JP6612234B2 - Cgrp受容体アンタゴニストのための製剤 - Google Patents
Cgrp受容体アンタゴニストのための製剤 Download PDFInfo
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- JP6612234B2 JP6612234B2 JP2016542091A JP2016542091A JP6612234B2 JP 6612234 B2 JP6612234 B2 JP 6612234B2 JP 2016542091 A JP2016542091 A JP 2016542091A JP 2016542091 A JP2016542091 A JP 2016542091A JP 6612234 B2 JP6612234 B2 JP 6612234B2
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Classifications
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- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A—HUMAN NECESSITIES
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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Description
(i)連続撹拌によって均一な溶液が形成されるまで、室温で、またはより高温(約40℃)で、水溶性界面活性剤を親水性担体に溶解する工程;
(ii)追加の賦形剤(例えば、香味剤)を工程(i)の溶液に溶解する工程;
(iii)水溶性賦形剤(例えば、抗核形成ポリマー、甘味料、香味剤)を水に溶解する工程;
(iv)連続撹拌によって、工程(iii)の溶液を工程(ii)の溶液と混合する工程;
(v)均一な溶液が形成されるまで、連続撹拌によって、室温または40℃で、(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−カルボキサミド三水和物を工程(iv)の溶液に溶解する工程;
(vi)1つ以上の賦形剤を工程(v)の溶液に溶解する工程
を含む方法を含む。
[実施例1]
(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−カルボキサミド三水和物(化合物I)を有する経口液体製剤
1)VitE−TPGS(4mm未満の小片として)をプロピレングリコールに加え、ガラス瓶中でその混合物を約40℃に加温する(撹拌棒および磁石撹拌器/ヒーターを使用)。
イヌにおける(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−カルボキサミド三水和物(化合物I)経口液体製剤の薬物動態
曝露に対する溶液容量の効果を評価するために、イヌにおいて、2つの製剤を試験した;各溶液は、同じ用量の化合物Iを有していたが、溶液の容量は異なっていた。(少量の液体溶液の嚥下をシミュレートするために)シリンジによって、経口溶液製剤をイヌの喉の奥に送達した。経口溶液製剤と共に洗浄処理を行わなかった。この溶液について、0.75mLの高薬物濃度溶液および1.5mLの低薬物濃度溶液を使用した。PEG参照溶液については、10mgの用量を20mLのビヒクルに与え、その後に15mLの水を与える。
希釈した際の人工唾液中における(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−カルボキサミド三水和物(化合物I)の調製
pH6.2の人工唾液を用いて、化合物I経口液体製剤のサンプルを1:1または1:4の比で希釈した。人工唾液は、KH2PO4(12mM)、NaCl(40mM)、CaCl2(1.5mM)およびpH6.2にするためのNaOHを含む(参考文献:Ritschel and Thomson,Methods and findings in Experimental and Clinical Pharmacology,%,511−525,1983)。400RPMの磁気撹拌を使用した。希釈時の潜在的な沈殿速度を決定するために、サンプルを様々な時点で採取した。5分の時点では、0.45μmフィルタによる遠心ろ過を使用し、より長い時点では、1μmろ過および超遠心分離(80kRPM、25℃、15分、9/9の加速度/減速度)を使用した。分析標準濃度(0.1mg/mL)に合わせるために、50/50のACN/水でサンプルを希釈し、HPLCで分析した。使用したLC条件は、以下のとおりである:65%の0.1%H3PO4/35%のACNのアイソクラティック法、Chromolith SpeedROD RP−18e 50×4.6mmカラム、UV210nm、カラム温度40℃、流速3mL/分および注入量10uL。
(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−カルボキサミド三水和物(化合物I)経口液体製剤の粘度
粘度を測定するために、TRIOSソフトウェアを備え、TA Instruments ARES G2 strainによって制御されたレオメーターを使用した。サンプルの粘度が低いため、二重壁構造を使用した。すべての液体は、5〜20s−1の間のニュートン性であると思われる。等温保持時間には5分を選択したが、これは、等値に達すると考えられた。以下に示されるように、試験した3つの製剤はすべて、低粘度(<0.065)を示した。
Claims (17)
- 液体医薬組成物の約0.01重量%〜3.0重量%の量で存在する(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−カルボキサミドまたはその薬学的に許容される塩と、親水性担体ならびにVitE−TPGS、ポロキサマー、Tween20、Tween80またはSpan20およびそれらの2種以上の組み合わせからなる群より選択される少なくとも1つの水溶性界面活性剤を含む薬学的に許容される担体とを含む、液体医薬組成物であって、前記薬学的に許容される担体の容量が10mL未満である、液体医薬組成物。
- (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−カルボキサミド三水和物を含む、請求項1に記載の液体医薬組成物。
- 前記親水性担体が、水、グリコール、またはそれらの組み合わせを含む、請求項1に記載の液体医薬組成物。
- 前記薬学的に許容される担体が、更にグリコールエステルを含む、請求項1に記載の液体医薬組成物。
- グリコールが、プロピレングリコール、PEG−400、グリセロールおよびそれらの混合物からなる群より選択される、請求項3に記載の液体医薬組成物。
- グリコールエステルが、トリアセチン、クエン酸トリエチルおよびそれらの混合物からなる群より選択される、請求項4に記載の液体医薬組成物。
- 前記水溶性界面活性剤が、VitE−TPGS、ポロキサマー、ポロキサマーとTween20、ポロキサマーとTween80、ポロキサマーとSpan20、VitE−TPGSとTween20、VitE−TPGSとTween80およびVitE−TPGSとSpan20からなる群より選択される、請求項1に記載の液体医薬組成物。
- 前記水溶性界面活性剤が、前記組成物の約0.1重量%〜15.0重量%の量で存在する、請求項1に記載の液体医薬組成物。
- 前記水溶性界面活性剤が、前記組成物の2.5重量%〜10重量%の量で存在する、請求項8に記載の液体医薬組成物。
- 前記水溶性界面活性剤がVitE−TPGSまたはポロキサマーである、請求項9に記載の液体医薬組成物。
- (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−カルボキサミドまたはその塩が、前記組成物の0.25重量%〜2.0重量%の量で存在する、請求項1に記載の液体医薬組成物。
- 前記薬学的に許容される担体の容量が5mL未満である、請求項1に記載の液体医薬組成物。
- 抗核形成ポリマー、抗酸化剤、キレート剤、酸味剤、塩化ナトリウム、着色剤、甘味料および香味料からなる群より選択される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に記載の液体医薬組成物。
- プロピレングリコール、PEG−400、水、VitE−TPGS、ポビドン、スクラロース、メントールおよびミントまたはペパーミントフレーバーを含む、請求項1に記載の液体医薬組成物。
- 酸味剤をさらに含む、請求項14に記載の液体医薬組成物。
- 片頭痛を治療するための、請求項1に記載の液体医薬組成物。
- 片頭痛を治療するための、請求項12に記載の液体医薬組成物。
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PCT/US2014/055132 WO2015038736A2 (en) | 2013-09-16 | 2014-09-11 | Formulations for cgrp receptor antagonists |
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CN112022818A (zh) | 2014-02-05 | 2020-12-04 | 默沙东公司 | Cgrp-活性化合物的片剂制剂 |
US20210128724A1 (en) * | 2019-07-05 | 2021-05-06 | Allergan Pharmaceuticals International Limited | Cgrp antagonists and clostridial derivatives for the treatment of cortical spreading depression associated disorders |
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US7390798B2 (en) * | 2004-09-13 | 2008-06-24 | Merck & Co., Inc. | Carboxamide spirolactam CGRP receptor antagonists |
WO2008030524A2 (en) * | 2006-09-08 | 2008-03-13 | Merck & Co., Inc. | Liquid pharmaceutical formulations for oral administration of a cgrp antagonist |
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IL244356B (en) | 2020-09-30 |
NZ717327A (en) | 2021-10-29 |
BR112016005589A8 (pt) | 2018-02-06 |
KR20220108207A (ko) | 2022-08-02 |
CN112545981A (zh) | 2021-03-26 |
US20210330660A1 (en) | 2021-10-28 |
WO2015038736A3 (en) | 2015-11-12 |
RU2690006C2 (ru) | 2019-05-30 |
RU2016114537A (ru) | 2017-10-23 |
KR20210153745A (ko) | 2021-12-17 |
MX2016003394A (es) | 2016-10-28 |
CN105531275B (zh) | 2020-12-18 |
BR112016005589B8 (pt) | 2023-04-18 |
EP3915561A1 (en) | 2021-12-01 |
BR112016005589B1 (pt) | 2022-12-06 |
SA516370737B1 (ar) | 2021-05-27 |
CA2923426A1 (en) | 2015-03-19 |
KR20160055149A (ko) | 2016-05-17 |
IL244356A0 (en) | 2016-04-21 |
US20190070161A1 (en) | 2019-03-07 |
EP3046923A2 (en) | 2016-07-27 |
RU2016114537A3 (ja) | 2018-07-04 |
WO2015038736A2 (en) | 2015-03-19 |
JP2016530316A (ja) | 2016-09-29 |
AU2014318741B2 (en) | 2018-12-06 |
KR102337994B1 (ko) | 2021-12-13 |
CN105531275A (zh) | 2016-04-27 |
EP3046923A4 (en) | 2017-03-22 |
US20160220552A1 (en) | 2016-08-04 |
AU2014318741A1 (en) | 2016-03-10 |
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