Transdermal iontophoresis revisited

468

Transdermal iontophoresis revisited Ramesh Panchagnula*, Omathanu Pillai*, Vinod B Nair* and Poduri Ramarao† Iontophoresis evolved as a transdermal enhancement technique in the 20th century, primarily for the delivery of large and charged molecules. Significant achievements have been made in the understanding of underlying mechanisms of iontophoresis and these have contributed to the rational development of iontophoretic delivery systems. The major challenges in this area are the development of portable, cost effective devices and suitable semi-solid formulations that are compatible with the device and the skin. Some of the obstacles in transdermal iontophoresis can be overcome by combining iontophoresis with other physical and chemical enhancement techniques for the delivery of macromolecules. Iontophoresis also offers an avenue for extracting information from the body through the use of reverse iontophoresis, which has potential application in diagnosis and monitoring. The current research is focussed towards resolving the skin toxicity issues and other problems in order to make this technology a commercial reality. Addresses *Transdermal Drug Delivery Lab, Department of Pharmaceutics and † Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, SAS Nagar — 160 062 (Punjab), India Correspondence: Ramesh Panchagnula; e-mail: [email protected] or [email protected] Current Opinion in Chemical Biology 2000, 4:468–473 1367-5931/00/$ — see front matter © 2000 Elsevier Science Ltd. All rights reserved.

Introduction: iontophoresis — a century-old technique Surprisingly, the biomedical application of electricity dates back to the ancient Greeks, even long before the established discovery of electricity in the 18th century. It was not until the early part of the 20th century, however, that it emerged as one of the enhancement techniques in the pursuit of challenging the bioarchitecture of skin [1]. In retrospect, attention can be drawn to two significant events that happened on either side of the Atlantic at the beginning of the 20th century. One was the discovery of insulin in 1922 by Banting and Best, which revolutionised the use of proteins as therapeutic agents. Insulin has been in the limelight as the ‘fancied protein’ for the past several decades with many ‘firsts’ to its credit: it is one of the very few molecules that has given rise to two Nobel prizes. On the other side of the Atlantic, in France in 1908, Leduc for the first time demonstrated the specificity and control with which an electric current could be used to drive molecules across the skin, in a classic rabbit experiment [2]. Subsequently, both of these events developed into specialised areas of science and, in the later part of the 20th century, were amalgamated into a ‘hope’ for the delivery of the new-generation biotechnological drugs [3]. This hope is

infused with fresh blood by the therapeutic and commercial success of transdermal patches coupled with the technological advancements in bioengineering and microelectronics. Thus, iontophoresis has metamorphosed from a crude experimental technique to a highly sophisticated drug delivery technology that is moving closer to commercialisation. This article critically looks into the advancements made in the past century, focussing on recent developments, the current status and the opportunities that transdermal iontophoresis offers in this new millennium.

Mechanistic aspects: how far understood? Skin is a complex membrane and has great influence on the movement of molecules across it in the presence of an electric field. This has posed an obstacle to the determination of an exact relationship for iontophoretic transport. Nevertheless, significant progress has been made in understanding the different interactions and physical mechanisms governing iontophoretic delivery in terms of ion transport, electrodiffusion and electro-osmosis. Generally, a penetrant under the influence of electric current can take either an appendageal pathway (i.e. through a skin appendage, such as the hair follicles) or nonappendageal pathway. Normally, the former predominates in accordance with the established fact that ions tend to take the path of least resistance. Recently, this has been proved by laser scanning confocal microsocopy and vibrating probe electrode technique [4]. The contribution of follicular versus non-follicular transport depends primarily on the physico-chemical properties of the penetrant and the nature and properties of the limiting membrane. Research over the past few years has identified that nonfollicular transport also plays a significant role in the overall transport of ionic molecules. This route has been identified as the intercellular pathway consisting of polar regions in the lipid lamella, which has been confirmed using electron and fluorescence spectroscopy [5•]. These aqueous pathways are primarily due to the voltage-dependent pore formation in the stratum corneum and are attributed to the flip-flop movements of polypeptide helices in the stratum corneum. Higuchi and co-workers [6••] have studied the pore formation at low to moderate voltages and have found it is caused by an interaction of electrical field with the ionic charge and convective solvent flow. It remains unclear, however, whether these are constitutive or electrical-field-induced pores. The permselectivity of skin gives rise to electro-osmosis, which is one of the driving forces for the transport of molecules under the influence of an electric field. Extensive studies have unequivocally proven that electro-osmosis

Transdermal iontophoresis revisited Panchagnula et al.

469

Table 1 Iontophoretic products under different development stages Company

Device/system

Status

Dermion Inc. (Salt Lake City, Utah)

Wearable iontophoretic patches

Under development

Janssen Pharmaceutica (Bererse, Belgium)

On-demand delivery system of fentanyl for acute pain management

Phase III clinical trial

ALZA (Pala Alto, California; E-TRANS)

Electrotransport delivery of insulin

Under development

Cygnus (Redwood City, California; Gluco Watch)

Glucose monitoring system based on reverse iontophoresis

Awaiting US FDA approval

Becton Dickinson (Franklin Lakes, New Jersey)

Iomed Inc. (Salt Lake City, Utah)

Elan Corporation (Westmeath, Ireland; Panoderm)

Reusable power supply controllers

Under development

Lidocaine patches

Phase III clinical trials

IontoDex-dexamethasone sodium phosphate system for acute local inflammatory conditions

Phase III clinical trials

Hydromorphone for pain management

Phase IIb clinical trials

Disposable and reusable systems for delivery of anti-emetics and analgesics

Under development

Local delivery of antimicrobials to the skin

Under development

FDA, Food and Drug Administration.

makes a positive contribution to the transport of cations and negative contribution to transport of anions under normal physiological conditions, in addition to being a major mode of transport for neutral molecules [7]. Electro-osmosis becomes all the more important with large ions such as proteins compared with small ions, for which electrorepulsion plays a significant role. Very recent findings [8••] suggest that the charge of the skin rather than the charge of the permeant may dictate whether electrorepulsion or electro-osmosis is the predominant mechanism of transport. It might, therefore, be possible to manipulate the iontophoretic delivery by changing the pH of the formulation. However, the changes in skin charge distribution as a function of the physico-chemical properties of the permeant in realistic formulation conditions remains to be explored. Although the present literature contains ample evidence to support the existence of the paracellular route as a major transport pathway, the contribution of transcellular pathway in the overall transport process cannot be neglected. This is based on the observation [9] that at higher current densities there is a general perturbation of stratum corneum lipid organisation; the long-term implications of this on the recovery of skin are unknown at present. Biophysical studies have shown unquestionably that iontophoresis results in increased water content of skin [5•]. Based on similar findings of our laboratory [10] and the well-accepted lipid−protein partition theory of Barry [11], it can be hypothesized that the increased hydration may cause swelling of the aqueous pools in the lipid bilayers, ultimately resulting in perturbation of the lipid lamella. Once into the stratum corneum, the drug may branch into multiple pathways depending on the resistance of the

membrane and path of the electrical field. Short lag times observed with iontophoresis imply that the rate-limiting barrier may be the microcirculatory system of the dermis and not the stratum corneum. It is in this context that the isolated perfused porcine skin flap (IPPSF) proposed by Sage and Riviere [12] assumes importance in studying the role of vasoactive agents in modulating the iontophoretic delivery of drugs. In an effort to develop a solute-structure−iontophoretictransport relationship, several theoretical models have been proposed; namely, the Stokes−Einstein model, free volume model and pore restriction model [13••]. By undertaking studies with a range of solutes, varying from a few Daltons to a few thousand Daltons, Lai and Roberts [13••] found that the pore restriction model, which incorporates various determinants of iontophoretic transport, is the best of the three models for describing the iontophoretic transport of solutes. However, extensive studies need to be done with a series of small molecules and macromolecules to understand the exact role of the physico-chemical properties of penetrant in relation to iontophoretic delivery.

Devices: a key to commercialisation Design and construction of portable, efficient and cost effective devices is a thrust area of research today in iontophoresis. Many prototype devices are already on the market and typically includes a current-controlling mechanism (mostly microprocessor-based), a timer, a pulse controller and electrodes. Major companies that are involved in the development of iontophoresis equipment include Iomed Inc. (Salt Lake City, Utah), Empi Inc. (St Paul, Minnesota), Life Tech Inc. (Houston, Texas), Alza Corporation (Pala Alto, California), Beckton and Dickinson (Franklin Lakes, New

470

Next generation therapeutics

Jersey), Cygnus Inc. (Redwood City, California), Fournier (France) and Hisamitsu (Japan). Table 1 gives a representative list of iontophoretic products that are under various stages of development. Empi’s Dupel device is a microprocessorcontrolled, two-channel device that allows treatment at two different sites or use of drug solutions of different polarities at the same time. The microprocessor design provides greater flexibility and, once the dosage and current amplitude is set, the device automatically takes care of the delivery. Other features include automatic current ramping-up, calculation of time and amount to be delivered. Once the treatment is complete, the device beeps and automatically ramps down the current. A patent from Becton and Dickinson [P1] describes a reusable controller for iontophoresis. Such reusable controllers will help to reduce the overall cost, which has been a major limitation for commercialisation.

Major concerns in the fabrication of devices are the mode of current delivery and type of current used. Continuous direct current may be useful for acute conditions and pulsed current may be preferable for chronic conditions dictated by chronopharmacology of the therapeutic agent and lesser propensity in causing skin irritation. Alternating current is reported to cause fewer ‘skin burns’ because of the reversal of polarity, which alternately generates hydrogen and hydroxyl ions thereby neutralizing the ions generated in one cycle [15]. This probably avoids pH shift and the pH shift induced skin irritation. Therefore, the pulse generator in the device should be able to generate a suitable waveform, with a proper frequency and duty cycle that achieves efficient delivery and at the same time causes reduced skin irritation.

Apart from the power source, the electrodes are the most critical parts of the device. The conventional electrodes that are used in iontophoresis can be classified as inert electrodes (metals such as stainless steel, platinum, carbon or aluminium) or reversible electrodes (Ag/AgCl). Although the so-called ‘inert’ electrodes are indeed inert with respect to taking part in the electrochemical reactions, they are known to cause electrolysis of water leading to pH shifts. This manifests in skin irritation, decreased delivery and decreased drug stability, in addition to influencing the direction of elctro-osmotic flow (O Pillai, VB Nair, P Ramarao, R Panchagnula, unpublished data). On the other hand, the reversible electrodes overcome this problem and are compatible with most of the drugs. They do cause precipitation of peptide and protein drugs, however, as well as generating ions that compete electrically with the drug ions and reduce the efficiency of delivery rates. Approaches to solve these problems have been the subject of many recent patents (for example, see [P2]). One of these approaches uses ion-exchange membranes to separate the electrode space and the drug space in the applicator structure, which first exchanges the drug with an ionexchange resin and then exchanges it with H+ or OH− ions generated during the device operation and thus removing the competing ions. Other related approaches include the formation of a precipitate by combination of a special metallic electrode and drug, or to cause neutralization whereby the coexisting competing ions are removed [P2].

The clinical application of iontophoretic delivery systems is synonymous with the development of suitable and stable drug formulations that can be amalgamated with the device. Semi-solid formulations, particularly gels, are the most obvious choice that would be compatible with the device and can match the contour of the skin. Prerequisites of such a dosage form include good electrical conductivity, optimal mechanical properties, good bioadhesion and acceptable viscoelastic properties that are imperative for patient compliance and clinical efficacy. Generally, there are two types of biopotential electrode gels: the ‘wet’ type that has been used in most commercial systems and solid ‘dry’ gels.

Several other approaches use unique buffering systems and bilayer designs that separate buffering and drug delivery layers. A novel, patented electrode system uses a mixture of electroconductive material, in which the polymer per se functions as an electrode as well as a functional polymer to immobilize the competitive ions [P2]. Consistent with the advances in microfabrication technology, photoetched devices have been developed where, through the use of divided type electrodes, an efficient distribution of current has been achieved, thereby improving the delivery of drugs and reducing the potential for skin damage caused by localised high current densities [14].

Formulations: the crucial link between the drug and the device

The wet-type gel electrodes are karaya-gum-based. These tend to creep and flatten out, exposing the skin to bare electrode. They are relatively expensive to manufacture and tend to irritate the skin, especially by the concentration of electrolytes, which differs greatly from physiological levels. Alternatively, dry hydrogels offer a number of advantages such as simple design, firm electrical contacts and low cost of manufacture. However, they are less conductive and less wet than the ‘wet’ gels [16]. A number of excipients have been investigated for the preparation of conducting gels, varying from natural polymers to the following synthetic polymers: agar-agar, gelatin, natural gums, Polyjel-HV, Lubrijel MS, HPMC, PVA, PVP, poly(dimethylaminopropylacrylamide) gel, hydrophilic microporous membrane, polymer electrolytes (e.g. poly(ethylene oxide)), hydrogel-containing ion exchange resins, methyl cellulose and PVP hydrogels. Ionic polymers used in hydrogels may tend to inhibit the release of ionic drugs, particularly proteins, by forming a complex and this can be overcome by use of gels devoid of ionic polymers [17]. Moreover, the complications arising from the swelling behaviour of hydrogels can be avoided by using either swollen hydrogels at equilibrium or addition of polymers such as dextran [16]. Further developments that are being pursued include the use of a hydratable gel pad that allows the drug pH to remain stable without the addition of buffers, and use of

Transdermal iontophoresis revisited Panchagnula et al.

471

humectants to prevent the loss of conducting properties of hydrogels with time [P3].

iontophoresis and chemical enhancers that may create new opportunities for the delivery of macromolecules.

Iontophoresis in conjunction with other enhancement techniques

Reverse iontophoresis: a noninvasive diagnostic tool

Most studies have been done with solutions, although the final, clinically acceptable formulation will be a semisolid formulation, such as a gel, which can be easily fabricated into an electropatch, as indicated earlier. Chemical enhancers might be required to achieve the desired flux from gel formulations depending on the release behaviour and structure of the gels. Moreover, the combination of enhancers and iontophoresis may require less current and enhancer, thereby reducing the irritation and other skin toxicity issues associated with the use of either of them alone.

The versatility of iontophoresis can be appreciated from the symmetry of the technique, which allows molecules to move in and out of the skin under the influence of electro-osmosis. The acceptance of iontophoresis as a standard diagnostic procedure for cystic fibrosis opened up a new avenue for noninvasive diagnosis and monitoring of biomolecules and ions from the body through reverse iontophoresis. Guy’s group [25] deserve special mention in this regard for their extensive studies on reverse iontophoresis of glucose, which has made this technology ready to enter the market.

Research in this direction is relatively new, though several chemical enhancers (namely, fatty acids, terpenes, azone, aprotic solvents, alcohols, glycols and surfactants) have been tried. The majority of the studies have concentrated on the use of enhancers that modulate the lipid bilayer of the skin by one or more mechanisms, resulting in an additive or synergistic effect [18,19].

Glucowatch (Cygnus Inc., USA) is a wrist-worn device that can continuously detect and monitor glucose levels through skin non invasively and is awaiting approval from the US Food and Drug Administration. This, if introduced, will alleviate the discomfort of diabetics that is associated with the conventional finger prick method of glucose measurement, although will not replace the information obtained from standard home blood glucose monitoring devices (see http://www.cygn.com).

The anionic surfactants seem to be useful in producing an additive or synergistic effect with iontophoresis, probably by incorporation into the lipid bilayer and/or by increasing the negative charge of the skin [20]. It is also important to note that the use of enhancers might not always result in an additive or synergistic effect and, in fact, may sometimes reduce the flux achieved with iontophoresis alone [20,21]. Therefore, the combined effect of chemical and iontophoretic enhancement will depend on the physico-chemical properties of the penetrant, polarity of the electrodes, properties of the enhancer and its behaviour under the influence of an electric field. Furthermore, the effects and side effects of the combination are usually decided by the chemical enhancer, rather than iontophoresis [22]. An interesting possibility is the use of high voltage pulses for a short time period (electroporation) followed by conventional iontophoresis with lesser current strengths. This would result in the initial creation of pores in the skin through which transport of molecules can take place by iontophoresis [P4]. Moreover, the creation of new pathways by electroporation results in more even charge distribution, hence reducing the potential for skin irritation [23]. Also, this may be a useful approach for macromolecules such as insulin that would otherwise be difficult to deliver by iontophoresis alone, as has been suggested recently [24•]. The ‘ionosonic’ transdermal drug delivery is a novel approach that uses iontophoresis along with sonophoresis [P5]. Other obvious approaches would be the initial electroporation followed by a combination of chemical enhancers and iontophoresis, or sonophoresis along with

Reverse iontophoresis also offers some promise for developing a skin sensitivity testing system that measures PGE2 levels through the skin [26]. Very recently, Merino et al. [27] have demonstrated the possibility of measuring systemic amino acid levels, particularly phenylalanine, using reverse iontophoresis, which may be useful for diagnosing metabolic disorders. There are, however, some issues that need to be addressed: for example, the development of sensors that can measure very low analyte concentrations precisely and reliably; the reduction in equilibration and measurement times; and the internal calibration of the system so as to develop useful and practical diagnostic systems. In spite of the fact that reverse iontophoresis is a later entrant to the field than iontophoresis, it is far ahead of iontophoresis, holding enormous commercial potential as a routine noninvasive diagnosis and monitoring technology. Moreover, reverse iontophoresis in conjunction with transdermal iontophoresis is the closest opportunity for realizing the delivery scientist’s dream of a truly ‘closed loop biofeedback’ drug delivery system.

Issues to be resolved In spite of the rapid progress of iontophoresis over the past hundred years, there are several unresolved issues posing impediments to this technology becoming a commercial reality. Most of the literature describes in vitro studies that claim an enhancement of several orders of magnitude compared with the lesser, or close to nil, passive flux, thereby raising questions about the transformation of the ‘enhancement’ into meaningful blood levels. Therefore, the actual iontophoretic flux becomes more important than the enhancement ratio. This is particularly true with macromolecules such as insulin for which there have been a number of iontophoretic studies

472

Next generation therapeutics

with hardly any report demonstrating that iontophoresis can achieve even the basal levels of insulin in vivo in humans. Use of highly charged analogues of large peptides may be one of the viable options to make them suitable for transdermal iontophoresis [28]. On the other hand, very few clinical studies have been carried out for iontophoresis, probably because it differs from the ‘classical clinical studies’ in the regulatory considerations and apprehensions of the study subjects. Another major reason for this dearth of studies is that the long term safety and efficacy of iontophoresis still remains to be proved unequivocally. It is, however, true that the in vitro ‘effects’ of an electrical field are sometimes magnified and may not happen to such an extent in vivo, considering the large surface area and inherent repair mechanisms of the skin. This can be very well appreciated from the fact that electric current has been used for a long time in dermatology, chiropractice, physiotherapy and sports medicine with no serious adverse affects or safety issues. But systematic toxicity studies using sophisticated analytical techniques need to be done before iontophoresis can gain wide acceptance as a drug delivery technology. There are several promising approaches to resolve the safety issues of iontophoresis that include the use of switching technique, in which the polarity of electrodes can be reversed periodically thereby reducing the skin irritation and at the same time increasing the surface area available for drug delivery [29]. Recently [30], it has been found that co-administration of anti-inflammatory agents, such as hydrocortisone, can lead to a reduction in skin irritation without affecting the delivery and pharmacokinetics of metoclopropamide. One of the main issues with regard to the formulation is ensuring the stability of the drug under the influence of an electric field and, until now, only a few studies have been carried out on this aspect [31,32]. Of particular importance is the stability of peptides, for which, in addition to ensuring stability under an electric current, it is important to preserve their unique physical, chemical and biological characteristics. Rehydratable gels, control of pH shifts and inclusion of stabilisers are some of the areas where more research needs to be done. Issues with regard to devices include miniaturization, incorporation of built-in safety aspects to avoid excessive currents, compatibility of the devices with the formulation as well as with the skin, and development of reusable devices — all of which are not insurmountable with the ongoing advancements in microelectronics and bioengineering. The issues highlighted are complex, obviating the need for a multidisciplinary approach to withstand the rigorous scrutiny of the regulatory process en route to commercialisation.

hydrophilic macromolecules, placing both a therapeutic and commercial need for developing a suitable drug delivery technology. It is in this perspective that the two earlier discoveries (insulin and iontophoresis) amalgamated at the end of the 20th century. Iontophoresis with specificity and control to its credit has undergone a renaissance over the past three decades and has reached a stage close to commercialisation. Iontophoresis will perhaps become the major platform technology for delivery of drugs belonging to class III of the recently proposed biopharmaceutics classification system [33]. The experience gained so far has, to a large extent, cleared the clouds of overenthusiasm (of delivering very large peptides such as insulin) and now presents a more realistic view of its potential (immediate opportunities for delivery of smaller peptides). Parallel developments in the field of bioengineering and microelectronics have helped to strengthen this cause. The present approach for smaller molecules is to utilise the dimension of ‘rapid onset’ and ‘precise control’ (only matched by intravenous infusion) achievable with iontophoresis rather than the dimension of enhancement. Strikingly, iontophoresis in the ‘reverse’ direction has already moved ‘to the fore’ in the race with iontophoresis for commercialisation. To be more realistic, iontophoresis might not be the ‘hope’ for all the molecules in this era of molecular medicine but some of the therapeutic areas in which iontophoresis may be useful include pain management, growth disorders, osteoporosis, opthalmology, cardiovascular, fertility control, sleep disorders and vaccines. The major impediments to the progress of iontophoresis are inadequate efficiency of iontophoretic transport and lack of sufficient chronic toxicity data. Nevertheless, iontophoresis is an attractive and competitive technology for drug delivery, but will have to overcome much tougher obstacles than its passive counterparts before it can make a lasting impact in the years to come.

Acknowledgements Two of the authors (OP and VBN) are supported by research fellowships form the Department of Science and Technology (DST), New Delhi, India. The authors wish to place on record the significant contributions made by Richard Guy and Michael S Roberts in understanding the mechanistic aspects of iontophoresis, which have taken this technology to the doorsteps of commercialisation. The continued support by AT Florence to Ramesh Panchagnula and his group is gratefully acknowledged. We thank CL Kaul (Director, National Institute of Pharmaceutical Education and Research, India) for his constant support and encouragement to our drug delivery group.

References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest •• of outstanding interest 1.

Nair V, Pillai O, Poduri R, Panchagnula R: Transdermal iontophoresis. Part I: basic principles and considerations. Methods Find Exp Clin Pharmacol 1999, 21:139-151.

2.

Banga AK, Chien YW: Iontophoretic delivery of drugs: fundamentals, developments and biomedical applications. J Control Rel 1988, 7:1-24.

3.

Pillai O, Nair V, Poduri R, Panchagnula R: Transdermal Iontophoresis. Part II: peptide and protein delivery. Methods Find Exp Clin Pharmacol 1999, 21:229-240.

Conclusions The beginning of the ‘biotechnological revolution’ in the later half of the 20th century has led to a ‘rush’ of polar and

Transdermal iontophoresis revisited Panchagnula et al.

4.

Guy RH: Iontophoresis − recent developments. J Pharm Pharmacol 1998, 50:371-374.

5. •

Jadoul A, Bouwstra JA, Preat V: Effects of iontophoresis and electroporation on the stratum corneum: review on the biophysical studies. Adv Drug Deliv Rev 1999, 35:89-105. This review describes various biophysical changes that take place after iontophoresis and electroporation. In both cases, there is an increase in skin hydration and disorganization of lipid bilayers; however, electroporation causes a larger decrease in skin resistance compared with iontophoresis. Some of these changes are partly reversible and depend on the electrical charge that is transferred. 6. ••

Higuchi WI, Li SK, Gahnem AH, Zhu H, Song Y: Mechanistic aspects of iontophoresis in human epidermal membrane. J Control Rel 1999, 62:13-23. This article is a compilation of the extensive work done by Higuchi's group in understanding the pore formation at low to moderate voltages. They have found that the pore induction can be correlated to the change in electrical conductance of human epidermal membrane provided an appropriate background electrolyte is selected with comparable ionic size to the permeant. The preexisting pores have been found to be 10–20 Å in size and the electrical-fieldinduced pores have also been found to be of the same size. Further, at low voltages, negatively charged pores have been found to be predominant, although there are effectively some positive and neutral pores. On the other hand, at high voltages only negatively charged pores seem to be present. 7.

Pikal MJ: The role of electroosmotic flow in transdermal and iontophoresis. Adv Drug Deliv Rev 1992, 9:201-237.

8. ••

Guy RH, Kalia YN, Charro MBD, Merino V, Lopez A, Marro D: Iontophoresis: electrorepulsion and electroosmosis. J Control Rel 2000, 64:129-132. This paper delineates the role of electrorepulsion and electro-osmosis to the overall iontophoretic flux. The authors schematically represent a qualitative relationship between relative flux and relative molecular size to illustrate the relative contributions of electrorepulsive, electro-osmotic and passive fluxes to the total iontophoretic transport of cationic species. From the relationship it can be deduced that, for low molecular solutes, electrorepulsion is the dominant driving force, whereas electro-osmosis takes the upper hand as the molecular weight increases. On the basis of this relationship, the authors suggest the novel idea of delivering high molecular weight anions from the anode exclusively making use of electro-osmotic effect. Therefore, this article reveals the possibility of manipulating the contribution of electrorepulsion and electro-osmosis to the total iontophoretic flux ranging form 0–100% in the laboratory by varying the pH, lipophilicity and conformational flexibility of the permeant. 9.

Hinsberg WHMCV, Verhoef JC, FiSpies JA, Bouwstra GS, Gooris HE, Junginger HE, Bodde HE: Electroperturbation on the human skin barrier in vitro (II): effects on stratum corneum lipid ordering and ultrastructure. Microsc Res Tech 1997, 37:200-213.

10. Pillai O, Nair VB, Panchagnula R: A comparative study of chemical vs iontophoretic enhancement through skin using ATR-FTIR. J Pharm Pharmacol 1999, 51s:303.

473

18. Bhatia KS, Singh J: Mechanism of transport enhancement of LHRH through porcine epidermis by terpenes and iontophoresis: permeability and lipid extraction studies. Pharm Res 1998, 15:1857-1862. 19. Oh SY, Jeong SY, Park TG, Lee JH: Enhanced transdermal delivery of AZT (Zidovudine) using iontophoresis and penetration enhancer. J Control Rel 1998, 51:161-168. 20. Chesnoy S, Durand D, Doucet J, Couarraze G: Structural parameters involved in the permeation of propranolol HCl by iontophoresis and enhancers. J Control Rel 1999, 58:163-175. 21. Wearley L, Chien YW: Enhancement of the in vitro skin permeabiliy of azidothymidine (AZT) via iontophoresis and chemical enhancer. Pharm Res 1990, 7:34-40. 22. Choi EH, Lee SH, Ahn SK, Hwang SM: The pretreatment effect of chemical skin penetration enhancers in transdermal drug delivery using iontophoresis. Skin Pharmacol Appl Skin Physiol 1999, 12:326-335. 23. Singh J, Maibach H: Irritancy of topical chemicals. In Dermal Absorption and Toxicity Assessment. Edited by Roberts MS, Walters KA. New York: Marcel Dekker; 1998:371-414. 24. Banga AK, Bose S, Ghosh TK: Iontophoresis and electroporation: • comparisons and contrasts. Int J Pharm 1999, 179:1-19. This is a recent review that compares iontophoresis to electroporation in terms of mode of application and pathways of transport, and suggests the possibility of combining them for effective delivery of macromolecules. Further, the article gives an account of various iontophoretic devices under commercial development. The authors, in addition, give a brief overview of delivery of particulates into skin using electroincorporation. 25. Guy RH: A sweeter life for diabetics? Nat Med 1995, 1:1132-1133. 26. Mize NK, Buttery M, Daddona P, Morales C, Cormier M: Reverse iontophoresis: monitoring prostaglandin E2 associated with cutaneous inflammation in vivo. Exp Dermatol 1997, 6:298-302. 27.

Merino V, Lopez A, Hochstrasser D, Guy RH: Noninvasive sampling of phenylalanine by reverse iontophoresis. J Control Rel 1999, 61:65-69.

28. Langkjaer L, Brange J, Grodsky GM, Guy RH: Iontophoresis of monomeric insulin analogues in vitro: effects of insulin charge and skin pretreatment. J Control Rel 1998, 51:47-56 29. Tomohira Y, Machida Y, Onishi H, Nagai T: Iontophoretic transdermal absorption of insulin and calcitonin in rats with newly devised switching technique and addition of urea. Int J Pharm 1997, 155:231-239.

11. Barry BW: Lipid-protein partition theory of skin penetration enhancement. J Control Rel 1991, 15:237-248.

30. Cormier M, Chao ST, Gupta SG, Haak R: Effect of transdermal iontophoresis codelivery of hydrocortisone on metoclopropamide pharmacokinetics and skin induced reactions in human subjects. J Pharm Sci 1999, 88:1030-1035.

12. Sage BH Jr, Riviere JE: Model systems in iontophoresis: transport efficacy. Adv Drug Deliv Rev 1992, 9:265-287.

31. Seth SC, Allen LV Jr, Pinnamaraju P: Stability of hydrocortisone salts during iontophoresis. Int J Pharm 1994, 106:7-14.

13. Lai PM, Roberts MS: An analysis of solute structure-human •• epidermal transport relationship in epidermal iontophoresis using the ionic mobility: pore model. J Control Rel 1999, 58:323-333. This research paper examines a range of published iontophoretic data using the ionic mobility-pore model. This model was found to provide an excellent regression for iontophoretic permeability, as it incorporates determinants such as solute size, mobility, total current applied, presence of extraneous ions, permselectivity of epidermis as well as solute pore interaction term. The pore size estimated by using this model (6.8–17 Å) is consistent with transport through the polar, intercellular and transappendageal pathways. Therefore, the ionic mobility-pore model can better describe the iontophoretic transport than the other models proposed earlier by the authors.

32. Huang YY, Wu SM: Stability of peptides during iontophoretic transdermal delivery. Int J Pharm 1996, 131:9-23.

14. Hage M, Akatani M, Kikuchi J, Ueno Y, Hayashi M: Transdermal iontophoretic delivery of insulin using a photoetched microdevice. J Control Rel 1997, 43:139-149. 15. Howard JP, Drake TR, Kellogg DL: Effect of alternating current iontophoresis on drug delivery. Arch Phy Med Rehabil 1995, 76:463. 16. Lai PM, Roberts MS: Iontophoresis. In Dermal Absorption and Toxicity Assessment. Edited by Roberts S, Walters KA. New York: Marcel Dekker; 1998:371-414. 17.

Gupta SK, Kumar S, Bolton S, Behl CR, Malick AW: Effect of chemical enhancers and conducting gels on iontophoretic transdermal delivery of cromolyn sodium. J Control Rel 1994, 31:229-236.

33. Amidon GL, Lennernäs H, Shah VP, Crison JR: A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 1995, 12:413-420.

Patents P1. Flower RJ, Mcarthur WA, Stropkay SE, Tanner MW: Iontophoretic drug delivery system − has disposable housing with reservoirs and high current power source and removable reusable controller. 1996, WO 9610041. P2. Ziping L: High efficiency electrode system for iontophoresis. 1998, US 5766144. P3. Naruhito H: Device structure for iontophoresis. 1999, US 5908400. P4. Hofmann AG: Method and apparatus for a combination of electroporation and iontophoresis for the delivery of drugs and genes. 1999, US 5968006. P5. Henley JL: Programmable apparatus for reducing substance dependency in transdermal drug delivery. 1996, US 5538503.