摘要
包虫病是新疆农牧区特定环境中主要地方病之一，新疆包虫病高
流行区人间感染率为31.5％，患病率为5％，是新疆一些地区农牧民
因病致死的重要原因。在包虫病的防治措施中，阿苯达唑是目前国内
外首选的治疗药物，但目前市售阿苯达唑制剂由于溶解性低、胃肠吸
收差，以及对常见的肝包虫病缺乏靶向性的限制，尚不能充分发挥其
药效，这是目前新疆地方病防治中迫切需要解决的课题之一。本课题
应用纳米技术，通过对阿苯达唑纳米球靶向载体系统的研究，达到提
高药物溶解度、生物利用度、病灶靶向性和治疗指数的目的。
目的：1.系统研究阿苯达唑的理化性质：阿苯达唑（Albendazole，
ABZ），为广谱抗寄生虫药物，对治疗包虫病和神经型囊尾蚴病均有效。
由于阿苯达唑的溶解性低、胃肠吸收差及体内分布广泛等原因，致使
临床治疗包虫病效果不理想。运用电离平衡理论对阿苯达唑理化性质
进行研究，通过分配系数平衡溶解法和溶解度-pH曲线法测定阿苯达唑
在水、常用有机溶媒中的溶解度，油水分配、增溶方法和重要溶解常
数pK_a。筛选适宜的增溶剂达到改善阿苯达唑溶解性的目的。测定阿苯
达唑在人体血浆中的蛋白结合率，为筛选制备靶向新剂型和提高药物
的治疗指数提供科学依据。2.纳米球的研究：应用纳米技术制备TDDS
制剂—阿苯达唑纳米球。利用阿苯达唑油水分配系数高，溶于醋酸和
生物胶—氰基丙烯酸正丁酯在酸性条件下缓慢聚合成纳米球特性，选
择适宜的增溶剂和稳定剂，乳化聚合法制成阿苯达唑纳米球（ABZ-
PBCA-NP）载体制剂，以改善ABZ的溶解性和提高药物在肝、脾和肺中
博士论文一阿苯达哇口服纳米球的制备及其组织靶向性研究
的浓度，提高生物利用度和抗包虫疗效。以载药量、包封率和控制粒径
等为指标，对ABZ纳米球的工艺进行系统研究。筛选二步和三步乳化
聚合法制备纳米球的制备处方工艺，优化和确定了三步种于乳化聚合
法的最佳处方工艺。3．新型纳米球载体制剂的理化特性：考察PBCA十P
对药物的吸附特征，ABZ干BCA－NP的理化性质，稳定性和流变学特性，达
到控制质量，安全有效的目的。4．纳米球的体外释药与在体吸收规律：
探讨纳米球载体中ABZ在人工胃液、生理盐水、不同PH磷酸缓冲液中
的累积释药动力学规律。比较纳米球载体制剂和混悬剂的大鼠在体胃
肠吸收率，探明药物吸收、血药浓度与溶解度之间的关系。平衡透析法
测定ABZ和ABZ纳米球的人血浆蛋白结合率。5．新型药物载体的药物
动力学及靶向性研究：分别口服和腹腔注射二种剂型阿苯达哩，研究
药物在动物体内血浆、肝、脾等重要脏器组织的药物经时动力学过程
和组织分布特性，研究靶向载体药物ABZ干BCAWP和非靶向制剂ABZ混
悬剂口服和腹腔注射后，血浆及肝组织动力学参数，确定靶制剂的寻靶
特性和靶器官。应用多靶向指标评价载体制剂的寻靶器官一肝、脾和
肺的靶向性。同时，肝细胞体外培养对靶向载体药物ABZ干BCA－－NP和非
靶向制剂ABZ的摄入差异，计算出靶向效率。
方法：1．根据难溶物质的溶解平衡理论，推论油／水分配系数法测
定阿苯达哩的PK。的原理，建立相关测定方法。应用液体闪烁法测定
钮－－ABZ含量，平衡透析法考察ABZ的人体血浆蛋自结合率。2．乳化聚合
法制备纳米球：选用临床使用的504生物胶一氰基丙烯酸正丁酯oCA）
为载体材料，以包封率、载药量和粒径为综合指标，系统地比较了一步、
二步和三步乳化聚合法制备ABZ干BCA－NP的生产工艺；利用ABZ溶于
醋酸和 BCA在酸性条件下聚合缓慢的特点，分别考察了注入速度、搅拌
速度及表面活性剂等因素对纳米球的粒径、载药量和包封率的影响。
2
博士论文一阿苯达哩口服纳米球的制备及其组织靶向性研究
并分别采用正交试验法和均匀设计法优化出二步法和三步法的处方工
艺。3．纳米球质量控制：采用等温吸附法测定了纳米球体的吸附性和
载药特性。同时，考察了室温放置、光照和高温高湿下纳米球的物理
稳定性和化学稳定性，并对纳米球的凝聚动力学、流变动力学方面进
行系统试验。分别采用磷钨酸染色、甲醛和饿酸双重固定法制片，透射
电镜门EM）观察纳米球的形态，SAS统计其算术平均径。4．动态透析法
测定ABZ干BCA什P在不同介质中的释药规律。大鼠在体肠吸收循环试
验测定6h内ABZ混悬剂和ABZ－PBCA－NP的小肠吸收速率，揭示在体吸
收动力学规律和ABZ的体外累积释药与在体肠吸收的相关性。建立了
药物的溶解度与胃吸收的相关方程。5．纳米球组织分布及组织靶向性
评价：采用放射性标记法和液体闪烁技术分别考察了口服和灌胃刃ABZ
混悬剂和’H－ABZ－PBCA－NP后小鼠体内血浆、脏＃组织中’H－ABZ的动态
分布。以二种剂型的不同给药途径后，小鼠血浆、肝、脾、?
Experimental study on preparation
of oral albendazole nanoparticles
and its organ tissue targets
Abstracts
IObjictivel Echinococcosis is one of the worldwide distribution
in humans and zoic parasitic diseases. It is also one of major endemic
diseases which can cause the death of the herdsmen in the pastoral areas
in northwest China including Xinjiang. According to the relative papers data
report, the infection rate of echinococcosis is 31.5% and the morbidity
rate is about 5% in high epidemic areas in Xinjiang. Albendazole
(methyl[5-(propylthio)-LH-benzimidazole-2-yl] carbamate, ABZ) is a
broad-spectrum antihelminthic drug and first choice for the treatment of
human cystic echinococcosis which has also been considered as effective drug
against human echinococcosis and neurocysticercosis. However, its
therapeutical effect was unsatisfactory due to poor solubility , less
gastrointestinal absorption and lower targeting effect after oral administration.
The purpose of this study is to improve the therapeutic effect of albendazole
by making new dosage forms, and studing so called nanoparticle the
drug targeting function and increasing ABZ concentration in liver, spleen
and lung in humans.
Firstly, Albendazole physichemical characteristics were determined for
change drug dosage form including the solubility in water and some
organic solvents, oil-water partition coefficient, the pK~. The better
solubilizers were experimentally selected for increasing its solubility.
Secondly, for improvement its bioavailability and absorption in humans,
albendazole-polybutycyanocrylate-nanoparticle (ABZ-PBCA-NP) was made
8
by three kinds of emulsification-polymerized methods. The satisfied
prescription and the best techniques were selected for increase of drug-load,
entrapment efficiency, size control and the distribution for nanoparticle.
Thirdly, for the confirmation of the stability and safety, ABZ-PBCA-NP
stability and fluxion had been studied as follows: (1) to look into released
rule for nanoparticle, the released test of albendazole was processed in
different medium in vitro; (2) to investigate the relationship between
albendazole release and its absorption in stomach and intestine, the
albendazole absorption rate in different pH solutions have been determined
by using rat抯 intestinal infusion suit; (3) to examine free albendazole
concentration in body, the serum protein binding rate had been compared
between albendazole and ABZ-PBCA-NP. Finally, to validate
nanopartilce targeting features time-course in blood and tissue
distributions were compared with albendazole suspension and ABZ-PBCA-
NP after single dose with oral and peritoneal injection in rats.
Pharmacokinetics parameters of non-targeting drug (albendazole suspension)
and targeting drug (ABZ-PBCA-NP ) in sera and liver were dealt with 3p8?
computer programs. To ascertain targeting organs of nanoparticles
multi-parameters index was introduce as the estimating standard.
LMethodl Albendazole pKa values were determined by oil-water
partition method. The concentration of 3H-albendazole was measured by
the liquid scintillation counting. The serum protein binding rate of ABZ and
ABZ-PBCA-NP was determined by the equlibrium dialysis method(ED).
Making procedure for entrapment efficiency , loading drug and size as
synthesis index, t
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