DOI:10.16438/j.0513-4870.2010.09.019·1170·药学学报Acta Pharmaceutica Sinica 2010, 45 (9): 1170−1176盐酸雷诺嗪缓释片处方优化及犬体内药代动力学的研究李长军, 于艳玲, 杨清敏, 李颖, 张宇红, 王晶翼*(齐鲁制药有限公司药物研究院, 山东济南 250100)摘要: 通过研制盐酸雷诺嗪缓释片 (RH-ST), 研究其在犬体内的药代动力学, 并与盐酸雷诺嗪普通片(RH-CT) 进行比较。
采用3种缓释骨架材料羟丙基甲基纤维素 (HPMC K4M) /乙基纤维素 (EC 100cp) /丙烯酸树脂 (Eudragit®RL100) 组合应用, 并以正交试验设计确定三者的最佳处方量, 达到12 h的缓释。
用液质联用法测定6只Beagle犬单剂量给药及多剂量给药后不同时间血浆中盐酸雷诺嗪的浓度, 并与RH-CT比较, 按照Loo-Riegelman方程计算药物吸收分数, 通过BAPP2.0程序计算药动学参数。
HPMC K4M、EC 100 cp和Eudragit®RL100三者的用量均影响药物的释放, 随着用量增加, 释放变慢; 影响程度由高到低依次为HPMCK4M、EC 100 cp、Eudragit®RL100。
RH-ST体外可达12 h缓释, 释药动力学符合Higuchi方程。
单剂量口服RH-CT和RH-ST后, 体内血药浓度经时过程均符合双室模型, RH-ST体内吸收与体外释放相关性较好。
与RH-CT相比[(0.79 ± 0.33) h], Beagle犬多剂量口服RH-ST的达峰时间(T max) 明显延长[(3.00 ± 0.50) h], 相对生物利用度大于80%。
多种骨架材料的组合应用, 有效地降低了缓释片的片重, 并且在体内外均能缓慢释放, 降低血药浓度波动, 提高患者的顺应性。
关键词: 盐酸雷诺嗪; 缓释片; 正交试验; 药代动力学中图分类号: R943 文献标识码:A 文章编号: 0513-4870 (2010) 09-1170-07Optimizaion of the formulation of ranolazine hydrochloridesustained-release tablet and its pharmacokinetics in dogsLI Chang-jun, YU Yan-ling, YANG Qing-min, LI Ying, ZHANG Yu-hong, WANG Jing-yi*(Research and Development Division, Qilu Pharmaceutical Co., Ltd, Jinan 250100, China)Abstract: Ranolazine hydrochloride sustained-release tablet (RH-ST) was prepared and its release behavior in vitro was studied. The pharmacokinetic characteristics and bioavailability in six Beagle dogs after oraladministration of RH-ST and ranolazine hydrochloride common tablets (RH-CT) as reference were compared.Three kinds of matrix, hydroxypropylmethylcellulose (HPMC K4M), ethylcellulose (EC 100cp) and acrylicresins (Eudragit®RL100) were selected as functional excipients to keep ranolazine hydrochloride (RH) releasefor 12 hours. Through orthogonal designs, the polymers were quantified and the optimized cumulative releaseprofile was obtained. The single oral dose of RH-ST 500 mg and RH-CT 333.3 mg was given to six dogsusing a two way crossover design. Plasma levels were determined by LC-MS and the absorption fractions werecalculated according to Loo-Riegelman formula. The steady-state concentration of RH in plasma of six dogsand its pharmacokinetics behaviors after continuous oral administration of RH-ST and RH-CT at different timeintervals were studied by LC-MS. The steady-state pharmacokinetic parameters were computed by softwareprogram BAPP2.0. With the increase of the amount of the matrix, the drug release was decreased. The mostimportant factor influencing drug release is the quantity of HPMC K4M. Drug release within the period (from0 h to 12 h) fitted well into Higuchi model. The correlation coefficient (r) between the dissolution in vitro inrelease media of the distilled water and the absorptin fraction in vivo was 0.955 0. To compare with RH-CT,收稿日期: 2010-04-15.*通讯作者Tel: 86-531-83129968, Fax: 86-531-83126688, E-mail: jingyi.wang@李长军等: 盐酸雷诺嗪缓释片处方优化及犬体内药代动力学的研究·1171·RH-ST in vivo has a steady and slow release behavior, T max was obviously delayed (3.00 ± 0.50) h and the relative bioavailability was over 80 percentage. The combined use of multiple polymers can decrease the tablet weight effectively, and the drug release rate can be decreased both in vitro and in vivo.Key words: ranolazine hydrochloride; sustained-release tablet; orthogonal design; pharmacokinetics盐酸雷诺嗪 (ranolazine hydrochloride, RH) 是雷诺嗪的盐酸盐。
两者作用机制相同, 均是新型的抗心绞痛药, 为部分脂肪酸氧化酶 (pFOX) 抑制剂。
雷诺嗪缓释片是由美国CV治疗公司研发, Ⅲ期临床实验[1]数据可知, 普通片无法对心脏提供持续性保护作用, 同时多次服药导致患者顺应性差。
对于盐酸雷诺嗪的普通片及缓释片均未在国内外上市, 开发本品的缓释制剂可弥补临床空白, 具有重要意义。
盐酸雷诺嗪与雷诺嗪的溶解性及缓释制剂规格均存在较大差异(雷诺嗪0.5 g相当于其盐酸盐0.6 g), 因此缓释骨架辅料的种类、用量的筛选, 研制的难度也各不相同。
雷诺嗪的溶解度随pH上升而迅速下降[2], 需选用pH依赖性辅料确保在肠道的良好吸收; 而盐酸雷诺嗪溶解度在pH 1～6.8内几乎不受影响, 均大于1 g·mL−1。
因此仅靠单一的骨架材料较难制备符合要求的RH缓释片, 同时为达到12 h缓释, 需增加骨架材料用量, 从而导致片重大约在900～1 000 mg, 患者难以吞咽。
为开发水溶性药物的缓释制剂, 文献[3, 4]报道多选用单独以亲水凝胶骨架材料HPMC 延缓药物释放, 用量达总片重的20%～30%, 或选用HPMC与EC的组合。
本品通过前期的处方筛选, 选用HPMC和EC为骨架材料, 并以非pH依赖性的Eudragit®RL100有机溶剂为黏合剂制备盐酸雷诺嗪缓释片 (RH-ST), 充分发挥了三者阻滞药物释放的性能。
通过正交设计优化骨架片处方, 采用上述3种缓释骨架材料组合应用, 三者总量仅180 mg左右, 使得易溶于水的药物达到约12 h缓释, 不仅有效地降低了总片重(约700 mg), 而且避免了初始阶段药物的突释及后期药物释放不完全的现象; 建立了具有缓释特征的动力学方程; 以普通片 (RH-CT) 为对照, 采用液质联用法分别测定6只Beagle犬的单剂量给药及多剂量给药体内血药浓度, 并进行了盐酸雷诺嗪缓释片体内外相关性的评价。
材料与方法仪器RUD异形压片机(德国科力安); 快速搅拌制粒机(上海信谊制药技术装备公司); RC806智能溶出仪(天津天大天发公司); 紫外可见分光光度计(上海棱光技术有限公司); 1100HPLC/MS高效液相/质谱联用仪(美国Agilent公司)。
药品及试剂盐酸雷诺嗪 (RH, 齐鲁制药有限公司); 羟丙基甲基纤维素(hydroxypropylmethylcellulose, HPMC K4M), 乙基纤维素(ethylcellulose, EC 100cp), 欧巴代(上海Colorcon公司); 丙烯酸树脂 (Eudragit® RL100, 德国Degussa公司); 硬脂酸镁(山东聊城阿华制药有限公司); 无水乙醇(济南三恩化工公司)。