CN108338978B - 一种s-羧甲基-l-半胱氨酸肠溶微丸胶囊 - Google Patents
一种s-羧甲基-l-半胱氨酸肠溶微丸胶囊 Download PDFInfo
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Abstract
本发明公开一种含S‑羧甲基‑L‑半胱氨酸肠溶微丸,该肠溶微丸含有丸芯、隔离层和肠溶层,肠溶层含有水性丙烯酸类肠溶包衣材料,经包衣包裹而制得。本发明同时公开含有S‑羧甲基‑L‑半胱氨酸微丸的S‑羧甲基‑L‑半胱氨酸肠溶胶囊。本发明的S‑羧甲基‑L‑半胱氨酸肠溶胶囊在胃中不会溶解,对胃的刺激小;且在贮存过程中质量稳定。
Description
技术领域
本发明属于医药制剂技术领域,具体而言,本发明涉及一种含有S-羧甲基-L-半胱氨酸的微丸制剂。
背景技术
S-(羧甲基)-L-半胱氨酸,又名羧甲司坦,于1961年由法国Joullie公司首先开发并应用于临床,为粘痰溶解药,可影响支气管腺体的分泌,使低粘度的唾液粘蛋白的分泌增加,高粘度的岩藻粘蛋白的产生减少,且可直接作用于粘蛋白的二硫键,使粘蛋白分子裂解而降低痰液粘滞性,易于咯出;可提高粘膜纤毛清除率;降低气道高反应性。CMC进入体内后易脱去羧甲基形成半胱氨酸,其所含的巯基能与活性氧(reactive oxygen species,ROS)等的亲电子基团相互作用,发挥直接抗氧化作用;此外,半胱氨酸亦是谷胱甘肽(GSH)的前体,能再合成具有生物活性的GSH,增加体内GSH的浓度,起到间接抗氧化作用。CMC口服吸收良好,起效快,服用4小时即可见明显疗效,用于治疗慢性支气管炎、肺气肿、慢性阻塞性肺病(COPD)、支气管哮喘等疾病引起的痰液粘稠和咳痰困难。
作为一种祛痰药物,S-(羧甲基)-L-半胱氨酸在我国的生产和使用十分普遍,常用的剂型包括片、颗粒、口服溶液等,但其结构中存在两个羧基,呈酸性,使得该药物对消化道有刺激作用,可引起胃部不适、恶心、呕吐等不良反应。服用该药易损伤胃肠粘膜,导致出血、溃疡甚至穿孔等严重副作用。药品说明书中明确注明“消化道溃疡活动期患者禁用”。作为一种祛痰药物,S-(羧甲基)-L-半胱氨酸在我国临床使用十分普遍,常用的剂型包括片、颗粒、口服溶液等,如李莉等对羧甲司坦分散片的制备及其相关质量进行研究,(羧甲司坦分散片的制备及其相关质量评价《中国生化药物杂志》,2001,22(1):38-39;陈庆东对普通片剂的制备工艺进行了研究(羧甲司坦片制剂工艺的研究,《海峡药学》,2009,21(11):23-24;CN105012351A公开了一种羧甲司坦口含片。但现有的制剂均未解决药物对消化道刺激的副作用。同时,S-(羧甲基)-L-半胱氨酸普通制剂长期存放的稳定性欠佳,有效期仅24月。因此,通过制剂手段减轻S-(羧甲基)-L-半胱氨酸的刺激,并提高稳定性,具有较高的临床价值。
发明内容
为了避免S-(羧甲基)-L-半胱氨酸在胃酸性环境中被破坏,减轻对胃部的酸性刺激,更好的发挥药物的作用,方便患者服用,增强药物的稳定性,本发明提供一种S-(羧甲基)-L-半胱氨酸的肠溶微丸胶囊,它到达小肠时,溶解并释放出活性组分,由于在胃中肠溶衣不会溶解,从而减少了胃部刺激症状,在药物的主要吸收部位小肠溶解,提高S-(羧甲基)-L-半胱氨酸的生物利用度,且稳定性好,易于保存。
本发明所述的S-(羧甲基)-L-半胱氨酸肠溶微丸胶囊包括含药丸芯和药学上可以接受的隔离层和肠溶层。
其中,含药丸芯含有S-羧甲基-L-半胱氨酸、卡波姆和粘合剂。隔离层含有滑石粉、粘合剂和聚乙二醇。肠溶层包含水性丙烯酸类肠溶包衣材料、二甲基硅油以及增塑剂;所述增塑剂选自PEG8000、柠檬酸三乙酯或三醋酸甘油酯。所述丸芯通过挤出滚圆法制备。
在本发明中,我们出人意料地发现使用以水性丙烯酸类肠溶包衣系统93A(93A),二甲基硅油,以及一种选自PEG8000、柠檬酸三乙酯或三醋酸甘油酯的增塑剂所配制的特定肠溶层材料包衣后,在肠液中崩解速度、溶出度和稳定性等方面远远优于其他肠溶辅料制备的S-(羧甲基)-L-半胱氨酸肠溶制剂。此外,本发明选用的肠溶包衣材料可以用水溶解,较之其它需用有机溶解的包衣材料在使用时生产工艺更简单,操作也更为安全。
具体地,本发明所述的肠溶微丸基于该制剂重量含有50%~80%的丸芯,1%~10%的隔离层及10%~45%肠溶层。
其中,所述的微丸丸芯含有S-羧甲基-L-半胱氨酸、卡波姆和粘合剂;所述丸芯基于该制剂重量含有:30%~75%S-羧甲基-L-半胱氨酸,1%~20%卡波姆,0.5%~16%粘合剂。更为优选地,所述的微丸丸芯基于该制剂重量含有:40%~70%S-羧甲基-L-半胱氨酸,3%~15%卡波姆,2%~10%粘合剂。
上述的含药丸芯可以通过挤出滚圆法制备得到。
其中,所述隔离层含有滑石粉、粘合剂和聚乙二醇。所述的隔离层基于该制剂重量含有:0.5%~10%滑石粉,0.2%~2%粘合剂,0.1%~2%聚乙二醇。优选地,所述的隔离层基于该制剂重量含有:1%~8%滑石粉,0.5%~1.5%粘合剂,0.5%~1.5聚乙二醇。所述粘合剂为羟丙纤维素或羟丙甲纤维素。
其中,所述的肠溶层基于该制剂重量含有:1%-12%的水性丙烯酸类肠溶包衣材料,0.01%-0.5%二甲基硅油,0.05%-3%选自PEG8000、柠檬酸三乙酯或三醋酸甘油酯的增塑剂。优选地,所述的肠溶层基于该制剂重量含有:6%-10%的水性丙烯酸类肠溶包衣材料,0.05%-0.3%二甲基硅油,0.1%-2%选自PEG8000、柠檬酸三乙酯或三醋酸甘油酯的增塑剂。
本发明所述的肠溶微丸含有丸芯,隔离层及肠溶层,该微丸的处方如下所述。所述的微丸丸芯基于该制剂重量含有:30%~75%S-羧甲基-L-半胱氨酸,1%~20%卡波姆,0.5%~16%粘合剂;所述的隔离层基于该制剂重量含有:0.5%~10%滑石粉,0.2%~2%粘合剂,0.1%~2%聚乙二醇;所述的肠溶层基于该制剂重量含有:1%-12%的水性丙烯酸类肠溶包衣材料,0.01%-0.5%二甲基硅油,0.05%-3%选自PEG8000、柠檬酸三乙酯或三醋酸甘油酯的增塑剂。
进一步地,上述的微丸丸芯基于该制剂重量含有:40%~70%S-羧甲基-L-半胱氨酸,3%~15%卡波姆,2%~10%粘合剂;所述的隔离层基于该制剂重量含有:1%~8%滑石粉,0.5%~1.5%粘合剂,0.5%~1.5聚乙二醇;所述的肠溶层基于该制剂重量含有:6%-10%的水性丙烯酸类肠溶包衣材料,0.05%-0.3%二甲基硅油,0.1%-2%选自PEG8000、柠檬酸三乙酯或三醋酸甘油酯的增塑剂。
将本发明所述的S-羧甲基-L-半胱氨酸肠溶微丸填充至胶囊中,即可制得S-羧甲基-L-半胱氨酸肠溶胶囊。
本发明所述的S-羧甲基-L-半胱氨酸肠溶胶囊可以避免在胃酸性环境中被破坏,减轻了对胃部的刺激,提高药物的稳定性;到达吸收部位小肠后再释放出活性成分,提高S-羧甲基-L-半胱氨酸的生物利用度。同时由于包裹了隔离层和肠衣层,微丸更易于保存。本发明的有益效果通过以下实验进一步说明,但不局限于下述实施例。
具体实施例
以下为本发明的具体实施方式,所述的实施例是为了进一步描述本发明,但并不限制本发明。
实施例1
丸芯
S-羧甲基-L-半胱氨酸 250mg;
卡波姆 100mg;
羟丙甲纤维素 80mg。
隔离层
滑石粉 5mg;
羟丙甲纤维素 5mg;
聚乙二醇 2mg。
肠溶层
水性丙烯酸类肠溶包衣系统93A 30mg;
二甲基硅油 0.3mg;
PEG8000 3mg。
制法:
(1)含药丸芯:称取处方量的羟丙甲纤维素,加水溶解为黏合剂;称取处方量的S-羧甲基-L-半胱氨酸和卡波姆,混合均匀,过100目筛,以羟丙甲纤维素溶液为黏合剂制软材。启动挤出滚圆设备,选择筛板孔径为0.8mm,转速4000转/分钟,挤出滚圆,得到小丸;干燥,过20目筛,即得含药丸芯。
(2)隔离层:称取处方量的隔离层材料,以适量乙醇溶解,即得隔离层。
(3)肠溶层:称取处方量的肠溶层材料,以纯化水分散后,得肠溶层。
(4)依次以隔离层和肠溶层包裹S-羧甲基-L-半胱氨酸含药丸芯,即得S-羧甲基-L-半胱氨酸肠溶微丸。计算装量后装入2号胶囊,即得S-羧甲基-L-半胱氨酸肠溶微丸胶囊。
实施例2
丸芯
S-羧甲基-L-半胱氨酸 250mg;
卡波姆 50mg;
羟丙甲纤维素 30mg。
隔离层
滑石粉 4mg;
羟丙纤维素 2mg;
聚乙二醇 1mg。
肠溶层
水性丙烯酸类肠溶包衣系统93A 20mg;
二甲基硅油 0.2mg;
柠檬酸三乙酯 2mg。
制法:
(1)含药丸芯:称取处方量的羟丙甲纤维素,加水溶解为黏合剂;称取处方量的S-羧甲基-L-半胱氨酸和卡波姆,混合均匀,过100目筛,以羟丙甲纤维素溶液为黏合剂制软材。启动挤出滚圆设备,选择筛板孔径为0.8mm,转速4000转/分钟,挤出滚圆,得到小丸;干燥,过20目筛,即得含药丸芯。
(2)隔离层:称取处方量的隔离层材料,以适量乙醇溶解,即得隔离层。
(3)肠溶层:称取处方量的肠溶层材料,以纯化水分散后,得肠溶层。
(4)依次以隔离层和肠溶层包裹S-羧甲基-L-半胱氨酸含药丸芯,即得S-羧甲基-L-半胱氨酸肠溶微丸。计算装量后装入2号胶囊,即得S-羧甲基-L-半胱氨酸肠溶微丸胶囊。
实施例3
丸芯
S-羧甲基-L-半胱氨酸 250mg;
卡波姆 10mg;
羟丙纤维素 10mg。
隔离层
滑石粉 8mg;
羟丙纤维素 2mg;
聚乙二醇 2mg。
肠溶层
水性丙烯酸类肠溶包衣系统93A 20mg;
二甲基硅油 0.2mg;
三醋酸甘油酯 3mg。
制法:
(1)含药丸芯:称取处方量的羟丙甲纤维素,加水溶解为黏合剂;称取处方量的S-羧甲基-L-半胱氨酸和卡波姆,混合均匀,过100目筛,以羟丙甲纤维素溶液为黏合剂制软材。启动挤出滚圆设备,选择筛板孔径为0.8mm,转速4000转/分钟,挤出滚圆,得到小丸;干燥,过20目筛,即得含药丸芯。
(2)隔离层:称取处方量的隔离层材料,以适量乙醇溶解,即得隔离层。
(3)肠溶层:称取处方量的肠溶层材料,以纯化水分散后,得肠溶层。
(4)依次以隔离层和肠溶层包裹S-羧甲基-L-半胱氨酸含药丸芯,即得S-羧甲基-L-半胱氨酸肠溶微丸。计算装量后装入2号胶囊,即得S-羧甲基-L-半胱氨酸肠溶微丸胶囊。
试验例1
将本发明制备的上述三种肠溶微丸胶囊进行崩解时限(黄海LB-812A型六管崩解仪,上海黄药检仪器有限公司)的检查,并与其他常规肠溶辅料制备的肠溶微丸胶囊(含药丸芯、隔离层及填充胶囊与本发明实施例1相同)和市售产品进行比较。结果显示在本发明制备的肠溶微丸胶囊在盐酸溶液(pH1.0)中2小时均不崩解,在磷酸盐缓冲液(pH6.8)中崩解时限明显优于常规肠溶辅料制备的肠溶微丸胶囊及市售产品,具体结果见表1。
表1崩解时限比较结果
试验例2
将本发明制备的上述三种肠溶微丸胶囊分别在盐酸溶液(pH1.0)和磷酸盐缓冲液(pH6.8)中测定30分钟内溶出率,并与市售产品进行比较。结果显示在表2中。
表2溶出率比较结果(%)
如表2结果显示,本发明制备的S-羧甲基-L-半胱氨酸肠溶微丸,在酸中释放度较小,pH6.8缓冲液中释放度良好。
试验例3稳定性比较试验
S-羧甲基-L-半胱氨酸易吸湿,高温下较不稳定,目前市售制剂的贮存条件为“密封,置阴凉(不超过20℃)干燥处保存”。有效期为24月。
为了进一步验证本发明对稳定性的影响,我们把本发明的药品和目前市售的同类产品进行了加速试验比较。试验条件为40℃,6个月。检测仪器为Waters2695型高效液相色谱仪。结果显示在表3中。
表3稳定性比较结果(%)
如表3结果显示,本发明的肠溶微丸显示出良好的稳定性。
以上所述,仅是本发明的较佳实施例而已,并非对本发明做任何形式上的限制,故凡未脱离本发明技术方案的内容,依据本发明的技术实质对以上实施例所做的任何简单修改、等同变化或修饰,均仍属于本发明技术方案的范围内。
Claims (9)
1.一种S-羧甲基-L-半胱氨酸肠溶微丸,其特征在于,所述肠溶微丸含有丸芯、隔离层、肠溶层,所述丸芯含有S-羧甲基-L-半胱氨酸;所述肠溶层含有水性丙烯酸类肠溶包衣材料93A、二甲基硅油以及增塑剂。
2.根据权利要求1所述的S-羧甲基-L-半胱氨酸肠溶微丸,其特征在于,所述增塑剂选自PEG8000、柠檬酸三乙酯或三醋酸甘油酯。
3.根据权利要求1所述的S-羧甲基-L-半胱氨酸肠溶微丸,其特征在于,所述肠溶微丸基于该制剂重量含有50%~80%的丸芯,1%~10%的隔离层以及10%~45%的肠溶层。
4.根据权利要求1所述的S-羧甲基-L-半胱氨酸肠溶微丸,其特征在于,所述丸芯含有S-羧甲基-L-半胱氨酸、卡波姆和粘合剂;所述隔离层含有滑石粉、粘合剂和聚乙二醇。
5.根据权利要求4所述的S-羧甲基-L-半胱氨酸肠溶微丸,其特征在于,所用粘合剂为羟丙纤维素或羟丙甲纤维素。
6.根据权利要求1所述的S-羧甲基-L-半胱氨酸肠溶微丸,其特征在于,所述的微丸丸芯基于该制剂重量含有:30%~75%S-羧甲基-L-半胱氨酸,1%~20%卡波姆,0.5%~16%粘合剂;所述的隔离层基于该制剂重量含有:0.5%~10%滑石粉,0.2%~2%粘合剂,0.1%~2%聚乙二醇;所述的肠溶层基于该制剂重量含有:1%-12%的水性丙烯酸类肠溶包衣材料93A,0.01%-0.5%二甲基硅油,0.05%-3%选自PEG8000、柠檬酸三乙酯或三醋酸甘油酯的增塑剂。
7.根据权利要求6所述的S-羧甲基-L-半胱氨酸肠溶微丸,其特征在于,所述的微丸丸芯基于该制剂重量含有:40%~70%S-羧甲基-L-半胱氨酸,3%~15%卡波姆,2%~10%粘合剂;所述的隔离层基于该制剂重量含有:1%~8%滑石粉,0.5%~1.5%粘合剂,0.5%~1.5聚乙二醇;所述的肠溶层基于该制剂重量含有:6%-10%的水性丙烯酸类肠溶包衣材料93A,0.05%-0.3%二甲基硅油,0.1%-2%选自PEG8000、柠檬酸三乙酯或三醋酸甘油酯的增塑剂。
8.根据权利要求6或7所述的S-羧甲基-L-半胱氨酸肠溶微丸,其特征在于,所述丸芯通过挤出滚圆法制备。
9.一种含有权利要求1-7中任意一项所述的S-羧甲基-L-半胱氨酸肠溶微丸的胶囊制剂。
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