【作者】 张洁；

【导师】 李铜铃；

【作者基本信息】 四川大学 ， 药剂学， 2007， 硕士

【摘要】 本课题的目的是以生物药剂学理论为指导，研制以NZTD为主药，能在体内缓慢释放12h的胃滞留型缓释片。研究药物在胃肠道的吸收速率和吸收动力学可以为口服制剂的研制提供理论指导，所以在研制处方之前，建立了NZTD在大鼠胃肠道的原位灌注模型，对NZTD吸收动力学进行研究。分别建立了测定胃灌注液中NZTD浓度以及同时测定肠灌注液中NZTD和酚红浓度的高效液相色谱方法。对NZTD大鼠胃肠道吸收动力学研究的结果表明：NZTD在大鼠胃中吸收较好(高、中、低三个浓度的灌注液2h的平均吸收百分率为80.9±4.46％，在小肠各段都有吸收只是吸收较差。结合NZTD人体药物动力学数据(T_max约为1.2 h，T_1／2约为2h)以及NZTD普通片剂的临床给药方案(300 mg·d^-1或150 mg，b．i．d．ort．i．d．)，考虑将其制成能够缓慢释放12h的胃滞留型缓释片，以达到减小血药浓度波动，提高患者用药顺应性的目的。初步建立了NZTD缓释片释放度的高效液相色谱测定方法，以释放度、颗粒流动性和片剂外观为指标，对NZTD缓释片进行处方工艺筛选。在基本处方的基础上选择主要骨架材料种类及用量，加入一定比例的崩解剂和表面活性剂以调整NZTD缓释片的释放行为，最终得到优化处方。按选定处方制备三批样品，测定释放度，结果表明：本课题研制的NZTD缓释片体外释放具有较好的重现性和均一性，体外释药特征符合缓释制剂的设计要求。在NZTD缓释片的质量评价研究中，建立了NZTD缓释片的鉴别方法；确定了缓释片中NZTD的HPLC含量测定方法，并建立了NZTD缓释片的释放度测定方法，并把2、6、10小时的释放度限度初步定为标示量的20～30％、55～65％、80％以上；建立了NZTD缓释片有关物质的检查方法。对NZTD缓释片质量评价研究结果表明，NZTD缓释片质量研究方法科学合理，NZTD缓释片质量可控。同时对NZTD缓释片体外释放规律进行研究。研究结果表明：Higuchi模型为最佳拟合模型，Ritger-Peppas方程释放参数n=0.7529，0.45＜n＜0.89，说明NZTD缓释片中NZTD的释放机制是扩散和骨架溶蚀协同作用的结果。稳定性影响因素实验表明，NZTD缓释片在光照条件下稳定，在高温和高湿条件下不稳定。在高温条件下，缓释片的外观、有关物质检查、释放度和含量测定均产生明显改变；在高湿条件下，NZTD缓释片的部分检查项目的检查结果发生了改变。提示NZTD缓释片成品应采用防潮包装，置阴凉干燥处保存。本课题在生物药剂学理论的指导下，以NZTD的胃肠道吸收特征为基础进行制剂研制，减少了制剂开发的盲目性。本课题的研究结果为今后NZTD其它剂型设计的处方工艺、质量评价、稳定性研究等方面提供参考。更多还原

【Abstract】 The objective of this study was to develop NZTD gastric retention sustained-release tablet which could steadily release drug in 12 hours in vivo, under the direction of biopharmaceutics.Absorption kinetics of NZTD was studied by method of in situ perfusion of rat before NZTD formulation developed because the preparation of oral formulation could be guided by absorption rate and kinetics. HPLC methods were established respectively to determine the concentration of NZTD in gastric juice and the concentration of NZTD and phenolsulfnphthalein in the intestinal perfusate. The result indicates that NZTD can be well absorbed in stomach of rat and the average absoption rate of high, middle and low dose in 2 hours is 80.9±4.46%, and the absorption of NZTD in intestine of rat is poor. Considering of the pharmacokinetics data of NZTD(T_max is about 1.2h , T_1/2 is about 2h) and its clinical dosage regimen (300 mg·d^-1 or 150 mg, b.i.d, or t.i.d.), we prepared to design its sustained-release formulation, in order to diminish the fluctuation of blood concentration of NZTD and elevate the compliance of patients.The HPLC method was established for the content determination of NZTD in the NZTD sustained-release tablet. The formulation and preparation technology was filtrated by the index of dissolution, granule fluidity and appearance of tablet. Based on the basic formulation , the type and usage amount of main backbone materials was chosen and a certain proportion of disintegrating agent and surfactant was added to adjust the dissolution behavior of the sustained-release tablet. The dissolution profile of 3 bathes of tablet indicate that the dissolution of NZTD sustained-release tablet had well reproducibility and homogenicity and accorded with demond of sustained-release formulation.The identification methods and the HPLC method for the content determination of NZTD were set up in the quality study of the NZTD sustained-release tablet. The dissolution rate at 2 h, 6 h, 10 h was 20～30%、55～65% and above 80% respectively in regulation . The examining method of the correlated material was founded. The studying results according to items of the quality evaluating showed the evaluating method was reasonable and the quality of the NZTD sustained-release tablet was under the control. The release mechanism was studied, the Higuchi equation was the best one. The release parameter of n of Ritger-Peppas equation equals to 0.7529,0.45＜n＜0.89, it means that the release mechanism is the synergism of diffusion and matrix erosion.The stability showed that light had not abvious effect on the NZTD sustained-release tablet but high temperature and high humidity influenced its stability. The result suggested that it should be packed in moistureproof material and stored in dry, cool and shady place.The NZTD sustained-release tablet was prepared based on the absorption kinetics of NZTD in stomach and intestine under the direction of biopharmaceutics. The research result of this study could to be reference of the other dosage form of NZTD.更多还原