【作者】 张国雨；

【导师】 金青；

【作者基本信息】 青岛科技大学 ， 药剂学， 2009， 硕士

【摘要】 盐酸小檗碱是广泛应用于畜牧业治疗胃肠炎、细菌性痢疾等疾病的广谱抗菌药,但其易溶于水,口服给药后生物利用度低,以普通注射剂型注射后药物代谢较快,需要频繁注射。本课题以脂质体为药物载体,将盐酸小檗碱制成缓释注射剂,以达到减少注射次数,保持血药浓度平稳,提高其生物利用度的目的。实验以空白脂质体的粒径及粒度分布为评价标准,对薄膜分散法、超声分散法、注入法、逆向蒸发法等常见的脂质体制备方法进行筛选,确定注入法为最优制备方法;以盐酸小檗碱脂质体的包封率为评价标准,对影响其质量的制备工艺参数进行正交优化,确定其最佳制备工艺:盐酸小檗碱溶液浓度为3.0mg/ml、水浴孵化温度为65℃,孵化时间为30min;建立了盐酸小檗碱缓释注射剂的质量标准,对多批盐酸小檗碱缓释注射剂进行质量考察,其脂质体平均粒径在250nm,包封率为83%~85%,两周后的渗漏率在1%左右,体外溶出2h、6h、12h后,溶出度分别为27.4%、59.9%和78.7%,具有缓释效果;对盐酸小檗碱缓释注射剂进行了加速试验和长期实验,结果表明盐酸小檗碱缓释注射剂在4℃±2℃下避光保存一年,其外观性状、PH、脂质体平均粒径基本不变,药物含量稳定;通过兔体实验对盐酸小檗碱缓释注射剂进行了药物代谢动力学的初步研究,结果盐酸小檗碱注射剂和盐酸小檗碱缓释注射剂的药物达峰时间分别为0.395h和3.06h,后者能在2～10小时内维持较稳定血药浓度,具有明显的缓释效果。本课题以注入法制备盐酸小檗碱脂质体,优化制备了盐酸小檗碱缓释注射剂,并对其稳定性进行考察,确立了贮存条件,建立了盐酸小檗碱缓释注射剂的质量标准,并初步研究了盐酸小檗碱缓释注射剂的药代动力学,为水溶性药物缓释注射剂的研究提供了可靠的理论依据。更多还原

【Abstract】 Berberine treatment is widely used in animal husbandry gastroenteritis, bacillary dysentery and other diseases of the broad-spectrum antimicrobial agents. Due to good solvency in water, its oral bioavailability is comparatively low. As ordinary injection, its obvious disadvantage was rapid drug metabolism. In order to improve the bioavailability, to maintain stable plasma concentration and to reduce the injection times, berberine hydrochlorid was made into sustained-release injections with liposomes as drug carriers.In this research, taking the particle size and particle size distribution of blank liposomes as standards for the evaluation of thin-film dispersion method, ultrasonic dispersion method, injection method, and reverse evaporation method, some common methods of preparation for liposomes were studied and assessed ,and injection method was regarded as the best excellent one;Taking liposome encapsulation efficiency of berberine hydrochloride as standards for the evaluation , parameters which could affect the quality of the preparation process were optimized with a orthogonal method. The best preparation process: the concentration of berberine hydrochloride solution was 3.0mg / ml, incubation temperature of water bath was 65℃, and incubation time was 30minutes; The quality standards of berberine hydrochloride sustained-release injection was established, multi-batch injection of berberine hydrochloride sustained-release quality were inspected, and its average particle size liposomes was in the 250nm , encapsulation efficiency was 83% ~ 85%, the leakage rate was about 1% after two weeks, the dissolutions in vitro after 2h, 6h and 12h dissolved were respectively 27.4%, 59.9% and 78.7%, with sustained-release effect; The acceleration test and long-term experiments were taken to inspect the sustained-release injection, results showed that berberine hydrochloride sustained-release injections were able to be preserved for one year in 4℃±2℃under the light, with the appearance of characters, PH , drug content and the average particle size of liposomes was basically unchanged; By the rabbit experiments on injection of berberine hydrochloride sustained-release to study the pharmacokinetics preliminarily, the results were that the peak time of the berberine hydrochloride injection and berberine sustained-release injection were 0.395h and 3.06h, and the latter could maintain a more stable blood concentration in 2 to 10 hours with a clear sustained-release effect .In this experiment, the berberine hydrochloride sustained-release injections were prepared by injection method of liposomes , and the preparation method for the injection was optimized with a orthogonal method, the stability of the injections was studied , the storage conditions were determined and the quality standards were established. Most of all, the preliminary study on the injection of berberine hydrochloride sustained-release pharmacokinetics provided a reliable theoretical basis.更多还原