Post on 09-Apr-2018
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
2
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
3
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
4
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
5
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).
6
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
7
• 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.
8
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
9
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).
10
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
11
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).
12
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.
13
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.
14
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.
15
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.
16
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.
17
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.
18
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.
19
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
20
• 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.
21
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,
22
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,
23
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
24
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.
25
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.™
Catalent Pharma Solutions 14SchoolhouseRoadSomersetNJ08873USA
global +18667203148eu +0080088556178
www.catalent.comsolutions@catalent.com
ZydisisaregisteredtrademarkofCatalentPharmaSolutions
OptiGel,OptiMeltandOptiShellaretrademarksofCatalentPharmaSolutions
GRASTEKisaregisteredtrademarkofMerck&Co.,Inc.
GrazaxisaregisteredtrademarkofALK-AbellóA/SCorp
SMARTisaregisteredtrademarkofXhale,Inc.
˝Copyright2015CatalentPharmaSolutions,Inc.Allrightsreserved.