CN101229163A - 一种含有左旋氨氯地平与匹伐他汀的药用组合物 - Google Patents
一种含有左旋氨氯地平与匹伐他汀的药用组合物 Download PDFInfo
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Abstract
本发明涉及一种含有左旋氨氯地平与匹伐他汀的药用组合物及其制备方法。它是以左旋氨氯地平与匹伐他汀或这两种药物药学上可接受的盐为药用活性成分，与药学上可接受的辅料混合形成的药用组合物。以左旋氨氯地平与匹伐他汀或这两种药物药学上可接受的盐为原料，加入一些特定的种类和比例的辅料，按照本发明所说明的技术手段可制备开发成片剂、胶囊、软胶囊剂、咀嚼片、口崩片、口含片、滴丸剂等口服制剂。本发明的药用组合物可用于治疗各种类型高血压。
Description
技术领域
本发明涉及一种含有左旋氨氯地平与匹伐他汀的药用组合物及其制备方法。属于医药技术领域。
背景技术
左旋氨氯地平是二氢吡啶类钙拮抗剂(钙离子拮抗剂或慢通道阻滞剂)。心肌和平滑肌的收缩依赖于细胞外钙离子通过特异性离子通道进入细胞。本品选择性抑制钙离子跨膜进入平滑肌细胞和心肌细胞，对平滑肌的作用大于心肌。其与钙通道的相互作用决定于它和受体位点结合和解离的渐进性速率，因此药理作用逐渐产生。左旋氨氯地平的活性是右旋体的1000倍，是消旋体的两倍。本品是外周动脉扩张剂，直接作用于血管平滑肌，降低外周血管阻力，从而降低血压。治疗剂量下，体外实验可观察到负性肌力作用，但在整体动物实验中未见。本品不影响血浆钙浓度。15项随机双盲、安慰剂对照的临床试验证实了本品的抗高血压作用。轻中度高血压患者每日服药一次，可以24小时降低卧位和立位血压，长期使用不引起心率或血浆儿茶酚胺显著改变。降压效果平稳，峰谷值差别不大。降压效果和剂量相关，降压幅度与治疗前血压相关，中度高血压者(舒张压105-114mmHg)的疗效比轻度高血压者(舒张压90-104mmHg)高，血压正常者服药后没有明显作用。本品降低舒张压的作用在老年人和年轻人中相似，降低收缩压的作用对老年人更强。本品缓解心绞痛的准确机制尚不明确，但可能在运动时，本品通过降低外周阻力(后负荷)减少心脏做功和速率血压乘积，减少心肌氧需治疗劳力型心绞痛；通过抑制钙离子、肾上腺素、5-羟色胺和血栓素A2引起的冠状动脉和小动脉收缩，恢复缺血区血供治疗自发性心绞痛。8项临床试验中5项显示，本品显著延长运动诱发劳力型心绞痛的时间；部分研究显示本品延长ST段改变1mm的时间，并降低心绞痛发作频率。该作用具有持续性，并且不显著影响血压和心率。在一项50例自发性心绞痛患者中进行临床试验显示，本品每周可以减少4次心绞痛发作(安慰剂每周减少1次)。心功能正常的患者服用本品后测定静息和运动状态下血流动力学，心脏射血分数有所增加，但对dP/dt或左室舒张末压/容积无显著影响。
他汀类药物具有显著降低血浆胆固醇(CH)和低密度脂蛋白胆固醇(LDL-C)的作用。一般可使血总胆同醇(TC)下降30％～40％，LDL-C下降35％～45％，三酰甘油(TG)下降10％～20％，使高密度脂蛋白(HDL)升高5％～10％。他汀类药物通过抑制羟戊二酰辅酶A(HMG CoA)还原酶，而阻碍肝内CH的合成，同时还可增强肝细胞膜LDL受体的表达，故使血CH及LDLc浓度降低。他汀类药物结构中的侧链部分与HMGCoA有相类似的结构。因而能与HMG-CoA还原酶产生竞争性结合而抑制其活性。他汀类各药对HMG-CoA还原酶亲和力不同，故作用强度有差别。他汀类药物是新型降脂药物，这类药物可以降低老年病人的总胆固醇和低密度脂蛋白胆固醇，适合于高胆固醇血症、高甘油脂血症及动脉粥样硬化的治疗。
匹伐他汀是日本Nissan Chem公司研发的新的HMG-CoA还原酶抑制剂，它和瑞舒伐他汀都被称为“超级他汀”，其主要特点是对酶的选择性和降脂作用在他汀类中最强，同时血浆半衰期长，剂量小和服用次数少。匹伐他汀的作用机制是通过竞争性抑制HMG CoA还原酶，进而减少胆固醇的生物合成。血中胆固醇浓度的降低可使肝脏内LDL-胆固醇受体下调，使LDL-胆固醇从血中的清除加快。此外匹伐他汀具有抗增殖作用，特别是对粥样硬化病变的血管内膜平滑肌细胞，并可抑制细胞外基质的产生。
据研究表明，高血压病人常伴有血脂异常，血脂异常可进一步的促进高血压的恶化，二者在疾病的发展过程中起到了相辅相成的作用，所以对于高血压病人，在降压治疗的同时也需重视对血脂的控制。左旋氨氯地平与匹伐他汀的联合应用将有效的解决这一问题，二者的复方将协同发挥降压、降脂的作用，有效的控制高血压病人的病情。
发明内容
本发明为一种含有左旋氨氯地平与匹伐他汀的药用组合物，它是以左旋氨氯地平或其药用盐与匹伐他汀或其药用盐为活性成分，与药学上可接受的辅料混合形成的药用组合物。
在所述的药用组合物中，左旋氨氯地平的单位制剂含量为1.0mg～30mg。优选为2.5mg～15mg。匹伐他汀的单位制剂含量为0.2mg～6mg。优选为0.5mg～3mg。左旋氨氯地平与匹伐他汀的重量比为2∶1～10∶1，优选为4∶1～6∶1。
所述的药用组合物，可制成口服制剂。包括片剂、胶囊、软胶囊剂、咀嚼片、口崩片、口含片、滴丸剂。
所述的药用组合物，用于治疗各种类型高血压。特别适用于血脂增高明显的高血压病人，并且根据病情选择不同单位剂量的药用组合物。
具体实施方式
通过以下实例来对本发明的左旋氨氯地平与匹伐他汀或这两种药物药学上可接受的盐(以下用量均以左旋氨氯地平和匹伐他汀计)的制剂做进一步具体说明，但并不仅限于以下实例。
实施例1左旋氨氯地平与匹伐他汀片剂
处方：
| 组分 | 用量 |
| 左旋氨氯地平匹伐他汀微晶纤维素预胶化淀粉乳糖硬脂酸镁95％乙醇共制成 | 2.5g1g60g15g30g2.5g适量1000片 |
制备方法：
将左旋氨氯地平、匹伐他汀、微晶纤维素、预胶化淀粉、乳糖分别过80目筛，混合均匀后，加入95％乙醇适量制软材，20目筛制粒，干燥，18目筛整粒，加入硬脂酸镁，混合均匀后采用适宜冲模压制片剂，即得。
实施例2：左旋氨氯地平与匹伐他汀胶囊剂
处方：
| 组分 | 用量 |
| 左旋氨氯地平匹伐他汀微晶纤维素0.5％PVP-k 30乙醇溶液滑石粉共制成 | 5g1g85g适量3.5g1000粒 |
制备方法：
将左旋氨氯地平、匹伐他汀、微晶纤维素分别过80目筛，混合均匀后，加入0.5％PVP-k 30乙醇溶液适量制软材，24目筛制粒，干燥，24目筛整粒，加入处方量的滑石粉，混合均匀后装入适宜的胶囊壳中即得。
实施例3：左旋氨氯地平与匹伐他汀软胶囊剂
处方：
| 组分 | 用量 |
| 左旋氨氯地平匹伐他汀PEG400丙二醇吐温-80共制成 | 2.5g1g170g10g7.5g1000粒 |
制备方法：
先将约80％PEG400加热至40-60℃，加入左旋氨氯地平、匹伐他汀，搅拌使溶解，再加入处方量的丙二醇、吐温-80，搅拌均匀后，续加余量PEG400，得到澄明溶液；调整内容物重量，压制，即得。
实施例4：左旋氨氯地平与匹伐他汀咀嚼片剂
处方
| 组分 | 用量 |
| 左旋氨氯地平 | 10g |
| 匹伐他汀微晶纤维素甘露醇阿司巴甜桔子香精0.5％PVP-K30乙醇溶液共制成 | 2g220g30g6g10g适量1000片 |
制备方法：
将均过80目筛的左旋氨氯地平、匹伐他汀、微晶纤维素、甘露醇混合均匀，用0.5％PVP-K30乙醇溶液制软材，16目筛制粒，干燥、12目筛整粒，加入阿司巴甜、桔子香精，混合均匀，压片，即可。
实施例5：左旋氨氯地平与匹伐他汀口腔崩解片剂
处方
| 组分 | 用量 |
| 左旋氨氯地平匹伐他汀CMS-NaL-HPC甘露醇微晶纤维素阿斯巴甜柠檬香精淀粉浆滑石粉共制成 | 2.5g1g9g8g60g45g3.5g2.5g适量1.5g1000片 |
制备方法：
将均过80目筛的左旋氨氯地平、匹伐他汀、甘露醇、阿斯巴甜、柠檬香精、L-HPC、部分微晶纤维素，用淀粉浆制软材，制粒，干燥、整粒，加入余量的微晶纤维素、CMS-Na、滑石粉，混合均匀，压片，即可。
实施例6：左旋氨氯地平与匹伐他汀口含片
处方
制备方法：
将均过80目筛的左旋氨氯地平、匹伐他汀、蔗糖、木糖醇混合均匀，用95％乙醇溶液制软材，16目筛制粒，干燥、12目筛整粒，加入处方量阿司巴甜、桔子香精、薄荷脑，混合均匀，压片，即可。
实施例7：左旋氨氯地平与匹伐他汀滴丸剂
处方
| 组分 | 用量 |
| 左旋氨氯地平匹伐他汀PEG6000S-40共制成 | 10g2g80g40g1000粒 |
制备方法：
将左旋氨氯地平与匹伐他汀过80目筛，备用；另将PEG6000、S-40混合后加热至约60℃使熔融；将左旋氨氯地平与匹伐他汀加热至熔融液中搅拌均匀，移至滴斗中，保温约60℃，调节滴头大小，以-25--5℃的二甲基硅油或液体石蜡为冷却相，进行滴制，过滤，洗涤、选丸，即可。
实施例8：大鼠的降压降脂实验
方法：取6月龄自发性高血压大鼠，测定基础血压后，随机分为6组，每组10只。分别为：左旋氨氯地平+匹伐他汀组A(比例为5mg∶1mg)，氨氯地平+匹伐他汀组B(比例为5mg∶1mg)，左旋氨氯地平组C(5mg)，氨氯地平组D(5mg)，匹伐他汀组E(1mg)及生理盐水对照组F。各组均灌胃给以相应药物，药物均以生理盐水配制，灌胃容积为1ml/100g体重，每日一次，连续用4周，每周末给药后2h测定大鼠血压血脂，观察各组大鼠的血压及血脂变化情况。
结果：各组大鼠血压变化情况见表1，A～D组血压较对照组比较均有显著下降，效果强弱依次是A＞B＞C＞D，E、F两组血压无明显变化。血脂变化情况见表2、表3，与对照组相比各治疗组均有降脂的作用，但含有匹伐他汀组降脂效果较明显。实验期间，只有D组有一只大鼠，E组有两只大鼠出现水肿，其它组未见不良反应。
表1各组大鼠血压变化情况
KPa
| 0w | 1w | 2w | 3w | 4w | |
| ABCDEF | 18.08±1.2617.30±1.3417.42±2.0318.02±1.5917.98±2.1917.45±1.81 | 16.23±1.0216.69±2.1617.21±1.2317.97±3.0417.32±3.4918.59±2.31 | 14.13±2.3115.24±1.5615.26±2.1316.29±3.1616.68±1.8918.92±1.94 | 11.13±1.0913.56±3.0113.63±2.8414.56±3.1215.17±2.1619.23±2.03 | 9.48±2.4611.68±2.1712.59±1.1614.26±1.6816.82±1.6320.03±2.11 |
表2各组大鼠总胆固醇变化情况
mmol/L
| 0w | 1w | 2w | 3w | 4w | |
| ABCDEF | 9 19±3.468.16±2.139.23±2.318.65±1.238.03±3.217.89±1.26 | 7.46±2.167.68±2.458.98±1.358.49±2.167.23±1.598.59±3.12 | 6.18±2.446.59±1.358.16±2.387.98±3.156.48±2.167.98±2.13 | 5.82±1.646.05±2.377.77±1.698.06±3.215.77±1.648 66±1.32 | 5.11±1.455.34±1.347.64±3.017.96±2.165.48±2.369.01±2.15 |
表3各组大鼠低密度酯蛋白变化情况
mmol/L
| 0w | 1w | 2w | 3w | 4w | |
| ABCDEF | 6.79±1.266.57±2.165.49±1.436.36±2.845.84±3.125.66±1.63 | 5.34±1.565.61±2.355.64±2.366.01±1.065.35±1.695.79±2.32 | 4.57±2.415.11±3.054.98±2.015.78±1.364.38±1.566.13±1.59 | 3.84±3.024.12±1.695.06±1.235.62±2.073.67±2.375.87±2.16 | 3.16±1.363.21±2.354.56±1.265.16±3.023.34±1.466.25±2.17 |
由实验结果可以看出复方左旋氨氯地平+匹伐他汀可有效的降低血压、血脂，并且控制二者的波动，不良反应小，适合高血压病人长期服用。
Claims (7)
1.本发明为一种含有左旋氨氯地平与匹伐他汀的药用组合物，其特征在于，它是以左旋氨氯地平或其药用盐与匹伐他汀或其药用盐为活性成分，与药学上可接受的辅料混合形成的药用组合物。
2.权利要求1所述的药用组合物，其特征在于，所述的左旋氨氯地平的单位制剂含量为1.0mg～30mg。优选为2.5mg～15mg。
3.如权利要求1所述的药用组合物，其特征在于，所述的匹伐他汀的单位制剂含量为0.2mg～6mg。优选为0.5mg～3mg。
4.如权利要求1所述的药用组合物，其特征在于，所述的左旋氨氯地平与匹伐他汀的重量比为2∶1～10∶1，优选为2∶1～6∶1。
5.如权利要求1所述的药用组合物，其特征在于，可制成口服制剂。
6.如权利要求5所述的药用组合物，其特征在于，所述的口服制剂包括片剂、胶囊、软胶囊剂、咀嚼片、口崩片、口含片、滴丸剂。
7.权利要求1～6所述的任意一种药用组合物，用于治疗各种类型高血压。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102085192B (zh) * | 2009-12-08 | 2014-08-20 | 北京以岭生物工程技术有限公司 | 瑞舒伐他汀钙口腔崩解片及其制备方法 |
| CN112843001A (zh) * | 2019-11-26 | 2021-05-28 | 宜昌东阳光长江药业股份有限公司 | 一种氨氯地平制剂及其制备方法 |
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- 2008-01-18 CN CNA2008100564329A patent/CN101229163A/zh active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102085192B (zh) * | 2009-12-08 | 2014-08-20 | 北京以岭生物工程技术有限公司 | 瑞舒伐他汀钙口腔崩解片及其制备方法 |
| CN112843001A (zh) * | 2019-11-26 | 2021-05-28 | 宜昌东阳光长江药业股份有限公司 | 一种氨氯地平制剂及其制备方法 |
| CN112843001B (zh) * | 2019-11-26 | 2024-04-26 | 宜昌东阳光长江药业股份有限公司 | 一种氨氯地平制剂及其制备方法 |
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