CN1262929A - 治疗血吸虫病的药物及其制造方法 - Google Patents
治疗血吸虫病的药物及其制造方法 Download PDFInfo
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- CN1262929A CN1262929A CN99100676A CN99100676A CN1262929A CN 1262929 A CN1262929 A CN 1262929A CN 99100676 A CN99100676 A CN 99100676A CN 99100676 A CN99100676 A CN 99100676A CN 1262929 A CN1262929 A CN 1262929A
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- amino acid
- medicine
- salt
- schistosomicide
- treatment
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
一种治疗血吸虫病的药物,其特征在于该药物由下述成分和配比组成(重量份数):N-磷酰化氨基酸或其盐0.5—5、赋形剂0—100、润滑剂0—2、调味剂0—1、NaCl0—10。本发明的药物具有杀灭吸收虫和抑制肝内虫卵肉芽肿形成的显著疗效及毒性较低的优点,且制造方法简单,成本低廉,适合广泛推广应用。
Description
本发明涉及医药技术领域,特指一种治疗血吸虫病的药物及其制造方法。
众所周知血吸虫病是严重危害人类健康的寄生虫病,在世界上许多国家都有流行,目前常用治疗血吸虫病的药物大体分为两类:
第一类是吡喹酮,化学名称为2-(环己甲酰基)-1,2,3,6,7,11b-六氢-4H-吡嗪并[2,1-a]异喹啉-4-酮,其制造方法包括如下5个步骤:
1、将异喹啉与苯甲酰氯及氰化钠反应,生成氰基苯甲酰二氢异喹啉;
2、接着在加热加压下,用镍催化加氢反应,再经分子重排,生成1-苯甲酰氨甲基-1,2,3,4-四氢异喹啉;
3、再与氯乙酰氯缩合反应,生成1-苯甲酰氨甲基-2一氯乙酰基-1,2,3,4-四氢异喹啉;
4、再于加热及叔丁醇钾存在下进行环化反应,生成2-苯甲酰-1,2,3,6,7,11b-六氢-4H-吡嗪并[2,1-a]异喹啉-4-酮;
5、接着在磷酸液中水解,再用环己甲酰氯进行酰化反应,生成吡喹酮;
主要缺陷是合成路线较长,工艺十分复杂,价格昂贵。
第二类是酒石酸锑钾,对杀灭血吸虫有效,但毒性较大,小鼠试验,口服半致死量LD50 0.6g/kg,腹腔注射半致死量LD50 52mg/kg,静脉注射半致死量LD50 65mg/kg。
针对上述缺陷,本发明人经过长期的研究和实践,创造出本发明的技术方案。
本发明的目的在于提供一种治疗血吸虫病的药物及其制造方法,用简便的方法合成了一种对杀灭血吸虫和抑制肝内虫卵肉芽肿形成具有特效的N-磷酰化氨基酸或其盐药物,克服现有技术的弊端,达到制造容易、成本低廉、疗效显著和降低毒副作用的目的。
本发明的目的是这样实现的:一种治疗血吸虫病的药物,其特征在于该药物由下述成份和配比组成(重量份数):
N-磷酰化氨基酸或其盐 0.5-5
赋形剂 0-100
润滑剂 0-2
调味剂 0-1
NaCl 0-10
其中R1、R2为H或含有1-7个碳原子的直链或支链的烷基或芳基或盐基;
AA为氨基酸残基;
R3为H或盐基。
该R1、R2为相同或不同的烷基或芳基,包括甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、新戊基、己基、庚基、苯基、苄基。
该AA包括天然的氨基酸残基、D-构型的氨基酸残基或DL-构型的氨基酸残基。
该R、R2或R3的盐基包括下述成份的盐:钾、钠、钙、镁、锌或乙二胺、乙醇胺、乙二醇胺、氨基葡萄糖。
该赋形剂包括淀粉、纤维素衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、琼脂、碳酸钙、碳酸氢钠、乳糖。
该润滑剂包括滑石粉、硬脂酸钙、硬脂酸镁、聚乙二醇。
该调味剂包括香味剂、甜味剂、果味剂。
其制造方法包括合成N-磷酰化氨基酸或其盐,再按配比与赋形剂、润滑剂、调味剂或NaCl进行组配和成型,具体步骤如下:
(一)合成N-磷酰化氨基酸或其盐:
用氨基酸或其酯与二烷基亚磷酸酯在水、醇,有机碱及四氯化碳存在条件下,温度-20~50℃,时间2-12小时,反应合成N-磷酰化氨基酸,再通过柱层析法或重结晶法精制,制成高纯度的N-磷酰化氨基酸,或将其与无机或有机碱反应制成N-磷酰化氨基酸盐;
(二)与赋形剂、润滑剂、调味剂进行组配制成片剂或胶囊剂,按下述的配比进行组配(重量份数):
N-磷酰化氨基酸或其盐 0.5-5
赋形剂 0-100
润滑剂 0-2
调味剂 0-1
将上述组合物混合均匀后,用压片机按常规制成片剂,或装入胶囊中制成胶囊剂,该胶囊剂可不加调味剂;
(三)与NaCl进行组配制成注射针剂:
将N-磷酰化氨基酸或其盐0.5-5份与NaCl 0-10份进行混配或加入蒸馏水搅拌溶解过滤,在灭菌条件下将混配剂或滤液装入安瓶中制成本发明的注射针剂或冻干剂。
该有机碱包括三乙胺、吡啶、二异丙基乙基胺、N-甲基吗啉。
本发明的主要优点是:
1、本发明的药物具有杀灭血吸虫和抑制肝肉虫卵肉芽肿形成的显著疗效及毒性较低的优点。
2、本发明的药物制造方法简单,成本低廉,适合广泛推广应用。
下面结合较佳实施例对本发明进一步说明。
实施例1
本发明的治疗血吸虫病的片剂药物成份和配比为:
N-(O,O)-二正丁基磷酰脯氨酸 10毫克
赋形剂:玉米淀粉 50毫克
乳糖 187毫克
润滑剂:硬脂酸镁 3毫克
调味剂:蔗糖 0.1毫克
其制造方法如下:
(一)合成N-(O,O)-二正丁基磷酰脯氨酸:
在200ml反应瓶中,加入4.6gL-脯氨酸、20ml水、40ml三乙胺和20ml乙醇,冰盐浴冷却下滴加9ml二正丁基亚磷酸酯与20ml四氯化碳的混合液,室温反应2小时。加入100ml水,减压蒸馏除去有机溶剂。水溶液用乙醚和乙酸乙酯各洗涤2次,在冰盐浴冷却下用1N盐酸调PH至3。用乙酸乙酯60ml萃取三次,合并萃取液,用饱和氯化钠溶液60ml洗涤3次,用无水硫酸镁干燥。减压蒸馏除去有机溶剂,残余物用乙酸乙酯-石油醚重结晶,制得10g白色固体N-(O,O)-二正丁基磷酰脯氨酸。
(二)进行组配制成片剂;
按上述配比将N-(O,O)-二正丁基磷酰脯氨酸、玉米淀粉、乳糖、硬脂酸镁和蔗糖混合均匀、过筛,用压片机压制成每片重250mg的片剂,每片中含活性成份N-(O,O)-二正丁基磷酰脯氨酸10mg。
实施例2
本发明的治疗血吸虫病的胶囊剂药物的成份和配比为:
Nα,Nε-二(O,O)-二异丙基磷酰赖氨酸钠 10毫克
赋形剂纤维素衍生物 188毫克
润滑剂硬脂酸钙 2毫克
制造方法:
(一)合成Nα,Nε-二(O,O)-二异丙基磷酰赖氨酸钠:
在200ml反应瓶中,加入5克L-赖氨酸、20ml水、40ml二甲基吗啉和20ml乙醇,以冰盐浴冷却下滴加10ml二异丙基磷酰氯与20ml四氯化碳的混合液,反应3小时,加水100ml减压蒸馏除去有机溶剂,水溶剂用乙醚和乙酸乙酯各洗涤2次,用HCl调PH3,再用实施例l相同的方法萃取、洗涤、干燥、蒸馏和提纯,制成Nα,Nε-二(O,O)-二异丙基磷酰赖氨酸,再与等当量的NaOH反应,制成Nα,Nε-二(O,O)-二异丙基磷酰赖氨酸钠。
(二)进行组配制成胶囊剂:
按上述配比将Nα,Nε-二(O,O)-二异丙基磷酰赖氨酸钠、纤维素衍生物和硬脂酸钙混合均匀,过筛,装入硬明胶胶囊中,每个胶囊重200mg,含活性成份Nα,Nε-二(O,O)-二异丙基磷酰赖氨酸钠10mg。
实施例3:
本发明的治疗血吸虫病的注射针剂药物的成份和配方为:
N-(O,O-二乙基)-磷酰酪氨酸 2毫克
氯化钠 10毫克
制造方法如下:
(一)合成N-(O,O-二乙基)-磷酰酪氨酸:
选用二乙基磷酰氯与D-酪氨酸为原料,用与实施例1相同的方法合成N-(O,O-二乙基)-磷酰酪氨酸。
(二)进行组配制成注射针剂:
按上述配比将N-二乙基磷酰酪氨酸2毫克,氯化钠10毫克混均,在无毒条件下装入安瓶内,制成注射冻干剂,含活性成份N-(O,O-二乙基)-磷酰酪氨酸2mg,使用时注入蒸馏水。当然也可以制作时,注入蒸馏水,再装入安瓶内,制成2ml的针剂。
实施例4:
本发明的治疗血吸虫病的药物的动物试验应用效果。
用本发明的治疗血吸虫病的药物对小鼠进行动物试验,其试验方法和效果如下:
一、实验动物:BALB/c健康雌性小鼠由上海科学院实验动物中心提供,体重18±2g,共30只,随机均分为3组。每鼠按常规法经皮肤感染日本血吸虫尾蚴30±2条。
二、动物给药:小鼠感染血吸虫后4周,组I给本发明的药物有效成份6mg/天,均为腹腔注射,连续10天;组II给常用药物吡喹酮每天30mg/kg,口服3天,用作药物治疗对照;组III给生理盐水作为感染对照。
三、动物解剖:用药后3周(相当于感染后7周),剖杀小鼠,从胸主动脉灌注取虫,取左叶肝,0.5g用于虫卵计数:余置于10%福尔马林溶液,固定24小时后,制备5μg厚度的连续石蜡切片,H-E染色,光镜下观察,测量单个虫卵肉芽肿直径(μm),并计算其平均面积(μm2)和体积(μm2)。
四、实验结果:感染小鼠用药后3周剖杀后的观察结果,详见表1及表2。
表1 本发明的药物对日本血吸虫感染小鼠体内成虫和虫卵检获数的影响
*计算每克肝组织内的虫卵数(EPG)
组别 | 鼠数 | 检获成虫均数 | 肝内虫卵均数* | ||||
X | SD | 减虫率% | X | SD | 减卵率% | ||
IIIIII | 654 | 7.607.4015.00 | 4.724.558.29 | 49.3350.660 | 276.01278.46996.20 | 41.37159.92162.26 | 72.2972.040 |
从表1试验结果表明连续给药10天后,本发明的药物取得显著的治疗效果:
1、本发明的药物组I与未给药组III的小鼠比较成虫计数减小49.33%,即减小一半;肝内虫卵数减小72.29%,即减小近2/3。
2、本发明的药物组I与目前常用的吡喹酮组II比较具有相同的杀血吸虫的成虫和虫卵的功效。
表2 本发明的药物对感染日本血吸虫小鼠肝内虫卵肉芽肿的影响。
注:表中数据均为30个肉芽肿数的平均值。
组别 | 鼠数 | 肉芽肿数 | 平均直径(μm) | 平均面积(μm2) | 平均体积(μm2) | ||||||
X | SD | 减小率% | X | SD | 减小率% | X | SD | 减小率% | |||
IIIIII | 654 | 303030 | 173.75194.38260.23 | 39.0945.0750.39 | 33.2325.310 | 24.7431.0555.14 | 11 3814.0821.08 | 55.1343.690 | 29.6042.1397.97 | 20.8328.7256.54 | 69.7957.000 |
从表2试验结果表明连续给药10天后,本发明的药物取得显著的治疗效果:
1、本发明的药物组I与注射生理盐水的组III比较,肝内虫卵肉芽肿的平均直径减小86.48μm,减小率为33.23%;肝内虫卵肉芽肿的平均面积减小30.4μm2减小率为55.13%;肝肉虫卵肉芽肿的平均体积减小68.37μm3、减小率为69.79%。
2、本发明的药物组I与常用药物吡喹酮组II比较,肝内虫卵肉芽肿的平均直径减小20.63μm,减小率为7.92%;肝内虫卵肉芽肿的平均面积减小6.31μm2减小率为11.44%;肝肉虫卵肉芽肿的平均体积减小12.5μm3、减小率为12.79%。
证明本发明的药物对肝内血吸虫卵肉芽肿的疗效优于常用药物吡喹酮。
实施例5
本发明的药物对小鼠的急性毒性实验:
本发明的药物对小鼠的急性毒性实验,委托北京医科大学测试,采用口服灌胃和腹腔注射两种途径,各分成5组,每组10只小鼠,剂量从高至低,根据给药7天内各组小鼠死亡率,按简化机率法计算LD50。实验结果见表3和表4。
表3 小鼠口服本发明的药物急性毒性实验结果
组号 | 浓度(mg/ml) | 剂量g/kg | 动物数(只) | 死亡数(只) | 死亡率(%) |
12345 | 625575529487448 | 25.023.021.219.517.9 | 1010101010 | 97520 | 907050200 |
用简化机率法计算LD50=21.82g/kg,(具体推算略)
表4 小鼠腹腔注射本发明的药物急性毒性实验结果。
组号 | 浓度(mg/ml) | 剂量g/kg | 动物数(只) | 死亡数(只) | 死亡率(%) |
12345 | 1311171059484 | 5.244.684.203.763.36 | 1010101010 | 97521 | 9070502010 |
用简化机率法计算LD50=4.184g/kg,(具体推算略)
从上述实验结果证明本发明的药物毒性较小。
实施例6
本发明的药物临床应用实验,选自愿试用本发明药物的血吸虫病患者5人,口服本发明实施例1的片剂药物,每次10mg/kg,每日三次,从服药后,每天检验排便中的虫卵,实验前均为阳性,测定排便中虫卵转为阴性的开始时间,见表4
表4
患者姓名 | 感染血吸虫病时间 | 排便中虫卵转阴性时间天 |
赵女士 | 2个月 | 3 |
陈男孩 | 1个月 | 2 |
李先生 | 半 年 | 6 |
宋先生 | 1 年 | 8 |
张女孩 | 3个月 | 4 |
从上述试用结果表明:本发明的药物对治疗血吸虫病具有显著疗效。
Claims (9)
2、如权利要求1所述的治疗血吸虫病的药物,其特征在于:该R1、R2为相同或不同的烷基或芳基,包括甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、新戊基、己基、庚基、苯基、苄基。
3、如权利要求1所述的治疗血吸虫病的药物,其特征在于:该AA包括天然的氨基酸残基、D-构型的氨基酸残基或DL-构型的氨基酸残基。
4、如权利要求1所述的治疗血吸虫病的药物,其特征在于:该R1、R2或R3的盐基包括下述成份的盐:钾、钠、钙、镁、锌或乙二胺、乙醇胺、乙二醇胺、氨基葡萄糖。
5、如权利要求1所述的治疗血吸虫病的药物,其特征在于:该赋形剂包括淀粉、纤维素衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、琼脂、碳酸钙、碳酸氢钠、乳糖。
6、如权利要求1所述的治疗血吸虫病的药物,其特征在于:该润滑剂包括滑石粉、硬脂酸钙、硬脂酸镁、聚乙二醇。
7、如权利要求1所述的治疗血吸虫病的药物,其特征在于:该调味剂包括香味剂、甜味剂、果味剂。
8、一种治疗血吸虫病的药物的制造方法,其特征在于:该制造方法包括合成N-磷酰化氨基酸或其盐,再按配比与赋形剂、润滑剂、调味剂或NaCl进行组配和成型,具体步骤如下:
(一)合成N-磷酰化氨基酸或其盐:
用氨基酸或其酯与二烷基亚磷酸酯在水、醇,有机碱及四氯化碳存在条件下,温度-20~50℃,时间2-12小时,反应合成N-磷酰化氨基酸,再通过柱层析法或重结晶法精制,制成高纯度的N-磷酰化氨基酸,或将其与无机或有机碱反应制成N-磷酰化氨基酸盐;
(二)与赋形剂、润滑剂、调味剂进行组配制成片剂或胶囊剂,按下述的配比进行组配(重量份数):
N-磷酰化氨基酸或其盐 0.5-5
赋形剂 0-100
润滑剂 0-2
调味剂 0-1
将上述组合物混合均匀后,用压片机按常规制成片剂,或装入胶囊中制成胶囊剂,该胶囊剂可不加调味剂;
(三)与NaCl进行组配制成注射针剂:
将N-磷酰化氨基酸或其盐0.5-5份与NaCl 0-10份进行混配或加入蒸馏水搅拌溶解过滤,在灭菌条件下将混配剂或滤液装入安瓶中制成本发明的注射针剂和冻干剂。
9、如权利要求8所述的制造方法,其特征在于:该有机碱包括三乙胺、吡啶、二异丙基乙基胺、N-甲基吗啉。
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