[生物医药论文精品]脂质体电动色谱用于评价药物透皮吸收

脂质体电动色谱用于评价药物透皮吸收A1A0A0A3A3A4A2A4A2A5A6A7A8A9A10A11A12A13A14A15A16A17A18A19A20A21A22A23A24A25A26A27A28A27A28A29A3022A31A32A33A34A35A36A37A38A39A40A41A42A43KA44A45A46A47A48A49A50A51A52A53A38A54A55A56A57LOGKPA58LOGKA59A60A61A62A63A64A36A56A57A65A66A67A68A30A69A40A41A70A71A72A73QUANTITATIVERETENTIONACTIVITYRELATIONSHIPS,QRARSA26A74A75A74A75A67A68A76A53A38A54A55A56A57LOGKPA58LOGKA77A78A43A69A77A36A37A38OHA77NHA79A57A80A65A58A65A66A39A81A72A82A83A44A81A72A73A57R20902A26A74A84A85A86A87A88A89A90A91A52A92A29A53A38A54A55A73A57A82A93A94A95A76A96A97A39A98A46A99A100A26A101A102A103A104A85A86A87A105A88A89A90A91A105A54A55A56A57A105A47A48A49A50PREDICTINGSKINPERMEABILITYUSINGLIPOSOMEELECTROKINETICCHROMATOGRPPHYABSTRACTOBJECTIVETOESTIMATEDRUGPENETRATIONTHROUGHSKINUSINGLIPOSOMEELECTROKINETICCHROMATOGRAPHYMETHODSTHERETENTIONFACTOROFTWENTYTWOSTRUCTUREDIVERSELYCOMPOUNDSWEREDETERMINED,QUANTITATIVERETENTIONACTIVITYRELATIONSHIPSWERECONSTRUCTEDBETWEENSKINPERMEATIONCOEFFICIENTSANDLOGKANDOTHERPHYSICOCHEMICALPARAMETERSBYSTEPWISEREGRESSIONMETHODRESULTSAQUANTITATIVERETENTIONACTIVITYRELATIONSHIPSQRARSWASCONSTRUCTEDBETWEENCOMPOUNDSKINPERMEABILITYCOEFFICIENTLOGKPANDLOGK,MOLECULARWEIGHT,THECOUNTSOFOHANDNHOFMOLECULEBYSTEPWISEREGRESSIONMETHODR20902CONCLUSIONSINAWORD,LEKCISAPROMISINGRAPIDTOOLTOPREDICTDRUGPENETRATIONTHROUGHSKINKEYWORDSLIPOSOMEELECTROKINETICCHROMATOGRAPHYSKINPERMEATIONCOEFFICIENTSSTEPWISEREGRESSION借助毛细管电泳仪，把脂质体溶液加入到毛细管中作为运行溶液，脂质体作为一种假固定相PSEUDOSTATIONARY，加压运行后，测试溶质依靠其自身的电泳属性以及分配进入脂质体程度的不同而分离，称之为脂质体电动色谱LIPOSOMEELECTROKINETICCHROMATOGRAPHY,LEKC。LEKC作为一种定量分析技术，不具有什么特别的优势，但由于脂质体的组成、结构及性质与生物膜的相似性，脂质体作为一种类生物膜，用于研究药物与生物膜的相互作用时有其独特的优势。目前对于LEKC的研究报道主要集中在基础研究方面，包括脂质体在毛细管电泳中的迁移机制13，LEKC中药物与脂质体的作用机制等方面47，应用研究报道较少89。当前，药物化学高速发展，化合物数目急剧G3698加，同时中药中G15176G2559数目G5234G3835的G3837G9994化合物，G17837G1135G18129G1363G5483G17878G4464体G1881药动学特G5461的药物G12591G17885成为G7044药G5332发的G10954G20060，脂质体同G3837G9994生物膜结构G990的相似性与毛细管电泳的G5567速高G6940性相结合，为G12373G11784G17837一G10954G20060G6564G1391G1114G5390有G2159的G5049具。G11394G13944由G15932G11394、G11507G11394G2656G11394G991组G13467G989G18108分组成，G8504G3818G17836有G8747G14158、G11394脂G14158、毛G3230等G19480属G3132。G15932G11394由G1881G2533G3818G2499分为G1128G4630，G2375基G4630、G7852G4630、G12902G4630、G17891G7138G4630G2656G16294质G4630，其中G15932G11394中的G16294质G4630性质与其G4439G2520G4630有较G3835G5058G5334，G7171药物G17891G11394G2572G6922的主要G4643G19568。G16294质G4630主要由G16294G15519G11345G2656脂类成分组成，G17837G1135脂类成分包括G11979脂、G19820G11979脂、G13978固G18267G2656一G1135脂G13950G18252。G16294质G4630中不G4396在主动G17728运的G8975性G15519G11345，G4448G1852G7171一G1022G15999动G17728运的G4643G19568。G3252G8504，G6117G1216有G10714由G16760为药物的G17891G11394G2572G6922与其G1158脂性G4506G2011相G1863。G7424G7003G6922集G111422G1022有G11394G13944G9195G17891G13007数LOGKP的化合物，G6323在药物在LEKCG990的G1457G11053G3252G4388G2656G17891G11394G2454数之G19400G5326G12447一种定量G1457G11053G713G8975性G1863G13007，用于G20056测G7422G11705化合物的G17891G11394G2572G6922，G2033G8505G13783G4531G4439G1216与G17891G11394G2454数的相似性。1实验条件11试药、试剂及仪器试药G726G14531、G19400G14531G1120G18222、G8694化G2499的G7506、G18242G8943G14464、G2464G8707G14464G18252等为G8796G19463药G12197G3835学药剂、药分教研室G6564G1391。试剂G726G15519黄G11979脂G11979脂酰G13978碱G2559量975，PC，购自G990海东尚实业有限公司；G3835豆G11979脂酰丝氨G18252G11979脂酰丝氨G18252919，PS，G8694化G11979脂HPC，G13978固G18267CHOL，购自北京百威昂医药技术G5332发有限公司；POLYBRENEPB、DEXTRANSULFATEDSMWAV500000、壬基G14531G18242，购自ALDRICHSIGMA公司；G989羟甲基氨基甲烷TRIS、4羟乙基哌嗪乙磺G18252HEPES购自，G1120甲基亚砜DMSO、甲G18267等均为分析纯试剂。仪G3132G726JY922D超声波细胞粉碎机宁波G7044芝G12197G3132研究所；LS230型激光衍射G12902径分析仪贝克曼G713库尔特公司；HPCE10毛细管电泳仪G3835连江申分离G12197学技术公司。12电泳条件熔融石英毛细管河北永年锐沣色谱G3132件有限公司，总长43CM，进样端距检测窗38CM，G1881径50M；温度G726室温；电压G7261020KV；检测波长210NM。G1852G7044熔融石英毛细管的G20056处G10714G7261MNAOH溶液冲洗30MIN；01MNAOH溶液冲洗10MIN；重蒸水冲洗20MIN。涂G4630毛细管的制备G726将G1852G7044熔融石英毛细管G20056处G10714后，以5PB溶液冲洗15MIN，静置10MIN；以3DS溶液冲洗15MIN，静置30MIN，重蒸水冲洗10MIN备用。13脂质体的制备称取G17878量G11979脂至250ML圆底烧G10954中，加入G8707仿G713甲G1826791，V/V10ML溶解；60水浴减压蒸馏30MIN除去有机溶剂；将G20056热至60的20MM的PH55G11979G18252盐缓冲溶液加入烧G10954中，水化分散；探头超声20MIN，G2454数设置为超声3S，G19400歇2S，功率200W；G9994后经022M微孔滤膜过滤，充氮气4条件G991冷藏备用。14溶质在LEKC上保留因子的计算101LIPREOEORTTTTTKEQ11LIPROORTTTTTKEQ2公式1、2分别为中性G2656荷电溶质G1457G11053G3252G4388的计G12651公式，TR、TEO、TLIP分别为溶质在LEKCG990的G1998G4804时G19400、电G9195G8981G1998G4804时G19400甲G18267、G1120甲基亚砜等G7643G16772、脂质体G1998G4804时G19400壬基G14531G18242等G7643G16772，TA106为G5114电溶质在CZEG991的运行时G19400。2结果与讨论21定量保留活性关系的建立为G5326G12447一种定量G1457G11053G713G8975性G1863G13007，用于G20056测G7422G11705化合物的G17891G11394G2572G6922，G6922集G111422G1022有G11394G13944G9195G17891G13007数LOGKP的化合物，分别G18331用G2559有G13978固G18267脂质体G2656不G2559有G13978固G18267脂质体测定其LEKCG1457G11053G3252G4388，结G7536G16277G159321。G159321TAB1对LOGKCHOLG6122LOGK与LOGKP之G19400进行相G1863性研究，G8821有发G10628G4439G1216之G19400有G7186G14891的相G1863性。LIEN等G1166G7378报道G3926G991的LOGKPG20056测G8181型，G16277EQ4213。LOGKPK1LOGPK2MWK3HBK4EQ3LOGP为G8503G17775G18267/水分配G13007数，MW为分G4388量，HBG6363G1207的G7171化合物G8694G19202的数目，K1、K2、K3为G3250G5414G13007数，K4为G3250G5414G5132数。为G5326G12447化合物LEKCG1457G11053G3252G4388与LOGKP之G19400的G20056测G8181型，G6117G1216G5353入G1114MW/100、OSNS、OHSNHS、PSA等G10714化G2454数，以G17892G8505G3250G5414方G8873G2088除不G7186G14891的G2454数，G7380后G5353入的G2454数中G2494G1457G11053G1114MW/100G2656OHSNHS，G3250G5414结G7536G16277G991G726LOGKP042013LOGKCHOL092009100MW037008OHSNHS020018EQ4R20935,SE0379,N22LOGKP044017LOGK089010100MW040009OHSNHS010019EQ5R20923,SE0410,N22为与G8503G17775G18267/水G13007G13491作以G8616较，同样进行G3250G5414处G10714，结G7536G3926G991G726LOGKP019010LOGP097011100MW026013OHSNHS037031EQ6R20911,SE0441,N22G1186G990G17860等式G11487，以G2559有G13978固G18267脂质体的LEKCG5326G12447G1114G7380G3921的相G1863G8181型，G2375EQ4，G3252为EQ4有G11540G7380高的相G1863G13007数R20935G2656G7380G4579的均方G7693G16835G5058SE0379；而以G8503G17775G18267G18水G13007G13491G5326G12447的G8181型相对较G5058，G3252为EQ6有G11540G7380G3835的均方G7693G16835G5058SE0441G2656G7380G1314的相G1863G13007数R20911。G1186等式的G13007数G11487，LOGK、LOGP与LOGKPG8503相G1863，而MW/100、OHSNHS与LOGKPG17139相G1863。G3252为LOGK、LOGPG7171化合物的G1158脂性G2454数，G17837G1075G8503G16840G7138G1114化合物的G1158脂性G3698加G7368有G2045于其G9195G17891进入G11394G13944，而G1158水性的化合物G2029不G7143G9195G17891进入；MW/100G1207G15932的G7171分G4388体G12227，G6563G17860的G7171分G4388体G12227对其G1186水相分配进入生物膜及G17902过生物膜G6205散的G5445G2721；OHSNHSG6363G1207的G7171化合物分G4388的G8694G19202G1391体数目，与LOGKP的G17139相G1863G16840G7138化合物分G4388G8694G19202G1391体数目G3698加不G2045于其G9195G17891进入G11394G13944。22模型验证由于所G6922集的化合物数目较少，G2494有22G1022，不G17287以分为测试集G2656G20576G16789集对相G1863G8181型进行G20576G16789，所以G6117G1216G18331用G1114LEAVEONEOUT的方G8873进行G8181型G20576G16789。所G16871LEAVEONEOUTG8181型G20576G16789G4613G7171在总的数G6466N中去G6493一G1022数G6466，用G1325G991的数G6466N1G5326G12447G8181型G7481G20056测去G6493的G17837G1022数G6466，G3926G8504类G6524，经过NG8437G17857G1207计G12651，G2375G2499G14731G5483NG1022G20056测数G6466，将G2419试G20576G1552与测试G1552进行相G1863G8616较G7481G13783G4531所G5326G12447G8181型的G20056测G14033G2159。G18331用G16825方G8873分别对EQ4、EQ5、EQ6进行G8181型G20576G16789，G2520G20056测G1552G16277G159322，相G1863散G9869G3282G16277G32821、2、3。G159322TAB2G32821FIG1G32822FIG2G32823FIG3G1186G32821、2、3G2499G11487G1998，基于LEKCG5326G12447的EQ4G20056测的LOGKPG1552与试G20576G1552有G7380G3921的相G1863性R20934，而基于G8503G17775G18267G18水G13007G13491G5326G12447的EQ6的G20056测G14033G2159相对较G5058R20911。G17837G7171由于脂质体与G8503G17775G18267G18水G13007G13491的G7424质G5058别G17908成的，LOGPG6563G17860的G1177G7171化合物分G4388G5430G5589在G1016相中的分配，而化合物的解离G10378G5589G5390G9884G5445G2721其在G11394G13944中的G9195G17891性。23与文献模型的比较把G7003G10498报道的G11394G13944G9195G17891G8181型与G6117G1216G5326G12447的G8181型加以G8616较，总结G16277G159323。FLNN等14G7380G1820报道G1114LOGKP与LOGP之G19400的相G1863性，R2026，所测试的化合物有90种，分G4388量G118618750，LOGPG118636；POTTS等14在FLNN研究的基础G990，G5353入G1114分G4388量，G5194减少G1114化合物数量至42种，R2082；LIEN等15G2460在POTTS的基础G990G5353入G8694G19202G20045HB，进一G8505减少测试化合物至23种，R2093；BARBATO等16用IAMG13783G4531G111410种药物的G1158脂性，经过G13783G4531发G10628除G11107水作用G2159G3818其G4439作用G2159G5390度的总G2656LOGKIAM与LOGKPG2588G17139相G1863，R2091；MEDINAHERNANDEZ等17用BMC测定化合物G1158脂性，在G5353入熔G9869G20045的基础G990，测试G111443种化合物，R2079。G2520G1022G20056测G8181型所测试的化合物数目种类不一样，G7092G8873进行G11464G6521G8616较。但G1186相G1863G13007数G11487，G6117G1216所G5326G12447的G8181型G13485G1998G1114G7380G3921的结G7536，G5194G1000所测试的化合物性质、结构G7368G3822样，G7368具G1207G15932性，G2490G3818LEKC技术的高G17902量G12591G17885优势G1075G7171G990G17860G8181型所G7092G8873G8616G6323的。G159323TAB33结论测定G111422G1022化合物PH55条件G991的LEKCG1457G11053G3252G4388，G18331用G17892G8505G3250G5414的方G8873，G5353入其G4439G10714化G2454数，G5326G12447G1114药物G17891G11394G2454数LOGKP与LOGK、MW/100、OHSNHS之G19400的G20056测G8181型。结G7536G15932G7138G2559有G13978固G18267脂质体所G5326G12447的G8181型G8616G8821有G13978固G18267脂质体所G5326G12447的G8181型，相G1863G13007数G7368高、方程均方G7693G16835G5058G7368G1314。G18331用LEAVEONEOUT方G8873对G8181型进行G1114G20576G16789，结G7536G1075G15932G7138G1114较之G8503G17775G18267/水G13007G13491，脂质体在G7424质G990G7368为G6521G17829于生物膜。与G7003G10498报道的其G4439G20056测G8181型相G8616较，G7424研究所测试的化合物性质、结构G7368G3822样，G8181型G7368具G1207G15932性，LEKC技术G1075G7368具高G17902量G12591G17885优势。参考文献1WIEDMERSK,HOLOPAINENJM,MUSTAKANGASP,ETAL,LIPOSOMEASCARRIERSINELECTROKINETICCAPILLARYCHROMATOGRAPHYJ,ELECTROPHORESIS,2000,21319131982WIEDMERSK,HAUTALAJ,HOLOPAINENJM,ETAL,STUDYONLIPOSOMESBYCAPILLARYELECTROPHORESISJ,ELECTROPHORESIS,2001,22130513133WIEDMERSK,JUSSILAM,HOLOPAINENJM,ETAL,CHOLESTEROLCONTAININGPHOSPHATIDYLCHOLINELIPOSOMESCHARACTERIZATIONANDUSEASDISPERSEDPHASEINELECTROKINETICCAPILLARYCHROMATOGRAPHYJ,JSEPSCI,2002,254274374BURNSST,KHALEDIMG,RAPIDDETERMINATIONOFLIPOSOMEWATERPARTITIONCOEFFICIENTUSINGLIPOSOMEELECTROKINETICCHROMATOGRAPHYJ,JPHARMSCI,2002,91160116125BURNSST,AGBODJANAA,KHALEDIMG,CHARACTERIZATIONOFSALVATIONPROPERTIESOFLIPIDBILAYERMEMBRANESINLIPOSOMEELECTROKINETICCHROMATOGRAPHYJ,JCHROMATOGRA,2002,9731671766CARROZZINOJM,KHALEDIMG,INTERACTIONOFBASICDRUGSWITHLIPIDBILAYERSUSINGLIPOSOMEELECTROKINETICCHROMATOGRAPHYJ,PHARMRES,2004,21232723357CARROZZINOJM,KHALEDIMG,PHEFFECTSONDRUGINTERACTIONSWITHLIPIDBILAYERSBYLIPOSOMEELECTROKINETICCHROMATOGRAPHYJ,JCHROMATOGRA,2005,10793073168RNSKOVE,GOTTFRIESJ,ERICKSONM,ETAL,EXPERIMENTALMODELINGOFDRUGMEMBRANEPERMEABILITYBYCAPILLARYELECTROPHORESISUSINGLIPOSOMES,MICELLESANDMI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