輔料全部關于報告1、23三個由于專家要求不能-分論壇b19-jim presentation june

EnablingTechnologiestoImproveOralBioavailabilityofPoorlySolubleCompounds朱海健博1 新化學實體（NCEs）Ascombinatorialchemistryandreceptorbasedin-vitroscreensarebeingusedtodiscoverpotentialleadseries,theNCE’sareHighlylipophiliccompoundswithpoorLargemolecularweightpeptides/proteinspoorPolarcompoundswithhighcrystaldensityandlowaqueousLipinski’sruleof es

潛在的前沿系列化合物

生物藥劑學分類系統(tǒng)MostNCEsareBCSClass2 BCSBCSClassHighHighBCSClassLowHighBCSClassHighLowBCSClassLowLowBCS1BCS2BCS4GLAmidonetal,PharmRes1995,12(3),

GLAmidonetal,PharmRes1995,12(3),RequirementRequirementfor“Good”Solubility（溶解度”好”的要求CALipinski,JPharmacolToxicolMeth,2000,44,4

改善藥物溶解度的技PhysicalSolidPhysicalSolidAmorphousChemicalMoresolubleNewchemical微粉化/增自 釋藥系藥Mini-WETMini-WET高壓均質OverallStrategy（總體策略微粉NANO-納米MOLECULAR(固體分散體/溶液, 釋藥系統(tǒng),納米乳pHControl/控制pH值pHControl/控制pH值l/潤濕Nano-溶液AmorphousSolid無定形固體分散AIRJET氣COLLOID潤濕/懸浮液/膠體DosageForms(solvent噴霧干燥LIQUIDFILLPOWDERINBOTTLEAmorphousStructure（無定形結構Amorphousmaterial（無定形物質a(solid)stateofmatterwhichlackslongrangeorder（一種原子排列不規(guī)則的(無序)固體物質Crystalline（晶型 Nanocrystalline（納米晶 Amorphous（無定形7Lower結晶Lower結晶（動力學亞穩(wěn)定（最終將結晶GToslowdowncrystallization（延緩結晶GLowermolecularmobility（減少分子運動AdvantagesofAmorphousSolidDispersion(Polymer)freeImproveWhenAPIhaslessthandesirableproperties,suchPartiallycrystalline(ordifficulttoImproveIncreasesolid-statestabilityofInhibitnucleationandgrowthinaqueous

增 MethodsofGeneration（無定形分散體 方法Hot DissolutionRateandBioavailability（提高溶出速率和生物利用度Ritonavir(Abbott):BCSClass~10XincreaseinintrinsicdissolutionD.Lawetal,JPharmSci,2004,93(3),

SignificantincreaseinDependenceonSampleGenerationMethod（取決于樣 方法

Z.Dongetal,Int.JPharm,2008,355,

ThermalStabilityofAmorphousMaterial（無定形物質的熱穩(wěn)定性

Indomethacin,Tg=42At0°C,nocrystallizationforfiveNegligiblemolecularmobilityTg–T≥50

吲哚美辛Tg42當Tg–T≥50°C時，分子運 RHStabilityofAmorphous（無定形的濕度穩(wěn)定性Wateractsasplasticizerinamorphoussamples吲哚美辛)tolowerTgandincreasemolecularV.Andronisetal,JPharmSci,1997,86(3), StabilizationStabilizationbyPolymer（通過聚合物提高穩(wěn)定性5%PVPphysical5PVPdispersionPVP90(Tg=172oC)=聚維酮90(Tg=172oCT.Matsumotoetal,PharmRes,1999,16(11),PolymersUsedInSolidDispersions-DispersantImmediaterelease:Cationic(E100andEDelayedcontrolledrelease:anionic(L100-55,S100andL100)Sustainedrelease:neutral(NE,NM,RLandPolyvinylPolyvinylpyrrolidone(PVP,Kollidons,Copovidone(PVP/PVAccopolymer,CelluloseHPMCAS(LF,MFandHPMC,HPC,EC,Polyethyleneglycols/Oxides(PEGsandPolyvinylalcohol:

用于固體分散體中的聚合物聚乙酸乙烯酯聚乙烯吡咯烷酮(PVP,Kollidons,共聚維酮(PVP/PVAccopolymer,纖維素衍生物HPMCAS(LF,MFandHPMC,HPC,EC,聚乙二醇及其氧化物(PEGsand聚乙烯醇FelodipineFelodipinePVPSolidDispersion（非洛地平-PVP固態(tài)分散體APIOnly（原料藥 SolidDispersion（固體分散體I.Ivanisevic,JPharmSci,2010,99(5):4005-DispersantAPIstructuredictatespolymerHydrogenVanderCo-solventDispersantsystemdependsBCSDose,Drugloading,&

Hypromellosephthalate(HP-Hypromellosephthalate(HP-Hypromelloseacetatesuccinate(LHypromelloseacetatesuccinate(MHypromelloseacetatesuccinate(HCelluloseacetateEUDRAGITL100-EUDRAGITMiscibilityofAPI-Polymer API聚合物體系的混溶DetermineXRPD(computational,pairfunctionSpectroscopy(IR,ByQuestionstoPhase

X-射線粉末衍射（計算機配對分布函數(shù)光譜（IR，拉曼顯微通過預問EntericPolymer:HPMC 腸溶聚合物HPMCROHPMCASs(Tg=120-135

RO OR OR OR

OH3gradesofL,M,andHcorrespondingto ORdependentreleaseprofilesoflow(pH~5),(pH~5.5)andControlledreleaseagents,entericcoatingagents,film-formingagents,sustainedreleaseagentsandmorerecentlyassolubilityenhancingagents patiblewithacids,peroxides,andotheroxidizingmaterialsAcetylandsuccinoylgroupsarecapableofacceptinghydrogenbondfromAPIstostabilizethesolidLimitedorganicsolventViscoussolutionischallenginginsprayPlasticizersmaybenecessaryformeltLowdegradation

n/

pH值依賴型釋放性能低(pH~5中(pH~5.5)高(pH~DrugCesamet?EliLilly（禮來制藥Gris-PEG?Isoptin?SR-E240Kaletra?HIVNimotop?Rezulin?Sporanox?Incivek?(Kalydeco?ItraconazoleSolid

伊曲康唑固態(tài)分散MarketedasSporanoxProof-of-concept,treatedasaNew

D.Engersetal,JPharmSci,2010,99,3901-D.Engersetal,JPharmSci,2010,99,3901-BalanceofAPILoadingandStability（API載藥量平衡的穩(wěn)定性As- After S.Janssensetal,EurJPharmSci,2008,35,203-S.Janssensetal,IntJPharm,2008,355,100- SolidDispersionDosageDevelopment(固體分散體制劑研發(fā)

MeltExtrusionSpray

ClinicalMeltExtrusionMeltExtrusionSolidstate固態(tài)屬Estimationof可混合性估溶解藥物與聚合物的共容

OpticalMicroscopy光學顯微

MeltMeltExtrusionChemical

FilmCasting剝膜注FilmCasting剝膜注HotHotMeltExtrusionvsSprayDrying(熱熔擠出vs噴霧干燥 Spray SprayHotMeltHotMeltorSprayMelting)MPdrug＜DTImportanceofdrugStability&

OrganicSolubility有機溶