Evaluation of Sucrose Laurate as an Intestinal Permeation Enhancer for Macromolecules: Ex Vivo and In Vivo Studies.

Fiona Mccartney,Mónica Rosa,David J Brayden

doi:10.3390/pharmaceutics11110565

Abstract

Oral delivery of macromolecules requires permeation enhancers (PEs) adaptable to formulation. Sucrose laurate (SL) (D1216), a food grade surfactant, was assessed in Caco-2 monolayers, isolated rat intestinal tissue mucosae, and rat intestinal instillations. Accordingly, 1 mM SL increased the apparent permeability coefficient (Papp) of [14C]-mannitol and reduced transepithelial electrical resistance (TEER) across monolayers. It altered expression of the tight junction protein, ZO-1, increased plasma membrane potential, and decreased mitochondrial membrane potential in Caco-2 cells. The concentrations that increased flux were of the same order as those that induced cytotoxicity. In rat colonic tissue mucosae, the same patterns emerged in respect to the concentration-dependent increases in paracellular marker fluxes and TEER reductions with 5 mM being the key concentration. While the histology revealed some perturbation, ion transport capacity was retained. In rat jejunal and colonic instillations, 50 and 100 mM SL co-administered with insulin induced blood glucose reductions and achieved relative bioavailability values of 2.4% and 8.9%, respectively, on a par with the gold standard PE, sodium caprate (C10). The histology of the intestinal loops revealed little damage. In conclusion, SL is a candidate PE with high potential for emulsion-based systems. The primary action is plasma membrane perturbation, leading to tight junction openings and a predominant paracellular flux.

Highlights

Intestinal permeation enhancers (PEs) are present in the majority of solid-dose formulations currently in clinical trials for oral macromolecule delivery [1,2]
Neither control monolayers exposed to medium alone nor monolayers exposed to 0.05 mM Sucrose laurate (SL) displayed reduction in transepithelial electrical resistance (TEER)
0.5 mM SL reduced TEER to a nadir at 20 min, which was fully reversed after 24 h recovery in Dulbecco’s modified Eagle’s medium (DMEM) (Figure 2A). 1 mM SL reduced TEER for min, but it was not Pharmraecveuetricssib2l0e1.9,T1h1e, xbFaOsaRlPPEaEpRp RfoErV1I4ECW-mannitol in control monolayers was 0.99 ± 0.10 × 10−6 cm·s−1 in7 of the apical-to-basolateral direction

Summary

Introduction

Intestinal permeation enhancers (PEs) are present in the majority of solid-dose formulations currently in clinical trials for oral macromolecule delivery [1,2]. First generation PEs include medium-chain fatty acids (MCFAs), MCFA derivatives, bile salts, acyl carnitines, and EDTA [3] Though their mild perturbation action on intestinal epithelia in the high concentrations that are required in vivo is typical of surfactant-based detergents, the capacity of the intestine to undergo rapid epithelial cell turnover has not made the lack of specific mechanisms a barrier for the use of most of these PEs in oral peptide clinical trials to date [4]. Pharma hndaeanewsdliavcmnehraueynmnrudeifcmeaarclasttieunanrntiiidnntgyapbPrilseeEscsualiveinnsei.crosaIrilnaoslntamudtdoadicitetrhsiooelmniikn,oeclPleryhecuaabsrleemecdafaoufirshmneaausonflcaalintoaiowlunansnstd—daeburriesnltgilatueynsl,dashtatiohbgrelhyeycracoisvasknet raapsssirosowonvceiiltdaloetaetsmdhfeoowrrieimnthtcuhrulaeaanstisinaoengdn iffnioncrramenWmucileiaatnlthitaoadnnledsicn—arcderugeenasulsleoeasftsiopntrrhyeeefficryliicsncakiaccnaya.slpsaronocdviaicdteleidnmiwcoairltehretuhsesaiannrgcahnnieinnwcGrceehnmeeemrnaittcaiaollnine1ncrtMietayCsFePAEinss in oral macromolecule eafsfiicnatceyst.inal PEs to call ueuspptoaobnnWl[is[11hi0t0e,h1,d11d1]ien,],coaaounduryerasfpaoopprfrmpporaaroetcsachclsiwhuniiawtcsaaabtloslaesntfcodoarnsccoltiarhnnaeilctFfahoDlerrAmeFs-uDaelpaaArptci-roahonpvipneinrdGolfvieopenoideddr-fabaotdaiosoddenidtia1vsdeyMdssitCtteoiFmvsAeesss.e OatiofsfMistnheCteeeFsMAitfisCnMwaFlACePrFseE,Assasoltrdoweiaucedamrylel (lctcttaMpfidtsaSrhasroaoulriiuLiberrnarfCeacqebfrml)lcr-Flieu,FsaaossoecDt,MdutAi—cnunssetbrlyAeetlswaieect(rsn,ehCetcaoctefissan5ytoaoocd1sotiu2i2tootoenidnfoau)5sudmronsietbswlmruD[soieailp1minnimx[natda4sa1igcsghuhd]crc(2altliFatl(ei]aiscphahitis.idnn.uioagtsreevMaiernaru.c6ehibp,atlainro–tesioottadelog1eurwnriaet(ah41nctt(rCtoin)hCreaic[cc)mvoa1yr1beh,ru10lesi22)waasacltl)er.]afi,esoi,t.ocwhnrrIelsbdnaanirYi,sfexacucmluleCochpesetmerttcah1annaoatumC2tutiehtbtgtocssrees1ielate,saF2eetnh(ylshbtpDtSlptdsuiiaseeoaotLrgoAircie6rffntfh)oenatacas,–seaisuloefbcM1crdcsont[nnslu4o1beoewatocsolm2edaet[fitilfa]tn1trn5opiot.fn2taee2wtfwtarsMr]ddorah5r.aaltcdaeofiooDtcusYsouririrwrfoorrdtaatesioeeimhnnt,ltvor(isPebicFmevotouCfnEaeoiomleflgal1cudaorr2i0ttuamomtnb,arh.iuoda3rstiodeilceauftlsocinmulbletlmap1eeieyaenapl)Msois,stla)tsiosiuaitt,cceonteowsrw[capr,nnsoi1orlscaotiChot3tbmhotstdi]sirP1iefennc2etilioaeEniahffihctflanietleleieasimtsisdecncngucp—tmsuputteoairiarlscdrrleylootsaeoedCq-o[sfttosmbi1foitudnaseooif4attpifncipfrn]sstaeuooomoetaen(rmrl-orirtdciom2db.uaeefneywneldalcp.0usta,trtatoym.rttltsdh3speaPeiotsuooeoar-ttrEmPcestnexlcafhrucfEmorisitiMoorcentoebreisirsmmiinisnmee(an.nl[aCin1cuolctlCOamha3y1tlllluti0iuia]ea,ffnnag)soccortai.itihiitoautrcrnfcnohImetai-laingdxnea2eersll opfotshseibfialitttiyesacciodm. pared to the salt form of the fatty acid

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