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PubMed1994

Iontophoresis in drug delivery: basic principles and applications.

Passive delivery of most compounds across different epithelia is limited due to the barrier properties afforded by these epithelia. Iontophoresis is a novel drug delivery system designed to improve the delivery rate of compounds. The technique generates an electrical potential gradient that facilitates the movement of solute ions across the membrane. Iontophoresis has been used has been used greatest success in therapy of hyperhidrosis. The potential of iontophoresis for systemic delivery is being rediscovered, and the technique has been observed to be particularly effective for ionic drugs. It also enhances transdermal permeation of neutral compounds by the process of electroosmosis. The recent enthusiasm for iontophoresis may also be attributed to successful production of therapeutically active protein and peptide drugs by employing recombinant DNA technology. Because of their charged nature and relatively large molecular size, iontophoresis may provide means for their effective delivery. This review discusses the basic principles and applications of iontophoresis in dermatology, ophthalmology, otolaryngology, and dentistry. In addition, the systemic applications of iontophoresis with emphasis on protein and peptide delivery are reviewed.

Animals↗

PubMed1995

Changes of dentinal tubules following fluoride iontophoresis.

Fluoride(F) iontophoresis is preferred over topical application to provide long lasting dentin desensitization. The purpose of this study was to evaluate the changes in dentinal tubules following fluoride iontophoresis under SEM observation. Teeth were divided mainly into 3 groups: controls, NaF treated teeth with iontophoresis and those without inotophoresis. A battery operated device was used to apply electric current to teeth. All the teeth were prepared for scanning electron microscopy after treatments. Fluoride treatment, either non-iontophoretic or iontophoretic, produced granular precipitation in dentinal tubules and reduced tubular diameter. In 5-minute non-iontophoretic NaF treated teeth, the depth of precipitate penetration was 75 microns on average where the granules were small and sparse. In the 5-minute iontophoretic NaF treated teeth, the average penetration of precipitation reached 250 microns in one application whereas in three applications to teeth the average depth of penetration reached 830 microns. Fluoride iontophoresis resulted in obstruction of dentinal tubules. Both the frequency and duration od treatment under constant current and voltage affected the size of particles, the form of precipitation and the depth of penetration. Larger particle size and deeper fluoride penetration were observed in iontophoresis treated teeth compared to non-iontophoresis treated teeth. Therefore, repeated fluoride iontophoresis treatment is suggested to ensure long lasting densensitization effects.

Dentin↗

PubMed1996

A comparison of topical tannic acid versus iontophoresis in the medical treatment of palmar hyperhidrosis.

This is a report comparing the efficacy of tannic acid lotion (an astringent) and iontophoresis in the medical treatment of idiopathic hyperhidrosis. Ten patients with long-standing symptomatic idiopathic palmar hyperhidrosis were recruited into the study. One palm was treated with daily tannic acid (20%) lotion and the opposite palm with iontophoresis. Visual scoring using a visual analog scale by patients and assessors showed the mean score to be significantly lower on the iontophoresis treated palm than the tannic acid treated palm. There was significant reduction in the severity of hyperhidrosis on the iontophoresis treated palm after treatment. There was also a significant reduction in transepidermal water vapour loss on the iontophoresis treated palms. The study indicated that iontophoresis is an effective medical treatment for idiopathic hyperhidrosis. The disadvantage of iontophoresis is its short-lived effect. Patients need to undergo the treatment weekly to achieve euhidrosis.

Administration, Topical↗

PubMed1988

Iontophoresis of tobramycin for the treatment of experimental Pseudomonas keratitis in the rabbit.

Iontophoresis of tobramycin sulfate was employed to treat bacterial keratitis induced in rabbits by an intrastromal injection of Pseudomonas aeruginosa. Quantitation of bacterial killing was achieved by culturing corneal homogenates and counting viable bacteria per cornea after treatment. When the rabbits received two iontophoretic treatments, iontophoresis significantly reduced the number of bacterial colony-forming units, compared with the use of an eyecup without current or two subconjunctival injections of 20 mg of tobramycin sulfate, and with untreated controls. The results of iontophoresis were not significantly different from those involving treatment with topical fortified drops (40 mg/mL). A single iontophoresis treatment was compared with the use of an eyecup without current or less fortified topical drops (13.6 mg/mL), as well as with untreated controls. Iontophoresis was significantly better than either the eyecup or the topical fortified tobramycin drops in reducing viable bacteria in the corneas. Iontophoresis may be a useful adjunct in the treatment of severe corneal bacterial infections.

Animals↗

PubMed1989

Transscleral iontophoresis of dexamethasone.

Transscleral iontophoresis has been suggested to be a potentially useful noninvasive technique in intravitreal introduction of ionizable drugs, such as cefazolin sodium, ticarcillin disodium, and gentamicin sulfate. To investigate the usefulness of this technique in the administration of corticosteroids, we performed transscleral iontophoresis of dexamethasone sodium phosphate (300 mg/mL, 20 mmol/L edetic acid [EDTA]) into rabbits at a current of 1.6 mA for 25 minutes. Eyes were enucleated at different time intervals and frozen in liquid nitrogen. The frozen vitreous bodies and adherent sensory retina were collected and sonicated, and dexamethasone levels were measured using high-pressure liquid chromatography. In addition, to study the facilitation of drug transport by cryotherapy, a second group of rabbits were given a single application of cryotherapy (-78 degrees C, 45 seconds) 3, 7, and 14 days before iontophoresis in the same region. Without cryotherapy, the initial level of dexamethasone in the vitreous body-sensory retina after iontophoresis was 139.3 +/- 51.5 mg/L (mean +/- SE) (n = 6) with a half-life of less than 2 hours. In the cryotreated group, the levels of dexamethasone immediately after iontophoresis 3, 7, and 14 days after cryotherapy were 61.5 +/- 31.7 (n = 6), 88.4 +/- 55.1 (n = 6), and 112.2 +/- 32.5 (n = 6) mg/L, respectively, indicating that levels were lower compared with the group without cryotherapy. Our results suggest that a high dose of dexamethasone can be delivered by using this noninvasive technique and that cryotherapy before iontophoresis does not increase drug levels in the vitreous body.

Animals↗

PubMed1996

The effect of saline iontophoresis on skin integrity in human volunteers. I. Methodology and reproducibility.

This study, conducted in 36 human volunteers, was an evaluation of the effects of saline iontophoresis on skin temperature, irritation, and barrier function. The major objectives were to assess the effects of low-level ionic currents, to validate the proposed methodology of assessment, and to establish reproducibility in repeated saline iontophoresis applications. This was the first of a multistage study designed to assess the safety of 24-hr saline iontophoresis episodes at selected currents and current densities. Since an iontophoresis patch challenges the skin barrier both by occluding the skin surface and by passing ionic current through the skin, the experimental protocol was designed to permit measurement of the contribution of each of these processes to the overall response. In this first stage we investigated the effect of 10 min of current delivery, at 0.1 mA/cm2 on a 1-cm2 area patch and 0.2 mA/cm2 on a 6.5-cm2 area patch compared to unpowered control patches. Twelve subjects were tested under each condition on two separate occasions to examine reproducibility of the response variable measurements. A further 12 subjects were tested once under the 0.2 mA/cm2, 6.5-cm2 condition. Skin irritation was evaluated via repeated measurements of transepidermal water loss, capacitance, skin temperature, skin color, and a visual scoring system, before the iontophoresis episode and after patch removal. No damage to skin barrier function in terms of skin-water loss or skin-water content was detected. Slight, subclinical, short-lasting erythema was observed for both conditions. Assessment of correlation coefficients showed highly statistically significant indications of reproducibility for all five response variables measured. The experimental design, in combination with a repeated measures analysis, provided clear separation of the occlusion and ionic current components of the iontophoretic patch challenge. Further, the repeated measures analysis gave a highly sensitive assessment of skin irritation and resolution after patch removal. We conclude that the experimental methodology is appropriate for assessing possible changes in skin integrity resulting from saline iontophoresis under similar operating conditions for longer durations and for other skin challenges from which a subclinical response is expected.

Body Temperature↗

PubMed1998

Cutaneous vasodilation induced by local warming, sodium nitroprusside, and bretylium iontophoresis on the hand.

Local warming alone induces a cutaneous vasodilation considered as maximal. The argument that local warming generates a maximum flow is being tested by vasodilation with alternate approaches to see if a greater vasodilation is possible: blockade of the release of transmitters from the adrenergic nerve endings with bretylium tosylate or direct pharmacological action on vascular smooth muscle using sodium nitroprusside. Nine healthy subjects participated in two experiments in which SkBF was measured simultaneously by laser Doppler flowmetry on the dorsal aspects of both hands. In the first protocol the vasodilator effects of 20 min of local warming at 44 degreesC were measured on one hand and the effects of iontophoresis of sodium nitroprusside on the other. The second protocol was like the first except that iontophoresis of bretylium tosylate instead of sodium nitroprusside was performed. Local warming induced an increase of SkBF from 17.6 +/- 4.4 to 140.2 +/- 33.2 AU (P < 0.01) while it rose from 16.7 +/- 4.0 to 114.7 +/- 11.0 AU (P < 0.001) during sodium nitroprusside iontophoresis. During the second protocol local warming induced an increase of SkBF from 14.9 +/- 2.1 to 117.7 +/- 25.4 AU (P < 0.01) while it rose from 19.6 +/- 2.6 to 120.5 +/- 11.3 AU (P < 0.001) during bretylium iontophoresis. However, in both experiments, the increase of SkBF attained during iontophoresis did not differ significantly from the increase achieved by local warming. We conclude that the effects of iontophoresis of sodium nitroprusside or of bretylium produce a cutaneous vasodilation as high as a local warming on the dorsal aspect of the hand.

Adult↗

PubMed1999

Nonspecific microvascular vasodilation during iontophoresis is attenuated by application of hyperosmolar saline.

Iontophoretic administration of acetylcholine chloride (ACh) and sodium nitroprusside (SNP) combined with laser Doppler skin blood perfusion measurements are used for determination of endothelial-dependent and -independent vasodilation. However, the method is biased by nonspecific vasodilation. The primary aim of this study was to investigate if iontophoresis-induced nonspecific vasodilation may be attenuated by addition of high molar concentrations of NaCl to the iontophoresis solutions. Secondary we investigated the applicability of 5 mol/liter NaCl solution as vehicle for ACh and SNP in this method. Skin perfusion changes were determined for iontophoresis of pure vehicles, deionized water and 5 mol/liter NaCl solution, in 12 healthy volunteers. Responses in skin perfusion to iontophoresis of ACh and SNP dissolved in both vehicles were also investigated. Addition of 5 mol/liter NaCl to deionized water significantly attenuated the nonspecific vasodilation and lowered the potential applied over the skin. The inter- and intraindividual coefficients of variation to ACh and SNP responses became, however, higher using hyperosmolar vehicle. During iontophoresis of SNP (in deionized water) we were unable to distinguish between SNP and vehicle effects. This study shows that the nonspecific vasodilation induced by iontophoresis can be attenuated by addition of 5 mol/liter NaCl, possibly due to lower electrical potential over the skin. However, the variability of the method was not improved. When deionized water was used as vehicle the effect of SNP could not be differentiated from that of the vehicle. This was not the case for ACh.

Acetylcholine↗

PubMed2004

Transdermal iontophoresis of insulin: IV. Influence of chemical enhancers.

Transdermal iontophoresis per se may not be able to achieve significant permeation of large peptides like insulin, thereby necessitating the use of combination strategies involving chemical enhancers and iontophoresis. The study investigated effect of pre-treatment with commonly used vehicles such as ethanol (EtOH), propylene glycol (PG), water and their binary combinations, dimethyl acetamide (DMA), 10% dimethyl acetamide in water, ethyl acetate (EtAc) and isopropyl myristate (IPM) on insulin iontophoresis. Solvents, which acted on the lipid bilayer, were able to produce a synergistic enhancement with iontophoresis. The binary solvent systems produced either additive or no effect, when combined with iontophoresis. FT-IR studies showed that EtOH, DMA, EtAc caused lipid extraction and the former two also caused changes in skin proteins, whereas IPM caused increase in lipid fluidity. TGA studies showed that EtOH and PG caused dehydration of skin. Skin barrier property was severely compromised with DMA, followed by EtOH and EtAc, while IPM and PG had relatively minimum skin barrier altering potential. Thus, this study demonstrates the possibility of achieving higher permeation of large peptides like insulin by combining iontophoresis with chemical enhancers that act on the intercellular lipids.

Adjuvants, Pharmaceutic↗

PubMed2004

A protocol for iontophoresis of acetylcholine and sodium nitroprusside that minimises nonspecific vasodilatory effects.

Iontophoresis of vasoactive substances is a promising tool for studying pharmacological aspects of the (patho)physiology of the microvasculature. However, nonspecific microvascular responses are a common problem in most protocols used. We studied the effect of current density (mA/cm2), charge density (mC/cm2), drug concentration (mass %) and vehicle concentration (M) on the nonspecific vasodilatation during iontophoresis of sodium chloride, acetylcholine (ACh) and sodium nitroprusside (SNP). We found that nonspecific vasodilatation depended on current density and charge density in both anodal and cathodal iontophoresis. The responses to ACh and SNP were dependent on current density, charge density and drug concentration. We found that by limiting current density (<0.01 mA/cm2) and charge density (<7.8 mC/cm2) and with adjusted concentrations for drugs and vehicles, it is possible to prevent nonspecific effects during iontophoresis of ACh and SNP, while maximum drug effects (plateaus in the dose-response curves) are still obtained. These new findings are important for future iontophoresis studies in which vasoactive drugs are used to assess microvascular function because the presented approach has advantages compared to older techniques, which mainly have attempted to suppress or compensate for the nonspecific responses during iontophoresis by the use of local anaesthetics or the measurement of drug-minus-vehicle responses, both of which present well-known experimental shortcomings.

Acetylcholine↗

PubMed2005

Possible therapeutic use of vasodilator iontophoresis.

BACKGROUND: Investigation into the effects of a novel vasodilator delivery method (for the eventual treatment of scleroderma related digital ulceration) on healthy controls is reported. When Raynaud's phenomenon (episodic cold-induced colour changes of the fingers) occurs in the context of scleroderma, it can be extremely severe, leading to ulceration and sometimes gangrene. The current treatment of choice for scleroderma-related critical digital ischaemia and/or ulceration is intravenous prostanoid therapy, necessitating hospitalisation. However, iloprost is often poorly tolerated and may be ineffective. METHODS: This study utilises a newly designed iontophoresis chamber which has the potential to allow a therapeutic, rather than diagnostic application for vasodilatory iontophoresis. Ten healthy controls underwent whole finger iontophoresis with 1% acetylcholine chloride for 2 min at 100 microA. Iontophoresis with varying treatment times and currents was carried out on a subset of subjects to determine the effect on perfusion increase. RESULTS: A significant increase in perfusion following iontophoresis was found, compared to the adjacent, untreated finger (P < 0.001). Maximum increase as a percentage from baseline, mean [SD] = 100 [66]%. Both treatment time and current have an approximately linear relationship with perfusion increase. CONCLUSIONS: Iontophoresis of the whole finger administers drugs locally with no systemic effects and warrants further investigation as a therapy.

Acetylcholine↗

PubMed1993

Transscleral iontophoresis of foscarnet.

Current local treatments of cytomegalovirus retinopathy may result in serious intraocular complications. Using an animal model, we investigated transscleral iontophoresis as a technique for delivery of foscarnet to the vitreous. Using a probe tip surface area of 0.19 mm2, a current of 1 mA, and a duration of ten minutes, transscleral iontophoresis of 0.5 ml of a 24-mg/ml foscarnet solution was administered to 72 normal rabbits. Vitreous aspiration was performed at 12 intervals (15 minutes, 30 minutes, and one, two, four, eight, 16, 24, 32, 40, 48, and 60 hours) after iontophoresis, and samples were analyzed by high-performance liquid chromatography to determine the vitreous pharmacokinetics of foscarnet. A peak foscarnet concentration of 200 +/- 31 microM (mean +/- standard deviation) was attained four hours after iontophoresis and was well below the concentration reported to cause retinal toxicity. Therapeutic levels were maintained until 60 hours after iontophoresis. The elimination half-life was approximately 24 hours. No toxic effects to anterior chamber structures were observed by biomicroscopy. Transscleral iontophoresis of foscarnet may provide an effective and safe technique for local treatment of cytomegalovirus retinopathy in patients with acquired immunodeficiency syndrome.

Animals↗

PubMed1989

Transscleral and transcorneal iontophoresis of ketoconazole in the rabbit eye.

The authors assessed the efficacy of transscleral and transcorneal iontophoresis of ketoconazole as a method of drug delivery to the aqueous humor, vitreous, and cornea of the rabbit eye. Transscleral iontophoresis (4-6 mAmps for 15 minutes) achieved peak ketoconazole concentrations in the aqueous 1 hour after treatment (10.2 micrograms/ml) and remained at fungicidal therapeutic concentrations for 8 hours; in the vitreous, a peak concentration of 0.1 microgram/ml occurred between 1 and 2 hours posttreatment. Transcorneal iontophoresis (1.5 mAmps for 15 minutes) achieved peak corneal concentration of 27.6 micrograms/ml and peak aqueous concentrations of 1.4 micrograms/ml, both 1 hour after iontophoresis. Fungicidal therapeutic drug concentrations were sustained for 2 hours both in the cornea and in the aqueous. These concentrations were compared with those obtained after subconjunctival injection (peak values): 0.8 microgram/ml in aqueous, 5.9 micrograms/ml in cornea, and 0.7 microgram/ml in vitreous, all within 1 hour of injection. Aqueous and corneal concentrations were significantly higher after transscleral and transcorneal iontophoresis than subconjunctival injection (P less than 0.05). Iontophoresis is proposed as an effective means of delivering high concentrations of ketoconazole to the anterior segment of the eye.

Animals↗

PubMed2003

Transdermal delivery of insulin from poloxamer gel: ex vivo and in vivo skin permeation studies in rat using iontophoresis and chemical enhancers.

Gels are considered to be the most suitable delivery vehicle for iontophoresis, as they can be easily amalgamated with the iontophoretic delivery system and can also match the contours of the skin. Insulin was used as a model peptide for large peptides in the molecular weight range of 3-7 kDa. A gel formulation of insulin was formulated using poloxamer 407 and was evaluated by ex vivo and in vivo skin permeation studies in rat with chemical enhancer and/or iontophoresis. The poloxamer gel was physically and chemically stable during the storage period. In ex vivo studies, both linoleic acid and menthone in combination with iontophoresis showed a synergistic enhancement of insulin permeation. The plasma insulin concentration (PIC) was highest with linoleic acid pre-treatment, in agreement with ex vivo permeation studies, but the reduction in plasma glucose levels (PGL) was comparable to iontophoresis. Menthone pre-treatment resulted in rapid attainment of peak PIC, but the reduction in PGL was less than other treatment groups. There was no direct relation between PIC and PGL and is attributed to the fact that the action of insulin in mediated by a cascade of cellular mechanisms, before a reduction in PGL is observed. However, iontophoresis either alone or in combination with linoleic acid produced a reduction in PGL to the extent of 36-40%. A combination of chemical enhancers and iontophoresis caused greater skin irritation than when either of them was used alone.

Administration, Cutaneous↗

PubMed1998

Development and evaluation on transdermal delivery of enoxacin via chemical enhancers and physical iontophoresis.

Iontophoresis and enhancers were performed to enhance percutaneous absorption of enoxacin so as to compare the enhancement between these two enhancing methods. The cationic surfactant of benzalkonium chloride showed the highest enhancing activity for enoxacin for all pH values of buffer vehicles. The enhancement factor of sodium laurylsulfate showed a dose-dependent property between the range of 0.1% to 3.0% concentration. Nonionic surfactant of Polysorbate 80 did not exhibit any enhancing effect on the percutaneous absorption of enoxacin. The highest enhancement factor of iontophoretic delivery was observed at pH 5.0 solution of anodal iontophoresis for cationic enoxacin. The cathodal iontophoresis of negative molecules and anodal iontophoresis of neutral molecules showed lower enhancing effect for enoxacin. The fact that the skin residuals of enoxacin after iontophoresis showed both tremendous and current density-dependent amounts for cationic enoxacin suggested local skin and soft tissue infections might be treated by this physical enhancement method. Combination of benzalkonium chloride and iontophoresis exerted a synergistic effect for anionic enoxacin in pH 10.0, which was possibly due to the shielding of negative charge in skin and the water molecules carried by chloride.

Administration, Cutaneous↗

PubMed2001

Regional variations in skin barrier function and cutaneous irritation due to iontophoresis in human subjects.

The effect of saline iontophoresis on skin barrier function and irritation was investigated on three body sites (abdomen, chest and upper arm) in order to select an appropriate site for iontophoretic delivery of drugs. Thirty healthy human volunteers were recruited according to specific entry criteria. Ten subjects, five males and five females, were assigned to each body site group. Skin barrier function and irritation was examined after 4 h of saline iontophoresis at a current density of 0.2 mA/cm(2) on a 6.5 cm(2) area in terms of the measured responses: transepidermal water loss (TEWL), skin capacitance, skin temperature and visual scores. Alterations in TEWL due to iontophoresis were not observed in the upper arm and chest; however, changes in TEWL at the abdomen were observed and returned to baseline 2 h after patch removal. Similarly, changes in capacitance due to iontophoresis returned to baseline (P>0.05) at the three body sites 2 h after patch removal except under the anode at the abdomen (P<0.05). There was a significant increase in skin temperature due to iontophoresis at the anode and the cathode (P<0.05) at the upper arm. Edema was not observed. At patch removal, the erythema score was significantly (P<0.001) elevated in comparison to baseline at the three body sites. Erythema resolved within 24 h except at the chest under the anode, where the erythema score was still higher (P<0.01) than the baseline. Papules appeared in five subjects at the active anode site on the chest. In three of the subjects, these papules did not resolve until 24 h post patch removal. Thus, there was regional variation in the function of the skin and irritation due to iontophoresis. Irritation was greater at the chest than at the abdomen or upper arm.

Abdomen↗

PubMed2000

Transdermal iontophoresis revisited.

Iontophoresis evolved as a transdermal enhancement technique in the 20th century, primarily for the delivery of large and charged molecules. Significant achievements have been made in the understanding of underlying mechanisms of iontophoresis and these have contributed to the rational development of iontophoretic delivery systems. The major challenges in this area are the development of portable, cost effective devices and suitable semi-solid formulations that are compatible with the device and the skin. Some of the obstacles in transdermal iontophoresis can be overcome by combining iontophoresis with other physical and chemical enhancement techniques for the delivery of macromolecules. Iontophoresis also offers an avenue for extracting information from the body through the use of reverse iontophoresis, which has potential application in diagnosis and monitoring. The current research is focussed towards resolving the skin toxicity issues and other problems in order to make this technology a commercial reality.

Administration, Cutaneous↗

PubMed2001

X-ray microanalysis of cryopreserved human skin to study the effect of iontophoresis on percutaneous ion transport.

PURPOSE: To study at the ultrastructural level which part of the skin is associated with percutaneous iodide transport by passive diffusion and iontophoresis. METHODS: Following passive diffusion or iontophoresis of iodide, the morphology and the ion distribution of the skin was preserved by rapid freezing. The skin was kept frozen until and during examination by transmission electron microscopy (TEM) and X-ray microanalysis (XRMA). The intrinsic electron absorbing characteristics of cryopreserved skin allow direct TEM examination without additional staining. XRMA can be used to obtain in a relatively nondestructive way in situ information on ion distributions across the skin. RESULTS: After passive diffusion, iodide was mainly found in the stratum corneum (SC), whereas there was little iodide in the viable epidermis. Iontophoresis up to 300 microA/cm2 did not significantly affect this distribution. With iontophoresis at 1,000 microA/cm2, the amount of iodide increased dramatically and was equally distributed over the SC and viable epidermis. The presence of iodide in the SC suggests that iodide is present inside corneocytes. CONCLUSIONS: Iontophoresis up to 300 microA/cm2 does not significantly perturb skin structures in contrast to iontophoresis at 1,000 microA/cm2. The presence of iodide inside corneocytes suggests the possibility of transcellular percutaneous iodide transport.

Administration, Cutaneous↗