yfx盐酸多西环素论文:盐酸多西环素壳聚糖微囊的制备及其在家兔体内的药动学研究ccc.doc
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1、 盐酸多西环素论文:盐酸多西环素壳聚糖微囊的制备及其在家兔体内的药动学研究【中文摘要】盐酸多西环素(Doxycycline Hyclate)为广谱抗生素,兽医临床应用广泛。但其性质不稳定性.口服和注射刺激性较大,因而在一定程度上限制了盐酸多西环素的应用。药物微囊化后不但可以提高药物的稳定性,延缓药物释放从而延长药物在体内的作用时间,减少对胃的刺激,还可进一步制成其它剂型,如散剂、片剂、颗粒剂、注射剂等以方便临床应用。目前,有关盐酸多西环素微囊的制备国内外尚未见报道。因此,本实验采用乳化交联法制备盐酸多西环素壳聚糖微囊,并对所得微囊的各项性质及其在家兔体内的药动学进行了研究。建立反相高效液相色谱
2、法(RP-HPLC)测定微囊中盐酸多西环素的载药量和包封率。色谱条件为:色谱柱KromasilC18柱(4.6mm150mm,5um),流动相:0.05molL-1草酸铵溶液-二甲基甲酰胺-0.2mol/L磷酸氢二铵溶液-甲醇(53:33:4:10),流速:1.0 mL/min,检测波长:280 nm,柱温:35。在所选定的色谱条件下,盐酸多西环素峰与辅料及溶剂峰分离良好,盐酸多西环素在10.0-120.0g/mL浓度范围内与峰面积呈良好线性关系,回归方程为:A=18503.14C-9789.27,r=0.9997(n=7),回收率在98.81%-100.10%之间,日内RSD及日间RSD均小
3、于2%(n=5)。证明该方法准确可靠、方便快捷,可用于盐酸多西环素微囊中药物含量及包封率的测定。以包封率和载药量为主要考察指标,在单因素实验基础上结合正交实验设计法优选出盐酸多西环素壳聚糖微囊的最佳制备处方,即:壳聚糖浓度:2%,司盘-80:5,药物与壳聚糖质量比:2:5,甲醛:1.5%。按以上处方制得微囊平均载药量和包封率分别为20.60%,85.54%。本实验对盐酸多西环素壳聚糖微囊的形态、粒径、包封率、载药量、体外释药特性及稳定性等药剂学特性进行了考察和评价。扫描电镜下可见微囊呈较规整的球形,平均粒径为10um,分布均匀,分散性较好。体外释放实验表明盐酸多西环素原料药3h释放达到90%以
4、上,而微囊在48h后仅约释放出80%。可见,微囊化后具有明显的缓释效应。稳定性实验表明,药物微囊化后能显著提高其稳定性。通过给家兔分别灌服盐酸多西环素水溶液(A组)和其壳聚糖微囊的水分散液(B组)研究盐酸多西环素壳聚糖微囊在家兔体内的药动学特征。以HPLC法测定血浆中盐酸多西环素含量.所得数据以DAS2.0药动学软件处理,进行房室模型拟合,以AIC值最小,R2值最大为判断依据,结果表明两组药时数据均符合一级吸收二室模型(权重=1),计算药代动力学参数如下:A组:Ka为(1.2560.708)1/h,T1/2为(1.1570.526)h,T1/2为(2.1890.377)h, AUC(0-)为(
5、11.8340.194)mg/L*h, Cmax为(1.740.002)mg/L, Tmax为(30.000)h,其拟合方程为:C=13.709e-1.256t+7.876e-0.703t-21.585e-0.323t。B组:Ka为(0.2040.11)1/h,T1/2为(7.512.87)h,T1/2为(9.0041.596)h, AUC(0-)为(35.2010.353)mg/L*h. Cmax为(1.1020.004)mg/L, Tmax为(120.000)h.拟合方程为:C=12.705e-0.204t+12.879e-0.100t-25.584e-0.078t。研究结果表明,乳化交联
6、法制备盐酸多西环素壳聚糖微囊工艺简单,质量可控,重现性好。所得微囊各项特性符合制剂要求,且具有很好的缓释效果和稳定性,有利于延长药物作用时间,提高药物稳定性,减少给药次数,因此,将盐酸多西环素微囊化具有良好的开发应用前景。【英文摘要】As a broad-spectrum antibiotic Doxycycline hyclate is widely used in the veterinary clinic. Because of its instability, oral dosage forms and injection of doxycycline usually have gre
7、at intimulation.and its storage and application were limited in a certain extent. Microencapsulation could not only enhance pharmacal stability, prolonged drugs release time, but also lessen harm to stomach. Microcapsules can also further be made into other dosage forms for clinical application conv
8、enient, such as pulveres, tablet, granules, injection et al. At present, there has no report about doxycycline hyclate microcapsules at home and abroad.,In this study, biodegradable chitosan was selected as the membrane material and doxycycline hyclate microcapsules were prepared by emulsifying cros
9、slinking method.Characters of doxycycline hyclate-chitosan microcapsules and its pharmacokinetics in health rabbits were evaluated.An RP-HPLC method of higher specialty was used to detect the content and entrapment efficiency. The analysis was performed on a Kromasil Cig (4.6mmx 150mm, Sum) analytic
10、al column. The mobile phase was composed of a mixture of 0.05 mol/Lammonium oxalate solution-N.N-dimethyl fomamide-0.2 mol/Lammonium monohydric phosphate solution-methanol (53:33:4:10) at a flow rate of 0.8mL/min. Doxycycline hyclate was detected at 280nm and at a 35column temperature. The results i
11、ndicated that the excipients and solvent in the microcapsule could be well separated from the drug under such a designated chromatogram condition. A good linear relationship was found between peak area and the concentration of doxycycline hyclate in the range of 10.0-120.0ug/mL. Linear regression eq
12、uation was A=18503.14C-9789.27, (r=0.9997.n=7), the average recoveries were between 98.81%and 100.10%(n=5).RSD values of intra-day and inter-day were less than 2%(n=5).It had showed that this method were specific, accurate, reliable, sensitive and applicable for the content and entrapment efficiency
13、 determination of doxycycline hyclate microcapsules.Encapsulation efficiency and drug loading were used as the main index of examination, and the orthogonal design was used to optimize the prescripton of doxycycline hyclate-chitosan microcapsules on the base of single factor experiments. Under the o
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