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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
14、ptimal prescripton.20.60%and 85.54%were got as the mean drug loading and entrapment efficiency of doxycycline hyclate-chitosan microcapsules.In this work, surface morphology, particle size and particle size distribution, drug encapsulation efficiency, drug loading.stability, drug release kinetics in
15、 vitro of drug-loaded microparticles were investigated. SEM observation showed the drug-loaded microparticles exhibited sphere-like shape and average particle size was about l0um with narrow particle size distribution. In vitro release studies revealed that the drug-loaded microparticles substantial
16、ly improved the sustained-release property. It can be seen that the free doxycycline hyclate rapidly release up to 90%in 3h, drug-loaded microparticles exhibited an accumulative release of 80%after 48h.The results indicated that microencapsulation could highlighted extend release property. And the s
17、tability study showed that microencapsulation could enhanced stability of doxycycline hyclate.Doxycycline hyclate solution (A group) and microcapsule suspension liquid (B group)were administrated on health rabbits orally to study the pharmacokinetic of doxycycline hyclate microcapsule. Using doxycyc
18、line hyclate solution as a reference, their pharmacokinetic differences were compared. Plasma drug concentration was determined by RP-HPLC. and the pharmacokinetic parameters were analyzed by DAS2.0 pharmacokinetic program. The results showed that data of A, B group was in line with a two-compartmen
19、t model (weight=1). The main pharmacokinetic parameters and the fitting equation were as follows:A group:Ka was (1.2560.708)1/h, T1/2a was (1.1570.526)h. T1/2p was (2.1890.377)h, AUC(0-) was (11.8340.194)mg/L*h, Cmax was (1.740.002)mg/L, Tmax was (30.000)h, the fitting equation was C=13.709e-1.256t+
20、7.876e-0.703t-21.585e-0.323t .B group:Ka was (0.2040.11)1/h. T1/2a was (7.512.87)h. T1/2was (9.0041.596)h, AUC(0-) was (35.2010.353)mg/L*h. Cmax was (1.1020.004)mg/L. Tmax was (120.000)h. the fitting equation was C=12.705e-0.204t+12.879e-0.100t-25.584e-0.078tcStudies on the preparation and pharmacok
21、inetics of doxycycline hyclate microcapsules showed the emulsifying crosslinking method was simple and of good reproducibility. and the quality was adjustable. The characteristics of microcapsules were live up to the preparations requirements and had preferable sustained-release, stability, being in
22、 favor of prolonging the action time.improving doxycycline hyclates stability in microcapsule, reduing the administration times. So microcapsulating the doxycycline hyclate has good development and application prospects.【关键词】盐酸多西环素 壳聚糖微囊 质量评价 药物动力学【英文关键词】Doxycycline hyclate Chitosan microcapsules Qu
23、ality evaluation Pharmacokinetic【目录】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摘要4-6ABSTRACT6-8英文缩写词表9-12第一章 文献综述12-291. 微囊研究进展及在药物新制剂研发中的应用12-181.1. 微囊的定义121.2. 药物微囊化的优点及其应用12-131.3. 微囊的制备方法13-161.4. 药物微囊化的应用16-171.5. 微囊化技术存在的问题及发展方向17-182. 壳聚糖及其在药物传递系统中的应用18-232.1. 壳聚糖的性质18-192.2. 壳聚糖在药物传递系统中的应用19-212.3. 壳聚糖微囊的制备
24、研究21-222.4. 壳聚糖微囊存在的问题及应用前景22-233. 盐酸多西环素研究进展23-293.1. 理化性质233.2. 盐酸多西环素药效学研究进展23-243.3. 盐酸多西环素的耐药性243.4. 盐酸多西环素药动学研究24-263.5. 盐酸多西环素毒副作用相关研究263.6. 盐酸多西环素新制剂研究26-29第二章 选题背景和研究目的与意义29-311. 选题背景29-302. 研究目的与意义30-31第三章 盐酸多西环素壳聚糖微囊的制备31-391. 实验材料311.1. 仪器311.2. 试剂312. 实验方法31-332.1. 盐酸多西环素壳聚糖微囊的制备312.2.
25、单因素考察实验31-322.3. 正交实验设计32-332.4. 最佳处方工艺验证333. 结果与分析33-363.1. 单因素实验结果33-353.2. 正交实验结果35-363.3. 最佳处方验证结果364. 讨论分析36-385. 小结38-39第四章 盐酸多西环素壳聚糖微囊的理化性质研究39-521. 实验材料391.1. 仪器391.2. 试剂392. 实验方法39-422.1. 微囊形态及粒径分布392.2. 盐酸多西环素含量测定方法的确立39-402.3. 载药量及包封率测定40-412.4. 药物释放度测定412.5. 微囊稳定性考察41-423. 结果42-493.1. 外观
26、形态423.2. 粒径分布42-433.3. 含量测定43-463.4. 体外释放度463.5. 稳定性考察结果46-494. 讨论分析49-505. 小结50-52第五章 盐酸多西环素壳聚糖微囊在家兔体内的52-621. 实验材料521.1. 实验动物及试剂521.2. 仪器522. 实验方法52-542.1. 给药剂量52-532.2. 溶液的配制532.3. 给药及血样采集532.4. 血浆样品处理532.5. 血浆中盐酸多西环素含量测定方法的建立53-542.6. 数据处理543. 结果与分析54-593.1 方法专属性54-553.2. 标准曲线55-563.3. 精密度及回收率实验结果563.4. 药动学结果56-594. 讨论分析59-605. 小结60-62第六章 结论与创新62-631. 结论622. 创新62-63参考文献63-70致谢70
