辛伐他汀改善

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参考文献：谢国祥,郭宝福,陈洋,等.食用小龙虾致横纹肌溶解综合征事件的流行病学调查[J].现代预防医学,2012,39(20).MechanismofAction

1.InhibittheactivityofHMG-CoAreductase,blockthesynthesisofendogenouscholesterol2.IncreasetheuptakeofLDL,decreaseLDLinplasmaSyntheticroute

Uselovastatinasrawmaterial,whichcanbeeasilyacquiredbysemisynthesisofmouldmetabolites蒋军荣,金红日.辛伐他汀合成进展[J].浙江化工,2006,37(02):20-22.SAR尤启冬.药物化学。第7版.北京：人民卫生出版社，2011,186HowtomakeZocorbetter1.ADR2.Extensivedruginteractions3.Strongfirst-passeliminationPoorwatersolubilityLowbioavailability（<5%)HowtoalleviatetheADR?Structuralmodification

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

HowtoalleviatetheADR?StructuralmodificationsimvastatinRosuvastainRosuvastain：1.muchlowerED50(morepotent)2.metabolisedbyCYP2C9,lessinteractionswithotherdrugs(CYP3A4mainlyfortherestdrugs,includingsimvastatin)参考文献：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%参考文献：彭霞.辛伐他汀固体分散体的研究[D].西南大学,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±51.49参考文献：陈祝康.辛伐他汀自微乳化释药系统的研究[D].复旦大学,2008.combinationtherapyDevelopcompoundpreparationsofsimvastatinandotherdrugs(suchasniacin,ezetimibe）Advantages:1,potentiationofhypolipidemic2,reducethedoseofsimvastatin3,relievetheoccurrenceofmuscledamage参考文献：1.BACKESJM，GIBSONCA，HOWARDPA．Optimallipidmodification:therationaleforcombinationth