缓释型伊维菌素固体分散体的研究

发布时间：2018-05-27 21:13

本文选题：伊维菌素 + 缓释　；参考：《中国农业大学》2017年博士论文

【摘要】：利用固体分散体技术研制缓释型伊维菌素固体分散体(IVM-SD),延长IVM在动物体内的持效期,减少给药次数,将有助于提高药物的抗寄生虫效果。本研究以伊维菌素(Ivermectin,IVM)为目标药物,固体分散体(Solid dispersion,SD)为载药系统,氢化蓖麻油(hydrogenated castor oil,HCO)作为缓释载体,采用溶剂-熔融法制备缓释型伊维菌素固体分散体(IVM-SD)。对IVM-SD的理化性质、体外释药动力学和稳定性进行了系统评价,通过给自然感染兔耳螨虫的兔子皮下注射IVM-SD混悬注射剂评价其临床治疗效果。首先,本研究以IVM为目标药物,HCO为载体,采用溶剂-熔融法制备出了 IVM-SDs。并采用偏光显微镜、扫描电镜观察IVM-SD的形态特征,用高效液相色谱测定IVM-SD中IVM的含量和制备过程中的IVM回收率;通过傅里叶红外光谱和核磁共振技术检测IVM-SD中药物和载体的相容性和相互作用;采用X射线粉末衍射法、差示扫描量热法、热台显微镜分析IVM-SD中IVM的相容性和存在状态;通过热重分析等测定IVM-SD降解温度和样品干燥程度等;通过溶出度试验对IVM-SD进行了释药动力学研究,检测IVM-SD体外缓释效果并分析释放机制;用MDCK细胞对IVM-SD的细胞毒性进行了评价。含量和回收率的测定表明溶剂-熔融法是制备IVM-SD的有效方法。偏光显微镜和扫描电镜下IVM-SDs中IVM与HCO形成一个整体,呈现为均一的不规则颗粒,而IVM-PMs中药物和载体独立存在。X射线粉末衍射分析表明SD1:3,SD1:5,SD1:7中,IVM以无定型存在于固体分散体中,而且傅里叶红外光谱显示产生了分子间氢键,这有助于提高固体分散体的稳定性。核磁共振结果说明IVM-SDs制备过程中没有产生新的化学物质。差示扫描量热结果表明药物与载体之间有很好的相容性,热重分析法结果显示制备成IVM-SDs提高了 IVM的热稳定性,而且制备时使用的溶剂已彻底除去。热台显微镜分析再次表明SD1:3,SD1:5中IVM以无定型存在。体外溶出实验结果表明,IVM-SDs在体外具有明显的缓释作用,其溶出符合Higuchi模型,属于扩散释放,载体比例是影响药物溶出的关键因素。细胞毒性试验结果显示IVM-SD提高了 IVM对MDCK细胞的安全性。为了给IVM-SD的贮存条件提供选择依据,并了解其长期贮存过程中的变化,开展了 IVM-SD稳定性试验:影响因素试验(光照4500 lx,高温60℃,高湿度90%),加速试验(40℃,相对湿度75%)、长期稳定性试验(常规条件25℃,冷冻条件-20℃,冷藏条件5℃,相对湿度60%)和UVA光稳定性试验。影响因素试验结果显示:IVM-SD在强光照射下颜色变微黄;在高温条件下颜色变黄并结块;在高湿条件下外观没有明显变化。加速试验和长期稳定性试验的结果表明:IVM-SDs在40-C(相对湿度75%)储存6个月,在25℃、5℃和-20℃(相对湿度60%)储存12个月,样品没有发生重结晶,IVM仍以无定型稳定存在。但是在40℃条件下,样品出现轻微结块现象,DSC图谱显示IVM-SD的吸热峰面积变宽,可能是载体发生了老化。在各个储存条件下,不同药物-载体比例的IVM-SD,溶出初始速率都有减慢。UVA光稳定性试验结果显示HCO对IVM有很好的光保护作用,这可能与氢键的产生有关。根据稳定性试验结果,IVM-SD在避光、干燥、低温下贮存可以利于样品的性质稳定。给自然感染兔耳螨虫的兔子皮下注射IVM-SD(SD1:3)混悬注射剂评价其临床治疗效果。结果表明IVM-SD(2mg/kg)单次颈部皮下注射给药可以有效杀灭兔耳螨虫,14d时杀灭效率达100%,持效期长达42 d,明显长于伊维菌素普通注射剂(害获灭)。本研究利用固体分散体技术,成功制备缓释型伊维菌素固体分散体。通过对理化性质、释药动力学、稳定性和药效学等方面的研究表明:所研制的IVM-SD具有安全、质量稳定和缓释的特点,用其制备而成的IVM-SD混悬注射剂,能彻底杀灭兔耳螨、持效期长达42 d。本研究解决了临床上治疗寄生虫感染时频繁给药的问题,促进畜牧业持续健康发展,保障畜产品消费安全。并为兽药新制剂的研制提供借鉴和理论基础。
[Abstract]:The development of sustained release ivermectin solid dispersion (IVM-SD) by solid dispersion technique, prolonging the duration of IVM in the animal and reducing the number of drug delivery will help to improve the anti parasitic effect of the drug. This study uses the Ivermectin (IVM) as the target drug, the solid dispersion (Solid dispersion, SD) as the drug loading system, the hydrogenated castor Hydrogenated castor oil (HCO) was used as a sustained-release carrier to prepare sustained-release ivermectin solid dispersion (IVM-SD) by solvent melting method. The physical and chemical properties of IVM-SD, the release kinetics and stability of IVM-SD in vitro were systematically evaluated. By subcutaneous injection of IVM-SD suspension injection to rabbits with natural infection of the rabbit ear mites, the clinical evaluation was made. First, in this study, IVM was used as the target drug, HCO was used as the carrier, IVM-SDs. was prepared by solvent melting method, and polarizing microscope was used to observe the morphological characteristics of IVM-SD. The content of IVM in IVM-SD and the recovery rate of IVM in the preparation process were measured by high performance liquid chromatography; Fourier infrared spectroscopy and nuclear magnetic resonance technique were used. The compatibility and interaction of drugs and carriers in IVM-SD were detected. The compatibility and existence of IVM in IVM-SD were analyzed by X ray powder diffraction, differential scanning calorimetry, thermal table microscope, and the degradation temperature of IVM-SD and the drying degree of samples were measured by thermogravimetric analysis. The release kinetics of IVM-SD was carried out by dissolution test. The effect of the release of IVM-SD in vitro was detected and the release mechanism was analyzed. The cytotoxicity of IVM-SD was evaluated with MDCK cells. The determination of the content and recovery showed that the solvent melting method was an effective method for the preparation of IVM-SD. The IVM and HCO formed a whole in IVM-SDs under polarizing microscope and scanning electron microscope, showing the uniform irregular particles, The independent existence of.X ray powder diffraction analysis in IVM-PMs shows that in SD1:3, SD1:5, SD1:7, IVM exists in the solid dispersion in amorphous form, and the Fourier infrared spectrum shows the hydrogen bond between molecules, which helps to improve the stability of solid dispersion. The results of nuclear magnetic resonance show that the process of IVM-SDs preparation is not produced. The results of differential scanning calorimetry showed that there was a good compatibility between the drug and the carrier. The thermo gravimetric analysis showed that the preparation of IVM-SDs increased the thermal stability of IVM, and the solvent used in the preparation had been completely removed. The thermal stage microscope analysis again showed that the IVM in the SD1:5 was amorphous. In vitro dissolution test. The results showed that IVM-SDs had a significant release effect in vitro, and its dissolution accords with the Higuchi model, which belongs to the diffusion release, and the carrier ratio is the key factor affecting the dissolution of the drug. The cytotoxicity test results show that IVM-SD improves the safety of MDCK cells by IVM. In order to provide the selection basis for the storage conditions of IVM-SD, and to understand its long-term storage. In the process of storage, IVM-SD stability test was carried out: influence factors test (light 4500 LX, high temperature 60, high humidity 90%), accelerated test (40 C, relative humidity 75%), long-term stability test (conventional condition 25, freezing condition -20, 5 C, relative humidity 60%) and UVA photostability test. The influence factor test results showed IV The color becomes yellowed under strong light, and the color becomes yellow and caked under high temperature conditions. The appearance of M-SD has no obvious change in the high humidity condition. The results of accelerated and long-term stability tests show that IVM-SDs is stored for 6 months at 40-C (relative humidity 75%) and stored at 25, 5 and -20 (relative humidity 60%) for 12 months, and the recrystallization does not occur in the sample. IVM still exists with amorphous stability. But at 40 C, the sample appears slight caking. DSC atlas shows that the acreage of the endothermic peak of IVM-SD is broadened. It may be that the carrier is aging. Under various storage conditions, the IVM-SD of different drug carrier ratio and the initial rate of dissolution have slowed down.UVA light stability test results showing HCO to IVM There is a good light protection effect, which may be related to the production of hydrogen bonds. According to the results of stability test, IVM-SD can be used to avoid light, dry and low temperature storage for the stability of the sample. A IVM-SD (SD1:3) suspension injection for rabbits with natural infection of the rabbit ear mites is subcutaneously evaluated for its clinical treatment effect. The results show that IVM-SD (2mg/kg) single time The subcutaneous injection of the cervix could effectively kill the rabbit ear mites. The killing efficiency of 14d was 100% and the duration was 42 d, which was obviously longer than the common injections of ivermectin. The solid dispersion of the sustained-release ivermectin was successfully prepared by the solid dispersion technique. The research and other studies show that the developed IVM-SD has the characteristics of safety, quality stability and sustained release. The IVM-SD suspension injection made by it can kill the ear mites of rabbit completely, and the duration of its holding effect is 42 d.. The study solves the problem of frequent drug delivery in the clinical treatment of parasite infection, promote the healthy development of animal husbandry and guarantee the animal products. Consumption safety. It also provides reference and theoretical basis for the development of new veterinary drug preparations.
【学位授予单位】：中国农业大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：S859.5

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