CN108553439B - 一种含s-羧甲基-l-半胱氨酸的肠溶片剂 - Google Patents
一种含s-羧甲基-l-半胱氨酸的肠溶片剂 Download PDFInfo
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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Abstract
本发明提供一种含S‑羧甲基‑L‑半胱氨酸的药物组合物,该药物组合是一种包含片芯、隔离层和肠溶包衣层的肠溶片剂。本发明提供的S‑羧甲基‑L‑半胱氨酸肠溶片在胃中不会溶解,对胃的刺激小;在药物的主要吸收部位小肠溶解,提高了S‑羧甲基‑L‑半胱氨酸的生物利用度,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,本发明涉及一种肠溶片剂及其制备方法。
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-半胱氨酸的肠溶片剂,它到达小肠时,溶解并迅速地释放出活性组分,由于在胃中肠溶层不会溶解,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-半胱氨酸肠溶片剂含有片芯和药学上可以接受的包裹片芯的隔离层以及外层的肠溶包衣层。
其中,片芯优选的组分含有:S-(羧甲基)-L-半胱氨酸和可药用的赋形剂,所述赋形剂选自填充剂、崩解剂、粘合剂、润滑剂中的一种或几种。所述填充剂选自预胶化淀粉、淀粉、乳糖、甘露醇和微晶纤维素中的一种或多种。所述崩解剂选自羧甲基淀粉钠、交联聚维酮、交联羧甲基纤维素钠、低取代羟丙基纤维素和玉米淀粉中的一种或多种。所述润滑剂选自硬脂酸、硬脂酸镁、硬脂酸钙、硬脂酸锌中的一种或多种。所述粘合剂选自羟丙甲纤维素、聚乙烯吡咯烷酮K30、淀粉浆和羧甲基纤维素钠的一种或多种。
更为优选地,本发明的赋形剂中的填充剂选自微晶纤维素;崩解剂选自低取代羟丙基纤维素、玉米淀粉;粘合剂选自羧甲基纤维素钠;所述的润滑剂选自硬脂酸镁。
具体的,本发明所述肠溶片剂的片芯基于该制剂重量它含有:
20%-80%的S-羧甲基-L-半胱氨酸;
2%-30%的微晶纤维素
5%-30%的低取代羟丙基纤维素;
1%-20%的玉米淀粉;
0.5%-10%的羧甲基纤维素钠;
0.1%-5%的硬脂酸镁。
优选的,本发明所述肠溶片剂的片芯基于该制剂重量它含有:
40%-75%的S-羧甲基-L-半胱氨酸;
5%-20%的微晶纤维素
10%-20%的低取代羟丙基纤维素;
5%-10%的玉米淀粉;
2%-5%的羧甲基纤维素钠;
0.5%-2%的硬脂酸镁。
本发明肠溶片剂的隔离层选自水溶性纤维素,优选羟丙甲纤维素。所述隔离层基于该制剂重量它含有:1%-5%羟丙甲纤维素。
本发明包衣层材料包括水性丙烯酸类肠溶包衣材料、二甲基硅油、增塑剂,所述增塑剂选自PEG8000、柠檬酸三乙酯或三醋酸甘油酯。其中,水性丙烯酸类肠溶包衣材料选自水性丙烯酸类肠溶包衣系统93A(Acryl-93A)。
所述肠溶包衣层基于该制剂重量它含有:
1%-12%的水性丙烯酸类肠溶包衣材料;
0.01%-0.5%的二甲基硅油;
0.05%-3%的增塑剂,所述增塑剂选自PEG8000、柠檬酸三乙酯或三醋酸甘油酯。
优选地,本发明所述肠溶包衣层基于该制剂重量它含有:
0.05%-0.3%的二甲基硅油;
0.1%-2%的增塑剂,所述增塑剂选自PEG8000、柠檬酸三乙酯或三醋酸甘油酯。
丙烯酸树脂由于其安全无毒、在体内不被酶破坏、不吸收也不参与新陈代谢、成膜性好而成为最常用的高分子薄膜包衣材料,它是由丙烯酸和甲基丙烯酸及其酯,以一定比例共聚而成的一类高分子聚合物。
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(Acryl-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,S-(羧甲基)-L-半胱氨酸肠溶片剂在肠液中崩解速度、溶出度等方面远远优于其他肠溶辅料制备的S-(羧甲基)-L-半胱氨酸肠溶片剂,稳定性明显优于市售产品。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。
本发明还提供了一种制备如上文所述的S-羧甲基-L-半胱氨酸肠溶片剂的方法,步骤如下:
1)制备片芯:称取处方量的S-羧甲基-L-半胱氨酸、填充剂、崩解剂、粘合剂、润滑剂,混合均匀后,过筛,用水制软材,过筛,所得湿颗粒干燥,压片;
2)以水为分散介质制备隔离层;
3)以水为溶剂制备肠溶层;
4)制备肠溶片:取S-羧甲基-L-半胱氨酸素片,先包隔离层,再包肠溶包衣层,即得S-羧甲基-L-半胱氨酸肠溶片。
更具体地,上述的S-羧甲基-L-半胱氨酸肠溶片剂的制备方法,步骤如下:
1)制备片芯:称取处方量的S-羧甲基-L-半胱氨酸、微晶纤维素、低取代羟丙基纤维素、玉米淀粉、羧甲基纤维素钠和硬脂酸镁,混合均匀后,过100目筛,用水制软材,过24目筛,所得湿颗粒干燥,压片。
2)制备隔离层:称取处方量的羟丙甲纤维素,以处方量的纯化水分散即得。
3)制备肠溶层:称取处方量的水性丙烯酸类肠溶包衣系统93A、二甲基硅油、选自PEG8000、柠檬酸三乙酯或三醋酸甘油酯的增塑剂,以处方量的纯化水分散即得。
4)制备肠溶片:取S-羧甲基-L-半胱氨酸素片,先包隔离层,再包肠溶层,即得S-羧甲基-L-半胱氨酸肠溶片。
通过本发明处方和工艺制备的S-羧甲基-L-半胱氨酸肠溶片能够避免在胃酸性环境中被破坏,减轻了对胃部的刺激;直接到达吸收部位小肠,迅速溶解并释放出活性成分,提高S-羧甲基-L-半胱氨酸的生物利用度。同时由于包裹了肠衣层,片剂更易于保存。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
片芯
隔离层
羟丙甲纤维素 6mg;
肠溶层
水性丙烯酸类肠溶包衣系统93A 36.5mg;
二甲基硅油 0.37mg;
PEG8000 2.5mg。
制法:
称取处方量的片芯材料,混合均匀后,过100目筛,用水制软材,过24目筛,所得湿颗粒干燥,压片。称取处方量的羟丙甲纤维素,以处方量的纯化水分散得隔离层。称取处方量的肠溶层材料,以纯化水分散后,得肠溶层。依次以隔离层和肠溶层包裹S-羧甲基-L-半胱氨酸素片,即得S-羧甲基-L-半胱氨酸肠溶片。
实施例2
片芯
隔离层
羟丙甲纤维素 4mg;
肠溶层
水性丙烯酸类肠溶包衣系统93A 73mg;
二甲基硅油 0.73mg;
三醋酸甘油酯 5mg。
制法:
称取处方量的片芯材料,混合均匀后,过100目筛,用水制软材,过24目筛,所得湿颗粒干燥,压片。称取处方量的羟丙甲纤维素,以处方量的纯化水分散得隔离层。称取处方量的肠溶层材料,以纯化水分散后,得肠溶层。依次以隔离层和肠溶层包裹S-羧甲基-L-半胱氨酸素片,即得S-羧甲基-L-半胱氨酸肠溶片。
实施例3
片芯
隔离层
羟丙甲纤维素 16mg;
肠溶层
水性丙烯酸类肠溶包衣系统93A 73mg;
二甲基硅油 1mg;
柠檬酸三乙酯 10mg。
制法:
称取处方量的片芯材料,混合均匀后,过100目筛,用水制软材,过24目筛,所得湿颗粒干燥,压片。称取处方量的羟丙甲纤维素,以处方量的纯化水分散得隔离层。称取处方量的肠溶层材料,以纯化水分散后,得肠溶层。依次以隔离层和肠溶层包裹S-羧甲基-L-半胱氨酸素片,即得S-羧甲基-L-半胱氨酸肠溶片。
试验例1
将本发明制备的上述三种包合物肠溶片剂进行崩解时限(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片(片芯及隔离层与本发明实施例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片剂在盐酸溶液(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片及市售产品,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片分别在盐酸溶液(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-半胱氨酸肠溶片,在酸中的释放度较小,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,本发明的肠溶制剂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 (6)
1.一种S-羧甲基-L-半胱氨酸肠溶片剂,其特征在于,所述肠溶片剂包括含有S-羧甲基-L-半胱氨酸的片芯、包裹片芯的隔离层以及外层的肠溶包衣层,所述隔离层选自羟丙甲纤维素,肠溶包衣层材料为水性丙烯酸类肠溶包衣材料93A、二甲基硅油、增塑剂;所述片芯含有活性成份S-羧甲基-L-半胱氨酸和赋形剂,所述赋形剂选自填充剂、崩解剂、粘合剂、润滑剂中的一种或几种;所述增塑剂选自PEG8000、柠檬酸三乙酯或三醋酸甘油酯。
2.根据权利要求1所述的S-羧甲基-L-半胱氨酸肠溶片剂,其特征在于,所述填充剂选自微晶纤维素;所述崩解剂选自低取代羟丙基纤维素、玉米淀粉;所述粘合剂选自羧甲基纤维素钠;所述润滑剂选自硬脂酸镁。
3.根据权利要求2所述的S-羧甲基-L-半胱氨酸肠溶片剂,其特征在于,所述片芯基于该制剂重量它含有:
20%-80%的S-羧甲基-L-半胱氨酸;
2%-30%的微晶纤维素;
5%-30%的低取代羟丙基纤维素;
1%-20%的玉米淀粉;
0.5%-10%的羧甲基纤维素钠;
0.1%-5%的硬脂酸镁。
4.根据权利要求1所述的S-羧甲基-L-半胱氨酸肠溶片剂,其特征在于,所述隔离层基于该制剂重量它含有1%-5%羟丙甲纤维素。
5.根据权利要求4所述的S-羧甲基-L-半胱氨酸肠溶片剂,其特征在于,所述肠溶包衣层基于该制剂重量它含有:
1%-12%的水性丙烯酸类肠溶包衣材料93A;
0.01%-0.5%的二甲基硅油;
0.05%-3%的增塑剂,所述增塑剂选自PEG8000、柠檬酸三乙酯或三醋酸甘油酯。
6.制备权利要求1-5中任何一项的S-羧甲基-L-半胱氨酸肠溶片剂的方法,其特征在于,步骤如下:
1)制备片芯:称取处方量的S-羧甲基-L-半胱氨酸、填充剂、崩解剂、粘合剂、润滑剂,混合均匀后,过筛,用水制软材,过筛,所得湿颗粒干燥,压片;
2)以水为分散介质制备隔离层;
3)以水为溶剂制备肠溶层;
4)制备肠溶片:取步骤1)制得的片芯,先包隔离层,再包肠溶层,即得S-羧甲基-L-半胱氨酸肠溶片。
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