發(fā)布時(shí)間：2018-07-20 08:45

【摘要】：阿苯達(dá)唑(albendazole,ABZ),屬于苯并咪唑類驅(qū)蟲藥,具備低溶解性和高滲透性的特征,是Ⅱ類生物藥劑學(xué)分類系統(tǒng)的藥物,具有在體內(nèi)吸收不完全,生物利用度低的特點(diǎn)。為了提高阿苯達(dá)唑的生物利用度,本文擬采用固體分散體技術(shù),制備阿苯達(dá)唑固體分散體,以期通過(guò)改變阿苯達(dá)唑的晶體結(jié)構(gòu)提高藥物的溶出度。并確定阿苯達(dá)唑固體分散體在犬體內(nèi)的生物利用度。本研究在建立了紫外分光光度法測(cè)定ABZ含量的基礎(chǔ)上,以聚乙二醇4000、6000、泊洛沙姆188為單一載體,用不同的方法制備阿苯達(dá)唑固體分散體,通過(guò)體外溶出度試驗(yàn),篩選出最佳的單一載體以及最佳的制備方法。將篩選出PEG6000和P188進(jìn)行聯(lián)合,利用熔融法按照比例1:1、1:2、1:4、1:8、2:1、4:1、8:1制備阿苯達(dá)唑固體分散體,以期篩選最佳的載體組合。其中阿苯達(dá)唑與載體的比例為1:5,通過(guò)體外溶出度試驗(yàn)篩選出聯(lián)合載體的最佳比例,然后按照阿苯達(dá)唑與載體的比例為1:1、1:3、1:4、1:5、1:7制備固體分散體,通過(guò)體外溶出度試驗(yàn),確定最佳用量,最后用相溶解度試驗(yàn)和溶出度試驗(yàn)確定阿苯達(dá)唑固體分散體的最佳制備工藝。將制備好的固體分散體進(jìn)行物相鑒定。結(jié)果顯示:PEG6000和P188利用熔融法制備阿苯達(dá)唑固體分散體時(shí)累積溶出度最高,當(dāng)PEG6000和P188的比例為1:2時(shí),累積溶出度可以達(dá)到89.23%,阿苯達(dá)唑與聯(lián)合載體的比例為1:3時(shí),阿苯達(dá)唑固體分散體的累積溶出度最高,可以高達(dá)94.17%,顯著高于物理混合物和原料藥。相溶解度試驗(yàn)表明,當(dāng)PEG6000和P188聯(lián)合時(shí),對(duì)阿苯達(dá)唑的增溶效果顯著高于單一載體;X-射線表明阿苯達(dá)唑固體分散體主要以無(wú)定型態(tài)存在,紅外光譜顯示藥物與載體之間未發(fā)生化學(xué)反應(yīng),電鏡掃描進(jìn)一步驗(yàn)證阿苯達(dá)唑固體分散體由原來(lái)的晶體狀態(tài)變?yōu)榉蔷B(tài)狀態(tài)。以阿苯達(dá)唑市售片劑為參比制劑,考察自制阿苯達(dá)唑固體分散體與市售片劑的相對(duì)生物利用度。建立了高效液相色譜與質(zhì)譜聯(lián)用的方法測(cè)定犬血漿中ABZ及其代謝產(chǎn)物的濃度。利用液-液提取的方法處理血漿樣品,二氯甲烷進(jìn)行提取,以非那西汀作為內(nèi)標(biāo)物。采用CAPCELL PAK C18的色譜柱,以乙腈-水(0.1%甲酸)作為流動(dòng)相進(jìn)行梯度洗脫。選用多反應(yīng)監(jiān)測(cè)模式,正離子掃描,進(jìn)行母離子和子離子的掃描,。通過(guò)方法學(xué)驗(yàn)證該方法簡(jiǎn)單可行,阿苯達(dá)唑的檢測(cè)限為0.5 ng/m L,定量限為1 ng/m L;血漿中阿苯達(dá)唑亞砜的檢測(cè)限為1ng/m L,定量限為2.5 ng/m L;血漿中阿苯達(dá)唑砜的檢測(cè)限為1 ng/m L,定量限為2.5 ng/m L。在藥代動(dòng)力學(xué)試驗(yàn)中,固體分散體中ABZ、ABZSO、ABZSO2在犬血漿中的AUC(0-∞)分別為:(424.48±35.17)、(6699.03±889.18)、(3469.42±649.39)μg/L*h,市售片劑中ABZ、ABZSO、ABZSO2在犬血漿中的AUC(0-∞)分別為:(188.66±33.43)、(3536.07±630.62)、(1049.55±172.15)μg/L*h,則固體分散體相對(duì)于市售片劑的生物利用度:ABZ:225.00%;ABZSO:189.45%。ABZSO2:330.56%。表明阿苯達(dá)唑固體分散體可以顯著提高其體內(nèi)的生物利用度,為開發(fā)新的制劑奠定了基礎(chǔ)。綜上:阿苯達(dá)唑固體分散體的最佳制備工藝為:以熔融法為制備方法,聯(lián)合載體中PEG6000:P188=1:2,ABZ:聯(lián)合載體=1:3。且體內(nèi)試驗(yàn)表明,該方法制備的固體分散體可以顯著提高其體內(nèi)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.
【學(xué)位授予單位】：東北農(nóng)業(yè)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類號(hào)】：S859.795

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本文編號(hào)：2132929