Plasma pharmacokinetics and synovial concentrations of S-flurbiprofen plaster in humans

Yataba, Ikuko; Otsuka, Noboru; Matsushita, Isao; Kamezawa, Miho; Yamada, Itsunari; Sasaki, Shinsai; Uebaba, Kazuo; Matsumoto, Hideo; Hoshino, Yuichi

doi:10.1007/s00228-015-1960-6

Cited by 26 publications

(37 citation statements)

References 18 publications

(17 reference statements)

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“…We also showed that SFP was a 1000‐fold more potent than RFP at inhibiting PGE 2 production from peritoneal leukocytes stimulated with bacterial suspensions (IC 50 = 14 n m for SFP and 17 000 n m for RFP, respectively) Furthermore, we demonstrated that the skin permeability of SFP, the active ingredient of SFPP, was superior to that of ketoprofen or loxoprofen contained in the respective patches in Healthy SD rats, and also that application of SFPP was associated with the most potent analgesic efficacy and inhibitory effect on PGE 2 production in the AIA model among the three patches compared . Based on a clinical study, we reported that in knee OA patients, a higher drug penetration into the synovial tissues was observed for SFPP as compared to the FP patch . PGE 2 production is increased in the synovial fluid of OA patients .…”

Section: Discussionmentioning

confidence: 58%

“…We previously demonstrated the superior skin permeability of SFP as compared to that of FP in the yucatan micropig (YMP) model in vitro . Another clinical study demonstrated superior percutaneous absorption and greater tissue penetration of the active ingredient of SFPP as compared to that of an FP patch . We demonstrated in a previous study that topical application of SFPP produced an immediate and strong analgesic effect in a rat model of adjuvant‐induced arthritis (AIA) .…”

Section: Introductionmentioning

confidence: 99%

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Analgesic effect of S (+)-flurbiprofen plaster in a rat model of knee arthritis: analysis of gait and synovial fluid prostaglandin E2 levels

Fukumoto

Tajima

Hori

et al. 2018

Journal of Pharmacy and Pharmacology

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ObjectivesWe developed S (+)‐flurbiprofen plaster (SFPP), a novel NSAID patch containing S (+)‐flurbiprofen (SFP), a potent cyclooxygenase (COX) inhibitor. The purpose of this study was to assess efficacy of SFPP by analysing its effect on the gait disturbance and measuring the prostaglandin E2 (PGE 2) production in synovial fluid in a rat model of knee arthritis.MethodsKnee inflammation was induced in rats by intra‐articular injection of a yeast suspension. Subsequently, an NSAID patch containing SFP, ketoprofen or loxoprofen was applied over the affected knee. Gait was assessed at 2, 4 and 6 h after application of the patch. The PGE 2 concentration in the synovial fluid was measured after the gait assessment.Key findingsApplication of SFPP (0.125, 0.25, 0.5 or 1 mg/sheet) was followed by a decrease in the visual gait score at all the doses examined. In the case of the other two NSAID patches, only the ketoprofen patch (1 or 2 mg/sheet) and loxoprofen patch (5 mg/sheet) produced a decrease in the visual gait score. All of the NSAID patches decreased the PGE 2 production in the synovial fluid.ConclusionsThese results suggest the potential usefulness of SFPP as an analgesic patch in patients with inflammatory joint pain.

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Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Analgesic effect of S (+)-flurbiprofen plaster in a rat model of knee arthritis: analysis of gait and synovial fluid prostaglandin E2 levels

Fukumoto

Tajima

Hori

et al. 2018

Journal of Pharmacy and Pharmacology

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“…Although topical NSAIDs have a lower risk of gastrointestinal disorder compared with oral NSAIDs,6 the use of SFPP might increase the risk due to its high percutaneous absorption and systemic exposure 19. Nevertheless, the study results demonstrated low incidence of gastrointestinal disorder in SFPP groups (0%, 0.8%, and 0.7% in SFPP 10, 20, and 40 mg, respectively), indicating that SFPP had a similarly low risk as that of existing topical NSAIDs.…”

Section: Discussionmentioning

confidence: 69%

“…In a study conducted in healthy adult males, SFPP provided sustained and stable plasma levels of S-flurbiprofen 19. Furthermore, a study in knee OA patients demonstrated higher synovial transfer of S-flurbiprofen compared with that of an existing flurbiprofen patch formulation 19.…”

Section: Introductionmentioning

confidence: 99%

The efficacy and safety of S-flurbiprofen plaster in the treatment of knee osteoarthritis: a phase II, randomized, double-blind, placebo-controlled, dose-finding study

Yataba¹,

Otsuka²,

Matsushita³

et al. 2017

JPR

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BackgroundNonsteroidal anti-inflammatory drug (NSAID) patches are convenient for use and show much less gastrointestinal side effects than oral NSAIDs, whereas its percutaneous absorption is not sufficient for the expression of clinical efficacy at satisfactory level. S-flurbiprofen plaster (SFPP) has shown dramatic improvement in percutaneous absorption results from animal and clinical studies. In this study, the efficacy and safety of SFPP were compared with placebo in patients with knee osteoarthritis (OA) to determine its optimal dose. This was a multicenter, randomized, double-blind, parallel-group comparative study.Patients and methodsEnrolled 509 knee OA patients were treated with placebo or SFPP at 10, 20, or 40 mg applied on the affected site once daily for 2 weeks. The primary endpoint for efficacy was improvement in knee pain on rising from the chair assessed by visual analog scale (VAS). The other endpoints were clinical symptoms, pain on walking, and global assessment by both investigator and patient. Safety was evaluated by observing adverse events (AEs).ResultsVAS change in knee pain from baseline to trial end was dose-dependent, least squares mean was 29.5, 31.5, 32.0, and 35.6 mm in placebo and SFPP 10, 20, and 40 mg, respectively. A significant difference was observed between placebo and SFPP 40 mg (P=0.001). In contrast, the effect of SFPP at a dose ≤20 mg was not significantly different from that of placebo. The proportion of the patients who achieved 50% pain relief was 72.4% in 40 mg and 51.2% in placebo (P<0.001). In all other endpoints, SFPP 40 mg showed significant improvement compared with placebo. The incidence of AEs was not different across all four groups, and no severe AEs were observed.ConclusionClinically relevant pain relief was observed in all groups including placebo. Especially 40 mg showed remarkable pain relief in not only primary endpoint but also all the other endpoint with significant differences over placebo. The safety profile of SFPP 40 mg was not different from that of placebo. Therefore, 40 mg was determined as the optimal tested dose.

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“…We showed in an experimental study using rats that the NSAID patch developed by us, the S-flurbiprofen plaster (SFPP), containing an (S)-enantiomer of flurbiprofen, was demonstrated to rapidly suppress inflammatory pain in the rat AIA model and also to show superior absorbability as compared to ketoprofen and loxoprofen patches [6]. Furthermore, we reported that the superior percutaneous absorption and greater tissue penetration of SFP into the human synovial tissue following application of SFPP in knee osteoarthritis (OA) patients [7].…”

Section: Introductionmentioning

confidence: 99%

S(+)-Flurbiprofen Shows Potent PGE2 Inhibitory Activity in Inflammatory Cells, Superior Cell Transport Activity and Skin Permeability

Toda¹,

Sugimoto²,

Endo³

et al. 2016

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We developed a novel topical non-steroidal anti-inflammatory drug (NSAID)patch, S(+)-flurbiprofen plaster, (SFPP), containing S(+)-flurbiprofen (SFP), an enantiomer of flurbiprofen (FP).In a previous study conducted in an animal model, we showed good skin absorption and potent analgesic efficacy of SFPP. In this study, to examine the superior features, as an NSAID patch, of SFP as compared to FP and R(−)-flurbiprofen (RFP), we tested the stereospecificity of SFP actions on Prostaglandin E2 (PGE2) inhibition in rat inflammatory leukocytes and in the binding activity of the drug to cells, and also the in vitro skin permeability of the drug in the Yucatan micropig (YMP). SFP showed potent inhibitory activity on PGE2 production from peritoneal leukocytes stimulated with a bacterial suspension, as compared to RFP and FP. The half maximal (50%) inhibitory concentration (IC50) values were 14 nM for SFP, 52 nM for FP, and 17,000 nM for RFP. In the cell binding study, significant and rapid increase of SFP binding to polymorphonuclear leucocytes (PMNs) was observed at 5 min after incubation, eventually reaching a steady state. SFP showed significantly higher binding activity for the inflammatory leucocytes as compared to RFP, suggesting its superior transfer potency. The skin permeability profile of SFP, RFP and FP in the YMP model showed that the rank order of the cumulative amount of permeated compounds in the * Corresponding author. Y. Toda et al. 306skin was SFP > RFP > FP. The steady-state permeation rate (Flux) of SFP was significantly higher than that of FP (4.89 and 1.55 mg/cm 2 /h, respectively, p = 0.0068), indicating the remarkably superior skin permeability of SFP. SFP exerted potent inhibitory activity on PGE2 production and superior binding activity to the PMNs and skin permeability, as compared to FP and RFP. These results suggest that SFP possesses favorable characteristics for use as an active ingredient in the NSAID patch.

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Plasma pharmacokinetics and synovial concentrations of S-flurbiprofen plaster in humans

Cited by 26 publications

References 18 publications

Analgesic effect of S (+)-flurbiprofen plaster in a rat model of knee arthritis: analysis of gait and synovial fluid prostaglandin E2 levels

Analgesic effect of S (+)-flurbiprofen plaster in a rat model of knee arthritis: analysis of gait and synovial fluid prostaglandin E2 levels

The efficacy and safety of S-flurbiprofen plaster in the treatment of knee osteoarthritis: a phase II, randomized, double-blind, placebo-controlled, dose-finding study

S(+)-Flurbiprofen Shows Potent PGE2 Inhibitory Activity in Inflammatory Cells, Superior Cell Transport Activity and Skin Permeability

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