【作者】 陈束叶；

【导师】 李铜铃；

【作者基本信息】 四川大学 ， 药剂学， 2007， 硕士

【摘要】 盐酸帕罗西汀（PX）是新型的5-羟色氨再摄取阻滞剂类（SSRI）抗抑郁药，比传统的三环类、单胺氧化酶抑制剂类抗抑郁药具有更强的选择性和更少的不良反应，PX的机体耐受性好，治疗指数高，能够用于多种精神疾病的治疗。PX能够有效改善各种强迫症（OCD）、广泛性焦虑症（GAD）、惊恐障碍、社交障碍、创伤后应激障碍（PTSD）等，尤其值得一提的是，PX是唯一一个被美国FDA批准作为治疗GAD的SSRI类药物，其2003年9月上市的控释片是第一个用做治疗妇女经前恐惧症（PMDD）的缓控释制剂。此外，在戒毒治疗、男性早泄治疗、功能性胃肠道失调的治疗方面，PX都有广泛的应用。普通的PX片经口服后存在明显的首过效应，体内代谢呈现非线性特征，连续服用达到稳态后，血药浓度及半衰期在个体间差异非常显著，尤其在老年患者中，药物代谢明显变慢．往往出现较年轻者更高的血药浓度，所以该药的使用需要根据不同个体调整使用剂量。本课题从PX吸收机理的研究入手，根据吸收特征指导制剂研制。建立了大鼠原位灌注模型研究PX的吸收行为，并对模型的影响因素进评价和控制，对所得到的数据经统计分析，确保了最终结果的准确性。从PX在胃肠道的吸收特征可知，PX在胃中基本无吸收，在0．94、2．82、9．42 mg·kg^-1给药剂量下，每小时胃吸收PX的平均吸收百分率分别为：3．20％、3．85％和1．77％；PX在小肠、结肠部位有广泛吸收，且吸收过程为被动转运，在0．94、2．82、9．42 mg·kg^-1给药剂量下，十二指肠肠、空肠、回肠、结肠的吸收速率分别为：0．599，0．605，0．616，0．590；0．608，0．632，0．590，0．607和0．601，0．579，0．632，0．625 h^-1，各部位吸收PX的速度无显著性差异。根据PX吸收特征结合体内代谢特点，最终确定研制小规格的快速释放片剂。随后对辅料进行筛选，选择了亲水辅料为主的处方R21，并进一步研究了生产工艺，评价了压力、筛号等因素对产品质量的影响，最终得到了比较简便的PX片生产工艺，并制备了三批中试样品。为了进一步评价制剂的质量、调整合适的处方、选择包装贮存的条件，对所研制的PX片进行了质量和稳定性的评价。所建立的HPLC法采用ODS柱分析PX片的含量和杂质，操作简便、检测成本低，经过验证，该法准确可靠，灵敏度高。从对三批样品的质量评价结果可知，所研制的PX片质量均符合要求。影响因素实验结果提示该品需要避光密封保存。加速实验及18个月长期留样考察结果提示，该品稳定性较好，含量和杂质均符合要求。本课题所研制的PX片还需要进一步评价其临床疗效和体内生物利用度，考察本品相比市售片是否具有更小的首过代谢率和更高的体内生物利用度。该部分工作将在本品取得国家临床批件后开展。更多还原

【Abstract】 Paroxetine hydrochloride （PX） is a new type of SSRI depressant, which is more selective than traditional TCAs and MAOIs and has fewer side-effects. PX is safe and effective in treating various mental disorders, including depression, obsessivecompulsive disorder （OCD）, generalized anxiety disorder （GAD）, panic disorder （PD）, social phobia, and posttraumatic stress disorder （PTSD）. Compared to other SSIRs, PX is the only one permitted for GAD treatment by US.FDA. In the year 2003, a new PX-CR tablet was licenced by US.FDA for controlling women premenstrual dysphoric disorder （PMDD）. Besides, PX is variously used for treatment of premature ejaculation, drug addiction and functional dyspepsia.In the pharmacokinetics process, PX is characterized by the first pass metabolism in the liver after oral administration in vivo. The metabolism process is nonlinear and variable among different people. It is validated that both average plasma concentration and the elimination half life at steady state after multi-doses administration varied greatly among different people, especially in elderly people. Therefore, dose adjustment is necessary.Considering PX pharmacokinetics, this research begins with the study of PX absorption mechanism, in which an in situ method is performed and evaluated. From the study we can come to the conclusion that PX is passively absorbed in rats and this absorption process complied with first-order regulation mechanism, under the dosage of 0.94、2.82、9.42 mg·kg^-1, PX is poorly absorbed in stomach with the average absorption rate are 3.20%、3.85% and 1.77% per hour, and well absorbed in all intestine segments with the average absorption rate constant K_a, of 0.599、0.608 and 0.601 h^-1 in duodenum, 0.605、0.632 and 0.579 h^-1 in jejunum, 0.616、0.590 and 0.632 h^-1 in ileum and 0.590, 0.607 and 0.625 h^-1 in colon respectively, and there is no evidence that showed the difference in absorption rate among different intestine segments under the dosage range of 10-100 mg·d^-1.According to this result we then developed one kind of fast-releasing tablet, and prepared three batches of PX tablets for further study. The development focused on the PX-excipient compatibility test and dissolution behavior. Finally it is decided that R21 is chosen as the formula to prepare PX tablet.In the following study, we developed a simple, precise and reliable HPLC method for content, impurity and dissolution determination of PX tablets. The relative factors influence tests indicated that light may have some influence on the stability of PX, so tablets need to be well sealed under opacity cover. The examination results of 3 batches of PX tablets showed that they were qualified and constant in 18 months.The further study of clinical evaluation will be performed after the permission of SFDA.更多还原