塞来昔布微丸的研究

发布时间：2018-11-04 18:15

【摘要】：塞来昔布是COX-2酶选择性抑制剂,有很强的特异性。塞来昔布目前用于治疗关节炎、风湿性关节炎等,具有广阔的市场前景。塞来昔布的水溶性差,在使用过程中存在释放不均匀的现象,溶出是其体内吸收的限速步骤,进而导致药物生物利用度低且吸收差异较大。因此本论文希望通过改变剂型来改变塞来昔布在体内的生物利用度。微丸制剂丸心径较小,不受胃肠道转运规律及消化道消化规律运输节律的影响,给药系统在体内吸收的个体间差异性小,吸收动力学重现性好,生物利用度高,所以微丸制剂为代表的多单元型给药系统(multiple-unit drug delivery system)以其特有的优越性,逐渐成为目前缓控释制剂的研究热点之一,也成为本篇论文所研究的主要内容。本论文研究了塞来昔布速释及缓释膜控微丸处方以及包衣锅造粒法制备塞来昔布速释、缓释微丸的制备工艺。最终确定塞来昔布速释微丸以羟丙甲基纤维素(HPMC)为速释包衣膜,塞来昔布缓释膜控微丸以丙烯酸树脂为缓释包衣材料。通过考察表面活性剂的浓度、溶出介质的pH、以及搅桨速度对塞来昔布速释、缓释微丸的释放度的影响,确定塞来昔布速释、缓释微丸的最佳溶出条件为0.5%十二烷基硫酸钠的水溶液,搅桨速度为50转。其中缓释微丸的释放机制符合Higuchi方程,为扩散与骨架溶蚀双重机制,且以扩散为主。除此之外还对塞来昔布速释及缓释微丸的稳定性进行了初步的研究,实验结果表明:塞来昔布速释、缓释微丸在强光照、高温、高湿下均稳定;加速试验结果表明样品在6个月内未发生明显变化。通过塞来昔布速释、缓释微丸的药动学的初步研究,确定速释、缓释微丸的药动学参数。速释微丸:t1/2为6h左右;Tmax为3h左右;Cmax为0.7mg/L(100mg/kg)、1.4mg/L(200mg/kg)、2.8mg/L(400mg/kg),缓释微丸:t1/2为4h左右;Tmax为8h左右;Cmax为1.4mg/L(100mg/kg)、2.8mg/L(200mg/kg)、5.6mg/L(400mg/kg)。绘制了药时曲线。
[Abstract]:Celecoxib is a selective inhibitor of COX-2 and has strong specificity. Celecoxib is currently used in the treatment of arthritis, rheumatoid arthritis and so on, with broad market prospects. The water solubility of celecoxib is poor, and there is a phenomenon of uneven release in the process of use. Dissolution is the speed limiting step of its absorption in vivo, which leads to low bioavailability and great difference in absorption. Therefore, we hope to change the bioavailability of celecoxib in vivo by changing the dosage form. The heart diameter of pellets was small and not affected by the laws of gastrointestinal tract transport and digestive tract digestion. The drug delivery system had little difference in individual absorption in vivo, good reproducibility of absorption kinetics and high bioavailability. Therefore, the multi-unit drug delivery system (multiple-unit drug delivery system) represented by pellets has gradually become one of the research hotspots of slow and controlled release preparations, and has become the main content of this paper. In this paper, the formulation of celecoxib rapid release and sustained-release film controlled pellets and the preparation of celecoxib rapid release pellets and sustained-release pellets were studied. Finally, it was determined that celecoxib rapid release pellets were coated with hydroxypropylcellulose (HPMC) and celecoxib sustained-release film controlled pellets with acrylic resin as the coating material. The effects of the concentration of surfactant, the pH, of dissolution medium and the speed of paddle on the release of celecoxib and sustained-release pellets were investigated to determine the rapid release of celecoxib. The optimum dissolution conditions of the pellets were 0.5% sodium dodecyl sulfate aqueous solution and 50 rotations of agitating speed. The release mechanism of sustained-release pellets accords with the Higuchi equation, which is the dual mechanism of diffusion and skeleton dissolution, and diffusion is the main mechanism. In addition, the stability of celecoxib rapid release and sustained release pellets was studied. The results showed that celecoxib rapid release and sustained release pellets were stable under strong light, high temperature and high humidity. The accelerated test results showed that the sample did not change significantly within 6 months. The pharmacokinetic parameters of celecoxib and sustained-release pellets were determined by the preliminary study of pharmacokinetics of Celecoxib and sustained-release pellets. Rapid release pellets: t 1 / 2 is about 6 h, Tmax is about 3 h, Cmax is 0.7mg/L (100mg/kg), 1.4mg/L (200mg/kg), 2.8mg/L (400mg/kg), sustained release pellets: t 1 / 2 is about 4 h, Tmax is about 8 h; Cmax is 1.4mg/L (100mg/kg), 2.8mg/L (200mg/kg), 5.6mg/L (400mg/kg). The drug time curve was drawn.
【学位授予单位】：辽宁大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943

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