CN1211365C - 培哚普利的新盐及含有它的药物组合物 - Google Patents
培哚普利的新盐及含有它的药物组合物 Download PDFInfo
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- CN1211365C CN1211365C CNB031071481A CN03107148A CN1211365C CN 1211365 C CN1211365 C CN 1211365C CN B031071481 A CNB031071481 A CN B031071481A CN 03107148 A CN03107148 A CN 03107148A CN 1211365 C CN1211365 C CN 1211365C
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- Prior art keywords
- perindopril
- salt
- pharmaceutical composition
- same
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Public Health (AREA)
- Hospice & Palliative Care (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Indole Compounds (AREA)
- Peptides Or Proteins (AREA)
Abstract
本发明涉及培哚普利的一种新盐和含有它的药物组合物。药物。
Description
本发明涉及培哚普利的新盐以及含有它的药物组合物。培哚普利,或(2S)-2-[(1S)-乙酯基丁基氨基]-1-氧代-丙基-(2S,3aS,7aS)全氢吲哚-羧酸,一种血管紧张素I转换酶抑制剂(CEI),是一种已知的特别是用于治疗动脉高血压和心力衰竭的化合物。
专利说明书EP0049658中早已述及培哚普利。在该欧洲专利中,与通常所提及的一样,提及本发明的化合物可以与可药用的无机或有机碱或酸形成的加成盐的形式存在。在该专利中描述的化合物为非盐形式,当以举例的方式提及与可药用碱或酸形成的加成盐时,主要给出的是钠盐或马来酸盐。
但在该产品的开发过程中已证明很难找到一种不仅具有良好的生物利用度,而且具有适合制备和贮存药物组合物的足够稳定性的可药用盐。
在最初对该产品进行的研究中,证明培哚普利的叔丁基胺盐具备满足产品开发要求的性质,而且目前市售的正是这种培哚普利的叔丁基胺盐。
已研究了培哚普利的非盐形式,并研究了其马来酸盐和钠盐。在温度和湿度的稳定性研究过程中发现:钠盐由于与大气接触后立即转化为油而不利于处理;至于其非盐形式和马来酸盐,在这些条件下迅速降解(50℃时,产物在8天内降解约25-30%)。
因此与所研究的其它形式的培哚普利相比,唯有其叔丁基胺盐显示最佳的稳定性。但由于培哚普利固有的脆性,其叔丁基胺盐并不能够提供产品对热和湿度的稳定性问题的完全解决方案。的确,培哚普利叔丁基胺盐的片剂在一些国家销售时必须用额外的包装措施保护。而且,即使在温带气候国家,其不稳定性已使得其片剂不可能获得超过两年的贮存期限。最后,对片剂的销售而言,不得不印上“贮存温度在30℃或30℃以下”。
这些限制尤其在组织和费用方面当然麻烦,看来为减少叔丁基胺盐的限制条件,尝试开发一种新的培哚普利的盐尤其有用。
研究了众多盐类,如上文中所示,证明不能使用药学领域通常使用的盐。
另一方面,令人惊奇的是,已发现培哚普利的精氨酸盐,除了是新的外,较所有其它已研究的盐,尤其是较培哚普利的叔丁基胺盐,还具备完全意想不到的优点。
本发明因此涉及培哚普利的精氨酸盐、其水合物以及包含它的药物组合物。
培哚普利的精氨酸盐优选地为其天然精氨酸(L-精氨酸)的盐。
本发明的药物组合物因而包含培哚普利的精氨酸盐以及一种或多种无毒的、可药用的适当赋形剂。
在本发明的药物组合物当中,尤其可提及那些适于经口施用、肠胃外施用或经鼻施用的片剂或糖衣丸、舌下片、胶囊、糖锭、栓剂、霜剂、软膏剂、皮肤凝胶等。
本发明的药物组合物优选地为速释片。
有效剂量依病人的年龄和体重、疾病的性质和严重程度、以及施用途径(可为经口、鼻、直肠或肠胃外施用)而变化。
本发明的药物组合物中含有的精氨酸盐的量为0.2至10mg,优选1至10mg。这些药物组合物用于高血压和心力衰竭的治疗。
这种盐的基本特性为:与叔丁基胺盐相比,这种盐对热和湿度有非常好的稳定性。
在非常精确的温度和湿度条件下进行的长期稳定性研究得出如下表所示的结果。
在那项研究中,用反相高压液相色谱法,以含有庚磺酸钠且pH为2的水相和乙腈(67/33)为洗脱液测定培哚普利。用紫外法于215nm波长处进行产品的检测。
用含有2.4mg培哚普利精氨酸盐或2.0mg培哚普利叔丁基胺盐的速释片(两种片剂各自含有1.7mg培哚普利)进行研究,在开始贮存于不同温度和不同相对湿度(%R.H.)下六个月后对片剂进行分析。
这项研究中所用的精氨酸盐为L-精氨酸盐。它是按照有机化学的成盐的传统方法制备而得。
条件六个月 | 培哚普利叔丁基胺盐剩余百分含量(%) | 培哚普利精氨酸盐剩余百分含量(%) |
25℃ 60%R.H. | 101.0 | 99.5 |
30℃ 60%R.H. | 94.4 | 98.1 |
40℃ 75%R.H. | 67.2 | 98.6 |
上表所示结果非常清楚地显示出精氨酸盐相比叔丁基胺盐而言,前者具有非常好的稳定性。的确,六个月后,精氨酸盐几乎没有发生降解而叔丁基胺盐的降解率接近33%。
这些结果完全意想不到,而且不可能由有关本品的文献介绍推断或由它们暗示而得。
这些结果允许我们在有关药物组合物的包装方面较少考虑那些麻烦的限制条件,而且也能为我们的药物组合物获得至少三年的贮存期限。
Claims (5)
1.培哚普利的精氨酸盐及其水合物。
2.药物组合物,其包含作为活性成分的培哚普利精氨酸盐及其水合物,并包含一种或多种可药用赋形剂。
3.根据权利要求2的药物组合物,其特征在于它以速释片的形式存在。
4.根据权利要求2或权利要求3的药物组合物,其特征在于它含有0.2至10mg的培哚普利精氨酸盐。
5.根据权利要求2至4中任意一项所述的药物组合物在制备用于治疗高血压和心力衰竭的药物中的用途。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0204847 | 2002-04-18 | ||
FR0204847A FR2838648B1 (fr) | 2002-04-18 | 2002-04-18 | Nouveau sel de perindopril et les compositions pharmaceutiques qui le contiennent |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1451656A CN1451656A (zh) | 2003-10-29 |
CN1211365C true CN1211365C (zh) | 2005-07-20 |
Family
ID=8871521
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB031071481A Expired - Lifetime CN1211365C (zh) | 2002-04-18 | 2003-03-07 | 培哚普利的新盐及含有它的药物组合物 |
Country Status (38)
Country | Link |
---|---|
US (1) | US6696481B2 (zh) |
EP (1) | EP1354873B1 (zh) |
JP (1) | JP3737488B2 (zh) |
KR (1) | KR100542468B1 (zh) |
CN (1) | CN1211365C (zh) |
AP (1) | AP1787A (zh) |
AR (1) | AR039428A1 (zh) |
AT (1) | ATE271036T1 (zh) |
AU (2) | AU2003222921A1 (zh) |
BR (1) | BR0300709A (zh) |
CA (1) | CA2423825C (zh) |
CR (1) | CR7576A (zh) |
DE (1) | DE60300011T2 (zh) |
DK (1) | DK1354873T3 (zh) |
EA (1) | EA005676B1 (zh) |
EC (1) | ECSP045441A (zh) |
ES (1) | ES2224092T3 (zh) |
FR (1) | FR2838648B1 (zh) |
GE (1) | GEP20074211B (zh) |
HK (1) | HK1057367A1 (zh) |
HR (1) | HRP20041079B1 (zh) |
IL (1) | IL164424A (zh) |
IS (1) | IS2842B (zh) |
MA (1) | MA27115A1 (zh) |
ME (1) | ME00454B (zh) |
MX (1) | MXPA03002346A (zh) |
NO (1) | NO324323B1 (zh) |
NZ (1) | NZ524478A (zh) |
OA (1) | OA12806A (zh) |
PL (1) | PL359321A1 (zh) |
PT (1) | PT1354873E (zh) |
RS (1) | RS51694B (zh) |
SI (1) | SI1354873T1 (zh) |
TN (1) | TNSN04206A1 (zh) |
TR (1) | TR200401793T4 (zh) |
UA (1) | UA79463C2 (zh) |
WO (1) | WO2003087050A2 (zh) |
ZA (1) | ZA200301395B (zh) |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2395195A (en) * | 2002-11-18 | 2004-05-19 | Cipla Ltd | Preparation of perindopril from carboxy-protected precursor, & perindopril monohydrates for use as angiotensin converting enzyme (ACE) inhibitors |
PT1729739T (pt) | 2004-03-29 | 2016-12-01 | Servier Lab | Processo para a preparação de uma composição farmacêutica sólida |
SI21800A (sl) | 2004-05-14 | 2005-12-31 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Nov postopek sinteze perindoprila |
DE602005009918D1 (de) * | 2005-01-06 | 2008-11-06 | Ipca Lab Ltd | Verfahren zur Synthese von (2S,3aS,7aS)-1-(S)-Alanyl-octahydro-1H-2-carbonsäurederivaten und Verwendung in der Synthese von Perindopril |
US7728151B2 (en) * | 2005-03-14 | 2010-06-01 | Lupin Limited | Process for the purification of perindopril |
FR2894825B1 (fr) * | 2005-12-21 | 2010-12-03 | Servier Lab | Nouvelle association d'un inhibiteur du courant if sinusal et d'un inhibiteur de l'enzyme de conversion et les compositions pharmaceutiques qui la contiennent |
FR2897866B1 (fr) * | 2006-02-28 | 2008-04-18 | Servier Lab | Forme cristalline alpha du sel d'arginine du perindopril, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
FR2897865B1 (fr) * | 2006-02-28 | 2008-04-18 | Servier Lab | Forme cristalline beta du sel d'arginine du perindopril, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
GB0624087D0 (en) * | 2006-12-01 | 2007-01-10 | Selamine Ltd | Ramipril combination salt |
GB0624084D0 (en) * | 2006-12-01 | 2007-01-10 | Selamine Ltd | Ramipril amino acid salts |
GB0624090D0 (en) * | 2006-12-01 | 2007-01-10 | Selamine Ltd | Ramipril amine salts |
SI22542A (sl) * | 2007-06-04 | 2008-12-31 | Diagen D.O.O. | Stabilna formulacija amorfnih soli perindoprila, postopek za njeno pripravo v industrijskem merilu in njena uporaba za zdravljenje hipertenzije |
EP2682388B1 (en) | 2008-06-24 | 2018-01-10 | Mylan Laboratories Limited | Novel polymorphic forms of perindopril (l)-arginine and process for the preparation thereof |
AU2009212902A1 (en) * | 2008-09-03 | 2010-03-18 | Apotex Pharmachem Inc. | Amorphous form of an L-arginine salt of perindopril and processes of preparation thereof |
CN101766598A (zh) * | 2008-12-31 | 2010-07-07 | 东英(江苏)药业有限公司 | 含有培哚普利的药物组合物 |
GB0910692D0 (en) | 2009-06-20 | 2009-08-05 | Teva Pharma | Compound |
SI23149A (sl) | 2009-09-21 | 2011-03-31 | Silverstone Pharma | Nove benzatinske soli ACE inhibitorjev, postopek za njihovo pripravo in njihova uporaba za zdravljenje kardiovaskularnih bolezni |
FR2961105B1 (fr) * | 2010-06-15 | 2013-02-08 | Servier Lab | Utilisation de l'association d'un inhibiteur du courant if sinusal et d'un inhibiteur de l'enzyme de conversion de l'angiotensine pour le traitement de l'insuffisance cardiaque |
FR2985511B1 (fr) * | 2012-01-05 | 2014-01-03 | Servier Lab | Forme cristalline delta du sel d'arginine du perindopril, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
FR2985512B1 (fr) * | 2012-01-05 | 2014-06-20 | Servier Lab | Procede de preparation du sel de l-arginine du perindopril |
CN103172696B (zh) * | 2012-12-19 | 2014-12-17 | 宁波美诺华药业股份有限公司 | 一种γ晶型的培哚普利精氨酸盐的制备方法 |
FR3040303B1 (fr) * | 2015-08-27 | 2019-04-05 | Les Laboratoires Servier Suivi Par Sabine Goudeau-Wenger | Composition pharmaceutique comprenant un inhibiteur de la hmg-coa reductase et un inhibiteur eca |
FR3050380B1 (fr) | 2016-04-20 | 2020-07-10 | Les Laboratoires Servier | Composition pharmaceutique comprenant un betabloquant, un inhibiteur de l'enzyme de conversion et un antihypertenseur ou un ains. |
EP3842035A1 (en) | 2019-12-23 | 2021-06-30 | KRKA, d.d., Novo mesto | Composition for the preparation of perindopril arginine granules, a method for their preparation and pharmaceutical composition comprising the granules |
SI26268A (sl) | 2021-11-18 | 2023-05-31 | Zupet Rok | Postopek za pripravo hidratirane oblike perindopril l-arginina |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2503155A2 (fr) * | 1980-10-02 | 1982-10-08 | Science Union & Cie | Nouveaux imino diacides substitues, leurs procedes de preparation et leur emploi comme inhibiteur d'enzyme |
FR2811320B1 (fr) * | 2000-07-06 | 2002-08-23 | Adir | Nouvelle forme cristalline alpha du sel de tert-butylamine du perindopril, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
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2002
- 2002-04-18 FR FR0204847A patent/FR2838648B1/fr not_active Expired - Lifetime
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2003
- 2003-02-17 AP APAP/P/2004/003154A patent/AP1787A/en active
- 2003-02-17 DK DK03290383T patent/DK1354873T3/da active
- 2003-02-17 AT AT03290383T patent/ATE271036T1/de active
- 2003-02-17 EP EP03290383A patent/EP1354873B1/fr not_active Expired - Lifetime
- 2003-02-17 AU AU2003222921A patent/AU2003222921A1/en not_active Abandoned
- 2003-02-17 DE DE60300011T patent/DE60300011T2/de not_active Expired - Lifetime
- 2003-02-17 TR TR2004/01793T patent/TR200401793T4/xx unknown
- 2003-02-17 ME MEP-2008-688A patent/ME00454B/me unknown
- 2003-02-17 ES ES03290383T patent/ES2224092T3/es not_active Expired - Lifetime
- 2003-02-17 GE GEAP8501A patent/GEP20074211B/en unknown
- 2003-02-17 OA OA1200400279A patent/OA12806A/en unknown
- 2003-02-17 RS YU90904A patent/RS51694B/en unknown
- 2003-02-17 WO PCT/FR2003/000507 patent/WO2003087050A2/fr active Application Filing
- 2003-02-17 SI SI200330002T patent/SI1354873T1/xx unknown
- 2003-02-17 PT PT03290383T patent/PT1354873E/pt unknown
- 2003-02-17 UA UA20041109440A patent/UA79463C2/uk unknown
- 2003-02-20 ZA ZA200301395A patent/ZA200301395B/xx unknown
- 2003-02-21 US US10/371,865 patent/US6696481B2/en not_active Expired - Lifetime
- 2003-02-24 NO NO20030849A patent/NO324323B1/no not_active IP Right Cessation
- 2003-02-27 AU AU2003200700A patent/AU2003200700C1/en not_active Revoked
- 2003-02-28 NZ NZ524478A patent/NZ524478A/en not_active IP Right Cessation
- 2003-03-07 CN CNB031071481A patent/CN1211365C/zh not_active Expired - Lifetime
- 2003-03-18 MX MXPA03002346A patent/MXPA03002346A/es active IP Right Grant
- 2003-03-20 KR KR1020030017434A patent/KR100542468B1/ko active IP Right Grant
- 2003-03-21 BR BR0300709-0A patent/BR0300709A/pt not_active Application Discontinuation
- 2003-03-24 PL PL03359321A patent/PL359321A1/xx not_active Application Discontinuation
- 2003-03-25 JP JP2003083250A patent/JP3737488B2/ja not_active Expired - Lifetime
- 2003-04-03 CA CA002423825A patent/CA2423825C/fr not_active Expired - Fee Related
- 2003-04-03 EA EA200300334A patent/EA005676B1/ru unknown
- 2003-04-16 AR ARP030101332A patent/AR039428A1/es not_active Application Discontinuation
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2004
- 2004-01-10 HK HK04100189A patent/HK1057367A1/xx not_active IP Right Cessation
- 2004-10-05 IL IL164424A patent/IL164424A/en active IP Right Grant
- 2004-10-15 TN TNP2004000206A patent/TNSN04206A1/en unknown
- 2004-10-27 IS IS7516A patent/IS2842B/is unknown
- 2004-11-03 MA MA27926A patent/MA27115A1/fr unknown
- 2004-11-17 HR HRP20041079AA patent/HRP20041079B1/hr not_active IP Right Cessation
- 2004-11-18 EC EC2004005441A patent/ECSP045441A/es unknown
- 2004-11-18 CR CR7576A patent/CR7576A/es unknown
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