PLA-α-细辛脑纳米粒经鼻腔、静脉给药后药物动力学研究
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摘要
采用乳化溶剂挥发法制备聚乳酸(PLA)-α-细辛脑纳米粒,并与静脉注射给药比较,研究PLA-α-细辛脑纳米粒鼻腔给药后药物的体内分布及脑组织的靶向性。结果显示:鼻腔给药和静脉注射后的脑靶向系数分别为1.65与1.16,PLA-α-细辛脑纳米粒鼻腔给药后的绝对生物利用度为74.2%,脑靶向效率为142.24%,鼻-脑传递百分比为29.83%。荧光标记法显示,PLA-α-细辛脑荧光纳米粒经鼻腔给药后,香豆素-6在脑组织中的荧光强度最大,达到脑靶向给药的目的;PLA-α-细辛脑荧光纳米粒静脉注射给药后,香豆素-6在肝组织中的荧光强度远高于鼻腔给药,表明PLA-α-细辛脑纳米粒经鼻腔给药可降低药物导致的肝毒性。此外,PLA-α-细辛脑荧光纳米粒经鼻腔给药后,香豆素-6在肺组织中的荧光强度较弱,解决了气流粉碎法制备的α-细辛脑干粉经鼻腔给药到达肺部量较多的缺点。体内研究表明:与静脉注射相比,PLA-α-细辛脑纳米粒鼻腔给药后的脑靶向性优于静脉注射。
PLA-α-asarone nanoparticles were prepared by using organic solvent evaporation method,and their in vivo distribution and brain targeting after intranasal administration were studied as compared with intravenous administration.The results showed that brain targeting coefficient of PLA-α-asarone nanoparticles after intranasal and intravenous administration was 1.65 and 1.16 respectively.The absolute bioavailability,brain-targeting efficiency and the percentage of nasal-brain delivery of PLA-α-asarone nanoparticles were 74.2%,142.24 and 29.83%,respectively after intranasal administration.The results of fluorescence labeling showed that the fluorescent intensity of coumarin-6 in the brain tissue was the highest after intranasal administration of PLA-α-asarone fluorescent nanoparticles,achieving the purpose of brain-targeted drug delivery.The fluorescent intensity of coumarin-6 in liver tissue after intravenous administration of PLA-α-asarone nanoparticles was much higher than that after intranasal administration,indicating that intranasal administration of PLA-α-asarone nanoparticles could decrease drug-induced hepatotoxicity.In addition,the fluorescent intensity of coumarin-6 in lung tissue was weaker after intranasal administration,which solved the shortcomings of intranasal administration of α-asarone dry powder prepared by airflow pulverization method.In vivo studies indicated that PLA-α-asarone nanoparticles after intranasal administration had a stronger brain targeting as compared with intravenous administration.
PLA-α-asarone nanoparticles were prepared by using organic solvent evaporation method,and their in vivo distribution and brain targeting after intranasal administration were studied as compared with intravenous administration.The results showed that brain targeting coefficient of PLA-α-asarone nanoparticles after intranasal and intravenous administration was 1.65 and 1.16 respectively.The absolute bioavailability,brain-targeting efficiency and the percentage of nasal-brain delivery of PLA-α-asarone nanoparticles were 74.2%,142.24 and 29.83%,respectively after intranasal administration.The results of fluorescence labeling showed that the fluorescent intensity of coumarin-6 in the brain tissue was the highest after intranasal administration of PLA-α-asarone fluorescent nanoparticles,achieving the purpose of brain-targeted drug delivery.The fluorescent intensity of coumarin-6 in liver tissue after intravenous administration of PLA-α-asarone nanoparticles was much higher than that after intranasal administration,indicating that intranasal administration of PLA-α-asarone nanoparticles could decrease drug-induced hepatotoxicity.In addition,the fluorescent intensity of coumarin-6 in lung tissue was weaker after intranasal administration,which solved the shortcomings of intranasal administration of α-asarone dry powder prepared by airflow pulverization method.In vivo studies indicated that PLA-α-asarone nanoparticles after intranasal administration had a stronger brain targeting as compared with intravenous administration.
引文
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[25]张龙开,许日鑫,蒋梅,等.β-细辛醚微乳鼻腔给药脑内靶向性评价[J].中草药,2014,45(1):86.
[26]黄秋艳,熊磊,孔淑君,等.苍艾挥发油经鼻吸收的药代动力学及组织分布[J].中国实验方剂学杂志,2016,22(23):94.
[27]鞠凤,潘林梅,郭立玮,等.经鼻给药α-细辛脑m PEG-PLA微粒的制备与体外释放研究[J].中国中药杂志,2015,40(24):4847.
[28]臧巧真,唐涛,龙凯花,等.α-细辛脑纳米粒离子敏感型鼻用原位凝胶的制备及体外释放行为[J].中国医院药学杂志,2015,35(23):2115.
[2]Huang C,Li W G,Zhang X B,et al.Alpha-asarone from Acorus gramineus,alleviates epilepsy by modulating A-type GABA receptors[J].Neuropharmacology,2013,65C(5):1.
[3]杨正鸿,吴闯.α-细辛脑在人体的生物利用度研究[J].中国医院药学杂志,1997,17(4):165.
[4]武晓玉,张玉萌,栗晓东,等.细辛脑制剂致过敏性休克文献分析[J].中国药物应用与监测,2011,8(6):364.
[5]黄亮,陈力,韩璐,等.细辛脑注射液118例不良反应文献分析[J].中南药学,2011,9(2):157.
[6]Betbeder D,Sperandio S,Latapie J P,et al.Biovector nanoparticles improve antinociceptive efficacy of nasal morphine[J].Pharm Res,2000,17(6):743.
[7]Matthias V W,Nathalie W,Rémi R,et al.Development of siRNA-loaded chitosan nanoparticles targeting galectin-1 for the treatment of glioblastoma multiforme via intranasal administration[J].J Control Release,2016,227:71.
[8]Eameema M,Raju D,Anjali J,et al.Intranasal delivery of nanoparticle encapsulated tarenflurbil:a potential brain targeting strategy for Alzheimer's disease[J].Eur J Pharm Sci,2016,92:224.
[9]陆瑾,展冠军,郭立玮,等.PLA-α-细辛脑纳米粒的制备、表征及其对鼻黏膜的毒性[J].中国实验方剂学杂志,2017,23(10):12.
[10]陈伟,刘玉玲,贺玖明,等.液相色谱-串联质谱法测定兔血浆中α-细辛脑的浓度[J].药物分析杂志,2006,26(10):1364.
[11]王媛媛,王淑君.α-细辛脑静脉注射乳剂在大鼠体内的药动学研究[J].中国药剂学杂志,2012,10(2):39.
[12]Wang F,Jiang X,Lu W.Profiles of methotrexate in blood and CSF following intranasal and intravenous administration to rats[J].Int J Pharm,2003,263:1.
[13]Chow H S,Chen Z,Matsuura G T.Direct transport of cocaine from the nasal cavity to the brain following intranasal cocaine administration in rats[J].J Pharm Sci,1999,88:754.
[14]石森林,徐莲英,吴瑾瑾,等.灯盏花素不同给药途径脑内药物分布的比较[J].药学学报,2009,44(5):515.
[15]Lu J,Fu T M,Qian Y Y,et al.Distribution ofα-asarone in brain following three different routes of administration in rats[J].Eur J Pharm Sci,2014,63:63.
[16]Panyam J,Labhasetwar V.Dynamics of endocytosis and exocytosis of poly(D,L-lactide-co-glycolide)nanoparticles in vascular smooth muscle cell[J].Pharm Res,2003,20:212.
[17]Panyam J,Zhou W Z,Prabha S,et al.Rapid endo-lysosomal escape of poly(DL-lactide-co-glycolide)nanoparticles:implications for drug and gene delivery[J].Faseb J,2002,16:1217.
[18]Grainger C I,Greenwell L L,Lockley D J.Culture of Calu-3 cells at the air interface provides a representative model of the airway epithelial barrier[J].Pharm Res,2006,23:1482.
[19]Xia H,Gao X,Gu G,et al.Penetratin-functionalized PEG-PLA nanoparticles for brain drug delivery[J].Int J Pharm,2012,436:840.
[20]李晓芳,马艳结,张晓,等.包载荧光探针香豆素-6的PLGA纳米粒的制备[J].中国现代应用药学,2011,28(8):740.
[21]王俊腾,林东海,秦利芳,等.单甲氧基聚乙二醇-聚乳酸羟基乙酸共聚物纳米粒在大鼠鼻黏膜的转运研究[J].药学学报,2013,48(5):752.
[22]Dong Y,Feng S S.Poly(d,1-lactide-co-glycolide)/montmorillonite nanoparticles for oral delivery of anticancer drugs[J].Biomaterials,2005,26:6068.
[23]Zhang Q,Jiang X,Jiang W,et al.Preparation of nimodipine-loaded microemulsion for intranasal delivery and evaluation on the targeting efficiency to the brain[J].Int J Pharm,2004,275:85.
[24]高科攀,蒋新国.载药纳米粒的脑内递药系统[J].中国新药与临床杂志,2004,23(4):246.
[25]张龙开,许日鑫,蒋梅,等.β-细辛醚微乳鼻腔给药脑内靶向性评价[J].中草药,2014,45(1):86.
[26]黄秋艳,熊磊,孔淑君,等.苍艾挥发油经鼻吸收的药代动力学及组织分布[J].中国实验方剂学杂志,2016,22(23):94.
[27]鞠凤,潘林梅,郭立玮,等.经鼻给药α-细辛脑m PEG-PLA微粒的制备与体外释放研究[J].中国中药杂志,2015,40(24):4847.
[28]臧巧真,唐涛,龙凯花,等.α-细辛脑纳米粒离子敏感型鼻用原位凝胶的制备及体外释放行为[J].中国医院药学杂志,2015,35(23):2115.