Akimoto Tomoko, Nagase Yu
Department of Applied Chemistry, School of Engineering, Tokai University, 1117 Kitakaname, Hiratsuka, Kanagawa 259-1292, Japan.
J Control Release. 2003 Mar 7;88(2):243-52. doi: 10.1016/s0168-3659(03)00006-3.
The syntheses of alkyldisiloxanes containing sugar moiety with various alkyl chain length were investigated, in order to develop a silicone-based transdermal penetration enhancer which was expected to show a low irritation to the skin. 1-Alkyl-3-beta-D-glucopyranosyl-1,1,3,3-tetramethyldisiloxanes (Glc-SiCs) were prepared by two-step hydrosilylations of 1-alkene and 1-allyl-beta-D-glucose tetraacetate with 1,1,3,3-tetramethyldisiloxane in the presence of bis(benzonitrile)platinum dichloride as the catalyst, followed by hydrolysis of the acetyl groups with sodium methoxide. The enhancing effect of Glc-SiCs on the percutaneous drug penetration was evaluated by in vitro experiments using a two-chamber diffusion cell. Antipyrine (ANP) and indomethacin (IND) were used as hydrophilic and hydrophobic model drugs, respectively, and the amount of drug permeating through the rat abdominal skin with or without Glc-SiCs was estimated by HPLC. As a result, Glc-SiCs exhibited a enhancing effect on the permeation of both drugs through the skin, which was influenced by the alkyl chain length of Glc-SiCs. In addition, it was suggested that a suitable balance of polarity would be necessary to appear the high enhancing effect, where Glc-SiCs with octyl and decyl groups exhibited the highest enhancing effect. From the determination of kinetic parameters in the drug permeation, it was also found that this enhancing effect was due to the increase of both partition and diffusion coefficients of drug permeation through the skin. By experiments to determine the amount of cholesterol extracted from the skin, the defatting effect would be one of the functions of Glc-SiCs which resulted in the high enhancing activity. Furthermore, according to the Draize test, it was confirmed that Glc-SiCs showed a low irritation to the skin.
为了开发一种对皮肤刺激性低的有机硅基透皮促进剂，研究了不同烷基链长度的含糖部分的烷基二硅氧烷的合成。1-烷基-3-β-D-吡喃葡萄糖基-1,1,3,3-四甲基二硅氧烷（Glc-SiCs）是通过1-烯烃和1-烯丙基-β-D-葡萄糖四乙酸酯与1,1,3,3-四甲基二硅氧烷在二氯双（苄腈）铂作为催化剂存在下进行两步硅氢加成反应制备的，然后用甲醇钠水解乙酰基。使用两室扩散池通过体外实验评估Glc-SiCs对药物经皮渗透的促进作用。分别使用安替比林（ANP）和吲哚美辛（IND）作为亲水性和疏水性模型药物，并通过高效液相色谱法估计有或没有Glc-SiCs时透过大鼠腹部皮肤的药物量。结果，Glc-SiCs对两种药物透过皮肤的渗透均表现出促进作用，这受到Glc-SiCs烷基链长度的影响。此外，表明要出现高促进作用需要合适的极性平衡，其中具有辛基和癸基的Glc-SiCs表现出最高的促进作用。通过测定药物渗透的动力学参数，还发现这种促进作用是由于药物透过皮肤的分配系数和扩散系数均增加。通过测定从皮肤中提取的胆固醇量的实验，脱脂作用将是导致高促进活性的Glc-SiCs的功能之一。此外，根据Draize试验，证实Glc-SiCs对皮肤的刺激性低。
