CN116473942A - 一种氯雷他定缓释胶囊及其制备方法 - Google Patents
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Abstract
本发明属于医药口服固体制剂技术领域,涉及一种氯雷他定缓释胶囊及其制备方法,本申请提供了一种含氯雷他定的缓释胶囊,其中氯雷他定与柠檬酸和水杨酸熔融混合制备含药丸芯,丸芯外包衣缓释层、速释层、保护层。不仅可以有效解决人体在胃酸不足情况下氯雷他定溶出速度慢的问题,而且药物释放均匀,可达到长效、增加疗效的目的。
Description
技术领域
本发明属于医药口服固体制剂技术领域,具体涉及一种氯雷他定缓释胶囊及其制备方法。
背景技术
变态反应又称过敏反应,近代医学将此反应称为抗原-抗体反应。全球普通人群中约10%-45%有过敏性疾病,且发病率正在不断增加.我国约有2亿人患有过敏性疾病,世卫组织已把过敏性疾病列为“21世纪重点研究和预防的疾病”随着人类生存环境的改变,致敏原的增加,变态反应性疾病的发病率有增长的趋势,我国过敏人群也在不断增加,尤其季节过敏人数上升曲线变化十分明显,对过敏性疾病的防治已成为刻不容缓的任务,抗过敏药市场的发展潜力巨大。氯雷他定是第二代抗组胺药物分子结构中的两性离子特征使其无明显的中枢抑制作用,临床主要用于防治过敏性鼻炎、慢性特发性荨麻疹、过敏性哮喘和特异性皮炎等疾病。美国FDA公开资料显示氯雷他定片剂、口腔崩解片剂等的制备均采用微粉化的原料。药物微粉化可显著提高制剂的溶出速率,但微粉化也存在药物粉末容易再聚集、原辅料难以混合均匀等诸多缺点。
氯雷他定是水不溶性物质,其溶解特性为:在强酸溶液中溶解,而在弱酸溶液或水中几乎不溶。目前氯雷他定片中其质量标准仅对其在较强的盐酸溶液(pH=2)中的溶出度进行测定,实际上市售氯雷他定片在该环境下溶出度较高,但在弱酸环境和中性环境下其溶出度较低,而胃液分泌过少的患者或者医源性导致的胃液分泌过少的患者,一旦服用普通氯雷他定片,首先在胃内其制剂的释放行为可能会因为pH的升高而受到影响,而药物一旦进入肠道内,氯雷他定释放度会更低,其临床效果也因此而受到影响。
针对此问题,本发明采用氯雷他定与柠檬酸、水杨酸熔融结合使用挤出滚圆制备含药丸芯,再使用流化床包衣机进行缓释层、速释层、保护层包衣,最后进行胶囊填充氯雷他定缓释胶囊。为氯雷他定的溶解、溶出制造适合的酸性环境可以明显优化氯雷他定的高pH溶出性能,更好地适应胃酸不足患者的需求。
发明内容
本发明的目的在于克服现有技术的缺点和不足,提供一种具有作用持久、服药次数少、血药浓度平稳、安全性更高的氯雷他定缓释胶囊。现有技术采用湿法制粒、挤出滚圆、流化床包衣工艺生产,工艺流程复杂,控制要求较高。
本发明的提供的一种氯雷他定缓释胶囊,由缓释微丸和空心胶囊两部分组成,缓释微丸制备过程包括含药丸芯、缓释层、速释层、保护层。按重量百分比计算,所述缓释微丸由70-75%的含药丸芯、5-10%的缓释包衣层、10-15%的速释包衣层和保护层组成。
所述的氯雷他定缓释胶囊,其中含药丸芯应确保颗粒具有可接受的成型性、圆整度、脆碎度等,可选辅料包括微晶纤维素、淀粉、甘露醇、蔗糖、二氧化硅或其组合;优选选自甘露醇、微晶纤维素、二氧化硅或其组合;最终优选微晶纤维素,因为其良好的成型性,所制颗粒圆整度高、脆碎度低。本发明特别采用氯雷他定与柠檬酸、水杨酸结合的方法,即含药丸芯包括:氯雷他定、柠檬酸、和水杨酸以2:1:1的质量比熔融混合,然后与微晶纤维素制备软材。
所述的氯雷他定缓释胶囊,其中缓释组分的缓释层含有成膜材料,成膜材料选自乙基纤维素、聚甲基丙烯酸胺酯或组合,缓释层还含有增塑剂,增塑剂选自聚乙二醇、羟丙甲纤维素、枸橼酸三乙酯、甘油或其组合。最终优选胃溶型成膜材料乙基纤维素,还含有滑石粉作为抗粘剂。
所述的氯雷他定缓释胶囊,其中速释层含有氯雷他定、聚维酮k30、聚乙二醇的混合溶液。
所述的氯雷他定缓释胶囊,其中保护层含有胃溶型成膜材料羟丙基甲基纤维素、纯化水。优选地,如上所述的含药丸芯中各组分的质量用量比为:氯雷他定:柠檬酸:水杨酸=2:1:1,熔融后混合物:微晶纤维素:共聚维酮:纯化水=1:3:0.2:10;
优选地,如上所述的缓释层中各组分的质量用量比为:乙基纤维素:95%乙醇:纯化水:滑石粉=1:16:1:0.5;
优选地,如上所述的速释层中各组分的质量用量比为:氯雷他定:聚维酮k30:聚乙二醇:纯化水:95%乙醇=1:1.5:2:5:5;
优选地,如上所述的保护层中各组分的质量用量比为:羟丙基甲基纤维素:纯化水1:8。
制备过程:
1)所述氯雷他定缓释胶囊的制备方法,含药丸芯采用将氯雷他定和柠檬酸、水杨酸加热至熔融,维持熔融状态加入微晶纤维素和共聚维酮水溶液以及纯化水制软材,使用湿法制粒机,设置搅拌600rpm,切碎1000rpm,过程中看软材湿润程度加入纯化水;
挤出滚圆:之后挤出滚圆制备含药丸芯并用流化床沸腾干燥.挤出滚圆工艺包括挤出和滚圆两个步骤,挤出步骤将软材挤压通过筛孔成致密条状,滚圆步骤的锯齿底盘将挤出物料条切碎,离心作用将切碎颗粒滚圆,并致密。挤出设置转速40-50rpm,滚圆设置转速1000-1300rpm,控制制备的微丸圆整,大小均匀,无明显细粉,不黏连;
干燥:使用流化床干燥,进风温度设置60℃,进风风量控制100-140m3/h,控制水分不超过4%;
筛分:制得微丸过筛20-30目,收集过筛后微丸进行下一步包衣。
2)所述的氯雷他定缓释胶囊的制备方法,缓释层采用乙基纤维素与95%乙醇和纯化水按比例配制溶液,在干燥的微丸上进行包衣,流化床参数设置进风风量40-60m3/h、进风温度40-60℃、雾化压力200-300kPa、物料温度30-40℃,加入滑石粉作为抗粘剂。
3)所述的氯雷他定缓释胶囊的制备方法,速释层采用将氯雷他定和共聚维酮溶于95%乙醇中,同时将聚乙二醇溶于水中,然后将两种溶液混合得速释层含药包衣液。流化床设置参数进风风量40-60m3/h、进风温度40-60℃、雾化压力300-400kPa、物料温度30-40℃。
4)所述的氯雷他定缓释胶囊的制备方法,保护层采用羟丙基甲基纤维素先用热水搅拌分散后,加入冷水搅拌冷却后即可溶解。流化床设置参数进风风量40-60m3/h、进风温度40-60℃、雾化压力300-360kPa、物料温度30-40℃。
所述的氯雷他定缓释胶囊的制备方法,将得到的氯雷他定缓释微丸装入明胶胶囊壳中,每粒胶囊含氯雷他定10mg。
具体实施例
下面结合具体实施例对本发明作进一步详细说明,但本发明的实施例方式并不受下述实施例的限制,其他任何在本发明实质的基础上所作的进一步改变、修饰、替代、组合以及简化均应视为等效替换,包含在本发明的能保护范围之内。
实施例1:氯雷他定缓释胶囊
处方组成10000粒
含药丸芯制备工艺:
1)所述氯雷他定缓释胶囊的制备方法,含药丸芯采用将氯雷他定和柠檬酸、水杨酸按比例160摄氏下加热至熔融,维持熔融状态5分钟,加入微晶纤维素和共聚维酮水溶液以及纯化水制软材,使用湿法制粒机,设置搅拌600rpm,切碎1000rpm,过程中看软材湿润程度加入纯化水;
挤出滚圆:之后挤出滚圆制备含药丸芯并用流化床沸腾干燥.挤出滚圆工艺包括挤出和滚圆两个步骤,挤出步骤将软材挤压通过筛孔成致密条状,滚圆步骤的锯齿底盘将挤出物料条切碎,离心作用将切碎颗粒滚圆,并致密。挤出设置转速40-50rpm,滚圆设置转速1000-1300rpm,控制制备的微丸圆整,大小均匀,无明显细粉,不黏连;
干燥:使用流化床干燥,进风温度设置60℃,进风风量控制100-140m3/h,控制水分不超过4%;
筛分:制得微丸过筛20-30目,收集过筛后微丸进行下一步包衣。
缓释层制备工艺:
2)缓释层采用乙基纤维素与95%乙醇和纯化水按比例配制溶液,在干燥的微丸上进行包衣,流化床参数设置进风风量40-60m3/h、进风温度40-60℃、雾化压力200-400kPa、物料温度30-40℃,加入滑石粉作为抗粘剂。
速释层制备工艺:
3)速释层采用将氯雷他定和共聚维酮溶于95%乙醇中,同时将聚乙二醇溶于水中,然后将两种溶液混合得速释层含药包衣液。流化床设置参数进风风量40-60m3/h、进风温度40-60℃、雾化压力300-400kPa、物料温度30-40℃。
保护层制备工艺:
4)保护层采用羟丙基甲基纤维素先用热水搅拌分散后,加入冷水搅拌冷却后即可溶解。流化床设置参数进风风量40-60m3/h、进风温度40-60℃、雾化压力300-360kPa、物料温度30-40℃。
5)胶囊填充,将得到的氯雷他定缓释微丸装入明胶胶囊壳中。
实施例2:氯雷他定缓释胶囊
处方组成10000粒
含药丸芯制备工艺:
1)所述氯雷他定缓释胶囊的制备方法,含药丸芯采用将氯雷他定和柠檬酸、水杨酸按比例160摄氏下加热至熔融,维持熔融状态5分钟,加入微晶纤维素和共聚维酮水溶液以及纯化水制软材,使用湿法制粒机,设置搅拌600rpm,切碎1000rpm,过程中看软材湿润程度加入纯化水;
挤出滚圆:之后挤出滚圆制备含药丸芯并用流化床沸腾干燥.挤出滚圆工艺包括挤出和滚圆两个步骤,挤出步骤将软材挤压通过筛孔成致密条状,滚圆步骤的锯齿底盘将挤出物料条切碎,离心作用将切碎颗粒滚圆,并致密。挤出设置转速40-50rpm,滚圆设置转速1000-1300rpm,控制制备的微丸圆整,大小均匀,无明显细粉,不黏连;
干燥:使用流化床干燥,进风温度设置60℃,进风风量控制100-140m3/h,控制水分不超过4%;
筛分:制得微丸过筛20-30目,收集过筛后微丸进行下一步包衣。
缓释层制备工艺:
2)缓释层采用乙基纤维素与95%乙醇和纯化水按比例配制溶液,在干燥的微丸上进行包衣,流化床参数设置进风风量40-60m3/h、进风温度40-60℃、雾化压力200-400kPa、物料温度30-40℃,加入滑石粉作为抗粘剂。
速释层制备工艺:
4)速释层采用将氯雷他定和共聚维酮溶于95%乙醇中,同时将聚乙二醇溶于水中,然后将两种溶液混合得速释层含药包衣液。流化床设置参数进风风量40-60m3/h、进风温度40-60℃、雾化压力300-400kPa、物料温度30-40℃。
保护层制备工艺:
4)保护层采用羟丙基甲基纤维素先用热水搅拌分散后,加入冷水搅拌冷却后即可溶解。流化床设置参数进风风量40-60m3/h、进风温度40-60℃、雾化压力300-360kPa、物料温度30-40℃。
5)胶囊填充,将得到的氯雷他定缓释微丸装入明胶胶囊壳中。
实施例3:氯雷他定缓释胶囊
处方组成10000粒
含药丸芯制备工艺:
1)所述氯雷他定缓释胶囊的制备方法,含药丸芯采用将氯雷他定和柠檬酸、水杨酸按比例160摄氏下加热至熔融,维持熔融状态5分钟,加入微晶纤维素和共聚维酮水溶液以及纯化水制软材,使用湿法制粒机,设置搅拌600rpm,切碎1000rpm,过程中看软材湿润程度加入纯化水;
挤出滚圆:之后挤出滚圆制备含药丸芯并用流化床沸腾干燥.挤出滚圆工艺包括挤出和滚圆两个步骤,挤出步骤将软材挤压通过筛孔成致密条状,滚圆步骤的锯齿底盘将挤出物料条切碎,离心作用将切碎颗粒滚圆,并致密。挤出设置转速40-50rpm,滚圆设置转速1000-1300rpm,控制制备的微丸圆整,大小均匀,无明显细粉,不黏连;
干燥:使用流化床干燥,进风温度设置60℃,进风风量控制100-140m3/h,控制水分不超过4%;
筛分:制得微丸过筛20-30目,收集过筛后微丸进行下一步包衣。
缓释层制备工艺:
2)缓释层采用乙基纤维素与95%乙醇和纯化水按比例配制溶液,在干燥的微丸上进行包衣,流化床参数设置进风风量40-60m3/h、进风温度40-60℃、雾化压力200-400kPa、物料温度30-40℃,加入滑石粉作为抗粘剂。
速释层制备工艺:
5)速释层采用将氯雷他定和共聚维酮溶于95%乙醇中,同时将聚乙二醇溶于水中,然后将两种溶液混合得速释层含药包衣液。流化床设置参数进风风量40-60m3/h、进风温度40-60℃、雾化压力300-400kPa、物料温度30-40℃。
保护层制备工艺:
4)保护层采用羟丙基甲基纤维素先用热水搅拌分散后,加入冷水搅拌冷却后即可溶解。流化床设置参数进风风量40-60m3/h、进风温度40-60℃、雾化压力300-360kPa、物料温度30-40℃。
5)胶囊填充,将得到的氯雷他定缓释微丸装入明胶胶囊壳中。
对比例1:氯雷他定缓释胶囊
处方组成10000粒
同时参照上述方法在上述配方的基础上分别做出以下变化制备对照产品:不熔融混合任何酸的氯雷他定为原料制备,其他工艺步骤同实施例1、例2。
随机取各实施例和对比例制备的样品各10粒,照溶出度测定法(中国药典2010年版二部附录XC第二法),以0.lmol/L盐酸溶液900ml为溶剂,转速为每分钟50转,依法操作,分别于5、10、15、30分钟时,取溶液5ml,滤过,取续滤液作为供试品溶液;另精密称取105℃干燥至恒重的氯雷他定对照品适量,加0.1mol/L盐酸溶液溶解并定量稀释成每lml中约含氯雷他定11ug的溶液,作为对照品溶液。精密量取供试品溶液及对照品溶液各20ul注入液相色谱仪,记录色谱图,按外标法以峰面积计算,即得。
表1所得实施例和对比例溶出度结果
Ph=1
由表1可知:对比例的5分钟、10分钟溶出稍慢,其他实施例都与参比制剂溶出相仿。
表2所得实施例和对比例溶出度结果
Ph=2
实施例 | 5分钟 | 10分钟 | 15分钟 | 30分钟 |
实施例1 | 94.6 | 97.8 | 99.5 | 99.8 |
实施例2 | 94.0 | 98.9 | 99.9 | 99.8 |
实施例3 | 93.6 | 99.5 | 99.6 | 100.1 |
对比例1 | 74.0 | 84.8 | 89.6 | 100.0 |
参比制剂1 | 95.4 | 97.8 | 99.9 | 99.7 |
由表2可知:可见在模拟一般胃液的pH 2的环境下,除对比例1外各种药剂均能实现快速溶出。
表3所得实施例和对比例溶出度结果
Ph=6.8纯化水
实施例 | 5分钟 | 10分钟 | 15分钟 | 30分钟 |
实施例1 | 66.3 | 68.3 | 77.3 | 88.9 |
实施例2 | 63.2 | 73.0 | 75.5 | 84.3 |
实施例3 | 69.5 | 73.2 | 75.4 | 83.2 |
对比例1 | 44.9 | 48.3 | 55.2 | 60.1 |
参比制剂1 | 59.3 | 62.3 | 70.2 | 77.6 |
由表3可知:药品的溶解性能都受到了明显的影响,除对比例1除外其他30分钟溶出都超过70%。pH 4-7的胃酸pH在大量饮水、进食或疾病情况下都可能出现,溶出效果变差意味着这些情况下药剂中的氯雷他定起效时间明显变慢,不能充分适应治疗过敏、感冒、鼻炎等问题的要求。
2、实施例和对比例所得胶囊剂的稳定性比较
将实施例和对比例制备所得的胶囊剂分别置于高温(40℃)、高湿(相对湿度75±5%)的恒温恒湿箱内加速试验6个月,分别于0天、6个月检测有关物质。
表4实施例和对比例加速6个月稳定性的比较
由表4的数据可知,经过加速试验分析结果可以看出,采用本发明制备的胶囊在加速条件后产品杂质含量远低于实施例和原研参比制剂,所得产品质量稳定性更好。同时,在经过加速试验后产品的杂质仍符合质量标准,显著提高了产品的储存期限,有效延长了产品的保质期。
Claims (9)
1.一种氯雷他定缓释胶囊,其特征在于:所述缓释胶囊包含含药丸芯、缓释层、速释层、保护层,其中,含药丸芯由氯雷他定、水杨酸、柠檬酸或苹果酸、微晶纤维素或甘露醇组成;缓释层由胃溶型成膜材料乙基纤维素的乙醇溶液组成,速释层由氯雷他定、聚维酮k30或共聚维酮、聚乙二醇的混合溶液组成;保护层由胃溶型成膜材料羟丙基甲基纤维素溶液组成。
2.根据权利要求1所述的氯雷他定缓释胶囊,其特征在于:以重量份数计,所述缓释胶囊的含药丸芯组成如下:
3.根据权利要求1所述的氯雷他定缓释胶囊,其特征在于:以重量份数计,所述缓释胶囊的缓释层包衣组成如下:
4.根据权利要求1所述的氯雷他定缓释胶囊,其特征在于:以重量份数计,所述缓释胶囊的速释层包衣组成如下:
5.根据权利要求1所述的氯雷他定缓释胶囊,其特征在于:以重量份数计,所述缓释胶囊的保护层包衣组成如下:
羟丙基甲基纤维素 10~20份
纯化水 50~100份。
6.一种制备权利要求1所述氯雷他定缓释胶囊的制备方法,其特征在于,所述制备方法包括如下步骤;
(1)含药丸芯制备:含药丸芯制备工艺包括制软材、挤出滚圆、流化床干燥、筛分;
(2)流化床包衣机对含药丸芯进行缓释层、速释层、保护层包衣;
(3)胶囊填充:将得到的氯雷他定缓释微丸装入明胶胶囊壳。
7.根据权利要求6所述的氯雷他定缓释胶囊的制备方法,其特征在于:所述氯雷他定缓释胶囊制备过程为:
含药丸芯的制备:将氯雷他定和柠檬酸、水杨酸加热至熔融,加入微晶纤维素和共聚维酮水溶液以及纯化水制软材,使用湿法制粒机,入纯化水;
挤出滚圆:挤出滚圆工艺包括挤出和滚圆两个步骤,挤出步骤将软材挤压通过筛孔成致密条状,滚圆步骤的锯齿底盘将挤出物料条切碎,离心作用将切碎颗粒滚圆;;
干燥:使用流化床干燥,控制水分不超过4%;
筛分:制得微丸过筛20-30目,收集过筛后微丸进行下一步包衣。
8.根据权利要求6所述的氯雷他定缓释胶囊的制备方法,其特征在于:所述缓释层采用乙基纤维素与95%乙醇和纯化水按比例配制溶液,在干燥的微丸上进行包衣,流化床参数设置进风风量40-60m3/h、进风温度40-60℃、雾化压力200-300kPa、物料温度30-40℃,加入滑石粉作为抗粘剂,所述速释层采用将氯雷他定和共聚维酮溶于95%乙醇中,同时将聚乙二醇溶于水中,然后将两种溶液混合得速释层含药包衣液,流化床设置参数进风风量40-60m3/h、进风温度40-60℃、雾化压力300-400kPa、物料温度30-40℃;所述保护层采用羟丙基甲基纤维素先用热水搅拌分散后,加入冷水搅拌冷却后即可溶解。流化床设置参数进风风量40-60m3/h、进风温度40-60℃、雾化压力300-360kPa、物料温度30-40℃。
9.根据权利要求6所述的氯雷他定缓释胶囊的制备方法,其特征在于:步骤(3)为:胶囊充填:将得到的氯雷他定缓释微丸装入明胶胶囊壳中,每粒胶囊含氯雷他定10mg。
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