盐酸雷诺嗪缓释片处方优化及犬体内药代动力学的研究  

Optimizaion of the formulation of ranolazine hydrochloride sustained-release tablet and its pharmacokinetics in dogs

作　　者：李长军 于艳玲 杨清敏 李颖 张宇红 王晶翼 

机构地区：[1]齐鲁制药有限公司药物研究院,山东济南250100

出　　处：《药学学报》2010年第9期1170-1176,共7页Acta Pharmaceutica Sinica

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(HPMCK4M)/乙基纤维素(EC100cp)/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12h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。HPMCK4M、EC100cp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、EC100cp、Eudragit?RL100。RH-ST体外可达12h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(Tmax)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。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,RH-ST in vivo has a steady and slow release behavior, Tmax 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.

关 键 词：盐酸雷诺嗪 缓释片 正交试验 药代动力学 

分 类 号：R943[医药卫生—药剂学]