阿苯达唑固体分散体的制备及其在犬体内药代动力学研究
发布时间：2018-07-20 08:45
【摘要】：阿苯达唑(albendazole,ABZ),属于苯并咪唑类驱虫药,具备低溶解性和高渗透性的特征,是Ⅱ类生物药剂学分类系统的药物,具有在体内吸收不完全,生物利用度低的特点。为了提高阿苯达唑的生物利用度,本文拟采用固体分散体技术,制备阿苯达唑固体分散体,以期通过改变阿苯达唑的晶体结构提高药物的溶出度。并确定阿苯达唑固体分散体在犬体内的生物利用度。本研究在建立了紫外分光光度法测定ABZ含量的基础上,以聚乙二醇4000、6000、泊洛沙姆188为单一载体,用不同的方法制备阿苯达唑固体分散体,通过体外溶出度试验,筛选出最佳的单一载体以及最佳的制备方法。将筛选出PEG6000和P188进行联合,利用熔融法按照比例1:1、1:2、1:4、1:8、2:1、4:1、8:1制备阿苯达唑固体分散体,以期筛选最佳的载体组合。其中阿苯达唑与载体的比例为1:5,通过体外溶出度试验筛选出联合载体的最佳比例,然后按照阿苯达唑与载体的比例为1:1、1:3、1:4、1:5、1:7制备固体分散体,通过体外溶出度试验,确定最佳用量,最后用相溶解度试验和溶出度试验确定阿苯达唑固体分散体的最佳制备工艺。将制备好的固体分散体进行物相鉴定。结果显示:PEG6000和P188利用熔融法制备阿苯达唑固体分散体时累积溶出度最高,当PEG6000和P188的比例为1:2时,累积溶出度可以达到89.23%,阿苯达唑与联合载体的比例为1:3时,阿苯达唑固体分散体的累积溶出度最高,可以高达94.17%,显著高于物理混合物和原料药。相溶解度试验表明,当PEG6000和P188联合时,对阿苯达唑的增溶效果显著高于单一载体;X-射线表明阿苯达唑固体分散体主要以无定型态存在,红外光谱显示药物与载体之间未发生化学反应,电镜扫描进一步验证阿苯达唑固体分散体由原来的晶体状态变为非晶态状态。以阿苯达唑市售片剂为参比制剂,考察自制阿苯达唑固体分散体与市售片剂的相对生物利用度。建立了高效液相色谱与质谱联用的方法测定犬血浆中ABZ及其代谢产物的浓度。利用液-液提取的方法处理血浆样品,二氯甲烷进行提取,以非那西汀作为内标物。采用CAPCELL PAK C18的色谱柱,以乙腈-水(0.1%甲酸)作为流动相进行梯度洗脱。选用多反应监测模式,正离子扫描,进行母离子和子离子的扫描,。通过方法学验证该方法简单可行,阿苯达唑的检测限为0.5 ng/m L,定量限为1 ng/m L;血浆中阿苯达唑亚砜的检测限为1ng/m L,定量限为2.5 ng/m L;血浆中阿苯达唑砜的检测限为1 ng/m L,定量限为2.5 ng/m L。在药代动力学试验中,固体分散体中ABZ、ABZSO、ABZSO2在犬血浆中的AUC(0-∞)分别为:(424.48±35.17)、(6699.03±889.18)、(3469.42±649.39)μg/L*h,市售片剂中ABZ、ABZSO、ABZSO2在犬血浆中的AUC(0-∞)分别为:(188.66±33.43)、(3536.07±630.62)、(1049.55±172.15)μg/L*h,则固体分散体相对于市售片剂的生物利用度:ABZ:225.00%;ABZSO:189.45%。ABZSO2:330.56%。表明阿苯达唑固体分散体可以显著提高其体内的生物利用度,为开发新的制剂奠定了基础。综上:阿苯达唑固体分散体的最佳制备工艺为:以熔融法为制备方法,联合载体中PEG6000:P188=1:2,ABZ:联合载体=1:3。且体内试验表明,该方法制备的固体分散体可以显著提高其体内生物利用度。
[Abstract]:Albendazole (ABZ), belonging to the benzimidazole repellent, is characterized by low solubility and high permeability. It is a drug of class II Biopharmacology classification system. It has the characteristics of incomplete absorption in the body and low bioavailability. In order to improve the bioavailability of albendazole, a solid dispersion technique is adopted to prepare a system. In order to improve the dissolution of the drug by changing the crystal structure of albendazole, and determining the bioavailability of albendazole solid dispersion in dogs, this study was based on the establishment of a UV spectrophotometric method for the determination of ABZ content, with PEG 40006000 and Poisson Losham 188 as a single carrier. Albendazole solid dispersion was prepared by the method of dissolution test in vitro. The best single carrier and the best preparation method were screened out. PEG6000 and P188 were selected and the albendazole solid dispersion was prepared by melting method in proportion to 1:1,1:2,1:4,1:8,2:1,4:1,8:1, in order to screen the best carrier combination. The proportion of benzalazole and carrier was 1:5. The optimum proportion of the combined carrier was screened by the dissolution test in vitro. Then the solid dispersion was prepared according to the proportion of albendazole and carrier 1:1,1:3,1:4,1:5,1:7. The optimum dosage was determined by the dissolution test in vitro. Finally, the albendazole was determined by the phase solubility test and dissolution test. The optimum preparation process of bulk dispersion. The results showed that the cumulative dissolution rate of PEG6000 and P188 was highest when the albendazole solid dispersion was prepared by melting method. When the proportion of PEG6000 and P188 was 1:2, the cumulative dissolution rate could reach 89.23%. The ratio of albendazole to the combined carrier was 1:3, The cumulative dissolution of albendazole solid dispersion was the highest, which could be as high as 94.17%, significantly higher than the physical mixture and the drug. The solubility test showed that when PEG6000 and P188 were combined, the solubilization effect of albendazole was significantly higher than that of the single carrier; X- ray showed that the albendazole solid dispersion was mainly in the amorphous state and infrared spectrum. There was no chemical reaction between the drug and the carrier. The electron microscope scan further verified that the albendazole solid dispersion changed from the original crystal state to the amorphous state. The relative bioavailability of the homemade albendazole solid dispersion and the market tablets was investigated by using the tablets of albendazole, and a high performance liquid chromatography was established. The concentration of ABZ and its metabolites in dog plasma was measured with mass spectrometry. The plasma samples were treated by liquid liquid extraction, and dichloromethane was extracted with phenacetin as an internal standard. The gradient elution of acetonitrile water (0.1% formic acid) was used as the flow phase of CAPCELL PAK C18. The multi reaction monitoring model was selected. The method is proved to be simple and feasible. The detection limit of albendazole is 0.5 ng/m L and the quantitative limit is 1 ng/m L; the detection limit of albendazole is 1ng/m L and the quantitative limit is 2.5 ng/m L; the detection limit of albendazole sulfone in plasma is 1 ng/m L, and the quantitative limit is 2.5 ng/m L. In the pharmacokinetic test, the AUC (0- infinity) of ABZ, ABZSO and ABZSO2 in the dog plasma is (424.48 + 35.17), (6699.03 + 889.18) and (3469.42 + 649.39) mu g/L*h, ABZ, ABZSO, and ABZSO2 in the marketing tablets are (188.66 + 33.43), (3536.07 + 630.62), (3536.07 + 630.62), (1049.55 + 172.15) micron, and solids The bioavailability of the dispersions relative to the marketed tablets: ABZ:225.00%; ABZSO:189.45%.ABZSO2:330.56%. showed that the albendazole solid dispersion could significantly increase the bioavailability of the body and lay the foundation for the development of the new preparation. PEG6000:P188=1:2 and ABZ: combined with =1:3. in vivo and in vivo experiments showed that the solid dispersion prepared by this method could significantly improve its bioavailability in vivo.
【学位授予单位】：东北农业大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：S859.795
本文编号：2132929
[Abstract]:Albendazole (ABZ), belonging to the benzimidazole repellent, is characterized by low solubility and high permeability. It is a drug of class II Biopharmacology classification system. It has the characteristics of incomplete absorption in the body and low bioavailability. In order to improve the bioavailability of albendazole, a solid dispersion technique is adopted to prepare a system. In order to improve the dissolution of the drug by changing the crystal structure of albendazole, and determining the bioavailability of albendazole solid dispersion in dogs, this study was based on the establishment of a UV spectrophotometric method for the determination of ABZ content, with PEG 40006000 and Poisson Losham 188 as a single carrier. Albendazole solid dispersion was prepared by the method of dissolution test in vitro. The best single carrier and the best preparation method were screened out. PEG6000 and P188 were selected and the albendazole solid dispersion was prepared by melting method in proportion to 1:1,1:2,1:4,1:8,2:1,4:1,8:1, in order to screen the best carrier combination. The proportion of benzalazole and carrier was 1:5. The optimum proportion of the combined carrier was screened by the dissolution test in vitro. Then the solid dispersion was prepared according to the proportion of albendazole and carrier 1:1,1:3,1:4,1:5,1:7. The optimum dosage was determined by the dissolution test in vitro. Finally, the albendazole was determined by the phase solubility test and dissolution test. The optimum preparation process of bulk dispersion. The results showed that the cumulative dissolution rate of PEG6000 and P188 was highest when the albendazole solid dispersion was prepared by melting method. When the proportion of PEG6000 and P188 was 1:2, the cumulative dissolution rate could reach 89.23%. The ratio of albendazole to the combined carrier was 1:3, The cumulative dissolution of albendazole solid dispersion was the highest, which could be as high as 94.17%, significantly higher than the physical mixture and the drug. The solubility test showed that when PEG6000 and P188 were combined, the solubilization effect of albendazole was significantly higher than that of the single carrier; X- ray showed that the albendazole solid dispersion was mainly in the amorphous state and infrared spectrum. There was no chemical reaction between the drug and the carrier. The electron microscope scan further verified that the albendazole solid dispersion changed from the original crystal state to the amorphous state. The relative bioavailability of the homemade albendazole solid dispersion and the market tablets was investigated by using the tablets of albendazole, and a high performance liquid chromatography was established. The concentration of ABZ and its metabolites in dog plasma was measured with mass spectrometry. The plasma samples were treated by liquid liquid extraction, and dichloromethane was extracted with phenacetin as an internal standard. The gradient elution of acetonitrile water (0.1% formic acid) was used as the flow phase of CAPCELL PAK C18. The multi reaction monitoring model was selected. The method is proved to be simple and feasible. The detection limit of albendazole is 0.5 ng/m L and the quantitative limit is 1 ng/m L; the detection limit of albendazole is 1ng/m L and the quantitative limit is 2.5 ng/m L; the detection limit of albendazole sulfone in plasma is 1 ng/m L, and the quantitative limit is 2.5 ng/m L. In the pharmacokinetic test, the AUC (0- infinity) of ABZ, ABZSO and ABZSO2 in the dog plasma is (424.48 + 35.17), (6699.03 + 889.18) and (3469.42 + 649.39) mu g/L*h, ABZ, ABZSO, and ABZSO2 in the marketing tablets are (188.66 + 33.43), (3536.07 + 630.62), (3536.07 + 630.62), (1049.55 + 172.15) micron, and solids The bioavailability of the dispersions relative to the marketed tablets: ABZ:225.00%; ABZSO:189.45%.ABZSO2:330.56%. showed that the albendazole solid dispersion could significantly increase the bioavailability of the body and lay the foundation for the development of the new preparation. PEG6000:P188=1:2 and ABZ: combined with =1:3. in vivo and in vivo experiments showed that the solid dispersion prepared by this method could significantly improve its bioavailability in vivo.
【学位授予单位】：东北农业大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：S859.795
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