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PolyoxyethylatednonionicsurfactantsandtheirapplicationsintopicaloculardrugdeliveryJimJiaoPfizerGlobalResearchandDevelopment,PfizerInc.,EasternPointRoad,Groton,CT,06340,USA聚氧乙烯非离子型表面活性剂及其在眼睛局部给药制剂中的应用吉姆娇美国康涅狄格州格鲁顿东点路，辉瑞公司全球研究开发中心，06340AbstractTopicaldosingofophthalmicdrugstotheeyeisawidelyacceptedrouteofadministrationbecauseofconvenience,easeofuse,andnon-invasiveness.However,ithasbeenwellrecognizedthattopicaloculardeliveryenduresalowbioavailabilityduetotheanatomicalandphysiologicalconstraintsoftheeyewhichlimitdrugabsorptionfromthepre-cornealsurface.Nonionicsurfactantsasversatilefunctionalagentsintopicaloculardrugdeliverysystemsareuniquelysuitedtomeetthechallengesthroughtheirpotentialabilitytoincreasebioavailabilitybyincreasingdrugsolubility,prolongingpre-cornealretention,andenhancingpermeability.Thisreviewattemptstoplaceinperspectivetheimportanceofpolyoxyethylatednonionicsurfactantsinthedesignanddevelopmentoftopicaloculardrugdeliverysystemsbyassessingtheircompatibilitywithcommonophthalmicinactiveingredients,theirimpactonproductstability,andtheirrolesinfacilitatingoculardrugstoreachthetargetsites.摘要向眼睛输送局部剂量的眼科药物，由于方便，易操作及无创伤性，被大家广泛采用。然而，现在已充分认识到，由于解剖和生理方面的构造，限制了药物在眼睛前角膜表面的吸收，眼睛局部给药制剂存在生物利用度低的缺点。眼睛局部给药制剂中的非离子表面活性剂作为通用功能成分特别适合用来克服这一难点，他们通过增加药物的溶解度，延长在前角膜的保留时间和增加渗透性，从而能潜在地提高药物的生物利用度。本文试图从聚氧乙烯非离子型表面活性剂在眼睛局部给药制剂的设计和开发中的重要性这一角度进行阐述，评估了聚氧乙烯非离子型表面活性剂和药物中其他非活性组分的兼容性，它们对产品的稳定性影响，以及它们在促进药物到达病灶的作用。Polyoxyethylatednonionicsurfactant;Surfaceactiveagent;Micelle;Solubility;Oculartopicaldrugdelivery;Permeability关键词：聚氧乙烯非离子表面活性剂、表面活性剂、胶束、溶解性、眼局部给药、渗透性1.IntroductionInthepastdecadenonionicsurfactantshavefoundincreasingapplicationsinpharmaceuticalpreparationsduetotheimplementationofhighthroughputtechniquesforscreeningnewcompoundsforpharmacologicalactivity.Thehighthroughputhasproducedalargenumberofnewtherapeuticcandidateswithpooraqueoussolubility[1].Thesepoorlywatersolublecandidates,categorizedasclassIIorIVcompoundsaccordingtothebiopharmaceuticalclassificationscheme(BCS)[2],imposeasignificantchallengeforscientistsindrugdevelopmenttoprovideeffectivedeliverysystems.SeveralapproachesutilizingnonionicsurfactantstoincreasethebioavailabilityoftheBCSII/IVcompoundsandtherebytheefficacyofthedrugshaveincreasinglybeentakensuchaslipidbaseddeliverysystems,drug-polymeramorphousdispersions,andparticlesizereduction[3].1。引言在过去的十年中，由于药物高通量筛选技术的应用，非离子表面活性剂在药物制剂中的应用越来越广泛。高通量筛选技术筛选出了大量有生物活性但是水溶性却很差的候选药物[1]。根据生物制药的分类方案（BCS），这些水溶性差的候选药物被归类为II类或IV类化合物[2]，它们对药物开发中负责提供有效输送系统的科学家来说，形成了一个重大的挑战。越来越多通过使用非离子表面活性剂，增加BCS第II/IV族化合物的生物利用度，由此提高药物疗效的方法被采用，比如脂质为基础的交付系统，药物-聚合物非晶形分散体以及减小药物颗粒尺寸。Pooraqueoussolubilityofcompoundsaffectspharmaceuticalproductdevelopmentinnearlyalltherapeuticareasincludingophthalmology.Despitetheaccessibilityofthefrontoftheeye,efficientdeliveryofdrugtotreatvariousoculardisordersisachallengetotheformulationscientistinadditiontotheoftenlowdrugsolubility.Themajorityofophthalmicmedicationsareformulatedaseyedropsdeliveredtopicallytotheeye.Duetoanatomicalconstraints,thevolumethatcanbeadministeredislimitedtoapproximately30μL.This,togetherwiththeefficientclearancesystemthatexistsinthefrontoftheeye,makesitdifficulttomaintainaneffectivepre-oculardrugconcentrationforadesiredlengthoftime[4].Thebioavailabilityofeyedropsistypicallylessthan5%inspiteoffrequentinstillations.在包括眼科的几乎所有治疗领域，水溶性差的化合物会影响医药产品的开发。尽管很容易接近眼睛的前面部位，但有效地传递药物来治疗各种眼疾对制剂学家来说仍然是个挑战，更不用说药物常常具有低的溶解度。由于解剖学上的限制，可以给药的体积是有限的，约30μL。加上眼睛前部存在有效清理外来物的系统，使得进入眼中的药物难以维持一个有效的浓度，以及所希望的保留时间[4]。因此尽管频繁滴注，眼药水的生物利用度通常小于5％。Variousformulationstrategieshavebeenusedtoincreaseaqueoussolubilityofactivepharmaceuticalingredientsandpre-ocularretentionofeyedrops.Themostsuccessfulofthesehasbeentheinclusionofpolymericsurfaceactiveagents,particularlythoseabletoundergoatransitionfromasolutiontoagelundertheconditionsofthepre-ocularareaandthosethatcaninteractwiththemucouslayerontheeyesurface.Differentdosageformsincludingmicellarsystems,emulsions,liposomes,andnanosizedsuspensionswhichgenerallyrequirethepresenceofsurfaceactiveagentshavealsobeenreportedtobeusefultoovercomeinsufficientdrugsolubilityandincreaseefficiencyofdrugdelivery,especiallywhenthetargetsiteisintro-ocular.各种制作制剂的策略已经被用来增加药物活性成分的水溶解性和眼药水在眼角膜上的停留时间。最成功的方法包括使用聚合物表面活性剂，特别是那些能经受住眼角膜清理外来物系统以及能与眼睛粘膜层表面交互作用的活性剂，把药物从水溶液转变成凝胶的方法。不同的剂型包括胶束系统，乳剂，脂质体，和纳米尺寸的悬浮液，这些一般需要含表面活性剂成分。也有报道，这些制剂能有效克服药物的溶解度不足，增加药物输送的效率，特别是当病灶位于眼球内部时。Nonionicsurfactantsarethemajortypeofsurfaceactiveagentsusedinophthalmicdeliverysystemssincetheiradvantageswithrespecttocompatibility,stability,andtoxicityarequitesignificantcomparedtothecationic,anionic,oramphotericcounterparts[5]and[6].Theyaregenerallylesstoxic,lesshemolytic,andlessirritatingtotheocularsurface,andtendtomaintainnearphysiologicalpHvalueswheninsolution.Thenonionicmoleculesarecomprisedofbothpolarandnon-polarsegments,possessingabroadrangeofinterfacialactivityandversatilefunctionsaswettingagents,emulsifiers,solubilizers,ocularpermeabilityenhancers,andinsomecasesP-glycoproteininhibitors.非离子型表面活性剂是药科药物输送系统里表面活性剂的主要类型，与阳离子，阴离子，或两性离子活性剂同行相比[5]和[6]，