ADVANTAGES:

Along with the benefits of bypassing hepatic first pass effect, and higher patient compliance, then additional advantages that the iontophoretic technique offers can be summarized as follows:

1. Delivery of ionized and unionized drugs

2. Enabling continuous or pulsatile delivery of drug (depending on the current applied)

3. Permitting easier termination of drug delivery

4. Offering better control over the amount of drug delivered since the amount of Compound delivered depends on applied current, duration of applied current, and area of skin exposed to the current

5. Restoration of the skin barrier function without producing severe skin irritation

6. Improving the delivery of polar molecules as well as high molecular weight compounds

7. Ability to be used for systemic delivery or local (topical) delivery of drugs

8. Reducing considerably the inter and intra-individual variability since the rate of drug Delivery is more dependent on applied current than on stratum corneum characteristics²

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 (DC) 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 for anodal iontophoresis, the situation would be reversed.

Neutral molecules have been observed to move by convective flow as a result of electro-osmotic and osmotic forces on application of electric current .Electro migration 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. Thus 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^3,4

MECHANISM:

Like charges repel. Hence the charged ion is repelled into the skin from a similar charged electrode. The skin being negatively charged at physiological pH acts as a cationselective membrane and favors movement of cations through anodal iontophoresis. Anodal iontophoresis also causes convective motion of the solvent occurring in response to movement of counterions. This process of electro-osmosis is involved in the motion of neutral compounds as well as positively charged ions. Due to the complex nature of iontophoretic delivery, a number of attempts have been made to define the rate of iontophoretic delivery. 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. Srinivasan and Higuchi and Pikal and Shah studied the contributions of osmotic flow and incorporated this fact into several equations.

The increased flux during iontophoresis would include:

1. Flux due to the electrochemical potential gradient across the skin;

2. Change in the skin permeability due to the electric field applied; and

3. Electroosmotic Water flow and the resultant solvent drag.

J ^ionto= J ^electric+ J ^passive+ J ^convective

J ^electricis the flux due to electric current application; J ^passivewas the flux due to passive delivery through skin; and J^convectivewas 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. Evidence 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. Other 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, potential-dependent pore formation has also been observed .⁵

Reverse iontophoresis: a noninvasive diagnostic tool:

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 non- invasive diagnosis and monitoring of biomolecules and ions from the body through reverse iontophoresis.

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. Reverse iontophoresis also offers some promise for developing a skin sensitivity testing system that measures PGE2 levels through the skin. Very recently, scientist 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.⁶

Factors affecting iontophoresis:

I. Composition of formulation:

Ø Concentration of drug solution

Ø pH of donor solution

Ø Ionic strength

Ø Viscosity

Ø Presence of co-ions

II. Physicochemical properties of the permeant:

Ø Molecular size

Ø Charge

Ø Polarity

Ø Molecular weight

III. Experimental conditions:

Ø Current strength

Ø Current profile

Ø Electrode material

Ø Biological Factors

Ø Regional blood flow

Ø Condition of skin and Skin pH

§ Drug concentration: Increasing drug concentrations results in greater drug delivery to a certain degree

§ pH: The pH of the solution can be adjusted and maintained by larger molecules, such as ethanolamine: ethanolamine hydrochloride rather than the smaller hydrochloric acid and sodium hydroxide. An increase in ionic strength of the system will also increase the competition for the available current, especially since the active drugs are generally potent and present in a smaller concentration than these extraneous ion

§ Ionic strength: as increase in ionic strength will decrease drug delivery,

§ Viscosity: The migration of the drug is inversely related to the viscosity.

§ Presence of co-ions : If buffer ions are included, they compete with the drug for the delivery, decreasing the quantity of drug delivered, especially since buffer ions are generally smaller and more mobile than the larger active drug

§ Physicochemical variable: The drug should be water soluble, low-dose and ionizable with a high charge density. Smaller molecules are more mobile but large molecules are also iontophoresable

§ Current strength: Since current can easily be controlled by the use of electronics, it is a convenient mean to control delivery of drugs to the body. However, a large increase beyond the permissible limits causes irritation and can damage the skin

§ Current profile: Mostly, in the studies conducted on animals in vitro, current is kept constant and very low voltage of about 10 V is applied

§ Electrode material: Iontophoretic studies have been conductedusing both platinum wire and Ag/AgCl wires. However, platinum electrodes or other inert electrodes like nickel or stainless steel have been found to cause pH drift and gas bubbling due to decomposition of water and thus causing production of H+ and OH- ions

§ Regional blood flow: During iontophoresis, the dermal blood supply determines the systemic and underlying tissue solute absorption. Blood supply however, does not appear to affect the drug penetration fluxes through the epidermis during iontophoretic delivery.

§ Condition of skin: In iontophoresis, skin condition also affects the penetrating properties of permeant. Feldman et al., showed that the passive diffusion of hydrocortisone occured maximally fromthe area with numerous hair follicle while lesser in area with thickest stratum corneum^7,8

Applications of iontophoresis:

1. Treatment of hyperhydrosis:

Hyperhydrosis (also called hyperhidrosis) is a condition that most often results in excessive sweating in the hands and feet. Tap water iontophoresis is one of the most popular treatments used in this condition. The procedure uses a mild electrical current that is passed through tap water to temporarily shut off sweat glands. A hand and foot is each placed in a different water basin and the electric current is gradually increased to the required level and maintained for 20 min followed by a gradual decrease. The underlying mechanism of how iontophoresis helps treat this ailment is not fully understood. According to one hypothesis, iontophoresis may induce hyperkeratosis of the sweat pores and obstruct sweat flow and secretion (although no plugging of the pores has been found). Other proposed mechanisms include impairment of the electrochemical gradient of sweat secretion and a biofeedback mechanism. Successful induction of hypohidrosis by tap-water iontophoresis requires the application of 15–20 mA to each palm or sole for 30 min per session for 10 consecutive days, followed by one or two maintenance sessions per week .The advantage of using tap water iontophoresis is that the patient can conduct the procedure at home.⁹

2. Topical delivery:

The ability to control the delivery rates of drugs by changes in current makes iontophoresis an attractive technique to use.Yamashita et al. studied the efficacy of iontophoretic delivery of calcium for treating hydrofluoric acid-induced burns.The authors conducted the experiments using rats as in vivo models.Hydrofluoric acid burns were induced by dispensing 50% hydrofluoric acid on the backs of the rats under anesthesia and the rats were divided into five groups: control group (untreated) one group treated with 2.5% calcium gluconate jelly applied once for the duration of the experiment on the burn area on the back of the rat, third group treated with intradermal and subcutaneous calcium gluconate injection and the last group was subjected to calcium chloride iontophoresis at 1.5 V.Burn areas were used as a measure to assess the efficacy of treatment and pathologic findings were classified microscopically into five stages at 1 week: stage 1, epidermal burn; stage 2, superficial dermal burn; stage 3, deep dermal burn; stage 4, full-thickness burn; and stage 5, burn affecting the skeletal muscle. They observed that burn areas were significantly reduced by iontophoresis more than any other mode of calcium administration, and iontophoresis was more efficacious than topical or injection therapy for experimental hydrofluoric acid burns.Topical delivery of anesthetics during dermal surgery remains the most common topical application of iontophoresis.

Hydrochloride salts of anesthetics of the amide type like lidocaine, bupivacaine, etidocaine, mepivacaine, prilocaine and ropivacaine have been widely studied. Lidocaine been successfully formulated in an iontophoretic patch for dermal anesthesia (Vyteris, Inc., Fairlawn, NJ, USA).^10,11

3. Non-invasive monitoring of glucose:

Electro osmotic flow generated by application of low level current has been used for extraction of glucose through the skin. As the direction of glucose flow is in the opposite direction (in outward direction in skin) to conventional iontophoresis, it is called reverse iontophoresis. This property in combination with in situ glucose sensors has been used in GlucoWatchw Biographer (Cygnus Inc.,Redwood City, CA, USA) . This device allows noninvasive extraction glucose across the skin, allowing a diabetic’s glycemia to be evaluated every 10 min over several hours. The Biographer is constituted of a small Wristwatch device containing sampling and detection devices, electronic circuitry, and a digital display. As the negatively charged skin at physiological pH is subject to iontophoresis by the electrodes in the device, the sodium ions move from the anode towards the cathode and create a convective flow. Glucose thus gets transported to the cathode with the solvent where it is oxidized by glucose oxidase to release hydrogen peroxide. This is then detected by the custom designed biosensor in the system. Research in the near future could link the detection level to release of insulin as per the needs of the patient which would be another substantial step towards creating a ‘closed loop biofeedback’ drug delivery system. Another study by Merino et al. has demonstrated sampling of phenylalanine by reverse iontophoresis. The limitations of these noninvasive biological sampling techniques would be in their ability to measure reliably and accurately low levels of analytes.^12,13

4. Delivery of antisense oligonucleotides:

Antisense oligonucleotides bind to the mRNA of the disease-causing genes and inhibit their expression so as to block synthesis of disease related proteins. These oligonucleotides are usually delivered by injection and hence an alternative route for systemic delivery is desirable. The transdermal delivery route is attractive because it may enable the localized delivery of the oligonucleotide into skin layers, which is desirable in conditions such as dermatitis and psoriasis. IL-10 over-expression for example, is one of the important pathogenic factors in skin lesions resulting from atopic dermatitis (AD). Thus, the regulation of IL-10 production is a potential solution for immunotherapeutic intervention in AD. A study has been conducted by Sakamoto et al. which included the topical delivery of an antisense oligonucleotide for mouse IL-10 and the observation of the therapeutic effect on the AD skin lesions of mice. By using iontophoresis the authors were able to deliver 30% of the applied dose locally to the dermis and the epidermis. Topically delivered oligonucleotide decreased the levels of mRNA and protein of IL-10 in the lesions of mice and the dorsal lesions disappeared with repeated topical application. It was concluded that this delivery system offered potential therapy for established dermatitis patients.¹⁴

5. Peptide delivery:

This seems to be one of the most promising applications of iontophoretic transdermal delivery. Transdermal delivery itself offers the advantages of bypassing first pass metabolism and gastrointestinal degradation as well as patient compliance over the existing oral and parenteral routes of administration for peptide delivery. An additional advantage that it offers specifically for proteins and peptides is the avoidance of strong proteolytic conditions as found in the gastrointestinal tract. Chien et al. have studied the delivery of oligopeptide, vasopressin, with transdermal periodic iontotherapeutic system (TPIS). The TPIS procedure delivered a d. c. pulse with various combinations of waveforms, frequency, on/off ratio and current intensity for specified application time. The results suggested that in the absence of TPIS, the rate of skin permeation of vasopressin was negligible but in the presence of TPIS, not only did the flux increase 190-fold but the lag time was also reduced by almost 9 h. Over the years a wide range of proteins and peptides such as LHRH, salmon calcitonin, and human parathyroid hormone have been studied for transdermal delivery via iontophoresis.^5,15,16

REFERENCES:

1. Kevin Li et al. Evaluation of constant current alternating current iontophoresis for transdermal drug delivery Journal of Controlled Release 110 (2005) 141– 150

2. Y. Wang et al. Transdermal iontophoresis: combination strategies to improve transdermal iontophoretic drug delivery European Journal of Pharmaceutics and Biopharmaceutics 60 (2005) 179–191.

3. Aarti Naik et al. Transdermal drug delivery: overcoming the skin’s barrier function research focus reviews PSTT Vol. 3, No. 9 September 2000

4. B.W. Barry et al. Novel mechanisms and devices to enable successful Transdermal drug delivery European Journal of Pharmaceutical Sciences 14 (2001) 101–114

5. Yie W. Chien et al. facilated transdermal delivery of therapeutics peptides and Protein by iontophrotic delivery device, Journal of Controlled Release, 13 (1990) 263-278

6. Ramesh Panchagnula et al. Transdermal iontophoresis revisited Current Opinion in Chemical Biology 4 (2000) 468–473

7. Sanjula Baboota et al. Iontophoresis - An Approach for Controlled Drug Delivery: A Review, Current Drug Delivery, 4(2007) 1-10

8. Reena Rai et al. Iontophoresis in dermatology, Dermatology 4(2005) 236-241

9. Jl shen et al a new strategy of iontophoresis for hyperhydrosis, journal of American academy of dermatology 22 (1990) 239-241.

10. J. Singh, H.I. Maibach et al. Topical Iontophoretic Drug Delivery in vivo: Historical Development, Devices and Future Perspectives,] Dermatology vol.187, no. 4, 1993

11. Philip W. Ledger et al. Skin biological issues in electrically enhanced Transdermal delivery, Advanced Drug Delivery Reviews, 9 (1992) 289-307

12. Ramesh Panchagnula et al. Transdermal iontophoresis revisited, Current Opinion in Chemical Biology, 4 (2000) 468–473

13. M. Paranjape et al. A PDMS dermal patch for non-intrusive transdermal glucose sensing, Sensors and Actuators A 104 (2003) 195–204

14. Yannic B. Schuetz et al. Effect of amino acid sequence on transdermal iontophoretic peptide delivery, European Journal of Pharmaceutical Sciences 26 (2005) 429–437

15. Richard H. Guy et al. Structure–permeation relationships for the non invasive Transdermal delivery of cationic peptides by iontophoresis european journal of pharmaceutical sciences 29 (2006) 53–59

16. Aarti Naik et al. Effect of amino acid sequence on transdermal iontophoretic peptide delivery, European Journal of Pharmaceutical Sciences , 26 (2005) 429–437

Received on 19.01.2010

Accepted on 17.02.2010

Research Journal of Pharmaceutical Dosage Forms and Technology. 2(3): May-June 2010, 215-219