CN106727380B - 一种铝镁匹林片(ⅱ)及其制备工艺 - Google Patents
一种铝镁匹林片(ⅱ)及其制备工艺 Download PDFInfo
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Abstract
本发明属于制药技术领域，特别涉及一种铝镁匹林片(Ⅱ)及其制备工艺。该铝镁匹林片(Ⅱ)由阿司匹林层和缓冲层压片制成，阿司匹林层由阿司匹林、甘露醇、玉米淀粉、酒石酸、明胶、柠檬黄铝色淀、二氧化硅制成；缓冲层由甘羟铝、重质碳酸镁、甘露醇、玉米淀粉、明胶、二氧化硅制成。通过本发明制备工艺制得的铝镁匹林片(Ⅱ)具有更好的溶出速率，杂质较现有产品中杂质指标明显降低。
Description
(一)技术领域
本发明属于制药技术领域，特别涉及一种铝镁匹林片(Ⅱ)及其制备工艺。
(二)背景技术
铝镁匹林片最早于2001年在日本由LION公司研发上市，商品名为BUFFERIN。其中小剂量规格作为抗血小板剂推向市场。
铝镁匹林片的主要成分阿司匹林又名醋柳酸、乙酰水杨酸，其发展已有100多年的历史，在全世界广泛的医疗实践中，逐渐发现它不仅是解热镇痛药，而且还可以治疗许多疾病，对于某些病还是特效药。阿司匹林治疗心血管病，已成为最新的有效疗法。医学界普遍认为它具有降低血液凝聚的能力，有抗血栓和溶化血栓的作用。
对于有心脏病或中风史的病人，阿司匹林可以使心肌梗死继发残废或再次梗死的危险率降低约25％，可以使不稳定型心绞痛的危险性发作降低35％以上，可以使暂短性缺血性发作的病人，出现中风或导致死亡的情况减少25％。
尽管阿司匹林在抗血小板聚集等多个治疗领域发挥着重要的作用，但其对胃粘膜刺激较大，胃肠道副作用发生率较高，不适合长期服用，制约了在临床的使用。为此，对阿司匹林刺激胃肠道的问题进行研发和公关，获得了“铝镁匹林片(Ⅱ)”这一最新成果，其主要优点是一方面可以减低阿司匹林对胃的不良刺激，显著降低胃粘膜糜烂和溃疡的发生率；另一方面还可增加其吸收度，碱性药物可使胃排空加速，从而使阿司匹林迅速进入主要吸收部位——小肠。
不过，在前期研究阶段发现，铝镁匹林片(Ⅱ)产品的溶出在标准介质(0.1M盐酸)中溶出较慢，有关物质中的杂质有明显上升趋势，这直接影响了一致性及BE实验的风险。为了克服这一不足，寻找一种对阿司匹林稳定、工艺简单、溶出好、杂质无上升趋势、稳定的升级产品及其制造方法非常必要。
(三)发明内容
本发明为了弥补现有技术的不足，提供了一种具有更好的溶出趋势、杂质较现有产品中杂质指标明显降低的铝镁匹林片(Ⅱ)及其制备工艺，解决了现有技术中存在的问题。
本发明是通过如下技术方案实现的：
一种铝镁匹林片(Ⅱ)，由阿司匹林层和缓冲层压片制成，所述阿司匹林层由如下重量份数的原料制成：阿司匹林81份、甘露醇38-42份、玉米淀粉8-12份、酒石酸0.6-1.0份、明胶0.1-0.14份、柠檬黄铝色淀0.03-0.07份、二氧化硅0.9-1.3份；所述缓冲层由如下重量份数的原料制成：甘羟铝11份、重质碳酸镁22份、甘露醇28-32份、玉米淀粉27-31份、明胶0.12-0.18份、二氧化硅0.8-1.2份。
所述阿司匹林层由如下重量份数的原料制成：阿司匹林81份、甘露醇40.88份、玉米淀粉10份、酒石酸0.85份、明胶0.12份、柠檬黄铝色淀0.05份、二氧化硅1.1份；所述缓冲层由如下重量份数的原料制成：甘羟铝11份、重质碳酸镁22份、甘露醇30份、玉米淀粉29.85份、明胶0.15份、二氧化硅1份。
该铝镁匹林片(Ⅱ)的制备方法，包括如下操作步骤：
(1)取阿司匹林层上述原料阿司匹林、酒石酸和甘露醇，分别粉碎后过80目筛；取阿司匹林层上述原料玉米淀粉，过80目筛，得阿司匹林粉、酒石酸粉、甘露醇粉和玉米淀粉A，备用；
(2)取阿司匹林层上述重量份数的明胶，加入明胶重量份数94.3倍的水，搅拌均匀得明胶溶液，向明胶溶液中加入明胶重量份数104.7倍的95％(体积分数)乙醇，搅拌均匀，制成明胶粘合剂A，备用；
(3)按阿司匹林层的上述重量份数，称取阿司匹林粉、酒石酸粉、甘露醇粉和玉米淀粉A和柠檬黄铝色淀，置槽型混合机内，开启搅拌混合均匀，得混合物料A；
(4)按阿司匹林层的上述重量份数，取步骤(2)的明胶粘合剂A加入到步骤(3)的混合物料A中，制软材；采用18目筛制粒，55-60℃鼓风干燥，颗粒水分≤2.0％，得干燥颗粒A；
(5)将步骤(4)的干燥颗粒A采用20目筛整粒，外加阿司匹林层中上述重量份数的二氧化硅，得阿司匹林层，备用；
(6)取缓冲层原料甘羟铝、重质碳酸镁、甘露醇和玉米淀粉，分别过80目筛，备用；
(7)取缓冲层上述重量份数的明胶，加入明胶重量份数94.3倍的水，搅拌均匀得明胶溶液，向明胶溶液中加入明胶重量份数104.7倍的95％(体积分数)乙醇，搅拌均匀，制成明胶粘合剂B，备用；
(8)称取步骤(6)过筛的甘羟铝、重质碳酸镁、甘露醇和玉米淀粉，置槽型混合机内，开启搅拌混合均匀，得混合物料B；
(9)按缓冲层的上述重量份数，向步骤(8)混合物料B中加入步骤(7)制得的明胶粘合剂B，制软材；采用18目筛制粒，55-60℃鼓风干燥，颗粒水分≤3.0％，得干燥颗粒B；
(10)将步骤(9)的干燥颗粒B采用20目筛整粒，外加缓冲层中上述重量份数的二氧化硅，得缓冲层，备用；
(11)将步骤(5)所得阿司匹林层和步骤(10)所得缓冲层采用双层压片机压片，即得。
本发明制备方法的有益效果为：
1、本发明铝镁匹林片(Ⅱ)通过创新性的采用甘露醇、玉米淀粉和明胶粘结剂，获得的新处方具备更好的溶出趋势，在制定新的质量标准中将溶出度限度标示量由原来的80％提高到了85％。另通过对有关物质进行专项研究，方法学验证采用新处方及新的制备工艺，杂质指标明显降低，经过加速试验和长期稳定性试验，证明铝镁匹林片(Ⅱ)及其制备工艺技术先进，疗效好。
2、本发明铝镁匹林片(Ⅱ)通过各成分之间特定量的配比，协调，片芯溶出明显变快，产品稳定性好，有利于于阿司匹林在小肠吸收，避免对胃的刺激和损害。
3、本发明铝镁匹林片(Ⅱ)的制备工艺经优化筛选，工艺科学稳定，质量可控。用于下述需使用阿司匹林抑制血小板粘附和聚集，但患者不能耐受阿司匹林的胃肠道反应时：不稳定心绞痛、急性心肌梗塞、局部缺血性脑血管障碍等。本品无明显毒副作用，用药安全，是一种有效的抑制血小板粘附和聚集的制剂。
(四)附图说明
图1为本发明实施例1铝镁匹林片(Ⅱ)溶出曲线-pH1.0盐酸；
图2为本发明实施例2铝镁匹林片(Ⅱ)溶出曲线-pH1.0盐酸；
图3为本发明实施例3铝镁匹林片(Ⅱ)溶出曲线-pH1.0盐酸；
图4为本发明实施例1铝镁匹林片(Ⅱ)的与市售铝镁匹林片(Ⅱ)溶出曲线对比；
图5为本发明实施例2铝镁匹林片(Ⅱ)的与市售铝镁匹林片(Ⅱ)溶出曲线对比；
图6为本发明实施例3铝镁匹林片(Ⅱ)的与市售铝镁匹林片(Ⅱ)溶出曲线对比。
(五)具体实施方式
下面结合实施例对本发明作进一步说明，但本发明并不局限于此。
实施例1：
一种铝镁匹林片(Ⅱ)，由阿司匹林层和缓冲层压片制成，所述阿司匹林层由如下重量的原料制成：阿司匹林81g、甘露醇40.88g、玉米淀粉10g、酒石酸0.85g、明胶0.12g、柠檬黄铝色淀0.05g、二氧化硅1.1g；所述缓冲层由如下重量的原料制成：甘羟铝11g、重质碳酸镁22g、甘露醇30g、玉米淀粉29.85g、明胶0.15g、二氧化硅1g。
该铝镁匹林片(Ⅱ)的制备工艺，采用如下操作步骤：
(1)取阿司匹林层上述原料阿司匹林、酒石酸和甘露醇，分别粉碎后过80目筛；取阿司匹林层上述原料玉米淀粉，过80目筛，得阿司匹林粉、酒石酸粉、甘露醇粉和玉米淀粉A，备用；
(2)取阿司匹林层上述重量的明胶，加入明胶重量94.3倍的水，搅拌均匀得明胶溶液，向明胶溶液中加入明胶重量104.7倍的95％(体积分数)乙醇，搅拌均匀，制成明胶粘合剂A，备用；
(3)按阿司匹林层的上述重量，称取阿司匹林粉、酒石酸粉、甘露醇粉和玉米淀粉A和柠檬黄铝色淀，置槽型混合机内，开启搅拌混合均匀，得混合物料A；
(4)按阿司匹林层的上述重量，取步骤(2)的明胶粘合剂A加入到步骤(3)的混合物料A中，制软材；采用18目筛制粒，55-60℃鼓风干燥，颗粒水分≤2.0％，得干燥颗粒A；
(5)将步骤(4)的干燥颗粒A采用20目筛整粒，外加阿司匹林层中上述重量份数的二氧化硅，得阿司匹林层，备用；
(6)取缓冲层原料甘羟铝、重质碳酸镁、甘露醇和玉米淀粉，分别过80目筛，备用；
(7)取缓冲层上述重量的明胶，加入明胶重量94.3倍的水，搅拌均匀得明胶溶液，向明胶溶液中加入明胶重量104.7倍的95％(体积分数)乙醇，搅拌均匀，制成明胶粘合剂B，备用；
(8)称取步骤(6)过筛的甘羟铝、重质碳酸镁、甘露醇和玉米淀粉，置槽型混合机内，开启搅拌混合均匀，得混合物料B；
(9)按缓冲层的上述重量，向步骤(8)混合物料B中加入步骤(7)制得的明胶粘合剂B，制软材；采用18目筛制粒，55-60℃鼓风干燥，颗粒水分≤3.0％，得干燥颗粒B；
(10)将步骤(9)的干燥颗粒B采用20目筛整粒，外加缓冲层中上述重量的二氧化硅，得缓冲层，备用；
(11)将步骤(5)所得阿司匹林层和步骤(10)所得缓冲层采用双层压片机压片，即得。
实施例2
一种铝镁匹林片(Ⅱ)，由阿司匹林层和缓冲层压片制成，所述阿司匹林层由如下重量的原料制成：阿司匹林81g、甘露醇38g、玉米淀粉8g、酒石酸0.6g、明胶0.1g、柠檬黄铝色淀0.03g、二氧化硅0.9g；所述缓冲层由如下重量的原料制成：甘羟铝11mg、重质碳酸镁22g、甘露醇28g、玉米淀粉27g、明胶0.12g、二氧化硅0.8g。
该铝镁匹林片(Ⅱ)的制备工艺，采用如下操作步骤：
(1)取阿司匹林层上述原料阿司匹林、酒石酸和甘露醇，分别粉碎后过80目筛；取阿司匹林层上述原料玉米淀粉，过80目筛，得阿司匹林粉、酒石酸粉、甘露醇粉和玉米淀粉A，备用；
(2)取阿司匹林层上述重量的明胶，加入明胶重量94.3倍的水，搅拌均匀得明胶溶液，向明胶溶液中加入明胶重量份数104.7倍的95％(体积分数)乙醇，搅拌均匀，制成明胶粘合剂A，备用；
(3)按阿司匹林层的上述重量，称取阿司匹林粉、酒石酸粉、甘露醇粉和玉米淀粉A和柠檬黄铝色淀，置槽型混合机内，开启搅拌混合均匀，得混合物料A；
(4)按阿司匹林层的上述重量，取步骤(2)的明胶粘合剂A加入到步骤(3)的混合物料A中，制软材；采用18目筛制粒，55℃鼓风干燥，颗粒水分≤2.0％，得干燥颗粒A；
(5)将步骤(4)的干燥颗粒A采用20目筛整粒，外加阿司匹林层中上述重量份数的二氧化硅，得阿司匹林层，备用；
(6)取缓冲层原料甘羟铝、重质碳酸镁、甘露醇和玉米淀粉，分别过80目筛，备用；
(7)取缓冲层上述重量的明胶，加入明胶重量94.3倍的水，搅拌均匀得明胶溶液，向明胶溶液中加入明胶重量104.7倍的95％(体积分数)乙醇，搅拌均匀，制成明胶粘合剂B，备用；
(8)称取步骤(6)过筛的甘羟铝、重质碳酸镁、甘露醇和玉米淀粉，置槽型混合机内，开启搅拌混合均匀，得混合物料B；
(9)按缓冲层的上述重量，向步骤(8)混合物料B中加入步骤(7)制得的明胶粘合剂B，制软材；采用18目筛制粒，55℃鼓风干燥，颗粒水分≤3.0％，得干燥颗粒B；
(10)将步骤(9)的干燥颗粒B采用20目筛整粒，外加缓冲层中上述重量的二氧化硅，得缓冲层，备用；
(11)将步骤(5)所得阿司匹林层和步骤(10)所得缓冲层采用双层压片机压片，即得。
实施例3
一种铝镁匹林片(Ⅱ)，由阿司匹林层和缓冲层压片制成，所述阿司匹林层由如下重量的原料制成：阿司匹林81g、甘露醇42g、玉米淀粉12g、酒石酸1.0g、明胶0.14g、柠檬黄铝色淀0.07g、二氧化硅1.3g；所述缓冲层由如下重量的原料制成：甘羟铝11g、重质碳酸镁22g、甘露醇32g、玉米淀粉31g、明胶0.18g、二氧化硅1.2g。
该铝镁匹林片(Ⅱ)的制备工艺，采用如下操作步骤：
(1)取阿司匹林层上述原料阿司匹林、酒石酸和甘露醇，分别粉碎后过80目筛；取阿司匹林层上述原料玉米淀粉，过80目筛，得阿司匹林粉、酒石酸粉、甘露醇粉和玉米淀粉A，备用；
(2)取阿司匹林层上述重量的明胶，加入明胶重量94.3倍的水，搅拌均匀得明胶溶液，向明胶溶液中加入明胶重量104.7倍的95％(体积分数)乙醇，搅拌均匀，制成明胶粘合剂A，备用；
(3)按阿司匹林层的上述重量，称取阿司匹林粉、酒石酸粉、甘露醇粉和玉米淀粉A和柠檬黄铝色淀，置槽型混合机内，开启搅拌混合均匀，得混合物料A；
(4)按阿司匹林层的上述重量，取步骤(2)的明胶粘合剂A加入到步骤(3)的混合物料A中，制软材；采用18目筛制粒，60℃鼓风干燥，颗粒水分≤2.0％，得干燥颗粒A；
(5)将步骤(4)的干燥颗粒A采用20目筛整粒，外加阿司匹林层中上述重量份数的二氧化硅，得阿司匹林层，备用；
(6)取缓冲层原料甘羟铝、重质碳酸镁、甘露醇和玉米淀粉，分别过80目筛，备用；
(7)取缓冲层上述重量的明胶，加入明胶重量94.3倍的水，搅拌均匀得明胶溶液，向明胶溶液中加入明胶重量104.7倍的95％(体积分数)乙醇，搅拌均匀，制成明胶粘合剂B，备用；
(8)称取步骤(6)过筛的甘羟铝、重质碳酸镁、甘露醇和玉米淀粉，置槽型混合机内，开启搅拌混合均匀，得混合物料B；
(9)按缓冲层的上述重量，向步骤(8)混合物料B中加入步骤(7)制得的明胶粘合剂B，制软材；采用18目筛制粒，60℃鼓风干燥，颗粒水分≤3.0％，得干燥颗粒B；
(10)将步骤(9)的干燥颗粒B采用20目筛整粒，外加缓冲层中上述重量的二氧化硅，得缓冲层，备用；
(11)将步骤(5)所得阿司匹林层和步骤(10)所得缓冲层采用双层压片机压片，即得。
效果试验评价：
一、溶出度研究
1、样品信息
2、溶出均一性
取本发明实施例的自制中试三批样品各12片，照拟定的方法(中国药典2015年版四部通则0931第一法)，以pH1.0盐酸溶液900ml为溶出介质，转速为每分钟75转，依法操作，经5、10、15、30、45分钟时，分别取溶液10ml，滤过，并及时在操作容器中补充相同温度、相同体积的介质。溶出曲线结果见下表1-3，附图1-3为表1-3所对应的溶出曲线图。
由结果可知，中试三批5min的溶出量RSD均小于20％，其余各点的溶出量RSD均小于10％，溶出均一性良好，不同批次之间各时间点的累积溶出量也基本一致，表明不同批次间重现性良好。
表1(16084402)溶出曲线-pH1.0盐酸溶液
表2(16084401)溶出曲线-pH1.0盐酸溶液
表3(16084403)溶出曲线-pH1.0盐酸溶液
3、本发明铝镁匹林片(II)与市售铝镁匹林片(II)的溶出曲线对比结果见下表4-6，附图4-6为表4-6对应的溶出曲线图。
表4(16084402)与市售品(5611301)溶出曲线对比
| 取样时间(min) | 16084402 | 5611301 |
| 0 | 0 | 0 |
| 5 | 49.76 | 30.21 |
| 10 | 71.38 | 56.07 |
| 15 | 85.26 | 71.53 |
| 30 | 96.50 | 90.23 |
| 45 | 100.5 | 98.5 |
表5(16084401)与市售品(5611301)溶出曲线对比
| 取样时间(min) | 16084402 | 5611301 |
| 0 | 0 | 0 |
| 5 | 36.40 | 29.75 |
| 10 | 62.26 | 55.49 |
| 15 | 79.11 | 70.71 |
| 30 | 95.38 | 89.83 |
| 45 | 98.30 | 98.2 |
表6(16084403)与市售品(5611301)溶出曲线对比
| 取样时间(min) | 16084402 | 5611301 |
| 0 | 0 | 0 |
| 5 | 46.63 | 31.08 |
| 10 | 69.05 | 55.38 |
| 15 | 79.95 | 7167 |
| 30 | 95.67 | 89.99 |
| 45 | 100.1 | 98.3 |
由表4-6的对比曲线结果及附图4-6的溶出曲线图可知，本发明实施例1-3的铝镁匹林片(II)较市售的现有品牌溶出速度快，确保了铝镁匹林片(II)中有效成分阿司匹林在体内能够快速释放并发挥药效，及时缓解患者的症状，避免对患者胃肠造成刺激和损伤。
4、溶出度检测
取本发明铝镁匹林片(II)及市售铝镁匹林片(II)，照本品溶出度测定法测定。结果均取自各批标准介质溶出曲线45min取样累积溶出量，结果见表7。
表7溶出度样品检查结果
| 批号 | 16084402 | 16084401 | 16084403 | 5611301 |
| 溶出量(％) | 100.5 | 98.30 | 100.1 | 98.11 |
由表7并结合附图4-6可知，本发明铝镁匹林片(II)的溶出度较对比例铝镁匹林片(II)溶出度高。
二、杂质研究
1、样品信息
2、样品检测
采用拟定的有关物质方法，对本发明实施例的中试产品及市售铝镁匹林片(II)样品分别进行有关物质检测，由结果可知，本发明实施例的中试产品较市售铝镁匹林片(II)样品杂质大幅度降低。结果见下表8。
表8样品检测结果
Claims (2)
1.一种铝镁匹林片(Ⅱ)，其特征是：由阿司匹林层和缓冲层压片制成，所述阿司匹林层由如下重量份数的原料制成：阿司匹林81份、甘露醇38-42份、玉米淀粉8-12份、酒石酸0.6-1.0份、明胶0.1-0.14份、柠檬黄铝色淀0.03-0.07份、二氧化硅0.9-1.3份；所述缓冲层由如下重量份数的原料制成：甘羟铝11份、重质碳酸镁22份、甘露醇28-32份、玉米淀粉27-31份、明胶0.12-0.18份、二氧化硅0.8-1.2份；
所述的铝镁匹林片(Ⅱ)的方法，包括如下操作步骤：
(1)取阿司匹林层上述原料阿司匹林、酒石酸和甘露醇，分别粉碎后过80目筛；取阿司匹林层上述原料玉米淀粉，过80目筛，得阿司匹林粉、酒石酸粉、甘露醇粉和玉米淀粉A，备用；
(2)取阿司匹林层上述重量份数的明胶，加入明胶重量份数94.3倍的水，搅拌均匀得明胶溶液，向明胶溶液中加入明胶重量份数104.7倍的95％(体积分数)乙醇，搅拌均匀，制成明胶粘合剂A，备用；
(3)按阿司匹林层的上述重量份数，称取阿司匹林粉、酒石酸粉、甘露醇粉和玉米淀粉A和柠檬黄铝色淀，置槽型混合机内，开启搅拌混合均匀，得混合物料A；
(4)按阿司匹林层的上述重量份数，取步骤(2)的明胶粘合剂A加入到步骤(3)的混合物料A中，制软材；采用18目筛制粒，55-60℃鼓风干燥，颗粒水分≤2.0％，得干燥颗粒A；
(5)将步骤(4)的干燥颗粒A采用20目筛整粒，外加阿司匹林层中上述重量份数的二氧化硅，得阿司匹林层，备用；
(6)取缓冲层原料甘羟铝、重质碳酸镁、甘露醇和玉米淀粉，分别过80目筛，备用；
(7)取缓冲层上述重量份数的明胶，加入明胶重量份数94.3倍的水，搅拌均匀得明胶溶液，向明胶溶液中加入明胶重量份数104.7倍的95％(体积分数)乙醇，搅拌均匀，制成明胶粘合剂B，备用；
(8)称取步骤(6)过筛的甘羟铝、重质碳酸镁、甘露醇和玉米淀粉，置槽型混合机内，开启搅拌混合均匀，得混合物料B；
(9)按缓冲层的上述重量份数，向步骤(8)混合物料B中加入步骤(7)制得的明胶粘合剂B，制软材；采用18目筛制粒，55-60℃鼓风干燥，颗粒水分≤3.0％，得干燥颗粒B；
(10)将步骤(9)的干燥颗粒B采用20目筛整粒，外加缓冲层中上述重量份数的二氧化硅，得缓冲层，备用；
(11)将步骤(5)所得阿司匹林层和步骤(10)所得缓冲层采用双层压片机压片，即得。
2.根据权利要求1所述的一种铝镁匹林片(Ⅱ)，其特征是：所述阿司匹林层由如下重量份数的原料制成：阿司匹林81份、甘露醇40.88份、玉米淀粉10份、酒石酸0.85份、明胶0.12份、柠檬黄铝色淀0.05份、二氧化硅1.1份；所述缓冲层由如下重量份数的原料制成：甘羟铝11份、重质碳酸镁22份、甘露醇30份、玉米淀粉29.85份、明胶0.15份、二氧化硅1份。
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