【摘要】：作為大環(huán)內(nèi)酯類，替米考星是在泰樂(lè)菌素的基礎(chǔ)上通過(guò)化學(xué)半合成制備的抗菌藥。該藥具有較廣的抗菌譜，臨床上應(yīng)用于治療由革蘭氏陰性菌和革蘭氏陽(yáng)性菌引起的畜禽呼吸道疾病。但是替米考星存在水溶解性差的問(wèn)題，為了解決難溶性藥物替米考星溶出效果差的缺陷，開(kāi)發(fā)幾種藥物劑型，增加該藥的臨床應(yīng)用。在本文研究中，分別使用脂質(zhì)體、固體分散體和腸溶顆粒包衣技術(shù)來(lái)提高替米考星的溶出度和抑菌效果。對(duì)制備出來(lái)的三種制劑分別采用不同的表征方法進(jìn)行檢測(cè)，并且評(píng)價(jià)其優(yōu)劣。本文研究?jī)?nèi)容和結(jié)果如下： ①建立紫外分光光度法對(duì)替米考星的測(cè)量及其標(biāo)準(zhǔn)曲線，探索替米考星脂質(zhì)體包封率的測(cè)量方法。即分別使用SephadexG-25和SephadexG-50測(cè)定脂質(zhì)體的洗脫曲線和回收率，并測(cè)定脂質(zhì)體的包封率。然后采用納米粒度及Zeta電位分析儀，測(cè)量按照不同處方以及不同方法制備的脂質(zhì)體平均粒徑和Zeta電位。經(jīng)過(guò)比較優(yōu)化后確認(rèn)最佳工藝，結(jié)果表明：采用薄膜法制備的脂質(zhì)體包封率達(dá)到51.28%，而硫酸銨梯度法、pH梯度法和逆向蒸發(fā)法制備脂質(zhì)體，包封率分別為30.06%、41.65%和45.83%。薄膜法、硫酸銨梯度法、pH梯度法和逆向蒸發(fā)法制備脂質(zhì)體粒徑分別為103.7nm、78.21nm、81.66nm和248.6nm；Zeta電位則分別為-31.7mV、-19.3mV、-24.1mV和-5.28mV。 ②采用溶劑法和熔融法制備不同比例的替米考星固體分散體，并用DSC-TGA、X衍射和FTIR等手段共同對(duì)分散體進(jìn)行了表征，結(jié)果均表明：替米考星與載體發(fā)生了一定的分子作用，替米考星均分散于載體中。 ③使用不同的配方和包衣材料，制備了替米考星腸溶包衣顆粒，獲得了優(yōu)化處方和工藝條件。并用紫外分光光度法測(cè)定三種處方及其各包衣增重比例的顆粒中替米考星含量，以及體外腸溶特征。 ④針對(duì)替米考星釋藥特征，1）完成了脂質(zhì)體釋放度實(shí)驗(yàn)，并且對(duì)薄膜法脂質(zhì)體釋放曲線進(jìn)行擬合，獲得其一級(jí)動(dòng)力學(xué)方程:ln(100Q)0.2980t4.5087(r2=0.9739)。2）測(cè)試了腸溶包衣顆粒在胃液和腸液中的溶出度。3）固體分散體的溶出曲線顯示：替米考星/聚乙二醇五個(gè)比例的固體分散體溶出速率均很快，在5min時(shí)即完全溶出，達(dá)到98%以上；而替米考星/聚乙烯吡咯烷酮-乙基纖維素則表現(xiàn)出一定的滯后溶出，，但是藥物的積累溶出度也達(dá)到了85%以上。 ⑤體外抑菌實(shí)驗(yàn)表明：在原料藥和三種制劑五個(gè)樣品中，脂質(zhì)體的抑菌能力略小于原料藥；腸溶包衣顆粒的抑菌能力與原料藥的無(wú)顯著差別，菌種上的敏感度略有差別。替米考星/聚乙二醇固體分散體的抑菌效果最佳。替米考星/聚乙烯吡咯烷酮-乙基纖維素有一定的緩釋作用，但在短時(shí)間內(nèi)能實(shí)現(xiàn)替米考星的溶出，可抑制細(xì)菌的生長(zhǎng)。 通過(guò)體外溶出度實(shí)驗(yàn)和抑菌實(shí)驗(yàn)研究表明：經(jīng)過(guò)三種方式處理后的替米考星溶出度得到了不同程度的改善，并且各制劑的體外抑菌效果與其體外溶出有一定的相關(guān)性。
[Abstract]:As macrolides, the tilmicosin is an antibacterial agent prepared by chemical and semi-synthesis on the basis of telosin. The composition has a wide antibacterial spectrum and is clinically applied to the treatment of livestock and poultry respiratory diseases caused by gram-negative bacteria and gram-positive bacteria. However, in order to solve the problem of poor water solubility of the tilmicosin, several kinds of drug dosage forms were developed to increase the clinical application of the drug. In this study, the solubility and the antibacterial effect of temetaka were improved by using liposome, solid dispersion and enteric coating technique, respectively. The three preparations were tested by different characterization methods, and their advantages and disadvantages were evaluated. The contents and results of this study are as follows: The measurement of tilmicosin and its standard curve by the method of ultraviolet spectrophotometry, and the measurement of the encapsulation rate of the tilmicosin liposome is explored. Methods: The elution profile and the recovery rate of the liposomes were determined by SephadexG-25 and Sephadex G-50, respectively. Sealing rate. The mean particle size and Zeta of the liposomes prepared according to different formulations and different methods were then measured using a nano-particle size and a Zeta potential analyzer. The results showed that the entrapment efficiency of the liposomes prepared by the thin film method was 51. 28%, and the liposome was prepared by the gradient method, the pH gradient method and the reverse evaporation method. The encapsulation rate was 30. 06%, 41. 65% and 45. 8, respectively. The particle size of the liposomes was 103.7nm, 782.21nm, 81.66nm and 248.6nm, respectively. The Zeta potential was -31.7 mV, -193.3mV, -24.1 mV and -5.28, respectively. In this paper, the solid dispersion of tilmicosin was prepared by solvent method and melting method, and the dispersion was characterized by DSC-TGA, X-ray diffraction and FTIR. In the carrier, different formulations and coating materials were used to prepare the tilmicosin enteric coated granules, which was excellent. the formula and the process conditions are defined, and the content of the tilmicosin in the particles of the three prescriptions and the weight-increasing proportion of each coating is determined by the ultraviolet spectrophotometry, and in-vitro enteric-soluble features. The present invention has completed the liposome release experiment for the tilmicosin release profile, and the film-method liposome release curve is fitted. The first-order kinetic equation was obtained: ln (100Q) 0. 2980t4. 5087 (r2 = 0.9739). 2) The solubility of the enteric coated granules in the gastric juice and the intestinal fluid was tested. The whole solution is more than 98%, and the tilmicosin/ polyethylene dialkanone-ethyl cellulose shows a certain hysteresis and dissolution, but the drug accumulation and dissolution In vitro antibacterial experiments show that the antibacterial ability of the liposome is slightly less than that of the drug substance in the five samples of the drug substance and the three preparations, and the antibacterial capacity of the enteric coated particles and the drug substance are not significant. The difference is that there is a slight difference in the sensitivity of the species. The antibacterial effect of the solid dispersion of the dialcohol is the best. The tilmicosin/ polyethylene dialkanone-ethyl cellulose has a certain slow-release effect, but it can be realized in a short time The dissolution of the test star can inhibit the growth of the bacteria, and the in vitro dissolution degree experiment and the bacteriostatic experimental study show that the solubility of the tilmicosin after three methods has been improved to a different degree, and the in vitro of each preparation
【學(xué)位授予單位】：重慶大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R96

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