Determination of the transdermal bioavailability of a newly developed diclofenac sodium patch in comparison with a reference preparation.

Two different transdermal diclofenac (CAS 15307-86-5) formulations (Olfen Patch 140 mg diclofenac sodium as test preparation and 180 mg diclofenac epolamine plaster, equivalent to 140 mg diclofenac sodium, as reference preparation) were investigated in 24 healthy male and female volunteers in order to compare the transdermal bioavailability between both treatments following topical multiple dose administration. Subjects were applied 2 plasters of test and reference formulation at a dose interval of 12 h for 4 consecutive days. Test and reference preparation were administered in randomised sequence at a marked spot at the left upper arm under non-fasting conditions. For determination of diclofenac concentrations, pre-dose (trough) values were taken during steady-state build-up and during the period of switch-over between both preparations on days 1-3 and 5-7. Blood samples for pharmacokinetic profiling were taken on days 4 and 8 at pre-defined time points up to 24 h following drug administration (after the 7th resp. 15th dose). Treatments were not separated by a wash-out phase. Considering the short half-life of diclofenac, it was appropriate that a switch-over design was chosen without wash-out periods between treatments. Diclofenac plasma concentrations were determined by means of a validated LC-MS/MS method (limit of detection: 0.06 ng/ml; lower limit of quantification: 0.15 ng/ml). For the test preparation, maximum plasma concentrations of 3.36 ng/ml (C(max, 0-12)), 3.73 ng/ml (C(max, 12-24)) and 3.84 ng/ml (C(max, 0-24)) as well as areas under the plasma concentration-time curve (AUC) of 31.11 ng x h/ml (AUC(0-12), 34.83 ng x h/ml (AUC(12.24)) and 65.94 ng x h/ml (AUC(0-24)) were determined. For the reference preparation, these values were 1.55 ng/ml (C(max, 0-12)), 1.45 ng/ml (C(max, 12-24) and 1.57 ng/ml (C(max, 0-24)) as well as 13.28 ng x h/ml (AUC(0-12)), 12.68 ng x h/ml (AUC(12-24)) and 25.96 ng x h/ml (AUC(0-24)). For the test preparation, peak-to-trough fluctuations (% PTF) of 34.78% (% PTF(0-12)), 38.50% (% PTF(12-24)) and 43.68% (% PTF(0-24)) were observed. Corresponding values for the reference preparation were 35.82% (% PTF(0-12), 31.36% (% PTF(12-24)) and 40.55% (% PTF(0-24)). In order to evaluate comparable bioavailability of both preparations, 90% confidence intervals of the test/reference ratios were determined. Thereby, for all dose intervals considered and all AUC parameters calculated, the extent of diclofenac absorption from the test preparation markedly exceeds those values obtained for the reference preparation. Likewise, maximum plasma concentrations, as a measure for the rate of absorption, were higher after the test preparation. With respect to peak-to-trough fluctuation of plasma diclofenac levels, both plaster preparations were comparable for the morning dose interval 0-12 h as well as for the 0-24 h period.