盐酸米诺环素缓释片人体药动学及其缓释特征研究

Pharmacokinetics and Extended-Release Characteristics of Minocycline Hydrochloride Extended-release Tablets in Healthy Volunteers

目的通过对健康受试者口服不同剂量盐酸米诺环素缓释片后的药动学研究,探讨其在中国人体内的药动学特征,并以普通片为对照制剂,比较研究缓释片的缓释行为,为临床用药提供依据。方法 12名中国健康志愿者采用多剂量单序列给药设计方案,进行低、中、高(45,90,135 mg)3剂量组单次给药和中剂量组多次给药试验,并进行普通片(100 mg)的单剂量和多剂量试验。采用高效液相色谱-质谱(HPLC-MS)测定血药浓度。结果盐酸米诺环素缓释片低、中、高3剂量组单次给药后的主要药动学参数如下:ρmax分别为(0.477 0±0.128 0)、(1.011±0.191)、(1.500±0.281)μg·mL-1,t max分别为(3.3±1.1)、(3.6±0.8)、(3.4±0.7)h,t1/2分别为(17.1±5.4)、(18.3±4.9)、(17.9±3.4)h,AUC0-t分别为(9.391±3.019)、(20.01±3.07)、(31.81±6.80)μg·h·mL-1;中剂量组多次给药的主要药动学参数为:ρav为(0.844 0±0.225 0)μg·mL-1,DF为(1.1±0.2),ρssmax为(1.438±0.383)μg·mL-1,t max为(3.5±0.8)h,t1/2为(19.3±4.4)h,AUC0-t为(31.18±9.39)μg·h·mL-1;普通盐酸米诺环素片100 mg单次给药的主要药动学参数如下:ρmax为(1.418±0.427)μg·mL-1,t max为(2.6±0.7)h,t1/2为(16.9±3.9)h,AUC0-t为(25.35±5.80)μg·h·mL-1;普通盐酸米诺环素片100 mg多次给药的主要药动学参数如下:ρav为(1.229±0.377)μg·mL-1,DF为(1.3±0.2),ρmax为(2.188±0.652)μg·mL-1,t max为(2.3±0.7)h,t1/2为(17.7±2.4)h,AUC0-t为(44.83±16.29)μg·h·mL-1。结论受试者单次口服45、90、135 mg盐酸米诺环素缓释片后,血浆中米诺环素的ρmax和AUC0-t随给药剂量的增大而增大,呈现线性药动学特征;无性别差异。多次给药研究发现,在相同给药间隔内米诺环素在健康受试者体内的暴露量增加约50%。与普通片比较发现,盐酸米诺环素缓释片具有明显的缓释特征。

OBJECTIVE To investigate the pharmacokinetics of single and multiple oral doses of minocycline hydrochloride extended-release tablets and evaluate its extended-release characteristics by comparing with ordinary tablets. METHODS Twelve healthy volunteers received a single oral dose of 45, 90 and 135 mg minoeycline hydrochloride extended-release tablets respectively with a 10-day washout period. After the single-dose study, the volunteers participated in the multiple dose study in which each volunteer received 90 mg per day for 10 consecutive days. The ordinary tablets were administered by single and multiple doses as reference preparation in the end. The concentrations of minocycline in human plasma were determined by LC-MS method. RESULTS The main pharmacokinetic parameters of a single dose of minocycline hydrochloride extended-release tablets of 45, 90 and 135 mg in 12 healthy volunteers were as follows ：Pmax （0. 477 0 ± 0. 128 0）, （ 1. 011 ± 0. 191 ） and （ 1. 500 ± 0. 281 ） μg · mL^- 1, tmax （3.3 ± 1.1 ）, （ 3.6 ± 0.8） and（3.4±0.7） h, t1/2（17.1 ±5.4）,（18.3±4.9） and（17.9±3.4） h, AgC0-t（9.391 ±3.019）,（20.01 ±3.07） and （31.81 ± 6. 80） μg · h · mL^-1, respectively. And those of multiple-dose of minocycline hydrochloride extended-release tablets of 90 mg were as follows：p,v （0. 844 0 ±0. 225 0） μg · mL^-1, DF（ 1.1 ±0. 2）, Pmax（ 1. 438 ±0. 383） μg · mL^-1 , tmax（3- 5 ±0. 8） h, t1/2 （19. 3 ±4.4） h, AUC0-t,（31.18 ±9.39） μg · h · mL^-1. The main pharmacokinetic parameters of a single dose of ordinary minocycline hydrochloride tablets of 100 mg were as follows ：Pmax （ 1. 418 ± 0. 427 ） μg · mL^-1, tmax （ 2. 6 ± 0. 7 ） h, t1/2 （ 16. 9 ± 3.9 ） h, AUC0-t （25.35 ± 5.80） μg · mL^-1, and those of multiple-dose of ordinary minocycline hydrochloride tablets at 100 mg were as follows：ρav（1. 229 ±0. 377） μg · mL^-1, DF（1.3 ±0. 2）, ρmax（2. 188±0.652） μg · mL^-1 , tmax（2. 3 ±0.7） h, t1/2（17.7 ±2.4） h,AUC0-t（44.83 ± 16.29） μg · mL^-1, respectively. CONCLUSION In the range of 45 - 135 mg, the AUC0-t and ρmax Of minocycline hydrochloride extended-release tablets increased in a dose-dependent manner after single-dose administration, indicating linear pharmacokinetics. No significant gender differences were found. An accumulation of 50% in AUC0-toeeurred after multiple-dose administration. The minocycline hydrochloride extended-release tablets have extended-release character comparing with ordinary tablets.