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##*高云华(中国科学院理化技术研究所,北京010101)由于皮肤的屏障作用使大部分药物无法以透皮给药方式达到治疗效果最近几年一种用于提高药物经皮渗透性的微针透皮给药技术被开发出来,此技术结合皮下注射与透皮贴片的双重释药优点,透皮贴片上有数十至数百枚微针,贴于皮肤可增加药物的渗透性,特别是对于大分子药物如多肽蛋白和疫苗等经皮渗透性显著提高,能够达到治疗效果本文重点介绍了国内外微针透皮给药系统的开发现状,特别是体内外研究和临床研究成果:微针;经皮给药系统;外治法;进展:R965.2:A:1006-978X(2005)03-0003-051(TransdermalDrugDeliverySystem,TDDS)(TransdermalTherapeuticSystem,TTS)[1],,1981AlzaCiba(TransdermalScop),2003,,,9[2],,(TransdermScop,)(Catapress-TDDS,)(Nitro-Dur,)(FrandorTape,)(Estradio,l)(Eastragest,)(Duragesic,)(Habito,l)(Testoderm,)[3-6]:/0;;;;;,TDDS,(,10Lm~25Lm),,,,[7]:20mg,10h,500,200e,-(logK)-1~4,*本项目获国家/8630计划MEMS重大专项支持(编号:2003AA404170)2005年获国家/8630计划滚动支持(编号:2005AA404010),[8],,[9]2,,()()[10]()[11][12-13],()[14]()[15](,)[16](,)[17]1(passivedrug-in-adhesive(DIA)transdermalpatches)(Ionto-phoresis)(Sonophoresis)(Micropora-tion)(,),,1TDD[18]LogP(e)(mg/day)PassiveDIA500U215010Gel500U215020Iontophoresis20Sonophoresis20Microporation30/#3#200561432,,(Jetinjection),,,,,,,2//xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx:X:,XX:,XXX:,,,,,,,31(请参阅封三),(),(),1998Herry[19],2(请参阅封三),,3(请参阅封三),,150Lm,3mm@3mm400,,[20]150Lm,100,,10~38,2,,,,,,:,500Lm,,[21]44.1体外透皮给药研究,,,,,,Henry[19](),150Lm,0.0915cm2400Franz,37e(PBS),(BSA)25nm50nm,BSA,,,(623)1000,10s,10000,1h,25000,Jung-HwanPark[22]PLGA,440Lm,,4h95%,120h80%(4)4p,u(请参阅封三图5)[23],(0.1mM,1mL)(416Da)(623Da)A-2a(17000Da)(18000Da)#4#JournalofExternalTherapyofTCMJun2005,14(3)(48000Da)(66000Da)A(150000Da)(1000000Da)6SD,,,,1.6cm/h2@10-5cm/h,100000A-2a(17000Da)(18000Da)(48000Da)(66000Da)A(150000Da)(1000000Da),10-2cm/h,,7000Da[24],,(48000Da)(6000Da)9.8@10-6cm/h3.3@10-3cm/h[25],6?从左到右依次为葛根素(416Da)钙黄绿素(623Da)A-2a干扰素(17000Da)重组人肿瘤坏死因子(18000Da)重组人红细胞生成素(48000Da)牛血清蛋白(66000Da)A型肉毒毒素(150000Da)和重组酵母乙肝疫苗(1000000Da)4.2动物体内透皮研究4.2.1ALZAALZA(2001622),1981ALZA(TransdermalScop),90,Mac-roflux,7(请参阅封三)(micropro-jectionarray),(patchappl-icator)ALZA,500Lm,8cm2,2cm24.2.1.1[26]Macroflux20-mer430Lm,2cm2480,,,,100;,,700Lm~800Lm16mg/d,4.2.1.2Matriano[27]330Lm,1cm22cm2,190/cm2,100Lm,300Lm,5s20Lg,50desmopressin[28]MichelCormierMacrofluxm,2cm2desmopressin,5min~15min,desmopressin85%,30%,desmopressin60min,(IV),4.2.2BDDNABD(Becton,DickinsonandCompany),,50Lm~200Lm,1cm2Mikszta[29]DNADNA,2800DNA,,#5#20056143DNA4.2.3GeorgiaTechGeorgiaTechMRPrausnitz[30-31],,[32],,90b105,1000Lm,75Lm@200Lm,(请参阅封三图9),4h,80%()4.2.4(请参阅封三图5),(Chitosan),,,10(66000Da),a,24h,b,,,24h,,24h30%,,,A-1b(300bp+5400bp),,10200Lm,130Lm,,,4.3临床研究ALZATheratechnologies,[33]11(请参阅封三图11)(hPTH(1-34)OH),200Lm,40LgMacroflux,10(FITC-BSA)(n=3)(,24h)a,b3M,(MTS),MacrofluxMTS5,,20,,,,:[1].[M]..:,1992:1.[2]GaryWC,EmilieBeskar.TransdermalandTransdermal-likeDeliverySystemOpportunitiesa[J],BusinessBriefing:Pharmatech,2004,p:1-6.[3]AkimotoT,NagaseY.Noveltransdermaldrugpenetrationenhancer:synthesisandenhancingeffectofalkyldisiloxanecompoundscontainingglucopyranosylgroup[J].JControlRe,l2003,88:243-252.[4]TakanashiY,HigashiyamaK,KomiyaH,eta.lThiom-entholderivativesasnovelpercutaneousabsorptionenhanc-ers[J].DrugDevIndPharm,1999,25:89-94.[5]WilliamsAC,BarryBW.Skinabsorptionenhancers[J].CritRevTherDrugCarrierSyst,1992,9:305-253.[6]CevcG..Transfersomes,liposomesandotherlipidsuspen-sionsontheskin:permeationenhancement,vesiclepenetra-#6#JournalofExternalTherapyofTCMJun2005,14(3)tion,andtransdermaldrugdelivery[J].CritRevTherDrugCarrierSyst,1996,13:257-388.[7]OngpipattnakulB,BurnetteRR,PottsRO,eta.lEvidencethatoleicacidexistsinaseparatephasewithinstratumcor-neumlipids[J].PharmRes,1991,8:350-354.[8]FininBC,MorganTM.Transdermalpenetrationenhancers:applications,limitations,andpotential[J].JPharmSci,1999,88:955-958.[9]CostelloCT,JeskeAH.Iontophoresis:applicationsintransdermalmedicationdelivery[J].PhysTher,1995,75:554-563.[10]KaliaYN,NaikA,GarrisonJ,eta.lIontophoreticdrugdelivery[J].AdvDrugDelivRev,2004,56(5):619-658.[11]MitragotriS,KostJ.Low-frequencysonophoresis:Are-view[J].AdvDrugDelivRev,2004,56(5):589-601.[12]PrausnizMR,MitragotriS,LangerR.Currentstatusandfuturepotentialoftransdermaldrugdelivery[J].NatureReviews,drugdiscovery,2004,3:115-124.[13]PrausnitzMR.Reversibleskinpermeabilisationfortrans-dermaldeliveryofmacromolecules[J].Crit.Rev.TherDrugCarSyst,1997,14:455-483.[14]PrausnitzMR,EdelmanER,GimmJA,eta.lTransder-maldeliveryofheparinbyskinelectroporation.Biotechnolo-gy,1995,(13):1205-1209.[15]PartidosCD.Deliveringvaccinesintotheskinwithoutnee-dlesandsyringes[J],ExpertReviewofVaccines,2003,2(6):753-761.[16]AmsdenBG,GoosenMFA.Transdermaldeliveryofpep-tideandproteindrugs:anoverview[J].AIChEJ,1995,(41):1972-1997.[17]FangJY,LeeWR,ShenSC,eta.lTransdermaldeliveryofmacromoleculesbyerbium:YAGlaser[J].J.Contro.lRelease(inpress).[18]GordonRD,PetersonTA.MythsAboutTransdermalDrugDelivery[J],MSDrugDeliveryTechnology,2003,3(4)1-7.[19]HenryS,McAllisterDV,AllenMG.MicrofabricatedM-icroneedles:ANovelApproachtoTransdermalDrugDeliver-y[J].JournalofPharmaceuticalSciences,1998,87(8):922-925.[20]KaushikS,HordAH,DensonDD,eta.lLackofpainas-sociatedwithmicrofabricatedmicroneedles[J],Anesth.Analg.2001,(