盐酸雷诺嗪缓释片处方优化及犬体内药代动力学的研究

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HPMC

K4M、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) 09-1170-07

Optimizaion of the formulation of ranolazine hydrochloride

sustained-release tablet and its pharmacokinetics in dogs

LI 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 oral

administration 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 acrylic

resins (Eudragit®RL100) were selected as functional excipients to keep ranolazine hydrochloride (RH) release

for 12 hours. Through orthogonal designs, the polymers were quantified and the optimized cumulative release

profile was obtained. The single oral dose of RH-ST 500 mg and RH-CT 333.3 mg was given to six dogs

using a two way crossover design. Plasma levels were determined by LC-MS and the absorption fractions were

calculated according to Loo-Riegelman formula. The steady-state concentration of RH in plasma of six dogs

and its pharmacokinetics behaviors after continuous oral administration of RH-ST and RH-CT at different time

intervals were studied by LC-MS. The steady-state pharmacokinetic parameters were computed by software

program BAPP2.0. With the increase of the amount of the matrix, the drug release was decreased. The most

important factor influencing drug release is the quantity of HPMC K4M. Drug release within the period (from

0 h to 12 h) fitted well into Higuchi model. The correlation coefficient (r) between the dissolution in vitro in

release 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@