Bonferoni Maria Cristina, Sandri Giuseppina, Rossi Silvia, Ferrari Franca, Gibin Sara, Caramella Carla
Department of Pharmaceutical Technology, School of Pharmacy, Vle Taramelli 12, 27100 Pavia, Italy.
Eur J Pharm Sci. 2008 Feb 5;33(2):166-76. doi: 10.1016/j.ejps.2007.11.004.
In the present work the employment of chitosan citrate (Chs citrate) as multifunctional polymer in vaginal applications was evaluated. Potential properties of penetration enhancement and protease inhibition could be expected because of the capability of citrate to bind divalent cations such as calcium, that is involved in the regulation of gap and tight junctions, and zinc, that is essential co-factor for some proteases. A comparison was performed with chitosan HCl (Chs HCl). Ex vivo drug permeation experiments were performed on pig vaginal mucosa, by application of 3.0% (w/w) chitosan gels. Acyclovir (5.0%, w/w) and ciprofloxacin HCl (0.3%, w/w) were used as low molecular weight model drugs. Fluorescein isothiocyanate dextran MW 4400 (FD4) was used as hydrophilic high molecular weight fluorescent probe (0.2%, w/w). In the case of low MW drugs the amount penetrated into pig vaginal mucosa was measured by extraction from tissue slices and HPLC detection. From the samples maintained in contact with FD4, slices were cut perpendicularly to the surface and observed by means of confocal laser scanning microscopy (CLSM). FD4 permeation was also measured in in-vitro cell culture model (Caco-2). The penetration enhancing capacity of Chs citrate was comparable to that of Chs HCl. Both Chs citrate and Chs HCl were tested for the inhibition of the proteolytic enzymes carboxypeptidase A and leucine aminopeptidase. In both cases Chs citrate showed a significantly higher inhibition of enzymatic activity with respect to Chs HCl.
在本研究中，评估了壳聚糖柠檬酸盐（Chs柠檬酸盐）作为多功能聚合物在阴道给药中的应用。由于柠檬酸盐能够结合二价阳离子，如参与缝隙连接和紧密连接调节的钙，以及某些蛋白酶必需的辅助因子锌，因此有望具有渗透增强和蛋白酶抑制的潜在特性。与壳聚糖盐酸盐（Chs HCl）进行了比较。通过应用3.0%（w/w）的壳聚糖凝胶，在猪阴道黏膜上进行了离体药物渗透实验。阿昔洛韦（5.0%，w/w）和盐酸环丙沙星（0.3%，w/w）用作低分子量模型药物。异硫氰酸荧光素葡聚糖MW 4400（FD4）用作亲水性高分子量荧光探针（0.2%，w/w）。对于低分子量药物，通过从组织切片中提取并进行HPLC检测来测量渗透到猪阴道黏膜中的量。对于与FD4接触的样品，将切片垂直于表面切割，并通过共聚焦激光扫描显微镜（CLSM）进行观察。还在体外细胞培养模型（Caco-2）中测量了FD4的渗透。Chs柠檬酸盐的渗透增强能力与Chs HCl相当。对Chs柠檬酸盐和Chs HCl都进行了对蛋白水解酶羧肽酶A和亮氨酸氨肽酶抑制作用的测试。在两种情况下，Chs柠檬酸盐对酶活性的抑制作用均显著高于Chs HCl。
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