Synergistic effects of iontophoresis and jet injector pretreatment on the in-vitro skin permeation of diclofenac and angiotensin II.

A non-needle syringe (jet injector) was utilized to increase skin permeation of drugs by iontophoresis. Briefly, physiological saline was initially flushed by the injector to make a pore in the stratum corneum of excised hairless rat skin, and the iontophoretic skin permeation of two model compounds, sodium diclofenac and angiotensin II, was followed using a 2-chamber diffusion cell. Constant voltage and constant current iontophoresis treatments were evaluated. Pretreatment using the jet injector alone resulted in about 13- and 22-fold increases in the steady-state flux of diclofenac and angiotensin II, respectively, through the skin, compared with non-treated controls. Jet injector pretreatment with constant voltage iontophoresis further enhanced skin permeation of diclofenac and angiotensin II, and the enhancement was also greater than that by constant voltage iontophoresis alone. Thus, a synergistic effect was observed. The ratio of enhancement was greater compared with the control. Jet injector pretreatment with constant current iontophoresis, however, did not always yield higher skin permeation of the drugs than injector pretreatment alone, although the lag time was shortened. The difference in the enhancement between the constant voltage- and constant current iontophoresis can be explained by the electric current through the excised skin. Constant current iontophoresis after a short period of constant voltage iontophoresis with multiple jet injector pretreatments may be the best way to increase drug permeability while preventing severe skin damage.

Analysis of skin permeation-enhancing mechanism of iontophoresis using hydrodynamic pore theory.

The effects of constant DC iontophoresis (0-1.5 mA/0.966 cm(2)) on the permeation of three hydrophilic compounds, antipyrine (ANP, M.W. 188.23), sucrose (SR, M.W. 342.30) and 1-kestose (KT, M.W. 506.73), through excised hairless rat skin were evaluated using hydrodynamic pore theory. The electro-osmotic flow caused by iontophoresis was measured using deuterium oxide (D(2)O). The penetration-enhancing mechanism of iontophoresis was found to increase solvent flow through electro-osmosis and pore enlargement and/or new pore production in the skin barrier, together with enhancement of electrochemical potential difference across the skin. These effects were closely related to the strength of the current applied. The electro-osmotic flow of D(2)O (J(D(2)O)) greatly enhanced the skin permeation clearance of all hydrophilic penetrants (CL(drug)). Pore production was classified into reversible and irreversible processes, which resulted from lower (0-0.5 mA/0.966 cm(2)) and higher (0.5-1. 5 mA/0.966 cm(2)) currents, respectively. Thus, the enhancing effects of iontophoresis on skin permeation of nonionic hydrophilic compounds can be explained by increase in pore size and higher solvent flow.

Analysis of in vitro iontophoretic skin permeation of sodium benzoate by transport numbers of drug and additives.

Effect of species and concentrations of pharmaceutical additives on the iontophoretic transport of benzoate anion through excised hairless rat skin was investigated using a 2-chamber iontophoretic diffusion cell equipped with platinum electrodes at 0 mA for 4h (control) followed by a constant direct current of 0.5 mA for another 4h. One cell facing the stratum corneum was filled with sodium benzoate solution, and the other cell facing the dermis with lithium chloride (LiCl), potassium chloride (KCl) or tetraethylammonium bromide (TEA-Br) solution. Iontophoretic delivery rate of benzoate anion that permeated through skin increased with an increase in the sodium benzoate concentration while maintaining a constant KCl concentration. In contrast, a flux of benzoate anion decreased with an increase in KCl concentration and a constant concentration of sodium benzoate. When KCl was replaced by LiCl or TEA-Br, the flux of benzoate anion was almost the same. These phenomena were evaluated by a concept of transport numbers: theoretical values of benzoate anion flux were very close to the observed data. Potential difference between the skin during the permeation study was also measured between two salt bridges which were connected via calomel electrodes to a potentiometer. It gradually decreased to a certain level in each case, but increased again in some cases. This gradual decrease and increase in the potential difference, in spite of a constant current, were theoretically explained by a gradual increase of ion concentration in the skin membrane and depletion of the cation in the receiver cell, respectively. Analysis of ionic mobility and concentration of penetrants gave a great deal of information on iontophoretic drug permeation through skin.

Non-invasive sampling of lactic acid ions by iontophoresis using chloride ion in the body as an internal standard.

Non-invasive sampling of lactic acid, as a model endogenous compound, through hairless rat skin by iontophoresis was investigated using a two-chamber iontophoretic diffusion cell equipped with platinum electrodes and a pulse depolarization iontophoretic system. Chloride ion in the body was used as an internal standard. First, an in vitro experiment on the permeation of lactate and chloride ions through hairless rat skin was carried out to determine the flux ratio of these ions. The cathode side of the cell (dermis side) was filled with physiological saline containing lactic acid (0.5556, 1.111, 1.667 or 2.222 mmol cm-3) and the anode side (epidermis side) with phosphate buffer (pH 7.4). The amount of lactate and chloride ion permeated from the dermis side to the epidermis side through the skin at a constant current of 3.0 mA was determined using an automatic lactic acid analyser and high-performance ion chromatography, respectively. For construction of a calibration curve of lactic acid in the dermis side, the ionic mobility ratio of lactic acid/chloride ion (UCl/Ulac) was determined using a computer simulation program from the flux ratio of lactic acid and chloride ion and the applied concentration of lactic acid in the dermis side. Second, an in vitro non-invasive sampling experiment of lactic acid through rat skin was carried out at a constant current of 2.0 or 3.0 mA and 2.222 or 1.111 mmol cm-3 of lactic acid in the dermis side, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of depolarizing and direct current systems on iontophoretic enhancement of transport of sodium benzoate through human and hairless rat skin.

A direct current (DC) system and a pulsed depolarization (PD) system were evaluated for their iontophoretic permeation of sodium benzoate, as a model drug, through hairless rat and human skin. Approximately the same initial permeation of sodium benzoate through the hairless rat skin was obtained at 0.1 mA for the DC device and at 3.0 mA for the PD device. Study of the drug's permeation was performed using a two-chamber iontophoretic diffusion cell, over two cycles of three successive on-off experimental conditions [stage I (off) 0-4 h, II (on) 4-6 h, III (off) 6-10 h, saline washing 10-24 h, IV (off) 24-28 h, V (on) 28-30 h and VI (off) 30-34 h]. Skin permeation rate during stage IV of the iontophoresis as compared with the control group through hairless rat or human skin for the DC system was 2-4 times that in stage I, whereas in the same stage using the PD system it was almost the same as in stage I. Impedance of skin decreased during the application of either system (stage II); however, the value significantly recovered during stage III only in the case of the PD system use on human skin. Histological observation revealed no tissue alteration in the hairless rat skin after using either system. When the DC or PD system was applied to volunteers, the minimum current density producing pain was 0.016 or 2.7 mA cm-2, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)