CN104001176B - 血小板adp受体拮抗剂和b族维生素的药物组合物 - Google Patents
血小板adp受体拮抗剂和b族维生素的药物组合物 Download PDFInfo
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- CN104001176B CN104001176B CN201410258352.7A CN201410258352A CN104001176B CN 104001176 B CN104001176 B CN 104001176B CN 201410258352 A CN201410258352 A CN 201410258352A CN 104001176 B CN104001176 B CN 104001176B
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Abstract
本发明涉及一种含有血小板ADP受体拮抗剂和B族维生素的药物组合物，由治疗有效量的血小板ADP受体拮抗剂及其药用前体、活性代谢产物或盐类中的一种、治疗有效量的B族维生素的一种或几种、和药学上可接受的载体组成；其中，血小板ADP受体拮抗剂包括噻氯匹定、氯吡格雷、普拉格雷、替格瑞洛、依诺格雷等，B族维生素包括维生素B6、维生素B12、叶酸类化合物，优选叶酸类化合物。本发明还涉及该组合物在制备用于预防血栓栓塞性疾病的药物中的用途。由本发明提供的药物组合物制成的药物，在有效抑制血小板功能的基础上，具有更显著的预防或延缓血栓栓塞性疾病的效果。此外，本发明还可使患者服药方便，增加依从性。
Description
技术领域
本发明涉及一种含有口服血小板ADP受体拮抗剂和B族维生素的药物组合物及其用途，尤指一种预防或治疗血管栓塞性疾病的药物组合物，属于药学领域。
背景技术
我国心脑血管疾病发病率呈逐年上升趋势，据卫生部统计，我国目前约有7000万中风及其后遗症患者，有6000万冠心病患者。血栓形成和栓塞是心肌梗塞、脑卒中等心脑血管事件发生的直接原因，血栓栓塞性疾病已成为人类健康的主要杀手，而抗血小板治疗是预防这类疾病发生的重要干预手段【高旭光.预防缺血性卒中的抗血小板治疗.中华脑血管病杂志，2010；4(1)：37～41】。
血小板是外周血液中三种有形成分之一，其基本生理功能包括粘附、变形、聚集、释放和分泌颗粒内容物(如ADP、5-HT)等，一旦血管内壁受损，处于静息状态的血小板被激活，形成聚集体，并提供磷脂表面，促进血液凝固，最终纤维蛋白包绕血小板聚集体形成血栓。抗血小板药物(或称血小板抑制药)能够抑制血小板粘附、聚集和释放等，阻止血栓形成，故可用于血栓栓塞性疾病的一级、二级预防。根据作用机制，抗血小板药物可分为环氧化酶抑制剂、血小板ADP受体拮抗剂、血小板膜糖蛋白复合物GPⅡb/Ⅲa受体拮抗剂、磷酸二酯酶抑制剂等。
ADP(二磷酸腺苷)是体内重要的血小板激动剂。血小板膜表面有3个受体位点，即P2Y1、P2Y12和P2X1受体，其中P2Y1和P2Y12是ADP的特异性受体，也是ADP受体拮抗剂的靶点。血小板ADP受体拮抗剂是临床上重要的抗血小板药物，主要有噻氯匹定(ticlopidine，抵克立得)、氯吡格雷(clopidogrel，波立维)、普拉格雷(prasugrel)、替格瑞洛(ticagrelor,倍林达)、依诺格雷(Elinogrel，PRT060128)等。其中，氯吡格雷需在肝脏转变成活性代谢产物才发挥作用，引起血小板膜ADP受体不可逆改变，逐渐产生抗血小板作用，长期使用易导致氯吡格雷抵抗，发生率约5％-35％。普拉格雷是第三代ADP受体拮抗剂，不会出现药物抵抗，疗效优于氯吡格雷，但出血风险有所增加。替格瑞洛不需经肝脏代谢，可直接发挥作用，对血小板的抑制率高于氯吡格雷，但出血率也比较高。
从循证医学研究结果看，血小板ADP受体拮抗剂虽然对于血栓形成有较好的预防效果，但也存在着一些弊端，其中最令人担忧的副作用是存在出血风险【SibbingD,etal.Antiplateleteffectsofclopidogrelandbleedinginpatientsundergoingcoronarystentplacement.JThrombHaemost,2010；8(2):250～256】，这与药物使用剂量有关，替格瑞洛还有致呼吸困难的不良反应；其次，血管内皮损伤是诱导血栓形成的重要因素，而ADP受体拮抗剂的药理作用机制并不涉及血管内皮保护。因此，血小板ADP受体拮抗剂在用于预防血栓栓塞性疾病方面仍需要改进或优化治疗策略。
B族维生素包括维生素B1、维生素B2、维生素PP、维生素B6、维生素B12、叶酸、泛酸和生物素等，对机体新陈代谢、红细胞形成、保持神经及免疫系统功能具有重要作用。B族维生素属于水溶性维生素，经肠道吸收，由尿排出体外，在人体内存留时间短暂，很少蓄积，所以必须经常从体外摄取以满足营养和代谢需要。B族维生素缺乏可导致诸多不良后果，包括神经系统紊乱、消化障碍、皮肤皱裂、贫血和心脏损害等。其中，叶酸、维生素B6、维生素B12缺乏时影响同型半胱氨酸的代谢，现认为后者是一种心血管危险因素，与血管内皮损伤、血栓形成等可能有关。
发明内容
本发明的目的是克服血小板ADP受体拮抗剂临床应用存在的不足，提供一种更为高效的防治血栓栓塞性疾病的药物组合物，这种高效体现在该组合物除了具有更好的抗血小板效果外，还能同时提供血管内皮保护、从而更有效地防治血栓形成，其临床应用价值优于单用血小板ADP受体拮抗剂。
为实现上述目的，本发明采用以下技术方案：
一种药物组合物，包括：
(1)药用剂量的血小板ADP受体拮抗剂及其活性药用前体、活性代谢产物、或盐类中的一种；
(2)药用剂量的B族维生素的一种或几种；
(3)药剂学上可接受的载体。
上述的“药用剂量”是指具有协同、预防或治疗的药理作用的量。上述血小板ADP受体拮抗剂选自噻氯匹定、氯吡格雷、普拉格雷、替格瑞洛、依诺格雷等中的一种。
本发明所述组合物中，B族维生素选自维生素B6、维生素B12、叶酸类物质中的一种或几种。其中，叶酸类物质包括叶酸、甲酰四氢叶酸、5-甲基四氢叶酸(L-甲基叶酸)、叶酸盐、叶酸或叶酸盐的活性代谢产物和可在体内释放生成叶酸的物质；维生素B6包括吡哆醇、吡哆醛、吡哆胺、磷酸吡哆醛、磷酸吡哆胺及上述物质的衍生物和可在体内释放或生成该类化合物的物质；维生素B12包括钴胺素、甲钴胺素、5’-脱氧腺苷钴胺素、羟钴胺素、氰钴胺素及其他钴胺素的衍生物和可在体内释放或生成钴胺素的物质。
在本发明中，血小板ADP受体拮抗剂的药用剂量范围分别为：噻氯匹定(100～600mg)、氯吡格雷(25～200mg)、普拉格雷(2.5～60mg)、替格瑞洛(50～200mg)、依诺格雷(10～200mg)。这些药物更佳的治疗有效量分别为：噻氯匹定(250～500mg)、氯吡格雷(50～100mg)、普拉格雷(5～20mg)、替格瑞洛(90～180mg)、依诺格雷(50～150mg)。
在本发明中，B族维生素的药用剂量范围分别为维生素B6(1～50mg)、维生素B12(0.05～2mg)、叶酸类化合物(0.1～5mg)。这些药物更佳的治疗有效量分别为维生素B6(5～30mg)、维生素B12(0.1～1mg)、叶酸类化合物(0.4～2mg)。
通过实验研究发现，B族维生素(尤其叶酸)对血管内皮损伤具有一定保护作用，当与血小板ADP受体拮抗剂合用时，能增强后者对血栓形成的预防效果，并能适量减少后者的使用剂量(从而有利于减少其出血的副作用)。
根据本发明，药物组合物中的活性成分是组合物中的基本组分，其中一个活性成分来自于血小板ADP受体拮抗剂中的一种，另一个活性成分为B族维生素的一种或多种，该药物组合物的剂型包括但不限于普通片剂、双层片剂、多层片剂、缓释片剂、单室控释片剂、双室控释片剂、微孔型控释片剂、舌下含片、口腔速崩片、分散片、肠溶片、延迟释放片、定时/位释放片、普通胶囊、肠溶胶囊、缓释胶囊、控释胶囊、含有微丸或小片的胶囊、含有微丸或小片的pH依赖型胶囊、颗粒剂、丸剂、口服液、膜剂或贴剂。
在本发明中，可药用载体或赋形剂可制成普通口服制剂，包括普通片剂、普通胶囊、颗粒剂等，制成片剂时所述可药用载体包括有助于将活性化合物配制成药用制剂的赋形剂和辅料，如微晶纤维素、无机盐类、乳糖、氯化钠、柠檬酸、亚硫酸钠、淀粉、纤维素衍生物、预胶化淀粉，羧甲基淀粉钠，羟丙基淀粉，低取代羟丙基纤维素，交联羧甲基淀粉钠，交联聚乙烯吡咯烷酮，蔗糖、糊精、糖粉、葡萄糖等的一种或几种物质的组合物，属于本领域常识。
在本发明中，可药用载体或赋形剂可制成缓释制剂，包括赋形剂和辅料等。
在本发明中，可药用载体或赋形剂可制成缓释胶囊、控释胶囊，含有微丸或小片的胶囊，含有微丸或小片的pH依赖型胶囊，二联胶囊等，包括赋形剂和辅料等。
术语“药用剂量”是指为达到有效控制或治疗疾病的目的，临床医生根据患病个体病情严重程度对患病个体施与药物的剂量。应当理解本发明提供的药物药用剂量不是对本发明的限制，而是对本发明的优选，通常情况下，在该剂量优选范围内，该药物能够对患病个体产生有效的治疗效果。患病个体是指患有疾病的独立存在的生命体，在本发明中，生命体尤指人类。应当理解，现有技术中，人类药用剂量或药用剂量范围可与哺乳动物，如大鼠、小鼠等进行换算以得出适合相应动物适用的药用剂量或剂量范围。
本发明提供的药物组合物中的化合物在相同的制剂中可以同时施与患病个体，也可分别地相继施与患病个体。若是相继施与患病个体，则第二个(或附加的)活性成分施与的延迟不应当导致活性成分联合带来的有益效果的损失。若是同时施与患病个体，组合物中的化合物可以混合存在于同一个药物制剂形式中，也可以以同样的制剂形式分别独立存在。若是以同样的制剂形式分别独立存在，则药物组合物可以变通的以“组合药盒”形式存在。“组合药盒”是一种盒状容器，内置一种或多种剂量形式的药物组合及其使用说明书，在本发明中优选所述的抗血小板药物中的一种和B族维生素的一种或多种。
本发明的另一个目的是提供含有药用剂量的血小板ADP受体拮抗剂及其活性代谢产物或其盐类中的一种、药用剂量的B族维生素的一种或多种和可药用载体的药物组合物在制备用于抑制血栓形成、预防血栓栓塞性疾病的药物中的用途。
本发明的优点：本发明提供了含有药用剂量的血小板ADP受体拮抗剂及其活性代谢产物或其盐类中的一种、药用剂量的B族维生素的一种或多种和可药用载体的药物组合物。血小板ADP受体拮抗剂和B族维生素的联合效果并不是各个活性物质的各自作用的简单相加，而是在药物的抗血小板作用得到更佳改善的基础上减少药物副作用、进一步降低血栓栓塞性疾病发生的风险。也就是说，血小板ADP受体拮抗剂和B族维生素联合用药取得了协同防治效果，因此是更适宜的抗血小板药物。
下面结合具体实施方式对本发明做进一步说明，并非对本发明的限定，凡依照本发明内容进行的任何本领域的等同替换，均属于本发明的保护范围。
具体实施方式
实施例1.制备复方硫酸氢氯吡格雷/叶酸薄膜包衣片(1000片量)
[注]硫酸氢氯吡格雷97.8g相当于氯吡格雷75g。
制备方法：按处方量称量硫酸氢氯吡格雷、叶酸和PEG6000，备用。将称量好的处方量硫酸氢氯吡格雷和PEG6000加入制粒机中，50℃±5℃制粒。过30目筛整粒，得药物颗粒，称量羟丙纤维素、甘露醇、无水乳糖、微晶纤维素、山嵛酸甘油酯和硬脂富马酸钠，将称量好的药物颗粒和辅料投入混合机中混合20min，出料，得中间体颗粒。将中间体检验，合格后进行压片，硬度4-8kg，即得素片。素片取样检验合格后进行薄膜包衣。称取薄膜包衣预混剂欧巴代，用纯化水配制成12％的混悬液作为包衣液进行包衣，即得薄膜衣片。制备过程中注意避光，制成的片剂需铝塑泡罩包装，避光保存。制成的复方片剂中每片含氯吡格雷75mg、叶酸0.4mg。
实施例2.制备复方普拉格雷/叶酸片(1000片量)
制备方法：将辅料过80目筛，备用。取普拉格雷10g、叶酸0.8g、甘露醇45g、微晶纤维素80g、乳糖50g混合均匀，加入适量的10％羟丙甲纤维素溶液，制软材，过20目尼龙筛制成湿粒，60±5℃干燥2小时，控制颗粒的含水量为1.5％以下，20目筛整粒，再与硬脂酸镁混合均匀，压片。制备过程中注意避光，制成的片剂需铝塑泡罩包装，避光保存。制成的复方片剂中每片含普拉格雷10mg、叶酸0.8mg。
实施例3.制备复方替格瑞洛/5-甲基四氢叶酸胶囊(1000粒量)
制备方法：取处方量5-甲基四氢叶酸、替格瑞洛按照等量递增法混合均匀，备用；再与甘露醇、羧甲淀粉钠、磷酸氢钙混合均匀后，过80目筛，加入聚乙二醇400、5％羟丙甲纤维素溶液适量，制软材，24目筛制粒，50℃干燥约6h过24目筛整粒，控制颗粒的含水量为2-3％，将干燥后的颗粒与处方量硬脂酸镁、滑石粉混合均匀，得到的颗粒中间体进行含量检测，检测合格后，装入空心胶囊即得。制成的胶囊中每粒含替格瑞洛90mg、5-甲基四氢叶酸0.8mg。
实施例4.氯吡格雷+叶酸对大鼠血小板聚集的抑制作用
【方法】
SD大鼠30只，雌雄各半，体重250～280g，随机分3组，每组10只。对照组(生理盐水)、氯吡格雷+叶酸组(7.5+0.04mg/kg)、氯吡格雷组(7.5mg/kg)，灌胃给药，每日一次，共7天。动物经上述给药方法给药后，禁食12小时不禁水，于次日给药2小时后，用戊巴比妥钠30-40mg/kg腹腔麻醉，仰卧位固定，分离腹主动脉，插入聚乙烯管取血5ml于试管内(管内按血和抗凝剂9:1预置0.5ml枸橼酸钠抗凝)，全血按1000r/min离心10分钟，上层即为富含血小板血浆(PRP)。再将余液按4000r/min离心10分钟，取上清即为少含血小板血浆(PPP)。调PRP中血小板浓度约600-700×109个/L。根据比浊法，将有300ulPRP和磁力搅拌棒的比浊管置于血小板聚集仪，37℃±0.1恒温2分钟，经PPP标定后，搅拌情况下，加入诱导剂ADP诱导聚集，测定血小板最大聚集率。
【结果】
实验结果表明，与对照组相比，氯吡格雷组和氯吡格雷+叶酸组的血小板最大聚集率均有明显降低，差异有显著性(均P<0.01)，且氯吡格雷和叶酸合用对降低血小板最大聚集率强于单独使用氯吡格雷(P<0.05)，提示叶酸在抗血小板聚集中起一定作用(表1)。
表1氯吡格雷+叶酸对大鼠血小板的影响(X±SD，n＝10)
注：与生理盐水组比较，*P<0.01，与氯吡格雷组比较，△P<0.05
实施例5.氯吡格雷+叶酸对载脂蛋白E基因敲出小鼠的影响
【方法】
载脂蛋白E基因敲出小鼠30只，雌雄各半，体重20～25g，每组10只，以西方饮食(普通饲料+猪油+胆固醇)喂养，建立动脉硬化模型，随机分3组，即模型组(生理盐水)、氯吡格雷+叶酸组(7.5+0.08mg/kg)、氯吡格雷组(7.5mg/kg)，3组均灌胃给药，每日一次，并继续西方饮食喂养，共8周。动物经上述方法给药后，禁食12小时但不禁水，于次日给药2小时后，用戊巴比妥钠30-40mg/kg腹腔麻醉，眼球取血，测定可溶性血管细胞粘附分子-1(sVCAM-1)、可溶性细胞间粘附分子-1(sICAM-1)。分离胸主动脉分3段，剥离外膜脂肪组织，制成病理切片，采用图像分析系统测量血管横断面的管壁厚度、斑块截面积，3段标本加以平均。
【结果】
通过实验，氯吡格雷组和氯吡格雷+叶酸组，与模型组相比，sVCAM-1和sICAM-1浓度降低，差异有显著性；主动脉横截面组织切片，模型组有明显斑块形成，含大量泡沫细胞，管壁厚度、斑块截面积显著大于用药组；在实验中，合用氯吡格雷和叶酸对载脂蛋白E基因敲出小鼠的影响明显强于单独使用氯吡格雷(P<0.05)，提示叶酸在保护血管内膜损伤中起一定作用(表2)。
表2氯吡格雷+叶酸对载脂蛋白E基因敲出小鼠的影响(X±SD，n＝10)
注：与生理盐水组比较，*P<0.05，与氯吡格雷组比较，△P<0.05
实施例6.普拉格雷+叶酸对大鼠血栓湿重的影响
【方法】
SD大鼠30只，雌雄各半，体重250～280g，随机分3组，每组10只。对照组(生理盐水)、普拉格雷+叶酸组(1.0+0.08mg/kg)、普拉格雷组(1.0mg/kg)，灌胃给药，每日一次，共7天。动物经上述给药方法给药后，禁食12小时不禁水，于次日给药2小时后，用戊巴比妥钠30-40mg/kg腹腔麻醉，仰卧位固定，分离右侧颈总动脉和左侧颈外静脉，在聚乙烯管中放一段长5cm的预先称重的4号丝线，并用肝素生理盐水充满聚乙烯管。当聚乙烯管的一端插入左颈外静脉后，在将聚乙烯管的另一端插入右颈总动脉。打开动脉夹，开放血流15分钟后中断血流，迅速取出丝线称重，总重量减去原丝线重量即为血栓湿重。
【结果】
实验表明，与对照组相比，普拉格雷组和普拉格雷+叶酸组静脉血栓湿重分别减小38％和55％，差异有显著性。在实验中，合用普拉格雷和叶酸对减小血栓大小明显强于单独使用普拉格雷(P<0.05)，提示叶酸在抑制血栓的形成中起一定作用(表3)。
表3普拉格雷+叶酸对大鼠血栓湿重的影响(X±SD，n＝10)
注：与生理盐水组比较，*P<0.05，与普拉格雷组比较，△P<0.05
实施例7.替格瑞洛+5-甲基四氢叶酸(5-MTHF)对大鼠血栓形成时间的影响
【方法】
SD大鼠30只，雌雄各半，体重250～280g，随机分3组，每组10只。对照组(生理盐水)、替格瑞洛+5-MTHF组(9.0+0.08mg/kg)、替格瑞洛组(9.0mg/kg)，灌胃给药，每日一次，共7天。动物经上述给药方法给药后，禁食12小时不禁水，于次日给药2小时后，用戊巴比妥钠30-40mg/kg腹腔麻醉，仰卧位固定，分离右侧颈总动脉，钩上实验性体内血栓形成仪的刺激电极和温度探头，在刺激强度为2mA的条件下持续刺激4分钟，记录动脉血栓形成的时间。
【结果】
通过实验发现，与对照组相比，替格瑞洛组和替格瑞洛+5-MTHF组的动脉血栓形成时间分别推迟，差异有显著性。在实验中，合用替格瑞洛和5-MTHF对血栓形成时间的延长明显强于单独使用替格瑞洛(P<0.05)，提示5-MTHF在延长血栓的形成中起一定作用(表4)。
表4替格瑞洛+5-MTHF对大鼠血栓形成时间的影响(X±SD，n＝10)
注：与生理盐水组比较，*P<0.05，与替格瑞洛组比较，△P<0.05。
Claims (5)
1.一种用于抗血小板治疗的药物组合物，组成是：
(1)75mg的氯吡格雷；
(2)0.4-0.8mg的叶酸；和
(3)药剂学上可接受的载体。
2.权利要求1所述的药物组合物，其特征在于：所述药物组合物的制药剂型为片剂、胶囊剂或颗粒剂。
3.权利要求1所述的药物组合物在制备用于抗血小板治疗药物中的用途。
4.权利要求1所述的药物组合物在制备用于预防、延缓血栓栓塞性疾病药物中的用途。
5.根据权利要求4所述的用途，其特征在于：所述血栓栓塞性疾病是缺血性卒中、心肌梗死、急性冠状动脉综合征、外周动脉栓塞。
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Address after: 518057, Guangdong, Nanshan District, Shenzhen central high tech incubator No. 16 biological three, No. 3 building, building 3 Patentee after: SHENZHEN KANGMUBAO NUTRITION AND HEALTH Co.,Ltd. Address before: 518057, Guangdong, Nanshan District, Shenzhen central high tech incubator No. 16 biological three, No. 3 building, building 3 Patentee before: SHENZHEN TAILEDE NUTRITION AND HEALTH Co.,Ltd. |
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Address after: 518057 3rd Floor, No. 16 Biological Incubator Phase III Building, High-tech Middle Road, Nanshan District, Shenzhen City, Guangdong Province Patentee after: SHENZHEN FULAITE NUTRITION & HEALTH Co.,Ltd. Address before: 518057 3rd Floor, No. 16 Biological Incubator Phase III Building, High-tech Middle Road, Nanshan District, Shenzhen City, Guangdong Province Patentee before: SHENZHEN KANGMUBAO NUTRITION AND HEALTH Co.,Ltd. |
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Effective date of registration: 20230515 Address after: 518057 the 1st and 2nd floors of Building 2, phase III of biological incubator, No.16, Gaoxin Zhongyi Road, central high tech Zone, Nanshan District, Shenzhen City, Guangdong Province; the east side of the 1st floor and the 2nd and 3rd floors of building 3 Patentee after: SHENZHEN AUSA PHARMACEUTICAL Co.,Ltd. Patentee after: SHENZHEN FULAITE NUTRITION & HEALTH Co.,Ltd. Patentee after: SHENZHEN AUSA PHARMED Co.,Ltd. Address before: 518057 3rd Floor, No. 16 Biological Incubator Phase III Building, High-tech Middle Road, Nanshan District, Shenzhen City, Guangdong Province Patentee before: SHENZHEN FULAITE NUTRITION & HEALTH Co.,Ltd. |