CN112999178A - 一种依折麦布匹伐他汀钙复方双层片剂 - Google Patents
一种依折麦布匹伐他汀钙复方双层片剂 Download PDFInfo
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- CN112999178A CN112999178A CN202110226224.4A CN202110226224A CN112999178A CN 112999178 A CN112999178 A CN 112999178A CN 202110226224 A CN202110226224 A CN 202110226224A CN 112999178 A CN112999178 A CN 112999178A
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- ezetimibe
- pitavastatin calcium
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Abstract
本发明公开了一种依折麦布匹伐他汀钙复方双层片剂,活性成分依折麦布和匹伐他汀钙,其为由两种活性成分分别与其他辅料制粒并混合均匀,压成双层片后所得。本发明采用双层压片技术,且依折麦布和匹伐他汀钙分开制粒,能有效减少依折麦布对匹伐他汀钙的干扰,减少杂质增长,增加药物的稳定性。同时本发明依折麦布部分工艺为一步制粒,解决了湿法制粒工艺中主药含量不均匀的问题,且配置粘合剂的溶剂为水,避免有机溶剂对环境的污染,使工艺更简单,成本更低廉,更适用于大生产。
Description
技术领域
本发明属于药物制剂技术领域,具体涉及一种依折麦布匹伐他汀钙复方双层片剂及其制备方法。
背景技术
高脂血症是指血脂水平过高,可直接引起一些严重危害人体健康的疾病,如动脉粥样硬化、冠心病、胰腺炎等,高脂血症可分为原发性和继发性两类。原发性与先天性和遗传有关,是由于单基因缺陷或多基因缺陷,使参与脂蛋白转运和代谢的受体、酶或载脂蛋白异常所致,或由于环境因素(饮食、营养、药物)和通过未知的机制而致。继发性多发生于代谢性紊乱疾病(糖尿病、高血压、黏液性水肿、甲状腺功能低下、肥胖、肝肾疾病、肾上腺皮质功能亢进),或与其他因素年龄、性别、季节、饮酒、吸烟、饮食、体力活动、精神紧张、情绪活动等有关。
依折麦布是一种强效的降脂药物,其作用机制与其它降脂药物不同(如:他汀类,胆酸螯合剂(树脂类),苯氧酸衍生物和植物性固醇酯化物)。依折麦布附着于小肠绒毛刷状缘,抑制胆固醇的吸收,从而降低小肠中的胆固醇向肝脏中的转运,使得肝脏胆固醇贮量降低从而增加血液中胆固醇的清除。依折麦布不增加胆汁分泌(如胆酸螯合剂),也不抑制胆固醇在肝脏中的合成(如他汀类)。与安慰剂比较,依折麦布抑制小肠对胆固醇吸收的54%。他汀类减少肝脏合成胆固醇。两种药物合用可以进一步降低胆固醇水平,优于两种药物的单独应用。
依折麦布选择性抑制胆固醇吸收的同时并不影响小肠对甘油三酯、脂肪酸、胆汁酸、孕酮、乙炔、雌二醇及脂溶性维生素A、D的吸收。依折麦布和HMG-CoA还原酶抑制剂联合使用与任何一种药物单独治疗相比能有效改善血清中TC,LDL-C,ApoB,TG及HDL-C水平。依折麦布单独使用或与HMG-CoA还原酶抑制剂联合使用对心血管疾病发病率与死亡率的效果还未建立。
冠心病是威胁人类健康和生命的常见病和多发病,以低密度脂蛋白(LDL)升高为特征的高胆固醇血症则是诱发冠心病的主要危险因子之一。常用的降血脂药如烟酸类、树脂类或贝特类等,降脂作用均低于他汀类药物。他汀类药物共同的作用机制均属于3-羟-3-甲基-戊二酰辅酶A(HMG-CoA)还原酶抑制剂,目前在世界广泛应用的主要有6种:洛伐他汀,普伐他汀,辛伐他汀,西立伐他汀,氟伐他汀和阿托伐他汀。
匹伐他汀钙的作用机制目前认为是抑制细胞内胆固醇合成早期阶段的限速酶,即HMG-COA还原酶,使细胞内游离胆固醇减少,继而反馈性上迢细胞表面低密度脂蛋白(LDL)受体的表达,使细胞LDL受体数目增多及活性增强,加速了循环血液中极低密度脂蛋白(VLDL)残粒或中密度脂蛋白(IDL)和LDL的清除。此外,它还可抑制肝内VLDL的合成,其降低总胆固醇(TC)和LDL-C的作用较为明显,同时也降低三酰甘油(TG)和升高高密度脂蛋白胆固醇(HDL-C)。
发明内容
本发明的目的在于将依折麦布片和匹伐他汀钙片的药理作用结合,在治疗杂合子家族性高胆固醇血症又可以治疗纯合子家族性高胆固醇血症,同时减少服药次数,且本发明采用双层压片技术控制杂质增长速度以增加药物的稳定性,同时本发明依折麦布部分工艺为一步制粒,解决了湿法制粒工艺中主药含量不均匀的问题,且配置粘合剂的溶剂为水,避免有机溶剂对环境的污染,使工艺更简单,成本更低廉,更适用于大生产。
本发明所述双层片剂采用的工艺分为3部分:1)依折麦布部分:将配方量的依折麦布细粉加入含有粘合剂及增溶剂的溶液中,混匀;再将填充剂、崩解剂加入流化床中预热后将粘合剂喷入进行制粒、干燥、整粒后加入折算后润滑剂混匀;2)匹伐他汀钙部分:将配方量的匹伐他汀钙细粉与其它辅料混合均匀后干法制粒、整粒后混匀;3)依折麦布匹伐他汀钙部分:将1)与2)中的中间体压片即得依折麦布匹伐他汀钙复方双层片。与常规口服依折麦布普通制剂和常规口服匹伐他汀钙普通制剂相比本发明的依折麦布匹伐他汀钙双层片口服给药后治疗范围更广,能减少给药次数。
具体而言,本发明的目的是通过如下技术方案实现的:
一种依折麦布匹伐他汀钙复方双层片剂;按质量计,所述双层片剂包括以下成分:
a)依折麦布部分:
b)匹伐他汀钙部分:
所述的依折麦布部分的填充剂选自乳糖和微晶纤维素中的一种或多种,优选乳糖和微晶纤维素的混合物料;匹伐他汀钙部分的填充剂选自乳糖或微晶纤维素中的一种或多种,优选乳糖。
所述依折麦布部分的增溶剂选自月桂基硫酸钠、吐温80或泊洛沙姆中的一种或多种,优选月桂基硫酸钠。
所述依折麦布部分的粘合剂选自聚维酮K30水溶液、明胶溶液或蔗糖溶液中的一种或多种,优选聚维酮K30溶液;匹伐他汀钙部分的粘合剂选自羟丙甲纤维素、乙基纤维素或甲基纤维素中的一种或多种,优选羟丙基纤维素。
所述崩解剂选自交联羧甲基纤维素钠、低取代羟丙基纤维素或微晶纤维素中的一种或多种,依折麦布崩解剂优选交联羧甲基纤维素钠;匹伐他汀钙崩解剂优选低取代羟丙基纤维素。
所述匹伐他汀钙稳定剂选择硅酸铝镁、磷酸钙或碳酸钙中的一种或多种,优选硅酸铝镁。
所述的润滑剂选自硬脂酸镁、二氧化硅、硬脂酸富马酸钠、硬脂酸锌、硬脂酸或硬脂酸钙中的一种或多种,优选硬脂酸镁。
本发明相对于现有技术而言,具有以下有益效果:
本发明所提供的含有依折麦布匹伐他汀钙复方双层片剂药品含量均匀,溶出稳定,治疗范围广,环境友好,制备工艺简单。
相比于现有技术中(例如CN201410158848.7)通过将羟丙基纤维素和依折麦布溶于乙醇,将甘露醇溶于水溶液中,以临界二氧化碳流体压力10~50MPa,温度35~60℃条件下得到羟丙基纤维素、依折麦布、甘露醇的超细颗粒混粉,再与其它辅料粉末直压的依折麦布工艺,本发明依折麦布部分工艺更简单,不需要昂贵的设备,避免有机溶剂对环境的污染,使杂质增长变慢、药物溶出更稳定。
经6个月的加速测试,该片剂在40℃相对湿度75%的环境下仍具有良好的稳定性。
附图说明
图1为实施例1依折麦布溶出曲线;
图2为实施例1匹伐他汀钙溶出曲线;
图3为实施例2依折麦布溶出曲线;
图4为实施例2匹伐他汀钙溶出曲线;
图5为实施例3依折麦布溶出曲线;
图6为实施例3匹伐他汀钙溶出曲线;
图7为实施例4依折麦布溶出曲线;
图8为实施例4匹伐他汀钙溶出曲线;
图9为实施例5依折麦布溶出曲线;
图10为实施例5匹伐他汀钙溶出曲线;
图1-10中,横坐标为时间,单位为min;纵坐标为溶出度,单位为%。
具体实施方式
下面结合具体实施方式对本发明做进一步阐述和说明。本发明中各个实施方式的技术特征在没有相互冲突的前提下,均可进行相应组合。
实施例1:
1)依折麦布:
2)匹伐他汀钙:
其制备方法为
(1)混合:
将配方量的依折麦布细粉加入含有聚维酮K30和月桂基硫酸钠的水溶液中并混合均匀。
(2)制粒、干燥:
将交联羧甲基纤维素钠、乳糖、微晶纤维素放入流化床预热后,将(1)中混合物进喷入流化床进行一步制粒,粘合剂喷完后流化床继续加热使物料干燥;
(3)整粒:
将(2)中物料进行整粒;
(4)总混:
将(3)中物料与折算后硬脂酸镁混合均匀;
(5)预混
将配方量的匹伐他汀钙与乳糖、低取代羟丙基纤维素、羟丙甲纤维素、硅酸铝镁、硬脂酸镁混和均匀;
(6)制粒
将(5)中物料进行干法制粒;
(7)整粒
将(6)中物料进行整粒;
(8)总混
将(7)中物料混合均匀;
(9)压片
将(4)和(8)中的中间产品选取圆形浅凹冲模压片,最终制得含有依折麦布匹伐他汀钙复方双层片剂。
需要说明的是,作为本实施例的可替换实现方式,所述依折麦布的填充剂微晶纤维素和乳糖还可替换为玉米淀粉或可压性淀粉;所述匹伐他汀钙的填充剂乳糖还可以替换成微晶纤维素或玉米淀粉;所述依折麦布的增溶剂月桂基硫酸钠还可以替换成泊洛沙姆或吐温80;所述依折麦布的崩解剂交联羧甲基纤维素钠还可以替换成低取代羟丙基纤维素或微晶纤维素;所述匹伐他汀钙的崩解剂低取代羟丙基纤维素还可以替换成微晶纤维素或交联羧甲基纤维素钠;所述润滑剂硬脂酸镁还可以替换为硬脂酸富马酸钠、硬脂酸锌、硬脂酸、硬脂酸钙;所述依折麦布的粘合剂聚维酮K30还可以替换成明胶溶液或蔗糖溶液;所述匹伐他汀钙的稳定剂硅酸铝镁还可以替换成碳酸钠或磷酸钙,所述匹伐他汀钙的粘合剂羟丙甲纤维素还可以替换成甲基纤维素或乙基纤维素。
上述替换技术方案与本实施例的技术效果并无明显差异。
实施例2:
1)依折麦布:
2)匹伐他汀钙:
其制备方法为
(1)混合:
将配方量的依折麦布细粉加入含有明胶和泊洛沙姆的水溶液中并混合均匀。
(2)制粒:
将低取代羟丙基纤维素、玉米淀粉放入流化床预热后,将(1)中混合物进喷入流化床进行一步制粒,粘合剂喷完后流化床继续加热使物料干燥;
(3)整粒:
将(2)中物料进行整粒;
(4)总混:
将(3)中物料与折算后硬脂酸镁混合均匀;
(5)预混
将配方量的匹伐他汀钙与微晶纤维素、交联羧甲基纤维素钠、羟丙甲纤维素、磷酸钙、硬脂酸镁混和均匀;
(6)制粒
将(5)中物料进行干法制粒;
(7)整粒
将(6)中物料进行整粒;
(8)总混
将(7)中物料混合均匀;
(9)压片
将(4)和(8)中的中间产品选取圆形浅凹冲模压片,最终制得含有依折麦布匹伐他汀钙复方双层片剂。
实施例3:
1)依折麦布:
2)匹伐他汀钙:
其制备方法为
(1)混合:
将配方量的依折麦布细粉加入含有聚维酮K30和吐温80的水溶液中并混合均匀。
(2)制粒:
将微晶纤维素、交联羧甲基纤维素钠放入流化床预热后,将(1)中混合物喷入流化床进行一步制粒,粘合剂喷完后流化床继续加热使物料干燥;
(3)整粒:
将(2)中物料进行整粒;
(4)总混:
将(3)中物料与折算后硬脂酸锌混合均匀;
(5)预混
将配方量的匹伐他汀钙与低取代羟丙基纤维素、乙基纤维素、乳糖、碳酸钠、硬脂酸锌混和均匀;
(6)制粒
将(5)中物料进行干法制粒;
(7)整粒
将(6)中物料进行整粒;
(8)总混
将(7)中物料混合均匀;
(9)压片
将(4)和(8)中的中间产品选取圆形浅凹冲模压片,最终制得含有依折麦布匹伐他汀钙复方双层片剂。
实施例4:
1)依折麦布:
2)匹伐他汀钙:
其制备方法为
(1)混合:
将配方量的依折麦布细粉加入含有聚维酮K30和月桂基硫酸钠的水溶液中并混合均匀。
(2)制粒:
将乳糖、交联羧甲基纤维素钠、微晶纤维素放入流化床预热后,将(1)中混合物喷入流化床进行一步制粒,粘合剂喷完后流化床继续加热使物料干燥;
(3)整粒:
将(2)中物料进行整粒;
(4)总混:
将(3)中物料与折算后硬脂酸镁混合均匀;
(5)预混
将配方量的匹伐他汀钙与低取代羟丙基纤维素、羟丙甲纤维素、乳糖、硅酸铝镁、硬脂酸镁混和均匀;
(6)制粒
将(5)中物料进行干法制粒;
(7)整粒
将(6)中物料进行整粒;
(8)总混
将(7)和(4)中物料混合均匀;
(9)压片
将(8)中的中间产品选取圆形浅凹冲模压片,最终制得含有依折麦布匹伐他汀钙复方片剂。
实施例5:
1)依折麦布:
2)匹伐他汀钙:
其制备方法为
(1)混合:
将配方量的依折麦布细粉加入含有聚维酮K30和月桂基硫酸钠的水溶液中并混合均匀。
(2)制粒:
将配方量乳糖、交联羧甲基纤维素钠、微晶纤维素放入湿法制粒机后,将(1)中混合物喷入湿法制粒机进行湿法制粒;
(3)干燥:
将(2)中物料放入流化床中加热干燥;
(4)整粒:
将(3)中干燥后物料进行整粒;
(5)总混:
将(4)中物料与折算后硬脂酸镁混合均匀;
(6)预混
将配方量的匹伐他汀钙与低取代羟丙基纤维素、羟丙甲纤维素、乳糖、硅酸铝镁、硬脂酸镁混和均匀;
(7)制粒
将(6)中物料进行干法制粒;
(8)整粒
将(7)中物料进行整粒;
(9)总混
将(8)中物料混合均匀;
(10)压片
将(9)及(5)中的中间产品选取圆形浅凹冲模压片,最终制得含有依折麦布匹伐他汀钙复方双层片剂。
收率对比:
实施例1、实施例2、实施例3、实施例4、实施例5收率均在要求范围内。
溶出检测:
测试样品的溶液配制方法为:按照溶出度与释放度测定法通则(《中国药典》通则0931第三法),结果如下表及附图所示:
1)依折麦布
2)匹伐他汀钙
从上表及附图的实验结果中可知,本发明实施例1、实施例2、实施例3制备的依折麦布匹伐他汀钙复方双层片剂在pH4.5介质及pH6.8介质中溶出均一稳定,能保证药物完全释放溶出,保证两种活性成分的治疗效果,相比之下,实施例4制备的依折麦布匹伐他汀钙片中依折麦布部分溶出偏慢,实施例5制备的依折麦布匹伐他汀钙片中依折麦布部分溶出偏快,且RSD值偏大,不能保证药物能完全释放溶出。
实施例6:样品含量及含量均匀度检测:
含量及含量均匀度的测定:按《中国药典》通则0941含量均匀度检查法通则检测。含量均匀度结果判定:A+2.2S≤15
结果如下表所示:
从上表的实验结果中可知,本发明实施例1、实施例2、实施例3、实施例4制备的依折麦布匹伐他汀钙复方双层片剂含量均匀度均符合规定,实施例5制备的依折麦布匹伐他汀钙复方双层片剂含量均匀度超出规定。本发明能保证药物分散均匀及每片药物的有效性。
实施例7:样品稳定性有关物质检测,其实验结果如下表所示:
备注:实施例1、实施例2、实施例3、实施例5均为复方双层片,实施例4为复方单层片;杂质Ⅰ、杂质Ⅱ为依折麦布的主要杂质,杂质Ⅲ、杂质Ⅳ为匹伐他汀钙的主要杂质。
结论:从上表结果中可知,本发明实施例1、实施例2、实施例3、实施例5加速条件下有关物质均符合法定标准,且杂质增长缓慢,实施例4杂质增长超限,且增长快速,由实验结果可知双层复方片比单层复方片总杂更少,实施例1、2、3均能在6个月中保持含量及溶出稳定,实施例4含量呈下降趋势,实施例5依折麦布含量差异较大,由实验结果可知依折麦布制粒工艺中一步制粒比湿法制粒依折麦布含量更均匀。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (9)
2.根据权利要求1所述的双层复方片剂,其特征在于:依折麦布部分的填充剂选自乳糖和微晶纤维素中的一种或多种;匹伐他汀钙部分的填充剂选自乳糖或微晶纤维素中的一种或多种。
3.根据权利要求1所述的双层复方片剂,其特征在于:所述的润滑剂选自硬脂酸镁、二氧化硅、硬脂酸富马酸钠、硬脂酸锌、硬脂酸、硬脂酸钙中的一种或多种。
4.根据权利要求1所述的双层复方片剂,其特征在于:所述依折麦布部分的增溶剂选自月桂基硫酸钠、吐温80或泊洛沙姆中的一种或多种。
5.根据权利要求1所述的双层复方片剂,其特征在于:所述依折麦布部分的粘合剂选自聚维酮K30水溶液、明胶溶液或蔗糖溶液中的一种或多种;匹伐他汀钙部分的粘合剂选自羟丙甲纤维素、乙基纤维素或甲基纤维素中的一种或多种。
6.根据权利要求1所述的双层复方片剂,其特征在于:所述崩解剂选自交联羧甲基纤维素钠、低取代羟丙基纤维素或微晶纤维素中的一种或多种。
7.根据权利要求1所述的双层复方片剂,其特征在于:所述匹伐他汀钙稳定剂选自硅酸铝镁、磷酸钙或碳酸钙中的一种或多种。
8.一种权利要求1所述的含有依折麦布匹伐他汀钙双层复方片剂的制备方法,其特征在于,包括如下步骤:
1)依折麦布部分物料制备:
将配方量的依折麦布细粉加入到含有粘合剂及增溶剂的溶液中,混匀;
将配方量的崩解剂、填充剂放入流化床预热后将粘合剂喷入制粒;
粘合剂喷完后流化床继续加热使物料干燥;
干燥后颗粒整粒后与折算后润滑剂混合均匀;
2)匹伐他汀钙部分物料制备:
将配方量的匹伐他汀钙原料与其他辅料混合均匀后干法制粒;
将干法制粒后颗粒整粒后混合均匀;
3)将步骤1)和步骤2)所得混合均匀后的两种物料压制成双层片。
9.根据权利要求8所述的双层复方片剂的制备方法,其特征在于:所述依折麦布部分物料制备的制粒工艺为一步制粒。
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