双氯芬酸钠巴布剂的研制及体内外透皮动力学研究
|
摘要
双氯芬酸钠(DCS)是世界上使用最广泛的非甾体抗炎药之一。但其半衰期短,且存在明显的胃肠刺激、造成胃肠紊乱及溃疡等问题。为更好的发挥其药效,减少不良反应,延长作用时间,实验将DCS制成一种交联型巴布剂。
本研究建立了DCS溶液的紫外分光光度测定法,该法准确可靠,操作方便快捷。考察不同介质中DCS的溶解度,并测定其油水分配系数,为实验设计和分析提供理论依据。
通过对处方基质的筛选,最终选择部分中和的聚丙烯酸钠NP700为巴布剂基质骨架材料,卡波姆980和羧甲基纤维素钠(CMC-Na)为增粘剂,甘羟铝为交联剂,高岭土为填充剂,甘油为保湿剂,EDTA为交联调节剂,PEG400为消泡剂。通过单因素考察及正交试验法,以初粘力、持粘力和感官评价作为综合指标,优化巴布剂处方。
采用Franz扩散池和离体小鼠皮肤,以促渗倍数和时滞为考察指标,研究DCS体外透皮扩散动力学行为。实验考察基质pH值以及几种促渗剂对DCS巴布剂体外透皮行为的影响。结果表明,DCS在pH6.5较pH5.5透皮速率低；与空白对照组相比,吐温80无明显促渗效果,氮酮促渗效果较小且时滞长,油酸、薄荷醇与冰片在浓度分别为3%、3%和1%促渗效果显著。经二元联合促渗研究,选择3%薄荷醇和1%冰片作为DCS的促渗剂。
自制DCS巴布剂质量评价表明,巴布剂膏体外观、赋形性、含膏量、初粘力、皮肤追随性和膜残留量均符合要求,三个月的加速试验表明巴布剂性质稳定。体外释放研究表明DCS呈Higuchi模型释放,体外透皮速率为110.55μg·cm-2·h-1,12h累积透过率为38.86%。
自制DCS巴布剂家兔体内药动学研究表明,DCS透皮效果好,生物利用度高,相对生物利用度为150.30%,且与体外透皮效果相关性良好。
Diclofenac sodium, a kind of widely used nonsteroidal antiinflammatory drugs, has a lot of problems, such as having a short biologic half-life, stimulating gastrointestinal tract, causing gastrointestinal disorder, and gastric ulcer. In order to bring its effect into full play, reduce adverse effects, prolong its effect time, the study developed a kind of cross-linking cataplasm of DCS.
Firstly, a method for analyzing DCS content with UV spectrophotometry was proposed. This method was accurate, reliable and easy to operate. Some physic-chemical properties of DCS were determined, such as the solubility in different mediums, oil-water partition coefficient. This research provided theory basis for the design and analysis during this study.
With selection of each element, choosing sodium polyacrylate NP700 as framework material of cataplasm, Carbopol 980 and CMC-Na as tackifiers, dihydroxyaluminium aminoacetate as cross-linking agent, kaolin as filler, glycerol as humectant, EDTA as cross-linking regulator, PEG400 as defoaming agent. The single factor test and orthogonal test were used to design formulations with tacking strength, holding strength and sensory evaluation as comprehensive indicators.
An improved Franz diffusion cell and excised mouse skin were applied, preliminarily studying percutaneous absorption of DCS with different pH and penetration enhancers in vitro with the enhancing rate and lag time as the indicators. The result showed that percutaneous rate of DCS at pH 6.5 was lower than pH 5.5. Compared with the blank group, tween 80 had no significant permeation effect on DCS; azone had a slight effect with longer lag time; oleic acid, menthol and borneol had significant effect on DCS with the content of 3%,3% and 1%, respectively. The result of joint effect of two kinds of penetration enhancers showed that 3% menthol and 1% borneol had the most significant effect.
The result of quality evaluation showed that DCS cataplasm developed met the requirements in appearance, formability, ointment content, tacking strength, adhesion, residue and stability with accelerated test for three months. The drug release characteristic of DCS in vitro coincided with the Higuchi model; the percutaneous rate was 110.55μg·cm-2·h-1, and accumulated transmission rate was up to 38.86% for 12h.
The research of pharmacokinetics of DCS cataplasm in rabbits showed that the relative bioavailability was 150.30%. And the transmission of DCS in vitro was well correlative with the absorption fraction in vivo.
本研究建立了DCS溶液的紫外分光光度测定法,该法准确可靠,操作方便快捷。考察不同介质中DCS的溶解度,并测定其油水分配系数,为实验设计和分析提供理论依据。
通过对处方基质的筛选,最终选择部分中和的聚丙烯酸钠NP700为巴布剂基质骨架材料,卡波姆980和羧甲基纤维素钠(CMC-Na)为增粘剂,甘羟铝为交联剂,高岭土为填充剂,甘油为保湿剂,EDTA为交联调节剂,PEG400为消泡剂。通过单因素考察及正交试验法,以初粘力、持粘力和感官评价作为综合指标,优化巴布剂处方。
采用Franz扩散池和离体小鼠皮肤,以促渗倍数和时滞为考察指标,研究DCS体外透皮扩散动力学行为。实验考察基质pH值以及几种促渗剂对DCS巴布剂体外透皮行为的影响。结果表明,DCS在pH6.5较pH5.5透皮速率低；与空白对照组相比,吐温80无明显促渗效果,氮酮促渗效果较小且时滞长,油酸、薄荷醇与冰片在浓度分别为3%、3%和1%促渗效果显著。经二元联合促渗研究,选择3%薄荷醇和1%冰片作为DCS的促渗剂。
自制DCS巴布剂质量评价表明,巴布剂膏体外观、赋形性、含膏量、初粘力、皮肤追随性和膜残留量均符合要求,三个月的加速试验表明巴布剂性质稳定。体外释放研究表明DCS呈Higuchi模型释放,体外透皮速率为110.55μg·cm-2·h-1,12h累积透过率为38.86%。
自制DCS巴布剂家兔体内药动学研究表明,DCS透皮效果好,生物利用度高,相对生物利用度为150.30%,且与体外透皮效果相关性良好。
Diclofenac sodium, a kind of widely used nonsteroidal antiinflammatory drugs, has a lot of problems, such as having a short biologic half-life, stimulating gastrointestinal tract, causing gastrointestinal disorder, and gastric ulcer. In order to bring its effect into full play, reduce adverse effects, prolong its effect time, the study developed a kind of cross-linking cataplasm of DCS.
Firstly, a method for analyzing DCS content with UV spectrophotometry was proposed. This method was accurate, reliable and easy to operate. Some physic-chemical properties of DCS were determined, such as the solubility in different mediums, oil-water partition coefficient. This research provided theory basis for the design and analysis during this study.
With selection of each element, choosing sodium polyacrylate NP700 as framework material of cataplasm, Carbopol 980 and CMC-Na as tackifiers, dihydroxyaluminium aminoacetate as cross-linking agent, kaolin as filler, glycerol as humectant, EDTA as cross-linking regulator, PEG400 as defoaming agent. The single factor test and orthogonal test were used to design formulations with tacking strength, holding strength and sensory evaluation as comprehensive indicators.
An improved Franz diffusion cell and excised mouse skin were applied, preliminarily studying percutaneous absorption of DCS with different pH and penetration enhancers in vitro with the enhancing rate and lag time as the indicators. The result showed that percutaneous rate of DCS at pH 6.5 was lower than pH 5.5. Compared with the blank group, tween 80 had no significant permeation effect on DCS; azone had a slight effect with longer lag time; oleic acid, menthol and borneol had significant effect on DCS with the content of 3%,3% and 1%, respectively. The result of joint effect of two kinds of penetration enhancers showed that 3% menthol and 1% borneol had the most significant effect.
The result of quality evaluation showed that DCS cataplasm developed met the requirements in appearance, formability, ointment content, tacking strength, adhesion, residue and stability with accelerated test for three months. The drug release characteristic of DCS in vitro coincided with the Higuchi model; the percutaneous rate was 110.55μg·cm-2·h-1, and accumulated transmission rate was up to 38.86% for 12h.
The research of pharmacokinetics of DCS cataplasm in rabbits showed that the relative bioavailability was 150.30%. And the transmission of DCS in vitro was well correlative with the absorption fraction in vivo.
引文
[1]罗小琴,杨志文.双氯芬酸钠明胶微球的制备及体内外释药的研究[J].药品评价.2006,3(1)：37-39.
[2]尤启东.药物化学[M].北京：化学工业出版社.2003,188-190.
[3]B.H. Mccaeberg, C.E. Argoff. Topical diclofenac epolamine patch 1.3% for treatment of acute pain caused by soft tissue injury [J]. Int. J. Clin. Pract..2010,64(11):1546-1553.
[4]宾驰.双氯芬酸制剂研究进展[J].现代中西医结合杂志.2010,19(23)：2983-2985.
[5]崔福德.药剂学[M].北京：人民卫生出版社.2007,189.
[6]缪玉山,倪冲,史家明.双氯灭痛凝胶剂的制备和临床应用[J].铁道医学杂志.2000,28(1)：45-46.
[7]王玮,周建平,任逢晓,等.双氯芬酸钠脂质体凝胶的制备及其药动学和刺激性评价[J].中国药学杂志.2007,42(16)：1236-1240.
[8]孙考祥,洪霞,张颖.双氯芬酸钠眼膏的研制[J].中国医药药学杂志.2001,21(7)：393-395.
[9]鞠凤阁,朱照静,王丽娟,等.双氯芬酸钠眼用温敏凝胶的处方优化及体外释放[J].中国医药药学杂志.2009,29(7)：541-545.
[10]刘利娥,刘洁,阎素清,等.双氯芬酸胆碱滴眼液的制备和含量测定[J].华西药学杂志.2001,16(4)：297-298.
[11]Shimamura T,Tairabune T, Kogo T, et al. Investigation of the release test method for the topical application of pharmaceutical preparations:Release test of cataplasm including nonsteroidal anti-inflammatory drugs using artificial sweat[J]. Chemical & pharmaceutical bulletin.2004,52(2):167-171.
[12]王军.双氯芬酸钠巴布剂的制备及体外透皮研究[J].中国药师.2009,12(5)：573-575.
[13]余从洪,宋金春,王玉广,等.双氯芬酸钠贴片的制备及体外释放、透皮吸收测定[J].中国医药药学杂志.2005,25(8)：738-740.
[14]熊辉,陈永刚,李铮铮.双氯芬酸钠中空栓的制备及质量控制[J].中国药房.2008,19(13)：1001-1002.
[15]吴世民,张咸伟,李跃琼,等.双氯芬酸钠栓预镇痛对肛肠术后的镇痛作用[J].中国医药导报.2008,5(11)：88-89.
[16]范碧亭.中药药剂学[M].上海：上海科技出版社.1997,320.
[17]颜耀东.缓释控释制剂的设计与开发[M].北京：中国医药科技出版社.2006,408.
[18]林新文,左亚杰.中药巴布剂的研究进展及展望[J].中国药业.2007,16(24)：68-70.
[19]王艳艳,徐希明,余江南.中外巴布剂研究现状分析[J].中国药事.2009,23(6)：603-606.
[20]柯仲成,曹国将,韩小祥.中药巴布剂的研究进展[J].安徽中药学院学报.2006,25(2)：56-58.
[21]Nina Dragicevic-Cucic. Temoporfin-loaded liposomal gels:Viscoelastic properties and in vitro skin penetration[J]. Int. J. Pharm..2009,37(3):77-84.
[22]徐晖,王绍宁,谷野,等.巴布膏剂研制的一些问题[J].中医外治杂志.2005,14(6)：3.
[23]徐瑾.巴布剂应用于中药领域的研究概况[J].湖南中医杂志.2006,22(1)：81-83.
[24]林新文,左亚杰.中药巴布剂的研究进展及展望[J].中国药业.2007,16(24)：68-70.
[25]刘淑芝.中药巴布剂研究现状分析及展望[J].中医外治杂志.2005,14(5)：3-5.
[26]郭圣荣.药用高分子材料[M].北京：人民卫生出版社.2009,198-230.
[27]隋帆,崔亚男,管华.醋氯芬酸巴布剂制备工艺研究[J].亚太传统医药.2009,5(4)：23-24.
[28]傅云峰,杨中林.均匀设计法优选巴布剂基质配方[J].海峡药学.2007,19(3)：14-16.
[29]T. Goto, M. Morishita, N.J. Kavimandan, et al. Gastrointestinal transit and muco-adhesive characteristics of complexation hydrogels in rats [J]. J. Pharm. Sci.2006, 95:462-469.
[30]Anna M.Wokovich. Transdermal drug delivery system (TDDS) adhesion as a criticalsafety, efficacy and quality attribute[J]. European Journal of Pharmaceutics and Biopharmaceutics.2006,64:1-8.
[31]蔡丽娟,杨金荣,董伟林.吲哚美辛巴布剂体外释放度的研究[J].天津医药.2009,37(2)：145-162.
[32]Jianhua Zhang, Zhipeng Liu. A Novel Hydrophilic Adhesive Matrix with Self-Enhancement for Drug Percutaneous Permeation Through Rat Skin[J]. Pharmaceutical Research,2009,26(6):1398-1406.
[33]潘林梅,郭立玮,袁铸人,等.中药巴布剂产业化问题探讨[J].中国药房.2007,18(30)：2394-2396.
[34]Chien-Chi Lin, Andrew T.Metters. Hydrogels in controlled release formulation:Network design and mathematical modeling[J]. Advanced Drug Delivery Reviews.2006,58: 1379-1408.
[35]杨基森.巴布剂[M].贵阳：贵州科技出版社.2003,22-23.
[36]Srinivas s.Godavarthy. Design of Improved Permeation Enhancers for Transdermal Drug Delivery [J]. J. Pharm. Sci.2009,98(11):4085-4099.
[37]石恩娴,刑桂琴.不同透皮促进剂对复方黄芩巴布剂中黄芩苷透皮吸收的影响[J].山西医科大学学报.2008,39(1)：36-37.
[38]Naruhito HIGO. The Recent Trend of Transdernal Drug Delivery System Development [J]. The Pharmaceutical Society of Japan.2007,127(4):655-662.
[39]R. Jayachandra Babu. Cardiovascular effects of transdermally delivered bupranolol in rabbits:Effect of chemical penetration enhancers [J]. Life Science.2008,28:273-278.
[40]D. Friend, P. Catz, J. Heller, et.al. Transdermal delivery of levonorgestrel Ⅰ. Alkanols as permeation enhancers [J]. J. Control. Release.1998,7:243-250.
[41]S. Andega, N. Kanikkannan, M. Singh. Comparison of the effect of fatty alcohols on the permeation of melatomin between porcine and human skin [J]. J. Control. Realease.2001, 77:17-25.
[42]A.C. Watkinson, D.M. Green, K.R. Brain, el. at. Skin penetration of a series of nonoxynol homologuesin:K.R. Brain, V.J. James, K.S. Waters (Eds.) [J]. Perspectives in Percutaneous Penetration.1998,5b:54-59.
[43]梅兴国.药物新剂型与制剂新技术[M].北京：化学工业出版社.2006,180-183.
[44]郭坚固,刘献阳,杨晶晶.不同渗透促进剂对双氯芬酸钠凝胶的透皮作用[J].食品与药品,2008,10(05)：14-16.
[45]刘强,万新祥,黄小平.药物的油水分配系数及透皮吸收速率常数的相关性研究[J].第一军医大学分校学报.2000,23(01)：5-6.
[46]宋桂军,柳菡,冯芳,等.替米沙坦油水分配系数的测定及其意义[J].药物分析杂志.2007,27(11)：1704-1706.
[47]梁秉文.中药经皮给药制剂技术[M].北京：化学工业出版社,2006,68.
[48]奚炜,胡晋红,朱全刚,等.正交设计法优化巴布剂基质处方[J].药学服务与研究.2004,4(1)：80-82.
[49]许可,许沛虎,曹智华,等.丁臾巴布剂基质的设计[J].中成药.2007,29(12)：1768-1771.
[50]国家药典委员会.中华人民共和国药典[S].第二部.北京：化学工业出版社.2005,78-79.
[51]卢毅,张彤,陶建生.卡波姆在药剂学中的应用[J].中国医药工业杂志.2007,38(6)：457-460.
[52]余从洪,宋金春,王玉广,等.双氯芬酸钠贴片的制备及体外释放、透皮吸收测定[J].中国医院药学杂志.2005,25(8)：738-740.
[53]李琳,侯玉艳,谢景文,等.透皮促进剂在透皮吸收制剂中的应用[J].医药导报.2001,20(6)：383-384.
[54]Adrian C. Williams, Brian W. Barry. penetration enhancers [J]. Advanced Drug Delivery Reviews.2004,56:603-618.
[55]刘艺萍,张玲,余伟民,等.基质pH及促渗剂对阿昔洛韦水凝胶贴剂体外透皮性能的影响[J].中国医药工业杂志,2010,41(4)：266-268.
[56]梁秉文.中药经皮给药制剂技术[M].北京：化学工业出版社,2006,38-40.
[57]庆林.透皮吸收促进剂的研究应用[J].中国医学中华实用中西医杂志.2001,1(14)：11.
[58]刘纯,金梦瑶,张学农.双氯芬酸钠丝素蛋白-壳聚糖缓释微球的制备及体内外评价[J].中国药学杂志.2009,44(21)：1642-1647.
[59]孔焕宇.中药巴布膏剂黏性的质量评价[J].中医外治杂志.2006,15(3)：3-5.
[60]刘淑芝,费虹,汤亚池,等.中药巴布剂制备工艺的实验研究[J].中国实验方剂学杂志.2001,7(3)：9-11.
[61]杜建平,施之琪,柳俊.均匀设计法优选痹痛消巴布剂基质配方研究[J].广东药学院学报.2009,25(3)：230-233.
[62]台小华,潘玲,韩建伟.骨痛愈巴布剂的研制[J].中国药师,2009,12(5)：271-273.
[63]刘继勇,胡晋红,朱全刚,等.盐酸西替利嗪巴布剂的研制及体外释放特性[J].中国新药杂志.2004,13(7)：616-619.
[64]朱芳海,奚念珠.优选最佳数学模型用于固体制剂体外溶出试验数据处理程序的设计[J].药学学报.1994,29(6)：459-463.
[65]梁文权.生物药剂学与药物动力学[M].北京：人民卫生出版社.2003,155-163.
[66]林佳亮,王庭贤,苏云驰,等.双氯芬酸钠贴剂绝对生物利用度和局部组织药物浓度的研究[J].中国药师,2004,7(11)：834-836.
[67]张宝军,曾凡波,陆喆,等.酮洛芬巴布贴片在兔体内的相对生物利用度研究[J].医药导报.2007,26(4)：367-368.
[68]韩璐,林家亮,苏云驰,等.双氯芬酸钠贴剂相对生物利用度与局部组织药物浓度测定[J].医药导报.2008,27(2)：168-171.
[69]梁文权.生物药剂学与药物动力学[M].北京：人民卫生出版社.2003,329-335.
[70]蒋新国.生物药剂学与药物动力学[M].北京：高等教育出版社.2009,458-460.
[2]尤启东.药物化学[M].北京：化学工业出版社.2003,188-190.
[3]B.H. Mccaeberg, C.E. Argoff. Topical diclofenac epolamine patch 1.3% for treatment of acute pain caused by soft tissue injury [J]. Int. J. Clin. Pract..2010,64(11):1546-1553.
[4]宾驰.双氯芬酸制剂研究进展[J].现代中西医结合杂志.2010,19(23)：2983-2985.
[5]崔福德.药剂学[M].北京：人民卫生出版社.2007,189.
[6]缪玉山,倪冲,史家明.双氯灭痛凝胶剂的制备和临床应用[J].铁道医学杂志.2000,28(1)：45-46.
[7]王玮,周建平,任逢晓,等.双氯芬酸钠脂质体凝胶的制备及其药动学和刺激性评价[J].中国药学杂志.2007,42(16)：1236-1240.
[8]孙考祥,洪霞,张颖.双氯芬酸钠眼膏的研制[J].中国医药药学杂志.2001,21(7)：393-395.
[9]鞠凤阁,朱照静,王丽娟,等.双氯芬酸钠眼用温敏凝胶的处方优化及体外释放[J].中国医药药学杂志.2009,29(7)：541-545.
[10]刘利娥,刘洁,阎素清,等.双氯芬酸胆碱滴眼液的制备和含量测定[J].华西药学杂志.2001,16(4)：297-298.
[11]Shimamura T,Tairabune T, Kogo T, et al. Investigation of the release test method for the topical application of pharmaceutical preparations:Release test of cataplasm including nonsteroidal anti-inflammatory drugs using artificial sweat[J]. Chemical & pharmaceutical bulletin.2004,52(2):167-171.
[12]王军.双氯芬酸钠巴布剂的制备及体外透皮研究[J].中国药师.2009,12(5)：573-575.
[13]余从洪,宋金春,王玉广,等.双氯芬酸钠贴片的制备及体外释放、透皮吸收测定[J].中国医药药学杂志.2005,25(8)：738-740.
[14]熊辉,陈永刚,李铮铮.双氯芬酸钠中空栓的制备及质量控制[J].中国药房.2008,19(13)：1001-1002.
[15]吴世民,张咸伟,李跃琼,等.双氯芬酸钠栓预镇痛对肛肠术后的镇痛作用[J].中国医药导报.2008,5(11)：88-89.
[16]范碧亭.中药药剂学[M].上海：上海科技出版社.1997,320.
[17]颜耀东.缓释控释制剂的设计与开发[M].北京：中国医药科技出版社.2006,408.
[18]林新文,左亚杰.中药巴布剂的研究进展及展望[J].中国药业.2007,16(24)：68-70.
[19]王艳艳,徐希明,余江南.中外巴布剂研究现状分析[J].中国药事.2009,23(6)：603-606.
[20]柯仲成,曹国将,韩小祥.中药巴布剂的研究进展[J].安徽中药学院学报.2006,25(2)：56-58.
[21]Nina Dragicevic-Cucic. Temoporfin-loaded liposomal gels:Viscoelastic properties and in vitro skin penetration[J]. Int. J. Pharm..2009,37(3):77-84.
[22]徐晖,王绍宁,谷野,等.巴布膏剂研制的一些问题[J].中医外治杂志.2005,14(6)：3.
[23]徐瑾.巴布剂应用于中药领域的研究概况[J].湖南中医杂志.2006,22(1)：81-83.
[24]林新文,左亚杰.中药巴布剂的研究进展及展望[J].中国药业.2007,16(24)：68-70.
[25]刘淑芝.中药巴布剂研究现状分析及展望[J].中医外治杂志.2005,14(5)：3-5.
[26]郭圣荣.药用高分子材料[M].北京：人民卫生出版社.2009,198-230.
[27]隋帆,崔亚男,管华.醋氯芬酸巴布剂制备工艺研究[J].亚太传统医药.2009,5(4)：23-24.
[28]傅云峰,杨中林.均匀设计法优选巴布剂基质配方[J].海峡药学.2007,19(3)：14-16.
[29]T. Goto, M. Morishita, N.J. Kavimandan, et al. Gastrointestinal transit and muco-adhesive characteristics of complexation hydrogels in rats [J]. J. Pharm. Sci.2006, 95:462-469.
[30]Anna M.Wokovich. Transdermal drug delivery system (TDDS) adhesion as a criticalsafety, efficacy and quality attribute[J]. European Journal of Pharmaceutics and Biopharmaceutics.2006,64:1-8.
[31]蔡丽娟,杨金荣,董伟林.吲哚美辛巴布剂体外释放度的研究[J].天津医药.2009,37(2)：145-162.
[32]Jianhua Zhang, Zhipeng Liu. A Novel Hydrophilic Adhesive Matrix with Self-Enhancement for Drug Percutaneous Permeation Through Rat Skin[J]. Pharmaceutical Research,2009,26(6):1398-1406.
[33]潘林梅,郭立玮,袁铸人,等.中药巴布剂产业化问题探讨[J].中国药房.2007,18(30)：2394-2396.
[34]Chien-Chi Lin, Andrew T.Metters. Hydrogels in controlled release formulation:Network design and mathematical modeling[J]. Advanced Drug Delivery Reviews.2006,58: 1379-1408.
[35]杨基森.巴布剂[M].贵阳：贵州科技出版社.2003,22-23.
[36]Srinivas s.Godavarthy. Design of Improved Permeation Enhancers for Transdermal Drug Delivery [J]. J. Pharm. Sci.2009,98(11):4085-4099.
[37]石恩娴,刑桂琴.不同透皮促进剂对复方黄芩巴布剂中黄芩苷透皮吸收的影响[J].山西医科大学学报.2008,39(1)：36-37.
[38]Naruhito HIGO. The Recent Trend of Transdernal Drug Delivery System Development [J]. The Pharmaceutical Society of Japan.2007,127(4):655-662.
[39]R. Jayachandra Babu. Cardiovascular effects of transdermally delivered bupranolol in rabbits:Effect of chemical penetration enhancers [J]. Life Science.2008,28:273-278.
[40]D. Friend, P. Catz, J. Heller, et.al. Transdermal delivery of levonorgestrel Ⅰ. Alkanols as permeation enhancers [J]. J. Control. Release.1998,7:243-250.
[41]S. Andega, N. Kanikkannan, M. Singh. Comparison of the effect of fatty alcohols on the permeation of melatomin between porcine and human skin [J]. J. Control. Realease.2001, 77:17-25.
[42]A.C. Watkinson, D.M. Green, K.R. Brain, el. at. Skin penetration of a series of nonoxynol homologuesin:K.R. Brain, V.J. James, K.S. Waters (Eds.) [J]. Perspectives in Percutaneous Penetration.1998,5b:54-59.
[43]梅兴国.药物新剂型与制剂新技术[M].北京：化学工业出版社.2006,180-183.
[44]郭坚固,刘献阳,杨晶晶.不同渗透促进剂对双氯芬酸钠凝胶的透皮作用[J].食品与药品,2008,10(05)：14-16.
[45]刘强,万新祥,黄小平.药物的油水分配系数及透皮吸收速率常数的相关性研究[J].第一军医大学分校学报.2000,23(01)：5-6.
[46]宋桂军,柳菡,冯芳,等.替米沙坦油水分配系数的测定及其意义[J].药物分析杂志.2007,27(11)：1704-1706.
[47]梁秉文.中药经皮给药制剂技术[M].北京：化学工业出版社,2006,68.
[48]奚炜,胡晋红,朱全刚,等.正交设计法优化巴布剂基质处方[J].药学服务与研究.2004,4(1)：80-82.
[49]许可,许沛虎,曹智华,等.丁臾巴布剂基质的设计[J].中成药.2007,29(12)：1768-1771.
[50]国家药典委员会.中华人民共和国药典[S].第二部.北京：化学工业出版社.2005,78-79.
[51]卢毅,张彤,陶建生.卡波姆在药剂学中的应用[J].中国医药工业杂志.2007,38(6)：457-460.
[52]余从洪,宋金春,王玉广,等.双氯芬酸钠贴片的制备及体外释放、透皮吸收测定[J].中国医院药学杂志.2005,25(8)：738-740.
[53]李琳,侯玉艳,谢景文,等.透皮促进剂在透皮吸收制剂中的应用[J].医药导报.2001,20(6)：383-384.
[54]Adrian C. Williams, Brian W. Barry. penetration enhancers [J]. Advanced Drug Delivery Reviews.2004,56:603-618.
[55]刘艺萍,张玲,余伟民,等.基质pH及促渗剂对阿昔洛韦水凝胶贴剂体外透皮性能的影响[J].中国医药工业杂志,2010,41(4)：266-268.
[56]梁秉文.中药经皮给药制剂技术[M].北京：化学工业出版社,2006,38-40.
[57]庆林.透皮吸收促进剂的研究应用[J].中国医学中华实用中西医杂志.2001,1(14)：11.
[58]刘纯,金梦瑶,张学农.双氯芬酸钠丝素蛋白-壳聚糖缓释微球的制备及体内外评价[J].中国药学杂志.2009,44(21)：1642-1647.
[59]孔焕宇.中药巴布膏剂黏性的质量评价[J].中医外治杂志.2006,15(3)：3-5.
[60]刘淑芝,费虹,汤亚池,等.中药巴布剂制备工艺的实验研究[J].中国实验方剂学杂志.2001,7(3)：9-11.
[61]杜建平,施之琪,柳俊.均匀设计法优选痹痛消巴布剂基质配方研究[J].广东药学院学报.2009,25(3)：230-233.
[62]台小华,潘玲,韩建伟.骨痛愈巴布剂的研制[J].中国药师,2009,12(5)：271-273.
[63]刘继勇,胡晋红,朱全刚,等.盐酸西替利嗪巴布剂的研制及体外释放特性[J].中国新药杂志.2004,13(7)：616-619.
[64]朱芳海,奚念珠.优选最佳数学模型用于固体制剂体外溶出试验数据处理程序的设计[J].药学学报.1994,29(6)：459-463.
[65]梁文权.生物药剂学与药物动力学[M].北京：人民卫生出版社.2003,155-163.
[66]林佳亮,王庭贤,苏云驰,等.双氯芬酸钠贴剂绝对生物利用度和局部组织药物浓度的研究[J].中国药师,2004,7(11)：834-836.
[67]张宝军,曾凡波,陆喆,等.酮洛芬巴布贴片在兔体内的相对生物利用度研究[J].医药导报.2007,26(4)：367-368.
[68]韩璐,林家亮,苏云驰,等.双氯芬酸钠贴剂相对生物利用度与局部组织药物浓度测定[J].医药导报.2008,27(2)：168-171.
[69]梁文权.生物药剂学与药物动力学[M].北京：人民卫生出版社.2003,329-335.
[70]蒋新国.生物药剂学与药物动力学[M].北京：高等教育出版社.2009,458-460.