大黄酚-羟丙基-β-环糊精包合物的制备及药代动力学研究

大黄酚—羟丙基-β-环糊精包合物的制备及药代动力学研究摘要：

目的：本研究旨在制备大黄酚—羟丙基-β-环糊精包合物，并探究其药代动力学特性。

方法：采用溶剂辅助热力学法制备大黄酚—羟丙基-β-环糊精包合物，并通过XRD、FTIR、TG等手段对其进行表征。将包合物与一般大黄酚进行体外药代动力学研究，比较两者在自然介质中的溶解性、血清蛋白结合率、血浆半衰期等参数。

结果：制备的大黄酚—羟丙基-β-环糊精包合物具有明显的结晶性和分散性。与一般大黄酚相比，其溶解性大幅提高，血清蛋白结合率显著降低，血浆半衰期延长。

结论：大黄酚—羟丙基-β-环糊精包合物能够显著提高大黄酚的溶解性，降低其蛋白结合率，具有良好的生物利用度和药效，可作为一种潜在的疏通胆道药物。

关键词：大黄酚，羟丙基-β-环糊精，包合物，药代动力学，溶解度，血清蛋白结合率，血浆半衰期

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