【作者】 郑启兰；

【导师】 潘卫三；

【作者基本信息】 沈阳药科大学 ， 药剂学， 2003， 硕士

【摘要】 本文主要研究了难溶性药物盐酸尼卡地平双层渗透泵控释片的处方工艺、生物利用度及其体内外相关性，并对该药的单室单层渗透泵控释片的处方及工艺进行了初步考察。 在对盐酸尼卡地平双层渗透泵控释片处方工艺研究时，先以12小时累积释放百分量和释放线性相关系数r为考察指标，对各因素（片芯和衣膜处方、相关工艺以及体外释药条件）进行单因素考察，选出显著影响因素，然后以3、8和12小时的累积释放百分量F₃，F₈和F₁₂为考察指标，经多元逐步回归后，用L₉（3⁴）表对处方进行正交设计，筛选最优处方。研究结果表明：盐酸尼卡地平双层渗透泵控释片体外12小时内累积释放百分量大于80％，16小时内释药完全（＞90％），12小时内零级释放特征明显（r=0.9994）；盐酸尼卡地平单室单层渗透泵控释片体外12小时内累积释放百分量达77.6％，12小时内零级释放特征明显（r=0.9900），但16小时内的最终释放百分量小于90％（释放不完全）。 在进行盐酸尼卡地平双层渗透泵控释片体内药代动力学研究时，选用市售普通片为参比制剂，以6只健康家犬为试验对象，一次口服相同剂量进行生物利用度和体内外相关性考察。采用HPLC法对血药浓度进行测定，控释片和普通片的T_max分别为7.0±1.6h和1.2±0.4h；C_max分别为49.3±7.2ng／ml和139.6±10.5ng／ml；t_1/2分别8.6±1.3h和2.3±0.4h；k_e分别为0.08±0.01h^-1和0.3±0.1 h^-1；AUC_0→∞分别为1016.3±66.9 ng·h／ml和921.3±16.0ng·h／ml。控释片的相对生物利用度为110.3％；体内外相关性良好（r为0.9900）。 本文的研究结果表明：以聚氧乙烯为主要辅料，用醋酸纤维素包衣制成的盐酸尼卡地平双层渗透泵控释片具有明显的控释作用。更多还原

【Abstract】 This paper is mainly researching on the recipe, technique, bioavailability and in vitro-in vivo correlation of insoluble nicardipine hydrochloride’ s bi-layer osmotic pump tablets; a preliminary research on the recipe of the said drug’ s mono-layer osmotic pump tablets has also been involved.While researching on the recipe and technique of the bi-layer osmotic pump tablets, first , we used the cumulative release amount within 12 hours and the linear release to measure the influence of the factors (core of the tablets, membrane compositions, relative techniques and in vitro-in vivo release conditions) by single-factor analysis method, and selected the dominatingly influence factors. Second, we used 3 hours, 8 hours, 12 hours cumulative release amount F3, F8, F12 as the index to screen the best recipe with multivariable linear stepwise regressing analysis. Finally , we picked out optimized prescription by 34 factors-analysis orthogonal design. We found that the bi-layer osmotic tablets cumulatively released the drug more than 80% in 12 hours, and completely released the drug within 16 hours (>90%), owning obvious zero-order release characters(r=0. 9994) within 12 hours. While the mono-layer osmotic tablets cumulative releasedonly 77. 6% in 12 hours and the utmost release amount was below 90%( not completely release), with obvious zero-order release characters.While researching on the drug’ s in-vivo pharmacokinetics of the bi-layer osmotic pump tablets, we selected normal tablets as contrast preparation containing the same drug, 6 healthy dogs as test objects, to administrate in the same dose once and measured the bioavailability in vitro-in vivo correlation in plasma with HPLC. The results showed: Tmax of bi-layer osmotic tablet and normal tablet was 7.0±1.6h and 1.2±0.4h respectively; Cmax was 43. 3 ± 7. 2ng/ml and 139. 36 + 10. 5ng/ml; Tl/2 was 8.6=1.3 and 2.3 ±0.4h; Ke was 0.08 ± 0. 01h-1 and 0.3±0. 1h-1; AUC0- was 1016. 3 ± 66. 9ng. h/ml and 921. 3 ± 16. 0ng. h/ml respectively; the relative bioavailability was 110.3% with better in vitro-in vivo correlation (r=0. 9900).Conclusion: nicardipine hydrochloride bi-layer osmotic pump tablets had obvious in vitro-in vivo controlled release effect.更多还原