盐酸普萘洛尔透皮性质及微乳系统研究
|
摘要
经皮给药系统具有能够回避肝脏首过效应,药物释放平稳,给药方便的特点,目前不断有成熟产品上市。但是具有适宜的油水分配系数和较低的给药剂量药物通过经皮给药途径才能够达到体内有效药物浓度。
盐酸普萘洛尔由于具有高度水溶性和较高的治疗剂量被选定为模型药物。萜类是目前公认的安全有效促渗剂,尤其是对于水溶性化合物。本文首先考察了不同结构(醚类、单环单萜、双环单萜和倍半萜)代表萜类促渗剂对盐酸普萘洛尔透皮性质的影响。实验选用的萜均能显著增加药物透皮速率、减少迟滞时间。进一步研究表明,上述萜能够不同程度增加药物角质层分配系数、改善角质层脂质流动性,对于脂质含量却没有影响。活化能实验结果表明,桉树脑和薄荷醇显著减小模型药物透皮活化能,薄荷醇与对照组比较没有显著差异,冰片、樟脑和红没药醇存在下,药物的透皮活化能显著增加。
通过混合油相法确定了两个系统盐酸普萘洛尔微乳制剂的组成成分,并分别对两个系统进行相图绘制。根据相图特点,分别对两个系统采用单纯形网格法和单因素轮换法进行优化。优化结果:系统1为水19%,苯甲醇40%,吐温20 28%,丙二醇12%,系统2为水12.64%,油酸55.28%,吐温80 15.79%,乙醇15.79%。两系统均有良好的稳定性。由于系统2优化微乳具有更高的透皮速率(41.01μg/cm2h),因此对其进行离子对、角质层含水量、萜类促渗剂和增稠剂因素对透皮性质考察。离子对中,对硝基苯甲酸对优化微乳增渗作用显著。通过适量添加胆固醇不仅改变角质层含水量,增加优化微乳的透皮速率,同时使药物透皮吸收更加平稳。5%薄荷醇对微乳透皮速率影响大于离子对等因素。在使用薄荷醇基础上,增稠剂中aerosil200能够在不改变微乳结构情况下增加该制剂的黏度,结合体外实验确定用于体内实验微乳处方为油酸50.28%,吐温80 15.79%,乙醇15.79%,水12.64%,薄荷醇5.00%,在此基础上按重量添加aerosil200 5%。
体内实验表明,微乳组较片剂组T1/2(Ke),Tpeak和MRT均显著提高,Cmax显著降低。这说明微乳组药物释放平稳,维持药效时间长,血药浓度波动小。
本论文通过制备盐酸普萘洛尔的透皮微乳,解决了该药作为心血管药物在临床使用时存在的问题,提高了其在治疗过程中的安全性、有效性及患者的顺应性。
Transdermal drug delivery system has characters as avoiding hepatic first pass effect, stability of drug release, convenience of drug administration, and mature products of this administration route were commercially available. But the drug having both appropriate oil/water partition coefficient and low daily dosage, can reach effective drug concentration in vivo through transdermal administration, for the reason of skin barrier.
Hydrochloride propranolol was selected as the model drug for its water soluble character and high daily dosage. Terpenes were accepted commonly as safe and efficient transdermal enhancer, especially for that being hydrophilic. We studied effect of terpene enhancer with different structure on transdermal permeation profile of model drug. The results showed that all terpene selected enhanced transdermal permeation flux and decreased the lag time of hydrochloride propranolol. And further mechanism research showed that the terpenes increased SC partition coefficient of this drug, elevated fluidization of SC lipids, had no effect on lipids amount in SC. The results of activity energy calculation were abserved as that, compared with that of the control, cineol and menthanol decreased activity energy of model drug permeation, menthone didn’t change it, while bornel, camphor and bisaborlol increased activity energy.
Two systems of microemulsion components were selected according to the results of solubility research of model drug in oil phase mixture, and the pseudo ternary phase diagram of them were draw. With characters of phase diagram, simplex lattice method and single factor alternative method were used to optimize formulation of microemulsion respectively. The results of optimization were like these showed as below. The optimized formulation of system1 was composed as that, water19%, benzoyl40%, tween20 28%, propranl glycol12%. The optimized formulation of system 2 was composed as that, water12.64%,oleic acid 55.28%,tween80 10.79%,ethanol10.79%. The optimized formula of both two system showed good stability. With the permeation flux into consideration, the optimized formula of system 2 were selected for further investigation, which were effect of ion pair, water content in SC, terpene concentration, rheology controller. Being the ion pair, o-nitro benzoic acid improved drug permeation flux significantly. The appropriate amount addition of cholesterol, which change water content in SC, increased not only permeation flux, but also the stability of drug release. And the extend of drug permeation enhancement by 5% menthanol was more significant than that by ion pair, water content in SC. aerosil200 increased the viscosity of optimized formula without change its microemulsion character. And the formula for in vivo investigation was designed as, oil acid 50.28%, tween 80 15.79%, ehtanol 15.79%, water12.64%,menthanol 5.00%,in which aerosil200 was added at 5% of components above(w/w).
The results of research in vivo was showed that, compared with the tablet group, the T1/2(Ke),Tpeak and MRT were elevated significantly, and the Cmax was decreased in microemulsion group. The results illuminated that microemulsion prepared released drug stably, enlarged drug effect time and decreased fluctuant of blood-drug concentration.
In this paper, we prepared transdermal microemulsion of hydrochloride propranolol, which is used as cardiovascular drug with some promble in clinical application. And the new route of administration improved safety, efficiency of the drug and compliance of patient
盐酸普萘洛尔由于具有高度水溶性和较高的治疗剂量被选定为模型药物。萜类是目前公认的安全有效促渗剂,尤其是对于水溶性化合物。本文首先考察了不同结构(醚类、单环单萜、双环单萜和倍半萜)代表萜类促渗剂对盐酸普萘洛尔透皮性质的影响。实验选用的萜均能显著增加药物透皮速率、减少迟滞时间。进一步研究表明,上述萜能够不同程度增加药物角质层分配系数、改善角质层脂质流动性,对于脂质含量却没有影响。活化能实验结果表明,桉树脑和薄荷醇显著减小模型药物透皮活化能,薄荷醇与对照组比较没有显著差异,冰片、樟脑和红没药醇存在下,药物的透皮活化能显著增加。
通过混合油相法确定了两个系统盐酸普萘洛尔微乳制剂的组成成分,并分别对两个系统进行相图绘制。根据相图特点,分别对两个系统采用单纯形网格法和单因素轮换法进行优化。优化结果:系统1为水19%,苯甲醇40%,吐温20 28%,丙二醇12%,系统2为水12.64%,油酸55.28%,吐温80 15.79%,乙醇15.79%。两系统均有良好的稳定性。由于系统2优化微乳具有更高的透皮速率(41.01μg/cm2h),因此对其进行离子对、角质层含水量、萜类促渗剂和增稠剂因素对透皮性质考察。离子对中,对硝基苯甲酸对优化微乳增渗作用显著。通过适量添加胆固醇不仅改变角质层含水量,增加优化微乳的透皮速率,同时使药物透皮吸收更加平稳。5%薄荷醇对微乳透皮速率影响大于离子对等因素。在使用薄荷醇基础上,增稠剂中aerosil200能够在不改变微乳结构情况下增加该制剂的黏度,结合体外实验确定用于体内实验微乳处方为油酸50.28%,吐温80 15.79%,乙醇15.79%,水12.64%,薄荷醇5.00%,在此基础上按重量添加aerosil200 5%。
体内实验表明,微乳组较片剂组T1/2(Ke),Tpeak和MRT均显著提高,Cmax显著降低。这说明微乳组药物释放平稳,维持药效时间长,血药浓度波动小。
本论文通过制备盐酸普萘洛尔的透皮微乳,解决了该药作为心血管药物在临床使用时存在的问题,提高了其在治疗过程中的安全性、有效性及患者的顺应性。
Transdermal drug delivery system has characters as avoiding hepatic first pass effect, stability of drug release, convenience of drug administration, and mature products of this administration route were commercially available. But the drug having both appropriate oil/water partition coefficient and low daily dosage, can reach effective drug concentration in vivo through transdermal administration, for the reason of skin barrier.
Hydrochloride propranolol was selected as the model drug for its water soluble character and high daily dosage. Terpenes were accepted commonly as safe and efficient transdermal enhancer, especially for that being hydrophilic. We studied effect of terpene enhancer with different structure on transdermal permeation profile of model drug. The results showed that all terpene selected enhanced transdermal permeation flux and decreased the lag time of hydrochloride propranolol. And further mechanism research showed that the terpenes increased SC partition coefficient of this drug, elevated fluidization of SC lipids, had no effect on lipids amount in SC. The results of activity energy calculation were abserved as that, compared with that of the control, cineol and menthanol decreased activity energy of model drug permeation, menthone didn’t change it, while bornel, camphor and bisaborlol increased activity energy.
Two systems of microemulsion components were selected according to the results of solubility research of model drug in oil phase mixture, and the pseudo ternary phase diagram of them were draw. With characters of phase diagram, simplex lattice method and single factor alternative method were used to optimize formulation of microemulsion respectively. The results of optimization were like these showed as below. The optimized formulation of system1 was composed as that, water19%, benzoyl40%, tween20 28%, propranl glycol12%. The optimized formulation of system 2 was composed as that, water12.64%,oleic acid 55.28%,tween80 10.79%,ethanol10.79%. The optimized formula of both two system showed good stability. With the permeation flux into consideration, the optimized formula of system 2 were selected for further investigation, which were effect of ion pair, water content in SC, terpene concentration, rheology controller. Being the ion pair, o-nitro benzoic acid improved drug permeation flux significantly. The appropriate amount addition of cholesterol, which change water content in SC, increased not only permeation flux, but also the stability of drug release. And the extend of drug permeation enhancement by 5% menthanol was more significant than that by ion pair, water content in SC. aerosil200 increased the viscosity of optimized formula without change its microemulsion character. And the formula for in vivo investigation was designed as, oil acid 50.28%, tween 80 15.79%, ehtanol 15.79%, water12.64%,menthanol 5.00%,in which aerosil200 was added at 5% of components above(w/w).
The results of research in vivo was showed that, compared with the tablet group, the T1/2(Ke),Tpeak and MRT were elevated significantly, and the Cmax was decreased in microemulsion group. The results illuminated that microemulsion prepared released drug stably, enlarged drug effect time and decreased fluctuant of blood-drug concentration.
In this paper, we prepared transdermal microemulsion of hydrochloride propranolol, which is used as cardiovascular drug with some promble in clinical application. And the new route of administration improved safety, efficiency of the drug and compliance of patient
引文
[1] A Kogan, N Garti. Microemulsions as transdermal drug delivery vehicles. Advances in Colloid and Interface Science 123–126 (2006) 369–385
[2] J.H. Schulman, W. Stoeckenius, L.M. Prince, Mechanism of formation and structure of microemulsions by electron microscopy, J. Phys. Chem. 63 (1959) 1677–1680
[3] I. Danielsson, B. Lindman, The definition of microemulsion Colloid. Surf. 3 (1981) 391–392
[4]M. Kreilgaard, E.J. Pedersen, J.W. Jaroszewski, NMR characterisation and transdermal drug delivery potential of microemulsion systems, J. Control. Release 69 (2000) 421–433.
[5] R. Aboofazeli, C.B. Lawrence, S.R. Wicks, M.J. Lawrence, Investigations into the formation and characterization of phospholipids microemulsions III. Pseudo-ternary phase dia grams of systems containing water-lecithin-isopropyl myris tate and either an alkanoic acid, amine, alkanediol, poly ethylene glycol alkyl ether or alcohol as co-surfactant, Int. J. Pharm. 111 (1994) 63–72.
[6]J. Lawrence, Surfactant systems: microemulsions and vesicles as vehicles for drug delivery, Eur. J. Drug Metab Pharmacokinet. 3 (1994) 257–269
[7] A.C. Lam, R.S. Schechter, The theory of diffusion inmicroemulsions, J. Colloid Interface Sci. 120 (1987) 56–63.
[8]B. Lindman, M.E. Moseley, P. Stilbs, Fourier-transformNMR self-diffusion and microemulsion structure, J. ColloidInterface Sci. 83 (1981) 569–582.
[9]E. Peira, P. Scolari, M.R. Gasco, Transdermal permeation of apomorphine through hairless mouse skin from microemulsions sions, Int. J. Pharm. 226 (2001) 47–51
[10]Y.S. Rhee, J.G. Choi, E.S. Park, S.C. Chi, Transdermal delivery of ketoprofen using microemulsions, Int. J. Pharm. 228 (2001) 161–170.
[11]M. Trotta, F. Pattarino, M.R. Gasco, Influence of counter ions on the skin permeation of methotrexate from water–oil microemulsions, Pharm. Acta Helv. 71 (1996) 135–140.
[12] M Kreilgaard. Influence of microemulsions on cutaneous drug delivery. Adv Drug Deliv Rev 2002;54:S77-S98
[13] AC Williams, BW Barry. Interactions of surfactants (edge activators) and skin penetration enhancers with liposomes .Adv Drug Deliv Rev 2004;56:603-626
[14] H Tanojo, A BosvanGeest, JA Bouwstra, et al. Thermochim Acta 1997;293:77.
[15] M Goodman, BW Barry. Drug interaction and location in liposomes: correlation with polar surface areas. Int J Pharm 1989;57:29-36
[16]F. Dreher, R Walde, R Walther, E. Wehrli Interaction of a lecithin microemulsion gel with human stratumcorneum and its effect on transdermal transport. Journal of Controlled Release 45 (1997) 131-140
[17] PC Rigg, BW Barry. Electrical conductivity through snake and human skin membranes. J Invest Dermatol 1990;94:235-239.
[18] R Reeta. A Guptaa, Swantrant K, et al. NMR characterisation and transdermal drug delivery potentialof microemulsion systems. Journal of Controlled Release 69 (2000) 421–433
[19] AC Sintov, L Shapiro. New microemulsion vehicle facilitates percutaneous penetration in vitro and cutaneous drug bioavailability in vivo. J Control Release 2004;95:173-181
[20] RR Gupta, SK Jain, M Varshney. AOT water-in-oil microemulsions as a penetration enhancer in transdermal drug delivery of 5-fluorouracil . Colloids and Surfaces B: Biointerfaces 2005;41:25-32
[21] J.arvinen, K., J.arvinen, T., Urtti, A.,. Ocular absorption following topical delivery. Adv. Drug Deliv. Rev. 1995,16, 3–19.
[22] D.P Evitts,. O Olejnik,. D.G.Musson, Bilgood, A.M., 1991.Aqueous ophtalmic microemulsions of tepoxalin. European patent application 0 480 690 A1.
[23] S Benita,. S.Muchtar, 1992. Ophthalmic compositions. Patent NoEP 0521 799 A1.
[24] S.Benita, M.Y.Levy, Submicron emulsions as colloidal drug carriers for intravenous administration: comprehensive physicochemical characterization. J. Pharm. Sci. 1993,82 (11), 1069.
[25] N. Naveh, S. Muchtar, S. Benita. Pilocarpine incorporated into a submicron emulsion vehicle causes an unexpectedly prolonged ocular hypotensive effect in rabbits. J. Ocul. Pharmacol. 1994, 10 (3), 509–520.
[26] G.F.Cooney, V. Jeevanandam, S. Choudhury, et al.. Comparative bioavailability of Neoral and Sandimmune in cardiac transplant recipients over 1 year. Transplant. Proc. 1998, 30, 1892–1894.
[27] C.J.Porter, W.N.Charman.. In vitro assessment of oral lipid based formulations.Adv. Drug Deliv. Rev. 2001, 50 (Suppl. 1), S127–S147.
[28]X Y Sha, G Y Yan, Y J Wu. Effect of self-microemulsifying drug delivery systems containing Labrasol on tight junctions in Caco-2 cells. European Journal of Pharmaceutical Sciences2005, 24 , 477–486
[29] TR Kommuru, B Gurley, MA Khan, Reddy IK. Int J Pharm 2001;212:233.
[30] C.R.Behl, H.K.Pimplaskar, A.P.Sileno, et al. Effects of physicochemical properties and other factors on systemic nasal drug delivery. Adv. Drug Deliv. Rev. 1998, 29, 89–116.
[31]Illum, L.,. Transport of drugs from the nasal cavity to the central nervous system. Eur. J. Pharm. Sci. 2000,11, 1–18.
[32] A.Yoshida, M.Yamamoto, T. Iloh, et al. Utility of 2-hydroxypropyl- -cyclodextrin in an intramuscular injectable preparation of nimodipine. Chem. Pharm. Bull. 1990, 38, 176–179.
[33] M.Glertlova, K.Ondrias. Nifedipine and nimodipine solubility in the presence of diheptanoyl phosphatidylcholine. Pharmazie 1992, 47, 861–863.
[34] Q Z Zhang, X G Jiang. Preparation of nimodipine-loaded microemulsion for intranasal delivery and evaluation on the targeting efficiency to the brain. International Journal of Pharmaceutics 2004,275, 85–96
[35]L Li, I Nandi, K H. Kim. Development of an ethyl laurate-based microemulsion for rapid-onset intranasal delivery of diazepam. International Journal of Pharmaceutics 2002, 237, 77–85
[36]余东升,姚昶,潘立群.黄芪注射液浓缩液微乳的制备.山东中医药大学学报,2007,31(2):148—151
[37]张莉,向东,洪净,等.肝靶向去甲斑蝥素微乳的研究.药学学报,2004,39(8):650—655.
[38] L He,G L Wang,Q Zhang.An alternative paclitaxel microemulslon formulation:hyper sensitivity evaluation and pharmacokinetic profile.J Pharm,2003,250(1):45—50.
[39]范贤,孟庆顺.盐酸普萘洛尔在精神疾病中的临床应用.中华统代临床医学杂志.2007 (5)2,168
[40] T. Walle, T. Fagan, D. Conrad, et al.. Presystemic and systemic glucosonidation of propranolol. Clin.Pharmacol. Ther. 1979,76, 167–172.
[41] T.Sawamoto, S.Haruta, Y.Kurosaki, et al.Prediction of plasma concentrationprofile of orally administereddrugs based on gastrointestinal transit kinetics and absorbability in rats. J. Pharm. Pharmacol. 1997,49, 450–457.
[42]X. Zhao, J.P. Liu, X. Zhang, Y. Li. Enhancement of transdermal delivery of theophylline using microemulsion vehicle. International Journal of Pharmaceutics 2006, 327,58–64
[43] C. Mohammad, V. Manoj, C.Jadish, et al. Effect of the composition of lecithin/n-propanol/isopropyl myristate/water microemulsions on barrier properties of mice skin for transdermal permeation of tetracaine hydrochloride: In vitro. Colloids and Surfaces B: Biointerfaces 2006, 50,18–25
[44]Y S. Rhee, J G. Choi, E S. Park, et al. Transdermal delivery of ketoprofen using microemulsions . International Journal of Pharmaceutics 228 (2001) 161–170
[45]孙洁胤周芝芳刘放.苦参素油水分配系数及pH值对其的影响.浙江省医学科学院学报. 2006年17卷1期,19-21
[46] X P. Zhan, S J. Chen, G C. Tang, et al. A new poly (2- hydroxyl -3-phenoxypropylacrylate,4-hydroxybutyl acrylate, diethyl maleate) membrane controlled clonidine linear release in the transdermal drug delivery system. European Polymer Journal 2007, 43, 1588–1594
[47]郑俊民,李启先.经皮给药新剂型.北京:人民卫生出版社,1997.6.
[48] A.Pagliara , B.Testa , PA.Carrupt , et a1 . Molecular properties and pharmacokinetic behavior of cetirizine,a zwitterionic HI—receptor antagonist[J].J MedChem ,1998,41(6):853·63.
[49] B G. Plember,G. Caron,G. Ermondi,et a1.Lipophilicity behaviour of the zwitterionic anti—histamine cetirizine in phosphatidylcholine liposomes/ water systems.Pharm Res. 2001.18(5):694-701.
[50] A C. Williams, B W. Barry. Penetration enhancers. Advanced Drug Delivery Reviews 56 (2004) 603– 618
[51] A. Nokhodchi, K. Sharabiani.The effect of terpene concentrations on the skin penetration of diclofenac sodium International Journal of Pharmaceutics 2006,1-9
[52] H.R. Moghimi, A.C. Williams, B.W. Barry, Enhancement by terpenes of 5-fluorouracil permeation through the stratum corneum: model solvent approach, J. Pharm. Pharmacol. 50 (9) (1998) 955– 964
[53] F. Dreher a, R Walde, R Walther b, et al.. Interaction of a lecithin microemulsion gel with human stratum corneum and its effect on transdermal transport. Journal of Controlled Release 1997, 45, 131-140
[54] R.C.Wester, H.I. Maibach, L. Sedik, et al. In vitro percutaneous absorption of cadmium from water and soil into human skin, Fundam. Appl. Toxicol. 1992, 7, 1–5
[55] P.A. Cornwell, B.W. Barry, The routes of penetration of ions and 5-fluorouracil across human skin and the mechanisms of action of terpene skin penetration enhancers, Int. J. Pharm. 1993, 94, 189– 194.
[56] R.N.A.H. Lewis, R.N. Mc Eelhaney. Fourier transform infrared spectroscopy in the study hydrated lipids and lipid bilayer membranes, in: H.H. Mantsch, D. Chapman (Eds.), Infrared Spectroscopy of Biomolecules, Wiley-Liss, New York, 1996, pp. 159–202
[57] P.A. Cornwell. B.W. Barry, J A. Bouwstra. Modes of action of terpene penetration enhancers in human skin; differential scanning calorimetry, small-angle X-ray diffraction and enhancer uptake studies. International Journal of Pharmaceutics 1996,127, 9-26
[58]A. Naik, R.H. Guy, Infrared spectroscopic and differential scanning calorimetric investigations of the stratum corneum barrier function, in: R.O. Potts, R.H. Guy (Eds.), Mechanism of Transdermal Drug Delivery, Marcel Dekker, New York, 1997, pp. 87–149
[59]M.A. Yamne, A.C. Williams, B.W. Barry, Terpene penetration enhancers in propylene glycol /water co-solvent systems: effectiveness and mechanism of action, J. Pharm. Pharmacol. 1995, 47, 978–989
[60]H.K. Vaddi, P.C. Ho, Y.W. Chan, et al. Terpenes in ethanol: haloperidol permeation and partition through human skin and stratum corneum changes. Journal of Controlled Release 2002, 81, 121–133
[61] N.A. Megrab, A.C. Williams, B.W. Barry, Oestradiol permeation across human skin, silastic and snake skin membranes: the effects of ethanol /water co-solvent system, Int. J. Pharm. 1995,116, 101–112.
[62] G.M. Golden, D.B. Guzek, R.R. Harris, et al. Lipid thermotropic transitions in human stratumcorneum, J. Invest. Dermatol. 1986, 86, 255–259.
[63] H.R. Moghimi, A.C. Williams, B.W. Barry, Enhancement by terpenes of 5-fluorouracil permeation through the stratum corneum: model solvent approach, J. Pharm. Pharmacol. 1998,50 (9) : 955– 964
[64] A.K. Jain, A K Jain, N S Thomas, Transdermal drug delivery of imipramine hydrochloride.I. Effect of terpenes. Journal of Controlled Release 2002, 79, 93–101
[65] U.Schmalfub, R.Neubert, W. Wohlrab, Modification of drug penetration intohuman skin using microemulsions. J. Controlled Release 1997, 278-285
[66]K.R.Brain,K.A.Walters. Molecular modeling of skin permeation enhancer by chemical agents. In Hadgraft. J. and Walters. K.A.(Eds). Pharmaceutical skin penetration enhancement, Marcel Dekker. New York. Basel. Hong Kong. 1993.pp.389-416.
[67] N.A. Megrab, A.C. Williams, B.W. Barry, Oestradiol permeation across human skin, silastic and snake skin membranes: the effects of ethanol /water co-solvent system, Int. J. Pharm. 1995,116, 101–112.
[68] R. Pagano, T.E. Thompson, Spherical bilayer membranes:electrical and isotopic studies of ion permeability, J. Mol.Biol. 1968, 38, 41– 57.
[69] P.A. Cornwell, B.W. Barry, The routes of penetration of ions and 5-fluorouracil across human skin and the mechanisms of action of terpene skin penetration enhancers, Int. J. Pharm. 1993, 94, 189– 194
[70] Sunil Thomas Kumar Narishetty, Ramesh Panchagnula. Transdermal delivery of zidovudine: effect of terpenes and their mechanism of action. Journal of Controlled Release 2004, 95, 367– 379
[71] T. Ogiso, T. Hirota, I. Masahiro, et al. Effect of temperature on percutaneous absorption of terodiline and relationship between penetration and fluidity of stratum corneum lipids. Int. J.Pharm. 1998, 176, 63–72
[72] F. Akomeah , T Nazir, Effect of heat on the percutaneous absorption and skin retention of three model penetrants. European Journal of Pharmaceutical Sciences 2004, 21, 337–345
[73] H. Hsiao, M T. Sheu. Preparation of microeraulsions using polyglyeerin fatty acid esters as surfactant for the delivery of protein drugs Pharm Sci.1996.85(2):138—143.
[74] Y S. Rhee, J G. Choi, Eun-Seok Park. Transdermal delivery of ketoprofen using microemulsions. International Journal of Pharmaceutics 2001, 228, 161–170
[75]陆彬,张正全.用三角相图法研究药用微乳的形成条件.药学学报2001.36(1):58—62
[76]徐秉玖.药物统计学,北京医科大学(北京, 1999) 242-245
[77]余建英,何旭宏.数据统计分析与SPSS应用[M].人民邮电出版社.北京2003. 204-215
[78]林艳琼,甘勇,王晓东,等.地塞米松眼用微乳的研究.中国药学杂志,2006, 4l(5) 358-362
[79]董红宾,欧阳五庆,黎璐,等. Vc与VE复方微乳的制备及其质量评价.西北农林科技大学学报(自然科学版),2007,35(1):58-62
[80]D. Krajisnik, E. Park. Characterization of Tween80 based microemulsion drug delivery vehicles for an amphiphilic drug. J. Pharm. Pharmacol. 1998, 50 (9) :955– 964
[81] A. Arellano, S. Santoyo, C. Martin. Enhancing effect of t oil acid on the in vitro percutaneous absorption of diclofenac sodium. J. Invest. Dermatol 1996,130, 141-145
[82] Michele Trotta, Elena Ugazio, Elena Peira, Influence of ion pairing on topical delivery of retinoic acid from microemulsions. Journal of Controlled Release 86 (2003) 315–321
[83] M. Trotta, F. Pattarino, M.R. Gasco. Influence of counter ions on the skin permeation of methotrexate from water-oil microemulsions. Pharmaceutics Acta Helvetiae 71 (1996) 135-140
[84] F. Dreher a, R Walde, R Walther b, E. Wehrli. Interaction of a lecithin microemulsion gel with human stratum corneum and its effect on transdermal transport. Journal of Controlled Release 45 (1997) 131-140
[85] A. Pardo, Y. Shin, S. Cohen, Kinetics of transdermal permeation of an organic ion pair: Physostigmine salicylate, J. Pharm. Sci. 81 (1992) 990–995.
[86] M. Begofia, I. Graciela, B. Josh. Delivery of a hydrophilic solute through the skin from novel microemulsion systems. European Journal of Pharmaceutics and Biopharmaceutics 1997, 43, 37-42
[87] H.K. Vaddi , P.C. Ho , Y.W. Chan , S.Y. Chan. Terpenes in ethanol: haloperidol permeation and partition through human skin and stratum corneum changes. Journal of Controlled Release. 2002, 81, 121–133
[88] X. Zhao, J.P. Liu, X. Zhang, Y. Li. Enhancement of transdermal delivery of theophylline using microemulsion vehicle. International Journal of Pharmaceutics 2006, 327, 58–64
[89] R.Lapasin, M.Grassi, N Coceani. Effects of polymer addition on the rheology of o/w microemulsions. Rheol. Acta. 2001,40, 185–192.
[90] C.Valenta, K.Schultz,. Influence of carrageenan on the rheology and skin permeation of microemulsion formulations. J. Control. Release. 2004,95, 257–265.
[91] D. Gulsen, A.Chauhan. Dispersion of microemulsion drops in HEMA hydrogel: a potential ophthalmic drug delivery vehicle. Int. J. Pharm. 2005,292,95–117.
[92] P. ?piclin, M. Homar, A. Zupanˇciˇc-Valant. Sodium ascorbyl phosphate in topical microemulsions. International Journal of Pharmaceutics 2003, 256, 65–73
[93]梁文权.生物药剂学和药物动力学(第二版).人民卫生出版社(北京,2003), 155
[94]张先洲,孟书舫,祝红达,等.氯雷他定胶囊在健康人体的生物等效性.中国医院药学杂志,2007,27(10): 1390-1392 [95尤海生,董亚琳,邢建峰,等.灯盏乙素在大鼠体内药代动力学及组织分布的研究.中国中药杂志, 2007, 32(16): 1688-1692
[96]李曼玲,殷文光,刘淑芝,等. FLU—HPLC测定复方吴茱萸巴布膏中阿魏酸血药浓度及药动学研究.中国药学杂志,2007, 42(21):1649-1651
[97]李建伟,白小红,翁惠,等.液相微萃取-后萃取光化学荧光高效液相色谱法测定生物样品中甲氨蝶呤的含量.中国医院药学杂志, 2007, 27(11): 1514-1517
[2] J.H. Schulman, W. Stoeckenius, L.M. Prince, Mechanism of formation and structure of microemulsions by electron microscopy, J. Phys. Chem. 63 (1959) 1677–1680
[3] I. Danielsson, B. Lindman, The definition of microemulsion Colloid. Surf. 3 (1981) 391–392
[4]M. Kreilgaard, E.J. Pedersen, J.W. Jaroszewski, NMR characterisation and transdermal drug delivery potential of microemulsion systems, J. Control. Release 69 (2000) 421–433.
[5] R. Aboofazeli, C.B. Lawrence, S.R. Wicks, M.J. Lawrence, Investigations into the formation and characterization of phospholipids microemulsions III. Pseudo-ternary phase dia grams of systems containing water-lecithin-isopropyl myris tate and either an alkanoic acid, amine, alkanediol, poly ethylene glycol alkyl ether or alcohol as co-surfactant, Int. J. Pharm. 111 (1994) 63–72.
[6]J. Lawrence, Surfactant systems: microemulsions and vesicles as vehicles for drug delivery, Eur. J. Drug Metab Pharmacokinet. 3 (1994) 257–269
[7] A.C. Lam, R.S. Schechter, The theory of diffusion inmicroemulsions, J. Colloid Interface Sci. 120 (1987) 56–63.
[8]B. Lindman, M.E. Moseley, P. Stilbs, Fourier-transformNMR self-diffusion and microemulsion structure, J. ColloidInterface Sci. 83 (1981) 569–582.
[9]E. Peira, P. Scolari, M.R. Gasco, Transdermal permeation of apomorphine through hairless mouse skin from microemulsions sions, Int. J. Pharm. 226 (2001) 47–51
[10]Y.S. Rhee, J.G. Choi, E.S. Park, S.C. Chi, Transdermal delivery of ketoprofen using microemulsions, Int. J. Pharm. 228 (2001) 161–170.
[11]M. Trotta, F. Pattarino, M.R. Gasco, Influence of counter ions on the skin permeation of methotrexate from water–oil microemulsions, Pharm. Acta Helv. 71 (1996) 135–140.
[12] M Kreilgaard. Influence of microemulsions on cutaneous drug delivery. Adv Drug Deliv Rev 2002;54:S77-S98
[13] AC Williams, BW Barry. Interactions of surfactants (edge activators) and skin penetration enhancers with liposomes .Adv Drug Deliv Rev 2004;56:603-626
[14] H Tanojo, A BosvanGeest, JA Bouwstra, et al. Thermochim Acta 1997;293:77.
[15] M Goodman, BW Barry. Drug interaction and location in liposomes: correlation with polar surface areas. Int J Pharm 1989;57:29-36
[16]F. Dreher, R Walde, R Walther, E. Wehrli Interaction of a lecithin microemulsion gel with human stratumcorneum and its effect on transdermal transport. Journal of Controlled Release 45 (1997) 131-140
[17] PC Rigg, BW Barry. Electrical conductivity through snake and human skin membranes. J Invest Dermatol 1990;94:235-239.
[18] R Reeta. A Guptaa, Swantrant K, et al. NMR characterisation and transdermal drug delivery potentialof microemulsion systems. Journal of Controlled Release 69 (2000) 421–433
[19] AC Sintov, L Shapiro. New microemulsion vehicle facilitates percutaneous penetration in vitro and cutaneous drug bioavailability in vivo. J Control Release 2004;95:173-181
[20] RR Gupta, SK Jain, M Varshney. AOT water-in-oil microemulsions as a penetration enhancer in transdermal drug delivery of 5-fluorouracil . Colloids and Surfaces B: Biointerfaces 2005;41:25-32
[21] J.arvinen, K., J.arvinen, T., Urtti, A.,. Ocular absorption following topical delivery. Adv. Drug Deliv. Rev. 1995,16, 3–19.
[22] D.P Evitts,. O Olejnik,. D.G.Musson, Bilgood, A.M., 1991.Aqueous ophtalmic microemulsions of tepoxalin. European patent application 0 480 690 A1.
[23] S Benita,. S.Muchtar, 1992. Ophthalmic compositions. Patent NoEP 0521 799 A1.
[24] S.Benita, M.Y.Levy, Submicron emulsions as colloidal drug carriers for intravenous administration: comprehensive physicochemical characterization. J. Pharm. Sci. 1993,82 (11), 1069.
[25] N. Naveh, S. Muchtar, S. Benita. Pilocarpine incorporated into a submicron emulsion vehicle causes an unexpectedly prolonged ocular hypotensive effect in rabbits. J. Ocul. Pharmacol. 1994, 10 (3), 509–520.
[26] G.F.Cooney, V. Jeevanandam, S. Choudhury, et al.. Comparative bioavailability of Neoral and Sandimmune in cardiac transplant recipients over 1 year. Transplant. Proc. 1998, 30, 1892–1894.
[27] C.J.Porter, W.N.Charman.. In vitro assessment of oral lipid based formulations.Adv. Drug Deliv. Rev. 2001, 50 (Suppl. 1), S127–S147.
[28]X Y Sha, G Y Yan, Y J Wu. Effect of self-microemulsifying drug delivery systems containing Labrasol on tight junctions in Caco-2 cells. European Journal of Pharmaceutical Sciences2005, 24 , 477–486
[29] TR Kommuru, B Gurley, MA Khan, Reddy IK. Int J Pharm 2001;212:233.
[30] C.R.Behl, H.K.Pimplaskar, A.P.Sileno, et al. Effects of physicochemical properties and other factors on systemic nasal drug delivery. Adv. Drug Deliv. Rev. 1998, 29, 89–116.
[31]Illum, L.,. Transport of drugs from the nasal cavity to the central nervous system. Eur. J. Pharm. Sci. 2000,11, 1–18.
[32] A.Yoshida, M.Yamamoto, T. Iloh, et al. Utility of 2-hydroxypropyl- -cyclodextrin in an intramuscular injectable preparation of nimodipine. Chem. Pharm. Bull. 1990, 38, 176–179.
[33] M.Glertlova, K.Ondrias. Nifedipine and nimodipine solubility in the presence of diheptanoyl phosphatidylcholine. Pharmazie 1992, 47, 861–863.
[34] Q Z Zhang, X G Jiang. Preparation of nimodipine-loaded microemulsion for intranasal delivery and evaluation on the targeting efficiency to the brain. International Journal of Pharmaceutics 2004,275, 85–96
[35]L Li, I Nandi, K H. Kim. Development of an ethyl laurate-based microemulsion for rapid-onset intranasal delivery of diazepam. International Journal of Pharmaceutics 2002, 237, 77–85
[36]余东升,姚昶,潘立群.黄芪注射液浓缩液微乳的制备.山东中医药大学学报,2007,31(2):148—151
[37]张莉,向东,洪净,等.肝靶向去甲斑蝥素微乳的研究.药学学报,2004,39(8):650—655.
[38] L He,G L Wang,Q Zhang.An alternative paclitaxel microemulslon formulation:hyper sensitivity evaluation and pharmacokinetic profile.J Pharm,2003,250(1):45—50.
[39]范贤,孟庆顺.盐酸普萘洛尔在精神疾病中的临床应用.中华统代临床医学杂志.2007 (5)2,168
[40] T. Walle, T. Fagan, D. Conrad, et al.. Presystemic and systemic glucosonidation of propranolol. Clin.Pharmacol. Ther. 1979,76, 167–172.
[41] T.Sawamoto, S.Haruta, Y.Kurosaki, et al.Prediction of plasma concentrationprofile of orally administereddrugs based on gastrointestinal transit kinetics and absorbability in rats. J. Pharm. Pharmacol. 1997,49, 450–457.
[42]X. Zhao, J.P. Liu, X. Zhang, Y. Li. Enhancement of transdermal delivery of theophylline using microemulsion vehicle. International Journal of Pharmaceutics 2006, 327,58–64
[43] C. Mohammad, V. Manoj, C.Jadish, et al. Effect of the composition of lecithin/n-propanol/isopropyl myristate/water microemulsions on barrier properties of mice skin for transdermal permeation of tetracaine hydrochloride: In vitro. Colloids and Surfaces B: Biointerfaces 2006, 50,18–25
[44]Y S. Rhee, J G. Choi, E S. Park, et al. Transdermal delivery of ketoprofen using microemulsions . International Journal of Pharmaceutics 228 (2001) 161–170
[45]孙洁胤周芝芳刘放.苦参素油水分配系数及pH值对其的影响.浙江省医学科学院学报. 2006年17卷1期,19-21
[46] X P. Zhan, S J. Chen, G C. Tang, et al. A new poly (2- hydroxyl -3-phenoxypropylacrylate,4-hydroxybutyl acrylate, diethyl maleate) membrane controlled clonidine linear release in the transdermal drug delivery system. European Polymer Journal 2007, 43, 1588–1594
[47]郑俊民,李启先.经皮给药新剂型.北京:人民卫生出版社,1997.6.
[48] A.Pagliara , B.Testa , PA.Carrupt , et a1 . Molecular properties and pharmacokinetic behavior of cetirizine,a zwitterionic HI—receptor antagonist[J].J MedChem ,1998,41(6):853·63.
[49] B G. Plember,G. Caron,G. Ermondi,et a1.Lipophilicity behaviour of the zwitterionic anti—histamine cetirizine in phosphatidylcholine liposomes/ water systems.Pharm Res. 2001.18(5):694-701.
[50] A C. Williams, B W. Barry. Penetration enhancers. Advanced Drug Delivery Reviews 56 (2004) 603– 618
[51] A. Nokhodchi, K. Sharabiani.The effect of terpene concentrations on the skin penetration of diclofenac sodium International Journal of Pharmaceutics 2006,1-9
[52] H.R. Moghimi, A.C. Williams, B.W. Barry, Enhancement by terpenes of 5-fluorouracil permeation through the stratum corneum: model solvent approach, J. Pharm. Pharmacol. 50 (9) (1998) 955– 964
[53] F. Dreher a, R Walde, R Walther b, et al.. Interaction of a lecithin microemulsion gel with human stratum corneum and its effect on transdermal transport. Journal of Controlled Release 1997, 45, 131-140
[54] R.C.Wester, H.I. Maibach, L. Sedik, et al. In vitro percutaneous absorption of cadmium from water and soil into human skin, Fundam. Appl. Toxicol. 1992, 7, 1–5
[55] P.A. Cornwell, B.W. Barry, The routes of penetration of ions and 5-fluorouracil across human skin and the mechanisms of action of terpene skin penetration enhancers, Int. J. Pharm. 1993, 94, 189– 194.
[56] R.N.A.H. Lewis, R.N. Mc Eelhaney. Fourier transform infrared spectroscopy in the study hydrated lipids and lipid bilayer membranes, in: H.H. Mantsch, D. Chapman (Eds.), Infrared Spectroscopy of Biomolecules, Wiley-Liss, New York, 1996, pp. 159–202
[57] P.A. Cornwell. B.W. Barry, J A. Bouwstra. Modes of action of terpene penetration enhancers in human skin; differential scanning calorimetry, small-angle X-ray diffraction and enhancer uptake studies. International Journal of Pharmaceutics 1996,127, 9-26
[58]A. Naik, R.H. Guy, Infrared spectroscopic and differential scanning calorimetric investigations of the stratum corneum barrier function, in: R.O. Potts, R.H. Guy (Eds.), Mechanism of Transdermal Drug Delivery, Marcel Dekker, New York, 1997, pp. 87–149
[59]M.A. Yamne, A.C. Williams, B.W. Barry, Terpene penetration enhancers in propylene glycol /water co-solvent systems: effectiveness and mechanism of action, J. Pharm. Pharmacol. 1995, 47, 978–989
[60]H.K. Vaddi, P.C. Ho, Y.W. Chan, et al. Terpenes in ethanol: haloperidol permeation and partition through human skin and stratum corneum changes. Journal of Controlled Release 2002, 81, 121–133
[61] N.A. Megrab, A.C. Williams, B.W. Barry, Oestradiol permeation across human skin, silastic and snake skin membranes: the effects of ethanol /water co-solvent system, Int. J. Pharm. 1995,116, 101–112.
[62] G.M. Golden, D.B. Guzek, R.R. Harris, et al. Lipid thermotropic transitions in human stratumcorneum, J. Invest. Dermatol. 1986, 86, 255–259.
[63] H.R. Moghimi, A.C. Williams, B.W. Barry, Enhancement by terpenes of 5-fluorouracil permeation through the stratum corneum: model solvent approach, J. Pharm. Pharmacol. 1998,50 (9) : 955– 964
[64] A.K. Jain, A K Jain, N S Thomas, Transdermal drug delivery of imipramine hydrochloride.I. Effect of terpenes. Journal of Controlled Release 2002, 79, 93–101
[65] U.Schmalfub, R.Neubert, W. Wohlrab, Modification of drug penetration intohuman skin using microemulsions. J. Controlled Release 1997, 278-285
[66]K.R.Brain,K.A.Walters. Molecular modeling of skin permeation enhancer by chemical agents. In Hadgraft. J. and Walters. K.A.(Eds). Pharmaceutical skin penetration enhancement, Marcel Dekker. New York. Basel. Hong Kong. 1993.pp.389-416.
[67] N.A. Megrab, A.C. Williams, B.W. Barry, Oestradiol permeation across human skin, silastic and snake skin membranes: the effects of ethanol /water co-solvent system, Int. J. Pharm. 1995,116, 101–112.
[68] R. Pagano, T.E. Thompson, Spherical bilayer membranes:electrical and isotopic studies of ion permeability, J. Mol.Biol. 1968, 38, 41– 57.
[69] P.A. Cornwell, B.W. Barry, The routes of penetration of ions and 5-fluorouracil across human skin and the mechanisms of action of terpene skin penetration enhancers, Int. J. Pharm. 1993, 94, 189– 194
[70] Sunil Thomas Kumar Narishetty, Ramesh Panchagnula. Transdermal delivery of zidovudine: effect of terpenes and their mechanism of action. Journal of Controlled Release 2004, 95, 367– 379
[71] T. Ogiso, T. Hirota, I. Masahiro, et al. Effect of temperature on percutaneous absorption of terodiline and relationship between penetration and fluidity of stratum corneum lipids. Int. J.Pharm. 1998, 176, 63–72
[72] F. Akomeah , T Nazir, Effect of heat on the percutaneous absorption and skin retention of three model penetrants. European Journal of Pharmaceutical Sciences 2004, 21, 337–345
[73] H. Hsiao, M T. Sheu. Preparation of microeraulsions using polyglyeerin fatty acid esters as surfactant for the delivery of protein drugs Pharm Sci.1996.85(2):138—143.
[74] Y S. Rhee, J G. Choi, Eun-Seok Park. Transdermal delivery of ketoprofen using microemulsions. International Journal of Pharmaceutics 2001, 228, 161–170
[75]陆彬,张正全.用三角相图法研究药用微乳的形成条件.药学学报2001.36(1):58—62
[76]徐秉玖.药物统计学,北京医科大学(北京, 1999) 242-245
[77]余建英,何旭宏.数据统计分析与SPSS应用[M].人民邮电出版社.北京2003. 204-215
[78]林艳琼,甘勇,王晓东,等.地塞米松眼用微乳的研究.中国药学杂志,2006, 4l(5) 358-362
[79]董红宾,欧阳五庆,黎璐,等. Vc与VE复方微乳的制备及其质量评价.西北农林科技大学学报(自然科学版),2007,35(1):58-62
[80]D. Krajisnik, E. Park. Characterization of Tween80 based microemulsion drug delivery vehicles for an amphiphilic drug. J. Pharm. Pharmacol. 1998, 50 (9) :955– 964
[81] A. Arellano, S. Santoyo, C. Martin. Enhancing effect of t oil acid on the in vitro percutaneous absorption of diclofenac sodium. J. Invest. Dermatol 1996,130, 141-145
[82] Michele Trotta, Elena Ugazio, Elena Peira, Influence of ion pairing on topical delivery of retinoic acid from microemulsions. Journal of Controlled Release 86 (2003) 315–321
[83] M. Trotta, F. Pattarino, M.R. Gasco. Influence of counter ions on the skin permeation of methotrexate from water-oil microemulsions. Pharmaceutics Acta Helvetiae 71 (1996) 135-140
[84] F. Dreher a, R Walde, R Walther b, E. Wehrli. Interaction of a lecithin microemulsion gel with human stratum corneum and its effect on transdermal transport. Journal of Controlled Release 45 (1997) 131-140
[85] A. Pardo, Y. Shin, S. Cohen, Kinetics of transdermal permeation of an organic ion pair: Physostigmine salicylate, J. Pharm. Sci. 81 (1992) 990–995.
[86] M. Begofia, I. Graciela, B. Josh. Delivery of a hydrophilic solute through the skin from novel microemulsion systems. European Journal of Pharmaceutics and Biopharmaceutics 1997, 43, 37-42
[87] H.K. Vaddi , P.C. Ho , Y.W. Chan , S.Y. Chan. Terpenes in ethanol: haloperidol permeation and partition through human skin and stratum corneum changes. Journal of Controlled Release. 2002, 81, 121–133
[88] X. Zhao, J.P. Liu, X. Zhang, Y. Li. Enhancement of transdermal delivery of theophylline using microemulsion vehicle. International Journal of Pharmaceutics 2006, 327, 58–64
[89] R.Lapasin, M.Grassi, N Coceani. Effects of polymer addition on the rheology of o/w microemulsions. Rheol. Acta. 2001,40, 185–192.
[90] C.Valenta, K.Schultz,. Influence of carrageenan on the rheology and skin permeation of microemulsion formulations. J. Control. Release. 2004,95, 257–265.
[91] D. Gulsen, A.Chauhan. Dispersion of microemulsion drops in HEMA hydrogel: a potential ophthalmic drug delivery vehicle. Int. J. Pharm. 2005,292,95–117.
[92] P. ?piclin, M. Homar, A. Zupanˇciˇc-Valant. Sodium ascorbyl phosphate in topical microemulsions. International Journal of Pharmaceutics 2003, 256, 65–73
[93]梁文权.生物药剂学和药物动力学(第二版).人民卫生出版社(北京,2003), 155
[94]张先洲,孟书舫,祝红达,等.氯雷他定胶囊在健康人体的生物等效性.中国医院药学杂志,2007,27(10): 1390-1392 [95尤海生,董亚琳,邢建峰,等.灯盏乙素在大鼠体内药代动力学及组织分布的研究.中国中药杂志, 2007, 32(16): 1688-1692
[96]李曼玲,殷文光,刘淑芝,等. FLU—HPLC测定复方吴茱萸巴布膏中阿魏酸血药浓度及药动学研究.中国药学杂志,2007, 42(21):1649-1651
[97]李建伟,白小红,翁惠,等.液相微萃取-后萃取光化学荧光高效液相色谱法测定生物样品中甲氨蝶呤的含量.中国医院药学杂志, 2007, 27(11): 1514-1517