Controlled Iontophoretic Transport of Huperzine A across Skin in Vitro and in Vivo: Effect of Delivery Conditions and Comparison of Pharmacokinetic Models

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) (r² = 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.