Kalaria Dhaval R, Patel Pratikkumar, Merino Virginia, Patravale Vandana B, Kalia Yogeshvar N
School of Pharmaceutical Sciences, University of Geneva & University of Lausanne , 30 Quai Ernest Ansermet, 1211 Geneva, Switzerland.
Mol Pharm. 2013 Nov 4;10(11):4322-9. doi: 10.1021/mp4004173. Epub 2013 Sep 30.
The aim of this study was to investigate constant current anodal iontophoresis of Huperzine A (HupA) in vitro and in vivo and hence to evaluate the feasibility of using electrically assisted delivery to administer therapeutic amounts of the drug across the skin for the treatment of Alzheimer's disease. Preliminary experiments were performed using porcine and human skin in vitro. Stability studies demonstrated that HupA was not degraded upon exposure to epidermis or dermis for 12 h and that it was also stable in the presence of an electric current (0.5 mA · cm(-2)). Passive permeation of HupA (2 mM) was minimal (1.1 ± 0.1 μg · cm(-2)); iontophoresis at 0.15, 0.3, and 0.5 mA · cm(-2) produced 106-, 134-, and 184-fold increases in its transport across the skin. Surprisingly, despite the use of a salt bridge to isolate the formulation compartment from the anodal chamber, which contained 133 mM NaCl, iontophoresis of HupA was shown to increase linearly with its concentration (1, 2, and 4 mM in 25 mM MES, pH 5.0) (r(2) = 0.99). This was attributed to the low ratio of drug to Cl¯ (in the skin and in the receiver compartment) which competed strongly to carry current, its depletion, and to possible competition from the zwitterionic MES. Co-iontophoresis of acetaminophen confirmed that electromigration was the dominant electrotransport mechanism. Total delivery across human and porcine skin was found to be statistically equivalent (243.2 ± 33.1 and 235.6 ± 13.7 μg · cm(-2), respectively). Although the transport efficiency was ∼ 1%, the iontophoretic delivery efficiency (i.e., the fraction of the drug load delivered) was extremely high, in the range of 46-81% depending on the current density. Cumulative permeation of HupA from a Carbopol gel formulation after iontophoresis for 6 h at 0.5 mA · cm(-2) was less than that from solution (135.3 ± 25.2 and 202.9 ± 5.2 μg · cm(-2), respectively) but sufficient for therapeutic delivery. Pharmacokinetic parameters were determined in male Wistar rats in vivo (4 mM HupA; 0.5 mA · cm(-2) for 5 h with Ag/AgCl electrodes) using two-compartment models with either constant or time-variant input rates. A superior fit was obtained using the time-variant model, and the input rate in vivo was significantly greater than that in vitro. Based on these results and the known pharmacokinetics, it was estimated that therapeutic amounts of HupA could be delivered for the treatment of Alzheimer's disease using a reasonably sized patch.
本研究的目的是在体外和体内研究石杉碱甲（HupA）的恒流阳极离子电渗疗法，从而评估使用电辅助给药方式将治疗剂量的该药物经皮给药用于治疗阿尔茨海默病的可行性。在体外使用猪皮和人皮进行了初步实验。稳定性研究表明，HupA暴露于表皮或真皮12小时不会降解，并且在有电流（0.5 mA·cm⁻²）的情况下也稳定。HupA（2 mM）的被动渗透极少（1.1±0.1 μg·cm⁻²）；在0.15、0.3和0.5 mA·cm⁻²的电流下进行离子电渗疗法，其透过皮肤的转运量分别增加了106倍、134倍和184倍。令人惊讶的是，尽管使用盐桥将制剂隔室与含有133 mM NaCl的阳极室隔开，但HupA的离子电渗疗法显示出随其浓度（在25 mM MES，pH 5.0中为1、2和4 mM）呈线性增加（r² = 0.99）。这归因于药物与Cl⁻（在皮肤和接受室中）的比例较低，Cl⁻强烈竞争载流，其消耗以及两性离子MES可能的竞争。对乙酰氨基酚的共离子电渗疗法证实电迁移是主要的电转运机制。发现经人和猪皮的总给药量在统计学上相当（分别为243.2±33.1和235.6±13.7 μg·cm⁻²）。尽管转运效率约为1%，但离子电渗给药效率（即给药的药物负载分数）极高，根据电流密度在46 - 81%的范围内。在0.5 mA·cm⁻²下进行6小时离子电渗疗法后，来自卡波姆凝胶制剂的HupA累积渗透量低于溶液中的累积渗透量（分别为135.3±25.2和202.9±5.2 μg·cm⁻²），但足以用于治疗给药。使用具有恒定或时变输入速率的二室模型在雄性Wistar大鼠体内（4 mM HupA；使用Ag/AgCl电极在0.5 mA·cm⁻²下进行5小时）测定药代动力学参数。使用时变模型获得了更好的拟合，并且体内输入速率明显大于体外。基于这些结果和已知的药代动力学，估计使用尺寸合理的贴片可以递送治疗剂量的HupA用于治疗阿尔茨海默病。
