CN112220765A - 一种含有辛伐他汀的口服制剂及其制备方法 - Google Patents
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Abstract
本发明公开了一种含有辛伐他汀的口服制剂及其制备方法，由如下方法制备：将辛伐他汀经羟丙基‑β‑环糊精(HP‑β‑CD)包合，形成的包合物极易溶于水，极大提高了药物的稳定性，促进药物在体内的释放，增加吸收，提高生物利用度，降低用药个体间差异。本发明制备的辛伐他汀口服制剂克服了原料难溶于水，且普通片剂存在溶出度低，生物利用度低的问题，制得的口服制剂崩解迅速，质量稳定，体内吸收好，提高了产品质量，保证了产品在长期储存过程中的稳定性。
Description
技术领域
本发明涉及药物制剂领域，具体涉及一种含有辛伐他汀的口服制剂及其制备方法。
背景技术
他汀类药物是目前国际上最流行的调血脂药物，可用于治疗原发性高胆固醇症等，目前，辛伐他汀已成为治疗高血脂的首选药物之一。辛伐他汀由美国默克公司开发，商品名舒降之 (规格有5mg、10mg、20mg、40mg多种规格)，国内外生产厂家有多家。因为辛伐他汀原料易降解，因此市售产品处方中多含丁基羟基茴香醚(BHA抗氧剂)、抗坏血酸(抗氧剂)和一水柠檬酸等组分。其中抗坏血酸不稳定，遇光照和湿热后易氧化变质，产生黄色物质；柠檬酸吸湿性强且长期使用会刺激人体胃肠道分泌过多胃液，增加文昌到负担，造成病人的不适；丁基羟基茴香醚(BHA)有一定的致癌性，且实验发现，上述物质易引入新的杂质，从而导致有关物质的升高。因此如果能够去除产品中的酸性保护剂和抗氧剂，将大大提高药品的安全性。
现有技术中，专利CN103191072B公开了一种辛伐他汀片剂，其采用脂质体包合物与药学上可用的辅料直接压片而成，在实际生产过程中用到卵磷脂，卵磷脂极易被氧化，从而影响药物稳定性，同时给设备清洁带来极大难度，难以实现大批量生产。专利CN105106198B 公开了一种高稳定的辛伐他汀片剂及其制备方法，采取在处方中加入抗氧剂丁羟基茴香醚，并采取湿法制粒低温干燥的方式来获得高稳定性的辛伐他汀片，但是丁羟基茴香醚具有一定的致癌性，采取湿法制粒，低温和高温结合，工艺操作复杂，对生产设备要求较高，为生产带来极大不便。此外，由于辛伐他汀在水中溶解度很低，几乎不溶，经口途径仅有5％药物以活性成分进入人体循环，因此如何在保证药物稳定性的前提下提高生物利用度，是目前急需解决的问题。
羟丙基-β-环糊精呈无定型，极易溶于水，在药物制剂方面有广泛应用，主要被应用于难溶性药物的增溶和提高药物的稳定性，此外还可以促进药物在体内的释放，增加吸收，提高生物利用度，同时还可以掩盖不良气味。
考虑到以上问题，本研究创新性的将辛伐他汀经羟丙基-β-环糊精(HP-β-CD)包合，包合后极易溶于水，极大提高了药物的稳定性，促进药物在体内的释放，增加吸收，提高生物利用度，降低用药个体间差异。
发明内容
本发明提供一种含有辛伐他汀的口服制剂及其制备方法，它含有辛伐他汀、羟丙基-β- 环糊精、和填充剂、崩解剂、粘合剂和润滑剂组成。工艺简单可行，且保证药物的稳定性，促进药物在体内的释放，增加吸收，提高生物利用度。本发明的目的是通过以下步骤实现的：
所述的一种含有辛伐他汀的口服制剂及其制备方法，其特征在于，该辛伐他汀的口服制剂包括辛伐他汀、羟丙基-β-环糊精、填充剂、崩解剂、粘合剂和润滑剂组成。
所述的一种含有辛伐他汀的口服制剂及其制备方法，其特征在于，所述的填充剂为甘露醇、微晶纤维素、玉米淀粉、多孔淀粉中的一种。
所述的一种含有辛伐他汀的口服制剂及其制备方法，其特征在于，所述的崩解剂为微晶纤维素、羧甲纤维素、羧甲纤维素钙、交联羧甲基纤维素钠、交联聚维酮、羟丙基淀粉等中的一种。
所述的一种含有辛伐他汀的口服制剂及其制备方法，其特征在于，所述的润滑剂为滑石粉、硬脂酸镁中的一种。
所述的一种含有辛伐他汀的口服制剂及其制备方法，其特征在于，所述的粘合剂为2％的聚乙烯吡咯烷酮水溶液。
1、所述的一种含有辛伐他汀的口服制剂及其制备方法，其特征在于，辛伐他汀1份，羟丙基 -β-环糊精1-3份，粘合剂30-70份，填充剂10-50份，崩解剂2～10份，润滑剂0.05-3份。
所述的一种含有辛伐他汀的口服制剂及其制备方法，其特征在于，所述的包合物的制备方法，包括以下步骤：
(1)将羟丙基-β-环糊精溶于水制成饱和溶液，得溶液A；
(2)辛伐他汀溶于无水乙醇中，溶解得溶液B。
在磁力搅拌下，将溶液B缓缓滴入溶液A中，全部加入后室温继续搅拌2-4h，静置12h，过滤减压干燥或冷冻干燥，得包合物。
所述的一种含有辛伐他汀的口服制剂及其制备方法，其特征在于，其制备方法为：先用羟丙基-β-环糊精与辛伐他汀形成包合物，再将所得包合物与填充剂、崩解剂混合均匀，加粘合剂制成软材，过筛制粒，干燥后加入润滑剂，压片即得。
辛伐他汀原料难溶于水，且普通片剂存在溶出度低，生物利用度低的问题，本发明的优点在于，将辛伐他汀经羟丙基-β-环糊精(HP-β-CD)包合，形成的包合物极易溶于水，极大提高了药物的稳定性，促进药物在体内的释放，增加吸收，提高生物利用度，降低用药个体间差异。
具体实施方式
下面实施例只为进一步说明本发明，不以任何形式限制本发明。
实施例1
本实施例提供一种含有辛伐他汀的口服制剂及其制备方法，所述的口服制剂由以下制备步骤得到：
| 名称 | 用量/g |
| 辛伐他汀 | 10 |
| 羟丙基-β-环糊精 | 50 |
| 2％的聚乙烯吡咯烷酮 | 300 |
| 微晶纤维素 | 200 |
| 交联聚维酮 | 50 |
| 硬脂酸镁 | 2 |
制备方法：
将羟丙基-β-环糊精溶于水制成饱和溶液，得溶液A；辛伐他汀溶于无水乙醇中，溶解得溶液B。在磁力搅拌下，将溶液B缓缓滴入溶液A中，全部加入后室温继续搅拌2-4h，静置12h，过滤减压干燥或冷冻干燥，得包合物。
将所得包合物与微晶纤维素、交联聚维酮混合均匀，加2％的聚乙烯吡咯烷酮水溶液制成软材，过筛制粒，干燥后加入硬脂酸镁，压片即得。
实施例2
本实施例提供一种含有辛伐他汀的口服制剂及其制备方法，所述的口服制剂由以下制备步骤得到：
| 名称 | 用量/g |
| 辛伐他汀 | 10 |
| 羟丙基-β-环糊精 | 30 |
| 2％的聚乙烯吡咯烷酮 | 500 |
| 多孔淀粉 | 100 |
| 交联羧甲基纤维素钠 | 30 |
| 滑石粉 | 8 |
制备方法：
将羟丙基-β-环糊精溶于水制成饱和溶液，得溶液A；辛伐他汀溶于无水乙醇中，溶解得溶液B。在磁力搅拌下，将溶液B缓缓滴入溶液A中，全部加入后室温继续搅拌2-4h，静置12h，过滤减压干燥或冷冻干燥，得包合物。
将所得包合物与多孔淀粉、交联羧甲基纤维素钠混合均匀，加2％的聚乙烯吡咯烷酮水溶液制成软材，过筛制粒，干燥后加入滑石粉，压片即得。
实施例3
本实施例提供一种含有辛伐他汀的口服制剂及其制备方法，所述的口服制剂由以下制备步骤得到：
| 名称 | 用量/g |
| 辛伐他汀 | 10 |
| 羟丙基-β-环糊精 | 60 |
| 2％的聚乙烯吡咯烷酮 | 600 |
| 甘露醇 | 300 |
| 羟丙基淀粉 | 60 |
| 滑石粉 | 15 |
制备方法：
将羟丙基-β-环糊精溶于水制成饱和溶液，得溶液A；辛伐他汀溶于无水乙醇中，溶解得溶液B。在磁力搅拌下，将溶液B缓缓滴入溶液A中，全部加入后室温继续搅拌2-4h，静置12h，过滤减压干燥或冷冻干燥，得包合物。
将所得包合物与甘露醇、羟丙基淀粉混合均匀，加2％的聚乙烯吡咯烷酮水溶液制成软材，过筛制粒，干燥后加入滑石粉，压片即得。
对比实施例1(参考专利CN110051636A)
| 名称 | 用量/g |
| 辛伐他汀 | 10 |
| 微晶纤维素 | 50 |
| 乳糖 | 30.15 |
| 预胶化淀粉 | 5.75 |
| 硬脂酸镁 | 2 |
| 叔丁基-4羟基茴香醚(BHA) | 0.1 |
| 低取代羟丙基纤维素 | 2 |
制备方法：
将辛伐他汀与等量乳糖混合均匀，雾化后加入BHA的异丙醇溶液，再加入剩余重量的乳糖，混合后热风干燥，剩余物粉碎；加入预胶化淀粉混合，雾化加入异丙醇湿法制粒，热风干燥后，整粒；加入低取代羟丙基纤维素、微晶纤维素、硬脂酸镁混合均匀，压片即得。对比实施例2(参考专利103191072B)
| 名称 | 用量/g |
| 辛伐他汀 | 10 |
| 卵磷脂 | 10 |
| 羟丙基-β-环糊精 | 120 |
| 无水乙醇 | 1000 |
| 乳糖 | 400 |
| 交联聚维酮 | 15 |
| 硬脂酸镁 | 6 |
制备方法：
将辛伐他汀、羟丙基-β-环糊精羟丙基-β-环糊精和卵磷脂溶于无水乙醇中，搅拌减压干燥，除去乙醇，得辛伐他汀脂质体包合物；加入乳糖、交联聚维酮、硬脂酸镁混合均匀，直接压片即得。
验证实施例
1、释放度试验
取本品，照中国药典(附录XD第一法)溶出度测定法，以含0.5％十二烷基硫酸钠的0.01mol/L磷酸二氢钠缓冲液900ml为溶出介质，转速每分钟50转，依法操作，经30min时，取溶液10ml，滤过，取续滤液作为供试品溶液。
表1释放度测定结果
2、稳定性试验
表2稳定性考察结果汇总
3、药代动力学试验
实施例1-3和对比实施例1-2进行药代动力学实验，每组雄性SD大鼠6只，体重190-210g，随机分组，灌胃给药，给药剂量20mg/kg，分别于给药后5min、15min、30min、60min、90min、 120min、240min、480min、720min经眼眶静脉采血，置于肝素化试管中，测定其血药浓度，计算Cmax、AUC，并同市受辛伐他汀片(商品名：舒降之@)对比，进一步计算对于舒降之@的Cmax、AUC的比值。
表3药代动力学测定结果
| 实施例 | Cmax比值 | AUC(0-t)比值 |
| 实施例1 | 9.1 | 9.1 |
| 实施例2 | 9.8 | 9.6 |
| 实施例3 | 10.2 | 10.7 |
| 对比实施例1 | 1.2 | 1.8 |
| 对比实施例2 | 3.1 | 3.4 |
从结果看出，本发明实施例1-3在体外溶出30min内释放完全，明显优于对比实施例1-2；稳定性试验表明，本发明实施例1-3在加速过程中有关物质、含量均未有明显变化，而对比实施例1-2加速过程中出现含量降低、有关物质升高的情况，稳定性不如本发明；药代动力学研究表明，本发明实施例1-3可明显提高药物的生物利用度，对比实施例1-2效果明显不如本发明。
由上述数据可知，本发明将辛伐他汀经羟丙基-β-环糊精(HP-β-CD)包合，使之形成的包合物极易溶于水，极大提高了药物的稳定性，克服了原料难溶于水，且普通片剂存在溶出度低，生物利用度低的问题。本发明制得的辛伐他汀口服制剂崩解迅速，质量稳定，体内吸收好，提高了产品质量，保证了产品在长期储存过程中的稳定性。
Claims (8)
1.一种含有辛伐他汀的口服制剂及其制备方法，其特征在于，该辛伐他汀的口服制剂包括辛伐他汀、羟丙基-β-环糊精、填充剂、崩解剂、粘合剂和润滑剂组成。
2.根据权利要求1所述的含有辛伐他汀的口服制剂及其制备方法，其特征在于，所述的填充剂为甘露醇、微晶纤维素、玉米淀粉、多孔淀粉中的一种。
3.根据权利要求1所述的含有辛伐他汀的口服制剂及其制备方法，其特征在于，所述的崩解剂为羧甲纤维素、羧甲纤维素钙、交联羧甲基纤维素钠、交联聚维酮、羟丙基淀粉等中的一种。
4.根据权利要求1所述的含有辛伐他汀的口服制剂及其制备方法，其特征在于，所述的润滑剂为滑石粉、硬脂酸镁中的一种。
5.根据权利要求1所述的含有辛伐他汀的口服制剂及其制备方法，其特征在于，所述的粘合剂为2％的聚乙烯吡咯烷酮水溶液。
6.根据权利要求1所述的含有辛伐他汀的口服制剂及其制备方法，其特征在于，辛伐他汀1份，羟丙基-β-环糊精1-6份，粘合剂30-70份，填充剂10-50份，崩解剂2～10份，润滑剂0.05-3份。
7.根据权利要求1所述的含有辛伐他汀的口服制剂及其制备方法，其特征在于，所述的包合物的制备方法，包括以下步骤：(1)将羟丙基-β-环糊精溶于水制成饱和溶液，得溶液A；(2)辛伐他汀溶于无水乙醇中，溶解得溶液B；在磁力搅拌下，将溶液B缓缓滴入溶液A中，全部加入后室温继续搅拌2-4h，静置12h，过滤减压干燥或冷冻干燥，得包合物。
8.根据权利要求1所述的含有辛伐他汀的口服制剂及其制备方法，其特征在于，其制备方法为：先用羟丙基-β-环糊精与辛伐他汀形成包合物，再将所得包合物与填充剂、崩解剂混合均匀，加粘合剂制成软材，过筛制粒，干燥后加入润滑剂，压片即得。
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