法莫替丁口服脉冲控释微丸的研究

【作者】 张莉；

【导师】 陈大为；

【作者基本信息】 沈阳药科大学 ， 药剂学， 2001， 硕士

【摘要】 随着时间生物学的发展，人们认识到人体的许多生理现象如血压、心率、肾功能、胃酸分泌以及某些疾病如高血压、哮喘、风湿性关节炎等均具有节律性。定时给药系统可以根据人体需要释放药物，通过按需给药达到最佳疗效。本文以法莫替丁为模型药物，根据人体在晚间21：00～22：00间胃酸分泌达高峰的生理节律，制备了日服一次，释药两次的法莫替丁脉冲控释微丸胶囊剂。 建立了紫外分光光度法用于法莫替丁的制剂含量、释放度及基本性质的测定。对与处方设计密切相关的原料药的一些性质进行了考察。由所测表观油/水分配系数结果可知，法莫替丁脂溶性很小，故在文献报道的基础上，采用固相萃取的方法提取血样中的法莫替丁，建立了高效液相色谱法检测体内血药浓度，此法灵敏度高、专属性强、绝对回收率较高。 采用大鼠在体回流实验方法研究了法莫替丁在肠道的吸收情况。其于十二指肠、空肠、回肠和结肠的吸收速率常数分别为0.0541h^-1，0.0518h^-1，0.0500h^-1，0.0467h^-1，各值间无明显差别；并初步推断法莫替丁在大鼠体内主要以被动扩散方式吸收。故制成定时释放制剂是可行的。 本制剂分为两部分。速释微丸由挤出滚圆造粒机直接制得，本文对其工艺进行了优化。定时释放微丸制剂采用有机酸诱导机制，即在丸芯中加入有机酸，外层用水不溶性膜材进行包衣。丸芯亦由挤出滚圆法制得，微丸的包衣采用微型流化床包衣机，本文对其工艺进行了考察。由于定时释放微丸的释药行为由丸芯中有机酸与外层衣膜共同决定，故处方设计需同时兼顾这两方面。在单因素考察的基础上，应用L₉（3⁴）正交设计试验优化处方，筛选出了符合要求的定时释放微丸制剂。将速释微丸与定时释放微丸按剂量混合后装入胶囊，制成了可释 沈阳药科大学硕士学位论文 摘要 药两次的法莫替丁脉冲控释微丸制剂。 本文对法莫替丁定时释放微丸的释药动力学进行了研究，其体外 释放行为符合零级动力学过程。包衣小丸属膜控型释药系统，释药机 制是通过连续膜的溶解／扩散和通过水性通道的扩散共同起作用。定时 释放微丸为有机酸诱导型给药系统，其体外溶出曲线为典型的“ S”型 曲线，即药物在初期一段时间内不释放，之后再快速释放出来。本文上 通过大量实验对产生此种释药行为的机理进行了探讨。 本文以普通片为对照，利用HPLC法分别测定了三名健康受试者 口服法莫替丁定时释放微丸胶囊剂与脉冲控释微丸胶囊剂的药时曲线 并计算了药动学参数和相对生物利用度。定时释药微丸的时滞显著增 加，达峰时间明显滞后，说明其在体内具有显著的定时释放作用，相 对生物利用度为95．22％。脉冲控释微丸胶囊剂的药时曲线出现双峰（第 一次为速释微丸所致，第二次为定时释放微丸所致），达峰时间分别 为1．sh及12h，达峰浓度分另为82．1及44．3ng／ml，相对生物禾用度为 93．83％。体内外相关性结果表明，定时释放微丸胶囊剂的体外释放百 分率与体内吸收百分率间具有较好的相关性O＝0．9869卜更多还原

【Abstract】 With the development of chronobiology ,it is realized that many physiological phenomena such as blood pressure ,heart-beating rate, gastric acid secretion and many disease symptoms such as hypertension, asthma, rheumatic arthritis exhibit circadian rhythms. Time-controlled delivery system releases drug and achieves an effective drug level at the required time so that optimum therapy can be obtained.According to the fact that gastric acid secretion reaches its climax at 21:00?2:00 in the evening, we prepared an orally applicable time-controlled release capsule(TRC)using famotidine as the model drug, which was administered in the morning while reaching plasma concentration climax in the evening. At the same time, we prepared normal pellets which released drug immediately after administration. The two types of pellets were put into one capsule together in proportion in order to prepare famotidine pulsed release capsule(PRC)which released drug two times a day while being administered only once.Ultraviolet spectrophotomatry method was developed for assay during the study of physicochemical properties, content and drug release. Some physicochemical properties of famotidine were investigated, which were connected closely with phannaceutic form design. In order to increase extraction recovery, we use solid phase extraction (SPE)to extract famotidine from human plasma. Precise and reliable HPLC method was developed for in vivo assay.To clarify the absorption of famotidine from gastrointestine, the absorption was studied by utilizing the rat intestinal absorption recirculating method in situ. No significant difference of value of Ka was absorbed among duodenum, jejunum, ileum and colon. The mechanism of intestinal absorption was studied with different drug concentrations, which suggested that the intestinal absorption of famotidine was via passive transport mechanism.The pharmaceutic form design was devided into two parts. Nomal pellets3ABSTRACTwere prepared by extrusion-spheronization. Time-controlled release pellets were 搊rganic acid-induced type drug delivery system? The core pellets, which contained organic acid, were prepared by extrusion-spheronization also and the coating process was performed on a mini-fluidized bed spray coater. Because the drug release behavior was dependent on both organic acid and the polymer, orthogonal design test was used to obtain optimal formulation. We also studied some factors which affected the release of the drug from the time-controlled release pellets.The release profile of TRC pellets in vitro complied with zero order kinetics. The coated pellets were film-controlled release sysf em. The organic acidinduced drug delivery system has a typical sigmodical release profile which achieved a prolonged lag time, followed by rapid release. We studied the drug release mechanism on the basis of lots of experiment results.Plasma concentration-time profiles in three healthy volunteers after oral administration of TRC, PRC and normal pellets were determined by HPLC and the pharinacokinetic parameters of the three types of formulations were calculated. The lag time of TRC was dramatically prolonged and t~ was obviously delayed, indicating that TRC had positive effect of time-controlled release system. The plasma concentration-time profiles of PRC had two peaks. T,~1 and tm~2 were 1.5h and 12h. Cmaxi and Cm~ were 82.1 ng/ml and 44.3 nglml. The comparative bioavailabiity were 95.22% and 93.83% .Obvious correlation (r=O.9869) existed between absorption fraction in vivo and the release percentage in vitro.更多还原