CN109069436A - 含有氯吡格雷和阿司匹林的复合制剂 - Google Patents
含有氯吡格雷和阿司匹林的复合制剂 Download PDFInfo
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- CN109069436A CN109069436A CN201780018075.4A CN201780018075A CN109069436A CN 109069436 A CN109069436 A CN 109069436A CN 201780018075 A CN201780018075 A CN 201780018075A CN 109069436 A CN109069436 A CN 109069436A
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- clopidogrel
- compound formulation
- aspirin
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- acid
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Abstract
本发明涉及一种含有氯吡格雷和阿司匹林的复合制剂及其制备方法,其中所述复合制剂即使在储存和分布过程中也具有维持的稳定性,并显示了氯吡格雷片剂的快速崩解速率。
Description
技术领域
本发明涉及含有氯吡格雷和阿司匹林的复合制剂及其制备方法。
背景技术
在本发明中,氯吡格雷是一种血小板聚集抑制剂,可有效治疗外周和冠状动脉疾病(如中风、血栓形成、栓塞、心肌梗塞等),其化学名称为(+)-(S)-α-(2-氯苯基)-6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-乙酸甲酯。
氯吡格雷通过直接抑制已知在血栓形成中具有重要作用的二磷酸腺苷(下文称“ADP”)与其受体的结合以及抑制随后ADP介导的糖蛋白GPIIb/IIa复合物的活化,从而特异性抑制ADP诱导的血小板聚集。此外,氯吡格雷通过阻断血小板活化的扩增来抑制由除ADP之外的激动剂诱导的血小板聚集。
口服施用后,氯吡格雷在肝脏中代谢并形成活性代谢物,发挥其药理作用。活性代谢物选择性地和不可逆地修饰血小板中的ADP受体,从而抑制ADP与其受体的结合。因此,氯吡格雷的作用很大程度上取决于肝脏中代谢氯吡格雷的酶。
作为氯吡格雷的代表性药物原料的氯吡格雷硫酸氢盐(clopidogrel bisulfate)(或氯吡格雷硫酸氢盐,clopidogrel hydrogen sulfate)的化学名称是(+)-(S)-α-(2-氯苯基)-6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-乙酸甲酯硫酸盐(1:1)。它的分子量为419.9,其化学式为C16H16ClNO2S·H2SO4。
氯吡格雷硫酸氢盐用于减少血栓形成事件(例如,急性心肌梗塞(下文称为“MI”)、急性中风、确定的动脉疾病)。已经确定氯吡格雷硫酸氢盐可以减少缺血性中风、新MI,以及其他血管性死亡的联合终点事件(combined end point)。已知在患有急性冠状动脉综合征的患者中,氯吡格雷硫酸氢盐可降低心血管死亡、MI、中风或难治性缺血的联合终点事件。
此外,阿司匹林(通用名:乙酰水杨酸),作为预防血栓形成最有效的药物之一,常被用作止痛药(用于轻度疼痛和疼痛)、退热剂(用于发烧)和消炎药。阿司匹林还具有抗凝血(血液稀释)作用,用于长期以低剂量预防心脏病发作。
为了预防短暂性脑缺血发作和动脉血栓形成,通常每天一次或多次以30mg至1,200mg的量施用阿司匹林。由于阿司匹林可以防止危险的血凝块形成,因此它可以用于降低血管被血凝块阻塞时可能发生的心脏病发作、中风或其他问题的可能性。
即使长期低剂量的阿司匹林也会不可逆地阻断血小板中血栓素A2的合成,从而表现出抑制血小板聚集的作用,并且阿司匹林的这种血液稀释特性可用于降低心脏病发作的发生率。
此外,已知阿司匹林可激活肝脏中将氯吡格雷转化为活性代谢物的酶。在这方面,已经进行了许多研究以开发能够共同施用氯吡格雷和阿司匹林的制剂。然而,这种共同施用的问题在于两种不同药物直接接触会引起共晶现象。重要的是,由于阿司匹林是胃肠道吸收低的物质,因此需要施用超过一定量。然而,阿司匹林本身具有对胃肠道造成损害的性质,因此其剂量受到严格限制。在首先释放阿司匹林以增加氯吡格雷代谢的剂型中,这种风险进一步加剧。
此外,氯吡格雷及其盐是由于其物理性质差而非常难以配制的代表性药物。它们对水分敏感,因此当它们与水溶液接触时会聚集和凝胶化,从而导致崩解延迟。特别地,氯吡格雷及其盐具有高度吸湿性并且在水存在下水解,从而降低了它们的稳定性。因此,需要特别注意它们的储存。
在这种情况下,为了解决含有氯吡格雷的制剂的问题,即在它们的储存和分布(distribution)过程中它们的稳定性降低和当氯吡格雷制剂是片剂时崩解速率降低,本发明人完成了如下所述的本发明。
公开
技术问题
本发明的一个目的是提供一种在储存和分布过程中具有改善的稳定性的复合制剂,其含有氯吡格雷片剂和含阿司匹林的颗粒。含阿司匹林的颗粒可以是颗粒或丸粒的形式。
本发明的另一个目的是提供一种复合制剂,所述复合制剂中存在的氯吡格雷片剂的崩解速率增加。
此外,在本发明中,当含有氯吡格雷和阿司匹林的复合制剂以胶囊形式提供时,必须控制片剂大小以使片剂可以包含在胶囊内。然而,在这种情况下,随着片剂内氯吡格雷的含量增加,可能发生粘附(sticking)现象(在压片过程中粘在冲压机上)和顶裂(capping)现象。为了解决这些问题,本发明的又一个目的是提供一种氯吡格雷片剂,其通过将二氧化硅胶体与活性成分混合而预先制备,以及一种含有所述氯吡格雷片剂的复合制剂。
技术方案
在实现上述目的的一个方面,本发明提供了一种复合制剂,其包括:氯吡格雷片剂,所述氯吡格雷片剂含有氯吡格雷、其异构体或其药学上可接受的盐;和含阿司匹林的颗粒,所述颗粒包括含有阿司匹林、其异构体或其药学上可接受的盐的阿司匹林核心,和包覆所述核心的肠溶包衣层。
在本说明书中,关于“氯吡格雷”的公开部分可以解释为包括所有“氯吡格雷、其异构体或药学上可接受的盐”。
本发明的另一方面提供了一种制备复合制剂的方法,所述方法包括通过首先将氯吡格雷、其异构体或其药学上可接受的盐和二氧化硅胶体混合,然后向混合物中加入崩解剂来制备氯吡格雷片剂。
本发明人通过制备片剂形式的氯吡格雷(其包含氯吡格雷及其异构体、或其药学上可接受的盐),解决了复合制剂在储存和分布过程中稳定性降低的问题。
所述复合制剂可以是含有氯吡格雷片剂和含阿司匹林的颗粒的胶囊,并且在一个实施方案中,所述胶囊可以是硬胶囊。
当以片剂形式而不是颗粒形式待封入到胶囊中制备氯吡格雷时,可能出现氯吡格雷崩解延迟的问题。在这方面,本发明人通过调整基于氯吡格雷片剂的总重量崩解剂的含量为2wt%至8wt%,具体地3wt%至5wt%,来解决该问题。当崩解剂的含量小于所述氯吡格雷片剂总重量的2wt%时,不能得到所期望的崩解速率,而当所述崩解剂的含量大于8wt%时,可能产生暴露在大气中时片剂的稳定性变差的问题。在含有氯吡格雷和阿司匹林的公知复合制剂中存在的氯吡格雷片剂的整合时间(integration time)为12分钟或更长。然而,本发明的复合制剂的特征在于氯吡格雷能以比上述更快的速率崩解。由于本发明的复合制剂含有片剂形式的氯吡格雷,因此与氯吡格雷以颗粒形式含有时相比,可能存在崩解速度降低的问题。然而,通过如上所述增加崩解剂含量,可以降低崩解速率。此外,在本发明的复合制剂中,氯吡格雷可以在胃中先释放,阿司匹林颗粒可以在肠中稍后释放。然而,通过如上所述改善崩解速率,可以防止由氯吡格雷与阿司匹林直接接触引起的问题,从而提高活性成分的稳定性。
在存在于本发明的复合制剂中的氯吡格雷片剂中,通过含有崩解剂,崩解时间可以缩短至缩短的时间,具体地11分钟或更短,更具体地7分钟或更短。
崩解剂可以是选自下组中的至少一种:淀粉或改性淀粉(如羟基乙酸淀粉钠、玉米淀粉、马铃薯淀粉、预胶化淀粉等);粘土(如膨润土、蒙脱土、硅酸铝镁等);纤维素(如微晶纤维素、羟丙基纤维素、羧甲基纤维素等);藻酸盐(如海藻酸钠、海藻酸等);交联纤维素(如交联羧甲基纤维素钠等);树胶(如瓜尔豆胶、黄原胶等);及其混合物。更具体地,崩解剂可以是聚乙烯吡咯烷酮等。
另外,当将氯吡格雷片剂待封入胶囊中时,所述氯吡格雷片剂的重量可以为120mg至350mg,具体地150mg至250mg,更具体地为180mg至240mg,并且可以根据实际处方标准不同地制备。
将氯吡格雷片剂待封入胶囊中时,对氯吡格雷的片剂大小有限制,因此,氯吡格雷的重量相对于氯吡格雷片剂的重量可增加约50%或更高,因此存在一个问题,即可能发生粘附现象(在压片过程中粘在冲压机上)和顶裂现象。
为了解决上述问题,可以通过混合二氧化硅胶体和氯吡格雷,然后加入其他添加剂(例如崩解剂等)来制备氯吡格雷片剂。
另外,氯吡格雷片剂可含有干重损失小于5wt%,更优选1.5wt%或更低的赋形剂。特别地,当赋形剂的干重损失大于5wt%时,可能发生如粘附的压片问题。
赋形剂可选自下组:白糖、D-甘露醇、微晶纤维素、聚乙二醇、低取代羟丙基纤维素、二氧化硅胶体、及其组合。赋形剂可以为微晶纤维素(MCC)。另外,在一个实施方案中,赋形剂是MCC112。
在一个实施方案中,胶囊材料可以是明胶或羟丙基甲基纤维素(HPMC),并且优选HPMC,但胶囊材料不特别限于此。
在下文中,详细描述了本发明的复合制剂。同时,本文公开的每个解释和示例性实施例可以应用于其他解释和示例性实施例。也就是说,本文公开的各种因素的所有组合都属于本发明的范围。此外,本发明的范围不应受下文提供的具体公开内容的限制。
包含在本发明的复合制剂中的氯吡格雷和阿司匹林可以以药学上可接受的盐的形式存在。作为盐,可以使用由药学上可接受的游离酸形成的酸加成盐,但盐不特别限于此。
所述盐的种类没有特别限制。然而,优选盐对受试者(例如哺乳动物)安全有效的形式,但受试者不特别限于此。
术语“药学上可接受的”是指可在药物-医学决策范围内有效用于预期用途而不会引起过度毒性、刺激、过敏反应等的物质。
如本文所用,术语“药学上可接受的盐”是指衍生自药学上可接受的无机盐、有机盐或碱的盐。合适的盐的实例可包括盐酸、溴酸、硫酸、硝酸、高氯酸、富马酸、马来酸、磷酸、乙醇酸、乳酸、水杨酸、琥珀酸、甲苯-p-磺酸、酒石酸、乙酸、柠檬酸、甲磺酸、甲酸、苯甲酸、丙二酸、萘-2-磺酸、苯磺酸等。衍生自合适碱的盐的实例可包括碱金属(例如钠、钾等);碱土金属(如镁等);铵等。
酸加成盐可以通过常规方法制备,例如,将化合物溶解在过量的酸的水溶液中,并且使用水溶性的有机溶剂(例如,甲醇、乙醇、丙酮或乙腈)使盐沉淀,由此制备酸加成盐的方法。将等摩尔量的化合物和水中的酸或醇(例如乙二醇单甲醚)加热,然后将混合物蒸发至干,或者可以抽滤出沉淀的盐。
另外,可以使用碱制备药学上可接受的金属盐。可以通过例如将化合物溶解在过量的碱金属氢氧化物或碱土金属氢氧化物溶液中,过滤未溶解的化合物盐,并蒸发和干燥滤液,来制备碱金属盐或碱土金属盐。
更具体地,本发明的氯吡格雷的药学上可接受的盐可以选自下组:硫酸氢盐、树脂酸盐、右旋樟脑磺酸盐、苯磺酸盐、萘二磺酸盐一水合物、氯吡格雷盐酸盐、及其混合物。
二氧化硅胶体(气相二氧化硅:CAS号7631-86-9)在本发明中具有赋形剂的作用,并具有减少压片过程中压片问题的作用。
基于氯吡格雷片剂的总重量,二氧化硅胶体的含量可以为2wt%至10wt%。当二氧化硅胶体的含量低于上述范围的下限时,在压片过程中会发生粘附现象,因此难以连续商业生产;而当二氧化硅胶体的含量大于上述范围的上限时,在压片过程中发生顶裂现象,因此可能延迟崩解。
二氧化硅胶体具有约7nm至16nm的粒径和200m2/g至400m2/g的比表面积。
可以进一步包衣本发明的氯吡格雷片剂。氯吡格雷片剂可以用任何包衣材料包覆而没有限制,并且在一个实施方案中,包衣材料可以是
含阿司匹林的颗粒可以是粉末、颗粒、丸粒、迷你片剂的形式,并且在一个实施方案中,它可以是颗粒或丸粒。
具体地,含阿司匹林的颗粒可包括含有赋形剂的内核;外核,所述外核位于内核的外侧,并含有作为药理活性成分的阿司匹林、其异构体、或药学上可接受的盐,和粘合剂;以及肠溶包衣层,其位于外核外部并含有肠溶包衣剂。内核和外核相当于阿司匹林核心。具体地,内核的赋形剂可以是球形白糖,肠溶包衣层可以进一步含有增塑剂。
包覆阿司匹林核心的肠溶包衣层是指包覆阿司匹林核心以保护阿司匹林核心的层。作为包衣层的包衣材料的肠溶包衣剂,可以是可以在具有高pH的肠环境中崩解的没有限制的任何材料,例如,选自下组中的至少一种材料:虫胶、羟丙基甲基纤维素乙酸琥珀酸酯、羟丙基甲基纤维素邻苯二甲酸酯、乙酸纤维素邻苯二甲酸酯、乙酸纤维素、聚乙烯醇邻苯二甲酸酯、甲基丙烯酸酯-甲基丙烯酸甲酯共聚物、丙烯酸甲酯-甲基丙烯酸甲酯-甲基丙烯酸酯共聚物、甲基丙烯酸酯-丙烯酸乙酯共聚物、及其混合物。
其中,甲基丙烯酸酯-甲基丙烯酸甲酯共聚物优选为丙烯酸树脂(Eudragit)L100、丙烯酸树脂(Eudragit)L 12.5或丙烯酸树脂(Eudragit)L 100P(赢创德固赛(EvonikDegussa):德国)的共聚物,其中甲基丙烯酸酯与甲基丙烯酸甲酯的摩尔比为1:1;或丙烯酸树脂(Eudragit)S 100、丙烯酸树脂(Eudragit)S 12.5或丙烯酸树脂(Eudragit)S 100P的共聚物,其中甲基丙烯酸酯与甲基丙烯酸甲酯的摩尔比为1:2。
另外,丙烯酸甲酯-甲基丙烯酸甲酯-甲基丙烯酸酯共聚物优选为丙烯酸树脂(Eudragit)FS 30D(赢创德固赛:德国),其中丙烯酸甲酯、甲基丙烯酸甲酯和甲基丙烯酸酯的摩尔比为7:3:1。
此外,甲基丙烯酸酯-丙烯酸乙酯共聚物优选为丙烯酸树脂(Eudragit)L 30D-55或丙烯酸树脂(Eudragit)L 100-55(赢创德固赛:德国),其中甲基丙烯酸酯和丙烯酸乙酯的摩尔比为1:1。
在一个实施方案中,肠溶包衣层的含量可以为阿斯匹林颗粒总重量的2.0wt%至20wt%,在另一个实施方案中为5wt%至15wt%,在另一个实施方案中为5wt%至12wt%。当包衣层形成的量小于上述范围的下限时,在胃中可能发生意外溶解;而当包衣层形成的量大于上述范围的上限时,溶解速率可能会降低,耐酸性可能会差,从而生物利用度降低,并且在长期施用的情况下可能存在问题。
另外,氯吡格雷片剂或含阿司匹林的颗粒可进一步含有选自下组的添加剂:稀释剂、粘合剂、助流剂、稳定剂、薄膜包衣剂、增塑剂、及其混合物。
粘合剂可选自下组:羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、共聚维酮、聚乙二醇、轻质无水硅酸、合成硅酸铝、硅酸盐衍生物(例如硅酸钙、偏硅酸铝镁等)、磷酸盐(例如、磷酸氢钙等)、碳酸盐(例如碳酸钙等)、及其混合物,更优地选自下组:羟丙甲纤维素、聚乙烯吡咯烷酮、及其混合物。基于片剂或颗粒的总重量,粘合剂的含量可以为1wt%至5wt%,更具体地,1wt%至4wt%。
稀释剂可选自下组:碳酸钙、磷酸钙、纤维素、糊精、右旋糖、乙基纤维素、果糖、棕榈酸硬脂酸甘油酯、麦芽糖、蔗糖、淀粉、微晶纤维素、乳糖、葡萄糖、甘露醇、藻酸盐、碱土金属盐、粘土、聚乙二醇、磷酸二钙及其混合物。
助流剂可选自下组:滑石、硬脂酸及其盐、十二烷基硫酸钠、氢化植物油、苯甲酸钠、硬脂酰富马酸钠、单硬脂酸甘油酯、聚乙二醇、及其混合物,更优选硬脂酰富马酸钠。
稳定剂可选自下组:丁基化羟基甲苯(BHT)、丁基化羟基苯甲醚(BHA)、抗坏血酸、生育酚、乙二胺四乙酸(EDTA)、及其混合物。
薄膜包衣剂可选自下组:明胶、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、聚乙二醇、虫胶、乙基纤维素、甲基羟乙基纤维素、羟乙基纤维素、羧甲基纤维素钠、聚乙烯醇、聚乙烯吡咯烷酮、乙烯基吡咯烷酮-乙酸乙烯酯共聚物、丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸酯-乙基三甲基氯化铵共聚物(例如,产品名称:丙烯酸树脂(Eudragit)RS或RL,德固赛)、甲基丙烯酸甲酯-丙烯酸乙酯共聚物(例如,产品名称:丙烯酸树脂(Eudragit)NE30D,德固赛)、聚乙烯基乙酰基二甲基氨基乙酸酯、及其混合物。
增塑剂可选自下组:二醇、酯、油、甘油、甘油衍生物及其混合物。其中,二醇可选自下组:丙二醇、聚乙二醇、及其混合物;酯可以选自下组:邻苯二甲酸二乙酯、邻苯二甲酸二丁酯、癸二酸二丁酯、柠檬酸三乙酯、柠檬酸乙酰基三乙酯、柠檬酸乙酰基三丁酯、甘油三乙酸酯、及其混合物。油可选自下组:蓖麻油、椰子油、及其混合物;甘油和甘油衍生物可以选自下组:甘油、单硬脂酸甘油酯、及其混合物。
在本发明的复合制剂中,氯吡格雷片剂或含阿司匹林的颗粒可进一步含有快速释放材料以增加释放速率。所述快速释放材料可选自发泡剂、缓冲剂、及其混合物。
所述发泡剂可包括无机碳酸盐和有机酸。
所述缓冲剂可选自下组:碳酸钙、磷酸二氢钠、磷酸二钠、谷氨酸钠、柠檬酸钾、碳酸氢钠、柠檬酸钠、氢氧化钠、磷酸钙、磷酸氢钙、各种盐、以及它们的混合物。
在一个实施方案中,基于100重量份的氯吡格雷片剂,复合制剂中阿斯匹林总颗粒的含量可以为10至1,000重量份,具体地30至200重量份。
在一个具体实施方案中,所述复合制剂可含有75mg氯吡格雷和100mg阿司匹林;或75mg氯吡格雷和75mg阿司匹林。
在本发明的复合制剂中,氯吡格雷片剂在胃中先释放,阿司匹林颗粒在肠中释放。因此,可以防止阿司匹林对粘膜的损害,同时能够显示出氯吡格雷和阿司匹林之间相互补充的药物作用。此外,可以通过阻断氯吡格雷与阿司匹林之间的直接接触,防止共晶现象,从而可以防止成分或溶出特性的变化,并且提高药物的稳定性。
制备本发明复合制剂的方法包括:通过先将氯吡格雷、其异构体或其药学上可接受的盐与二氧化硅胶体混合,然后向混合物中加入添加剂,来制备氯吡格雷片剂;制备阿司匹林核心,其含有阿司匹林、其异构体或其药学上可接受的盐;用肠溶包衣剂包覆所述阿司匹林核心。另外,该方法可进一步包括将氯吡格雷片剂和包衣的阿司匹林颗粒填充到胶囊中。
本发明的复合制剂可进一步包含药学有效量的氯吡格雷片剂和含阿司匹林的颗粒。
如本文所用,术语“药学有效量”是指以适用于医学治疗的合理利益/风险比,足以治疗疾病的量。通常,药物有效量可以以每日0.001mg/kg至1,000mg/kg,优选0.05mg/kg至200mg/kg,更优选0.1mg/kg至100mg/kg的量施用一次或分剂量多次施用。然而,出于本发明的目的,考虑到各种因素(例如,要实现的反应的类型和水平、具体组合物(包括存在/不存在根据情况使用不同药剂)、患者的年龄、体重、一般健康状况、性别和饮食、施用时间、施用途径和组合物的排出率、治疗持续时间、与具体组合物一起使用或同时使用的药物、以及医学领域众所周知的其他因素),优选针对特定患者不同地应用特定的治疗有效剂量。
本发明的复合制剂可包括具有药物活性的其他组分。
本发明的制剂可以以粉末的形式制备,并且优选以固体的形式制备,但是制备液体形式的制剂并非不可能,因此不排除在本发明的范围。
本发明的制剂可以作为单独的治疗剂,与其他治疗剂组合施用,或者与常规治疗剂顺序或同时施用,并且可以施用一次或多次。
如本文所用,术语“施用”是指通过任何合适的方法将药物组合物引入患者,并且本发明的组合物可以通过口服或各种肠胃外途径施用,只要该组合物可以到达靶组织,并且优选通过口服施用。根据所需的施用方式,可以本发明的制剂可以以各种类型的制剂制备。在一个实施方案中,所述复合制剂可以是胶囊或硬胶囊的形式。胶囊材料可以是明胶或HPMC,优选HPMC。
可以预防性或治疗性地进行施用。
本发明的制剂可以每日一次或分剂量数次施用,但施用频率没有特别限制。
待施用本发明的制剂的受试者可以指包括人在内的所有动物。所述动物可以是哺乳动物,包括需要治疗类似症状的牛、马、绵羊、猪、山羊、骆驼、羚羊、狗、猫等,但所述动物不限于此。
本发明的有益效果
本发明的复合制剂可以通过将氯吡格雷片剂封闭在胶囊内防止氯吡格雷片剂的释放延迟,从而即使在储存和分布过程中也能保持稳定性,并且加速氯吡格雷片剂的崩解速率。另外,在本发明中,通过将二氧化硅胶体与活性成分混合,然后向其中添加其它添加剂来制备片剂,从而可以防止由于活性成分(即氯吡格雷及其异构体或其药学上可接受的盐)含量增加而发生的粘附(在压片过程中附着到冲压机)和顶裂现象。另外,本发明可以解决当将片剂包封在胶囊中时发生的问题。
设计本发明的复合制剂使得防止活性成分(氯吡格雷和阿司匹林)之间的直接物理接触,因此可以从根本上阻止这两种成分的共晶现象。另外,本发明通过排除共晶现象防止各种成分的理化性质的变化,可以防止制剂的成分、溶出特性和生物等效性的短期变化,并且可以提供改善的长期稳定性的效果。
另外,为了防止阿司匹林刺激和损害胃壁的问题,通过将阿司匹林包衣到肠溶衣层中来制备本发明的复合制剂,使得阿司匹林只能在肠中释放而不在胃中释放。因此,当口服施用本发明的复合制剂时,首先在胃中释放氯吡格雷,然后在肠中释放阿司匹林,从而可以保护胃壁。
此外,与氯吡格雷和阿斯匹林同时施用或以一定时间间隔施用相比,本发明的复合制剂的优点在于可以改善施用方便性和依从性。此外,由于两种药物的互补药物作用,本发明的复合制剂与常规制剂相比即使具有较小的量,也可以表现出相同的治疗效果,并且减少由于药物成分和制造成本带来的不利影响。
最佳实施方式
以下将通过参考下述实施例更详细地描述本发明。然而,这些实施例仅用于说明目的,本发明的范围不受这些实施例的限制。
对比例1和2
将氯吡格雷硫酸氢盐、PEG 6000、甘露醇300DC、MCC 102和L-HPC以如下表1中所示的量混合。表1中所示的每种含量代表每片的量。然后,将上述混合物进一步与二氧化硅胶体、滑石和硬脂酰富马酸钠混合并压片。结果,在压片过程中发生粘附和顶裂现象。
[表1]
实施例1
根据下表2中所示的成分和含量制备片剂。首先将氯吡格雷硫酸氢盐和二氧化硅胶体混合,并将混合物进一步与PEG 6000、甘露醇300DC、MCC 102和L-HPC混合。然后,向其中加入助流剂(即滑石和)并压片。表2中所示的每种含量代表每片的量。特别地,实施例1的片剂在压片过程中没有显示出粘附或顶裂现象,与在对比例1和2(进一步混合二氧化硅胶体,并且使用MCC 102)中制备的那些片剂不同。上述成分的含量示于下表2中。
[表2]
实施例2至7
为了进一步改善压片过程中的粘附和顶裂现象,使用具有低干重损失(1.5wt%)的MCC112。在将氯吡格雷硫酸氢盐和二氧化硅胶体混合后,将混合物进一步与PEG6000、甘露醇300DC、MCC112、L-HPC、CL-PVP和PVP K-30混合。然后,向其中加入助流剂并压片。各成分的含量在下表3中显示。表3中所示的每种含量代表每片的量。
[表3]
实施例8-10和对比例3-6
为了检查二氧化硅胶体对含有崩解剂的制剂的影响,实施例2-7中通过主要改变二氧化硅胶体的浓度来制备具有下表4中所示组成的片剂。
[表4]
实验实施例1.实施例2至7中的崩解试验
对实施例2-7中制备的片剂进行崩解试验。根据韩国药典的崩解试验方法(试验溶液:水)进行崩解试验。结果如下表5所示,并且Plavix 用作对照组。显示实施例2至7中的崩解时间在11分钟内,因此与对照组相比显示出降低。在实施例2至7中,可以在不存在压片问题的情况下进行压片。
[表5]
实验实施例2.实施例8至10和对比例3至6中的崩解试验,以及确认是否存在顶裂和粘附的试验
对实施例8至10和对比例3至6中制备的氯吡格雷片剂进行粘附和顶裂试验和崩解试验(与实验实施例1中相同的方法)。结果如下表6所示。
[表6]
(*‘X’代表粘附和/或顶裂的发生;‘O’代表没有发生粘附和顶裂问题;‘-’代表没有测量崩解时间。)
在对比例3和4中,使用1wt%(基于氯吡格雷片剂总重量)的二氧化硅胶体,在压片过程中发生粘着和/或顶裂问题;此外,在对比例5中,使用11wt%的二氧化硅胶体,在压片过程中出现了顶裂问题;在对比例6中,显示崩解时间高达15分钟。
相反,在实施例8至10中,使用3wt%或10wt%(基于氯吡格雷片剂总重量)的二氧化硅胶体,未发生粘附或顶裂,并且显示崩解时间小于11分钟。
从上述结果可以确认,含有崩解剂并含有2wt%或10wt%(基于氯吡格雷片剂总重量)范围内的二氧化硅胶体的那些片剂崩解时间降低,并且可以很好地制成片剂。
制剂实施例1
-氯吡格雷硫酸盐包衣片剂的制备
每片通过混合羟丙基纤维素(0.5mg)和8038Hp(3.5mg),和二氯甲烷(5wt%的有机溶剂)和乙醇(99.5wt%的有机溶剂)(作为有机溶剂)制备薄膜包衣溶液,并包衣实施例3中制备的纯氯吡格雷硫酸盐片剂。
-制备阿司匹林颗粒
除了上述制备之外,每个胶囊通过将阿司匹林(100mg,罗地亚(Rhodia),泰国)和羟丙基甲基纤维素(5.0mg,信越(Shin-Etsu),日本)溶解在二氯甲烷(600mg)和乙醇(300mg)的混合溶剂中,然后使用流化床包衣机(格拉特工艺技术有限公司(Glatt GmbHProcess Technology),德国)将混合物喷雾到平均粒度为600μm至710μm(30mg,IPS,意大利)的球形白糖颗粒上,形成外核。随后,通过将羟丙基甲基纤维素邻苯二甲酸酯(9.5mg,信越,日本,取代度:200731,粘度:40mPa·s)、羟丙基甲基纤维素(5mg,取代度:2910,粘度:15mPa·s)和柠檬酸三乙酯(0.5mg,森村商事株式会社(Morimura Bros Inc.),日本)溶解在二氯甲烷(250mg)和乙醇(250mg)的混合溶剂中,然后将混合物喷雾到外核上以形成肠溶衣层,来制备阿司匹林颗粒。
将氯吡格雷片剂(204mg)和阿司匹林颗粒(145mg)分别装入明胶和HPMC硬胶囊中,从而制备含有氯吡格雷(75mg)和阿司匹林(100mg)的复合制剂。
制剂实施例2
以与制剂实施例1相同的方法制备含有氯吡格雷(75mg)和阿司匹林(75mg)的复合制剂,不同之处在于使用实施例3中制备的纯氯吡格雷硫酸盐片剂,并且在制备阿司匹林颗粒过程中,每种成分的量如下表7所示变化。
[表7]
对比制剂实施例1
-氯吡格雷颗粒的制备
每个胶囊通过将氯吡格雷硫酸氢盐(97.875mg)和羟丙基甲基纤维素(25.5mg)溶解在无水乙醇(300mg)和二氯甲烷(1,000mg)的混合溶剂中,然后使用流化床包衣机(格拉特工艺技术有限公司,德国)将混合物喷雾到平均粒度为600μm至710μm(103.625mg,IPS,意大利)的球形白糖颗粒上,形成外核。随后,通过将羟丙基甲基纤维素邻苯二甲酸酯(20mg)和聚乙二醇(3.0mg)溶解在无水乙醇(200mg)和二氯甲烷(500mg)的混合溶剂中,然后将混合物喷雾到氯吡格雷的外核上以形成快速释放保护层,来制备氯吡格雷颗粒。
-制备阿司匹林颗粒
以与制剂实施例1相同的方法制备阿司匹林颗粒。
然后,将氯吡格雷片剂(245mg)和阿司匹林颗粒(145mg)分别装入明胶和HPMC硬胶囊中,从而制备含有氯吡格雷(75mg)和阿司匹林(100mg)的复合制剂。
实验实施例3.测试性质的变化
将制剂实施例1中制备的复合制剂分组,一组用明胶胶囊,另一组用HPMC胶囊。通过将胶囊暴露于40℃和75%RH的试验条件下对这些胶囊进行压力测试,并观察性质的变化。结果如下表8所示(O:良好状态,X:差状态)。
[表8]
作为压力测试的结果,明胶胶囊在4天之前没有发现性质变化,而HPMC胶囊外观没有变化,因此证实HPMC胶囊比明胶胶囊更稳定。
实验实施例4.稳定性测试
将制剂实施例1中制备的本发明复合制剂进行加速测试6个月(温度:40℃,75%RHPE瓶),评价结果如下表9所示。
对比制剂实施例1的复合制剂,杂质随时间明显增加,但制剂实施例1的复合制剂杂质显著减少。
[表9]
根据上述内容,本发明所属领域的技术人员将能够理解,在不修改本发明的技术方案或必要特征的情况下,本发明可以以其他特定形式实施。在这方面,本文公开的示例性实施方案仅用于说明目的,不应解释为限制本发明的范围。相反,本发明旨在不仅涵盖示例性实施例,而且涵盖可包括在由所附权利要求所限定的本发明的思想和范围内的各种替代形式、改型、等效形式和其他实施例。
Claims (16)
1.一种复合制剂,其特征在于,包括:
氯吡格雷片剂,所述氯吡格雷片包含氯吡格雷、其异构体或其药学上可接受的盐;和
含阿司匹林的颗粒,所述颗粒包括含有阿司匹林、其异构体或其药学上可接受的盐的阿司匹林核心,和包覆所述核心的肠溶包衣层。
2.如权利要求1所述的复合制剂,其特征在于,所述氯吡格雷片剂还包含崩解剂。
3.如权利要求2所述的复合制剂,其特征在于,基于所述氯吡格雷片剂的总重量,所述崩解剂的含量为2wt%至8wt%。
4.如权利要求2所述的复合制剂,其特征在于,所述崩解剂选自下组中的至少一种:羟基乙酸淀粉钠、玉米淀粉、马铃薯淀粉、预胶化淀粉、膨润土、蒙脱土、硅酸铝镁、微晶纤维素、羟丙基纤维素、羧甲基纤维素、海藻酸钠、海藻酸、交联羧甲基纤维素钠、瓜尔豆胶、黄原胶、交联聚乙烯吡咯烷酮(交联聚维酮)、及其混合物。
5.如权利要求1所述的复合制剂,其特征在于,所述氯吡格雷片剂还包含干重损失为5wt%或更少的赋形剂。
6.如权利要求5所述的复合制剂,其特征在于,所述氯吡格雷片剂还包含干重损失为1.5wt%或更少的赋形剂。
7.如权利要求5所述的复合制剂,其特征在于,所述赋形剂为微晶纤维素。
8.如权利要求1所述的复合制剂,其特征在于,所述氯吡格雷片剂还包含二氧化硅胶体。
9.如权利要求8所述的复合制剂,其特征在于,基于所述氯吡格雷片剂的总重量,所述二氧化硅胶体的含量为2wt%至10wt%。
10.如权利要求1所述的复合制剂,其特征在于,所述肠溶包衣层包含选自下组的至少一种肠溶包衣剂:虫胶、羟丙基甲基纤维素乙酸琥珀酸酯、羟丙基甲基纤维素邻苯二甲酸酯、乙酸纤维素邻苯二甲酸酯、乙酸纤维素、聚乙烯醇邻苯二甲酸酯、甲基丙烯酸酯-甲基丙烯酸甲酯共聚物、丙烯酸甲酯-甲基丙烯酸甲酯-甲基丙烯酸酯共聚物、甲基丙烯酸酯-丙烯酸乙酯共聚物、及其混合物。
11.如权利要求1-10中任一项所述的复合制剂,其特征在于,所述复合制剂配制成胶囊。
12.如权利要求11所述的复合制剂,其特征在于,所述胶囊的材料是明胶或羟丙基甲基纤维素(HPMC)。
13.如权利要求1所述的复合制剂,其特征在于,所述氯吡格雷片剂的崩解时间小于11分钟。
14.一种制备包含氯吡格雷片剂和阿司匹林核心的复合制剂的方法,其特征在于,包括:
首先将氯吡格雷、其异构体或其药学上可接受的盐和二氧化硅胶体混合,然后向混合物中加入崩解剂来制备氯吡格雷片剂;
制备阿司匹林核心,所述阿司匹林核心含有阿司匹林、其异构体或其药学上可接受的盐;和
用肠溶包衣剂包衣阿司匹林核心。
15.如权利要求14所述的方法,其特征在于,基于所述氯吡格雷片剂的总重量,所述崩解剂的含量为2wt%至8wt%。
16.如权利要求14所述的方法,其特征在于,基于所述氯吡格雷片剂的总重量,所述二氧化硅胶体的含量为2wt%至10wt%。
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WO2024124785A1 (zh) * | 2022-12-13 | 2024-06-20 | 山东诺明康药物研究院有限公司 | 一种硫酸氯吡格雷阿司匹林片及其制备方法和应用 |
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