Transdermal Iontophoretic Delivery Research Articles

Ambient Moisture-Driven Self-Powered Iontophoresis Patch for Enhanced Transdermal Drug Delivery.

Iontophoretic transdermal drug delivery (TDD) devices are known to enhance the transdermal transport of drugs. However, conventional transdermal iontophoretic devices require external power sources, wired connections, or mechanical parts, which reduce the comfort level for patients during extended use. In this work, a self-powered, wearable transdermal iontophoretic patch (TIP) is proposed by harvesting ambient humidity for energy generation, enabling controlled TDD. This patch primarily uses moist-electric generators (MEGs) as its power source, thus obviating the need for complex power management modules and mechanical components. A single MEG unit can produce an open-circuit voltage of 0.80V and a short-circuit current of 11.65µA under the condition of 80% relative humidity. Amplification of the electrical output is feasible by connecting multiple generator units in series and parallel, facilitating the powering of certain commercial electronic devices. Subsequently, the MEG array is integrated with the TDD circuit to create the wearable TIP. After 20 min of application, the depth of drug penetration through the skin is observed to increase threefold. The effective promotion effect of TIP on the transdermal delivery of ionized drugs is corroborated by simulations and experiments. This wearable TIP offers a simple, noninvasive solution for TDD.

Microcurrent Cloth-Assisted Transdermal Penetration and Follicular Ducts Escape of Curcumin-Loaded Micelles for Enhanced Wound Healing.

Larger nanoparticles of bioactive compounds deposit high concentrations in follicular ducts after skin penetration. In this study, we investigated the effects of microcurrent cloth on the skin penetration and translocation of large nanoparticle applied for wound repair applications. A self-assembly of curcumin-loaded micelles (CMs) was prepared to improve the water solubility and transdermal efficiency of curcumin. Microcurrent cloth (M) was produced by Zn/Ag electrofabric printing to facilitate iontophoretic transdermal delivery. The transdermal performance of CMs combined with M was evaluated by a transdermal system and confocal microscopy. The CMs/iontophoretic combination effects on nitric oxide (NO) production and inflammatory cytokines were evaluated in Raw 264.7 cells. The wound-healing property of the combined treatment was assessed in a surgically created full-thickness circular wound mouse model. Energy-dispersive X-ray spectroscopy confirmed the presence of Zn/Ag on the microcurrent cloth. The average potential of M was measured to be +214.6 mV in PBS. Large particle CMs (CM-L) prepared using surfactant/cosurfactant present a particle size of 142.9 nm with a polydispersity index of 0.319. The solubility of curcumin in CM-L was 2143.67 μg/mL, indicating 250-fold higher than native curcumin (8.68 μg/mL). The combined treatment (CM-L+M) demonstrated a significant ability to inhibit NO production and increase IL-6 and IL-10 secretion. Surprisingly, microcurrent application significantly improved 20.01-fold transdermal performance of curcumin in CM-L with an obvious escape of CM-L from follicular ducts to surrounding observed by confocal microscopy. The CM-L+M group also exhibited a better wound-closure rate (77.94% on day 4) and the regenerated collagen intensity was approximately 2.66-fold higher than the control group, with a closure rate greater than 90% on day 8 in vivo. Microcurrent cloth play as a promising iontophoretic transdermal drug delivery accelerator that enhances skin penetration and assists CMs to escape from follicular ducts for wound repair applications.

Polyindole:poly(4-styrenesulfonic acid) loaded agarose hydrogel for methotrexate sodium transdermal delivery via iontophoresis

The iontophoretic transdermal drug delivery system is an alternative route to the usual injection route. Agarose, a biopolymer with self-gelation, was served as a drug reservoir due to its well-connected porous structure and non-toxicity. PIn:PSS, a water soluble conductive polymer, was used as a drug carrier. Methotrexate sodium (MTX) loaded PIn:PSS (MTX-PIn:PSS) was embedded in the AG gel to investigate the in-vitro drug release and in-vitro drug release-permeation under the effects of the matrix pore sizes, electric fields, and pHs. The amount of MTX released increased with decreasing AG concentration due to a larger pore size. In the presence of electric field, the higher amount and rate of MTX release were obtained due to the electro repulsive force and the electroosmotic effect. Incorporating PIn:PSS as the drug carrier was shown here to improve the MTX release. The amount and rate of MTX release-permeation became lower due to the porcine skin and the low pH, but were improved under the applied electric field. The MTX-PIn:PSS in the AG gel is shown here to be an effective drug carrier to enhance and control the MTX release-permeation in the iontophoretic transdermal delivery.

Transdermal Delivery of Insulin Using Combination of Iontophoresis and Deep Eutectic Solvents as Chemical Penetration Enhancers: In Vitro and in Vivo Evaluations

A serious challenge in transdermal iontophoresis (IP) delivery of insulin (INS) is the low permeability of the drug across the skin. In this paper, we introduced deep eutectic solvent (DESs) as novel chemical penetration enhancers (CPEs) for transdermal IP of INS across rat skin, both in vitro and in vivo. Three different DESs based on choline chloride (ChCl), namely, ChCl/UR (ChCl and urea), ChCl/GLY (ChCl and glycerol), and ChCl/EG (ChCl and ethylene glycol) in the 1:2 molar ratios have been prepared. To evaluate the capability of studied DESs as CPEs for IP delivery of INS, the rat skin sample was treated with each DES. The effects of different experimental parameters (current density, formulation pH, INS concentration, NaCl concentration, and treatment time) on the in vitro transdermal iontophoretic delivery of INS were investigated. The in vitro permeation studies exhibited that INS was easily delivered employing ChCl/EG, and ChCl/GLY treatments, compared with ChCl/UR: the cumulative amount of permeated INS at the end of the experiment (Q24h) was found to be 131.0, 89.4, and 29.6 µg cm−2 in the presence of ChCl/EG, ChCl/GLY, and ChCl/UR, respectively. The differences in Q24h values of INS are due to the different capabilities of the studied DESs to treat the epidermis layer of skin. In vivo experiments revealed that the blood glucose level in diabetic rats could be decreased using ChCl/EG, and ChCl/GLY as novel CPEs in the IP delivery of INS. The presented work will open new doors towards searching for novel CPEs in the development of transdermal IP of INS.

Combination of lipid nanoparticles and iontophoresis for enhanced lopinavir skin permeation: Impact of electric current on lipid dynamics

Nanostructured lipid carriers (NLC)-loaded with lopinavir (LPV) were developed for its iontophoretic transdermal delivery. Electronic paramagnetic resonance (EPR) spectroscopy of fatty acid spin labels and differential scanning calorimetry (DSC) were applied to investigate the lipid dynamic behavior of NLC before and after the electrical current. In vitro release and permeation studies, with and without anodic and cathodic iontophoresis were also performed. NLC-LPV had nanometric size (179.0 ± 2.5 nm), high drug load (∼x223C 4.14%) and entrapment efficiency (EE) (∼x223C 80%). NLC-LPV was chemically and physically stable after applying an electric current. The electrical current reduced EE after 3 h (67.21 ± 2.64%), resulting in faster LPV in vitro release. EPR demonstrated that iontophoresis decreased NLC lipid dynamics, which is a long-lasting effect. DSC studies demonstrated that electrical current could trigger the polymorphic transition of NLC and drug solubilization in the lipid matrix. NLC-LPV, combined with iontophoresis, allowed drug quantification in the receptor medium, unlike unloaded drugs. Cathodic iontophoresis enabled the quantification of about 7.9 µg/cm2 of LPV in the receptor medium. Passive NLC-LPV studies had to be done for an additional 42 h to achieve similar concentrations. Besides, anodic iontophoresis increased by 1.8-fold the amount of LPV in the receptor medium, demonstrating a promising antiviral therapy strategy.

Numerical Simulation of Transdermal Iontophoretic Drug Delivery System

Transdermal Iontophoretic Drug Delivery System (TIDDS) is a non-invasive method of systemic drug delivery that involves by applying a drug formulation to the skin. The drug penetrates through the stratum corneum, epidermis and dermis layers. Once the drug reaches the dermal layer, it is available for systemic absorption via dermal microcirculation. However, clinical testing of new drug developed for the iontophoretic system is a long and complex process. Recently, most of those major pharmaceutical companies have attempted to consider computer-based bio-simulation strategies as a means of generating the data necessary to help make a better decision. In this work, we used computational modelling to investigate the TIDDS behaviour. Our interest is to study the efficacy of drug diffusion through transdermal delivery, including the thermal effect on the skin. We found that drug will be delivered more efficiently if the electrical potential and the position of electrodes are optimum. We analysed the drug diffusion time of the system using 1,3 and 5 mA DC source. In addition, we also modify the electrode distance from 10 mm to 30 mm long and analysed the effect of delivery time and d effect to the skin thermal. We conclude that, a high electrical current, as instance, a 5 mA DC, delivered the drug faster into the skin but increased the skin temperature because of skin joule heating effect. However, a 30 mm electrodes distance setting decreased the skin temperature significantly than the 10 mm distance with more than 9.7 °C under 5 mA DC and 60 minutes of operation. TIDDS enhanced drug delivery compared to oral consumption and might be suitable used for localizing treatments such as chronic disease. This work provides great potential and is useful to efficiently design of iontophoretic drug delivery system including new drugs delivery applications.

Current profile controlled transdermal delivery of pramipexole from an iontophoretic patch system in vitro and in vivo

The objective was to evaluate the transdermal iontophoretic delivery of pramipexole using constant and complex multi-phasic current profiles from an iontophoretic patch system in vitro and in vivo. Preliminary in vitro experiments were performed to optimize iontophoretic patch design and configuration. “Single” compartment systems containing only pramipexole dihydrochloride, and designed to maximize delivery efficiency, suffered from an insufficiency of chloride ions with anodal electrochemistry passing from an Ag/AgCl couple to an Ag dissolution electrode. Addition of NaCl to provide more chloride ions decreased pramipexole delivery efficiency due to competition between pramipexole and sodium cations. A “two-compartment” iontophoretic patch where the drug reservoir was separated from the anodal compartment, which now included NaCl, was shown to be a good compromise since it ensured Ag/AgCl electrochemistry at the anode and an acceptable delivery efficiency. In vivo studies using this iontophoretic patch demonstrated that the plasma concentration of pramipexole closely followed the variation of the applied continuous and multi-phasic current profiles and underlined the control provided by iontophoresis and its unique ability to rapidly change drug input rates. The applied current density and duration of current application were also shown to modulate pramipexole delivery to the brain and CSF.

Effective factors on iontophoretic transdermal delivery of memantine and donepezil as model drugs

The purpose of this study is to compare in vitro and in vivo release characteristics of memantine hydrochloride and donepezil hydrochloride in monolayer films those prepared by the solvent evaporation method. Eudragit EPO (EPO), hydroxypropyl methylcellulose (HPMC), and ethylcellulose (EC) were used as polymer matrix; polyethylene glycol (PEG) was used as a plasticizer, and glycerol (Gl) was used to give balanced monolayer film moisture content. The same matrix were used to load the same concentrations of the model drugs to compare their characteristic release properties and to minimalize the effect of formulation that may affect their specific release properties. Drug-loaded monolayer films were surrounded with cellophane membranes as a barrier on in vitro release studies. The in vivo studies were performed on the shaved (hairless) dorsal region of Wistar albino rats. Anodal iontophoresis was applied as a physical penetration enhancement method for a constant time of 1 h. Linear regression applied to calculate the correlation between the in vivo and in vitro results.Anodal iontophoresis were applied on drug-loaded monolayer films. Iontophoretic results were compared with passive diffusion results of drug-loaded monolayer films. Anodal iontophoresis studies were performed by applying two different current intensities to both lower and higher concentration drug-loaded monolayer films to evaluate the effect of concentration and intensity on the transported drug quantities.The transported average memantine hydrochloride (MEM) and donepezil hydrochloride (DON) concentrations after 24 h passive diffusion study were found as 166.13 ng/mL and, 73.56 ng/mL, respectively. These concentrations were increased to 10.59 μg/mL and, 636.81 ng/mL, respectively after 1 h 0.5 mA/cm2 anodal iontophoretic pre-treatment.The obtained results support the phenomenon; transported drug quantities through the skin from the selected matrix increased according to the concentration of the drug and, the current intensity that applied on iontophoretic pre-treatment. It was observed that the difference between the transported quantities of two drugs depends on mainly to the physicochemical properties of the drugs. Iontophoretic pre-treatment found more effective on transported quantities of memantine hydrochloride through the skin. This supports that the selected matrix and penetration enhancer is sufficient for memantine hydrochloride but not for donepezil hydrochloride. This suggests that the transported donepezil hydrochloride quantities through the skin may increase by the selection of suitable penetration enhancers or combination thereof in a suitable matrix.

Influencing factors and drug application of iontophoresis in transdermal drug delivery: an overview of recent progress.

Transdermal drug delivery is limited by the stratum corneum of skin, which blocks most molecules, and thus, only few molecules with specific physicochemical properties (molecular weight <500Da, adequate lipophilicity, and low melting point) are able to penetrate the skin. Recently, various technologies have been developed to overcome the strong barrier properties of stratum corneum. Iontophoresis technology, which uses a small current to improve drug permeation through skin, is one of the effective ways to circumvent the stratum corneum. This approach not only provides a more efficient, noninvasive, and patient-friendly method of drug delivery but also widens the scope of drugs for transdermal delivery. In this review, the mechanisms underlying iontophoresis and affecting factors are outlined. The focus will be on the latest advancements in iontophoretic transdermal drug delivery and application of iontophoresis with other enhancing technologies. The challenges of this technology for drug administration have also been highlighted, and some iontophoretic systems approved for clinical use are described.

Iontophoretic skin delivery systems: Success and failures.

Iontophoretic transdermal delivery uses a small electric current to push charged molecules into the skin under an electrode of same polarity and offers an attractive option to facilitate the delivery of macromolecules or hydrophilic molecules and to improve patient compliance. This technique has been used in physical therapy clinics for several decades, though the science was not always there to support claims of clinical effectiveness. Recently, this modality of treatment has undergone more systematic and rigorous investigations to withstand the scrutiny of regulatory authorities. In recent years various drugs have gained FDA approval for iontophoretic patches. This technique is gaining recognition due to better compliance rates, non-invasive drug delivery leading to fewer side effects, and sustained release of the drug. Furthermore, programmed delivery and bolus delivery systems have helped with customizing the drug dosage and frequency of dosage based on the patient's need.

Facilitated Transdermal Drug Delivery Using Nanocarriers-Embedded Electroconductive Hydrogel Coupled with Reverse Electrodialysis-Driven Iontophoresis.

We herein developed an iontophoretic transdermal drug delivery system for the effective delivery of electrically mobile drug nanocarriers (DNs). Our system consists of a portable and disposable reverse electrodialysis (RED) battery that generates electric power for iontophoresis through the ionic exchange. In addition, in order to provide a drug reservoir to the RED-driven iontophoretic system, an electroconductive hydrogel composed of polypyrrole-incorporated poly(vinyl alcohol) (PYP) was used. The PYP hydrogel facilitated electron transfer from the RED battery and accelerated the mobility of electrically mobile DNs released from the PYP hydrogel. In this study, we showed that fluconazole- or rosiglitazone-loaded DNs could be functionalized with charge-inducing agents, and DNs with charge modification resulted in facilitated transdermal transport via repulsive RED-driven iontophoresis. In addition, topical application and RED-driven iontophoresis of rosiglitazone-loaded DNs resulted in an effective antiobese condition displaying decreased bodyweight, reduced glucose level, and increased conversion of white adipose tissues to brown adipose tissues in vivo. Consequently, we highlight that this transdermal drug delivery platform would be extensively utilized for delivering diverse therapeutic agents in a noninvasive way.

Aging Effect on Iontophoretic Transdermal Drug Delivery

The skin is the largest organ of the human body, offering an accessible interface for the administration of drugs. The main obstacle to transdermal drug delivery is the skin's barrier properties, due essentially to the stratum corneum, the skin's outermost layer, which is impermeable to most drugs. There are several techniques used to modify the barrier properties of the stratum corneum and to enhance the permeation of drugs through the skin. One popular approach to overcome this barrier is iontophoresis, a technique where electric fields are applied to enhance the transport, by adding an electric potential gradient to a concentration gradient. Several factors affect iontophoresis transdermal drug delivery (TDD). Among them the mechanical properties of skin play an important role. The skin behaves like a viscoelastic material, and it is well known that transport in viscoelastic media is non-Fickian. Consequently, the traditional Fickian advection-diffusion iontophoretic models are inappropriate. As aging induces huge modifications in the mechanical properties of the skin, the models presented in this paper can provide clinicians with guidelines for personalized TDD. The paper is concerned with the analysis and numerical simulation of a non-Fickian viscoelastic model for iontophoretic transdermal drug transport. A multilayer approach is followed, where the polymeric drug reservoir and the properties of the main skin layers are taken into account. Numerical simulations illustrate the effect of aging in TDD and shed light on how to include it in personalized TDD protocols.

Self‐Powered Iontophoretic Transdermal Drug Delivery System Driven and Regulated by Biomechanical Motions

AbstractTransdermal drug delivery (TDD) systems with feedback control have attracted extensive research and clinical interest owing to their unique advantages of convenience, self‐administration, and safety. Here, a self‐powered wearable iontophoretic TDD system that can be driven and regulated by the energy harvested from biomechanical motions is proposed for closed‐loop motion detection and therapy. A wearable triboelectric nanogenerator (TENG) is used as the motion sensor and energy harvester that can convert biomechanical motions into electricity for iontophoresis without stored‐energy power sources, while a hydrogel‐based soft patch with side‐by‐side electrodes is designed to enable noninvasive iontophoretic TDD. Proof‐of‐concept experiments on pig skin with dyes as model drugs successfully demonstrate the feasibility of the proposed system. This work not only extends the application of TENG in the biomedical field, but may also provide a cost‐effective solution for noninvasive, electrically assisted TDD with closed‐loop sensing and treatment.

Simultaneous Transdermal Delivery of Buprenorphine Hydrochloride and Naltrexone Hydrochloride by Iontophoresis.

The opioids buprenorphine hydrochloride (BUP) and naltrexone hydrochloride (NTX) show promise as a combination treatment for addiction, but no means of delivering the two compounds in one medicine currently exist. In this paper, we report sufficient input rates of both these drugs from one iontophoretic transdermal drug delivery system. Experiments were performed using dermatomed pig skin mounted in glass side-bi-side cells. BUP and NTX were iontophoretically delivered together from the anode using direct constant current from Ag/AgCl electrodes. The transdermal drug fluxes and the masses of drugs in both the stratum corneum and the underlying epidermis/dermis were measured. The apparent electroosmotic flow was quantified using a neutral marker (acetaminophen). The effects of donor composition (drug concentration/molar fraction and pH), current density and profile, and the choice of receptor solution were assessed. Iontophoresis dramatically increased the flux of both drugs compared to passive control values. Target fluxes (calculated from literature clearance values and required therapeutic plasma concentrations) were greatly exceeded for NTX and were met for BUP. The latter accumulated in the skin and suppressed electroosmotic flow, inhibiting both its own flux and that of NTX. NTX, in turn, negatively influenced the flux of BUP via co-ion competition. Lowering current density by increasing the delivery area resulted in increased electroosmotic flow but did not significantly affect current-normalized drug fluxes. Delivering the drugs from both electrodes and reversing the polarity for every 2 h did not increase the flux of either compound. In summary, during iontophoresis, BUP and NTX inhibited each other's flux by two distinct mechanisms. While the more complex behavior of BUP complicates the optimization of this drug combination, iontophoresis nevertheless appears to be a feasible approach for the controlled codelivery of NTX and BUP through the skin.

PVA Cryogel as model hydrogel for iontophoretic transdermal drug delivery investigations. Comparison with PAA/PVA and PAA/PVP interpenetrating networks

The use of polyvinyl alcohol (PVA) cryogel as a model hydrogel for iontophoretic transdermal investigations is proposed. Due to the excellent combination of its properties, it could be used for evaluating iontophoretic transdermal delivery of variety of drugs, regardless of pKa, pH or presence of auxiliary ions. Applicability of PVA Cryogel for drug delivery purposes was compared to those of polyacrylic acid/polyvinyl alcohol (PAA/PVA) and polyacrylic acid/polyvinylpyrrolidone (PAA/PVP) adhesive interpenetrating networks. Swelling properties of PVA Cryogel were shown to be almost independent on pH and NaCl concentration, while swelling of PAA-based gels was significantly affected. Addition of PVA and PVP to PAA decreased swelling degrees and increased adhesivity and compression moduli. Iontophoretic experiments were performed using a donor gel/skin/receptor gel configuration; current density and delivery duration were varied. Dexamethasone sodium phosphate was used as model drug molecule. PVA Cryogel was used for investigating the influence of NaCl concentration, which can alter the amount of current carried by the drug ions and, therefore, the delivery rate. By using PVA Cryogel it was possible to easily determine the amount of drug permeated through the skin into the receptor gel, the amount retained by the skin and the amount remained in the donor hydrogel. Decreasing NaCl concentration in PVA Cryogel resulted in higher total amounts of drug delivered and significantly enhanced drug permeation through the lower layers of the skin into the receptor hydrogel.

Effect of Ethanol on Iontophoretic Transdermal Delivery of 5-Aminolevulinic Acid through Yucatan Micropig Full-thickness Skin

The effect of ethanol was investigated on iontophoretic transdermal delivery of 5-aminolevulinic acid through Yucatan micropig full-thickness skin. When 20 % ethanol was added into an aqueous 5-aminolevulinic acid solution, the iontophoretic permeation of 5-aminolevulinic acid through Yucatan micropig full-thickness skin was enhanced. The addition of ethanol also enlarged the partition of 5-aminolevulinic acid into Yucatan micropig full-thickness skin, which gave rise to enhancement of 5-aminolevulinic acid permeation. This result suggested that the combination system of iontophoretic delivery and 20 % ethanol could be a promising approach for the promotion of 5-aminolevulinic acid skin permeation.

Transdermal delivery of polidocanol from sol–gel patch: ex vivo skin permeation studies using iontophoresis for the treatment of varicose veins

A polidocanol (POL) doped sol–gel patch based transdermal iontophoretic drug delivery system (TIDDS) for the treatment of varicose veins is presented in this paper. The sol–gel surface morphology and internal microstructure were characterized using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). A timer based iontophoretic current supply unit was indigenously designed to deliver low current (5 mA) for drug delivery. Two silver electrodes delivered current to the sol–gel patch. It was observed that the drug dispersed in the sol–gel matrix diffused through solvent-filled capillary channels under the influence of the applied current. In vitro release profile of POL was tested on albino rat skin. The rate of delivery through the skin was evaluated by fluorescence spectroscopy measurements. The results indicated that the sol–gel patch under the influence of iontophoretic current allowed controlled release of the POL. Thus the sol–gel patch can be an efficient and an effective non-invasive alternative to deliver POL using iontophoresis to treat the region affected by varicose veins to reduce pain.

Savremeni farmaceutski oblici analgetika

Among novel pharmaceutical dosage forms of analgesics, whose number and diversity are continuously increasing over the past two decades, of particular importance are transdermal opioid analgesics (fentanyl, buprenorphine) for the treatment of chronic pain, fentanyl iontophoretic transdermal drug delivery system for suppression of acute postoperative pain, as well as compressed lozenges, buccal tablets and film, sublingual tablets and nasal sprays for fentanyl treatment of breakthrough cancer pain. To improve the efficacy of the migraine pain treatment, compared to the solid dosage forms (tablets) of tryptans, pharmaceutical preparations of sumatriptan (solution for subcutaneous injection, nasal spray and nasal powder) and zolmitriptan (orodispersible tablet) are developed and marketed for migraine pain treatment. The benefits of these pharmaceutical preparations are minimal invasiveness and suitability to meet the individual therapeutic needs of patients, including the pediatric population, in terms of onset and duration of action and delivered dose of the drug. In the last few years, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) have warned of fatal errors during use or abuse of fentanyl transdermal patches and have indicated the importance educating health workers and patients about potential risks. Also, novel pharmaceutical forms of fentanyl for treatment of acute pain can be prescribed and used exclusively within the framework of the FDA REMS (Risk Evaluation and Mitigation Strategy) program aimed to provide greater benefits from potential risks. There are still no precise attitudes about the importance of recently approved pharmaceutical products of analgesics, and clinical assessments of their relative efficacy and tolerance at the site of application are also needed.

Iontophoretic transdermal delivery using chitosan-coated PLGA nanoparticles for positively charged drugs

Recently, poly(dl-lactide-co-glycolide) (PLGA) nanoparticles prepared using a combination of an antisolvent diffusion method with preferential solvation was shown to be beneficial for the iontophoretic transdermal delivery of therapeutic agents. Also, this preparation method can contain a hydrophilic drug. However, since PLGA nanoparticles were negatively charged, it was difficult to apply iontophoresis for positively charged hydrophilic drugs. In this study, we prepared positively charged PLGA nanoparticles containing donepezil hydrochloride (DP). DP was used as a positively charged hydrophilic drug model. The PLGA nanoparticles were coated with chitosan hydroxypropyltrimonium chloride. The average particle diameter of the nanoparticles was 117.7±60.6nm and the surface charge number density changed from negative to positive. Ex vivo skin accumulation study was carried out using abdominal rat skin and a Franz-type diffusion cell with/without iontophoresis. When iontophoresis was applied, the DP concentration in the rat skin of chitosan-coated PLGA nanoparticles was 2.2 times higher than that of non-coated PLGA nanoparticles. This indicated that chitosan-coated PLGA nanoparticles were suitable for iontophoresis. To investigate the transdermal delivery route of the nanoparticles, we prepared chitosan-coated PLGA nanoparticles containing DP, coumarin-6, and rhodamine 6G. Coumarin-6 and rhodamine 6G were used as a trace marker of the PLGA nanoparticles and positively charged hydrophilic drug model, respectively. From the results of ex vivo accumulation test of this fluorescent nanoparticles, it was suggested that positively charged hydrophilic drugs reached the hair follicles as a nanoparticle, and then they were released from the nanoparticles.

Effect of terpenes on transdermal iontophoretic delivery of diclofenac potassium under constant voltage

Objective: The aim of the study was to enhance the transdermal delivery of diclofenac potassium (DP) from hydrogels by constant voltage iontophoresis (CVI). The other objective was to establish the safety and efficacy of CVI in rats.Materials and methods: Hydrogels of DP were developed using hydroxyethyl cellulose as matrix material and geraniol, l-menthol and thymol as iontophoretic efficiency enhancers (IEE). In vitro permeation of hydrogels under CVI (1.5 V) was performed in Franz diffusion cells across porcine skin. The ability of CVI to deliver therapeutic amount of DP in vivo was assessed in rat paw edema model.Results: CVI significantly (p < 0.05) increased the steady state flux of DP compared to the passive. The hydrogels containing geraniol and l-menthol enhanced the iontophoretic flux of DP by ∼4.75 and ∼4.49 fold, respectively compared to passive control. The in vivo studies indicated that CVI in combination with IEE, significantly reduced (p < 0.05) area under the curve (AUC) of % inflammation compared to passive treatment. An excellent correlation (r = 0.996) was noted between in vitro flux values and AUC of % inflammation.Conclusion: The preclinical studies conclusively demonstrated that CVI in combination with IEE’s such as geraniol or l-menthol has the potential to safely deliver therapeutic amounts of DP.