CN102558016A - 一种新型具有高度降脂活性的化合物及其制备方法 - Google Patents
一种新型具有高度降脂活性的化合物及其制备方法 Download PDFInfo
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- CN102558016A CN102558016A CN2012100324143A CN201210032414A CN102558016A CN 102558016 A CN102558016 A CN 102558016A CN 2012100324143 A CN2012100324143 A CN 2012100324143A CN 201210032414 A CN201210032414 A CN 201210032414A CN 102558016 A CN102558016 A CN 102558016A
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Abstract
本发明涉及一种新型具有高度降脂活性的化合物及其制备方法，以及其作为活性成分与药学上可接受的药用辅料制成的口服制剂，包括片、咀嚼片、分散片、口崩片、口含片、胶囊、软胶囊、滴丸剂、缓释片、缓释胶囊等。作为各种高血脂症的治疗及预防。
Description
技术领域
本发明为一种新型具有高度降脂活性的化合物及其制备方法，属于医药技术领域。
背景技术
高血脂是指血中胆固醇(TC)和/或甘油三酯(TG)过高或高密度脂蛋白胆固醇(HDL-C)过低，该病对身体的损害是隐匿、逐渐、进行性和全身性的。它的直接损害是加速全身动脉粥样硬化，因为全身的重要器官都要依靠动脉供血、供氧，一旦动脉被粥样斑块堵塞，就会导致严重后果。动脉硬化引起的肾功能衰竭等，都与高血脂症密切相关。大量研究资料表明，高血脂症是脑卒中、冠心病、心肌梗死、心脏猝死独立而重要的危险因素。近些年来，有多种降血脂药陆续上市，为高血脂患者增加了安全保障，但治疗效果仍然不够理想，所以寻求一种疗效好且稳定的降血脂药物仍然是今后新药开发的方向。
他汀类药物是一种选择性HMG-CoA还原酶抑制剂。HMG-CoA还原酶抑制剂是转变3-羟基-3-甲基戊二酰辅酶A为甲戊酸盐-胆固醇的前体的限速酶。他汀类药物的主要作用部位是肝-降低胆固醇的靶向器官。他汀类药物增加了肝LDL细胞表面受体数目，促进LDL的吸收和分解代谢，抑制了VLDL的肝合成，由此降低VLDL和LDL微粒的总数。由于无定形的他汀类药物稳定性差，所以目前上市的部分他汀类药物都是以钙盐的形式存在的，比如阿托伐他汀钙、匹伐他汀钙，但是钙盐的生产过程相对很复杂，生产成本较高。
发明内容
为提高药物活性，降低毒性，同时也为了简化他汀类药物的生产过程，降低生产成本，本发明提供一种以锌盐形式存在的他汀类药物及其制备方法，他汀类药物选自阿托伐他汀、匹伐他汀、辛伐他汀、普伐他汀、氟伐他汀、洛伐他汀。
其制备方法包括：首先用有机或无机钠盐将他汀(酸)转变为他汀钠盐，再与无机锌盐(优选氯化锌)反应制备相应的他汀锌盐。
本发明所述化合物可与药学上可接受的辅料组合，制成口服制剂：包括颗粒剂、普通片、咀嚼片、分散片、口崩片、口含片、胶囊、软胶囊、滴丸剂、缓释片、缓释胶囊等。
他汀类药物的锌盐的单位制剂含量为1.25mg～120mg，优选为5mg～40mg。它包括他汀类药物的锌盐与粘合剂、填充剂和崩解剂，填充剂和崩解剂的重量组成分别为10-60％，2-30％。还包括助流剂、润滑剂和矫味剂，重量组成分别为1-5％，0.2-3％，0.01-2％。
其中填充剂包括但不限于乳糖、蔗糖、葡萄糖、甘露醇、山梨醇、硫酸钙、葡萄糖酸 钙、磷酸氢钙、磷酸钙、碳酸钙、碳酸氢钙、淀粉、羧甲基淀粉、预胶化淀粉或者微晶纤维素；粘合剂包括但不限于淀粉、明胶糊精、麦芽糖糊精、蔗糖、阿拉伯胶、聚乙烯吡咯烷酮、各种粘度甲基纤维素、低粘度羧甲基纤维素、各种粘度乙基纤维素、各种粘度聚乙烯醇、聚乙二醇6000或者羟丙纤维素；崩解剂包括但不限于预胶化淀粉、微晶纤维素、海藻酸、纯木制纤维素、羧甲基淀粉钠、瓜耳豆胶、交联聚乙烯吡咯烷酮、甲基纤维素或者交联羧甲基纤维素钠；润滑剂包括但不限于硬脂酸镁、硬脂酸钙、滑石粉、单硬脂酸甘油酯、聚乙二醇4000、聚乙二醇6000、聚乙二醇8000、苯甲酸钠、己二酸、富马酸、硼酸、氯化钠、月桂醇硫酸钠或者月桂醇硫酸镁；矫味剂包括但不限于甜菊素、山梨醇、麦芽糖醇、甘草甜素、干茶叶素、环己氨基磺酸钠、香蕉香精、菠萝香精、薄荷香精、甜橙香精、茴香、香兰素、柠檬香精、樱桃香精或者玫瑰香精；本发明的药物制剂还包括润湿剂，为纯化水或者乙醇等。
具体实施方式
实施例1阿托伐他汀锌的制备：
将阿托伐他汀(5.0g，8.95mmol)溶解于乙醇(150ml)，加入新制的乙醇钠乙醇溶液(1.0M，9.0ml，9.0mmol)，室温搅拌5～10分钟后，缓慢滴加ZnCl2的乙醇溶液(0.2M，23ml)。反应液置于50℃水浴搅拌反应2小时后，自然冷却至室温，过滤。滤液浓缩至约20ml，加入200ml乙醚，过滤析出的沉淀，干燥后得到产品阿托伐他汀锌(6.1g，57.7％)。
实施例2匹伐他汀锌的制备：
将匹伐他汀(3.4g，8.07mmol)溶解于乙醇(100ml)，加入新制的乙醇钠乙醇溶液(1.0M，8.1ml，8.1mmol)，滴加完后，缓慢滴加ZnSO4的乙醇溶液(0.2M，20ml)。反应液置于50℃水浴搅拌反应2小时后，自然冷却至室温，过滤。滤液浓缩至约10ml，加入100ml乙醚，过滤析出的沉淀，干燥后得到产品匹伐他汀锌(2.5g，68.3％)。
实施例3辛伐他汀锌的制备：
辛伐他汀(5.6g，13.4mmol)溶解于乙醇(150ml)，加入NaOH水溶液(0.5M，26.8ml，13.4mmol)，室温搅拌反应30min后用0.1N稀盐酸调节pH至7，减压蒸除溶剂。所得残渣中加入60ml水和固体ZnCl2(0.91g，6.68mmol)。反应液置于30℃水浴搅拌反应2小时后，自然冷却至室温，过滤析出的沉淀，干燥后得到产品辛他汀锌(4.9g，81.0％)。
实施例4普伐他汀锌的制备：
普伐他汀(5.2g，12.2mmol)溶解于乙醇(150ml)，加入NaOH水溶液(0.5M，24.5ml，12.2mmol)，室温搅拌反应30min后用0.1N稀盐酸调节pH至7，减压蒸除溶剂。所得残 渣中加入50ml水和固体ZnCl2(0.83g，6.1mmol)。反应液置于30℃水浴搅拌反应2小时后，自然冷却至室温，过滤析出的沉淀，干燥后得到产品普他汀锌(4.9g，87.6％)。
实施例5氟伐他汀锌的制备：
将氟托伐他汀(6.2g，15.1mmol)溶解于乙醇(180ml)，加入新制的乙醇钠乙醇溶液(1.0M，15.0ml，15.0mmol)，再缓慢滴加ZnSO4的乙醇溶液(0.2M，37.5ml)。反应液置于50℃水浴搅拌反应2小时后，自然冷却至室温，过滤。滤液浓缩至约20ml，加入200ml乙醚，过滤析出的沉淀，干燥后得到产品氟伐他汀锌(5.2g，77.6％)。
实施例6洛伐他汀锌的制备；
洛托伐他汀(5.0g，12.4mmol)溶解于乙醇(150ml)，加入NaOH水溶液(0.5M，25.0ml，12.5mmol)，室温搅拌反应30min后用0.1N稀盐酸调节pH至7，减压蒸除溶剂。所得残渣中加入50ml水和固体ZnCl2(0.84g，6.2mmol)。反应液置于30℃水浴搅拌反应2小时后，自然冷却至室温，过滤析出的沉淀，干燥后得到产品洛伐他汀锌(4.6g，85.2％)。
以下各制剂规格均是以原型药物计
实施例7匹伐他汀锌片
制备方法：
1.向50℃的纯化水中加入处方量吐温80，充分搅拌溶解，加入羟丙纤维素使其水化，形成粘合剂。
2.将处方量匹伐他汀锌、碳酸钙、微晶纤维素、淀粉1500、交联羧甲基纤维素钠用等量递加法充分混合均匀。
3.在步骤2所得到的混粉中加入步骤1所得到的粘合剂制软材，18目筛制粒。
4.干燥步骤3所得到的颗粒，控制水分不大于2.0％。
5.在步骤4所得到的混合颗粒中加入硬脂酸镁，混合均匀，压片，即得。
实施例8阿托伐他汀锌胶囊
制备方法：
1.向50℃的纯化水中加入处方量吐温80，充分搅拌溶解，加入羟丙纤维素使其水化，形成粘合剂。
2.将处方量阿托伐他汀锌、碳酸钙、预胶化淀粉、淀粉1500、羧甲基淀粉钠用等量递加法充分混合均匀。
3.在步骤2所得到的混粉中加入步骤1所得到的粘合剂制软材，18目筛制粒。
4.干燥步骤3所得到的颗粒，控制水分不大于2.0％，过24目筛整粒。
5.在步骤4所得到的颗粒中加入淀粉，二氧化硅充分混合均匀。
6.在步骤5所得到的混合颗粒中加入硬脂酸镁，混合均匀，装填胶囊，即得。
实施例9阿托伐他汀锌分散片
制备方法：
先将原料粉碎过100目筛，将原料药、与其它辅料充分混合均匀后，压制成片。
实施例10大鼠的降脂实验
雄性Wistar大鼠(二级)，体重160～170g，于每天定量给予高脂饮食25g(高脂饲料配方：基础饲料∶胆固醇∶猪油∶胆酸盐∶甲基硫氧嘧啶＝8418∶4∶10∶1∶012)，持续26d，建立高血脂大鼠模型。
将造模成功的受试动物随机分为13组，每组10只。给药分组如下：A组：阿托伐他汀锌(2mg/kg)；A0组：阿托伐他汀钙(2mg/kg)；B组：匹伐他汀锌(0.2mg/kg)；B0组：匹伐他汀钙(0.2mg/kg)；C组：氟伐他汀锌(2mg/kg)；C0组：氟伐他汀钠(2mg/kg)；D组：普伐他汀锌(1mg/kg)；D0组：普伐他汀钠(1mg/kg)；E组：辛伐他汀锌(1mg/kg)；E0组：辛伐他汀(1mg/kg)；F组：洛伐他汀锌(2mg/kg)；F0组：洛伐他汀(2mg/kg)；及模型对照组，另取10只健康大鼠作为空白对照。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，模型对照及空白对照给予等体积的生理盐水，每周末给药后2h测定大鼠血脂，观察各组大鼠的血脂变化情况。
结果：
结果显示，个给药组均有显著的降低胆固醇的作用，与模型对照组比较有显著性差异，各他汀药物的锌盐的作用效果均要优于同种药物的其他盐形式，所以本发明所述的他汀锌盐具有一定的开发价值。结果见表1。
表1各组大鼠总胆固醇变化情况 
Claims (6)
1.一种新型具有高度降脂活性的化合物，其特征在于，是以锌盐形式存在的他汀类药物。
2.权利要求1所述的化合物，其特征在于，他汀类药物选自阿托伐他汀、匹伐他汀、辛伐他汀、普伐他汀、氟伐他汀、洛伐他汀。
3.权利要求1所述的化合物，其制备方法为：使他汀类化合物的钠盐与无机锌盐(氯化锌，硫酸锌，乙酸锌等)反应，生成目标锌盐化合物，通过沉淀等方式将其从反应混合物中分离出来。
4.权利要求1所述的药用化合物，可以与适宜药学辅料组合制成口服制剂：包括片剂、胶囊、软胶囊剂、咀嚼片、口崩片、口含片、滴丸剂。
5.权利要求1所述的药用化合物，其特征在于，所述的他汀类药物锌盐的单位制剂含量为1.25mg～120mg，优选为5mg～40mg。
6.权利要求1所述的组合物，用于各种高血脂症的治疗及预防。
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| CN101490015A (zh) * | 2006-04-13 | 2009-07-22 | 埃吉斯药物股份公开有限公司 | 瑞舒伐他汀锌盐 |
| CN102294032A (zh) * | 2011-09-09 | 2011-12-28 | 北京阜康仁生物制药科技有限公司 | 含有以锌盐形式存在的他汀类药物的药用组合物 |
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| CN101490015A (zh) * | 2006-04-13 | 2009-07-22 | 埃吉斯药物股份公开有限公司 | 瑞舒伐他汀锌盐 |
| CN102294032A (zh) * | 2011-09-09 | 2011-12-28 | 北京阜康仁生物制药科技有限公司 | 含有以锌盐形式存在的他汀类药物的药用组合物 |
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