Controlled delivery of ropinirole hydrochloride through skin using modulated iontophoresis and microneedles

Abstract The objective of this study was to investigate the effect of modulated current application using iontophoresis-and microneedle-mediated delivery on transdermal permeation of ropinirole hydrochloride. AdminPatch Õ microneedles and microchannels formed by them were characterized by scanning electron microscopy, dye staining and confocal microscopy. In vitro permeation studies were carried out using Franz diffusion cells, and skin extraction was used to quantify drug in underlying skin. Effect of microneedle pore density and ions in donor formulation was studied

Therapeutic Peptides and Protein

354hal.;26c

PII: S0167-7799(98)01238-4

R ecent advances in biotechnology have resulted in a significant increase in the number of therapeutic macromolecules that are reaching the market. Although earlier developments were restricted to recombinant DNA and monoclonal antibodies, the field of biotechnology has rapidly expanded into other areas, such as peptides, proteins, carbohydrates and oligonucleotides and other gene-based compounds. Clinical application of these bioactive macromolecules has been limited, in large part, by the difficulty of delivering them in a biologically active form. Transdermal administration is attractive because it avoids degradation in the liver or gastrointestinal tract, but normal skin is impermeable to most compounds, especially macromolecules. By reversibly overcoming the skin's barrier properties, electroporation may provide a way to deliver these agents. In this article, we provide an overview of electroporation and the ways it can be used to enhance drug delivery into and across tissues. We then focus specifically on the transdermal delivery of peptides, polysaccharides, oligonucleotides and genes, and evaluate their prospects for commercial and clinical application. More detailed information about electrically assisted transdermal delivery of conventional drugs and peptides can be found in two recent publications 1,2 . Electroporation of skin for drug delivery Although the electroporation of cell membranes was demonstrated in the early 1970s, electroporation of skin has only recently been shown to be feasible 3 . Electroporation is best known as a physical transfection method in which cells are exposed to a brief electrical pulse, which reversibly permeabilizes cell membranes and allows DNA or other macromolecules to enter the cells. The main laboratory application of electroporation is for DNA transfection. Although the exact mechanism by which electroporation works is not clear, the transient formation of nanometer-wide aqueous pores in the membrane is generally believed to occur. Until recently, electroporation had been primarily observed in the unilamellar phospholipid bilayers of cell membranes. However, it has been shown that electroporation of skin's stratum corneum is possible, even though the membranes found in this tissue differ significantly from normal cell membranes: stratum corneum contains multilamellar, intercellular lipid bilayers with few phospholipids and no living cells 3 . The ability to electroporate stratum corneum is significant because this tissue provides the main barrier to transdermal transport. Subsequent experiments addressing the transport of model compounds and electrical measurements have further supported the hypothesis that aqueous pathways can be created in skin by high-voltage pulsing 4,5 . This is in contrast to iontophoresis, another electrical technique for increasing transdermal transport, which involves the use of relatively small transdermal voltages (р10 V) to drive compounds across intact skin electrophoretically. Skin electroporation takes place only at large transdermal voltages (у50 V) and is associated with changes in the skin structure A broad range of molecules have been delivered by skin electroporatio

Effect of Modulated Alternating and Direct Current Iontophoresis on Transdermal Delivery of Lidocaine Hydrochloride

The objective of this study was to investigate the iontophoretic delivery of lidocaine hydrochloride through porcine skin and to compare the effects of modulated alternating and direct current iontophoresis. Continuous and modulated iontophoresis was applied for one hour and two hours (0-1 h and 4-5th h) using a 1% w/v solution of lidocaine hydrochloride. Tape stripping was done to quantify the amount of drug permeated into stratum corneum and skin extraction studies were performed to determine the amount of drug in stripped skin. Receptor was sampled and analyzed over predefined time periods. The amount of lidocaine delivered across porcine skin after modulated direct current iontophoresis for 2 h was 1069.87±120.03 μg/sq·cm compared to 744.81±125.41 μg/sq·cm after modulated alternating current iontophoresis for 2 h. Modulated direct current iontophoresis also enhanced lidocaine delivery by twelvefold compared to passive delivery as 91.27±18.71 μg/sq·cm of lidocaine was delivered after passive delivery. Modulated iontophoresis enhanced the delivery of lidocaine hydrochloride across porcine skin compared to the passive delivery. Modulated alternating current iontophoresis for duration of 2 h at frequency of 1 kHz was found to be comparable to the continuous direct current iontophoresis for 1 h

Microneedle-Assisted Transdermal Delivery of Lurasidone Nanoparticles

Lurasidone, an antipsychotic medication for schizophrenia, is administered daily via oral intake. Adherence is a critical challenge, given that many schizophrenia patients deny their condition, thus making alternative delivery methods desirable. This study aimed to deliver lurasidone by the transdermal route and provide therapeutic effects for three days. Passive diffusion was found to be insufficient for lurasidone delivery. The addition of chemical enhancers increased permeation, but it was still insufficient to reach the designed target dose from a patch, so a microneedle patch array was fabricated by using biodegradable polymers. For prolonged and effective delivery, the drug was encapsulated in Poly (lactic-co-glycolic acid) (PLGA) nanoparticles which were made using the solvent evaporation method and incorporated in microneedles. Effervescent technology was also employed in the preparation of the microneedle patch to facilitate the separation of the needle tip from the patch. Once separated, only the needle tip remains embedded in the skin, thus preventing premature removal by the patient. The microneedles demonstrated robust preformation in a characterization test evaluating their insertion capacity, mechanical strength, and the uniformity of microneedle arrays, and were able to deliver a dose equivalent to 20 mg oral administration. Therefore, the potential of a transdermal delivery system for lurasidone using microneedles with nanoparticles was demonstrated

Iontophoretic and Microneedle Mediated Transdermal Delivery of Glycopyrrolate

Purpose: The objective of this study was to investigate the use of iontophoresis, soluble microneedles and their combination for the transdermal delivery of glycopyrrolate. Methods: In vitro permeation was tested using full thickness porcine ear skin mounted onto Franz diffusion cells. Iontophoresis (0.5 mA/cm2) was done for 4 h using Ag/AgCl electrodes. For microneedles, three line array (27 needles/line) of maltose microneedles were used to microporate the skin prior to mounting. Pore uniformity was determined by taking fluorescent images of distribution of calcein into pores and processing the images using an image analysis tool, which measured the fluorescent intensity in and around each pore to provide a pore permeability index (PPI). The donor chamber contained 500 µL of a 1 mg/mL solution of glycopyrrolate, and the receptor chamber contained 5 mL of 50 mM NaCl in deionized water. Samples were collected at predetermined time points over a period of 24 h and analyzed by HPLC. Skin irritation testing was performed with a 3D cell culture kit of human skin. MTT assay determined cell viability; viability less than 50% was considered irritant. Results: A control experiment which investigated passive permeation of glycopyrrolate delivered an average cumulative amount of 24.92 ± 1.77 µg/cm2 at 24 h, while microneedle pretreatment increased permeability to 46.54 ± 6.9 µg/cm2. Both iontophoresis (158.53 ± 17.50 µg/cm2) and a combination of iontophoresis and microneedles (182.43 ± 20.06 µg/ cm2) significantly increased delivery compared to passive and microneedles alone. Glycopyrrolate solution was found to be nonirritant with cell viability of 70.4% ± 5.03%. Conclusion: Iontophoresis and a combination of iontophoresis with microneedle pretreatment can be effectively used to enhance the transdermal delivery of glycopyrrolate. Glycopyrrolate was found to be non-irritant to skin

Clinical Applications of Iontophoretic Devices in Rehabilitation Medicine

Interest within the healthcare profession in transdermal delivery of pharmaceuticals through passive, mechanical (phonophoresis) or electromotive (iontophoresis) forces has increased significantly throughout the past decade. The current review will examine the histology and cellular biology of the integument system as related to regulation of transcutaneous delivery of pharmaceutics, and examine currently accepted mechanism(s) of iontophoretic delivery. Additionally, a survey of current iontophoretic devices and electrodes available within the U.S. market, and the limitations of current technology will be presented. Experimental research supporting the use of iontophoresis for local delivery of pharmaceuticals will also be presented in conjunction with the outcomes of clinical investigations where iontophoresis was utilized for the local delivery of these pharmaceuticals. Topic areas to be covered within this section include iontophoresis of antibiotics into integument wounds, local anesthetics, and steroidal and nonsteroidal anti- inflammatory drugs. Finally, an examination of the benefits of combining various forces to enhance transcutaneous drug delivery and future direction(s) of research within this field will be discussed. The purpose of the present review is to provide both researchers and clinical practitioners with an objective basis for the current use of iontophoresis in rehabilitation medicine

Electrically and Ultrasonically Enhanced Transdermal Delivery of Methotrexate

In this study, we used sonophoresis and iontophoresis to enhance the in vitro delivery of methotrexate through human cadaver skin. Iontophoresis was applied for 60 min at a 0.4 mA/sq·cm current density, while low-frequency sonophoresis was applied at a 20 kHz frequency (2 min application, and 6.9 W/sq·cm intensity). The treated skin was characterized by dye binding, transepidermal water loss, skin electrical resistance, and skin temperature measurement. Both sonophoresis and iontophoresis resulted in a significant reduction in skin electrical resistance as well as a marked increase in transepidermal water loss value (p < 0.05). Furthermore, the ultrasonic waves resulted in a significant increase in skin temperature (p < 0.05). In permeation studies, the use of iontophoresis led to a significantly higher drug permeability than the untreated group (n = 4, p < 0.05). The skin became markedly more permeable to methotrexate after the treatment by sonophoresis than by iontophoresis (p < 0.01). A synergistic effect for the combined application of sonophoresis and iontophoresis was also observed. Drug distribution in the skin layers revealed a significantly higher level of methotrexate in the sonicated skin than that in iontophoresis and untreated groups. Iontophoresis and low-frequency sonophoresis were found to enhance the transdermal and intradermal delivery of methotrexate in vitro

Iontophoretic Devices: Clinical Applications and Rehabilitation Medicine

Interest within the healthcare profession in transdermal delivery of pharmaceuticals through passive, mechanical (phonophoresis) or electromotive (iontophoresis) forces has increased significantly throughout the past decade. The current review will examine the histology and cellular biology of the integument system as related to regulation of transcutaneous delivery of pharmaceutics, and examine currently accepted mechanism(s) of iontophoretic delivery. Additionally, a survey of current iontophoretic devices and electrodes available within the U.S. market, and the limitations of current technology will be presented. Experimental research supporting the use of iontophoresis for local delivery of pharmaceuticals will also be presented in conjunction with the outcomes of clinical investigations where iontophoresis was utilized for the local delivery of these pharmaceuticals. Topic areas to be covered within this section include iontophoresis of antibiotics into integument wounds, local anesthetics, and steroidal and nonsteroidal anti-inflammatory drugs. Finally, an examination of the benefits of combining various forces to enhance transcutaneous drug delivery and future direction(s) of research within this field will be discussed. The purpose of the present review is to provide both researchers and clinical practitioners with an objective basis for the current use of iontophoresis in rehabilitation medicine

Clinical Applications of lontophoretic Devices in Rehabilitation Medicine

Interest within the healthcare profession in transdermal delivery of pharmaceuticals through passive, mechanical (phonophoresis) or electromotive (iontophoresis) forces has increased significantly throughout the past decade. The current review will examine the histology and cellular biology of the integument system as related to regulation of transcutaneous delivery of pharmaceutics, and examine currently accepted mechanism(s) of iontophoretic delivery. Additionally, a survey of current iontophoretic devices and electrodes available within the U.S. market, and the limitations of current technology will be presented. Experimental research supporting the use of iontophoresis for local delivery of pharmaceuticals will also be presented in conjunction with the outcomes of clinical investigations where iontophoresis was utilized for the local delivery of these pharmaceuticals. Topic areas to be covered within this section include iontophoresis of antibiotics into integument wounds, local anesthetics, and steroidal and nonsteroidal anti- inflammatory drugs. Finally, an examination of the benefits of combining various forces to enhance transcutaneous drug delivery and future direction(s) of research within this field will be discussed. The purpose of the present review is to provide both researchers and clinical practitioners with an objective basis for the current use of iontophoresis in rehabilitation medicine