Ability in tissue penetration and clinical utility of S-flurbiprofen plaster for knee osteoarthritis

Purpose: Oral and topical nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely used to treat osteoarthritis (OA) and such use is recommended by various guidelines. In topical NSAIDs, ability in penetration of active ingredient into synovial tissue is essential for better therapeutic efficacy. We developed a new topical NSAIDs patch, S-flurbiprofen plaster (SFPP) for treatment of symptomatic OA. The active ingredient in the SFPP is S-flurbiprofen (SFP), an enantiomer of racemic flurbiprofen (FP) which is a strong COX inhibitor. Racemic FP patch has been commercially available in Europe, South Africa and Japan for many years. Here, we conducted two comparative studies in patients with knee OA in order to examine ability in tissue penetration and clinical utility of SFPP. Firstly, difference in concentrations of SFP in deep tissues (synovial tissue and synovial fluid) after application between SFPP and FP patch was examined in knee OA patients. Secondly, the clinical efficacy of SFPP was compared with FP patch in knee OA patients in randomized and well-controlled trial. Methods: Study 1: This was a randomized open-label, parallel group comparative study. Either SFPP (containing 20 mg of SFP, n = 10) or FP patch (containing 40 mg of FP, i.e., 20 mg of SFP, n = 9) was applied for 12 hours to the affected knee of OA patients who were scheduled for total knee arthroplasty. To compare SFP concentrations, synovial tissue and synovial fluid were collected during surgery at 31-55 minutes after patch removal. The applied patches were also collected to calculate the percutaneous absorption ratio. Study 2: This was a phase III, multi-center, randomized, active-controlled, and well-controlled trial. The study was carried out with both investigators and patients were blinded to the assigned treatment. A total of 633 symptomatic knee OA patients with Kellgren–Lawrence grade II or III were involved. Either SFPP (containing 40 mg of SFP, n = 316, once daily) or FP patch (containing 40 mg of FP, n = 317, twice daily) was applied for 2 weeks. The primary endpoint for treatment efficacy was improvement in knee pain assessed by visual analogue scale (VAS) when standing up from chair. The secondary and other efficacy endpoints were improvement in total clinical symptom score, and that in knee pain at walking assessed by VAS and investigator’s global assessment. Safety was also evaluated through the observation of adverse events (AEs). Results: Study 1: SFP concentrations in the synovial tissue and synovial fluid after application of SFPP were 14.8 times higher (p = 0.002, Figure 1A) and 32.7 times higher (p < 0.001) than those achieved by FP patch, respectively. The percutaneous absorption ratio of SFPP was also significantly higher (p < 0.001) than that of FP patch, with a mean value 7.6 times higher (Figure 1B). Concentrations of SFP in synovial tissue and synovial fluid were well correlated with the percutaneous absorption ratio, respectively (correlation coefficient; synovial tissue 0.785, synovial fluid 0.823). Study 2: VAS change in knee pain from baseline to the end of the trial was 40.9 mm with SFPP and 30.6 mm with FP patch (Figure 2). The VAS improvement rate in knee pain was 73.61% with SFPP and 53.33% with FP patch. Both results demonstrated the superiority of SFPP over the FP patch (p < 0.001). In clinical symptoms score, knee pain assessment at walking (VAS) and investigator’s global assessment, SFPP was also significantly better than FP patch (p < 0.001). The incidence of AEs by SFPP and FP patch at the application site such as dermatitis was 9.5% and 1.6%, respectively (p < 0.001). However no serious skin troubles such as photosensitivity were observed with SFPP. No significant difference was observed in the incidence of systemic AEs between the two groups.Figure 2. VAS changes in knee pain at standing up from chair. Data are presented as least squares mean + upper 95% confidence limit of change from baseline to the end of the trial. The significance level was set at 2.5% (one-sided, ANCOVA).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Conclusions: SFPP has a better ability in percutaneous absorption and tissue penetration than commercially available FP patch. SFPP has excellent potency in treatment of symptomatic knee OA.