[生物医药论文精品a]口服芹菜素固体脂质纳米粒制剂学及药物动力学研究

口服芹菜素固体脂质纳米粒制剂学及药物动力学研究A1A0A2A4A5A3A4A5A6A4A8A7A9A4A11A10A12A13A15A14A16A17A10A18A16A18A19A4A15A14A20A15A21A22A23A24A25A27A26A28A30A4A15A14A4A27A27A26A26A27A29A31A32A33A34A35A34A35A33A36A37A38A39A40A41A42A43A44A45A46A47A48A49A50A51A52A53A43A41A54A18A55A50A56A16A57A58A59A18A60A61A37A38A62A63A64A33A65A66A67A68A53A69A70A4ZETAA71A72A73A74A75A70A4A76A77A71A78A4XA77A79A80A77A4A48A81A82A83A84A85A86A87A44A45A46A47A48A49A50A51A52A53A43A41A54A18A55A50A88A89A90A41A44A45A46A91A92A93A12A39A94A95A4A86A87A96A10A97A98A99A44A45A46A47A48A49A50A51A52A53A43A16A58A18A100A101A62A102A103A102A103A33A76A77A71A78A104A87A51A52A53A43A105A106A107A108A109A51A52A53A12A110A111A105A53A112A88A113A114A53A115A12135NMA88ZETAA71A72A121890MVA88A74A75A16A57A116A117A118A119A50A120A43A117A118A121A122A123A124A117A118A125A101A62XA77A79A80A77A126A127A44A45A46A116A47A48A49A50A51A52A53A120A89A128A75A105A105A129A130A116A62A98A99A16A58A18A131A132A133A127A4A44A45A46A47A48A49A50A51A52A53A95A43A113A114AUC0TA1217337GH/MLA4A134A39A94A95A1253GH/MLA62A51A52A53A95A43CMAXA12307G/MLA4A127A135A136A137A39A94A95A431544G/MLA62A51A52A53A95A43A138A139A140A141A142A143KEA144A145A4A120232H1A4A145A137A39A94A95A62A102A146A102A146A33A44A45A46A47A48A49A50A51A52A53A43A147A39A148A57A149A66A69A12327A62A44A45A46A47A48A49A50A51A52A53A150A151A152A153A136A44A45A46A43A148A57A149A66A69A62A154A155A156A33A44A45A46A4A47A48A49A50A51A52A53A4A48A81A117A118A4XA77A79A80A77A4A16A57A58A59A181前言芹菜素（APIGENIN）13（5,7,4三羟基黄酮）属于黄酮类，广泛存在于伞形科植物旱芹叶；卷柏科卷柏全草；柏科圆柏叶中。芹菜素具有多种药理活性具体表现在抗肿瘤、抗炎症、降血压、抗动脉硬化和血栓症、抗焦虑、抗菌抗病毒以及抗氧化作用等方面。近年来，芹菜素的抗肿瘤作用得到人们的日益关注，其中抗乳腺癌、黑色素瘤、前列腺癌的作用最为显著。但是由于芹菜素的理化性质，水溶性较差，口服吸收差，生物利用度较低，在一定程度上限制了它的应用。本文采用固体脂质G13447G12871G12902G17837一G13485药G13007G13491作为G17745体，G4570芹菜素制G3803G6116G13447G12871G12902G9163G5760G9094G1889口服以G17810到G6925G2904其口服吸收的G11458的，G6564G20652生物利用度。2仪器与试药LC10ADG3423G20652G6940G9094G11468色G16901G1214，HW色G16901G5049作G12461，FA1104G11017G4388G3837G5191,NICOMP380G12902度G8991定G1214（G13666G3281PARTICLESIZINGSYSTEMSG1856G2508），H100G17891G4568G11017G19248（日G12447G1856G2508）TGL16GG3423G12175G5527G7438上G9035G4445G1153科G4410G1214G3132G2390,G5670G9213水G9032G19161HHSG3423G8755G14499G11477G13430G7083G2319G11115G1214G3132G2390。芹菜素（G13443度98，G2347G1152G19750G8913G2319药科G6228G5332G2469有限G1856G2508），PLURONICF68（G5515G3281BASF）G3835G16922G2377G11979脂（上G9035G3838G1267药G1006），G2345硬脂G18252G10988G8845G18243（G3837G8953G5078G2350G17854化G5049有限G1856G2508）。3方法31芹菜素固体脂质纳米粒（APSLN）的制备G12228G2474G3800方G18339PLURONICF68溶G16311于G14988G20323水水中，G7512G6116水G11468；G12228G2474G3800方G18339的G2345硬脂G18252G10988G8845G18243，G2164G9921到752G1363G10088G15713，G3800方G18339G11979脂溶于芹菜素G18267中，在G6617G6304G10378G5589G991G2010G6967到G10088G15713的G2345硬脂G18252G10988G8845G18243中，G7512G6116G8845G11468，G17902G8706G8680G6393G2447G1069G18267。G4570水G11468G2164G9921到G11468G2528的G9213度，注G1849G8845G11468中，G5670G9213G6617G6304，制G6116G2033乳。G17237G9921G4570G2033乳G17241G3780，G4472G9213水G1931G2376，G17819022MG5506G4392G9400G14192即得。32芹菜素囊泡粒径分布G2474“31”项G991制G3803的G13447G12871G12902稀释至一定浓度，采用LS230激光G12902度G1214G8991定G12902径及G12902度G2010布。33芹菜素固体脂质纳米粒ZETA电位的测定G2474“31”项G991制G3803的G13447G12871G12902，稀释至一定浓度，放G1849比色池中，G8991定ZETAG11017位值。34芹菜素固体脂质纳米粒显微形态G2474“311”项G991制G3803的G13447G12871G12902适G18339，用3G11979钨G18252染色，G17891G4568G11017G19248G991观察其G12902G4388形G5589。35芹菜素纳米粒体外释放的测定G2010别G24743ML的APSLN及等含G18339的AP对照溶G9094置G17891析袋中，释放介质为G11979G18252盐缓冲G9094（PH74）20G1069G18267，释放介质体积为50ML，在37G99150R/MIN低速G6617G6304，G5191行操作三份。每隔一定时间G4570G17891析介质全部G2474出，更换G11468应的新鲜介质，继续操作，G2474出的介质用045MG5506G4392G9400G14192G17819G9400，G2474续G9400G9094HPLC法G8991定AP浓度，计算累积释放率。36X射线衍射对冻干后纳米粒考察（XRD）为了考察G13447G12871G12902中药物的G2010G6967G10378G5589，对药物粉末，物理G9163合物及冻干后的G13447G12871G12902粉末样品进行了XG4568线衍G4568G2010析。37色谱条件建立SHIMADZU色G16901柱250MM46MM，流动G11468为01G11979G18252水溶G9094G1069腈体积比为4555，流速10ML/MIN，检G8991波长312NM，进样G18339为20L，内标为水飞蓟宾（SB）。38血浆样品处理精密吸G2474血浆样品02ML，置于15ML具塞尖底塑料试管中，依次G2164G1849400G/ML内标溶G909410L，甲G1826706ML，旋涡G9163合3MIN，G12175G5527（4000R/MIN）10MIN。G2474上清G9094用N2吹干，甲G1826701ML溶G16311，G17819G9400G12175G5527后进样，进行HPLCG2010析，记录色G16901图。G4570待G8991物与内标物的峰面积比代G1849标准曲线，计算各时间点样品中药物的浓度。39芹菜素纳米粒在大鼠体内的药物动力学研究G2474G3835鼠12只，随G7438G2010为两组（对照组和制剂组），实验前禁食12小时，G2010别灌胃上述两种制剂，剂G18339为20MG/KG。，G2010别于G13485药前和G13485药后025,05，1，2，3，4，6，8，12H血眼眶G2474血，4000R/MING12175G552710MIN，G2010G12175血浆按“38”项G991的方法G3800理，并进HPLC检G8991，代G1849标准曲线，计算不G2528时间点的血药浓度。4结果41芹菜素纳米粒的制备及制剂学考察经G17819G2345因素考察、正G1144试验后得到制G3803芹菜素G13447G12871G12902的最G1260G3800方，其G2265G4565率为624835，G13447G12871G12902G12902度G2010布（G16277图1）为G2345峰，G5191G3355G12902径为135503NM，ZETAG11017位为189。G17891G4568G11017G19248G991观察显G12046G2588类G10711形（G16277图2A，B），G12902度G2010布为80G713200NM，与G12902度G8991定G1214G8991定G13479G7536一G14280。G2265G16077药物后G13447G12871G12902形G5589G8821有G7138显G2476化。G13479G7536表G7138，制G3803的G13447G12871G12902G12902径较小，G12902度G2010布较G3355G2260。A1571A158A159A160A161A162A163A164A165A166A167A158A159A160A161A163A164A168A167A169A170A171A172A169A170A171A172ABA1722A158A159A160A161A162A163A164A165A166A167A158A159A160A161A163A164A165A166A167A168A173A174A175A176A177A178A165A166A167A168A174A175A176A17730,000A179AA179A180A181A182BA179A179A183A184A183A184A18342芹菜素纳米粒体外释放体G3818释放G11752G12362表G7138（图3），芹菜素固体G13447G12871G12902具有缓释G6940G7536，48H的累计是放率为854。在G5332G3999释放的前4H，375芹菜素G1186固体G13447G12871G12902中G5567速释放。释放曲线G12538合一G13435动G2159G4410（Y00598T43935，R09903）。G13792G17891析袋对药物释放G7092G5445G2721。A185A186A185A187A185A188A185A189A185A190A185A185A190A186A185A185A190A185A186A185A191A185A187A185A192A185A188A185A193A194A195A196A197A198A197A199A200A201A202A203A204A205A200A199A204A200A206A204A207A208A209A210A211A212A213A214A215A216A217A213A218A219A220A209A210A211A221A222A223A224A2253A226A227A228A229A230A231A232A233A234A235A227A228A230A231A232A233A236PH74PBS20A237A238A239A240A241A238A23943X射线衍射对冻干后纳米粒考察本G11752G12362G17902G17819XG4568线衍G4568考察G13447G12871G12902中药物的G2010G6967G10378G5589，G1186XG4568线衍G4568图G16901（图4A，B，C，D）G2499G16277芹菜素药物粉末是G13479G7242形G5347存在，物理G9163合物中药物G13479G7242的G10317G5461峰依G9994G7138显，G4570药物及物理G9163合物与APSLNG11468比，药物的G13479G7242峰G1955G4581，G16840G7138药物G3835部G2010是以G7092定形G10378G5589存在于G13447G12871G12902G1055中。G13792G4581部G2010药物以G13479G7242G5589吸G19480在G13447G12871G12902表面。G8504G2499G16789G7138体G3818释放前4H的G12373释是由于吸G19480在G13447G12871G12902表面的药物溶G16311G6164G14280。ABCDA2424XA243A244A245A243A246A244A245AA247A248A249A247A248A249A250A251A250BA252A253A254A255A45A253A253A254A250A251CA252A49A0A1A0A1A250A251DA252A247A248A249A11A2A3A4A5A247A248A11A2A3A4A19A6A19A644药物动力学试验结果按照“39”项G991方法，G13485药后不G2528时间点的血药浓度G16277表1，采用G7811形法计算的药动G2454G6980G16277表2。由上表G2499G11705,SLN组的CMAX（307G/ML）G7138显G20652于对照组（1544G/ML）。SLN组的G9052G19512速率G5132G6980KE较低，为0232H1，低于对照组为054H1；SLN组的G5191G3355AUC0T为17337GH/ML，G13792对照组为53GH/ML。G7693G6466药物代G16886动G2159G4410G6323合出的血药浓度G252时间曲线G991面积AUC0T的G6980G6466及G13485药剂G18339，G8726算芹菜素固体脂质G13447G12871G12902与G11468G2528G13485药剂G18339的芹菜素G2419料药的G11468对生物利用度为327。G13479G7536表G7138，G14270制的芹菜素固体脂质G13447G12871G12902与芹菜素G2419料药G11468比G7138显G6564G20652了生物利用度。A521APA47A7A8A9A10A12A13A14A15A16A13A17A18A47A7A9A10A12A13A14A15A16A13TIME/HAPSUSPENSIONAPSLN025015400310378011705037401070625007910864019514310407215440413307176340611004628631355604110071113602598011300280834021712A2004150104A212A22A23A24A25A26A27A13A28A29A30A31A24A25A26A27COMPARMENTPARAMETERSAPSUSPENSIONAPSLNT1/2H12832987KEH10540232V1/FL/KG78025166CL/FL/H/KG42151199AUC0TMG/LH443114408AUC0MG/LH447516684KAH106420606T1/2KAH10811435讨论51用G11017G19248照G10267来观察G13447G12871G12902的G5506观G13479G7512，不G2528的G13447G12871G12902G5506观形G5589G1075G1262有G6164不G2528，关于G13447G12871G12902的形G5589G13479G7512的G11752G12362，G3999G13468是G3281内G3818G11752G12362的G9921点。本文中G6164G13485出的G11017G19248照G10267中G13447G12871G12902G2588近G1296G10711形G13479G75124A325。52对于G5506G12902G2010G6967体G13007，G12902径及其G2010布的G8991定G2325G2010G18337G16213。因为其G14033G3827G5445G2721G13447G12871G12902的体内G2010布、G19786G2533性及G12295定性，G6937G12902径及其G2010布是G16792G1227G13447G12871G12902G2325G2010G18337G16213的质G18339G2454G6980。本文采用了激光G12902度G1214（光G6967G4568G2419理）对SLN的G12902径及其G2010布进行了G8991定，G13479G7536表G7138APSLNG9163G5760G9094的G5191G3355G12902径在135NMG5050G2503，G12902度G2010布G14551G3272比较G12376，体G13007比较G12295定。53芹菜素是一种G5468有前G7235的中药有G6940G6116G2010，但G11458前关于其G11468关制剂的G11752G12362G5468G4581。在水中不溶，口服吸收的生物利用度较低是G7422来G5332G2469芹菜素口服剂G3423的G19602G20076，采用固体脂质G13447G12871G12902G13485药后，生物利用度有了G5468G3835G6564G206526，在G1955G4581G13485药剂G18339的G5785G1929G991，G2499G17810到G11468G2528的G8847G11115G6940G7536。本文的G11752G12362G5088G7407G14033为中药有G6940G6116G2010芹菜素的新G3423制剂的G11752G12362和G5332G2469G6564G1391一定实验基G11796。54G13447G12871G12902在小G13940的吸收G7438理G5062经G5468G7138G11842了7，小于500NM的G13447G12871G12902G2499在胃G13940G17959的G8978G1246G8675G9119G5064G13479G19610中积累，并以G4448G6984G13479G7512G17902G17819G9119G5064G13479G19610中的MG13466G14002，G4570药物释放到G5502G10627中；G8504G3818，由于G13447G12871G12902的小G12902G4388G6940应，G13447G12871G12902对胃G13940G17959G3733具有较G5390的G21667G19480作用，G5322长了在胃G13940G17959的G1584G11053时间，G1186G13792G3698G2164了G13447G12871G12902的吸收G7438G1262。参考文献1SUNB,QUWQ,ZHANGXLTHERESEARCHPROGRESSIONINPHARMACOLOGICALACTIONOFAPIGENINJJOURNALOFCHINESEMEDICINALMATERIALSA33A34A35,2004,2775315342CHENDI,KENYONGDANIEL,MARINASCHEN,ETALDIETARYFLAVONOIDSASPROTEASOMEINHIBITORSANDAPOPTOSISINDUCERSINHUMANLEUKEMIACELLJBIOCHEMICALPHARMACOLOGY200569142114323TAJDARHUSAINKHAN,SARWATSULTANAAPIGENININDUCESAPOPTOSISINHEPG2CELLSPOSSIBLEROLEOFTNFANDIFNJTOXICOLOGY,20062172062124MEHNERTW,MADEXKSOLIDLIPIDNANOPARTICLESPRODUCTIONCHARACTERIZATIONANDAPPLICATIONSJADVDRUGDELIVREV,2001,472/31651965JORESK,MEHNERTW,DRECHSLERM,ETALINVESTIGATIONSONTHESTRUCTUREOFSOLIDLIPIDNANOPARTICLESSLNANDOILLOADEDSOLIDLIPIDNANOPARTICLESBYPHOTONCORRELATIONSPECTROSCOPY,FIELDFLOWFRACTIONATIONANDTRANSMISSIONELECTRONMICROSCOPYJJCONTROLRELEASE,2004,9522172276HUL,TANGX,CUIFSOLIDLIPIDNANOPARTICLESSLNSTOIMPROVEORALBIOAVAILABILITYOFPOORLYSOLUBLEDRUGSJPHARMPHARMACOL2004,5612152715357JANIP,HALBERTGW,LANGRIDGEJ,FLORENCEATNANOPARTICLEUPTAKEBYTHERATGASTROINTESTINALMUCOSAQUANTITATIONANDPARTICLESIZEDEPENDENCYPHARMPHARMACOL,1990,4212821826STUDIESONPHARMACYCHARACTERSANDPHARMACOKINETICSOFORALAPIGENINLOADEDSOLIDLIPIDNANOPARTICLEHUHAIYANG,LIUREN,LIUDAN,ZHAOXIULI,CHENDAWEISCHOOLOFPHARMACY,SHENYANGPHARMACEUTICALUNIVERSITY,SHENYANG,110016A36A37A38A39A40A41A42A43A44A46A48A50A51A53A54A43A46A55A56A57A43XA58A59A60