【摘要】：氟苯尼考又名氟甲砜霉素,是八十年代后期研究出的一種獸用廣譜抗菌藥。但是由于其在水中極難溶解,從而限制了它的臨床使用。目前增加氟苯尼考溶解度的方法主要有合成水溶性前藥,制備成固體分散體和使用DMF等有機(jī)溶劑助溶。但這些增溶方法都存在著如有害副產(chǎn)物殘留,增溶效果不理想以及溶劑對(duì)生物體刺激性大等缺點(diǎn),所以尋找一種合適的氟苯尼考增溶方法是非常有意義且十分必要的。難溶性藥物的粒徑與其溶出性質(zhì)的關(guān)系十分密切,根據(jù)Noyes-Whitney方程,物質(zhì)的溶出度和溶質(zhì)的表面積成正比,而減少粒徑可以增加物質(zhì)的表面積,從而改善藥物的溶解性。目前通過微粉化技術(shù)減小藥物粒徑來增加其溶解性的研究很受關(guān)注。本研究主要目的即通過Bottom-up的方法,運(yùn)用化學(xué)原理,使藥物先溶解,再吸出較小的藥物晶體。通過這種方式減小藥物粒徑從而增加其溶解度,并且這種方法降低了通過機(jī)械能微粉化而破壞藥物結(jié)構(gòu)的可能性并且有著低成本等優(yōu)點(diǎn)。實(shí)驗(yàn)使用改良后的溶劑反溶劑沉淀法,在反溶劑中加入穩(wěn)定劑來抑制晶體的成長(zhǎng),得到粒徑更小的氟苯尼考微晶體。通過單因素及正交實(shí)驗(yàn),篩選最優(yōu)制備條件以及穩(wěn)定劑。實(shí)驗(yàn)表明,在溶劑為丙酮,反溶劑為水,溶劑反溶劑比為1：9,穩(wěn)定劑為HPMC,濃度為4mg/ml,藥物濃度為160mg/ml時(shí),得到的氟苯尼考微晶體在37℃下其飽和溶解度達(dá)到最大,在此條件下微晶體的產(chǎn)率為73.96%。通過光學(xué)顯微鏡觀察氟苯尼考及其微晶體,結(jié)果顯示其微晶體外觀由針狀轉(zhuǎn)變成了球狀,且粒徑明顯減小。穩(wěn)定性實(shí)驗(yàn)表明氟苯尼考微晶體在光照,高溫,高濕條件性質(zhì)穩(wěn)定。對(duì)氟苯尼考及微晶體的溶解度及溶解速度研究表明,氟苯尼考微晶體在37℃下的飽和溶解度由原藥的2.12mg/ml增加到了3.13mg/ml,溶解速度較原藥明顯增加,微晶體在5 min時(shí)溶解度已經(jīng)達(dá)到了飽和溶解度的77.15%,而原藥僅達(dá)到了21.93%。DSC和x射線衍射證明氟苯尼考微晶體的晶型由原藥的2種轉(zhuǎn)變?yōu)榱艘环N,且通過對(duì)x射線衍射結(jié)果的分析發(fā)現(xiàn),氟苯尼考微晶體結(jié)晶度降低,這也改善了它的溶解性質(zhì)。通過比較氟苯尼考及其微晶體對(duì)健康家兔口服灌胃后的藥代動(dòng)力學(xué)特征,考察氟苯尼考微晶體與原藥生物利用度的差異。使用高效液相色譜法測(cè)定血漿中的氟苯尼考濃度,用DAS2.0藥動(dòng)學(xué)程序?qū)λ巹?dòng)學(xué)參數(shù)進(jìn)行分析,使用SPSS分析藥動(dòng)學(xué)參數(shù)差異。結(jié)果表明兩組實(shí)驗(yàn)的藥時(shí)數(shù)據(jù)都符合二室模型(權(quán)重=1/CC)其中原藥的主要藥動(dòng)學(xué)參數(shù)為：AUC(o-t)為4.20±1.23mg/l*h, Cmax為1.68±0.33μg/ml, Tmax為0.75±0.16h,MRT(0-t)為3.23±1.21h。氟苯尼考徽晶體的主要藥動(dòng)學(xué)參數(shù)：AUC(o-t)為6.66±1.35 mg/l*h, Cmax為2.18±0.37gg/ml,Tmax為1.42±0.38h, MRT(o-x)為2.75±0.42h。從結(jié)果可以看出,氟苯尼考微晶體的Cmax與AUC(o-t)顯著增加,相對(duì)生物利用度提高。本研究根據(jù)藥物重結(jié)晶的原理,通過改良后的溶劑反溶劑沉淀法成功制備了氟苯尼考微晶體,該制備方法操作簡(jiǎn)便,產(chǎn)率較高,條件要求低,成本十分低廉,適合工業(yè)化生產(chǎn)。與氟苯尼考相比,微晶體飽和溶解度、溶解速度和生物利用度顯著增加。本實(shí)驗(yàn)研究成果為氟苯尼考微晶體的進(jìn)一步推廣應(yīng)用奠定了實(shí)驗(yàn)基礎(chǔ),并為更好地發(fā)揮氟苯尼考在動(dòng)物疾病防治中的作用提供了新的思路,也為國(guó)內(nèi)獸用藥物的微粉化技術(shù)以及晶體研究提供了新的思路,對(duì)于促進(jìn)獸藥制劑技術(shù)的發(fā)展具有重要意義。
[Abstract]:Fluorobenzidine, also known as flumeomycin, is a broad-spectrum antibiotic for animals developed in the late 1980s. but because it is extremely difficult to dissolve in water, it limits its clinical use. At present, the method for increasing the solubility of the florfenone is mainly composed of a synthetic water-soluble prodrug, a solid dispersion prepared into a solid dispersion and an organic solvent such as DMF. however, it is very important and necessary to find a suitable method for solubilization of florfenin, such as residue of harmful by-product, unsatisfactory solubilization effect, and great irritation to organism. The relationship between the particle size of the insoluble drug and its solubility is very close. According to the Noyes-Whitney equation, the solubility of the substance is directly proportional to the surface area of the solute, while reducing the particle size can increase the surface area of the substance, thus improving the solubility of the drug. It is very important to study the solubility of drug by reducing the particle size of drug by micronization technology. The main purpose of this study is to use the method of Bottom-up, to use the chemical principle to dissolve the drug first, and then suck the smaller drug crystals. In this way, the drug particle size is reduced to increase its solubility, and this method reduces the possibility of destroying the drug structure by micronization of mechanical energy and has the advantage of low cost and the like. By using modified solvent anti-solvent precipitation method, stabilizer was added to the anti-solvent to inhibit the growth of crystal, so that the microcrystals with smaller particle size were obtained. The optimal preparation conditions and stabilizers were screened by single factor and orthogonal experiment. The experimental results show that when the solvent is acetone, the anti-solvent is water, the solvent-to-solvent ratio is 1: 9, the stabilizer is sodium hydride, the concentration is 4mg/ ml, and the concentration of the drug is 160mg/ ml, the saturated solubility of the obtained florfenol micro-crystal at 37 DEG C reaches the maximum, and the yield of the micro crystal under the condition is 73. 96%. The microcrystals were observed by optical microscopy. The results showed that the micro-crystal appearance was changed from needle shape to spherical shape, and the particle size was obviously reduced. The experimental results show that the microcrystals of fluorobenzidine are stable in light, high temperature and high humidity conditions. The study of the solubility and dissolution rate of florfenone and microcrystals shows that the saturated solubility of flubenignon microcrystals at 37 鈩，

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