Bioavailability and tolerability study of two new DHEP-medicated plasters in comparison with the marketed DHEP medicated plaster 1.3% (Flector®)

INTERVENTION: Test treatment 1: Diclofenac‐N‐(2‐hydroxyethyl)‐pyrrolidine (DHEP) medicated plaster 2.6%, corresponding approximately to 280 mg of diclofenac sodium Test treatment 2: Diclofenac‐N‐(2‐hydroxyethyl)‐pyrrolidine (DHEP) medicated plaster 3.9%, corresponding approximately to 420 mg of diclofenac sodium Reference formulation: Diclofenac‐N‐(2‐hydroxyethyl)‐pyrrolidine (DHEP) medicated plaster DHEP 1.3%, corresponding approximately to 140 mg of diclofenac sodium The study consisted of a screening visit, a treatment phase of three study periods separated by a wash‐out interval of at least 7 days between the second plaster application of the previous period and the first application of the next period and a final visit/early termination visit (ETV). One DHEP medicated plaster (test 1, 2.6% or test 2, 3.9% or reference, 1.3%) was applied once a day for 2 consecutive days in the three study periods according to a three‐way cross‐over randomised study design. The plasters were applied to the same application area of the same arm in the three study periods. CONDITION: DHEP‐medicated plaster ; Not Applicable PRIMARY OUTCOME: Pharmacokinetic profile of diclofenac in plasma after o.d. application for 2 consecutive days of DHEP‐medicated plaster ‐ plasma concentrations of diclofenac measured on day 1 at pre‐dose (0) and on days 2‐3 at pre‐dose (0) and 1, 2, 3, 4, 6, 8, 10, 12, 16, 20 and 24 h post‐dose (13 samples each study period) SECONDARY OUTCOME: Safety and tolerability after o.d. application for 2 consecutive days of DHEP‐medicated plaster, based on the following assessments: ; 1. Record of adverse events, assessed throughout the study; 2. Vital signs: blood pressure (BP) and heart rate (HR), measured at rest (5 min in sitting position) by the investigator or his deputy at the screening visit, on day ‐1, as well as on day 3 at 24 h post‐dose in each period, and in case of ETV. The vital signs measurement at 24 h post‐dose of day 3, period 3, was considered as the final assessment; 3. Electrocardiograms: a 12‐lead resting ECG performed in supine position and interpreted by the investigator at screening; 4. Physical examination and body weight: a physical examination, including measurement of BW, performed at screening and final visit/ETV; 5. Routine haematology, blood chemistry and urinalysis laboratory tests performed, under fasting conditions, at screening and at the final visit/ETV; 6. Local tolerability, assessed giving a score according to the a 4‐grade scale to each of the following parameters: Application site erythema, Application site dryness, Application site swelling, Application site exfoliation (If the score assigned was 1, 2 or 3, the local reaction was treated as an AE with intensity mild (score 1), moderate (score 2) or severe (score 3), while the severity of 0 score was none; 7. Plaster adhesiveness, assessed using the 5‐point scale in compliance with FDA suggested scoring system for adhesion of transdermal patches, immediately before plaster removal on days 2 and 3 INCLUSION CRITERIA: 1. Informed consent: signed written informed consent before inclusion in the study 2. Males/females, 18‐55 years old inclusive 3. Body Mass Index (BMI): 18.5‐30 kg/m2 inclusive 4. Vital signs: systolic blood pressure (SBP) 100‐139 mmHg, diastolic blood pressure (DBP) 50‐89 mmHg, heart rate (HR) 50‐90 bpm, measured after 5 min at rest in the sitting position 5. Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co‐operate with the investigator and to comply with the requirements of the entire study 6. Contraception and fertility (females only): females of child‐bearing potential were required to use at least one of the following reliable methods of contraception: 6.1. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit 6.2. A non‐hormonal intrauterine device [IUD] or female condom with spermici