[生物医药论文精品]冰片-薄荷脑低共熔物对纳米粒鼻腔给药载药入脑的影响

1冰片薄荷脑低共熔物对纳米粒鼻腔给药载药入脑的影响摘要目的考察中药冰片薄荷脑低共熔物对神经毒素纳米粒鼻腔给药吸收入脑的影响。方法采用125I同位素标记法，以清醒自由活动大鼠为实验模型，运用脑微透析取样技术，测定脑内神经毒素浓度的变化，并应用药动学软件计算药动学参数。结果中药冰片薄荷脑低共熔物纳米粒脑药动学符合二室模型，TMAX、CMAX、AUC、T1/2A1分别为068H、2732NG/ML、13268NGH/ML、31076H，其入脑的速度与程度均优于单用薄荷脑或者冰片。结论神经毒素纳米粒在冰片薄荷脑低共熔物作用下，可显著增加其鼻腔吸收入脑的药量，且能较快达到峰浓度，消除缓慢。关键词冰片薄荷脑低共熔物纳米粒鼻腔给药脑药动学EFFECTOFBORNEOL/MENTHOLUMEUTECTICMIXTUREONNASALBRAINDELIVERYOFNEUROTOXINLOADEDNANOPARTICLESABSTRACTOBJECTIVETOINVESTIGATETHEABSORPTIONENHANCENEFFECTOFBORNEOL/MENTHOLUMEUTECTICMIXTUREBO/MEONNASALBRAINDELIVERYOFNEUROTOXINLOADEDNANOPARTICLESMETHODSUSINGMICRODIALYSISSAMPLINGTECHNIQUEINAWAKEFREELYMOVINGRATS,THECOUNTERPERMINUTECPMOFDIALYSATESINRIGHTPAGOFNTLOADEDNANOPARTICLESWITHTHEBO/MEBO/MENTNP,RADIOLABELEDWITHSODIUM125IIODIDE,WEREMEASUREDINAGAMMACOUNTERFORRADIOACTIVITYAFTERCONVERTINGCPMINTOCORRESPONDINGCONCENTRATIONSOFNTBYINVIVORECOVERYOFMICRODIALYSISPROBES,THEPHARMACOKINETICPARAMETERSWERECALCULATEDRESULTSTHEBO/MENTNPCOULDBEABSORBEDINTOTHEBRAIN,MUCHBETTERTONTNPANDTHENANOPARTICLESWITHBORNEOLORMENTHOLUMONLY,ANDTHEPHARMACOKINETICSACCORDEDWITHTHETWOCOMPARTMENTMODELTHEPARAMETERSTMAX,CMAX,AUC,T1/2WERE068H,2732NG/ML,13268NGH/ML,31076HCONCLUSIONWITHADDINGBO/MEASABSORPTIONENHANCER,NTCOULDBESIGNIFICANTLYINCREASEDINTHEBRAINWITHTHEHELPOFNANOPARTILCESASCARRIERS,ANDTHETIMETOMAXIMALCONCENTRATIONWASSHORT,THEELIMINATIONPROCESSWASPROLONGED2KEYWORDSBORNEL/MENTHOLUMEUTECTICMIXTURENANOPARTICLESINTRANASALADMINISTERATIONBRAINPHARMACOKINETIC纳米药物载体系统具有靶向、缓释、保护药物等G3822G18337作用。G2081G7411实验G15932G713812纳米粒作为神经毒素G708NEUROTOXIN，NTG709的载体，G7094能保G6357药物的活G5627，G2460能增加药物的脑内G2559量。G1032G5214G990，NTG1039G16213的给药G7053G5347为G13920内G8892G45683，G1306G17227G6940慢G7083G7945HG709，G19602以G9397G17287G1032G5214G16213G8726。鼻腔给药G7171G17829G5192G7481G11752G12362较G3822的有G7407G6116为G3822G13969G12879药物G8892G4568给药G7379G1207G17896G5464的G7044型药物G1268G17767系统G1055G98045。G1306鼻腔G21667G14192吸收能G2159有G19492且清除较快，为G1114G6564G20652NT的G10995物G2045用度，G5529G20047加入吸收G1431G17839G2070。冰片G2656薄荷脑G7171G17829G5192G7481G11752G12362较G3822的中药吸收G1431G17839G2070。冰片具有G256G14471G20333G17220G12400，G5353药G990G15904G257G1055G6940，能有G6940G6925G2904鼻G21667G14192与BBB的G17902透G5627，G6564G20652药物脑内浓度67。薄荷脑具有较G5390的G1431G9195作用，对G8712G7484G18252等G3822G12193药物具有G14403G3921作用8。G4570冰片、薄荷脑G2058G6116低共熔G9163合物可以显著增加G1431G9195作用，G6564G20652药物G11115G6940，G1955G4581药物用量。G7424G16850G20076G13464G2081G7411G5049作中G2058G3803G1114体G3818G5627G17148G14403G3921的神经毒素纳米粒G727G5326G12447G1114以微透析技术为G5191G2500，测定脑内药物变化的G7053法。为中药吸收G1431G17839G2070的G12591G17885与考察G3892定G1114G14403G3921的G3534G11796。1G7460G702111药G2709与G16809G2070神经毒素中G3281G12197学G19510G7130G7138动物G11752G12362G6164G15515毒G11752G12362中G5527G708G13443度99G705，MW6700G709G727125INTG708138G/L199G104108BQG13443度大于99,标记G1058797G709G3809G7098大学药学G19510G6930G4568药学G6957G11752室协助标记G2656检测G727聚乳G18252G708PLAG709瑞士FLUKA公司G708MW250000G727批号WA18975G709G727冰片SIGMA公司G708G13443度980G727批号464437G709G727薄荷脑SIGMA公司G708G13443度985，批号89781G709。12仪器SN695B型智能G6930免测量仪G990海原子核G11752G12362G6164日环仪器G980厂G727微透析脑G12447体定位仪美G3281BAS公司G727微透析探针MD2200，G3818G546405MM，G14192长2MM，截留分子量为38KDAG727采用自G2058鼻腔给药装置专G2045G708专G2045号ZL2005200135255G709。13实验动物3SD大鼠，雄G5627，体G1833732020G，由浙江大学医学G19510动物实验中G5527G6564供。2G7053法21神经毒素纳米粒的G2058G3803采用实验室已优化的G2058G3803G7053法，大致如下称取50MGPLA溶于10ML乙G18252乙酯中，加入50L冰片薄荷脑低共熔物G708BO/MEG709G708冰片G13464加等量冰片、薄荷脑G13464加等量薄荷脑、空白G13464不加G709，形G6116有机相G708OG709，再G457050L10MG/ML的NTG8712溶液G708W1G709加入到有机相中，涡旋乳化30S形G6116初乳溶液G708W1/OG709，G45702ML05W/V胆G18252钠G8712溶液加入到初乳溶液，冰浴下探头超声乳化36SG70890WG709得G3809乳溶液G708W1/O/W2G709，G3809乳分散到100ML05G705G708W/VG709泊洛沙姆G708PLURONIC，F68G709G8712溶液中，并在真空条件下，旋转蒸发除去有机溶G2070，最后40000RPM/MIN超速离G552730MIN，冻干即得BO/MENTNP。22大鼠脑微透析手术如LI等910G6164述，大致G7053法如下SD大鼠戊巴比妥钠G70845MG/KGG709腹腔G8892G4568麻醉，固定于脑G12447体定位仪G990。按大鼠脑图谱，确定PAG部位G708G2081囟后7MM，脑G15932面下5MM，中线旁开08MMG709，G4570脑微透析探针埋植于右侧PAG腹G3818侧中，固定探针，缝合。术后五天不予实验，G4570大鼠G6930置于标准环境G708温度222G727相对湿度6010G705G727昼夜12H人G5049交G7379G727自由饮食G2656饮G8712G709中G10995活，作为大鼠手术后G10995理恢G3809阶段。实验G208124小时禁食G1306可自由饮G8712，并用G20293G2656G11884化G19090溶液G9760G13975G708100MG/KGG709以G20293G2656G11014G10378G14158。实验G13479G7475后，G10481G8527大鼠，对大脑G17839G15904G1931冻G2011片G16278察针G17959，位置不G8503者，G16825G13464数G6466G5335去。23脑微透析探针在体G3250收G10587的测定G7693G6466G7003G1049811，采用G2465G9195透法测定脑微透析探针在体G3250收G10587。取微透析手术G4448G6116恢G3809后的SD大鼠，戊巴比妥钠G70845MG/KGG709腹腔G8892G4568麻醉，G1475G10378固定于大鼠实验G7507G990，取G1998G12661G5527针，G4570微透析探针G6566入微透析G5225G5243中，在大鼠PAG部位用G2559G989G121935NG/ML，25NG/ML，50NG/MLG989G12193不同浓度的125INT的G9760G8981液G9760G8981，G8981量为2L/MIN，收G19610G19400G19560时G19400为15MIN，G5647时G1940015H。G12544G980G8437G2656最后G980G8437收G19610的透析液不作参考。G8611G1022收G19610时G19400G9869的透析液的125INT的浓度测G980G8437。在体内G2465透析G17819程中，由于125INT在脑G13464G13467中具有较G20652的G6205散能G2159，G6164以G1563G16786探针G2620G3272脑G13464G13467G19400液G708BRAININTERSTITIALFLUID，BIFG709中的NT浓度为G19658G708CBIF0G709。4体内G3250收G10587计算公G5347G3250收G10587G729G708CDIALYSATECPERFUSATEG709/CBIFCPERFUSATE24纳米粒鼻腔给药脑药动学实验取SD雄G5627大鼠20G2494，G19555机分G6116G3247G13464G17839G15904鼻腔给药G9167加冰片/薄荷脑低共熔G9163合物吸收G1431G17839G2070的神经毒素纳米粒G708NTNPG16G265G709、不G9167加吸收G1431G17839G2070的神经毒素纳米粒G708NTNPG16G266G709、单G10432G9167加冰片吸收G1431G17839G2070的神经毒素纳米粒G708NTNPG16G267G709、单G10432G9167加薄荷脑吸收G1431G17839G2070的神经毒素纳米粒G708NTNPG16G268G709G708G8611G2494大鼠给药相G5415于NT60G22037G/KG，冰片011MG/KG，薄荷脑038MG/KGG709。实验时G4570微透析探针植入微透析G5225G5243，探针G17902G17819PEG12661与微量G8905相G17842，30MIN后，向探针内G9760G8892人G5049脑G14046液，G8981速2G22037G47G18G80G76G81。G5191G15925G22G19G80G76G81后G17839G15904鼻腔给药。于给药后G8611G1956015MIN收G19610G980G8437透析液，采用自动G5670温G708G7134G709G1931冻收G19610器G17842G13505收G196105小时，置于收G19610样G2709的专用小G16809G12661中，并置于4冰G12677中保G4396，G5465测G6930G4568G5627G5390度G708CPMG709，并G6252算G6116NT实G19481浓度。G2045用体内G3250收G10587G7669G8503G1552得到G2520时G19400G9869NT实G19481浓度，并用药动学软件计算G2520参数。3G13479G753631神经毒素纳米粒的G2058G3803G6164得纳米粒大小均G980、G15932面G1821G9381，G5191均粒G5464为1068NM，ZETAG11017位G7132840MV，G2265G4565G10587为7060，载药量801G705。32脑微透析探针在体G3250收G10587脑微透析探针G6566入PAG部位，125INT的G5191均体内G3250收G10587G708G1014G3845G709为126G708SDG17G20G17G21G8G709。NT的体内G3250收G10587G708G1014G3845G709用于透析部位PAG的透析液中的实G19481药物浓度的G7669G8503。33纳米粒鼻腔给药脑内药物动G2159学不同吸收G1431G17839G2070NT纳米粒经大鼠鼻腔给药后G5191均脑内药物浓度时G19400G7366线G16277图1，PAG中NT的动G2159学G17819程符合二室模型，药动学参数G16277G159321。505101520253035000050100150200250300350400450500TIMEHCONCOFNTNG/MLNTNPSA0NTNPSA2NTNPSA3NTNPSA4图1G3247G12193药物G2058G2070鼻G21667G14192给药后脑内PAG部位药动学比较G708N5G709A5A6NTNPA7A6A8A9BO/MEA10A11A12A13A14A15NTNPA16NTNPA17A18A19A20A21A10A11A12A13A14A15NTNPA16NTNPA22A18A23A24A20A21BOA10A11A12A13A14A15NTNPA16NTNPA25A18A23A24A20A21MEA10A11A12A13A14A15NTNPFIG1PHARMACOKINETICSCOMPARISONOFPAGPOSITIONINBRAINAFTERNASALADMINISTRATIONBYFOURPHARMACEUTICALPREPARATIONG708N5G709ATTENTIONA18NTNPA26A18NTNPADDEDTHEABSORPTIONENHANCERBO/MEG727NTNPA17A18NTNPG727NTNPA22A18NTNPADDEDTHEABSORPTIONENHANCERBOG727NTNPA25A18NTNPADDEDTHEABSORPTIONENHANCERMEG159321药动参数G13479G7536N5TABLE1RESULTOFPHARMACOKINETICPARAMETERSN5PARAMETERSNTNPA26NTNPA17NTNPA22NTNPA256KAA271/HA2841858100792895329086A29A271/HA2805391041862930029079A30A271/HA2802230026790374204016T1/2A31H12857165570236602384T1/2A32H31076258701852217258T1/2A33A34H01656068780239402383K21A271/HA2804819039452976729074K10A271/HA2802495028430368404017K12A271/HA2800307000770040900004AUC05HNA35H/ML13268265766335205TMAXH068174082079CMAXNG/ML273245318271522由G13479G7536可G11705，G9167加中药吸收G1431G17839G2070G708低共熔物、冰片或薄荷G709的纳米粒可显著增加NT入脑的程度与速度，G13792应用冰片薄荷脑低共熔物G2029显著优于单G13443应用冰片或者薄荷脑。4G16764G16782G1823G7393G15892脑G4643G19568，实G10628脑靶向的G7053法G5468G38221214，如加入吸收G1431G17839G2070，如冰片、G3783聚G12970、G3822聚G12946G8700G18252G727G6925变G2070型，如载药纳米粒、微G10711G727G6925变给药G7053G5347，如鼻腔给药15等。实验室G2081G7411G5049作G6116G7536G15932G7138，单G10432G1363用NT鼻腔给药后，NTG1972G1058不能入脑吸收，G13792G4570NTG2058G6116纳米G2058G2070，实验G13479G7536NTNPSG266能G1363药物透G17819G15892脑G4643G19568入脑，并具有G980定G3332缓释作用。G1306G7171NT吸收量较G4581，G1032G5214用药G2070量较大。G7424G16850G20076采用中药吸收G1431G17839G2070G1474G20292纳米粒G17839G15904鼻腔给药，不G1177能G3827G1431G17839药物G17340G15892脑G4643G19568，且能增加神经毒素体内的稳定G5627。实验G13479G7536证G7138，G9167加冰片薄荷脑低共熔G9163G2656物的神经毒素纳米粒G13464能显著缩短达峰时G19400，升G20652AUCG1552，延长体循环时G19400。其原因可能G7171BO/ME延长药物在鼻腔中的滞留时G19400，G1431G17839药物的鼻G21667G14192吸收G727也可能G7171BO/ME打开BBB紧密G13479构，G1431G17839药物吸收入脑，从G13792G6564G20652脑内药物G2559量G727也可能G7171G990述原因的共同作用。7G5647G1055，G17902G17819中药G14471G20333G12879物G17148联合G1363用纳米药物载体系统能G3827显著G6564G20652蛋白G3822G13969G12879药物的脑内G2559量，为中枢神经系统疾病的治G11115G6564供G1114G7044的思路，具有G5468大的发展G2081景。G1306G7171G10628阶段中药吸收G1431G17839G2070与纳米G2058G2070G13479合G11752G12362较G4581，冰片薄荷脑低共熔物G1431G17839药物入脑的机G2058，以及如何G12591G17885更G3921的吸收G1431G17839G2070都有G5465G17839G980步G11752G12362。REFERENCES1CHENGQY,LIFZBRAINPHARMACOKINETICSOFNT1LOADEDNANOPARTICLESAFTERINTRANASALADMINISTRATIONINRATSJJCHINAPHARMUNIV中G3281药G12197大学学报,2007,38177792CHENGQY,LIFZPREPARATIONOFNEUROTOXININANOPARTICLESANDPHARMACOKINETICEVALUATIONAFTERINTRANASALADMINISTRATIONINRATSJCHINJPHARM中G3281医药G5049业杂志,2007,389636637,6613QIUMINL，QINGXM，DONGSHENGL，ETALCOMPARATIVESTUDYOFTHREESHORTCHAINNEUROTOXINSFROMTHEVENOMOFNAJAKAOUTHIAYUNNAN，CHINAJJNATTOXINS，2002，1132212294ILLUMLNASALDRUGDELIVERYPOSSIBILITIES,PROBLEMSANDSOLUTIONSJJCONTROLRELEAS,2003,87131871985ILLUMITRANSPORTOFDRUGSFROMTHENASALCAVITYTOTHECENTRALNERVOUSSYSTEMJEURJPHARMSCI,2000,1111126ZHAOBS,LIUQCOMPARISONBETWEENBORNEOLINDUCEDOPENINGOFBLOODBRAINBARRIERANDITSPATHOLOGICALOPENINGJTRADITCHINDRUGRESPHARMACOL中药G7044药与G1032G5214药理,2002,1352872907CHENXM,ZHUJB,SUNWD,ETALEFFECTOFABSORPTIONENHANCEROFBORNEOLONGINSENOSIDE