MakingZocorabetterdrug2015年12月9日Contents1.Basicinformation2.Physicochemicalproperties3.Developmenthistory&Indications4.Intracorporalprocess&Adversereactions5.MechanismofAction6.Syntheticroute&QSAR7.MakingZocorabetterdrugBasicinformationTradename:ZocorActivesubstance：simvastatinDevelopedbyMerckin1988,thesecondstatinsintheworld,methylizedderivativesoflovastatininsidechainsLaunchedinSwedenin1988，approvedbyUSFDAin1991.PhysicochemicalpropertiesWhitecrystallinepowder，odourless。Easilydissolvedinethanol,acetoneandacetonitrile,practicallyinsolubleinwater。meltingpoint：135～138℃。Needtobekeptindarkplace

Developmenthistorylovastatinsimvastatin

Activity:twiceasstrongaslovastatin

ButmuchhigherriskofrhabdomyolysismethylationIndications

1,hyperlipidaemia2,coronaryheartdisease,congestiveheartfailureandangina3,complicationsofdiabetesmellitustype24,preventingatherosclerosisthefirstchoiceofhyperlipidemiapatientswithhighcholesterolIntracorporalprocess

Aprodrugwithnoactivityuntillactonicringishydrolyzedtoaopenchainhydroxy-acidderivativesinvivo1.Absorption，distributionandmetabolism:mostlyintheliver;excretion:bileexcretion2.Strongfirst-passeliminationandlowbioavailability3.ExtensivedruginteractionsAdversereactions

1,rhabdomyolysisandmyodynia

(thecommonADRofallstatins,especiallyincombinedpharmacotherapywithfibratesandamiodarone，mechanismhasn’tbeenclearyet)

FDAhaswarnedoftheriskofseriousmuscledamageofsimvastatin2,urinarysystem:diuresis3,lupus-likesymptomes4,memoryimpairmentrhabdomyolysisandmyodyniaSymptom：pain,tenderness,swellingandweaknessofmuscleItisreportedthateatingexcessivecraymaycauserhabdomyolysis參考文獻(xiàn)：謝國(guó)祥,郭寶福,陳洋,等.食用小龍蝦致橫紋肌溶解綜合征事件的流行病學(xué)調(diào)查[J].現(xiàn)代預(yù)防醫(yī)學(xué),2012,39(20).MechanismofAction

1.InhibittheactivityofHMG-CoAreductase,blockthesynthesisofendogenouscholesterol2.IncreasetheuptakeofLDL,decreaseLDLinplasmaSyntheticroute

Uselovastatinasrawmaterial,whichcanbeeasilyacquiredbysemisynthesisofmouldmetabolites蔣軍榮,金紅日.辛伐他汀合成進(jìn)展[J].浙江化工,2006,37(02):20-22.SAR尤啟冬.藥物化學(xué)。第7版.北京：人民衛(wèi)生出版社，2011,186HowtomakeZocorbetter1.ADR2.Extensivedruginteractions3.Strongfirst-passeliminationPoorwatersolubilityLowbioavailability（<5%)HowtoalleviatetheADR?Structuralmodification

simvastatinFluvastatinFluvastatin:muchlowerincidenceofmuscledamage參考文獻(xiàn)：BRUCKERTE，HAYEMG，DEJAGERS，etal．Mildtomoderatemuscularsymptomswithhigh-dosagestatintherapyinhyperlipidemicpatients-ThePRIMOStudy［J］．CardiovascDrugsTher，2005，19(6):403-414．

HowtoalleviatetheADR?StructuralmodificationsimvastatinRosuvastainRosuvastain：1.muchlowerED50(morepotent)2.metabolisedbyCYP2C9,lessinteractionswithotherdrugs(CYP3A4mainlyfortherestdrugs,includingsimvastatin)參考文獻(xiàn)：FRANKREJR．Statininducedmyopathy［J］．JInsurMed，2009，41(2):132-135．1,CommonDosageformsinChPTablet,Capsule,Droppingpills,dispersibletablet,chewabletabletLowwatersolubilitypoororalabsorptionLowbioavailability（<5%)2,Preparationsinresearch:sustained-releasedroppingpills,microemulsion,liposome,solidlipidnanoparticles,cyclodextrininclusioncompound,soliddispersion,self-microemulsion

soliddispersionDrugsarehighlydispersedinsolidcarrierstoformthesoliddispersesystemwhichcanbeobtainedbyfusionmethod,solventmethodorsolvent-meltingmethodAdvantages:acceleratingandincreasingthedissolutionofinsolubledrugsBioavailabilityofsoliddispersionBeagledogssoliddispersionofsimvastatinsimvastatincapsuleasareferencepreparationonthemarketAUC0-∝（ng/mL*h)225.23±22.29132.98±28.29Cmax(ng/mL)81.55±14.3437.05±8.11Tmax(h)1.625±0.631.00±0.41relativebioavailability（%）169.38%參考文獻(xiàn)：彭霞.辛伐他汀固體分散體的研究[D].西南大學(xué),2013.self-microemulsionself-microemulsifyingdrugdeliverysystemisauniformandtransparentsolutioncomposedofoil,surfactantandcosurfactantorsmallamountofwaterDrugsarewrappedinoildropanddispersespontaneouslytoformO/WmicroemulsioninvivoAdvantages:1.Improvingthesolubilityofdrugs2.Increasepenetratingtotheintestinalepithelialcells,acceleratingabsorptionBioavailabilityofself-microemulsion

BeagledogsSimvastatinself-microemulsionsimvastatinsuspensionsAUC0-∝（ng/mL*h)215.56±58.28116.77±3.04Cmax(ng/mL)39.73±9.1128.54±7.76Tmax(h)0.84±0.260.99±0.32relativebioavailability（%）184.84±51.49參考文獻(xiàn)：陳?？?辛伐他汀自微乳化釋藥系統(tǒng)的研究[D].復(fù)旦大學(xué),2008.combinationtherapyDevelopcompoundpreparationsofsimvastatinandotherdrugs(suchasniacin,ezetimibe）Advantages:1,potentiationofhypolipidemic2,reducethedoseofsimvastatin3,relievetheoccurrenceofmuscledamage參考文獻(xiàn)：1.BACKESJM，GIBSONCA，HOWARDPA．Optimallipidmodification:therationaleforcombinationth