喷昔洛韦微乳经皮给药制剂的研究
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摘要
喷昔洛韦(Penciclovir,PCV)为第3代核苷类广谱抗病毒药,对Ⅰ型、Ⅱ型单纯疱疹病毒(HSV-Ⅰ,Ⅱ),水痘—带状疱疹(VZV),乙型肝炎病毒(HBV),非洲淋巴细胞瘤病毒(EBV)和巨细胞病毒(CMV)等病毒有抑制作用。但是药物口服生物利用度小,本身的经皮渗透能力较差,临床应用受限。
微乳作为经皮给药的载体,可提高难溶性药物的溶解度,形成较高的浓度梯度;微乳中药物的热力学活性增大使药物对皮肤的亲和力增大:微乳中的成分有渗透促进剂的作用,可降低角质层的屏障作用,促进药物对皮肤的渗透。为改善喷昔洛韦对皮肤的渗透,本课题将其制成微乳制剂,对其理化性质、体内外经皮渗透进行了研究。
考察了喷昔洛韦在不同介质中的饱和溶解度,以及不同表面活性剂和助表面活性剂的配伍情况,确定了微乳的基本处方组成。通过绘制微乳的伪三元相图,确定可形成微乳的区域。然后采用单纯形网格优化法,以对喷昔洛韦的溶解度和12h的单位面积累积渗透量作为响应指标,进行处方优化,得到优化处方为:油相(油酸)5%,表面活性剂(聚氧乙烯蓖麻油)20%,助表面活性剂(乙醇)30%,水45%。
制得的微乳在透射电镜下呈圆形或近似圆形,平均粒径为36.5nm,粘度为7.11±0.12mm~2·s~(-1)、折光率1.38±0.0005、电导率134.5±1.561μs·cm~(-1)、pH5.33±0.09。室温、避光条件下稳定性良好。
小鼠离体透皮试验研究了0.5%喷昔洛韦微乳液体、微乳凝胶及1%夫坦乳膏的经皮渗透动力学。结果表明所制备的喷昔洛韦微乳制剂的经皮渗透速率明显高于夫坦乳膏对皮肤的渗透速率(p＜0.05)。
小鼠在体透皮试验研究了喷昔洛韦在表皮和真皮中的分布情况。采用0.5%的喷昔洛韦微乳制剂作用后,在表皮、真皮中药物的含量都明显高于1%夫坦乳膏作用后的皮肤;喷昔洛韦微乳制剂能在15min内深入到皮肤深层发挥药效,并且具有缓释长效的作用。
皮肤刺激性实验表明喷昔洛韦微乳及喷昔洛韦微乳凝胶经单次或多次给药对皮肤均无刺激性,用药后能保证皮肤组织的完整性。
Penciclovir is a potent antiviralguanosine-type drug which maintains the antiviral activity against Herpes Symmplex Virus, Varicella Zoster Virus, Epstein-Barr Virus, Hepatitis Virus and Cytomegalovirus. However, it has a poor bioavailability of 5%～10% after oral administration, and a poor ability of permeation, the clinical use of penciclovir is limited.
There are several advantages of microemulsion for the dermal delivery of drugs. First, the concentration of the skin is increased due to large amount of drug can be incorporated in the formulation. Second, the increased thermodynamic activity of the drug may favor its partitioning into the skin. Third, the ingredients of microemulsion may reduce the diffusional barrier of the stratum corneum and increase the permeation rate of drug via skin by acting as permeation enhancers. In order to promote the ability of permeation for penciclovir into skin, penciclovir microemulsion was prepared and its physico-chemical property, the ability of permeation in vitro and in vivo were evaluated.
The basic components of the formulation were determined by investigating the saturated solubility of penciclovir in various medium and the interaction between oils, surfactants, and cosurfactants. The pseudoternary phase diagrams of microemulsion (ME) were drawn to determine the MEs area. A simplex lattice experiment design was applied to optimize the composition of microemulsions. The concentration of surfactant, cosurfactant and water were selected as independent variables, and the solubility and the cumulative amount of penciclovir permeated through excised mice skins per unit area(Qn) at 12 hours were selected as the response variables to optimize the ME formulation and the final formulation (containing oil (oleic acid) 5%, surfactant(Cremorphor EL) 20%, cosurfactant(ethanol) 30%, water 45%) had been found.
The MEs presented as small spherical drops under electron microscopy, with the average diameter of 36.5nm. Its basic character parameters such as viscosity, refraction, electric conductivity, pH were 7.11±0.12mm~2·s~(-1), 1.38±0.0005, 134.5±1.56－μs·cm~(-1), 5.33±0.09, respectively. The test of influencing factors and primary stability indicated that the penciclovir ME has a good stability at room temperature and no-light conditions.
In vitro the Qn of PCV of MEs at 12 hours was transdermal delivery kinetics were studied after applied 0.5%(w/w)PCV-ME, 0.5%(w/w)PCV-ME gel and l%(w/w)futan cream using the mice skin in vitro. The results show that the permeation rate was obviously higher following ME preparations application compared with that following the cream application(p<0.05).
In vivo the PCV concentrations in the epidermis and the dermis were investigated after applied 0.5%(w/w)PCV-ME, 0.5%(w/w)PCV-ME gel and l%(w/w)futan cream. The concentrations were obviously higher both in the epidermis and in the dermis following ME preparations application compared with that following the cream application(p<0.05). The ME preparations also show an ability of delayed-release.
The irritancy test indicated that PCV-ME and PCV-ME gel is safe for transdermal drug delivery after once or more times application,the integrity of skin could be guaranteed.
微乳作为经皮给药的载体,可提高难溶性药物的溶解度,形成较高的浓度梯度;微乳中药物的热力学活性增大使药物对皮肤的亲和力增大:微乳中的成分有渗透促进剂的作用,可降低角质层的屏障作用,促进药物对皮肤的渗透。为改善喷昔洛韦对皮肤的渗透,本课题将其制成微乳制剂,对其理化性质、体内外经皮渗透进行了研究。
考察了喷昔洛韦在不同介质中的饱和溶解度,以及不同表面活性剂和助表面活性剂的配伍情况,确定了微乳的基本处方组成。通过绘制微乳的伪三元相图,确定可形成微乳的区域。然后采用单纯形网格优化法,以对喷昔洛韦的溶解度和12h的单位面积累积渗透量作为响应指标,进行处方优化,得到优化处方为:油相(油酸)5%,表面活性剂(聚氧乙烯蓖麻油)20%,助表面活性剂(乙醇)30%,水45%。
制得的微乳在透射电镜下呈圆形或近似圆形,平均粒径为36.5nm,粘度为7.11±0.12mm~2·s~(-1)、折光率1.38±0.0005、电导率134.5±1.561μs·cm~(-1)、pH5.33±0.09。室温、避光条件下稳定性良好。
小鼠离体透皮试验研究了0.5%喷昔洛韦微乳液体、微乳凝胶及1%夫坦乳膏的经皮渗透动力学。结果表明所制备的喷昔洛韦微乳制剂的经皮渗透速率明显高于夫坦乳膏对皮肤的渗透速率(p＜0.05)。
小鼠在体透皮试验研究了喷昔洛韦在表皮和真皮中的分布情况。采用0.5%的喷昔洛韦微乳制剂作用后,在表皮、真皮中药物的含量都明显高于1%夫坦乳膏作用后的皮肤;喷昔洛韦微乳制剂能在15min内深入到皮肤深层发挥药效,并且具有缓释长效的作用。
皮肤刺激性实验表明喷昔洛韦微乳及喷昔洛韦微乳凝胶经单次或多次给药对皮肤均无刺激性,用药后能保证皮肤组织的完整性。
Penciclovir is a potent antiviralguanosine-type drug which maintains the antiviral activity against Herpes Symmplex Virus, Varicella Zoster Virus, Epstein-Barr Virus, Hepatitis Virus and Cytomegalovirus. However, it has a poor bioavailability of 5%～10% after oral administration, and a poor ability of permeation, the clinical use of penciclovir is limited.
There are several advantages of microemulsion for the dermal delivery of drugs. First, the concentration of the skin is increased due to large amount of drug can be incorporated in the formulation. Second, the increased thermodynamic activity of the drug may favor its partitioning into the skin. Third, the ingredients of microemulsion may reduce the diffusional barrier of the stratum corneum and increase the permeation rate of drug via skin by acting as permeation enhancers. In order to promote the ability of permeation for penciclovir into skin, penciclovir microemulsion was prepared and its physico-chemical property, the ability of permeation in vitro and in vivo were evaluated.
The basic components of the formulation were determined by investigating the saturated solubility of penciclovir in various medium and the interaction between oils, surfactants, and cosurfactants. The pseudoternary phase diagrams of microemulsion (ME) were drawn to determine the MEs area. A simplex lattice experiment design was applied to optimize the composition of microemulsions. The concentration of surfactant, cosurfactant and water were selected as independent variables, and the solubility and the cumulative amount of penciclovir permeated through excised mice skins per unit area(Qn) at 12 hours were selected as the response variables to optimize the ME formulation and the final formulation (containing oil (oleic acid) 5%, surfactant(Cremorphor EL) 20%, cosurfactant(ethanol) 30%, water 45%) had been found.
The MEs presented as small spherical drops under electron microscopy, with the average diameter of 36.5nm. Its basic character parameters such as viscosity, refraction, electric conductivity, pH were 7.11±0.12mm~2·s~(-1), 1.38±0.0005, 134.5±1.56－μs·cm~(-1), 5.33±0.09, respectively. The test of influencing factors and primary stability indicated that the penciclovir ME has a good stability at room temperature and no-light conditions.
In vitro the Qn of PCV of MEs at 12 hours was transdermal delivery kinetics were studied after applied 0.5%(w/w)PCV-ME, 0.5%(w/w)PCV-ME gel and l%(w/w)futan cream using the mice skin in vitro. The results show that the permeation rate was obviously higher following ME preparations application compared with that following the cream application(p<0.05).
In vivo the PCV concentrations in the epidermis and the dermis were investigated after applied 0.5%(w/w)PCV-ME, 0.5%(w/w)PCV-ME gel and l%(w/w)futan cream. The concentrations were obviously higher both in the epidermis and in the dermis following ME preparations application compared with that following the cream application(p<0.05). The ME preparations also show an ability of delayed-release.
The irritancy test indicated that PCV-ME and PCV-ME gel is safe for transdermal drug delivery after once or more times application,the integrity of skin could be guaranteed.
引文
[1]徐红,陆志华.带状疱疹的外用药物治疗[J].中国新医药,2006,2(9):90-92.
[2]张莉,于海洋.疱疹病毒感染性皮肤病[J].中国临床医生杂志,2007,35(10):11-14.
[3]Kleymann G.Agents and strategies in development for improved management of herpes simplex virus infection and disease[J].Expert Opin Investig Drugs,2005,14(2):135-61.
[4]Schmid-Wendtner MH,Korting HC.Penciclovir cream--improved topical treatment for herpes simplex infections[J].Skin Pharmacol Physiol,2004,17(5):214-218.
[5]Loregian A,Gatti R,Palu G,et al.Separation methods for acyclovir and related antiviral compounds[J].J Chromatogr B Biomed Sci Appl,2001,764:289-311.
[6]Smith RL,Morroni J,Wilcox CL.Lack of effect of treatment with penciclovir or acyclovir on the establishment of latent HSV-1 in primary sensory neurons in culture[J].Antiviral Res Antiviral Res,2001,52:19-24.
[7]Abdel-Hag N,Chearskul P,Al-Tatari H,et al.New antiviral agents[J].Indian J Pediatr,2006,73:313-321.
[8]Margiotta N,Bergamo A,Sava G,et al.Antiviral properties and cytotoxic activity of platinum(Ⅱ)complexes with 1,10- phenanthrolines and acyclovir or penciclovir[J].J Inorg Biochem,2004,98:1385-1390.
[9]Andrei G,De Clercq E,Snoeck R.In vitro selection of drug-resistant varicella-zoster virus(VZV)mutants(OKA strain):differences between acyclovir and penciclovir?[J].Antiviral Res.2004,61:181-187.
[10]Changez M,Varshney M.Aerosol-OT microemulsions as transdermal carriers of tetracaine hydrochloride[J].Drug Dev Ind Pharm,2000,26:507-512.
[11]Tenjarla S.Microemulsions:an overview and pharmaceutical applications[J].Crit Rev Ther Drug Carrier Syst,1999,16(5):461-521.
[12]Kreilgaard M.Influence of microemulsions on cutaneous drug delivery[J].Adv Drug Deliv Rev,2002,54:77-98.
[13]Lawrence MJ,Rees GD.Microemulsion-based media as novel drug delivery systems[J].Adv Drug Deliv Rev,2000,45:89-121.
[14]Baroli B,López-Quintela MA,Delgado-Charro MB,et al.Microemulsions for topical delivery of 8-methoxsalen[J].J Contronl Release,2000,69:209- 218.
[15]Dujardin N,Staes E,Kalia Y,et al.In vivo assessment of skin electroporation using square wave pulses[J].J Control Release,2002,79(1-3):219-227.
[16]Bose S,Ravis WR,Lin YJ,et al.Electrically-assisted transdermal delivery of buprenorphine[J].J Control Release,2001,73(2-3):197-203.
[17]李干佐,郭荣编著.微乳液理论及应用[M].北京:中国轻工业出版社,1995.12(4):7.
[18]王思玲,苏德森主编.胶体分散药物制剂[M].北京:人民卫生出版社,2006.163-165.
[19]Rhee YS,Choi JG,Park ES,et al.Transdermal delivery of ketoprofen using microemulsions[J].Int J Pharm,2001,228:161-170.
[20]Dreher F,Walde P,Walther P,et al.Interaction of a lecithin microemulsion gel with human stratum corneum and its effect on transdermal transport[J].J Control Release,1997,45:131-140.
[21]Delgado-Charro MB,Iglesias-Vilas G,Blanco-Méndez J,et al.Delivery of a hydrophilic solute through the skin from novel microemulsion systems[J].Eur J Pharm Biopharm,1997,43:37-42.
[22]Schmalfuβ U,Neubert R,Wohlrab W.Modification of drug penetration into human skin using microemulsions[J].J Control Release,1997,46:279-285.
[23]Lee PJ,Langer R,Shastri VP.Novel microemulsion enhancer formulation for simultaneous transdermal delivery of hydrophilic and hydrophobic drugs[J].Pharm Res,2003,20:264-269.
[24]Kreilgaard M,Pedersen EJ,Jaroszewski JW.NMR characterisation and transdermal drug delivery potential of microemulsion systems[J].J Control Release,2000,69:421-433.
[25]陈华兵,翁婷,常雪灵,等.布洛芬微乳的制备及其透皮吸收研究[J].中国 药学杂志,2004,39(1):43-45.
[26]Chen HB,Chang XL,Weng T,et al.A study of microemulsion systems for transdermal delivery of triptolide[J].J Control Rel,2004,98(3):427-436.
[27]Sintov AC,Shapiro L.New microemulsion vehicle facilitates percuta-neous penetration in vitro and cutaneous drug bioavailability in vivo[J].J Control Rel,2004,95(2):173-183.
[28]Sintov AC,Botner S.Transdermal drug delivery using microemulsion and aqueous systems:Influence of skin storage conditions on the in vitro permeability of diclofenac from aqueous vehicle systems[J].Int J Pharm,2006,311(1-2):55-62.
[29]Gupta RR,Jain SK,Varshney M.AOT water-in-oil microemulsions as a penetration enhancer in transdermal drug delivery of 5-fluorouracil[J].Colloids Surf.B:Biointerfaces,2005,41:25-32.
[30]Peltola S,Saarinen-Savolainen P,Kiesvaara J,et al.Microemulsions for topical delivery of estradiol[J].Int J Pharm,2003,254:99-107.
[31]Changez M,Varshney M,Chander J,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[J].Colloids Surf.B:Biointerfaces,2006,50:18-25.
[32]Zhao X,Liu JP,Zhang X,et al.Enhancement of transdermal delivery of theophylline using microemulsion vehicle[J].Int J Pharm,2006,327:58-64.
[33]Chen HB,Chang XL,Du DR,et al.Microemulsion-based hydrogel formulation of ibuprofen for topical delivery[J].Int J Pharm,2006,315:52-58.
[34]Mohammed C,Manoj V.Aerosol-OT microemulsions as transdermal,carriers of tatracaine hydrochloride[J].Drug Dev Ind Pharm,2000,26:507-512.
[35]陈华兵,翁婷,杨祥良.微乳在现代药剂学中的研究进展[J].中国医药杂志,2004,35(8):502-506.
[36]朱晓亮,陈志良,曾抗,等.微乳透皮给药系统研究现状及展望[J].广东医学2005,26(4):563-564.
[37]张立超,胡晋红.微乳透皮给药系统的研究进展[J].国外医学药学分册,2004,31(1):44-48.
[38]俞嫒,高申,陈琰,等.盐酸哌甲酯-卵磷脂微乳的制备及其透皮吸收作用[J].中国药学杂志,2005,40(11):843-845.
[39]Wu H,Weiner ND,Ramachandran C,et al.Topical transport of hydrophilic compounds using water-in-oil nanoemulsions[J].Int J Pharm,2001,220(2):63.
[40]Kamal MA,Iimura N,Nabekura T,et al.Enhanced skin permeation of diclofenac by ion-pair formation and further enhancement by microemulsion[J].Chem.Pharm.Bull(Tokyo),2007,55:368-71.
[41]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.
[42]Baboota S,Al-Azaki A,Kohli K,et al.Development and evaluation of a microemulsion formulation for transdermal delivery of terbinafine[J].PDA J Pharm Sci Technol,2007,61:276-285.
[43]Chen H,Mou D,Du D,et al.Hydrogel-thickened microemulsion for topical administration of drug molecule at an extremely low concentration[J].Int J Pharm,2007,341:78-84.
[44]Liu H,Wang Y,Han F,et al.Gelatin-stabilised microemulsion-based organogels facilitates percutaneous penetration of Cyclosporin A in vitro and dermal pharmacokinetics in vivo[J].J Pharm Sci,2007,96:3000-3009.
[45]Changez M,Varshney M,Chander J,et al.Effect of the composition of lecithin/n-propanol/isopropyl myristate/water microemulsion on barrier properties of mice skin for transdermal permeation of tetracaine hydrochloride:In vitro[J].Colloids Surf B:Biointerfaces,2006,50:18-25.
[46]Valenta C,Schultz K.Influence of carrageenan on the rheology and skin permeation of microemulsion formulations[J].J Control Release,2004,95(2):257-265.
[47]王唯红,翟光喜,张虞毅,等.雌二醇软膏体外透皮速率及其含量的HPLC 测定[J].中国医药工业杂志,2002,33(10):499-501.
[48]Paolino D,Ventura CA,Nisticò S,et al.Lecithin microemulsions for the topical administration of ketoprofen:percutaneous adsorption through human skin and in vivo human skin tolerability[J].Int J Pharm,2002,244(1-2):21-31.
[49]侯炜,杨占秋,曲虹,等.喷昔洛韦对单纯疱疹病毒感染小鼠的治疗作用[J].中国药学杂志,2003,38(12):921-924.
[50]王树岚.抗疱疹病毒药物的发展状况[J].天津药学,2000,12(3):21-22.
[51]林静雯,陈谦明,周红梅.抗疱疹病毒药物的研究进展[J].中华口腔医学杂志,2006,41(1):60-62.
[52]Kawakami K,Yoshikawa T,Yasushi M,et al.Microemulsion formulation for enhanced absorption of poorly soluble drugs Ⅰ.prescription design[J].J Controlled Release,2002,81(1-2):65-74.
[53]Warisnoicharoen W,Lansley AB,Lawrence MJ.Nonionic oil-in-water microemulsions:the effect of oil type on phase behaviour[J].Int J Pharm,2000,198(1):7-27.
[54]Hua L,Weisan P,Jiayu L,et al.Preparation,evaluation,and NMR characterization of vinpocetine microemulsion for transdermal delivery[J].Drug Dev Ind Pharm,2004,30:657-666.
[55]Kogan A,Garti N.Microemulsions as transdermal drug delivery vehicles[J].Adv Colloid Interface Sci,2006,123-126:369-385.
[56]Attwood D,Mallon C,Taylor CJ.Phase studies of oil-in-water phospholipids microemulsions[J].Int J Pharm,1992,84:5-8.
[57]李干佐,郝京诚,李方,等.阳离子表面活性剂中相微乳液的形成和特征[J].物理化学学报,1995,11(6):553-337.
[58]Kale N J,Allen LV.Studies on microemulsions using Brij 96 as surfactant and glycerin,ethylene glycol and propylene glycol as cosurfactants[J].Int J Pharm,1989,57:87-93.
[59]Kale N J,Allen LV.Studies on microemulsions using Brij 96 as surfactant and glycerin,ethylene glycol and propylene glycol as cosurfactants[J].Int J Pharm,1989,57:87-93.
[60]汪杨,吴伟.油-吐温-醇-水体系伪三元相图在自微乳化制剂研究中的应用[J].中国医药工业杂志,2005,36(6):345-348.
[61]肖衍宇,宋赞梅,陈志鹏,等.水飞蓟素自微乳的制备[J].中国医药工业杂志,2005,36(11):678-681.
[62]Yuan Y,Li SM,Mo FK,et al.Investigation of microemulsion system for transdermal delivery of meloxicam[J].Int J Pharm,2006,321:117-123.
[63]赵建忠,晏马成.油酸微乳对利多卡因透皮吸收的影响[J].医药导报,2005,24(9):811-813.
[64]Hanan M.El-Laithy.Preparation and Physicochemical Characterization of Dioctyl Sodium Sul-fosuccinate(Aerosol OT)Microemulsion for Oral Drug Delivery[J].AAPS PharmSciTech 2003,4(1):Article 11.
[65]Araya H,Nagao S,Tomita M,et al.The novel formulation design of self-emulsifying drug delivery systems(SEDDS)type O/W microemulsion Ⅰ:enhancing effects on oral bioavailability of poorlywater soluble compounds in rats and beagle dogs[J].Drug Metab Pharrnacokinet,2005,20(4):244-256.
[66]张正全,陆彬.微乳给药系统研究概况[J].中国医药工业杂志,2001,32(3):139-142.
[67]洪伟,吴承祯.试验设计与分析-原理.操作.案例[M].中国林业出版社,2004:222-225.
[68]茆诗松,周纪芗,陈颖.试验设计[M].中国统计出版社,2004:356-358.
[69]任露泉等.试验优化设计与分析(第二版)[M].高等教育出版社2003:374-378
[70]Liu CH,Ho HO,Hsieh MC,et al.Studies on the in-vitro percutaneous penetration of indomethacin from gel systems in hairless mice[J].J Pharm Pharmacol,1995,47:365-372.
[71]Van Kamp HV,Bolhuis GK,Lerk CF.Optimization of a formulation for direct compression using a simplex lattice design[J].Pharm Weekbl Sci,1987,9:265-273.
[72]袁悦,李三鸣,王思玲,等.酮洛芬微乳经皮给药制剂的研究[J].中国药学杂志,2006,41(21):1647-1650.
[73]Donzelli BG,Ostroff G,Harman GE.Enhanced enzymatic hydrolysis of langostino shell chitin with mixtures of enzymes from bacterial and fungal sources[J].Carbohydr Res,2003,338:1823-1833.
[74]Jumaa M,Kleinebudde P,Miiller BW.Mixture experiments with the oil phase of parenteral emulsions[J].Eur J Pharm Biopharm,1998,46:161-167.
[75]Subramanian N,Ray S,Ghosal SK,et al.Formulation design of self-microemulsifying drug delivery systems for improved oral bioavailability of celecoxib[J].Biol Pharm Bull,2004,27:1993-1997.
[76]Krishna SS,Ray S,Thakur RS.Formulation and evaluation of mucoadhesive dosage form containing rosiglitazone maleate[J].Pak J Pharm Sci,2006,19:208-213.
[77]Li H,Pan WS,Wu Z,et al.Optimization of microemulsion containing vinpocetine and its physicochemical properties[J].Yao Xue Xue Bao,2004,39:681-685.
[78]Elkheshen S.Simplex lattice design for the optimization of the microencapsula-tion of a water soluble drug using poly(lactic acid)and poly(lactide co-glycolide)copolymer[J].J Microencapsul,1996,13(4):447-462.
[79]Ferrari F,Bertoni M,Bonferoni CM,et al.Dissolution enhancement of an insoluble drug by physical mixture with a superdisintegrant:optimization with a simplex lattice design[J].Pharm DevTechnol,1996,1:159-164.
[80]Ho HO,Huang FC,Sokoloski TD,et al.The influence of cosolvents on the in-vitro percutaneous penetration of diclofenac sodium from a gel system[J].J Pharm Pharmacol,1994,46:636-642.
[81]李华,潘卫三,吴振,等.长春西汀微乳的优化及其理化性质的考察[J].药学学报,2004,39(9):681-685.
[82]Boelsma E,Tanojo H,Boddé HE,et al.Assessment of the potential irritancy of oleic acid on human skin:Evaluation in vitro and in vivo[J].Toxicol In Vitro,1996,10:729-742.
[83]Schechter RS.Microemulsion and Related Systems[M].New York:Marcel Dekker,1998,1-200.
[84]廉云飞,李娟,平其能,等.吲哚美辛微乳的制备及经皮吸收研究[J].中国医药工业杂志,2005,36(3):148-151.
[85]Hsiu OH,Chili CH,Ming TS.Preparation of microemulsion using polyglycerol fatty acid esters as surfactant for the delivery of protein drugs[J].J Pharm Sci,1996,85(2):138-143.
[86]Cilek A,Celebi N,Tirnaksiz E Lecithin-based microemulsion of a peptide for oral administration:preparation,characterization,and physical stability of the formulation[J].Drug Deliv,2006,13(1):19-24.
[87]Peira E,Scolari P,Gasco MR.Transdermal permeation of apomorphine through hairless mouse skin from microemulsions[J].Int J Pharm,2001,226(1-2):47-51.
[88]Charman S A,Charman W N,Rogge M C,et al.Self-emulsifying drug delivery systems:formulation and biopharmaceutic evaluation of an investigation lipophilic compound[J].Pharm Res,1992,9(1):87-93.
[89]陈丽佳,周永良,黄田艺,等.5-氟尿嘧啶脂质体凝胶剂的制备和评价[J].海峡药学,2007,11:6-8.
[90]尚校军,马素英,秦瑞英.复方替硝唑凝胶剂的制备及临床应用[J].中国药业,2007,16(24):39-40.
[91]Biruss B,Kahlig H,Valenta C.Evaluation of an eucalyptus oil containing topical drug delivery system for selected steroid hormones[J].Int J Pharm,2007,328:142-151.
[92]Mei ZN,Chen HB,Weng T,et al.Solid lipid nanoparticle and microemulsion for topical delivery of triptolide[J].Eur J Pharm Biopharm.2003,56:189-196.
[93]Chang XL,Chen HB,Zhao XZ,et al.High- performance liquid chromatography determination of triptolide in vitro permeation studies[J].Anal Chim Acta,2005,534:215-221.
[94]Changez M,Chander J,Dinda AK.Transdermal permeation of tetracaine hydrochloride by lecithin microemulsion:in vivo[J].Colloids Surf B: Biointerfaces,2006,48:58-66.
[95]药物研究技术指导原则,国家食品药品监督管理局组织编写,2005,122-123.
[96]张美和,姜曜,蔡伟.复方利多卡因喷雾剂皮肤刺激性实验研究[J].中国现代医药杂志,2007,9(11):18-19.
[2]张莉,于海洋.疱疹病毒感染性皮肤病[J].中国临床医生杂志,2007,35(10):11-14.
[3]Kleymann G.Agents and strategies in development for improved management of herpes simplex virus infection and disease[J].Expert Opin Investig Drugs,2005,14(2):135-61.
[4]Schmid-Wendtner MH,Korting HC.Penciclovir cream--improved topical treatment for herpes simplex infections[J].Skin Pharmacol Physiol,2004,17(5):214-218.
[5]Loregian A,Gatti R,Palu G,et al.Separation methods for acyclovir and related antiviral compounds[J].J Chromatogr B Biomed Sci Appl,2001,764:289-311.
[6]Smith RL,Morroni J,Wilcox CL.Lack of effect of treatment with penciclovir or acyclovir on the establishment of latent HSV-1 in primary sensory neurons in culture[J].Antiviral Res Antiviral Res,2001,52:19-24.
[7]Abdel-Hag N,Chearskul P,Al-Tatari H,et al.New antiviral agents[J].Indian J Pediatr,2006,73:313-321.
[8]Margiotta N,Bergamo A,Sava G,et al.Antiviral properties and cytotoxic activity of platinum(Ⅱ)complexes with 1,10- phenanthrolines and acyclovir or penciclovir[J].J Inorg Biochem,2004,98:1385-1390.
[9]Andrei G,De Clercq E,Snoeck R.In vitro selection of drug-resistant varicella-zoster virus(VZV)mutants(OKA strain):differences between acyclovir and penciclovir?[J].Antiviral Res.2004,61:181-187.
[10]Changez M,Varshney M.Aerosol-OT microemulsions as transdermal carriers of tetracaine hydrochloride[J].Drug Dev Ind Pharm,2000,26:507-512.
[11]Tenjarla S.Microemulsions:an overview and pharmaceutical applications[J].Crit Rev Ther Drug Carrier Syst,1999,16(5):461-521.
[12]Kreilgaard M.Influence of microemulsions on cutaneous drug delivery[J].Adv Drug Deliv Rev,2002,54:77-98.
[13]Lawrence MJ,Rees GD.Microemulsion-based media as novel drug delivery systems[J].Adv Drug Deliv Rev,2000,45:89-121.
[14]Baroli B,López-Quintela MA,Delgado-Charro MB,et al.Microemulsions for topical delivery of 8-methoxsalen[J].J Contronl Release,2000,69:209- 218.
[15]Dujardin N,Staes E,Kalia Y,et al.In vivo assessment of skin electroporation using square wave pulses[J].J Control Release,2002,79(1-3):219-227.
[16]Bose S,Ravis WR,Lin YJ,et al.Electrically-assisted transdermal delivery of buprenorphine[J].J Control Release,2001,73(2-3):197-203.
[17]李干佐,郭荣编著.微乳液理论及应用[M].北京:中国轻工业出版社,1995.12(4):7.
[18]王思玲,苏德森主编.胶体分散药物制剂[M].北京:人民卫生出版社,2006.163-165.
[19]Rhee YS,Choi JG,Park ES,et al.Transdermal delivery of ketoprofen using microemulsions[J].Int J Pharm,2001,228:161-170.
[20]Dreher F,Walde P,Walther P,et al.Interaction of a lecithin microemulsion gel with human stratum corneum and its effect on transdermal transport[J].J Control Release,1997,45:131-140.
[21]Delgado-Charro MB,Iglesias-Vilas G,Blanco-Méndez J,et al.Delivery of a hydrophilic solute through the skin from novel microemulsion systems[J].Eur J Pharm Biopharm,1997,43:37-42.
[22]Schmalfuβ U,Neubert R,Wohlrab W.Modification of drug penetration into human skin using microemulsions[J].J Control Release,1997,46:279-285.
[23]Lee PJ,Langer R,Shastri VP.Novel microemulsion enhancer formulation for simultaneous transdermal delivery of hydrophilic and hydrophobic drugs[J].Pharm Res,2003,20:264-269.
[24]Kreilgaard M,Pedersen EJ,Jaroszewski JW.NMR characterisation and transdermal drug delivery potential of microemulsion systems[J].J Control Release,2000,69:421-433.
[25]陈华兵,翁婷,常雪灵,等.布洛芬微乳的制备及其透皮吸收研究[J].中国 药学杂志,2004,39(1):43-45.
[26]Chen HB,Chang XL,Weng T,et al.A study of microemulsion systems for transdermal delivery of triptolide[J].J Control Rel,2004,98(3):427-436.
[27]Sintov AC,Shapiro L.New microemulsion vehicle facilitates percuta-neous penetration in vitro and cutaneous drug bioavailability in vivo[J].J Control Rel,2004,95(2):173-183.
[28]Sintov AC,Botner S.Transdermal drug delivery using microemulsion and aqueous systems:Influence of skin storage conditions on the in vitro permeability of diclofenac from aqueous vehicle systems[J].Int J Pharm,2006,311(1-2):55-62.
[29]Gupta RR,Jain SK,Varshney M.AOT water-in-oil microemulsions as a penetration enhancer in transdermal drug delivery of 5-fluorouracil[J].Colloids Surf.B:Biointerfaces,2005,41:25-32.
[30]Peltola S,Saarinen-Savolainen P,Kiesvaara J,et al.Microemulsions for topical delivery of estradiol[J].Int J Pharm,2003,254:99-107.
[31]Changez M,Varshney M,Chander J,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[J].Colloids Surf.B:Biointerfaces,2006,50:18-25.
[32]Zhao X,Liu JP,Zhang X,et al.Enhancement of transdermal delivery of theophylline using microemulsion vehicle[J].Int J Pharm,2006,327:58-64.
[33]Chen HB,Chang XL,Du DR,et al.Microemulsion-based hydrogel formulation of ibuprofen for topical delivery[J].Int J Pharm,2006,315:52-58.
[34]Mohammed C,Manoj V.Aerosol-OT microemulsions as transdermal,carriers of tatracaine hydrochloride[J].Drug Dev Ind Pharm,2000,26:507-512.
[35]陈华兵,翁婷,杨祥良.微乳在现代药剂学中的研究进展[J].中国医药杂志,2004,35(8):502-506.
[36]朱晓亮,陈志良,曾抗,等.微乳透皮给药系统研究现状及展望[J].广东医学2005,26(4):563-564.
[37]张立超,胡晋红.微乳透皮给药系统的研究进展[J].国外医学药学分册,2004,31(1):44-48.
[38]俞嫒,高申,陈琰,等.盐酸哌甲酯-卵磷脂微乳的制备及其透皮吸收作用[J].中国药学杂志,2005,40(11):843-845.
[39]Wu H,Weiner ND,Ramachandran C,et al.Topical transport of hydrophilic compounds using water-in-oil nanoemulsions[J].Int J Pharm,2001,220(2):63.
[40]Kamal MA,Iimura N,Nabekura T,et al.Enhanced skin permeation of diclofenac by ion-pair formation and further enhancement by microemulsion[J].Chem.Pharm.Bull(Tokyo),2007,55:368-71.
[41]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.
[42]Baboota S,Al-Azaki A,Kohli K,et al.Development and evaluation of a microemulsion formulation for transdermal delivery of terbinafine[J].PDA J Pharm Sci Technol,2007,61:276-285.
[43]Chen H,Mou D,Du D,et al.Hydrogel-thickened microemulsion for topical administration of drug molecule at an extremely low concentration[J].Int J Pharm,2007,341:78-84.
[44]Liu H,Wang Y,Han F,et al.Gelatin-stabilised microemulsion-based organogels facilitates percutaneous penetration of Cyclosporin A in vitro and dermal pharmacokinetics in vivo[J].J Pharm Sci,2007,96:3000-3009.
[45]Changez M,Varshney M,Chander J,et al.Effect of the composition of lecithin/n-propanol/isopropyl myristate/water microemulsion on barrier properties of mice skin for transdermal permeation of tetracaine hydrochloride:In vitro[J].Colloids Surf B:Biointerfaces,2006,50:18-25.
[46]Valenta C,Schultz K.Influence of carrageenan on the rheology and skin permeation of microemulsion formulations[J].J Control Release,2004,95(2):257-265.
[47]王唯红,翟光喜,张虞毅,等.雌二醇软膏体外透皮速率及其含量的HPLC 测定[J].中国医药工业杂志,2002,33(10):499-501.
[48]Paolino D,Ventura CA,Nisticò S,et al.Lecithin microemulsions for the topical administration of ketoprofen:percutaneous adsorption through human skin and in vivo human skin tolerability[J].Int J Pharm,2002,244(1-2):21-31.
[49]侯炜,杨占秋,曲虹,等.喷昔洛韦对单纯疱疹病毒感染小鼠的治疗作用[J].中国药学杂志,2003,38(12):921-924.
[50]王树岚.抗疱疹病毒药物的发展状况[J].天津药学,2000,12(3):21-22.
[51]林静雯,陈谦明,周红梅.抗疱疹病毒药物的研究进展[J].中华口腔医学杂志,2006,41(1):60-62.
[52]Kawakami K,Yoshikawa T,Yasushi M,et al.Microemulsion formulation for enhanced absorption of poorly soluble drugs Ⅰ.prescription design[J].J Controlled Release,2002,81(1-2):65-74.
[53]Warisnoicharoen W,Lansley AB,Lawrence MJ.Nonionic oil-in-water microemulsions:the effect of oil type on phase behaviour[J].Int J Pharm,2000,198(1):7-27.
[54]Hua L,Weisan P,Jiayu L,et al.Preparation,evaluation,and NMR characterization of vinpocetine microemulsion for transdermal delivery[J].Drug Dev Ind Pharm,2004,30:657-666.
[55]Kogan A,Garti N.Microemulsions as transdermal drug delivery vehicles[J].Adv Colloid Interface Sci,2006,123-126:369-385.
[56]Attwood D,Mallon C,Taylor CJ.Phase studies of oil-in-water phospholipids microemulsions[J].Int J Pharm,1992,84:5-8.
[57]李干佐,郝京诚,李方,等.阳离子表面活性剂中相微乳液的形成和特征[J].物理化学学报,1995,11(6):553-337.
[58]Kale N J,Allen LV.Studies on microemulsions using Brij 96 as surfactant and glycerin,ethylene glycol and propylene glycol as cosurfactants[J].Int J Pharm,1989,57:87-93.
[59]Kale N J,Allen LV.Studies on microemulsions using Brij 96 as surfactant and glycerin,ethylene glycol and propylene glycol as cosurfactants[J].Int J Pharm,1989,57:87-93.
[60]汪杨,吴伟.油-吐温-醇-水体系伪三元相图在自微乳化制剂研究中的应用[J].中国医药工业杂志,2005,36(6):345-348.
[61]肖衍宇,宋赞梅,陈志鹏,等.水飞蓟素自微乳的制备[J].中国医药工业杂志,2005,36(11):678-681.
[62]Yuan Y,Li SM,Mo FK,et al.Investigation of microemulsion system for transdermal delivery of meloxicam[J].Int J Pharm,2006,321:117-123.
[63]赵建忠,晏马成.油酸微乳对利多卡因透皮吸收的影响[J].医药导报,2005,24(9):811-813.
[64]Hanan M.El-Laithy.Preparation and Physicochemical Characterization of Dioctyl Sodium Sul-fosuccinate(Aerosol OT)Microemulsion for Oral Drug Delivery[J].AAPS PharmSciTech 2003,4(1):Article 11.
[65]Araya H,Nagao S,Tomita M,et al.The novel formulation design of self-emulsifying drug delivery systems(SEDDS)type O/W microemulsion Ⅰ:enhancing effects on oral bioavailability of poorlywater soluble compounds in rats and beagle dogs[J].Drug Metab Pharrnacokinet,2005,20(4):244-256.
[66]张正全,陆彬.微乳给药系统研究概况[J].中国医药工业杂志,2001,32(3):139-142.
[67]洪伟,吴承祯.试验设计与分析-原理.操作.案例[M].中国林业出版社,2004:222-225.
[68]茆诗松,周纪芗,陈颖.试验设计[M].中国统计出版社,2004:356-358.
[69]任露泉等.试验优化设计与分析(第二版)[M].高等教育出版社2003:374-378
[70]Liu CH,Ho HO,Hsieh MC,et al.Studies on the in-vitro percutaneous penetration of indomethacin from gel systems in hairless mice[J].J Pharm Pharmacol,1995,47:365-372.
[71]Van Kamp HV,Bolhuis GK,Lerk CF.Optimization of a formulation for direct compression using a simplex lattice design[J].Pharm Weekbl Sci,1987,9:265-273.
[72]袁悦,李三鸣,王思玲,等.酮洛芬微乳经皮给药制剂的研究[J].中国药学杂志,2006,41(21):1647-1650.
[73]Donzelli BG,Ostroff G,Harman GE.Enhanced enzymatic hydrolysis of langostino shell chitin with mixtures of enzymes from bacterial and fungal sources[J].Carbohydr Res,2003,338:1823-1833.
[74]Jumaa M,Kleinebudde P,Miiller BW.Mixture experiments with the oil phase of parenteral emulsions[J].Eur J Pharm Biopharm,1998,46:161-167.
[75]Subramanian N,Ray S,Ghosal SK,et al.Formulation design of self-microemulsifying drug delivery systems for improved oral bioavailability of celecoxib[J].Biol Pharm Bull,2004,27:1993-1997.
[76]Krishna SS,Ray S,Thakur RS.Formulation and evaluation of mucoadhesive dosage form containing rosiglitazone maleate[J].Pak J Pharm Sci,2006,19:208-213.
[77]Li H,Pan WS,Wu Z,et al.Optimization of microemulsion containing vinpocetine and its physicochemical properties[J].Yao Xue Xue Bao,2004,39:681-685.
[78]Elkheshen S.Simplex lattice design for the optimization of the microencapsula-tion of a water soluble drug using poly(lactic acid)and poly(lactide co-glycolide)copolymer[J].J Microencapsul,1996,13(4):447-462.
[79]Ferrari F,Bertoni M,Bonferoni CM,et al.Dissolution enhancement of an insoluble drug by physical mixture with a superdisintegrant:optimization with a simplex lattice design[J].Pharm DevTechnol,1996,1:159-164.
[80]Ho HO,Huang FC,Sokoloski TD,et al.The influence of cosolvents on the in-vitro percutaneous penetration of diclofenac sodium from a gel system[J].J Pharm Pharmacol,1994,46:636-642.
[81]李华,潘卫三,吴振,等.长春西汀微乳的优化及其理化性质的考察[J].药学学报,2004,39(9):681-685.
[82]Boelsma E,Tanojo H,Boddé HE,et al.Assessment of the potential irritancy of oleic acid on human skin:Evaluation in vitro and in vivo[J].Toxicol In Vitro,1996,10:729-742.
[83]Schechter RS.Microemulsion and Related Systems[M].New York:Marcel Dekker,1998,1-200.
[84]廉云飞,李娟,平其能,等.吲哚美辛微乳的制备及经皮吸收研究[J].中国医药工业杂志,2005,36(3):148-151.
[85]Hsiu OH,Chili CH,Ming TS.Preparation of microemulsion using polyglycerol fatty acid esters as surfactant for the delivery of protein drugs[J].J Pharm Sci,1996,85(2):138-143.
[86]Cilek A,Celebi N,Tirnaksiz E Lecithin-based microemulsion of a peptide for oral administration:preparation,characterization,and physical stability of the formulation[J].Drug Deliv,2006,13(1):19-24.
[87]Peira E,Scolari P,Gasco MR.Transdermal permeation of apomorphine through hairless mouse skin from microemulsions[J].Int J Pharm,2001,226(1-2):47-51.
[88]Charman S A,Charman W N,Rogge M C,et al.Self-emulsifying drug delivery systems:formulation and biopharmaceutic evaluation of an investigation lipophilic compound[J].Pharm Res,1992,9(1):87-93.
[89]陈丽佳,周永良,黄田艺,等.5-氟尿嘧啶脂质体凝胶剂的制备和评价[J].海峡药学,2007,11:6-8.
[90]尚校军,马素英,秦瑞英.复方替硝唑凝胶剂的制备及临床应用[J].中国药业,2007,16(24):39-40.
[91]Biruss B,Kahlig H,Valenta C.Evaluation of an eucalyptus oil containing topical drug delivery system for selected steroid hormones[J].Int J Pharm,2007,328:142-151.
[92]Mei ZN,Chen HB,Weng T,et al.Solid lipid nanoparticle and microemulsion for topical delivery of triptolide[J].Eur J Pharm Biopharm.2003,56:189-196.
[93]Chang XL,Chen HB,Zhao XZ,et al.High- performance liquid chromatography determination of triptolide in vitro permeation studies[J].Anal Chim Acta,2005,534:215-221.
[94]Changez M,Chander J,Dinda AK.Transdermal permeation of tetracaine hydrochloride by lecithin microemulsion:in vivo[J].Colloids Surf B: Biointerfaces,2006,48:58-66.
[95]药物研究技术指导原则,国家食品药品监督管理局组织编写,2005,122-123.
[96]张美和,姜曜,蔡伟.复方利多卡因喷雾剂皮肤刺激性实验研究[J].中国现代医药杂志,2007,9(11):18-19.
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