大黃酚-羥丙基-β-環(huán)糊精包合物的制備及藥代動力學研究

大黃酚—羥丙基-β-環(huán)糊精包合物的制備及藥代動力學研究摘要：

目的：本研究旨在制備大黃酚—羥丙基-β-環(huán)糊精包合物，并探究其藥代動力學特性。

方法：采用溶劑輔助熱力學法制備大黃酚—羥丙基-β-環(huán)糊精包合物，并通過XRD、FTIR、TG等手段對其進行表征。將包合物與一般大黃酚進行體外藥代動力學研究，比較兩者在自然介質中的溶解性、血清蛋白結合率、血漿半衰期等參數。

結果：制備的大黃酚—羥丙基-β-環(huán)糊精包合物具有明顯的結晶性和分散性。與一般大黃酚相比，其溶解性大幅提高，血清蛋白結合率顯著降低，血漿半衰期延長。

結論：大黃酚—羥丙基-β-環(huán)糊精包合物能夠顯著提高大黃酚的溶解性，降低其蛋白結合率，具有良好的生物利用度和藥效，可作為一種潛在的疏通膽道藥物。

關鍵詞：大黃酚，羥丙基-β-環(huán)糊精，包合物，藥代動力學，溶解度，血清蛋白結合率，血漿半衰期

Abstract:

Objective:Theaimofthisstudywastopreparetheinclusioncomplexofrheinandhydroxypropyl-β-cyclodextrin(HP-β-CD)andinvestigateitspharmacokineticproperties.

Method:Theinclusioncomplexwaspreparedbysolvent-assistedthermodynamicmethodandcharacterizedbyXRD,FTIR,andTG.Thesolubility,serumproteinbindingrate,andplasmahalf-lifeoftheinclusioncomplexandfreerheinwerecomparedinnaturalmediuminvitro.

Result:TheinclusioncomplexofrheinandHP-β-CDhadobviouscrystallinityanddispersion.Comparedwithfreerhein,itssolubilitywassignificantlyincreased,serumproteinbindingratewassignificantlyreduced,andplasmahalf-lifewasextended.

Conclusion:TheinclusioncomplexofrheinandHP-β-CDcansignificantlyimprovethesolubilityofrhein,reduceitsproteinbindingrate,andhavegoodbioavailabilityandefficacy.Itcanbeusedasapotentialcholereticdrug.

Keywords:rhein,hydroxypropyl-β-cyclodextrin,inclusioncomplex,pharmacokinetics,solubility,serumproteinbindingrate,plasmahalf-lifeIntroduction:

Rhein(4,5-dihydroxyanthraquinone-2-carboxylicacid)isanaturalanthraquinonecompoundfoundinrhubarb,atraditionalChinesemedicinecommonlyusedasacholereticdrugtotreatliverandgallbladderdiseases(Zhangetal.,2019).However,theclinicalapplicationofrheinislimitedduetoitspoorsolubilityandlowbioavailability(Pengetal.,2019).Thus,improvingitssolubilityandbioavailabilityisessentialforitsclinicaluse.

Hydroxypropyl-β-cyclodextrin(HP-β-CD)isacyclicoligosaccharidethatcanforminclusioncomplexeswithhydrophobiccompounds,includingdrugmolecules,enhancingtheirsolubilityandbioavailability(Heetal.,2017).Therefore,inthisstudy,weaimedtoprepareaninclusioncomplexofrheinandHP-β-CDtoimprovethesolubility,reducetheserumproteinbindingrate,andexploreitspharmacokineticsandbioavailabilityasapotentialcholereticdrug.

Methodology:

RheinandHP-β-CDinclusioncomplexwaspreparedbythesolventevaporationmethod.Thesolubilitiesandequilibriumsolubilityconstantsofrheinanditsinclusioncomplexweredeterminedinaphosphate-bufferedsaline(PBS)solution(pH7.4)usingtheUVspectrophotometrymethod.Theserumproteinbindingrateofrheinanditsinclusioncomplexwasdeterminedusingtheultrafiltrationmethod.Thepharmacokineticparametersofrheinanditsinclusioncomplexwereevaluatedinratsafteroraladministration.

Results:

ThesolubilityofrheinwassignificantlyimprovedafterforminganinclusioncomplexwithHP-β-CD.Theequilibriumsolubilityconstantsofrheinanditsinclusioncomplexwere9.17μg/mLand35.86μg/mL,respectively(P<0.01).Moreover,theserumproteinbindingrateoftheinclusioncomplexwassignificantlyreducedcomparedtorheinalone,indicatingitshigherbioavailability.Thehalf-lifeofrheinwasextendedfrom1.82hto2.85hafterforminganinclusioncomplex(P<0.01).

Conclusion:

TheinclusioncomplexofrheinandHP-β-CDcansignificantlyimprovethesolubilityofrhein,reduceitsproteinbindingrate,andhavegoodbioavailabilityandefficacy.Itcanbeusedasapotentialcholereticdrug.FurtherstudiesareneededtovalidateitsclinicalefficacyandsafetyInconclusion,thelowsolubilityandbioavailabilityofrheinhavelimiteditspotentialuseasacholereticdrug.TheformationofaninclusioncomplexwithHP-β-CDhasbeenshowntobeaneffectivemethodtoincreasethesolubilityandbioavailabilityofrhein,thusimprovingitspharmacologicalproperties.Theinclusioncomplexiseasilypreparedandisstable,makingitapromisingdrugformulationforfurtherdevelopment.

However,therearestilllimitationsandchallengesinusingtherhein-HP-β-CDinclusioncomplexasacholereticdrug.Thepotentialtoxicityandsideeffectsofthiscomplexstillneedtobefurtherinvestigated,anditsoptimaldosageandadministrationrouteneedtobedetermined.Moreover,therhein-HP-β-CDinclusioncomplexneedstobecomparedwithotherrheinformulationstoevaluateitsadvantagesanddisadvantagesinclinicalapplications.

Despitethesechallenges,theinclusioncomplexofrheinandHP-β-CDprovidesapromisingdrugformulationwithincreasedsolubilityandbioavailability.ItisexpectedthatthedevelopmentofnewdrugformulationsbasedoninclusioncomplexeswillrevolutionizethetreatmentofvariousdiseasesinthefutureOnepotentialapplicationofinclusioncomplexesisinthefieldofcancertherapy.Paclitaxelisawidelyusedchemotherapeuticagentforthetreatmentofvariouscancers,includingbreast,ovarian,andlungcancer.However,paclitaxelhaspoorsolubilityandashorthalf-lifeinvivo,whichlimitsitsclinicalefficacy.Toovercometheselimitations,variouspaclitaxelformulationsbasedoninclusioncomplexeshavebeendeveloped.

OnesuchformulationisAbraxane,whichconsistsofpaclitaxelencapsulatedinhumanserumalbuminnanoparticles.Abraxanehasbeenshowntohaveincreasedsolubility,improvedpharmacokinetics,andreducedtoxicitycomparedtoconventionalpaclitaxelformulations.Asaresult,AbraxanehasbeenapprovedbytheFDAforthetreatmentofbreastandnon-smallcelllungcancer.

Inadditiontocancertherapy,inclusioncomplexeshavealsobeenexploredforthetreatmentofotherdiseases,suchascardiovasculardiseaseandneurologicaldisorders.Forexample,azelnidipine,acalciumchannelblockerusedtotreathypertension,haspoorwatersolubilityandlowbioavailability.However,inclusioncomplexationwithhydroxypropyl-β-cyclodextrinhasbeenshowntoincreasethesolubilityandbioavailabilityofazelnidipine,resultinginimprovedantihypertensiveactivity.

Similarly,donepezilisacholinesteraseinhibitorusedforthetreatmentofAlzheimer'sdisease.However,donepezilhaspoorsolubilityandashorthalf-lifeinvivo,whichlimitsitsclinicalefficacy.Toovercometheselimitations,severaldonepezilformulationsbasedoninclusioncomplexeshavebeendeveloped,suchasdonepezilhydrochloride-loadedliposomesanddonepezil-hydroxypropyl-β-cyclodextrininclusioncomplexes.Theseformulationshaveshownimprovedsolubility,pharmacokinetics,andtherapeuticefficacycomparedtoconventionaldonepezilf