经皮离子导入体外和体内的磷酸地塞米松钠：实验参数和皮肤类型对药物稳定性和传输动力学的影响。

Transdermal iontophoresis of dexamethasone sodium phosphate in vitro and in vivo: effect of experimental parameters and skin type on drug stability and transport kinetics.

机构信息

School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, Geneva, Switzerland.

出版信息

Eur J Pharm Biopharm. 2010 Jun;75(2):173-8. doi: 10.1016/j.ejpb.2010.03.011. Epub 2010 Mar 21.

DOI:10.1016/j.ejpb.2010.03.011

PMID:20332024

Abstract

The aim of this study was to investigate the cathodal iontophoresis of dexamethasone sodium phosphate (DEX-P) in vitro and in vivo and to determine the feasibility of delivering therapeutic amounts of the drug for the treatment of chemotherapy-induced emesis. Stability studies, performed to investigate the susceptibility of the phosphate ester linkage to hydrolysis, confirmed that conversion of DEX-P to dexamethasone (DEX) upon exposure to samples of human, porcine and rat dermis for 7 h was limited (82.2+/-0.4%, 72.5+/-4.8% and 78.6+/-6.0% remained intact) and did not point to any major inter-species differences. Iontophoretic transport of DEX-P across dermatomed porcine skin (0.75 mm thickness) was studied in vitro as a function of concentration (10, 20, 40 mM) and current density (0.1, 0.3, 0.5 mA cm(-2)) using flow-through diffusion cells. Increasing concentration of DEX-P from 10 to 40 mM resulted in a approximately 4-fold increase in cumulative permeation (35.65+/-23.20 and 137.90+/-53.90 microg cm(-2), respectively). Good linearity was also observed between DEX-P flux and the applied current density (i(d); 0.1, 0.3, 0.5 mA cm(-2); J(DEX) (microg cm(2) h(-1))=237.98 i(d)-21.32, r(2)=0.96). Moreover, separation of the DEX-P formulation from the cathode compartment by means of a salt bridge - hence removing competition from Cl(-) ions generated at the cathode - produced a 2-fold increase in steady-state iontophoretic flux (40 mM, 0.3 mA cm(-2); 20.98+/-7.96 and 41.82+/-11.98 microg cm(-2) h(-1), respectively). Pharmacokinetic parameters were determined in Wistar rats (40 mM DEX-P; 0.5 mA cm(-2) for 5h with Ag/AgCl electrodes and salt bridges). Results showed that DEX-P was almost completely converted to DEX in the bloodstream, and significant DEX levels were achieved rapidly. The flux across rat skin in vivo (1.66+/-0.20 microg cm(-2) min(-1)), calculated from the input rate, was not statistically different from the flux obtained in vitro across dermatomed porcine skin (1.79+/-0.49 microg cm(-2) min(-1)). The results suggest that DEX-P delivery rates would be sufficient for the management of chemotherapy-induced emesis.

摘要

本研究旨在探讨磷酸地塞米松（DEX-P）的体外和体内阴极电泳，并确定为治疗化疗引起的呕吐而输送治疗量药物的可行性。进行稳定性研究以研究磷酸酯键对水解的敏感性，结果证实DEX-P在暴露于人、猪和大鼠真皮样本 7 小时后转化为地塞米松（DEX）的程度有限（82.2+/-0.4%、72.5+/-4.8%和 78.6+/-6.0%保持完整），并且没有表明任何主要的种间差异。在体外，使用流通扩散池研究了磷酸地塞米松（DEX-P）在去皮的猪皮（0.75 毫米厚）中的离子电渗传递，作为浓度（10、20、40 mM）和电流密度（0.1、0.3、0.5 mA cm(-2))的函数。DEX-P 浓度从 10 增加到 40 mM，累积渗透量增加了大约 4 倍（35.65+/-23.20 和 137.90+/-53.90 microg cm(-2)，分别）。DEX-P 通量与施加的电流密度（i(d)；0.1、0.3、0.5 mA cm(-2)；J(DEX)（μg cm(-2) h(-1)）=237.98 i(d)-21.32，r(2)=0.96）之间也存在良好的线性关系。此外，通过盐桥将 DEX-P 制剂与阴极隔离开来 - 从而消除了在阴极产生的 Cl(-)离子的竞争 - 使稳态离子电渗通量增加了 2 倍（40 mM，0.3 mA cm(-2)；20.98+/-7.96 和 41.82+/-11.98 microg cm(-2) h(-1)，分别）。在 Wistar 大鼠中（40 mM DEX-P；5 小时内用 Ag/AgCl 电极和盐桥施加 0.5 mA cm(-2)）确定药代动力学参数。结果表明，DEX-P 在血液中几乎完全转化为 DEX，并且迅速达到显著的 DEX 水平。从输入速率计算的体内大鼠皮肤通量（1.66+/-0.20 μg cm(-2) min(-1)）与在去皮猪皮上体外获得的通量（1.79+/-0.49 μg cm(-2) min(-1)）没有统计学差异。结果表明，DEX-P 的输送速率足以管理化疗引起的呕吐。