摘要
马钱子(Strychnos nux-vomica L)是常用有毒中药,在传统用药中,马钱子和含马钱子的复方药物临床疗效卓越,通络止痛、散结消肿之功尤为显著。但口服治疗窗窄的问题严重制约了其临床应用。究其原因,这主要与其主要毒性成分士的宁(Strychnine)、马钱子碱(Brucine)等生物碱同时也是主要药效成分有关。现代研究表明,马钱子碱是马钱子生物碱中药理活性较高的主要成分,且毒性远低于士的宁。因此,将马钱子碱开发成使用方便、作用持久、安全有效的透皮给药制剂有着非常重要的临床意义。
为此本文详细做了马钱子碱的处方前研究,包括不同pH值下的油水分配系数、不同pH值下的透皮吸收性质、药物的血浆蛋白结合率等；考察并优选了亲脂性和亲水性两种基质的贴剂制备工艺,并对两种基质的贴剂体外透皮性能进行了比较；采用热板法、扭体法进行了贴剂的镇痛药效学研究；并在此基础之上,选用有效剂量进行了药物动力学的研究,比较了静脉给药和经皮给药的不同药动学行为。为今后这一新药的进一步研究开发提供了有力的科学依据。
马钱子碱体外经皮吸收性质的研究表明,在pH值分别为5,6,7.4,8,9时,马钱子碱的油水分配系数为0.04,0.25,3.59,11.02,26.05；体外经皮吸收的单位面积累积透过总量分别为：(125.08±11.29),(156.957±12.086),(140.442±18.011),(154.696±12.612),(166.412±5.469)μg·cm-2;累积透过百分率分别为：(56.785±7.825)%,(71.258±5.46)%,(63.760±8.176)%,(70.232±5.72)%,(75.551±2.48)%；透皮速率为：29.505,29.245,25.674,30.261,45.147μg·cm-2·h-1。可见随着pH值的增大,油水分配系数、单位面积透过量、透过百分率和透皮速率总体趋势随之增加。值得注意的是,在pH为9时,油水分配系数和透皮速率差异显著(p<0.01),但累计透过百分率无显著性差异。说明在pH值大于药物解离常数的情况下,油水分配系数随之显著增大,药物更易透过人体皮肤表面的亲脂性角质层,因此透皮速率也大大增加。但在相同上样量的情况下,药物的累积透过量并无显著增加,这可能与皮肤两侧的药物浓度差固定有关。
马钱子碱在高、中、低3个血药质量浓度的血浆蛋白结合率呈现非质量浓度依赖性,结合率在59%左右,属中等强度的蛋白结合率。
本文考察了油酸、吐温-80、Azone、二甲基亚砜、乙醇等五种促渗剂对马钱子碱溶液的促渗作用,结果表明大部分促渗剂对马钱子碱溶液的体外透过性能均有不同程度的提高,促渗性能依次为Azone>乙醇>二甲基亚砜>吐温-80>油酸,其中Azone促渗效果最为显著,与空白组相比,经皮吸收速度(力提高近4倍,单位面积透过量(Q)提高2.58倍。
本文选用L9(34)正交实验表对透皮贴剂进行了处方的优化。以贴剂的外观性状和累积渗透量为综合考察指标,其中贴剂的外观形状又包括均匀性、可涂展性、粘度、剥离强度等,进行综合打分。亲脂性基质贴剂的优选结果为：压敏胶(E100)：增塑剂(癸二酸二丁酯)：交联剂(丁二酸)=10：4：1,加25%增粘剂PEG400、3%促透剂氮酮；亲水性基质贴剂的优选结果为：羧甲基纤维素钠(CMC-Na):聚乙烯醇(PVA)：聚乙烯吡咯烷酮(PVP)K30：甘油=2：3：1：1.5,加3%促渗剂氮酮。(基质的浓度分别为CMC-Na:6.67%,PVA：20%,PVP：100%)。对两种基质的贴剂透皮性能的对比表明：亲脂性基质贴剂呈现先快后慢的释药特点,6h基本已经释药完全,对透皮曲线做切线得出释药速率Q=59.626t-0.436,释药过程符合Higuchi方程(R2=0.902)；而亲水性基质贴剂在24h内,呈现出持续恒速的释药特点,Q=5.2504t-0.6844(R2=0.994),更符合零级释药过程。因此,亲水性基质贴剂能够达到持续、恒速、缓慢释药的要求,保证体内血药浓度的平稳,更符合制备马钱子碱透皮贴剂的要求。
本文采用热板法对亲水性基质贴剂所做的药效学镇痛实验表明：给药组在60,120,240mg·kg-1这低、中、高三个剂量下,呈现出良好的剂量依赖性,由时辰-效应图可见,6h时各组镇痛效应达到最大值,其中高剂量的镇痛百分率达到约120%,与阳性药云南白药贴镇痛效应相当。由扭体法可以看出,与赋形剂组相比,在60,120,240mg·kg-1这低、中、高三个给药剂量下,中剂量和高剂量均表现出良好的扭体抑制作用,镇痛百分率均大于50%(P<0.01),而低剂量无明显的抑制作用(p>0.05)
本文还进行了马钱子碱溶液静脉注射和马钱子碱亲水性基质贴剂的药物动力学研究。通过DAS2.0软件的数据处理可以看出,MRT值分别为49.12min和451.89min,马钱子碱贴剂的MRT延长了近10倍,绝对生物利用度达到34.76%。与静脉注射相比,马钱子碱以贴剂的方式给药,经皮给药后的血药浓度峰值显著降低且更加平稳,并能维持相当长的时间,非常有利于马钱子碱在发挥疗效的同时显著降低毒性,也在一定程度上证实了经皮途径给药是避免马钱子碱毒性反应有效手段的推测。
Strychnos nux-vomica L is commonly used toxiferous Chinese medicine. In traditional clinical medication, Strychnos nux-vomica L and its compound medicine exhibit excellent therapeutic effect, particularly in dredging collaterals, causing analgesia, eliminating stagnation, and subsiding swelling. However, the narrow oral therapeutic window seriously restricts its clinical application. As a matter of fact, the reason is that Strychnine and Brucine are the main toxiferous components as well as the principal bioactive ingredients. In the modern research studies, Strychnine has great toxicity but little curative effect; therefore, in general, the analgesic effect is closely related to Brucine. Consequently, it possesses very important clinical significance to develop Brucine into safe transdermal delivery dosage forms with convenient and accurate medication and persistent therapeutic effect.
Thus, this paper conducts a detailed research study on the properties of Brucine, including oil-water partition coefficient, transdermal absorption capacities in vitro and its plasma protein binding rate at different PH values. Also, it explores and optimizes lipophilic and hydrophilic ground substances respectively in the patch preparation technology, and compares their transdermal absorption capacities in vitro. Besides, it adopts hot-plate test and acetic acid-induced writhing test in mice to examine the analgesic effect of patches, and on this basis, it selects effective dose to research pharmacokinetics in different ways of intravenous injection and transdermal medication. In short, this paper provides powerful scientific evidence for a successful production of Brucine hereafter.
The research study on Brucine's transdermal absorption capacities in vitro indicates that at PH of 5,6,7.4,8 and 9 individually, the respective oil-water partition coefficient of Brucine is 0.04, 025,3.59,11.02 and 26.05; the respective accumulated permeation volume dose per unit area of transdermal absorption in vitro is (125.08±11.29), (156.957±12.086), (140.442±18.011), (154.696±12.612) and (166.412±5.469)μg·cm-2; the respective accumulated permeation percent is (56.785±7.825)%, (71.258±5.46)%, (63.760±8.176)%, (70.232±5.72)% and (75.551±2.48)%; and the respective transdermal rate is 29.505,29.245,25.674,30.261 and 45.147μg·cm-2·h-1. Therefore, as the PH value rises, oil-water partition coefficient, accumulated permeation volume dose per unit area, accumulated permeation percent and permeation rate generally increase. In addition, it is noteworthy that at a PH of 9, oil-water partition coefficient and permeation rate have significant differences (p<0.01), while the accumulated permeation percent shows no difference. In fact, when PH value is greater than the dissociation constant of drugs (Brucine pka value is 8.20), oil-water partition coefficient increased remarkably and permeation rate also become faster because the drugs permeate the lipophilic horny layer on the surface of human skin more easily. Nevertheless, in the same circumstances, accumulated permeation volume dose has no significant increase probably because of the concentration gradient on two sides of the skin.
The plasma protein binding rate of Brucine presents non-quality concentration dependency in high, medium and low plasma quality concentration and the binding rate is moderate, about 59%.
This paper investigates how oleic acid, tween-80, Azone, dimethyl sulfoxide and ethanol promote the permeation capacities of Brucine solutions individually. The results demonstrate that most of them can promote permeation capacities in vitro to some extent and the order of promoting degree is Azone> ethanol> dimethyl sulfoxide> tween-80> oleic acid, among which, Azone has the most significant effect, compared with the control group, permeation rate (J) increases nearly four times and permeation volume dose per unit area (Q) 2.58 times.
In this paper, the formulation of transdermal patches is optimized by means of L9 (34) orthogonal design, which takes the characteristics of patches and accumulated permeation amount as indexes. Characteristics, including homogeneity,extensibility, viscosity and peeling strength are all taken into consideration. As a result, optimized lipophilic patch is acrylate Pressure-Sensitive Adhesive (E100):Plasticiser (Dibutyl Sebacate):Cross Linking Agent (Succinic Acid)= 10:4:1, plus 25% Tackifier (PEG400) and 3% Azone; while optimized hydrophilic patch is CMC-Na:PVA:PVP K30:Glycerol= 2:3:1:1.5, plus 3% Azone (The respective matrical concentration are CMC-Na:6.67%, PVA:20%, PVP:100%). The comparison between transdermal capacities of these two patches shows that lipophilic patches release quickly at first and later slowly, and basically complete releasing after 6 hours. According to the tangent line on the transdermal curve, the releasing rate Q=59.626t-0.436, and the process of releasing is in accordance with Higuchi equation (R2=0.902). Nonetheless, hydrophilic patches release at constant speed during the 24 hours, and Q=5.2504t-0.6844 (R2=0.994), which is more conform to the process of zero level releasing. Therefore, hydrophilic patches can release persistently and slowly at constant speed and guarantee stable blood drug level in vivo, which is Analgesic effect of hydrophilic patches has been examined by hot-plate test. The results reveal that medication group shows good dose dependent when given the dose of 60,120 and 240 mg·kg-1 respectively. From the hour-effect diagram, it can be seen that the analgesic effect of each group reached the maximum after 6 hours. Specifically, with high-dose given, the percent of analgesic effect was about 120%, which is almost equal to that of YunNanBaiYao patch. Besides, in the acetic acid-induced writhing test, compared with excipient group, medium dose and high does exhibit good writhing depressant effect in the dose of 60,120 and 240 mg·kg-1, and the percent of analgesic effect is more than 50%(P＜0.01), however, low dose does not have significant depressant effect (p>0.05).
In the end, this paper also has carried out pharmacokinetic research on Brucine solutions intravenous injection and Brucine patches. By the DAS2.0 data processing software, it can be seen that MRT of Brucine transdemal patches has extended nearly tenfold, with MRT 49.12min and 451.89min individually, besides, its absolute bioavailability has achieved 34.76%. Apparently, Brucine transdermal patches can extend clearance time. Therefore, compared with intravenous injection, transdermal medication can remarkably lower the peak of the blood drug level, make it more stable and maintain for longer time, which is beneficial to develop its curative effects and reduce its toxicity significantly in the mean time, and to some extent, confirms the hypothesis that transdermal medication is an efficient method to avoid toxic reaction of Brucine.
引文
[1]殷武.马钱子生物碱的镇痛研究[A].南京中医药大学硕士学位论文[D].南京：南京中医药大学,2000.
[2]朱建伟,武继彪,李成韶,等.马钱子碱镇痛作用及其药效动力学研究[J].中国中医药科技,2005,12(3)：166-167.
[3]朱建伟,武继彪,李成韶,等.复方马钱子碱的镇痛作用及其药效动力学初步观察[J].中国中医药信息杂志,2005,12(9)：36-37.
[4]张梅,李平,陈朝晖,等.马钱子碱对一氧化氮诱导软骨细胞凋亡的影响[J].中国临床康复,2003,7(26)：3554-3555.
[5]徐丽君,魏世超,陆付耳,等.马钱子若干组分治疗实验性关节炎的比较研究[J].同济医科大学学报,2001,30(6)：564-565.
[6]Yin W,Wang T S,Yin F Z,Cai B C. Analgesic and anti-inflammatory properties of brucine and brucine N-oxide extracted from seeds of Strychnos nux-vomica[J] J. Ethnopharmacol.,2003,88:205-214.
[7]赵红卫,翁世艾,朱燕娜,等.马钱子碱对小鼠淋巴细胞功能的影响[J].中国药理通报,1999,15(4)：354-356.
[8]Deng X K,Yin F Z,Cai B C,Yin W. The apoptotic effect of brucine from the seed of strychnos nux-vomica on human hepatoma cells is mediated via Bcl-2 and Ca2+involved mitochondrial pathway [J].Toxicol. Sci.,2006,91(1):59-69.
[9]邓旭坤,蔡宝昌,殷武.等.马钱子碱对小鼠肿瘤的抑制作用[J].中国天然药物,2005,3(6)：392-396.
[10]邓旭坤,蔡宝昌,殷武,等.Brucine对Heps荷瘤小鼠的抗肿瘤作用和毒性的研究[J].中国药理学通报,2006,22(1)：35-39.
[11]邓旭坤,蔡宝昌,吕晓宇,等.马钱子碱及其脂质体对移植性荷瘤小鼠抗肿瘤作用的对比研究[J].中草药,2006,37(3)：389-393.
[12]李明华,张贵卿,赵德华.马钱子碱对豚鼠心脏乳头肌慢反应动作电位的影响[J].中药药理与临床,1997,13(4)：19-21.
[13]李明华,万光瑞,朱明,等.马钱子碱对实验性心律失常的影响[J].新乡医学院学报,1997,14(2)101-103.
[14]周建英,卞慧敏,马骋,等.马钱子碱和马钱子碱氮氧化物抗血小板聚集及抗血栓形成作用的研究[J].江苏中医,1998,19(4)：41-43.
[15]Malone MH, St John-Allan KM, Bejar E. Brucine lethality in mice[J]. J Ethnopharmacol, 1992,35(3),295-297.
[16]吴贤仁,陈运立,陈协辉.大剂量马钱子中毒致呼吸心跳骤停1例[J].汕头大学医学院学报,1999,12(1)：37.
[17]李霆雷,王学峰,陈丹,等.马钱子碱癫痫模型的制备[J],中国中医急症,2007,16(2)：209-211.
[18]李晓天,陈西敬,王广基.口服马钱子碱后小鼠体内的药动学研究[J].中国药学杂志,2004,39(6)：452-454.
[19]李晓天,张丽容,王天奎,等.马钱子碱在小鼠体内的组织分布[J].中国临床药理学与治疗学,2006,11(3)：342-344.
[20]蔡宝昌,徐晓月,潘扬,等.马钱子生物碱在大鼠体内的组织分布[J].中国药理学通报,2004,20(4),421-424.
[21]徐晓月,蔡宝昌,潘扬,等.马钱子生物碱在大鼠体内的药代动力学研究[J].药学学报,2003,38(6)：458-461.
[22]宋金春,王玉广.马钱子碱微乳的制备及其体外透皮吸收的研究[J].中国药学杂志,2006,41(12)：928-931.
[23]张路,简江波,袁媛,等.纳米马钱子碱脂质体制备工艺研究[J],中成药,2005,27(6)：632-637.
[24]Qin X Q, Yuan Y, Liu C S. Preparation of liposomal brucine and its pharmaceutical/pharmacodynamic haracterization[J]. Acta Pharmacol Sin,2007,28(11):1851-1858.
[25]杨柏灿,王秋云,沈杰,等.运用纳米马钱子碱脂质体治疗类风湿性关节炎的临床研究[J].浙江中医药杂志,2007,42(1)：24-25．
[26]陆晓和,赵仲坤,苏丹.氮酮对吲哚美辛贴膜透皮吸收的影响[J].中国药科大学学报,1995,26(6)：335-336.
[27]RoySD,Marc QFlynn GL,et al.Controlled transdermal deliv-ery of fentanyl:characterizations of pressure-sensitive adhesivesfor matrix patch design[J].JPharm Sciences,1996,85(5):491-495.
[28]Anz J.Manufacture of UV-curable acrylicgels for percutaneousdelivery of drugs[P].Ger.Offen.DE 4336299 Al,1995-05-11.
[29]Kanikkannan N,Jayaswal SB,Singh J.Transdermal delivery of indomethacin:I.Release profile of drug from polymeric patches[J].Indian Drugs,1993,30(9):441-445.
[30]Minghetti P,Cilurzo F,Casiraghi A.Dermalpatches for the con-trolled release of miconazole:influence of the drug concentration on the technological characteristics[J].Drug Dev Ind Pharm,1999,25(5): 679-684.
[31]Rafiee-Tehrani M,Bayat H,Toliat T.Acrylicresins as rate-controlling membranes in propranolol transdermal multilaminate patch[J].Proc Int Symp Controlled Release Bioact Mater,1997,24:411-412.
[32]Noppe MJM,Garrevoet TC,Peeters J,et al.Transdermal pharmaceutical patches containing vorozole and skin permeation enhancer[P].PCT Int Appl WO 9706788 Al,1997-02-27.
[33]Deurer L,Hille T,Profitlich T,et al.Transdermal therapeutic system for administration of physostigmine to the skin,and its manufacture[P].Ger. DE 4238223 C1,1994-05-26.
[34]Yoneto K,Mutsumi F.Pharmaceutical adhesives containing vinylpyrrolidone(co) polymers, (meth) acrylic acid copolymers,softening agents,and rosins[P].JP 04368322 A2,1992-12-21.
[35]Togawa K,Nekama T,Yamaya S.Patches containing alkyl oleate and high concentration of pharmaceuticals[P].JP 09227363 A2,1997-09-02.
[36]Akemi H,Muraoka T,Higashio K,et al.Percutaneous absorption preparation[P].Eur Pat Appl.EP 711551 A2,1996-05-15.
[37]Li CH,Schonfeld E,Chu T,et al.Transdermal patches comprising pressure-sensitive polyacrylate adhesive crosslinked with aluminumacetylacetonate and a drug having a reactive aromatichydroxyl group[P].PCT Int.Appl.WO 9640087 A2,1996-12-09.
[38]Hashimoto M,Yoneto K.Flurazepam patches with good bioavailability[P].JP 09136835 A2,1997-05-27.
[39]Urtti AO,Sutinen MR,Paronen TP.Transdermal drug delivery-system.Brit[P].UK Pat.Appl.GB 2290964 Al,1996-01-17.
[40]Bahram F,Gokhale RD,Joseph V,et al.Transdermal albuterol-patches[P].Can Pat Appl,CA 2058059 AA,1992-09-12.
[41]CholHK.Composition for transdremal delivery system containing nonsteroidal anti-inflammatory drug as an active ingredient[P].Eur.Pat.Appl.EP 0827741 A2,1998.
[42]Ono M,Akazawa M,Seki M,et al.External preparation for application to the skincontaining lidocaine [P]. Eur Pat Appl,EP507160 Al,1992-10-07.
[43]姜伟.巴布剂的制备工艺及其产品[P].CN1123171A.1996-05-29．
[44]李小晶,彭红艳.超声波对中药红花透皮的实验研究[J].现代中西医结合杂志,2009,18(25)：3031-3031.
[45]郝劲松,郑俊民.药物经皮离子导入的转运机制[J].沈阳药科大学学报,1995,12(2)：151-156．
[46]董文霞,巴元明.中药离子导入法的临床应用概况[J].湖北中医杂志,2005,27(9)：56-57.
[47]Prausnitz M R, Bose V G, Langer R, et al.Electroporation of mammalian skin:a mechanism to enhance transdermal drug delivery[J].Proc Nat Acad Sci USA,1993;90(22):10504～10508
[48]Frederic M, Katrin K, Rein S, et al.Persistent Immune Responses Induced by a Human Immunodeficiency Virus DNA Vaccine Delivered in Association with Electroporation in the Skin of Nonhuman Primates[J].Human Gene Therapy,2009,20:1291-1307.
[49]Escobar-Chavez J J, la-Martinez D B, Villegas-Gonzalez M A, et al.Electroporation as an Efficient Physical Enhancer for Skin Drug Delivery[J].J Clin Pharm.2009,1-22.
[50]李凡,郝保华,李伟泽等.电致孔条件下巴布剂中青藤碱透皮吸收的药动学研究[J].第二军医大学学报,2008,29(9)：1096-1098.
[51]唐斌斌.秦艽多成分在电致孔作用下的透皮研究[D].西安：西北大学,2009：60.
[52]梁春杰,王薇,黄大鸣等.电超导透皮给药治疗小儿肺炎临床研究[J].实用医学杂志,2004,20(10)：1189-1190.
[53]梁媛媛,江键,崔黎丽等.驻极体促进药物透皮吸收的研究进展[J].中国医学物理学杂志,2007,24(4)：264-266.
[54]朱如彩,周作的.不同氮酮用量对复方苦参凝胶中苦参碱体外经皮渗透的影响[J].中国中医药信息 杂志,2006,13(11)：39-40.
[55]杨柳,冯星,巫志峰等.不同浓度氮酮对复方雷公藤贴片中阿魏酸体外透皮吸收的影响[J].湖南师范大学学报(医学版),2005,2(1)：15-17.
[56]杨巧丽,周雪琴,张志慧等.氮酮和油酸增强黄芩苷经皮渗透作用的研究[J].中草药,2006,37(7)：1011-1013.
[57]隋金婷,许贵军,殷翔等.氮酮、丙二醇对丁香贴剂中丁香苦苷透皮吸收的影响[J].中医药学报,2009,37(3)：46-48.
[58]Mohammed A, Abdul A,Yasmin S,et al.Status of terpenesas skin penetration enhancers[J].DrugDiscoveryToday,2007,12(23/24),1061-1067.
[59]蔡贞贞,魏莉,徐莲英.当归所含挥发油对阿魏酸透皮吸收的影响[J].中成药,1999,21(7)：333-335.
[60]Hao B H, Ma L, Xu H R, Yue Q f.The Research for the Absorption Function of Fragrant Traditional Chinese Medicine Drug to Capsaicin[J].Nat Prod Res Dev,2006,18:637-639.
[61]宁美英,郭颖志.脂质体促进药物透皮吸收的研究进展[J].Foreign Medical Sciences Section on Pharmacy,2004,31(5):302-308.
[62]吴亚妮,徐云龙,王伟.茶树油脂质体凝胶剂的体外透皮扩散研究[J].上海交通大学学报(农业科学版),2007,25(5)：455-458.
[63]张立超,胡晋红.微乳透皮给药系统的研究进展[J]. Foreign Medical Sciences Section on Pharmacy,2004,31(1)：44-48.
[64]张先洲,陈晓清,祝红达,潘细贵.青藤碱微乳与凝胶的皮肤渗透性比较[J].中国现代应用药学杂志,2008,25(6)：518-520.
[65]吴晓明,狄留庆,毕肖林等.穴贴定喘膏中挥发油不同环糊精包合物对透皮吸收的影响研究[J].中国医院药学杂志,2008,28(18)：1534-1536.
[66]何欣,欧阳五庆,赵兴华等.雷公藤多苷纳米乳透皮制剂的抗炎镇痛作用试验[J].中国兽医杂志,2008,44(8)：13-15.
[67]李英剑.吡罗昔康经皮贴剂的研究[D].硕士学位论文,2002：13-14.
[68]郑俊明.经皮给药新剂型[M].人民卫生出版社,2006：17.
[69]郑俊明.经皮给药新剂型[M].人民卫生出版社,2006：18.
[70]Wu Yin,Tian-Shan Wang,Fang-Zhou Yin,et al.Analgesic and anti-inflammatory properties of brucine and brucine N-oxide extracted from seeds of Strychnos nux-vomica[J].Journal of Ethnopharmacology, 2003(88):205-214.
[71]郑俊民.经皮给药新剂型.中国医药卫生出版社,1997.
[72]GlennVB,Mario G,Vinod PS,et al.Seale-up of adhesive transdermal drug Delivery syatems[J].European Journal of Pharmaceutics and Biopharmaceutics[J],1997,44(6):327-331.
[73]Ramesh P.Transdermal delivery of drugs [J].Indian J Pharmacol,1997,29 (4):140-156.
[74]丁平田,刘军田,郑俊民.用油／水分配系数预测药物的经皮渗透性[J].中国医药工业杂 志.1998,29(4)；186-190.
[75]曹露晔,陈子君,李云森,等.高效液相色谱法研究蓝萼甲素与大鼠血浆蛋白的结合率[J].中草药,2007,38(5)：693-695.
[76]郭宾,李川.药物与血浆蛋白结合的药理学基础及其研究进展[J].中国临床药理学与治疗学,2005,10(3)：241-253.
[77]梁秉文.经皮给药制剂.北京：中国医药科技出版社,1992,第一版.
[78]郑俊民.经皮给药新剂型.北京：人民卫生出版社,1997,第一版.
[79]陆斌.药物新剂型与新技术.北京：人民卫生出版社,1998,第一版.
[80]白志华,方晓玲.三七总皂苷中人参皂苷Rgl体外透皮吸收的实验研究[J].中成药,2006,28(5)：639-641.
[81]张志慧.黄芩苷透皮吸收性能及其经皮给药系统的研究[D].天津：天津大学硕士学位论文.2005：32.
[82]Cheien Y W.Tansdermal controlled systemic mediactions.New York:Marcel Dekker Inc,1987:93-112.
[83]郑俊民.经皮给药新剂型.1997年第一版,北京：人民卫生出版社,1997：18-24.
[84]Temin S C,et al. Handbook of adhesives.New York,NYNSA:Marcel Dekker,1990:133-135.
[85]Sates D. Handbook of pressure sensitive adhesive technology.New York:Van Norstrand Reinhold,1989:71-74.
[86]Qinglin S,Qiang QShuqing Z,et al.Study on the composition design of the water emulsion acrylates pressure sensitive adhensive. ChemicalEngineering,1996,24(2):65-67.
[87]Barry BW.Novel mechanisma and devices to enable successful transdermal drug delivery[J].Eur J Pharm Sci,2001,14(2):101-114.
[88]张梅,赵维娟,王金平.丁螺环酮体外经皮渗透性的实验研究[J].中国新药杂志,2005,14(5)：575-578.
[89]赵维娟,许景峰,刘梅.月桂氮酮促甲巯咪唑透皮吸收作用[J].中国医院药学杂志,1997,17,(11)：502-503
[90]王岩,周莉玲,凌家俊.促渗剂对青藤碱脂质体透皮贴剂经皮渗透的影响[J].中药材,2005,28(7)：567-570.
[91]韩冬,崔黎丽,李国栋.巴布剂透皮给药基质的研究[J].第二军医大学学报,2005,26(5)：572-573.
[92]Peteriet H,Beekert T,Nikui NS,et al.Acrylic resins as rate-controlling Membranes in novel formulation of a nine-day 17p-estradiol transdermal delivery system:in vitro and release modifier effect evaluation[J].Drug Development and Industrial Pharmacy,2001,27(5):431-437.
[93]Kotiyan PN,Vavia PR.Synihesis and characterization of anacrylate Pressure Sensitive adhesive for transdermal drug delivery [J].Polymers for Advanced Technologies,2002,13(2):137-143.
[94]Vibha S,Mare PV,Bharti PR.Acrylate terpolymer in fabrication of medieated Skin patches[J].Polymers for Advanced Technologies,2001,12(10):466-474.
[95]Dnyanesh N,Vavia PR.Acrylate-based Pressure sensitive adhesive in fabrication of transdermal therapeutic system[J].Polymers for Advanced Technologies,2003,14(11):502-507.
[96]吴铁,张志平.薄荷脑促进扑热息痛透皮吸收作用研究[J]．中国医院药学杂志,1992,12(3)：104-105.
[97]梁宁,温家顺,丘德运,等.薄荷脑在中药成方制剂中应用探讨[J],时珍国医国药,1999,10(6)：437.
[98]陈奇.中药药理研究方法学(第2版)[M].北京：人民卫生出版社,2006,346-351.
[99]陈军,胡巍,蔡宝昌等.马钱子碱在大鼠体内的药动学[J].中国药学杂志,2009,44(10),778-780.