CN1165309C - 含有左西孟旦和藻酸的稳定组合物 - Google Patents
含有左西孟旦和藻酸的稳定组合物 Download PDFInfo
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- CN1165309C CN1165309C CNB998053805A CN99805380A CN1165309C CN 1165309 C CN1165309 C CN 1165309C CN B998053805 A CNB998053805 A CN B998053805A CN 99805380 A CN99805380 A CN 99805380A CN 1165309 C CN1165309 C CN 1165309C
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- levosimendan
- alginic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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- 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
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- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
本发明涉及左西孟旦的药物组合物，其中包含藻酸以改善组合物中左西孟旦的稳定性。左西孟旦可用于治疗充血性心力衰竭。
Description
技术领域
本发明涉及含有左西孟旦，即[[4-(1，4，5，6-四氢-4-甲基-6-氧代-3-哒嗪基)苯基]亚肼基]丙二腈的(-)对映体作为活性组分、具有改进稳定性的药物组合物、尤其是口服药物组合物。左西孟旦可用于治疗充血性心力衰竭。
背景技术
EP 565546 B1中描述了左西孟旦，即[[4-(1，4，5，6-四氢-4-甲基-6-氧代-3-哒嗪基)苯基]亚肼基]丙二腈的(-)对映体及其制备方法。左西孟旦能有效地治疗心力衰竭，并且对肌钙蛋白有显著的钙依赖性结合。左西孟旦由式I代表：
Sundberg，S.等人在《美国心脏病学杂志》(Am.J.Cardiol.)，1995；75：1061-1066中描述了左西孟旦的血液动力学作用。Sandell，E.-P等人在《心血管药理杂志》(J.Cardiovasc.Pharmacol.)，26(Suppl.1)，S57-S62，1995中描述了左西孟旦静脉内给药和口服后在人体内的药代动力学。WO 93/21921中描述了左西孟旦在治疗心肌缺血中的应用。临床实验已经证实了左西孟旦在心力衰竭患者中的有益作用。
人们已经证明了难以制备左西孟旦的药物组合物、尤其是口服药物组合物。当与常规赋形剂混合时，左西孟旦表现出很差的稳定性，并且在贮存条件下易于降解。因此，需要活性组分在贮存条件下表现出改善的稳定性的左西孟旦药物制剂。
发明简述
出乎意料的是，我们发现藻酸能显著地改善左西孟旦在药物组合物中的稳定性。
因此，本发明提供了包含藻酸作为稳定改进剂、具有改进稳定性的左西孟旦药物组合物、尤其是口服药物组合物。
发明详述
本发明药物组合物通常含有占组合物重量约0.1-99％的藻酸。更一般的是，本发明药物组合物含有占组合物重量约5-70％、优选约10-40％的藻酸。
本发明组合物一般是口服组合物。这类组合物包括例如片剂、糖锭剂、胶囊剂、粉剂和颗粒剂形式的固体组合物。活性化合物在本发明组合物中的含量通常为占组合物重量的约0.01-100％、优选为0.1-20％、最优选为0.5-10％。根据患者的年龄、体重和身体状况，通常将左西孟旦以约0.1-10mg、优选0.5-5mg的剂量对患者给药，每天给药1次或数次。
除了左西孟旦和藻酸以外，本发明组合物还可包含可药用载体和赋形剂。可药用载体和赋形剂包括依据标准制药实践使用的、可与活性组分配伍的载体和赋形剂。对于口服片剂，合适的载体和赋形剂包括微晶纤维素例如Avicel PH101、乳糖、玉米淀粉、硬脂酸镁、硬脂酸、磷酸钙和滑石。对于口服胶囊剂，适用的载体和赋形剂包括微晶纤维素、乳糖、玉米淀粉、硬脂酸镁、硬脂酸和滑石。胶囊剂可通过将活性组分与载体和赋形剂混合、并将所得粉状混合物置于胶囊例如硬明胶胶囊中而制得。片剂可通过将活性组分与载体和赋形剂混合、并将所得粉状混合物压制成片而制得。
可将本发明组合物设计成迅速释放活性组分或以控制/延长方式释放活性组分的剂型。长效组合物一般是这样制得的：将药物、释放控制剂和可能的赋形剂混合，并将所得混合物压制成基体片，或者用释放控制包衣材料将活性组分核包衣，以获得包衣片剂或粒剂。常用的释放控制剂包括亲水性凝胶形成聚合物，例如以不同类型市购获得的羟丙基甲基纤维素，例如Methocel K100LV(分子量为26000g/摩尔)、MethocelK4M(分子量为86000g/摩尔)、Methocel K15M(分子量为120000g/摩尔)和Methocel K100M。这些等级的羟丙基甲基纤维素在2％水溶液(20℃)中的粘度分别为100cP、4000cP、15000cP和100000cP。
下述实施例是为了进一步举例说明本发明，而不是对本发明的限制。
实施例1：在贮存条件下比较本发明制剂(1和2)与参照制剂(1-4)的稳定性。
制剂1(硬明胶胶囊剂)：
左西孟旦 2mg
Methocel K100LV 46mg
藻酸 23mg
Avicel PH101 69.5mg
硬脂酸 1.5mg
制剂2(压制片)：
左西孟旦∶藻酸1∶10
参照制剂1(硬明胶胶囊剂)：
左西孟旦 2mg
Methocel K4M 35mg
Avicel PH101 101.6mg
硬脂酸 1.4mg
参照制剂2(硬明胶胶囊剂)：
左西孟旦 2mg
乳糖 197mg
硬脂酸镁 1mg
参照制剂3(压制片)：
左西孟旦∶乳糖1∶100
参照制剂4(压制片)：
左西孟旦∶硬脂酸镁1∶1
由颗粒部分和粉末部分组成的制剂1是如下所述制得的：将Methocel K100LV、藻酸和左西孟旦(1mg)在适当混合器例如Turbula混合器或Zanchetta容器混合器中混合直至均匀。通过击块法将所得混合物干法制粒(用制片机压缩)。将该压缩物过筛，收集0.7-1.7mm的颗粒。对于粉末部分，将Avicel PH101与左西孟旦(1mg)过筛，并在适当混合器例如Turbula混合器或Zanchetta容器混合器中混合直至均匀。在适当混合器例如Turbula混合器或Zanchetta容器混合器中将颗粒部分与粉末部分以及硬脂酸混合直至均匀。将所得混合物装入no 3型硬明胶胶囊中。
在参照制剂1和2中，材料是粉末形式。这些制剂是如下所述制得的：在适当混合器例如Turbula混合器或Zanchetta容器混合器中将各组分混合直至均匀。然后将所得混合物装入no 3型硬明胶胶囊中。
制剂2和参照制剂3与4是如下所述制得的：在适当混合器例如Turbula混合器或Zanchetta容器混合器中将各组分混合直至均匀。然后用常规制片机将所得混合物压制成片。
通过测定贮存后左西孟旦降解产物在制剂中的水平来评价制剂在贮存条件下的稳定性。结果如表1所示。
表1：贮存后本发明制剂(1-2)和参照制剂(1-4)中左西孟旦降解产物(OR-1420和OR-1368)的存在量。Rh＝相对湿度。
| 贮存条件 | 形成的OR-1420 | 形成的OR-1368 | 未知降解产物的量 | |
| 制剂1 | 9个月2-8℃ | 0 | 0 | 0 |
| 制剂2 | 8个月25℃，rh60％ | 0 | 0 | 0 |
| 参照制剂1 | 9个月2-8℃ | 0.25％ | 0.25％ | 1，0.05％ |
| 参照制剂2 | 3个月25℃，rh60％ | 1.32％ | 0.07％ | 5，0.54％ |
| 参照制剂3 | 3个月25℃，rh60％ | 0.75％ | 0.23％ | 10，0.93％ |
| 参照制剂4 | 7周25℃ | 0 | 0 | 1，1.0％ |
表1表明，如贮存8-9个月后没有任何左西孟旦降解产物所证实的那样，藻酸显著地改善了左西孟旦在贮存条件下的稳定性。相反，不含有藻酸的参照制剂表现出了左西孟旦降解产物的显著形成。
Claims (5)
1.含有左西孟旦作为活性组分和藻酸作为稳定改善剂的药物组合物，其中藻酸的含量为占组合物重量的5-99％，左西孟旦的含量占组合物重量的0.1-20％。
2.权利要求1的组合物，其中藻酸的含量为占组合物重量的5-70％。
3.权利要求2的组合物，其中藻酸的含量为占组合物重量的10-40％。
4.权利要求1-3任一项的组合物，其中所述组合物是口服组合物。
5.权利要求4的组合物，其中所述组合物是片剂、糖锭剂、胶囊剂、粉剂或颗粒剂。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI980902 | 1998-04-23 | ||
| FI980902A FI980902A (fi) | 1998-04-23 | 1998-04-23 | Levosimendaanin stabiileja koostumuksia |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1298303A CN1298303A (zh) | 2001-06-06 |
| CN1165309C true CN1165309C (zh) | 2004-09-08 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB998053805A Expired - Fee Related CN1165309C (zh) | 1998-04-23 | 1999-04-23 | 含有左西孟旦和藻酸的稳定组合物 |
Country Status (33)
| Country | Link |
|---|---|
| US (1) | US6531458B1 (zh) |
| EP (1) | EP1079834B1 (zh) |
| JP (1) | JP4475809B2 (zh) |
| KR (1) | KR100590622B1 (zh) |
| CN (1) | CN1165309C (zh) |
| AT (1) | ATE231395T1 (zh) |
| AU (1) | AU756338B2 (zh) |
| BG (1) | BG64766B1 (zh) |
| BR (1) | BR9909867A (zh) |
| CA (1) | CA2329232C (zh) |
| CZ (1) | CZ290911B6 (zh) |
| DE (1) | DE69905034T2 (zh) |
| DK (1) | DK1079834T3 (zh) |
| EA (1) | EA002428B1 (zh) |
| EE (1) | EE04143B1 (zh) |
| ES (1) | ES2191426T3 (zh) |
| FI (1) | FI980902A (zh) |
| GE (1) | GEP20032942B (zh) |
| HK (1) | HK1031998A1 (zh) |
| HR (1) | HRP20000703B1 (zh) |
| HU (1) | HUP0105446A3 (zh) |
| ID (1) | ID26650A (zh) |
| IL (2) | IL138950A0 (zh) |
| MX (1) | MXPA00010368A (zh) |
| NO (1) | NO318575B1 (zh) |
| NZ (1) | NZ507455A (zh) |
| PL (1) | PL192274B1 (zh) |
| PT (1) | PT1079834E (zh) |
| RS (1) | RS49955B (zh) |
| SK (1) | SK284600B6 (zh) |
| TR (1) | TR200003101T2 (zh) |
| WO (1) | WO1999055337A1 (zh) |
| ZA (1) | ZA200005630B (zh) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI980901A (fi) * | 1998-04-23 | 1999-10-24 | Orion Yhtymae Oyj | Levosimendaania säädellysti vapauttavia oraalisia koostumuksia |
| FI109659B (fi) * | 1999-09-10 | 2002-09-30 | Orion Yhtymae Oyj | Levosimendaanin farmaseuttisia liuoksia |
| FI20010233A0 (fi) * | 2001-02-08 | 2001-02-08 | Orion Corp | Menetelmä sydämen vajaatoiminnan hoitoon |
| WO2002064120A1 (fr) * | 2001-02-13 | 2002-08-22 | Taisho Pharmaceutical Co., Ltd. | Preparations de gel a usage interne |
| US20080194567A1 (en) * | 2005-03-14 | 2008-08-14 | Piero Pollesello | Combination Treatment for Enhancing Diuresis |
| JP2023507626A (ja) | 2019-12-16 | 2023-02-24 | テナックス・セラピューティクス，インコーポレイテッド | 駆出率が保たれた心不全を伴う肺高血圧症（ＰＨ－ＨＦ－ｐＥＦ）を治療するためのレボシメンダン |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1509866A (en) | 1975-06-10 | 1978-05-04 | Johnson & Johnson | Enteric coated digestive enzyme compositions |
| AU555304B2 (en) * | 1982-04-05 | 1986-09-18 | Merck Sharp & Dohme Limited | Stabilization of drugs in alginic acid and magnesium hydroxide granules |
| EP0123291A2 (en) | 1983-04-20 | 1984-10-31 | Kyowa Hakko Kogyo Co., Ltd. | Method for stabilizing interferon |
| US4906630A (en) * | 1985-11-22 | 1990-03-06 | Rorer Pharmaceutical Corporation | Method of increasing cardiac contractility using pharmaceutical compositions comprising benzodiazinone- pyridazinone or hydroxy-pyrazolyl compounds |
| US4716042A (en) * | 1986-06-16 | 1987-12-29 | American Home Products Corporation | Stabilized coated aspirin tablets |
| GB8903130D0 (en) | 1989-02-11 | 1989-03-30 | Orion Yhtymae Oy | Substituted pyridazinones |
| GB2251615B (en) * | 1991-01-03 | 1995-02-08 | Orion Yhtymae Oy | (-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]pro panedinitrile |
| GB2266841A (en) | 1992-05-06 | 1993-11-17 | Orion Yhtymae Oy | Compounds for use as anti-ischemic medicaments |
| GB9614098D0 (en) | 1996-07-05 | 1996-09-04 | Orion Yhtymae Oy | Transdermal delivery of levosimendan |
| FI973804A (fi) * | 1997-09-26 | 1999-03-27 | Orion Yhtymae Oy | Levosimendaanin oraalisia koostumuksia |
-
1998
- 1998-04-23 FI FI980902A patent/FI980902A/fi unknown
-
1999
- 1999-04-23 US US09/673,793 patent/US6531458B1/en not_active Expired - Fee Related
- 1999-04-23 KR KR1020007011789A patent/KR100590622B1/ko not_active IP Right Cessation
- 1999-04-23 IL IL13895099A patent/IL138950A0/xx active IP Right Grant
- 1999-04-23 BR BR9909867-9A patent/BR9909867A/pt not_active Application Discontinuation
- 1999-04-23 PL PL343722A patent/PL192274B1/pl not_active IP Right Cessation
- 1999-04-23 SK SK1555-2000A patent/SK284600B6/sk not_active IP Right Cessation
- 1999-04-23 ES ES99916943T patent/ES2191426T3/es not_active Expired - Lifetime
- 1999-04-23 DE DE69905034T patent/DE69905034T2/de not_active Expired - Lifetime
- 1999-04-23 EP EP99916943A patent/EP1079834B1/en not_active Expired - Lifetime
- 1999-04-23 HU HU0105446A patent/HUP0105446A3/hu unknown
- 1999-04-23 ID IDW20002368A patent/ID26650A/id unknown
- 1999-04-23 CN CNB998053805A patent/CN1165309C/zh not_active Expired - Fee Related
- 1999-04-23 CZ CZ20003779A patent/CZ290911B6/cs not_active IP Right Cessation
- 1999-04-23 CA CA002329232A patent/CA2329232C/en not_active Expired - Fee Related
- 1999-04-23 WO PCT/FI1999/000331 patent/WO1999055337A1/en active IP Right Grant
- 1999-04-23 MX MXPA00010368A patent/MXPA00010368A/es active IP Right Grant
- 1999-04-23 EE EEP200000616A patent/EE04143B1/xx not_active IP Right Cessation
- 1999-04-23 TR TR2000/03101T patent/TR200003101T2/xx unknown
- 1999-04-23 AT AT99916943T patent/ATE231395T1/de not_active IP Right Cessation
- 1999-04-23 NZ NZ507455A patent/NZ507455A/en unknown
- 1999-04-23 AU AU35248/99A patent/AU756338B2/en not_active Ceased
- 1999-04-23 EA EA200001097A patent/EA002428B1/ru not_active IP Right Cessation
- 1999-04-23 PT PT99916943T patent/PT1079834E/pt unknown
- 1999-04-23 RS YUP-640/00A patent/RS49955B/sr unknown
- 1999-04-23 JP JP2000545535A patent/JP4475809B2/ja not_active Expired - Lifetime
- 1999-04-23 GE GEAP19995638A patent/GEP20032942B/en unknown
- 1999-04-23 DK DK99916943T patent/DK1079834T3/da active
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- 2000-10-11 IL IL138950A patent/IL138950A/en not_active IP Right Cessation
- 2000-10-12 ZA ZA200005630A patent/ZA200005630B/en unknown
- 2000-10-19 HR HR20000703A patent/HRP20000703B1/xx not_active IP Right Cessation
- 2000-10-20 NO NO20005312A patent/NO318575B1/no not_active IP Right Cessation
- 2000-11-17 BG BG104958A patent/BG64766B1/bg unknown
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2001
- 2001-03-26 HK HK01102147A patent/HK1031998A1/xx not_active IP Right Cessation
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