Abstract
Apremilast (APR) is a selective phosphodiesterase 4 inhibitor administered orally in the treatment of moderate-to-severe plaque psoriasis and active psoriatic arthritis. The low solubility and permeability of this drug hinder its dermal administration. The purpose of this study was to design and characterize an apremilast-loaded microemulsion (APR-ME) as topical therapy for local skin inflammation. Its composition was determined using pseudo-ternary diagrams. Physical, chemical and biopharmaceutical characterization were performed. Stability of this formulation was studied for 90 days. Tolerability of APR-ME was evaluated in healthy volunteers while its anti-inflammatory potential was studied using in vitro and in vivo models. A homogeneous formulation with Newtonian behavior and droplets of nanometric size and spherical shape was obtained. APR-ME released the incorporated drug following a first-order kinetic and facilitated drug retention into the skin, ensuring a local effect. Anti-inflammatory potential was observed for its ability to decrease the production of IL-6 and IL-8 in the in vitro model. This effect was confirmed in the in vivo model histologically by reduction in infiltration of inflammatory cells and immunologically by decrease of inflammatory cytokines IL-8, IL-17A and TNFα. Consequently, these results suggest that this formulation could be used as an attractive topical treatment for skin inflammation.
Highlights
Inflammation constitutes a defense mechanism of the body
These results suggest that apremilast-loaded microemulsion (APR-ME) reduces the signs of inflammation induced by the action of Arachidonic Acid (AA)
Labrasol® is a non-ionic oil/water surfactant characterized by its low irritability for the skin and which is commonly used with Plurol® oleique in dermal formulations [42]
Summary
Inflammation constitutes a defense mechanism of the body. It is the response of the immune system against numerous harmful stimuli, among which include pathogens, toxic compounds and damaged cells [1]. Inappropriate or excessive inflammatory responses can trigger chronic damaged cells [1]. Inappropriate or excessive inflammatory responses can trigger chronic inflammation implicated in the pathogenesis of a wide variety of skin disorders [2]. Therapeutic treatment involves treating symptoms by interrupting the inflammatory process [3]. IAnPaRmwoadsiafipcpartoiovnedininth2e01s4igbnyatlhinegUpniattehdwSataytsesoFfocoedllsanbdelDonrugging to Administration (FDA) as oral therapy for the treatment of moderate-to-severe plaque psoriasis and the aicntnivaeteps(omriaotnicocayrtthersi)tisa[n9d,10a].dTahpitsivderu(gTcacueslelss)animinmtruacneelluslyarstaecmcumasulawtieolnl oafscyncolinc -aidmemnousninee cells (kermatoinnoocpyhtoessp)h[1a1te,1(2c]A. MInPt)h, erelsauslttidnegciandae,mnoodviefilcdatriuogn dineltihveersiygnsyalsitnegmpsaftohrwAayPsRohf acesllbsebeenlornegpionrgted in ordetro ttoheiminpnraotve e(mitosnsooclyutbesil)itayndanaddabpiotiavvea(iTlabceilliltsy) iimncmluudniengsyPstLemGAasnwaneollpaasrtnicolne-sim[1m3]u,naemcoelrlps hous solid(kedriastpineorcsyiotens)[[1141],,12n]a. Curroerdnetlryt,oAimPpRroisveavitsaisloalbulbeilintytaanbdlebtiofoarvmailaobfi1li0ty, 2in0claunddin3g0PmLGgAfonranooraplaratdicmlesin[1is3t]r,aatmioonrp[h1o7u].sHsooliwd ever, this driosupetersioofna[d14m],innaisntorsattriuocntuprerdesleipnitdscnarortiaebrsle[1d5]isaanddvnaanntoacgreystarel-lbaatseedd wfoirtmhualadtvioenrsse[1e6]f.feCcutsr,refnirtlsyt,-pass metaAbPoRliissmavaanildab, lme ionrteaobvleetrf,oirsmnooft1s0u, i2t0abanledf3o0rmpgatfioernotsrawl aidthmisnwisatrllaotiwonin[g17d].ifHfiocwuletvieesr,. Hcoorwneevuemr, th(SeCm)a, inwohbiscthaclleimofittsoptihcael fsopremeudlaotifontsraisntsodoevrmercaolmdeiftfhuessitorantuomf cvoarrnieouums (dSrCu),gs to achiwevheicthhleiminittsetnhdeesdpetehdeoraf ptreauntsidceermffeacl tdi[ff2u0–si2o2n].oDf vraurgioupserdmruegastitoonacthhireovue gthhetihnetenskdiend dtheepreapnedustiocn the physeiffceoccth[2e0m–2ic2a].l Dcrhuagrapcetremriesattiicosnothfrothueghdtrhuegskains dwepeellndassonthtehecphheymsiiccoaclhecmomicpalocshitairoanctearnisdticsphofysical proptheertdierusgoafsthweelclaarsrtiheer.cAhePmRiciasl coamtepgoosriitzioendaansdaphcylassicsalIVprodpreurgti,eas cocfothrdeicnagrriteor.tAhePRBisopcahteagromriazceedutical
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