CN1203078A - 增效抗疟药复方磷酸萘酚喹的制备方法 - Google Patents
增效抗疟药复方磷酸萘酚喹的制备方法 Download PDFInfo
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Abstract
一种增效抗疟药复方磷酸萘酚喹的制备方法,由一个有增效作用价值的化合物磷酸萘酚喹和另一个有同样增效作用价值的化合物青蒿素及其衍生物(或蒿琥酯、蒿甲醚、蒿乙醚、二氢青蒿素)以及添加符合药物学规定的添加剂混合制成复方,以提高该复方对疟疾的治疗效果。
Description
本发明涉及一种增效抗疟药复方磷酸萘酚喹的制备方法。
复方磷酸萘酚喹是由具有增效抗疟作用价值的抗疟药磷酸萘酚喹(简称萘酚喹)(I)和具有同样增效抗疟作用价值的青蒿素类抗疟化合物(II)按一定剂量比例组合而成。
磷酸萘酚喹在抗疟药领域是一个尚未被广泛应用的四氢萘酚类抗疟化合物，是一种新结构类型的疟原虫血液裂殖体(无性体)的杀灭剂。该药具有如下特点：①对多种抗药性疟原虫株引起的恶性疟和间日疟均有明显疗效；②临床用药量较小(成人治疗总量0.8-1.0克，预防量为0.4-0.5克)；③有持效抗疟作用，病人治愈率高(在上述剂量下，治愈率达98-100％)；④有增效抗疟作用价值(与其它抗疟药、尤其是与青蒿素类抗疟药伍用有明显的增效抗疟作用)；其不足之处是杀疟原虫速度较青蒿素类缓慢，若给与大剂量或超过治疗量(1克以上)时可产生一过性肝损伤。
青蒿素类化合物(II)，包括从黄花蒿(Artemisia amua L)分离提取出来的青蒿素(R＝O)以及半合成衍生物青蒿琥酯(R为-O-(C＝O)(CH2)2COONa)、蒿甲醚(R为O)(CH3)蒿乙醚(R为O-CH2CH3)和二氢青蒿素(R为OH)，均为同一类含有过氧基团倍半萜酯的新结构，是疟原虫血液内裂殖体(无性体)的杀灭剂。该类化合物的抗疟特点是：①对抗氯喹恶性疟疾有效；②对疟原虫红内期无性体杀灭速度快，因此控制疟疾症状快；③有增效抗疟作用价值(与萘酚喹伍用有明显的增效抗疟作用)，其缺点是在一般治疗剂量和短疗程(3天)时杀虫不彻底，原虫复燃率高(达50％以上)，需加大剂量和延长疗程(5-7天)才能彻底杀灭疟原虫而提高治愈率，但是往往由于剂量的增加和疗程的延长而导致药物毒性的增加，因此在临床应用上受到了极大的限制。
此外，当前占世界疟疾发病总数80％的恶性疟疾对常用抗疟药已产生抗药性虫株并迅速传播蔓延，虽然各国都在研制防治抗药性虫株的抗疟新药，但是疟原虫对新药产生抗药性的速度远比研制新药的速度快，以致新药的使用寿命大大缩短。有鉴于此，对于抗疟新药的研究必须采用两种或两种以上有增效作用价值的药物组成增效复方的研究渠道。
本发明提出的复方是经过大量实验证明相互有增效抗疟作用价值的萘酚喹与青蒿素类化合物中的青蒿素、或其衍生物青蒿琥酯、蒿甲醚、蒿乙醚或二氢青蒿素相配伍，按一定剂量比例组成复方，制成片剂，用于治疗和预防各种疟疾(包括抗药性的恶性疟及间日疟)。
鉴于萘酚喹具有对疟原虫红内期无性体有持效杀灭作用的特点以及青蒿素类化合物(包括蒿琥酯、蒿甲醚、蒿乙醚、青蒿素以及二氢青蒿素)均有对疟原虫红内期无性体快速杀灭的优势，其目的在于发挥两类抗疟药各具不同的优点，扬弃各有的弱点(如萘酚喹杀虫速度较缓慢，青蒿素类杀虫虽快而不彻底，原虫的复燃率高)，从中找出两药合适的剂量比例，组成有增效作用的复方，以发挥两药在抗疟治疗中的优势互补作用，既能延缓疟原虫产生抗药性的速度和时间，又可以达到较高的治愈率，而且可利用其持效作用的特点，作为长效预防药。
通过复方磷酸萘酚喹对鼠疟、猴疟以及人恶性疟的疗效和对鼠、狗的急性及长期毒性试验表明，萘酚喹和青蒿素(或青蒿琥酯、或蒿甲醚、或蒿乙醚或二氢青蒿素)对鼠疟的增效剂量比为1∶1-50；对猴疟和恶性疟的增效剂量比为1∶1-50 以该比例配制的复方进行毒性试验证明无增毒现象。
萘酚喹和青蒿素是以最佳剂量配比，在添加不影响药效或产生毒性的固体辅料情况下，配制成复方片剂。
本发明复方磷酸萘酚喹的技术方案及其实施例如下：
实施例一：复方磷酸萘酚喹的药物剂量配比
(一)通过动物试验确定本复方萘酚喹和青蒿素类化合物(青蒿素、或青蒿琥酯、或蒿甲醚、或蒿乙醚、或二氢青蒿素)的剂量配比关系和两药增效作用
用伯氏疟原虫(Plasmodium berghei)感染的小白鼠为试验模型，以正交试验设计和4日抑制试验法，测定各相加剂量组疟原虫抑制率，并以直线回归方程计算法分别求出各系列相加剂量的ED50和ED90。
(二)用相加线图示法分析复方的作用类型
在纵坐标和横坐标线上分别标出两个单药的ED90，并将其连成线作为相加线。凡两药相加剂量组ED90的点位于相加线附近者为药物间呈相加作用；位于相加线下方、并远离此线者为药物间有增效作用；位于相加线上方，且远离此线者为药物间的拮抗作用。
(三)增效指数的计算和复方中两个单药最佳配比的确定
以相加线以下或靠近相加线的点进行药物对比试验，并以复方中的单药ED50-ED90，分别与复方ED50、ED90中的单药剂量之比值为增效指数。选择复方中单药的增效指数均大于2以上较高者的复方两单药剂量比为最佳剂量比。
按此公式求出该复方抗鼠疟两药最佳剂量配比及增效指数。
实施例二：复方磷酸萘酚喹的药效评价
(一)鼠疟药效评价
采用“4日抑制试验”方法，在感染伯氏疟原虫的小白鼠中测定复方磷酸萘酚喹及其单药口服给药(灌胃)，每天一次，连续四天，测定伯氏鼠疟正常株和抗氯喹株的ED50、ED90(mg/kg/day.MKD)，并以抗氯喹株ED50或ED90除以正常株ED50或ED90求出抗性指数(或称抗性倍数)I50、I90。
(二)猴疟药效评价
用Davidson氏方法，设定萘酚喹和青蒿素不同三个剂量比例配伍组和两个单药剂量组，每组3只猴子。以诺氏猴疟原虫红内期无性体感染恒河猴，当疟原虫红细胞寄生率升至较高时，口服(灌胃)一次给药。观察各猴原虫24小时下降率、转阴时间及105天内有无再现(或称复燃)情况，以判断凡是萘酚喹与青蒿素配伍取得最佳疗效者，也即取得复方两药的最佳剂量配比。
(三)对恶性疟原虫的药效评价
采用氯喹敏感性体内试验(观察28天)方法，以萘酚喹、青蒿素片剂设定不同四个剂量比伍用，以及两个单药，一次口服给药，治疗无合并症疟疾病人。以退热时间、疟原虫24小时下降率、转阴时间和28天内疟原虫无性体有无再现(或复燃)来判断药效。凡是取得最佳疗效者，也是萘酚喹和青蒿素伍用所取得的最佳剂量配比。
实施例三：复方磷酸萘酚喹杀虫速度的测试
采用已感染鼠疟正常株高密度原虫血症的小白鼠一次灌胃给药治疗后，观察原虫数量变化，测定疟原虫下降90％、转阴时间及转阴率或复燃时间，并比较复方和单药的杀虫效果。
实施例四、复方磷酸萘酚喹对疟疾的治愈效果试验
采用一次给药，连续观察30天的方法，对感染疟原虫正常株的小鼠一次灌胃给药后，间隔3-4天检查疟原虫血症情况，直至30天血中不出现原虫者为完全治愈。
实施例五：复方磷酸萘酚喹抗药性观察
(一)交叉抗药性
以Peters氏“4日抑制试验”法，将复方及其组分单药萘酚喹和青蒿素分别对抗氯喹(RCQ)、抗萘酚喹(RNQ)和抗青蒿素(RQ)株及敏感株的鼠疟进行药物敏感性测试。以各药对于抗药株原虫与敏感株原虫的ED90之比，求出抗性指数(即抗性倍数)I90，从而判断疟原虫对复方药物的抗药性程度，其标准是：
I90＝1为敏感
I90＝2-10为轻度抗性
I90＝11-100为中度抗性
I90＞100为重度抗性
(二)延缓抗性
以口服(灌胃)给药，药物剂量递增法培育药物敏感的伯氏鼠疟原虫，使之产生药物抗性株，然后测定其抗性出现的时间及抗性强度。
实施例六：复方磷酸萘酚喹药理毒理学评价
(一)一般药理学试验
以小白鼠、大白鼠和猫为试验动物模型，药物剂量以复方对鼠疟敏感株药效ED90(MKD)的1、10倍；另设不给药对照组。动物一次口服(灌胃)给药后，进行各项药理指标观察和测定，即小白鼠自发性活动次数及其对热板致痛作用反应和大鼠体温以及猫的血压、心率、心电和呼吸频率的变化情况判断药物对神经、心血管和呼吸系统的影响。
(二)毒理学试验
按照国家《新药审批办法》条例进行复方急性毒性和长期毒性试验，以了解该复方有无增毒作用：
1.急性毒性试验
(1)小白鼠急性毒性试验
将小白鼠按体重随机分为10组，每组10只，雌雄各半，按萘酚喹与青蒿素合适剂量比例分别设计一次口服或腹控注射两种给药途径各5个剂量组，连续观察14天用Bliss法计算LD50、LD5，并以LD50与ED50，LD5与ED95分别算出化疗指数和安全系数。
另设萘酚喹、青蒿素单药各5个剂量组，一次口服给药，测定LD50，按Finney公式计算复方的混合毒力。混合毒力值＞2.7为增毒作用，＜0.4为毒力拮抗作用，0.5-2.6为毒力相加作用。
(2)大白鼠急性毒性试验
用Wistar大鼠，按萘酚喹与青蒿素设定比例设定5个剂量组，每组10只，雌雄各半，一次口服(灌胃)给药，观察14天，记录动物反应和死亡数，计算LD50、LD95。
(3)狗急性毒性试验
选6只健康雄性比格狗，用萘酚喹与青蒿素按设定比例的复方片剂，按Diechman50％计量递增法设6个剂量，每个剂量1只狗，一次口服给药，观察14天。记录中毒表现持续或消失时间，特点和死亡时间。未出现中毒表现的最高剂量为最大耐受剂量(MTD)，引起死亡最小剂量为近似致死剂量(ALD)。试验死亡狗需作尸检。
2.长期毒性试验
(1)大鼠长期毒性试验
以萘酚喹与青蒿素按设定比例设3个剂量组，用Wistar大白鼠随机分组，每个剂量组和正常对照(不给药)组各24只，雌雄各半，每天口服给药一次，连续14天。每天观察动物表现，停药后24小时，每组随机活杀2/3(雌雄各8只)，剩余1/3(雌雄各4只)继续观察至28天活杀。
观察项目：动物精神行为、活动、皮毛等变化情况，首药后每7天测每只鼠体重及摄食量一次；作血液学、血液生化学和病理组织学及骨髓涂片、切片检查，对各项检查数据进行统计学处理和显著性测定，综合分析各项检查结果，为复方对大鼠的中毒致死剂量、中毒剂量和基本安全剂量及中毒靶器官、病变的可逆性情况提供分析依据。
(2)狗的长期毒性试验
用健康比格狗，以萘酚喹和青蒿素按设定配比的复方片剂分3个剂量组另设不给药的正常对照组，每组6只狗，雌雄各半，每天口服给药一次，连续14天。停药后24小时活杀2/3(雌雄各2只)，余下1/3(雌雄各1只)继续观察至28天活杀。
观察项目：生理指标及临床表现包括：食欲、恶心、呕吐、大小便行动步态、精神状态、活动、抽搐，死亡状态等，每天逐项记录一次。体重、心率、食量、呼吸、体温等，每周测一次。
血液学试验、血液生化分析，尿液分析、心电图、眼底、骨髓涂片及切片和病理组织学检查等，所有检查数据均经统计学处理和显著性测定。
综合各项检查和观察结果，。确定复方对狗的中毒致死剂量、中毒剂量和基本安全剂量及中毒靶器官，病变的可逆性情况等。
Claims (6)
1.一种增效抗疟药复方磷酸萘酚喹的制备方法，该复方是由抗疟化合物磷酸萘酚喹(I)的增效剂量与青蒿素类抗疟化合物(II)增效剂量的组合制成复方片剂，
2.如权利要求1所述，一种增效抗疟药复方磷酸萘酚喹的制备方法，其特征在于该复方是由具有增效作用价值的磷酸萘酚喹(I)和有同样增效作用价值的青蒿素类化合物(II)中的青蒿素(R为O)共同组成，
3.如权利要求1.所述，一种增效抗疟药复方磷酸萘酚喹的制备方法，其特征在于具有增效抗疟作用价值的磷酸萘酚喹(I)还可以与：
(1)具有同样增效抗疟作用价值的青蒿素类化合物(II)中的青蒿琥酯(R为O-(C＝O)(CH2)2COONa)组成复方，
(2)或与具有同样增效抗疟作用价值的青蒿素类化合物(II)中的蒿甲醚(R为O-CH3)组成复方，
(3)或与具有同样增效抗疟作用价值的青蒿素类化合物(II)中的蒿乙醚(R为O-CH2CH3)组成复方，
(4)或与具有同样增效作用价值的青蒿素类化合物(II)中的二氢青蒿素(R为OH)组成复方
4.如权利要求1所述，一种增效抗疟药复方磷酸萘酚喹的制备方法，其特征在于该复方对鼠疟有效配伍剂量比是由1分磷酸萘酚喹(I)和1-50份青蒿素类化合物(II)中的任何一种化合物(如青蒿素或青蒿琥酯或蒿甲醚或蒿乙醚或二氢青蒿素)组成，
5.如权利要求1所述一种增效抗疟药复方磷酸萘酚喹的制备方法，其特征在于该复方对猴疟和人恶性疟的有效配伍剂量比是由1份磷酸萘酚喹(I)和1-50份青蒿素类化合物(II)中的青蒿素或蒿琥酯、或蒿甲醚、或蒿乙醚、或二氢青蒿素)组成，
6.如权利要求1所述一种增效抗疟药复方磷酸萘酚喹的制备方法，其特征在于该复方可在添加不影响药效的固体辅料情况下按组份单药的最佳剂量配比制成复方片剂。
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1327841C (zh) * | 2003-02-10 | 2007-07-25 | 沈恒 | 一种新型的抗疟药复方制备方法 |
| CN111249275A (zh) * | 2020-03-03 | 2020-06-09 | 云南省寄生虫病防治所 | 一种治疗间日疟的药物的配伍方案及其使用方法 |
| CN113440527A (zh) * | 2020-03-24 | 2021-09-28 | 中国科学院上海药物研究所 | 萘酚喹或含萘酚喹的组合制剂在抗冠状病毒中的应用 |
-
1997
- 1997-06-24 CN CN97111840A patent/CN1075946C/zh not_active Expired - Lifetime
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1327841C (zh) * | 2003-02-10 | 2007-07-25 | 沈恒 | 一种新型的抗疟药复方制备方法 |
| CN111249275A (zh) * | 2020-03-03 | 2020-06-09 | 云南省寄生虫病防治所 | 一种治疗间日疟的药物的配伍方案及其使用方法 |
| CN113440527A (zh) * | 2020-03-24 | 2021-09-28 | 中国科学院上海药物研究所 | 萘酚喹或含萘酚喹的组合制剂在抗冠状病毒中的应用 |
| CN113440527B (zh) * | 2020-03-24 | 2024-05-28 | 中国科学院上海药物研究所 | 萘酚喹或含萘酚喹的组合制剂在抗冠状病毒中的应用 |
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