【作者】 祝伟伟；

【导师】 翟光喜；

【作者基本信息】 山东大学 ， 药剂学， 2008， 硕士

【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±0.12mm²·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。更多还原

【Abstract】 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±0.12mm²·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.更多还原