纳米制剂

Stabilityofnano-preparation纳米粒子（Nanoparticle）：Alsocalledultrafineparticles,1~100nmparticlesortinystructuresinatomicclustersandmacroscopicobjectsatthejunctionofthetransitionregion.AtomMolecularMacroscopicobjectsNanoparticle1nm=?m0.1-1.0nm1-100nm1mmPropertiesofNanoparticles：surfaceeffectsmallsizeeffectquantumeffectsuperiorperformance纳米药物(nano-drug)定义将药物的微粒或者将药物吸附包裹在特定载体中，制成纳米尺寸范围内的微粒，然后以其为基础制成不同种类的剂型。Classificationofnano-drugnano-drugNanocarriersdrugs:Thedrugisdissolvedordispersedinnanoparticles.LikeLiposomes、Polymericmicelles.Thenewnanodrugs:Theuseofnano-structuresornano-features,foundsometreatmentordiagnosisdrugofefficiencyandlowtoxicitybasedonnewnano-particlesComparisonEthnodrug药物微粒大、表面反应活性低、活性中心少、催化效率低、吸附能力弱，并且对人体的毒性较大，疗效却不佳，且存在严重的量效效应，即疗效—剂量依赖关系Nano-drug(Features)：Solubilization：reduceparticlesize、controlofparticlesizedistribution，itcanincreasedsolubilityofthedrug,thedrugeasilyabsorbedTargetedrelease：vectorstabilizeefficacyofdrugAdhesivenessChangemechanismofmembranetransportControlledrelease：theuseofcarriermaterial,canslowdissolutionThestabilityofnano-preparationNanomedicinecrystalstabilityisaffectedbymanyfactors:formulationtypes(drypowder,nano-suspension)dispersionmedium(aqueousandnon-aqueous)routeofadministration(oral,inhalation,intravenousinjection),productiontechnology(top-downandbottom-up)thenatureofthedrugitself(smallmoleculesandbiologicalmacromolecules)1.FormulationsaffectthestabilityNano-drugarewidelyusedinoral,eye,lungandskindeliverysystems.Theyhavesamephenomenonofinstabilityfordifferentforms,suchasprecipitation,agglomerationandcrystalgrowth,butthesephenomenonhavedifferenteffectonclinical.Moreover,thechoiceofstabilizerarealsocloselyrelatedtoformulations.2.Thephysicalstabilityofnano-drugStabilityofNano-drug：physical,chemicalandbiologicalstabilitysedimentation物理化学aggregation的角度crystalgrowthcrystallinestatechange2.1SedimentationNano-druggenerallyhavethreekindsofprecipitation:agglomeration,looseaggregatesandopenfloc.Undertheactionofgravity,theprocessofparticlesdirectionalmovementandmakesthedispersionhappenedphaseseparationisknownassedimentation.Stokes公式：V=2r²（ρ1-ρ2）g/（9η）式中，V为微粒沉降速度，r为微粒半径，ρ1、ρ2分别为微粒和分散介质的密度，g为重力加速度，η为分散介质黏度。V=2r²（ρ1-ρ2）g/（9η）由Stokes公式可见，微粒沉降速度与微粒半径平方、微粒与分散介质的密度差成正比，与分散介质的黏度成反比。Primarymethodofreducingnano-drugsedimentation：①Reduceparticleradius；②Reducingthedensitydifferencebetweenthesolidparticlesandthedispersionmedium；③IncreasetheviscosityofthedispersionmediumFlocculantIntheflocculant,particlebeginssedimentationintheformoflooseflock.Thislooseflockcontainsalargedispersionmedium.Simpleagitationorshakingcanbeeasilydispersedagain,resumeitssuspendedstatequickly,thusovercomingtheproblemtorestoresuspendedstate例子：“开放式絮凝物”结构而获得稳定的纳米混悬剂将牛血清白蛋白溶于pH为7.4的磷酸盐缓冲液然后通过不锈钢针头从10cm高处滴加到旋转的不锈钢圆盘（内装干冰）上，液滴接触圆盘后形成薄层，冻结后将冻结物转入液氮中继续冻结最后减压、冷冻干燥即获得长径比（aspectratio）约24的牛血清白蛋白纳米棒。在-80℃条件下将牛血清白蛋白纳米棒粉末和七氟丙烷（HFA-227）混合，超声，装入压力容器中，制成压力定量吸入气雾剂。该制剂形成的絮状物室温放置一年稳定，具有很好的稳定性。此方法制备的纳米棒相互接触点间的范德华力较强，加入氢氟烷烃时，纳米棒间能相互锁定形成一个个开放的环状结构，抑制絮凝物结构的破坏。另外，由于纳米棒具有很高的长径比，所形成的絮凝物比球状结构形成的絮凝物密度低，能更好地填充整个制剂空间而更稳定。综上原因，使得这种“开放式絮凝物”可以有效地克服粒子沉降问题。2.2AggregationLargedispersion→surfacefreeenergy→aggregation→rapidsubsidence，crystalgrowth→Unevendistributionofdrugdose，capillaryclogging（injection）Stabilizersfullywettheparticlesurface,forminganelectrostaticrepulsiontoproducehighbarrier,inhibitaggregation.ElectrostaticrepulsionNano-drugStericstabilizationEvaluationnano-drugdispersionandstabilityofaggregationimportantparameteristheparticlesizeanddistributionParticlesizeanddistribution：dynamiclightscattering（DLS）、laserdiffraction（LD）、CoulterParticlemorphology：Scanningelectronmicroscopy、Transmissionelectronmicroscopy2.2.1ElectrostaticrepulsionDLVO（Derjaguin-Landau-Verwey-Overbeek）Inthemedium,theforceamongparticlescanbedividedtoelectrostaticrepulsionandvanderWaalsforces.Cross-overofparticlesurfacedoublelayerleadtorepulsionbetweentheparticles.ThevanderWaalsforcesbetweenmoleculesconstituteattractionbetweenparticles.Thedistancebetweenparticleandparticlesizeeffectsattraction.Particlesize,inter-particledistance,ζpotential,ionconcentrationeffectsrepulsive.ζ电位是双电层切平面处的电位，是衡量纳米药物稳定性的标准之一，绝对值越高，纳米药物越稳定，用激光多普勒电泳法测定。electrostaticstabilizationandstericstabilization:ζ≥20mV；electrostaticstabilization:ζ≥30mV2.2.2StericstabilizationContent:Adsorbedontheparticlessurfaceofthepolymercanhindertheparticlesclosedtoeachotherfromspace,therebyhamperingtheiraggregationRules：（1）Ontheonehand,thepolymerhaveastrongaffinitywithparticles；Ontheotherhand,thepolymerhaveastrongaffinitywithsolvent.（2）Polymerconcentration（3）SolventNano-drug（Waterasthemedium）Ionicstabilizer：十二烷硫酸钠（SDS）磷脂酰胆碱多库酯钠等Non-ionicstabilizer：吐温80、聚乙二醇（PEG）、聚乙烯醇（PVA）、聚乙烯吡咯烷酮（PVP）、羟丙基纤维素（HPC）、羟丙基甲基纤维素（HPMC）Itwasfoundthatthenon-ionicandionicstabilizercombinationhasasynergisticeffect,becauseitcanreducetherepulsionbetweenionicstabilizer，thustoincreasethedensityofstabilizerintheparticlesurface2.3Crystalgrowth纳米药物中的药物微粒大小不可能完全一致，在放置过程中，微粒的粒径大小和分布将不断变化，这一规律可用Ostwald-Freundlich方程进行描