Iontophoretic drug delivery systems

Iontophoretic drug delivery systems

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Amit Kumar Nayak1, Sanjay Dey2, Kunal Pal3 and Indranil Banerjee3 1 Department of Pharmaceutics, Seemanta Institute of Pharmaceutical Sciences, Mayurbhanj, India, 2Department of Pharmaceutics, School of Pharmacy, Techno India University, Kolkata, India, 3Department of Biotechnology and Medical Engineering, National Institute of Technology, Rourkela, India

Introduction The architecture and composition of uppermost layer of the skin (i.e., stratum corneum) serves as the barrier for the transdermal delivery of drugs (Das, Nayak, & Nanda, 2013; Jana, Ali, Nayak, Sen, & Basu, 2014; Jana, Manna, Nayak, Sen, & Basu, 2014). Currently, the development of various effective transdermal drug delivery systems has become one of the most popular and attractive research areas in the field of drug delivery research and development (Das et al., 2013; Lobo & Yan, 2018). The transdermal delivery of the drugs offers a significant potential for the patient-friendly administrations of numerous drugs in a noninvasive way. It also helps to avoid the hepatic first-pass metabolism of the drug molecules. Further, this method also facilitates the avoidance of chemical degradation in the potential hostile milieu of the gastrointestinal tract. Skin is the largest organ, which is easily accessible and available for the transdermal delivery of drugs. In case of the transdermal drug delivery, when the flux of the drug is controlled by the drug delivery system and not by the stratum corneum, the drug delivery occurs in a more reproducible way. This leads to the smaller intra- and intersubject variability. In such cases, the drug releasing from the transdermal systems can be monitored accurately (Naik, Kalia, & Guy, 2000). To achieve improved therapeutics by minimizing or limiting the barrier problem, several drug permeation/penetration techniques have been investigated and proposed. Among all the methods, the use of a constant electrical current (i.e., iontophoresis) to attain higher drug permeation/penetration has gained much attention in recent years (Dhal et al., 2017; Lobo & Yan, 2018). The process of iontophoresis deals with the permeation/penetration of the ionic or the neutral drugs across the skin barrier under the influence of an externally applied small electrical current (i.e., # 0.50 mA/cm2). Currently, it is considered as one of the prospective novel drug delivery approaches. This method has been successfully employed to enhance the skin permeation/penetration of numerous drug candidates (Lohe, Jadkar, Modekar, & Bhusare, 2016). The amount of drug

Bioelectronics and Medical Devices. DOI: https://doi.org/10.1016/B978-0-08-102420-1.00022-4 Copyright © 2019 Elsevier Ltd. All rights reserved.

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delivered by iontophoresis is directly proportional to the magnitude of the applied electrical current, application time, and contact area between the electrode and the skin interface. The applied electrical current can be customized to attain the effective drug input kinetics. It is possible to obtain a continuous or pulsatile drug release just by modulating the profile of the electrical current (Giri, Chakrabarty, & Ghosh, 2017; Lohe et al., 2016). The main advantage of the iontophoretic drug delivery system is its capability to deliver both high as well as low molecular weight drugs. In the current chapter, historical background, principle and mechanism, applications of iontophoretic drug delivery, and also various synergistic approaches with the iontophoresis are comprehensively reviewed.

Historical background The concept of iontophoresis was first described in 1747, in a publication by Giovanni Francesco Pivati (1689 1764). In this study, the aroma of Peruvian balsam, which was stored in a hermetically sealed glass cylinder, was reported to become apparent in the room under the influence of an electrical current. The aroma could be transmitted to another room by a conducting wire (Khan et al., 2011). Significant contributions in the field of iontophoresis were made by Bernard Raymond Fabre´-Palaprat (1773 1833), a French physician. Thereafter, further improvement in the technological development on the iontophoretic research was carried out by Benjamin Ward Richardson (1828 96), who was the first person to propose the clinical use of iontophoresis for dental applications. During the 1970s, electrical current induced delivery of substances through the porous membranes was extensively researched by Hermann Munk (1839 1912). Significant advancements in the field of iontophoretic approaches were noticed during the 19th century. During this period, the administration of metal ions and alkaloids were successfully investigated (Khan et al., 2011). At the beginning of the 20th century, Stephen Leduc (1900) introduced the term iontotherapy. He has been credited as formulating various laws pertaining to the process, which are still valid (Khan et al., 2011). The approaches of administering different pharmacological substances by the iontophoretic technique became popular since then. Until the early 20th century, the electrical current-mediated delivery of the substances was called cataphoresis. Fritz Frankenhauser first introduced the term iontophoresis, when the drugs and the other substances were delivered using an electrical current (Khan et al., 2011). The use of iontophoresis for the treatment of hyperhidrosis by ion transfer has been proposed by electrophoretic methodology. The treatment of hyperhidrosis by iontophoresis is one of the most popular applications of iontophoresis currently in the dermatological therapeutics. The transdermal delivery of numerous ionized drugs, which were previously excluded for transdermal delivery due to their slower diffusion rates across the skin layer, has been made possible by iontophoresis (Wang, Thakur, Fan, & Michniak, 2005).

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Principles and mechanisms of iontophoretic drug delivery Iontophoresis is generally reliant on the basic electrical principle that “like electrical charges repel each other” (Pal, Sagiri, Pattnaik, & Ray, 2014). Therefore at the time of iontophoresis, if the transport of a positively charged drug candidate is desired, the charged drug candidates are placed under the electrode of similar polarity (i.e., anode) (Dhote, Bhatnagar, Mishra, Mahajan, & Mishra, 2012). The drug is repelled by the electromotive force and thereby moves across the skin barrier toward the cathode (Giri et al., 2017). The ionic-electric field interaction is called the Nernst-Planck effect, and it is the largest contributor to the flux enhancement of small ions. The communication between the active and the passive electrodes along the skin surface are negligible. In other words, the movement of ionic drug molecules and ions results in the electrical connection among the electrodes (Lohe et al., 2016). When the cathode is positioned within the donor chamber of the diffusion cell to augment the permeation flux of an anionic drug, the process is known as cathodal iontophoresis. On the other hand, when the anode is positioned within the donor chamber, it is known as anodal iontophoresis. The flux of neutral drug molecules has been due to electroosmotic flow. In this case, the drug molecules move under the influence of convective flow caused by the osmotic forces and electroosmotic forces due to the flow of electrical current (Khan et al., 2011). A simple iontophoresis device contains two electrode chambers and a power source. A typical iontophoresis system employing an Ag/AgCl electrode has been shown in Fig. 16.1. Let us consider a formulation (D1A2) of an ionized drug molecule (D1), which is placed within the anodal chamber. The indifferent electrode chamber is positioned at the distal position on the skin surface. Though various kinds of electrodes are available for the iontophoresis applications, the most commonly used electrode system for iontophoresis is Ag/AgCl. This is because of the good pH-stability of the Ag/AgCl electrode system. Further, the electrostability of the Ag/AgCl electrode is very good. This results in the formation of a lower number of protons by the electrolysis during the iontophoresis process. The electrode system, which generates a large number of protons, lowers the pH of the anodal chamber. This may result in acid-induced skin burns. In some cases, the stability of the drug molecules can also be altered. The application of the electrical field induces directionality on the movement of ions, where the positively charged ions (cations; present in the anodal chamber) move in the direction of the cathodal chamber. On the other hand, the negatively charged ions (anions) concurrently move in the reverse direction toward the anodal chamber (Kalia, Naik, Garrison, & Guy, 2004). The electrochemical reaction occurring at the Ag anode requires the presence of Cl2 anions within the anodal chamber. This reduces the drug delivery efficiency using iontophoresis, as the NaCl (commonly employed to facilitate Cl2 anions) generates significant concentrations of highly mobile Na1 ions. These Na1 ions compete with the drug molecules during the transport process (Kalia et al., 2004). Further, the Cl2 ions react with Ag (metallic) electrode to form AgCl and get deposited over the electrode surface. The deposition is triggered by the lower solubility

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Constant current source e

e Anode (+)

Cathode (–) AgCl AgCl AgCl AgCl

Ag Ag Ag Ag Ag Ag Ag Ag Ag Ag Ag Ag Ag Ag

AgCl AgCl AgCl

Ag(s) + Cl–(aq)→AgCl (s) + e–

Na+

Cl–

Cl–

Na+

Cl–

Cl–

Na+

Cl–

Na+ Na+

A–

D+

Cl–

Na+

Na+

Na+

Cl–

Skin Cl– Na+

AgCl

AgCl (s) + e–→Ag(s) + Cl–(aq)

Na+

Cl–

Na+

Cl–

Cl–

Figure 16.1 A simple diagram of iontophoretic device containing an Ag/AgCl electrode. The anodal chamber comprises drug formulation (D1A2) containing the ionized drug molecule (D1) with its counter ion (A2) and Na1Cl2. Use of an electrical potential produces a current flowing through the electrical circuit. At the interface of the electrode solution, the Ag1 and Cl2 react and form insoluble AgCl, which is deposited on the surface of the electrode. The electromigration transports the cations, including the drug molecule, from the anodal chamber and into the skin. At the same time, the endogenous anions (primarily Cl2) move into the anodal chamber. In the cathodal chamber, Cl2 ions are released from the electrode and electroneutrality needs that either an anion is lost from the cathodal chamber. (Kalia, Y. N., Naik, A., Garrison, J., & Guy, R. H. (2004). Iontophoretic drug delivery. Advanced Drug Delivery Reviews, 56, 619 658. © 2003, with permission from Elsevier B.V.)

product of the AgCl. In the anodal chamber, for the maintenance of electroneutrality either a cation has to leave the chamber and enter into the skin or an anion has to move out of the skin and travel to the anodal compartment. On the other hand, in the cathodal chamber, AgCl is decreased by the electrons from the current supply source. This results in the production of Ag (metallic) and Cl2 ions (which goes into the solution). Moreover, this has to be balanced through the advent of a cation from the skin into the cathodal compartment or through an anion loss to maintain the electroneutrality. The circuit (electrical) is fulfilled by means of the endogenous inorganic ions, principally by Na1 and Cl2 ions (which are present in the skin). The molecular transportation of the drug(s) through the iontophoresis is made possible by any of the two principal mechanisms, namely, electrorepulsion and

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electroosmosis (Pal et al., 2014). The electrorepulsion mechanism is relevant when the drug molecules to be transported are the ionized species (charged). In contrast, the electroosmosis mechanism is predominantly applicable when the drug molecules are electrically neutral. The phenomenon of the electroosmosis mechanism may be related with ionization of the acidic groups present in the phospholipidic structure of cell membranes, which causes the movement of Na1 cations in the direction of the cathodal chamber so as to neutralize the charge difference. This results in the initiation of an osmotic flow of water in the direction of anodeto-cathode due to the movement of Na1 ions. For the duration of the water flow, the neutral drug molecules are also transported across the skin. The nature of the electrical potential gradient used during the iontophoresis plays a significant role in the drug transportation process. Apart from this, size, mobility, and polarity of the drug molecules also influence the iontophoretic transport process of the drug molecules. Further, the characteristics of the drug formulation can also tailor the drug transportation process (Malinovskaja-Gomez, Labouta, Schneider, Hirvonen, & Laaksonen, 2016).

Advantages and disadvantages of iontophoresis systems The skin surface presents a highly lipophilic character. Due to this reason, there is a restriction in the penetration/permeation of the hydrophilic, high molecular weight and electrically charged drug molecules across the skin layer (Lohe et al., 2016). Iontophoresis employs an electrical potential that maintains a constant electrical current across the active and the passive electrodes. It is possible to design either a continuous or a pulsatile drug delivery system just by tailoring the amplitude of the injected electrical current. The flow of current across the electrode system, through the human body, improves the delivery of both unionized and ionized drug molecules (Dhote et al., 2012). The main advantage of the iontophoresis is its ability to deliver a wide range of drug molecules into the systemic circulation in a noninvasive manner. Since the drug molecules are directly delivered into the systemic circulation, iontophoresis helps in bypassing the hepatic first-pass metabolism. This helps in improving the bioavailability of drugs. Further, it is possible to deliver accurate amounts of drug to the patients. This can be explained by the fact that the delivery of drugs is directly proportional to the quantum of electric current injected, which is dependent on the amplitude of the current and duration of electrical current applied. Due to this reason, the drug delivery is not dependent on the characteristics of skin layer. Most importantly, the alterations in the skin physiology during the drug transportation process are reversible (i.e., the skin physiology returns to its normogenic condition after the injection when the electric current is switched off) (Khan et al., 2011). Moreover, iontophoresis technique increases patient compliances due to its noninvasive manner of drug delivery. Just by switching off the electrical current, it is possible to terminate the drug delivery process. This renders the drug delivery termination process very simple and easy (Kalia et al., 2004).

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Therefore it eliminates the underdosing or overdosing possibilities by the continuous delivery of drugs at the predetermined therapeutic rates. Iontophoretic drug delivery system minimizes the occurrence of various side effects due to its ability to deliver the accurate amount of drug molecules as compared to the conventional drug delivery systems (including transdermal drug delivery) (Dhote et al., 2012). This technique is a suitable alternative for the delivery of potent proteins and peptides that are very short-acting in nature and need the delivery in the circadian pattern to induce the physiological rhythm (Lohe et al., 2016). Though there are several advantages, some shortcomings of the iontophoresis technique for the drug delivery are also identified (Hirvonen, 2005). During iontophoresis, an excessive current density induces pain. In some cases, changes in the electrode sizes have also been reported. If proper care is not taken during the device development and drug formulation process, electric shocks due to high current density and skin and underlying tissue burns have been reported by many researchers. Lastly, the use of iontophoretic drug delivery is clinically limited if the drug delivery is required for a brief period (Kalia et al., 2004).

Factors influencing the iontophoretic drug delivery Various factors influencing the ionotropic drug delivery can be categorized into four classes: physicochemical characteristics of drugs, drug formulation characteristics, and biological and experimental factors (Fig. 16.2).

Physicochemical characteristics of drugs Molecular weight and size of drugs: The molecular weight and size of the drugs are considered as two prime issues concerning the efficiency of iontophoretic drug delivery applications (Khan et al., 2011). The small-sized and more hydrophilic ions are transported at a faster rate as compared to the large-sized and less hydrophilic ions. The permeability coefficients of the drug molecules (whether charged or uncharged) across the skin are also dependent on the molecular sizes of drugs. With the increase in the molecular sizes of the drugs, the permeability coefficient decreases. Several investigations have reported that the permeation flux is a function of the molecular weights of drugs. It has been reported that during the drug delivery by the electrorepulsive iontophoresis approach, the transport of drugs reduced with the increment in the molecular weight of drugs (insulin , tripeptide , nucleotide , amino acid , chloride). During the study, all other parameters/ conditions were kept constant (Khan et al., 2011). Electrical charge of drug molecules: Electrical charges of the drug molecules are recognized as a significant parameter that can govern the transport phenomena of the drug molecules. In fact, the nature of the electrical charge on the drug molecules determines the mechanism through which the drug transport process will occur (e.g., electroosmosis and electrorepulsion) (Khan et al., 2011). It has been

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Factor influencing iontophoretic drug delivery

Physicochemical characteristics of drugs

Biological factors (1) Skin pH (2) Skin condition (3) Regional blood flow (4) Intra-and inter -subject variability

(1) Molecular weight and size of drugs (2) Electrical charge of drug molecules (3) Polarity of drug molecules (4) Concentration of drugs Experimental factors

Drug formulation characteristics

(1) Current density (2) Current strength (3) Pulsed current (4) Period of current apply (5) Electrode materials

(1) pH of formulation (2) Ionic strength (3) Presence of co-ions

Figure 16.2 Various factors influencing the ionotropic drug delivery.

observed that the transport of the cationic drug molecules occurs in a comparatively better manner as compared to the anions (peptides and amino acid molecules) (Kalia et al., 2004). Furthermore, an augmented positive electrical charge on the peptide drug molecule results in the very strong association of the drug molecules with the membrane. This results in the formation of a reservoir, which in turn can reduce the permeation rate of the peptide drugs (Batheja, Thakur, & Michniak, 2006). Polarity of drug molecules: In general, the hydrophilic drugs are recognized as the ideal drug candidates for achieving the optimal permeation flux. For example, the permeation flux of nalbuphine and its ester derivatives were increased as the lipophilicity of the drug was reduced (Khan et al., 2011). Concentration of drugs: The influence of the concentration of several drug molecules has already been studied. It has been observed that an increment in the drug concentration resulted in an apparent increase in the permeation flux for a number of drugs including ketorolac (Tiwari & Udupa, 2003), diclofenac (Koizumi et al., 1990), and metoprolol (Thysman, Pre´at, & Roland, 1992). The increment in the drug permeation fluxes is proportional to the increase in the drug concentration

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(Batheja et al., 2006). Though the drug concentration-dependent iontophoretic drug delivery has not been extensively researched, few of the researchers have found that the permeation of the drugs increased with the increment of the drug concentration in the reservoir (Khan et al., 2011; Lohe et al., 2016).

Drug formulation characteristics pH of the formulation: pH of the formulation is another important issue for achieving effective iontophoretic delivery of the drug molecules. The pH influences the iontophoretic delivery in two ways. First, the pH of the formulation affects the skin pH, thereby making the skin layer as permeation selective membrane. This phenomenon is generally observed when pH of the skin rises above pH 4. The occurrence of the phenomenon can be explained by the ionization of the carboxylic acid moieties present in the skin tissue. Thus the anodal iontophoresis improves the skin permeation of the cationic drug candidates. Second, the formulation pH also influences the ionization of drug molecules (Khan et al., 2011). A weakly basic drug molecule in the formulation will be ionized to a lesser extent when the pH of the formulation is greater than the pKa value. In such a case, the drug will not be transported through electromigration process during iontophoresis. The transport of such drug molecules across the skin mainly occurs via the electroosmosis (Batheja et al., 2006). Extensive researches have been carried out to investigate the pH-dependent penetration of various drug molecules, such as insulin, enalaprilat, lidocaine, and rotigotine (Khan et al., 2011; Lohe et al., 2016). Ionic strength: The iontophoretic permeation of drug molecules is dependent on the ionic strength of the drug delivery formulations (Thysman et al., 1992). An increase in the ionic strength of formulations reduces the drug permeation/transport rate. It has been reported that there is no significant influence of the ionic strength of formulations on the permeation/penetration of drug molecules up to an applied potential of 0.50 V (Khan et al., 2011). The effect of the ionic strength of formulations on permeation of drug molecules has been studied extensively by various research groups. The results have indicated an increase in the permeation flux at the lower concentration of the electrolytes (Khan et al., 2011). Presence of coions: An ion containing equal electrical charge of different kinds is known as coions. The buffering agents employed to maintain the pH of the donor medium is the main source of coions, which are commonly more mobile than the ionized drugs due to their small size (Khan et al., 2011). In the presence of coions, a competition among the coions and the drug molecules takes place. This results in the decrease of the fraction of the injected current being carried out by the drug molecules. Due to this reason, there is a reduction in the transdermal permeation of the drug molecules (Naik et al., 2000).

Experimental factors Current density: Current density is defined as the amount of current transported per unit of electrode surface area. The applied current should be sufficiently higher to

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facilitate the drug permeation/transportation rate of desired quantity (Khan et al., 2011). During iontophoresis, the applied current should not produce any kinds of adverse effects (like skin irritations and burns) on the skin. Further, there should be a quantitative relation among the applied current density and the drug permeation. A current density of 0.5 mA/cm2 has been recommended as the optimal current density for iontophoresis process (Batheja et al., 2006). Current strength: The applied current can be easily controlled by the electronics. A linear relationship among the strength of the applied current and the achieved permeation flux of drug molecules has been reported (Khan et al., 2011). A linear relationship in between the permeation flux across the skin surface area (1 cm2) and current (1 mA) has been observed. The duration of the applied current for more than 3 minutes should be avoided to minimize the side effects (e.g., local skin irritations, and burns) of the iontophoresis process (Khan et al., 2011). With the increase in the current strength, the chances of nonspecific vascular responses (i.e., vasodilatation) have been reported (Batheja et al., 2006). Pulsed current: The continuous utilization of direct current (i.e., proportional to the time) can decrease the flux for the iontophoresis owing to the polarization effects on the skin. This can be conquered by the application of the pulsed direct current. The pulsed direct current is injected in a periodic mode. Throughout the “off stage,” the skin depolarizes and comes back to the primary polarized condition (Khan et al., 2011). Period of current apply: The transportation of drugs depends on the period of the applied current. The amount of the drug delivered linearly increases with the increase in the time period of injection of the current (Khan et al., 2011). Electrode materials: The materials used for the fabrication of the electrodes for iontophoresis should be nontoxic. In recent years, the designing of the flexible electrodes has been proposed. The most frequently used electrodes are Ag/AgCl and zinc/zinc chloride (Zn/ZnCl2) electrodes. Other electrode materials include platinum and aluminum (Khan et al., 2011). Ag/AgCl electrodes are considered as the most ideal electrode for the iontophoretic delivery of drugs. This is due to the fact that the Ag/AgCl electrode can resist the alterations in the pH, which are usually observed while using Zn/ZnCl2 and platinum electrodes. As discussed previously, the alteration in the pH may lead to decrease in the iontophoretic drug delivery efficiency (Khan et al., 2011). The Ag/AgCl chloride electrodes liberate electrons during the iontophoresis process. This causes the precipitation of insoluble AgCl at the anodal surface. On the other hand, if the platinum electrodes are used, the chloride ions at the anode react with the water molecules to produce the hydronium ions which are immediately transferred to the donor chamber and the pH of the formulations are altered (Khan et al., 2011). These hydronium ions also compete with the similarly charged ions of the drug molecules. Thus the drug transport process is heavily compromised. Also, the generation of the hydronium ions causes skin irritations and even burns in some cases (Kalia et al., 2004). Electrode size: The drug transport process across the skin depends on the size and the positioning of electrodes. In general, the electrodes with larger areas can

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deliver drugs in higher quantities. The use of bigger electrodes results in the lower current density, which makes the electrode system more tolerated by the skin. Any loose contact in between the skin and the electrodes may cause skin burn, if the current density significantly increases at the skin-electrode contact points (Khan et al., 2011).

Biological factors Skin condition: The skin condition is an important biological issue that plays a significant role in governing the permeating characteristics of the drug molecules during iontophoresis (Khan et al., 2011). Regional blood flow: In conventional drug delivery, the vascularization of the dermal layer decides the systemic delivery properties of the drug absorption by the tissues. However, during the iontophoretic delivery of drugs, the blood flow does not greatly influence the permeation fluxes of the drugs across the epidermis layer of the skin (Khan et al., 2011). Intra- and intersubject variability: The iontophoresis process decreases the intraand the intersubject variability in the rate of drug delivery. This is contrary to the intrinsic shortcoming of the conventional passive drug delivery techniques (Khan et al., 2011).

Applications of iontophoretic drug delivery Iontophoretic delivery of nonsteroidal antiinflammatory drugs Topical delivery of different nonsteroidal antiinflammatory drugs (NSAIDs) by the passive drug delivery systems has already been investigated (Jogunola, 2013; Lobo & Yan, 2018; Nayak, Mohanty, & Sen, 2010; Jana, Ali, et al., 2014; Jana, Manna, et al., 2014). The permeation of various NSAIDs by iontophoresis has also been investigated thoroughly (Crevenna et al., 2015). Jogunola (2013) investigated the comparative therapeutic effectiveness of ketoprofen delivery by the transcutaneous electric nerve stimulation and iontophoresis. Hui et al. (2001) researched the pharmacokinetic parameters as well as the localized tissue distributions following 6 hours of iontophoretic diclofenac transport at both 0.2 and 0.5 mA/cm2 current densities. They reported that the plasma drug concentration reduced suddenly at the high current density. Hui et al. (2001) recommended that this was because of the rising chlorine ion concentrations on account of the electrode reaction at the silver chloride cathode, and hence, the drug depletion occurs in the chamber. Malinovskaja-Gomez et al. (2016) studied the transdermal iontophoretic transport of flufenamic acid combining with the nanoencapsulation technique. In this work, flufenamic acid-loaded polymeric nanoparticles made of poly(lactic-co-glycolic acid) (PLGA) were prepared and investigated for the iontophoretic transportation. These flufenamic acid-loaded PLGA nanoparticles were negatively charged, stable under the current profiles, and in contact with the skin layer. The transport of

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flufenamic acid from flufenamic acid-loaded PLGA nanoparticles was not found to be influenced by the iontophoresis, leading to significantly lesser drug permeation fluxes across the epidermis layer of the human skin as well as the full thickness of the porcine skin in comparison with that of the formulation containing free flufenamic acid. The overall results of this study clearly indicated that the pulsed current iontophoresis might be an effectual option as a substitute of the conventional constant current iontophoresis to augment the transdermal transport of drugs from the polymeric nanoparticles. Similarly, in two different reports, Tomoda et al. (2011) and Tomoda, Terashima, et al. (2012) reported improved transdermal delivery of indomethacin through the combination of iontophoresis and nanotechnology (using PLGA nanoparticles as polymeric carrier) in both in vitro and in vivo conditions. Some other investigations on the iontophoretic delivery of NSAIDs are listed in Table 16.1.

Table 16.1 Some investigations of the iontophoretic delivery of nonsteroidal antiinflammatory drugs (NSAIDs). Iontophoretic delivery of NSAIDs

References

Iontophoretic delivery of ketorolac or with placebo Topical iontophoretic delivery of diclofenac Transdermal iontophoretic delivery of ketoprofen through human cadaver skin and in humans Transfer of diclofenac sodium across excised guinea pig skin on high-frequency pulse iontophoresis Iontophoresis of topically applied diclofenac to healthy humans Microporation-assisted iontophoretic delivery of diclofenac sodium Iontophoresis-facilitated delivery of ketorolac Synergistic effect of iontophoresis and jet injector pretreatment on the in vitro skin permeation of diclofenac In vivo transdermal delivery of diclofenac by ion exchange iontophoresis with geraniol Transdermal iontophoresis of piroxicam from gels

Saggini et al. (1996) Kasha et al. (2012) Panus et al. (1997)

Iontophoretic delivery of piroxicam across the skin in vitro Enhanced skin permeation of diclofenac by iontophoresis Iontophoresis driven topically administered diclofenac in skeletal muscle and blood of healthy subjects Passive and iontophoretic delivery of three diclofenac salts across various skin types Influence of electrical and chemical factors on transdermal iontophoretic delivery of three diclofenac salts

Koizumi et al. (1990) Riecke et al. (2011) Patel, Joshi, Joshi, and Stagni (2015) Tiwari and Udupa (2003) Sugibayashi et al. (2000)

Kigasawa et al. (2009) Doliwa, Santoyo, and Ygartua (2001) Gay, Green, Guy, and Francoeur (1992) Varghese and Khar (1996) Crevenna et al. (2015) Fang, Wang, Huang, Wu, and Tsai (2000) Fang, Wang, Huang, Wu, and Tsai (2001)

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Iontophoretic delivery of opioids Opioids are mainly used as analgesics having the molecular weight of 300 500 Da. Under the physiological condition, the various opioid molecules generally possess the positive charge. Additionally, these are able to produce a pharmacological action at a comparatively low systemic concentration. The above discussed physicochemical as well as pharmacological characteristics make these opioid molecules suitable candidates for iontophoretic delivery to achieve better therapeutics effect. In an investigation, Takasuga et al. (2011) investigated the effectiveness of transdermal transport of tramadol via the anodal iontophoresis by employing Ag/AgCl electrodes. They studied the transdermal tramadol iontophoresis within both in vitro and in vivo conditions. The in vitro transdermal tramadol iontophoresis was studied across various excised animal skins such as excised porcine ear skin and excised abdominal skins of hairless mouse and guinea. The in vitro tramadol permeation flux was found to be augmented without any significant alterations among various skins. In the in vivo study in guinea pigs, the iontophoretic transport system was used to the abdominal skin position with a constant current supply of 250 μA/cm2 for a period of 6 hours. The plasma tramadol concentrations were measured and increased steadily and also attained at a steady state at 3 hours after the current supply started. These results suggested that the anodal iontophoresis presents the current controlled transdermal tramadol transport without any significant changes and also facilitates the transportation of therapeutically effective concentrations of tramadol. Minkowitz, Danesi, Ding, and Jones (2015) developed a needle-free iontophoretic transdermal system of fentanyl for the management of patient-controlled analgesia as well as postoperative pain in adult hospitalized patients. The development of the modernized and effective iontophoretic transdermal system of fentanyl may be a versatile device for the management of postoperative pain. In another research, the same research group investigated the effectiveness and safety profiles of the iontophoretic transdermal system of fentanyl and intravenous (IV) patientcontrolled analgesia with morphine for the management of pain following abdominal or pelvic surgery (Minkowitz et al., 2007). Some other investigations on the iontophoresis of opioids are listed in Table 16.2.

Iontophoretic delivery of steroids In general, steroids are given topically for the management of several dermatological and systemic conditions. But the passive transdermal transport of various steroids experiences damaging of the nail structure. In their research, Tomoda, Watanabe, et al. (2012) investigated the transdermal permeation of estradiol using a combination of iontophoresis and PLGA nanoparticles. This combination strategy demonstrated the augmented transdermal estradiol permeability. Essa, Bonner, and Barry (2002) also investigated estradiol delivery across the skin through employing a combination approach of ultradeformable liposomes loaded with estradiol and iontophoresis. Liu et al. (2008) developed Carbopol gel-based formulation containing solid lipid nanoparticles loaded triamcinolone acetonide acetate and investigated

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Table 16.2 Some investigations on the iontophoretic delivery of opioids. Iontophoretic delivery of opioids

References

Iontophoresis of fentanyl citrate in humans Iontophoretic delivery of fentanyl

Ashburn et al. (1995) Gupta et al. (1998), Gupta, Sathyan, Phipps, Klausner, and Southam (1999) Scott (2016) Mayes and Ferrone (2006)

Fentanyl iontophoretic transdermal system Fentanyl HCl patient-controlled iontophoretic transdermal system Delivery of nalbuphine and its prodrugs across skin by iontophoresis Iontophoretic transdermal delivery of buprenorphine Iontophoretic transdermal delivery of buprenorphine from solutions and hydrogels Transdermal iontophoretic delivery of hydromorphone Delivery of nalbuphine and its prodrugs across skin by iontophoresis

Bose et al. (2001) Fang, Sung, Wang, Chu, and Chen (2002)

the iontophoretic transport of the formulation to attain enhanced permeability of triamcinolone acetonide acetate. This approach also indicated an augmented delivery of triamcinolone acetonide acetate when the combination of solid lipid nanoparticles and iontophoresis was employed.

Iontophoretic delivery of local anesthetics Recently, local anesthetics have been applied topically, and numerous topical gels of local anesthetics are being investigated (Das et al., 2013). In the past few decades, several the investigations of the iontophoretic transport of local anesthetics were carried out by some research groups (Inoue et al., 2016; Manjunatha, Sharma, Narayan, & Koul, 2018). Manjunatha et al. (2018) investigated the iontophoretic transport of topical lidocaine hydrochloride permeation from two different concentrations of lidocaine hydrochloride (2.50% and 5%) across the human skin. In this investigation, the continuous iontophoresis as well as the modulated iontophoresis at 0.5 μA/cm2 of current density were used. The results of the investigation recommended that the modulated iontophoresis can be a potential alternative technique in the clinical settings sideways from the continuous iontophoresis. On the basis of clinical requisites, iontophoresis can be employed at 2.50% and 5% concentrations of lidocaine hydrochloride depending on the requirement of comparatively very shorter or shorter onset of actions. Inoue et al. (2016) reported the transport of lidocaine through the iontophoretic technique employing the combination of individual direct current and/or alternating current. The results of the study recommended that lidocaine was transported more speedily through the iontophoresis with the direct

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Table 16.3 Some investigations on the iontophoretic delivery of local anesthetics. Iontophoretic delivery of local anesthetics Transdermal lidocaine iontophoresis in isolated perfused porcine skin Iontophoresis of lidocaine with EMLA Alternating current iontophoresis of lidocaine using excised rat skin using calcium alginate gel as electrode material Lidocaine iontophoresis using either alternating or direct current in hairless rats Lidocaine iontophoresis using interferential current on pressure sense threshold and tactile sensation Iontophoresis of lignocaine with epinephrine into carious dentine for pain control Iontophoresis of lignocaine with epinephrine into exposed dentine Alternating current-iontophoresis of lidocaine hydrochloride on the permeability of human enamel and dentine Modulated alternating and direct current iontophoresis on transdermal delivery of lidocaine hydrochloride

References

Greenbaum et al. (1994) Ebisawa, Nakajima, and Haida (2014) Nakajima, Wakita, and Haida (2013) Yoosefinejad, Motealleh, and Abbasnia (2016) Smitayothin et al. (2015) Thongkukiatkun et al. (2015) Ikeda and Suda (2013)

Bhatia and Banga (2014)

EMLA, Eutectic mixture of local anesthetics.

current as compared with the alternating current. Ions were transported more rapidly when the voltage was switched from the direct current to the alternating current as compared to that from the alternating current to the direct current. The iontophoretic transport of lidocaine in combination with the direct current and the alternating current was measured to allow a kind of well competent drug delivery way, which may facilitate the advantages of both the forms of current (direct current and alternating current). In a study by Galinkin, Rose, Harris, and Watcha (2002), a comparison of the effectiveness of eutectic mixture of local anesthetics (i.e., a eutectic mixture of prilocaine and lidocaine in 2.5% of each) for the placing of IV cannulas in a same group of subjects was investigated and analyzed. The iontophoretic transport of lidocaine generated the equivalent dermal analgesia with a speedier onset as an additional benefit. Some other investigations on the iontophoretic delivery of local anesthetics are listed in Table 16.3.

Iontophoretic delivery of drugs acting on the central nervous system Several iontophoretic investigations for the delivery of drugs acting on the central nervous system have already been researched, and in most of the cases, enhanced drug transport was found (Das, Sen, Maji, Nayak, & Sen, 2017; Meidan, Al-Khalili, & Michniak, 2003). Luzardo-Alvarez, Delgado-Charro, and Blanco-Mendez (2001)

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studied an in vitro investigation of the iontophoretic transport of ropinirole across the skin of weanling pigs. The ropinirole availability in the salt form (hydrochloride salt) facilitated the drug delivery researchers to investigate the influence of drug concentrations in the formulation and the current intensity on the iontophoretic permeation flux of ropinirole in the donor chamber without the presence of competing ions. Under these experimental conditions, it was clearly revealed that even though the permeation flux was effectively independent of ropinirole concentrations at a predetermined current supply, significant and approximately proportionate increments in permeation flux of ropinirole were detected with the enhanced current supply. In another investigation, Das et al. (2017) studied the iontophoretic delivery of the risperidone from the transferosomal gel across the porcine skin. In this study, a current supply of 0.5 μA/cm2 was employed for the iontophoresis. The skin permeation flux of risperidone from the iontophoretic system containing optimized transferosomal gel of risperidone was found to be greater as compared to that of conventional risperidone containing optimized gel. A comparative ex vivo risperidone permeation profile of the optimized transferosomal gel with/without iontophoretic system was shown in Fig. 16.3. Some other investigations on the iontophoretic delivery of drugs acting on the central nervous system are listed in Table 16.4.

70

F-OI

F-O

Cumulative permeation (%)

60 50

40 30

20

10

0 0

2

4

6

8

10

12 14 Time (h)

16

18

20

22

24

Figure 16.3 A comparative ex vivo risperidone permeation pattern of the risperidone containing optimized transferosomal gel with (F-OI)/without (F-O) iontophoretic system under the influence of current supply, 0.5 mA/cm2 (Mean 6 SD, n 5 3). (Das, B., Sen, S. O., Maji, R., Nayak, A. K., & Sen, K. K. (2017). Transferosomal gel for transdermal delivery of risperidone. Journal of Drug Delivery Science and Technology, 38, 59 71. © 2017, with permission from Elsevier B.V.)

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Table 16.4 Some investigations on the iontophoretic delivery of drugs acting on the central nervous system. Iontophoretic delivery of drugs acting on the central nervous system

References

Transdermals reverse iontophoresis of valproate Transdermal iontophoresis of rotigotine

Delgado-Charro and Guy (2003)

In vitro iontophoresis of R-apomorphine across human stratum corneum Iontophoretic transdermal delivery of methylphenidate hydrochloride Transdermal iontophoresis of tacrine Iontophoretic delivery of buspirone hydrochloride across human skin using chemical enhancers Controlled iontophoretic delivery of pramipexole Simultaneous controlled iontophoretic delivery of pramipexole and rasagiline Transdermal iontophoretic delivery of domperidone Cutaneous iontophoretic delivery of rasagiline and selegiline across porcine and human skin Controlled delivery of ropinirole hydrochloride through skin using modulated iontophoresis and microneedles Transdermal delivery of granisetron by using iontophoresis Iontophoretic transport of diphenhydramine hydrochloride thermosensitive gel

Nugroho, Li, Grossklaus, Danhof, and Bouwstra (2004), Ackaert, Eikelenboom, Wolff, and Bouwstra (2010) Li et al. (2002) Singh et al. (1997) Kankkunen, Sulkava, Vuorio, Kontturi, and Hirvonen (2002) Meidan et al. (2003)

Kalaria, Singhal, Patravale, Merino, and Kalia (2018)

Kalaria, Patel, Patravale, and Kalia (2012)

Singh and Banga (2013)

Panzade, Heda, Puranik, Patni, and Mogal (2012) Vikram, Kiran, and Rahul (2007)

Iontophoretic delivery of cardiovascular drugs Numerous researches have been already carried out to study the iontophoresis of various cardiovascular drugs such as calcium channel blockers, β-blockers, and antihypertensives (Denet, Ucakar, & Pre´at, 2003). Nair, Vyas, Shah, and Kumar (2011) investigated the use of various permeation enhancers (such as dimethyl formamide, sodium lauryl sulfate, polyethylene glycol 400, and N-methyl 2-pyrrolidone) with combining iontophoretic process to augment the drug transport across the skin. They studied the influence of permeation enhancers on the iontophoretic

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Table 16.5 Some investigations on the iontophoretic delivery of cardiovascular drugs. Iontophoretic delivery of cardiovascular drugs

References

Transdermal delivery of atenolol

Anroop, Ghosh, Parcha, and Khanam (2009) Zakzewski and Li (1991)

Pulsed mode constant current iontophoretic transdermal metoprolol tartrate delivery Iontophoretic transdermal delivery of metoprolol tartrate through human epidermis in vitro Iontophoresis-facilitated transdermal delivery of verapamil Iontophoretically enhanced transdermal delivery of an ACE inhibitor Transdermal delivery of timolol and atenolol using electroporation and iontophoresis Iontophoretic in vivo transdermal delivery of β-blockers in hairless rats and reduced skin irritation by liposomal formulation Permeation of propranolol HCl by iontophoresis and enhancers

Wearley, Liu, and Chien (1989) Zakzewski, Amory, Jasaitis, and Li (1992) Denet et al. (2003) Conjeevaram, Chaturvedula, Betageri, Sunkara, and Banga (2003) Chesnoy, Durand, Doucet, and Couarraze (1999)

metoprolol tartrate delivery from the gel formulations through employing the combination approach of the use of permeation enhancers with iontophoretic process (where the current applied was 0.5 mA/cm2). The results of this investigation indicated that the combination of iontophoresis process employed with sodium lauryl sulfate enhanced the delivery of metoprolol tartrate and rendered the skin-drug depot, which ultimately liberated the drug over a longer period. Keerthi, Panakanti, and Yamsani (2012) investigated the iontophoretic transport of atenolol from a prepared transdermal patch containing atenolol to attain enhanced delivery atenolol. In this research, the effects of various chemical permeation enhancers like D-limonene and oleic acid along with the iontophoresis process in a combination approach was also investigated. The results of this investigation suggested that the combination of iontophoresis process with oleic acid as a chemical enhancer produced the significantly higher transdermal permeation of atenolol in comparison with that of the passive transdermal delivery of atenolol. In their research, Teong et al. (2017) investigated the antiosteoporotic actions of liposome-encapsulated propranolol in the ovariectomized rats by means of applying the transdermal iontophoresis technique. Some other investigations on the iontophoretic delivery of cardiovascular drugs are listed in Table 16.5.

Iontophoretic delivery of proteins and peptides In recent years, the effective transport of therapeutic proteins and peptides has become one of the popular research fields of medical as well as biomedical sciences (Nayak, 2010). During the last few decades, numerous investigations have

Bioelectronics and Medical Devices

Cumulative amount of insulin permeated μg/cm2) per unit area (μ

410

Iontophoresis

700

Normal condition

600 500 400 300 200 100 0 –100

0

5

10

15

20

25

Time (h)

Figure 16.4 Cumulative amount of in vitro insulin permeated through porcine skin per unit area versus time profile of optimized gels containing insulin-loaded transferosomes in the iontophoretic condition with the influence of current supply, 0.5 mA/cm2 and the normal condition (without using iontophoresis) (Mean 6 SE, n 5 3). (Malakar, J., Sen, S. O., Nayak, A. K., & Sen, K. K. (2012). Formulation, optimization and evaluation of transferosomal gel for transdermal insulin. Saudi Pharmaceutical Journal, 20, 355 363. © 2012, with permission from Elsevier B.V.)

successfully been conducted and reported for alternate delivery approaches to deliver insulin (Malakar, Sen, Nayak, & Sen, 2011). Under the iontophoresis condition, the stability of insulin was evaluated by Panchagnula, Bindra, Kumar, Dey, and Pillai (2006). To enhance the insulin permeation through the transdermal route, the utilizations of chemical permeation enhancers along with the iontophoresis approach was investigated in several researches, and the results of these research endeavors clearly suggested improved permeation of insulin by the combination of iontophoresis and chemical permeation enhancers (Pillai & Panchagnula, 2003). Malakar, Sen, Nayak, and Sen (2012) investigated in vitro insulin permeation from optimized gels containing insulin-loaded transferosomes across the porcine ear skin through iontophoresis using the current supply of 0.5 mA/cm2. They have measured that the higher permeation flux of the optimized gels containing insulin-loaded transferosomes by using iontophoretic condition in comparison with that of the normal condition (i.e., devoid of using iontophoresis) (Fig. 16.4). In another recent research by La Fountaine et al. (2017), insulin iontophoresis was investigated and the research clearly demonstrated that the responses of cutaneous microvascular perfusion to the iontophoresis of insulin are differentially influenced by the insulin resistance following spinal cord injury. Besides insulin iontophoresis, the iontophoretic transport of other therapeutic proteins and peptides was also investigated and reported by various research groups. Most of the researches on the iontophoretic transport of other therapeutic proteins and peptides indicated a promise to attain effectual fluxes

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Table 16.6 Some investigations on the iontophoretic delivery of proteins and peptides. Iontophoretic delivery of proteins and peptides Iontophoretic permeation of insulin across human cadaver skin Effect of electroporation and pH on the iontophoretic transdermal delivery of human insulin Passive and iontophoretic transport enhancement of insulin through porcine epidermis by depilatories Transepidermal transport enhancement of insulin by lipid extraction and iontophoresis Iontophoretic transdermal absorption of insulin and calcitonin in rats with newly devised switching technique and addition of urea Transdermal administration of salmon calcitonin by pulse depolarization iontophoresis in rats Transdermal iontophoretic delivery of salmon calcitonin Transdermal iontophoretic delivery of vasopressin and an analogue in rats Transdermal iontophoretic delivery of vapreotide acetate across porcine skin Pulsatile and continuous transdermal delivery of buserelin by iontophoresis Iontophoretic pulsatile transdermal delivery of human parathyroid hormone Effect of permeation enhancer pretreatment on the iontophoresis of luteinizing hormone releasing hormone through human epidermal membrane Controlled transdermal delivery of leuprorelin by pulsed iontophoresis and ion-exchange fiber

References

Tokumoto, Higo, and Sugibayashi (2006) Rastogi and Singh (2003) Rastogi and Singh (2002)

Nakamura et al. (2001) Chang, Hofmann, Zhang, Deftos, and Banga (2000)

Schuetz, Naik, Guy, Vuaridel, and Kalia (2005)

Suzuki et al. (2001) Smyth, Becket, and Mehta (2002) Malinovskaja et al. (2014)

(Malinovskaja, Laaksonen, & Hirvonen, 2014). Some other investigations on the iontophoretic delivery of peptides and proteins are listed in Table 16.6.

Miscellaneous Beside the above discussed drug categories, some other drugs like antibiotics, antiviral drugs, antidiabetic drugs, anticancer drugs, and ocular β-blockers, were also investigated for the iontophoretic transport, and enhanced permeation fluxes were achieved. Some reported investigations on the iontophoretic delivery of miscellaneous drugs are listed in Table 16.7.

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Table 16.7 Some investigations on the iontophoretic delivery of miscellaneous drugs. Iontophoretic delivery of miscellaneous drugs

References

Reverse iontophoresis of amikacin

Marra, Nicoli, Padula, and Santi (2013) Nicoli and Santi (2006) Fang, Sung, Lin, and Fang (1999)

Transdermal delivery of amikacin Transdermal iontophoretic delivery of enoxacin from various liposome-encapsulated formulations Enhanced transfollicular delivery of adriamycin with a liposome and iontophoresis In vitro skin permeability of azidothymidine via iontophoresis and chemical enhancer Enhanced transdermal delivery of zidovudine using iontophoresis and penetration enhancer Iontophoresis and permeation enhancers on the permeation of an acyclovir gel Iontophoretic cisplatin chemotherapy of basal and squamous cell carcinomas of the skin Passive and iontophoretic transdermal penetration of methotrexate 5-Fluorouracil iontophoretic therapy for Bowen’s disease Passive and iontophoretic permeation of glipizide gel Transdermal iontophoretic delivery of timolol maleate in albino rabbits

Han, Kim, and Kim (2004) Wearley and Chien (1990) Oh, Jeong, Park, and Lee (1998) Vaghani et al. (2010) Chang, Guthrie, Hayakawa, and Gangarosa (1993) Alvarez-Figueroa, Delgado-Charro, and Blanco-Mendez (2001)

Ghosh, Jain, Ashok, Patel, and Tarafdar (2009) Kanikkannan, Singh, and Ramarao (2000)

Conclusion In this chapter, the overview of various general issues related to the iontophoretic drug delivery approaches and recent researches in this area are comprehensively presented. The presented discussion obviously demonstrates that an extensive amount of research endeavors have been made into exploring and exploiting the achievability as well as practicability of the iontophoretic drug delivery approach as one of the effectual treatment platforms in the therapeutics of various kinds of drugs like NSAIDs, opioids, local anesthetics, steroids, drugs acting on the central nervous system, cardiovascular drugs, antibiotics, antiviral drugs, antidiabetic drugs, proteins and peptides, with their diverse physicochemical characteristics. Iontophoretic drug delivery approaches are able to offer a rational alternative on the pharmacokinetic grounds, where the drugs either have lower oral bioavailabilities and/or shorter halflives or are subjective to the multiple dosing. Considering the pharmacodynamic point of view, the iontophoretic drug delivery approaches present a clear therapeutical advantage over the existing conventional drug delivery routes. Since both the physicochemical characteristics and the pharmacological effectiveness of the iontophoretic substances are two important issues, an extensive consideration must be

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conferred to the choice of peptide therapy in the future. Moreover, the superior control by the iontophoretic drug delivery is a significant aspect when it approaches the administration of therapeutic protein and peptide drugs. The prospective of iontophoretic drug transport systems for customizing therapeutics in response to the individual what the patient requires possibly will become more applicable as the uprising of pharmacogenomic field starts to compose further therapeutic efficacy.

References Ackaert, O. W., Eikelenboom, J., Wolff, H. M., & Bouwstra, J. A. (2010). Comparing different salt forms of rotigotine to improve transdermal iontophoretic delivery. European Journal of Pharmaceutics and Biopharmaceutics, 74, 304 310. Alvarez-Figueroa, M. J., Delgado-Charro, M. B., & Blanco-Mendez, J. (2001). Passive and iontophoretic transdermal penetration of methotrexate. International Journal of Pharmaceutics, 212, 101 107. Anroop, B., Ghosh, B., Parcha, V., & Khanam, J. (2009). Transdermal delivery of atenolol: Effect of prodrugs and iontophoresis. Current Drug Delivery, 6, 280 290. Ashburn, M. A., Streisand, J., Zhang, J., Love, G., Rowin, M., Niu, S., . . . Mertens, M. J. (1995). The iontophoresis of fentanyl citrate in humans. Anesthesiology, 82, 1146 1153. Batheja, P., Thakur, R., & Michniak, B. (2006). Transdermal iontophoresis. Expert Opinion on Drug Delivery, 3, 127 138. Bhatia, G., & Banga, A. K. (2014). Effect of modulated alternating and direct current iontophoresis on transdermal delivery of lidocaine hydrochloride. BioMed Research International, 2014, 537941. Bose, S., Ravis, W. R., Lin, Y. J., Zhang, L., Hofmann, G. A., & Banga, A. K. (2001). Electrically-assisted transdermal delivery of buprenorphine. Journal of Controlled Release, 73, 197 203. Chang, B. K., Guthrie, T. H., Hayakawa, K., & Gangarosa, L. P. (1993). A pilot study of iontophoretic cisplatin chemotherapy of basal and squamous cell carcinomas of the skin. Archives of Dermatology, 129, 425 427. Chang, S. L., Hofmann, G. A., Zhang, L., Deftos, L. J., & Banga, A. K. (2000). Transdermal iontophoretic delivery of salmon calcitonin. International Journal of Pharmaceutics, 200, 107 113. Chesnoy, S., Durand, D., Doucet, J., & Couarraze, G. (1999). Structural parameters involved in the permeation of propranolol HCl by iontophoresis and enhancers. Journal of Controlled Release, 58, 163 175. Conjeevaram, R., Chaturvedula, A., Betageri, G. V., Sunkara, G., & Banga, A. K. (2003). Iontophoretic in vivo transdermal delivery of β-blockers in hairless rats and reduced skin irritation by liposomal formulation. Pharmaceutical Research, 20, 1496 1501. Crevenna, R., Burian, A., Oesterreicher, Z., Lackner, E., Jager, W., Rezcicek, G., . . . Zeitlinger, M. (2015). Iontophoresis driven concentrations of topically administered diclofenac in skeletal muscle and blood of healthy subjects. European Journal of Clinical Pharmacology, 71, 1359 1364. Das, B., Nayak, A. K., & Nanda, U. (2013). Topical gels of lidocaine HCl using cashew gum and Carbopol 940: Preparation and in vitro skin permeation. International Journal of Biological Macromolecules, 62, 514 517.

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Das, B., Sen, S. O., Maji, R., Nayak, A. K., & Sen, K. K. (2017). Transferosomal gel for transdermal delivery of risperidone. Journal of Drug Delivery Science and Technology, 38, 59 71. Delgado-Charro, M. B., & Guy, R. H. (2003). Transdermals reverse iontophoresis of valproate: A non invasive method for therapeutic drug monitoring. Pharmaceutical Research, 20, 1508 1513. Denet, A. R., Ucakar, B., & Pre´at, V. (2003). Transdermal delivery of timolol and atenolol using electroporation and iontophoresis in combination: A mechanistic approach. Pharmaceutical Research, 20, 1946 1951. Dhal, D., Mohanty, A., Yadav, I., Uvanesh, K., Kulanthaivel, S., Banerjee, I., . . . Giri, S. (2017). Magnetic nanoparticle incorporated oleogel as iontophoretic drug delivery system. Colloids and Surfaces B: Biointerfaces, 157, 118 129. Dhote, V., Bhatnagar, P., Mishra, P. K., Mahajan, S. C., & Mishra, D. K. (2012). Iontophoresis: A potential emergence of a transdermal drug delivery system. Scientia Pharmaceutica, 80, 1 28. Doliwa, A., Santoyo, S., & Ygartua, P. (2001). Transdermal iontophoresis and skin retention of piroxicam from gels containing piroxicam: Hydroxypropyl-beta-cyclodextrin complexes. Drug Development and Industrial Pharmacy, 27, 751 758. Ebisawa, T., Nakajima, A., Haida, H., et al. (2014). Evaluation of calcium alginate gel as electrode material for alternating current iontophoresis of lidocaine using excised rat skin. Journal of Research in Medical and Dental Science, 61, 41 48. Essa, E. A., Bonner, M. C., & Barry, B. W. (2002). Iontophoretic estradiol skin delivery and tritium exchange in ultradeformable liposomes. International Journal of Pharmaceutics, 240, 55 66. Fang, J., Wang, R., Huang, Y., Wu, P. C., & Tsai, Y. (2000). Passive and iontophoretic delivery of three diclofenac salts across various skin types. Biological and Pharmaceutical Bulletin, 23, 1357 1362. Fang, J. Y., Sung, K. C., Lin, H. H., & Fang, C. L. (1999). Transdermal iontophoretic delivery of enoxacin from various liposome-encapsulated formulations. Journal of Controlled Release, 60, 1 10. Fang, J. Y., Sung, K. C., Wang, J. J., Chu, C. C., & Chen, K. T. (2002). The effects of iontophoresis and electroporation on transdermal delivery of buprenorphine from solutions and hydrogels. Journal of Pharmacy and Pharmacology, 54, 1329 1337. Fang, J. Y., Wang, R. J., Huang, Y. B., Wu, P. C., & Tsai, Y. H. (2001). Influence of electrical and chemical factors on transdermal iontophoretic delivery of three diclofenac salts. Biological and Pharmaceutical Bulletin, 24, 390 394. Galinkin, J. L., Rose, J. B., Harris, K., & Watcha, M. F. (2002). Lidocaine iontophoresis versus eutectic mixture of local anesthetics (EMLA) for IV placement in children. Anesthesia & Analgesia, 94, 1484 1488. Gay, C. L., Green, P. G., Guy, R. H., & Francoeur, M. L. (1992). Ionotophoretic delivery of piroxicam across the skin in vitro. Journal of Controlled Release, 22, 57 68. Ghosh, B., Jain, A., Ashok, P., Patel, B., & Tarafdar, K. (2009). Passive and iontophoretic permeation of glipizide gel: An in vitro and in vivo study. Current Drug Delivery, 6, 444 450. Giri, T. K., Chakrabarty, S., & Ghosh, B. (2017). Transdermal reverse iontophoresis: A novel technique for therapeutic drug monitoring. Journal of Controlled Release, 246, 30 38. Gupta, S. K., Bernstein, K. J., Noorduin, H., Van Peer, A., Sathyan, G., & Haak, R. (1998). Fentanyl delivery from an electrotransport system: Delivery is a function of total current, not duration of current. The Journal of Clinical Pharmacology, 38, 951 958.

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Greenbaum, S. S., & Bernstein, E. F. (1994). Comparison of iontophoresis of lidocaine with a eutectic mixture of lidocaine and prilocaine (EMLA) for topically administered local anesthesia. Journal of Dermatologic Surgery and Oncology, 20, 579 583. Gupta, S. K., Sathyan, G., Phipps, B., Klausner, M., & Southam, M. (1999). Reproducible fentanyl doses delivered intermittently at different time intervals from an electrotransport system. Journal of Pharmaceutical Sciences, 88, 835 841. Han, I., Kim, M., & Kim, J. (2004). Enhanced transfollicular delivery of adriamycin with a liposome and iontophoresis. Experimental Dermatology, 13, 86 92. Hirvonen, J. (2005). Topical iontophoretic delivery. American Journal of Drug Delivery, 3, 67 81. Hui, X., Anigbogu, A., Singh, P., Xiong, G., Poblete, N., Liu, P., & Maibach, H. I. (2001). Pharmacokinetic and local tissue disposition of [(14)C]sodium diclofenac following iontophoresis and systemic administration in rabbits. Journal of Pharmaceutical Sciences, 90, 1269 1276. Ikeda, H., & Suda, H. (2013). Facilitatory effect of AC-iontophoresis of lidocaine hydrochloride on the permeability of human enamel and dentine in extracted teeth. Archives of Oral Biology, 58, 341 347. Inoue, T., Sugiyama, T., Ikoma, T., Shimazu, H., Wakita, R., & Fukayama, H. (2016). Drug delivery and transmission of lidocaine using iontophoresis in combination with direct and alternating currents. Journal of Research in Medical and Dental Science, 63, 71 77. Jana, S., Ali, S. A., Nayak, A. K., Sen, K. K., & Basu, S. K. (2014). Development and optimization of topical gel containing aceclofenac-crospovidone solid dispersion by “quality by design” approach. Chemical Engineering Research and Design, 92, 2095 2105. Jana, S., Manna, S., Nayak, A. K., Sen, K. K., & Basu, S. K. (2014). Carbopol gel containing chitosan-egg albumin nanoparticles for transdermal aceclofenac delivery. Colloids and Surfaces B: Biointerfaces, 114, 36 44. Jogunola, O. O. (2013). Relative therapeutic efficacy of ketoprofen iontophoresis and transcutaneous electrical nerve stimulation in the management of osteoarthritic knee pains: A pilot study. Nigerian Journal of Medical Rehabilitation, 16, 1 10. Kalaria, D. R., Patel, P., Patravale, V., & Kalia, Y. N. (2012). Comparison of the cutaneous iontophoretic delivery of rasagiline and selegiline across porcine and human skin in vitro. International Journal of Pharmaceutics, 438, 202 208. Kalaria, D. R., Singhal, M., Patravale, V., Merino, V., & Kalia, Y. N. (2018). Simultaneous controlled iontophoretic delivery of pramipexole and rasagiline in vitro and in vivo: Transdermal polypharmacy to treat Parkinson’s disease. European Journal of Pharmaceutics and Biopharmaceutics, 127, 204 212. Kalia, Y. N., Naik, A., Garrison, J., & Guy, R. H. (2004). Iontophoretic drug delivery. Advanced Drug Delivery Reviews, 56, 619 658. Kanikkannan, N., Singh, J., & Ramarao, P. (2000). Transdermal iontophoretic delivery of timolol maleate in albino rabbits. International Journal of Pharmaceutics, 197, 69 76. Kankkunen, T., Sulkava, R., Vuorio, M., Kontturi, K., & Hirvonen, J. (2002). Transdermal iontophoresis of tacrine in vivo. Pharmaceutical Research, 19, 704 707. Kasha, P. C., Anderson, C. R., Morris, R. L., Sembrowich, W. L., Chaturvedula, A., & Banga, A. K. (2012). Subcutaneous concentrations following topical iontophoretic delivery of diclofenac. Drug Discoveries & Therapeutics, 6, 256 262. Keerthi, H., Panakanti, P. K., & Yamsani, M. R. (2012). Design and characterization of atenolol transdermal therapeutic systems: Enhancement of permeability via iontophoresis. PDA Journal of Pharmaceutical Science and Technology, 66, 318 332.

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Further reading Ca´zares-Delgadillo, J., Ganem-Rondero, A., Quintanar-Guerrero, D., Lo´pez-Castellano, A. C., Merino, V., & Kalia, Y. N. (2010). Using transdermal iontophoresis to increase granisetron delivery across skin in vitro and in vivo: Effect of experimental conditions and a comparison with other enhancement strategies. European Journal of Pharmaceutical Sciences, 39, 387 393. Pikal, M. J., & Shah, S. (1990). Transport mechanisms in iontophoresis. III. An experimental study of the contributions of electroosmotic flow and permeability change in transport of low and high molecular weight solutes. Pharmaceutical Research, 7, 222 229.