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Examination of iontophoretic transport of ionic drugs across skin: Baseline studies with the four-electrode system
Abstract
Recognition of the voltage drop across a membrane as the driving force for the flux of ions through it opens up new approaches to model iontophoretic transport of ionic drugs across skin. A theoretical equation relating the flux enhancement (relative to the passive diffusion flux) to the applied voltage drop across a membrane is given. A 4-electrode potentiostat system, ideally suited for maintaining a constant voltage drop across a membrane in a two-chamber diffusion cell is described. It is shown that the predictions of the flux enhancement equation are in reasonable agreement with the experimental results obtained with the four electrode potentiostat system for an artificial membrane and for hairless mouse skin.
... The low permeability of drug molecules through stratum corneum is the limiting factor for developing transdermal delivery system of therapeutic agents. To enhance the permeability of drug molecules, many studies have been reported [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Occlusive dressing technique (ODT), which hydrates stratum corneum is the simplest method [4]. ...
... As chemical modifications, penetration enhancers [5], there are sulphoxides that makes dimethylsulphoxide (DMSO) or Azone [6,7], pyrrolidones that makes N-mechyl-2-pyrrolidone (NMP) [8], fatty acids that makes oleic acid [7,9], alcholos, fatty alcholos and glycols that makes ethanol or propylene glycol, terpenes and terpenoids that makes menthol, limonene or 1,8-cineole as representatives [8,10,11], etc. As physical modifications, iontophoresis (IP) which promotes skin permeability by using electropotential energy [12][13][14], electroporation (EP) by producing small pore on the surface of stratum corneum by adding pulse voltage [15], sonophoresis (SP) by using the effect of cavitation of ultrasonic wave [16] and microneedle by producing new peameation route [17] have been studied. Also prodrugs have been developed. ...
Nanoparticles effectively deliver therapeutic agent by penetrating into the skin. Indomethacin (IM) and coumarin-6 were loaded in PLGA nanoparticles with an average diameter of 100 nm. IM and coumarin-6 were chosen as a model drug and as a fluorescent marker, respectively. The surfaces of the nanoparticles were negatively charged. Permeability of IM-loaded PLGA nanoparticles through rat skin was studied. Higher amount of IM was delivered through skin when IM was loaded in nanoparticles than IM was free molecules. Also, iontophoresis was applied to enhance the permeability of nanoparticles. When iontophoresis with 3 V/cm was applied, permeability of IM was much higher than that obtained by simple diffusion of nanoparticles through skin. The combination of charged nanoparticle system with iontophoresis is useful for effective transdermal delivery of therapeutic agents.
... Abramson and Gorin (40) derived an equation to correlate the iontophoretic dosage with various components contributed by electrical mobility, electro-osmosis and simple diffusion. Masada et al. (41) also developed equations to define the enhancement of the in-vitro skin permeation flux of small molecules by iontophoresis, using a fourcompartment diffusion cell electrode system: ...
... Three factors seem to be of prime importance in determining the flux of an ionic drug by iontophoresis, the electrochemical potential gradient across the skin, an increase in skin permeability due to iontophoresis, and a current-induced water transport effect (41). ...
There has been much interest recently in the delivery of proteins and peptides following the research and development of biotechnology: derived drugs and other bioactive substances. This article summarizes the use of iontophoresis to deliver proteins and peptides across the skin. This technique offers considerable promise for delivering drugs in therapeutic amounts by bypassing the gastrointestinal tract (GIT) and liver metabolism. This article discusses the theory underlying iontophoretic drug delivery and the devices available. The future development of these systems would require the use of specialized approaches to enhance delivery of larger molecules but overall there is considerable optimism.
... A significant portion of the drugs indicated that there was not quite enough skin porousness in uninvolved assessments. The transdermal pervasion of medication particles is influenced to a large extent by the outflow characteristics of medication from utilization and the construction of the medication conveyance framework [51][52][53] . Natural solvents and dynamic surface experts can also promote percutaneous retention by changing the penetrability of skin. ...
: The skin is the human body's biggest organ, with a surface region of
around 2 m2
. Generally, the skin was seen as an impermeable boundary. Yet, as of
late, it has been progressively perceived that unblemished skin can be utilized as a
port for the topical or ceaseless foundational organization of medications. For drugs
that have short half-lives, a transdermal course gives a consistent method of
organization, to some degree like that given by intravenous implantation. In contrast
to intravenous implantation, the passage is non-intrusive, requiring no
hospitalization. A method of reasoning to investigate this course exists just for
medications exposed to a broad first pass digestion when given orally or those that
must be taken a few times each day. That being said, just powerful medications can
be directed through this course since there are monetary and restorative motivations
not to surpass the fixed estimate past a specific farthest point. Sedate transportation
has recently been confronted with two significant challenges. The first is achieving
zero request arrival of pharmaceuticals for extended periods. The second is pulsatile
or triggered medication discharge, which is the regulated arrival of medications in
response to a boost. Polymer-based controlled drug transportation frameworks are
becoming increasingly popular due to their ability to maintain pharmaceutical
concentration.
... Iontophoresis is a localized, noninvasive rapid process in which absorption of watersoluble charged particles is facilitated across tissue barriers with the aid of physiologically acceptable levels of voltage drop/electric field through electrostatic effects [25][26][27]. The electrical potential, along with the concentration gradient, provides the necessary driving force for the transfer of drug molecules across the tissue layers [28]. ...
Drug delivery to the eye still is a challenge due to its intricate anatomical structure. Posterior segment delivery is much more challenging due to the acellular nature of the vitreous humor and the longer diffusion distance to the retina. Iontophoresis is a noninvasive technique that facilitates the movement of charged drug molecules into tissues by an electric field. Using iontophoresis, it is possible to achieve therapeutic concentrations faster by modulating the intensity and duration of the applied current. Transscleral iontophoretic delivery is gaining pace and is considered as an alternative for a safe and more effective treatment to retinal disorders. This chapter intends to highlight various aspects of iontophoresis, with a special emphasis on transscleral delivery of drugs and drug-loaded nanocarrier systems for treating disorders in the back of the eye. Finally, a section on toxic effects of iontophoresis to various ocular tissues is included.
... Nonequilibrium thermodynamic models of transdermal iontophoresis are fascinating because upon application of current model, skin will not be under equilibrium conditions. Hence, only a limited number of attempts have been made to apply the infrastructure to transdermal iontophoresis [54][55][56]. The application of nonequilibrium thermodynamics for modeling biological membrane transport was spearheaded by Kedem and Katchalsky [57][58][59]. ...
In vivo skin permeation studies are considered gold standard but are difficult to perform and evaluate due to ethical issues and complexity of process involved. In recent past, a useful tool has been developed by combining the computational modeling and experimental data for expounding biological complexity. Modeling of percutaneous permeation studies provides an ethical and viable alternative to laboratory experimentation. Scientists are exploring complex models in magnificent details with advancement in computational power and technology. Mathematical models of skin permeability are highly relevant with respect to transdermal drug delivery, assessment of dermal exposure to industrial and environmental hazards as well as in developing fundamental understanding of biotransport processes. Present review focuses on various mathematical models developed till now for the transdermal drug delivery along with their applications.
... Many techniques were evaluated to enhance the permeability of drug molecules. For instance, occlusive dressing technique (ODT) [4], chemical modifications such as penetration enhancers [5][6][7][8][9][10][11], physical modifications such as iontophoresis (IP) [12][13][14], electroporation [15], sonophoresis [16], and microneedle [17] have been studied. The combination of physical and chemical enhancement techniques has been studied [18,19]. ...
Indomethacin-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles with an average diameter of 100 nm were prepared by using a combination of an antisolvent diffusion method with preferential solvation (bare nanoparticles). Polyvinyl alcohol (PVA)-coated indomethacin-loaded PLGA nanoparticles with an average diameter of 100 nm were also prepared by emulsification and the solvent evaporation method (PVA-coated nanoparticles). Bare nanoparticles do not have a hydrophilic stabilizer on the surface; therefore, they have high hydrophobicity and negative charges. Electrophoretic mobility of bare nanoparticles at 5 mM NaCl solution was about 68 times higher than that of PVA-coated nanoparticles. Permeability of bare nanoparticles through rat skin was significantly higher than that of PVA-coated nanoparticles when iontophoresis was applied ex vivo. Indomethacin amount inside the skin after the permeation study by using bare nanoparticles was much higher than that by using PVA-coated nanoparticles. Indomethacin transition to circulation and accumulation in muscle by the transdermal delivery of indomethacin-loaded PLGA nanoparticles were significantly enhanced by using the combination of bare nanoparticles and iontophoresis in vivo. As for transdermal route of nanoparticles, both bare and PVA-coated nanoparticles were revealed to penetrate through the transfollicular pathway, and the migration of nanoparticles to follicles was enhanced by the application of iontophoresis. PLGA nanoparticles prepared by the antisolvent diffusion with preferential solvation are beneficial for iontophoretic transdermal delivery of therapeutic agents.
... 0378-5173/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved PH S0378-5173(96)0461 6-9 Iontophoresis is a technique by which charged bioactive molecules are transferred from an electrolytic solution into and through a tissue by means of a direct electric current (Masada et al., 1989; Banga and Chien, 1988; Bellantone et al., 1986 ). Though this technique has been used during several decades for specific delivery purposes there is still considerable lack of basic knowledge of this phenomenon (Glikfeld et al., 1988; Miller and Smith, 1989 ). ...
The electrical conductance of lidocaine hydrochloride (LidH+Cl-) in aqueous solution at 25.00°C has been established by precision conductometry over a concentration interval from 0.3 to 6.6 mM. Assuming any ion pairing between the LidH+ and Cl- ions to be negligible, a conductance equation has been derived in which the equilibrium between LidH +, Lid and H + is considered. This equation involves the dissociation constant of LidH+, Ka, and the limiting molar conductivity of LidH-, ⋌o(LidH +), as adjustable parameters. The mobility correction factor used to correct the mobility of the ions for ion atmosphere effects is in accord with the conductance function of Fuoss, Hsia, and Fernandez-Prini (FHFP equation). A computer program was developed to find the values of Ka and ⋌o(LidH +) resulting in the best fit of the conductance equation to the experimental points (minimum standard deviation between experimental and computed A-values). With the distance parameter set equal to the Bjerrum radius, q = 0.357 nm, we obtained pKa(LidH+) = 7.16(molarity scale), λ0(LidH+) = 17.87 cm2Ω−1 mol−1. Our pKa- value is 0.7 units lower than the previously reported potentiometrically determined value, 7.85.
... Enhancement factor was calculated as E = J i / J p , where, J i is the flux of the drug during iontophoresis, and J p is the flux of drug during passive diffusion , Masada et al., 1989. Fraction change in flux is determined by deducting the passive flux from iontophoretic flux and then divided by iontophoretic flux i.e., J i -J p / J i . ...
The effect of different concentrations of drug and permeation enhancer (Dimethylsulfoxide) on iontophoretic transport of salbutamol sulphate was investigated in vitro. The iontophoretic transport was measured at constant (optimum) current density and pH as a function of varied concentration of drug, and at a fixed drug concentration as a function of permeation enhancer to know (i) how does drug concentration affect the efficiency of delivery? (ii) to what extent permeation enhancer affects the percutaneous delivery of drugs? (iii) what would be the combined effect of iontophoresis and permeation enhancer on permeation of drugs? Results showed that the use of different concentrations of drug in donor half cell (4, 8 and 16 mg/ml) increases the steady state flux both in passive diffusion (at pH 10.3) and iontophoresis (anodal at pH 7.4 and cathodal at pH 11) using 0.3 mA/cm 2 current density. With the use of different concentrations of permeation enhancer (5, 10, 15 % w/v) in passive diffusion significantly increased (p < 0.05, t-test) the transport of drug and enhancement was 4, 6 and 7.6 folds respectively compared to the control. The maximum steady state flux was obtained with the use of 15 % w/v DMSO. Iontophoresis in conjugation with permeation enhancer had a significant synergistic effect in terms of transport of drug across skin.
... The low permeability of drug molecules through stratum corneum is the limiting factor for developing transdermal delivery system of therapeutic agents. To enhance the permeability of drug molecules through stratum corneum, many studies have been reported [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. The permeability of drugs through skin is improved by enhancers, but enhancers induce irritation, cause damage, and reduce the skin barrier function. ...
Estradiol is a therapeutic agent for treatment of perimenopausal symptoms and osteoporosis. Conventional oral or intravenous administration of estradiol has many problems, such as, metabolization in gastrointestinal tract and liver, pain by using an injection needle, rapid increase of drug levels in blood and fast clearance with unwanted side effects including thrombosis, endometriosis and uterus carcinoma. The use of nanocarriers for transdermal delivery has been studied because of their ability to deliver therapeutic agents for long time with a controlled ratio, escaping from the first pass effect by liver. In this study, permeability of estradiol-loaded PLGA nanoparticles through rat skin was studied. Higher amount of estradiol was delivered through skin when estradiol was loaded in nanoparticles than estradiol was free molecules. Also, iontophoresis was applied to enhance the permeability of nanoparticles. When iontophoresis was applied, permeability of estradiol-loaded PLGA nanoparticles was much higher than that obtained by simple diffusion of them through skin, since they have negative surface charges. They were found to penetrate through follicles mainly. Also, enhanced permeability effect of estradiol by using nanoparticle system and iontophoresis were observed in vivo. The combination of charged nanoparticle system with iontophoresis is useful for effective transdermal delivery of therapeutic agents.
... Electrorepulsion is the direct effect of the applied electric field on a charged permeant. The second mechanism, electroosmosis, results from the fact that the skin supports a net negative charge at physiological pH [42,43]. ...
The delivery of drugs into systemic circulation via skin has generated much attention during the last decade. Transdermal therapeutic systems propound controlled release of active ingredients through the skin and into the systemic circulation in a predictive manner. Drugs administered through these systems escape first-pass metabolism and maintain a steady state scenario similar to a continuous intravenous infusion for up to several days. However, the excellent impervious nature of the skin offers the greatest challenge for successful delivery of drug molecules by utilizing the concepts of iontophoresis. The present review deals with the principles and the recent innovations in the field of iontophoretic drug delivery system together with factors affecting the system. This delivery system utilizes electric current as a driving force for permeation of ionic and non-ionic medications. The rationale behind using this technique is to reversibly alter the barrier properties of skin, which could possibly improve the penetration of drugs such as proteins, peptides and other macromolecules to increase the systemic delivery of high molecular weight compounds with controlled input kinetics and minimum inter-subject variability. Although iontophoresis seems to be an ideal candidate to overcome the limitations associated with the delivery of ionic drugs, further extrapolation of this technique is imperative for translational utility and mass human application.
In this study, we aimed to verify the influence of the particle diameter of elastic liposomes for transdermal delivery on immune responsiveness by evaluating the amount of antibody. Albumin from chicken egg white (OVA) solution and elastic liposomes with mean volume diameter of 40 nm and 130 nm were percutaneously administrated to mice. We prepared 40-nm elastic liposomes using mechanochemical process and 130-nm elastic liposomes using extrusion process. Subcutaneous injection of OVA was also as a positive control. Forty-nanometer elastic liposomes significantly promoted antibody production compared with the OVA solution and 130-nm elastic liposomes. Furthermore, this result was nearly equivalent to that of the subcutaneous injection of OVA solution. Besides, skin permeability study shows that coumarin-6 used as a fluorescent label encapsulated in 40-nm elastic liposomes were 2.2 times more permeated than 130-nm elastic liposomes in the skin. From the observation of confocal laser microscopy images, 40-nm elastic liposomes accumulated more in the stratum corneum and deeper follicle compared to 130-nm elastic liposomes. It has been reported that particles with a diameter of 40 nm are more captured by antigen presenting cells. Thus, we considered that the 40-nm elastic liposomes are useful for percutaneous immunization.
Postmenopausal osteoporosis among older women, which occurs by ovarian hormone deficiency, is one of the major public health problems. 17 β-estradiol (E2) is used to prevent and treat this disease as a drug of hormone replacement therapy. In oral administration, E2 is significantly affected by first-pass hepatic metabolism, and high dose administration must be needed to obtain drug efficacy. Therefore, alternative administration route is needed, and we have focused on the transdermal drug delivery system. In this study, we have prepared E2-loaded poly(DL-lactide-co-glycolide) (PLGA) nanoparticles for osteoporosis by using a combination of an antisolvent diffusion method with preferential solvation. The average particle diameter of the nanoparticles was 110.0 ± 41.0 nm and the surface charge number density was 82 times higher than that of conventional E2-loaded PLGA nanoparticles. Therapeutic evaluation of E2-loaded PLGA nanoparticles was carried out using ovariectomized female rats. Therapeutic efficacy was evaluated to measure bone mineral density of cancellous bone using an X-ray CT system. When the E2-loaded PLGA nanoparticles were administrated once a week, bone mineral density was significantly higher than that of non-treated group at 60 days after start of treatment. Also, in the group administered this nanoparticles twice a week, the bone mineral density increased significantly at 45 days after start of treatment. From these results, it was revealed that E2-loaded PLGA nanoparticles with iontophoresis were useful to recover bone mineral density of cancellous bone, and it was also suggested that they extend the dosing interval of E2.
Background:
Estradiol is one of the therapeutic agents for osteoporosis. We have reported transdermal permeability of estradiol-loaded nanoparticles, and permeability effect of estradiol was enhanced by using nanoparticle system and iontophoresis [Colloids and Surfaces B: Biointerfaces97 (2012), 84-89].
Objective:
This study was conducted in vivo to evaluate therapeutic efficacy of the estradiol-loaded PLGA nanoparticles for osteoporosis.
Methods:
Prior to the in vivo study, we have determined the surface charge density of the particles and found they have negatively charged polyelectrolyte layers on the surfaces. Ovariectomized female Sprague-Dawley rats were used as an animal model of osteoporosis. They were separated into three groups by administration route of estradiol-loaded PLGA nanoparticles, passive diffusion group, iontophoresis group and control. After treatment, we have measured bone mineral density of spine using an X-ray computed tomography system.
Results:
Bone mineral density after iontophoresis was significantly higher than that of passive diffusion and control group. By usage of iontophoresis, the nanoparticles were permeated through follicles and migrated into capillary vessel around follicles, and the loaded drug reached effective blood concentration in plasma of rat.
Conclusions:
From this study, we found that the combination with charged nanoparticle system and iontophoresis is useful to osteoporosis treatment.
Hypertension is the most common cardiovascular disease; its prevalence increases with advancing age. Oral route has the drawbacks namely poor bioavailability due to hepatic metabolism (first pass) and the tendency to produce rapid blood level spikes (both high and low), leading to a need for high and/or frequent dosing, which can be both cost prohibitive and inconvenient. Also injectable administration is invasive nature which may painful, requires skill, and may cause infection, therefore injection are not suitable for self or home sitting administration. Propranolol HCl is a nonselective, beta-adrenergic receptor-blocking agent indicated in the management of hypertension Propranolol is highly lipophilic and is almost completely absorbed after oral administration. However, it undergoes high first-pass metabolism by the liver and on average, only about 25% of propranolol reaches the systemic circulation. Gellan gum at concentration 0.6% w/w optimized. This showed a flux value of 32.814 μg/cm2/hour and 3.039 μg/cm2/hr at viscosity of 490.32 ± 6.01 cps. Propranolol HCL permeation through human cadaver skin via iotophoresis and passive application. It was observed that in comparison to passive permeation study, iontophoretic permeation exhibited more flux. Also, various permeation enhancers were combined with the iontophoresis to study the synergistic effect, but no increase in flux was recorded with them. From the results it was concluded that iontophoretic gellan gum based gel of propranolol HCl can be formulated for the management of hypertension.
The goal of delivery system is to get optimal therapeutic management. But, it still remains a challenge in the field of pharmaceuticals for delivery of ionic species and some non ionic. Several transdermal approaches have been used and recently there has been a great attention in using iontophoretic technique for the transdermal drug delivery of medications, both ionic and non ionic. This technique of facilitated movement of ions across a membrane under the influence of an externally applied electric potential difference is one of the most promising physical skin penetrations enhancing method. The payback of using iontophoretic technique includes improved systemic bioavailability ensuing from bypassing the first metabolism. Variables due to oral administration, such as pH, the presence of food or enzymes and transit times can all be eliminated. This article is an overview of the history of iontophoresis, mechanism, principles and factors influencing iontophoresis and its application for various dermatological conditions.
Transdermal iontophoresis is a process which enhances skin permeation of ionized species by an electrical field as driving force. The aim of this present study was to investigate the transdermal iontophoresis of a newly designed capsaicin derivative, sodium nonivamide acetate (SNA). Studies of electrical and physicochemical factors acting on the kinetics of in vitro iontophoresis were performed. Iontophoresis increased the transdermal penetration flux of SNA as compared to the passive diffusion in this study. Several application modes which possessed the same electrical energy had been researched. The iontophoretic flux of SNA increased following the decrease of donor buffer pH values. This trend could be due to the physiological property of skin and electro-osmotic flow presented. Comparing the various application modes, the discontinuous on/off cyclic current mode showed higher penetration capacity than did continuous mode which was due to the intensity of effective current which would not decay for on/off cyclic application of iontophoresis. The result of the present study is particularly helpful in the development of a SNA transdermal iontophoretic delivery system.
When delivered locally to the arterial wall by passive fluid transfer systems such as perforated balloons, water-soluble compounds in aqueous solution are not readily taken up by tissue, show low levels of cellular localization, and are quickly lost by wash-out. One approach to improve delivery is addition of an “active” component to the catheter system to change the nature of the drug-to-tissue interaction. Using an iontophoretic balloon catheter to deliver antisense oligonucleotide (ODN) to pig coronary arteries after balloon angioplasty, we determined the quantity and localization of ODN in the tissue. By radiolabeling, 7.3 ± 2.4 μg ODN was present at 30 min, 1.5 ± 0.6 at 2 h, 0.52 ± 0.35 at 24 h, and 0.26 ± 0.11 at 7 d. By fluorescent labeling, circumferential medial uptake and adventitial delivery at the site of medial injury was observed, with primarily cellular localization. The iontophoretic catheter thus appears to be a useful device for ODN delivery to arterial tissue. Cathet. Cardiovasc. Diagn. 41:354–359, 1997. © 1997 Wiley-Liss, Inc.
The potential of transdermal iontophoresis to facilitate drug delivery was evaluated by studying the transport kinetics of model compounds salicylate (anion), phenylethylamine (cation), mannitol (polar neutral compound of low molecular weight), and inulin (polar neutral compound of high molecular weight) using an excised human skin model. The transport kinetics of solutes were determined across both intact and cellophane-tape-stripped dermatomed skin both in the presence and absence of applied current to probe the mechanisms of iontophoretic delivery. Iontophoresis effectively enhanced delivery of all compounds relative to passive transport. The skin is shown to be both ion selective and size selective. On the basis of results from present work and other studies, the “aqueous pathway” of iontophoretic transport is further reinforced.
A theory of charge, fluid-mass, and solute (including macromolecular) transport through porous media is applied to describe transport phenomena across the external layer of mammalian skin. Linear relationships are derived between transport fluxes and applied fields. These relationships introduce six effective transdermal transport coefficients. Formulas for each of these coefficients are provided. The practical relevance of these parameters is emphasized in the specific context of transdermal drug delivery. By employing typical physiological values for the various geometrical and physicochemical parameters that appear in the formulas for the transdermal transport coefficients, predictions are made for transport rates of charge, fluid mass, and solute species across a uniform-thickness skin sample contained within a diffusion-cell apparatus. These results are used to explore transdermal phenomena involving forced convection, current flow, electroosmosis, iontophoresis, and molecular diffusion (including convective dispersion). Comparisons with existing transdermal drug delivery data are made. On the basis of these comparisons, the theory suggests that transdermal transport in the presence of an electrical field may occur through corneocytes of the stratum corneum. The theory confirms the importance of a shunt route for small ion transport, as well as an intercellular route of transport for passive diffusion of noncharged substances. These latter conclusions, also based on comparisons with experimental data, are consistent with previous statements in the literature. A new form of solute transport enhancement, termed transdermal convective dispersion, is included in the theory, and methods for its measurement are described. Generalizations and future applications of the theory are discussed.
The effect of dermal blood flow on the transdermal iontophoresis of five monovalent cationic solutes has been investigated using an in vivo rat model. The iontophoretic flux of solutes from topical application sites was shown, using anesthetized and sacrificed rats, to be independent of the dermal blood supply. The presence of a viable blood supply significantly affected the extent of penetration of solutes into deeper underlying tissues during iontophoresis. Higher tissue concentrations of solutes were found in the upper tissue layers of sacrificed rats, with no blood supply, compared to those in anesthetized rats. In all animals the highest concentration of solute after 2 h iontophoresis was found in the epidermis. Iontophoretic application of solutes to skin with the epidermis removed resulted in significantly lower fluxes than from sites where the skin was intact. These findings suggest that local blood flow determines systemic and underlying tissue solute absorption but not epidermal penetration fluxes during iontophoretic delivery. Finally, the dependence of iontophoretic transport of a solute on the solute's size in vivo was similar to relationships previously reported for excised human skin studies.
An electrodiffusion cell and measurement system has been developed to study the factors governing the transport of ionized drugs through skin under the influence of an electric field. The system allows the determination of transport rates in vitro under conditions of either constant current or constant voltage across the skin. Both accelerating and retarding voltages may be applied. To test the method, the iontophoretic transport of a negatively charged bone resorption agent, etidronate disodium (ethanehydroxydiphosphonate, EHDP) was measured across excised human skin. An enhancement factor of 50-70 over passive diffusion was obtained using a constant current density of 140 μA-cm−2, and a factor of approximately 100 was obtained with a constant applied voltage of -0.5 V. At the lowest power levels tested (14 μA-cm−2 or -0.25 V) the enhancements were in reasonable agreement with the predictions of a constant field model for electrodiffusion; however, at higher power levels a phenomenological parameter, the drug transference number in the membrane, appeared to be more useful. Neither the constant current nor the constant voltage mode was found to be a completely satisfactory way of controlling drug delivery in this model. A current-voltage regimen in which both parameters are varied may be required in order to achieve consistent results.
The techniques of iontophoresis and electroporation can be used to enhance topical and transdermal drug delivery. Iontophoresis applies a small low voltage (typically 10 V or less) continuous constant current (typically 0.5 mA/cm2 or less) to push a charged drug into skin or other tissue. In contrast, electroporation applies a high voltage (typically, >100 V) pulse for a very short (μs-ms) duration to permeabilize the skin. This electric assistance of drug delivery across skin will expand the scope of transdermal delivery to hydrophilic macromolecules such as the drugs of biotechnology. These two techniques differ in several aspects such as the mode of application and pathways of transport but can be used together for effective drug delivery. Iontophoresis is already used clinically in physical therapy clinics and is close to commercialization for development of a systemic delivery patch with miniaturized circuits and similar in overall size to a passive patch. The use of electroporation for drug delivery is relatively new and is being actively researched.
Overall flux enhancement of ions during iontophoresis is due primarily to the electrochemical potential gradient. However, secondary effects such as convective solvent flow and, in biological membranes, permeability increases due to the applied field, may also contribute to flux enhancement. The modified Nernst-Planck theory includes a solvent flow velocity term and predicts uncharged molecules are enhanced or retarded depending on the polarity of the applied field. In this study, mannitol was employed as a probe permeant and the mannitol flux was used as a measure of the solvent flow contribution during iontophoresis across human epidermal membrane. Membrane alterations due to the applied field were also assessed, as was the extent of reversibility of the membrane changes. Mannitol transport was enhanced in the anode to cathode polarity and retarded in the cathode to anode polarity. This was interpreted to mean that significant solvent flow across human skin occurred during iontophoresis. Solvent flow velocity was found to be proportional to the magnitude of the applied field and independent of the system polarity. Membrane alterations occurred at the highest voltage investigated in this study (i.e., 1000 mV). These changes appeared to reverse over time as indicated by the current and transport data.
An uncharged solute is not directly affected by the electrochemical potential gradient (the primary driving force), but its flux during iontophoresis can be influenced by secondary factors such as convective water flow and increase in skin permeability. These secondary effects are not dependent on whether the permeant is charged or neutral and are likely to affect all permeants. Using a neutral, polar solute (glucose) as the permeant, the relative contributions of the skin permeability increase and water flow effects to the iontophoretic flux of a non-electrolyte across hairless mouse skin were assessed using the four-electrode potentiostat system coupled to a diffusion cell. It is shown that the convective water flow at pH 7.4 is in the direction of the current and can assist or impede the iontophoretic flux depending on whether the current is in the same direction as the flux or in the opposite direction. All applied voltage drops across the skin cause an increase in permeability which appears to occur rapidly. At low applied voltage drops (⩽ 0.125 V) across the skin, the water flow contribution to the flux appears to be quite small. As the applied voltage drop across the skin is increased, the water flow contribution becomes increasingly important and at 0.5 V, it becomes greater than the skin permeability increase effect.
Iontophoresis offers the potential for controlled delivery of potent solutes through the skin for local and systemic effects. Such transport is dependent on the nature and magnitude of the electric field applied and on the nature of the solute. In this review, emphasis is placed on the importance of solute structure in transdermal delivery using iontophoretic systems. It is suggested that a ‘free volume’ model describes much of the available data and that the average free volume corresponds to a solute with an M of 135 or a radius of about 0.3 nm. Solutes of a size smaller than this volume normally show a moderate iontophoretic flux, whereas solutes with a size which is an order of magnitude larger have very low or negligible fluxes. The rate of iontophoretic delivery for a given solute is shown to be a function of not only the size, charge and polarity of a solute but also its behaviour in the transdermal system being applied. Determinants of solute transport include the nature of the vehicle used, the iontophoretic conditions applied and the nature of the skin barrier.
Transdermal drug delivery has attracted considerable attention in recent years and the potential advantages of this mode of administration have been well documented [1]. The transdermal delivery of peptides and small proteins is of particular interest, since percutaneous administration overcomes many of the problems associated with conventional means of administering these potent therapeutic agents. The major obstacles to the passive permeation of peptidic agents are their hydrophilicity and size; however, therapeutically significant dosage levels have been achieved in vivo using either electrical or chemical enhancement.
The enhanced transport of cations and anions across porous membranes under an applied electric field is found to be asymmetric. This asymmetry may be due to the interaction between the direct effect of the field and convective solvent flow, which has been shown to be directional. The modified Nernst-Planck equations are used to model cation, anion, and neutral solute transport enhancement under an applied electric field. The mechanism of solvent flow is examined via electro-osmotic velocity equations. Uncharged solutes have been used to determine the solvent velocity during iontophoresis. The direct electric field effects on ion transport enhancement were then separated from the convective solvent flow contribution and the asymmetry in cation/anion flux enhancement was assessed. Results of experiments using model charged and uncharged solutes demonstrate the utility of the model and electro-osmosis may he used to explain the cation/anion asymmetry.
Two simple models for ionic mass transport across membranes are discussed in the context of iontophoretic delivery of drugs through skin. The constant field model is mathematically the most tractable and offers some insights into the time dependence of iontophoretic transport. However, for thick membranes or for systems in which the total ion concentrations on opposite sides of the membrane differ appreciably, the electroneutrality approximation is more appropriate. Since both of these conditions are likely to be found in skin iontophoresis studies, the electroneutrality model should provide a better starting point for analyzing the details of iontophoresis experiments than does the constant field model. Equations for the diffusion potential, ion transference numbers and partition coefficients and the current-voltage characteristic of the membrane are given, enabling one to calculate ionic fluxes and active/passive flux ratios for a given applied current or voltage. As an example, the flux and transference number of a monovalent drug ion driven across a membrane in the presence of sodium chloride are calculated. Finally, known discrepancies between the predictions of the homogeneous membrane models and available experimental data are examined, and suggestions are made for modifying the theory to resolve these differences.
Benzyl alcohol (BA), a non-electrolyte, was selected as a probe permeant to investigate its iontophoretic transport through human epidermis. The flux of BA and [3H]water were greater during anodal than cathodal iontophoresis. Increases in current density enhanced the permeability coefficient of BA during iontophoresis. The greater permeability of BA during anodal iontophoresis than cathodal may be due to permselective nature of human epidermis at physiological pH 7.4 for positively charged buffer ions and hence, associated [3H]water and BA. Thus, it is possible to enhance and control the transdermal transport of non-electrolyte by iontophoresis. Scanning electron microscopy of the human epidermis treated with iontophoresis showed greater loosening of epidermal cells and distention in intercellular space with increasing current densities.
Iontophoretic drug delivery implies the delivery of ionic (charged) drugs into the body by the use of electric current. The technique is not new and has been used clinically in delivering medication to surface tissues for several decades. However, its potential is recently being rediscovered for transdermal systemic delivery of ionic drugs including peptide/protein drugs which are normally difficult to administer except by parenteral route. The technique has been observed to enhance the transdermal permeation of ionic drugs severalfold, and this can expand the horizon of transdermal controlled drug delivery for systemic medication. However, miniaturization of iontophoretic devices and electrodes and prevention of any possibility of skin burns are required to make this technique useful for biomedical applications. While the literature on iontophoretic systemic drug delivery is relatively recent and not extensive, the published results on clinical usage and other related aspects can be quite informative and could stimulate and assist the readers to explore other biomedical applications. This article is intended to review old as well as very recent literature on the technique, methodology, clinical findings, influencing factors, relevant electronics and other related aspects of iontophoretic drug delivery, and to provide the readers a comprehensive overview of the state-of-art of this potential new area of biomedical research.
In many cases it is instructive to use a single human epidermal membrane (HEM) sample to perform successive in vitro permeability experiments under varied experimental conditions. This study focused upon the feasibility of such successive permeability experiments in side-by-side, two-chamber diffusion cells. It was shown that for permeability experimental protocols which involved performing one permeability experiment per day and extensive washing between permeability experiments, the barrier properties of HEM samples were altered significantly within the first 72 h of the protocol. However, if the HEM is supported in the diffusion cell with a porous synthetic membrane, a single HEM sample remains essentially unaltered with respect to mannitol permeability and electrical resistance for up to 5 days. This suggests that protecting the HEM from physical stress is an essential element in performing successive permeability experiments.
A physical model for the iontophoretic transport of a weak electrolyte across hairless mouse skin has been examined. The stratum corneum is modelled as parallel lipoidal and aqueous pore pathways for diffusion and is in series with a porous matrix representing the dermis-epidermis. It was assumed that only the undissociated species could penetrate the lipid phase while both charged and uncharged species could permeate the pore route. The applied electric field is assumed to influence only the charged species in the aqueous pore according to the Nernst-Planck theory. Experiments were done over a wide pH range using a four-electrode potentiostat system to control the voltage drop across the membrane. Butyric acid was chosen as the model weak electrolyte. Glucose was used to independently assess membrane damage and solvent flow effects. Permeability coefficients as a function of pH were determined both for butyric acid and glucose before, during and after iontophoresis. Experimental permeability coefficients semi-quantitatively followed the theoretical predictions.
In vitro iontophoretic transdermal delivery (ITD) of a tripeptide, enalaprilat (EP) and a non-peptide, cromolyn sodium (CS), across frozen hairless guinea pig (HGP) skin were investigated. Parameters for optimization of ITD included the influence of ionic strength (μ), buffer type and size, drug loading in the donor and the effect of pH. Drug permeation into the receptor compartment was monitored using HPLC assay methods developed for the study. An optimum μ of 6.66 mM in acetate buffer was found necessary for efficient ITD of CS. An exponential decrease in the flux of CS was observed with an increasing μ. Buffer ions larger than acetate ions inhibited the transport of CS ions. With an increase in the donor concentration of CS, a hyperbolic relationship for the increase in flux was observed. For EP, permeation was not detectable when μ was increased to greater than 31 mM in phosphate-buffered solution. With an increase in pH above the pKa1 (3.55) for EP, a linear decrease in flux was observed. Higher drug loading of EP in the donor compartment provided better permeation. Effect of freezing of HGP skin on the iontophoretic delivery of EP and CS was also evaluated. Flux values for either of the drugs studied were similar when frozen or fresh skins were used. Reversibility studies indicated that no gross current induced permeation changes occurred with the HGP skin. Passive permeation of either of the drugs investigated was negligible.
Nanoparticles effectively deliver therapeutic agent by penetrating into the rat skin in vivo. Indomethacin (IM) and coumarin-6 were loaded in PLGA nanoparticles with an average diameter of 100 nm. Indomethacin (IM) and coumarin-6 were chosen as a model drug and as a fluorescent marker, respectively. The surfaces of the nanoparticles were negatively charged. Permeability of IM-loaded PLGA nanoparticles through rat skin was studied in vivo. Higher amount of IM was delivered through skin when IM was loaded in nanoparticles than IM was free molecules. Also, iontophoresis was applied to enhance the permeability of nanoparticles. When iontophoresis was applied at 0.05 mA/cm(2), permeability of IM was much higher than that obtained by simple diffusion of nanoparticles through skin. The combination of charged nanoparticle system with iontophoresis is useful for effective transdermal systemic delivery of therapeutic agents.
ABSTRACT: Therapeutic administration of pharmaceuticals requires that safe and controlled delivery rates be achieved. Iontophoresis is a promising technique for delivering ionic drugs across the skin. Topical delivery of therapeutic agents by iontophoresis is attractive because the large surface area of skin provides for easy access. The top-most skin layer, the stratum corneum, does not favor the transport of most therapeutically active compounds under normal physiological conditions. Iontophoresis takes advantage of the negative background charge of skin which favors delivery of positively charged species. During iontophoresis a driving force for enhanced transport across skin is provided by an applied electric field. A limitation of the approach is that skin may be altered during the process. ABSTRACT (cont.): The object of this work was to identify the influence of electric fields on the physicochemical properties of skin. The effect of electrolyte solution composition on these properties was also studied. Electrochemical impedance spectroscopy was applied to monitor the properties of skin before, during and after iontophoresis. Statistical models were regressed to the data to identify nonstationary and nonlinear behavior. Results indicated that skin properties began to change as the potential across the skin exceeded a critical value. ABSTRACT (cont.): An adaptive modulation strategy was developed to prevent alterations to membrane properties during the impedance experiment. The delivery rate of lidocaine across the skin was studied by UV-vis absorption spectroscopy. A customized dual-beam diffusion cell was developed to account for the mildly nonstationary behavior of the spectroscopy system. The work indicated that applied current enhanced the transdermal flux of lidocaine. An additional goal of this work was to identify the influence of controlled variables on concentration and flux profiles within the skin. A one-dimensional steady-state mathematical model was developed to provide insight into the coupled phenomena that occur in the stratum corneum. The governing equations for the model account for diffusion and migration, homogeneous reactions in the electrolyte and the negative background charge of skin. Sample calculations are provided to demonstrate the complex nature of the interactions among the species in the system during iontophoresis. System requirements: World Wide Web browser and PDF reader. Mode of access: World Wide Web. Title from title page of source document. Document formatted into pages; contains xvii, 283 p.; also contains graphics. Thesis (Ph. D.)--University of Florida, 2002. Includes vita. Includes bibliographical references.
Transdermal iontophoresis is a method where the movement of ionic drugs (and sometimes also neutral drug molecules) across skin is enhanced using an externally applied potential difference. Iontophoretic devices contain three distinct components; 1) the drug reservoir which contains one electrode, the polarity chosen depends on the charge of the drug, 2) the return electrode and 3) the electronic controller. In this study ion-exchange fibers were investigated as a drug reservoir material for iontophoretic device. The parameters affecting the drug release from the ion-exchange fibers without applied current were studied experimentally and theoretically modeled using five model drugs and four different ion-exchange fibers. It was found that lipophilic drugs were retained more strongly and for longer in the fibers than hydrophilic drugs. The hydrophilic drugs were also released more readily from fibers containing strong ion-exchange groups, whereas the lipophilic drugs attached more strongly to strong ion-exchange groups and released more easily from the weak ion-exchange groups. The salt concentration and the choice of the salt also had an effect; when using equimolar amounts of sodium chloride at lower salt concentrations, more drug was released. Incorporation of calcium chloride in the bathing solution increased considerably both the drug release rate and the total amount of drug released when compared to sodium chloride alone. The drug release from the fibers were studied in vitro and in vivo using iontophoresis. Due to significantly different release properties, tacrine and metoprolol were chosen for screening of their suitability for this kind of iontophoretic system, using an in-house designed in vitro cell. It was found that the rate of tacrine release from the device could be controlled by adjusting the salt concentration and the current density used but the rate of metoprolol release could not be controlled this way. A semi-quantitative and pragmatic interpretation of the results also showed that it should be possible to manufacture a transdermal iontophoretic patch to delivery tacrine. It was also determined in vivo that clinically relevant plasma concentrations of tacrine could be achieved in a human volunteer using an in-house designed and manufactured iontophoretic transdermal drug delivery patch.
The shortened analogue of growth hormone releasing factor (GRF) Ro 23-7861 (1) has a molecular weight of 3929 daltons [equivalent to GRF (1-29)] and is more potent than the endogenous GRF (1-44). The in vitro hairless guinea pig model and vertical and horizontal diffusion cell assemblies were used to study the effect of iontophoresis on the permeability to skin of 1. The transport of 1 across the skin was studied by monitoring the rate of its appearance in the receiver compartment with a radioimmunoassay. No permeability of 1 was observed without iontophoresis, whereas with iontophoresis, the permeability of 1 was significant. For example, at a current density of 0.23 mA/cm2 and buffer concentration of 0.05 M, the flux of 1 was 56.8 +/- 8.21 ng/cm2.h. The flux of 1 was independent of the design of the permeation apparatus, the electrodes, the donor and receiver volumes, the type of current (constant or pulsed), and the frequency of the pulsed current. The flux of 1 increased curvilinearly with the increase in salt concentration of the buffer and linearly with the increase in current.
This paper explores the possibility of iontophoretically enhancing the in vitro transdermal flux of two polypeptides: leuprolide (a LHRH analogue; MW = 1209.4) and a cholecystokinin-8 analogue (CCK-8; MW = 1150.17). Control experiments at an applied voltage of 0.5 V across full-thickness human skin did not yield measurable fluxes of either polypeptide, suggesting that despite the expected iontophoretic flux enhancements, the intrinsic permeability of these polypeptides through skin may be too low to allow significant amounts of the drug to permeate. Therefore, pretreatment with ethanol (to simulate the effect of a chemical permeation enhancer) followed by iontophoresis was investigated with the aim of evaluating the potential of the enhancer plus ionophoresis as a means for controlled transdermal delivery of these polypeptides. The ethanol pretreatment dramatically increased the passive fluxes of both polypeptides, and iontophoresis produced further enhancements in their fluxes. Also, the experimental enhancement factors for leuprolide as a function of the applied voltage appeared to be generally lower than the predictions of the constant field theory. A synergism of iontophoresis with a chemical permeation enhancer may be a potential route for controlled transdermal delivery of these and other high molecular weight polypeptides.
The effect of iontophoresis on percutaneous absorption of formoterol fumarate (FF) was investigated in vitro with abdominal skin excised from guinea pig. By passive diffusion, the flux at steady state for stripped skin was about 230 times greater than that for intact skin. Therefore, it is suggested that stratum corneum is a barrier for the percutaneous absorption of FF. Penetrated amount of FF increased significantly with an increase in donor concentration from 0.035% to 0.07%. Under the constant current iontophoresis the large flux accompanied with the high applied voltage was shown at the beginning of iontophoresis. Thereafter the flux decreased with a decrease in applied voltage. Under the constant voltage iontophoresis a linear relationship between penetrated amount of FF and time was observed.
Three factors are of primary importance in determining the iontophoretic flux of a charged solute: the electrochemical potential gradient across the skin, an increase in skin permeability to passive transport due to iontophoresis (loosely defined as skin damage), and a current-induced water flux. The latter two factors can also affect the transport of uncharged solutes during iontophoresis. A method of correcting for the skin damage effect is introduced. The contributions of the water transport effect relative to that of the applied voltage drop for charged solutes is estimated. It is shown that the water transport contribution is generally lower than the contribution due to the applied voltage drop. The observed iontophonetic flux of the enhancement factors due to the applied voltage drop alone are compared with the theoretical predictions based on the constant field assumption. It is shown that the theoretical predictions are higher than the experimental observations. This work also examines, for the first time, a synergism of iontophoresis and pretreatment with a chemical penetration enhancer as a means for delivering high molecular weight polypeptides. It is shown that a 2-h pretreatment with absolute ethanol followed by iontophoresis dramatically increases the permeability coefficient of insulin through human skin.
The temperature dependence of in vitro permeation through human epidermal membrane (HEM) was determined for urea, mannitol, tetraethylammonium ion (TEA), and corticosterone. The effect of temperature upon HEM electrical resistance was also measured. The majority of the experiments involved measuring the permeability coefficients of a specific permeant at 27 degrees C and 39 degrees C for a given HEM sample, the electrical resistance was also measured at each temperature. Similar experiments were also conducted with a model synthetic porous membrane. The effect of temperature was quantitated as the ratio of the permeability at 39 degrees C to the permeability at 27 degrees C for each permeant. These ratios observed for HEM with urea, mannitol, and TEA as the permeants were 1.66 +/- 0.05, 1.76 +/- 0.14, and 1.71 +/- 0.11, respectively. The change in temperature was shown to have a similar effect upon the electrical conductance of the HEM samples. The observed ratio for corticosterone permeation was 4.5 +/- 0.4. The experimental ratios observed for the three polar/ionic permeants were shown to approach those obtained from the model porous membrane and differed greatly from the ratio observed for the more lipophilic corticosterone, indicating differences in the effective transport mechanism/pathway for these classes of permeants. The permeability of urea was also observed to be inversely proportional to the electrical resistance of the HEM samples; this relationship was shown to be independent of temperature over the temperature range studied. The temperature dependence data and the observed relationship between urea permeability and electrical resistance strongly support the existence of a porous permeation pathway through the HEM as an operative diffusional route for polar-ionic permeants.
The effects of applied voltage and the duration of application upon human epidermal membrane (HEM) alterations and recovery were investigated. All experiments were conducted using a two-chamber diffusion cell with constant DC voltage (250-4000 mV) applied over a predetermined period, and HEM changes were monitored by measuring the electrical resistance before and after voltage termination. The key findings were that the rate of decrease in resistance was strongly dependent upon the applied voltage, the reversible recovery times were dependent upon both the magnitude and the duration of the applied field (frequently were several orders of magnitude greater than times for attaining significant resistance reduction), and reversible recovery times were much longer when lower voltages were applied for longer times to attain the same decrease in electrical resistance than for higher voltages at short times. These findings closely parallel those obtained on electrical breakdown/recovery of bilayer membranes (electroporation). The second part of this work examined the hypothesis that decreases in HEM electrical resistance induced by the applied voltage are accompanied by proportional increases in HEM permeability. A study was designed to test this hypothesis involving a four-stage protocol with HEM: passive transport, 250-mV iontophoresis, 2000-mV iontophoresis for 10 min, then back to 250-mV iontophoresis. The data obtained strongly support the view that the HEM alterations induced by the electric field result in pore formation and in the expected changes in HEM permeability.
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)
An experimental methodology was developed to evaluate the physicochemical basis for in vitro-in vivo correlations in iontophoretic delivery situations. This experimental methodology can be used to quantitatively evaluate the extent of interaction between chemical permeation enhancers and iontophoresis for drug delivery. The inherent advantages of using Ag/AgCl electrodes are fully exploited to control pH and minimize depletion of permeant during prolonged periods of iontophoresis.
This study focused upon quantitatively determining the influence of permeant molecular size upon flux enhancement which results from electroosmosis. The first phase of the study involved validation of a fundamental model describing the molecular size dependence of flux enhancement which results from convective solvent flow. This was accomplished using a model synthetic membrane (stack of 50 Nuclepore membranes) and four model permeants with a molecular weight range of 60-504 (urea, mannitol, sucrose, and raffinose). The steady-state flux of each permeant was determined under passive conditions and applied voltages of 125, 250, 500, and 1000 mV using side-by-side diffusion cells and a four-electrode potentiostat system. On the basis of the permeability enhancement for each permeant at each applied voltage (relative to the passive permeability) it was possible to calculate the effective solvent flow velocity from each permeant at each field strength. An important finding was that the flux enhancement due to electroosmosis was strongly molecular weight dependent (i.e, the flux enhancement ratio was around 4 times greater for raffinose than for urea, with mannitol and sucrose yielding intermediate values), while the calculated effective flow velocity at each voltage was independent of the molecular weight of the permeant. This coupled with a linear correlation between flow velocity and applied voltage served to establish the validity of the method and model. The second phase of the study was an extension of the model to human epidermal membrane (HEM). These experiments involved simultaneously measuring the fluxes of [14C]urea and [3H]sucrose across HEM samples under passive, 250 mV, and 500 mV conditions. Similar to the Nuclepore system, the observed flux enhancement ratios with HEM were approximately 3 times greater for sucrose than for urea. A detailed analysis of the HEM data showed semiquantitative agreement between predictions of the model and experimental results.
Electrically-assisted transdermal delivery (EATDD) is the facilitated transport of compounds across the skin using an electromotive force. It has been extensively explored as a potential means for delivering peptides and other hydrophilic, acid-labile or orally unstable products of biotechnology. The predominant mechanism for delivery is iontophoresis, although electroosmosis and electroporation have also been investigated. The focus of this review is to put these different mechanisms in perspective and relate them to the drug and skin model system being investigated.
Transdermal drug delivery of ionized drugs can be enhanced by iontophoresis. Drug in the ionic form, contained in some reservoir, can be "phoresed" through the skin with a small current across two electrodes, one above the reservoir and one at a distal skin location. Positive ions can be introduced from the positive pole, or negative ions from the negative pole. The design and development of iontophoretic devices are rather simple. Some of the principles of operation and the advantages/disadvantages and clinical implications associated with these devices are outlined in this review.
The transfer of Cs+ ion across the interface of two immiscible electrolyte solutions, 0.05 M LiCl in water and 0.05 M tetrabutylammonium tetraphenylborate in nitrobenzene, was investigated by cyclic voltammetry with four-electrode system. The positive feedback was used for the elimination of the ohmic potential drop between the tips of the Luggin capillaries. The standard potential differences for Cs+ and tetrabutylammonium cations and for tetraphenyl-borate anion, which were deduced from the present experimental results, are in very good agreement with those calculated from the extraction data. The value of the diffusion coefficient of Cs+ ion in water DCs+(w)=2.4×10−5 cm2 s−1 was estimated. The kinetics of Cs+ ion transfer across the nitrobenzene/water interface is characterized by the apparent rate constant kappø=5.5×10−2 cm s−1 and by the formal charge transfer coefficient α=0.46.
Iontophoresis increases penetration of ionic drugs into surface tissues by repulsion of ions at the active electrode. However, we reported increased penetration of idoxuridine by either anode(+) or cathode(-). Although not highly ionized, idoxuridine forms anions in aqueous solution requiring introduction under the cathode(-). We postulated that increased penetration of idoxuridine after anodal(+)-iontophoresis may result from water movement associated with sodium ion transfer. When water is transported into tissue, nonelectrolytes may also be transported. The term iontohydrokinesis was adopted to describe water transport during iontophoresis, and no specific mechanism is implied by this new term. Iontohydrokinesis was studied after cathodal(-)- and anodal(+)-iontophoresis of dilute NaCl solutions containing [3H]-9-beta-D-arabinofuranosyladenine, (Ara-A), [3H]H2O and [3H]thymidine (dThd). Since Ara-A and dThd are nonconductive, any increase in penetration must be due to water transport by iontohydrokinesis. Anodal iontophoresis resulted in the following statistically significant increases in penetration compared to topical application: [3H]H2O, +155%; [3H]dThd, +429% and [3H]Ara-A, +488%. Cathodal(-)-iontophoresis resulted in statistically significant increases in penetration: [3H]H2O, +78% and [3H]dThd, +286%; the penetration of [3H]Ara-A increased +56% but this was not statistically significant. Electrical current does not change skin permeability.
The permeation of intact hairless mouse skin by alkanols was studied. The method is described, and data for the quasi-steady-state and nonstationary-state aspects of mass transfer are given. Partitioning data also are presented. The permeability coefficients increased exponentially up to a carbon chain length of about eight (octanol). There was a marked temperature dependency (Ea congruent to 19 kcal for the series), and the partitioning was biphasic, increasing exponentially for alkanols larger than butanol. These data are compared with literature data on human skin tissues, and great similarity in all facets of behavior is noted.