扎来普隆舌下喷雾剂在比格犬体内的相对生物利用度

1,2,3,1,1,610mg,Cmax(133.755.5)g/L(207.553.1)g/Ltmax(319.2)min(58.334.9)min,t1/2(33.718.6)min(31.215.2)min,AUCo-6h(12340.66702.7)g/(minL)(16303.73638.1)g/(minL)AUC0-(16390.414498)g/(minL)(16906.84347.3)g/(minL)(96.915.2)%(P0.05),t,;;;;R-332A1681-2476(2008)02-0097-05RelativebioavailabilityofzaleplonbysublingualsprayinhealthBeagledogWANGHui-tao,GUOYan-fang,GAOYong-liang,etal.DepartmentofPharmacy,ShanxiMedicalUniversity,Taiyuan030001,ChinaAbstractObjectiveTostudytherelativebioavailabilityofzaleplonbysublingualsprayinhealthybeagledogs.MethodsInarandomizedcrossoverstudy,6healthybeagledogsweregivenadoseof10mgzaleplonbysublingualsprayordispersibletablets.ZaleplonconcentrationinplasmawasdeterminedbyaRP-HPLC.ResultsAfteradministrationofsublingualsprayanddispersibletablets,thepharmacokineticparametersasfollowed:Cmaxwere(133.755.5)g/Land(207.553.1)g/L,tmaxwere(319.2)minand(58.334.9)min,t1/2were(33.718.6)minand(31.215.2)min,AUCo-6hwere(12340.66702.7)g/(minL)and(16303.73638.1)g/(minL),AUC0-were(16390.414498)g/(minL)and(16906.84347.3)g/(minL)respectively.Therelativebioavailabilityofsublingualspraywas(96.915.2)%,comparingwiththatofdispersibletablets.ConclusionThereisnosignificantdifferenceinpharmacokineticparametersbetweenthetwopreparations.Itisdemonstratedthatthetwopreparationsarebioequivalentbytwoone-sidettests.Keywordszaleplon;sublingualspray;bioavailability;Beagledog;reversedphrasehighperformanceliquidchromatography(RP-HPLC)(zaleplon,sonata)WyethAyerstLaboratoriesInc.,[1]FDA19998,[2]I(omega.1),:1030001,()2100850,3100850,,,,,,[3],1LC-10AT(),LC-10AT,SPD-10A,N2000();:QL-901,;:AnkeTDL-40Bcentrifuge;:79JournalofChineseModernTraditionalChineseMedicine200842(5mg20060504);:;:(estazolam),,20011003M);-,,810kg,22.1:--(50:55:95);:0.8ml/min;:230nm;:AgilentEclipsexDBC8(4.6mm150mm,5m);:302.2100ng/ml,0.5ml,3ml,1:11:23min,3000rpm10min,,N2,50l,,20l,2.3,,30min50l,HPLC,2.40.5ml,50l,102050100200ng/ml,,,,,2.50.5ml,50l,3(20100200ng/ml)(QC)5,,3,2.60.5ml,200ng/ml50l,3(20100200ng/ml)(QC),5,3,(%);,,,(%)2.710ng/ml5,RSD,2.86,12h2(10mg)4(10mg),,1,(0min)10203045607590120150180240360480min5ml,3000rpm10min,-4,33.1:(1:1):(2:1)HPLCFig.1:(2:1),,,,:(2:1):0.5ml10ml,50l(2g/ml),,:(2:1),3min,3000rpm10min2.4ml,30l--(HP--CD),45,N245,50l,,,20l3.2Fig289JournalofChineseModernTraditionalChineseMedicine200842AAceticetherasextractionsolution;BEtherASextractionsolutionCEther:n-hexane(1:1)asextractionsolution;DEther:n-hexane(2:1)asextractionsolutionFig.1HPLCchromatogramsofzaleplonandinternalstandardinblankplasma1zaleplon,2internalstandard;ABlankplasma;Bzaleplonandinternalstandard(IS)inblankplasma;CDogplasma30minafteradministrateofzaleplonatdosesof10mgandspikedwithISsolution.Fig.2Chromatogramsofzaleploninplasma,,3.3R(R=AT/AIS)Y=118.3R-6.291r2=0.999(n=3),10200ng/ml,Fig3Fig.3Calibrationcurve99JournalofChineseModernTraditionalChineseMedicine2008423.4Tab.1Tab.1intra-dayandinter-dayprecisionofzaleplonindogplasma(n=5)Concentration(ng/ml)intra-dayRSD(%)inter-dayRSD(%)20Ï18Ï.614l.9100æ9¸.712l.7200æ8¸.913l.5,3.5Tab.2Tab.2Recoveryofzaleplonindogplasma(n=5)Concentration(ng/ml)Absoluterecovery(%,xs)RSD(%)Relativerecovery(%,xs)RSD(%)20Ì65Î.46.59Ì.9100Ì.515.515à.4100â63Î.45.18Ì.0101â.78.88³.60200â61Î.56.811â.1108Ì.015.114à.03.61050.110.110.130.120.15,RSD13.5%,,10ng,Fig.43.7tmaxCmax;LnC-tkt1/2,t1/2=0.693/k;AUC0-t,AUCt-=C/k,AUC0-=AUC0-t+AUCt-AUC0-t;:tmaxWilcoxon,CmaxAUC0-tAUCt-,t,=0.05,,Tab.3,Fig.51zaleplon;2internalstandardFig.4ChromatogramforLLOQofzaleplonindogplasma001JournalofChineseModernTraditionalChineseMedicine200842Tab.3ThemainpharmacokineticparametersofzaleplonSublingualsprayandzaleplondispersibletabletsafteranoraldoseof10mgzaleplonin6healthydogs(xs,n=6)parametersTestReferenceCmax/g/L133\.754.5207ú.553.1tmax/min31\.39.258ã.334.9t1/2(k)/min33F.718.731ã.118.6MRT128F.6132.086ã.033.5AUC0-240/g/(minL)12340\.66702.616303ú.73638.1AUC0-/g/(minL)16390F.414498.016906ú.84347.3Fig.5Meanbloodplasmaconcentration-timecurvesofzaleplonafterasingleoraldoseof10mgzaleplonSublingualsprayanddispersibletabletsin6healthydog4,HPLC-MS,,,10ng/ml230nm,,,,,,,,,,--(HP--CD),HP--CD,,,,,,,CmaxAUCt,1..,2000,35(1):63-64.2BharathiCh,PrabaharK3J,PrasadCh,S.Impurityprofilestudyofzaleplon.PharmBiomedAnal.2007,44(1),101-109.3,,..,2004,24(7):402-404.(:2008-04-28)(:)101JournalofChineseModernTraditionalChineseMedicine200842