This technique is capable of expanding the range of compounds that can be delivered transdermally.⁷ Along with the benefits of bypassing hepatic first pass effect, and higher patient compliance, the additional advantages of iontophoretic techniques are, It is a non-invasive technique serve as a substitute for chemical enhancers.⁸ It eliminates adverse reaction and toxicity associated with presence of chemical enhancers in pharmaceutical formulation.⁹It required less quantities of drug in comparison to conventional transdermal drug delivery system (TDDS). TDDS of many ionized drug at therapeutic levels was precluded by their slow rate of diffusion under a concentration gradient, but iontophoresis enhanced flux of ionic drugs across skin under electrical potential gradient. It prevent variation in the absorption of TDDS. It eliminate the chance of over or under dosing by continuous delivery of drug programmed at the required therapeutic rate, provide simplified therapeutic regimen, leading to better compliance, allows a rapid termination or the modification, if needed, by simply by stopping drug input from the iontophoretic delivery system. Iontophoresis is important in systemic delivery of peptide/protein based pharmaceuticals, which are very potent, extremely short acting and often require delivery in a circadian pattern to simulate physiological rhythm, eg. Thyrotropin releasing hormone, somatotropine, tissue plasminogen activates, inter ferons, enkaphaline etc.¹⁰Self administration is possible. Constant current iontophoretic system automatically adjust the magnitude of the electric potential across skin which is directly proportional to rate of drug delivery and therefore, intra and inter-subject variability in drug delivery rate is substantially reduced, thus minimize inter and intra-patient variation.¹¹It eliminate the pain of needle insertion for local anesthesia. By minimizing the side effects, lowering the complexity of treatment and removing the need for a care to action, iontophoretic delivery improve adherence to therapy for the control of hypertension. It prevents contamination of drugs with reservoir for extended period of time.

The disadvantages of iontophoresis are, it is limited clinically to those applications for which a brief drug delivery period is adequate.¹² Excessive current density usually results in pain. Burns are caused by electrolyte changes within the tissues. The safe current density varies with the size of electrodes. The high current density and time of application would generate extreme pH, resulting in a chemical burn. Change in pH may cause the sweat duct plugging perhaps precipitate protein in the ducts, themselves or cosmetically hyperhydrate the tissue surrounding the ducts. High current density may cause electric shocks at the skin surface. Possibility of cardiac arrest due to excessive current passing through heart. Ionic form of drug in sufficient concentration is necessary for iontophoretic delivery. High molecular weight 8000-12000 results in a very uncertain rate of delivery.

3. PRINCIPLES OF IONTOPHORESIS

The iontophoretic technique is based on the general principle that like charges repel each other. Thus during iontophoresis, if delivery of a positively charged drug is desired, the charged drug is dissolved in the electrolyte surrounding the electrode of similar polarity, i.e. the anode in this example (Fig. 1). On application of an electromotive force the drug is repelled and moves across the stratum corneum towards the cathode, which is placed elsewhere on the body. Communication between the electrodes along the surface of the skin has been shown to be negligible, i.e. movement of the drug ions between the electrodes occurs through the skin and not on the surface. When the cathode is placed in the donor compartment of a Franz diffusion cell to enhance the flux of an anion, it is termed cathodal iontophoresis and vice versa.^13,14

Fig.1. Iontophoresis using a Ag/AgCl electrode system.

Neutral molecules have been observed to move by convective flow as a result of electro-osmotic and osmotic forces on application of electric current.¹⁵ Electromigration of ions during iontophoresis causes convective solvent motion and this solvent motion in turn ‘drags’ neutral or even charged molecules along with it. This process is termed as electro-osmosis. At pH values above 4, the skin is negatively charged, implying that positively charged moieties like Na⁺ molecules will be more easily transported as they attempt to neutralize the charge in the skin to maintain electroneutrality.¹⁶Thus the movement of ions under physiological conditions is from the anode to the cathode. For loss of each cation (sodium ion in this case) from the electrode in this process, a counterion, i.e. an anion, Cl^- moves in the opposite direction from the cathode to the anode. It is the transport number of each ion, which describes the fraction of the total current transferred by the ion and depends on the physicochemical properties of the respective ions. Na⁺ is greater than Cl^- and also the skin facilitates movement of Na⁺ more than Cl^-, hence there is a net increase in the NaCl in the cathodal compartment and net decrease in NaCl on the anodal side. Due to this electrochemical gradient, osmotic flow of water is induced from the anode to the cathode. If any neutral drug molecules are present at the anode at this time they can be transported through the skin along with the water. Such water movement often results in pore shrinkage at the anode and pore swelling at the cathode.¹⁷

The anodal compartment contains an ionizable drug D⁺ with its counter-ion A^-and Na⁺Cl^-. Application of an electric potential causes a current to flow through the circuit. At the electrode solution interface, the Ag⁺ and Cl^- react to form insoluble AgCl, which is deposited on the electrode surface. Electromigration transports the cations, including the drug molecule, from the anodal compartment and into the skin. At the same time, endogenous anions, primarily Cl^-, move into the anodal compartment. In the cathodal chamber, Cl^- ions are released from the electrode and electroneutrality requires that either an anion is lost from the cathodal chamberor that a cation enters the chamber from the skin.¹⁸

The Nernst-Planck equation has been used with modifications to predict iontophoretic enhancement ratios (ratio of steady state flux in presence of electric potential and in absence of potential) as the original equation lacks a term for convective electroosmotic flow.⁸ The increased flux during iontophoresis would include ¹⁹

1) Flux due to the electrochemical potential gradient across the skin

2) Change in the skin permeability due to the electric field applied

3) Electro-osmotic water flow and the resultant solvent drag.

J_ionto = J_electric + J_passive + J_convective

Jelectric is the flux due to electric current application;

Jpassive is the flux due to passive delivery through the skin; and Jconvective is the flux due to convective transport due to electro osmosis.

Pathways of molecular transport in iontophoresis: Skin appendages which include sweat glands and hair follicles are postulated to be involved in the major pathways of drug transport during iontophoresis.²⁰Evidence from studies comparing iontophoretic delivery in hairless and regular rats suggests a much larger contribution of the sweat glands and ducts as opposed to hair follicles in permeation.¹⁶Other pathways which have been shown to be involved in iontophoretic delivery include paracellular transport especially for water and uncharged polar solutes, artificial shunts due to temporary disruption of the organized structure of the stratum corneum,²¹ potential-dependent pore formation has also been observed.¹⁹

4. FACTORS AFFECTING IONTOPHORESIS

4.1 Physico-chemical parameters: The movement of drug ions across the skin is dependent not only the magnitude of apparent electric field, but also on physicochemical parameter as follows:

4.1.1pH: The iontophoretic drug delivery rate is dependent on the ionic form of drug
delivery, which is extremely effected by the pH of the system, when the skin
is maintained at a negative charge by exposing the solution with pH 4 or higher,
it facilitate the transdermal delivery of cationic drugs.²² Sanderson et alsuggested that the control of pH offers advantage of polarization effects on skin and enhance the selectivity of skin for catecholamine drug during iontophoretic delivery.¹² Many authors reported the pH dependent penetration enhancement of lidocaine, thyrotropin releasing hormone enalaprilate, insulin.^23,24

4.1.2 Drug salt form: It has been reported that different salt forms have different specific conductivities and that conductivity experiments in vitro will provide information concerning the general suitability of a drug for iontophoresis. The salt form of drugs must be considered along with the pH of the solution for determining the amount of drug in the ionized state.²⁵

4.1.3 Species variation: The wide differences in physical characteristics such as appendages per unit area, thickness and structural changes between human and laboratory rodent display a variation in penetration of drugs The average penetration of drugs is in order of rabbit > rat > guineas pig > human. Human skin is very much less permeable than other rodents but iontophoretic delivery of drug is 7-fold greater in human skin consists of greater negative charge/or greater area fraction of negative pores. Siddique et al observed that idiosyncrasy in hairless rats during the iontophoretic delivery of insulin.²⁶

4.1.4 Temperature: The penetration of drug through skin is affected by dual effect of both humidity and temperature. The iontophoretic delivery follows the Arrhenius equation and enhances drug permeation with temperature. K = Ae^-Ea/RT , where K= Specific rate constant, A= Arrhenius factor, Ea= Energy of activation, R= Gas constant, T= Temperature.²⁷

4.1.5 Concentration: The steady state flux of a number of solutes has been shown to increase as the solute concentration in the donor compartment is increased. An increase in concentration of butyrate,²⁸ and Arginine-vasopressin ²⁹ in the donor compartment was found to produce a proportional increase in their fluxes across skin. Linear increase in benzoate and gonadotropin releasing hormone (LHRH) flux with increasing concentrations of sodium benzoate and LHRH in the donor compartment has also been reported.^30,31 An increase in tissue levels of phosphorus after iontophoresis was also observed with an increase in phosphorus concentration.³² It is however possible that at higher drug concentrations, the transport may become independent of concentration, probably because of the saturation of the boundary layer relative to the donor bulk solution.³³

4.1.6 Buffer Systems: Buffer systems also affect the permeation of drugs by iontophoresis. It is important to optimize the concentration of buffer species in the system and should be sufficiently high to maintain good buffer capacity but should not reach an extent such that the current is mostly carried by the buffer species instead of drug special which may result the low efficiency of iontophoretic permeation.⁸

4.1.7 Ionic Compositions: In a solution of sodium chloride, there is an equal quantity of negative (Cl^-) and positive (Na⁺) ions. Migration of a sodium ion requires that an ion of the opposite charge should be in close vicinity. The latter ion of opposite charge is referred as a counter-ion. An ion of equal charge but of different type is referred as a co-ion. When using iontophoresis, it is important to know that pH adjustment is performed by adding buffering agents. The use of buffering agents as co-ions, which are usually smaller and more mobile than the ion to be delivered results in a reduction of the number of drug ions to be delivered through the tissue barrier by the applied current. In above example, when a positively charged drug is diluted in saline, the sodium ions will compete with the amount of drug ions to be delivered. Ideally, the use of a buffer system should be avoided in iontophoresis, but if this is not possible, alternative buffers, consisting of ions with low mobility or conductivity are preferred.³⁴

4.1.8 Electrodes: The electrode materials used for iontophoretic delivery are to be harmless to the body and sufficiently flexible to apply closely to the body surface. The most common electrodes are aluminum foil, platinum and silver/silver chloride electrodes used for iontophoretic drug delivery. A better choice of electrode is silver/silver chloride because it minimizes electrolysis of water during drug delivery. The positioning of electrodes in reservoir depends on the charge of the active drug. The distribution of drug within the skin depends on the size and position of electrodes. They are usually selected according to individuals needs. Larger electrode areas introduce the greater amounts of drug but lesser current density is tolerated to the skin in a non-linear manner. Metal electrodes touching to the skin produce burns with much lower current in composition to padded electrodes. A loose contact between the padded electrode and skin also produce burn due to uneven distribution of current. The safe current density varies with the
size of electrodes.³⁵

Fig. 2. Drug penetration pathway in low voltage iontophoresis and high voltage electroporation.

4.2 Electrical parameter

4.2.1 Current Strength: The current is limited to 1 mA due to patient comfort considerations. This current should not be applied for more than 3 min because of local skin irritation and burns. With increasing current, the risk of non specific vascular reactions (vasodilatation) increases. At a current of 0.4-0.5 mA/cm^2, such a vascular reaction is initiated after a few seconds of iontophoresis with deionised or tap water. This latter effect is probably due to current density being high enough a small area to stimulate the sensory nerve endings.^36,37

4.2.2 Current Density: Current density is the quantity of current delivered per unit surface area. The current density should be sufficiently high to provide a desired drug delivery rate. It should not produce harmful effects to the skin. There is quantitative relationship between the applied current density and amount of drug delivered.^8,38

4.2.3 Voltage: The ionic flux due to an applied voltage drop across a membrane is based on the fundamental thermodynamic properties of the system. The diffusion of drug during iontophoresis follows Nerst-Plank equation. It states that the flux of the ionic drug due to applied electric filed is directly proportional to the voltage drop and charge of the ion. Srinivasan et al, demonstrated ionic flux of Tetraethyl ammonium bromide (TEAB) with varying voltage drop (0.125, 0.250, 0.250, and 1.000). The enhancement factor for hairless mouse skin showed good agreement up to 0.5 volts and significantly higher at 1.0 volt due to skin damage but it is up to 0.25 V.⁸

4.2.4 Resistance: The electrical resistance of the skin varies widely with iontophoretic drug delivery. The resistance of the skin during iontophoretic application was much lower on sweat pores, especially when they discharge sweat. A slight fall in resistance occurs when electrode was interested in to the epidermis.⁸

4.2.5 Frequency/ Impedance: The frequency of the applied current charges depend on impedance of human skin ranges from 10 KHzs to 100 KHzs.³⁹ The impedance of the skin decreases at higher frequencies as less time is available to accumulate the charge on the skin surface during an applied pulse. The iontophoretic delivery of insulin decreases with increasing the frequency in the range of 50-2000 Hzs but Bagniefski and Burnett observed decrease in sodium ion flux with increase in frequency (10 KHzs). The theoretical relationship between impedance of skin and frequency follows this equation: 1/ZT = 1/ZR + 1/ZC.⁴⁰

4.2.6 On/Off Ratio: The on/off ratio electricity effects the relative proportion of polarization and depolarization of skin, which results the efficiency of transdermal iontophoretic drug delivery. The number of on/off cycles in each second is shown as frequency. For eg. the on/off ration 1 : 1 at frequency 2000 Hertz (0.5 ms/cycle) provides 0.25 ms depolarization period and same time for the polarization. Liu et al suggested that the on /off ration of 1 : 1 at 2000 Hertz yields better glucose control for iontophoretic insulin delivery than 4:1, 8:1 on/off ration. Apparently, 1:4 and 8:1 rations, results a residue polarization the skin from the previous cycle which reduce the efficiency of insulin delivery.³⁹

4.2.7 Wave Form: The waveform also affects the iontophoretic delivery of drug. The insulin delivery was highest at sinusoidal waveform than square and triangular waveform.³⁹

4.3 Operational parameters

4.3.1 Duration of Application: The transport of drug delivery depends on the duration of current applied in iontophoretic drug delivery. The iontophoretic penetration of drug linearly increased with increasing application time. The skin permeation of arginine vasopressin achieves higher plateau rate and in case of insulin delivery, 2-3 fold reduced the blood glucose levels with increase in duration of iontophoretic application.⁴¹

4.3.2 Mode of Current: Direct current (DC) iontophoretic dosing of drug inevitably develops a skin polarization potential, which reduce the efficiency of iontophoretic delivery and cause skin irritation, burning and redness, while pulsed DC dosing pattern is effective in comparison to simple DC application. Lelawong et al reported that the skin permeation rate of arginine vaspressine revealed no difference in the flux enhancement by simple DC and pulsed DC technique.⁴¹But, blood glucose level was markedly reduced by pulsed DC in comparison to simple DC in insulin delivery at the same current density. It also maintained at much lower levels for a longer period of time.⁴²

4.4 Efficiency of drug delivery: The efficiency of iontophoretic drug delivery can be defined as that fraction of all ions which cross the skin are drug ions for each mole of electrons flowing through the external circuit. This can be calculated from the slope of the plot of drug delivery rate (R) versus current (I), which flows the given equation: R = Ro + Fi. I where, Ro is the positive drug delivery using iontophoresis and Fi is the iontophoretic constant defined as the amount of drug (on a weight basis) delivered per uni-time per unit current.

4.5 Patient anatomical factors: Patient anatomical factors that influence the depth of penetration that is variable from patient to patient include skin thickness at the site of the application, presence of subcutaneous adipose tissue and the size of other structures, including skeletal muscle. Additionally, the presence and severity of inflammation can influence drug penetration due to the increased temperature which may increase and may serve to transport the drug throughout the body.^19,43,44

4.6 Stability of the drug during the Iontophoresis process: The drug undergoing iontophoresis must be stable in the solution environment up to the time of iontophoresis and also during the iontophoresis process. Oxidation or reduction of a drug not only decreases the total drug available but the degradation compounds posses the same charge as the drug ion, will complete with the drug ion and reduce the overall transport of drug.

Fig. 3. Permeabilization of the SC by cavitation upon low frequency ultrasound application.

5. IONTOPHORESIS: COMBINATIONS STRATEGIES

5.1 Iontophoresis in conjunction with Electroporation: Iontophoresis and electroporation are both methods of electrically assisted transdermal drug delivery. Iontophoresis is more commonly used to deliver lipophilic small molecular weight drugs, while electroporation seems more effective for the delivery of some macromolecules such as antisense oligonucleotides, peptides and proteins. Drug delivery with iontophoresis and electroporation are thought to utilize different penetration pathways (Fig. 2). Fluorescent microscopy and laser scanning confocal microscopy were used to visualize the FITC labeled phosphorothioate oligonucleotides transport at the tissue and cell level respectively in hairless rat skin after iontophoresis or electroporation. ⁴⁵ In the SC the transportation pathways for FITC labeled phosphorothioate oligonucleotides were more transcellular during electroporation and paracellular during iontophoresis. Another study performed by Piquett et al. showed at low trans SC voltages (<5 V) electrically driven transport of charged species occurs predominantly via pre-existing aqueous pathways.

In contrast, high voltage, (>50 V) has been hypothesized to involve electroporation within the multilamellar bilayer membranes of the SC, creating new aqueous pathways that contribute to a rapid, large increase in drug transport.⁴⁶Electroporation has the advantages ofquick drug effect onset,⁴⁷ delivery of macromolecules,⁴⁸ and resultant insignificant or minor skin damage.⁴⁹There was also evidence showing greater drug uptake by skin cells during electroporation.⁴⁵ Combination of iontophoresis and electroporation could possibly further enhance drug transport, and allow rapid delivery of a bolus dose and precise control of drug delivery modulation and programmability. However, in some cases, lowered combined effects than the effects with each individual treatment were also reported. Electrically assisted delivery of salmon calcitonin (sCT) (molecular weight 3600) was conducted by Chang et al. electroporation pulses (six pulses of 120 V, 10 ms each) followed by iontophoresis (0.5 mA/cm2) gave a flux about four times higher than with iontophoresis alone. Lag time of the iontophoretic delivery was shortened significantly as well. However, pulsing at lower voltages (60 and 100 V) followed by iontophoresis did not result in sCT transport increase over iontophoresis alone.⁵⁰ Pulsatile transdermal delivery of luteinizing hormone releasing hormone (LHRH) using electroporation followed by iontophoresis was studied by Riviere et al.The application of a single pulse (500 V, 5 ms as exponential) to initiate the experiment resulted in a nearly two-fold increase in LHRH concentration at the end of 30 min of iontophoresis (0.4mA/cm²). LHRH transport in a pulsatile manner was achieved by repeated processes of one pulse immediately followed by 30 min iontophoresis. Skin toxicity of electroporation together with iontophoresis was also evaluated in this study. Pulses of 0, 250, 500 and 1000 V were applied followed by constant current anodal iontophoresis of 0, 0.2, and 2.0 mA/cm2 for 30 min or 10 mA/cm2 for 10 min. At the gross microscopic level, immediately after or 4 h after treatment, erythema increased with increasing pulse voltage. Erythema, edema and petechiae all increased significantly with increased current in the absence of a pulse. The application of an electroporation pulse did not increase the iontophoretic-induced irritation with any current tested. All skin changes tended to decrease within 4 h after the treatments.⁵¹ Denet et al reported lowered transdermal delivery of lipophilic drug timolol with iontophoresis and electroporation combination than with iontophoresis alone. The decreased transport was explained as due to an accumulation of positively charged timolol in the SC, which was amplified by electroporation, and a resulting decrease of electroosmotic flux during iontophoresis.⁵² The practical application of combining electroporation with iontophoresis is still in its initial feasibility stage much like the commercial development of electroporation devices for transdermal delivery of drugs. Iontophoretic studies at least have resulted in some marketed medical device products and some drug-containing ones which are close to FDA approval.

5.2 Iontophoresis in conjunction with chemical enhancers: Although the use of iontophoresis results in much higher drug delivery if compared with conventional passive transdermal delivery, it still has limitations as a technique. Chemical enhancers can be used in combination with iontophoresis to achieve even higher drug penetration. In addition to increasing transdermal transport, a combination of chemical enhancers and electrically assisted delivery should also reduce the side effects such as irritation caused by high concentration of enhancers or stronger electric forces. The combined effects of enhancers and electrically assisted delivery depend on the physico-chemical properties of the penetrant, enhancer and their behavior under the influence of an electric field. Occasionally, the use of chemical enhancers was reported to result in reduced flux compared with using iontophoresis alone. However, more often synergistic effects have been reported such as those with fatty acids, and terpenes.^53,54

5.3 Iontophoresis in conjunction with sonophoresis (Fig. 3): Synergy between low-frequency ultrasound and iontophoresis would be expected since the techniques both enhance transdermal transport although through different mechanisms.⁵⁵ As a matter of fact, the disruption of SC lipid bilayer by the application of ultrasound can be utilized by further use of iontophoresis to increase transdermal drug transport to a greater degree. This combination has been found to enhance transdermal transport better than any of the single treatments alone. Iontophoresis combined with low frequency ultrasound was used in the transdermal delivery of sodium nonivamide acetate (SNA) by ⁵⁶ pretreatment of the skin with low frequency ultrasound (0.2 W/cm², 2 h) alone did not increase the skin permeation of SNA. The combination of iontophoresis (0.5 mA/cm²) and sonophoresis increased transdermal SNA transport more than iontophoresis alone. Another study also performed by Fang et al suggested that in some cases ultrasound could enhance drug permeation through hair follicles to a greater extent than through the bulk SC.⁵⁷

5.4 Iontophoresis in conjunction with microneedles: Few studies have reported the combination of iontophoresis with microneedle technologies. This combination provides the possibility of macromolecule transdermal delivery with precise electronic control. Lin et al designed a Macroflux and iontophoresis combined transdermal delivery system for the delivery of an antisense oligonucleotide ISIS 2302. The macroflux array, 2cm², had a microprojection density of 240/cm² and a needle length of 430 mm. Macroflux and iontophoresis combined system was made by assembling the Macroflux array, a drug reservoir, a membrane, a conductive gel and the iontophoretic electrode. Study results showed the system was capable of delivering therapeutically relevant amounts of ISIS 2302 into and through the stratum corneum.⁵⁸

5.5 Iontophoresis in conjunction with ion-exchange materials: For this combined technique, experimentally the ion exchange materials were initially immersed into drug solution for 3 h to overnight. Afterward, such a drug-loaded device (e.g. disc, a bundle of ion exchange fibers or hydrogel filled with ion exchange resins) was transferred to the donor part of a diffusion cell for in vitro or in vivo tests.^59-62 Conaghey et al studied the in vitro iontophoretic transdermal delivery of nicotine by ion exchange resins in agar hydrogel. Their results showed that these heterogeneous vehicles (i.e., hydrogel filled with resins) had several advantages over comparably simple agar hydrogel vehicles on account of this composite hydrogel’s versatility, capacities of drug storage and preventing pH decrease. The lowest pH value the skin experienced during iontophoresis with ion exchange resin was 6.31, where as using a simple hydrogel system, a lowest observed pH value was 3.0.⁶³ The successful in vivo delivery of therapeutic dosage of tacrine, an anti-Alzheimer’s disease agent, was demonstrated by Kankkunen et al. Smopexw-102 ion exchange fibers were used in their iontophoretic device on 10 healthy adult volunteers. The same group also studied the delivery of levodopa and metaraminol. Their results indicated that ion exchange fibers could be a good material to successfully store an easily degradable drug, such as levodopa, which could be easily oxidized in a basic aqueous environment.⁶² Drug stability was greatly enhanced by attaching levodopa to ion exchange fibers in an acidic environment.⁶¹

5.6 Others: Liposomal delivery system combining with iontophoresis, electroporation⁶⁴ for delivery of enkephalin formulated in liposomes has been developed. When enkephalin was delivered iontophoretically at its isoelectric point, from liposomes carrying positive or negative charge on their surface, resulted in permeation of radioactivity which was same or less than that of the controls when analyzed by liquid scintillation counting. In some cases the transferosomes drug delivery with iontophoresis for estradiol⁶⁵ and docetaxel⁶⁶ has also been exploited. Solid lipid nanoparticles in combination with iontophoresis for delivery of triamcinolone acetonide acetate.⁶⁷ Iontophoretic administration of triptorelin loaded nanospheres⁶⁸ has been developed.

6. ADVANCE BIOMEDICAL APPLICATION OF IONTOPHORESIS

Iontophoresis has wide applications in post-operative pain relief,⁶⁹ in dermatology for treatment of hyperhidrosis,⁷⁰ especially palmar and plantar –probably by obstructing the sweat ducts,^1,72 in ophthalmology for induction of various drugs like atropine, amikacin,⁷³ dexamethasone⁷⁴ iodide,⁷⁵ gentamycin^76,77 etc . For providing anesthesia⁷⁸ to external ear canal, middle ear and in maxillo facial prosthetics surgeries,⁷⁹ in dentistry to prevent dentin hypersensitivity and for providing local anesthetic for multiple tooth extraction.⁸⁰ In neurophysiological and neuropharmacological studies as a research tool, micro-iontophoresis for peripheral, central nervous system and smooth muscle preparations.^62,81 For delivery of magnesium sulphate in bursitis,⁸² calcium for myopathy, silver for osteomyelitis, local anaesthetics and steroids into elbow, shoulder and knee joints,⁸³ in cardiology for trans myocardial drug delivery of antiarrhythmic drugs.^84,85 Reverse iontophoresis for diagnosis and monitoring of chronic kidney disease and to track urea levels closely during a hemodialysis session,⁸⁶ also in measuring blood lactate level.⁸⁷ Its greatest advantage is in the transport of protein or peptide drugs which are very difficult to transport trasdermally due to their hydrophilicity and large molecular size.^88,89

7. CONCLUSION

Iontophoresis is gaining wide popularity as it provides a non invasive and convenient means of systemic administration of drugs with poor bioavailability profile, short half life and with multiple dosing schedules. Recently iontophoretic transdermal delivery of insulin, thyrotropin-releasing hormone, leuprolide, gonadotropin releasing hormone, arginine-vasopressin and some tripeptides has been demonstrated. Iontophoresis and the combination of this technique with other transdermal enhancement approaches have been widely investigated in recent years. The strides made in the development of electronic, formulation and material technologies has made clinical application of iontophoresis possible. Much success has been reported in the literature concerning the delivery of small chemical compounds as well as oligonucleotides and peptides. Combination of iontophoresis with electroporation, chemical enhancers, sonophoresis, microneedle and ion-exchange material may provide easier and more accurate delivery of macromolecules and poorly water soluble compounds. The skin irritation associated with iontophoresis has been addressed by several studies and it is an issue preventing wide application of the technology. However, the combination with other enhancement techniques may result in the need for less intense levels of current to reach therapeutically effective delivery amounts, and this will dramatically reduce the skin irritation problem.

8. ACKNOWLEDGEMENT

We would like to thank Mrs. Fatma. Rafiq. Zakaria Hon’ble Chairman, Maulana Azad Education Trust for her kind support.

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Received on 19.05.2009

Accepted on 13.06.2009

Research Journal . of Pharmaceutical Dosage Forms and Technology. 1(1): July.-Aug. 2009, 05-12