【摘要】 目的 研制瑞格列奈-阿卡波糖速缓释双层片，提高降糖药物的疗效，以实现速效和长效的互补。方法 采用两次压片法以交联羧甲基纤维素钠（CCMC-Na）作为超级崩解剂及羟丙基甲基纤维素K4M（HPMC K4M）作为骨架材料制备速缓释双层片。在单因素考察的基础上，采用星点设计-效应面法优化处方，结合综合评分法确定速释层与缓释层的最佳工艺并进行验证。对按最优处方所制双层片的体外释药行为进行考察，并采用兔模型进行体内药效学和药代动力学研究。结果 最优处方为速释层中葡甲胺用量为1.57 mg，CCMC-Na为5.10 mg，乳糖为39.83 mg；缓释层中HPMC K4M用量为60.27 mg，微晶纤维素（MCC）用量为30.61 mg，聚乙烯吡咯烷酮K30（PVP K30）浓度为28.57%。在体外释放实验中，双层片中瑞格列奈可在30 min达到累计释放最大值，释放量达95.34%，阿卡波糖可缓释释放长达12 h；瑞格列奈的释放符合一级释放的简单扩散特征，阿卡波糖的释放是扩散与溶蚀协同作用的过程。在体内药效学实验中，2型糖尿病兔模型连续给药3周后，双层片组8 h随机血糖水平与两单药组相比差异有统计学意义（P<0.01）。在体内药代动力学研究中，双层片中瑞格列奈t_1/2z明显缩短，在0.583 h迅速达到C_max，且C_max明显升高，约为普通片的1.28倍；阿卡波糖的t_1/2z与t_max延长，分别约为普通片的1.75倍和2.7倍，C_max显著降低，血药浓度波动小，达到了缓释的目的。结论 制备的瑞格列奈-阿卡波糖速缓释双层片具有联合用药与双相释药的双重效果，可为糖尿病等慢性疾病剂型的开发提供思路。更多还原

【Abstract】 Objective To optimize the formulation of repaglinide-acarbose immediate-sustained-release bilayer tablets,to improve drug the efficacy and balance the rapid effect and long-term effect.Methods Immediate-sustained-release bilayer tablets were prepared by two-time tableting method with croscarmellose sodium （CCMC-Na） as the super disintegrant and hydroxypropyl methyl cellulose K4M （HPMC K4M） as the backbone material.Based on single factor analysis,the Box-behnken response surface design was used to determine the optimal parameters of the immediate-release layer and the sustained-release layer by combining the comprehensive scoring method and verification.The in vitro release characteristics of bilayer tablets according to the optimal formula were systematically studied,while the pharmacodynamics and pharmacokinetics were assessed with a rabbit model.Results The optimal formula was 1.57 mg meglumine,5.10 mg CCMC-Na and 39.83 mg lactose in the immediate-release layer,while 60.27 mg HPMC K4M,30.61 mg microcrystalline cellulose and 28.57% polyvinylpyrrolidone （PVP） K30 in the sustained-release layer.In the in vitro release experiment,repaglinide in the bilayer tablets reached the maximum cumulative release at 30 min,the release reached 95.34%,and the release of acarbose was sustained up to 12 h.The release of repaglinide conformed to the simple diffusion characteristics of primary release,and the release of acarbose was a synergistic process of diffusion and dissolution.In the in vivo pharmacodynamic experiment,after 3 weeks of continuous administration in type 2 diabetes rabbit model,the 8-hour random blood glucose level of the bilayer tablets group was significantly different from that of the two monotherapy groups （P<0.01）.In the in vivo pharmacokinetic study,repaglinide t_1/2z was significantly shortened and C_max rapidly occurred at 0.583 h,while C_max was also significantly increased,about 1.28 times that of ordinary tablets.The t_1/2z and t_max of acarbose were prolonged,about 1.75 times and 2.7 times of that of ordinary tablets,respectively.The C_max was much reduced,and the fluctuation of blood concentration was small,achieving slow release.Conclusion The prepared repaglinide-acarbose immediate-sustained-release bilayer tablets exhibit a dual mechanism of combined administration and biphasic release,offering valuable insights for the development of chronic disease formulations,particularly in diabetes management.更多还原