CN116850248B - 咳克平胶囊及其制备方法 - Google Patents
咳克平胶囊及其制备方法 Download PDFInfo
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- CN116850248B CN116850248B CN202311060849.3A CN202311060849A CN116850248B CN 116850248 B CN116850248 B CN 116850248B CN 202311060849 A CN202311060849 A CN 202311060849A CN 116850248 B CN116850248 B CN 116850248B
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- chlorpheniramine maleate
- mesoporous silica
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Abstract
本发明涉及一种咳克平胶囊及其制备方法,属于中药制剂领域。其由中药颗粒和马来酸氯苯那敏颗粒组成,所述中药颗粒其由百部140重量份、地黄140重量份、麦冬140重量份、枇杷叶170重量份、苦杏仁50重量份、浙贝母220重量份、前胡50重量份、五味子50重量份、甘草50重量份以及药学上所接受的辅料所制成;所述马来酸氯苯那敏颗粒其由1.4重量份马来酸氯苯那敏和介孔二氧化硅材料组成。
Description
技术领域
本发明涉及一种咳克平胶囊及其制备方法,属于中药制剂领域。
背景技术
随着中西医结合的深入发展,中西药并用防治疾病的情况日趋普遍,因而中西药复方制剂也越来越受到关注。咳克平胶囊就是一种典型的中西药并用的中西药成方制剂,其由吉林通化万通药业研发,主要用于治疗咳嗽、咳痰不爽、平喘消炎、咽干喉痛以及唇舌干燥等。
现有技术中,咳克平胶囊的处方为:百部140g、地黄140g、麦冬140g、枇杷叶170g、苦杏仁50g、浙贝母220g、前胡50g、五味子50g、甘草50g、马来酸氯苯那敏1.4g。制备方法为:取浙贝母、马来酸氯苯那敏分别粉碎成细粉,备用;苦杏仁、前胡、五味子加8倍量50%乙醇提取二次,每次2小时,合并提取液并滤过,滤液减压回收乙醇并浓缩至相对密度为1.25-1.30(60℃)的清膏,备用。药渣与其余百部等五味药材加8倍量水煎煮三次,每次1.5小时,合并煎液并滤过,滤液浓缩至相对密度为1.25-1.30(60℃)的清膏,将上述清膏与浙贝母细粉混匀,干燥,粉碎,加入马来酸氯苯那敏细粉,混匀,制成颗粒,装入胶囊,制成1000粒,即得。
经过十几年的临床应用表明,咳克平胶囊取得了较好的疗效,由于其疗效快、治疗效果稳定,深受医生和患者的欢迎。但是,由于咳克平胶囊是中西药联合制剂,制剂中的西药成分马来酸氯苯那敏在治疗中被发现生物利用度不高,这可能与中药成分较为复杂,在制剂过程中中药成分与马来酸氯苯那敏形成了复合物或缀合物有关,从而影响了马来酸氯苯那敏在人体中的吸收,这也解释了后续发现的咳克平胶囊中马来酸氯苯那敏稳定性不佳的问题原因,其也可能与中药成分与马来酸氯苯那敏在制剂过程中相互作用有关。
因此为了进一步提高咳克平胶囊的疗效和制剂稳定性,有必要开发一种新的咳克平胶囊。
发明内容
本发明的第一方面是提供一种咳克平胶囊,其由中药颗粒和马来酸氯苯那敏颗粒组成,所述中药颗粒其由百部140重量份、地黄140重量份、麦冬140重量份、枇杷叶170重量份、苦杏仁50重量份、浙贝母220重量份、前胡50重量份、五味子50重量份、甘草50重量份以及药学上所接受的辅料所制成;所述马来酸氯苯那敏颗粒其由1.4重量份马来酸氯苯那敏和介孔二氧化硅材料组成。
在一种实施方案中,所述介孔二氧化硅材料为TUD-1、SBA-15或MCM-41中的一种或多种;在优选的实施方案中,所述所述介孔二氧化硅材料为TUD-1,孔径在5-15nm之间,粒径在0.6-0.8mm之间。
在另一种实施方案中,所述马来酸氯苯那敏颗粒还包含叶酸和单双硬脂酸甘油酯;在进一步地实施方案中,叶酸和单双硬脂酸甘油酯的重量比为1:1-5;优选为1:2-4。介孔二氧化硅材料与叶酸和单双硬脂酸甘油酯的重量比2:1。
在又一种实施方案中,所述马来酸氯苯那敏和介孔二氧化硅材料的重量比为0.5-1:1;优选为0.7:1。
在又一种实施方案中,所述马来酸氯苯那敏颗粒还包含辅料,所述辅料为乙基纤维素,乙基纤维素与马来酸氯苯那敏的重量比为1:1-2;优选为1:1.4。
在又一种实施方案中,在中药颗粒中,所述药学上所接受的辅料为微粉硅胶,所述微粉硅胶与浙贝母的重量比为0.05-0.2:1,优选为0.1:1。
在本发明中,所述咳克平胶囊中不包含硬脂酸镁。
本发明的第二方面是提供一种所述咳克平的制备方法,具体包括:
1)中药颗粒制备:取浙贝母粉碎成细粉,备用;苦杏仁、前胡、五味子加8倍量50%乙醇提取二次,每次2小时,合并提取液并滤过,滤液减压回收乙醇并浓缩至相对密度为1.25-1.30(60℃)的清膏,备用。药渣与其余百部等五味药材加8倍量水煎煮三次,每次1.5小时,合并煎液并滤过,滤液浓缩至相对密度为1.25-1.30(60℃)的清膏,将上述清膏与浙贝母细粉混匀,干燥,粉碎,得中药提取物;取22g微粉硅胶,加入中药提取物中,搅拌混匀,用70%乙醇制粒,干燥;
2)马来酸氯苯那敏颗粒制备方法为:取介孔二氧化硅材料,加入无水乙醇,向溶剂体系中添加叶酸和单双硬脂酸甘油酯,然后向溶剂体系中加入马来酸氯苯那敏,室温下搅拌2h后,旋转蒸发去除溶剂,获得负载马来酸氯苯那敏的介孔二氧化硅颗粒。取乙基纤维素加入到颗粒中,用70%乙醇制粒,干燥即得。
3)将中药颗粒与马来酸氯苯那敏颗粒混合,装入胶囊,即得。
本发明的第三方面是提供所述咳克平胶囊在制备治疗咳嗽、咳痰不爽、平喘消炎、咽干喉痛以及唇舌干燥疾病药物中的应用。
本发明提供通过采用介孔二氧化硅材料,较好的改善了咳克平胶囊中马来酸氯苯那敏的生物利用度低和稳定性较差的问题,并且通过对中药颗粒的辅料筛选,解决了马来酸氯苯那敏颗粒在胶囊中差异度较大的问题。
具体实施方式
下面将结合本发明实施例,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1负载马来酸氯苯那敏的介孔二氧化硅颗粒的制备
(一)介孔二氧化硅材料的筛选
试验方法:取0.2g介孔二氧化硅材料,加入无水乙醇,然后向溶剂体系中加入0.2g马来酸氯苯那敏,室温下搅拌2h后,将介孔二氧化硅材料取出,测定乙醇溶液中马来酸氯苯那敏的含量,各组二氧化硅材料如下:
材料名称 | 孔径 | 粒径 | |
组1 | SBA-15 | 5-15nm | 0.6-0.8mm |
组2 | TUD-1 | 5-15nm | 0.6-0.8mm |
组3 | MCM-41 | 2-10nm | 0.6-0.8mm |
对所获得的负载药物颗粒进行负载率测定,负载率=(加入药物重量-乙醇溶液中残留药物重量)/加入药物重量
具体结果如下:
从上述结果可以看出,各种不同的介孔二氧化硅材料对氯苯那敏的负载量具有明显影响,以TUD-1材料负载率最高。
(二)改善药物负载率的辅料筛选
在载药介孔二氧化硅颗粒制备中,为了改善负载率,本领域一般是通过改性二氧化硅材料来改善药物负载率,通过添加氨基、羟基等官能团,从而提高介孔二氧化硅材料与药物之间的负载率,但是改性二氧化硅材料一般成本较高,不利于大规模生产,因此本发明通过添加辅料这种低成本方式来改善二氧化硅材料的负载率。
试验方法:负载颗粒制备方法试验(一),区别在于在制备过程中,添加不同的药物辅料,添加量为0.1g,然后考察各组负载药物颗粒的负载率。
各组辅料为:
辅料 | |
组1 | 聚乙二醇400 |
组2 | 叶酸 |
组3 | 枸橼酸三乙酯 |
组4 | 单双硬脂酸甘油酯 |
具体结果如下:
(三)改善药物负载率的复合辅料筛选
在试验(二)的基础上,本发明将叶酸和单双硬脂酸甘油酯按不同比例组合来考察介孔二氧化硅材料的负载率变化。
试验方法:同试验(二),区别在辅料由叶酸和单双硬脂酸甘油酯组成,具体配比为:
叶酸 | 单双硬脂酸甘油酯 | |
组1 | 0.033g | 0.067g |
组2 | 0.05g | 0.05g |
组3 | 0.067g | 0.033g |
具体结果如下:
负载率 | |
组1 | 78.4% |
组2 | 65.8% |
组3 | 66.2% |
结果表明当叶酸与单双硬脂酸甘油酯的比值小于1:1时,介孔二氧化硅材料对马来酸氯苯那敏的负载率更高。
(四)制粒辅料的筛选
试验方法:取0.2g介孔二氧化硅材料,加入无水乙醇20ml,向溶剂体系中添加0.033g叶酸和0.067g单双硬脂酸甘油酯,然后向溶剂体系中加入0.14g马来酸氯苯那敏,室温下搅拌2h后,旋转蒸发去除溶剂,获得负载马来酸氯苯那敏的介孔二氧化硅颗粒。
取0.34g负载马来酸氯苯那敏的介孔二氧化硅颗粒,0.1g药用辅料,用70%乙醇制粒,干燥。
按照中国药典2020版第四部通则0931第三法(小杯法)测定颗粒溶出度,具体为以稀盐酸2.5ml加水至250ml为溶出介质,加入负载马来酸氯苯那敏的介孔二氧化硅颗粒,桨叶搅拌,转速每分钟50转,经45分钟时取样,测定溶出介质中药物含量并计算溶出度。
具体结果如下:
药用辅料 | 溶出度 | |
组1 | 微晶纤维素 | 76.3% |
组2 | 淀粉 | 81.6% |
组3 | 乳糖 | 53.4% |
组4 | 乙基纤维素 | 86.8% |
结果表明,当采用乙基纤维素作为制粒辅料时,颗粒溶出度最佳。另外,本发明取等量的马来酸氯苯那敏和乙基纤维素在相同条件下制粒并检测溶出度,其溶出度仅为21.5%,这表明使用介孔二氧化硅材料后可以极大地提高马来酸氯苯那敏溶出度。
实施例2咳克平胶囊中中药颗粒的制备
本发明发现将马来酸氯苯那敏负载于介孔二氧化硅材料后并单独制粒,然后与中药颗粒混合时,其在中药颗粒中分散度不佳,从而导致马来酸氯苯那敏颗粒在每粒胶囊中含量差异度较大,这可能与单独对中药提取物进行制粒后,中药颗粒具有一定粘性有关,因此有必要对中药颗粒添加一定辅料来改善中药颗粒的流动性。
试验方法:
中药处方为:百部140g、地黄140g、麦冬140g、枇杷叶170g、苦杏仁50g、浙贝母220g、前胡50g、五味子50g、甘草50g。
中药颗粒制备:取浙贝母粉碎成细粉,备用;苦杏仁、前胡、五味子加8倍量50%乙醇提取二次,每次2小时,合并提取液并滤过,滤液减压回收乙醇并浓缩至相对密度为1.25-1.30(60℃)的清膏,备用。药渣与其余百部等五味药材加8倍量水煎煮三次,每次1.5小时,合并煎液并滤过,滤液浓缩至相对密度为1.25-1.30(60℃)的清膏,将上述清膏与浙贝母细粉混匀,干燥,粉碎,得中药提取物327g。
取22g不同药用辅料,加入中药提取物中,搅拌混匀,用70%乙醇制粒,干燥,然后测定各组堆密度和休止角。
具体结果如下:
药用辅料 | 堆密度 | 休止角 | |
组1 | 微粉硅胶 | 0.54g/ml | 29.18 |
组2 | 微晶纤维素 | 0.43g/ml | 33.84 |
组3 | 淀粉 | 0.37g/ml | 37.55 |
组4 | 乳糖 | 0.45g/ml | 34.73 |
结果表明,采用微粉硅胶作为辅料时可以明显改善中药颗粒的流动性。
将组1制备的中药颗粒和马来酸氯苯那敏颗粒混匀,按标示量装入胶囊,马来酸氯苯那敏颗粒制备方法为:取2g介孔二氧化硅材料,加入无水乙醇200m l,向溶剂体系中添加0.33g叶酸和0.67g单双硬脂酸甘油酯,然后向溶剂体系中加入1.4g马来酸氯苯那敏,室温下搅拌2h后,旋转蒸发去除溶剂,获得负载马来酸氯苯那敏的介孔二氧化硅颗粒。取1g乙基纤维素,用70%乙醇制粒,干燥即得。
随机抽取胶囊10粒,测定每粒胶囊中马来酸氯苯那敏含量,计算平均值及标准差,以标准差与平均值的比值作为差异度。
结果如下:
差异度 | |
组1 | 1.43% |
对比例1 | 8.92% |
对比例1为对中药提取物不添加任何辅料,直接制粒,然后与马来酸氯苯那敏颗粒混合,装囊。
实施例3咳克平胶囊的制备
处方为:百部140g、地黄140g、麦冬140g、枇杷叶170g、苦杏仁50g、浙贝母220g、前胡50g、五味子50g、甘草50g、1.4g马来酸氯苯那敏。
中药颗粒制备:取浙贝母粉碎成细粉,备用;苦杏仁、前胡、五味子加8倍量50%乙醇提取二次,每次2小时,合并提取液并滤过,滤液减压回收乙醇并浓缩至相对密度为1.25-1.30(60℃)的清膏,备用。药渣与其余百部等五味药材加8倍量水煎煮三次,每次1.5小时,合并煎液并滤过,滤液浓缩至相对密度为1.25-1.30(60℃)的清膏,将上述清膏与浙贝母细粉混匀,干燥,粉碎,得中药提取物。
取22g微粉硅胶,加入中药提取物中,搅拌混匀,用70%乙醇制粒,干燥。
马来酸氯苯那敏颗粒制备:取2g介孔二氧化硅材料,加入无水乙醇200ml,向溶剂体系中添加0.33g叶酸和0.67g单双硬脂酸甘油酯,然后向溶剂体系中加入1.4g马来酸氯苯那敏,室温下搅拌2h后,旋转蒸发去除溶剂,获得负载马来酸氯苯那敏的介孔二氧化硅颗粒。取1g乙基纤维素加入到颗粒中,用70%乙醇制粒,干燥即得。
将中药颗粒与马来酸氯苯那敏颗粒混合,装入胶囊,制成1000粒,即得。
实施例4咳克平胶囊中马来酸氯苯那敏的生物利用度研究
取雄性SD大鼠,体重200g左右,随机分组,每组5只,分别灌胃给予实施例3制备的咳克平胶囊内容物和对比例制备的咳克平胶囊内容物,各组给药剂量均为800mg/kg,分别与30min、1h、2h、4h、8h、16h和24h进行眼眶取血,采用HPLC方法对各时间点血样中马来酸氯苯那敏含量进行检测,计算血药浓度,并通过DAS2.0软件,计算各组制剂的生物利用度,具体结果如下:
AUC(0-24h) | |
实施例3 | 9.13±1.62mg/L*ha |
对比例1 | 2.85±0.54mg/L*h |
对比例2 | 3.41±0.61mg/L*h |
对比例1为中国专利CN104888071A说明书实施例1所公开的方法制备的咳克平胶囊。
对比例2同实施例3,区别仅在于不使用介孔二氧化硅材料,采用等量马来酸氯苯那敏与乙基纤维素直接制粒后,再与中药颗粒混合。
a表示与对比例1和对比例2组相比,P<0.01
实施例5咳克平胶囊中马来酸氯苯那敏的稳定性研究
在高温高湿条件下(温度为45℃±2℃,相对湿度为75%±5%RH)进行稳定性试验(12个月),通过HPLC检测方法测定各组胶囊中的马来酸氯苯那敏活性成分含量,在保存后0个月、3个月和6个月后的马来酸氯苯那敏含量相对于标示量的百分比。
具体结果如下:
对比例1为中国专利CN104888071A说明书实施例1所公开的方法制备的咳克平胶囊。
对比例2制备方法同实施例3,区别仅在于不使用介孔二氧化硅材料,采用等量马来酸氯苯那敏与乙基纤维素直接制粒后,再与中药颗粒混合。
对比例3制备方法同实施例3,区别在于,对中药颗粒不添加任何辅料直接制粒,在与马来酸氯苯那敏颗粒混合时添加22g硬脂酸镁,经检测证明胶囊中马来酸氯苯那敏含量差异度为2.71%。
结果表明,实施例3制备的咳克平胶囊可以较好的解决马来酸氯苯那敏的稳定性问题,并且明显优于原咳克平胶囊(对比例1)。并且本发明发现添加硬脂酸镁虽然可以较好地解决马来酸氯苯那敏在胶囊中的含量差异度问题,但是其会极大的影响马来酸氯苯那敏的稳定性。
Claims (4)
1.一种咳克平胶囊,其由中药颗粒和马来酸氯苯那敏颗粒组成,所述中药颗粒其由百部140重量份、地黄140重量份、麦冬140重量份、枇杷叶170重量份、苦杏仁50重量份、浙贝母220重量份、前胡50重量份、五味子50重量份、甘草50重量份以及药学上所接受的辅料所制成;所述马来酸氯苯那敏颗粒其由1.4重量份马来酸氯苯那敏、介孔二氧化硅材料、乙基纤维素、叶酸和单双硬脂酸甘油酯组成;
所述介孔二氧化硅材料为TUD-1,孔径在5-15nm之间,粒径在0.6-0.8mm之间;
所述叶酸和单双硬脂酸甘油酯的重量比为1:1-5;
介孔二氧化硅材料与叶酸和单双硬脂酸甘油酯的重量比2:1;
所述马来酸氯苯那敏和介孔二氧化硅材料的重量比为0.5-1:1;
所述乙基纤维素与马来酸氯苯那敏的重量比为1:1-2;
所述马来酸氯苯那敏颗粒制备方法为:取介孔二氧化硅材料,加入无水乙醇,向溶剂体系中添加叶酸和单双硬脂酸甘油酯,然后向溶剂体系中加入马来酸氯苯那敏,室温下搅拌2h后,旋转蒸发去除溶剂,获得负载马来酸氯苯那敏的介孔二氧化硅颗粒;取乙基纤维素加入到颗粒中,用70%乙醇制粒,干燥即得。
2.如权利要求1所述的咳克平胶囊,其特征在于,在中药颗粒中,所述药学上所接受的辅料为微粉硅胶,所述微粉硅胶与浙贝母的重量比为0.05-0.2:1。
3.一种如权利要求1-2任一项所述的咳克平胶囊的制备方法,具体包括:
1)中药颗粒制备:取浙贝母粉碎成细粉,备用;苦杏仁、前胡、五味子加8倍量50%乙醇提取二次,每次2小时,合并提取液并滤过,滤液减压回收乙醇并浓缩至在60℃下相对密度为1.25-1.30的清膏,备用;药渣与百部、地黄、麦冬、枇杷叶、甘草加8倍量水煎煮三次,每次1.5小时,合并煎液并滤过,滤液浓缩至在60℃下相对密度为1.25-1.30的清膏,将上述清膏与浙贝母细粉混匀,干燥,粉碎,得中药提取物;取22g微粉硅胶,加入中药提取物中,搅拌混匀,用70%乙醇制粒,干燥;
2)马来酸氯苯那敏颗粒制备方法为:取介孔二氧化硅材料,加入无水乙醇,向溶剂体系中添加叶酸和单双硬脂酸甘油酯,然后向溶剂体系中加入马来酸氯苯那敏,室温下搅拌2h后,旋转蒸发去除溶剂,获得负载马来酸氯苯那敏的介孔二氧化硅颗粒;取乙基纤维素加入到颗粒中,用70%乙醇制粒,干燥即得;
3)将中药颗粒与马来酸氯苯那敏颗粒混合,装入胶囊,即得。
4.如权利要求1-2任一项所述的咳克平胶囊在制备治疗咳嗽、咳痰不爽、平喘消炎、咽干喉痛以及唇舌干燥疾病药物中的应用。
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