Advances in Textile Engineering -...

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Biofunctional TextilesManuel J Lis1*; Meritxell Martí2; Luisa Coderch2; Cristina Alonso2; Fabricio M Bezerra3; Ana P Immich4; José A

Tornero1

1INTEXTER-UPC, Colon, 15. 08222 Terrassa. Barcelona. Spain.

2Institute of Advanced Chemistry of Catalonia (IQAC-CSIC). Jordi Girona 18-26. 08034 Barcelona, Spain

3Textile Engineering, Federal University of Technology – Paraná, 635 Marcilio Dias St., Apucarana, 86812-60,Parana,

Brazil

4Universidade Federal de Santa Catarina, Departamento das Engenharias, Campus Blumenau, SC – Brasil

*Correspondence to: Manuel J Lis, INTEXTER-UPC, Colon, 15. 08222 Terrassa. Barcelona. Spain

Email: manuel-jose.lis@upc.edu

Chapter 1

Advances in TextileEngineering

Abstract

TheaimofthechapteristostatedifferentnewpossibilitiesthattextilesubstratesofferformorespecializedfunctionsasBiomedicaldevices,Cos-metics,Skintreatment,andwhicharethemechanismsinvolvedinsuchnewapplications.Howtoquantifythetransportphenomenafromthesubstratetotheskin,ortosurroundingdifferentmedium,inwhichtheyhavetobeused.

Textilesarecovering80%ofthehumanbodyandabigpercentageofthatisinclosecontactwithskin.Ifthesystemofvehiculizationoftheactiveprinciplesis,carefully,designed,thereservoireffectofthepolymericchainsoffiberscanplayavery interesting role in thedeliveryof theactiveprin-ciple.

Microencapsulation, lipidic aggregates and nanofibers, have shownverypromisingexperimentalresults.Theseresultswillhelptootherresearch-erstodevelop,moreaccuratesystems,whichwillvalorizetextilesubstrates,fibersandtissuesfortheuseinmoresophisticatedfields.

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AdvancesinTextileEngineeringLi

1. Introduction

1.1. Textile substrates, as “active systems”

Biofunctionaltextilesarethetextileswithsmartandnewpropertiesandaddedvalue,especiallyrelatedtocomfortorspecificfunctions.Suchtextilesconstitute thebasisfor thedeliverysystemofcosmeticorpharmaceuticalsubstanceswhenthetextilecomesintocontactwiththeskin.Asmostofthehumanbodyiscoveredwithsomesortoftextile,thepotentialofbiofunctionaltextilesisconsiderable.Textilesthathavefunctionalpropertiesfortheskinhavebeenstudiedandpatentedinrecentyears[1,2].

Sincetimeimmemorial,textilefabricshavebeenimprovedtoassistskinfunctionbyensuringhomeostasisofthewholebody.Practicalfunctionsofclothingincludeprovidingthehumanbodywithprotectionagainsttheweather–strongsunlight,extremeheatorcold,andrainorsnow–andagainstinsects,noxiouschemicalsandcontactwithabrasivesubstances.Clothingoffersprotectionagainstanythingthatmightinjurethenakedhumanbody.Thisisbecausetextileshavealwaysbeenconsideredasa“second skin”forhumanbeings.

Asaresultofnewtechnologies,technicalbioactiveorbiofunctionaltextilesarecurrentlybeingproduced.Suchfabricsareabletoabsorbsubstancesfromtheskinorreleasetherapeuticorcosmeticcompoundstoit.Thetextileindustrytogetherwithmedicalknowledgehaspavedthewayforenrichingtheuseoftextilefabricsbecauseoftheirinteractionwiththeskin[3].

Percutaneousabsorptionisaninterdisciplinarysubjectthatisrelevanttoanumberofwidelydivergentfields.Transdermaldevicesmaybeconsideredasoneoftheprecursorsofbiofunctional textilesgiven that theydeliveracompoundwitha therapeuticeffect into thebody[4,5].

Bioactivetextilesarenew,innovativetextileproductsthatarepushingbacktheboundariesoftextileapplications.Theycanactas“reservoirsystems”andareabletocontinuallyreleasecontrolleddosesofactivesubstancesfromthetextiletotheskin.Severalactivecompoundshave been applied onto textiles using different vehicles asmicro or nanocapsules in ordertoimprovethefixationonthefabricandtheprogressiveandeffectivereleaseoftheactiveprincipleintothedifferentskinlayers(stratum corneum,epidermisordermis).

1.2. Mechanisms involved and their quantification

1.2.1. Transdermal drug release into the skin

Transdermaldrugreleaseisaviableadministrationrouteforpowerful,low-molecular-weighttherapeuticagentsthatmustbepreciseinitscontrolofdrugadministration.Thesystemshouldensuretherequireddosesandavoidtheminimumtoxicconcentration[6].Thisstrategy

AdvancesinTextileEngineering

is especially recommended formany drugs that are difficult to take because theymust bedeliveredslowlyoveraprolongedperiodtohaveabeneficialeffect.Forinstance, thedrugreleasemodellingofbiodegradablepolymericsystemsasencapsulationtechnologiesintextileshasnotyetprogressedappreciablyduetoitshighcomplexity.

Transdermaladministrationalsocantakeadvantageofchemicalandphysicalstrategiesthat can improve skin permeability and allow for drug penetration [7-14]. Specifically,transdermal drug delivery is a viable administration route for powerful, low-molecular-weighttherapeuticagentsthateithercanorcannotwithstandthehostileenvironmentofthegastrointestinaltract[6].Regardlessofthenecessityforphysical-chemicalenhancement,forthe reliable and effective design of transdermal delivery systems, knowledge of the skin’sstructure(seeFigure 1)anditspropertiesisfundamental[9].

Empiricalanalysisofthepermeationofdrugsthroughtheskinisbasedonapproachessuchasaneuralnetworkmodellingtopredictthepermeabilityofskin[15-22].

GuyandHadgraft[23]developedamathematicalmodelforinvestigatingtheeffectofthevariationinthicknessduringdrugreleasethroughtheskin.Accordingly,theexperimentalpermeation data are fitted by the following equation, which suitable for describing thepermeationofadrugthroughathinmembrane:

whereMt is thetotalamountofdrugthatpassesthroughthelayersofskin,Ls is the thicknessof thestratum corneum andL0 the formulation thicknessoverperiod t.Ds is the diffusioncoefficientofthedrugthroughthedifferentskinlayers,andKisapartitioncoefficient

Figure 1: Schematicrepresentationofthetransportprocessesinvolvedindrugreleasefromtheformulationuptoitsuptakethroughthedermalcapillaries[6].

betweentheskinlayersandthedrugformulation(typicallyK=concentrationinskinlayer/concentrationinvehicle).

1.2.2. Release mechanisms from vehicles and substrates

Thereleaseofanactiveagentinanon-erodiblecore-shellsystemcanshowdifferentprofilesofdelivery.InFigure2,fourpossibletheoreticalcurves(A,B,CandD)showtheglobalbehaviorsofthereleasephenomenaindifferentsituations.

CurveAshowsaperfectreleaseprofile.Itshowsasystemwheretherateofdeliveryiscontrolledbythediffusionoftheactiveagentmoleculesthroughtheexternalmembrane.Therateofreleasedependsstronglyontheinternal-externalconcentrationgradient.

If there exist somemolecules that are retained in the shell, then a lag-time on thereleasewillbeobtained.Then,therewillbetwocontrollingstepsanddiffusionwillundergoatransitionalintermediatestate.CurveAinFigure2displaysasystemwithnolag-time.Whentheencapsulatedmaterialmigratestotheexternalmembraneofthemicrocapsule,therewillbea“burst-effect,”asshownbylineB.

Ifthemicrocapsuleactsasamicrosphere(theentireamountofactiveagentisdistributedinthepolymermatrix),theHiguchiequationisusefulupto60%release.Inthiscase,aplotofpercentreleasedversussquarerootoftimeislinear,asshownbylineC.First-orderreleaseisrepresentedbycurveD.ThecurvewillbelinearwhentheLogofthepercentageofcorematerialremaininginthecapsuleisplottedversustime[25].

Themainaimistoapplyamathematicmodelbasedonthephenomenologyinvolved,toexplainin vitropermeationexperimentswithabiofunctionaltextileusingdifferentmolecules,astracers.

TheKorsenmeyer-Peppas,equation(2),canbeusedtoaccountforthecoupledeffectsof

Figure 2: Theoretical release curves expected for different types of non-erodible delivery systems.A,Membranereservoir-typefreeoflagtimeandbursteffects;B,sameasA,withbursteffects;C,matrixormonolithicspherewithsquareroottime-release;D,systemwithfirst-orderrelease[24].

Fickiandiffusionandviscoelasticrelaxationinpolymersystemsbyincludingbothprocesses:

WhereMtistheamountofdrugreleasedattimet,M∞isthemaximalamountofthereleased drug at infinite time, k is the rate constant of drug release, and n is a diffusionalexponentthatdependsonthesystemgeometry,andthevalueofnisindicativeofthereleasemechanismoftheactiveagent.

Eq(2)hasbeenusedfrequentlyintheliteraturetodescribetherelativeimportanceoftransportmechanismsasshowninTable1[26-32].

Historically,thefirstmathematicalmodelofdrugpermeationthroughtheskinwasthatproposedbyHiguchi.Sincetheestablishmentofthemodel,manyotherauthorshaveconductedexcellentresearchstudiesonthistopic,developingseveralmodelsbasedonchangesinactiveprincipleconcentrations

ThetransportinpolymericorganizedsystemscanbedescribedbyFick’ssecondLaw,sothediffusionoftheactiveagentcanbeassumedasaplanesurfaceforshorttimesofliberation,usingtheHiguchiequation(eq.4)fortocalculatetheapparentdiffusioncoefficient,usingtheapproximationofeq.(3),whereDistheapparentdiffusioncoefficientofdrugrelease,andδisthewidthoftheplanarmatrix.

Themostwidelyusedmodel todescribedrugrelease frommatrices isderivedfromHiguchiforaplanegeometry,whichisapplicableforsystemsofdifferentshapesaswell.

2. Active Principles used in Micro/Nanoencapsulation for textiles

2.1. Polymers

Encapsulation isoneof the techniquesused to apply substances to textiles [33,34].Biodegradablepolymermicro-ornanoparticlesareofgreatinterestasdrugdeliverysystemsbecauseof theirability tobe reabsorbedby thebody.Syntheticaliphatic linearpolyesters,suchaspoly-ε-caprolactone (PCL), areoftenused inbiomedical applications [35]because

n Drug Delivery Systems

n≤0.5 FickianDiffusionMechanism

0.5<n<1 AnomalousDiffusion

n≥1 Non-FickianDiffusionMechanism(zero-ordermodel)

Table 1: Drugdeliverymodelsbasedontheparametern.

theyarebiocompatible,non-toxicandhavecertainadvantagesoverotherpolymerssuchasPLA(polylacticacid):(a)thepolymersaremorestableunderambientconditions;(b)theyaresignificantlylessexpensiveand,(c)theyarereadilyavailableinlargequantities[36].

2.2. Ibuprofen

Ibuprofen was used as active principle-tracer. Ibuprofen is an anti-inflammatorysteroid.Itisusedtorelievesymptomsofarthritis,primarydysmenorrhoea,fever,andasananalgesic,especiallywherethereisaninflammatorycomponent.Ibuprofenappearstohavethelowestincidenceofgastrointestinalreactionsadverseofallnon-selectivenon-steroidalanti-inflammatorydrugs(NSAIDs).However,thisonlyoccursatlowerdosesofibuprofenbecausetheusuallyadvisablemaximumdailydose is1,200mg.Adverseeffects includedyspepsia,nausea,ulcers/bleedinggastrointestinal, increasedhepaticenzymes,diarrhoea,constipation,epistaxis,headache,dizziness,priapism,rash,saltandfluidretention,andhypertension.

2.3. Caffeine

Caffeineisotheractiveprincipleusedtopreparebiofunctionalcottontextiles.Caffeinewasselectedgivenitsuse inseveralspecific therapiesanditswidespreaduse incosmeticsbecauseofitsstimulatingactivityonfatmetabolism(anti-celluliteaction)[37-39].Especialemphasiswasplacedonthereleaseofthisactiveprinciplefromtheformulationsandfromthecottonfabricsandonitstransdermaldeliveryinordertoreachthetargetcompartmentoftheskin.

2.4. Gallic Acid (GA)

GAwasselectedandincorporatedintopolyamide(PA)throughmicrospherespreparedfrompoly-ε-caprolactone(PCL).Gallicacid(GA)waschosenastheactiveagenttoobtainabiofunctionaltextilewithantioxidantproperties.Antioxidantsarenaturalagentsthatareusedtoprevent the external aggressionofoxidative stress inhumanbeings.The route to applydifferent compounds is clearly through the skin.When topically applied, these exogenousantioxidantshavebeendemonstratedtodiminishtheeffectsoffreeradicalsbyusingdefensemechanismssimilarorcomplementarytothoseofendogenousantioxidants[40-41].

2.5. In vitro drug release experimental results

AfterGAencapsulationandapplicationontocotton(CO)andpolyamide(PA)fabrics,theresultsobtainedareshowninFigure 3.

Figure 3: SEMmicrographsofPCL-MicrosphereswithGA.A)Cottonfabric(x1000).B)Polyamidefabric(x1000)

COfibersallow themicrospheres tobeplaced incornersandspaceswhichcreateaproperfiberstructureandPAaccepts themicrospheresbetweenfibers.Visually,PAretainsmoremicrospheres thanCO.This is in accordancewith thehigher amountofdryproductpresentinthePAfabric.

Toperformtheanalysisofthemechanismofthedrugdeliverysystem,thetreatedfabricsamplesweresubmergedintoasemi-infinitebathofphysiologicalsaline,andeveryxminutes,abathaliquotewaspickedupandanalysedbyHPLC.

InFigure 4,itcanbeseenthatPAreleasesGAmorequicklythanCO,andPAreachesequilibriumbeforeCO.

UsingEq.(2)on thevaluesof thefirststeps(Figure 4), theexponentn isobtained,whichisindicativeofthedrugdeliverymechanism(Table 2).

3. Lípids as Vehicles for Skin Treatment

Liposomes are vesiclesmade up of lipids that can encapsulate different compoundsfor applicationonto textiles.Liposomeshavebeenused asmodels for complexbiologicalmembranes in biophysical and medical research owing to their lipid bilayer structural

Figure 4: KineticreleaseofGA(M)appliedontextilefabricsinabathofserumat37°C.

Table 2: nvaluesobtainedfromfittingdrugreleaseexperimentaldatabyequation2.

n Drug delivery systemCOfabric 0.46 FickiandiffusionPAfabric 0.63 Anomalousdiffusion

similarity.Moreover,theyhavebeenthesubjectofnumerousstudiesgiventheirimportanceasmicroencapsulationdevicesfordrugdeliveryandtheirapplicationsincosmetics[41-45].Inrecentyears,liposomeshavebeenusedinthetextileindustryasdyeingauxiliaries,mainlyforwooldyeing[46,47]orasadispersingauxiliaryfordispersedyes[48,49].

Wool isakeratinized tissuewhose internal lipidshavebeenextractedandanalyzed.Theselipidsarerichincholesterol,freefattyacids,cholesterolsulphateandceramidesandtheyresemblethosefoundinmembranesofotherkeratinizedtissuessuchashumanhairorstratum corneumfromskin,becauseoftheircapacitytoformstablebilayerstructures.Accordingly,IWLcouldberegardedasanewandnaturalformtoencapsulatedifferentactiveagentsorasactiveagentsforskincare[50,52].

3.1. In vitro percutaneous absorption experiments (Franz diffusion cells) and cutaneous effectivity

Forthesestudies,pigskinwasusedwithathicknessofapproximately500±50μm.Skindiscswitha2.5cminnerdiameterwerepreparedandfittedintostaticFranz-typediffusioncells.

Acontrolskindisc(withoutproductapplicationontheskinsurface)wasusedtoruleoutpossibleinterferencesintheanalysisbyHPLC-UV.AccordingtotheOECDmethodology[5],theskinpenetrationstudieswereperformedfor24hofclosecontactbetweenthetextileandtheskin.Toincreasethecontactpressurebetweenthetextilefabricandskin,permeationexperimentswerealsocarriedoutbyplacingasteelcylinderonthetextile-skinsubstrateataconstantpressureinaccordancewithstandardconditions(125g/cm2)(ISO105-E04,1996)(seeFigure 5).

Aftertheexposuretime,thereceptorfluidwascollected,thefabricswereremovedfromtheskinsurfaceandcollectedtogetherwiththetopofthecell.Thestratum corneumoftheskinwasremovedusingadhesive.Theepidermiswasseparatedfromthedermisafterheatingtheskin[53].

The efficacy of the biofunctional textiles in close contactwith skinwas studied by

Figure 5:Diagramofin vitropercutaneousabsorptionexperiments.

measuringchangesintransepidermalwaterloss(TEWL)asanindexofskinbarrierrepair,whereasthewater-holdingcapacitywasmeasuredaschangesinskincapacitance[54].

Skintapestrippingisan in vivomethodologyusedtodemonstratethepenetrationoftheprincipleintotheoutermostlayersofvolunteerforearmskin[55,56].Thisisaminimallyinvasive technique to sequentially remove SC by the repeated application of appropriateadhesivetapes[57].

Usingthesemethodologies,itwasconcludedthatliposomes,especiallythosepreparedwithIWL,weresuitablevehiclesforapplyingagivenactiveprincipleontotextiles.

3.2. Gallic Acid (GA) encapsulated in lipid structures

GAwasencapsulatedintoliposomesandappliedtodifferentfabrics,cotton,polyamide,polyester,acrylicandwool,usingbathexhaustionandthepad-dryprocesses.GAabsorption-desorptionbehaviorofthedifferenttextileswascomparedusingthetwomethodologies(byweightdifferenceandbyextractionanddetection).

Also,GAwasencapsulatedinliposomesandinmixedmicellesforapplicationtocottonandpolyamide.GAabsorption-desorptionbehaviorofthetextileswasalsodeterminedusingthetwoimpregnationmethods.

3.2.1. Liposome/Mixed Micelle Preparation for Gallic Acid

Liposomesof4%ofEmulmetik900 (PC)and2%GAwerepreparedusing thefilmhydrationmethodreportedelsewhere[58].Mixedmicelles(30wt%ofsurfactant,4wt%ofPCand2wt%GA)werepreparedsolubilizingallcompoundsindistilledwater;solubilisationwasperformedbygentlyshakinguntilclearsolutionswereobtained.

ParticlesizesofliposomesandmixedmicellesweremeasuredbyusingDynamicLightScattering(DLS),todeterminesizedistribution,polydispersityindexandzetapotentialofthetwolipidicstructures.

Toquantify theGAentrappedin thevesicles, liposomeformulationwasprecipitatedandseparatedfromthesupernatantbycentrifugation.TheefficacyentrapmentpercentageofGAinliposomeswasdeterminedwiththeamountoftheactiveprinciplepresentinthewholeliposomesolutionaswellasinthesupernatant,usingaGAcalibrationcurve.

3.2.2. Textile application and absorption/desorption process.

Theapplicationofliposomesorthemixedmicellesontothefabricswasperformedbybathexhaustionandthefoulardpaddingprocess[59].

Liposomes and mixed micelles were also applied to textiles in triplicate with bathexhaustion, liquor ratio1/5,at60ºCfor60minwithmanual stirringevery10minutes.Toquantifytheamountofliposomesormixedmicellesabsorbedintothefabrics,thedrysampleswereweightedbeforeandafter24happlicationunderstandardambientconditions(20±2ºCand65±5%relativehumidity).

Treated fabrics were washed in three different water baths at room temperature. Inallcases,thedrysampleswereweightedbeforeandafter24hofthewashingprocessunderstandardambientconditions.Thefirstwashingstepwasperformedwithdeionisedwater(1/5liquorratio)for5minwithmagneticstirring.Asecondwashwascarriedoutwithdeionisedwater(1/10liquorratio)for5minwithmagneticstirring,andthethirdwash,withdeionisedwater(1/25liquorratio)for5minwithmagneticstirring.Particlesizeandzetapotentialweremeasuredinthebathsaftertheexhaustiontreatmentandinthebathsafterthefirstandthirdwashingsasdescribedfortheinitialformulations.

ThehighersubstantivityofthephospholipidliposomesforsomefiberslikePAC,PAandWOwasclearlydemonstratedbyanabsorptionlevelhigherthan15%forallthesefibers.Desorptionwithwaterwas also evaluated for all the treated fabrics.Results of remainingliposomeinpercentagearealsodescribedinTable 3.

Asinthecaseofthepaddingprocess,thehighestdesorptionwasobtainedforthemostsyntheticPACandPESfabrics, followedbyCOandWO.Thehighest retainedamountofliposomeswasobtainedforthePAfabric.

Bothliposomesandthetextilefibersareusuallyelectricallycharged.Theyaresurroundedbyacloudofionswhichcarryanequalandoppositecharge.Thezetapotentialisthevoltagedifference between the droplet surface and the liquid beyond the charge cloud. InitialGAliposomeformulationappliedtotextileshasanacidicpHof3.3withazetapotentialof-4mV.However, in thewashingbaths thepHrises toaround5.0and thezetapotential toaround-50mV.Theincreaseinthewaterlayersaroundanegativechargeduetodilutionrendersthezetapotentialmorenegative.Moreover,thenatureofthechemicaldissociablegroupsinthetextilefibersurfaceinducesanegativezetapotentialofthefibers,seeTable4[60,61].

Table 3: Percentageofliposomeabsorbedanddesorbedonthedifferentfabrics,CO,PA,PES,PACandWOusingthebathexhaustionmethodology.(%owf:percentageoverweightoffiber)

Ini. weightg Fin. weight % owf Weight 1st washing % owf Weight total washing % owf

CO 2.00±0.01 10.99±0.39 7.32±2.43 5.58±0.39

PA 2.05±0.04 16.34±1.23 12.73±1.94 7.31±0.64

PES 2.07±0.01 14.05±1.15 9.64±1.53 2.05±0.50

PAC 1.98±0.06 17.44±1.09 13.20±0.93 4.25±0.33

WO 2.04±0.04 17.15±0.90 12.95±1.05 6.17±0.51

COisthemosthydrophilicfiber,itshigherswellingcapacityyieldingtosmallerzetapotentialvalues than the hydrophobic fibers. PAC and, especially PES fibers contain sulfonic andcarboxylicgroups,respectively,contributingtothemostnegativezetapotential.BecauseWOhas carboxylic and amino groups near the surface, negative or positive zeta potentials arefoundwhenthepHisoverorunderitsisoelectricpoint3.5.PAhasamoderatehydrophilicity,inferiortocottonbutsuperiortoPESandPAC.Moreover,itsweaklybasicaminogroupsandweaklyacidiccarboxylicacidgroupsgiverisetotheionicpropertiessimilartoWO.

IntheabsorptionprocessatpH3.3,mostofthefabricshaveaneutralorcationiccharacterwiththeresultthatabsorptionissimilar.InthewashingbathsatpH≈5andmorenegativezetapotential,textilesalsohavehighernegativevalues.ThedesorptionofthePESandPAC(thefiberswiththemostnegativezetapotential)isthereforeabout85%and75%,respectively.Bycontrast,desorptionofWO,PAandCO(thefiberswiththeleastnegativezetapotential)isabout65%,55%and50%,respectively.ThehighestfixationpropertiesdemonstratedbythelowestdesorptionofPAandCO,togetherwiththehighestcomfortpropertiesofthesefiberswhenincontactwiththeskin,endorsetheirapplicationascosmeticbiofunctionaltextiles.

In mixed micelles, the two constituent phospholipids and the surfactant agent arestructuredtogetherinsmallmicelles,givingrisetoatransparentsolution.However,dilutionofmixedmicellespromotestheseparationofthesurfactantandthephospholipidswithformationofliposomes.Thisresultsinalargeincreaseinsize,givingrisetoaturbidsolution[62].Theabsorptionofmicellesbytextilescouldbemaintainedafterawashingprocessbecauseofanexpectedincreaseinsizeofthevehiclesinsidethefiber.Thiscouldenhancethefixationintextileswithlessdesorptionasoccursintheskin[63,64].

Thiswasexpected,owingtoliposomeformationwithdilution.Besides,zetapotentialisalwaysnegativewithsmallvaluesforthetwoconcentratedformulationsaround-4mV(Table5).They increasewith dilution in absolute value to -20mV for themixedmicelles and to-50mVforliposomes.Theseincreasesinnegativelychargedareduetotherepulsionchargesinthedilutions,whichincreasethecolloidstability.

Table 4:Z-potentialsoftextilefibersinaqueousneutralmedia(83).

CO PA PES PAC WO

PotZ.(mV) -33 -42 -74 -47 -45

Asintheliposomeformulation,theapplicationoftheactiveagentvehiculizedinmixedmicelles(36%ofdryproductand2%GA)tothetextilesubstrates,COandPAwasperformedbythefoulardprocessinanattempttoachieveapick-upofapproximately90-100%.

Whenmixedmicelleswereappliedtothefabrics,thereweredifferencesofabout35%betweenthecalculatedamountofproductimpregnated(34-35%)andtheproductfoundinthefabricafterheatingattheStenter(22-23%).Thiscouldmeanthatthesurfactant,whichisthemaincomponentofthemixedmicelles,hashighersubstantivityforwaterthanforthetextiles.COandPAincorporatealmostthesameamountofproduct(about23%)whichismuchhigherthantheamountofproductabsorbedwithliposomes(seeTable 3).Desorptionwithwaterwasalsoevaluatedforthetwofabrics.ResultsofremainingmixedmicellesinpercentagearealsodescribedinTable 6andaregraphicallyrepresentedinFigure6.Forcomparison,theresultsobtainedwithliposomesarealsoshown.

ThesamemixedmicellesformulationwasappliedtocottonandPAbybathexhaustionasdescribedintheexperimentalsection.TheinitialweightswiththepercentagesofdryproductcalculatedbyweightdifferencebetweendryinitialfabricanddryfabricafterbathexhaustionareshowninTable 7.

Table 5: Meansize,polydispersityindexandZpotentialofinitialliposomeandmixedmicelleformulationsandtheirdilutions.

Formulation Mean Size (nm) Polydispers. Index Z-Potential (mV)

Liposome4%PC 717.40±56.25 0.74±0,03 -4.3±0.30

Liposome0.4%PC 407.47±24.07 0.79±0,03 -46.3±1.08

Liposome0.2%PC 367.80±8.51 0.84±0,10 -49.2±0.90

Liposome0.1%PC 395.07±28.84 0.60±0,14 -57.1±0.20

Mix.Micelle4%PC 8.05±0.08 0.13±0.02 -4.07±0.01

Mix.Micelle0.4%PC 8.23±0.17 0.10±0,01 -8.69±1.28

Mix.Micelle0.2%PC 10.53±0.06 0.14±0.05 -20.47±1.17

Mix.Micelle0.1%PC 55.35±0.08 0.09±0.01 -19.13±0.29

Table 6: Percentage(%owf)ofmixedmicellesabsorbedanddesorbedonCOandPAusingthefoulardprocess.

Ini. weight g Pick-uptot.% lip%

Fin. weight% owf

Weight 1st washing.% owf

Weight total washings.% owf

CO 2.01±0.10 95.28±3.2234.3 22.23±1.50 7.07±1.0 1.11±0.13

PA 2.06±0.01 97.6±0.535.1 23.05±0.63 7.44±0.6 0.26±0.17

Table 7: PercentageofmixedmicellesabsorbedanddesorbedonCOandPAusingthebathexhaustionmethodology.

Ini. weightg

Fin. weight%

Weight 1st w.%

Weight total w.%

CO 2.05±0.04 35,43±2.73 12.72±0.44 2.42±0.06

PA 2.08±0.02 40,14±4.23 18.29±1.98 3.91±0.11

Whenmixedmicelleswereappliedtothefabricsbybathexhaustion,asintheliposometreatments, higher absorptionwasobtained for the two fabricswith respect to thepad-dryprocess,withhighersubstantivityforPA.Thehighertemperatureofbathexhaustion(60ºC)withrespecttothefoulardprocess(30ºC)couldaccountforthis.Desorptionwithwaterwasalsoevaluatedforallfabrics.ResultsofremainingmixedmicellesinpercentagearealsodescribedinTable 7andarerepresentedinFigure 6includingtheresultsobtainedwithliposomes.

Asinthecaseofthefoulardprocess,despitethehighabsorption,considerablyhigherdesorptionwasobtainedforthemixedmicellestreatedfabricswithrespecttotheliposometreatedfabrics.Moreover,PApresentshigherabsorptionandlessdesorptionthanCOinthecaseof liposomesandmixedmicelles treatments. Interactionof lecithinwithCOhasbeenreported to bemainly at the surface through a coating layer,whereas interactionwith PAoccursintheinteriorofthefiber[65].

ThehigherabsorptionofmixedmicellesinCOandespeciallyinPAcouldbeduetothepresenceofOramix in30%.The increase inparticle sizewithdilution in thewashingbaths,whichcouldattain50-100nm,doesnotpreventdesorption.Bycontrast,alargeamountofdesorptionoccurs inmixedmicelles treatedfabrics.DesorptionofPAandCOliposometreatedfiberswasabout50%,whereasdesorptionofPAandCOmixedmicellestreatedfibersattained90%.Thesizeofthelipidstructuresofliposomesandmixedmicelleswasevaluatedintheinitialandwashingbathsoftheexhaustiontreatments(Table 8)todetermineitspossibleinfluenceonproductdesorption.

Figure 6: Absorptionanddesorptionoftotalproduct(GAinliposomeormixedmicelles)appliedtocottonandpolyamidebybathexhaustion.

Theincreaseinparticlesizeofthesestructures(seeTable8)didnotpreventtheirexitfromthefiberswithlessdesorptionasexpected.Bycontrast,desorptionwasmaximum.Thiscouldbeduetoahigherpermeabilityoftextilescomparedwithhumanskininwhichthiseffectwasnotobserved[63,64].

TheloweramountofGA,bothrealandtheoretical,inCOandPAtreatedwithmixedmicelleswith respect to those treatedwith liposomesshouldbenoted.The realamountofGAevaluatedbyHPLCinCOfibersisalwayslowerforthetwovehiclesthantheamountcalculated.ThisisnotthecaseforthePAfiber.Thesephenomenasuggestalowsubstantivity

Table 8: Size(Z-Average)andPolydispersityIndex(Pdl)ofdifferentbathsofCOandPAsubjectedtobathexhaustionwithliposomesandmixedmicelles.

Treatment Analyzed BathSize (Z-Average) Diameter (nm)

Cotton/Liposomes

InitialBath 525.6±26.1 0.68±0.03

Bathafterexhaustiontreatment 375.3±64.6 0.51±0.12

Bathafter1stwaterwashing(10ml) 474.3±32.2 0.68±0.20

Bathafter3rdwaterwashing(50ml) 623.5±18.8 0.52±0.03

Cotton/Mixed Micelles

InitialBath 6.9±0.8 0.98±0.04

Polyamide/Liposomes

InitialBath 525.6±26.0 0.68±0.03

Polyamide/Mixed Micelles

InitialBath 6.6±0.8 0.97±0.04

Figure 4: RealandtheoreticalGApercentagesoftreatedandwashedtextiles.

fortheGAforcottonandamuchgreatersubstantivityforPA.ItcanthereforebeconcludedthatthevehiculizationefficiencyofliposomeswithrespecttomixedmicellesisalwaysgreaterforpolyamidethanforCO.Thusabiofunctionaltextilewithmorethan5%ofGAisobtainedevenafterthreeconsecutivewashings.

4. Electrosupun Nanofibers as Biomedical Devices

4.1. Introduction

Overthepast20years,theinteractionsofthefieldsofpolymerandmaterialssciencewith the pharmaceutical industry have resulted in the development ofwhat are known asdrugdeliverysystems(DDSs),orcontrolled-releasesystems[66-69].Drugdeliverysystemscanbeclassifiedaccordingtothemechanismthatcontrolsthereleaseofthedrug[70],suchas diffusion-controlled systems, chemically controlled systems, solvent-activated systems,modulated-releasesystemsandbioerodible-releasesystems[69-74].

Oneofthemostpromisingbiodegradablepolymersforuseinbioerodible-releasesystemsispoly(lacticacid)(PLA),Fig5,becauseofitsmechanicalandbiologicalproperties.

PLAisathermoplasticpolyesterderivedfromrenewableresources,suchascornstarch.PLAhasahydrolyticdegradationmechanism,anditiscapableofdegradingintoinnocuouslacticacidandthenintoCO2andwater,whichareabsorbedbythebody.PLAisusedinmedicalimplantsintheformofscrews,pins,rodsandasamesh[75-77].Dependingontheexacttypeused,PLAdegradesinthebodywithin6monthsto2years[77].Thisgradualdegradationisdesirableforasupportstructurebecauseitgraduallytransferstheloadtothebodyastheorganheals.

Here, the properties of a different drug-delivery system,which consists of differentnanofibermembraneconfigurations,wereexamined.Themembraneconfigurationwasbasedon sandwiching the drug between two adjacent layers of electrospun PLAmembranes todetermine themass transport behavior of the drug through different polymericmembraneconfigurations.

SimilarstudieshavebeenconductedbyFiedetal.[78]withthepurposeofdevelopingultrafiltrationmembranes. Tiemessen et al. [79] have also described a so-called occlusionsimulation model based on sandwiching the stratum corneum between sticky siliconemembranestoprovideameansforsimulatingskinpenetrationunderocclusion.

Figure 5:ChemicalstructureofPLA

TheelectrospunPLAmembraneswereshowntoprovideausefulmechanicalsupportforthedrug.Theinitialstudiesonthesandwichmodelalsorevealedthatthismodelprovidesanelegantmeanstokineticallycontrolthewateruptakebythedrug.AlthoughthePLAmembraneisbiodegradableorerodible(i.e.,asystemthatdisintegratesovertime),thisphenomenoncanbeirrelevantwhentheentiredrugisreleasedbeforethedissolutionofthepolymerbecomesimportant.Therefore,themembranescouldbeconsiderednon-erodible.

Therefore,thisnewsystemcanbedirectlyusedintheprophylacticperiodofpatientswho recentlyunderwent anoperation,when in situ application is required. In somecases,thisparticularmembranecanactnotonlyasacarrierbutalsoascavityfillerwiththerapeuticagents.

Here, thepolymeric solutionused toproducenanofiberswasobtainedbydissolving10%ofthesolutionweightofpoly(lacticacid)indichloromethaneunderconstantmagneticagitationandataconstantroomtemperatureof23-25°C.ThemagneticagitationremainedconstantuntilthePLAwascompletelydissolved,whichwasindicatedbythesolutionbecomingtranslucent andwhenno solid particleswere detected.Complete dissolutionwas achievedafter1hourofagitation.

Toconducttheexperiment,ahighvoltagepowersupply,aspinneret(acapillarytubewithverysmalldiameter)andagroundedcollectorplate(aplateusuallycomposedofmetal)wererequired,asseeninFigure 6.

Duringtheelectrospinningprocess,astrongelectrostaticfieldisappliedtoapolymersolutionheld inasyringewithacapillaryoutlet.Apendent-shapeddropletof thepolymersolutionfromthecapillaryoutletisdeformedintoaTaylorcone[80]bytheelectrostaticfield.Whenthevoltagesurpassesathresholdvalue,theelectricforceovercomesthesurfacetensionofthedropletandachargedjetofthesolutionisejectedfromthetipoftheTaylorcone.Asthejetmovestowardacollectingmetalscreen(counterelectrode),thesolventevaporatesandanon-wovenfabricmatisformedonthescreen[81].TheprocesscanbeseeninFigure 7.

Figure 6: Electrospinningdevicecontainingallessentialelements:highvoltage,spinneret,metalcollector

4.2. Experimental results of Nanofibers formation

When applying the former conditions specified, PLA nanofibers are formed, as thefollowingfiguresshow.

Figure 7: ElectrospinningofPLAunderoptimalconditions

Figure 8:SEMofPLAfibersunderoptimalhighvoltageconditions(orderofmagnitude1000x).

Figure 9: SEMofPLAwithbeaddefects;orderofmagnitude250x

Figure 10:SEMofPLAfiberswithincreasingflowrate;orderofmagnitude4000x.

4.3. Sandwich configuration with Ibuprofen or Caffeine

Ibuprofen, or caffeine, was placed between two adjacent layers of the polymericmembranes.Whenthefirstlayeroftheelectrospunmembranewasdriedandsolidified,thedrug,whichwas in a driedmedium,was evenly dispersed on themembrane surface.Theamount of drugwas controlled using an analytical balance.After placing the drug on themembranesurface,asecondmembranelayerwaselectrospunoverthefirstlayertocoverthedrug[82].

4.4. Drug-Delivery Mechanisms

Thecapabilityofthepolymericmembranetodeliverthedrugwasdeterminedthroughtriplicatemeasurementsofthedrugreleasekineticsintoafluidphase.

Thedrugreleasekineticsweredeterminedusingbatchmethodsformembranesoperatingindifferentconditions,suchasmembranesobtainedafterdifferentelectrospinningperiods(5,10and20minutes)andsandwichmembraneswithdifferentdrugamounts(5,10and15mg).Foreachoperatingcondition,theexperimentwasrepeated3times.

Toperformtheexperiment,thesandwichmembraneswereplacedbetweenconcentricringsinametallictamboursystem,asshowninFigure13,toensureuniformmasstransferalong thesurfaceof themembranefromthesolidphase to thefluidphaseand tosoavoidbendingstress.

Figure 11:SEMofporousPLAfiberduetohighroomhumidity

Figure 12: SEMofnanofibersproducedbyoptimizedelectrospinningprocess;orderofmagnitude15000x.

Afteradjustingthesandwichmembranesinthemetallictamboursystem,theywereplacedinacoveredcontainerwith100mLofphysiologicalserumasthefluidphase,withapH7.4.Thecontainerspreparedfortheanalysesweremaintainedinabathwithaconstanttemperatureof37°C.Thesamplesweretakenforanalysisatregulartimeintervals,andtheconcentrationsofdrugreleasedintothefluidphaseweredeterminedthroughspectrophotometrictechniquesinaShimadzuUV-2401PCUV-visspectrophotometerwithawavelengthof263nm.

4.5. Controlled Drug Release Mathematical Modeling

Theresultsobtainedfromthekineticstestswereusedforthemathematicalmodelingofthecontrolleddrugrelease,followingtheapproachexplainedbeforeinImmichetal.[83]andin1.2.2.

4.6. Scanning Electron Microscopy (SEM)

The surface morphologies and thicknesses (δ) of the polymeric membranes wereexaminedusingascanningelectronmicroscope(JEOL/JSM-5610).Afterthesamplesweredriedovernightatroomtemperature,eachspecimenwassputtered-coatedwithgoldpowderbeforebeingexaminedwiththeSEM.Forthethicknessmeasurement,3differentregionsofthetransversalareaofthemembraneweremeasured,andtheaveragevalueofthesemeasurementswasused.

Themembrane thicknesswas determined for the PLAmembranes obtained after 5,10 and20minutes of electrospinningwithdifferent amounts of ibuprofen.The results arepresentedinTable 9.

Figure 13:Masstransferconfigurationdeviceonthedrug-deliveryexperiment

ThedifferencesinthemorphologiesofthePLAmembraneswithdifferentelectrospinningtime intervals were analyzed and the difference in the amount of fibers in each obtainedmembraneisnoticeable.InthePLAmembraneobtainedafter5minutesofelectrospinning,itcanbeseenemptyspacesamongthefibers.Theseemptyspacesfacilitatemasstransferenceofthefluidphasethroughthemembrane,whichisreadilyconducivetodrugrelease.Whenthereisanincreaseintheamountoffibersandconsequently,areductionintheamountofemptyspace,themolecularmobilitybecomesdifficultandconsequently,itreducesmasstransportthroughthemembrane.

Thediameterofthefiberinapuremembraneobtainedafter20minutesofelectrospinning(withoutthedrug)wasalsomeasuredusingSEM,andtheaveragediameterisapproximately150nmwhendisregardingthebeadeffect.

4.7. Ibuptofen delivery from PLA electrospun membrane

TheinfluenceofthemembranethicknessonthereleasekineticsofibuprofenthroughPLAmembraneswasstudiedataninitialdrugamountof5mg(Figure 14).

AlthoughthePLAmembraneisbiodegradableorerodible,inthisstudy,thephenomenon

Table 9: ThicknessofPLAmembranesfordifferentibuprofenamounts.

Electrospinning time(min) Ibuprofen amount (mg) Membrane thickness (mm)

5 5 0.0662

5 10 0.0926

5 15 0.1190

10 5 0.0927

10 10 0.1130

10 15 0.1423

20 5 0.1192

20 10 0.1424

20 15 0.1655

Figure 14: KineticsofibuprofendeliveryfromPLAmembranesafter5minuteselectrospinningAftertheinitialburst,thepolymerstructureswells,stabilizesandtrapsthedrug.Theresultisacontinuousandslowersustainedreleaseprocess.

wasnegligiblebecausetheentiredrughadalreadybeenreleasedbeforethedissolutionofthepolymerbecameimportant.Therefore, themembraneswereconsidered tobenon-erodible.Figure14presentskineticsbehaviorwithamoreintenseinitialburst,whichleadstoareleaseofapproximately0.05g/Lofibuprofen(100%ofinitialdrugconcentration)duringthefirststageofthedrugdelivery.

MorecontrolledreleaseprocessesareobservedinkineticspresentedinFigures15and16,withalessintensebursteffectandaninitialdrugreleaseofapproximately0.03g/L(30%ofinitialdrugconcentration)and0.02g/L(13%ofinitialdrugconcentration),respectively.Thisdecreaseinthebursteffectintensityisduetoanincreaseinmembranethicknessafter10and20minutesofelectrospinning,whichdelayedmasstransferencethroughthepolymericmembranetotheexternalfluidphase.

Inadditiontothedecreaseofthebursteffectindrugreleaseforthemembraneobtainedafter20minutesofelectrospinning,anincreaseinthepseudo-equilibriumtimeoftotaldrugreleasewasalsoobservedduetothemembranethickness,whichisconsiderablygreaterthanthatofthemembraneobtainedafter5minutesofelectrospinning.Thisthickermembranealsorestrainsandcontrolsdrugmobilityandtransportthroughthemembrane.

Figure 15:KineticsofIbuprofendeliveryfromPLAmembranesafter10minuteselectrospinning

Figure 16:KineticsofibuprofendeliveryfromPLAmembranesafter20minuteselectrospinning

Theamountofibuprofenwithinthemembraneisalsoimportantwhendeterminingthetimerequiredforthetotalreleaseofthedrug.Whentheamountofibuprofenincreasesfrom5to10mg,thetimerequiredforthetotalreleaseofthedrugincreasesby72%onaverage.Thereisnosignificantincreaseintimeforthetotalreleaseofthedrugwhentheamountofibuprofenincreasesfrom10to15mg.Membraneswith10and15mgofibuprofenhavesimilarbehaviorduringthereleasingprocess.

Becausethekineticscurvesforthereleaseofibuprofen,whichareillustratedinFigures14,15and16,exhibitthetypicalbehaviorforreservoir-typemembranes,itcanbeassumedthat thedrug transportmechanismthrough thesemembranes isusuallyasolution-diffusionmechanism.Though, this isnotsufficient toprovethemechanismofdrugrelease.Forthatreason, the releasingmechanism(n)of ibuprofenwascalculated,according toPowerLawequation(2)[83].

The releasingmechanismpresented inTable 10, forpolymericmembranesobtainedafter5minutesofelectrospinning,donotdescribeanyestablishedmechanismofdrugrelease.Itmeansthemechanismofreleaseisneitheradiffusion-controlleddrugrelease(n=0.5)noraswelling-controlleddrugrelease(n=1),wheretherelaxationprocessofthemacromoleculesoccurringuponwaterimbibitionintothesystemistheratecontrollingstep.Here,thereasonforthereleaseofibuprofenmustbethelargeporosityofthethin5minutemembranethatdoesnotrestrictthemoleculesofibuprofenfrompassingthrough.

However, for membranes obtained after 10 and 20 minutes of electrospinning, theexponentntakesavalueof0.5orverycloseto0.5.Itindicatesthatdiffusionisthemechanismcontrolling the release of ibuprofen.Therefore, drug transport initially occurs through thedissolutionof thedrug through themembrane,which is followedbydiffusion through thesamemembraneanddesorptiontotheothersideofthemembrane.Consideringthatthereleaseofibuprofeniscontrolledbydiffusion,itispossibletoapplytheclassicalHiguchiequation(eq.3),todeterminethemasstransportcoefficient,andthentheapproachofFick’ssecondlaw

Table 10: MechanismofdrugreleaseforPLAmembranes.

Electrospinning time (min) Ibuprofen amount (mg) n (releasing mechanism)

5 5 0.18

5 10 0.30

5 15 0.31

10 5 0.22

10 10 0.50

10 15 0.50

20 5 0.25

20 10 0.40

20 15 0.40

todeterminetheapparentdiffusivityofibuprofenthroughthePLAmembranesobtainedafter10and20minutesofelectrospinning.

ThedatapresentedinTable 11showsthatthemasstransportcoefficient,KH,(equation(4))forthereleaseofibuprofenthroughelectrospinningmembranes,decreasedwhenmembranethicknessisincreased(from10to20min.electrospinning).Thisresultisduetothereinforcementoffibers,whichbecomedenserandnoteasilypenetrable.Thisfiber reinforcementreducestheemptyspacesavailableforibuprofenparticlemobility,whichrestrainsitstransferencetotheexternalmedium.Increasingthedrugconcentrationfurtherdecreasestheavailableemptyspacesformasstransference,whichconsequentlydecreasesthemasstransportcoefficient.

Table11alsoshowsthediffusivity(D)values,whichappeartoincreaseforthe10min.electrospinningmembranewhentheinitialdrugconcentrationisincreased.

Increasingtheelectrospinningtimefrom10to20min.producesevendensermembranesthat are full of fiberswith a compact internal structure and less empty spaces for particlemobilityandtransport.Therefore,increasingtheibuprofenconcentrationfillsevenmoreoftheemptyspacesinthemembrane,whichdecreasesthepossibilityofinternaltransportandconsequentlydecreasesthemasstransportcoefficientandrestrainsthedrugdelivery,asshowninTable 11.

Unlikethe10min.electrospinningmembrane,thediffusivityofibuprofenthroughthe20min.electrospinningmembraneispracticallyconstantwithincreasingdrugconcentration,as the variation in the diffusivity values is insignificant. This is due to the uniformity ofmembranethickness.Theminorvariationindiffusivityshownforthe20min.electrospinningmembranecouldbeattributedtotheoreticalfittinguncertainty.Here,itispossibletomaintainthepercentageofdrugreleasedisregardingtheamountofdruginthereservoir.TheaveragevalueofdiffusivityshowninTable 11is2.5E-08cm2/s,inaccordancewiththecommonrangeofdrugdiffusivitiesinvariousmembranes[84,85].

Table 11: DrugreleaseparametersforPLAmembranesobtainedafter10and20minutesofelectrospinning.

Electrospinning time (min)

Ibuprofen amount (mg) KH Diffusivity (cm2/s)

10 5 0.033 1.8395E-08

10 10 0.030 2.2564E-08

10 15 0.029 3.3436E-08

20 5 0.028 2.1899E-08

20 10 0.026 2.6895E-08

20 15 0.023 2.8468E-08

5. References

1.Wachter,R.,WEUTHEN,M.,PANZER,C.&PAFF,E.2005.Liposomesareusedastextilefinisheswhichnotonlyimproveelasticityandhandbutcanalsobe transferred toskincontact.PatentnºEP1510619-A2.DE10339358-A1.US2005058700-A.

2.GUARDUCCI,M.2006.Producthavingparticularfunctionalpropertiesfortheskinandprocessforthepreparationthereof.Patentno.WO/2006/106546.

3.Hipler,U.C.andElsner,P.(2006).Biofunctionaltextilesandtheskin.In:BurgG(eds)Curr.Probl.Dermatol.1sted.vol.33.asel:Karger.

4.4.SCHAEFER,H.,REDELMEIER,T.E.1996.In:Skinbarrier:Principlesofpercutaneousabsorption,Karger.BaselandNewYork.

5.OCDE,SkinAbsorption:InVitroMethod,Guideline428,GuidelinesfortheTestingofChemicals,Paris,France,(2004).

6.KaliaYN,GuyRH.Modelingtransdermaldrugrelease.AdvancedDrugDeliveryReviews,2001;48:159-172.

7.BakerRW,LonsdaleHK.1974.Controlledrelease:mechanismsandrates,ControlledReleaseofBiologicallyActiveAgents,PlenumPress,NewYork15–72.

8.GrassiM,GrassiG,LapasinR,ColomboI.2007.Understandingdrugreleaseandabsorptionmechanisms,TaylorandFrancisGroup,Chapter9,583-584.

9.HarlandRS,PeppasNA,Ontheaccurateexperimentaldeterminationofdrugdiffusioncoefficientsinpolymers,S.T.P.PharmSci,1993;3:357.

10.TojoK,SunY,GhannamMM,ChienYW.Characterizationofamembranepermeationsystemforcontrolleddeliverystudies,AIChEJ,1985;31:741-746.

11.LaghouegN,PauletJ,TaverdetJL,VergnaudJM.Oralpolymer–drugdeviceswithacoreandanerodibleshellforconstantdrugdelivery,IntJPharm,1989;50:133-139.

12.LavasanifarA,GhalandariR,AtaeiZ,ZolfaghariME,MortazaviSA.Microencapsulationof theophyllineusingethylcellulose:invitrodrugreleaseandkineticmodelling,JMicroencapsul,1997;14:91-100.

13. Lorenzo-Lamosa ML, Remuñan-López C, Vila-Jato JL, Alonso HJ. Design of microencapsulated chitosanmicrospheresforcolonicdrugdelivery,JContrRel,1998;52:109-118.

14.OuriemchiEM,VergnaudJM.Processesofdrugtransferwiththreedifferentpolymericsystemswithtransdermaldrugdelivery,ComputTheorPolymSci,2000;10:391-401.

15.CarrerasN,AcuñaV,MartíM,LisMJ.DrugreleasesystemofibuprofeninPCL-microspheres.ColloidPolymSci291:157–165.2013

16.16.YamashitaF,HashidaM,Mechanistic andempiricalmodelingof skinpermeationofdrugs,AdvancedDrugDeliveryReviews,2003;55:1185-1199.

17.17.GrassiM.2007.Membranesindrugdelivery,inHandbookofmembraneseparations:chemical,pharmaceutical,andbiotechnologicalapplications,Sastre,A.M.,Pabby,A.K.,Rizvi,S.S.H.,Eds.,MarcellDekker.

18.FlynnGL,YalkowskySH,RosemanTJ.Masstransportphenomenaandmodels:theoreticalconcepts,JPharmSci,1974;63:479.

19.GrassiM,GrassiG.Mathematicalmodellingandcontrolleddrugdelivery:matrixsystems,CurrDrugDeliv,2005;2:97.

20.InoueSK,GuentherRB,HoagSW,Algorithmtodeterminediffusionandmasstransfercoefficients,inProceedingsoftheConferenceonAdvancesinControlledDelivery,145(1996).

21.GrassiM,GrassiG,LapasinR,ColomboI.2007.Understandingdrugreleaseandabsorptionmechanisms,TaylorandFrancisGroup,Chapter9,583-584.

22.Colombo I,GrassiM, LapasinR, Pricl S.Determination of the drug diffusion coefficient in swollen hydrogelpolymericmatricesbymeansoftheinversesectioningmethod,J.Contr.Rel.1997;47:305-314.

23.GuyRH,HadgraftJ.Atheoreticaldescriptionrelatingskinpenetrationtothethicknessoftheappliedmedicament.IntJPharm,1980;6:321–332.

24.Pharmacy-EncyclopediaOfControlledDrugDelivery,V1&2,(1999)495-497.

25.MathiowitzE.Pharmacy-EncyclopediaofControlledDrugDelivery.vol1&2.Wiley,Providence,1999.

26.AbdekhodaieMJ,ChengY–L.Diffusionalreleaseofadispersedsolutefromplanarandsphericalmatricesintofiniteexternalvolume.JournalofControlledRelease1997;43:175-182.

27. Siepmann J, Lecomte F,BodmeierR.Diffusion- controlled drug delivery systems:Calculation of the requiredcompositiontoachievedesiredreleaseprofiles.JournalofControlledRelease1999;60:379-389.

28.SiepmannJ,KranzH,BodmeierR,PeppasNA.HPMC–MatricesforControlledDrugDelivery:AnewModelCombiningDiffusion, Swelling, andDissolutionMechanisms and Predicting the ReleaseKinetics. PharmaceuticalResearch1999;16:1748-1756.

29.SiepmannJ,PeppasNA.Modellingofdrugreleasefromdeliverysystemsbasedonhydroxypropylmethylcellulose(HPMC),AdvancedDrugDeliveryReviews2001;48:139-157.

30. Kumari K, Kundu PP. Studies on in vitro release of CPM from semi-interpenetrating polymer network (IPN)composedofchitosanandglutamicacid.BulletinofMaterialsScience2008.;31:159-167.

31. Brazel, C.S., Peppas, N.A., 2000. Modeling of drug release from swellable polymers. European Journal ofpharmaceuticsandbiopharmaceutics,49,47-58.

32.PeppasNA,KeysKB,Torres –LugoM,LowmanAM.Poly (ethyleneglycol) – containinghydrogels in drugdelivery.JournalofControlledRelease1999;62:81-87.

33.RubioL,AlonsoC,CoderchL,ParraJL,MartíM,CebriánJ,NavarroJA,LisM,ValldeperasJ,Skindeliveryofcaffeinecontainedinbiofunctionaltextiles,TextResJ,2010;80:1214-1221.

34.MartiM,MartínezV,CarrerasN,AlonsoC,LisM,ParraJL,CoderchL.Textileswithgallicacidmicrospheres:invitroreleasecharacteristics.J.ofMicroencapsulation,2014;Doi:10.3109/02652048.2014.885605.

35.ShaoabingZ,XianmoD,HuaY.Biodegradablepoly(ε-caprolactone) -poly (ethyleneglycol)blockcopolymers:characterizationandtheiruseasdrugcarriersforacontrolleddeliverysystem.Biomaterials,2003;24:3563-3570.

36.36.HUTMACHER,D.W.2000.Scaffoldintissueengineeringboneandcartilage.Biomaterials,21,2529-2543.

37.W.J.Yen,B.S.Way,L.W.Chang,P.D.Duh,Antioxidantpropertiesofroastedcoffeeresidues,J.Agric.FoodChem.,53,(2005)2658-2663.

38.ParraJ.L.,PonsL.1995,in:Cons.Gen.Col.Of.Farm.(Ed),CienciaCosmética,Madridpp.512.

39.ConneyA.H.,LuY.P.,LouY.R.,HuangM.T.2002.InhibitoryeffectsofteaandcaffeineonUV-inducedcarcinogenesis:Relationshiptoenhancedapoptosisanddecreasedtissuefat,Eur.J.CancerPrev.11:S28-S36.

40.Thiele,J.J.,Dreher,F.,Packer,L.,2000.Antioxidantdefensesystemsinskin,in:P.Elsner,H.Maibach(eds)Drugs

vs.Cosmetics:Cosmeceutical?.Dekker,NewYork,pp.145-187.

41.TingWW,VestCD,SontheimerR.Practical and experimental consideration considerationof sunprotection indermatology.IntJDermatol2003;42:505-513.

42.LianT,HoRJY.Trendsanddevelopmentsinliposomedrugdeliverysystems.JPharmSci,2001;90:667-680.

43.43.TeschkeO,deSouzaEF.Liposomestructure imagingbyatomic forcemicroscopy:verificationof improvedliposomestabilityduringabsorptionofmultipleaggregatedvesicles.Langmuir,2002;18:6513-6520.

44.BetzG,AeppliA,MenshutinaN,LeuenbergerH.Invivocomparisonofvariousliposomeformulationsforcosmeticapplication.IntJPharm,2005;296:44-54.

45.AggarwalA,DayalA,KumarN.Microencapsulationprocessesandapplicationintextileprocessing.Colourage,1998;45(8):15-24.

46.MartíM,delaMazaA,ParraJL,CoderchL.DyeingWoolalLowTemperatures:NewMethodUsingLiposomes.TextResJ,2001;71(8):678-682.

47.MontazerM,ValidiM,ToliyatT.Influenceoftemperatureonstabilityofmultilamellarliposomesinwooldyeing.JLiposomeRes,2008;16(1):81-89.

48.MartíM,delaMaza,A.ParraJ.L.andCoderch,L.RoleofLiposomesinTextileDyeing.Liposomes,LipidBilayersandModelMembranes.FrombasicResearchtoApplication.Pabst,G.,Kucerka,N.,Nieh,M-P.,Katsaras,J.eds.CRCPress2014

49.MartíM,delaMazaA,ParraJLandCoderchL,LIPOSOMEASDISPERSINGAGENTINTODISPERSEDYEFORMULATIONTextileResearchJournal81(4):379-387;2011

50.RamirezR,MartíM,ManichAM,ParraJL,CoderchL.CeramidesExtractedfromWool:PilotPlantSolvent.TextileResJ,2008;78:73-80.

51.CoderchL,FonollosaJ,MartíM,GardeF,de laMazaA,ParraJL.ExtractionandAnálisisofCeramidesfromInternalWoolLipids.JAmOilChemSoc,2002;79:1215-1220.

52.CoderchL,FonollosaJ,dePeraM,delaMazaA,ParraJL,MartíM.Compositionsofinternallipidextractofwoolandusethereofinthepreparationofproductsforskincareandtreatment.2001:PatentnºWO/2001/004244.

53.Carreras,N.,Acuña,V.,Martí,M.,Lis,M.J.,2013.DrugreleasesystemofibuprofeninPCL-microspheres.ColloidPolySci.,291,157-165.

54.RamírezR,MartíM,BarbaC,MéndezS,ParraJL,CoderchL.SkinEfficacyofliposomescomposedofinternalwoollipidsrichinceramides.JCosmetSci,2010;61:235-245.

55.RougierA,DupuisD, LotteC,RouguetR, ShaeferH. In vivo correlation between stratum corneum reservoirfunctionandpercutaneousabsorption.JInvestDermatol,1983;81:275-278.

56.RougierA,DupuisD,LotteC,RoguetR,WesterRC,MaibachHI.Regionalvariationinpercutaneousabsorptioninman:measurementbythestrippingmethod.ArchDermatolRes,1986;278:465–469.

57.PinkusH.Examinationoftheepidermisbythestripmethodofremovinghornylayers.I.Observationonthicknessofthehornylayer,andonmitoticactivityafterstripping.JInvestDermatol,1951;16:383–386.

58.RamónE,AlonsoC,CoderchL,DelaMazaA,LópezO,ParraJL,NotarioJ.LiposomesasAlternativeVesiclesforSunFilterFormulations.DrugDelivery,2005;12:83-88.

59.MartíM,RodríguezaR,CarrerasN,LisM,ValldeperasJ,CoderchL,ParraaL.Monitoringof the icrocapsule/liposomeapplicationontextilefabrics,J.oftheTextileInstitute103:19-23,2012

60.Carrión,F.J.(1986).Characterizationoftheelectricdoublelayerintextilefibersanditsinfluenceontheabsorptionofsurfactants.Bol.Intexter.,90,25-47.

61.Cutler,W.G.andDavis,R.C.(1972).Ed.DetregencyTheoryandTestMethods.PartI,Vol5,SurfactantSciencesSeries.Ed.MarcelDekkerInc.NewYork.

62.López,O.,delaMaza,A.,Coderch,L.,López-Iglesias,C.,Wehrli,E.andParra,J.L.(1998).DirectformationofmixedmicellesinthesolubilizationofphospholipidliposomesbyTritonX-100.FEBSLetters,426,314-318.

63. López, O., de la Maza, A., Barbosa, L., García Antón, J.M., Cebrián, J., Albiñana, N. (2009). Cosmetic ofdermopharmaceuticalcompositionofmixedMicelles.Pat.WO/2009/106338.

64.López,O.,Cócera,M.,López-Iglesias,C.,Walter,P.,Coderch,L.,Parra,J.L.anddelaMaza,A.(2002).Reconstitutionofliposomesinsidetheintercellularlipiddomainofthestratumcorneum.Langmuir,18,7002-7008.

65.Baptista,A.L.F.,Countinho,P.J.G.,RealOliveira,M.E.C.D.andRochaGomes,J.I.N.(2004).Lipidinteractionwithtextilefibersindyeingconditions.Progr.ColloidPolymSci.,123,88-93.

66.Y.C.Kim,J.H.Park,M.R.Prausnitz,Microneedlesfordrugandvaccinedelivery,AdvDrugDelivRev.64(2012)1547–1568.

67.J.H.Park,G.Saravanakumar,K.Kim,I.C.Kwon,Targeteddeliveryoflowmoleculardrugsusingchitosananditsderivatives,AdvDrugDelivRev.62(2010)28–41.

68.Y.Zhang,H.F.Chan,K.W.Leong,Advancedmaterialsandprocessingfordrugdelivery:Thepastandthefuture,AdvDrugDelivRev.65(2013)104–120.

69.A.M.Wokovicha, S. Prodduturia,W.H.Douba,A.S.Hussainb, L. F.Buhse,Transdermal drug delivery system(TDDS)adhesionasacriticalsafety,efficacyandqualityattribute,EurJPharmBiopharm.64(2006)1–8.

70.J.Siepmann,N.A.Peppas,Higuchiequation:Derivation,applications,useandmisuse,IntJPharm.418(2011)6–12.

71.A.Davidsona,B.A.Qallafb,D.B.Dasc,Transdermaldrugdeliverybycoatedmicroneedles:Geometryeffectsoneffectiveskinthicknessanddrugpermeability,

ChemEngResDes.86(2008)1196–1206.

72.R.Langer,L.G.Cima,J.A.Tamada,E.Wintermantel,FuturedirectionsinBiomaterials,Biomaterials.11(1990)738-745.

73.G.Ponchel,J.M.Irache,C.Durrer,D.Duchene,Proc.Int.Symp.ControlledReleaseBioactMater.21(1994)31-32.

74.A.T.Raiche,D.A.Puleo,ModulatedreleaseofbioactiveproteinfrommultilayeredblendedPLGAcoatings,IntJPharm.311(2006)40–49.

75.B.Guptaa,N.Revagadea,J.Hilborn,Poly(lacticacid)fiber:Anoverview,ProgPolym.Sci.32(2007)455–482.

76.R.Auras,L.-T.Lim,S.E.M.Selke,H.Tsuji,Poly(LacticAcid):Synthesis,Structures,Properties,Processing,andApplications,JohnWiley&Sons,Inc,NewYork,2010.

77.A.C.Vieira,J.C.Vieira,R.M.Guedes,A.T.Marques,ExperimentaldegradationcharacterizationofPLA-PCL,PGA-PCL,PDOandPGAfibers,17thInternationalCommitteeonCompositeMaterials,2009.

78.R.W.Field,K.F.Yunos,Z.Cui. Separation of proteins using sandwichmembranes,Desalination. 246 (2009)224–232.

79.H.L.G.M.Tiemessen,H.E.Bodd,H.E.Junginger.Asiliconemembranesandwichmethodtomeasuredrugtransportthroughisolatedhumanstratumcorneumhavingafixedwatercontente.IntJPharm.56(1989)87-94.

80.D.H.Reneker,A.L.Yarin,Electrospinningjetsandpolymernanofibers,Polymer49(2008)2387-2425.

81.J.Zeng,X.Xu,X.Chen,Q.Liang,X.Bian,L.Yang,X.Jing,Biodegradableelectrospunfibersfordrugdelivery,JControlRelease.92(2003)227–231.

82.D.F.Stamatialis,B.J.Papenburg,M.Gironés,S.Saiful,S.N.M.Bettahalli,S.Schmitmeier,M.Wessling,Medicalapplicationsofmembrane:Drugdelivery, artificialorgansans tissueengineering, JMembraneScience.308 (2008)1-34.

83.A.P.S.Immich,M.J.LisArias,N.Carreras,R.L.Boemo,J.A.Tornero.Drugdeliverysystemsusingsandwichconfigurationsofelectrospunpoly(lacticacid)nanofibermembranesandibuprofen.MaterialsScienceandEngineeringC33(2013)4002–4008.

84.J.Siepmann,N.A.Peppas,Modelingofdrugreleasefromdeliverysystemsbasedonhydroxylpropylmethylcellulose(HPMC),AdvDrugDelivRev.48(2001)139-157.

85.Y.Chen,Y.Zhang,X.Feng,Animprovedapproachfordeterminingpermeabilityanddiffusivityrelevanttocontrolledrelease,ChemEngSci.65(2010)5921–5928.

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