MIT生物医学工程课件20

13.051J/20.340JLecture20DrugDelivery:ControlledReleaseIIIDeliveryMethods1.TransdermalDrugdeliverythroughtheskintosystemiccirculationtraditional:crèmes/ointmentsnovel:controlledreleasepatchesTransdermalAdvantages:¾effectivesystemicdelivery(vs.GI)¾highpatientcompliance¾constantraterelease(membrane-based)¾easilyterminated(patchremoval)DeviceDesignsa)membranebasedlaminatedlayersdrugreservoirMetallizedpolymer)backing(PET,PE,PP)(mineraloilorpolyisobutylenepolymermembrane(PP,PVC,PAN,pressure-sensitiveEVA,silicone)adhesive(PIB)peelstrip23.051J/20.340J⇒Releaserateconstant(rate-limitedbydiffusionthroughmembrane)b)monolithicpatchMetallizedpolymerdrugreservoir(polymer)backing(PET,PE,PP)drugcrystalspressure-sensitiveadhesive(PIB)⇒C0CSDrugdissolutioninpolymermatrixcontrolsreleaserateDisadvantagestoTransdermalDeliverya)lowskinpermeabilitytodrugsstratumcorneum~10-15µm(deadtissue,lipidbilayers)pore/follicleepidermis~50-100µm(livingcells,nerves)dermis:(cells,nerves,vessels)33.051J/20.340JƒStratumcorneumishydrophobic–limitsdrugpenetrationƒEpidermisishydrophilicƒMainentrytovasculatureviapores(small%ofsurface)Methodstoenhancepermeability:i)penetrationenhancers“shield”interactions,i.e.,amphiphiles(traditionalcrèmes:H2O/oil+lipids)ii)iontophoresis–mildelectricalcurrent(0.5mA/cm2)appliedtoskinatdeliverysiteincreasespenetrationrateofchargedtherapeuticagents+−ex.,VyterislidocaineE-fielddriveschargeddrugsthruskintransdermaldeliveryiii)microneedles–penetratethestratumcorneumorepidermisex.,3Mhollowplasticiv)ultrasoundneedlesystemforvaccinedelivery(L100µm)b)drugsbindtoskin–desorptionbecomesrate-limitingstepc)allergicreaction—triggeredbyadhesive43.051J/20.340J2.ColloidalDrugDeliveryvehiclesSphericalparticlesofpolymersorlipidswithdispersed,adsorbed,covalentlyboundorencapsulatedtherapeuticagentsnanospheres/nanocapsules/microspheresmicrocapsulesliposomesAdministrationRoutesa)Oralƒreleaseddrugisabsorbedinsmallintestineƒphagocytosisofdeliveryvehicles(dia.10µm)insmallintestineviaM-cells(lymphatictissue)ofPeyer’spatchesAdvantages:-patientacceptance-convenientIssues:-pooruptake—rapidlymetabolized-chemicalinstabilityinGItract53.051J/20.340Jb)Subcutaneousinjectionƒphagocytosis,depositioninlymphnodes(dia.10µm)ƒparticlescollectatinjectionsite(dia.30µm)Advantages:-patientcanadminister-doesnotrequiredigestion(nauseatedpatients)Issues:-poordistributiontotarget-localtissueirritation/toxicityc)Intravenousadministrationƒsystemiccirculationfordia.4µm(smallestcapillary)ƒinteractionwithreticularendothelialsystem(RES)ƒphagocytosisinliver,spleen,lungs,lymphnodesAdvantages:-effectivesystemictreatment-doesnotrequiredigestionIssues:-shortcirculationtimes-lowpenetrationofendothelialliningofvasculature(requiresdia.5nm)63.051J/20.340JTypesofVehiclesa)Nanospheres(10nm-1µm)/microspheres(1-10µm)Drugisdissolvedordispersedinapolymermatrix,oradsorbedtopolymerbeadsurfaceProcessingMethods:Emulsion-basedƒEmulsionpolymerizationwithdrugdispersion-surfactantgrowingincorporatingdrugoligomermonomerpolymernanosphereGrowingpolymerchainsareimmiscibleinsolvent-Micellesform,incorporatingthepolymeranddrug-Canbeaqueousororganicbasedsynthesis,dependingonpolymerandtherapeuticagent-Examples:polyacrylamide/antigenvaccines,biodegradablepoly(alkylcyanoacrylate)/doxorubicinchemotherapeuticsPMMA/antigenvaccines(influenza,HIV)73.051J/20.340JƒEmulsificationofpolymeranddrug-Preformedpolymerdissolvedinvolatileorganicsolvent(ex.,chloroform,methylenechloride,ethylacetate)-Organicsolutionismechanicallydispersedinaqueousphasecontainingsurfactantorstabilizer,forminganemulsion-Drugincorporatedinorganic(iflipophilic)oraqueous(ifhydrophilic)phase,orlateradsorbed-NanoparticlesrecoveredbyevaporationoforganicsolventorprecipitationthroughdilutionwithwaterAqueousphase(waterOrganicphase(solvent,&stabilizingagent)polymer&drug)hSolventevaporationDilution/precipitationEx:PLGA/testosteroneEx:PLA/savoxepine(aEmulsificationneurolepticdrug)83.051J/20.340J-Matrices:PLA,PGA,PLGA,PCL(polycaprolactone),PHB(poly(hydroxybutyrate)),polyorthoesters(acidsensitive)InfluencesonNanosphereRelease/DegradationRate•Molecularweight•Crystallinity•Diameter•Waterpermeability•Tg•pHSensitivityb)Nanocapsules/microcapsulesDrugordrugdispersioninmatrixisenclosedbyapolymermembrane/outerlayerWhatistheadvantageofthisapproach?93.051J/20.340JProcessingMethods:ƒInterfacialpolymerizationofpolyamides- Emulsionformedwithaciddichloridemonomer&drugindispersedoilphase,diaminemonomerinwaterphase- monomersmigratetooil/waterinterfaceandpolymerizebycondensationreaction,encapsulatingthedrugNH2-R-NH2+R’(COCl)2→(ClCO)-R’-CONH-R-NH2+HClamidebond-trichloridesandtriaminesaddedascrosslinkingagents103.051J/20.340Jƒ InterfacialCoacervation- encapsulatingpolymerdissolvedinorganicphase-drugparticlesareaddedtoorganicsolution- asecondpolymerimmisciblewiththefirst(orothernonsolvent)isaddedtosuspension,inducingphaseseparation-encapsulatingpolymerprecipitatesontothedrugparticlesurfaces,formingacapsuledrug2ndpolymer/particlesnonsolventaddedadded113.051J/20.340JƒComplex