CN103877064A - 一种非诺贝特胶囊剂及其制备工艺 - Google Patents
一种非诺贝特胶囊剂及其制备工艺 Download PDFInfo
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Abstract
本发明涉及一种非诺贝特胶囊剂及其制备工艺，该胶囊剂是将含药颗粒与润滑剂混匀后填充胶囊壳而成，所述的含药颗粒是以含非诺贝特和氨丁三醇的乙醇溶液作为粘合剂，与药学上可接受的其它辅料湿法制粒所得。本发明采用乙醇溶解非诺贝特、氨丁三醇后以溶液形式加入其他辅料中，成功制备了快速溶出的非诺贝特胶囊剂。
Description
技术领域
本发明属于药物制剂技术领域，具体而言，涉及一种固体口服制剂，尤其涉及一种非诺贝特胶囊剂及其制备工艺。
背景技术
非诺贝特是目前临床上常用的调脂药物之一，它通过竞争性抑制胆固醇合成酶系中限速酶甲基羟戊二酰辅酶A还原酶，使胆固醇合成减少；同时通过增加低密度脂蛋白受体数目以及增加脂蛋白酶活性使极低密度脂蛋白清除增加等以取得较好的治疗高脂血症的作用，尤其对于单纯的高甘油三脂血症或以高甘油三脂升高为主的混合型血脂异常常作为首选药物。另外，非诺贝特还可以通过促进尿酸排泄来降低血尿酸浓度以达到治疗血尿酸的目的。
非诺贝特作为一种常用的降血脂药， 其反复用药无蓄积性，使得其相较于同类降血脂药物更安全有效， 而且非诺贝特在调节血脂的同时，能够有效的维持白细胞脂质代谢的平衡，并且调节炎性细胞因子的产生，自上市以来在临床上得到了广泛的应用。随着人类生活水平的提高，伴随着的是各种血脂类疾病的发生率也增加，故非诺贝特作为调节血脂疗效极佳的药物进行深层次开发并投入市场，具有极大的经济价值和社会效应。但是非诺贝特难溶的属性以及溶出度差，使得非诺贝特的生物利用度低，如何在保证安全有效的情况下提高非诺贝特溶出度，从而提高其生物利用度，一直是制药领域研究的一个重大课题。
目前，国内许多制药公司常用微粉化、与表面活性剂共微粉化及固体分散体技术、缓释制剂和纳米颗粒制剂的方法来提高非诺贝特生物利用度。其中代表性的专利技术包括：CN1360499A采用微粉化的非诺贝特与作为增溶剂的粘合性纤维衍生物以及表面活性剂的结合来提高活性成分的量从而提高生物利用度；中国专利 20081016197.2 公开了一种自微乳的液态非诺贝特制剂其组成为非诺贝特、MCT、 油酸、EL-35、 1,2-丙二醇（5:20:20:40:20，W/W），均采用大量的表面活性剂，存在对胃肠道的刺激及毒性问题。
CN1496738A与CN102188398A都通过采用与表面活性剂共微粉化技术适度提高了非诺贝特的生物利用度， 但是药物的纳米颗粒制造技术以及大量的表面活性剂的使用给现代企业的规模化生产和患者的药品顺应性带来了极大的难题。
CN101502497B 公开了一种非诺贝特药物组合物，其处方为非诺贝特，聚乙二醇 6000 或泊洛沙姆，山嵛酸甘油酯或甘油棕榈酸酯，聚乙二醇月桂酸油酯或乙二醇单乙基醚，聚氧乙烯氢化蓖麻油或聚氧乙烯蓖麻油。该发明利用原辅料本身的物理化学性质，通过把药物微粒化与微粒化药物分散相结合，再经过超声振荡或高压均质技术获得非诺贝特片剂。该方法的出发点思路很好，但是工艺设备要求高，生产成本高昂，不适应企业规模化生产需求。
CN102424653A 公开了一种非诺贝特药物组合物，其组合物包括阿托伐他汀钙、非诺贝特、明胶、可压性淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、羧甲基纤维素钠、麦芽糖糊精、月桂基硫酸钠、硬脂酸镁、碳酸氢钠。该发明采用粉末X射线衍射测定法和直接压片的工艺，工艺操作简便，但是对设备要求有严格的限制，产品有较好的崩解时限和溶出度，但是处方复杂，直接压片对设备要求高。
CN102188398A公开了一种非诺贝特药物组合物，通过添加水溶性载体材料如聚乙二醇类、聚维酮类、含有聚氧乙烯基的表面活性剂、水溶性纤维素衍生物、有机酸类和糖类及醇类等从而提高非诺贝特的生物利用度，但是该技术需要大量的水溶性载体材料，对非诺贝特的疗效有一定的影响。
CN102784116A公开一种高溶出度非诺贝特分散片及其制备方法，该分散片包含主药、填充剂、崩解剂、增溶剂、润滑剂及适量粘合剂。生产的分散片崩解迅速，分散均匀，服用方便，溶出度比普通片剂高20%以上。但是对于难溶性的非诺贝特而言，仅仅快速崩解，对溶出度提高有限。同时文件中也加入了表面活性剂，存在对胃肠道刺激及毒性问题。
通过检索发现，现有技术均未能提供一种制备工艺简单、溶出迅速、毒副作用小的非诺贝特固体口服制剂。
发明内容
鉴于非诺贝特特难溶的属性以及其制剂溶出度差的问题，本发明人通过大量试验研究提高其溶出度的方法，曾将非诺贝特溶于有机溶剂，然后将此溶液作为粘合剂在药用辅料上制粒，因药物以分子状态分散，有可能会提高溶出度。但实验结果表明，溶出度有所提高，但药物未完全溶出，这可能是在制粒过程中，随着有机溶剂的挥发，粘合剂溶液中药物析出晶体颗粒，因此不能完全溶出。进一步地，发明人考虑到如果在有机溶剂中加入一种药学上可接受的增溶剂，将可能会进一步提高溶出度。为此，发明人进行了大量创造性劳动后意外地发现，当在非诺贝特的乙醇溶液中加入氨丁三醇，然后在药学上可接受的辅料上制粒并压片后，非诺贝特溶出迅速，20min内完全溶出。
基于以上研究，本发明的目的在于提供一种制备工艺简单、溶出迅速、毒副作用小的非诺贝特胶囊剂。
具体地，本发明的目的最终通过如下技术实现：
一种非诺贝特胶囊剂，该胶囊剂是将含药颗粒与润滑剂混匀后填充胶囊壳而成，所述的含药颗粒是以含非诺贝特和氨丁三醇的乙醇溶液作为粘合剂，与药学上可接受的其它辅料湿法制粒所得。
优选地，如上所述非诺贝特胶囊剂，其中所述含非诺贝特和氨丁三醇的乙醇溶液中，非诺贝特与氨丁三醇的重量比为1:0.05-0.3。
进一步优选地，如上所述非诺贝特胶囊剂，其中所述含非诺贝特和氨丁三醇的乙醇溶液中，非诺贝特与氨丁三醇的重量比为1:0.10-0.15。
本发明所述非诺贝特胶囊剂，其中所述的润滑剂为滑石粉；所述药学上可接受的其它辅料包括填充剂、崩解剂。所述的填充剂选自乳糖、微晶纤维素、淀粉、预胶化淀粉和甘露醇中的一种或几种。所述的崩解剂选自交联聚维酮、交联羧甲基纤维素钠、低取代羟丙基纤维素和羧甲基淀粉钠中的一种或几种。
本发明还提供了上述非诺贝特胶囊剂的制备工艺，该工艺包括如下步骤：
（1）将非诺贝特、氨丁三醇溶解在乙醇中，形成含非诺贝特和氨丁三醇的乙醇溶液；
（2）将步骤（1）得到的乙醇溶液作为粘合剂，在药学上可接受的其它辅料上湿法制粒，干燥，加入润滑剂混合均匀，填充胶囊壳。
在上述非诺贝特胶囊剂的制备工艺中，所述的润滑剂为滑石粉；所述药学上可接受的其它辅料包括填充剂、崩解剂。优选地，其中的填充剂选自乳糖、微晶纤维素、淀粉、预胶化淀粉和甘露醇中的一种或几种。优选地，其中的崩解剂选自交联聚维酮、交联羧甲基纤维素钠、低取代羟丙基纤维素和羧甲基淀粉钠中的一种或几种。
与现有技术相比，本发明涉及的非诺贝特胶囊剂及其制备工艺具有如下优点和显著进步性：（1）溶出迅速。本发明创造性地采用乙醇溶解非诺贝特、氨丁三醇后以溶液形式加入其他辅料中，成功制备了快速溶出的非诺贝特胶囊剂，20min内几乎完全溶出。（2）毒副作用小。本发明不含有任何表面活性剂，因此不存在对胃肠道刺激及毒性问题。（3）制备工艺简单。本发明不需要将非诺贝特原料微粉化处理，也不需要复杂的制剂设备，易于工业化大生产。
具体实施方式
现通过以下实施例来进一步描述本发明的制备过程和实施效果，实施例仅用于例证的目的，不限制本发明的范围，同时本领域普通技术人员根据本发明所做的显而易见的改变和修饰也包含在本发明范围之内。
实施例1 非诺贝特胶囊的制备
非诺贝特 100g
氨丁三醇 12g
乳糖 100g
微晶纤维素 100g
交联聚维酮 40g
滑石粉 4.2g
制备工艺：
（1）将非诺贝特、氨丁三醇溶解在适量60℃乙醇中；
（2）处方量称取乳糖、微晶纤维素和交联聚维酮，混合均匀；
（3）将步骤（1）得到的溶液在步骤（2）的混合辅料上制粒，50℃干燥，16目筛整粒，干颗粒中加入滑石粉混合均匀，填充胶囊壳。
实施例2 非诺贝特胶囊的制备
非诺贝特 100g
氨丁三醇 30g
微晶纤维素 200g
羧甲基淀粉钠 50g
滑石粉 4.5g
制备工艺：
（1）将非诺贝特、氨丁三醇溶解在适量70℃乙醇中；
（2）处方量称取乳糖、微晶纤维素和羧甲基淀粉钠，混合均匀；
（3）将步骤（1）得到的溶液在步骤（2）的混合辅料上制粒，50℃干燥，14目筛整粒，干颗粒中加入滑石粉混合均匀，填充胶囊壳。
实施例3 非诺贝特胶囊的制备
非诺贝特 100g
氨丁三醇 6g
微晶纤维素 200g
交联聚维酮 30g
滑石粉 4g
制备工艺：
（1）将非诺贝特、氨丁三醇溶解在适量70℃乙醇中；
（2）处方量称取乳糖、微晶纤维素和羧甲基淀粉钠，混合均匀；
（3）将步骤（1）得到的溶液在步骤（2）的混合辅料上制粒，50℃干燥，14目筛整粒，干颗粒中加入滑石粉混合均匀，填充胶囊壳。
对比实施例1 非诺贝特胶囊的制备
非诺贝特 100g
氨丁三醇 12g
乳糖 100g
微晶纤维素 100g
交联聚维酮 40g
滑石粉 4.2g
制备工艺：
（1）处方量称取非诺贝特、氨丁三醇、乳糖、微晶纤维素和交联聚维酮，混合均匀；
（2）加入适量乙醇制粒，50℃干燥，14目筛整粒，干颗粒中加入滑石粉混合均匀，填充胶囊壳。
对比实施例2 非诺贝特胶囊的制备
非诺贝特 100g
乳糖 100g
微晶纤维素 100g
交联聚维酮 40g
滑石粉 4.2g
制备工艺：
（1）将非诺贝特溶解在适量70℃乙醇中；
（2）处方量称取乳糖、微晶纤维素和交联聚维酮，混合均匀；
（3）将步骤（1）得到的溶液在步骤（2）的混合辅料上制粒，50℃干燥，14目筛整粒，干颗粒中加入滑石粉混合均匀，填充胶囊壳。
实施例4 非诺贝特胶囊的溶出度测定
分别取实施例1-3和对比实施例1-2制备的非诺贝特胶囊样品，照溶出度测定法（附录XC 第二法）， 以1.0%十二烷基硫酸钠溶液1000ml为溶出介质，转速为每分钟 100转,依法操作，经20分钟时，取溶液10ml,滤过，精密量取续 滤液5ml,置50ml量瓶中，用水稀释至刻度，摇匀，作为供试品 溶液；另取非诺贝特对照品约lOmg,精密称定，置100ml量瓶 中，加无水乙醇溶解并稀释至刻度，摇匀，精密量取5ml，置50ml量瓶中，加溶出介质5ml，用水稀释至刻度，摇匀，作为对照品溶液。取上述二种溶液，照紫外-可见分光光度法（附录IV A),在289nm的波长处测定吸光度,计箅每粒的溶出量。限度为标示量的60%,应符合规定。
溶出度测定结果见表1。
表1 各实施例制备的非诺贝特胶囊的溶出度比较
从表1的试验统计结果可知，本发明实施例1-3制备的非诺贝特胶囊溶出迅速，20min基本完全溶出，远远高于中国药典中60min溶出不低于60%的要求；对比实施例1未将非诺贝特、氨丁三醇溶解在乙醇中，溶出效果较差；对比实施例2仅将非诺贝特溶解在乙醇中，未加入氨丁三醇，在制粒过程中，随着乙醇的挥发，粘合剂溶液中药物析出晶体而聚集，导致药物不能完全以分子状态分散开，因此溶出效果差。
Claims (10)
1.一种非诺贝特胶囊剂，该胶囊剂是将含药颗粒与润滑剂混匀后填充胶囊壳而成，其特征在于：所述的含药颗粒是以含非诺贝特和氨丁三醇的乙醇溶液作为粘合剂，与药学上可接受的其它辅料湿法制粒所得。
2.根据权利要求1所述非诺贝特胶囊剂，其特征在于：所述含非诺贝特和氨丁三醇的乙醇溶液中，非诺贝特与氨丁三醇的重量比为1:0.05-0.3。
3.根据权利要求2所述非诺贝特胶囊剂，其特征在于：所述含非诺贝特和氨丁三醇的乙醇溶液中，非诺贝特与氨丁三醇的重量比为1:0.10-0.15。
4.根据权利要求1或2或3所述非诺贝特胶囊剂，其特征在于：所述的润滑剂为滑石粉。
5.根据权利要求1或2或3所述非诺贝特胶囊剂，其特征在于：所述药学上可接受的其它辅料包括填充剂、崩解剂。
6.根据权利要求5所述非诺贝特胶囊剂，其特征在于：所述的填充剂选自乳糖、微晶纤维素、淀粉、预胶化淀粉和甘露醇中的一种或几种。
7.根据权利要求5所述非诺贝特胶囊剂，其特征在于：所述的崩解剂选自交联聚维酮、交联羧甲基纤维素钠、低取代羟丙基纤维素和羧甲基淀粉钠中的一种或几种。
8.一种根据权利要求1或2或3所述非诺贝特胶囊剂的制备工艺，其特征在于该工艺包括如下步骤：
（1）将非诺贝特、氨丁三醇溶解在乙醇中，形成含非诺贝特和氨丁三醇的乙醇溶液；
（2）将步骤（1）得到的乙醇溶液作为粘合剂，在药学上可接受的其它辅料上湿法制粒，干燥，加入润滑剂混合均匀，填充胶囊壳。
9.根据权利要求8所述非诺贝特胶囊剂的制备工艺，其特征在于：所述药学上可接受的其它辅料包括填充剂、崩解剂。
10.根据权利要求9所述非诺贝特胶囊剂的制备工艺，其特征在于：所述的填充剂选自乳糖、微晶纤维素、淀粉、预胶化淀粉和甘露醇中的一种或几种；所述的崩解剂选自交联聚维酮、交联羧甲基纤维素钠、低取代羟丙基纤维素和羧甲基淀粉钠中的一种或几种。
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