CN112587495A - 一种阿司匹林和硫酸氢氯吡格雷复方制剂及其制备方法 - Google Patents
一种阿司匹林和硫酸氢氯吡格雷复方制剂及其制备方法 Download PDFInfo
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- CN112587495A CN112587495A CN202011471072.6A CN202011471072A CN112587495A CN 112587495 A CN112587495 A CN 112587495A CN 202011471072 A CN202011471072 A CN 202011471072A CN 112587495 A CN112587495 A CN 112587495A
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- aspirin
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- hydrogen sulfate
- enteric
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Classifications
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- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
本发明公开一种阿司匹林和硫酸氢氯吡格雷复方制剂及其制备方法,由阿司匹林肠片芯和硫酸氢氯吡格雷速释颗粒混合压片而成,属于药物制剂领域。所述阿司匹林肠片由含药素片经过肠溶包衣及其隔离层包衣两层包衣组成,由于采用滑石粉和单硬脂酸甘油酯两种抗粘剂联合使用,单硬脂酸甘油酯具有疏水作用,有助于减缓水杨酸的产生,阿司匹林稳定性更好,无需增加内隔离层;硫酸氢氯吡格雷颗粒经过热融制粒而成。本发明可以达到氯吡格雷或其药用盐在胃部迅速释放,阿司匹林肠溶片可以在肠道释放的特性。本发明制备生产过程顺畅,生产能力高,稳定性好等优势。
Description
技术领域
本发明属药物技术领域,涉及一种阿司匹林和硫酸氢氯吡格雷复方制剂及其制备方法。
背景技术
硫酸氢氯吡格雷由法国赛诺菲制药股份有限公司(Sanofi PharmaceuticalsInc)和百时美施贵宝公司(Bristol-Myers Squibb Company)联合开发并推广的一种血小板聚集抑制剂,最早于1997年11月17日在美国被批准上市,上市剂型为片剂,规格为75mg,批准适应症为用于减少以下患者的动脉粥样硬化事件(心肌梗死、中风及血管性死亡):近期中风患者,近期心肌梗死患者或确诊的外周动脉疾病患者。随后,该产品又有新的规格(25mg、300mg)和新适应症(用于急性冠脉综合症)在多个国家和地区被批准上市。
阿司匹林通过对血小板环氧酶的抑制,不可逆地抑制血小板的聚集,可以有效的预防血栓的形成。阿司匹林对消化道黏膜会造成损伤,长期服用有可能造成患者胃、十二指肠黏膜溃疡和出血。阿司匹林肠溶片可以减少阿司匹林对胃黏膜直接刺激。在血小板细胞的高密度颗粒上,存在二磷酸腺苷(ADP)的P2Y12受体,会加速血小板的凝聚过程,而氯吡格雷是P2Y12受体的阻断剂,能不可逆地抑制血小板的聚集作用。阿司匹林与氯吡格雷的作用机制不同,从两种不同途径发挥出抗血小板的作用,在联合应用时可以产生作用相加的协同效应,称之为“双抗”。对于缺血性心脑血管疾病的极危人群以及支架术后的患者,体内的血小板处于高凝状态,所以需要采用“双抗”的方式来抑制血小板的活性,可以采用阿司匹林与氯吡格雷的联用。
赛诺菲公司的硫酸氢氯吡格雷阿司匹林组合片剂于2008年8月在新加坡批准,商品名CoPlavix,之后于2015年11月在欧洲批准,商品名DuoPlavin,现已在70多个国家/地区获得批准。为了减少阿司匹林对胃肠道的刺激,日本赛诺菲公司开发了新型组合片,即阿司匹林肠溶片作为内芯,硫酸氢氯吡格雷作为外层,组合成包芯片,并于2013年9月在日本上市,商品名ComPlavix,规格:氯吡格雷75mg/阿司匹林100mg。原研专利CN105407877中介绍了此新型组合片的处方工艺,内芯与外层由两个隔离层之间插入耐胃酸层组成的三层包衣分开,耐胃酸层包含至少一种耐酸聚会物和相对于耐酸聚合物重量至少40%的滑石粉。
专利CN105407877中描述,滑石粉用量相对于耐胃酸聚合物重量40%以上,才能得到完整的耐胃酸的片剂,25%的滑石粉不能耐受包芯片的二次压制过程,产生不耐酸的阿司匹林内芯。按照原研专利CN105407877中实例1的肠溶包衣处方配制包衣液,滑石粉容易沉降,且常温下包衣液有少许絮凝现象,容易堵枪,包衣过程不够流畅,并且采用三层包衣,工艺繁琐,生产能力低。
单硬脂酸甘油酯是蜡状物,不溶于水,但在热水中强力震荡后,能形成稳定的水合分散体,可减少肠溶材料的粘性,常替代滑石粉作为肠溶包衣的抗粘剂,研究过程中发现其不但可以单独使用,还可以与滑石粉联合使用,减少包衣过程中包衣液的沉降,增加包衣膜的柔韧性,降低包芯片压制过程中裂片出现胃酸不耐受的风险;并且由于其疏水的性质,可以减少水系包衣过程中水份的带入,增加遇水不稳定物质的稳定性。
针对以上问题,本申请通过干法制粒的方式,制备阿司匹林淀粉化颗粒,通过玉米淀粉的包裹,减少阿司匹林的黏涩,提高压片过程的顺畅性,肠溶包衣时通过增加单硬脂酸甘油酯减少滑石粉用量,提高肠溶包衣液的稳定性,使得包衣过程更容易控制,与硫酸氢氯吡格雷颗粒包芯压片时,有更好的耐压能力,制备的硫酸氢氯吡格雷阿司匹林复方片生产过程顺畅,并且采用该处方制备的阿司匹林肠溶片相比赛诺菲原研制剂有更好的稳定性。
发明内容
本发明专利的目的是提供一种阿司匹林和硫酸氢氯吡格雷复方片剂及其制备方法,针对上市片剂包衣配方容易沉降,包衣过程不好控制、阿司匹林水解产物水杨酸增长高的问题,本发明通过研究,优化肠溶包衣处方和工艺,解决阿司匹林肠溶包衣过程滑石粉沉淀、堵抢等问题,提高工艺流畅性同时改善其样品稳定性。同时,还提供了一种阿司匹林硫酸氢氯吡格雷复方片剂的制备方法,该方法肠溶包衣过程顺畅,阿司匹林肠溶片耐压性好,工序相对简单,复方制剂稳定性好,适合批量生产及其储存运输。
一种阿司匹林和硫酸氢氯吡格雷复方制剂,由阿司匹林肠溶片和硫酸氢氯吡格雷颗粒加入外加辅料压片后制成薄膜包衣片,阿司匹林肠溶片自内至外由含药素片、肠溶层包衣和隔离层包衣组成,所述的肠溶层包衣包含包衣材料和相对于包衣材料重量20-40%的滑石粉以及2%-10%的单硬脂酸甘油酯。
进一步地,所述复方制剂由片芯、外层颗粒、底层包衣和外层包衣组成,所述片芯为阿司匹林肠溶片,所述外层颗粒由硫酸氢氯吡格雷颗粒、微晶纤维素、低取代羟丙纤维素、氢化蓖麻油、蔗糖硬脂酸酯组成,底层包衣由羟丙甲纤维素、滑石粉和乙醇组成,外层包衣为薄膜包衣预混剂,具体组成如下:阿司匹林肠溶片143~151份、硫酸氢氯吡格雷颗粒235~240份、微晶纤维素95~100份、低取代羟丙纤维素10~11份、氢化蓖麻油3~4份、蔗糖硬脂酸酯2.0~2.5份、羟丙甲纤维素5.5~6.0份、滑石粉0.8~1.0份、乙醇70~75份、薄膜包衣预混剂10~15份。
本发明阿司匹林肠溶片由含药素片、肠溶层包衣和隔离层包衣组成,其处方组成:
A:肠溶层包衣增重20%-30%,更优选22%-26%;
B:隔离层包衣增重1-8%,更优选2%-6%。
本发明阿司匹林含药片芯由填充剂、粘合剂和助流剂制得,以阿司匹林质量计,辅料占比如下:
填充剂5-12%,更优选6-10%;
粘合剂5-12%,更优选6-10%;
助流剂0.1-2%,更优选0.5-1%;
所述粘合剂,选自于低取代羟丙纤维素(L-HPC)、玉米淀粉、共聚维酮(PVP/VA)、羟丙甲纤维素(HPMC)、聚维酮(PVP)和乙基纤维素(EC)中的至少一种;
所述的填充剂,选自于预胶化淀粉、糊精、微晶纤维素(MCC)、乳糖、甘露醇、山梨醇、碳酸钙等常用固体制剂填充剂中的至少一种;
所述的助流剂,选自于胶态二氧化硅、滑石粉、硬脂富马酸钠、蔗糖脂肪酸脂等常用固体制剂助流剂中的至少一种。
所述肠溶层包衣组成由包衣材料、抗粘剂、增塑剂和表面活性剂组成,包衣材料选用Eudragit L30D-55、Eudragit L100、Eudragit L30D-55/NE30D、CAP、HPMCP中的一种或两种以上任意比例的混合物,其中,抗粘剂为滑石粉和单硬脂酸甘油酯联合使用,滑石粉占包衣材料重量的20-40%,单硬脂酸甘油酯占包衣材料重量的2-10%;增塑剂为枸橼酸三乙酯,占包衣材料重量的10~20%,表面活性剂为吐温80,占包衣材料重量的3~8%;隔离层包衣由包衣材料和增塑剂按照质量比3~5:1混合而成,包衣材料为羟丙甲纤维素和聚维酮中的至少一种,所述增塑剂选自于聚乙二醇、甘油和甘油三醋酸酯中的至少一种或两种以上任意比例的混合物,优选聚乙二醇6000。
本发明硫酸氢氯吡格雷颗粒组成为:硫酸氢氯吡格雷40~45%,填充剂35~40%、聚乙二醇2000-6000 10~15%、低取代羟丙纤维素5~6%、维生素E 0.05~0.1%、预胶化淀粉6~7%,填充剂选择无水乳糖、淀粉和甘露醇中的一种或两种以上任意比例的混合物。具体地,硫酸氢氯吡格雷颗粒组成为:硫酸氢氯吡格雷41.4%,无水乳糖36.12%、聚乙二醇-6000 11.13%、低取代羟丙纤维素5.14%、维生素E 0.08%、预胶化淀粉6.13%。
优选地,所述复方制剂中阿司匹林和硫酸氢氯吡格雷的规格为100mg/75mg。
本发明硫酸氢氯吡格雷阿司匹林复方制剂,其为薄膜包衣片,包衣有两层组成,底层为隔离层包衣,外层为薄膜包衣。
本发明重量为450mg-600mg,优选480mg-580mg,更优选520mg-550mg。
本发明提供一种阿司匹林和硫酸氢氯吡格雷复方制剂的制备方法,包括步骤如下:
(1)将硫酸氢氯吡格雷颗粒,加入微晶纤维素、低取代羟丙纤维素加入三维运动混合机中混合均匀;加入氢化蓖麻油、蔗糖硬脂酸酯再混合均匀;
(2)加入阿司匹林肠溶片和硫酸氢氯吡格雷颗粒,采用直径10~11mm浅凹冲压片,压力3KN-12KN进行压片,控制片重差异±5%,片子硬度4-10kgf;
(3)包衣
包衣液配制:
将底层包衣配制成固含量为6.0~6.5%的包衣液,底层包衣增重1.0-2.0%;
将外层包衣配制成固含量为18~12%得包衣液,外层包衣增重2.0-3.0%。
其中,阿司匹林肠溶片的制备过程如下:
(1)阿司匹林含药素片的制备:将阿司匹林粉碎(1.0mm以下)后和粘合剂混合均匀;将混合后的物料加入干法制粒机中制粒,制备的颗粒用振荡筛进行筛分,收集20~80目筛之间颗粒;将制备的阿司匹林颗粒、填充剂和助流剂加入三维运动混合机中混合均匀;压片,控制硬度3-6kgf;
(2)肠溶层包衣:
溶液A:将吐温80和1/2量的枸橼酸三乙酯、单硬脂酸甘油酯加入到70-80℃的热水中,制成固含量10~20%的溶液,搅拌溶解后匀质乳化分散,降温至30℃以下;
溶液B:把剩余枸橼酸三乙酯、滑石粉加入到纯化水中乳化5-10min,制成固含量18~22%的溶液;
将配置好的溶液A搅拌条件下加入到溶液B中,搅拌条件下将该混悬液和包衣材料混合,继续搅拌1至少h后过60目筛;包衣,干燥,肠溶层包衣增重20%-30%;
(3)隔离层包衣的制备:
称取包衣材料和增塑剂,搅拌条件下加入称量好的纯化水中,继续缓慢搅拌使其完全溶解制成固含量8~10%的包衣液;包衣,隔离层包衣增重1-8%。
所述硫酸氢氯吡格雷颗粒的制备过程如下:
(1)预处理
取5倍重量的预胶化淀粉加入到维生素E中,搅拌将维生素E吸附,至无明显油状物;将剩余预胶化淀粉,及上述物料加入到湿法混合制粒机内制粒,过60目摇摆式颗粒机;
(2)混合
将称量好的硫酸氢氯吡格雷、聚乙二醇2000-6000加入三维运动混合机中,混合均匀后加入称量好的低取代羟丙纤维素、无水乳糖、维生素E预胶化淀粉混合粉,混匀;
(3)制粒,20目摇摆式颗粒机进行整粒。
本发明制备的硫酸氢氯吡格雷阿司匹林复方制剂,用于抑制血小板聚集,减少动脉粥样硬化患者的心肌梗塞,暂时性脑缺血或中风发生率,治疗由血小板聚集诱导的病例状况。
具体实施方式
以下结合具体实施例对本发明的技术方案作进一步详细说明,但不作为本发明保护范围的限制。
本申请中的固含量均指质量分数。
实施例1-3阿司匹林素片的制备
表1:阿司匹林素片的制备处方
制备工艺:
1、将阿司匹林采用锤式粉碎机2000rpm粉碎后,过1.0mm筛网后和玉米淀粉一起加入三维运动混合机中25Hz混合30min;
2、将混合后的物料加入干法制粒机中,输料转速25-50r/min,压轮转速10-25r/min,油压5~8MPa,破碎转速120r/min,预整粒筛8目,预整粒转速60-80r/min,终整粒筛20目,终整粒转速60-80r/min。制备的颗粒用振荡筛(20目、80目)进行筛分,收集20~80目筛之间颗粒。
3、将制备的阿司匹林淀粉化颗粒、微晶纤维素和胶态二氧化硅加入三维运动混合机中25Hz混合20min。
4、采用直径7.0mm浅凹冲进行压片,控制硬度3-6kgf。
实施例4-8:阿司匹林肠溶片芯的制备
表2:阿司匹林肠溶片芯的制备处方
制备工艺:
1、肠溶层包衣:
实施例4-5
包衣液的配置:
A:将处方量的吐温80和1/2量的枸橼酸三乙酯、单硬脂酸甘油酯加入到适量70-80℃的热纯化水中配制固含量15%的溶液,搅拌溶解后匀质乳化分散,乳化结束后加入剩余(除去配置A的热水和配置B的纯化水后)纯化水,搅拌均匀降温至30℃以下;
B:把剩余1/2量的枸橼酸三乙酯、滑石粉加入到适量纯化水中匀浆匀质乳化5-10min,制成固含量20%的溶液;
将配置好的溶液A搅拌条件下加入到溶液B中,搅拌条件下将该混悬液加入到尤特奇L30D水分散体(固含量30wt%)中,继续搅拌1h后过60目筛。
包衣参数:将片芯投放入流化床中,设定风机频率20-30Hz,进风温度40-50℃,对片芯进行预热,控制物料温度在30-35℃,开启雾化压力0.1-0.3MPa,开启蠕动泵蠕动泵喷液,控制转速3-15rpm,注意监测包衣过程物料温度及流化状态,可根据实际情况调整参数,防止片芯粘连。包衣结束后控制物料温度36℃-42℃干燥40min。
实施例6-7
包衣液的配置:
将处方量的吐温80和枸橼酸三乙酯、单硬脂酸甘油酯加入到适量70-80℃的热水中配制固含量15%的溶液,搅拌溶解后匀质乳化分散,乳化结束后加入剩余纯化水,搅拌均匀降温至30℃以下。搅拌条件下将该混悬液加入到尤特奇LD30水分散体(固含量30wt%)中,继续搅拌1h后过60目筛,包衣液固含量为15%。
包衣参数:将片芯投放入流化床中,设定风机频率20-30Hz,进风温度40-50℃,对素片进行预热,控制物料温度在30-35℃,开启雾化压力0.1-0.3MPa,开启蠕动泵蠕动泵喷液,控制转速3-15rpm,注意监测包衣过程物料温度及流化状态,可根据实际情况调整参数,防止片芯粘连。包衣结束后控制物料温度36℃-42℃干燥40min。
实施例8
包衣液的配置:
取枸橼酸三乙酯、滑石粉加入到适量纯化水中匀浆匀质乳化5-10min。搅拌条件下将该混悬液加入到尤特奇L30D水分散体中,包衣液中固含量为25%,继续搅拌1h后过60目筛。
包衣参数:将片芯投放入流化床中,设定风机频率20-30Hz,进风温度40-50℃,对片芯进行预热,控制物料温度在28-32℃,开启雾化压力0.1-0.3MPa,开启蠕动泵蠕动泵喷液,控制转速3-15rpm,注意监测包衣过程物料温度及流化状态,可根据实际情况调整参数,防止片芯粘连。包衣结束后控制物料温度36℃-42℃干燥40min。
2、隔离层包衣
包衣液的配置:
称取包衣材料羟丙甲纤维素(E5)、聚乙二醇-6000,搅拌条件下加入称量好的纯化水中,继续缓慢搅拌使其完全溶解制成固含量为9%的包衣液。
包衣参数:设定风机频率20-30Hz,进风温度40-60℃,对片芯进行预热,控制物料温度在35-42℃,开启雾化压力0.1-0.3MPa,开启蠕动泵蠕动泵喷液,控制转速3-15rpm,注意监测包衣过程物料温度及流化状态,可根据实际情况调整参数,防止片芯粘连。
实施例9硫酸氢氯吡格雷颗粒的制备
表3:硫酸氢氯吡格雷颗粒的制备处方
制备工艺:
1、预处理
取约5倍重量的预胶化淀粉加入到维生素E中,搅拌将维生素E吸附,至无明显油状物。将剩余预胶化淀粉,及上述物料加入到湿法混合制粒机内,设置搅拌80-100rpm,切碎1000-1200rpm,混合5min后出料,过60目摇摆式颗粒机;
2、混合
将称量好的硫酸氢氯吡格雷、聚乙二醇6000加入SYH-400三维运动混合机中,转速25Hz,混合10min。加入称量好的低取代羟丙纤维素(内加)、无水乳糖、维生素E预胶化淀粉混合粉,转速25Hz,混合20min。
3、制粒
启动LGL-120沸腾干燥机,设置进风温度60-80℃,风机频率20-35Hz,预热10min,停止加热,当出风温度低于45℃时,停机,
加入预混合粉,进风温度60-80℃,风机频率20-35Hz,当物料温度达到55~70℃时维持3~10min,至无明显细粉;停止加热,当物料温度低于45℃时停止进风,抖袋2-5min;打开物料仓,翻料,将上层细粉翻至下层,重复上述操作,进行二遍制粒,当物料温度低于45℃时停止进风,抖袋2-5min,出料,20目摇摆式颗粒机进行整粒。
实施例10硫酸氢氯吡格雷阿司匹林复方片的制备
表4:硫酸氢氯吡格雷阿司匹林复方片的制备处方
1、混合
将实施例9的硫酸氢氯吡格雷颗粒,加入微晶纤维素、低取代羟丙纤维素加入三维运动混合机中,转速25Hz混合30min;加入氢化蓖麻油、蔗糖硬脂酸酯再混合10min。
2、压片:使用ZPW22A旋转式压片机,采用直径11mm浅凹冲压片,往料斗中加入待压的实施例4-8阿司匹林肠溶片芯(分别加入)开启振荡器,运行正常后,加入硫酸氢氯吡格雷总混后颗粒,调整第一层充填深度及其第二层充填深度,点动转台转速进行压片调试(转速范围6-8r/min,振荡器转速18-25r/min),确保片芯在中心位置,设定压片机主压3KN-12KN,控制片重差异±5%,片子硬度4-10kgf。
3、包衣
包衣液配制:
底层包衣液:按处方量称取乙醇(无水)加入到搅拌桶内,打开搅拌,缓慢加入羟丙甲纤维素,加完后搅拌10min,使其充分分散,在一直搅拌的状态下加入纯化水,然后加入滑石粉,继续搅拌1h。
外层包衣液:按处方量称取纯化水加入到搅拌桶内,打开搅拌,加入薄膜包衣预混剂(胃溶型),继续搅拌45-60min后,过80目筛。
包衣:采用高效包衣机,参考经验参数设置加热温度50-70℃,根据实际情况调节包衣锅转速3-10rpm、调节蠕动泵转速使包衣效果达到最好。底层包衣:控制物料温度为35-
42℃,底层包衣增重1.0-2.0%时,停止喷液,进行干燥,干燥20-30min。外层包衣:控制物料温度为35-42℃,外层包衣增重2.0-3.0%时,停止包衣,进行干燥,干燥35-45min。
干燥结束后,降温出片。
表5:硫酸氢氯吡格雷阿司匹林片制备搭配
实施例10硫酸氢氯吡格雷阿司匹林复方制剂、溶出情况考察及稳定性考察实验
1.溶出检测方法
溶出度照高效液相色谱法(中国药典2015年版四部通则0512)测定。
色谱条件及系统适用性试验以十八烷基硅烷键合硅胶为填充剂,以乙腈-冰醋酸-水(36∶9∶55)为流动相,检测波长为240nm,柱温30℃,流速1.2ml/min。精密称取阿司匹林对照品、硫酸氢氯吡格雷对照品、水杨酸对照品适量,加1%冰醋酸甲醇溶液溶解并稀释至刻度,摇匀,制成每1ml中约含阿司匹林及硫酸氢氯吡格雷均为0.1mg、水杨酸0.01mg的溶液,作为系统适用性溶液。理论塔板数按阿司匹林峰计算应不低于3000,阿司匹林峰与水杨酸峰的分离度应符合要求。
测定:按外标法以峰面积计算每片中阿司匹林、硫酸氢氯吡格雷和水杨酸的含量,将水杨酸含量乘以1.304后,与阿司匹林含量相加即得每片缓冲液中阿司匹林释放量,分别求出各取样时间点的累积释放量。
2.溶出曲线测定方法
取本品,照溶出度与释放度测定法(通则0931第一法方法1),转速为100转/min,依法操作,取样量为5ml(手动取样)或1.5ml(自动取样),并即时补充相同体积的溶出介质。
pH1.0+pH6.8介质
酸中溶出量:以0.1mol/L盐酸溶液900ml为溶出介质,于5min、10min、15min、20min、30min、45min、60min、90min、120min时,取溶出液滤过,取续滤液作为供试品溶液。
缓冲液中溶出量:弃去上述各溶出杯中酸液,立即加入温度为37±0.5℃的pH6.8磷酸盐缓冲液900ml,于5min、10min、15min、20min、30min、45min、60min、90min、120min时,取溶出液滤过,取续滤液作为供试品溶液。
3、有关物质测定方法
有关物质取本品10片,精密称定,研细。取细粉适量(约相当于氯吡格雷75mg),精密称定,置50ml量瓶中,加甲醇振摇使溶解并稀释至刻度,摇匀,滤过,取续滤液作为供试品溶液(临用新制)。
照高效液相色谱法(中国药典2015年版四部通则0512),用十八烷基硅烷键合硅胶为填充剂,以甲醇-戊烷磺酸钠溶液(0.96g/L,用磷酸调节pH值至2.5)(5:95)为流动相A,以甲醇-乙腈(5:95)为流动相B,流速为每分钟1.0ml,紫外检测器,检测波长为220nm,进行梯度洗脱,按外标法以峰面积计算。
4、含量测定
照高效液相色谱法(中国药典2015年版四部通则0512)测定。
测定法取本品10片,分别置100ml量瓶中,加1%冰醋酸甲醇溶液适量,振摇,使硫酸氢氯吡格雷及阿司匹林溶解,用1%冰醋酸甲醇溶液稀释至刻度,摇匀,滤过,精密量取续滤液5ml,置50ml量瓶中,用1%冰醋酸甲醇溶液稀释至刻度,摇匀,作为供试品溶液。精密量取20μl注入液相色谱仪,记录色谱图。另取阿司匹林对照品、硫酸氢氯吡格雷对照品,精密称定,加1%冰醋酸的甲醇溶液溶解并稀释制成每lml中约含阿司匹林、硫酸氢氯吡格雷各约为0.1mg的溶液,同法测定。按外标法以峰面积计算每片的含量,求得10片的平均含量,即得。
测定结果:
表6:不同处方阿司匹林素片崩解情况
检查项目 | 实施例1 | 实施例2 | 实施例3 |
崩解时间 | 4-7s | 5-8s | 4-7s |
实验结果可知:各个处方准备的阿司匹林淀粉化过程顺畅,颗粒收率相差不大,并且各个处方制备的阿司匹林素片崩解时间相差不大,都能快速崩解。
表7:硫酸氢氯吡格雷阿司匹林复方制剂及其赛诺菲制剂(9K083A)(阿司匹林)在pH1.0+pH6.8介质中溶出曲线对比
表8:硫酸氢氯吡格雷阿司匹林复方制剂及其赛诺菲制剂(9K083A)(硫酸氢氯吡格雷)在pH1.0介质中溶出曲线对比
实验结果显示:样品5阿司匹林肠溶片芯(40%滑石粉,不加单硬脂酸甘油酯)经过二次压片后,片芯不耐压,出现不耐酸的情况。样品1、2、3和4的肠溶片芯经过压片后耐酸性良好,说明肠溶片包衣膜软性良好,但是样品3、4复方片剂阿司匹林溶出较原研赛诺菲制剂较快,而样品1、2采用抗粘剂单硬脂酸甘油酯和不同用量(相对于尤特奇质量40%、20%)的滑石粉联合使用,片芯包衣膜柔韧性增加,当增加压片压力至12KN(样品7)时,仍旧可以保持肠溶片芯的完整性,溶出曲线和赛诺菲样品一致,并且肠溶液不容易沉降,不堵塞喷枪,包衣过程顺畅。
表9:影响因素(有关物质)考察结果
表10:影响因素(溶出度)考察结果
表11:影响因素(含量)检查结果
表12:长期实验条件下自制样品和赛诺菲样品实验数据
本发明的阿司匹林肠溶片由含药素片经过肠溶包衣及隔离层包衣两层包衣组成,无需增加内隔离层,生产工序简单。产品质量稳定,杂质可控,可以实现氯吡格雷或其药用盐在胃部迅速释放,阿司匹林肠溶片在肠道释放的特性,复方制剂可以减少患者用药频率,提高患者依从性。本发明还具有生产过程顺畅,生产能力高,工艺稳定性好,生产成本较低等优势。
Claims (9)
1.一种阿司匹林和硫酸氢氯吡格雷复方制剂,由阿司匹林肠溶片和硫酸氢氯吡格雷颗粒压片后制成薄膜包衣片,其特征在于,阿司匹林肠溶片自内至外由含药素片、肠溶层包衣和隔离层包衣组成,所述的肠溶层包衣包含包衣材料和相对于包衣材料重量20-40%的滑石粉以及2%-10%的单硬脂酸甘油酯。
2.根据权利要求1所述阿司匹林和硫酸氢氯吡格雷复方制剂,其特征在于,所述复方制剂由片芯、外层颗粒、底层包衣和外层包衣组成,所述片芯为阿司匹林肠溶片,所述外层颗粒由硫酸氢氯吡格雷颗粒、微晶纤维素、低取代羟丙纤维素、氢化蓖麻油、蔗糖硬脂酸酯组成,底层包衣由羟丙甲纤维素、滑石粉和乙醇组成,外层包衣为薄膜包衣预混剂,
具体组成如下:阿司匹林肠溶片143~151份、硫酸氢氯吡格雷颗粒235~240份、微晶纤维素95~100份、低取代羟丙纤维素10~11份、氢化蓖麻油3~4份、蔗糖硬脂酸酯2.0~2.5份、羟丙甲纤维素5.5~6.0份、滑石粉0.8~1.0份、乙醇70~75份、薄膜包衣预混剂10~15份。
3.根据权利要求1所述阿司匹林和硫酸氢氯吡格雷复方制剂,其特征在于,所述肠溶层包衣组成由包衣材料、抗粘剂、增塑剂和表面活性剂组成,包衣材料选用Eudragit L30D-55、Eudragit L100、Eudragit L30D-55/NE30D、CAP、HPMCP中的一种或两种以上任意比例的混合物,其中,抗粘剂为滑石粉和单硬脂酸甘油酯联合使用,滑石粉占包衣材料重量的20-40%,单硬脂酸甘油酯占包衣材料重量的2-10%;增塑剂为枸橼酸三乙酯,占包衣材料重量的10~20%,表面活性剂为吐温80,占包衣材料重量的3~8%;隔离层包衣由包衣材料和增塑剂按照质量比3~5:1混合而成,包衣材料为羟丙甲纤维素和聚维酮中的至少一种,所述增塑剂选自于聚乙二醇、甘油和甘油三醋酸酯中的至少一种或两种以上任意比例的混合物。
4.根据权利要求1所述阿司匹林和硫酸氢氯吡格雷复方制剂,其特征在于,所述阿司匹林含药素片由填充剂、粘合剂和助流剂制得,以阿司匹林质量计,填充剂5-12%,粘合剂5-12%, 助流剂0.1-2%;所述粘合剂选自于低取代羟丙纤维素、玉米淀粉、共聚维酮、羟丙甲纤维素、聚维酮和乙基纤维素中的至少一种;所述填充剂选自于预胶化淀粉、糊精、微晶纤维素、乳糖、甘露醇、山梨醇和碳酸钙中的至少一种;所述助流剂选自于胶态二氧化硅、滑石粉、硬脂富马酸钠和蔗糖脂肪酸脂中的至少一种。
5.根据权利要求1或2所述阿司匹林和硫酸氢氯吡格雷复方制剂,其特征在于,硫酸氢氯吡格雷颗粒组成为:硫酸氢氯吡格雷40~45%,填充剂35~40%、聚乙二醇2000-6000 10~15%、低取代羟丙纤维素5~6%、维生素E 0.05~0.1%、预胶化淀粉6~7%,填充剂选择无水乳糖、淀粉和甘露醇中的一种或两种以上任意比例的混合物。
6.根据权利要求1或2所述阿司匹林和硫酸氢氯吡格雷复方制剂,其特征在于,所述复方制剂中阿司匹林和硫酸氢氯吡格雷的规格为100mg/75mg。
7.权利要求1至6任一所述阿司匹林和硫酸氢氯吡格雷复方制剂的制备方法,其特征在于,过程如下:
(1)将硫酸氢氯吡格雷颗粒,加入微晶纤维素、低取代羟丙纤维素加入三维运动混合机中混合均匀;加入氢化蓖麻油、蔗糖硬脂酸酯再混合均匀;
(2)加入阿司匹林肠溶片和硫酸氢氯吡格雷颗粒,采用直径10~11mm浅凹冲压片,压力3KN-12 KN进行压片,控制片重差异±5%,片子硬度4-10kgf;
(3)包衣
包衣液配制:
将底层包衣配制成固含量为6.0~6.5%的包衣液,底层包衣增重1.0-2.0%;
将外层包衣配制成固含量为18~12%得包衣液,外层包衣增重2.0-3.0%。
8.根据权利要求7所述所述阿司匹林和硫酸氢氯吡格雷复方制剂的制备方法,其特征在于,所述阿司匹林肠溶片的制备过程如下:
(1)阿司匹林含药素片的制备:将阿司匹林粉碎后和粘合剂混合均匀;将混合后的物料加入干法制粒机中制粒,制备的颗粒用振荡筛进行筛分,收集20~80目筛之间颗粒;将制备的阿司匹林颗粒、填充剂和助流剂加入三维运动混合机中混合均匀;压片,控制硬度3-6kgf;
(2)肠溶层包衣:
溶液A:将吐温80和1/2量的枸橼酸三乙酯、单硬脂酸甘油酯加入到70-80℃的热水中,制成固含量10~20%的溶液,搅拌溶解后匀质乳化分散,降温至30℃以下;
溶液B:把剩余枸橼酸三乙酯、滑石粉加入到纯化水中乳化5-10min,制成固含量18~22%的溶液;
将配置好的溶液A搅拌条件下加入到溶液B中,搅拌条件下将该混悬液和包衣材料混合,继续搅拌至少1h后过60目筛;包衣,干燥,肠溶层包衣增重20%-30%;
(3)隔离层包衣的制备:
称取包衣材料和增塑剂,搅拌条件下加入称量好的纯化水中,继续缓慢搅拌使其完全溶解制成固含量8~10%的包衣液;包衣,隔离层包衣增重1-8%。
9.根据权利要求7所述阿司匹林和硫酸氢氯吡格雷复方制剂,其特征在于,所述硫酸氢氯吡格雷颗粒的制备过程如下:
(1)预处理
取5倍重量的预胶化淀粉加入到维生素E中,搅拌将维生素E吸附,至无明显油状物;将剩余预胶化淀粉,及上述物料加入到湿法混合制粒机内制粒,过60目筛;
(2)混合
将称量好的硫酸氢氯吡格雷、聚乙二醇2000-6000加入三维运动混合机中,混合均匀后加入称量好的低取代羟丙纤维素、无水乳糖、维生素E预胶化淀粉混合粉,混匀;
(3)制粒 ,过20目筛。
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