血压平喷雾剂中主要活性成分的鼻黏膜吸收特性研究
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摘要
血压平喷雾剂由夏枯草、菊花、赤芍、辛夷、肉桂、川芎、当归、薄荷组方制备而成,用于治疗高血压。在前期实验和临床研究中发现,血压平喷雾剂3g/次(生药量)就能发挥良好的降压效果,而产生良好降压效应的原因是什么?一方面可能是由于鼻腔独特的生理构造,不仅可避免口服给药的首过效应,而且通过鼻腔与脑部之间通路,药物还可绕过血脑屏障；另一方面可能是由于血压平复方中多种化学成分间的相互影响,改变了有效成分的ADME过程。
对于鼻腔给药存在的优势是已经被证实的。为了对后一种推测进行论证,本课题首先从吸收的角度入手,采用大鼠在体鼻腔循环灌流法研究血压平复方中主要的活性成分鼻黏膜吸收的情况,旨在确定血压平喷雾剂中主要活性成分的鼻黏膜吸收特征,为血压平喷雾剂的剂型选择及辅料的筛选提供理论依据。
本文通过对复方中各味药的化学成分及药理作用的文献综述,确定血压平复方中与降压密切相关的成分,分别为芍药苷、丹皮酚、肉桂酸、绿原酸、阿魏酸,并建立了这五个成分的HPLC含量测定方法。
本文选用大鼠在体鼻腔循环灌流法研究活性成分的鼻黏膜吸收情况,由于目前常用的食管插管方法实验操作难度大、成功率低的弊端,故将食管插管改为气管插管。并通过三种模型药物(滴通鼻炎水、呋麻滴鼻液、血压平喷雾剂)对改进后的鼻腔在体循环灌流法进行可行性验证,确定改进后试验方法的可行性。
在改进的鼻腔在体循环灌流法的基础上,对各主要活性成分的鼻腔吸收特征进行研究,包括渗透压、pH值、流速、给药体积、给药浓度。从而确定最佳的实验条件为流速1.8mL/min,给药体积为10mL,丹皮酚、肉桂酸、绿原酸、阿魏酸的鼻黏膜吸收均为被动扩散且吸收良好。同时发现芍药苷的吸收状况不太理想,但其在复方中吸收良好。
针对芍药苷吸收差的现象,本文研究了丹皮酚、肉桂酸、绿原酸、阿魏酸配伍对芍药苷吸收的影响,以及挥发油对其吸收的作用。结果表明,混合物对芍药苷的鼻黏膜吸收有一定的促进作用,但与制剂中的吸收还有一定差距。在加入挥发油后,吸收得到了进一步的改善。
在制剂中辅料的加入会对药物的吸收产生影响,为此本文对加入辅料后芍药苷的鼻黏膜吸收情况进行了考察。结果表明壳聚糖和羟丙基.β.环糊精的吸收促进作用最强,可以作为血压平喷雾剂的药剂辅料。
XueYaPing spray is used to cure hypertension, which is composed of Spica prunellae, Flos chrysanthemi, Radix paeoniae rubre, Flos magnoliae, Cortex cinnamomi, Rhizoma chuanxiong, Radix angelicae sinensis and Herba menthae. In the earlier experiment and clinical research, we find that the concentration of xueyaping spray which can exert therapeutic effects is only 3g/time. What is the reason for the good therapeutic effect? On the one hand maybe the special structure of the nasal is not only avoid of first pass effect, but also the medicine can bypass the blood brain barrier though the pathway between brain and nasal. On the other hand, the interaction of the complex components of xueyaping prescription maybe changes the ADME process of these active components.
The advantage of Nasal drug delivery is confirmed. In order to demonstrate the second idea, the subject beginning with the absorption of the nasal membrane, study the situation of the absorption by in situ nasal recirculation method in xueyaping prescription. The goal is to confirm the absorptive characteristics of the main active components. So that it can supply theoretical evidences for the selection of dosage form and excipients.
To review the study on chemical constituents and pHarmacological activities of this prescription, we confirm these active components closely related to decrease blood pressure. They are chlorogenic acid, Ferulic Acid, peoniflorin and Cinnamic acid. This article establishes a HPLC method for the determination of these components in XueYaPing spray.
The absorption of active components in the nasal membrane is evaluated by nasal circulatory perfusion test in vivo in this article. However, this method has many deficiencies:the intubation in esopHageal is very difficult, and the successful rate is very low. so we decide to intubate in tracheal, and then we use three model medicine(Ditong biyan shui, Fuma dibiye, Xueyaping spray) to verify weather this new improved circulatory perfusion is feasible.
Based on the improved nasal circulatory perfusion method, we study the absorption of the main active componets in nasal, including osmotic pressure, pH, flow rate, volume and concentration of administration. Finally, the optimum parameters are as follows:flow rate is 1.8mL/min, the volume is 10mL, the nasal absorption of chlorogenic acid, Ferulic Acid, Peoniflorin, Paeonol and Cinnamic acid is passive transport, and the absorption is good. Meanwhile we find that the absorption of single Peoniflorin is not so ideal, but in the Xueyaping prescription the result shows good absorption.
Accroding to the poor absorption of Peoniflorin, we study weather the volatile oil and the mixture compatibility of chlorogenic acid, Ferulic Acid, Paeonol and Cinnamic acid have an influence on the absorption of Peoniflorin. The results show that the mixture has a certain promoting influence on the absorption, but it still has a certain distance compared with the spray. This situation is better improved when the volatile oil is added to the mixture.
Also we find that the excipients which are added to the spray have an influence on the absorption of the medicine. So we choose Peoniflorin has a poor absorption to investigate the excipients. The results show that chitosan and HP-P-CD have a strong promoting influence on the absorption, and they can be used to the spray as supplementary agents.
对于鼻腔给药存在的优势是已经被证实的。为了对后一种推测进行论证,本课题首先从吸收的角度入手,采用大鼠在体鼻腔循环灌流法研究血压平复方中主要的活性成分鼻黏膜吸收的情况,旨在确定血压平喷雾剂中主要活性成分的鼻黏膜吸收特征,为血压平喷雾剂的剂型选择及辅料的筛选提供理论依据。
本文通过对复方中各味药的化学成分及药理作用的文献综述,确定血压平复方中与降压密切相关的成分,分别为芍药苷、丹皮酚、肉桂酸、绿原酸、阿魏酸,并建立了这五个成分的HPLC含量测定方法。
本文选用大鼠在体鼻腔循环灌流法研究活性成分的鼻黏膜吸收情况,由于目前常用的食管插管方法实验操作难度大、成功率低的弊端,故将食管插管改为气管插管。并通过三种模型药物(滴通鼻炎水、呋麻滴鼻液、血压平喷雾剂)对改进后的鼻腔在体循环灌流法进行可行性验证,确定改进后试验方法的可行性。
在改进的鼻腔在体循环灌流法的基础上,对各主要活性成分的鼻腔吸收特征进行研究,包括渗透压、pH值、流速、给药体积、给药浓度。从而确定最佳的实验条件为流速1.8mL/min,给药体积为10mL,丹皮酚、肉桂酸、绿原酸、阿魏酸的鼻黏膜吸收均为被动扩散且吸收良好。同时发现芍药苷的吸收状况不太理想,但其在复方中吸收良好。
针对芍药苷吸收差的现象,本文研究了丹皮酚、肉桂酸、绿原酸、阿魏酸配伍对芍药苷吸收的影响,以及挥发油对其吸收的作用。结果表明,混合物对芍药苷的鼻黏膜吸收有一定的促进作用,但与制剂中的吸收还有一定差距。在加入挥发油后,吸收得到了进一步的改善。
在制剂中辅料的加入会对药物的吸收产生影响,为此本文对加入辅料后芍药苷的鼻黏膜吸收情况进行了考察。结果表明壳聚糖和羟丙基.β.环糊精的吸收促进作用最强,可以作为血压平喷雾剂的药剂辅料。
XueYaPing spray is used to cure hypertension, which is composed of Spica prunellae, Flos chrysanthemi, Radix paeoniae rubre, Flos magnoliae, Cortex cinnamomi, Rhizoma chuanxiong, Radix angelicae sinensis and Herba menthae. In the earlier experiment and clinical research, we find that the concentration of xueyaping spray which can exert therapeutic effects is only 3g/time. What is the reason for the good therapeutic effect? On the one hand maybe the special structure of the nasal is not only avoid of first pass effect, but also the medicine can bypass the blood brain barrier though the pathway between brain and nasal. On the other hand, the interaction of the complex components of xueyaping prescription maybe changes the ADME process of these active components.
The advantage of Nasal drug delivery is confirmed. In order to demonstrate the second idea, the subject beginning with the absorption of the nasal membrane, study the situation of the absorption by in situ nasal recirculation method in xueyaping prescription. The goal is to confirm the absorptive characteristics of the main active components. So that it can supply theoretical evidences for the selection of dosage form and excipients.
To review the study on chemical constituents and pHarmacological activities of this prescription, we confirm these active components closely related to decrease blood pressure. They are chlorogenic acid, Ferulic Acid, peoniflorin and Cinnamic acid. This article establishes a HPLC method for the determination of these components in XueYaPing spray.
The absorption of active components in the nasal membrane is evaluated by nasal circulatory perfusion test in vivo in this article. However, this method has many deficiencies:the intubation in esopHageal is very difficult, and the successful rate is very low. so we decide to intubate in tracheal, and then we use three model medicine(Ditong biyan shui, Fuma dibiye, Xueyaping spray) to verify weather this new improved circulatory perfusion is feasible.
Based on the improved nasal circulatory perfusion method, we study the absorption of the main active componets in nasal, including osmotic pressure, pH, flow rate, volume and concentration of administration. Finally, the optimum parameters are as follows:flow rate is 1.8mL/min, the volume is 10mL, the nasal absorption of chlorogenic acid, Ferulic Acid, Peoniflorin, Paeonol and Cinnamic acid is passive transport, and the absorption is good. Meanwhile we find that the absorption of single Peoniflorin is not so ideal, but in the Xueyaping prescription the result shows good absorption.
Accroding to the poor absorption of Peoniflorin, we study weather the volatile oil and the mixture compatibility of chlorogenic acid, Ferulic Acid, Paeonol and Cinnamic acid have an influence on the absorption of Peoniflorin. The results show that the mixture has a certain promoting influence on the absorption, but it still has a certain distance compared with the spray. This situation is better improved when the volatile oil is added to the mixture.
Also we find that the excipients which are added to the spray have an influence on the absorption of the medicine. So we choose Peoniflorin has a poor absorption to investigate the excipients. The results show that chitosan and HP-P-CD have a strong promoting influence on the absorption, and they can be used to the spray as supplementary agents.
引文
[1]庄林根.药物气雾剂的研究概况[J].中国药学杂志,1992,27(10)：620-622
[2]蒋兴国.药物的鼻腔黏膜吸收[J].中国新药杂志,2003,12(11)：902-905
[3]毛世瑞,史哲,毕殿洲.安乃近溶液鼻勃膜吸收的研究[J].中国药学杂志,1997,32(2)：87-90
[4]孙寒静,黄天来,宓穗卿,等.芎冰喷雾剂脑内药物动力学研究[J].中药新药与临床药理,2003,14(3)：177-179
[5]程巧鸳,李范珠.神经毒素纳米粒大鼠鼻腔给药的脑药物动力学研究[J].中国药科大学学报,2007,38(1)：77-79
[6]X Gao, B Wu, Q Zhang, et al. Brain delivery of vasoactive intestinal peptide enhanced with the nanoparticles conjugated with wheat germ agglutinin following intranasal administration [J]. Journal of Controlled Release,2007,121(3):156-167
[7]D Betbeder, S Sperandio, JP Latapie, et al. BiovectorTM Nanoparticles Improve Antinociceptive Efficacy of Nasal MorpHine [J]. PHarmaceutical research,2000,17(6):743-748
[8]L Illum. Nanoparticulate systems for nasal delivery of drugs:A real improvement over simple systems [J]. Journal of PHarmaceutical Sciences,2007,96(3):473-483
[9]Ahn BN, Kim SK, Shim CK. Proliposomes as an intranasal dosage from for the sustained delivery of propranolol [J]. J Control Release,1995,34:203-205
[10]张奕,蒋新国.鼻腔给药新剂型[J].中国医院药学杂志,1999,19(8)：485-488
[11]毛世瑞,毕悦,毕殿洲.盐酸尼卡地平鼻黏膜用明胶微球的工艺研究[J].沈阳药科大学学报,2002,19(2)：79-82
[12]Aspden T J. Chitosan as a nasal delivery system:evaluation of insulin absorp tion enhancement and effect on nasal membrane integrity using rat models [J]. Eur J PHarm Sci,1996,8(1):23-31
[13]Lim S T, Martin G P, Berry D J,et al. Preparation and evaluation of the in vitro drug release properties and mucoadhesion of novel microspHere of hualuronic acid and chitosan [J]. J Controlled Release,2000, 66(23):281-292
[14]Ugwoke M I, Exaud S, VanDen M G, et al. Bioavailability of apomorpHine following intranasal administration of mucoadhesive drug delivery systems in rabbits [J]. Eur J PHarm Sci,1999,9(2):213
[15]Takenaga M, Serizawa Y, Azeclu Y, et al. Microparticle resins as a potential nasal drug delivery system for insulin [J]. J Controlled Release,1998,52(12):81-87
[16]Maitani Y, Nakamura K, Suenaga H, et al. The enhancing effect of soybean- derived sterylglucoside and β-sitosterol-β-glucoside on nasal absorption in rabbits [J]. Int J PHar m,2002,200(1):17-26
[17]刘素筠,张剑宇,段秀兰,等.胰岛素鼻黏膜给药的实验研究[J].中华医学杂志,1998,78(2)：149
[18]Zhang Y, Jiang XG, Yao J. Lowering of sodium deoxycholate-induced nasal ciliotoxicity with cyclodextrins [J]. Acta PHarmacol Sin,2001,22(11):1045-1050
[19]Dahlback M, Eirefelt S, Backstrom K, et al. Enhanced insulin absorption in the rabbit air ways and lung by sodium dioctyl sulfosuccinate [J]. J Aerosol Med,2002,15(1):27-36
[20]Hussain M A, LimMSL, Raghavan K S, et al. A pHospHinic acid dipeptide analogue to stabilize peptide drug during their intranasal absorption [J]. PHarm Res,1992,9(5):626-628
[21]毛厌草,狄留庆,赵晓莉,等.鼻腔给药系统研究现状及在中医药复方中的研究展望[J].中医药导报,2007,13(10)：94-96
[门国家药典委员会.中华人民共和国药典,2005年版1部[M].北京：化学工业出版社,2005
[2]中国药科大学,中国医药科技出版社.中药辞海：第2卷[Z].北京：中国医药科技出版社,1995,2022-2025
[3]Kajima H, Ogura H. Triter penoidsfrom Prunella vul garis[J]. PHytochemistr y,1986,25(3):729-733
[4]Kajima H, Tominga H, SatoS, et al. Pentac yclictriter penoidsfrom Prunella vul garis[J]. PHytochemistr y,1987,26(4):1107-1111
[5]Ka jimaH, Tomin gaH, SatoS, et al. Twonovelhexa cyclictriter penoidsfrom Prunella vul garis [J]. PHytochemistry,1988,27(9):2921-2925
[6]孟正木,何立文.夏枯草化学成分研究[J].中国药科大学学报,1995,26(6)：329-331
[7]张颖君,杨崇仁.法国产夏枯草中的两个新的乌索烷型三萜皂甙[J].云南植物研究,1995,17(4)：468-472
[8]王祝举,赵玉英,涂光忠,等.夏枯草化学成分的研究[J].药学学报,1999,34(9)：679-681
[9]田静,肖志艳,陈雅研,等.夏枯草皂苷A的结构鉴定[J].药学学报,2000,35(1)：29-31
[10]Ka jimaH, SatoN, HatanoA, et al. Sterol glucosides from Prunella vul garis [J]. PH ytochemistry, 1990,29(7):2351-2355
[11]DmitrukSI, DmitrukSE, Berezovska yaTP, et al. Flavonoidsof Prunella vul garis[J]. KhimPrir Soedin, 1987, (3):449-450
[12]DmitrukSI. Coumarinsof Prunella vul garis [J]. KhimPrirSoedin,1986, (4):510-511
[13]JainM, SaxenaVK. Chemical examination of the fat from the leaves of Brunella vul garis [J]. JInstChem(India),1984,56(3):133-134
[14]NatherovaL, RezacovaA. PHarmaco Gnostic studies of 3s peciesofthe genus Prunella L. [J]. ActaFac PHarmUnivComeniana,1972,21:33-61
[15]TabbaHD, Chan gRS, SmithsK. Isolation, purification and characterization of Prunellin, ananti-HIVcomponent from a queousextracts of Prunella vur garis [J]. Antiviral Res,1989,11(5-6):263-273
[16]杨鹿佳,李肇琪,浦帆,等.夏枯草精油组成的GC/FT-IR分析[J].药物分析杂志,1988,8(5)：264-266
[17]何晓燕,赵淑梅,宫汝淳.夏枯草对家兔降压作用机理的研究[J].通化师范学院学报,2002,23(5)：100
[18]刘保林,朱丹妮,王刚,等.夏枯草醇提物对小鼠血糖的影响[J].中国药科大学报,1995,26(1)：44-46
[19]陈淑利,徐声林,陈兵钊.夏枯草提取物降血糖作用的药理学研究[J].中国现代应用药学杂志,2001,18(6)：436
[20]蒋岩,尹建豪,孙晓媛,等.夏枯草对动物脾腺、脾脏和肾上腺的影响[J].甘肃医药,1988,7(4)：4
[21]郑昱,乔成栋,苑伟,等.夏枯草胶囊对溃疡性结肠炎大鼠外周血T淋巴细胞亚群表达的影响[J].中国中西医结合消化杂志,2004,12(1)：10.
[22]Ryu SY, Oak MH, Yoon SK, et al. Anti-allergic and anti-iflammatory triterpenes from the herb of Prunella vulgaris[J]. PlantaMed,2000,66(4):358-360
[23]盛丽,高农,张晓非.19味中药对琳球茵流行株的敏感性研究[J].中国中医药信息杂志,2003,10(4)：48.
[24]肖丽英,黄焯坡.23种中草药对耐药金葡菌的敏感性探讨[J].时珍国医国药,2000,12(10)： 878
[25]Kageyama S.KurokawaM, ShirakiK.Extract of Prunella vulgarspikes inhibits HIV replication at reversetran scription in vitrod can be absorbed from intestine in vivo [J]. Antivi-CHem-Chemother,2000, 11(2):157
[26]Xu HX, Lee SH, Lee SF, et al. Isolation an d characterization an anti-HSV polysaccharide from Prunella vulgaris [J]. Antivir-Res,1999,44(1):43
[27]王琨,董惠芳,章晓鹰等.夏枯草对SGC-790细胞的影响[J].上海医学检验杂志,2000,15(5)：305
[28]周荣耀,徐中伟,倪爱娣,等.夏枯草注射液治疗肺癌胸水的临床和实验研究[J].浙江中西医结合杂志,2001,11(1)：5
[29]徐中伟,周荣耀,王文海,等.夏枯草注射液对胸膜纤维化形成的机理研究[J].上海中医药大学学报,2001,15(2)：49
[30]江苏新医学院.中药大辞典,下册[M].上海：上海科技出版社,1997：2008
[31]国家药典委员会.中国药典,Ⅰ部[S]. 北京：化学工业出版社,1985：126
[32]李英霞,彭广芳,王小梅,等.菊花的药理研究进展[J].时珍国医国药,1998,9(6)：580
[33]贾凌云,孙启时,黄顺旺.滁菊花中黄酮类化学成分的分离与鉴定[J].中国药物化学杂志,2003,13(3)：159
[34]刘金旗,沈其权,刘劲松,等.贡菊化学成分的研究[J].中国中药杂志,2001,26(8)：547
[35]栾连学,孔礼富,杨学运,等.杭白菊化学成分研究[J].现代应用药学,1992,9(4)：160,159
[36]胡立宏,陈仲良.杭白菊的化学成分研究：两个新三萜酯的结构测定[J].植物学报,1997,39(1)： 85
[37]胡立宏,陈仲良.杭白菊的化学成分研究：正戊基果糖甙的结构测定[J].植物学报,1997,39(2)： 181
[38]Chang Qi Hu, Ke Chen, Qian Shi, et al. Anti-aids agents,10. acacetin-7-O-β-D-galact opyranoside, an anti-HIV principle from Chrysanthem um morifolium and astructure activity correlation with some related flavonoids [J]. Journal of Natural Products,1994,57(1):42
[39]Satoshi Terashi ma, Mineo Shimizu, Syunji Horie, et al. Studies on aldose reductase inhibitors from natural products. IV. Constituents and aldose reductase effect of Chrysanthem um morifolium, Bixa orellana and Ipomoeabatatas [J]. Chem. PHarm. Bull,1991,39(12):3346
[40]邢振荣,马金民,沈雁书,等.不同品种及产地的杭菊成分测定[J].中草药,1992,23(3)：129
[41]黄保民,周刚.均匀设计法对怀菊花总黄酮提取工艺的研究[J].中医研究,1996,9(4)：8
[42]刘金旗,工兰,刘劲松,等.菊花叶黄酮类化合物的实验分析[J].中国中医药科技,2002,9(4)：226
[43]刘金旗,吴德林,王兰,等.菊花中黄酮苷的含量分析[J].中草药,2001,32(4)：308
[44]胡碧波,蒋惠娣,杨俊,等.HPLC法测定不同采收期杭白菊中木犀草素及其菅的含量[J].浙江大学学报(医学版),2004,33(1)：29
[45]Motohiko Ukiya, Toshihiro Akihisa, Ken Yasukawa,et al. Constituents of Compositae Plants.2. triter penediols, triols, and their 3-O-Triterpene fatty acid esters from edible Chrysanthemum flower extract and their anti-inflammat ory effects [J]. J. Agric. Food,2001,49:3187
[46]刘伟,郭庭江.不同产地菊花中挥发油的GC-MS分析[J].河南中医学刊,1995,10(5)：12
[47]黄保民,刘杰.气质联用法对怀菊花及“大怀菊”挥发油化学成分的分析与比较[J].中医研究,1997,10(5)：14
[48]鲍忠定,秦志荣,许荣年,等.杭白菊挥发油化学成分的气相色谱-质谱联用技术分析[J].食 品科学,2003,24(6)：120
[49]A. Shahat, S. Apers, L. Pieters, et al. Is olati on and complete NMR assignment of the numbing principle from Chrysanthem um morifolium [J]. Fitoterapia,2001,72:89
[50]Rong Tsao, Athula B. Attygalle, Frank C. Schroeder, et al. Is obutylamides of unsaturated fatty acids from Chrysanthem um morifolium associated with host-plant risistance against the western flower tmips [J]. J. Nat. Prod.,2003,66:1229
[51]蒋惠娣,夏强.杭白菊的心血管药理作用及其机制研究进展[J].世界科学技术-中药现代化,2002,4(2)：31
[52]蔡宝昌,潘扬,吴皓,等.国外天然药物抗病毒研究简况[J].国外医学中医中药分册,1997,19(3)： 31
[53]李献平,刘世昌.四大怀药对家蚕奉命及生长发育的影响[J].中国中医杂志,1990,15(9)：51
[54]李献平,刘敏,刘世昌,等.四大怀药延缓衰老作用的研究[J].中西医结合杂志,1991,11(8)：486
[55]胡春,丁霄霖.菊花提取物对实验动物抗疲劳和降血脂作用的研究[J].食品科学,1996,17(10)：58
[56]苏祝成,叶立杨.杭白菊浸提液的不同萃取分离物对O2自由基清除作用研究[J].食品科学,1995,16(2)：60
[57]胡春,丁霄霖.菊花提取物对人红细胞膜的保护作用研究[J].食品科学,1996,17(2)：7
[58]Ken Yasukawa, Toshihir o Akihisa, Yoshimasa Kasahara, et al. Inhibitory effect of heliantriol C; a component of edible Chrysanthemum, ontumor promoti on by 12-O-tetradecanoylpHorbol-13-acetate in two-stage carcinogenesis in mouse skin [J]. PHytomedicine,1998,5:215
[59]Mot ohiko Ukiya, Toshihir o Akihisa, Harukuni Tokuda, et al. Constituents of Compositae plants III. Anti-tumor promoting effects and cytotoxic activity against human cancer cell lines of triter pene diols and triols from edible Chrysanthemum flowers [J]. Cancer Letters,2002,177:7
[60]中华人民共和国药典委员会编.《中华人民共和国药典》一部,2000年版.北京：化学工业出版社,2002：125
[61]胡世林,付桂兰,冯学锋,等.不同产地和部位赤芍中芍药苷的含量测定[J].中国中药杂志,2000,25(12)：714-716
[62]陈海生,廖时萱,洪志军,等.川赤芍化学成分的研究[J].中国药学杂志,1993,28(3)：137-138
[63]刘超,王静,杨军.赤芍总甙活血化瘀作用的研究[J].中药材,2000,23(9)：557-560
[64]李文,殷小杰,廖福龙,等.六种产地赤芍对大鼠抗凝血及抗血小板聚集作用的比较[J].中国实验方剂学杂志,2001,7(6)：30-31
[65]廖福龙,李文,殷小杰,等.用扫描仪评价不同产地赤芍提取物对红细胞聚集的抑制作用[J].中国血液流变学杂志,2001,11(3)：175-178
[66]赵春景,王芳,赫飞.赤芍对乙肝黄疽患者红细胞通透性的影响[J].中医药研究,1999,15(5)：42-43
[67]邓常青,柯庆,贺石林.赤芍抗凝血作用的实验研究[J].中药药理与临床,1991,7(1)：20-23
[68]徐红梅,刘青云,戴敏,等.赤芍总甙抗血栓作用研究[J].安徽中医学院学报,2000,19(1)：46-47
[69]郑丽丽,阎西艴,张永珍,等.赤芍对高脂兔血小板胞浆游离钙、红细胞膜Ca2+,Mg2+-ATP酶活性的影响[J].中国中西医结合杂志,1996,16(5)：295-296
[70]吴家斌,舒贵扬.赤芍801对肾病综合征患者血脂和血液流变学的影响[J].中药药理与临床,2001,17(1)：45-46
[7门于永红,王瑞英.赤芍、尼群地平对家兔实验性动脉粥样硬化病灶的消退作用[J].临床心血管 病杂志,1996,12(3)：164-167
[72]梁日欣,黄璐琦,刘菊福,等.药对川芎和赤芍对高脂血症大鼠降脂、抗氧化及血管内皮功能的实验观察[J].中国实验方剂学杂志,2002,8(1)：43-45
[73]楚正绪,谭建权,张亚霏.赤芍提取物对烫伤大鼠早期心肌力学的影响[J].中成药,1989,12(7)：23-25
[74]黄志勇,余金甫,熊桂先.赤芍对油酸致成人呼吸窘迫综合征治疗作用的观察[J].中国危重病急救医学,1995,7(5)：257-259
[75]楚正绪,谭建权,张亚霏.赤芍提取物对烫伤大鼠肠细膜微循环的影响[J].中华整形烧伤外科杂志,1990,6(2)：128-130
[76]何丽娜,杨军,何素冰,等.赤芍总甙对原代培养大鼠神经细胞损伤模型的保护作用[J].中国临床药理学与治疗学,2000,5(1)：28-31
[77]杨军,马传庚.赤芍总苷治疗缺血性脑血管病作用及其机制[J].安徽医科大学学报,2001,36(2)：164-165
[78]黄孔威,傅乃武.赤芍对实验肿瘤生长和转移的影响及药理作用的研究[J].中华肿瘤杂志,1983,5(1)：24-27
[79]丁罡,宋明志,于尔辛.丹参、赤芍对大鼠Walker256癌肝转移影响机制的研究[J].中国癌症杂志,2001,11(4)：364-366
[80]陈晓宇,宗云奎.三种中草药及其复方体外对HBsAg、HBeAg分泌的抑制[J].中国药物与临床,2002,2(1)：46-48
[81]李凌,杨大国,陶艳艳.赤芍承气汤对重型肝炎内毒素血症的影响[J].浙江中西医结合杂志,2002,12(9)：538-540
[82]李洪武,朱文元,夏明玉,等.5种上调酪氨酸酶活性中药乙醇提取液对棕黄色豚鼠背部皮肤的增色作用[J].临床皮肤科杂志,2001,30(2)：69-71
[83]Hsu FL, Lai CW, Cheng JT. Antihyperglycemic effects of paeoni-florin and 8-debenzoylpaeoniflorin, glucosides from the root ofPaeonia lactiflora [J]. Planta Med,1997,63(4):323-325
[1]池玉美,狄留庆,崔小兵,等.HPLC双波长梯度洗脱同时测定通塞脉微丸中绿原酸、阿魏酸、甘草苷的含量[J].中国药学杂志,2007,42(17)：1348-1350
[2]狄留庆,张丽云,沈金文,等.HPLC测定血压平滴鼻剂中芍药甙的含量[J].中国中药杂志,1999,24(1)：35-36
[3]蔡少青,谢丽华,王建华,等.中药玄参中哈巴俄苷和肉桂酸的高效液相色谱法测定[J].药物分析杂志,2000,20(3)：191-194
[4]Hussain A, Hirai S, Bawarshi R, et al. Nasal absorption of propranolol from different dosage forms by rats and dogs [J]. J PHarm Sci,1980,69:1411-1413
[5]王晖,薛漫清.呋塞米的鼻腔吸收及薄荷醇的促进作用[J].中国临床药理学与治疗学,2000,5：59-60
[6]祝美华,沈丽霞,张新房.滴通鼻炎水质量标准研究[J].中成药,2008,30(7)：10-12
[7]李传响,刘红.HPLC法测定呋麻滴鼻液中盐酸麻黄碱的含量[J].中国药师,2006,9(10)：974
[8]Hirai, S., Yashiki, T., Matsuzaw, H. Absorption of drugs from the nasal mueosa of rats [J]. Int. J. PHarm.1981,7:317-327
[9]Heng, R. C., Kimura, R., Nassar, R. B., et. al. Mechanism of nasal absorption of drugs I: PHysieoehemical Parameters influeneing the rate of in situ nasal absorption [J]. J. PHarm. Sci.1985,74: 608-611
[10]崔景斌,奚念朱,蒋新国.鼻腔作为全身给药途径的研究[J].中国药学杂志,1998,18：493-496
[2]蒋兴国.药物的鼻腔黏膜吸收[J].中国新药杂志,2003,12(11)：902-905
[3]毛世瑞,史哲,毕殿洲.安乃近溶液鼻勃膜吸收的研究[J].中国药学杂志,1997,32(2)：87-90
[4]孙寒静,黄天来,宓穗卿,等.芎冰喷雾剂脑内药物动力学研究[J].中药新药与临床药理,2003,14(3)：177-179
[5]程巧鸳,李范珠.神经毒素纳米粒大鼠鼻腔给药的脑药物动力学研究[J].中国药科大学学报,2007,38(1)：77-79
[6]X Gao, B Wu, Q Zhang, et al. Brain delivery of vasoactive intestinal peptide enhanced with the nanoparticles conjugated with wheat germ agglutinin following intranasal administration [J]. Journal of Controlled Release,2007,121(3):156-167
[7]D Betbeder, S Sperandio, JP Latapie, et al. BiovectorTM Nanoparticles Improve Antinociceptive Efficacy of Nasal MorpHine [J]. PHarmaceutical research,2000,17(6):743-748
[8]L Illum. Nanoparticulate systems for nasal delivery of drugs:A real improvement over simple systems [J]. Journal of PHarmaceutical Sciences,2007,96(3):473-483
[9]Ahn BN, Kim SK, Shim CK. Proliposomes as an intranasal dosage from for the sustained delivery of propranolol [J]. J Control Release,1995,34:203-205
[10]张奕,蒋新国.鼻腔给药新剂型[J].中国医院药学杂志,1999,19(8)：485-488
[11]毛世瑞,毕悦,毕殿洲.盐酸尼卡地平鼻黏膜用明胶微球的工艺研究[J].沈阳药科大学学报,2002,19(2)：79-82
[12]Aspden T J. Chitosan as a nasal delivery system:evaluation of insulin absorp tion enhancement and effect on nasal membrane integrity using rat models [J]. Eur J PHarm Sci,1996,8(1):23-31
[13]Lim S T, Martin G P, Berry D J,et al. Preparation and evaluation of the in vitro drug release properties and mucoadhesion of novel microspHere of hualuronic acid and chitosan [J]. J Controlled Release,2000, 66(23):281-292
[14]Ugwoke M I, Exaud S, VanDen M G, et al. Bioavailability of apomorpHine following intranasal administration of mucoadhesive drug delivery systems in rabbits [J]. Eur J PHarm Sci,1999,9(2):213
[15]Takenaga M, Serizawa Y, Azeclu Y, et al. Microparticle resins as a potential nasal drug delivery system for insulin [J]. J Controlled Release,1998,52(12):81-87
[16]Maitani Y, Nakamura K, Suenaga H, et al. The enhancing effect of soybean- derived sterylglucoside and β-sitosterol-β-glucoside on nasal absorption in rabbits [J]. Int J PHar m,2002,200(1):17-26
[17]刘素筠,张剑宇,段秀兰,等.胰岛素鼻黏膜给药的实验研究[J].中华医学杂志,1998,78(2)：149
[18]Zhang Y, Jiang XG, Yao J. Lowering of sodium deoxycholate-induced nasal ciliotoxicity with cyclodextrins [J]. Acta PHarmacol Sin,2001,22(11):1045-1050
[19]Dahlback M, Eirefelt S, Backstrom K, et al. Enhanced insulin absorption in the rabbit air ways and lung by sodium dioctyl sulfosuccinate [J]. J Aerosol Med,2002,15(1):27-36
[20]Hussain M A, LimMSL, Raghavan K S, et al. A pHospHinic acid dipeptide analogue to stabilize peptide drug during their intranasal absorption [J]. PHarm Res,1992,9(5):626-628
[21]毛厌草,狄留庆,赵晓莉,等.鼻腔给药系统研究现状及在中医药复方中的研究展望[J].中医药导报,2007,13(10)：94-96
[门国家药典委员会.中华人民共和国药典,2005年版1部[M].北京：化学工业出版社,2005
[2]中国药科大学,中国医药科技出版社.中药辞海：第2卷[Z].北京：中国医药科技出版社,1995,2022-2025
[3]Kajima H, Ogura H. Triter penoidsfrom Prunella vul garis[J]. PHytochemistr y,1986,25(3):729-733
[4]Kajima H, Tominga H, SatoS, et al. Pentac yclictriter penoidsfrom Prunella vul garis[J]. PHytochemistr y,1987,26(4):1107-1111
[5]Ka jimaH, Tomin gaH, SatoS, et al. Twonovelhexa cyclictriter penoidsfrom Prunella vul garis [J]. PHytochemistry,1988,27(9):2921-2925
[6]孟正木,何立文.夏枯草化学成分研究[J].中国药科大学学报,1995,26(6)：329-331
[7]张颖君,杨崇仁.法国产夏枯草中的两个新的乌索烷型三萜皂甙[J].云南植物研究,1995,17(4)：468-472
[8]王祝举,赵玉英,涂光忠,等.夏枯草化学成分的研究[J].药学学报,1999,34(9)：679-681
[9]田静,肖志艳,陈雅研,等.夏枯草皂苷A的结构鉴定[J].药学学报,2000,35(1)：29-31
[10]Ka jimaH, SatoN, HatanoA, et al. Sterol glucosides from Prunella vul garis [J]. PH ytochemistry, 1990,29(7):2351-2355
[11]DmitrukSI, DmitrukSE, Berezovska yaTP, et al. Flavonoidsof Prunella vul garis[J]. KhimPrir Soedin, 1987, (3):449-450
[12]DmitrukSI. Coumarinsof Prunella vul garis [J]. KhimPrirSoedin,1986, (4):510-511
[13]JainM, SaxenaVK. Chemical examination of the fat from the leaves of Brunella vul garis [J]. JInstChem(India),1984,56(3):133-134
[14]NatherovaL, RezacovaA. PHarmaco Gnostic studies of 3s peciesofthe genus Prunella L. [J]. ActaFac PHarmUnivComeniana,1972,21:33-61
[15]TabbaHD, Chan gRS, SmithsK. Isolation, purification and characterization of Prunellin, ananti-HIVcomponent from a queousextracts of Prunella vur garis [J]. Antiviral Res,1989,11(5-6):263-273
[16]杨鹿佳,李肇琪,浦帆,等.夏枯草精油组成的GC/FT-IR分析[J].药物分析杂志,1988,8(5)：264-266
[17]何晓燕,赵淑梅,宫汝淳.夏枯草对家兔降压作用机理的研究[J].通化师范学院学报,2002,23(5)：100
[18]刘保林,朱丹妮,王刚,等.夏枯草醇提物对小鼠血糖的影响[J].中国药科大学报,1995,26(1)：44-46
[19]陈淑利,徐声林,陈兵钊.夏枯草提取物降血糖作用的药理学研究[J].中国现代应用药学杂志,2001,18(6)：436
[20]蒋岩,尹建豪,孙晓媛,等.夏枯草对动物脾腺、脾脏和肾上腺的影响[J].甘肃医药,1988,7(4)：4
[21]郑昱,乔成栋,苑伟,等.夏枯草胶囊对溃疡性结肠炎大鼠外周血T淋巴细胞亚群表达的影响[J].中国中西医结合消化杂志,2004,12(1)：10.
[22]Ryu SY, Oak MH, Yoon SK, et al. Anti-allergic and anti-iflammatory triterpenes from the herb of Prunella vulgaris[J]. PlantaMed,2000,66(4):358-360
[23]盛丽,高农,张晓非.19味中药对琳球茵流行株的敏感性研究[J].中国中医药信息杂志,2003,10(4)：48.
[24]肖丽英,黄焯坡.23种中草药对耐药金葡菌的敏感性探讨[J].时珍国医国药,2000,12(10)： 878
[25]Kageyama S.KurokawaM, ShirakiK.Extract of Prunella vulgarspikes inhibits HIV replication at reversetran scription in vitrod can be absorbed from intestine in vivo [J]. Antivi-CHem-Chemother,2000, 11(2):157
[26]Xu HX, Lee SH, Lee SF, et al. Isolation an d characterization an anti-HSV polysaccharide from Prunella vulgaris [J]. Antivir-Res,1999,44(1):43
[27]王琨,董惠芳,章晓鹰等.夏枯草对SGC-790细胞的影响[J].上海医学检验杂志,2000,15(5)：305
[28]周荣耀,徐中伟,倪爱娣,等.夏枯草注射液治疗肺癌胸水的临床和实验研究[J].浙江中西医结合杂志,2001,11(1)：5
[29]徐中伟,周荣耀,王文海,等.夏枯草注射液对胸膜纤维化形成的机理研究[J].上海中医药大学学报,2001,15(2)：49
[30]江苏新医学院.中药大辞典,下册[M].上海：上海科技出版社,1997：2008
[31]国家药典委员会.中国药典,Ⅰ部[S]. 北京：化学工业出版社,1985：126
[32]李英霞,彭广芳,王小梅,等.菊花的药理研究进展[J].时珍国医国药,1998,9(6)：580
[33]贾凌云,孙启时,黄顺旺.滁菊花中黄酮类化学成分的分离与鉴定[J].中国药物化学杂志,2003,13(3)：159
[34]刘金旗,沈其权,刘劲松,等.贡菊化学成分的研究[J].中国中药杂志,2001,26(8)：547
[35]栾连学,孔礼富,杨学运,等.杭白菊化学成分研究[J].现代应用药学,1992,9(4)：160,159
[36]胡立宏,陈仲良.杭白菊的化学成分研究：两个新三萜酯的结构测定[J].植物学报,1997,39(1)： 85
[37]胡立宏,陈仲良.杭白菊的化学成分研究：正戊基果糖甙的结构测定[J].植物学报,1997,39(2)： 181
[38]Chang Qi Hu, Ke Chen, Qian Shi, et al. Anti-aids agents,10. acacetin-7-O-β-D-galact opyranoside, an anti-HIV principle from Chrysanthem um morifolium and astructure activity correlation with some related flavonoids [J]. Journal of Natural Products,1994,57(1):42
[39]Satoshi Terashi ma, Mineo Shimizu, Syunji Horie, et al. Studies on aldose reductase inhibitors from natural products. IV. Constituents and aldose reductase effect of Chrysanthem um morifolium, Bixa orellana and Ipomoeabatatas [J]. Chem. PHarm. Bull,1991,39(12):3346
[40]邢振荣,马金民,沈雁书,等.不同品种及产地的杭菊成分测定[J].中草药,1992,23(3)：129
[41]黄保民,周刚.均匀设计法对怀菊花总黄酮提取工艺的研究[J].中医研究,1996,9(4)：8
[42]刘金旗,工兰,刘劲松,等.菊花叶黄酮类化合物的实验分析[J].中国中医药科技,2002,9(4)：226
[43]刘金旗,吴德林,王兰,等.菊花中黄酮苷的含量分析[J].中草药,2001,32(4)：308
[44]胡碧波,蒋惠娣,杨俊,等.HPLC法测定不同采收期杭白菊中木犀草素及其菅的含量[J].浙江大学学报(医学版),2004,33(1)：29
[45]Motohiko Ukiya, Toshihiro Akihisa, Ken Yasukawa,et al. Constituents of Compositae Plants.2. triter penediols, triols, and their 3-O-Triterpene fatty acid esters from edible Chrysanthemum flower extract and their anti-inflammat ory effects [J]. J. Agric. Food,2001,49:3187
[46]刘伟,郭庭江.不同产地菊花中挥发油的GC-MS分析[J].河南中医学刊,1995,10(5)：12
[47]黄保民,刘杰.气质联用法对怀菊花及“大怀菊”挥发油化学成分的分析与比较[J].中医研究,1997,10(5)：14
[48]鲍忠定,秦志荣,许荣年,等.杭白菊挥发油化学成分的气相色谱-质谱联用技术分析[J].食 品科学,2003,24(6)：120
[49]A. Shahat, S. Apers, L. Pieters, et al. Is olati on and complete NMR assignment of the numbing principle from Chrysanthem um morifolium [J]. Fitoterapia,2001,72:89
[50]Rong Tsao, Athula B. Attygalle, Frank C. Schroeder, et al. Is obutylamides of unsaturated fatty acids from Chrysanthem um morifolium associated with host-plant risistance against the western flower tmips [J]. J. Nat. Prod.,2003,66:1229
[51]蒋惠娣,夏强.杭白菊的心血管药理作用及其机制研究进展[J].世界科学技术-中药现代化,2002,4(2)：31
[52]蔡宝昌,潘扬,吴皓,等.国外天然药物抗病毒研究简况[J].国外医学中医中药分册,1997,19(3)： 31
[53]李献平,刘世昌.四大怀药对家蚕奉命及生长发育的影响[J].中国中医杂志,1990,15(9)：51
[54]李献平,刘敏,刘世昌,等.四大怀药延缓衰老作用的研究[J].中西医结合杂志,1991,11(8)：486
[55]胡春,丁霄霖.菊花提取物对实验动物抗疲劳和降血脂作用的研究[J].食品科学,1996,17(10)：58
[56]苏祝成,叶立杨.杭白菊浸提液的不同萃取分离物对O2自由基清除作用研究[J].食品科学,1995,16(2)：60
[57]胡春,丁霄霖.菊花提取物对人红细胞膜的保护作用研究[J].食品科学,1996,17(2)：7
[58]Ken Yasukawa, Toshihir o Akihisa, Yoshimasa Kasahara, et al. Inhibitory effect of heliantriol C; a component of edible Chrysanthemum, ontumor promoti on by 12-O-tetradecanoylpHorbol-13-acetate in two-stage carcinogenesis in mouse skin [J]. PHytomedicine,1998,5:215
[59]Mot ohiko Ukiya, Toshihir o Akihisa, Harukuni Tokuda, et al. Constituents of Compositae plants III. Anti-tumor promoting effects and cytotoxic activity against human cancer cell lines of triter pene diols and triols from edible Chrysanthemum flowers [J]. Cancer Letters,2002,177:7
[60]中华人民共和国药典委员会编.《中华人民共和国药典》一部,2000年版.北京：化学工业出版社,2002：125
[61]胡世林,付桂兰,冯学锋,等.不同产地和部位赤芍中芍药苷的含量测定[J].中国中药杂志,2000,25(12)：714-716
[62]陈海生,廖时萱,洪志军,等.川赤芍化学成分的研究[J].中国药学杂志,1993,28(3)：137-138
[63]刘超,王静,杨军.赤芍总甙活血化瘀作用的研究[J].中药材,2000,23(9)：557-560
[64]李文,殷小杰,廖福龙,等.六种产地赤芍对大鼠抗凝血及抗血小板聚集作用的比较[J].中国实验方剂学杂志,2001,7(6)：30-31
[65]廖福龙,李文,殷小杰,等.用扫描仪评价不同产地赤芍提取物对红细胞聚集的抑制作用[J].中国血液流变学杂志,2001,11(3)：175-178
[66]赵春景,王芳,赫飞.赤芍对乙肝黄疽患者红细胞通透性的影响[J].中医药研究,1999,15(5)：42-43
[67]邓常青,柯庆,贺石林.赤芍抗凝血作用的实验研究[J].中药药理与临床,1991,7(1)：20-23
[68]徐红梅,刘青云,戴敏,等.赤芍总甙抗血栓作用研究[J].安徽中医学院学报,2000,19(1)：46-47
[69]郑丽丽,阎西艴,张永珍,等.赤芍对高脂兔血小板胞浆游离钙、红细胞膜Ca2+,Mg2+-ATP酶活性的影响[J].中国中西医结合杂志,1996,16(5)：295-296
[70]吴家斌,舒贵扬.赤芍801对肾病综合征患者血脂和血液流变学的影响[J].中药药理与临床,2001,17(1)：45-46
[7门于永红,王瑞英.赤芍、尼群地平对家兔实验性动脉粥样硬化病灶的消退作用[J].临床心血管 病杂志,1996,12(3)：164-167
[72]梁日欣,黄璐琦,刘菊福,等.药对川芎和赤芍对高脂血症大鼠降脂、抗氧化及血管内皮功能的实验观察[J].中国实验方剂学杂志,2002,8(1)：43-45
[73]楚正绪,谭建权,张亚霏.赤芍提取物对烫伤大鼠早期心肌力学的影响[J].中成药,1989,12(7)：23-25
[74]黄志勇,余金甫,熊桂先.赤芍对油酸致成人呼吸窘迫综合征治疗作用的观察[J].中国危重病急救医学,1995,7(5)：257-259
[75]楚正绪,谭建权,张亚霏.赤芍提取物对烫伤大鼠肠细膜微循环的影响[J].中华整形烧伤外科杂志,1990,6(2)：128-130
[76]何丽娜,杨军,何素冰,等.赤芍总甙对原代培养大鼠神经细胞损伤模型的保护作用[J].中国临床药理学与治疗学,2000,5(1)：28-31
[77]杨军,马传庚.赤芍总苷治疗缺血性脑血管病作用及其机制[J].安徽医科大学学报,2001,36(2)：164-165
[78]黄孔威,傅乃武.赤芍对实验肿瘤生长和转移的影响及药理作用的研究[J].中华肿瘤杂志,1983,5(1)：24-27
[79]丁罡,宋明志,于尔辛.丹参、赤芍对大鼠Walker256癌肝转移影响机制的研究[J].中国癌症杂志,2001,11(4)：364-366
[80]陈晓宇,宗云奎.三种中草药及其复方体外对HBsAg、HBeAg分泌的抑制[J].中国药物与临床,2002,2(1)：46-48
[81]李凌,杨大国,陶艳艳.赤芍承气汤对重型肝炎内毒素血症的影响[J].浙江中西医结合杂志,2002,12(9)：538-540
[82]李洪武,朱文元,夏明玉,等.5种上调酪氨酸酶活性中药乙醇提取液对棕黄色豚鼠背部皮肤的增色作用[J].临床皮肤科杂志,2001,30(2)：69-71
[83]Hsu FL, Lai CW, Cheng JT. Antihyperglycemic effects of paeoni-florin and 8-debenzoylpaeoniflorin, glucosides from the root ofPaeonia lactiflora [J]. Planta Med,1997,63(4):323-325
[1]池玉美,狄留庆,崔小兵,等.HPLC双波长梯度洗脱同时测定通塞脉微丸中绿原酸、阿魏酸、甘草苷的含量[J].中国药学杂志,2007,42(17)：1348-1350
[2]狄留庆,张丽云,沈金文,等.HPLC测定血压平滴鼻剂中芍药甙的含量[J].中国中药杂志,1999,24(1)：35-36
[3]蔡少青,谢丽华,王建华,等.中药玄参中哈巴俄苷和肉桂酸的高效液相色谱法测定[J].药物分析杂志,2000,20(3)：191-194
[4]Hussain A, Hirai S, Bawarshi R, et al. Nasal absorption of propranolol from different dosage forms by rats and dogs [J]. J PHarm Sci,1980,69:1411-1413
[5]王晖,薛漫清.呋塞米的鼻腔吸收及薄荷醇的促进作用[J].中国临床药理学与治疗学,2000,5：59-60
[6]祝美华,沈丽霞,张新房.滴通鼻炎水质量标准研究[J].中成药,2008,30(7)：10-12
[7]李传响,刘红.HPLC法测定呋麻滴鼻液中盐酸麻黄碱的含量[J].中国药师,2006,9(10)：974
[8]Hirai, S., Yashiki, T., Matsuzaw, H. Absorption of drugs from the nasal mueosa of rats [J]. Int. J. PHarm.1981,7:317-327
[9]Heng, R. C., Kimura, R., Nassar, R. B., et. al. Mechanism of nasal absorption of drugs I: PHysieoehemical Parameters influeneing the rate of in situ nasal absorption [J]. J. PHarm. Sci.1985,74: 608-611
[10]崔景斌,奚念朱,蒋新国.鼻腔作为全身给药途径的研究[J].中国药学杂志,1998,18：493-496