Abstract
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 skin 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/cm2/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.
Highlights
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat chronic pain of musculoskeletal disorders such as rheumatoid arthritis (RA) and osteoarthritis (OA)
We previously showed that SFP inhibits human cyclooxygenase (COX)-1 and COX-2 more potently than other traditional NSAIDs
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 to show superior absorbability as compared to ketoprofen and loxoprofen patches [6]
Summary
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat chronic pain of musculoskeletal disorders such as rheumatoid arthritis (RA) and osteoarthritis (OA). It is generally assumed that NSAIDs exert their effects by specific inhibition of cyclooxygenase (COX) activity, thereby inhibiting the production of PGs, including PGE2, a major mediator of inflammatory pain [1]. Chronic oral administration of NSAIDs is associated with the risk of a wide range of adverse effects, including gastrointestinal disorder. The transdermal patch method that allows percutaneous absorption of NSAIDs has been used as an alternative [2]. Topical NSAIDs offer various advantages, including avoidance of hepatic first-pass metabolism, and a lower risk of gastrointestinal adverse effects [3]. One of the disadvantages of topical NSAIDs is poor absorption of the drug. We sought to develop a novel topical NSAID patch containing a potent NSAID that would show efficient absorption of the drug
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