Iontophoretic transdermal delivery of haloperidol

The in vitro iontophoretic transdermal delivery of haloperidol (HP) across pig skin was investigated. Anodal iontophoresis considerably increased HP skin penetration and accumulation as compared to the passive controls.The effect of NaCl and HP concentrations on the vehicle were also studied. As expected, HP iontophoretic transport decreased with NaCl content. On the other hand, HP concentration did not modify its electrotransport in the range of concentrations between 0.4 and 0.9 mg/mL, except at 24 hours. The influence of the current density (0.20-0.50 mA/cm2) was also investigated. The iontophoretic transport of HP tends to increase with current density. On the whole, this work shows that iontophoresis may be used to improve the topical application of HP for the treatment of chronic psychosis.     

Iontophoretic Transdermal Delivery of Haloperidol

The in vitro iontophoretic transdermal delivery of haloperidol (HP) across pig skin was investigated. Anodal iontophoresis considerably increased HP skin penetration and accumulation as compared to the passive controls.

The effect of NaCl and HP concentrations on the vehicle were also studied. As expected, HP iontophoretic transport decreased with NaCl content. On the other hand, HP concentration did not modify its electrotransport in the range of concentrations between 0.4 and 0.9 mg/mL, except at 24 hours. The influence of the current density (0.20–0.50 mA/cm²) was also investigated. The iontophoretic transport of HP tends to increase with current density. On the whole, this work shows that iontophoresis may be used to improve the topical application of HP for the treatment of chronic psychosis.     

Passive and iontophoretic transdermal penetration of chlorpromazine

The in vitro iontophoretic transdermal delivery of chlorpromazine (CPZ) across pig skin was investigated. Anodal iontophoresis considerably increased CPZ skin penetration and accumulation compared with the passive controls. The effect of CPZ concentration in the donor solution was studied (1.4-8.2 mM). A higher penetration was observed with an increase of the concentration. In addition, the effect of NaCl concentration was also studied (154-200 mM). As expected, CPZ iontophoretic transport decreased with NaCl content. Finally, the influence of the current density (0.20-0.50 mA/cm(2)) was investigated. The iontophoretic transport of CPZ tends to increase with current density, although this effect was not statistically significant between 0.35 and 0.5 mA/cm(2). On the whole, this work shows that iontophoresis may be used to improve the transdermal delivery of CPZ for the treatment of chronic psychosis.     

Passive and Iontophoretic Transdermal Penetration of Chlorpromazine

The in vitro iontophoretic transdermal delivery of chlorpromazine (CPZ) across pig skin was investigated. Anodal iontophoresis considerably increased CPZ skin penetration and accumulation compared with the passive controls.

The effect of CPZ concentration in the donor solution was studied (1.4–8.2 mM). A higher penetration was observed with an increase of the concentration. In addition, the effect of NaCl concentration was also studied (154–200 mM). As expected, CPZ iontophoretic transport decreased with NaCl content. Finally, the influence of the current density (0.20–0.50 mA/cm²) was investigated. The iontophoretic transport of CPZ tends to increase with current density, although this effect was not statistically significant between 0.35 and 0.5 mA/cm². On the whole, this work shows that iontophoresis may be used to improve the transdermal delivery of CPZ for the treatment of chronic psychosis.     

Transdermal Iontophoresis of Rotigotine Across Human Stratum Corneum in Vitro: Influence of pH and NaCl Concentration

PURPOSE: The aim of this study was to characterize the influence of pH and NaCl concentration on the transdermal iontophoretic transport of the dopamine receptor agonist rotigotine across human stratum corneum (HSC). METHODS: Rotigotine transport was studied in vitro in side by side diffusion cells according to the following protocol: 6 h of passive diffusion, 9 h of iontophoresis, and 5 h of passive diffusion. A current density of 0.5 mA cm(-2) was used. The influence of donor phase pH (4, 5, and 6) and different concentrations of NaCl (0.07 and 0.14 M) on rotigotine iontophoretic flux were examined. The acceptor phase was phosphate-buffered saline (PBS) at pH 7.4 except in one series of experiments aimed to study the effects of rotigotine solubility on its iontophoretic transport. In this study, PBS at pH 6.2 was used. In separate studies. 14C-mannitol was used as a marker to determine the role of electro-osmosis during iontophoresis. RESULTS: The estimated iontophoretic steady-state flux (Flux(ss)) of rotigotine was influenced by the pH of the donor solution. At a drug donor concentration of 0.5 mg ml(-1), the iontophoretic flux was 30.0 +/- 4.2 nmol cm(-2) h(-1) at pH 6 vs. 22.7 +/- 5.5 nmol cm(-2) h(-1) at pH 5. However, when the donor concentration was increased to 1.4 mg ml(-1), no significant difference in iontophoretic rotigotine transport was observed between pH 5 and 6. Increase of NaCl concentration from 0.07 M to 0.14 M resulted in a decrease of the rotigotine Flux(ss) from 22.7 +/- 5.5 nmol cm(-2) h(-1) to 14.1 +/- 4.9 nmol cm(-2) h(-1). The contribution of electro-osmosis was estimated less than 17%. Probably due to the lipophilic character of the drug, impeding the partitioning of rotigotine from HSC to the acceptor compartment, steady-state transport was not achieved during 9 h of iontophoresis. CONCLUSIONS: Both pH and NaCl concentration of the donor phase are crucial on the iontophoretic transport of rotigotine. Electro-repulsion is the main mechanism of the iontophoretic transport of rotigotine.     

Iontophoretic enhancement of timolol across human dermatomed skin in vitro

The objective of this study was to assess the in vitro the iontophoretic delivery of Timolol across human dermatomed skin in order to determine whether therapeutic doses of this drug can be delivered. Anodal iontophoresis of Timolol was performed by manipulating the donor vehicle and the current density. It was observed that by reducing simultaneously the competitive ions (NaCl) from 8 to 4 g/l and the pH from 7.4 to 4.7, the iontophoretic flux was significantly increased by a factor of 1.5 (669+/-81 microg/cm h). In order to simulate the situation in a transdermal patch, the iontophoretic delivery of Timolol was also studied after adding an artificial porous membrane placed between the Timolol formulation and the human dermatomed skin. No significant difference was observed in the steady state flux across the skin when an artificial membrane was added. Furthermore, a linear relationship was found between current density and steady state flux. These results indicate that the iontophoretic delivery of Timolol can be accurately controlled by the applied current. Assuming a one to one in vitro/in vivo correlation the Timolol transport in vitro results in therapeutic plasma concentrations in humans with very low current densities limiting possible skin irritation.     

In vitro iontophoretic transport of ketorolac: synthetic membrane as a barrier

The effect of different factors on the iontophoretic transport of ketorolac was analyzed. In vitro experiments were performed in a diffusion cell with a cellulose membrane as a barrier. The results indicated that an increase in current density or drug concentration enhanced the transmembrane permeation of the drug. The presence of extraneous ions (such as NaCl) or an increase in viscosity of the donor medium slowed down the iontophoretic transport of the drug. The pH does not seem to be an important factor determining iontophoretic transport of ketorolac as statistically insignificant difference was observed in flux at pH 5.6, 7.2, and 8. Also, the relative importance of the transport contributions involved in iontophoresis, namely diffusive iontophoretic and electro-osmotic fluxes, was investigated using glucose as a nonionizable drug. The results indicated that the total flux of ketorolac is a result of two contributions: passive diffusion and iontophoretic flux. The contribution of electro-osmosis appears to be negligible.     

Combined effects of iontophoretic and chemical enhancement on drug delivery. II. Transport across human and murine skin

This paper reports measurements of the release characteristics of the model drug salbutamol from a liquid crystalline vehicle across both human and hairless murine skin in vitro. The use of oleic acid and iontophoresis as penetration enhancement techniques, used separately and simultaneously, was also investigated. Over a period of 12h, salbutamol base did not diffuse from the vehicle across excised human skin while, in contrast, over a period of 2h, the drug passively transported across hairless murine skin. The diffusion co-efficient for the drug in this tissue was estimated to be 4.54+/-0.60x10(-9)cm(2)s(-1) with a permeability co-efficient of 7.03+/-0.83x10(-7)cms(-1). A current of density of 0.39mAcm(-2) facilitated a significant transport of salbutamol from the liquid crystalline vehicle across excised human skin but with a small (<0.1) transport number. The quantity of salbutamol transported across excised hairless murine skin under the same conditions was significantly greater with a transport number of 0.68. The alteration of the permeability of the tissue was less than that of the human skin and a full recovery of the pre-iontophoretic permeability of murine skin was consistently observed. The incorporation of either oleic or lauric acid into the monoglyceride component of the vehicle at a concentration of 0.1M had a marked effect on the transport of salbutamol across both human and murine skin. The initial passive permeation of the drug across the skin was not affected but the rate of drug delivery during iontophoresis was typically observed to increase by a factor greater than two. The post-iontophoretic transport of salbutamol across either tissue was also substantially enhanced in the presence of the fatty acid. The analogous use of stearic acid did not significantly influence the iontophoretic or the post-iontophoretic transport of salbutamol across excised human skin. The investigation also revealed a synergistic combination of the fatty acid and anodal iontophoresis to enhance the in vitro transport of other drug substances, including nicotine and diltiazem hydrochloride across murine skin. Oleic acid increased both the iontophoretic and post-iontophoretic transport of nicotine, so that the enhancement of drug delivery was greater than that caused by the current alone. The investigation also indicated that the barrier properties of the skin recover following the constant current iontophoresis in the presence of oleic or lauric acids.     

Electronically facilitated transdermal delivery of human parathyroid hormone (1-34)

Electronically facilitated transdermal delivery of human parathyroid hormone (1-34), hPTH (1-34), was investigated in vitro, using dermatomed porcine skin. The effect of iontophoretic current density, electroporative pulse voltages and also electroporation followed by iontophoresis was investigated on the in vitro percutaneous absorption of hPTH (1-34). Iontophoresis at 0.5 mA/cm2 current density significantly enhanced (P<0.05) the flux of hPTH (1-34) in comparison to passive flux. Electroporation pulses of 100, 200 and 300 V significantly increased (P<0.05) the flux of hPTH (1-34) in comparison with the passive as well as iontophoretic flux at 0.5 mA/cm2. The electroporative flux of hPTH (1-34) was found to vary linearly (R2 = 0.97) with the pulse amplitude. The principal barrier of the skin, stratum corneum, was found perturbed following the pulses as evident by light microscopy studies. The application of electroporation pulses followed by iontophoresis further increased the flux by several fold. The flux of hPTH (1-34) with the electroporation pulses of 100 and 300 V followed by iontophoresis at 0.2 mA/cm2 was 10- and 5-fold higher, respectively, in comparison to the flux with corresponding pulses alone. This shows the synergistic effect of iontophoresis in combination with electroporation on skin permeability of hPTH (1-34). The results indicate the possibility of designing controlled transdermal delivery systems for hPTH (1-34) using electroporation followed by iontophoresis.     

Mechanisms Involved in lontophoretic Transport of Angiotensin

Purpose. The feasibility of using iontophoresis to enhance the permeation rate of a model peptide was investigated in vitro using hairless mouse skin. Methods. Angiotensin 2 (AT 2) was employed as a permeant probe, using optimum iontophoresis conditions. A number of physicochemical parameters (donor ionic strength; valence of competitive ions; pH of donor solution) were studied with the aim of exploring the mechanisms involved in the iontophoretic transport through the skin: electrokinetic transport or convective transport. For this purpose, the magnitude of the convective solvent flow was also evaluated by the permeation of (³H) H₂O. The interest of pulsed currents for peptide delivery was also investigated and the effect of current density and frequency was studied. Results. AT 2 transport was found to be enhanced 20-fold in comparison to passive permeation and was found to be proportional to the current density with direct currents as with pulsed currents. Conclusions. Although the flux enhancement of ions during iontophoresis is due principally to the electrical potential gradient, secondary effects such as convective solvent flow contribute also to flux enhancement of peptide delivery. This effect is dependent of physicochemical conditions of formulation.     

Characterization of the pore transport properties and tissue alteration of excised human skin during iontophoresis

Pores through which charged carriers move during iontophoresis were demonstrated by the use of the cathodic (-) iontophoretic transport of fluorescein from the epidermis to the dermis. Both dermatomed (0.8-mm) human cadaver skin and full-thickness female human breast skin were investigated. The density of pores, as visualized by fluorescein transport, was approximately 2-5 cm-2. A set of microelectrodes rastered across the visualized pore gave a maximal response when directly above the pore, demonstrating that the pore was a locus of charge transport. Fluorescein was also sometimes observed at the diffusion cell-tissue interface. This indicates that edge damage had occurred as the result of clamping the tissue in a diffusion cell. Studies were conducted to determine if tissue damage occurred during iontophoretic transport. The electrical resistance across excised skin was measured at 0.2 Hz and found to decrease initially by approximately an order of magnitude after the application of an iontophoretic current of 0.16 mA/cm2 for 1 h. The electrical resistance then increased, reaching a plateau value which was lower than the original tissue resistance before application of an iontophoretic current. Controls were carried out to demonstrate that the observed electrical resistance changes were not just due to tissue hydration effects. These results imply that the passage of current through excised human skin at clinically acceptable current densities can lead to tissue damage which is not fully reversible.     

Stability of peptides during iontophoretic transdermal delivery

Degradation of thyrotropin releasing hormone (TRH) and insulin was investigated during iontophoretic transdermal delivery in vitro in varied buffer solutions and under various experimental conditions. A large current density enhanced deterioration of TRH during transdermal iontophoresis. Skin or external electrical potential increased the rate of deterioration, as did elevated temperatures. Peptide transformations took place and were significantly influenced by the physiological and pathological status of the skin and the electrochemical conditions during iontophoresis. Skin metabolism and electrical deterioration during iontophoretic transdermal transport was significant, especially at elevated temperature. Decreased temperature or added agents decreased the rate of degradation.     

Iontophoretic transdermal delivery of buspirone hydrochloride in hairless mouse skin

The transdermal delivery of buspirone hydrochloride across hairless mouse skin and the combined effect of iontophoresis and terpene enhancers were evaluated in vitro using Franz diffusion cells. Iontophoretic delivery was optimized by evaluating the effect of drug concentration, current density, and pH of the vehicle solution. Increasing the current density from 0.05 to 0.1 mA/cm² resulted in doubling of the iontophoretic flux of buspirone hydrochloride, while increasing drug concentration from 1% to 2% had no effect on flux. Using phosphate buffer to adjust the pH of the drug solution decreased the buspirone hydrochloride iontophoretic flux relative to water solutions. Incorporating buspirone hydrochloride into ethanol:water (50:50 vol/vol) based gel formulations using carboxymethylcellulose and hydroxypropylmethylcellulose had no effect on iontophoretic delivery. Incorporation of three terpene enhancers (menthol, cineole, and terpineol) into the gel and when combined with iontophoresis it was possible to deliver 10 mg/cm²/day of buspirone hydrochloride.     

Effect of lactic acid and iontophoresis on drug permeation across rabbit ear skin

The aim of this paper was to explore the efficacy of lactic acid as permeation enhancer for drug molecules across the skin. Three model permeants were chosen: acetaminophen (non-ionized), buspirone hydrochloride (cationic drug) and ibuprofen lysine (anionic drug). We also explored the association of lactic acid and iontophoresis as a means of enhancing drug delivery. Permeation experiments were performed in vitro, using rabbit ear skin as barrier. The results obtained indicate that lactic acid has some effects on model drug permeation across the skin. The effect was more evident with the anionic drug ibuprofen. Cathodal intophoresis increased ibuprofen transport, but when lactic acid was associated with cathodal iontophoresis, a concentration-dependent reduction of ibuprofen iontophoretic flux was observed, probably for the competition by the co-ion. The application of electric current (anodal iontophoresis) to a solution of acetaminophen produced an increase in its transport, due to the presence of an electroosmotic contribution; however, the effect of the association of anodal iontophoresis and lactic acid produced no further enhancement.     

Transdermal iontophoresis of insulin: III. Influence of electronic parameters

Transdermal iontophoresis is a physical enhancement strategy primarily for charged molecules and offers a number of advantages for the delivery of peptides and proteins. The singular advantage of iontophoresis lies in the precise control of dose by manipulating the current protocol. The objective of the present investigation was to understand the role of electronic parameters on iontophoretic transport of large peptides using insulin as a model peptide. Ex vivo permeation experiments were conducted using excised rat skin and the influence of varying current strengths, duration, on/off ratios and switching iontophoresis on insulin permeation were studied. High performance liquid chromatography (HPLC), polyacrylamide gel electrophoresis (SDS-PAGE) and thin layer chromatography (TLC) were used to assess the electrochemical stability of insulin; while Fourier transform infra-red (FT-IR) spectroscopy and thermogravimetric analysis (TGA) were used to understand the biophysical changes in skin during iontophoresis. The permeation of insulin was found to increase as a function of current strength and duration of current application. Skin barrier integrity and electrochemical stability of insulin was dependent on the charge applied during iontophoresis. FT-IR spectroscopy and TGA studies showed that the skin hydration increased with increase in the charge applied and thus facilitated the transport of insulin. Periodic iontophoresis did not show any significant difference in insulin permeation compared with continuous current application; 1:1 on/off ratio resulted in higher amount of insulin permeation, while flux was highest with mixed duty cycle. Switching iontophoresis was useful in reducing the pH shift and in improving the electrochemical stability of insulin at pH 3.6 and 7.4, respectively. The electroosmotic flow was influenced by the pH of the donor medium, as well as by the electrode polarity during switching and non-switching iontophoresis. Overall, the study demonstrates the issues related to the optimization of electronic parameters for the iontophoretic delivery of a large peptide.     

The Electrical Characteristics of Human Skin in Vivo

Purpose. The objectives of this study were to investigate the impedance properties of human skin in vivo and to examine the effect of iontophoresis upon them. Methods. Having established the intra- and inter-individual variation in basal values of skin impedance, the effect of varying iontophoretic current density, ionic strength and counter-ion on the rate of recovery of skin impedance after iontophoresis was investigated. Results. Passage of an iontophoretic current caused a significant reduction in the magnitude of the skin impedance. Increasing the current density caused an even greater reduction in the value of the skin impedance and slowed the rate of recovery. Reduction of the ionic strength resulted in an increase in the rate of recovery following iontophoresis. A significant increase in the rate of recovery was observed when CaCl₂ replaced NaCl as the electrolyte. Although visual inspection revealed the presence of greater erythema when CaCl₂ was used, there was an absence of the mild sensation experienced by volunteers when using NaCl. The last part of the study established a correlation between transepidermal water loss and impedance analysis as complementary methods for probing skin barrier function in vivo. The data were fitted to an equivalent circuit consisting of a resistor in parallel with a constant-phase element and a mechanistic model proposed to explain the electrical properties of the skin. Conclusions. The first comprehensive investigation of the effect of iontophoresis on the electrical properties of human skin in vivo has been described. It would appear from the results, and from their interpretation, that impedance spectroscopy may be an effective method to quantify the impact of iontophoresis on the skin, and to determine the extent to which proposed drug delivery regimens will perturb skin barrier function.     

Intradermal delivery of antisense oligonucleotides by the pulse depolarization iontophoretic system

The intradermal delivery of an antisense oligonucleotide was examined by iontophoresis. In this experiment, the antisense sequence of [(32)P]-labeled phosphodiester oligonucleotide ([(32)P]D-oligo, 18-mer) hybridizing to mouse interleukin 10 (IL-10) mRNA was used as a model D-oligo. In in vitro iontophoretic experiments, isolated hairless mouse skin was used with a horizontal diffusion cell. The enhancing effect of pulse depolarization (PDP) iontophoresis on the [(32)P]D-oligo permeation through the skin was better, and the skin irritation was less, than those of constant direct current (CDC) iontophoresis. The apparent fluxes of [(32)P]D-oligo were enhanced with the increasing current densities and [(32)P]D-oligo concentrations in the donor solution, whereas the enhanced flux decreased with the increasing NaCl concentrations in the donor solution. An optimum electric current was observed for the intradermal delivery of [(32)P]D-oligo, and intact [(32)P]D-oligo was detected within the skin after iontophoresis for 6 h. These results suggest that PDP iontophoresis may be useful for the intradermal delivery of antisense oligonucleotides.     

In vivo iontophoretic administration of ropinirole hydrochloride

This work explores the possibility of achieving therapeutic levels of the anti-Parkinsonian drug, ropinirole hydrochloride (RHCl), by transdermal iontophoretic delivery. An in vivo study was performed in hairless rats during which RH(+) was delivered at one current intensity (0.58 mA identical with 0.12 mA/cm(2)) and at three different drug concentrations (25, 125, and 250 mM). In vivo RH(+) flux and transport number were deduced from the steady-state plasma concentration values. Plasma concentration profiles and RH(+) transport numbers were independent of the drug donor concentration. The average iontophoretic input rate was about 3 micromol/h. Postiontophoresis transepidermal water loss (TEWL) was monitored and biopsies were histologically examined to identify any effects of iontophoresis on the skin. TEWL was elevated only at the anodal sites. TEWL recovery was faster for the "no-drug" control anodal sites, which suggests a combined effect of the drug and current on the skin. In conclusion, (1). the in vivo iontophoretic transport of RH(+) is independent of the drug donor concentration, and (2). iontophoresis can deliver therapeutic amounts of RH(+).     

Physicochemical considerations in the iontophoretic delivery of a small peptide: in vitro studies using arginine vasopressin as a model peptide.

Transdermal iontophoresis (TI) is a physical enhancement technique to facilitate the delivery of primarily charged molecules across the skin. TI of peptides is influenced by a complex interplay of several factors and one of the main issues in optimizing iontophoretic delivery of peptides is to improve the transport efficiency.From this perspective, this study investigates the effect of the physicochemical parameters on the TI of a peptide arginine vasopressin (AVP). The permeation of AVP showed a linear dependence on the concentration of drug in the donor medium. The iontophoretic flux of AVP was strongly influenced by the pH of the donor solution. Increasing the pH from 5.16 to 7.4 resulted in a decrease in the enhancement ratio by 4.5 times. When the ionic strength was increased by varying the amount of NaCl from 0.05 to 0.25 M the flux was found to decrease by 3.2 times. Replacing normal saline in the receptor compartment by HEPES buffer showed a resultant four times increase in drug permeation. The physiochemical parameters of the donor medium play a significant role in the efficiency of drug delivery by iontophoresis for a small peptide like AVP. Though electrorepulsion would be expected to be the main mechanism involved in the movement of charged molecules across the skin by iontophoresis, for peptides in the molecular weight range of AVP, other associated secondary effects like osmosis, electroosmosis and counter ion flow may also play a significant role in transport across the skin.     

Effect of chemical penetration enhancer and iontophoresis on the in vitro percutaneous absorption enhancement of insulin through porcine epidermis

The purpose of this study was to investigate the effect of chemical enhancers (fatty acids and limonene) and iontophoresis on the in vitro permeability enhancement of insulin through porcine epidermis. The following fatty acids were used: palmitic (C16:0), palmitoleic (C16:1), stearic (C18:0), oleic (C18:1), linoleic (C18:2), and linolenic (C18:3). Franz diffusion cells and the Scepter iontophoretic power source were used for the percutaneous absorption studies. Cathodal iontophoresis was performed at 0.2 mA/cm2 current density. Iontophoresis in combination with chemical enhancers synergistically increased (p<0.05) the in vitro permeability of insulin. Linolenic acid (C18:3) produced greater permeability of insulin through epidermis than did other fatty acids during passive (44.45 x 10(-4) cm/h) and iontophoretic (78.03 x 10(-4) cm/h) transport. Lispro insulin flux was significantly (p<0.05) greater through linolenic acid and limonene pretreated epidermis compared to untreated controls during both passive and iontophoretic transports. Using limonene as a penetration enhancer, a linear increase in the passive and iontophoretic flux of lispro insulin was observed with donor concentrations increasing from 100 IU/mL to 300 IU/mL. Iontophoretic flux through limonene-treated epidermis using 0.5 mA/cm2 current density and 300 IU/mL insulin donor solution was 45.63 IU/cm2/day. Using an iontophoretic patch size of 10 cm2, we would be able to deliver 50 IU of insulin within 3 h.