CN103316016A - 一种含有卡马西平的药物组合物及其应用 - Google Patents
一种含有卡马西平的药物组合物及其应用 Download PDFInfo
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Abstract
本发明公开了一种含有卡马西平的药物组合物及其应用，该药物组合物用于治疗癫痫，其中活性成分由卡马西平和牛蒡苷元组成。本发明的药物组合物可延长癫痫发作潜伏期、负调控NOS的活性并降低NO含量，治疗癫痫的疗效显著；因剂量减半，患者长期服用副作用小。
Description
技术领域
本发明属于医药技术领域，具体而言，涉及一种含有卡马西平的药物组合物及其应用。
背景技术
癫痫（epilepsy）俗称“羊癫疯、羊角风、羊羔疯或者羊痫风”，早在两千二百年前的《黄帝内经》中就有所记载，是大脑神经元突发性异常放电，导致短暂的大脑功能障碍的一种慢性疾病。
西医根据癫痫病因不同分成特发性癫痫和继发性（症状性）癫痫两大类。前者指这类患者的脑病并无可以解释症状的结构变化或代谢异常，而与遗传因素有较密切的关系。症状性癫痫因于多种脑部病损和代谢障碍，如先天性疾病、产前期和围生期疾病（产伤是婴儿期癫痫的常见病因）、高热惊厥后遗、难产、外伤、感染、中毒、颅内肿瘤、脑血管疾病、营养代谢性疾病等。癫痫的产生与神经元异常放电相关。人体休息时，一个大脑皮质锥体细胞的放电频率一般保持在1～10次/秒之间，而在癫痫病灶中，一组病态神经元的放电频率可高达每秒数百次。痫灶细胞群高频重复放电，使其轴突所直接联系的神经元产生较大的突触后电位，从而产生连续传播，直至抑制作用（包括痫性周围抑制性神经细胞的活动，胶质细胞对兴奋性物质的回收，以及病灶外抑制机构的参与）使发作终止。
由于传播途径及范围不同而引起各种形式发作。痫性活动可能仅牵涉一个区域的大脑皮质而不再扩散，引起单纯部分性发作；兴奋在前中央回或后中央回通过放电后细胞外钾离子的增多而传导到邻近神经元，造成杰克逊（Jackson）癫痫；痫性活动常由大脑皮质通过下行投射纤维传播到丘脑和中脑网状结构，引起意识丧失，再由弥散性丘脑投射系统传布到整个大脑皮质，产生继发的全面性强直一阵挛发作。另外，癫痫并发症包括：（1）晚期的外伤性特发性羊角风常伴有加重的趋势，可由局部性发作而演变为全身性发作，严重有记忆力减退，人格障碍智力低下等表现。（2）识别障碍：对事物的辨别能力差，的包括梦样状态，时间感知的歪曲，不真实感，分离状态。（3）情感障碍：表现为不愉快的状态，带有自卑感或伴有抑郁。（4）语言障碍：可产生部分失语或重复语言多。（5）记忆障碍：对熟悉事物产生没有体验过的感觉，或对过去经受过的事物的不能快速回忆。（6）错觉：表现在与物体的真实大小、距离、外型产生差异。（7）可并发穿透性颅脑损伤硬脑膜下血肿及脑内血肿脑挫伤颅骨骨折等疾病。（8）幻觉：在没有任何外界变化的情况下可产生视、听、味、空间感及物体成像等方面的变化和错觉。
癫痫的治疗目前西医主要采用抗癫痫药物，控制率70％～80％ ，但仍有20％左右的患者难治。并且由于癫痫病需要长期甚至终身高剂量服药，药物的毒副作用影响非常大，如卡马西平用于治疗癫痫时，开始每日服用剂量是200-400mg（2-4片），每周逐渐增加至最大量1600mg，长期如此大剂量的服用此药可导致患者认知功能障碍。
发明内容
鉴于现有技术的不足，本发明的目的在于提供了一种低剂量使用卡马西平治疗癫痫的药物组合物。经过大量动物实验研究，本发明的发明人提出了将卡马西平和牛蒡苷元制备成药物组合物，并筛选出了前后两者的最佳剂量配比，在药效学试验中显示出意想不到的效果。
本发明人创造性地将卡马西平和牛蒡苷元联合制备成药物组合物，用于治疗癫痫患者。通过大量临床前试验研究，另本发明人意想不到的是，低剂量的卡马西平和牛蒡苷元的联合应用表现出了惊人的抗癫痫的协同作用。
本发明的目的是这样实现的：一种含有卡马西平的药物组合物，所述的药物组合物用于治疗癫痫，所述的药物组合物中活性成分由卡马西平和牛蒡苷元组成。
本发明的目的还可以这样实现：
上述含有卡马西平的药物组合物，其中所述的药物组合物中活性成分由重量比为10-40:1的卡马西平和牛蒡苷元组成。
优选地，上述含有卡马西平的药物组合物，其中所述的药物组合物中活性成分由重量比为20-30:1的卡马西平和牛蒡苷元组成。
优选地，上述含有卡马西平的药物组合物，其中所述的药物组合物是固体口服制剂。按照卡马西平和牛蒡苷元的重量比，通过固体口服制剂的常规制备技术，可将该组合物制备成片剂、胶囊。
进一步优选地，上述含有卡马西平的药物组合物，其中所述的固体口服制剂中每单位制剂含有100-200mg卡马西平，含有5-10mg牛蒡苷元。
再进一步优选地，上述含有卡马西平的药物组合物，其中所述的固体口服制剂中每单位制剂含有100mg卡马西平，含有5mg牛蒡苷元。
NO在中枢神经系统中有神经保护与毒性双重作用，一方面下调了N-甲基-D-天冬氨酸(NMDA)受体调控的离子通道，避免细胞内钙超载，另一方面也防止NO+向NO-转，从而阻止NO与超氧阴离子反应所致的神经毒性作用，起到了抗癫痫作用，并且具有保护神经元的作用。一般认为NO在癫痫中的作用存在量效关系，低量时NO有抗痫作用，高量时有致痫作用。本发明将卡马西平与牛蒡苷元联合应用对癫痫的治疗效果显著，高、低两个剂量都对癫痫发作潜伏期有明显的延长效果，且可负调控NOS的活性，使NO合成量显著减小，降低NO的毒性作用，抑制癫痫的发作。由此可见，上述的活性成分由卡马西平和牛蒡苷元组成的组合物具有协同治疗癫痫模型小鼠的显著疗效。因此，本发明的第二个目的在于提供一种医药新用途，即上述组合物在制备预防或治疗癫痫的药物中的用途。
通过对本发明的组合物的药效学研究，在实验中意外地发现，卡马西平与牛蒡苷元的联合使用在延长癫痫发作潜伏期、负调控NOS的活性并降低NO含量方面存在着明显的协同性作用。另外试验还发现，在达到同一药效水平的前提下，本发明组合物中卡马西平使用剂量降低一半，这就显著降低了药物的不良反应。
具体实施方式
以下通过动物试验例的形式对本发明的上述内容再作进一步的详细说明，但不应将此理解为本发明上述主题的范围仅限于以下的实例，凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例1 卡马西平/牛蒡苷元对癫痫小鼠模型的影响
健康雄性昆明系小鼠72只，体重18-22g，适应环境3d后随机将全部小鼠分为如下六组：正常对照组、模型对照组、卡马西平组、牛蒡苷元组、复方低剂量组、复方高剂量组，每组12只。除正常对照组外其余五组用于建立癫痫模型，方法如下：在首次服药前均根据体重(50mg/kg)腹腔注射戊四氮。于注射后第2天开始，连续7d，每天各组小鼠于早中晚各1次按表1的受试物和剂量灌胃给药(给药体积0.3-0.4m1)。于最后一次服药4h后，正常对照组注射生理盐水，其余各组小鼠第2次腹腔注射戊四氮50mg/kg。
表1 实验动物分组及给药
| 分组 | 样本量（只） | 剂量 |
| 正常对照组 | 12 | 0.4ml纯化水 |
| 模型对照组 | 12 | 0.4ml纯化水 |
| 卡马西平组 | 12 | 90mg·kg-1·d-1卡马西平 |
| 牛蒡苷元组 | 12 | 4.5mg·kg-1·d-1牛蒡苷元 |
| 复方低剂量组 | 12 | 45mg·kg-1·d-1卡马西平 + 2.3mg·kg-1·d-1牛蒡苷元 |
| 复方高剂量组 | 12 | 90mg·kg-1·d-1卡马西平 + 4.5mg·kg-1·d-1牛蒡苷元 |
将注射后的小鼠放入观察箱中观察行为学变化。秒表记录从腹腔注射至发生癫痫的时间，此为癫痫发作潜伏期。观察第1次腹腔注射戊四氮后各组小鼠癫痫的发作潜伏期，经7d治疗给药后第2次腹腔注射戊四氮，再次观察其发作潜伏期。除牛蒡苷元组外，各治疗组小鼠的癫痫发作潜伏期比模型对照组[(76.9±16.8)s]都有明显的延长，其中复方高剂量组效果最为明显，此组小鼠的发作潜伏期为(206.2±23.4)s ，与卡马西平组相比有显著性差异（P＜0.05）。具体结果参见表2。
表2 各组受试物对癫痫小鼠发作潜伏期的影响（s）
| 分组 | 样本量（只） | 给药前潜伏期 | 给药后潜伏期 |
| 模型对照组 | 12 | 78.2±15.0 | 76.9±16.8 |
| 卡马西平组 | 12 | 80.8±17.9 | 163.3±24.7★★ |
| 牛蒡苷元组 | 12 | 79.5±15.6 | 88.6±28.5 |
| 复方低剂量组 | 12 | 78.8±19.1 | 177.0±21.6★★ |
| 复方高剂量组 | 12 | 81.0±18.4 | 206.2±23.4★★●▼▼ |
★与模型对照组比较，P＜0.05；★★与模型对照组比较，P＜0.01；
●与卡马西平组较，P＜0.05；●●与卡马西平组比较，P＜0.01；
▼与牛蒡苷元组比较， P＜0.05；▼▼与牛蒡苷元组比较，P＜0.01。
第2次腹腔注射戊四氮记录潜伏期数据后，立即将小鼠在冰上断头取脑，分离出海马，漂洗残血，放于吸水纸上沥干水分，称重后放入液氮保存。将海马按1：10比例加入预冷的生理盐水中，冰浴超声粉碎(500W，3s)1O次，即为海马匀浆。海马匀浆液于4℃，1500×g，离心10 min，弃沉淀，取上清液测测定一氧化氮合酶（NOS）和NO的含量。NOS催化体内L-精氨酸和分子氧反应生成NO，因此，NOS活性与NO的含量呈正相关。过量的NO引起海马细胞毒性，导致癫痫发作。与正常对照组相比，模型对照组小鼠海马NOS活性和NO含量都大幅度上升；与模型对照组、各单药组相比，复方各组小鼠海马细胞中NOS活性和NO含量都明显下降（（P＜0.05或P＜0.01）。具体结果参见表3。
表3 各组受试物对癫痫小鼠海马中NOS、NO的影响
| 分组 | 样本量（只） | NOS（U/mg蛋白） | NO（μmol/g蛋白） |
| 正常对照组 | 12 | 0.851±0.042 | 2.158±0.247 |
| 模型对照组 | 12 | 1.913±0.164 | 5.814±0.710 |
| 卡马西平组 | 12 | 0.978±0.069★★ | 2.644±0.422★★ |
| 牛蒡苷元组 | 12 | 1.797±0.088 | 5.220±0.649 |
| 复方低剂量组 | 12 | 0.871±0.076★★▼▼ | 1.908±0.317★★●●▼▼ |
| 复方高剂量组 | 12 | 0.406±0.080★★●●▼▼ | 1.375±0.183★★●●▼▼ |
★与模型对照组比较，P＜0.05；★★与模型对照组比较，P＜0.01；
●与卡马西平组较，P＜0.05；●●与卡马西平组比较，P＜0.01；
▼与牛蒡苷元组比较， P＜0.05；▼▼与牛蒡苷元组比较，P＜0.01。
Claims (7)
1.一种含有卡马西平的药物组合物，所述的药物组合物用于治疗癫痫，其特征在于：所述的药物组合物中活性成分由卡马西平和牛蒡苷元组成。
2.根据权利要求1所述含有卡马西平的药物组合物，其特征在于：所述的药物组合物中活性成分由重量比为10-40:1的卡马西平和牛蒡苷元组成。
3.根据权利要求2所述含有卡马西平的药物组合物，其特征在于：所述的药物组合物中活性成分由重量比为20-30:1的卡马西平和牛蒡苷元组成。
4.根据权利要求1-3任一项所述含有卡马西平的药物组合物，其特征在于：所述的药物组合物是固体口服制剂。
5.根据权利要求4所述含有卡马西平的药物组合物，其特征在于：所述的固体口服制剂中每单位制剂含有100-200mg卡马西平，含有5-10mg牛蒡苷元。
6.根据权利要求4所述含有卡马西平的药物组合物，其特征在于：所述的固体口服制剂中每单位制剂含有100mg卡马西平，含有5mg牛蒡苷元。
7.权利要求1-3任一项所述药物组合物在制备治疗癫痫的药物中的用途。
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