替米考星长效注射液的研制

发布时间：2018-07-05 04:55

  本文选题：替米考星 + 长效注射液　； 参考：《河南大学》2014年硕士论文

【摘要】：替米考星(Tilmicosin)为一种由泰乐菌素半合成的大环内酯类禽畜用抗生素,具有很强的抗菌活性,抗菌谱广,无交叉耐药性。替米考星原料药分为两种：替米考星碱和替米考星磷酸盐,受其理化性质影响,临床使用剂型多为其磷酸盐制剂,如目前兽药市场上较为常见的剂型主要为磷酸替米考星注射液(30%),饮水剂(25%),预混剂(20%)。本研究通过筛选合适的有机复合溶媒、缓释剂、抗氧剂等,制备了替米考星长效注射液,并对其稳定性、安全性、有效性进行了研究。具体研究内容包括： 1.文献综述 概述了国内外替米考星的一些研究概况,包括替米考星的理化性质、作用机制、抗菌活性、不良反应、临床应用等,对替米考星及其制剂进行了初步的概述。又介绍了兽用缓释制剂的研究进展,重点介绍了注射用长效制剂的类型、优点等,以及兽用长效制剂的研究现状、存在的问题、发展前景等,对本研究的背景进行了综合性的阐述。 2.替米考星体外分析方法的建立 建立了替米考星的HPLC分析方法,替米考星进样量在0.16ug-0.8ug范围内线性关系良好；平均回收率为99.32%,重复性好,RSD为0.22%；日内精密度和日间精密度RSD均小于2%；结果表明建立的替米考星长效注射液的HPLC分析方法回收率、重复性和精密度均符合要求,可为长效替米考星注射液的处方设计、稳定性考察等提供一种灵敏,准确,可靠的检测方法。 3.替米考星长效注射液的制备与处方优化 通过处方前研究,考察了替米考星原料药的理化性质,对其pH、溶解性、稳定性等进行了初步研究,为处方设计打下基础。通过处方筛选初步确定了注射液规格、注射用非水溶媒、抗氧剂、金属离子络合剂、缓释剂,利用正交试验优化了替米考星长效注射液的最佳处方,确定了最佳制备工艺。通过体外释放试验验证了替米考星长效注射液的缓释效果,结果表明,制备的替米考星长效注射液具有良好的缓释效果。 4.替米考星长效注射液的稳定性评价 对替米考星长效注射液进行了影响因素试验(高温试验、高湿试验、强光试验),加速试验,长期试验,初步考察了替米考星长效注射液的稳定性。结果表明替米考星长效注射液稳定性较好,符合制剂要求。对光、热敏感,保存时应注意避免光照、高温。 5.替米考星长效注射液的安全性评价 研究制备的替米考星长效注射液注射方法为皮下注射或肌注,禁止静脉注射。根据相关规定,对替米考星长效注射液进行了皮肤刺激性实验、局部刺激性实验和急性毒性试验。结果显示：替米考星长效注射液对家兔皮肤刺激性很小；对家兔肌肉和兔耳无明显刺激,判定该制剂能够供肌注和皮下注射使用；对小鼠的急性毒性实验测得半数致死量LDso为595.36mg/kg,半数致死量LD5o的95%可信限为：528～689mg/kg,属于低毒药物。表明本研究制备的替米考星长效注射液具有较低的毒性及刺激性,临床使用比较安全,适用于皮下注射、肌肉注射。 6.替米考星长效注射液的体外抑菌作用研究 采用2倍稀释法考察替米考星长效注射液、磷酸替米考星溶液、磷酸泰乐菌素溶液对致病性大肠杆菌、金黄色葡萄球菌、多杀巴氏杆菌和链球菌等常见致病菌的体外抑菌活性。结果表明替米考星长效注射液对上述常见致病菌具有很好的抗菌活性,对常见致病菌的敏感性强于磷酸替米考星和磷酸泰乐菌素,最低抑菌浓度均小于磷酸替米考星溶液和磷酸泰乐菌素溶液,表明替米考星长效注射液具有较好的抗菌作用。
[Abstract]:Tilmicosin ( Tilmicosin ) is a kind of macrolide semi - synthetic macrolide antibiotics . It has strong antibacterial activity , wide antibacterial spectrum and no cross - resistance . It is divided into two kinds : tilmicosin injection ( 30 % ) , drinking agent ( 25 % ) and premix ( 20 % ) .

1 . Literature review

This paper summarizes the research situation of tilmicosin at home and abroad , including the physical and chemical properties of tilmicosin , mechanism of action , antibacterial activity , adverse reaction , clinical application , etc . It also introduces the research progress of tilmicosin and its preparation .

2 . Establishment of external analytical method for tilmicosin

The HPLC analysis method of tilmicosin was established , and the linear relationship was good in the range of 0.16ug - 0.8ug for tilmicosin injection .
The average recovery was 99.32 % , the repeatability was good , RSD was 0.22 % .
The RSD of intra - day precision and inter - day precision was less than 2 % .
The results show that the HPLC analysis method of tilmicosin long - acting injection has satisfactory recovery , repeatability and precision , which can provide a sensitive , accurate and reliable detection method for the prescription design and stability study of tilmicosin injection .

Preparation and prescription optimization of tilmicosin long - acting injection

The physicochemical properties of tilmicosin drug substance were studied by pre - prescription study . The pH , solubility and stability of tilmicosin were studied . The optimal formulation of tilmicosin long - acting injection was determined by orthogonal test . The results showed that the sustained release effect of tilmicosin long - acting injection was verified by in vitro release test . The results showed that the prepared tilmicosin long - acting injection has good sustained - release effect .

4 . Evaluation of stability of tilmicosin long - acting injection

The stability of tilmicosin long - acting injection was investigated by high temperature test , high humidity test , strong light test , accelerated test and long - term test . The results showed that the tilmicosin long - acting injection has good stability and meets the requirements of the preparation .

Safety evaluation of tilmicosin long - acting injection

The injection method of tilmicosin long - acting injection prepared by the study was subcutaneous injection or intramuscular injection , and intravenous injection was inhibited . According to the relevant regulations , the skin irritation experiment , local irritation experiment and acute toxicity test were carried out on tilmicosin long - acting injection . The results showed that the tilmicosin long - acting injection had little irritation to skin of rabbits ;
There was no obvious irritation to rabbit muscle and rabbit ear , and it was determined that the preparation could be used for intramuscular injection and subcutaneous injection .
LD50 LDso was 595.36 mg / kg , and the 95 % confidence limit of LD50 LD5o was 528 锝，

本文编号：2099007