硝苯地平双层渗透泵片的制备及家兔体内药动学研究

Preparation and Pharmacokinetics of Nifedipine Osmotic Pump Tablets in rabbits

目的:以硝苯地平为模型药物制备渗透泵制剂,并进行家兔体内药动学研究。方法:与AdalatR○GITS硝苯地平控释片比较,采用相似因子法对处方进行考察优化;将制备的硝苯地平渗透泵片和自制的普通片,分别对家兔单剂量口服给药,采用HPLC法对给药后家兔血浆中药物浓度进行测定。结果:通过处方优化,制备了难溶性药物硝苯地平24 h的控释制剂;渗透泵控释片和普通片的达峰时间分别为(12.05±0.28)h和(5.98±0.47)h,峰浓度分别为(0.299±0.035)mg.L-1和(0.452±0.038)mg.L-1,相对生物利用度为119.5%±7.2%。结论:通过制备双层渗透泵片,能够实现硝苯地平体外溶出实验下24 h零级释药,能显著延长硝苯地平家兔体内达峰时间,降低峰浓度,并且提高了药物的生物利用度。

Objective： To investigate the formulations and pharmacokinetics of nifedipine double-layer osmotic pump tablets. Methods： In present study, nifedipine was as the model drug to prepare the hilayer osmotic pump tablets. The effects of many factors including formulation of drug layer, push layer and membrane, release media on the in-vitro release behavior of nifedipine tablets were investigated. The plasma nifedipine concentration of osmotic pump tablets and self-prepared ordinary tablets after single oral administration in rabbits were determined by HPLC. The pharmacokinetic parameters were calculated with the DAS 2.0 software. Results： The comprehensive formulation research showed that the release profile was influenced by PEO （POLYOX WSR N-12K） level of both layers and the diethyl phthalate （DEP） amount. The in-vivo pharmacokinetics research showed that the drug concentration-time curves fitted to a two- compartment model. The pharmacokinetic parameters for the single oral administration of the osmotic pump tablets and ordinary tablets were tmax（12.05±0.28）h and （5.98±0.47）h, Cmax （0.299±0.035）mg·L^-1 and （0.452± 0.038） mg·L^-1, AUC0-∞ （4.010±0.353） mg·h·L^-1 and（3.355±0.441）mg·h·L^-1, respectively.The relative bioavailability of osmotic pump tablets was 119.5%±7.2%. Conclusion： The results indicated that the optimal formulation had the excellent zero-order release character in vitro from 0-24 hours, and had the slow releasing characteristics after single dosage administration in rabbits.