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The effect of moxibustion on the in vitro and in vivo skin permeation of salicylate was evaluated in rats. First, the effect of moxibustion pretreatment on the elimination pharmacokinetics of salicylate after i.v. injection in rats was determined: no clear difference was observed in the plasma profiles of salicylate (SA) with or without moxibustion pretreatment. However, much higher skin and muscle concentrations of salicylate were observed after its i.v. injection. Next, an in vitro skin permeation study of SA was performed after moxibustion pretreatment. Moxibustion pretreatment increased the skin permeation of SA, and the extent of the increase in SA skin permeation was related to the strength of moxibustion ignition. More intense treatments produced higher skin permeation. A similar enhancement effect on the skin permeation of SA was observed in in vivo studies. Interestingly, the skin/plasma and muscle/plasma ratios of SA were markedly increased by moxibustion pretreatment. These results were due to the induction of enhanced skin permeation and lower clearance into the cutaneous vessels by moxibustion ignition. Combination treatment involving moxibustion and the topical application of drugs such as NSAID may be useful for increasing local pharmaceutical effects by enhancing the drug concentration in the skin and muscle underneath the topical application site., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The presence of endogenous competing counterions is a main reason for the generally low efficiency of transdermal iontophoretic drug delivery. The objective of the present study was to test the hypothesis that the incorporation of an ion-exchange membrane (Ionac) in an iontophoresis system to hinder transdermal transport of these counterions can enhance iontophoretic delivery. The properties of Ionac were characterized in passive and iontophoretic transport experiments. Iontophoretic transport across human epidermal membrane (HEM) and across HEM in series with Ionac was then studied. To assess the effect of HEM electrical resistance upon Ionac-assisted iontophoresis, HEM resistance was reduced in the iontophoresis experiments with alternating current (AC). Salicylate (SA) was the negatively charged permeant first tested in this study. Mannitol was the model permeant to examine the effects of electroosmosis. At the completion of the SA study, experiments were performed with acyclovir (ACV), an antiviral drug with limited water solubility. When Ionac was used to enhance SA transdermal fluxes, higher SA fluxes were observed with HEM of lower resistances in Ionac-assisted iontophoresis. Up to a four-fold flux enhancement was achieved when the electrical resistance of HEM was reduced using an AC iontophoresis method. For ACV, two-fold flux enhancement was observed in Ionac-assisted iontophoresis compared with the conventional iontophoresis baseline. In all experiments, the contribution of electroosmosis to drug transport was less than 10%. The present study has demonstrated the potential of a new approach using a positively charged ion-exchange membrane to enhance transdermal iontophoretic transport of negatively charged drugs.

The effects of two vasoactive agents, phenylephrine and tolazoline, were determined on the dermatopharmacokinetics and systemic disposition of model compounds, salicylate (SA) and FITC-dextran 4 kDa (FD-4), following their intracutaneous (i.c.) injection. The determined blood flow in skin was lowered and increased by i.c. injection of phenylephrine and tolazoline, respectively. Dermatopharmacokinetics and the systemic disposition of SA and FD-4 with and without vasoactive agents were analyzed using a compartment model. As a result, the rate constant, k(sc), from skin to systemic circulation of SA after i.c. injection with phenylephrine was almost zero, and the rate constant, k(sm), from skin to muscle increased about 2.4-fold compared with the control group (without vasoactive agents). In contrast, the rate constants, k(sc) and k(sm), after i.c. injection of SA with tolazoline were increased about 1.9- and 2.5-fold, respectively, compared with the control. In FD-4 disposition, k(sc) and k(sm) decreased to about 0.3-fold and increased to about 4.0-fold compared with the control after i.c. injection with phenylephrine. The k(sc) and k(sm) of FD-4 increased with tolazoline about 2.2- and 4.3-fold compared with the control, respectively. These data suggest that these vasoactive agents can be used to modify the dermatopharmacokinetics of topically or intracutaneously applied drugs.

Using advanced topical formulations containing potential chemical enhancer(s) or physical penetration-enhancing tools capable of delivering entrapped drug(s) directly into skin tissues with little influence of the stratum corneum barrier, local and systemic drug disposition may be markedly similar to direct injection into the skin and muscle. The objective of this study is to investigate the dermatopharmacokinetics and systemic drug disposition after topical application and topical injection. Salicylate (SA) disposition in the skin and muscle as administration sites, and in the systemic circulation were evaluated following intracutaneous (i.c.) injection of an isotonic solution of SA-Na (dose; 3.08 micromol). Subcutaneous (s.c.) and intramuscular (i.m.) injection were also evaluated for comparison. Dermatopharmacokinetics and systemic disposition of SA after i.c. and s.c. injections were analyzed using a 4-compartment model consisting of skin, muscle, and central and peripheral compartments, whereas SA disposition after i.m. injection was analyzed using a 3-compartment model consisting of muscle, and central and peripheral compartments. Moreover, the absorption rate constant of SA after i.c. injection (0.073 min(-1)) was slightly lower than that after s.c. injection (0.083 min(-1)), and much lower than that after i.m. injection (0.327 min(-1)). In addition, higher osmolarity and a larger volume of SA-Na injectant increased the retention of SA in the skin and decreased the absorption rate to the systemic circulation after i.c. injection. The effect of injection volume on SA disposition after i.c. injection was not so marked compared with that of osmotic pressure. These results are useful to design an injection-type topical delivery system.

The pharmacokinetic parameters, i.e. peak concentration (c(max)); peak time (t(max)); area under the curve (AUC); elimination rate constant (k); absorption rate constant (k(a)); Drug clearance (cl(t)), and the volume of distribution (v(d)) of sodium salicylate administered in fractionated coconut oil (FCO) have been compared with that from an aqueous and glycerin vehicles using a three-way crossover study in 12 rabbits. The results of the study show that all of the pharmacokinetic parameters tested differ significantly when administered in oily rather than aqueous or glycerin vehicles. No statistically significant difference was found between any of the above mentioned parameters when comparison was made between aqueous and glycerin formulations. The results indicate that sodium salicylate is absorbed at a lower rate but to a greater extent from oily formulation. Possible reasons for these differences are discussed and is suggested, therefore, that the oily formulation might be used as a sustained release preparation.

The process of systemic absorption and tissue targeting efficacy of salicylate (SA) following intracutaneous (i.c.), subcutaneous (s.c.) and intramuscular (i.m.) injections of its sodium salt in rats were evaluated by determining the drug concentration at the injection site and surrounding tissues. After i.c. and s.c. injections, SA was absorbed into the systemic circulation from the muscular vessels as well as the cutaneous or subcutaneous vessels beneath the injection site, and the AUC of the drug in the muscle was extremely high. Following i.m. injection, SA was rapidly absorbed into the systemic circulation mostly from the muscular vein. These results suggested that i.c. and s.c. injections have high degrees of targeting efficacy to the muscle, whereas i.m. injection is not appropriate for drug retention in muscle. In contrast, most of the topically applied drug was absorbed from the cutaneous vessels, and little drug migration to the muscle was observed. Thus, the skin pharmacokinetics of SA after i.c. injection was also markedly different from those after topical application on the skin. These results suggested that the i.c. and s.c. injections may be a good means to improve the targeting ability of drugs to the muscle as well as the skin.