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.     

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 methotrexate

The in vitro iontophoretic transdermal delivery of methotrexate (MTX) across pig skin was investigated. Cathodal iontophoresis considerably increased MTX skin permeation and accumulation as compared to the passive controls. The effect of NaCl and MTX concentrations in the vehicle were also studied. As expected, MTX iontophoretic transport decreased with NaCl content. On the other hand, MTX concentration did not modify its electrotransport in the range of concentrations considered (4.4-6.6 mM). The influence of the current density (0.25-0.5 mA/cm2) was also investigated. The iontophoretic transport of MTX tends to increase with current density although this effect was not always statistically significant. Finally, the possibility of using anodal iontophoresis from an acid (pH 4.0-5.0) donor solution to deliver MTX was explored. This was limited due to the low solubility of MTX in acid pH. On the whole, this work that iontophoresis may be used to improve the topical application of MTX for the treatment of psoriasis.     

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.     

Transdermal iontophoretic delivery of selegiline hydrochloride,in vitro

Transdermal iontophoretic delivery of selegiline hydrochloride (SH) across dermatomed human skin was studied. Electrochemical stability and various factors affecting the skin permeation were investigated. SH was stable under the influence of an electrical field. The permeation of SH was very low by passive delivery (2.29?±?0.05 μg/cm²/h) as compared to iontophoresis at 0.5 mA/cm² (65.10?±?5.04 μg/cm²/h). An increase in drug concentration from 1 to 20?mg/mL increased the iontophoretic flux by 13-fold. Optimal pH and salt (NaCl) concentration for iontophoretic delivery of SH were found to be pH 5 and 100?mM, respectively. Overall, with 20?mg/mL SH and a current density of 0.4 mA/cm², a maximum flux of 305.5?μg/cm²/h was obtained. Based on reported pharmacokinetic parameters, input target delivery rate to achieve effective plasma concentration of SH (2.2?ng/mL) was calculated. With a surface area of 40?cm², iontophoretic delivery can provide six to seven times higher levels of SH than the target delivery rate, which enables lowering of the dose and/or patch surface area. Further in vivo studies will be required to prove the efficacy of ionophoresis for enhanced delivery of SH.     

Transdermal iontophoresis of sodium nonivamide acetate evaluated by in vivo microdialysis and histologic study

By using an intradermal microdialysis technique 22 h after the transdermal iontophoretic delivery of sodium nonivamide acetate (SNA), a synthetic derivative of capsaicin, the amount of SNA in the extracellular space was measured. Transdermal iontophoresis is a process that enhances skin permeation of ionized species by using an electric field as a driving force. Iontophoresis increased the amount of SNA in dialysate compared with passive diffusion in this study. By using various polymers incorporated in formulations, indicated hydrogels showed higher capacity for SNA delivery than solution formulations. This result was possibly attributable to the antinucleant ability of polymers resulting in the increase of thermodynamic activity of SNA in formulations. Pretreatment with isopropyl myristate, a lipophilic penetration enhancer, on rat skin enhanced transdermal delivery of SNA both for passive and iontophoretic penetration, indicating the possibility of reducing the surface area of the administrations site in clinical use. Microscopic examination revealed no or slight changes in the skin after iontophoretic treatment compared with penetration enhancer pretreatment. The histologic results also suggested iontophoretic treatment with 0.5 mA/cm² current density of not more than 7‐h application duration may be acceptable clinically. Drug Dev. Res. 46:87–95, 1999. © 1999 Wiley‐Liss, Inc.     

Effect of Electroporation on Transdermal lontophoretic Delivery of Luteinizing Hormone Releasing Hormone (LHRH) in Vitro

Electroporation, the creation of transient, enhanced membrane permeability using short duration (microseconds to millisecond) electrical pulses, can be used to increase transdermal drug delivery. The effect of an (electroporative) electric pulse (1000 V, = 5 msec) on the iontophoretic transport of LHRH through human skin was studied in vitro. Fluxes achieved with and without a pulse under different current densities (0- 4 mA/cm²) were compared. The results indicated that the application of a single pulse prior to iontophoresis consistently yielded higher fluxes (5—10 times the corresponding iontophoretic flux). For example, at 0.5 mA/cm² fluxes were 0.27 ± 0.08 and 1.62 ± 0.05 µg/hr/cm² without and with the pulse, respectively. At each current density studied, the LHRH flux decreased after iontophoresis, approaching pre-treatment values. The results show that electroporation can significantly and reversibly increase the flux of LHRH through human skin. These results also indicate the therapeutic utility of using electroporation for enhanced transdermal transport.     

Transdermal Delivery of Cytochrome C—A 12.4 kDa Protein—Across Intact Skin by Constant–Current Iontophoresis

Purpose To demonstrate the transdermal iontophoretic delivery of a small (12.4 kDa) protein across intact skin. Materials and Methods The iontophoretic transport of Cytochrome c (Cyt c) across porcine ear skin in vitro was investigated and quantified by HPLC. The effect of protein concentration (0.35 and 0.7 mM), current density (0.15, 0.3 or 0.5 mA.cm⁻² applied for 8 h) and competing ions was evaluated. Co-iontophoresis of acetaminophen was employed to quantify the respective contributions of electromigration (EM) and electroosmosis (EO). Results The data confirmed the transdermal iontophoretic delivery of intact Cyt c. Electromigration was the principal transport mechanism, accounting for ∼90% of delivery; correlation between EM flux and electrophoretic mobility was consistent with earlier results using small molecules. Modest EO inhibition was observed at 0.5 mA.cm⁻². Cumulative permeation at 0.3 and 0.5 mA.cm⁻² was significantly greater than that at 0.15 mA.cm⁻²; fluxes using 0.35 and 0.7 mM Cyt c in the absence of competing ions (J _tot  = 182.8 ± 56.8 and 265.2 ± 149.1 μg.cm⁻².h⁻¹, respectively) were statistically equivalent. Formulation in PBS (pH 8.2) confirmed the impact of competing charge carriers; inclusion of ∼170 mM Na⁺ resulted in a 3.9-fold decrease in total flux. Conclusions Significant amounts (∼0.9 mg.cm⁻² over 8 h) of Cyt c were delivered non-invasively across intact skin by transdermal electrotransport.     

In vitro and in vivo evaluation of a hydrogel-based prototype transdermal patch system of alfuzosin hydrochloride

The first-line therapy for moderate to severe benign prostatic hyperplasia is the oral therapy by alfuzosin hydrochloride. Unfortunately, the oral therapy of alfuzosin is associated with several route-specific systemic side-effects. The current study was aimed to develop a prototype transdermal patch system for alfuzosin using a hydrogel polymer and optimize the drug delivery through the skin for systemic therapy. The prospective of different chemical enhancers (polyethylene glycol (PEG 400), isopropyl myristate, propylene glycol, menthol and L-methionine; 5% w/v) and iontophoresis (0.3?mA/cm²) in the alfuzosin delivery across the full thickness rat skin was assessed in vitro. In vivo iontophoretic studies were carried out using selected patch system (PEG 400) for a period of 6?h in Sprague-Dawley rats. Passive permeation studies indicated that the incorporation of chemical agents have moderate effect (~?4- to 7-fold) on the alfuzosin skin permeability and reduced the lag time. Combined approach of iontophoresis with chemical enhancers significantly augmented the drug transport (~ 43- to 72-fold). In vivo pharmacokinetic parameters revealed that the iontophoresis (transdermal patch with PEG 400) significantly enhanced the C_max (~ 3-fold) and AUC_0-α (~ 4-fold), when compared to control. The current study concludes that the application of iontophoresis (0.3?mA/cm²) using the newly developed agaorse-based prototype patch with PEG 400 could be utilized for the successful delivery of alfuzosin by transdermal route.     

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(+).     

Iontophoretic Delivery of Apomorphine In Vitro: Physicochemic Considerations

Purpose. To examine the mechanisms of transdermal iontophoretic delivery of apomorphine. Methods. Anodal iontophoresis of R-apomorphine across human stratum corneum was determined in vitro. The effects on the flux of the following parameters were studied: stability of drug, pH of donor solution, concentration of NaCl, and type of Na⁺ co-ions. Results. Ascorbic acid was effective to prevent apomorphine degradation. The iontophoretic transport of apomorphine was strongly influenced by the pH of the donor formulation. Increasing the pH from 3 to 6 resulted in an increase in the iontophoretic apomorphine flux from 27.9 ± 4.4 nmol/cm²*h to 78.2 ± 6.9 nmol/cm²*h. Upon decreasing NaCl concentration from 8 to 2 g/L, the iontophoretic flux was not significantly changed. Replacing NaCl in the donor formulation by tetraethylammonium chloride or tetrabutylammonium chloride resulted in 1.3 fold greater steady-state flux. Conclusions. For optimized apomorphine iontophoretic delivery, a constant pH of the donor formulation is of great importance. The results suggest that although flux enhancement during iontophoresis is largely due to the electrical potential gradient, secondary effects, such as convective flow and electroosmosis may also contribute.     

Influence of electrical and chemical factors on transdermal iontophoretic delivery of three diclofenac salts

The aim of this present study was to investigate the in vitro transdermal iontophoretic delivery of three diclofenac salts--diclofenac sodium (DFS), diclofenac potassium (DFP), and diclofenac diethylammonium (DFD). A series of physicochemical and electrical variables which might affect iontophoretic permeation of diclofenac salts was studied. Application of 0.3 mA/cm2 current density significantly increased the transdermal flux of diclofenac salts as compared to passive transport. The iontophoretic enhancement increased in the order of DFS>DFP>DFD. The permeability coefficient of diclofenac salts all decreased with increasing donor concentration during iontophoresis. The addition of buffer ions and salt ions such as NaCl, KCl, and C4H12ClN reduced the permeation of diclofenac salts due to competition. However, this effect was lesser for DFD than for DFS and DFP. Comparing the various application modes of iontophoresis, the discontinuous on/off mode showed lower but more constant flux than the continuous mode.     

A Review of: “Excipient Development for Pharmaceutical,Biotechnology, and Drug Delivery Systems”

The feasibility of delivering hydromorphone by transdermal iontophoresis to obtain therapeutically effective analgesic concentrations for the management of cancer-related pain was evaluated. Anodal iontophoresis was performed, and the effect of current strength, current duration, solution pH, presence of buffer ions, and drug concentration on the transdermal permeation of hydromorphone was investigated in vitro. Freshly excised full‐thickness hairless rat skin and side-by-side permeation cells connected to the Phoresor II^TM with Ag/AgCl electrodes was used. The flux of hydromorphone was observed to significantly increase (P < 0.05) from 72.04–280.30 μg/cm²/h with increase in current strength from 0.10–0.50 mA. A linear relationship was obtained between hydromorphone flux and current strength. Furthermore, the flux of hydromorphone was influenced by solution pH and presence of buffer ions. Also, the in vitro permeation flux of hydromorphone was observed to significantly increase (P < 0.05) with a 10-fold increase in hydromorphone hydrochloride concentration from 0.01–0.10 M. However, with further increase to 0.50 M, there was no significant difference in flux. These results show that by manipulating electronic and formulation variables, the transdermal iontophoretic delivery of hydromorphone can be controlled, and therapeutically effective concentrations of hydromorphone for the management of cancer-related pain can be obtained.     

Human Calcitonin Delivery in Rats by Iontophoresis

Abstract— In-vitro iontophoresis (0·33 mA cm⁻²) of calcitonin (50 μg mL⁻¹, pH 4) was performed with the hairless rat skin model. Direct current was as potent as pulse current (2·5 kHz on/off 1/1) iontophoresis in promoting transdermal permeation of calcitonin. Increase in duration of current application from 20 min to 1 h did not increase calcitonin flux. Results suggest that calcitonin can be blocked in the skin pores through which it travels or can accumulate in the skin and be progressively released from the depot. Invivo experiments showed that transdermal iontophoretic administration of calcitonin induced a hypocalcaemic effect in rats.     

Effect of iontophoresis on in vitro transdermal absorption of almotriptan

The aim of the present work was to characterize the in vitro transdermal absorption of almotriptan through pig ear skin. The passive diffusion of almotriptan malate and its iontophoretic transport were investigated using current densities of 0.25 and 0.50 mA/cm². In vitro iontophoresis experiments were conducted on diffusion cells with an agar bridge without background electrolytes in the donor compartment. Although both current densities applied produced a statistically significant increment with respect to passive permeation of almotriptan (p < 0.01), that of 0.50 mA/cm² proved to be the best experimental condition for increasing the transport of almotriptan across the skin. Under these experimental conditions, the transdermal flux of the drug increased 411-fold with respect to passive diffusion, reaching 264 ± 24 μg/cm² h (mean ± SD). Based on these results, and taking into account the pharmacokinetics of almotriptan, therapeutic drug plasma levels for the management of migraine could be achieved via transdermal iontophoresis using a reasonably sized (around 7.2 cm²) patch.     

Transdermal Iontophoretic Delivery of Propofol: A General Anaesthetic in the Form of its Phosphate Salt

The main objective of this study was to investigate the feasibility of delivery of propofol phosphate (PP), a prodrug of propofol, via transdermal route using iontophoresis in combination with chemical permeation enhancers (CPEs). PP, a prodrug, was synthesized and its structure was characterized. In vitro passive and iontophoretic drug transport studies were carried out using Franz diffusion cell across freshly excised hairless rat skin at different concentrations of PP in combination with CPE. Among all the CPEs screened, 0.1% sodium dodecyl sulfate (SDS) increased the passive transdermal flux to 13.43 ± 0.73 μg/(cm² h) from 8.52 ± 0.82 μg/(cm² h) (control). Cathodal iontophoresis in combination with 0.1% SDS synergistically enhanced the flux [249.24 ± 6.12μg/(cm² h)] of PP. The Pharmacokinetic studies were performed in rat model to assess the feasibility of transdermal delivery of PP. The amount of propofol present in plasma samples in control group (passive) was below the detectable levels at all the time points during the study. The plasma concentration—time profile of iontophoresis group of rats was fit to a noncompartmental model and the pharmacokinetic parameters were calculated. These studies suggest the plausibility of achieving therapeutically relevant levels of propofol when delivered via transdermal route by combining iontophoresis with CPE.     

Optimization of Iontophoretic Parameters for the Transdermal Delivery of Methotrexate

The aim of this work was to study the in vitro factors affecting transdermal iontophoretic delivery of methotrexate across hairless rat skin. Initial screening studies evaluated the effect of ionic strength and donor concentration. A response surface model using factorial design shows an increase in the cumulative amount of methotrexate delivered (Y₁) with an increase in current density (X₁) and time of application (X₂). However, 10 min iontophoresis and 0.05 mA/cm² current density did not show an increase in delivery with an increase in current density or time of application, respectively. The factorial design was able to identify the optimal parameters that would have been difficult to predict with a conventional one at a time-experimental approach.     

Transdermal iontophoretic delivery of triptorelin in vitro

The feasibility of delivering triptorelin ([D-Trp6]LHRH) by transdermal iontophoresis was evaluated in vitro. Peptide electrotransport at different current densities and donor concentrations was measured across porcine ear skin. The concomitant delivery of an electroosmotic marker enabled calculation of the respective contributions of electromigration (EM) and electroosmosis (EO) to iontophoretic delivery. At a given concentration (3 mM), a threefold increase in current density produced a corresponding increase in the cumulative amount of peptide present in the receptor compartment. Conversely, doubling the concentration to 6 mM produced a twofold reduction in the amount of peptide delivered, partly due to a concentration-dependent inhibition of EO. EM was revealed to be the predominant transport mechanism, accounting for 80% of overall delivery. Finally, despite the inhibition of EO, the results indicate that application of an iontophoretic current of 0.8 mA over a relatively small contact area (4 cm2) would provide a delivery rate of 36 microg/h, largely sufficient for therapeutic requirements.     

Iontophoresis of Bases,Nucleosides, and Nucleotides

Purpose. To investigate whether transdermal iontophoresis may be potentially useful for delivery of oligonucleotide drugs, the electro-transport of representative bases (uracil and adenine), nucleosides (uridine and adenosine) and nucleotides (AMP, ATP, GTP and imido-GTP) across mammalian skin in vitro has been considered. Methods. While the passive permeability of all compounds investigated (from 1 mM solutions at pH 7.4) was very low, the application of constant current iontophoresis (0.55 mA/cm²) significantly enhanced the transport of both charged and uncharged species. Results. The efficiency of delivery depended only weakly upon lipophilicity, varied quite linearly with concentration (for AMP and ATP), was inversely sensitive to molecular weight, and was strongly influenced by charge. Neutral solutes were delivered better from the anode than the cathode, as expected; post-iontophoresis, passive permeabilities were greater than those of the untreated controls, suggesting that iontophoretically-induced changes in barrier function cannot be completely repaired in in vitro model systems. The triphosphate nucleotides, ATP and GTP, were essentially completely metabolized (presumably to their corresponding mono-phosphates) during their iontophoretic delivery, while imido-GTP was apparently resistant to enzymatic attack; however, comparison of the transport data from AMP and ATP suggested that ATP metabolism occurred primarily after the rate-limiting step of iontophoresis. Conclusions. The results obtained are consistent with the general patterns of behavior previously observed in investigations of amino acid and peptide electrotransport. It remains to be seen whether extension of the research described here to larger oligonucleotide species is a feasible long-term objective.