To investigate the impact of application site on the evaluation of formulation differences of flurbiprofen cataplasms based on pharmacokinetic parameters in Chinese subjects.

An open label, randomized, single-dose, two-sequence, two-period cross-over study under fasting condition was conducted. 12 subjects 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.

The median t_max 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 (C_max, 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) and 24.00 (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 (C_max, 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^-1 respectively, and the geometric mean ratios and 90% CI (A/B) of the main pharmacokinetic parameters (C_max, 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.

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.