基于扩散、溶胀和渗透泵机理的定时脉冲给药系统研究

【作者】 张彦；

【导师】 张志荣；

【作者基本信息】 四川大学 ， 药剂学， 2004， 博士

【摘要】 本文以哮喘的一线治疗药物硫酸特布他林为模型药物,研究制备了硫酸特布他林定时脉冲片,对其释药行为及释药机理进行了较为深入的探讨,并初步探索将该释药机理推广应用于制备其他药物的脉冲片。 哮喘是有明显节律性发作的疾病,夜间发作的几率是白天的100多倍,采用时辰治疗的需要十分迫切。因此,本文以药动学和药效学也具有时辰节律性的β₂受体激动剂硫酸特布他林为模型药物,采用多层包衣的方法研制了硫酸特布他林定时脉冲片。考察了片芯组成的多个因素,以及片芯中氯化钠用量、溶胀层厚度对于硫酸特布他林定时脉冲片释药行为的影响。稳定性试验结果表明,湿度对硫酸特布他林定时脉冲片的影响比较大,在强光、高热及加速试验条件下均稳定。 本文从膨胀动力学和吸水动力学角度较为深入地探讨了硫酸特布他林定时脉冲片的释药机理。脉冲片体外释药规律的考察结果表明:介质pH和搅拌速度对脉冲片的释药行为无影响,随释放介质渗透压升高,脉冲片的释药时滞延长,稳态释药速率降低。求算了水分在控释衣膜中的扩散系数,测定了脉冲片在释药过程中的体积变化及释药前后衣膜的变化,对脉冲片的释药过程、时滞的形成等问题作了合理的解释,并推测出脉冲片的释药机理包括:渗透泵机理、扩散机理和膨胀作用,其中渗透泵机理占主要地位。 以家犬为试验对象进行了药物动力学研究。建立了一种具有较高灵敏度和精密度的柱切换高效液相-紫外检测法测定血浆中硫酸特布他林的浓度。试验组给予时滞长、短不同的双脉冲片组,对照组给予普通片。借鉴不连续吸收药动学模型,建立了简化的双吸收部位药动更多还原

【Abstract】 Terbutaline pulsatile tablets were prepared in this research. Release behaviors and mechanism were investigated deeply. Furthermore, other three drugs were applied to prepare pulsatile tablets based on the same mechanism.Bronchial asthma is a disease with proven chronopathological rhythms. Since asthma attack is much more common during the night, especially 2:00-8:00 a.m., chronotherapeutical treatment of asthma is necessary. Terbutaline, a β2-agonist known to exhibit chronopharmacokinetic and chronopharmadynamic rhythms, was adopted as the model drug, and multi-layered pulsatile tablets were prepared. Effects of many factors on the release behavior of terbutaline pulsatile tablets were investigated. These factors include ingredients of core tablets, the amount of NaCl in the core tablets, coating level of swelling agent, etc. the results of stability tests indicated that terbutaline pulsatile tablets were stable under strong light, high temperature and accelerated conditions. However, pulsatile tablets were sensitive to humidity.The mechanism of drug release from this pulsatile system was investigated in virtue of the dynamics of swelling and water uptake. No significant difference in drug release behavior was observed for release study in media with different pH of under different rotation speed. With the increase of osmotic pressure of the dissolution medium, the lag time was prolonged and the drug release rate decreased. The diffusion coefficient of water in the outer coat was calculated. The increase oftablets volume and the change of outer membrane during the release study were examined. Logical explanations for drug release behavior and the lag time were given based on above results. It was indicated that diffusion, swelling and osmotic pumping mechanism were involved in drug release from pulsatile tablets, but the latter was more dominant.Pharmacokinetic study was carried out in six dogs. The dogs were administered, in a crossover design, either the immediate-release tablets containing terbutaline sulphate 30 mg (control group) or the pulsatile tablets with different lag-times (test group). A pharmacokinetic model for double sites GI absorption was built on the basis of multiple sites discontinuous GI absorption. The pharmacokinetic parameters of test group and control group were as follows: AUCo-m were (3275±431) h ? ng/ml and (1691±377) h ? ng/ml; and MRT were (14.6±0.6) h, and (5.2±0.6)h; Cmax of test group were (237.0 + 41.1) ng/ml and (219.8 + 55.0)ng/ml, while Cmax of control group was(332.2 + 126.4)ng/ml; Tmax of test group were (5.00±0.55) and (12.3 ±0.5)h, while Tmax of control group was (1.9±0.60) h; Tiagoftest group were (2.38±0.4) and (9.93 ± 1.1 )h, while Tiag of control group was( 0.21 +0.04 )h. results of ANOVA and two one-sided tests showed that they were bioequivalent, but significant difference was observed in Cmix. Also, significant difference was observed in Tmax, Tiag and MRT based on the results of paired t-test.Pulsatile tablets of other three drugs, including water soluble salbutamol, water insoluble ibuprofen and nifidipine, were prepared. The results of in-vitro release study showed that rotation speed and pH value of dissolution media have no effect on drug release behavior of the threekinds of pulsatile tablets. With the increase of osmotic pressure of the dissolution medium, the lag time was prolonged and the drug release rate decreased. The in-vitro release behaviors of the three kinds of pulsatile tablets were similar to terbtalline pulsatile tablets, indicating that combination of swelling, diffusion and osmotic pumping mechanism can be generally applicable to prepare pulsatile tablets. However, it should be paid attention to that the lag time of water soluble drug was longer than that of water insoluble drug at the same coating level, and steady released rate of water soluble drug was smaller that that of water insoluble drug.更多还原