CN102697779B - 高溶散速率的伊来西胺药物组合物及其制法 - Google Patents
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Abstract
本发明涉及一种用于高溶散速率的伊来西胺药物组合物及其制备方法，所述药物组合物主要包括80-120目的伊来西胺与药学上可接受的第一辅料制得的30-50目的颗粒，所述药物组合物的溶出度在70-85%。本发明药物组合物最优选的两种形式是干混悬剂和胶囊剂。本发明的有益效果在于，与传统片剂相比，本发明的高溶散速率的伊来西胺药物组合物在胃肠液中分散快、吸收好、生物利用度提高10-15%，患者依从性好。当其制成胶囊时，具有整洁、美观、容易吞服，减少了药物对咽、喉的刺激性；当制成干混悬剂时，特别适合于老人、儿童和吞咽有苦难的患者服用。同时本发明的制备方法，工艺简单，适合于工业化生产。
Description
技术领域
本发明属于药物制剂领域，具体涉及高溶散速率的伊来西胺药物组合物及其制备方法。
背景技术
伊来西胺为胡椒碱（piperine）的衍生物之一，是由中国传统抗癫痫中药处方白胡椒中提炼而来的一种抗癫痫药物。伊来西胺是一种广谱抗癫痫药，大量动物模型的药理实验和临床实验证实其抗癫痫作用显著，毒副作用小。药理作用机制可能与其升高动物脑内5-羟色胺含量有关。
伊来西胺为白色或微黄色结晶性粉末；无臭，无味；在氯仿、乙醚中易溶，在乙醇、四氯化碳中溶解，在水中不溶。目前伊来西胺在临床上应用的只有片剂，剂型单一，同时片剂溶散速率较低，起效慢，生物利用度低。为解决上述技术问题，专利CN200680036519公开了伊来西胺制备透皮释药剂型的可能。CN200680046195公开了离子液体及制备含有伊来西胺的离子液体组合物的方法。CN200680046859公开了用冷冻干燥的方法制得伊来西胺速溶剂等。对于提高生物利用度，上述方法都存在过于复杂、难以工业化生产、成本过高的缺陷。
发明内容
本发明的目的在于提供一种用于治疗癫痫的高溶散速率的具有较高生物利用度的伊来西胺药物组合物及其制备方法，具有工艺简单，质量稳定，疗效好，适合工业化生产。该伊来西胺药物组合物可以制成适合小儿或老人患者服用的干混悬剂和适合成人服用的胶囊剂。下面详细介绍本发明技术方案。
本发明的高溶散速率的伊来西胺药物组合物，包括80-120目的伊来西胺与药学上可接受的第一辅料制得的30-50目的颗粒，所述药物组合物的溶出度在70-85%。
最优选的是，高溶散速率的伊来西胺药物组合物主要包括100目的伊来西胺与药学上可接受的第一辅料制得的40目的颗粒。
为了适合儿童、老人用药，高溶散速率的伊来西胺药物组合物为干混悬剂，每制剂单位含伊来西胺10-400mg，所述第一辅料包括填充剂、助悬剂和粘合剂，所述干混悬剂还包括润滑剂。
本发明的干混悬剂也可称为混悬颗粒剂。
上述干混悬剂中，助悬剂可以选自但不限于阿拉伯胶、卡波姆、黄原胶、桃胶、海藻酸钠、甲基纤维素、羧甲基纤维素钠、羟丙基纤维素。
为了适合成人用药，高溶散速率的伊来西胺药物组合物为胶囊剂，每粒含伊来西胺10-400mg，所述第一辅料为填充剂、粘合剂，所述胶囊还包括润滑剂。
本发明的伊来西胺药物组合物中所用的填充剂选自但不限于淀粉、糊精、乳糖、蔗糖、甘露醇、葡萄糖、微晶纤维素、可压性淀粉、木糖醇、山梨醇。
本发明的伊来西胺药物组合物中所用的粘合剂选自择蒸馏水、乙醇、淀粉浆、糊精、明胶浆、聚乙烯吡咯烷酮、聚乙二醇、羧甲基纤维素钠、甲基纤维素钠、乙基纤维素钠、羟丙基纤维素。
本发明的伊来西胺药物组合物中所用的润滑剂可以选择硬脂酸、硬脂酸镁、滑石粉、微粉硅胶、氢化植物油、聚乙二醇。
本发明还提供了一种制备高溶散速率的伊来西胺药物组合物的方法，包括以下步骤：
（1）将伊来西胺、填充剂分别过100目筛备用；
（2）按照处方量称量，将伊来西胺与辅料混合均匀，加粘合剂制成符合条件的软材；
（3）将软材过40目筛制粒，45-55℃之间干燥，40目筛整粒，加入处方量的润滑剂；
（4）中间体检测；
（5）灌装、包装，即得。
在制备本发明干混悬剂时，在上述第（1）步骤中，将伊来西胺、填充剂和助悬剂分别过100目筛备用。
本发明的有益效果在于，与传统片剂相比，本发明的高溶散速率的伊来西胺药物组合物在胃肠液中分散快、吸收好、生物利用度提高17%以上，患者依从性好。当其制成胶囊时，具有整洁、美观、容易吞服，减少了药物对咽、喉的刺激性；当制成干混悬剂时，特别适合于老人、儿童和吞咽有苦难的患者服用。同时本发明的制备方法，工艺简单，适合于工业化生产。
下面通过试验例来对本发明做进一步说明
试验例1溶出度实验
（1）仪器与试药
仪器：RCZ-8A智能药物溶出仪（天津大学精密仪器厂）
试药：伊来西胺干混悬剂，伊来西胺胶囊，伊来西胺片
（2）方法：紫外-可见分光光度法（中国药典2010版二部附录ⅣA）测定含量
检测波长326nm
试验参数：
溶出方法：中国药典2010版二部附录ⅩC第二法
溶出介质：1%的十二烷基硫酸钠溶液100ml；转速为每分钟50转
时限：45分钟
（3）测定结果
取按上述实施例制备的伊来西胺干混悬剂和胶囊剂三批，市售的伊来西胺片剂进行试验，测定结果见下表
由此可以看出，本发明的伊来西胺干混悬剂和胶囊与市售的伊来西胺片剂相比，具有更高的溶出度。
试验例2生物利用度试验
1材料与方法
1.1药品、仪器与试剂
试验药：本发明的伊来西胺干混悬剂，50mg/袋；伊来西胺胶囊，50mg/粒。参比制剂：伊来西胺片，50mg/片，北京斯利安药业有限公司生产。伊来西胺对照品：中国药品食品药品检定研究院提供。试剂：甲醇为色谱纯，水为纯化水。仪器：Agilent 1100液相色谱仪。
1.2受试者根据《中华人民共和国药典》2010年版附录XIX B“药物制剂人体生物利用度和生物等效性试验指导原则”及《化学药品和治疗用生物制品研究指导原则》中化学药品制剂人体生物利用度和生物等效性研究指导原则的要求，选取30名健康男性志愿者，年龄（23.3±1.9）岁，体重（67.0±5.4）kg，身高（1.74±0.05）m，体重指数（22.1±1.1）kg/m2。受试者均无心、肝、肾、代谢异常等病史，无慢性胃肠道疾病，无吸烟、嗜酒等不良嗜好。经全面体检，血、尿常规，肝、肾功能，X线透视，血压及心电图均无异常发现。受试者均签署知情同意书，临床试验方案经医学伦理委员会审核批准。
1.3试验设计采用3制剂、3周期的二重3X3拉丁方式试验设计。
1.4给药方法受试者随机分为3组，服药顺序为：第1组先服试验干混悬剂，再服参比制剂，最后服试验胶囊；第2组先服参比制剂，再服试验胶囊，最后服试验干混悬剂；第3组先服试验胶囊，再服试验干混悬剂，最后服参比制剂。试验前禁食过夜(10以上)，然后空腹单次用250mL温水送服药物50mg。试验期间统一低脂清淡饮食，忌烟酒，禁饮含咖啡因类成分饮料。避免剧烈活动和长时间卧床。试验前2周至试验期间不用任何其它药物。
清洗期为2周。
1.5血样采集分别于服药前,服药后10,20,30,40min,1,2,3,4,5,6,8,10,12,24,36,48,72h时取静脉血5mL置肝素处理的试管中,离心分离血浆,-20℃冰箱保存至分析。
1.6血药浓度测定方法
1.6.1色谱条件色谱柱：Phenomenex Kromasil C18色谱柱（250mmX4.6mm，5μm）；流动相：甲醇-水（77:23）；检测波长343nm；流速1.O ml.min-1;进样量10μL;柱温20℃。
1.6.2血浆样品处理取血浆0.2ml，加内标液50μl(伊来西胺10mg.L-1)，旋涡振荡10s，加入甲醇1.0mL，旋涡振荡30s，16000r.min-1离心5min；吸上清液100μL置于微量瓶中，取10μL进样。
1.7方法学考察
1.7.1标准曲线制备用空白血浆稀释伊来西胺标准储备液成终浓度为1、10、50、100、200、500μg.L-1的血浆样品，按第1.6.2项处理。以峰面积比值(伊来西胺／内标，R)对血浆浓度(C)进行线性回归分析得回归方程：R=0.04580C一0.002455，r=0．9998，最低检测浓度为1.0μg.L-1。
1.7.2回收率、精密度和稳定性考察配制终浓度为5、50、450μg.L-1的血浆样品各5份，按第1.6.2项处理，连续测定5d，计算回收率和精密度，结果测得的相对标准差RSD％<10％。另将此样品分别于室温下放置24h，3次冷冻-解冻循环，-20℃放置1个月后按第1.6.2项处理，结果测得的相对标准差RSD％<10％，表明血浆样品稳定。
1.8数据处理采用DAS1.0程序分别计算各受试者的有关药代动力学参数。受试药-时曲线下面积(AUCT)及参比制剂-时曲线下面积(AUCR)按梯形面积法计算；峰浓度(Cmax)和达峰时间(Tmax)均为实测值。相对生物利用度(F)按公式：F=AUCT／AUCR×100％计算。
2.结果
本试验显示，干混悬剂与普通片的tmax、Cmax、AUC0-24h、AUC0-∞均有显著性差异，干混悬剂的生物利用度高于普通片剂17%。
下面结合具体实施例对本发明作进一步的说明。
具体实施方式
实施例1：伊来西胺胶囊
制备工艺：
（1）将原辅料分别过100目筛备用；
（2）按照处方量称量，将伊来西胺与淀粉混合均匀后，加入乙醇（50%）适量进行湿润，制成软材；
（3）将软材过40目筛制粒，45-55℃之间干燥，40目筛整粒，然后加入处方量的硬脂酸镁，混合均匀；
（4）中间体检测；
（5）胶囊灌装、抛光、包装，即得伊来西胺胶囊，规格25mg（以伊来西胺计）。
实施例2：
伊来西胺胶囊处方：
制备工艺：
（1）将原辅料分别过100目筛备用；
（2）按照处方量称量，将伊来西胺与乳糖混合均匀后，加入乙醇（50%）适量进行湿润，制成软材；
（3）将软材过40目筛制粒，45-55℃之间干燥，40目筛整粒，然后加入处方量的微粉硅胶，混合均匀；
（4）中间体检测；
（5）胶囊灌装、抛光、包装，即得伊来西胺胶囊，规格50mg（以伊来西胺计）。
实施例3：
伊来西胺干混悬剂（混悬颗粒剂）处方：
制备工艺：
（1）将原辅料分别过100目筛备用；
（2）按照处方量称量，将伊来西胺与蔗糖、甘露醇、黄原胶混合均匀后，加入乙醇（50%）适量进行湿润，制成软材；
（3）将软材过40目筛制粒，45-55℃之间干燥，40目筛整粒，然后加入处方量的微粉硅胶，混合均匀；
（4）中间体检测；
（5）灌装、包装，即得来西胺干混悬剂（混悬颗粒剂），规格50mg（以伊来西胺计）。
实施例4：
伊来西胺干混悬剂（混悬颗粒剂）处方：
制备工艺：
（1）将原辅料分别过100目筛备用；
（2）按照处方量称量，将伊来西胺与乳糖、卡波姆混合均匀后，加入乙醇（50%）适量进行湿润，制成软材；
（3）将软材过40目筛制粒，45-55℃之间干燥，40目筛整粒，然后加入处方量的微粉硅胶，混合均匀；
（4）中间体检测；
（5）灌装、包装，即得来西胺干混悬剂（混悬颗粒剂），规格150mg（以伊来西胺计）。
以上所述实施例仅仅是本发明的优选实施方式进行描述，并非对本发明的范围进行限定，在不脱离本发明设计精神的前提下，本领域普通技术人员对本发明的技术方案作出的各种变形和改进，均应落入本发明的权利要求书确定的保护范围内。
Claims (1)
1.一种高溶散速率的伊来西胺药物组合物，其特征在于，所述药物组合物主要包括100目的伊来西胺与药学上可接受的第一辅料制得的40目的颗粒，所述药物组合物为干混悬剂，每制剂单位含伊来西胺10-400mg；所述伊来西胺与第一辅料的重量份比例为1：30-40；所述第一辅料包括填充剂、助悬剂和粘合剂，所述干混悬剂还包括润滑剂；所述填充剂为蔗糖和甘露醇，所述助悬剂为黄原胶；所述润滑剂为微粉硅胶；所述药物组合物的溶出度为70-85％，所述干混悬剂包括如下重量份各组分：
伊来西胺50 蔗糖1800 甘露醇50 黄原胶60 微粉硅胶40。
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Address after: 150025 Heilongjiang city of Harbin province Shenyang Limin Development Zone, East Street Zhuhai people Lunanli biomedical research center of life medicine venture building, No. 315 Patentee after: Heilongjiang children doctor biological medicine science and Technology Co.,Ltd. Address before: 150025 Heilongjiang city of Harbin province Shenyang Limin Development Zone, East Street Zhuhai people Lunanli biomedical research center of life medicine venture building, No. 315 Patentee before: HEILONGJIANG BAITONG CHILDREN MEDICINE RESEARCH CO.,LTD. |
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Effective date of registration: 20220707 Address after: 150000 No. 315, life medicine entrepreneurship building, Limin biomedical research and development center, East Shenyang Street and South Zhuhai Road, Limin Development Zone, Harbin, Heilongjiang Province Patentee after: HEILONGJIANG CHILDREN DOCTOR CHILDREN BIOLOGY PHARMACY Co.,Ltd. Address before: 150070 No.2, 1st floor, unit 6, no.508-2, Xinyang Road, Daoli District, Harbin City, Heilongjiang Province Patentee before: HARBIN KUNMENG PHARMACEUTICAL TECHNOLOGY Co.,Ltd. |