【作者】 李继忠；

【导师】 潘卫三；

【作者基本信息】 沈阳药科大学 ， 药物制剂， 2008， 硕士

【摘要】 以可生物降解的高分子材料为载体，通过制剂新技术将药物制成微球、微囊、纳米粒、凝胶等剂型，用作缓控释注射剂的研究，是近年来药剂学研究的热点之一。长春西汀是一种有效的抗心脑血管病药物，极难溶，口服生物利用度约为7％左右。本文以其为模型药物，尝试了制备长春西汀原位凝胶及原位微球注射剂，以期达到延长药物的作用时间、减少用药次数和提高生物利用度的目的。本研究首先采用高效液相色谱法（HPLC法）建立了长春西汀原位凝胶和原位微球中药物的含量和释放度的测定。通过单因素考察试验，以药物含量和体外释放为依据筛选出长春西汀原位凝胶注射剂的较优处方。由于长春西汀原位微球变量较多，利用球面设计优化方法优化并得到长春西汀原位微球最优处方。释药机理的研究结果表明长春西汀原位凝胶和原位微球的释药过程符合药物扩散机制或药物扩散和骨架溶蚀协同作用的机制。稳定性的影响因素试验结果表明，长春西汀原位凝胶及原位微球对高温、高湿和光照均比较稳定；加速试验结果表明长春西汀原位凝胶及原位微球经过包装后稳定性良好。对自制长春西汀原位凝胶、原位微球和长春西汀苯甲酸卞酯溶液注射剂进行了家兔体内药动学研究，其体内分析方法采用HPLC法。结果表明：长春西汀原位凝胶、原位微球和苯甲酸卞酯溶液的T_max依次为2、4和1h；C_max依次为（410．5±76．8）、（2121．6±121．3）和（2757．1±172．9）ng·ml^-1；AUC_0-∞依次为（665．1±59．3）、（842．6±71．1）和（560．4±47．4）ng·d·ml^-1。以长春西汀溶液为参比制剂，原位凝胶和原位微球的相对生物利用度分别为17．6％和24．8％。采用Loo-Riegelman法计算，长春西汀原位凝胶的体内外相关性显著(df=23，0．597<r_1-0．001/2<0．652)；以长春西汀溶液的血药浓度数据为权函数，采用脱卷积法进行了长春西汀原位微球的体内外相关性评价，经检验相关性显著(df=30，r_{1-0．001／2}=0．554)。更多还原

【Abstract】 Using new technologies and biodegradable polymers to develop microshperes, nanoparticles and gel is one of the most promising area in pharmacy. Vinpocetine is a kind of effective drug for cerebrovascular disease. However, it is almost aqueous insoluble, which significantly restricts its bioavailability to 7%. In this paper, vinpocetine was used as the model drug to prepare in situ forming gel and microparticles, with the aim to prolong its action time, reduce the times of administration and enhance the bioavailability.In this paper, the HPLC method, which was suitable to detect vinpocetine in formulations, was firstly established. By single factor tests, the optimal formula of in situ forming gel was obtained. Because there were quite a few factors influencing the in situ forming microparticles, the spherical symmetric design-response surface methodology was utilized to optimize the formulation.The study on the drug release mechanism showed that the the releasing process was fitted to diffusion, or the synergism of diffusion and bulk erosion. The stability test indicated that both the in situ forming gel and microparticles were stable when exposed to high temperature, high humidity and light. The accelerated test showed that both the formulations were rather stable after package.The pharmacokinetics study on the prepared vinpocetine in situ forming gel, microparticles and BB solution was carried out with rabbits. The analytical procedure was based on HPLC method. The results revealed that the T_max,C_max and AUC_0-t of in situ gel, in situ microparticles and BB solution were 2h, 410.5±76.8 ng·ml^-1, 618.4±96.5 ng·d·ml^-1; 3h, 2121.6±121.3 ng·ml^-1, 813.6±71.6 ng·d·ml^-1; 1h, 2757.1±172.9 ng·ml^-1, 486.5±47.5 ng·d·ml^-1 respectively. Using vinpocetine BB solution as the reference, the bioavailability of the vinpocetine in situ forming gel and microparticles were 17.6% and 24.8%, respectively. Calculated with Loo-Riegelman method, the in vitro-in vivo correlation of vinpocetine in situ forming gel was significant(df=23, 0.597<r_1-0.001/2 <0.652). Based on the vinpocetine plasma concentration as the weight function, the in vitro-in vivo correlation of in situ forming microparticles was significant calculated with convolution(df=30, r_1-0.001/2=0.554).更多还原