CN1218702C - 疟疾预防药物组合物 - Google Patents
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Abstract
本发明公开一种疟疾预防药物组合物，包括磷酸萘酚喹、本芴醇中的一种与阿奇霉素复合，其中，所述磷酸萘酚喹或本芴醇与阿奇霉素的复合重量比为4∶1～1∶4，较为1∶1～1∶2；最佳为1∶1。本发明以磷酸萘酚喹和本芴醇为主同时伍配有持效作用的组分阿奇霉素，为一种对疟疾具有长效预防作用，延缓或克服药物的抗性产生，延长药物有效使用期限的药物组合物。
Description
技术领域
本发明涉及医药领域，具体涉及一种预防疟疾的复方药。
背景技术
疟疾是世界上最严重的虫媒传染病之一。目前全球仍有90多个国家、24亿人生活在疟疾流行区，每年有5亿人发病，200多万人死亡。我国近年疟疾呈逐年上升趋势，仍有19个省市自治区有疟疾流行。自上世纪60年代恶性疟原虫对氯喹产生抗性以来，抗药性疟原虫已遍布于全球所有恶性疟流行地区，抗性程度不断增强，且由单一抗性向多药抗性发展。我国70年代研制出的青蒿素及其衍生物，由于其全新结构及高效、速效，在抗疟药研究史上树立了新的里程碑。我国抗疟药的研究在世界是领先的，除青蒿素及其衍生物外，近年还研制出本芴醇、磷酸萘酚喹、复方蒿甲醚(蒿甲醚+本芴醇)、复方磷酸萘酚喹(磷酸萘酚喹+青蒿素)等新药，但所有这些药物都属于治疗用药，没有预防作用。国外在疟疾预防药研究上尽管做了大量工作，但真正拿出的药物只有美军研制的甲氟喹，虽然该药有长效预防作用，但由于其严重的神经、精神毒性和抗性的迅速出现使其应用受到极大限制。我国上世纪70年代使用的疟疾预防药防II(周效磺胺+乙胺嘧啶)和防III(哌喹+周效磺胺)，均由于抗性的原因而失去作用。目前，全球均没有可选择的疟疾预防药。由于疟原虫产生抗性的速度比新药研究的速度还快，WHO积极提倡使用复方进行疟疾防治。本发明通过对现有的长半衰期的药物进行科学配伍实验，以期找到具有增效作用、预防作用、克服和延缓抗性产生的新复方，以解决目前没有疟疾预防药的问题。
发明内容
本发明的目的在于以磷酸萘酚喹和本芴醇为主同时伍配其它有持效作用的组分，提供一种对疟疾具有长效预防作用，延缓或克服药物的抗性产生，延长药物有效使用期限的药物组合物。
本发明提供的一种疟疾预防药物组合物，包括磷酸萘酚喹、本芴醇中的一种与阿奇霉素复合。
其中，所述磷酸萘酚喹或本芴醇与阿奇霉素的复合重量比为4∶1～1∶4，较佳为1∶1～1∶2；最佳为1∶1。
上述疟疾预防药物组合物，还包括其它药学上可接受的辅料，所述辅料为淀粉、羧甲基淀粉钠、微晶纤维素、乳糖、蔗糖、聚乙烯吡咯烷酮、羟丙基纤维素、可压性淀粉、微粉硅胶、硬脂酸镁、交联聚乙烯吡咯烷酮或聚乙二醇中的一种或几种。
本发明同时提供上述药物组合物在疟疾预防上的应用。
本发明将萘酚喹或本芴醇与阿奇霉素按4∶1～1∶4组成复方药，对疟疾具有长效预防作用，在动物模型上预防可达3～4周；毒性实验的数据显示，本发明组合物两组分药组成的复方不增毒，靶器官无改变；交叉抗药性实验显示复方能延缓单药抗性产生的速度，降低抗性程度；延缓抗药性实验表明本发明组合物能明显延缓抗性产生的时间，并可降低抗性程度。
附图说明
图1为萘酚喹伍用阿奇霉素正交设计实验结果ED90相加线；
图2为本芴醇伍用阿奇霉素正交设计实验结果ED90相加线。
具体实施方式
为更清楚地公开，以下从几方面叙述本发明。
本发明要提供的为以磷酸萘酚喹和本芴醇为主同时复配其它有持效作用的组分，对疟疾具有长效预防作用的药物组合物。本发明通过正交实验方法寻找到了恰当的配伍组分阿奇霉素。
实验一：配伍试验
材料与方法
采用正交设计组方，用4天抑制试验测定的方法，以伯氏疟原虫K173株与昆明小白鼠为实验动物模型。
实验及结果
1、正交设计组方实验：
采用正交设计和4天抑制性实验的方法，以相加线判断组方后的作用类型，用统计方法计算出ED90增效指数的理论值，将组分A药(萘酚喹或本芴醇)和B药(配伍组分)的ED90连接称为相加线。如组方中A药及B药ED90的点落在相加线周围，且靠近相加线，为相加作用；落在相加线上且远离此线，为拮抗作用；落在相加线下方且远离此线，为协同或增效作用。
萘酚喹伍用阿奇霉素正交设计实验结果见图1。本芴醇伍用阿奇霉素正交设计实验结果见图2。
实验结果表明萘酚喹与阿奇霉素配伍的剂量范围，萘酚喹0.75-6.00mk/kg，阿奇霉素5.0-20.0mg/kg。在这个剂量范围配伍，对鼠疟原虫抑制率大于70％，ED50和ED90剂量小于组分药，表明组方对鼠疟原虫具有较强的作用。从图1相加线可以看出，萘酚喹与阿奇霉素配伍，经实验测出ED90各点均分布在相加线附近或落在相加线下方，有的点远离相加线。根据药物间作用类型判断为具有增效作用。本芴醇与阿奇霉素配伍的剂量范围，本芴醇0.63-5.00mk/kg，阿奇霉素5.0-20.0mg/kg。图2表明，本芴醇与阿奇霉素配伍，组方药ED90各点多数落在相加线的下方，且有的点远离此线，作用类型为协同增效作用。
2、组方配比实验：
以4天抑制实验测出各系列剂量组的ED50和ED90，并与组分药ED50和ED90比较，求出ED90的增效指数。增效指数大的且组方中两个组分药效指数最好均大于2的比为最佳组方比。
表1-3不同比例萘酚喹与阿奇霉素配伍对鼠疟K173株的增效作用
| 萘酚喹∶阿奇霉素 | ED90(mg/kg) | 增效指数 |
| 复方 萘 阿 | 复方 萘 阿 | |
| 4∶12∶11∶11∶21∶4 | 2.94 2.35 0.594.01 2.67 1.343.73 1.87 1.873.45 1.15 2.309.05 1.81 7.24 | 17.7 1.6 16.112.9 1.4 11.510.3 2.0 8.39.0 3.0 6.04.2 2.1 2.1 |
实验结果表明，萘酚喹与阿奇霉素以表列比例配伍，复方ED90增效指数均大于4，仅个别比例组分单药的增效指数小于2。综合评价，萘酚喹和阿奇霉素配伍的合适比例范围是4∶1至1∶4，较佳为1∶1至1∶2，最佳配比为1∶1。
表1-4不同比例本芴醇与阿奇霉素配伍对鼠疟K173株的增效作用
| 本芴醇∶阿奇霉素 | ED90(mg/kg) | 增效指数 |
| 复方 本 阿 | 复方 本 阿 | |
| 4∶12∶11∶11∶21∶4 | 4.04 3.23 0.814.62 3.08 1.545.53 2.77 2.776.11 2.04 4.0711.3 2.26 9.04 | 19.2 1.8 17.411.6 1.9 9.78.7 3.3 5.46.8 3.1 3.74.5 2.8 1.7 |
实验结果可见，本芴醇与阿奇霉素以表列比例配伍，复方ED90增效指数均大于4，仅个别比例组分单药的增效指数小于2；综合评价，本芴醇和阿奇霉素配伍的合适比例范围是4∶1至1∶4，较佳为1∶1至1∶2，最佳配比是1∶1。
实验二：鼠疟药效试验
本试验以伯氏疟原虫K173株与小鼠体内实验系统，采用正交设计4天抑制试验和药后不同时间攻虫的方法，对萘酚喹阿奇霉素复方和本芴醇阿奇霉素复方进行系统的药效实验观察。
交叉抗药性试验
采用4天抑制实验法，将组方最佳比及组分药分别对高度抗氯喹株(RCQ/K173)进行敏感性测试，并用直线回归法计算出各药的ED50和ED90，以敏感株ED90与抗药株ED90之比，求出抗性指数I90，以I90判断交叉抗药性的程度。标准是：I90＜2为敏感；I90＝2-10为轻度抗性交叉；I90＝11-100为中度抗性交叉；I90＞100为重度抗性交叉。
实验结果表明，萘酚喹与阿奇霉素配伍，其抗性指数I90为1.9。本芴醇与阿奇霉素配伍，其抗性指数I90为2.2。平行测定的氯喹抗性指数I90为163.4，详见表2-1。本实验结果显示，复方可降低单药的抗性水平，且与氯喹无交叉抗性。
表2-1萘酚喹、本芴醇、阿奇霉素及其配伍对鼠疟抗氯喹株交叉抗性试验结果
| 药物 | 敏感株ED90(mg/kg) | 抗氯喹株ED90(mg/kg) | 抗性指数(I90) |
| 萘阿配伍本阿配伍萘酚喹本芴醇阿奇霉素磷酸氯喹 | 3.732.383.812.6115.472.11 | 7.075.2410.859.4920.07344.81 | 1.92.22.93.61.3163.4 |
抑制性预防试验
选择萘酚喹与阿奇霉素以2∶1、1∶1和1∶2的不同比例，本芴醇与阿奇霉素以2∶1、1∶1和1∶2的不同比例，在给药后7天、14天、21天和28天从各实验组及对照组分别取出10只动物，腹腔攻虫107个原虫寄生的红细胞。攻虫后7-10天分别取尾血涂制薄血膜，检疟原虫。比较不同比例组合物对鼠疟原虫的保护时间。
实验结果表明，两组合物以2∶1比例配伍，有二周的完全保护，第三、四周为部分保护。两组合物以1∶2比例配伍，一周完全保护，四周部分保护。两组合物以1∶1比例配伍，四周的保护率为90-100％，见表2-2。由此可见，两组合物以1∶1比例配伍，其预防效果优于其它比例。
表2-2不同比例的组合物对鼠疟K173株预防效果比较
| 萘(本)∶阿 | 阳性数/总数(只) | |||
| 第一周 | 第二周 | 第三周 | 第四周 | |
| 萘∶阿2∶11∶11∶2本∶阿2∶11∶11∶2 | 0/100/100/100/100/100/10 | 0/100/103/100/100/103/10 | 2/100/105/103/100/104/10 | 4/100/105/103/101/104/10 |
延缓抗药性试验
采用药物剂量递增培育抗性的方法。每7天传一代，每代设两个剂量组，D3-D5每天灌胃给药一次，D7每只小鼠取尾血涂制薄血膜，常规染色后镜检疟原虫。选高剂量组原虫寄生率在2％以上的小鼠作为转种下一代的供血鼠。培育开始剂量为各药的ED90，以后视原虫寄生率情况酌情增加药物剂量，其中一组维持上一代剂量，另一组增加药物剂量。在培育过程中，每5代用4天抑制实验测出各药的ED90，并与亲代的ED90比较，求出抗性指数I90。以原虫从敏感到出现轻度抗性计算药物产生抗性的时间；以抗性指数I90的大小判断药物的抗性水平。其标准是：I90＜2为敏感；2-10为轻度抗性；10-100为中度抗性；＞100为重度抗性。
实验结果见表2-3，从表中可以看出培育到40代时，阿奇霉素、萘酚喹、本芴醇的抗性指数I90分别为28.9、28.6和205。而萘阿组合和本阿组合的抗性指数分别为7.4和7.8。表明本组合物能明显延缓抗性产生的时间，并可降低抗性程度。
表2-3萘酚喹、本芴醇与阿奇霉素配伍延缓抗药性试验结果
| 药物 | 代数 | 天数 | ED90 | I90 |
| 阿奇霉素 | 2040 | 140280 | 177.7447.5 | 11.528.9 |
| 萘酚喹 | 2040 | 140280 | 75.0108.8 | 19.728.6 |
| 本芴醇 | 2040 | 140280 | 100500 | 40205 |
| 萘阿组方 | 2040 | 140280 | 6.627.6 | 1.87.4 |
| 本阿组方 | 2040 | 140280 | 4.723.4 | 1.67.8 |
通过本组实验可以表明：萘酚喹阿奇霉素组合物以及本芴醇阿奇霉素组合物具有增效作用，两药配伍的最佳配比为1∶1。两组合物在鼠疟模型上有4周的长效预防作用，且与氯喹无交叉抗药性。萘酚喹阿奇霉素组合物与本芴醇阿奇霉素组合物，能延缓单药抗性产生的速度，降低抗性程度。由此可见，本组合物是一个有前途的疟疾预防复方。
实验三：毒性试验
本发明依据新药注册的要求，进行了组合物的单次给药和重复给药的毒性试验。
单次给药的急性毒性试验以小鼠为模型，通过口服给药，做了组分单药的口服试验。动物均给药一次，连续观察14天，记录中毒表现及死亡情况，用Bliss法计算半数致死剂量(LD50)，结果见表3-1，根据毒性分级标准属低毒级。用Finney氏公式进行混合毒性的测定，根据该公式：理论LD50/实测LD50的比值如在0.5-2.6之间为毒性相加，比值＜0.4为拮抗，比值＞2.7为增毒。萘酚喹阿奇霉素组合物理论LD50/实测LD50＝0.63，毒性为轻度相加。本芴醇阿奇霉素组合物理论LD50/实测LD50＝0.83，毒性为轻度相加。
表3-1.小鼠急性毒性试验结果
| 组别 | LD50(mg/kg) |
| 萘阿组合物萘酚喹阿奇霉素本阿组合本芴醇 | 1865(1718.0-2024.0)679.5(614.6-751.3)4372(3913.0-4884.7)4555(3729.3-4988.5)＞10000 |
本发明还进行了复方与组分单药对大鼠和Beagle犬的长期毒性试验。大鼠120只，分为6组，每组20只，雌雄各半。Beagle犬24只，每组6只，雌雄各半，连续口服给药14天。末次给药后24h，各组动物活杀1/2，进行血液、血生化、病理等检查，确定中毒剂量及靶器官。其余1/2继续观察28天后活杀，进行同样的指标检测，以了解毒性反应是否可逆。结果表明，大鼠的中毒剂量为160MKD，安全剂量为40MKD；犬的中毒剂量为80MKD，安全剂量为10MKD。毒性的靶器官为肝脏，敏感指标为血清AST、ALT、ALP。毒性反应是可逆的。用大鼠所做的复方与组分单药的长期毒性试验显示，复方不增毒，靶器官无改变。
本发明的疟疾预防药物组合物，还可以在萘酚喹与阿奇霉素或本芴醇与阿奇霉素组合时加入其它药学上可接受的辅料，如淀粉、羧甲基淀粉钠、微晶纤维素、乳糖、蔗糖、聚乙烯吡咯烷酮、羟丙基纤维素、可压性淀粉、微粉硅胶、硬脂酸镁、交联聚乙烯吡咯烷酮或聚乙二醇等，用已知的方法制成各种可以接受的剂型，如常规片剂、胶囊、分散片、颗粒剂等常规制剂，也可以制成缓释和控释剂型，在此不一一例举。
Claims (4)
1、一种疟疾预防药物组合物，为由磷酸萘酚喹或本芴醇与阿奇霉素按重量比4∶1～1∶4组合后加入药学上可接受的辅料制备得到。
2、根据权利要求1所述的疟疾预防药物组合物，其特征在于，所述磷酸萘酚喹或本芴醇与阿奇霉素的重量比为1∶1～1∶2。
3、根据权利要求1所述的疟疾预防药物组合物，其特征在于，所述磷酸萘酚喹或本芴醇与阿奇霉素的重量比为1∶1。
4、根据权利要求1所述的疟疾预防药物组合物，其特征在于，所述辅料为淀粉、羧甲基淀粉钠、微晶纤维素、乳糖、蔗糖、聚乙烯吡咯烷酮、羟丙基纤维素、可压性淀粉、微粉硅胶、硬脂酸镁、交联聚乙烯吡咯烷酮或聚乙二醇中的一种或几种。
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