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NANOPHARMACEUTICALS

EXPECTATIONSANDREALITIESOF MULTIFUNCTIONALDRUG DELIVERYSYSTEMS

VOLUME1

Editedby

RANJITA SHEGOKAR,PhD

CapnomedGmbH,Zimmern,Germany

Elsevier

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Contributors

HendAbd-Allah DepartmentofPharmaceuticsand IndustrialPharmacy,FacultyofPharmacy,Ain ShamsUniversity,Egypt

MonaAbdel-Mottaleb DepartmentofPharmaceuticsandIndustrialPharmacy,FacultyofPharmacy, AinShamsUniversity,Egypt;PEPITEEA4267, Univ.BourgogneFranche-Comté,Besançon,France

AnnisCaturAdi FacultyofHealth,Universityof Airlangga,Surabaya,Indonesia

MuktaAgrawal RungtaCollegeofPharmaceutical SciencesandResearch,Bhilai,Chhattisgarh,India

AmitAlexander RungtaCollegeofPharmaceutical SciencesandResearch,Bhilai,Chhattisgarh,India

MahavirBhupalChougule TranslationalBiopharmaEngineeringNanodeliveryResearchLaboratory,DepartmentofPharmaceuticsandDrug Delivery,SchoolofPharmacy,UniversityofMississippi,University,MS,UnitedStates;PiiCenterfor PharmaceuticalTechnology,ResearchInstituteof PharmaceuticalSciences,UniversityofMississippi, University,MS,UnitedStates;NationalCenter forNaturalProductsResearch,ResearchInstitute ofPharmaceuticalSciences,UniversityofMississippi,University,MS,UnitedStates

JuanBueno ResearchCenterofBioprospecting andBiotechnologyforBiodiversityFoundation (BIOLABB),Armenia,Quindío,Colombia

J.R.Campos DepartmentofPharmaceuticalTechnology,FacultyofPharmacy,UniversityofCoimbra(FFUC),PolodasCiênciasdaSaude,Coimbra, Portugal

AnneMarieClark CAS,aDivisionoftheAmerican ChemicalSociety,Columbus,OH,UnitedStates

DianaDiaz-Arévalo MolecularBiologyandImmunologyDepartment,FundacionInstitutodeInmunologíadeColombia-FIDIC,SchoolofMedicine

andHealthSciences,UniversidaddelRosario, Bogota,DC,Colombia

RihamI.El-Gogary DepartmentofPharmaceutics andIndustrialPharmacy,FacultyofPharmacy, AinShamsUniversity,Egypt

N.B.Jadav CentreforPharmaceuticalEngineering Sciences,FacultyofLifeSciences,Universityof Bradford,Bradford,UnitedKingdom

AnC elkaB.Kovacevic DepartmentofPharmaceuticalTechnology,InstituteofPharmacy,Facultyof BiologicalSciences,Friedrich-SchillerUniversity Jena,Jena,Germany

AtsarinaLarasati ResearchCenterforNanosciences andNanotechnology,BandungInstituteofTechnology,Bandung,Indonesia

PeterMattei CAS,aDivisionoftheAmerican ChemicalSociety,Columbus,OH,UnitedStates MahaNasr DepartmentofPharmaceuticsandIndustrialPharmacy,FacultyofPharmacy,Ain ShamsUniversity,Egypt

A.Paradkar CentreforPharmaceuticalEngineering Sciences,FacultyofLifeSciences,Universityof Bradford,Bradford,UnitedKingdom

HeniRachmawati SchoolofPharmacy,Bandung InstituteofTechnology,Bandung,Indonesia; ResearchCenterforNanosciencesandNanotechnology,BandungInstituteofTechnology,Bandung, Indonesia

KobraRostamizadeh ZanjanPharmaceuticalNanotechnologyResearchCenter,ZanjanUniversityof MedicalSciences,Zanjan,Iran;CenterforPharmaceuticalBiotechnologyandNanomedicine,NortheasternUniversity,Boston,MA,UnitedStates

A.Santini DepartmentofPharmacy,Universityof Napoli “FedericoII”,Napoli,Italy

ShailendraSaraf UniversityInstituteofPharmacy, Pt.RavishankarShuklaUniversity,Raipur,Chhattisgarh,India

SwarnlataSaraf UniversityInstituteofPharmacy, Pt.RavishankarShuklaUniversity,Raipur,Chhattisgarh,India

P.Severino UniversidadeTiradentes(Unit),Aracaju, Sergipe,Brazil;InstitutodeTecnologiaePesquisa, LaboratoriodeNanotecnologiaeNanomedicina (LNMed),Aracaju,Sergipe,Brazil;Tiradentes Institute,Dorchester,UnitedStates

RanjitaShegokar CapnomedGmbH,Zimmern, Germany

A.M.Silva SchoolofBiologyandEnvironment,UniversityofTras-os-MonteseAltoDouro(UTAD),Vila Real,Portugal;CentreforResearchandTechnology ofAgro-EnvironmentalandBiologicalSciences (CITAB),UniversityofTras-os-MonteseAltoDouro (UTAD),VilaReal,Portugal

S.B.Souto DepartmentofEndocrinology,S.Joao Hospital,AlamedaProf.Hern^ aniMonteiro,Porto, Portugal

E.B.Souto DepartmentofPharmaceuticalTechnology,FacultyofPharmacy,UniversityofCoimbra (FFUC),PolodasCiênciasdaSaude,Coimbra, Portugal;CEB-CentreofBiologicalEngineering, UniversityofMinho,Braga,Portugal

AsurSrinivasan CAS,aDivisionoftheAmerican ChemicalSociety,Columbus,OH,UnitedStates

AmandaStarling-Windhof CAS,aDivisionofthe AmericanChemicalSociety,Columbus,OH, UnitedStates

TinaTomeo CAS,aDivisionoftheAmerican ChemicalSociety,Columbus,OH,UnitedStates

VladimirP.Torchilin CenterforPharmaceutical BiotechnologyandNanomedicine,Northeastern University,Boston,MA,UnitedStates

MingtaoZeng CenterofEmphasisinInfectiousDiseases,DepartmentofMolecularandTranslational Medicine,PaulL.FosterSchoolofMedicine,Texas TechUniversityHealthSciencesCenterElPaso,El Paso,TX,UnitedStates

Preface

Thebookseriestitled ExpectationsandRealitiesofMultifunctionalDrugDeliverySystems coversseveralimportanttopicsondrug-delivery systems,regulatoryrequirements,clinicalstudies, intellectualpropertiestrends,newadvances, manufacturingchallenges,etc.writtenbyleading industryandacademicexperts.Overall,the chapterspublishedinthisseriesreﬂectthebroadnessofnanopharmaceuticals,microparticles, otherdrugcarriersandtheimportanceofthe respectivequality,regulatory,clinical,GMPscale up,andregulatoryregistrationaspects.

Thisseriesisdestinedto ﬁlltheknowledge gapthroughinformationsharingandwithorganizedresearchcompilationbetweendiverse areasofpharma,medicine,clinical,regulatory practices,andacademics.

ExpectationsandRealitiesofMultifunctionalDrug DeliverySystems isdividedintofourvolumes:

Volume1:Nanopharmaceuticals

Volume2:DeliveryofDrugs

Volume3:DrugDeliveryTrends

Volume4:DrugDeliveryAspects

Thespeci ﬁcobjectivesofthisbookseriesare to:

(1)provideaplatformtodiscussopportunities andchallengesindevelopmentof nanomedicineandotherdrug-delivery systems;

(2)discusscurrentandfuturemarkettrends;

(3)facilitateinsightsharingwithinvarious areasofexpertise;and

(4)establishcollaborationsbetweenacademic scientists,andindustrialandclinical researchers.

Innovativecutting-edgedevelopmentsin micro-nanotechnologyoffernewwaysofpreventingandtreatingdiseaseslikecancer,malaria,HIV/AIDS,tuberculosis,andmanymore. Theapplicationofmicro-nanoparticlesindrug delivery,diagnostics,andimagingisvast. Hence, Volume1: Nanopharmaceuticals,in thebookseriesmainlyreviewsadvancesin drugdeliveryareaviatargetedtherapywith improveddrugefﬁciencyatalowerdose,transportationofthedrugacrossphysiologicalbarriersaswellasreduceddrug-relatedtoxicity.

OneofthecontributionsbyCamposetal. (Chapter1) discussestheinﬂuenceofphysicochemicalfactorsaffectinglong-termstability, releaseandtoxicologicalpro ﬁlesofsolidlipid nanoparticles.Thischapteralsoreviewsthe importanceofcompositionandadministration routesstudiedforlipidnanocarriersystems.

InanothermanuscriptbyRachmawatietal. (Chapter2),theauthorshighlightthecurrent statusofdrugdeliverydevelopmentforherbal bioactives.Alongwithvariousmucosalbiocarriers,theauthorsdescribebiokineticand clinicaltranslationchallengeswithherbaldeliveryandlimitationswithregulatoryprocedures. Inthischapterherbalnanocarrierslikelipid nanoparticles,nanosuspensionsetc.are discussedindetail.

Chapter3 byRostamizadehetal.describes thedevelopmentofpolymericmicellesformultipledrugdeliveryinoncology.Theco-loadingof twoormoredrugsispossibleusingpolymeric micelles.Theauthorsdescribethetypesof polymersemployed,preparationmethods,and characterizationtechniquesforsuchcarrier systems.Furthermore,widerapplicationslike chemotherapeuticdelivery,stimuli-responsive drugdelivery,andtargeted-drugdeliveryvia suchcarriersisdiscussedindetail.Ontheother hand,hyaluronicacidnanoparticlesarebeing widelyexploredinnanomedicines.Thepromising nanocarrierstodeliverdrugsinconjugated,selfassembled,orinnanocomplexformarediscussed inthebookchapterbyNasretal.in Chapter4.The authorsconﬁrmthatthecurrentresearch showsimpressiveresearch ﬁndingsinareaslike osteoarthritis,tissueengineering,cancertargeting,theranosticapplications,andsoon,which areunderfurtherexplorationbyindustry.

TheworkbyJadavandParadkar (Chapter5) isaimedatdiscussingwidelystudieddrug deliverysystemsinacademicsandinindustry, i.e.soliddispersions.Variousaspectslikeclassiﬁcationofsoliddispersions,theirformulation optimization,processingandphysicochemical characterizationarereviewedinthischapter.

Chapter6 byBuenohighlightstheimportanceofunderstandingnanotoxicityatearly stagesofdevelopment.Althoughnanocarriers haveshownpromisingresultsindelivering drugsattargetsitesorlocations,theaccumulationofnanoparticlesatcellularandtissue levelsinexcesscausestoxicity.Currentliterature containsverylimitedinformationonthistopic. Thischapterreviewsvariousaspectsofnanotoxicityandprovidesinformationonkeyconcepts forevaluationofthetoxicity.

ThetopicpresentedbyDiaz-Arévaloetal. (Chapter7) describesthesystemicreviewof nanoparticles-basedvaccinedevelopment.Initial resultsofnanocarrierslikeliposomes,viruslike particles,metallicandnonmetallicparticles,and polymericnanoparticlesinvaccinetherapyare

promisingalthoughsomelimitationslikestability andcytotoxicityneedstobeovercome.

Chapter8 byKovacevicdiscussesdeliveryof poorlysolubleandlow-permeabledrugsvia lipidnanocarriers.Anoverviewofavailable mechanisticstudiesinmodelandinrealcell membranesforbetterunderstandingofcell internalizationprocessesisprovided.

ThechapterbyAlexanderetal. (Chapter9) reviewsapproachesforeffectivebraindrugdeliveryusingnasalmucosa.Thisroutecandeliver drugseffectivelyattargetsiteswithimproved therapeuticperformanceofdrugs.Inaddition, theauthorsexplainlimitationsofthisdrugdeliveryrouteandregulatorymarketapproval challenges.

Starling-Windhofetal. (Chapter10) address industryandtechnologytrendsintheintellectualproperty(IP)landscapeofpharmaceutical drugdeliveryover3decades.Itisfascinating toseetheglobalpicture;itmakesscientists awareofthetrendsandspecialinterestsof speci ﬁ cgeographicalregionsormarkets. ThischapterprovidesinformationonIPtrends inoral,topical,andparenteraldrugdelivery area.Guidanceonemergingtrendsand IP-monitoringstrategiesarealsopresented.

Insummary,Iamsurethisbookvolumeand thecompletebookserieswillprovideyougreat insightsinareasofmicro-nanomedicines,drug deliverysciences,newtrends,andregulatory aspects.

O.Farokhzad,R.Langer,andtheNational CancerInstitutearegratefullyacknowledgedfor thebookcoverimage,whichrepresentsthepotentialofnanopharmaceuticalsintargetingdrug molecules.Thisphotographpresentedoncover pagecapturesinteractionsofsurface-modiﬁed polymericnanoparticleswithprostatecancer cells itisanidealexamplefordrugtargeting.

Alltheeffortsofexperts,scientists,and authorsarehighlyacknowledgedforsharingtheir knowledge,ideas,andinsightsaboutthetopic.

RanjitaShegokar,PhD Editor

Solidlipidnanoparticles(SLN): predictionoftoxicity,metabolism,fate andphysicochemicalproperties

J.R.Campos1,P.Severino2,3,4,A.Santini5,A.M.Silva6,7, RanjitaShegokar 8,S.B.Souto9,E.B.Souto1,10

1DepartmentofPharmaceuticalTechnology,FacultyofPharmacy,UniversityofCoimbra(FFUC),Polo dasCi^ enciasdaSaude,Coimbra,Portugal; 2UniversidadeTiradentes(Unit),Aracaju,Sergipe,Brazil;

3InstitutodeTecnologiaePesquisa,LaboratoriodeNanotecnologiaeNanomedicina(LNMed),Aracaju, Sergipe,Brazil; 4TiradentesInstitute,Dorchester,UnitedStates; 5DepartmentofPharmacy,Universityof Napoli “FedericoII”,Napoli,Italy; 6SchoolofBiologyandEnvironment,UniversityofTras-os-Montese AltoDouro(UTAD),VilaReal,Portugal; 7CentreforResearchandTechnologyofAgro-Environmental andBiologicalSciences(CITAB),UniversityofTras-os-MonteseAltoDouro(UTAD),VilaReal, Portugal; 8CapnomedGmbH,Zimmern,Germany; 9DepartmentofEndocrinology,S.JoaoHospital, AlamedaProf.Hern^ aniMonteiro,Porto,Portugal; 10CEB-CentreofBiologicalEngineering, UniversityofMinho,Braga,Portugal

1.Introduction

Solidlipidnanoparticles(SLNs)gained greaterattentionasadrugdeliverysystem whenin1991M € ullerdevelopedthem [1].This promisingdrugcarriersystemisattheinterface inthepreexistinglipidsystems(emulsionsand liposomes)andpolymericnanoparticlesystems. Lipidnanoparticles,knownasSLNsornanostructuredlipidcarriers(NLCs),havespeci ﬁc featuresofstructureandcomposition,showing bene ﬁtsincomparisontoconventional

formulations [2].Variouscontrolleddrugdeliverysystemslikepolymer-basedcontrolledreleasesystems,hydrogels,aswellasnanoandmicroparticleshavebeenintroducedin recentyearsinordertoimprovesolubility,stabilityandbioavailabilityofpoorlywater-soluble drugs.Inthiscontext,lipidnanoparticlesoffer attractiveandidealpropertiesfordrugorgene delivery.Theseparticles(eithercomposedof solidlipidsonlyinSLNs,orofablendofsolid andliquidlipidsinNLCs)stabilizedwithsurfactantshavetheadvantagesofothercolloidal

particles(polymericnanoparticles,fatemulsions,andliposomes)byovercomingtheirlimitations [3,4].Takingaccounttheirpolymeric andlipidrawmaterials,severalmodifications ofdrugdeliverysystemshavebeenproposed toincreasethebioavailabilityofloadeddrugs. SLNsaremadeofasolidlipidmatrixandasurfactantlayerandtheycanloadpoorlywatersolubledrugs,deliveringthematdefinedrates andwithimprovedbioavailability [5].These colloidaldrugdeliverysystemsprotectthe drugagainstchemicaldegradationandmodify itsreleasepro filesincethedrugisentrappedin thesolidlipidmatrix [6,7].Thesenanoparticles ofsphericalshapehaveameansizeof 40 1000nm [8,9].Thelipidmatrixiscomposed ofasolidlipid(oramixtureofsolidandliquid lipids)ina0.1% 30%(w/w)concentration dispersedinaqueousmedium,andtheirstability isensuredbythepresenceofasurfactantina 0.5% 5%(w/w)concentration [8] andcanbe usedforlipophilicorhydrophilicdrugs [9].Triglycerides(tristearin),sterols(cholesterol),partialglycids(glycerylmonostearate),fattyacids (stearicacid),aswellaswaxes(cetylpalmitate) areespeciallyusedaslipidsintheSLNs.Inthese systemsemulsi fiersandpolymersareusedas stabilizersinordertoavoidaggregationofthe particles.Examplesofstabilizersarebilesalts (e.g.,taurodeoxycholate),lecithins,andcopolymersofpolyoxyethyleneandpolyoxypropylene (Poloxamer) [10].

Itisclearthatlipidnanocarriersareidealfor sensitivebioactivecompounds.SLNsexhibit biocompatibility,matrixwithlipophilicnature protectingactivecompoundsofchemicaldegradation,drugtargeting,controlledreleaseproﬁle, andhighdrugpayload [9,12].Moreover,they aresuitableforindustrialproductionmainly becausetheyareeasytoscaleup,arestableunder sterilizationconditions,andtheyhavetheadvantageofbeingnon-toxicorofverylowtoxicity, becauseoftheircompositioninGenerally

RecognizedasSafe(GRAS)excipients [4,6] SLNsarebiodegradable(fulfillingtherequirementsofpreclinicalsafety)andarealsostablein blood,withprolongedlifetimeinthebloodstream [13 15].Inaddition,comparedtoliposomes, SLNsexhibithighencapsulationefficiency,stabilityagainstlightandoxygen,donotneedorganic solventsfortheirpreparation,andhavehigh drug-loadingcapacity(mainlyforlipophiliccompounds) [12,15,16].Ontheotherhand,SLNshave alsolimitations,mainlyattributedtotheriskof polymorphictransitions(from a to b0 ,andfrom b0 to b)whichcausesstabilitychallengesduring administrationorstorage,resultingindrug expulsionfromtheparticlesandeventualparticle sizeincrease [6,10,17].Thesedisadvantagesare relatedtothecrystallizationbehaviorandlipid matrix’spolymorphictransitions,whichdepend onthetypeoflipidsusedfortheproductionof SLNs [6].Therearevariousmethodsdescribed intheliteraturetoproduceSLNsbasedon solidifiedemulsiontechnologies:highshearhomogenizationandultrasound,highpressure (hotandcold)homogenization,oil/water(O/ W)andwater/oil/water(W/O/W)microemulsions,aswellassolventevaporation [10]. Thesetechniquesinterferewithvariouscharacteristicsoftheparticles,mainlyinmorphology.Accordingtotheliterature,themostcommonly appliedmethodsarethosethatusehighpressure homogenizers(HPH).M € ullerandLuckdevelopedtheHPHtechnique(EuropeanPatentNo. 0605497)forobtainingnanoemulsionsforlargescaleparenteralnutrition [10].Therearediverse kindsofequipmentwithvarioussizes,pricesas wellasdifferentcapacities.Thedifferentequipmentsworkbypullingtheliquidinhighpressure (100 2000bar)throughanarrowpiston(nanometerscale),whichisacceleratedoverasmall distanceatahighspeed(over1000km/h).This fluidissubjectedtohighstress,disruptingthe macroscopicoildropletsbycavitationforces andthusgeneratingthenanodroplets [10].In

thehotprocess,thehotpreemulsionispassed throughthehothomogenizertoobtainnanoemulsions,whicharethencooleddowninorder tosolidifyandcrystallizethehotinnerliquid phasetoobtainSLNs.Inthecoldprocess,the drugis firstlygroundmilledinamortarmill withthesolidlipidatroomtemperature,and thentheobtainedpowderisdispersedinan aqueoussurfactantsolution,whichisthensubjectedtoHPH.Theinfluenceofthetypeof homogenizer,pressure,andnumberofcycles employed,andthetemperatureusedtoobtain theidealparticlesize,havebeenintensivelystudied.Dependingonthetypeoflipid,itispossible touselipidconcentrationsabove40%andobtain theparticlesizedistributioninalowrange (polydispersityindex <0.2) [18].ToobtainSLNs frommicroemulsions,Gascoandcollaborators developedatechniquethathasbeenmodified bynumerousresearchers.Inthistechnique, SLNsareproducedbydilutingahotoil-in-water (O/W)microemulsioninhighvolumeofcoldwater(0 4o C).Theinternalphaseofthismicroemulsioniscomposedoflow-meltinglipidsand, whenincontactwiththecoldwater,theysuffer crystallizationandformSLNs [18 20].Thetype oflipidsusedtomakethemicroemulsion,the preparationparameters(stirringandtemperature),rateofmicroemulsion’sadditioninthe coldwater,volumeofwater,andthetechnique usedtoremovetheexcesswater,allaffectthe characteristicsofobtainednanoparticles [18]. Thistechniqueisthereforedifficulttoscaleup. Marengohasdevelopedadevicethatprocesses 100mLofmicroemulsionandcanproduce SLNsofmeansizebelow100nm [20].

Thebiomedicalapplicationsoflipidnanoparticlesaremanyfold.Indeed,theycanbeusedas drugandgenecarriers,andascontrastagents forimaginganalysis [21].Inrecentyears, differentadministrationroutes(e.g.,oral,parenteral,dermal,pulmonary,rectal,ocular)have

beenexploredfordrugdeliveryusinglipid nanoparticles.Componentsoflipidnanoparticles(lipidsandsurfactants)determinethe productquality,itsphysicochemicalproperties, aswellastheadministrationroute [4] (Table 1.1).Inthischapter,theconceptbehindthe SLNsandtheirphysicochemicalproperties, pharmacokinetics,andbiopharmaceuticsand theirtoxicologicaltestingarediscussed.

2.Toxicityproﬁling

SLNsareknowntobestableinaqueous dispersion,allowstheencapsulationofhydrophilicandlipophilicdrugs,areadaptableto severaladministrationroutes,canmodifythe releaseproﬁleandavoidtheiradverseeffects (protectingthedrugfromundesirableinteractionsordirectingittoitstarget) [30].However, theirtoxicologicalpro ﬁlehastobeverywell characterizedinvitrobeforeanypre-clinical andclinicalstudies [31].Thereisarelationship betweenthesizeoftheparticlesandtheir toxicity,asthelowerthesize,thehigherthesurfaceareaandthehigherthereactivity.AprerequisitetobemarketableistheGRASstatus oftheexcipientsofSLNs [32],butadditional nanotoxicologicalstudiesareneededtoallow theunderstandingoftheeffectofnanoparticles inthebody [14,33,34].Nanotoxicologyhelpsin identifyingtheSLNformulationstobeselected forpreclinicalstudiesbyevaluatingtheirsafety, tolerance,andcytotoxicity.

Preclinicaltoxicologicalstudiesallowto determinetheconcentrationofsubstancesthat causetoxiceffects,andallowidentiﬁcationof targetorganspredisposedtotheseeffects.Preclinicalsafetytestsrequiretheappropriateselectionoftheanimalspecies,age,physiological status,theadministrationroute,dosageformas wellasthetreatmentregime.Preclinical

TABLE1.1 CommonlyusedlipidsinthecompositionofSLNs/NLCs.

NameChemicalstructureSurfactantSystemDrug

Therapeutic applicationReferences

Tristearin Dihexadecyl phosphate SLNs Pulmonary delivery [22] PEGsSLNs Oraldelivery [23]

Glyceryl monostearate

MixtureofTween 80andSpan80 SLNs [24]

Stearicacid Omega-3PUFASLNsResveratrolOral delivery [25]

CystamineSLNs [26] Tween80NLCs [27] Cholesterol PluronicF-68NLCsSimvastatinOral delivery [28] VitaminE O O O O O R n O D-a-tocopheryl polyethyleneglycol succinate(TPGS) NLCsRapamycinOcular delivery [29]

toxicologicalevaluationofanewcompoundcan provideinformationaboutacute,subacute,subchronic,andchronictoxicity.Beforeanypreclinicalstudy,cytotoxicityassessmentiscarriedout incellculture,alsoallowingthestudyofthe interactionbetweennanoparticlesandcells. Theuseofprimarycells(isolateddirectlyfrom theanimals)providesmorerealistictoxicological results.Ontheotherhand,invivostudiesevaluatetheorganismasawhole.Therefore,invivo studiesarerelevanttodeterminethelocation andconcentrationofthedruginthetissues,and systemictoxicity [35].Systemswithlargequantitiesofsurfactants(e.g.,nanoemulsions)have higherriskofexhibitingcytotoxicity,sincethese agentsinteractwithcellmembranescomposed ofphospholipids.Likewise,theirproductionrequirestheuseoforganicsolvents,whichmay alsoincreasetheriskoftoxicologicaleventsif poorlyremoved.Althoughprecisedeterminationofthetoxicitycanonlybequanti ﬁed invivo,thereareseveralinvitrotoxicological teststhatprovidepreliminaryinformation [10,14,36].Invitrostudieshaveshownthat SLNsareacceptableatconcentrations <1mg/ mL(totallipids),andwithparticlediameter >500nmcanbelesstolerated,whichcanbe explainedbytheiraggregation.Itwasalso shownthatthestabilizedformulations composedofseveralsurfactantsarelessbiocompatibleincomparisontothosebasedononesurfactantonly.Forpolysorbate80andpoloxamer 188,twosurfactantsmostlyusedinSLNsformulations,enoughevidencehasbeenfoundto determinetheirsafety [14].Itisclearthatthe knowledgeofthetoxicologicalproﬁleofanymaterialandthebiocompatibilityofthedrugdeliverysystemsarecrucialfortheimplementationof drugtherapies,buttheinformationof

nanoparticle-baseddrugtherapiesavailableis stillverylimited [8]

3.Physicochemicalproperties

ThecharacterizationofSLNsusuallyrequiresthedeterminationoftheparticlesize andzetapotential,morphologicalevaluation, determinationoftheloadingcapacityand encapsulationef ﬁciency,kineticsofdrug release,aswellasthenanoparticlesover timeandstoragetemperature.

3.1Encapsulationparameters

Determinationoftheamountofdrugassociatedwiththenanoparticlesisacrucialparameter forthecharacterizationofSLNs.Thistaskis howeverdifficultbecauseofthesmallsizeof theparticles,whichcompromisestheseparation ofthefreedrugfractionfromtheassociatedfraction.Ultracentrifugationisthemostcommonly usedseparationprocedure,afterwhichthe non-loadeddrugisquanti fiedinthesupernatant.Fromthedifferencebetweentotaldrug andthedrugfoundinthesupernatant,the drugconcentrationassociatedwithnanostructuresiscalculated [37,38].Ultra filtrationcanbe coupledtotheprocessofultracentrifugation.In thisapproach,amembrane(100kDa)isusedto separatetheaqueousphasefromthenanoparticles.Althoughthefreedrugconcentrationin thistechniqueisdeterminedintheultra filtrate, thedrugfractionassociatedwiththenanostructuresisalsofoundbythedifferencebetweenthe totalandfreeconcentrations [39].Encapsulation ef ficiency(EE%)andloadingcapacity(LC%)are determinedusingthefollowingequations [40]:

3.2Particlesize

Sizeandpolydispersityindexareparameters thatindicatethestabilityofthenanoparticles. AnoptimizedSLNformulationshouldexhibit ameanparticlesizelessthan1 mm,together withasmallpolydispersityindex.Severalparametersaffecttheparticlesizeandpolydispersity,e.g.,compositionoftheformulation (mixtureofsurfactants,lipidstructuralproperties,andalsoincorporateddrug),methodsand conditionsoftheproduction(time,temperature, stirringvelocity,pressure,etc) [41].Thereisa relationshipbetweentheproportionofsurfactant/lipidandtheparticlesize,i.e.,thegreater theconcentrationofsurfactant,thesmallerthe particlesize [42].Thetemperatureusedinthe HPHtechniqueisanotherparameterthatinterfereswiththeparticlesize.Intheproductionof SLNsandNLCs,thelipidphaseisheatedup toatemperaturehigherthanthemeltingpoint ofthesolidlipid.The ﬁnalstepisthecooling downofthesystemssothatthelipidrecrystallizestosolidifythelipiddroplets [43].Homogenizationatlowtemperatures(i.e.,belowthe meltingpointofthesolidlipid)favorstheincreaseofparticlesize,buttemperaturesnear themeltingpointimprovethehomogenization andlowerparticlesizescanbeobtained.Similarly,thehotHPHprocedureproducesparticles withlowermeansizeandpolydispersitythan thecoldprocedure [41].Generally,theparticle sizeincreaseswhenlipidsoflongfattyacid chainsareemployed.Theuseofmixturesof short-andlong-chainfattyacidsmaytherefore reducethemeanparticlesizeandpolydispersity indexofSLNs/NLCs [4,44].

3.3Zetapotential

Zetapotentialisanotherparameterusedto evaluatethelong-termstabilityoftheparticles anditsassessmentisinstrumentalforthephysicochemicalcharacterizationofthenanoparticles' dispersion.Whendeterminingthezetapotential, itispossibletounderstandtheinteractions betweentheparticleandthedrug.Thisparametershowsthesurfaceelectricalchargeofthe particles,whichismodiﬁedbychangesinthe interfacewiththedispersingmediumsincethere isadissociationoffunctionalgroupsontheparticle'surfaceandadsorptionofionicspeciesof theaqueousdispersionmedium [39].Themeasurementofthisparameterallowstoclarifythe stabilityoftheformulationduringitsstorage time.Thehigherthezetapotential,thehigher theelectrostaticrepulsionbetweentheparticles, resultinginreductionoftheriskofparticles' aggregation.Accordingtoliterature,azeta potentialhigherthanthe30mVmodulusguaranteesthestabilityofSLNs [45].However,there areSLNformulationswithzetapotentialbelow |30mV|thatremainstableovertimedueto thestereochemicalstabilityofferedbysurfactants [46].Changingaformulationbyvarying theconcentrationofitscomponents,allows understandingwhichofthosewhether contributetothestereochemicalstabilityorto theelectrostaticstability [47].Differentialscanningcalorimetry,basedonthestudyofthepeaks ofSLNformulationrecordedonthethermogram,allowsassessingifthedrugisloaded withintheparticlesandeventuallyitscontributiontothesurfaceelectricalchargeofSLNs [48].

3.4Particlemorphology

Tolearnabouttheshapeandsizeofnanoparticles,scanning(SEM)andtransmissionelectron microscopy(TEM)arecommonlyused [50] Atomicforcemicroscopy(ATM)isanothertechniquethatgivesinformationwithhighresolutioninthreedimensionsatthenanometerscale (evensurfacedetailsattheatomiclevel),andis alsousedtounderstandthesurfacemorphology ofnanoparticles [39].

3.5Differentialscanningcalorimetry

Thephysicalandchemicalchangesofasamplecanbemeasuredasafunctionofitstemperature;differentialscanningcalorimetry(DSC) quanti fiesthelossorheatgainresultingfrom thesechanges.TherearetwotypesofDSCinstruments:(1)thepowercompensateDSC, whichismadeoftwoseparateovens;and(2) theheat- fluxDSC,whichhasonlyanoventhat heatsupthereferenceandsamplepans.The sampleandreferencereceivetheheatthrough thesamplepan,whichisplacedinadiscthat isthemainsourceofheat.Bothdifferential heat flowandsampletemperaturearemonitored,andthecalorimetricsensitivityismaintainedbythesoftwarelinearizationofthecell calibration [52].Theendothermicprocesses,i.e., thosethatabsorbheat,includefusion(melting), boiling,sublimation,vaporization,desolvation, aswellassolid-solidtransitions.Thecrucial exothermicprocess,i.e.,theonethatreleasesenergy,iscrystallization.Theseanalyzescanbe usedtoidentifymaterials,investigatetheirpurity,polymorphismorsolvation,analyzequantitativeandqualitativedegradation,aging,glass transitiontemperature,aswellastheiraffinity toothersubstances.DSCisusefultoobtain informationaboutthedegreeofcrystallinityof thelipidmatrixandpolymorphicbehaviour.In

DSCanalysis,ameltingpointdepressionisusuallyobservedwhentransformingthebulklipid intolipidnanoparticles [48,52]

3.6Stabilityofformulationsandrelease proﬁle

Thestabilityoftheloadeddrugwithinlipid nanoparticlesisdependentonthechemical compositionofthelipidmatrix(e.g.,typeof lipid,surfactant)andproductionprocedure. Uponstorage,triglyceridesundergopolymorphicchangesthatmayresultindrugexpulsion fromthelipidnanoparticles [53] .Surfactants alsoplayarelevantroleonthecrystallization behaviorofthelipidnanoparticles,i.e., whethertherecrystalli zationoftheparticles occursontotheirsurfaceorwithinthelipid core [54] .Thelong-termstabilityoflipidnanoparticlesoverstorageisthereforedependent onthelipidandsurfactantcompositionofthe particlesandoftheproductionprocedure [55] .Thepresenceofimperfectionsinthelipid matrixoffershighercapacitytoaccommodate drugmolecules,improvingtheloadingcapacityoftheparticles [19,56] .Toachieveamodifi edreleasepro fi leoftheloadeddrug,the particlesshouldhoweverretainthedrugduringstorageuntiltheir administration.To increasetheencapsulationef fi ciency,theuse ofmixedlipids(havingfattyacidswith differentliquidandsolidchainlengths)isusuallyrecommended.Theseblendscreatesmall liquidreservoirsinsidetheparticles ashappensintheNLCs delayingthepolymorphic changesoverstorage [18,53,57] .Theencapsulationef fi ciencyoflipophilicdrugsisalso higherinSLNsandNLCsthanhydrophilic drugs.Toloadtheselatterinlipidmatrices, otherstrategiesareneededsuchasthedevelopmentofinsolublecon jugatesbetweenthe

lipidandthedrugbyacovalentbonding [58, 59] .Hydrophilicdrugsmightshowhigher risktobepartitionedtotheaqueousphaseduringtheproductionofSLNsandcreateadrugenrichedshellmodel.Indeed,uponcoolingof thedispersions,thelipidsolidi fi es fi rst,crystallizesandformsthecoresinwhichthehydrophilicdrugwillbeprecipitatingontotheir surface.ThistypeofSLNs(drug-enrichedshell model)doesnotexhibitamodi fi edreleaseprofi lebutratherafastreleaseattributedtothe presenceofdrugontothesurfaceofthe SLNs.Fordrugsthatsolidify fi rst(e.g.,of meltingpointhigherthanthatofthesolid lipid)orforlipophilicdrugs,adrugenriched coremodelcanbeproduced,whichexhibitsa modi fi edreleasepro fi le [17] .Typicalmethods usedforassessmentofthe invitro releaseare thedialysisandthestaticordynamicFranz diffusionmethods.Theassayscanbedesigned sothatisotonicityandpHvaluecanbe adjustedtomimictheintendedadministration route,andcanalsoincludetheeffectofprotein adsorption,plasmacompatibility,wholeblood compatibilityandsterilisation.Itisknownthat inaphysiologicalenvironment,proteinscan bindthesurfacesofnanoparticles,forminga nanoparticle proteincomplexthatin fl uences thebiologicalresponse.Nanoparticlescanbe incubatedwithbulkserum,plasmaandalso withsolutionsofindividualproteins,inorder toevaluatewhichphysicalpropertiesare responsiblefortheproteinbindingontotheir surface [60] ,suchasthetypeofpolymerused tostabilizetheparticles [61,62] .Freeze-drying mayalsobeusedtoenhancethelong-term stabilityofSLNsandNLCs.Lipid nanoparticlescanbetransformedinadry producttoimprovetheirphysicochemical stability [63]

4.Administrationroutesanddrug bioavailability

Pharmaceuticalnanotechnologycomesupasa strategytoimprovethebioavailabilityofpoorlywatersolubledrugs,enhancingtheirtherapeutic effectivenessandreducingtheriskofadversereactions [64 67].SLNshavebeenextensively exploitedasaninterestingapproachtoimprove thedrug’sbioavailabilityinparticularthoseof classIIandIVofthebiopharmaceuticalclassificationsystem(BCS) [64,67].Indeed,duetotheir lipidcomposition,theymayactasabsorptionenhancers [67].Ontheotherhand,surfactantssurroundingtheparticlesbesidesensuringtheir stericstabilityinaqueousdispersion,theyinduce specificsurface-chemicalpropertiesandmayalso modulatethebiopharmaceuticalprofile.Forthe selectionofthebestsurfactant,severalparameters havetobetakenintoaccounte.g.,hydrophiliclipophilicbalance(HLB)values,theireffecton thelipidpolymorphismandontheparticlesize. TheHLBvaluesforthestabilizationofoil-inwaterdispersionsvarybetween8 18 [68].The rightchoiceofthesurfactantminimizesthe riskofproductionofparticles’ aggregateswhich maycompromisethestabilityofthedispersion invitroanditsperformanceinvivo [45].

4.1Topicalanddermalroutes

Theadministrationofdrugsthroughtheskin maycontributetoincreasethedrug’ sbioavailabilityasitovercomesthe ﬁ rst-passmetabolism.Thisadministrationroutereducesthe ininter/intra-patientvariationandincreases patientcompliance.However,itisalsoassociatedwithinteractionsofdrugand/orexcipients withskinthatmaycauseirritation [69] .The

Another random document with no related content on Scribd:

Nobody heah, Phinney man, Dick an’ Dandy heah!”

An’ de gentleman catch de ol’ lady an’ tear him up to inch pieces.

[Contents]

73. THE SINGING BIRD. [NOTE]

a.Fine Waiting Boy.

AlfredWilliams,MaroonTown.

A gentleman have him servant, and one day he said to de servant, “Collin, go an’ look about de horse harness my buggy.” An’ Collin go an’ harness him master horse an’ put in de buggy. Well, him master drive on an’ him drive on till him get to a well; an’ de master said, “I want some water.” An’ Collin said, “Massa, der’s a well is down before.” An’ he an’ Collin come out de buggy against de well-side, an’ meanwhile de massa sit against de well-side, Collin pitch him master in de well. An’ Collin tu’n back an’ go on half way wid de buggy, an’ when he get home de missus ask him, “Where is de master?” an’ Collin said, “He goin’ pay a visit an’ comin’ to-morrow; de buggy goin’ meet him.” Collin go de day wid de buggy. When he went back, de missus said, “Where is de master?” He said, “Go to pay a visit, won’t be back till to-morrow.” When Collin gone, de nex’ servant in de yard say, [84]“Missus, hear what little bird singing?” Missus come to de doorway an’ listen, an’ hear de little bird whistling,1

Fine wait-in’ boy, fine wait-in’ boy, Throw his mas-ter in-to a well, Col-lin, Col-lin, no ben see da lit-tle bird up-on tree so long?

When de missus hear de little bird singing so, couldn’t understand, called a sensible person understand de bird. An’ go search de well, fin’ de master body, an’ go tak Collin hang him.

[Contents]

b. The Golden Cage.

WilliamHarris,Maggotty

A king had a daughter. He had two servants who did not like the daughter. One day the two servants were going to the well for water and the daughter said she wanted to go with them. And they catch the little girl and cast her in the well. Three days after, the little girl went home to her father an’ the father catch the two servants and throw themin the well. And he get his child and thus end the story.

♩ = 84

Cheep, cheep, cheep, cheep I brought a news to tell you Cheep, cheep, cheep, cheep I brought a news to tell you Miss Chee Chee take you, one dear love an’ cast her in-to a well Be qui-et, be qui-et, I will make a gold-en cage an’ put you in-to it No, no, no, no Same me will do it to dear love too, you will do with me the same.

[MP3 ↗ | MusicXML ↗]

[85]

Sung by Mrs. Williams. ↑

[Contents]

MargaretMorris,MaroonTown,Cock-pitcountry.

Two sister dey to house. One sister fe servant to a Busha1 in one pen2, an’ tell de Busha marry odder sister. De sister name Miss Grace my fair lady, de older sister Lady Wheel. An’ Miss Wheel servant to him sister. Busha gone to him work, never come back till midnight. Busha come, never hear not’ing stir. Till one day him gone out, Miss Wheel call Miss Grace to let dem go pick peas. So dem went away an’ tek a basket pick de peas, an’ have a baby in de hand, Miss Grace my fair lady baby. An’ when dem pickin’ de peas aroun’ sea-ball, Miss Wheel mek Miss Grace tek off dress an’ Miss Wheel shove Miss Grace my fair lady in de hole. She pick up de peas an’ come home, tek water wash her breast, tek de baby fe her own self; when night come, suckle de baby. So when de Busha come home midnight, she give him de dinner, eat an’ drink dat time, no notice him wife at all. T’ree day after dat he keep on coming but never notice. Till a day when he come, he ax fo’ de servant. Say, “No, my dear, I sen’ her out to de common, soon come.” De husban’ fall in sleep an’ never hear if de servant come in. Till one day when de husban’ coming back, one of de neighbor call to him, “Busha, you don’ hear what harm done in your house?” He say no. Dem tell him he mustn’t even drink cold water into de house de night an’ him hear what alarm done. So de Busha go, an’ what de lady gi’ him he never tek, never drink cold water even. Him force him an’ he never touch it. An’ de Busha lay down midnight an’ seem to doze asleep, but he no ’sleep

Have a little dog an’ call de dog “Doggie.” Dog see when dead woman come. She call to de dog,

“Han’ me my baby, my little doggie.”