JP5415771B2 - 新規なエポプロステノール製剤およびその製造方法 - Google Patents
新規なエポプロステノール製剤およびその製造方法 Download PDFInfo
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- JP5415771B2 JP5415771B2 JP2008553381A JP2008553381A JP5415771B2 JP 5415771 B2 JP5415771 B2 JP 5415771B2 JP 2008553381 A JP2008553381 A JP 2008553381A JP 2008553381 A JP2008553381 A JP 2008553381A JP 5415771 B2 JP5415771 B2 JP 5415771B2
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- JP
- Japan
- Prior art keywords
- solution
- epoprostenol
- diluent
- arginine
- sodium
- 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.)
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- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 title 1
- LMHIPJMTZHDKEW-XQYLJSSYSA-M Epoprostenol sodium Chemical compound [Na+].O1\C(=C/CCCC([O-])=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 LMHIPJMTZHDKEW-XQYLJSSYSA-M 0.000 claims description 102
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- 239000004475 Arginine Substances 0.000 claims description 32
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- 238000000034 method Methods 0.000 claims description 28
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Description
1. 約0.5〜0.7℃/分の速度で約−30℃以下に棚を冷却させ、約30〜45分間にわたりまたは生成物の温度が約−25℃以下に達するまで棚をこの温度に保持する工程。
2. 生成物の温度が約−38±2℃以下に達するまで棚温度を約−45℃±2℃以下に低下させる工程。
3. 約6時間以上にわたり生成物をこの温度に保持する工程。
4. チャンバー圧力が50ミリトール以下の領域に達するまで真空を適用する工程。
5. 真空適用後も約45分間以上にわたり棚温度を約−45±2℃に保持する工程。
1. 真空下に保持しながら約20±2℃/時の加熱速度で約0℃±2℃に棚温度を上昇させ、生成物温度が約−3±2℃以上に達するまで乾燥を継続する工程。
2. 真空下に保持しながら約25±2℃に棚温度を上昇させて乾燥サイクルを継続し、生成物の温度が約20±2℃以上に達するまで乾燥を継続する工程。
現在市販されているエポプロステノールの一形態(フローラン)の安定性を理解するために、本発明者らは、凍結乾燥されたエポプロステノール入りバイアルおよび希釈剤を、Physician’s Desk Reference(PDR)に記載の組成に従って調製した。注射用フローランは、静脈内(IV)投与に供すべく製剤化された滅菌ナトリウム塩である。凍結乾燥されたフローラン入りバイアルはそれぞれ、0.5mgまたは1.5mgのエポプロステノールと等価なエポプロステノールナトリウム、3.76mgのグリシン、2.93mgの塩化ナトリウム、および50mgのマンニトールを含む。pHを調整するために水酸化ナトリウムが添加されていることもある。本発明者らは、この処方を用いてフローラン模擬製品を作製した。
エポプロステノールと50mg/mlのアルギニンとを含む溶液を調製し、5℃におけるこの溶液の安定性を調べた。得られたデータを表4に示す。
次の一連の実験では、エポプロステノールおよびアルギニンを含む溶液のpHを水酸化ナトリウムで13.0に調整し、凍結乾燥させた。1mlの注射用水で凍結乾燥物を再構成した後、再構成溶液は、50mg/mlのアルギニンおよび0.5mg/mlのエポプロステノールを含む。溶液のpHは13.0である。安定性データを5℃については表6に、29℃については以下の表7に示す。
次の開発段階で、本発明者らは、凍結乾燥用のバルク溶液のpHを10.5〜13.0に調整して異なる賦形剤の存在下でいくつかの凍結乾燥製剤をスクリーニングした。試験製剤の組成を表8に詳細に示し、安定性データを以下の表9にまとめる。
1. 1バイアルあたりエポプロステノール(0.5mg)/アルギニン(50mg)/マンニトール(50mg)/pH13を含むものを3バッチ
2. 1バイアルあたりエポプロステノール(0.5mg)/アルギニン(50mg)/マンニトール(50mg)/pH12を含むものを1バッチ
3. 1バイアルあたりエポプロステノール(0.5mg)/アルギニン(50mg)/トレハロース(50mg)/pH13を含むものを2バッチ
4. 1バイアルあたりエポプロステノール(0.5mg)/アルギニン(50mg)/トレハロース(50mg)/pH12を含むものを1バッチ
5. pH12および13に調整されたフローラン組成物を含むものを1バッチずつ。
これらの各バッチの湿分含有率は、7〜10%の範囲内であった。
本発明に係る製剤が室温におけるIV注入に適しているかを調べるために、希釈試験をも行った。種々の大量非経口溶液剤中において24時間にわたる注入時の温度を模倣すべく25℃および30℃で安定性試験を行った。
乳酸加リンゲル液中における希釈安定性についても調べ、以下の表29〜30に示した。
Claims (26)
- (a)(i)エポプロステノールまたはその塩と(ii)アルギニンとを含むバルク溶液を提供する工程と、
(b)前記バルク溶液のpHを13以上に調整する工程と、
を含み、
前記工程(b)が、水酸化ナトリウムおよび水酸化カリウムの少なくとも1種を添加することにより達成される、エポプロステノール組成物の製造方法。 - (c)前記バルク溶液を凍結乾燥させる工程をさらに含む、請求項1に記載の方法。
- 工程(c)が凍結サイクルとそれに続く一次乾燥サイクルおよび二次乾燥サイクルとを含む、請求項2に記載の方法。
- 前記凍結サイクルが、
(i)凍結乾燥チャンバー内の棚上に前記バルク溶液を配置する工程と、
(ii)約0.5〜0.7℃/分の速度で−30℃以下に前記棚を冷却させる工程と、
(iii)30〜45分間にわたりまたは前記バルク溶液の温度が−25℃以下に達するまで−30℃以下に保持する工程と、
(iv)前記バルク溶液の温度が−38±2℃に達するまで前記棚の温度を−45±2℃に低下させる工程と、
(v)前記バルク溶液を6時間以上にわたり−38±2℃に保持する工程と、
(vi)前記チャンバーの圧力が50ミリトール以下に達するまで真空を適用する工程と、
(vii)真空適用後45分間以上にわたり前記棚の温度を−45±2℃に保持する工程と、
を含む、請求項3に記載の方法。 - 前記一次乾燥サイクルが、
(i)毎時20±2℃の加熱速度で0±2℃に前記棚の温度を上昇させ、生成物の温度が−3±2℃以上に達するまで真空下で乾燥を継続する工程と、
(ii)25±2℃に前記棚の温度を上昇させ、前記生成物の温度が20℃以上に達するまで乾燥を継続する工程と、
を含む、請求項3に記載の方法。 - 前記二次乾燥サイクルが、
(i)3±2℃/時の速度で45±2℃に前記棚の温度を上昇させ、前記生成物の温度が38±2℃以上に達するまで乾燥を継続する工程と、
(ii)前記チャンバーの圧力を窒素で増加させながら真空を解除する工程と、
(iii)前記チャンバーの圧力が大気圧に達した場合、窒素ブリーディングを中断し、窒素雰囲気下に前記組成物を閉じ込める工程と、
を含む、請求項3に記載の方法。 - エポプロステノールまたはその塩とアルギニンとの比が1:25〜1:200である、請求項1に記載の方法。
- 前記バルク溶液が増量剤をさらに含む、請求項1に記載の方法。
- 前記増量剤が、ヒドロキシルエチルデンプン(HES)、ソルビトール、ラクトース、デキストラン、マルトース、マンノース、リボース、スクロース、マンニトール、トレハロース、ラクトース、デキストラン、シクロデキストリン、グリシン、およびポリビニルピロリジン(PVP)からなる群から選択される、請求項8に記載の方法。
- 前記増量剤が1〜10%の割合で存在する、請求項8に記載の方法。
- 前記塩がエポプロステノールナトリウムである、請求項1に記載の方法。
- (d)第1の希釈剤で前記バルク溶液を希釈する工程、をさらに含む、請求項1に記載の方法。
- 前記工程(d)において、希釈された前記バルク溶液を第2の希釈剤で希釈することをさらに含む、請求項12に記載の方法。
- 前記第2の希釈剤は、生理食塩水または乳酸加リンゲル液である、請求項13に記載の方法。
- (a)エポプロステノールまたはその塩と、(b)アルギニンと、(c)水と、水酸化ナトリウムおよび水酸化カリウムの少なくとも1種と、を含み、13超のpHを有する、安定な溶液。
- エポプロステノールナトリウムとアルギニンとの比が1:25〜1:200である、請求項15に記載の溶液。
- 増量剤をさらに含む、請求項15に記載の溶液。
- 前記増量剤が、ヒドロキシルエチルデンプン(HES)、ソルビトール、ラクトース、デキストラン、マルトース、マンノース、リボース、スクロース、マンニトール、トレハロース、ラクトース、デキストラン、シクロデキストリン、グリシン、およびポリビニルピロリジン(PVP)からなる群から選択される、請求項17に記載の溶液。
- 前記増量剤が1〜10%の割合で存在する、請求項17に記載の溶液。
- 前記塩がエポプロステノールナトリウムである、請求項15に記載の溶液。
- アテローム硬化症、動脈硬化症、鬱血性心不全、狭心症、および高血圧症からなる群から選択される疾患の治療用の薬剤を製造するための、請求項15に記載の溶液の、使用。
- 再構成溶液を形成するために、第1の希釈剤で前記溶液を再構成することをさらに含む、請求項21に記載の使用。
- 前記第1の希釈剤が、注射用水、0.9%塩化ナトリウム溶液、乳酸加リンゲル液、リンゲル液、炭酸ナトリウム溶液、または重炭酸塩溶液である、請求項22に記載の使用。
- 希釈溶液を形成するために第2の希釈剤で前記再構成溶液を希釈することをさらに含む、請求項22に記載の使用。
- 前記希釈溶液が血液適合性である、請求項24に記載の使用。
- 前記再構成溶液が自己保存される、請求項22に記載の使用。
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CN101410119B (zh) | 2006-02-03 | 2012-03-07 | 埃科特莱茵单一股份公司 | 依前列醇制剂及其制备方法 |
CA2698721A1 (en) * | 2007-09-07 | 2009-03-12 | United Therapeutics Corporation | Buffer solutions having selective bactericidal activity against gram negative bacteria and methods of using same |
PL2461812T3 (pl) * | 2009-08-07 | 2014-12-31 | Scipharm Sarl | Kompozycja do leczenia mukowiscydozy |
CN101669904B (zh) * | 2009-09-29 | 2011-06-22 | 北京中海康医药科技发展有限公司 | 一种依前列醇脂质纳米粒及制备方法 |
US20120321728A1 (en) * | 2011-06-15 | 2012-12-20 | Ven Subbiah | Nutritional formula for managing angina pectoris |
JP5917034B2 (ja) * | 2011-07-15 | 2016-05-11 | ニプロ株式会社 | カルシウムブロッカーを含有する固形医薬組成物 |
CN103585119A (zh) * | 2013-11-13 | 2014-02-19 | 北京泰德制药股份有限公司 | 一种包含依前列醇及其药用盐的稳定化制剂及其制备方法 |
ITMI20142149A1 (it) * | 2014-12-16 | 2016-06-16 | L I A Di Giuseppe Capasso | Apparato di diagnosi differenziale in medicina adattato per determinare la sequenza di test ottimale atta ad identificare una patologia secondo criteri di appropriatezza diagnostica |
HU231031B1 (hu) * | 2016-03-23 | 2019-12-30 | CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. | Megnövelt stabilitású epoprostenol nátrium és eljárás előállítására |
MX2019006938A (es) | 2016-12-14 | 2019-09-06 | Respira Therapeutics Inc | Metodos y composiciones para trataminto de hipertension pulmonar y otros trastornos del pulmon. |
CN109330982A (zh) * | 2018-09-13 | 2019-02-15 | 常州市第四制药厂有限公司 | 依前列醇冻干粉及其制备方法 |
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GB2021581B (en) | 1978-05-17 | 1982-10-20 | Wellcome Found | Stabilisation of pgl derivatives |
ZA787353B (en) * | 1978-05-17 | 1980-08-27 | Wellcome Found | Pharmaceutical formulations |
US7230014B1 (en) * | 1997-10-14 | 2007-06-12 | Eisai Co., Ltd. | Pharmaceutical formulation comprising glycine as a stabilizer |
US6803386B2 (en) * | 2002-01-16 | 2004-10-12 | United Therapeutics Corporation | Prostacyclin derivative containing compositions and methods of using the same for the treatment of cancer |
DE10225551A1 (de) * | 2002-06-06 | 2003-12-24 | Schering Ag | Verwendung von oral verfügbaren Prostacyclinderivaten für die Herstellung eines Arzneimittels zur Behandlung von Krankheiten, die mit Knochenmarködemen assoziiert sind |
EP1720519A1 (en) | 2004-03-04 | 2006-11-15 | Wyeth | Lyophilization method to improve excipient crystallization |
CN101410119B (zh) | 2006-02-03 | 2012-03-07 | 埃科特莱茵单一股份公司 | 依前列醇制剂及其制备方法 |
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US8598227B2 (en) | 2013-12-03 |
WO2007092343A2 (en) | 2007-08-16 |
CA2868998A1 (en) | 2007-08-16 |
CN101410119B (zh) | 2012-03-07 |
KR20090004867A (ko) | 2009-01-12 |
DK1993557T3 (en) | 2015-12-07 |
EP1993557A4 (en) | 2012-07-25 |
US20130018093A1 (en) | 2013-01-17 |
CA2641393C (en) | 2014-12-16 |
HUE026166T2 (en) | 2016-05-30 |
WO2007092343A3 (en) | 2008-01-17 |
BRPI0707488B8 (pt) | 2021-05-25 |
SI1993557T1 (sl) | 2016-01-29 |
BRPI0707488B1 (pt) | 2020-05-26 |
CA2641393A1 (en) | 2007-08-16 |
EP1993557A2 (en) | 2008-11-26 |
US8318802B2 (en) | 2012-11-27 |
JP2009525344A (ja) | 2009-07-09 |
CN101410119A (zh) | 2009-04-15 |
US20090088468A1 (en) | 2009-04-02 |
ES2558705T3 (es) | 2016-02-08 |
PT1993557E (pt) | 2016-02-10 |
BRPI0707488A2 (pt) | 2011-05-03 |
EP1993557B1 (en) | 2015-11-11 |
KR101351668B1 (ko) | 2014-01-14 |
PL1993557T3 (pl) | 2016-05-31 |
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