兽用左氧氟沙星缓释颗粒剂的研究

发布时间：2018-03-01 19:45

本文关键词： 左氧氟沙星缓释颗粒释放度稳定性质量标准　出处：《武汉工程大学》2015年硕士论文　论文类型：学位论文

【摘要】：细菌感染是一种严重危害家禽生长发育的疾病。据报道,全世界家禽细菌感染的发病率高达50%~70%,爆发细菌感染时家禽的死亡率达到20%~30%,我国养鸡业每年由于细菌感染所导致的鸡死亡数量约为3亿只,造成的直接经济损失约30亿元,造成的间接损失约100亿元。细菌感染是集约化养鸡业中最为重要的疾病之一,其防治方法主要有免疫控制法和药物治疗法,免疫控制法可起到预防作用,但是当细菌感染爆发时则主要依赖药物治疗,据统计,全球抗菌药的年消费额超过3亿美元。所以,研究高效、低毒、广谱的抗菌药物的新剂型、新制剂成为抗细菌感染药物开发和应用的非常重要的途径。在兽医临床上,已有恩诺沙星、二氟沙星、达氟沙星、氧氟沙星等多种类型抗细菌感染药物使用。其中氟喹诺酮类药物因具有低毒、抗菌谱广和原料价格低等优势,在兽医临床上的应用很广泛,主要用于治疗敏感菌所致的呼吸道、尿道感染,同时可以促进动物的日增重,并且提高饲料转化率。左氧氟沙星是氧氟沙星的光学活性L-型异构体,体外抗菌活性是消旋体的2倍,是右旋体的8~128倍,它是第一个成功上市的具有较好抗肺炎球菌活性的氟喹诺酮类药物,分别于1993年和1997年在日本和美国上市,已经用于3亿多名患者的治疗,出现耐药性的情况极少,对多数肠杆菌科细菌有较强的抗菌活性,对化脓性链球菌、肺炎链球菌、金黄色葡萄球菌等革兰氏阳性菌和肺炎支原体、衣原体也有一定的抗菌作用,在临床上应用广泛。但是左氧氟沙星半衰期为6小时,相对较短,在兽医临床使用中,给药较频繁,这将增加家禽的应激反应,而且会因血药浓度的波动增大不良反应的几率,将其制成缓释颗粒混于饲料中给家禽使用正好可以解决这个问题。本文对高效广谱抗菌药左氧氟沙星的缓释颗粒剂进行了比较系统的研究,主要工作如下:(1)综述了左氧氟沙星的结构、理化性质、作用机理,并介绍了新制剂技术缓释制剂技术,以期用缓释制剂技术来减缓左氧氟沙星的释放,减少服药次数,减少家禽的应激反应。在此基础上,根据左氧氟沙星原料药和辅料的理化性质、质量标准,选择不同用量的骨架材料、填充剂、粘合剂和润滑剂制备左氧氟沙星缓释颗粒剂,分别测定其在0.5、1、2、4、6、9、12h药物的累积释放度,以2、6、12h的累积释放度为考察指标,初步确定处方由左氧氟沙星、蜡质骨架材料硬脂酸、亲水性骨架材料HPMC、填充剂淀粉、粘合剂PVP、润滑剂滑石粉组成,制备方法为湿法制粒。(2)通过单因素考察和正交设计实验,考查了左氧氟沙星缓释颗粒的最佳处方。确定最优处方为(以1000g计):左氧氟沙星:250g;硬脂酸:170g;HPMC:500g;淀粉:30g;PVP:50g,滑石粉:适量,用溶出度法对制备的缓释颗粒释放度进行了考察,并研究了左氧氟沙星缓释颗粒的释药机制,研究结果表明Higuchi方程是最优的拟合模型。(3)为了能够有效的控制产品的质量,对左氧氟沙星缓释颗粒的质量标准进行了比较系统的研究,包括性状、鉴别、含量测定、释放度测定等一系列研究,研究结果表明该制剂制备工艺和产品的质量都比较稳定。拟定的质量标准(草案)可以有效地控制产品质量。(4)对左氧氟沙星缓释颗粒进行了稳定性考察。加速试验、长期试验结果表明:模拟市售包装的左氧氟沙星缓释颗粒在40±2℃,相对湿度75±5%的实验条件下放置6个月,温度25±2℃,相对湿度60±5%的条件下放置12个月,样品质量稳定。
[Abstract]:Bacterial infection is a serious harm to the growth and development of poultry disease. According to reports, the world poultry and the incidence of bacterial infection was as high as 50%~70%, the outbreak of bacterial infection in poultry mortality rate reached 20%~30%, the poultry industry in our country every year because the number of bacterial infections caused by chicken deaths of about 300 million, causing direct economic losses of about 3 billion yuan, indirect losses of about 10 billion yuan. Bacterial infection in intensive poultry industry is one of the most important disease prevention methods include immune control method and drug treatment method, immune control method can play a preventive role, but when the outbreak of bacterial infection is mainly dependent on the drugs, according to statistics, the year spending more than $300 million in global antibacterial drugs. Therefore, research on efficient, low toxicity, broad-spectrum antimicrobial new formulations, new preparation has become an important way to the development and application of anti bacteria drugs in animals. Clinical medicine, has two difloxacin, enrofloxacin, danofloxacin, ofloxacin and other types of anti infection drug use. The fluoroquinolones with low toxicity, wide antibacterial spectrum and raw materials, low price advantage, application in veterinary clinic is very extensive, mainly used for the treatment of sensitive bacteria caused by respiratory tract infection, at the same time. The increasing promotion of animal weight, and increase the feed conversion rate. Levofloxacin is optically active isomer of L- ofloxacin, in vitro antibacterial activity is 2 times that of racemic dextroisomer is 8~128 times, it is the first successful listing of fluoroquinolones has better anti pneumococcal activity, were listed in Japan and the United States in 1993 and 1997, has been used to treat more than 300 million patients, the emergence of drug resistance situation, has strong anti bacteria activity against Enterobacteriaceae, to fester Streptococcus, Streptococcus pneumoniae, Staphylococcus aureus and gram positive bacteria and Mycoplasma pneumoniae, Chlamydia has antibacterial effect, is widely used in clinic. However, levofloxacin has a half-life of 6 hours, relatively short, in veterinary clinical use, administered more frequently, which will increase the stress in poultry, and likely due to fluctuations in plasma concentrations increased adverse reactions, the sustained-release particles mixed in the feed for poultry use can solve this problem. Sustained-release granule antibiotic levofloxacin based on broad-spectrum were studied systemically. The main work is as follows: (1) reviews the structure of levofloxacin. Physical and chemical properties, action mechanism, and introduces the new preparation technology of sustained-release preparation technology, in order to use levofloxacin sustained-release preparation technology to slow down the release, reduce the frequency of administration, poultry should be reduced Shock response. On this basis, according to the physicochemical properties of levofloxacin, pharmaceutical raw materials and excipients quality standards, selection of skeleton material, different amount of fillers, binders and lubricants for preparation of levofloxacin sustained-release granules were measured in 0.5,1,2,4,6,9,12h drug cumulative release, the cumulative release ratio of 2,6,12h as index, preliminary to determine the prescription by levofloxacin, wax skeleton material, stearic acid, hydrophilic matrix material HPMC, starch filler, adhesive lubricant PVP, talc powder, preparation method for wet granulation. (2) by using single factor test and orthogonal experiment, to examine the best prescription of levofloxacin sustained-release granules. The optimal prescription for (to 1000g): levofloxacin: 250g; stearic acid: 170g; HPMC:500g; 30g; PVP:50g: starch, talcum powder amount, with the dissolution of sustained-release pellets prepared by release of the test The police, and study the drug release mechanism of levofloxacin sustained-release particles, the results show that the Higuchi equation was the best fitting model. (3) in order to effectively control the product quality to the quality standard of levofloxacin sustained-release granules were studied systematically, including character, identification, content determination, dissolution etc. a series of studies, the results show that the quality of the preparation process and products are relatively stable. The quality standard (Draft) can effectively control the quality of the products. (4) of levofloxacin sustained-release granules. Investigated the stability of accelerated test, long-term test results show that the levofloxacin particle simulation commercial packaging in the 40 plus or minus 2 DEG C for 6 months the experimental conditions of relative humidity of 75 + 5%, 25 + 2 degrees Celsius temperature, relative humidity for 12 months was 60 + 5%, the quality of the sample.

【学位授予单位】：武汉工程大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：S859.79

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