、前記錠剤が約12kPから約18kPの硬度を有し、そして、37℃の水性HCl(pH1.8)を用いたUSP 31−NF26 第701章に準拠する標準的な錠剤崩壊試験において、前記錠剤が約5分未満で完全な崩壊を達成する、錠剤を提供する。
(a)(i)約210ミクロン未満のd50値、(ii)約50ミクロン未満のd10値、および(iii)約470ミクロン未満のd90値により特徴付けられる粉末塩化ナトリウムと、
(b)クロスカルメロースナトリウムと
を含む崩壊系を含み、
ここで、前記粉末塩化ナトリウムおよび前記クロスカルメロースナトリウムが1:1重量比で存在し、錠剤中に存在する押出物の量が、錠剤中に分散された約9wt.%から約10wt.%の式Iの化合物を提供するように選択される。
(式中、「Rb」はそれぞれ−Hであり、または「Rb」はそれぞれ−Fである)。
a)水溶性ポリビニルピロリドン/酢酸ビニルコポリマー(PVP−VAコポリマー)マトリックスと、その中に分散された:
(i)式Iaの活性化合物、またはその薬学的に許容可能な塩:
(式中、Rbの全ては−H、またはRbの全ては−Fのどちらかである)と、
(ii)トセフェロールポリエチレングリコールスクシネート(TPGS)と
を含む押出物であって、前記式Iaの化合物が前記押出物の約5wt%から約23wt.%を構成し、TPGSが前記押出物の少なくとも約5wt.%を構成する押出物と、
b)(i)クロスカルメロースナトリウムと、(ii)粉末塩化ナトリウムとを含む崩壊系であって、
前記崩壊系が前記製剤の約20wt.%を構成し、前記製剤が約12kPから約18kP、好ましくは約12kPから約16kPの硬度を有する錠剤を提供することをさらに特徴とし、37℃の模擬胃液(pH1.8)900ml中、50rpmで運転されるUSP 2パドルを備えたパドル撹拌装置で、USP 30 NF25 第711章に準拠する溶解試験に供されるとき、錠剤がその中に含有された式Iaの化合物の少なくとも約90%を約20分未満で放出する崩壊系と
を含む製剤を提供する。
1つの態様において本発明は、約12kPから約16kP、およびいくつかの実施形態において12kPから約18kPの硬度を有するように製剤がひとたび加圧成形されると、その中に含有されたAPIの90%超を約20分未満で放出する錠剤を提供する(U.S.Department of Health and Human Services,Food and Drug Administration,Center for Drug Evaluation and Researchにより1997年8月に刊行された「Guidance for Industry,Dissolution Testing of Immediate Release Solid Oral Dosage Forms」、1〜13頁、およびその中の錠剤硬度が上回る参考文献に概説された手順に従って、900mlの模擬胃液(pH1.8)、37℃中、50rpmで運転されるUSP 2パドルを備えた標準的溶解装置での溶解試験に供される場合)量で、本発明の押出物、粉末塩化ナトリウムおよびクロスカルメロースナトリウムを含む崩壊系、ならびに他の賦形剤、例えば、希釈剤、流動化剤および滑沢剤を含む錠剤の調製に適合した製剤を提供する。
[実施例I]
Kollidon(登録商標)64、TPGSおよび(S)−N−((3S,5S,6R)−6−メチル−2−オキソ−5−フェニル−1−(2,2,2−トリフルオロエチル)ピペリジン−3−イル)−2’−オキソ−1’,2’,5,7−テトラヒドロスピロ[シクロペンタ[b]ピリジン−6,3’−ピロロ[2,3−b]ピリジン]−3−カルボキサミド(FIa−H)を含む押出物、打錠製剤ならびにそこから調製された錠剤の調製:
図2に関して、水溶性ポリマーマトリックスおよびその中に分散されたAPIを含む押出物は、
(i)1:3.75のAPI:マトリックスポリマーの重量比を有する予混合物を提供する、結晶性FIa−Hおよびポリビニルピロリドン/酢酸ビニルコポリマー(マトリックスポリマー)の量を乾式混合して、FIa−H/マトリックスポリマー予混合物を形成すること、
(ii)API予混合物:TPGS、19:1の重量比を提供するAPI/マトリックス予混合物の量および溶融アルファ−トコフェロール/ポリエチレングリコールスクシネート(TPGS)の量を、押出機に入れること、ならびに
(iii)約20wt%の活性APIを含むマトリックス(ポリビニルピロリドン−酢酸ビニルコポリマー/TPGS)中にAPIの固溶体を含む押出物を提供するバレル温度、送り速度およびスクリュー回転速度に押出機装置を維持すること
により調製した。
Kollidon(登録商標)64、TPGSおよび(S)−N−((3S,5S,6R)−6−メチル−2−オキソ−1−(2,2,2−トリフルオロエチル)−5−(2,3,6−トリフルオロフェニル)ピペリジン−3−イル)−2’−オキソ−1’,2’,5,7−テトラヒドロスピロ[シクロペンタ[b]ピリジン−6,3’−ピロロ[2,3−b]ピリジン]−3−カルボキサミド)(FIa−F))を含む押出物、打錠製剤ならびにそこから調製された錠剤の調製:
実施例Iに示された一般的な調製を用いて、1.421KgのFIa−F(全ての「Rb」が−Fである式Iaの化合物)を、25.0L Fielder Granulator、「速」に設定したインペラ速度、「高」に設定したチョッパー速度で4.320Kgのマトリックスポリマーと混合した。インペラおよびチョッパー速度を維持しながら、造粒機に0.300KgのTPGSを5分にわたって添加した。この混合材料を158℃の産物温度、20g/分の粉末送り速度、および2〜4バールに維持したダイ圧力を提供するように設定したThermo−Fisher 16mm押出機で熱溶融押し出しし、4.52Kgの押出物を得た。
Claims (21)
- 前記押出物中の前記ポリマーマトリックスが水溶性ポリビニルピロリドン/酢酸ビニル(PVP−VA)コポリマーである、請求項1の錠剤。
- 前記崩壊系が、粉末塩化ナトリウムおよびクロスカルメロースナトリウムを含む、請求項1の錠剤。
- 前記崩壊系が、1:1重量比の粉末塩化ナトリウムおよびクロスカルメロースナトリウムを含む、請求項2の錠剤。
- 前記錠剤が約12kPから約18kPの硬度を有し、そして、前記錠剤が、37℃の模擬胃液(pH1.8)900ml中、50rpmで運転されるUSP 2パドルを備えたパドル撹拌装置で、USP 30 NF25 第711章に準拠する溶解試験に供されるとき、前記錠剤中に含有された前記式Iの化合物の少なくとも約90%を約20分未満で放出する、請求項2の錠剤。
- 前記錠剤が1.75MPaの引張強度を有し、そして、前記錠剤が、37℃の模擬胃液(pH1.8)900ml中、50rpmで運転されるUSP 2パドルを備えたパドル撹拌装置で、USP 30 NF25 第711章に準拠する溶解試験に供されるとき、前記錠剤中に含有された前記式Iの化合物の少なくとも約90%を約20分未満で放出する、請求項2の錠剤。
- 前記押出物中の前記分散剤が、d−アルファ−トコフェリルポリエチレングリコールスクシネート(TPGS)である、請求項1から7のいずれかの錠剤。
- (a)マンニトールと、(b)コロイダルシリカと、(c)微結晶セルロースと、(d)フマル酸ステアリルナトリウムとをさらに含む、請求項1から8のいずれかの錠剤。
- 前記APIが、(S)−N−((3S,5S,6R)−6−メチル−2−オキソ−1−(2,2,2−トリフルオロエチル)−5−(2,3,6−トリフルオロフェニル)ピペリジン−3−イル)−2’−オキソ−1’,2’,5,7−テトラヒドロスピロ[シクロペンタ[b]ピリジン−6,3’−ピロロ[2,3−b]ピリジン]−3−カルボキサミドである、請求項8または請求項9の錠剤。
- 前記APIが、(S)−N−((3S,5S,6R)−6−メチル−2−オキソ−5−フェニル−1−(2,2,2−トリフルオロエチル)ピペリジン−3−イル)−2’−オキソ−1’,2’,5,7−テトラヒドロスピロ[シクロペンタ[b]ピリジン−6,3’−ピロロ[2,3−b]ピリジン]−3−カルボキサミドである、請求項8または請求項9の錠剤。
- 前記押出物が前記錠剤の約50wt.%を構成し、前記押出物が約5wt.%から約23wt.%の式Iの化合物で構成される、請求項1から12のいずれかの錠剤。
- 前記粉末塩化ナトリウムが、(i)約210ミクロン未満のd50値、(ii)約50ミクロン未満のd10値、および(iii)約470ミクロン未満のd90値を有する、請求項1から12のいずれかの錠剤。
- 前記押出物の前記水溶性ポリマーマトリックスが、約6:4のポリビニルピロリドン/酢酸ビニルモノマー単位比を有するコポリマーである、請求項1から11のいずれかの錠剤。
- 錠剤に加圧成形するのに適した製剤であって、
a)水溶性ポリビニルピロリドン/酢酸ビニルコポリマー(PVP−VAコポリマー)マトリックスと、その中に分散された:
(i)式Iaの活性化合物、またはその薬学的に許容可能な塩:
(式中、Rbの全ては−H、またはRbの全ては−Fのどちらかであり、
式中、Raは独立して−Hまたは−Fである)と、
(ii)トセフェロールポリエチレングリコールスクシネート(TPGS)と
を含む押出物組成物であって、
前記式Iaの化合物が前記押出物の約5wt%から約23wt.%を構成し、TPGSが前記押出物の少なくとも約5wt.%を構成する押出物組成物と、
b)(i)クロスカルメロースナトリウムと、(ii)粉末塩化ナトリウムとを含む崩壊系と
を含む前記製剤であって、
前記崩壊系が前記製剤の約20wt.%を構成する、前記製剤。 - (a)マンニトールと、(b)コロイダルシリカと、(c)微結晶セルロースと、(d)フマル酸ステアリルナトリウムとをさらに含み、前記粉末塩化ナトリウムが、(i)約210ミクロン未満のd50値、(ii)約50ミクロン未満のd10値、および(iii)約470ミクロン未満のd90値により特徴付けられる、請求項16の製剤。
- 式Iaの化合物:粉末塩化ナトリウム:クロスカルメロースナトリウムの重量比が9:10:10である、請求項16または請求項17の製剤。
- 前記式Iaの化合物が、(S)−N−((3S,5S,6R)−6−メチル−2−オキソ−1−(2,2,2−トリフルオロエチル)−5−(2,3,6−トリフルオロフェニル)ピペリジン−3−イル)−2’−オキソ−1’,2’,5,7−テトラヒドロスピロ[シクロペンタ[b]ピリジン−6,3’−ピロロ[2,3−b]ピリジン]−3−カルボキサミド、または(S)−N−((3S,5S,6R)−6−メチル−2−オキソ−5−フェニル−1−(2,2,2−トリフルオロエチル)ピペリジン−3−イル)−2’−オキソ−1’,2’,5,7−テトラヒドロスピロ[シクロペンタ[b]ピリジン−6,3’−ピロロ[2,3−b]ピリジン]−3−カルボキサミドである、請求項16から18のいずれかの製剤。
- 前記押出物が、前記製剤の約50wt.%を提供する量で存在する、請求項16から19のいずれかの製剤。
- 約175MPaの引張強度を有する錠剤を提供するために、請求項16から20のいずれかの製剤をタブレット成形機で加圧成形して作られる錠剤。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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CN105126111A (zh) * | 2015-09-30 | 2015-12-09 | 清华大学 | 提高索拉非尼生物利用度的制剂 |
MX2020009856A (es) * | 2018-03-25 | 2020-10-08 | Biohaven Pharm Holding Co Ltd | Rimegepant para trastornos relacionados con el peptido relacionado con el gen para calcitonina (cgrp). |
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