盐酸氨溴索喷雾剂在中国健康受试者中的生物等效性研究

Bioequivalence studies of ambroxol hydrochloride spray in healthy Chinese subjects

目的评价盐酸氨溴索喷雾剂与原研盐酸氨溴索喷雾剂(试验1)、盐酸氨溴索喷雾剂与原研盐酸氨溴索口服溶液(试验2)在中国健康受试者空腹/餐后条件下的生物等效性。方法本研究均采用单中心、随机、开放、两序列、两周期交叉设计。受试者被随机分配到T-R序列组和R-T序列组,分别单次口服受试制剂(盐酸氨溴索喷雾剂)或参比制剂(试验1为原研盐酸氨溴索喷雾剂;试验2为原研盐酸氨溴索口服溶液)30 mg。采用液相色谱-串联质谱(LC-MS/MS)法测定氨溴索的血药浓度,计算主要药代动力学参数。结果在试验1空腹条件下,受试者口服受试制剂或参比制剂后,氨溴索的C_(max)分别为(158.21±30.59)和(162.88±30.86)ng·mL^(-1),AUC_(0-t)分别为(1193.24±270.47)和(1154.43±250.60)ng·h·mL^(-1),AUC_(0-∞)分别为(1228.23±288.97)和(1187.42±266.70)ng·h·mL^(-1),三者的几何调整均值(GLSM)比值的90%CI分别为93.44%~100.73%,100.69%~105.54%和100.68%~105.61%;在试验1餐后条件下,受试者口服受试制剂或参比制剂后,氨溴索的C_(max)分别为(94.60±14.04)和(90.78±13.03)ng·mL^(-1),AUC_(0-t)分别为(1139.20±205.82)和(1083.74±177.57)ng·h·mL^(-1),AUC_(0-∞)分别为(1179.28±222.34)和(1122.86±194.38)ng·h·mL^(-1),三者的GLSM比值的90%CI分别为100.59%~110.20%,101.56%~110.54%和101.51%~110.52%;在试验2空腹条件下,受试者口服受试制剂或参比制剂后,氨溴索的C_(max)分别为(139.47±32.99)和(152.51±40.69)ng·mL^(-1),AUC_(0-t)分别为(1000.49±229.80)和(1051.30±261.58)ng·h·mL^(-1),AUC_(0-∞)分别为(1024.42±240.19)和(1076.13±274.50)ng·h·mL^(-1),三者的GLSM比值的90%CI分别为85.41%~95.08%,90.66%~96.60%和90.63%~96.74%;在试验2餐后条件下,受试者口服受试制剂或参比制剂后,氨溴索的C_(max)分别为(92.22±13.89)和(89.89±13.52)ng·mL^(-1),AUC_(0-t)分别为(1053.45±182.74)和(1038.71±200.91)ng·h·mL^(-1),AUC_(0-∞)分别为(1087.70±199.18)和(1072.19±216.37)ng·h·mL^(-1),三者的GLSM比值的90%CI分别为98.48%~107.24%,99.46%~106.24%和99.54%~106.39%。结论盐酸氨溴索喷雾剂与原研盐酸氨溴索喷雾剂和原研盐酸氨溴索口服溶液在中国健康受试者空腹/餐后条件下均具有生物等效性。

Objective To evaluate the bioequivalence of ambroxol hydrochloride spray and original ambroxol hydrochloride spray(Test 1),and the bioequivalence of ambroxol hydrochloride spray and original ambroxol hydrochloride oral solution(Test 2)in fasting/fed state in healthy Chinese subjects.Methods A single center,random,open,two sequences,two period crossover design was utilized.The subjects were randomly assigned to T-R group and R-T group,and received a single oral dose of 30 mg of the test preparation(ambroxol hydrochloride spray)or the reference preparation(original ambroxol hydrochloride spray of Test 1;original ambroxol hydrochloride oral solution of Test 2),respectively.The plasma concentration of ambroxol was determined by liquid chromatography-tandem mass spectrometry(LC-MS/MS),then the main pharmacokinetic parameters were calculated.Results In the fasting state of Test 1,the C_(max)of ambroxol in test preparation and reference preparation were(158.21±30.59)and(162.88±30.86)ng·mL^(-1),the AUC_(0-t)were(1193.24±270.47)and(1154.43±250.60)ng·h·mL^(-1),and the AUC_(0-∞)were(1228.23±288.97)and(1187.42±266.70)ng·h·mL^(-1),respectively.90%CIs for their geometric least squares mean(GLSM)ratios were 93.44%~100.73%,100.69%~105.54%and 100.68%~105.61%,respectively.In the fed state of Test 1,the C_(max)of ambroxol in test preparation and reference preparation were(94.60±14.04)and(90.78±13.03)ng·mL^(-1);the AUC_(0-t)were(1139.20±205.82)and(1083.74±177.57)ng·h·mL^(-1),and the AUC_(0-∞)were(1179.28±222.34)and(1122.86±194.38)ng·h·mL^(-1),respectively.90%CIs for their GLSM ratios were100.59%~110.20%,101.56%~110.54%and 101.51%~110.52%,respectively.In the fasting state of Test 2,the C_(max)of ambroxol in test preparation and reference preparation were(139.47±32.99)and(152.51±40.69)ng·mL^(-1);the AUC_(0-t)were(1000.49±229.80)and(1051.30±261.58)ng·h·mL^(-1),and the AUC_(0-∞)were(1024.42±240.19)and(1076.13±274.50)ng·h·mL^(-1),respectively.90%CIs for their GLSM ratios were85.41%~95.08%,90.66%~96.60%and 90.63%~96.74%,respectively.In the fed state of Test 2,the C_(max)of ambroxol in test preparation and reference preparation were(92.22±13.89)and(89.89±13.52)ng·mL^(-1);the AUC_(0-t)were(1053.45±182.74)and(1038.71±200.91)ng·h·mL^(-1),and the AUC_(0-∞)were(1087.70±199.18)and(1072.19±216.37)ng·h·mL^(-1),respectively.90%CIs for their GLSM ratios were 98.48%~107.24%,99.46%~106.24%and 99.54%~106.39%,respectively.Conclusions Ambroxol hydrochloride spray was bioequivalent to both original ambroxol hydrochloride spray and original ambroxol hydrochloride oral solution in the fasting/fed state in healthy Chinese subjects.