3D Pharming: Direct Printing of Personalized ... · Powder bed 3D printing,a technology originated...

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2016Vol. 2 No. 1: 3

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Polymer SciencesISSN 2471-9935

© Under License of Creative Commons Attribution 3.0 License | This article is available in: http://periodontics-prosthodontics.imedpub.com/

DOI: 10.4172/2471-9935.100011

Giovanny F. Acosta-Vélez1 and Benjamin M. Wu2,3

1 Department of Chemical and Biomolecular Engineering, University of California, USA

2 Department of Bioengineering, University of California, USA

3 DivisionofAdvancedProsthodonticsandtheWeintraubCenterforReconstructiveBiotechnology, University of California, USA

Corresponding author: Giovanny F. Acosta-Vélez

[email protected]

Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, 420 Westwood Plaza, Los Angeles, CA 90095, USA.

Citation: Acosta-Vélez GF, Wu BM. 3D Pharming:DirectPrintingofPersonalizedPharmaceuticalTablets.PolymSci.2016,2:1.

Introduction Currently, the ten top-grossing drugs in the United States effectivelybenefitonly4to25percentofthepatientsthattakethem [1]. For instance, some drugs have been proven to have higherefficienciesinpeoplewithcertaingeneticvariations,whileothershavebeenprovenharmfultoparticularethnicgroups[2,3].Morespecifically,apersondiagnosedwithcancerback in2004mighthave received a treatmentonly effectiveon tenpercentof thepopulationandcausedsignificant sideeffects.AdvancesinthefieldofPharmacogenomics,thestudyofhowthegeneticmakeupof a person affects their particular drug response, are

providingmorepreciseinformationaboutthedosageandchoiceof drug thatwould best benefit a specific individual based ontheirgeneticmakeup[4,5].Incontrastnowadays,abiopsytissueof that person could be genetically screened, predictingwhichtreatmentwouldmorereliablytreatthepathologicalcondition[6].

Personalizedmedicineaimstoprovidepatientswithtreatmentstailored to their pathophysiology. This is done by coupling apatient’spharmacogenomicswith informationabout theirdiet,environment,lifestyle,microbiome,andepigenetics[7].Thisnewapproach forprescriptiondrugsrequires technologycapableofproducing tablets with a variety of dosage strengths in order to

3D Pharming: Direct Printing of Personalized Pharmaceutical Tablets

AbstractPersonalizedmedicineaimstotailordrugcombinationanddosagemanufacturingtothespecificneedsofapatientbytakingintoconsiderationitsgeneticprofile,phenotypic response, and pathophysiology. New technologies are needed to enable the rapidmanufacturingof custompharmaceutical tablets in a scalablemanner,whilemeetingqualityassuranceregulatorystandards.3DPharming,theuse of 3D Printing to directly fabricate personalized pharmaceutical tablets, isunderintensedevelopmentbymanyinvestigatorsduetoitsunprecedentedcontrolfor:1)stabilityofmultipledrugswithinapill;2)precisedoseofeachdrug;and3)releasekineticsofeachcomponentbyincorporatingdesignedstructuresthatcanmodulatedissolutionanddiffusionprofiles.Additionally,ithasthepotentialto scale in order to meet the economics and quality that the pharmaceuticalindustry demands. This article reviews the manufacture of pharmaceuticaltablets throughpowderbed inkjet3Dprintingand fuseddepositionmodelling,thetwo3Dprintingtechniqueswiththegreatestprogresstowardspersonalizedpharmaceutical tablets. The engineering of pills through these two methods,featuringvarieddissolutionprofiles,chemicalcomplexions,dosages,andmultipledrugsincorporation,isthoroughlydiscussed.

Keywords:3DPharming;Pharmaceuticaltablets;3DPrinting

Abbreviations: 4-ASA: 4-Aminosalicylic Acid; 5-ASA: 5-Aminosalicylic Acid;CAD: Computer-Aided Design; CJP: Continuous Jet Printing; DSC: DifferentialScanning calorqimetry; DOD: Drop On Demand; EGDT: Ethylene Glycoldithiol;FastDisintegrating/DissolvingTablet;FDT:FDM:FusedDepositionModelling;GI:Gastrointestinal;HME:HotMeltExtrusion;HPMC:HydroxypropylMethylcellulose;IBD: Inflammatory Bowel Disease; PETMP: Pentaerythritol Tetrakis(3-mecaptopropionate); PCL: Polycaprolactone; PDMS: Polydimethylsiloxane;PEO:PolyethyleneOxide;PLA:PolylacticAcid;PVA:PolyvinylAlcohol;USFDA:U.S.Food andDrug Administration;USP:United States Pharmacopeia; XRPD: X-RayPowderDiffraction

Received: May24,2016; Accepted: June13,2016;Published: June16,2016

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satisfy the specificmedicalneedsofeach individual. Currently,pharmaceutical companies manufacture tablets with universalpredetermined dosage amounts [8]. This method requireslargefacilitieswithhighproductioncosts,trainedpersonnelforitsoperation, and involvesa varietyofprocessing steps [9]. Tomake personalized medicine a reality, a paradigm shift in thewayoraldrugformsarecurrentlymanufacturedisrequired.Thenew strategy should have the ability to reproducibly generate awiderangeofdosagesandhaveashortmanufacturingtime.These features would allow tablet manufacture technology toadapt to the rapid changeover of formulations experienced byscientistswithinR&Dandclinicaltrialstudies,acceleratingdrugdevelopment. Additionally, it should be economically viable,have minimal space and operational training requirements,comply with standards of regulation agencies, and able to bedigitally controlled by healthcare staff [10]. 3D printing wasfirstdemonstrated in1996asapromisingcandidatetoreplaceconventional tableting techniques [11]. In 2015, the U.S. Foodand Drug Administration agency (FDA) granted the approvalof Spritam® (levetiracetam), the first 3D printed tablet for thetreatmentofepilepticseizures[12].This landmarkeventmarksamilestonein3DPharmingandmotivatesfurtherdevelopmentofthistechnologytowardsthefabricationofcustomizedtabletsand improved personalized medicine. 3D Pharming promises toenable rapidpoint-of-care formulationswithpatient-specificdosages [13]. Furthermore, 3D Pharming provides control over drugreleasekineticsthroughmethodsthatpreciselymanipulatethe spatial distribution of multiple drugs within a pill, as wellas theirdiffusiongradients [14].Thispotential reduction inthenumber of tablets prescribed, combined with their improved efficacy, could result in enhanced patient compliance [15].Finally,theeconomicbenefitsofthistechnologyincludereducedmanufacturingandinventorywastesandthepotentialtogrowtoanindustrializedscale[16].

The term 3D Pharming encompasses the various 3D printingand 2D material deposition technologies that are used tocreatepersonalizeddosage forms. This reviewpaperwill focuson recent advances in 3D Pharming efforts between 1996 andFebruary 2016. During this period, powder bed inkjet printingandfuseddepositionmodeling(FDM)were3Dprintingplatformscommonlyused,sincethesematerialdepositiontechniquesallowforthefabricationofstructureswith2Dand3Dspatialgradients.In contrast, platforms that build structures through energydeposition, such as stereolithography, cannot produce point-to-pointvariations incompositionofmatterwithoutcombiningwith secondary 2D material deposition techniques. A specialfocus is given to the advantages and limitations of these twotechniques,aswellastothedifferentmaterialsutilizedamongthem for immediate and sustained drug delivery applications.Effortstowardstheinclusionofmultipledrugsandthesynthesisof polypills are reviewed. Finally, the challenges ahead and future workrequiredtomake3DPharmingarealityareevaluated.

Powder Bed Inkjet 3D PrintingInkjetprintingtechnologyisbasedontwomaindropletformationtechniques: continuous jet (CJ) printing and drop on demand(DOD)printing.CJprintingreliesonapressurizedflowtoproduce

a continuous stream of charged droplets. After being releasedthrough a nozzle, these droplets are directed by electrostaticplates into the substrate intended for their deposition, ordeviatedintoawasterecirculationlinewhennotneededfortheprintingprocess[17].DODprintinghasamorepreciseandlesswastefulexecution,producingdroplets thataredispensedonlywhenrequiredbytheprocess,withvolumesaslowas1-300pL[18,19]andfrequenciesofupto10,000Hz.[20].DODprintheadsare primarily actuated by thermal and piezoelectric trigger mechanisms.Thermalprintheadshaveembeddedresistorsthatproduceheatupontheinductionofanelectricalcurrent.Thisheatcreatesabubblewithinthevolatilematerialbeingprintedthatmobilizesasmallvolumeoutofthenozzle,resulting indropletformation.Thermalinkjetprintingrequirestheuseofhighvaporpressure solvents and produces high temperatures that, although shortlived,canresultinthedegradationofheat-liablebioactivecompounds. These factors limit the use of thermal printheadsfor pharmaceutical applications [21]. In contrast, piezoelectricprintheads incorporatepiezoelectricmaterials thatexpandandcontractwhen induced to an electrical current. These physicaldeflectionsgeneratethepressurerequiredtomobilizeliquidoutofthenozzleintheformofdroplets[22].Thecapacityofoperatingatroomtemperaturewithlessvolatileandmorebiocompatibleliquidsmakesthepiezoelectricprintingtechnologymoresuitablefor the development of drug delivery devices [14,23].

Powderbed3Dprinting,atechnologyoriginatedatMIT,makesuseofan inkjetprintheadtodeposita layerofbindersolutiononto a powder bed containing thematerial desired for objectconstruction [24,25]. The object is defined through the useof computer-aided design (CAD) software and digitally slicedin detailed pieces of information that delineate each one ofthe layers to be printed through the process. After each layerdeposition, a piston that supports the powder bed is loweredallowing a subsequent layer of powder to be spread andselectively bound, as depicted in Figure 1 [26]. This process isrepeatedseveraltimes,stackinglayersofsolidifiedmaterialuntilapredetermined3Dgeometry isproduced.Excesspowdernotbound is then removed exposing the final product, which cango through further processing to tune its finalmechanical andphysicalproperties[27].Thistechnologyallowsfordirectcontroloverboth,themacroandmicrostructureofobjects,enablingthecreationof complex biochemical devices. Incorporatingpatientspecificanatomicaldataintotheprocesshavemadepossiblethecreationofimplants,prosthetics,diagnosticplatforms,anddrugdelivery systems [28]. Based on the literature research done, Wu etal.conductedthefirstexperimentsinvolving3DPharmingbyprintingmulti-drug delivery devices in 1996 [11]. In this study,the releaseprofilesofmethyleneblueandalizarinyellowdyes

Figure 1 Powder bed 3D printing procedure schematic.Reproducedwithpermissionfrom[26].

Spread Powder

Cylinder PowderJoinedPowder

Print Layer

Inkjet Head

Drop Piston

Piston

Figure 1 Powder bed 3D printing procedure schematic. Reproduced with permission from [26].

3© Under License of Creative Commons Attribution 3.0 License


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werecontrolledbymanipulatingthethree-dimensionalpositionof dyes within the device, its microstructure, and chemical composition.Asquaregridpatternof5cellsby5cellscomposedofpolyethyleneoxide(PEO)wasprintedanddyeswerelocalizedin predefined patterns within the squares. A polycaprolactone(PCL) sheetwas printed at the top and bottom of this grid tosealitandpreventdyediffusionuponresorption,yieldingatwo-dimensionaldiffusionprofilelimitedtotheplaneofthedevice.Invitroreleasestudiesshowedamultiphasicreleaseprofileofthedyes incorporated.

Kastra et al. demonstrated that the drug release mechanisms of these newly conceived devices could be controlled by the chemical propertiesofthebinderutilizedanditsfinalconcentrationwithinthepill[29].EudragitE-100,acationicmethacrylicestercopolymersolubleunderacidicconditionsbelowpH5,wasusedasabinderto fabricate cellulose tablets with an erosion dominated drug release mechanism. Tablets with diffusion controlled releaseprofilesweremadebyutilizingEudragitRLPOasbinder.EudragitRLPO is a permeable and insoluble ammonio-methacrylic acidcopolymer and its properties have no dependence on pH.Dissolutionstudiesof these tablets in simulated intestinalfluiddemonstratedanincreaseindrugreleasetimewithanincreasedbinder content within the tablet printed. The hardness andfriability of the designed drug delivery devices were comparable to commercially available compressed tablets. Moreover, using fluoresceinasamodeldrug, itwasshownthatthis technologycan precisely control the dosage of drugs by achieving loads in the pico moles range.

Taking advantage of the control that binders offer over drugrelease mechanisms, Rowe et al. made use of diverse binders to fabricatetabletswithcomplexdrugreleaseprofiles[30].Adevicewith an immediate-extended release profile of the moleculechlorpheniramine was fabricated by using E-100 as a binder forhalfof thepillandE-RLPOfor thesecondhalf,asshown inFigure 2A.Theimmediatereleasesectiondeliveredthefullloadofchlorpheniraminemaleatewithinthefirst30minutesof thedissolution process. The extended release part maintained asustainedreleaseforaperiodof6hours(Figure 2B). A tablet with apulsereleaseprofileofdiclofenacwasdesignedtotriggerdrugrelease in both gastric and intestinalfluidbyusingvariousbinderssensitive to pH values characteristic of these areas. E-100wasusedtoprintasectionofthepillsensitivetothelowpHfoundin gastricfluid,whereasEudragit L-100, ananionicmethacrylicester copolymer sensitive to solutionswithpHvaluesabove6,wasusedtoachievedrugreleaseinintestinalfluid.Additionally,breakawaytabletswerefabricatedtoextendthedistributionofdrugswithlowpharmacokinetictransportratesthroughoutthegastrointestinalwall.

Wang et al. fabricated cubic drug delivery devices with a near-zero controlled release profile containing pseudoephedrinehydrochloride[31].Thedevicewascomposedofhydroxypropylmethylcellulose(HPMC)andKollidonSRasmainmaterials.Thecubicshellportionofthedevicewasprintedbyutilizinga15%triethylcitratesolutioninethanolasbinder.Aninnercubiccorewasprintedwithanaqueousbinder containing50%byweightof pseudoephedrine hydrochloride. The system’s drug release

mechanismwasdominatedbydiffusion of thedrug located attheinnercorethroughtheshelllayerandoutintothedissolutionmedium. Control of the release profile was shown by thetuningoftheHPMCtoKollidonSRratio,achievingformulationswith drug release profile times of 8, 12, and 16 hours as theconcentration of HPMC increased, respectively. This near-zerorelease profile proved to be independent of pH changes inthe dissolution medium, paddle stirring rate, or the inclusionof a sinker. To increase the drug loadwithin the tablets, Yu etal. fabricated tablets by pre-mixing the active acetaminophenwith the main excipients located in the powder bed, ratherthan incorporating the drug through the binder [32]. Tabletswith acetaminophen concentrations as high as 68% byweightwere produced. Furthermore, a zero-order release profile wasachievedbyprintinginsolublelayersatthetopandbottomofthecylindricaldevice,resultinginatwo-dimensionalreleaseprofile.Moreover, the devices included a radial gradient of the release-retardation material ethyl cellulose. This gradient decreasedtowards the inner part of the tablet, while the void space was gradually increased (Figure 3A).Thecombinationofthesefactorsallowedforahigherdrugdiffusionasthetableteroded,causingaconstantreleaseratethroughoutthedissolutionprocess.Figure 3B shows the erosionprocess of thedevice after 0, 1, 3, 5, 7,and10hoursofdissolution.The incorporationof centralholesin compressed tablets has been used to promote zero-order release profiles bymaintaining a constant surface area duringthe simultaneous erosion of its inner aperture and outer layer [33,34]. More recently, Yu et al. fabricated doughnut-shapedacetaminophen tablets and obtained zero-order drug release profilesbyprintinginsolubleandimpermeabletopandbottom

Figure 2 (A)Schematicof immediate-extended release tabletand (B) its corresponding drug release profile.Reproduced with permission from [30].

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layers, resulting in a 2-dimensional drug release limited to theplaneofthedevice[35].Otherdesignparameters,suchasinnerapertureradius,annularthickness,height,andnumberofbinderpasses per layer were manipulated. Results showed that the total drug releasetimeincreasedwithdecreasinginnerradiusesandincreasing number of binder passes.

Powder bed 3D printing has also been applied towards thefabrication of fast disintegrating/dissolving tablets (FDTs). Yuet al. produced FDTswith average disintegrationtimes of 23.4seconds[36].Thiswasachievedbyprintingtabletswithcompacttop, bottom, and lateral layers, while leaving loose powder inthemiddlesectionofthepillresultinginanareaofhighporosityand permeability (Figure 4). Binder was dispensed in selected areasofthemiddlesectionofthepilltoincreaseitsmechanicalstability.Invitrodissolutiontestsshowedthat98.5%oftheactiveacetaminophenwasreleasedwithin2minutes.TheFDTshadanacceptableharnessvalueof63.4±5.4N/cm2.However,friabilitystudiesdemonstratedanunsatisfactorymasslossof3.55±1.16%.Thiswascorrectedinafurtherstudybyincrementingthenumberofbinderpasses through theprintingprocessandnotprintingselectedareasinthemiddlesectionofthetablet,resultinginanetweightlossof0.92±0.14%[37].Netweightlossvaluesbelow1%areconsideredacceptablebasedonregulationsbytheUnitedStates Pharmacopeia (USP).

In2015,theFDAapprovedthefirstFDTmanufacturedthroughpowderbed3Dprinting [12].ThecompanyApreciadesignedatabletcontainingtheactivelevetiracetam,adrugforthetreatmentofepilepsy,withadissolutiontime of about 15 seconds in saliva or10mLofwater[38].Thisadvancementhighlightsthepotential

within this technology for the development of specialized drug forms with features not achievable through compression or other conventional tablet fabricationmethods. Nonetheless, prior toitsimplementationasadefinitereplacementofcurrenttabletingtechniques, this technology would require improvements inseveralareassuchasthecombinationofmultipledrugsathighdosages,printingtime,andtheproductionofporous,hollow,andmore complex architectures for the further regulation of drugreleaseprofiles.

Fused Deposition Modelling (FDM)Fused deposition modelling (FDM) was patented in 1989 byScottCrump, co-founderof Stratasys Ltd, anddevelopedas analternativetotheinherentlimitationsofpowderbed3Dprinting[16,39].Thistechniqueinvolvesthemelting,extrusion,andlayerbylayerdepositionofmaterialsthataftersolidificationresultinobjectswithpredeterminedstructures(Figure 5) [40].Tocontroltheporesizeandtheconfigurationoftheobject,variablessuchas raster angle and thickness, space between rasters, and the extrusiontipdiametercanbemanipulated.Theappropriateheattransfercharacteristicsandrheologicalpropertiesare themostcriticalmaterialqualitiesevaluatedforFDMuse.Moltenmetals,self-hardeningwaxes,andthermoplasticmaterialssuchasnylon,acrylonitrile butadiene styrene, and polyvinyl chloride have been utilizedsuccessfully[16,28].Figure 3 (A) Drug delivery device with material gradients. (B)

Erosionprocessofthedeviceafter0,1,3,5,7,and10 hours ofdissolution.Reproducedwithpermissionfrom [32].

1 2 3 4

12 mm9 mm6 mm3 mm

A

B

Figure 3 (A) Drug delivery device with material gradients. (B) Erosion process of the device after 0, 1, 3, 5, 7, and 10 hours of dissolution. Reproduced with permission from [32].

Figure 4 Schematic of fast disintegrating tablets with boundregions within the middle of the device. Reproduced with permissionfrom[36].

Bound Region

Powder Region

Figure 5 Fused deposition modelling procedure schematic.Reproduced with permission from [40].

The lament is fedinto the extruder

Filament (polymer drug) spool

The lament is fedinto the heater block

The material isdischarged from the

nozzle of the printhead

Polymer drugmelts/softens in the heater block and is

fed inbto the nozzle

X/Y/Z movement of thesample stage or the print

head allow the depositionof the material in a 3D

manner

3D printed tablets

Figure 5 Fused deposition modelling procedure schematic. Reproduced with permission from [40].



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Among the advantages of FDM are its lower costs, the ability to printmultiplepolymersinasinglestructure,andthecapacitytocreatehollowandporousobjectswithgoodmechanicalstrengths[28].ThesecharacteristicsenableFDMasasuitabletechniqueforthemanufacturingofpersonalizedtabletsandtheirsubsequentdischargeatdispense/point-of-carelocations.Challengesofthisprocess include the limited amount of thermoplasticmaterialswith appropriate rheological properties and the possibledegradation of incorporated drugs, caused by the exposure ofactiveingredientstohightemperatures.Thesefactorscombinetoseverelylimitthechoiceofextrusionmaterialsfortabletprinting.Theconceptofextrudingamaterialcontaininganactivedrugfor3D Pharmingwas first used by Khaled et al. in 2014 [41]. Theauthorsprintedbi-layertabletsloadedwiththeactiveguaifenesin,anexpectorantusedtoreducechestcongestion.Thefabricatedtablets contained an immediate release compartment composed of HPMC 2910 as binder, in combinationwithmicrocrystallinecelluloseandsodiumstarchglycolateasdisintegrants.Theotherhalfof thepill featureda sustained releasesectionconstitutedofHPMC2208andpoly(acrylicacid)ashydrophilicmatrix.Thesematerials were processed separately and combined with the active,resultinginthesynthesisoftwoviscouspastesthatwereusedasfeedstockfortheprintingprocess.Adissolutionanalysisof the tabletswasperformedwhere thepillswereexposed toanacidicmediumrepresentativeofthestomachforaperiodof2hours, followedbyexposuretoa0.2MtrisodiumphosphatedodecahydratesolutionwithapHof6.8, representativeof thesmallintestine.Theauthorsreportedcompletedepletionofthedrug inthe immediatereleasecompartmentwithinthefirst30minutesofdissolution,whilemaintainingasustainedreleaseforaperiodof12hours.ItwasdemonstratedthatthedrugreleaserateatthesustainedreleasesectioncouldbecontrolledbytuningtheconcentrationofHPMC2208inthepaste,showingadecreasein release rateastheHPMC2208wasincreased.Releaseprofileswere similar to commercially available guaifenesin tablets.

EventhoughKhaledetal.demonstratedtheextrusionofexcipientscontainingactivesfortheprintingofpharmaceuticaltablets,theirprocedure was carried at room temperature and the materials werenotmeltedpriortoextrusion,bothintrinsiccharacteristicsof FMD. FDM per se was first applied for 3D Pharming whenGoyanesetal.printedfluorescein-loadedpolyvinylalcohol(PVA)filamentsin2014[42].Theauthorsloadedfluoresceinbyswellingthe polymer filaments in a fluorescent-ethanol solution. Theamountoffluoresceinincorporatedintothefilamentswas0.29%w/w,mainlylocatedatthesurfaceofthefilamentsduetoaslowdiffusionofthedrugintothepolymer.Tabletswithdifferentinfillpercentages (Figure 6) wereprintedbyextrudingthedrugloadedfilamentsatatemperatureof220°C.Dissolutiontestscarriedoutin a bicarbonate buffer at pH 6.8 demonstrated that the drugreleaseratecouldbetunedbychangingtheinfillpercentageofthe tablets, with lower percentages resulting in faster releaserates.

The team later demonstrated the importance of adequatedrug selection by the incorporation of two isomericmolecules[43]. The aminosalicylates 5-aminosalicylic acid (5-ASA) and4-aminosalicylic acid (4-ASA) were incorporated into separate PVA filaments resulting in tablets with drug loads of 0.063 ±

0.001%w/wand0.236±0.004%w/w,respectively.Eventhoughthese molecules are isomers, 5-ASA had a faster release rate than 4-ASA.Moreover,differentialscanningcalorimetry(DSC)analysisofthe4-ASAtabletafterprintingshowedadrugdegradationof50%,statingthelimitationofthetechniqueregardingthermallylabile molecules.

Showrya et al. used FDM to print ellipse-shaped tablets loaded with the steroid prednisolone and demonstrated the weight and dosage accuracy that can be achieved through the FMD technique [10]. PVA filaments were immersed in a methanolsolutioncontainingprednisolone,achievingadrugloadof1.9%w/w.Themassofthepillswasmanipulatedbytuningthevolumeofthetablets.Tabletswithweightsof2,3,4,5,7.5,and10mgwereprintedatanextrusiontemperatureof230°Cwithadosageaccuracyrangeof88.7-107%.ThermalanalysisbyDSCandx-raypowderdiffraction(XRPD)confirmedthatthedrugloadedexistedin the amorphous form within the tablets.

An important aspect considered during the design of pharmaceuticaltabletsisitsshapeanditseffectondrugreleaseprofiles.Toevaluatethisaspect,tabletswithseveralgeometriesincluding cube, pyramid, cylinder, sphere, and torus, were printed and their drug release profiles were analyzed [44]. InanefforttoincreasethedrugcontentwithinPVAfilaments,thedrugparacetamolwasincorporatedbyhotmeltextrusion(HME),a technique in which multiple materials are extruded at hightemperatures to obtain a homogeneousmixture with uniformshape[45-47].Thedrugloadachievedinthetabletsprintedwas3.78% w/w. During dissolution studies, tablets with differentgeometriesandequivalentsurfaceareasresultedindrugreleaseratesinthefollowingorder;pyramid>torus>cube>sphereandcylinder.Thisresultindicatedthatdrugreleaserateisdependentonthesurfacearea/volumeratioofthetablet,withhigherratiosproducing faster release rates. In this case the pyramid designhad the highest surface area/volume ratio (1.169) while thespherehadthelowest(0.634).

HME has also been utilized to create drug loaded filamentsmade out of methacrylic polymers. Pietrzac et al. incorporated the drug theophylline into Eudragit RL, Eudragit RS, and Eudragit E,and3Dprintedtabletswithadrug loadingof50%anddoseaccuracybetween91and95percent [9]. Itwasdemonstratedthat the mass of the tablet and its printed volume followed a linearrelationship.Moreover, increasingtheprintingresolutionoftheprocessdidnotaffectthefinalmassloadedintothetablet,butresultedinhigherprintingtimes.Goyanesetal.expandedtheapplicationofFDMbyincorporatingfluidbedcoatingtechniques

Figure 6 Cross-sectional view of fluorescein infused devicesfeaturing different infill percentages underUV light. Reproduced with permission from [42].

10% In ll 50% In ll 90% In ll

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intothepillsmanufactured,inanefforttodeveloppHcontrolleddrugreleaseprofiles[48].Thedrugbudesonide,commonlyusedtotreat inflammatoryboweldisease (IBD),wasembedded intoPVAthroughHMEresultinginfilamentswithadrugloadof4.14±0.273%.Tabletscontaining9mgofbudesonidewere3DprintedandcoatedwithanEudragitL100basedsolution.Drugreleasestudies demonstrated that budesonide release began at the mid-small intestine and maintained a sustained release up to thedistalintestineandcolon.FMDhasalsobeenutilizedtofabricatehollowcapsulardevices fordrug incorporation.Melocchi et al.created hydroxypropyl cellulose filaments and demonstratedthe feasibility of FMD for this purpose by comparing the product obtained to capsules manufactured by injection molding [49].Capsules made through both methods were loaded with 80 mg of acetaminophen and dissolution tests showed similar drugrelease profiles. This technique features advantages over thepowderbed3Dprintingtechnologysuchastheabilitytoproducemore complex structures, print multiple materials in a singletablet,andalowercostsofequipment.Yet,moreeffortstowardsthereductionofdrugdegradationduetoheatexposureandthedevelopmentofmorematerialssuitableforFDMarerequired.

Multiple Drugs IncorporationSincethefirstpublicationonthistopic[11],oneofthegoalsof3DPharminghasbeentodeliverpatient-specificcombinationsofmultipledrugsintoasingletablet,customizedtotheneedsofthepatient in termsofdrugchoiceanddosage.Thisadvancementwould reduce the number of pills consumed by patients on adaily basis and potentially enhance patient compliance [15].3D Pharming has been applied within several studies in order to incorporatemultipledrugs intoone tablet,while controllingtheirindividualreleaserates,profiles,andreleasemechanisms.These are critical parameters to take into considerationduringthe design of a drug delivery device such as pharmaceuticaltablets, as they define the location and the time where thedrug release occurs within the gastrointestinal (GI) track, aswell as the concentration of drug secreted through a definedperiod of time. Sun et at. demonstrated a novel techniqueto create customized drug release profiles within a tablet,producingprofileswith a constant rateof release,pulsed rate,increasedrate,anddecreasedraterelease[50].Intheirstudy,animpermeablepolylacticacid(PLA)tabletwas3Dprinted,leavinganopeningatthetopofittoallowfordrugdiffusion,asobservedin Figure 7A.Tofillthetablet,apre-polymersolutionwascastedin polydimethylsiloxane (PDMS) molds with different shapesandcuredbyexposingthesolutiontoUVlightforaperiodof10minutes. Theprecursor solutionwas composedof 4-pentenoicanhydride, pentaerythritol tetrakis (3-mercaptopropionate)(PETMP), and/or ethylene glycol dithiol (EGDT; 3,5 -dioxa-1,8-dithioocatne) as crosslinker, using 1-hydroxycyclohexyl phenylketoneasphotoinitiator.Afterpolymerization, thedrug loadedmaterial was located inside the tablet and the void spaces were filledbydrug-freepre-polymersolutionandexposedtoUVlight,culminatingthetabletfabrication.OrangeGandBrilliantBlueGwereutilizedasmodeldrugs.Figure 7B shows how the release profilesofthetwodyesaredirectlydependentontheshapeofthepolymerizedsolutionintroduced.Thestudy showed a novel

techniqueforthereleaseofmultipledrugswithinatabletwithdiverse customized releaseprofiles.Moreover, the release ratecould be further modified by manipulating the ratio betweenPETMPand thecrosslinkerEGDT,with lowercrosslinking ratiosresultinginfasterdrugreleaserates.

In a different study, Goyanes et al. used FDM tomanufacturetabletscontainingthemoleculesparacetamolandcaffeine[51].ThefilamentsusedfortheprintingprocessweremadebymixingeachdrugperseparatewithPVAandapplyingHME.Filamentswithtwodifferentdrugconcentrationsweremadeforeachmolecule,achievingdrugloadsof4.3%and8.2%forparacetamoland4.7%and 9.5% for caffeine. In order to obtain diverse drug releaseprofiles, tablets with two different designs were 3D printed.Thefirstdesign featured1mmalternate layersofcaffeineandparacetamol, as shown in Figure 8A.Theseconddesign,namedDuoCaplets (9.0mm length x3.34mmdiameter), consistedofa capsule shaped core containing one drug in the inside of the tablet and an outer layer where the opposite drug was located (Figure 8B). Release studies were performed in a bicarbonate bufferatdifferentpHvaluestosimulatevarioussectionsoftheGI track. Results demonstrated a simultaneous releaseof bothdrugs within the model featuring alternate layers, whereas the DuoCaplets model showed release of the drug located at the outer layer followed by the drug located at the inner side of the capsule. Itwas also demonstrated that the release rate of thedrugsincreasedwithanincreaseddrugconcentrationwithinthefilamentsextruded.

Besidesachievingcontrolofthereleaseprofileofmultipledrugsthroughadjustmentsonthetablet’sdesign,otherstudieshaveincorporated diverse drug release mechanisms to regulate this parameter. Khaled et al. designed a polypill containing the drugs captopril, nifedipine, and glipizidine, a combination of drugsused to treatdiabetics suffering fromhypertension [52].Thesedrugswerereleasedthroughtwodifferentmechanisms:diffusionand osmosis. The drug captopril was incorporated within an

Figure 7 (A) Schematic of polymer precursor solution curingprocedure and tablet manufacture. (B) Effect ofpolymer geometryondissolutionprofiles.Reproducedwith permission from [50].

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osmoticpumpdesignedbyincorporatingsodiumchlorideasanosmogen in themixtureofexcipientsextruded,which resultedin aporous shell upondissolutionof the sodiumchloride. Thedrugsnifedipineandglipizidewere incorporatedwithinHPMC,a material that swells upon exposure to a liquid medium andpromotes a sustained release of the drugs encapsulated. Release studies demonstrated that the drug captopril showed a zero order drugreleaseprofile,inducedbytheosmoticpumpdesigned.Thedrugs nifedipine and glipizidine followed a Kormeyer-Peppas or firstorder releasekinetics thatvariedwith theactive/excipientratio utilized. These pills were printed by extruding pastesof excipients and actives at room temperature, a techniquedeveloped by Khaled et al. previously discussed in the Fused DepositionModellingsection[41].

The team subsequently printed a polypill containing 5 drugs:pravastatin, atenolol, ramipril, aspirin, and hydrochlorothiazide[53].Developedtotreatandpreventamultitudeofcardiovasculardiseases and high blood pressure, the drugs were incorporated and segregated through different compartments in a singletablet (Figure 9).Thedrugsaspirinandhydrochlorothiazidewerelocated within immediate release compartments containing sodium starch glycolate as disintegrant, which induced the release of100%of thedrugwithin thefirst30minutesofdissolution.Thedrugspravastatin, atenolol, and ramiprilwere located intocompartmentscontainingHMPC,designatedtohaveasustainedrelease that continued for aperiodof 720minutes. This studyrepresents themaximumamount of drugs incorporated into asingle 3D printed tablet to date.

Conclusion and Future DirectionsThe literature is replete with exciting demonstrations of 3DPharming that can enable personalized medicine by producing patient specific formulations with speed and precision.Additionally,therequiredequipmentiscapableofbeinginstalledandoperatedindiversesettings,includingtraditionalpharmaciesaswellaspointofcarelocationssuchashospitalsandresidentialcare facilities. Besides being highly scalable and cost effective,the precise amount of drugs and excipients deposited duringpillfabricationcanbetracked,offeringunprecedentedaccesstoqualityassurance.Mostexcitingly,thepatientspecificformulationsanddosagescanbeadjustedaccordingtophenotypicevidenceofintendedresultsandundesirablesideeffects.Thisinformationcanbeloadedintothepatient'sindividualdatabase.

Additionaleffortsarerequiredinordertoincreasethespeedof

productionandsatisfythehighdemandfortabletsloadedwithmultiple drugs at tailored dosages. Besides powder printingand FDM, other technologies that deposit matter throughphysiologicalanddrug-compatiblemannersarebeingdeveloped.PolyJet printing, a technology that dispenses photocurablepolymer solutions intoa tray,would reduce themanufacturingtime of oral drug forms by maximizing the speed capabilitiesinherent of inkjet printing. More importantly, the engineeringofbiocompatiblematerials thatmaximizedrug stability for theapplicationofsuchtechnologywouldprovideanovelalternativetowards3DPharming.Differentexcipientmaterialsareneededtoprinthydrophilic/hydrophobicdrugswithvaryingdegreesofsolubility.Inaddition,theseexcipientsmustbecompatiblewitheachotherandwiththedepositiontechnology.

Beyond the scientific and engineering challenges, there arealso regulatory obstacles that need to be addressed for the implementation of this technology. Advantages of depositingdrugs drop-by-drop include precise control over dosage, high spatial resolutiontocreatecompositionalgradients,andabilitytomonitorwithvideocameraforqualityassurance.Acommonlimitation for both CJ and DOD printheads for 3D Pharmingis that many drugs are poorly soluble in most biocompatibleprintable fluids, and they may need to be deposited indispersions or particulate forms. Practical quality assurancemonitoringsubsystemsthatallowreal-timeandhighresolutiondeterminationofdrugdosingwillbeneeded toensurepatientsafetyandefficacy.

An analysis of the economical feasibility of this paradigm shiftwithinthepharmaceuticalindustryisneededregardingequipmentexpenditures, drug production, and adjustment of currentregulations to overview novel protocols and pharmaceuticalapparatuses. Currently, a tablet containing a variety of drugs would be considered by the FDA as a new combination drugformulation, requiring extensive clinical trials to assess itseffectiveness and guarantee patient safety. Additionally, eachlocationoperatinga3Dprinterfortheproductionanddischargeof pharmaceutical prescriptions would require certification asaGMP facility. Efforts from regulatingagencies in concertwiththe scientific community are required to develop regulationsthat ensure the safety of patients while promoting scientificadvancement.

Thechoiceofdrugcombinationanddosethatsuitsapatient’sphysiologywillcomefromacombinationofclinicalphenotypic

Figure 8 Schematic of tablets containing multiple drugs. (A)Multilayer device and (B) DuoCaplet. Reproducedwith permission from [51].

A B

Figure 8 Schematic of tablets containing multiple drugs. (A) Multilayer device and (B) DuoCaplet. Reproduced with permission from [51].

Figure 9 Schematic of the polypill design featuring 5 drugswithinimmediateandextendedreleasecompartments.Reproduced with permission from [53].

Dots

Immediate release compartment

Controlled porosity celluloseacetate membrane

Extended release compartments

12 mm diameter

1.8 mm

height 4.05 m

m height

formulations

RamiprilAtenolol Pravastatin

ASA & HCT formulation

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findings, pharmacogenomics data, and optimization searchalgorithms. Studies have demonstrated that primary care physicians do not feel confident regarding their ability toanalyzedataderivedfromgenetictests[54].Reformstomedicalcurriculums, development of specialist training for medical geneticists, and implementation of personalized medicinecertifications for on-going physicians aremeasures required tosatisfy the demandof professionals in this newemerging field[55].Furthermore,effortstodeveloptheinfrastructurerequiredto store the biomedical data acquired and guidelines defininghow this information is used to drive the identification andqualification of diverse biomarkers are necessary [56]. Since

optimizationsearchalgorithmstendtoimprovewithincreasingdata, guidelines will be needed to balance performance versus sharing of big data.

3D Pharming brings us a step closer to personalized medicine. Thenumerouscuttingedgetechnologiesdescribedinthisreviewarebeingdevelopedtoovercomebasiclimitations.Thispowerfultransformationmust be carefully controlled to protect societyandindividualprivacy,whilemaximizingsafetyandefficacy.

Competing and Conflicting InterestsTheauthorsdeclarethattheyhavenocompetingorconflictinginterests.



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