Iontophoretic transport of zinc phthalocyanine tetrasulfonic acid as a tool to improve drug topical delivery

Phthalocyanines have been used as systemic photosensitizers because of their high affinity towards tumour tissue, and the high rates of reactive oxygen species produced when they are irradiated during photodynamic therapy. However, the topical administration of these compounds is limited by their large size, poor hydrosolubility and ionic character. This study aimed to investigate the iontophoretic delivery of charged zinc phthalocyanine tetrasulfonic acid (ZnPcS4) from a hydrophilic gel to different skin layers by means of in-vitro and in-vivo studies. Six hours of passive administration was insufficient for ZnPcS4 to cross the stratum corneum (SC) and to reach the epidermis and dermis. No positive effect was reached when anodal iontophoresis was performed, showing that the drug-electrode attraction effect was higher than the electro-osmosis contribution at a pH of 5.5. Cathodal iontophoresis, however, was able to transport significant amounts of the drug to the viable epidermis. In addition, the absence of NaCl in the formulation significantly increased (by five-fold) the amount of ZnPcS4 that crossed the SC and accumulated in the epidermis and dermis. It was possible to visualize the drug accumulation in the follicle openings and in the epidermis, even after SC removal. In-vivo experiments in rat skin showed that these results were maintained in an in-vivo model, even with only 15 min of iontophoresis. In addition, confocal analysis of the treated skin showed a homogeneous distribution of ZnPcS4 in the viable epidermis after this short period of cathodal iontophoresis.     

Passive and iontophoretic transdermal penetration of methotrexate

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

The influence of positive or negative charges in the passive and iontophoretic skin penetration of porphyrins used in photodynamic therapy

Meso-tetra-(N-methylpiridinium-4-yl)-porphyrin (TMPyP) and meso-tetra-(4-sulfonatophenyl)-porphyrin (TPPS₄) are photosensitizing drugs (PS) used in photodynamic therapy (PDT). Based on the fact that these compounds present similar chemical structures but opposite charges at pH levels near physiological conditions, this work aims to evaluate the in vitro and in vivo influence of these electrical charges on the iontophoretic delivery of TMPyP and TPPS₄, attempting to achieve maximum accumulation of PS in skin tissue. The iontophoretic transport of these drugs from a hydrophilic gel was investigated in vitro using porcine ear skin and vertical, flow-through diffusion cells. In vivo experiments using rats were also carried out, and the penetration of the PSs was analyzed by fluorescence microscopy to visualize the manner of how these compounds were distributed in the skin after a short period of iontophoresis application. In vitro, both passive and iontophoretic delivery of the positively charged TMPyP were much greater (20-fold and 67-fold, respectively) than those of the negatively charged TPPS₄. TPPS₄ iontophoresis in vivo increased the fluorescence of the skin only in the very superficial layers. On the other hand, iontophoresis of the positively charged drug expressively increased the rat epidermis and dermis fluorescence, indicating high amounts of this drug throughout the skin layers. Moreover, TMPyP was homogeneously distributed around and into the nuclei of the skin cells, suggesting its potential use in topical PDT.     

Synthesis, in vitro evaluation, and antileishmanial activity of water-soluble prodrugs of buparvaquone

Water-soluble phosphate prodrugs of buparvaquone (1), containing a hydroxynaphthoquinone structure, were synthesized and evaluated in vitro for improved topical and oral drug delivery against cutaneous and visceral leishmaniasis. The successful prodrug synthesis involved a strong base; e.g., sodium hydride. Buparvaquone-3-phosphate (4a) and 3-phosphonooxymethyl-buparvaquone (4b) prodrugs possessed significantly higher aqueous solubilities (>3.5 mg/mL) than the parent drug (相似文献   

Iontophoretic transdermal delivery of haloperidol

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

Iontophoretic Transdermal Delivery of Haloperidol

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

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

Facilitated skin penetration of lidocaine: combination of a short-term iontophoresis and microemulsion formulation

The objective of this study was to demonstrate the potential of the application of a short-term iontophoresis on the topical delivery of lidocaine hydrochloride from a microemulsion-based system. Five- and 10-min durations of anodal iontophoresis applied onto porcine skin were examined in combination with a microemulsion containing 2.5% lidocaine hydrochloride. A similar combination (10-min iontophoresis with microemulsion in the anodal electrode) was also examined in vivo in a rat model. It was shown in vitro that by combining microemulsion application with a 10-min iontophoresis of 1.13 mA/cm2 electric current density, a significantly increased flux was obtained compared with a combination of aqueous drug solution with the same iontophoresis protocol. In vivo studies revealed that 57.71 +/- 18.65 and 18.43 +/- 9.17 microg cm(-2) were reached in the epidermis and dermis, respectively, at t = 30 min of microemulsion application, when iontophoresis was applied for 10 min. In contrast, the application of aqueous solution-iontophoresis resulted in a relatively lower drug accumulation (21.44 +/- 10.42 and 5.30 +/- 2.25 microg cm(-2) in the epidermis and dermis, respectively, at t = 30) with more rapid clearance of the drug from the skin. Ten-minute application of a low-current electric field on a new topical microemulsion appears to make significant changes in skin permeability. The potential advantages of this procedure include significantly increased flux, accumulation of a large skin drug depot, short lag times, reduced irritation (compared to long-term iontophoresis), simplicity and ease of compliance.     

Constant voltage ‘Iron’tophoresis

The objective of this study was to investigate the feasibility of rapid administration of iron via transdermal route as an alternative to parenteral route of administration. In vitro drug delivery studies were carried out using porcine epidermis mounted on Franz diffusion cells. The effect of chemical permeation enhancers and physical techniques (constant voltage iontophoresis, electroporation and combination of electroporation with iontophoresis) on the transport of ferric pyrophosphate (FPP) was studied. Transepidermal water loss (TEWL) and electrical resistance were measured in order to see the effect of these techniques on the skin barrier function. The amount of FPP permeated was not enhanced significantly with the use of any of the enhancers (P?>?0.05). It was found that constant voltage iontophoresis (0.5, 2 or 4?V) for about 30?min across electroporated epidermis (120?V, 100 pulses, 10?ms at 5 Hz) enhanced the delivery of FPP over control in the range of 2- to 42-fold. Hence, a therapeutically required dose of iron could be delivered by transdermal route using electrically-mediated techniques.     

Effect of polyethylene glycols on the trans-ungual delivery of terbinafine

Topical nail drug delivery could be improved by identifying potent chemical penetration enhancers. The purpose of this study was to assess the effect of polyethylene glycols (PEGs) on the trans-ungual delivery of terbinafine. In vitro permeation studies were carried out by passive and iontophoresis (0.5 mA/cm2) processes for a period of 1 h using gel formulations containing different molecular weight PEGs (30%w/w). The release of drug from the loaded nail plates and the possible mechanisms for the enhanced delivery was studied. Passive delivery using formulation with low molecular weight PEGs (200 and 400 MW) indicated moderate enhancement in the permeation and drug load in the nail plate, compared to the control formulation. However, the effect of low molecular weight PEGs was predominant during iontophoresis process with greater amount of terbinafine being permeated (≈35 μg/cm2) and loaded into the nail plate (≈2.7 μg/mg). However, little or no effect on drug delivery was observed with high molecular weight PEGs (1000- 3350 MW) in passive and iontophoresis processes. Release of drug from the nail plates loaded by iontophoresis using low molecular weight PEG (400 MW) exhibited sustain effect which continued over a period of 72 days. The enhancement in drug permeation by low molecular weight PEGs is likely due to their ability to lead to greater water uptake and swelling of nail. This study concluded that the low molecular weight PEGs are indeed a promising trans-ungual permeation enhancer.     

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 (Q_24h) 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 Q_24h 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.     

Pilot study of topical delivery of mono-L-aspartyl chlorin e6 (NPe6): implication of topical NPe6-photodynamic therapy

Photodynamic therapy (PDT) is an evolving cancer treatment with promising results in treating malignant tumors by photoactivation of a photosensitizer with a specific wavelength. The second generation photosensitizer mono-L-aspartyl chlorin e6 (NPe6) was reported to have significant efficacy in killing cancer cells in vitro and in vivo. Though topical application might yield a higher local concentration and less systemic side effect, no data concerning topical absorption of NPe6 is available even though the drug has already been used in clinical trial for several years. To evaluate the possibility of topical delivery of NPe6 via an animal model, escalated concentrations of NPe6 were applied to BALB/c mouse skin for a different time periods after barrier disruption with tape stripping. Since NPe6 fluorescence intensity and drug concentration in tissue was well correlated, we evaluated drug penetration depth with frozen sections of treated and non-treated skin under a fluorescence microscope. An on-line fluorescence imaging system was used to monitor the NPe6 fluorescence kinetics in the skin. The fluorescence microscope confirmed successful topical delivery of NPe6 in mouse skin with or even without barrier disruption. Orange to red NPe6 fluorescence appeared at the epidermis, dermis, and even the muscular layer when using 10 mg/ml NPe6 application. The fluorescence intensity peaked at 1 h and revealed a dose-dependent response pattern. NPe6 treated versus non-treated skin showed a statistically significant difference by Student's t-test (P<0.05). The results described here suggest that topical delivery of NPe6 is possible. It showed fast and deep penetration into mouse skin. This implies that NPe6 might be useful as a topical photosensitizer for PDT in treating skin cancers.     

电致孔-离子导入技术对胰岛素经皮给药促渗作用的研究

目的:以胰岛素为模型药物,大鼠的离体皮肤为皮肤模型,采用电致孔-离子导入联合物理促渗新技术,进行体外经皮导入生物大分子药物的研究。方法:以胰岛素为实验药物,采用经皮被动扩散方法,分别考察人体、家兔、小鼠、大鼠离体皮肤的透皮速率,从而进行皮肤模型的筛选;在预实验的基础上,选择pH值分别为4.0、6.0、7.4的三种渗透介质,采用离子导入法,考察渗透介质对胰岛素经皮渗透量的影响,从而确定渗透介质最适pH;应用电致孔-离子导入并用、电致孔、离子导入技术,在生理pH7.4、阴极转运条件下,对胰岛素的经皮渗透量进行考察,并与胰岛素的被动扩散经皮给药进行比较。结果:胰岛素对人体、家兔、小鼠、大鼠皮肤的透皮速率分别为0.78±0.03×10-1u/cm2·h、2.25±0.18×10-1u/cm2·h、2.02±0.19×10-1u/cm2·h、1.12±0.14×10-1u/cm2·h;在pH值分别为4.0、6.0、7.4的三种渗透介质中,胰岛素的经皮渗透速率分别为18.28±1.06×10-1u/cm2·h、9.42±0.29×10-1u/cm2·h、8.66±0.40×10-1u/cm2·h;采用电致孔-离子导入并用、离子导入、电致孔技术对胰岛素经皮促渗时,胰岛素的渗透速率分别达到19.63±6.37×10-1u/cm2·h、8.66±0.40×10-1u/cm2·h、1.83±0.07×10-1u/cm2·h。结论:电致孔-离子导入并用技术能够显著地促进生物大分子体外经皮给药的渗透速率。     

Topical iontophoretic delivery

At present, transdermal iontophoresis is used in the topical delivery of local anesthetics and anti-inflammatory agents. The treatment of hyperhidrosis and the diagnosis of cystic fibrosis are other clinical applications of iontophoresis. Also, a glucose-monitoring device has been developed utilizing the principle of reverse iontophoresis. Commercial iontophoretic systems that would continuously deliver therapeutic agents into the systemic circulation, corresponding to the passive transdermal patches, do not exist at the moment; however, Alza Corporation has announced that it has received an approvable letter from the US FDA regarding a new drug application for Ionsys®, an iontophoretic, fentanyl-containing, transdermal analgesic. There is currently a lot of interest in the potential of closed-loop systems, which not only sense changes in the concentration of the analyte in the skin and in the subdermal tissues, but also administer a drug in response to the fluctuating concentration/need. Thus, self-regulated or patient-regulated systems that allow medication to be administered at home would enable controlled therapy, while accounting for the individual needs of the patient. Predictable and controlled non-invasive drug delivery on the one hand, and putative adverse effects on the other, determine the success of topical iontophoretic systems and methods. The often unavoidable skin sensitization/irritation and other adverse reactions have to be related to the therapeutic benefit(s) of (bio)molecule administration; for example, the potential for skin irritation associated with pain control medication is quite different (in terms of acceptability) to skin irritation associated with cancer treatment. An additional obstacle in the path to successful transdermal delivery is the stability issue of the (bio)molecule in the drug delivery system, skin, and target tissue.     

Iontophoresis of lecithin vesicles of cyclosporin A

Site-specific immunosuppression with topical cyclosporin A (CsA) has broad clinical implications in the treatment of skin disorders like psoriasis, pyoderma gangrenosum, lichen planus, cutaneous graft-versus-host disease and contact hypersensitivity and the temporary treatment of skin allografts on burn wounds. However, like any other peptide drug, its skin delivery is hindered by the barrier property of stratum corneum and the physicochemical properties of CsA. We have attempted to deliver CsA across human cadaver epidermis in vitro using colloidal systems like microemulsion and lecithin vesicles and iontophoresis. Although, passive diffusion did not result in permeation of quantifiable amounts of CsA, anodal iontophoresis of the negatively charged colloidal systems facilitated the permeation. Electroosmosis and compromised epidermis might have contributed to the higher skin flux. Lecithin vesicles were better than microemulsion for the iontophoretic delivery of CsA and appear to have potential in site-specific immunosuppression.     

Examination of penetration routes and distribution of ionic permeants during and after transscleral iontophoresis with magnetic resonance imaging

Previously, transscleral and transcorneal iontophoretic delivery was studied and compared to passive delivery and intravitreal injection using nuclear magnetic resonance imaging (MRI). The objective of the present study was to employ MRI to further investigate the factors affecting transscleral iontophoretic delivery. In the present study, anodal and cathodal constant current transscleral iontophoresis were conducted with excised sclera in side-by-side diffusion cells in vitro and with rabbits in vivo. The total current and duration of application were 2 and 4mA (current density 10 and 20mA/cm(2)) and 20-60min, respectively. The delivery and distribution of the model permeants manganese ion (Mn(2+)) and manganese ethylenediaminetetraacetic acid complex (MnEDTA(2-)) into the eye during iontophoresis were determined with MRI and compared with the results obtained in previous studies of subconjunctival injection and passive delivery. Both anodal and cathodal iontophoresis provided significant enhancement in ocular delivery compared to passive transport in the in vitro and in vivo experiments. Transscleral iontophoretic delivery was related to the position and duration of the iontophoresis application in vivo. Permeants were observed to be delivered primarily into the anterior segment of the eye when the pars plana was the application site. Extending the duration of iontophoresis at this site allowed the permeants to be delivered into the vitreous more deeply and to a greater extent than when the application site was at the back of the eye near the fornix. The present results show that electrode placement was an important factor in transscleral iontophoresis, and the ciliary body (pars plana) was determined to be the pathway of least resistance for iontophoretic transport. These new findings continue to support the utility of MRI as a noninvasive technique in ocular drug delivery research and testing.     

Enhancing effect of switching iontophoresis on transdermal absorption of glibenclamide

Glibenclamide(GLI) is widely used as an oral hypoglycemic drug in the treatment of non-insulin dependent diabetes mellitus (NIDDM). We investigated The enhancing effect of switching iontophoresis on the transdermal absorption and reduction of skin irritation to develop a transdermal dosage form of GLI. The 0.1% of Gli suspensions in 0.2 M tris-HCl buffer of pH 7.4, 8.0 and 8.5 were prepared as donor solutions. We examined drug permeation through the excised rat abdominal skin, drug absorption in rats and reduction of skin irritation after application of switching iontophoresis for 1 h using DC 10 V. The solubility of GLI in 0.2 M tris-HCl buffer increased with a rise in pH. In the permeation study, GLI was permeated continuously and the cumulative amount of permeated GLI increased using an alkaline donor solution. In the drug absorption study, the application group of pH 8.5 gave higher plasma concentration levels than those of pH 7.4 and 8.0 groups. The skin irritation evoked by the application of iontophoresis was pathologically studied. A total irritation score (TIS) was estimated as a judging standard for the skin damage. The TIS value increased dependently with a rise in pH. However, it was considered that the skin irritations were not serious and small matters. The results demonstrate the possibility of iontophoretic transdermal administration of GLI and the effect of drug solubility in the donor solution on the absorption of GLI.     

Evaluation of transdermal iontophoresis of enoxacin from polymer formulations: in vitro skin permeation and in vivo microdialysis using Wistar rat as an animal model

Polymers were used in vehicles to form hydrogel matrices in this study to evaluate the in vitro permeation and in vivo microdialysis of enoxacin. The highest transdermal delivery determined by area under flux-time curve (AUC) and intracutaneous enoxacin concentration were observed in methylcellulose (MC) and polyvinylpyrrolidone (PVP) hydrogels, respectively. To avoid the pH shift in vehicles during iontophoresis, buffer species were added to formulations to increase the buffer capacity. As expected, the permeability of enoxacin of anodal iontophoresis was larger than that of cathodal iontophoresis. Combination of benzalkonium chloride, a cationic surfactant as an enhancer, and iontophoresis exerted an enhancing effect for anionic enoxacin at pH 10.0. However, no effect or a negative effect was detected for cationic enoxacin in deionized water or pH 5.0 buffer, due to the shielding of the negative charge in the skin. The skin residue of enoxacin was slightly increased after the incorporation of Azone in PVP hydrogel. The result of in vivo microdialysis was in accordance with that of in vitro study. The effect of Azone on the intracutaneous enoxacin was more significant for in vivo microdialysis than in the in vitro study indicating the clinical feasibility of Azone for iontophoretic delivery. Microdialysis can be considered as a useful technique to investigate the pharmacokinetics of transdermal iontophoresis in vivo.     

Improving the direct penetration into tissues underneath the skin with iontophoresis delivery of a ketoprofen cationic prodrug

Current topical nonsteroidal anti-inflammatory drugs (NSAIDs) showed marginal efficacy in treatment of musculoskeletal disorders due to their fast clearance by skin blood flow and thus little direct penetration into the underlying muscle and joint tissues. Using ketoprofen (Kt) as a model NSAID and converting it to a cationic ester prodrug ketoprofen choline chloride (KCC), this study was to investigate the iontophoresis delivery of the prodrug KCC for improving the drug retention in the skin and the direct penetration into underlying tissues. From in vitro flux study, anodal iontophoresis of KCC showed 5 times higher flux than cathodal iontophoresis of Kt across human epidermis skin, and also 1.5 times higher across full thickness rat skin. From in situ dual agar gel model rat study, anodal iontophoresis of KCC showed 35 times more drug penetrating across the live skin into underlying agar gel and 22 times more drug retained in the skin than those from cathodal iontophoresis of Kt. Co-iontophoresis of a vasoconstrictor phenylephrine with KCC did not show better result than the iontophoresis of KCC alone. Overall, iontophoresis delivery of the cationic prodrug KCC showed great potential for direct penetration into local tissues underneath the skin.     

Transdermal delivery of indomethacin by iontophoresis

The objective of this study was to construct a modified equation for the delivery of a drug by iontophoresis. Indomethacin was selected as a model since it has been widely used as a non-steroidal anti-inflammatory drug (NSAID) for external pharmaceutical preparations. The experiments were performed under a constant current in vivo using rat abdominal skin, and the plasma concentration was monitored by HPLC. Pharmacokinetic parameters were obtained from the plasma concentration profiles after intravenous injection. A theoretical value of the transdermal delivery of drug by iontophoresis was calculated from the plasma concentration and pharmacokinetic parameters. The experimental value was evidently higher than the theoretical one, suggesting the enhancement of passive diffusion with an increase of applied current. The modified equation was proposed for the delivery of a drug by iontophoresis incorporating enhanced passive diffusion.     

Iontophoretic enhancement of timolol across human dermatomed skin in vitro

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