【摘要】 目的 考察在中国受试者中不同部位给药对基于药代动力学参数评价氟比洛芬凝胶贴膏制剂差异评估的影响。方法 用空腹、随机、开放、单剂量、两序列、两周期、双交叉试验设计。12例受试者被随机分配至A-B组或B-A组，每组6例，其中每组各有3例，分别于腿部及背部给药。用经方法学验证的液相色谱质谱串联法（LC-MS/MS）测定血浆中氟比洛芬的浓度，应用Phoenix WinNonlin8.1计算主要药代动力学参数。结果 12例受试者空腹外用贴敷氟比洛芬凝胶贴膏A（n=12，腿部给药6例；背部给药6例）和氟比洛芬凝胶贴膏B（n=12，腿部给药6例；背部给药6例）后，血浆中氟比洛芬的中位t_max分别为8.50（4.00,24.00）和19.50（4.00,24.00）h，主要药代动力学参数C_max分别为（66.26±62.84）和（32.68±23.32） ng·mL^-1,AUC_0-t分别为（1215.19±749.72）和（771.72±394.14）h·ng·mL^-1,AUC_0-∞分别为（1286.57±720.36）和（870.24±351.99）h·ng·mL^-1，两制剂（制剂A/制剂B）主要药代动力学参数C_max、AUC_0-t、AUC_0-∞的几何均值比及90%置信区间分别为170.59%（139.21%～209.04%）、152.05%（135.60%～170.48%）、145.47%（126.21%～167.67%）。腿部给药后，氟比洛芬凝胶贴膏A（n=6）与氟比洛芬凝胶贴膏B（n=6），血浆中氟比洛芬的中位t_max分别为17.50（10.00,24.00）和24.00（24.00,24.00） h，主要药代动力学参数C_max分别为（20.56±7.76）和（15.30±6.79）ng·mL^-1,AUC_0-t分别为（727.03±267.78）和（500.59±186.09）h·ng·mL^-1,AUC_0-∞分别为（845.73±288.00）和（636.69±166.74）h·ng·mL^-1，两制剂（制剂A/制剂B）主要药代动力学参数C_max、AUC_0-t、AUC_0-∞的几何均值比及90%置信区间分别为139.60%（123.24%～158.13%）、 146.70%（124.74%～172.51%）、 130.61%（100.76%～169.30%）。背部给药后，氟比洛芬凝胶贴膏A（n=6）与氟比洛芬凝胶贴膏B（n=6），血浆中氟比洛芬的中位t_max分别为4.00（4.00,7.00）和9.00（4.00,15.00）h，主要药代动力学参数C_max分别为（111.95±60.14）和（50.05±20.64）ng·mL^-1,AUC_0-t分别为（1703.35±770.04）和（1042.86±361.53）h·ng·mL^-1,AUC_0-∞分别为（1727.41±769.57）和（1064.87±354.32）h·ng·mL^-1，两制剂（制剂A/制剂B）主要药代动力学参数C_max、AUC_0-t、AUC_0-∞的几何均值比及90%置信区间分别为208.46%（139.61%～311.25%）、157.59%（123.51%～201.08%）、156.24%（122.10%～199.93%），与腿部给药相比较，背部给药的制剂差异更大。结论 本研究提示，不管是腿部给药还是背部给药，氟比洛芬凝胶贴膏A经皮肤吸收的吸收速度与吸收程度可能均高于氟比洛芬凝胶贴膏B；相对于腿部给药，背部给药的药物吸收速度和程度可能更高；在基于药代动力学参数评价制剂差异方面，腿部给药体现的制剂差异更小，提示背部给药的制剂差异区分力可能更好。更多还原

【Abstract】 Objective To investigate the impact of application site on the evaluation of formulation differences of flurbiprofen cataplasms based on pharmacokinetic parameters in Chinese subjects.Methods An open label,randomized,single-dose,two-sequence,two-period cross-over study under fasting condition was conducted.12subjects were randomized to A-B group or B-A group,with 6 subjects in each group,and 3 subjects in each group were applied to the leg and back respectively.The concentration of flurbiprofen in plasma was determined by methodologically validated liquid chromatography-mass spectrometry（LC-MS/MS）,and the main pharmacokinetic parameters were calculated by Phoenix WinNonlin 8.1.Results The median tmax of flurbiprofen in plasma were 8.50（4.00,24.00） and 19.50（4.00,24.00） h respectively in 12 subjects（n=12;applied to leg:n=6;applied to back:n=6） after applying flurbiprofen cataplasms A and B,and the main pharmacokinetic parameters of flurbiprofen were as followed,C_max were（66.26±62.84） and（32.68±23.32） ng·mL^-1,AUC_0-t were（1 215.19±749.72）and（771.72±394.14） h · ng · mL^-1,AUC_0-∞ were（1 286.57±720.36） and（870.24±351.99） h·ng · mL^-1,respectively,and the geometric mean ratios and 90% CI（A/B） of the main pharmacokinetic parameters(Cmax,AUC_0-t,AUC_0-∞) were 170.59%（139.21%-209.04%）、152.05%（135.60%-170.48%）、145.47%（126.21%-167.67%）,respectively.The median t_max of flurbiprofen in plasma were 17.50（10.00,24.00） and24.00（24.00,24.00） h respectively in 6 subjects（applied to leg） after applying flurbiprofen cataplasms A and B,and the main pharmacokinetic parameters of flurbiprofen in plasma were as followed,C_max were（20.56±7.76） and（15.30±6.79） ng·mL^-1,AUC_0-t were（727.03±267.78） and（500.59±186.09） h·ng·mL^-1,AUC_0-∞ were（845.73±288.00） and（636.69±166.74） h·ng·mL-1 respectively,and the geometric mean ratios and 90% CI（A/B） of the main pharmacokinetic parameters(Cmax,AUC_0-t,AUC_0-∞) were 139.60%（123.24%-158.13%）,146.70%（124.74%-172.51%）,130.61%（100.76%-169.30%） respectively.The median t_max of flurbiprofen in plasma were 4.00（4.00,7.00） and 9.00（4.00,15.00） h respectively in 6 subjects（Applied to back） after applying flurbiprofen cataplasms A and B,and the main pharmacokinetic parameters of flurbiprofen in plasma were as followed,C_max were（111.95±60.14） and（50.05±20.64） ng · mL^-1,AUC_0-t were（1 703.35±770.04） and（1 042.86±361.53） h·ng·mL^-1,AUC_0-∞ were（1 727.41±769.57） and（1 064.87±354.32） h·ng · mL^-1respectively,and the geometric mean ratios and 90% CI（A/B） of the main pharmacokinetic parameters(Cmax,AUC_0-t,AUC_0-∞) were 208.46%（139.61%-311.25%）,157.59%（123.51%-201.08%）,156.24%（122.10%-199.93%） respectively,compared to leg application,greater formulation difference was observed in back application.Conclusion This study suggested that regardless of application sites（leg or back）,flurbiprofen cataplasms A exhibited higher on the rate and extent of absorption than that of flurbiprofen cataplasms B,and back application showed potentially greater drug absorption rate and extent than leg application,the formulation differences based on pharmacokinetic parameters were less pronounced when applied to leg.These findings indicate that back application may provide better discriminatory power for evaluating formulation differences.更多还原