【作者】 卢哲；

【导师】 唐星；

【作者基本信息】 沈阳药科大学 ， 药剂学， 2005， 硕士

【摘要】 盐酸环丙沙星（Ciprofloxacin Hydrochloride）是第三代氟喹诺酮类合成抗菌药的优秀代表，具有抗菌谱广、抗菌活性强、口服吸收完全、体内分布广的特点，在临床应用中取得了令人满意的效果。但随着近年来该药的广泛应用，各种不良反应屡见报道，为进一步降低环丙沙星的不良反应发生率，使患者服用更加方便，提高患者的依从性，德国拜耳公司研制的每同一次的环丙沙星缓释片FDA已批准上市。该产品含有35％速释部分和65％缓释部分，其药效、药动学及临床研究结果表明环丙沙星缓释制剂与其普通制剂相比更加安全有效。本研究采用离心造粒法制备了盐酸环丙沙星微丸，作为速释丸；应用缓释包衣技术制备了盐酸环丙沙星缓释微丸，并重点对缓释微丸进行研究；最后将35％速释丸和65％缓释丸填充胶囊，组成一个剂量，制备了盐酸环丙沙星缓释胶囊。建立了紫外分光光度法测定盐酸环丙沙星的药物浓度，用于含量测定及释放度测定，经方法学验证，适用于本品的体外质量控制。测定了盐酸环丙沙星在0.1mol·L^-1HCl、1-1000ml HCl、pH4.5～7.4的缓冲液中的溶解度：pH＜5.5时盐酸环丙沙星的溶解度＞20mg·ml^-1；当pH接近等电点时，溶解度显著下降均＜2mg·ml^-1。测定了盐酸环丙沙星在正辛醇／介质系统的表观油／水分配系数为0.4～1.3。使用国产离心造粒机采用粉末层积法，以MCC、乳糖为稀释剂，水为润湿剂，制备了盐酸环丙沙星普通微丸；以MCC、乳糖为稀释剂，枸橼酸为缓冲剂，水为粘合剂制备了缓冲素丸（作为速释部分）。比较了两种微丸的溶出性质，结果表明不含枸橼酸的微丸在pH＞5.5的介质中溶出缓慢，而加入了缓冲剂的微丸在各种pH介质中释放无显著性差异，在0.5小时内均可溶出完全。测定了微丸的粉体学性质，目标粒径18～24目的微丸收率约90％，外观圆整，有较强的机械强度。用流化床悬浮包衣法对微丸进行缓释包衣。采用Eudragit NE30D／Eudragit L30D-55水分散体混合作为包衣材料，制备了pH依赖型缓释微丸（T1，作为缓释部分）；采用EudragitRL 30D，Eudragit RS 30D水分散体混合作为包衣材料，制备了非pH依赖型缓释微丸（T2）。对二种包衣微丸释放度的影响因素进行考察，确定了最佳包衣工艺和包衣液处方组成。结果表明：T1和T2体外释药具有明显的缓释特征，T1释放机制符合Higuchi方程，T2释放机制符合一级释药模型。建立了反相高效液相色谱法测定家犬血浆及人尿中盐酸环丙沙星浓度的方法；以市售普通片为参比，分别进行了T1在家犬及健康受试者体内的药动学和相对生物利用度研究，采用统计矩法对家犬血药浓度数据进行处理：pH依赖型缓释微丸T1及参比制剂的Cmax分别为（3.05±0.67）和（7.46±2.4）μg·ml^-1，Tmax为（6.00±0.0）和（2.50±0.55）h，MRT为（12.23±2.92）和（5.66±1.7）h，相对生物利用度Fr=（97.10±9.61）％，结果表明，T1有很好的缓释效果，和参比制剂生物等效；将35％速释丸和65％缓释丸（T1）填充胶囊，组成一个剂量，其人尿药浓度数据处理结果：受试制剂与参比制剂的（dxu／dt）max分别为（25.92±3.70）和（40.54±16.55）mg·h^-1，Tmax为（4.17±1.60）和（2.58±0.66）h，MRT为（9.65±1.58）和（7.75±1.62）h，相对生物利用度Fr=（101.04±11.36）％，结果表明，受试制剂具有缓释特征，在尿液中的浓度均高于参比制剂，且其尿药浓度是盐酸环丙沙星对大多数尿路感染致病菌的MIC₉₀的几十到几百倍，鉴于盐酸环丙沙星属浓度依赖型抗生素，其缓释制剂主要用于治疗尿路感染，因此盐酸环丙沙星缓释微丸与盐酸环丙沙星普通片相比，维持较高杀菌浓度时间更长，更为有效。更多还原

【Abstract】 Ciprofloxacin hydrochloride （CP） is representative of the third generation of fluoroquinolones. It is a broad spectrum antibacterial drug with high antibacterial activity. The absorption of CP after oral administration is rapid and the distribution is wide. The aim of this work was designed to develop a kind of CP sustained-release pellets which would reduce dosing frequency, narrow the fluctuation of blood concentration and be more convenient for patients to use.Ultraviolet spetrophotometry was developed for assaying the content in the preparation and drug release from CP sustained-release pellets. According to the solubility of CP determined in different medium. When pH<5.5 the solubility is >20mg·ml^-1, and when pH is near to the pKa, the solubility is <2mg·ml^-1. The apparent partition coefficient in n-octanol/medium system is 0.4-1.3.Two kinds of CP pellets were prepared in a centrifugal granulator. One was prepared with MCC, lactose as dilute agent and water as moistening agent by powder layer technology, the other （tested as immediate release pellet） was prepared with MCC, lactose as dilute agent, citric acid as buffer and water as moistening agent. The dissolution profile of the two kinds of pellets indicated the dissolution of the non-buffer pellet was much slower than the buffer pellet in mediums of 7.4 >pH>5.5. Powder property of the pellets included citric acid was determined and the yield of objective pellets （18-24 mesh cut） was about 90%.A fluid-bed spray processor was adopted for the coating of the buffer pellets. The pH-dependent sustained-release pellets （T1 tested as extended release pellet） were coated with a combination of Eudragit NE30D and Eudragit L30D-55. The non-pH-dependent sustained-release pellets （T2） were coated with a combination of Eudragit RL 30D and Eudragit RS 30D. The influence factors on the release of CP from T1 and T2 were investigated. The technology and formulation of T1 and T2 were optimized, respectively. The results demonstrated that two kinds of coated pellets showed obviously sustain-release effect, and the drug release profiles in vitro followed Higuchi（T1） and first-order kinetics （T2）.HPLC method was performed to detect the concentration of CP in plasma of dogs and in urine of healthy volunteers. The plasma concentration of CP in six dogs were tested after a single oral administration of T1 with commercial tablets as a reference preparation. C_max, T_max and MRT of T1 were （3.05±0.67）μg·mL^-1, （6.00±0.0）h, （12.23±2.92）h, respectively, and the relative bioavailability was （97.10±9.61）%. The results showed that T1 and commercial tablets were bioequivalent, The capsules filled with 35% immediate release pellets and 65% extended release pellets（T1） were of oral administration of six healthy volunteers. The urinary concentration of CP was tested: （dxu/dt）max=（25.92±3.70） mg·mL^-1, Tmax=（4.17±1.60）h, MRT=（9.65±1.58）h, and the relative bioavailability was （101.04±11.36）%, respectively. The results indicated this dosage form had an improved pharmaceutical quality, which might enhance its therapeutic profile.更多还原