替米考星凝胶微丸的制备工艺及质量标准的研究

【作者】 王宁；

【导师】 赵正保；

【作者基本信息】 山西医科大学 ， 药物化学， 2009， 硕士

【摘要】 做为畜禽专用抗生素,替米考星具有极好的抗菌活性及药代动力学特征,其治疗畜禽感染疗效确切,效果显著,使用安全,但是由于其味道极苦,动物服用相当困难,而且替米考星禁止静注,因而对替米考星的使用带来一定影响。本课题首次对替米考星海藻酸钙凝胶微丸的制备工艺进行了考察。实验中以载药量和包封率为指标,通过单因素试验,对海藻酸钠浓度、氯化钙浓度、钙化时间、滴制参数、海藻酸钠与替米考星的配比等影响因素进行研究。通过海藻酸钠与替米考星的配比、氯化钙浓度、海藻酸钠浓度、钙化时间进行四因素三水平的正交试验。实验发现海藻酸钠浓度2%、氯化钙浓度2%、钙化时间1h左右、滴制参数(针头离液面的距离8cm左右、滴制的速度30d/min、针头型号为12号)、海藻酸钠与替米考星的比例1:5为最佳的制备工艺。在选定的制备工艺条件下可制备得到外观较好,载药量和包封率也较高的替米考星海藻酸钙凝胶微丸,而且降低了药物的苦味。利用高效液相色谱法建立替米考星海藻酸钙凝胶微丸的含量检测标准。采用反相高效液相法,用水-乙腈-四氢呋喃-二丁胺磷酸盐缓冲液(805:115:55:25)为流动相,柱温:30℃,检测波长:280nm,进样量:10μl。用外标峰面积法定量,以顺式和反式峰面积之和(Y)为纵坐标,替米考星的浓度(X)为横坐标作图,得一直线,求得回归方程,计算相关系数。得标准曲线方程为:Y=565252X+53867,R~2=0.9993。X在0.25—0.85mg/ml范围内呈良好线性关系。测得替米考星的含量为76.13%。通过含量测定、性状、鉴别、溶散时限的研究,为考察制剂的稳定性提供准确精密的方法,为制定制剂质量标准提供依据。本论文并对凝胶微丸的稳定性进行了加速试验和长期试验。通过高温试验、高湿试验、强光试验等初步考察了影响稳定性的几个主要因素。研究结果表明:微丸对光照比较敏感,故应避光保存;微丸在常温下具有较好的稳定性,但在高温60℃条件下加热24小时,微丸的色泽、含量均有很大改变,提示微丸应室温储存。本实验研究的替米考星海藻酸钙凝胶微丸的制备工艺成熟、可靠,具有较高的包封率和载药量,能有效地掩蔽替米考星的苦味;所建立的HPLC检测替米考星海在藻酸钙凝胶微丸中的含量准确、快速、重现性好;研究出了替米考星海藻酸钙凝胶微丸稳定的储存条件。本试验对提高替米考星的利用度和对其进一步研究开发提供了基础。更多还原

【Abstract】 Tilmicosin has been used specially for livestock and poultry as antibiotics because it has excellent antibacterial activity and pharmacokinetics characteristics.The curative effect of tilmicosin is certain, significant and safe.But due to its bitter taste it is very difficult to drive animals taking the medicine,in addition tilmicosin is forbidden to be used by intravenous injection.All of these limit the use oftilmicosin.To explore the optimum preparation technology of tilmicosin calcium alginate gel micro pills,the effect factors,such as the concentrations of sodium alginate and calcium chloride,the time of calcification,drip system parameters and the ratio of sodium alginate and tilmicosin were investigated by single-factor test, using drug loading and encapsulation efficiency as indicators.In addition,the best preparation technology was obtained by the four factor-three level orthogonal experiment with the ratio of sodium alginate and tilmicosin,the concentration of sodium alginate and calcium chloride and the time of calcification.The optimum preparation technology is afforded as follows:2%concentration of sodium alginate,2% concentration of calcium chloride,1 hour time of calcification,8cm distance between the solution surface and needle,30 drops/min speed of dripping,No 12 needle type and 1:5 ratio of sodium alginate and Tilmicosin. Under the optimum conditions,the gel micro pills enclosing Tilmicosin can be obtained,which have better appearance,higher drug loading and encapsulation and lower bitterness.RP-HPLC method was used to assay quantificationly the content of Tilmicosin containd in gel micro pills. Mobile phase was composed with water-acetonitrile-tetrahydrofuran-Phosphate Dibutylamine(805:115:55:25) buffer solution,the column temperature was about 30℃,the wavelength of detection was 280 nm,the sample injection volumn is 10μL.A good linear relationship were found between the peak area sum(Y) of cis and trans tilmicosins and their concentration(X).In 0.25-0.85mg/ml concentration range of tilmicosins,the regression equation is Y=565252X+53876,R~2=0.9993.The content of tilmicosins contained in calcium alginate gel micro pills was 76.13%.To explore the stability of micro pills under different conditions,influencing factors were tested, including high-temperature test,humidity test,the pilot light,accelerated test and long-term test.The experimental results showed that micro pills are sensitive to light and the color,cluster and content of tilmicosin were changed seriously after micro pills were heated on 60℃for 24 hours.But,the micro pills keep a good stability at room temperature.All of these evidence indicated that the micro pills can not be stored under higher temperature.In the thesis,the preparation technology of tilmicosin calcium alginate gel micro pills explored is perfect and stable with better appearance,higher drug -loading rate and lower bitterness.RP-HPLC method to assay quantificationly the content of tilmicosin containd in gel micro pills is accuate and rapid with good repeatability.At the same time,favorable storage conditions of tilmicosin calcium alginate gel micro pills is obtained.Micro pills should be preserved at lower temperature and away from the light.This thesis supply a beneficial base for tilmicosin researching and exploring futher.更多还原