【作者】 万慧杰；

【导师】 唐星；

【作者基本信息】 沈阳药科大学 ， 药剂学， 2005， 硕士

【摘要】 氧氟沙星（ofloxacin）是第三代氟诺酮类合成抗菌药，具有抗菌谱广、抗菌活性强、口服吸收完全、体内分布广、生物利用度高的特点，自应用于临床以来取得了令人满意的疗效。但随着应用的广泛，各种不良反应屡见报道，有些反应较严重，因此制备一种更为安全有效的制剂一直为人们所关注。据文献报道，氧氟沙星有效抑菌浓度低，对多数致病菌的MIC₉₀在1μg·mL^-1内，这一特点使缓释制剂的应用成为可能。因此制备一种更为安全有效的制剂十分必要。本文以减少副作用，针对治疗尿路感染为目的，研制了氧氟沙星缓释微丸 采用HPLC法进行微丸中药物的含量测定，UV法对释放度进行测定，HPLC法和UV法对大鼠肠吸收药物进行测定，建立了紫外高效液相色谱法测定血药浓度 处方前研究表明：氧氟沙星在水及各种生理范围内的介质中溶解度低（除在人工胃液中约为40.7mg／ml外，其他pH＞4.5介质均小于5mg／ml），油／水分配系数有显著的pH的依赖性。 采用大鼠在体灌流方案，通过不同肠段的结扎对氧氟沙星的吸收部位和吸收动力学进行实验研究。在2.0～10.0μg·mL^-1浓度范围内吸收量与浓度呈线性关系，无高浓度饱和现象，K_a值基本保持不变；在pH5.5至pH7.4范围内吸收受pH影响；各肠段的吸收速度常数有显著性差异，十二指肠、空肠、回肠的吸收速率常数分别为0.0544h^-1，0.0368h^-1，0.0032h^-1，在结肠几乎末检测到吸收。氧氟沙星吸收机制为被动转运，在小肠内的吸收呈现一级动力学特征。最佳吸收部位在十二指肠和空肠。 用离心造粒法制备氧氟沙星缓冲型和非缓冲型两种微丸，采用粉末层积法进行实验。以MCC与糖乳（1.5：1）为稀释剂，缓冲型和非缓冲型氧氟沙星微丸主药含量分别为70％、75％时易于操作。微丸目标粒径在18～24目之间。 采用流化床悬浮包衣法对氧氟沙星微丸进行缓释包衣。单因素考察最终确定pH依赖型氧氟沙星微丸的包衣液的处方组成和包衣工艺。包衣液采用Eudragit NE30 D与Eudragit L30D-55（1：8），包衣增重为4％，老化时间为24小时，增塑剂（PEG）、抗粘剂滑石粉及抗静电剂（SDS）分别占包衣聚合物量的20％、30％、0.15％。老化时间为24小时，释药机制研究表明：氧氟沙星pH依赖型缓释微丸释药符合一级动更多还原

【Abstract】 Ofloxacin,the third generation Fluoquinolone antimicrobial agent , has showed excellent antibacterial activity against gram negative and gram negative bacteria in vitro and in vivo.It is well absorbed when given orally,and moreover, it has a wide ditribution as well as a high absolute bioavailability.But along with the widely using in clinic practice,many side effect occurrence were reported frequently ,hence,a safer and more effective agent are indispensable to suferer . It was reported that Ofloxacin exhibits minimal inhibitory concentrations （MIC’s） of <1mg/Ml,which suggest the possibility of preparation the sustained-released pellets. The purpose of the present study was designed to develop a kind of Ofloxacin sustained -release pellets which would decrease adverse effects and focus on urinary tract infection and which would be more convenient for urinary tract infection patients to use.HPLC method was utilized to determine the ofloxacin content in pellets, UV method for assaying release of ofloxacin sustained- release capsules. HPLC and UV methods were developed to analyze the intestinal absorption of ofloxacin in rats. The HPLC method was established to monitor the plasma and urine level in vivo.The preformulation results showed that ofloxacin’s solubility in self-made gastric juice is 40.7mg/ml and sparingly soluble in various physiological pH fluids（>4.5）and the octanol/water partition coefficients increase with pH rising in various physiological pH fluids exhibiting pH-dependent characteristicThe absorption sites and the absorption kinetics were studied from various intestinal segments ligation using in situ perfusion method in rats. The research demonstrated that ofloxacin was poorly absorbed in intestine in general and mostly absorbed in the upper and middle small intestine. When the concentration was raised from 2.0 to 10.0μg·mL^-1, the uptake of ofloxacin increased and no saturation phenomenon occurred, whereas the absorption rate constant kept at a same level. The absorption of ofloxacin was influenced by pH value between pH 5.5 and pH 7.4. There were significant differences among the absorption rate constants in the varied intestinal segments. The absorption rate constants (h^-1) of duodenum, jejunum and ileum per 10cm were 0.0544 h^-1, 0.0368 h^-1,更多还原