多剂量口服硝苯地平控释片的人体药动学及生物等效性研究

Pharmacokinetics and Bioequivalence Study of Nifedipine Controlled-release Tablets after Multiple Doses Administration in Healthy Volunteers

关键词:  硝苯地平控释片  LC－MS/MS  连续给药  药代动力学  生物等效性

Key words:  nifedipine controlled-release tablets  LC-MS/MS  multiple doses  pharmacokinetics  bioequivalence

摘要:

目的 以聚维酮/共聚维酮替代聚氧乙烯作为促渗透聚合物制备新型渗透泵型硝苯地平控释片，研究多剂量口服硝苯地平控释片的人体药动学特点，计算相对生物利用度，并评价该制剂的生物等效性。方法 入选的24名男性健康受试者随机交叉给药，分别每日口服30 mg试验制剂或参比制剂，剂量均为30 mg·次-1·d-1，连续服药7 d。采用LC-MS/MS法测定血药浓度，用DAS软件计算药代动力学参数及相对生物利用度，并求证硝苯地平控释片试验制剂与参比制剂的生物等效性。结果 连续给予30 mg试验制剂和参比制剂后获得主要药代动力学参数如下：T1/2β分别为(9.0±2.2)h和(9.5±3.8)h；Tmax分别为(8.1±7.4)h和(6.7±4.1)h；Cssmax分别为(52.7±28.2)μg·L-1和(44.5±22.6)μg·L-1；Cssmin分别为(29.4±22.2)μg·L-1和(28.7±15.8)μg·L-1；AUC0-60分别为(1 087.4±671.6)μg·L-1·h和(1 040.2±518.4)μg·L-1·h；AUC0-∞分别为(1 113.1±677.2)μg·L-1·h和(1 074.5±519.8)μg·L-1·h，AUCSS分别为(809.1±454.0)μg·L-1·h和(713.9±382.2)μg·L-1·h。经计算试验制剂对于参比制剂的平均相对生物利用度F值：FAUCss为(115.2±29.2)%，FAUC0-60为(103.4±30.2)%，FAUC0-∞为(102.2±29.7)%。波动系数DF分别为(77.8±52.1)%和(55.5±30.5)%。两种制剂的Cmax、AUC0-60、AUC0-∞及AUCSS经对数转换后90%置信区间的计算结果为：Cmax(100.9～126.0)%，AUC0-60 (87.5～111.8)%，AUC0-∞ (86.8～110.3)%，AUCSS为(98.8～124.4)%，Tmax 经非参数秩和检验无显著性差异。整个试验期间，受试者均未出现药物不良反应。结论 两种硝苯地平控释片为生物等效制剂。聚维酮/共聚维酮可以替代聚氧乙烯作为渗透泵型控释制剂的主要功能性辅料。

Abstract:

OBJECTIVE Povidone/Copovidone were used as the main osmopolymers instead of Poly (ethylene oxide) (PEO) to prepare nifedipine controlled-release tablets of new osmotic pump type. The pharmacokinetic properties of nifedipine controlled-release tablets after multiple doses in healthy volunteers were studied, and the relative bioavailability of the test preparation was calculated and the bioequivalence was evaluated. METHODS Twenty four male healthy volunteers were enrolled in a randomized two-way crossover design. 30 mg nifedipine was administered per day during consecutive 7 d. The drug concentration in blood was determined with LC-MS/MS method. The pharmacokinetic parameters, relative bioavailability and the bioequivalence were calculated by DAS program. RESULTS The main pharmacokinetic parameters after multiple doses of test preparation and reference preparation were as follows：T1/2β (9.0±2.2)h and (9.5±3.8)h; Tmax (8.1±7.4)h and (6.7±4.1)h; Cssmax (52.7±28.2)μg·L-1 and (44.5±22.6)μg·L-1; Cssmin (29.4±22.2)μg·L-1 and (28.7±15.8)μg·L-1; AUC0-60 (1 087.4±671.6)μg·L-1·h and (1 040.2±518.4)μg·L-1·h; AUC0-∞ (1 113.1±677.2)μg·L-1·h and (1 074.5±519.8)μg·L-1·h，AUCSS (809.1±454.0)μg·L-1·h and (713.9±382.2)μg·L-1·h. The average relative bioavailability of the test preparation versus the reference preparation was as follows: FAUCss (115.2±29.2)%, FAUC0-60 (103.4±30.2)% and FAUC0-∞ (102.2±29.7)%. DF was (77.84±52.09)% and (55.48±30.54)%. The 90% confidence interval of Cmax, AUC0-60, AUC0-∞ and AUCss after longarithmic transform was (100.9-126.0)%, (87.5-111.8)%, (86.8-110.3)% and (98.8-124.4)% respectively. There was no significant difference in Tmax after non-parameter rank sum test. No adverse reaction was observed during the trial. CONCLUSION The test preparation was bioequivalent to the reference preparation. Povidone/Copovidone could replace PEO used as the main functional excipient of osmotic pump type controlled-release preparations.