非洛地平爆破型脉冲释放片的研究

发布时间：2018-05-20 23:12

  本文选题：非洛地平 + 脉冲给药系统　； 参考：《辽宁医学院》2014年硕士论文

【摘要】：目的 设计非洛地平脉冲释放片，通过均匀设计优化药物处方，使自制脉冲片能在预设时间爆破，并能有效快速释放药物。对自制脉冲片进行初步质量评价和稳定性考察。以大耳白兔为实验对象，建立非洛地平体内血药浓度测定方法，研究自制非洛地平爆破型脉冲释放片体内药动学和生物利用度。 方法 本研究在固定包衣工艺参数的条件下，对脉冲片释药行为有影响的因素进行考察如：片芯组成，包衣膜处方、体外释药条件、辅料等；筛选对非洛地平爆破型脉冲释放片释药行为有影响的膨胀剂、致孔剂、增塑剂等辅料。根据脉冲片药物释放10%所需时间为指标判定不同因素对脉冲片释放药物的影响。优化处方工艺采用均匀设计法优化。对自制片剂进行释放均一性、含量及均匀度进行测定，有关物质进行检查；考察样品稳定性。以市售非洛地平缓释片为参比制剂，自制脉冲片为受试制剂。参考有关文献及实践经验，建立非洛地平血药浓度测定方法，6只健康日本大耳白兔采用两制剂、双周期交叉设计单次空腹服用自制非洛地平脉冲片（规格：含药量5mg）和市售非洛地平缓释片（规格：含药量5mg）；采用HPLC法测定各时间点血药浓度，绘制体内药时曲线；根据各时间点血药浓度计算相关药动学参数。 结果 经过单因素考察及均匀设计优化得到最佳处方，片芯中膨胀剂为低取代羟丙基纤维素(L-HPC),含量占片芯重10%；包衣液中增塑剂为邻苯二甲酸二丁酯(DBP)，含量为8.5%(占EC的量)，致孔剂为PEG6000，含量为7%(占EC的量)；通过体外释放试验，制备的脉冲片，时滞为(4.1±0.2) h，在时滞后(1.5±0.2) h内，药物释放累积释药达到90%以上。大耳白兔口服给药后，测定其血药浓度，计算药动学参数。参比制剂与受试制剂主要药动学参数分别为：Tmax(3.50±0.547) h，(5.667±0.516) h；Cmax(51.23±5.12) ng·mL-1,（67.865±3.810）ng·mL-1；AUC0~48(351.161±42.052) ng·h·mL-1,(382.453±31.82)ng·h·mL-1;AUC0-∞(370.051±44.082)ng·h·mL-1，(409.524±18.024) ng·h·mL-1，相对生物利用度为(110.35±10.14)%，统计矩计算两种制剂平均滞留时间MRT(15.307±1.43)h与(13.488±1.63) h。 结论 非洛地平爆破型脉冲片制备工艺简单，，优化后处方达到4h爆破设计要求，并具有良好的释药行为。自制样品释放均一性良好，含量及均匀度、有关物质检查符合药典规定。自制脉冲释放片与参比制剂的药动学参数Cmax、Tmax、AUC0~48经生物等效性分析均存在显著性差异(P＜0.05)。本实验制备的脉冲片Tmax显著延迟，Cmax显著升高,根据体内药动学实验结果，初步判断自制非洛地平爆破型脉冲释放片，在体内延迟释药，具有明显的时滞及脉冲释药特点，有效提高非洛地平生物利用度，达到了实验预期的设计目的，为临床治疗与研究高血压给药方案提供有效参考。
[Abstract]:Purpose Felodipine pulse release tablets were designed and optimized by uniform design so that the self-made pulse tablets could burst at a preset time and release drugs quickly and effectively. The quality evaluation and stability of the self-made pulsating tablets were studied. A method for the determination of plasma concentration of felodipine in rabbits was established. The pharmacokinetics and bioavailability of felodipine explosive pulse release tablets were studied. Method In this study, under the condition of fixed coating process parameters, the factors affecting the drug release behavior of pulsed tablets were investigated, such as: core composition, coating film prescription, release conditions in vitro, excipients and so on; The excipients, pore-forming agents, plasticizers and other excipients which have influence on the release behavior of felodipine explosive pulse release tablets are screened. The effect of different factors on the release of pulse tablets was determined according to the 10% time required for drug release in pulsatile tablets. The optimum prescription process was optimized by uniform design method. The release uniformity, content and evenness of the tablets were determined, the related substances were examined and the stability of the samples was investigated. Felodipine sustained-release tablets were used as reference preparation and self-made pulsating tablets as test preparation. With reference to relevant literature and practical experience, a method for the determination of blood concentration of felodipine was established in 6 healthy Japanese white rabbits with two preparations. Double cycle cross design, single fasting administration of felodipine pulse tablets (specification: 5 mg) and commercial felodipine sustained-release tablets (specification: containing 5 mg), determination of blood concentration at different time points by HPLC method, drawing in vivo drug time curve; The related pharmacokinetic parameters were calculated according to the blood concentration at each time point. Result The best prescription was obtained by single factor investigation and uniform design optimization. The swelling agent in the core is low substituted hydroxypropyl cellulose L-HPCO, which accounts for 10% of the core weight, and the plasticizer in the coating solution is dibutyl phthalate (DBP) with a content of 8.5% (the amount of EC, the pore-forming agent is PEG6000, and the content is 7% of EC; through in vitro release test, The time delay was 4.1 卤0.2 h, and the cumulative drug release was over 90% within 1.5 卤0.2) h. Blood concentration and pharmacokinetic parameters were measured after oral administration in rabbits. 鍙傛瘮鍒跺墏涓庡彈璇曞埗鍓備富瑕佽嵂鍔ㄥ�﹀弬鏁板垎鍒�涓

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