contentsintroduction 2part one:Connectingthe 4DotsinDrugDeliverypart two:TheBioavailability 8Toolboxpart three:TheToolboxof2025 16part four: DeliveringChange 21

from molecule to dose form bioavailability toolkit to fast track development

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introduction

Whenitcomestodrugformulationchallenges,thereisnoone-size-fits-allsolution.

The3rdannualdrugdeliverylandscapesurvey*confirmsthatbioavailability,safety,efficacyandsolubilityarethetopchallengesfacedbyformulationscientists.Thepharmaceuticalandbiopharmaceuticalindustrieshavetoovercomenotonlyformulationchallengesbutalsothebusinesschallengesofbringingaproductsuccessfullytomarket.Thesurveyparticipants,avastmajorityofwhomareFormulationScientistsandR&DManagers,indicatedthatdevelopmenttime,selectingtheappropriatedrugdeliveryplatform,budgetandchoosingtherightexternalpartnerarethetopbusinesschallenges.Thesurveyalsoshowsamajorshiftintrendtowards“patient-centric”drugdesign.Oraldeliveryofmacromoleculeswasthetrendthatwillmostinfluencethedrugdeliverytechnologyinnextfiveyears,followedbyimprovingbioavailabilityofBCSClassIVdrugs.Inanutshell,FormulationScientistshaveathree-foldchallenge;designingasafe,effectiveandstabledosageform,ensuringitispatientfriendly,andbringingitfastertomarket.

Thedaysof“low-hangingfruit”inthedrugdiscoveryerawhenmostnewchemicalentities(NCE)werehighlypermeableandsoluble(BCSclassI)areover.AsdrugdiscoveryteamsdigdeeperintocompoundlibrariestoidentifyaNCE,thecompoundsareincreasinglybecominglesssolubleand/orpermeablethanpreviouslydevelopeddrugs.Itisestimatedthat

~70%ofNCEsareclassIIorIV,eitherpoorlysolubleinwater,havelowcellpermeabilityorboth.Inaddition,inthemidstofthetechnologyandbusinesschallenges,wecannotaffordtolosesightofendusers,i.e.,thepatients.

Traditionally,thetargetcustomerswerephysiciansbutthesurveyindicatesthattheindustryhasrealizedthatpatient-centricdrugdesignisamajor

trendandthekeytosucceedinthiscompetitivelandscape.Theleadingevidenceofthistrendincludesmoredirect-to-consumeradvertisingandarecentpatientfocuseddrugdevelopmentinitiativebytheFDAtogatherthepatient’sperspectiveontheirconditionandavailabletreatments.Interestingly,surveydatashowsthatalthoughtheindustryhasidentifiedthevalueofpatient-centricdrugdesign,ithasnotbeenverysuccessfulinapplyingit.Forinstance,tosuccessfullyapplypatient-centricdesign,thedrugproductshouldbeadaptedasperthepatient’spreferenceatearlierstagesofdrugdevelopmenttoavoidhighcostsatlatestages,apracticewhichisnotverycommonintheindustry.Also,whenaskedtoratethesignificantfactorsindrugdevelopment,patientadherence,patientdosingconvenience,andimpactonpatient’slikelydrugregimenreceivedverylowscores.

Thereisadefiniteneedforadrugdeliverystrategythatnotonlyovercomesformulationchallengesbutalsomeetspatientdemands.Industrypioneersinformulationtechnologyhavedevelopedabroadrangeofadvanceddrugdeliverytechnologies,whichareviabletoolstosolveformulationchallenges,improvepatientcompliance,andbringproductfastertomarket.Hereisabriefsnapshotofthetypeoftoolsavailabletoformulationscientists.

softgel technology:Forlast80+years,softgeltechnologyhasenabledmorethan50poorlysolubledrugstobecommercialized,makingitoneofthemostsuccessfuldrugdeliveryvehiclesforBCSclassIIcompounds.ItisalsoaprovenmethodtodeliverunstableAPI,lowdose,potentcompounds,lightandoxygensensitivecompounds.Softgeltechnologyhasutilizedlipid-baseddrugdeliverysystems(LBDDS)inwhichdrugisdeliveredinasolutionformandmaintainedinsolutionupondispersionintobiologicalfluidsuntilitreachesGItrack.LBDDSareusedtoovercomeissuescreatedbyAPIthat

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arepracticallyinsolubleinwaterandspontaneouslyemulsifyingastricjuices.Thereareanumberoftechnologiesthatcanaccommodateawiderrangeofdrugmoleculesandexcipients.Forinstance,onetechnologyutilizesaplantpolysaccharidebasedshellwhichallowsencapsulationoffillformulationsathighertemperatures,upto~70°Cforsemi-solidandhighlyviscousfillformulations.

Additionally,thereisanewtooltoimprovethedeliverycharacteristicsofmacromoleculesincludingpeptidesandproteins.Macromoleculesdeliveredthroughtheintravenousroutemayresultinpoorpatientcomplianceforlongtermtreatment.Thisnewtechnologyimprovesthebioavailabilityofmacromoleculesbyincorporatingpermeabilityenhancerswhichmodulateintestinalmembranepermeability.TheentericcoatingprovidestargeteddeliveryofAPIbypreventinggastricdegradationofmacromoleculesandreleasesthemacromoleculeatthesiteofabsorption.

solid dispersion system:SoliddispersiontechnologyhasemergedasaneffectivewaytoenhancedissolutionrateoflowsolubilityAPI.Thisversatiletechnologyoffersmultipleadvantagessuchasgeneratingstableandprocessableproductthatcanbefurtherformulatedintothedesireddosageform.HotmeltextrusionistheprocessofcreatingAPI-polymerdispersionbyapplyingheatandshearstresstocreateanamorphousdispersion.Thereisnoneedfortoxicorganicsolvents,whichmeansnorelatedexpenseortheenvironmentalhazardsassociatedwithremovingthem.Hotmeltextrusiontechnologycanaccomodate~90%ofdrugloading(theratiooftheactivedrugtothetotalcontentsofthedose)whichprovidesreducedpillburdenandenhancespatientcompliance.Hotmeltextrusionprocesseshavebeenproventoincreasebioavailabilityanddecreasetime-to-marketformultiplecompoundsincludingananti-inflammatorydrugandtoimproveproductdifferentiationandbrandperformanceforanalgesicproducts.

particle size reduction:Micronizationisanestablishedmethodofimprovingoralbioavailabilityofpoorlysolublecompounds.Thedrugparticlesareacceleratedutilizinghighvelocitycompressedgaswithinachambertoachievedesiredparticle

sizerange.ItissuitableforsensitiveAPIasthereisnoheatdegradationandtheprocessresultsinthermodynamicallystablecrystallineformofAPI.Themicronizationprocesshasatrackrecordofimprovingbioavailabilityofpotentandthermolabilecompounds,suchasoncologydrugs.Thistechnologyisalsowellknownintheindustryforbringingorphandrugsfastertomarketbycombiningexpertiseinparticlesizereductionandefficientmanufacturingprocesses.

fast dissolving technology:Ever-increasingdemandforfastdissolvingandpalatabledosageformsamongpediatricandgeriatricpopulationhasmadeitarapidlygrowingfield.Fastdissolvetechnologieshavebeenshowntoimprovepatientcompliancebyprovidingaconvenientdosageformforallergensandlargemolecules.Itisaunique,freeze-drieddosageformthatispalatable,doesnotrequirewater,andisresistanttomicrobialcontaminationduetolowmoisturecontent.Oralfastdissolvetabletscanbetailoredtomeetvariousdoserequirements.Atpresent,itcoversseventeentherapeuticareasinRxandOTCproducts.

Tosummarize,thereareavarietyoftoolstoovercomebioavailabilitychallengesofpoorlysolublecompounds.Itiscrucialtoselectatoolthatnotonlysolvesformulationchallengesbutalsodeliversanagreeabledosageformforpatients.ExplorefurtherchapterstolearnhowCatalentofferscommerciallyviableandfastertomarketsolutions.

*The3rdannualdrugdeliverylandscapesurveywassponsoredbyCatalentAppliedDrugDeliveryInstitute.Formoreinformation,visitwww.drugdeliveryinstitute.com

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part one Connecting the Dots in Drug Delivery

Thedaysof“low-hangingfruit”indrugdiscoveryareathingofthepast.Drugcandidatesareincreasinglymadeupofcomplex,poorlysolublemolecules–andthatposesabigchallenge:howcanwecontinuetoproduceeffectivemedicinesthatmeetpatientneeds.

Welcometothefirstpartofafour-articleseriesthatwillexploretheunprecedentedchallengesfacingpharmaceuticalscientists–inparticular,theabilitytooffergoodbioavailabilityandpatient-friendlydrugdeliveryforincreasinglycomplexnewmedicines.Wewillreviewthecurrentandemergingtechnologiesthatarelikelytoplayarole,discusstheneedforamorecollaborativeapproach,andspeculateonthefutureofdrugdeliveryinanattempttoconnectallthedots.

The High Fruit “Therehasbeenasignificanttrendoverthelast10-15yearsformoreandmorelipophilicdrugcandidates.Upto70percentofnewdrugcandidatesnowbelongtowhat’scalledBCSclassII,meaninglowsolubilitycompoundswithhighpermeability,”explainsRalphLipp,apharmaconsultantandfoundingadvisoryboardmemberofCatalent’sAppliedDrugDeliveryInstitute.

“Thesecompoundsareoftendifficulttodeliverorallyastheydonotdissolvefastenoughduringgastrointestinalpassage.Ingeneral,adrugthatisnotdissolvedcannotbeabsorbedintothebody.”

Butareductioninbioavailabilityisn’ttheonlyproblem.Poorsolubilityisalsooftenassociatedwithunacceptablevariabilityinbloodlevelsofthedrug,bothwithinandbetweenpatients

–anditincreasestheriskoffoodeffects.

Despitethechallenges,oraldosageforms(read:convenientandnon-invasive)remainthepreferredrouteofadministrationfortraditionalsmallmoleculedrugs,makinguparound40percentofallprescriptiondrugs(1).Inessence,todelivertheconvenientdosageformsthatpatientswant,wemustfindwaystoenhancethebioavailabilityofpoorlysolubledrugs.Todothat,weneedtoconnectmorethanafewdots...

Simple Solubility?Improvingsolubilityissimpleintheory:we(just!)needtobreakdownthecrystallatticestructurebeforethepatientingeststhemedicine.Inpracticethough,withthedemandsofstabilityandpatientacceptabilitytocontendwith,it’samuchtrickierproposition.Typically,thelatticecanbebrokendownbyapplyingheat,shearstressorsolventstotheAPIandaddingsuitableexcipients.Hot-meltextrusionorspraydryingtocreatesoliddispersions,self-emulsifyingdrugdeliverysystemsandnanocrystalformationarejustsomeofthetechniquesavailabletoaidformulationscientistsinrenderingtheinsolublesoluble.Andnewadvancesarebeingmadeeveryday(2).However,thereisnoone-size-fits-allsolution.Whatisneededisatoolboxapproach

–andthemoretoolsatourdisposal,thebetter!

Inthemidstofallthetechnologicaloptionsopentous,it’simportantthatwedon’tlosesightofourendusers.Indeed,wemustbeartheminmindattheearlieststagesofdevelopment.It’snotjustaboutfindingadrugdeliverystrategythatworks,butonethatworksforpatients.

“Thefirststepinpatient-centereddesignistounderstandthatpatientsarenotahomogeneousgroupbutmadeupofmanydifferentgroups,oftenwithvastlydifferentneeds,”saysLipp.“Forexample,wehaveanopportunityasanindustrytodomoretomeettheneedsofgeriatricpatients,whomakeupanincreasingproportionofthe

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population.”Thoseneedscouldincludeanythingfromdevelopingeasilydistinguishabletablets(toavoidnegativedruginteractionsinthishighlymedicatedpopulation)toimprovingpackagingtomakelifeeasierforthosewithrheumatoidarthritis.

Ageisjustonefactortoconsider–social,culturalandconveniencefactorsplayimportantrolestoo,andtherearesubtledifferencesbetweenterritories.Forexample,atabletmassofover300mgisconsideredacceptablebymostpatientsinEurope,butistoolargeinJapan.Evenbiologicdrugs,whichhavetraditionallybeendeliveredbyinjection,aremovingtowardsmorepatient-friendlyoptions,withinhalable,topicalandoraldosageformsbeingexploredbyresearchers(3,4,5).

Team DeliveryThediversechallengesinvolvedincreatingthebestformulationsforpatientswillnotbeovercomebysingleorganizations,operatinginavacuum.Tofillthegapsinourknowledge–andtogetthebestresultsforpatients–willrequireinputfromindustry,academia,andequipmentandchemicalsuppliers.

Lifesciencescompaniesarebecomingincreasinglyawarethatprecompetitivecollaborationisgoodforbusiness–andforpatients.PhRMAExecutiveVicePresidentWilliamChindescribesitasa“tidethatraisesallboats.”Companiesarealreadycomingtogethertoexplorediseasemechanismsandidentifypotentialdrugtargets.Toencourageasimilarknowledge-sharingapproachtospeedinnovationindrugdelivery,CatalentsetuptheAppliedDrugDeliveryInstitutein2012.LippsayshisrolewithintheInstitutetapsintoanabsolutepassionforimprovingdrugdeliveryforpatients.

“TheInstitute’smissionistobringtogetherscientistsfrombothindustryandacademia,withagoalofmovingtheneedlefordrugdeliveryasawhole–thatverymuchmatchesmyambitions.”

Inthefollowingthreearticles,we’llbeexploringsomeofthemostimportantstrategiesinthedrugdeliverytoolbox,includingthelatestadvancesinexistingtechniquessuchashotmeltextrusionlipid-basedsystems,emergingtechnologiessuchasnanotechnology,andcutting-edgeresearchonalternativestoinjectionformacromoleculedrugs.

references1. R.Lipp,“MajorAdvancesinOral

DrugDeliveryoverthePast15Years”,Am.Pharm.Rev.16,6(2013).

2. R.Lipp,“TheInnovatorPipeline:BioavailabilityChallengesandAdvancedOralDrugDeliveryOpportunities“,Am.Pharm.Rev.16,3(2013).

3. S.P.Hertel,G.WinterandW.Friess,“ProteinStabilityinPulmonaryDrugDeliveryviaNebulization”,Adv.DrugDeliveryRev.,InPress(2014)doi:10.1016/j.addr.2014.10.003

4. M-C.Chenetal.,“ChitosanMicroneedlePatchesforSustainedTransdermalDeliveryofMacromolecules”,Biomacromolecules,13(12),4022–4031(2012).

5. V.K.Pawaraetal.,“TargetingofGastrointestinalTractforAmendedDeliveryofProtein/peptideTherapeutics:StrategiesandIndustrialPerspectives”,J.Control.Rel.196,168–183(2014).

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technology prof ile Hot Melt Extrusion Technology: A Proven Bioavailability Enhancement Solution

The Challenge: How to Enhance Drug Bioavailability Around40%ofcurrentlymarketeddrugsarepoorlysoluble,andpotentiallymorethan70%ofdrugsindevelopmentarealsoclassifiedaspoorlysoluble(BCSClassII/IV),representinganincreasingindustrychallenge.Thebioavailabilityofthesedrugscanbeenhancedbycreatingaphysicallystableandprocessablenon-crystalline(amorphous)formoftheAPI.HotMeltExtrusion(HME)isatechnologythatgeneratessolubleamorphousformsthatarephysicallystableandprocessable,bycombiningcrystallineAPIwithasuitablepolymer,followedbycooling/precipitation,toproduceanextrudatethatcanbeformulatedintotabletsorgranulesforcapsules.RelativetocrystallineAPIs,theseamorphoussoliddispersionsimprovebioavailabilityinmorethan80%ofcases,thusenhancingR&Dproductivityandenablingeffectivedrugdevelopment.

OptiMelt™: Enabling Holistic Bioavailability EnhancementOptiMeltisCatalentPharmaSolutions’uniquecapabilitytoformulate,developandcommercializeHMEprocessesandintegratetheseintodifferentiatedfinaldosageforms.Itenablesholisticbioavailabilityenhancementbybroadlyaddressingmultiplebioavailabilityfactors,including:

• Optimizationofproductefficacy,safetyandreleaseproperties

• Increasingdevelopmentsuccessrates

• Reducingtimetomarket.

FollowinginitialAPIandpreformulationstudies,Catalentdevelopstherequiredformulationsthroughtheapplicationofarangeofformulationscreeningtechnologiesandanalyticalservices,andthroughitsclinicaldevelopmentandsupplyservices.ThecompanycanperformHMEprocessingfrombenchthroughpilotandcommercialscaleatfacilitiesinSomerset,NewJersey,USAandSchorndorf,Germany.

OptiMeltHMEprocessingcompriseshotmeltextrusionfollowedbydownstreampelletizing/millingtoproducethefinaldoseform.OptiMeltHMEisusedtoprepareextrudateofAPIsoliddispersionsinapolymer/excipientmatrix.Theformulationmaybeprocessedintoavarietyoffinaldosageforms,includingtablets,capsules,andeffervescent‘StickPacks’.Catalenthasextensivedoseformcapability,includingtabletingandencapsulationgranules,pluscontrolledreleasetechnologies,co-locatedwithitsHMEcapabilities.

Improved Therapeutic ProfilesOptiMelttechnologyimprovestherapeuticprofilesofnewdrugsinanumberofwaysandenablestreatmentoptimization,asfollows:

• Stableformulationsgiveincreaseddevelopmentsuccessrates

• Thewiderangeofdosefunctionalitymeansthatimmediateandcontrolledreleaseformulationsdelivermoredrugwhenitisneeded,whereitisneeded

• Thewiderangeofsolubilitiesanddispersionconcentrationspossiblegivestheflexibilitytoachievedesiredefficacyanddosing

• Veryhighdrugloading(upto90%)givesareduceddailypillburdenandenhancespatientcompliance

• Patientabusedeterrenceformulationsgivepatientsafetyandcompliance

• GreaterconsistencyforAPIswithhighfoodeffectabsorptiongivesenhancedefficacyandreducedpatientvariability

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• ThetastemaskingcapabilityofHMEformulationsgivesproductdifferentiationandenhancedpatientcompliance

• Thewiderangeofdoseforms,includingtablets,capsules,andfree-flowinggranules,resultsinapreferredpatientdoseform,thusenhancingcomplianceanddifferentiatingproducts.

case study: enhancing brand performance of an otc aspirin productThechallengewasthatalargecompanywantedtodevelopandlaunchaneffervescentaspirinOTCproductasalineextensiontoaverywellrecognizedbrand.Catalentpartneredwiththecompanyforproductformulation,scale-up,andcommercialmanufacturingtoprovide:

TheOptiMeltsolution:Catalentdevelopedandoptimizedaneffectivetabletformulationthroughtheapplicationof:

• Aninnovativeeffervescentaspirinformulation

• HMEprocessdevelopment

• Downstreamprocessinginwhichtheproductwasmilled,mixed,andfilledintoauniqueanddistinctsingle-dosepackagingsolution‘StickPacks’

• Scale-upandcommercialmanufacturing

Theresultwasasuccessfulproductlaunchwithauniqueformulation,complementingtheleadinganalgesicOTCbrand.

case study: increased bioavailability of a chronic inflammatory disease drugThechallengewasthatapoorlybioavailableproductfortreatingchronicinflammatorydiseaserequiredeffectiveformulationforPhase2development.Formulation,processdevelopment,anddownstreamtabletingwereallrequired.

TheOptiMeltsolution:Catalentdevelopedandoptimizedaneffectivetabletformulationthroughtheapplicationof:

• HMEpolymerscreeningandselection

• Drug/polymerformulationdevelopment

• DeterminationofHMEprocessingparameters

• Scale-upfromfeasibilitytodevelopmentusinga10mmextruder(50g)to18mmextruder(4kg)

• Downstreamtableting,includingextrudate/tabletformulationandtabletingoperatingparametersselection

TheresultwaseffectivePhase2developmentofthecustomer’scandidate,increasingthebioavailabilityanddecreasingthetimetomarket.

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part two The Bioavailability Toolbox

Howcanweovercomebioavailabilitychallengesinourincreasinglycomplexdrugpipeline?

Thereisno‘onesizefitsall’solutiontoovercomingpoorsolubilityandbioavailability,whiledeliveringanoraldosageformpreferredbypatients,aswediscussedinthefirstarticleintheseries(”ConnectingtheDotsinDrugDelivery”).Marryingacceptablesolubilitywithlong-termstabilityisatoughchallengethatrequiresanarrayofincreasinglyingeniousformulations.

Sincetheadventofcombinatorialchemistryandhigh-throughputscreeninginthe1990s,bioavailabilitychallengeshavebecomemoreandmorecomplex.Inresponse,newformulationsanddeliverymethodshaveemerged.Theresult?Scientistsnowhaveanarsenaloftechniquestochoosefrom.“Itusedtobethatmicronizationandtheparticle-formingstepwereallthatyouhad,butnowwiththedifferentformulationoptions,scientistshaveamuchgreaterchanceofimprovingbioavailability,”saysDavidIgo,DirectorofProductDevelopmentandManufacturingatCatalentPharmaSolutions.

Allthepatientseesisasimpletabletorcapsule–onlyapharmaceuticalscientistknowstheyearsofpainstakingworkthathavegoneintocreatingthatidealformulation.

Here,wetakeawhistle-stoptourofthetechnologyandtechniquesthatenableprogressinformulation,focusingonthelatestandgreatestadvances.

Amorphous APIsEarlyinthedrugdevelopmentprocess,aprocessofsolid-stateoptimizationcanincreasethesolubilityof

thenativeactivepharmaceuticalingredient(API),amuchlessexpensiveoptionthandevelopingcomplexformulationslateron.The‘goto’methodforacidicorbasiccompoundsistoidentifyasuitablecrystallinesaltoftheAPI,butforsomeoftoday’scandidatedrugseventhisoptionisnotstraightforward.

“Moleculesaregettingprogressivelybiggerandmorecomplex,andthiscomplexitymeansthat

saltformationissometimesnotsufficienttoachieveameaningfulimprovement

insolubility,”explainsIgo.

Anapproachthathasgrownrapidlyinpopularityoverthepastdecadeisthecreationofanamorphoussoliddispersion.Withnocrystalstructuretobreak

down,amorphouscompoundsaremuchmoreeasilydissolved

intheGItract,exhibiting10,000-foldincreasesinapparentsolubility(1).

AmorphoussolutionsareformedbycombiningtheAPIwithasuitablepolymer,byspraydrying,hotmeltextrusionorco-precipitation,dependingonthemeltingpointandhoweasilytheycanbedissolvedincommonorganicsolvents.

Thedownsideofamorphousformulationsisthatthephysicalformofthecompoundisgenerallylessthermodynamicallystablethanacrystallineform.Thiscanresultinashortershelf-lifeduetothepotentialofthedrugtoreverttoacrystallineformovertime.However,recrystallizationcanbepreventedbyunderstandingandcarefullymanagingtheproductstorageconditionrelativetotheglass-transitiontemperatureorselectionofthepolymericcarrier,incorporatingstabilizersintothepolymerorcontrollingpH(2).

Spray DrySpraydryinghasbeenthemostwidelyusedmethodtodate,withtheAPI–polymermixdissolvedinanorganicsolvent,atomizedandthenrapidlydriedwithhotairornitrogenintoafinepowder.Spraydryinghasallowedcommercializationofmanydrugsthatwouldotherwisehavefailed,saysFilipeGaspar,VicePresidentofR&Dat

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Hovione.“Itisanenablingtechnologyandwehaveworkedonmanyproductsthatonlybecamebioavailablebyadoptingitandinmanyothersthatbecameeffectivedrugsatmuchreduceddose.”

Sowhat’snextforspraydrying?Therehasbeenalotofprogressinprocessanalyticaltechnology,accordingtoGaspar,whichallowscontinuousmonitoringofcriticalqualityattributessuchasparticlesizeorsolventcontent.Otherareasofinnovationincludeadvancedmodelingoftheprocess,whichprovidesforseamlessscale-upandprocessoptimizationwithminimumtesting,optimizationinthecaptureofthepowdersandmoreefficientoperationandcleaningoftheunits.Consideringthecomparativelygentlenatureoftheprocessandrecentadvancesinsterilizationofspraydryers,MárcioTemtem(groupleader,ParticleDesign&PharmaceuticalDevelopmentatHovione)believesthenextlogicalstepwillbetoapplythetechniqueinthemanufactureofsterilebiopharmaceuticals,inplaceoffreeze-drying:“Thetechnologyhassignificantadvantagesoverlyophilizationintermsofcostandthroughput.Iwouldsayitisjustaquestionoftimebeforeitsusebecomeswidespread.”

Hot Topics in Hot Melt ExtrusionHotmeltextrusionhasbeenunderutilizedbythepharmaceuticalindustry,accordingtoMichaelRepka,ChairandProfessoratTheUniversityofMississippi.“Eventhoughhotmeltextrusionhasbeeninuseforyears,manypharmacompanieshavenotfullyacceptedit.Theyhavebeenmakingtabletsthesamewayfor40yearsandcanbereluctanttoreplaceoldertechnology.”

ButforAPIswiththerightproperties,theuseofhotmeltextrusionisrapidlygainingpopularity.Astheprocessreliesonheatandshearstresstoeffectmolecularmixingandcreateanamorphousdispersion,thereisnoneedfortoxicorganicsolvents–ortheexpenseandenvironmentalhazardofremovingthem.

Repka’slabexperimentswithavarietyofdifferentAPIs,polymers,temperaturesanddosageformstofindtheoptimumprocessandtotroubleshoot

problems,suchasrecrystallizationorhighmeltingpointdrugs.“Ultimately,ourresearchaimstomakehotmeltextrusionmoreefficientandideallydevelopplatformtechnologies,sowedon’thavetostartfromscratchforeverynewchemicalentity,”saysRepka.

Recently,thegroupwassuccessfulinusinghotmeltextrusionalongsidehigh-pressurehomogenizationtoproducesolidlipidnanoparticlesinacontinuousprocess(3).Repkabelievesthatcapitalizingontheinherentcontinuousprocessingcapabilitiesofhotmeltextrusionwillbecrucial,astheindustry(tentatively)movestowardscontinuousmanufacturing:“Ifyoucandevelopacontinuousratherthanbatchprocess,thatsavesatremendousamountoftimeandmoneyandpersonnel,whichmeansthatwecangettheproducttothepatientfaster.”

“Itwon’tcomeovernight”,saysRepka,“butastheequipmentbecomesbetterandbetter,andourunderstandingoftheprocessgrows,moreandmorepharmacompanieswillcometoaccepthotmeltextrusionasamainstay.”

Size MattersForacrystallinedrug,onewaytoincreasebioavailabilityistoreducetheparticlesize.Increasingthesurfaceareatovolumeratioincreasestherateofdissolutioninthegastrointestinaltract.It’snowpossibletoreliablyproducefineparticlesdowntothesubmicrorangeineithera‘topdown’(forexample,millingormicronization)or‘bottomup’(forexample,precipitation)fashion.Micronizationisthemostcommonapproach,withcompaniesofferingever-fasterandmoreefficientmillingtechniques.

Aswellasincreasingthesurfaceareatovolumeratio,nanoparticleshaveintrinsicpropertiesthatcanhelpovercomepoorbioavailability.Thetransitionfrommicro-tonano-scaledramaticallychangesthephysicochemicalpropertiesoftheparticles,increasingsaturationsolubility,speedofdissolution,andtheabilityoftheparticlestoadheretocellmembranes(4).

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Plus,therearespecialadvantageswhenitcomestotargetingcancer.RonakSavla,aRutgersUniversityResearchFellowsupportingtheCatalentAppliedDrugDeliveryInstitute,usedspeciallyengineerednanoparticlestodeliverhighlypotentcancerdrugsspecificallytothetumorsite(5).“Thereisaphenomenonknownastheenhancedpermeationandretentioneffectinsolidtumors–thebloodvesselsinthetumorbecomeleaky,allowingthenanoparticlestoexitthebloodstreamonlyatthetumorsiteratherthanelsewhereinthebody.”

Savlaalsoappliedcuttingedgetechniquestocreatenanoparticlesforpulmonary(inhaled)delivery(6).Particlesizeiskeyforinhaledformulations,asSavlaexplains:“Thelocationwherethedrugparticlesdepositishighlydependentonsize,soifyouwanttoreachthealveoli,deepinthelungs,youneedasmallerparticlesize,whereasifyouwanttoreachtheupperairwayorbronchus,youneedalargersize.”ItislikelytobeafewyearsbeforeweseetheresultsofSavla’sworkintheclinic,butexpertsagreethatnanoparticlesareakeydrugdeliverysystemforthefuture.

Fat ChanceLipophilicdrugsareoftenbetterabsorbedwhentakenalongsideafattymeal,afactwhichgivesacluetoanotherformulationapproachforhighlylipophiliccompounds.Self-emulsifyingdrugdeliverysystems(SEDDS)arecreatedbydissolvingtheAPIinamixtureofoil,surfactantsandotherexcipients,whichresultsinaliquidorpasteintermediatethatcanbeencasedinasoftgelorhardshellcapsule.Afteringestion,thecoatingdissolvesandthemixtureisreleasedintotheaqueousenvironmentofthegastrointestinaltract.Theexcipientsaddedearliercausethemixturetoemulsifyinthegastrointestinaltract,formingverysmall,easilyabsorbeddropletsofdissolvedAPI.

Manypoorlysolubledrugsalsohavelowpermeability.Lipid-baseddrugdeliverysystemsenhancepassivetransportthroughthelipophiliccellmembraneandtapintothebody’sownmechanismsforabsorbingfatsthroughthelymphaticsystem.Newdevelopmentsinsoftgeltechnologyhavemadeitpossibleforabroadrangeofdrugsto

bedevelopedusingthesetechniques.Coatedcapsulescannowdelayreleaseofthedruguntilthecapsulereachesthelowerintestine–usefulfordrugsthatmightcausegastricsideeffectsorwhereefficacywouldbedisruptedbytheacidicenvironmentofthestomach.Inaddition,abusedeterrentcoatingsareavailableforproductslikepseudoephedrine,whichcanotherwisebeconvertedby‘kitchenchemistry’toillegalmethamphetamine.

Whereasoliddosageformispreferred,solidSEDDShavebeendeveloped,usingsolidificationtechniques,suchasspraydrying,toconverttheliquidintermediateintoastandardsolidoraldosageform(7).

Winning CombinationsNaturally,theseapproachesdonotoperateinisolation–theyareallpartofthewiderdrugdeliverytoolkit,whereadvancesinoneareaoftentriggerexcitingnewdevelopmentsinothers.Forexample,amorphousdrugnanoparticleshaveshownalotofpromise,combiningastheydothehighsolubilityoftheamorphousstatewiththerapiddissolutionofnanoparticles(8).Inasimilarvein,theuseofnanoemulsionshaspreviouslybeenlimitedbyissuesofpalatabilityandformulation,butincombinationwithself-emulsificationandsoftgeltechnologies,nano-SEDDSarenowahotareaforresearch(9).

RalphLipp,foundingadvisoryboardmemberofCatalent’sAppliedDrugDeliveryInstitute,believescollaborationiskeytoaddressingbioavailabilitychallenges.“Itisveryimportantthatthereisgoodcommunicationbetweenthedrugdesignandformulationteamswithinanorganization.Weneedateamapproach;amoreholisticwayofdevelopingdrugs,”hesays.

CollaborationiscentraltothemissionoftheCatalentAppliedDrugDeliveryInstitute,whichbringsacademicandindustrialscientiststogethertoaddresscurrentdrugdeliverychallenges.DavidIgo,MichaelRepkaandFilipeGasparhaveallcontributedtotheInstitute’sregulareducationalsymposia.

Despitetherangeofoptionsnowavailable,scientistscan’trestontheirlaurels–they

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mustworkcontinuouslytoimproveandrefinecurrenttechnologies-andcomeupwithnewones.Gasparsays,“Today,thevastmajorityofnewdrugsarepoorlysolubleandthatisamajorchallenge,butitalsocreatesopportunitiesfornewtechnologiestobedevelopedintheindustry.”Soinnovationisalsoessential.

Inthenextarticleintheseries,we’llbegazingintoour(amorphous)crystalball,toseewhatdisruptivetechnologieswillbeshakingupdrugdeliveryintheyearstocome.

references1. C.Brough,andR.O.Williams3rd,“Amorphous

SolidDispersionsAndNano-CrystalTechnologiesForPoorlyWater-SolubleDrugDelivery”,IntJPharm.453(1),157-166(2013).

2. Y.HuangaandW-GDaib,“FundamentalAspectsOfSolidDispersionTechnologyForPoorlySolubleDrugs”,Acta.Pharm.SinicaB4(1),18-25(2014).

3. H.Patiletal.,“ContinuousManufacturingOfSolidLipidNanoparticlesByHotMeltExtrusion”,Int.J.Pharm.471(1-2),153-156(2014)

4. S.M.Alshahranietal.,“Stability-enhancedHot-meltExtrudedAmorphousSolidDispersionsviaCombinationsofSoluplus‰andHPMCAS-HF”,AAPSPharmSciTech(January2015).

5. R.Savlaetal.,“Tumor-TargetedResponsiveNanoparticle-BasedSystemsForMagneticResonanceImagingAndTherapy”,Pharm.Res.31(12),3487-3502(2014).

6. R.SavlaandT.Minko,“NanotechnologyApproachesForInhalationTreatmentOfFibrosis”,JDrugTarget.21(10),914-925(2013).

7. Tan,S.RaoandC.A.Prestidge,“TransformingLipid-BasedOralDrugDeliverySystemsIntoSolidDosageForms:AnOverviewOfSolidCarriers,PhysicochemicalProperties,AndBiopharmaceuticalPerformance”,Pharm.Res.30(12),2993-3017(2013)

8. W.S.Cheowetal.,“AmorphizationStrategyAffectstheStabilityandSupersaturationProfileofAmorphousDrugNanoparticles“,Mol.Pharmaceutics11(5),1611–1620(2014).

9. A.A.Dateetal.,“Self-NanoemulsifyingDrugDeliverySystems:FormulationInsights,ApplicationsAndAdvances”,Nanomedicine(Lond).5(10),1595-1616(2010).

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technology prof ile Softgel Technology: A Proven Drug Delivery Solution

The Challenge: Encapsulating and Optimizing Poorly Soluble Molecules TypicalchallengespresentedbyAPIsinrelationtoformulationissuesincludepooraqueoussolubility;poorpermeability;theoccurrenceofmultiplepolymorphicforms;APIsthatexistinliquidform;APIswithlowmeltingpoints;andpoorstability.

TypicalprocessingchallengesforAPIsincludetheformulationofliquid,pasteorsemi-soliddeliverysystems;processingofhighlypotentAPIs;theuniformityofthedose;containmentissues;handlingofcytotoxics;andscalabilityissues.

Inthecaseofsolubilitybeingsuchanissuewheredryformulationshavetobeused,thiscanleadtounevendistributionoftheAPIandexcipientsbeforetabletting,leadingtoproblemswithdosinganddeliveryofdrugs.

Thesechallengesslowdown,andevenderail,manydevelopmentprograms.

Softgel Technology: A Proven Drug Delivery Solution Catalent’sRPScherersoftgeltechnologyisaprovendrugdeliverysolutionforchallengingcompoundsthathashelpedbringmorethan50newdrugproducts(NDAs)tomarket.Softgelformulationsaretypicallycomprisedofasolutionorsuspensionofdruginalipophilic,hydrophilicormixedvehicle.Variousshellformulationsareavailabledependingontheapplication.Coloringandflavoringcanbeaddedtothefillorshell.

Softgelformulations,andtheexcipientsuponwhichthesesystemsarebased,areusuallyliquidorsemi-solidinnature.Thereisawide

rangeofexcipientsavailablewhichprovidesgoodscopefordevelopment.Catalenthas80+yearsofexpertisetoensuregoodmanufacturability,stabilityandoptimalin-vivoperformance.

Softgeltechnologyoffersthefollowingbenefits:

• Improvedbioavailabilityforagreaternumberofpoorlywater-solubleandpoorlypermeablecompounds

• Drugscanbereleasedfromtheshellrapidlyuponingestion,andtypicallymeettherequirementsforimmediatereleasedosageforms.

• Modifiedorcontrolledreleaseofcompoundscanbefacilitatedwithcoatings

• Improvedstabilityofformulations

• Improved‘swallowability’ofdoses,meetingcustomerpreferencesandlargerdoserequirements

• Greaterdoseuniformityandthereforeconsistentdeliveryof,forexample,highlypotentdrugs

• Resistancetotamperingthroughcrushingorbreakingdown

• Whenformulatedandpackagedwithappropriateexpertise,capsulesareabletomeettheICHrequirementsforstabilityuptoZoneIVb

• DevelopmentandscreeningofformulationsrequiresminimalamountofAPI

• Provideavarietyofbranddifferentiationoptions,suchascapsuleshape,size,color,andprintedoutercasings.

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OptiShell™ Technology: Advancing Softgel Technology with More Options, for More MoleculesCatalent’sOptiShellcapsuletechnologyutilizesapatentedplantpolysaccharide-derivedshellwhichprovidesacapsulethatcontainssemi-solidmatricesforthereleaseofpoorlysolubleand/orpoorlypermeabledrugcompounds.

Immediateorcontrolledreleaseofdrugsisenabledandawiderrangeofcompatiblefillexcipientsallowsenhanceddrugbioavailabilityandstability,andoffersmoresolutionsforsolvinguniquedrugdeliverychallenges.OptiShelltechnologyaddressesthefollowingchallenges:

• Encapsulationofhigherfilltemperature(upto70°C)forsemi-solidandhighlyviscousfillformulations

• HigherpHfillformulations

• Compoundswhichexhibitashorthalf-lifeandrequirefrequentdosing

• Drugsthathavehighpeakbloodlevelsandunacceptablesideeffects.

case study: catalent softgel solution developed for xhale adherence system Xhale,Inc.,amedicaltechnologycompanydevelopingpatient-centricmonitoringsolutionsforhealthcare,neededtodevelopabreath-basedadherencesystemtoverify,monitor,andreportinformationabouthowandwhenparticipantsinresearchstudiesweretakingstudymedicationsinclinicaltrials.ByworkingwithCatalentPharmaSolutions,XhalehasrecentlymadeavailableSMART‰SoftgelsforclinicalresearchusewithitsSMARTAdherenceSystem.TheSMARTSoftgels,manufacturedbyCatalent,arethefirstsolutionofferedbyXhaletoenableintegrationofbreath-detectableadherencemarkersintoabroadrangeofpharmaceuticalproducts,andhavedemonstratedstability,quickreleaseoftheadherencemarker,andfavorablepropertiestosupporttheirpharmaceuticaluse.

XhalechosetopartnerwithCatalentbecauseofitsexperienceandtrackrecordofRPSchererSoftgelinnovation.WorkingwithXhale,aCatalentRPSchererSoftgelproductwasdevelopedtofeatureaspecialshelltoreleasequicklywhilestillpreventingevaporativelossofAPIduringandaftermanufacturing.

TheSMARTAdherenceSystemisdesignedtoofferdefinitiveandnon-invasivemonitoringofmedicationadherence,utilizingexhaledbreathtoconfirmthatmedicationhasbeentakenbystudyparticipantsasdirected.TheSMARTAdherenceSystemisnowavailableforresearchuseinthecollectionandreportingofdefinitivetreatmentadherencedatainclinicalstudies.XhalehasfiledaTypeIV(Excipient)DrugMasterFilewiththeFDAthatcontainscomprehensiveinformationsupportingtheuseinclinicalstudiesoftheSMARTSoftgelsdevelopedbyCatalent.

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technology prof ile Particle Size Reduction Technology: A Proven Bioavailability Enhancement Solution for Crystalline Small Molecules

The Challenge: How to Enhance the Oral Bioavailability of Poorly Soluble DrugsParticlesizereductionisaconventional,well-proven,andstraightforwardtechnologyforimprovingtheoralbioavailabilityofpoorlysolublesmallmoleculesbyincreasingthesurfaceareaandhencethedissolutionrateofthecompound.IthasbeenusedforbioavailabilityenhancementofBCS(BiopharmaceuticalClassificationSystem)classIIa,borderlineclassIIb,andevenclassIVsmallmolecules.Airjetmicronizersreduceadrug’sparticlesizebyfluidizingthedrugwithinthechamberresultinginparticletoparticleimpactionathighvelocitiesuntilitreachesadesiredparticlesizerange.Acoarsefraction(D90)oflessthan5micronsisrecommendedforbioavailabilityenhancement.Micronizationisahighenergyprocesswithnoheatgenerationpredominantlyresultinginthermodynamicallystablecrystallineformofthepostmicronizeddrug.

Catalent Micron Technologies: A Versatile Platform Technology for Bioavailability EnhancementCatalentMicronTechnologiescomplimentstheCatalentPharmaSolutionsbioavailabilityenhancementplatformportfoliobyprovidingclientsvariedtailoredsolutionsfrompreclinicaltocommercialization.CatalentMicronTechnologieshavesuccessfullyprovidedcGMPparticlesize

reductionbioavailabilityenhancementsolutionsacrossawidecustomerbase,includingvirtualcompanies,bigpharma,genericsandAPImanufacturersatourstate-of-the-artfacilitiesinMalvern,PAandDartford,UK.TheyarelicensedbytheDEAtohandleandprocesscontrolledsubstancesScheduleIItoV.CatalentMicronTechnologieshasover25yearsofexpertisewithmicronization,millingandanalyticalservicestomanufacturehighqualitycGMPpharmaceuticalproduct.

Catalent Micron Technologies: A Straight-Forward Solution for Oral Bioavailability EnhancementBenefitsofCatalentMicronTechnologiesparticlesizereductionservicesfororalbioavailabilityenhancementofpoorlysolublesmallmoleculesinclude:

• EconomicProcess–Micronizationisahighyield(>98%),highthroughput,non-solventprocessresultinginlowAPI(ActivePharmaceuticalIngredient)waste,processingcosts,andlowenvironmentalwastehandlingandremoval

• Heat-FreeProcess–Duetothehighairvolumesusedduringairjetmilling,heatgenerationandtemperatureincreaseisnotobservedandsuitableforthermolabileAPIs

• ScalableProcess–MicronizationenablesoptimizationandcontrolofparticlesizefromR&Dthroughcommercialscale

• BroadAcceptance–Micronizationiswellunderstoodbyregulatoryagencies

• AdvancedProcesses–CatalentMicronTechnologieshavebenefitedfromyearsofcontinualimprovementanddriventocollaboratewithpharmaceuticalcompaniestoimprovecapabilitiesandservicescateredtotheever-evolvingpharmaceuticalindustry

• PotentCompounds–CatalentMicronTechnologieshascapabilitiesforR&Dfeasibilitystudiestocommercialization.

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case study: flexibility to address customers’ needs for an oncology drugOccasionally,micronizationofAPIalonemaynotachievethedesiredoralbioavailabilityenhancementforoptimaltherapeuticperformance.CatalentMicronTechnologiesisflexibletoaddressourcustomers’needswithcombinationtechnologies,includingtheco-micronizationofexcipient/APIblends.Ourexpertshaveworkedwithvariousblendcombinationsuntilthecustomerwasabletofindablendwiththedesiredtherapeuticperformance.Inaddition,CatalentMicronTechnologieslaunchedcryogenicmicronizationservicesin2014toaddresstheparticlesizereductionneedsforthermo-sensitivecompounds.Ourdrivetoprovidesuccessforourcustomershasfosteredthecontinualimprovementandgrowthoverthepast25yearsandwillcontinuetodosointhefuture.

case study: increased oral bioavailability of orphan drugsWiththeOrphanDrugActof1983,therehasbeenastrongdriveinthemarkettotreatrarediseases(e.g.Parkinson’sdisease,Ebola,…).Whiletherearemanychallengesintheorphandrugdevelopmentprocess,acceleratedregulatoryapprovalimprovesthefeasibilitytobringthedrugtomarketfaster.However,workingwithwell-respectedCMOswhocandeliverproductinatimelyfashionfortheclinicalstudieshasalwaysbeenachallenge.CatalentMicronTechnologieshasworkedgloballywithseveralpharmaceuticalcompaniestoaddressthisneedandchallengesfrompreclinicaltocommercializationformanyorphandrugssufferingfrompoororalbioavailability.Ourstrongexpertiseinparticlesizereductionandefficientmanufacturingprocesshaveprovidedmanycustomersquickturnaroundtimetomeettheirtighttimelinesforprovidinghighqualityproductfortheirpreclinicalandclinicalstudies.

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part three The Toolbox of 2025

Previously,inourseries–“ConnectingtheDotsinDrugDelivery”–weexaminedthecurrentstatusofdrugdelivery.Wesawhowtoday’snewtherapeuticsposetoughchallengesforformulationscientists,andhowcompaniesaretacklingthosechallengeswitharangeoftools,frommicronizationtohotmeltextrusion.Butwhattechniqueswillbeinthetoolbox10yearsfromnow?Wespeaktoacademicandindustryexpertstofindout.

on targetWith Hamid Ghandehari, Professor at University of Utah, Director of Utah Center for Nanomedicine and member of Catalent Applied Drug Delivery Institute Advisory Boards

What do you think will be the most important future trends in drug delivery?Foronething,wearegoingtocontinuetoseetheapprovaloftargeteddrugdeliverysystems,includingpolymericsystems.Thereareseveralmicellarpolymerstructuresthatareinvariousstagesofclinicaltrials,andIexpecttoseethoseintheclinicinthenextfewyears.

Inthenextdecade,wearegoingtoseelocaltriggered-releasedrugdelivery.Here,thedrugdeliverysystemisdeliveredtothetargetsiteandactivatedbylocalorexternaltriggerstoenhancethedeliveryoftheactiveagent.

What is Needed to Drive Continued Innovation?Twodecadesagothiswasaveryspecialtyfield,butnowalotmoreresearchisgoingon.Itisverysatisfyingtoworkwithayoungergeneration

ofscientistsandseetheirenthusiasm.Ithinkthefieldneedsmoreinnovationandnewmindstotakeittothenextlevel.Inparticular,weneedmoreclinician–scientistsinourrankstohelptranslatetechnologiesfortheclinic.

Broadsupportfromthepharmaindustryisessentialtobridgethegapbetweenacademiaandindustry,andspeedupcommercialization.Tothatend,theCatalentAppliedDrugDeliveryInstituteisreachingouttothebroaderscientificcommunity,aswellastheyoungergenerationwithworkshopsandacademicprizes.

How Did You Get Into the Field?Iwasreallyintherightplaceattherighttime.IcompletedmyundergraduatedegreeattheUniversityofUtahinthelate1980sandstayedonformyPhDintheearly1990s.Atthattime,theuniversityhadsomeofthepioneersindrugdelivery,includingmyPhDmentorJindrichKopecek–oneoftheworldleadersinpolymertherapeutics.Iwasinspiredtocontinuethisgreatwork.

Todeliverthedrugtotherightsiteattherighttimeissoimportant–itreallyimpactsonpatient’slivesbyreducingsideeffectsandimprovingefficacy.

What Are You Working on Right Now?Alotofdrugs,suchascancerchemotherapies,arefabulousatwhattheydo,buthavedevastatingoff-targetsideeffects,socanonlybeusedinsmalldoses–ornotatall.Weaimtoconfinethedeliveryofthosedrugstothetargettissue,forexamplecancercells,byusingnoveldrugdeliverysystems.

Inourlab,wetailor-makerecombinantpolymersforgenedeliveryapplications.Thesepolymersaremadeusinggeneticengineering,whichgivesusahighdegreeofcontroloverthesequenceandlength.Inparticular,weusethemtodelivergenestoaccessibleheadandnecksolidtumors.Theparticularpolymersweusearemadeofsilkandelastinblocks.Theyareliquidatroomtemperatureandwhenmixedwithviralgenecarriersandinjectedtheysolidifyatbodytemperatureandimprovelocalizationanddurationofgenetransfer.

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Inanotherproject,weuselocalhyperthermiatotargetdeliveryofpolymer–drugconjugatestoprostatetumors.Weuseplasmonicphotothermaltherapyorothermeansofhyperthermia,suchasultrasound,tomaximizethedeliveryofthepolymericsystemstothesiteofaction.Thisimprovesbloodflowinthetumorandenhancescellularuptakeofthecytotoxicagents.

Where Have You Seen the Most Promising Results?ThereareacoupleofareaswhereIthinkwehavehadparticularimpact.Byusingrecombinanttechniqueswehavebeenabletosustaintheexpressionofadenoviralsystemslocallyinheadandnecktumors.Morerecently,wehavedevelopedrecombinantpolymersystemsthatareresponsivetolocalenzymes,suchasmatrixmetalloproteinases,thatareoverexpressedintumors.Thisallowsgenetherapytobedeliveredprimarilyinthetumor.

Intheareaoftargeteddeliveryusinghyperthermia,wehaveshownthatbycarefullycontrollinglocaltemperaturewecanmagnifytheso-calledenhancedpermeabilityandretention(EPR)effect,wherebycertainsizesofmoleculestendtoaccumulateintumorcells.

dissolving delivery challengesWith Rosie McLaughlin, Director, Scientific Affairs at Catalent Pharma Solutions

What’s the focus of your work? Rightnow,I’mlookingatinnovativewaystoexpandontheZydis‰drugdeliveryplatform–afreeze-dried,orallydispersibletablet.Westartwithadispersionofactivepharmaceuticalingredient(API)intheformulationmatrix,andfreeze-dryittocreateaveryporous,lightweightproduct,whichdissolvesinthemouthinaroundthreesecondsandwithouttheneedforwater.Thedrugcanenterthebodyeitherbystandardgastrointestinalabsorptionorthroughtheoralmucosa,dependingontheAPI.Thesublingualarea(underthetongue)ishighlyvascularizedsocertainAPIscanbequicklytransportedthroughtheoralmucosaandintothebloodstream,bypassingfirst-passmetabolismandpotentiallyimprovingbioavailability.

What are your most exciting projects at the moment?There’salwayssomethingnewandexciting!Thebestthingiswhenwepushtheboundaries.AtthemomentI’mworkingontwonewdevelopments

-oneisanewAPIcoatingprocessdevelopedexclusivelyforCatalentbytheNewJerseyInstituteofTechnology.TheprocessinvolvesaResonanceAcousticMixer,whichusessoundenergytogeneratevibrationsfordry-coatingveryfineparticles,increasingdrugloadingandimprovingtastemasking.Previously,wehaven’tbeenabletousecoatedAPIsinZydis,sothisexpandsthenumberofdrugswecandevelopintheplatform.We’vealsobeendoingproof-of-conceptworkonoraldeliveryofvaccines,startingwithinfluenza.

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An oral flu vaccine could be quite a breakthrough…We’reusinginfluenzainourproof-of-conceptpreclinicaltrialsbecauseitissowellcharacterized,butwehopethetechnologymaybeapplicabletoawholerangeofvaccines.Theavailabilityofanoninjectable,roomtemperature-stablevaccinedeliverysystemcouldcertainlytransformthewholefield.Thisisparticularlytrueofthedevelopingworld,wherethelogisticsofcoldchainstorageareabigchallenge,causingsignificantwastage,andwheretrainedhealthcareworkersmaynotalwaysbeavailabletoadministerinjections.

What approach are you taking?Vaccines,exceptforsomeliveattenuatedviruseslikepolio,aregenerallydestroyedinthegastrointestinaltractifswallowed.UsingZydisBio,we’readministeringthevaccinesublingually,tobypasstheacidicenvironmentofthestomachandenzymesofthedigestivesystemandgodirectlyintothebloodstreamviatheoralmucosa.

Proteins,beinglargemolecules,havelesstendencytocrosstheoralmucosa.ButweknowitispossiblebecausewehavealreadyusedZydisBiotodeliveranallergyvaccine.Theactiveingredientisaproteinextract,whichisdeliveredsublinguallyandinducestoleranceinhayfeversufferers.Ourworkonoralvaccinesisanaturalcontinuation–thedifferenceisthatwe’renowtryingtotriggeranimmuneresponse,ratherthanimmunetolerance.Theresultssofarhavebeenencouraging,althoughitmaybeseveralyearsbeforeweseeclinicaltrials.

What challenges will tomorrow’s drug development scientists face?Bioavailabilitychallengeswillcontinuetobeaproblemfordrugmanufacturers.Asmoreandmorebiologicsbecomeavailable,theHolyGrailistofindnewroutesofadministrationtoimprovethepatientexperience–whetherthat’soral,inhalationormicroneedledelivery.

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technology prof ile Zydis‰ Fast Dissolve Technology

The Challenge: Finding Convenient Dosage Forms to Improve Patient ComplianceDifficultiesinensuringpatientcompliancewithdrugdosageregimesmaynotalwaysbethefaultofthepatient.Forexample,manypatientssufferdifficultiesinswallowing,particularlythoseinagingandpediatricpopulations.Psychiatricillnessesareoftenlinkedtopoorcomplianceandpatientsmay‘cheek’medications,causingissuesforcaregiversandthepotentialforpatientrelapse.Relatedtopatientcomplianceisspeed-of-onsetoftreatments,forexample,someconditions,suchasmigraines,requirearapidonsetofaction(thesymptomsofmigraines,however,oftenincludenausea,whichmakestakingnormalsolidoraldosesdifficult.).Convenientdosageformsimprovepatientcompliance,whilealsoprovidingthemeanstotreatacuteconditions,suchaspain,coughandcold,allergy,gastricdiscomfortandmore,thatrequireimmediatereliefinout-of-homeenvironments.

Zydis Fast Dissolve Technology: A Convenient Dosing SolutionCatalentPharmaSolutions,theleadingglobalproviderofadvanceddeliverytechnologiesanddevelopmentsolutionsfordrugs,biologics,consumerhealthproducts,vitamins,andminerals,offersZydisfastdissolvetechnologywhichprovidesaunique,freeze-dried,solid,orallydisintegratingtablet(ODT)dosageformthatdispersesalmostinstantlyinthemouthwithnowaterrequired.Withmorethan20productslaunchedin50countries,Zydisistheleadingbest-in-classODTtechnology.Catalent’sZydisteamoffersfeasibilityevaluationsaswellassupportacrosstheentirelifecycleofproductstoprovidesolutionsthatcanhavethepotentialtoenhancepharmacokineticsthroughpregastricabsorption,improvepatientcompliance,orprovideamarketingadvantageforavaluedbrand.

Catalentsupports6ofthetop10largestpharmaceuticalcompanieswithZydisfastdissolveformulations.SeventeendistincttherapeuticareasarecoveredinbothRxandOTCproducts,withmorethan1billiontabletsmanufacturedeachyear.

Zydis Fast Dissolve Solutions Meet Dosing ChallengesCatalent’sZydisbest-in-classfamilyoffastdissolvetechnologiescansatisfyarangeofdosingrequirements:

• ZydisODTisaunique,freeze-driedoralsoliddosageform,providingalmostinstantoraldispersion,typicallyinlessthan3seconds

• ZydisUltrahasafunctionalcoatingthatprovidesgreatertastemaskingcapabilitiesandallowsincreaseddoses

• ZydisGranulesenablethehighestdoseandprovidesmoretastemaskingoptions

• ZydisBioenablesdosingoflargemolecules,includingallergens,peptidesandviralvaccines,infastdissolveformulations.

BenefitsofZydisfastdissolvetechnologyinclude:

• Almostinstantaneousdispersioninthemouth,allowingforpotentialbuccalorsublingualabsorption

• Improvedcomplianceinmanytherapeuticmarkets

• Highsuitabilityfortreatingchildren,theelderly,pets,andanyonehavingtroubleswallowing

• Almostinstantdosingwithouttheneedforwater

• Moreefficientdelivery

• Possiblefasteronsetofactionandreductionofmetabolites

• Highsuitabilityforcertainindications

• Highsuitabilityfortreatingpainandotherconditionswhererapiddosingandabsorptionarerequired,includingallergiesandtravel-relatedillnesses

• Thepossibilityofreducedandlessfrequentdosage

• Enhancedmarketingappeal

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• Consumersatisfaction,asZydisfastdissolveformulationsareeasiertoswallowandfaster-acting

• Protectionfromcounterfeiting

• Provisionoftamperevidence.

case study: zydis bio technology and grazax®: revolutionizing allergy therapy ALK-Abellóisaglobalresearch-drivenpharmaceuticalcompanythatfocusesontheprevention,

diagnosisandtreatmentofallergies.BeforeALK-AbellópartneredwithCatalent,marketedallergenimmunotherapiesweredeliveredbyinjectionordrops,resultinginalimitedpatientpopulationandreducedpatientadherence.CatalentworkedwithALK-AbellótoapplyZydisfastdissolvetechnologytooneofthesetherapies,Grazax‰,tobringavastlysuperiorproducttomarket.Theoverallresultwasamarkedimprovementinpatienttolerability,preference,productstabilityandcompliance.ThisnewtechnologyhasallowedALK-Abellótodeliveronitspromisetoimprovethequalityoflifeforallergypatients.

ALK-AbellóapproachedCatalentwithchallengessimilartoothersintheindustry.Allergyinjection-basedtherapyhadbeenessentiallyunchangedforthepast100years.Thesetherapiesrequiredlengthypatient-specificdose-titrationphasesandrequiredpatientstogotospecialistclinicsformonthlysubcutaneousinjections,whichcontributedsignificantlytopatienttimespentaswellasout-of-pocketmedicalcost.Additionally,patientsneededtoundergosuccessfulcompletionoftherapyfor3years(3seasons,forseasonalallergies)iftheyweretoexpectlong-termprotection.Potentialpatientsweresubjecttostringentcriteriaforspecialisttherapies,whichlimitedtreatmenttoonlythemostseverecases.Finally,potentiallydangeroussystemicadverseeventshadoccurredwiththisclassoftherapeutics,requiringrisk/benefitassessmentsandavailabilityofrescuefacilities.

CatalentscientistspartneredwithALK-AbellótodevelopasuperioralternativedrugdeliverysolutionusingZydisBiotechnology.Thisuniquetechnologynotonlyenablesadministrationbysublingualdoses,butalsooffersanumberofuniquebenefitsthatdifferentiateitfromotherorally-disintegratingtablettechnologiesonthemarket,includingfastdispersion(<3seconds)andsmoothmouthfeel.

AsaresultofitspartnershipwithCatalent,ALK-AbellówasabletolaunchGrazax,thefirstpatient-friendlyallergenimmunotherapyusingZydisBiotechnology.

• Patientscanadministeradailysublingualdosethemselves,whichhasledtoincreasedpatientadherence.

• Thereductioninclinicalvisitsandeliminationofcomplexdosetitrationshasfurtherimprovedthepatientexperience.

• ALK-Abellówasalsoabletoimproveitsmarketpositionbyincreasingthepatientreachofthisimmunotherapytopediatricsandprimarycarepatients.

TheUSBiologicsApplicationwasapprovedin2014andGrastek‰isnowmarketedintheUS,EUandCanada.ManyadditionalallergensforallergicrhinitisandasthmaarecurrentlyindevelopmentusingZydisBiotechnology.

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part four Delivering Change

Alternativedeliveryroutesforlarge-moleculedrugsaresorelyneeded–couldanewconsortiumleadtheway?

Welcometothefourthandfinalpartofourseries,“ConnectingtheDotsinDrugDelivery”.Sofar,wehaveexaminedthechallengesfacingformulationscientists,exploredtheoptionsforimprovingbioavailability,andcaughtaglimpseofthetoolboxof2025.Acommonthreadhasbeentheneedforgreatercollaborationbetweenindustryandacademicpartners.Here,wetakeacloserlookatanexampleofthiscollaborationinaction–theNon-invasiveMacromoleculeDeliveryConsortium(NMDC),spearheadedbytheCatalentAppliedDrugDeliveryInstitute.Tofindoutmore,wespokewithtwokeyfiguresintheconsortium.

better biologicsRandy Mrsny is a Professor at The University of Bath, and Chair of the NMDC.

How did you get into drug delivery?Mytrainingwasalloverthemap–Istudiedbiochemistryandbiophysics,andembarkedonthepathtoamedicaldegree,butthendecidedtogetmyPhDinanatomyandcellbiologyinstead,beforereturningtobiophysicsformypostdoc.Ithenputmymultidisciplinaryskillstogooduseinthepharmaceuticalindustry,optimizingbiopharmaceuticaldrugdeliverysystemsforALZAandGenentech.Afterthat,Igotinvolvedwithseveralbiotechstart-ups,beforereturningtoacademiaintheUK,firstatCardiffUniversityandnowtheUniversityofBath,tosearchforanswerstomorefundamentalquestions.

What are your main research areas?Mygroupisfocusedonovercomingthebarriersthatlimitmacromolecularuptakeofpharmaceuticals.Thebody’sbarriershaveaseriesofendogenousmechanismsthatpreventthecasualuptakeoflargemoleculestoprotectusfromenvironmentalintoxication.Bylookingathowcertainpathogenssuccessfullyovercometheseendogenousmechanismsandenterthebody,mygrouphopestofindwaystomanipulatethemformacromoleculedelivery.

What did you set out to achieve with the NMDC?WhenIwasfirstcontactedbyCatalentAppliedDrugDeliveryInstitute,Iimmediatelythoughtitwasaveryinterestingapproachthatcoulddoalottohelpadvancethefield.Wedecidedearlyonthatakeygoalwastogetindustryandacademicsworkingtogether.Havingworkedinbothsectors,Iknowthatweneedacademicsthatthinkoutsideoftheboxandwhocanbringnewideastothetable,butjustasimportantly,weneedindustrypeopletoassesswhetherthoseideasarepracticalandtomoldthemintosomethingthatcanbesuccessfullydeveloped.Thegoaloftheconsortiumistogetthis‘goldendialogue’tohappen.

No easy task…Overtheyears,bigpharmacompanieshavebecomemorecautiousaboutclaimsmaderegarding‘breakthroughs’innon-invasivemacromoleculardrugdelivery-theyhaveseenalotofsnakeoilinthepast.Bygettingopendialoguegoingataveryearlystagetoaddressthepotentialandthelimitationsofvarioustechnologiesunderdevelopment,wehopetoavoidanyonegettingburned.Thisdialoguehassofarincludedaseriesofconferencesandpresentations,andtheformationoffourworkinggroupsinoral,transdermal,respiratoryandoculardelivery.

What are some of the most exciting projects underway in this area? Therearesomeveryinterestingprojectsgoingoninoculardelivery.Inrecentyears,advancesinoculardeliveryhavereallychangedpeople’slives–before,

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conditionslikemaculardegenerationinvariablyledtoblindness,butnowwehavedrugsthatcanstopthatprogressionandevenreverseit.However,currenttreatmentstypicallyrequireaninjectionintotheeyeeverymonth,whichisobviouslynotmuchfunforthepatient.Researchersarenowlookingatcontrolled-releasesystemsandothertechnologiestotakethatfrequencydowntoonceevery6monthsorso.

Are you optimistic about the future for noninvasive delivery?Thepharmaindustryistraditionallycautiousabouttakinganewpath.Theyfeelmostconfidentusingestablishedmodelsandstrategiestobringnewproductstomarket.Drugdeliveryapproachesthatmightovercomeendogenousbarriersofthebody,however,arenovelandthusthereisnoestablishedregulatorypathfordevelopingtheseapproaches.ButfrommyconversationswiththeFDA,Iunderstandthatregulatorsareveryinterestedinandsupportiveofnewdrugdeliverytechniques,whichwillbeencouragingtocompanies.WewanttobringrepresentativesofregulatorsintotheNMDCtogettheseconversationsoutintheopen.Gettingtheregulatorybodiesinvolvedonboardwillbecrucial;fortunately,theleadershipwithintheseagenciesappearsenthusiasticabouttheaddedpatientvalueandsocietalimpactthatnon-invasivemacromoleculardrugdeliverycanpotentiallyachieve.

breathing it inCraig Davies-Cutting is

Director of R&D for Inhaled

Products & Technologies at

Catalent and Co-Chair of the

Pulmonary and Nasal Delivery

working group of the NMDC.

How did you get involved with the NMDC? SincecompletingmyPhDonmetered-doseinhalers,I’vespentmycareerworkingwithinhaledtherapies.Overtheyears,therehasbeenalotofinterestfrompharmainthelungornasalcavityasaportalforthedeliveryofmacromolecules,andsincejoiningCatalentIhavebeeninvolvedinafewearlydevelopmentprogramsinvolvinglarge-moleculedrugs.WhentheCatalentInstitutesetuptheNMDC,IwasinagoodpositiontogetinvolvedinthePulmonaryandNasalDeliveryworkinggroup.

What makes inhalation an attractive delivery route for biopharma?Thelungsrepresentaverylargesurfaceareafordeliveryandsocouldofferarouteforenhancedbioavailabilityandrapid-onsetaction.Therearealsocommercialandregulatoryprecedentsaftertheapprovaloftwoinhalableinsulinproducts–Exuberain2006andAfrezzain2014–althoughExuberawasnotacommercialsuccessandwaslaterdiscontinued.

How does the consortium work to advance research?OneofthebestthingsabouttheInstituteisthatitisagnostic–thegoalistopromotedialoguebetweenindustrialistsandacademicstohighlightthekeychallengeswithinthedrugdeliveryspace.Tothatend,theNMDCheldaninauguralmeetinglastyearinSanDiego,bringingtogetherindustrialists,academicsandkeyopinionleaders,

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withinterestsinawiderangeofdeliverymethodsformacromolecules,fromoculartooraltopulmonary.Itwasagreatmeetingthatgotalotofthequestionsoutonthetable.Sincethen,thevariousworkinggroupshavepulledtogetherasynopsisofthekeyattributesandchallengesassociatedwiththatmodeofadministrationandbeguntoidentifyopportunitiesforadvancedresearch.

What are the research opportunities for inhaled delivery?Forthepulmonaryandnasaldeliveryworkinggroup,themostimmediateprioritiesare:

• Evaluatingexcipientsforlarge-moleculedelivery.Therearenoestablishedexcipientsspecificallyforusewithlargemolecules.

• Establishingappropriateclinicalbiomarkers.

• Developinginvitromodelstoclarifythemechanismbehindclearanceoflargemoleculesfromthelungs.

delivery method academic co-chair industry co-chair(s) catalent scientific lead

oral Dr. Edith Mathiowitz, Brown University

Dr. Siddhesh Patil, Takeda Julien Meissonnier, Executive Board, Catalent Institute

pulmonary/nasal Dr. Claus-Michael Lehr, University of Saarland

Dr. Ralph Niven, Novartis Dr. Craig Davies-Cutting, Executive Board, Catalent Institute

transdermal Dr. Bo Michniak-Kohn, Rutgers University

Dr. Steven M. Wick, 3M Dr. Ralph Lipp, Advisory Board, Catalent Institute

ocular Dr. Justin Hanes, Johns Hopkins University

Dr. Jim Cunningham, Allergan; Dr. Thierry Nivaggioli, Genentech

overall chair Randy Mrsny, University of Bath

non-invasive macromolecule consortium working group co-chair

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technology prof ile OptiGel™ Bio Technology: Meeting Formulation and Delivery Challenges for Macromolecular Drugs

The Challenge: Producing Oral Formulations of Macromolecular DrugsMacromoleculetherapieshavetraditionallybeenlimitedtoinjectableandinfuseddoseforms,duetoanumberofchallengesthatlimittheirbioavailabilityincluding:

• Poorabsorptionduetorigidmoleculargeometryandflexibility

• Permeationlimitationswithtightjunctionsandlimitedtranscellularpathways

• Degradationbyproteolyticenzymesofthestomachandlumen

• Harshacidicgastricconditions.

Oraldosingofdrugsispreferredbyinnovators,healthcareprofessionalsandpatients,asitoffersnumerousadvantagesoverinjectableandinfuseddoseforms.Theseadvantagesincludeconvenienceandadherence,self-administrationandpainlessdosing,dosingflexibility,accesstofrequentdosingtomaintainorextendtherapeuticefficacy,lower

manufacturingandtreatmentcosts,andamoreefficient

clinicalpath.Thechallenge,therefore,istoproduceoralformulationsofpoorlysolublemacromolecular

drugssuchaspeptidesandbiologics

OptiGel Bio Technology: An Oral Drug Delivery Solution for MacromoleculesOptiGelBiotechnologyisalipid-basedformulationthatincorporatesentericcoatingandtargetedpermeationenhancementtoincreasethebioavailabilityofmacromoleculeswithoutabsorbingotherunwantedtoxicmolecules,andthereforepotentiallyenablingoraldeliveryofmacromolecules.WhereastraditionalCatalent’sRPScherersoftgeltechnologiesenableimproveddeliveryofBCSClassIIandIVdrugs,OptiGelBioisanewsoftgeltechnologytopotentiallyenablethenon-invasivedeliveryofbiomolecules(BCSClassIIIdrugs).

OptiGelBioistheresultofyearsofresearchintoanon-invasivedeliverymethodforbiologicdrugsandprovidesaversatilesolutiontothedevelopmentchallengestraditionallyassociatedwiththeoraldeliveryofmacromolecules.Lipid-baseddrugdeliverysystems(LBDDS)notonlyovercomethesolubilitylimitationsofsomeAPIs,butoftenalsoprovidesomebenefitsinmodulatingthemembranepermeabilityofdrugs.

Whenamacromoleculeisdeliveredtothestomach,theAPIdegradesordenaturesuponexposuretotheacidicenvironment(pH1~3).TheentericcoatingoftheOptiGelBiosoftgelhelpsthemacromoleculepassthestomachanddelivertheAPItotheintestineallowingfortargeteddelivery.

Inthesmallintestine,themacromoleculescannotpermeatethroughtightjunctionsintheintestinalwallduetotheirsizeandsterichindrance.Theyarethenvulnerabletofurtherdegradationbyvariouspathways.OptiGelBiotechnologydissolvesthemacromoleculeinalipid-basedformulationinasoftgel.ThesoftgelcapsuledissolvesafterreachingtheintestineandonlythenreleaseslocallyhighconcentrationsofpermeationenhancersatthesametimeasreleasingAPI.Thepermeationenhancermoleculesopenupthetightjunctions,allowingthemacromoleculestopassthroughintothebloodstream.After30minutes,thetightjunctionscloseagainandtherefore,absorptionofunwantedtoxicmoleculesisavoided.

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OptiGelBiotechnologyemploysthesametargetedco-deliveryofpermeation-enhancingformulationsthathavebeensafelyappliedtoalreadymarketed,poorlywatersolubledrugs,tothedeliveryofmacromoleculesorpeptides.Suchlocalizeddeliveryallowsforhighertransientconcentrationsofpermeation-enhancingexcipientsalongsidetheactivepharmaceuticalingredient.Thetechnologyisapplicabletovariousclassesofmacromolecules,includingoligosaccharides,as

wellaspeptidesandsomeproteins,andCatalentisconductingresearchtofurtherexpanditsapplicationtothemorecomplexdeliverychallengesassociatedwithlargerandlessstablemolecules.

Tolearnmore,watcha90-secondvideoonourwebsite.

www.catalent.com/optigelbio

case study: optigel bio technology enables iv to oral therapy conversionAnearly-stagebiotechnologycompanyhaddevelopedanovelmacromolecularintravenous(IV)therapyforathrombolyticpost-surgicalindicationandapproachedCatalenttoenableconversionofthedoseformtooraldelivery.Theaimwastoreducemanufacturingcostsandimprovebothpatientcomplianceandtheclinicalpathefficiency.

Themacromoleculewassoluble,howeverithadahighmolecularweight(>2500Da),astrongnegativechargeandarigid,inflexiblegeometrywhichchallengedthedesireddeliveryacrossthewallsofthesmallintestineintotheblood.

Catalent’sformulationexpertizeandOptiGelBiotechnologyachievedanoptimizedoraltherapywhichcombinedboththedesiredpermeabilityenhancementandtargeteddelivery.

Astepwisescreeningapproachutilizingbothinvitroandinvivomodelswasadoptedtoevaluateformulationcandidatestoovercomethepermeabilitychallengeofthemacromolecule.Thesestudiesshowedthatformulationswithhigherlevelsoflipiddigestionproductshadenhancedbutvariablepermeability.

Despitetheimprovementsinbioavailability,thepharmacokineticvariabilityhighlightedtheneedfortargeteddeliveryutilizinganentericcoating.Screeningwasagainundertakentooptimizethecoatingformulation,percentageofcoating,plasticizer,andsolvent.

Thefinalformulationwasoptimizedandconfirmedbyimaging/pharmacokineticprofilinginwhichiodine-taggedcapsuleswereorallydosedandimagedwithPKsamplesusingacaninemodel.Thestudiesprovedthatentericcapsulebatchesweredeliveredinactiveformtothesmallintestinewithreducedvariabilityandenhancedbioavailability.

more products. better treatments. reliably supplied.™

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