HPMC修饰的氟苯尼考微晶体的制备、表征及其药动学研究
发布时间：2018-10-05 08:27
【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种兽用广谱抗菌药。但是由于其在水中极难溶解,从而限制了它的临床使用。目前增加氟苯尼考溶解度的方法主要有合成水溶性前药,制备成固体分散体和使用DMF等有机溶剂助溶。但这些增溶方法都存在着如有害副产物残留,增溶效果不理想以及溶剂对生物体刺激性大等缺点,所以寻找一种合适的氟苯尼考增溶方法是非常有意义且十分必要的。难溶性药物的粒径与其溶出性质的关系十分密切,根据Noyes-Whitney方程,物质的溶出度和溶质的表面积成正比,而减少粒径可以增加物质的表面积,从而改善药物的溶解性。目前通过微粉化技术减小药物粒径来增加其溶解性的研究很受关注。本研究主要目的即通过Bottom-up的方法,运用化学原理,使药物先溶解,再吸出较小的药物晶体。通过这种方式减小药物粒径从而增加其溶解度,并且这种方法降低了通过机械能微粉化而破坏药物结构的可能性并且有着低成本等优点。实验使用改良后的溶剂反溶剂沉淀法,在反溶剂中加入稳定剂来抑制晶体的成长,得到粒径更小的氟苯尼考微晶体。通过单因素及正交实验,筛选最优制备条件以及稳定剂。实验表明,在溶剂为丙酮,反溶剂为水,溶剂反溶剂比为1：9,稳定剂为HPMC,浓度为4mg/ml,药物浓度为160mg/ml时,得到的氟苯尼考微晶体在37℃下其饱和溶解度达到最大,在此条件下微晶体的产率为73.96%。通过光学显微镜观察氟苯尼考及其微晶体,结果显示其微晶体外观由针状转变成了球状,且粒径明显减小。稳定性实验表明氟苯尼考微晶体在光照,高温,高湿条件性质稳定。对氟苯尼考及微晶体的溶解度及溶解速度研究表明,氟苯尼考微晶体在37℃下的饱和溶解度由原药的2.12mg/ml增加到了3.13mg/ml,溶解速度较原药明显增加,微晶体在5 min时溶解度已经达到了饱和溶解度的77.15%,而原药仅达到了21.93%。DSC和x射线衍射证明氟苯尼考微晶体的晶型由原药的2种转变为了一种,且通过对x射线衍射结果的分析发现,氟苯尼考微晶体结晶度降低,这也改善了它的溶解性质。通过比较氟苯尼考及其微晶体对健康家兔口服灌胃后的药代动力学特征,考察氟苯尼考微晶体与原药生物利用度的差异。使用高效液相色谱法测定血浆中的氟苯尼考浓度,用DAS2.0药动学程序对药动学参数进行分析,使用SPSS分析药动学参数差异。结果表明两组实验的药时数据都符合二室模型(权重=1/CC)其中原药的主要药动学参数为：AUC(o-t)为4.20±1.23mg/l*h, Cmax为1.68±0.33μg/ml, Tmax为0.75±0.16h,MRT(0-t)为3.23±1.21h。氟苯尼考徽晶体的主要药动学参数：AUC(o-t)为6.66±1.35 mg/l*h, Cmax为2.18±0.37gg/ml,Tmax为1.42±0.38h, MRT(o-x)为2.75±0.42h。从结果可以看出,氟苯尼考微晶体的Cmax与AUC(o-t)显著增加,相对生物利用度提高。本研究根据药物重结晶的原理,通过改良后的溶剂反溶剂沉淀法成功制备了氟苯尼考微晶体,该制备方法操作简便,产率较高,条件要求低,成本十分低廉,适合工业化生产。与氟苯尼考相比,微晶体饱和溶解度、溶解速度和生物利用度显著增加。本实验研究成果为氟苯尼考微晶体的进一步推广应用奠定了实验基础,并为更好地发挥氟苯尼考在动物疾病防治中的作用提供了新的思路,也为国内兽用药物的微粉化技术以及晶体研究提供了新的思路,对于促进兽药制剂技术的发展具有重要意义。
[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，
本文编号：2252693
[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，
本文编号：2252693
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