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

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.

The effect of microneedles on the skin permeability and antitumor activity of topical 5-fluorouracil

Topical 5-fluorouracil(5-FU)is approved for the treatment of superficial basal cell carcinoma and actinic keratosis.However,5-FU suffers from poor skin permeation.Microneedles have been successfully applied to improve the skin permeability of small and large molecules,and even nanoparticles,by creating micron-sized pores in the stratum corneum layer of the skin.In this report,the feasibility of using microneedles to increase the skin permeability of 5-FU was tested.Using full thickness mouse skin mounted on Franz diffusion apparatus,it was shown that the flux of 5-FU through the skin was increased by up to 4.5-fold when the skin was pretreated with microneedles(500μm in length,50μm in base diameter).In a mouse model with B16-F10 mouse melanoma cells implanted in the subcutaneous space,the antitumor activity of a commercially available 5-FU topical cream(5%)was significantly enhanced when the cream was applied on a skin area that was pretreated with microneedles,as compared to when the cream was simply applied on a skin area,underneath which the tumor cells were implanted,and without pretreatment of the skin with microneedles.Fluorouracil is not approved for melanoma therapy,but the clinical efficacy of topical 5-FU against tumors such as basal cell carcinoma may be improved by integrating microneedle technology into the therapy.

COMPARATIVE TREATMENT OF ACNE VULGARIS USING PALOMAR LUX APPLIQU´E TECHNIQUE AND DIRECT INTRALESIONAL INJECTION

Intralesional injection of triamcinolone(TMC)preparations is an effective therapy for cystic acne lesions.However,invasive delivery techniques limit the use of this modality to a relatively narrow class of cases.Skin permeability can be enhanced through creating a lattice of microzones(islets)of light-induced limited thermal damage in the upper layers of epidermis.In this paper,we directly compared safety and efficacy of delivering TMC acetonide with this novel technique versus conventional intralesional injection for treatment of inflammatory acne lesions.A combination of an intense pulsed light system and a specially designed appliqu´e with a pattern of absorbing centers has been used to create the lattice of islets of damage(LID).Quantitative analysis has included estimation of the following parameters:redness,diameter,and height of acne lesions.Clinical photography has been used to document dynamics of lesion development at successive visits(two hours,24 hours and one week post-treatment).Seven subjects have participated in the study.No difference in lesion dynamics between the treatment and control groups was observed at two-hours follow-up.At 24-hours/one-week follow-ups,TMC-injected and TMC-LID-delivered groups have demonstrated 82%/93%and 80%/89%improvement in height of lesions in comparison to control(60%/68%).Delivery of TMC with the newly proposed LID technique is at least as effective as intralesional injection for treating inflammatory acne lesions.Enhancement of skin permeability using LID approach is a promising technique for accelerating delivery of various compounds to their target areas in the skin.