WO2011097857A1 - 抗高血压的药物组合物 - Google Patents

抗高血压的药物组合物 Download PDF

Info

Publication number
WO2011097857A1
WO2011097857A1 PCT/CN2010/073998 CN2010073998W WO2011097857A1 WO 2011097857 A1 WO2011097857 A1 WO 2011097857A1 CN 2010073998 W CN2010073998 W CN 2010073998W WO 2011097857 A1 WO2011097857 A1 WO 2011097857A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
indapamide
levamlodipine
antihypertensive
group
Prior art date
Application number
PCT/CN2010/073998
Other languages
English (en)
French (fr)
Inventor
杨彦玲
薛传校
张喜田
李环
宋森涛
Original Assignee
施慧达药业集团(吉林)有限公司
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 施慧达药业集团(吉林)有限公司 filed Critical 施慧达药业集团(吉林)有限公司
Priority to JP2011553272A priority Critical patent/JP5982715B2/ja
Priority to CA2727957A priority patent/CA2727957A1/en
Priority to AU2010286192A priority patent/AU2010286192B2/en
Priority to US13/123,609 priority patent/US8470363B2/en
Priority to EP10809124.0A priority patent/EP2374457B1/en
Publication of WO2011097857A1 publication Critical patent/WO2011097857A1/zh

Links

Classifications

    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the invention belongs to the field of pharmacy, and in particular to a pharmaceutical composition for antihypertensive. Background technique
  • Levoamlodipine is the first chiral resolution optical pure drug in China. It is also the world's first chiral antihypertensive drug. It is a long-acting, basic dihydropyridine calcium antagonist. It can be produced by a variety of methods, see references CN00102701.8 and CN03821593.4. It acts through a site (N-site) linked to dihydropyridine on the cell, blocks calcium ions from entering the myocardium and vascular smooth muscle cells, relaxes smooth muscle, reduces vascular resistance, and lowers blood pressure. Current clinical experimental evidence indicates that the therapeutic dose of levamlodipine has little or no effect on cardiac contractility and atrioventricular conduction. A drug with minimal sympathetic excitation in a sub-antagonist.
  • levamlodipine may cause edema due to the high dose of sodium chloride, and a considerable number of patients are discontinued, which is limited in clinical application.
  • Indapamide is a non-thiazide diuretic antihypertensive drug. It is a horizontal amine derivative with a half-life of 17 hours. Its metabolites still have antihypertensive effects, which are both diuretics and certain calcium antagonism.
  • the antihypertensive mechanism of indapamide is complex, including: 1 By affecting prostate substances, PGI2 (prostaglandin I 2 ) and PGE2 (prostaglandin E2 ) are elevated, making PCF2a (prostaglandin F2a ) and TXA2 (thromboxane A2 ) Lowering, thereby improving blood rheology, while PGE2 and PGI2 have the effect of dilating the coronary arteries and peripheral blood vessels; 2 by reducing the response of the blood vessel wall to sodium ions, inhibiting the calcium channel of the vascular wall cells and slightly inhibiting the distal renal tubules The reabsorption of sodium acts to relax the smooth muscle, dilate blood vessels, diuretic, and discharge sodium. Diuretics can reduce the edema caused by CCB caused by sodium retention, but indapamide has side effects that interfere with glucose metabolism. Long-term high-dose use can cause hypokalemia. Summary of the invention
  • the invention aims at the technical problem that the prior art levamlodipine induces edema side effects caused by sodium water retention during the decompression process of the single drug, and the technical problem of indapamine interfering with the side effect of glucose metabolism, and aims to provide an antihypertensive drug combination. Things.
  • the antihypertensive pharmaceutical composition of the present invention comprises levamlodipine or a pharmaceutically acceptable salt thereof, and indapamide.
  • the invention combines levamlodipine with indapamide, can reduce the dosage of levamlodipine and indapamide during treatment, and achieve the same or even better blood pressure lowering effect, and due to levamlodipine Low dose administration with indapamide, thereby reducing the side effects of sulphate induced by levamlodipine, and the side effects of indapamide interfering with glucose metabolism; in addition, the diuretic properties of indapamide can also be Further reduce the side effects of edema caused by sodium sulphate in the left amlodipine bow.
  • the weight ratio of the levamlodipine to the indapamide is 1: 0.04-1, preferably 1: 0.2-1.
  • the pharmaceutically acceptable salt is selected from one or more of the group consisting of: besylate, oxime sulfonate, acetate, aspartate, tartrate, maleate, sulfate , hydrochloride and hydrobromic acid
  • the antihypertensive pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient.
  • the content of levamlodipine is preferably
  • indapamide 0.1-30% by weight, more preferably 0.25-5 % by weight; the content of indapamide is preferably 0.01 to 5% by weight, more preferably 0.05 to 2.5% by weight.
  • the pharmaceutically acceptable excipient is selected from one or more of the group consisting of microcrystalline cellulose, pregelatinized starch, lactose, sodium hydroxymethyl starch, magnesium stearate, talc, and poly Vinyl pyrrolidone (referred to as PVP-k30).
  • the antihypertensive pharmaceutical composition of the present invention may further comprise: a pharmaceutically acceptable diluent, a binder, a disintegrant, a lubricant, a colorant, and/or a flavoring agent.
  • the antihypertensive pharmaceutical composition of the present invention can be formulated into an oral preparation such as a tablet or a capsule, and the tablet can be coated with a sugar coating, a film coating or not.
  • the positive progress of the present invention is as follows:
  • the present invention combines levoamlodipine with indapamide and has a good synergistic antihypertensive effect with each other.
  • the dose of levamlodipine and indapamide can be lowered while achieving the same or even better blood pressure lowering effect.
  • low-dose levamlodipine can also reduce the side effects of sulphate induced by levamlodipine, and the diuretic properties of indapamide can further reduce the side effects of levoamlodipine-induced edema caused by sodium retention.
  • low doses of indapamide can also reduce the side effects of indapamide interfering with glucose metabolism.
  • Co-made (piece) 1000 1000 Preparation process: levodo amlodipine besylate, indapamide, microcrystalline cellulose, pregelatinized starch, lactose, sodium hydroxymethyl starch into the mortar, grind and mix, go through 20 mesh, add appropriate amount 95% ethanol is made into soft material, sterilized by 20 mesh granulation, ventilated at 40 °C, dry granules are granulated with 16 mesh sieve, magnesium stearate is added, and the mixture is homogenized and then tableted.
  • Preparation process Put amlodipine besylate, indapamide, microcrystalline cellulose into a mortar, grind and mix, and pass through a 20 mesh sieve, and add an appropriate amount of 0.5% PVP-k30 ethanol solution to make a soft material.
  • the granules were sieved through a 20-mesh sieve, ventilated and dried at 40 ° C, and the dry granules were granulated with a 16-mesh sieve, and talc powder was added thereto, and the mixture was uniformly mixed, and then the gum was dispensed.
  • mice 50 healthy SHR rats, male and female, weighing 200-240 g, male and female rats were divided into 5 groups according to the high and low blood pressure.
  • the specific grouping method is shown in Table 3.
  • the rat electronic blood pressure meter was used, and the tail volume method was used to indirectly measure the systolic blood pressure when the rats were awake and quiet, and the tail artery systolic blood pressure was measured before, during, one, two, three, and four weeks.
  • Model blank group 10 same volume 0.9% saline

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Description

抗高血压的药物组合物 技术领域
本发明属于制药领域， 尤指一种抗高血压的药物组合物。 背景技术
近年来， 随着我国人民生活水平的不断提高及膳食结构的改变、 生活压 力的增大、 老年人口的增加， 高血压的发病率有逐步升高的趋势， 而且它会 引起心、 脑、 肾等器官的损害， 并与糖、 脂质代谢紊乱和糖尿病有密切的关 系， 明显降低患者的生活质量， 严重时甚至会危及到患者的生命。 而大量国 际权威高血压临床研究表明加大降压力度， 积极、 持久地使高血压患者的血 压降至 130/85毫米汞柱以下（最佳应降至 120/80毫米汞柱以下）， 可以有效 地减轻高血压引起的心脑肾等靶器官损害， 减少或推迟脑卒中、 冠心病、 心 绞痛、 心肌梗死、 肾功能衰竭、 动脉粥样硬化、 动脉瘤等并发症的发生， 降 低心脑血管事件率、 死亡率和病残率， 改善患者生活质量， 延长患者寿命。 根据世界卫生组织（WHO )对全球各种疾病的死亡统计， 以高血压等为代表 的心脑血管疾病死亡人数占总死亡人数比例的 36%, 因此提高人民对高血压 病的认识， 对早期预防、 及时治疗有极其重要的意义。
老年高血压的诊断与治疗 2008中国专家共识指出，联合用药治疗利用多 种不同机制降压， 降压效果好， 不良反应少、 更有利于靶器官的保护。 大量 研究表明， 为了达到积极、 强化降压的目的， 70-100%的患者需要联用两种 或两种以上的降压药物， 联合用药， 不仅由于药物的相加或协同作用， 可以 明显提高降压效果， 而且还可以减少药物的副作用， 提高了安全性和患者的 依从性。 艮多文献表明， 两种抗高血压药物的合理联合还可以互相 4氏消两种 联合成分各自存在的不利作用。 因此当使用单药常规剂量不能达标时， 推荐 釆用包括复方制剂在内的联合用药方案治疗高血压患者。
左旋氨氯地平是我国首例手性拆分光学纯药物， 也是世界首例手性拆分 抗高血压药物， 是一种长效、 碱性二氢吡啶类钙离子拮抗剂。 可通过多种方 法制得， 参见文献 CN00102701.8和 CN03821593.4。 它通过细胞上一种与二 氢吡啶相连的位点 （N位点）起作用， 阻滞钙离子跨膜进入心肌和血管平滑 肌细胞， 使平滑肌松弛， 血管阻力下降， 降低血压。 目前临床实验证据表明 治疗剂量的左旋氨氯地平对心脏收缩力及房室传导作用极微或没有， 是钙离 子拮抗剂中对交感神经兴奋作用最小的药物。 它还可以治疗心力衰竭的高血 压， 逆转心室肥厚， 改善心脏舒张期松弛功能， 保护肾功能， 轻微利尿， 预 防冠心病、 心肌梗死和脑卒中， 还能部分逆转异常的血压昼夜节律， 轻微抗 血小板， 抗心肌缺血， 抗心律失常， 增加胰岛素敏感性和一定的抗动脉粥样 硬化等作用。 但左旋氨氯地平在降压过程中可由于使用剂量较高易引发钠水 潴留造成水肿， 相当一部分患者因此停药， 临床应用上受到了一定的限制。
吲哒帕胺为非噻嗪类利尿降压药物， 是横胺类衍生物， 半衰期 17小时， 其代谢产物仍有降压作用， 既是利尿剂又具有一定的钙拮抗作用。 吲哒帕胺 降压机制复杂， 包括:①通过影响前列腺类物质， 使 PGI2 (前列腺素 I 2 ) 和 PGE2 (前列腺素 E2 )升高， 使 PCF2a (前列腺素 F2a ) 和 TXA2 (血栓素 A2 ) 降低， 从而改善血液流变学， 而 PGE2和 PGI2具有扩张冠状动脉和外 周血管的作用； ②通过减轻血管壁对于钠离子的反应， 抑制血管壁细胞的钙 离子通道以及轻微抑制肾远端小管对钠的再吸收起到松弛平滑肌、扩张血管、 利尿、 排钠等降压作用。 利尿剂可减轻 CCB引起的钠水潴留造成的水肿， 但 吲哒帕胺有干扰糖代谢的副作用， 长期大剂量使用可引起低钾血症。 发明内容
本发明针对现有技术中的左旋氨氯地平在单独用药降压过程中引发钠水 潴留造成水肿副作用， 吲哒帕胺干扰糖代谢副作用的技术问题， 目的在于提 供一种抗高血压的药物组合物。
本发明的抗高血压的药物组合物包括左旋氨氯地平或其药学上可接受的 盐， 以及吲哒帕胺。
本发明将左旋氨氯地平与吲哒帕胺联合使用， 可以降低治疗过程中左旋 氨氯地平与吲哒帕胺的用药剂量， 而达到相同甚至更优的降血压效果， 并且 由于左旋氨氯地平与吲哒帕胺的低剂量给药， 从而降低左旋氨氯地平引发钠 水潴留的水肿副作用， 和吲哒帕胺干扰糖代谢的副作用； 除此之外， 吲哒帕 胺的利尿性能也可以进一步降低左旋氨氯地平弓 )发钠水潴留的水肿副作用。
在本发明中， 所述左旋氨氯地平与所述吲哒帕胺的重量比为 1 : 0.04-1 , 优选为 1 : 0.2-1。
所述药学上可接受的盐选自下列盐组中的一种或几种： 苯磺酸盐、 曱磺 酸盐、 乙酸盐、 天冬酸盐、 酒石酸盐、 马来酸盐、 硫酸盐、 盐酸盐和氢溴酸
&。 本发明的抗高血压的药物组合物， 还包括制药学上可接受的辅料。
在本发明的抗高血压的药物组合物中， 左旋氨氯地平的含量优选为
0.1-30重量％, 更优选 0.25-5重量％； 吲哒帕胺的含量优选为 0.01-5重量％, 更优选 0.05-2.5重量％。
所述的制药学上可接受的辅料选自下列物质组中的一种或几种： 微晶纤 维素、 预胶化淀粉、 乳糖、 羟曱基淀粉钠、 硬脂酸镁、 滑石粉和聚乙烯吡咯 烷酮 (简称 PVP-k30 ) 。
本发明的抗高血压的药物组合物还可包括： 制药学上可接受的稀释剂、 粘合剂、 崩解剂、 润滑剂、 着色剂和 /或矫味剂。
本发明的抗高血压的药物组合物可以制成口服制剂， 如片剂或胶嚢剂， 片剂可加包糖衣、 薄膜衣或者不包衣。
本发明的积极进步效果在于： 本发明将左旋氨氯地平与吲哒帕胺联合用 药， 相互之间具有良好的协同降压作用。 在达到相同甚至更优的降血压效果 的同时， 可以降低左旋氨氯地平与吲哒帕胺的给药剂量。 不但如此， 低剂量 的左旋氨氯地平也可降低左旋氨氯地平引发钠水潴留的水肿副作用， 并且吲 哒帕胺的利尿性能还可进一步降低左旋氨氯地平引发钠水潴留的水肿副作 用。 除此之外， 低剂量的吲哒帕胺也可降低吲哒帕胺干扰糖代谢的副作用。 具体实施方式
实施例 1~2 复方片剂
表 1 实施例 1~2的复方片剂的组分及其用量 组分 实施例 1 实施例 2
苯磺酸左旋氨氯地 2.5(以左旋氨氯地平计） 0.2(以左旋氨氯地平计） 平 (g)
吲。达帕胺 (g) 0.1 0.02
微晶纤维素 (g) 30 40
预胶化淀粉g) 77.4 105.78
乳糖 (g) 30 40
羟曱基淀粉钠 (g) 9 12
硬脂酸镁 (g) 1 2
95%乙醇 适量 适量
共制成 （片） 1000 1000 制备工艺： 将苯磺酸左旋氨氯地平、 吲哒帕胺、 微晶纤维素、 预胶化淀 粉、 乳糖、 羟曱基淀粉钠放入研钵中研磨混合均勾， 过 20目 ， 加入适量 95%乙醇制成软材， 通过 20目 制粒， 在 40°C通风干燥， 干粒用 16目筛整 粒， 加入硬脂酸镁， 混合均勾后压片即得。
实施例 3~4 复方胶嚢
表 2 实施例 3~4的复方胶嚢的组分及其用量 组分 实施例 3 实施例 4
苯横酸左旋氨氯地平 (g) 2.5(以左旋氨氯地平 60(以左旋氨氯地平
计） 计）
吲。达帕胺 (g) 2.5 10
微晶纤维素 (g) 135 120
滑石粉 (g) 4 5.4
0.5%PVP-k30乙醇溶液 适量 适量
共制成 （粒） 1000 1000
制备工艺： 将苯磺酸左旋氨氯地平、 吲哒帕胺、 微晶纤维素放入研钵中 研磨混合均勾， 过 20目筛， 加入适量 0.5%PVP-k30乙醇溶液制成软材， 通 过 20目筛制粒， 在 40°C通风干燥， 干粒用 16目筛整粒， 加入滑石粉， 混合 均匀后分装胶嚢即得。
效果实施例 1 大鼠的降压试一险
实验方法： 取健康自发性高血压 SHR大鼠 50只， 雌雄各半， 体重 200-240g, 雌雄大鼠按照血压高低均衡地分为 5组， 具体分组方法见表 3 , 釆 用灌胃给药， 对于血压釆用大鼠电子血压仪， 尾容积法间接测定大鼠清醒安 静时的收缩压， 分别在用药前、 用药一周、 二周、 三周、 四周末进行尾动脉 收缩压测定。
表 3 SHR大鼠分组
组别 数量 (只） 给药药物及其剂量
模型空白组 10 同体积 0.9%生理盐水
左旋氨氯地平组 10 5mg苯磺酸左旋氨氯地平 /kg_-d
吲 p达帕胺组 10 5mg吲11达帕胺 /kg-d
复方低剂组 10 2.5mg苯磺酸左旋氨氯地平 /kg.d +0.5mg吲哒帕胺 /kg-d 复方高剂组 10 2.5mg苯磺酸左旋氨氯地平 /kg.d +2.5mg吲哒帕胺 /kg-d 备注： 表 1中 2.5mg苯磺酸左旋氨氯地平 /kg'd是以左旋氨氯地平计 实验结果： 左旋氨氯地平组、 吲哒帕胺组、 复方低剂组、 复方高剂组与 模型空白组比较具有显著的降压作用； 复方低剂组、 复方高剂组与左旋氨氯 地平组、 吲哒帕胺组比较具有显著的降压作用， 具体试验结果如表 4所示。 并且在水肿副作用方面， 模型空白组、 吲哒帕胺组、 复方低剂组、 复方高剂 组都没有出现水肿现象， 而左旋氨氯地平组却有 10%的水肿率发生。
表 4 左旋氨氯地平、 吲哒帕胺及其复方制剂给药对 SHR大 ^血压的影响 组别 用药前 1周末 2周末 3周末 4周末
(KPa) ( pa) (KPa) (KPa) (KPa) 模型空白组 27.09±1.24 27.23±1.1 1 26.81±1.25 26.96±1.44 27.14±1.34 左旋氨氯地 26.96±1.29 26.79±1.31 25.33±1.26# 24.55±1.28 23.87±1.28 平组
吲 p达帕胺组 27.02±1.39 26.88±1.38 25.85±1.38 25.56±1.35 25.36±1.36# 复方低剂组 26.72±1.78 26.55±1.82 24.79±1.69 " 23.73±1.56 " 22.68±1.53 ," 复方高剂组 26.79±1.44 26.61±1.45 24.78±1.39#" 23.67±1.32 A" 22.51±1.14#" 备注： #与模型空白组比较 p < 0.01 , *与左旋氨氯地平组比较 < 0.05 , A与左旋氨氯地 平组比 ¾ p < 0.01 , ■与吲哒帕胺组比较 p < 0.01。
结论： 左旋氨氯地平与吲哒帕胺的复方制剂比左旋氨氯地平和吲哒帕胺 具有更好的降压作用， 在降压效果上具有显著差异， 左旋氨氯地平与吲哒帕 胺联合用药对自发性高血压大鼠表现出了一定的协同作用， 优于两种药物单 独给药的疗效， 并且联合用药没有弓 I发钠水潴留的水肿副作用。

Claims

权利要求书
1. 一种抗高血压的药物组合物， 其特征在于包括左旋氨氯地平或其药学 上可接受的盐， 以及吲哒帕胺。
2. 如权利要求 1所述的抗高血压的药物组合物， 其特征在于所述左旋氨 氯地平与所述吲哒帕胺的重量比为 1 : 0.04-1。
3. 如权利要求 2所述的抗高血压的药物组合物， 其特征在于所述左旋氨 氯地平与所述吲哒帕胺的重量比为 1 : 0.2-1。
4. 如权利要求 1所述的抗高血压的药物组合物， 其特征在于所述药学上 可接受的盐选自下列盐组中的一种或几种： 苯磺酸盐、 曱磺酸盐、 乙酸盐、 天冬酸盐、 酒石酸盐、 马来酸盐、 硫酸盐、 盐酸盐和氢溴酸盐。
5. 如权利要求 1所述的抗高血压的药物组合物， 其特征在于还包括制药 学上可接受的辅料。
6. 如权利要求 5所述的抗高血压的药物组合物， 其特征在于左旋氨氯地 平的含量为 0.1-30重量％； 吲哒帕胺的含量为 0.01-5重量％。
7. 如权利要求 6所述的抗高血压的药物组合物， 其特征在于左旋氨氯地 平的含量为 0.25-5重量％； 吲哒帕胺的含量为 0.05-2.5重量％。
8. 如权利要求 5所述的抗高血压的药物组合物， 其特征在于所述的制药 学上可接受的辅料选自下列物质组中的一种或几种： 微晶纤维素、 预胶化淀 粉、 乳糖、 羟曱基淀粉钠、 硬脂酸镁、 滑石粉和聚乙烯吡咯烷酮。
9. 如权利要求 5所述的抗高血压的药物组合物， 其特征在于所述药物组 合物还包括： 制药学上可接受的稀释剂、 粘合剂、 崩解剂、 润滑剂、 着色剂 和 /或矫味剂。
10. 如权利要求 5所述的抗高血压的药物组合物， 其特征在于所述药物 组合物为片剂或胶嚢剂。
PCT/CN2010/073998 2010-02-09 2010-06-17 抗高血压的药物组合物 WO2011097857A1 (zh)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2011553272A JP5982715B2 (ja) 2010-02-09 2010-06-17 抗高血圧薬組成物
CA2727957A CA2727957A1 (en) 2010-04-27 2010-06-17 Pharmaceutical composition comprising levamlodipine and indapamide
AU2010286192A AU2010286192B2 (en) 2010-02-09 2010-06-17 Antihypertensive pharmaceutical composition
US13/123,609 US8470363B2 (en) 2010-02-09 2010-06-17 Antihypertensive pharmaceutical composition
EP10809124.0A EP2374457B1 (en) 2010-02-09 2010-06-17 Antihypertensive pharmaceutical composition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2010101079455 2010-02-09
CN2010101079455A CN101773500B (zh) 2010-02-09 2010-02-09 抗高血压的药物组合物

Publications (1)

Publication Number Publication Date
WO2011097857A1 true WO2011097857A1 (zh) 2011-08-18

Family

ID=42510176

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2010/073998 WO2011097857A1 (zh) 2010-02-09 2010-06-17 抗高血压的药物组合物

Country Status (5)

Country Link
US (1) US8470363B2 (zh)
JP (1) JP5982715B2 (zh)
CN (1) CN101773500B (zh)
AU (1) AU2010286192B2 (zh)
WO (1) WO2011097857A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102327263B (zh) * 2011-07-06 2013-03-06 宁夏康亚药业有限公司 复方降压药物组合物及复方降压片剂

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4755386A (en) * 1986-01-22 1988-07-05 Schering Corporation Buccal formulation
US6057344A (en) * 1991-11-26 2000-05-02 Sepracor, Inc. Methods for treating hypertension, and angina using optically pure (-) amlodipine
US5721263A (en) * 1993-06-07 1998-02-24 Takeda Chemical Industries, Ltd. Pharmaceutical composition for angiotensin II-mediated diseases
PL193976B1 (pl) * 2002-07-01 2007-04-30 Pliva Krakow Tabletka o przedłużonym działaniu zawierająca indapamid i sposób wytwarzania tabletki o przedłużonym działaniu zawierającej indapamid
CN1493285A (zh) * 2003-09-01 2004-05-05 启东盖天力药业有限公司 含吲哒帕胺和钙离子拮抗剂的复方降压制剂
WO2006043148A1 (en) * 2004-10-20 2006-04-27 Emcure Pharmaceuticals Limited Process for producing enantiomer of amlodipine in high optical purity
US20070237815A1 (en) * 2006-04-06 2007-10-11 Lawrence Solomon Dosage forms and methods comprising amlodipine and chlorthalidone
CN101229160B (zh) * 2008-01-25 2010-04-28 广东一品红药业有限公司 一种含有苯磺酸氨氯地平的降压药物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HE, GUOXIN: "Effects of combination of levoamlodipine and indapamide on systolic hypertension in elderly", HEBEI MEDICINE(CHINESE), vol. 11, no. 10, October 2005 (2005-10-01), pages 901 - 902, XP002671843 *

Also Published As

Publication number Publication date
AU2010286192B2 (en) 2013-10-03
CN101773500A (zh) 2010-07-14
US8470363B2 (en) 2013-06-25
JP5982715B2 (ja) 2016-08-31
CN101773500B (zh) 2012-05-23
JP2012514048A (ja) 2012-06-21
US20110263660A1 (en) 2011-10-27
AU2010286192A1 (en) 2011-08-25

Similar Documents

Publication Publication Date Title
AU2009338267B2 (en) Solid pharmaceutical composition comprising amlodipine and losartan and process for producing same
CN101347427A (zh) 一种沙坦化合物或其可药用盐和钙通道阻断剂或可药用盐的复方
CN101371834B (zh) 含有苯磺酸氨氯地平和坎地沙坦酯的药物组合物和药盒
AU2010276461B2 (en) Pharmaceutical composition of levamlodipine or pharmaceutically acceptable salt thereof and beta receptor blocking agent, and use thereof
WO2013152641A1 (zh) 一种盐酸乐卡地平和氯沙坦钾复方制剂及其制备方法
KR101303841B1 (ko) 고혈압 및 대사증후군 질환 치료용 약학적 조성물 및 이의 용도
WO2011097857A1 (zh) 抗高血压的药物组合物
CN103800336A (zh) 一种具有抗血栓活性药物的组合物
CN102058591A (zh) 一种左旋氨氯地平和替米沙坦的复方制剂
CN102327263B (zh) 复方降压药物组合物及复方降压片剂
CN103222960B (zh) 一种马来酸依那普利口服定时释放微丸及其制备方法
CA2727957A1 (en) Pharmaceutical composition comprising levamlodipine and indapamide
EP2374457B1 (en) Antihypertensive pharmaceutical composition
CN101869562B (zh) 左旋氨氯地平复方药物制剂
WO2011106951A1 (zh) 左旋氨氯地平复方药物组合物
CN103656609A (zh) 群多普利分散体药物组合物
CN102145000A (zh) 一种坎地沙坦酯和美托洛尔复方制剂
CN101361736A (zh) 一种沙坦化合物或其可药用盐和钙通道阻断剂或可药用盐的复方
CN101766610A (zh) 氨氯地平、甲磺酸依普罗沙坦复方制剂
CN105106962A (zh) 一种复方降压制剂及其应用
WO2013091574A1 (zh) 包含坎地沙坦或其酯以及氯噻酮的药物组合物及其应用

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 2727957

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2010809124

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2011553272

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 2010286192

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 13123609

Country of ref document: US

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10809124

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE