Iontophoresis: A Physical Approach to Transdermal Drug Delivery System
Swapnil Deshpande1*, Swaroop Lahoti2 , Rohit Shah3, Madhuri Shinde1, Sagar Motarwar3, Chaitrali Pawar3
1SCSSS’s Sitabai Thite College of Pharmacy, Shirur, Pune- 412 210.
2Y.B.Chavan College of Pharmacy, Rouza Baug, Aurangabad.
3RMP’s Bhalchandra College of Pharmacy, Gorhe (Kd), Pune- 411042
Corresponding author: swapnil.std@gmail.com
ABSTRACT:
In the last three decades, many advances have been made in the field of drug delivery, with resulting enhancements in the safety, efficacy and convenience of treatment for the patient. Some of the more dramatic developments include technologies that allow for the noninvasive transdermal delivery of several drugs. This delivery is accomplished by Iontophoresis, a process by which an electrical current is used to drive charged particles across the skin and is acts as a one of the most promising physical skin penetration enhancing method. In Iontophoresis, the application of constant electrical current enhances the transdermal transport of a charged drug molecule due to electro-repulsion. The electric field imposes a force on the drug molecule, which adds to the pure passive diffusion or the concentration gradient. During Iontophoresis, the skin permeability also increases due to changes in the structure of the skin caused by current flow. This review briefly describes the advantages, limitations of Iontophoretic drug delivery system and summarizes the experimental design along with electodes used for iontophoretic drug delivery system. Present review also provides an insight on iontophoretic electrochemistry. Various parameters which affect the transdermal absorption of drugs through iontophoresis like electrical, physicochemical and operational have also been reviewed in detail.
KEYWORDS: Iontophoresis, electric current, potential difference, transdermal, skin penetration.
INTRODUCTION:
At present, the most common form for delivery of drugs is the oral route because of the notable advantage of easy administration but it also has significant drawbacks namely poor bioavailability due to first pass hepatic metabolism and the tendency to produce rapid blood level spikes (both high and low) leading to a need for frequent dosing which can be both cost prohibitive and inconvenient1.
To overcome these difficulties there is a need for the development of new drug delivery system which will improve the therapeutic efficacy and safety of drugs by more precise (i.e. site specific), spatial and temporal placement within the body thereby reducing both the size and number of doses. New drug delivery system are also essential for the delivery of novel , genetically engineered pharmaceuticals (i.e. peptides, proteins) to their site of action, without incurring significant immunogenicity or biological inactivation.
Apart from these advantages the pharmaceutical companies recognize the possibility of repattening successful drugs by applying the concepts and techniques of controlled drug delivery system coupled with the increased expense in bringing new drug moiety to the market 1. One of the methods most often utilized has been transdermal delivery meaning transport of therapeutic substances through the skin for systemic effect. Closely related is percutaneous delivery, which is transport into target tissues, with an attempt to avoid systemic effects2.
There are two important layers in skin: the dermis and the epidermis. The outermost layer, the epidermis, is approximately 100 to 150 micrometers thick, has no blood flow and includes a layer within it known as the stratum corneum. This is the layer most important to transdermal delivery as its composition allows it to keep water within the body and foreign substances out. Beneath the epidermis the dermis contains the system of capillaries that transport blood throughout the body.
The stratum corneum develops a thin, tough, relatively impermeable membrane which usually provides the rate limiting step in transdermal drug delivery system. Sweat ducts and hair follicles are also paths of entry, but they are considered rather insignificant3.
Transdermal Drug Delivery System:
Transdermal drug delivery system is topically administered medicaments in the form of patches or gel that deliver drugs for systemic effects at a predetermined and controlled rate1.
A transdermal drug delivery (figure-1) device which provides an alternative route for administering medication or pharmaceuticals to be delivered across the skin barrier may be of an active or a passive design4. In theory, transdermal patches work very simply, by placing the drug in a relatively high dosage to the inside of a patch, which is worn on the skin for an extended period of time. Then, the drug enters the bloodstream directly through the skin by diffusion process. Since there is high concentration on the patch and low concentration in the blood the drug will keep diffusing into the blood for a long period of time, maintaining the constant concentration of drug in the blood flow5.
This approach to drug delivery offers many advantages over traditional methods. As a substitute for the oral route, transdermal drug delivery enables the avoidance of gastrointestinal absorption, enzymatic and pH associated deactivation. This method also allows for reduced pharmacological dosaging because it bypasses the gastrointestinal metabolic pathway. The patch also permits constant dosing, multi-day therapy with a single application as well as the capacity to terminate drug effects rapidly via patch removal, are all further advantages of this route6.
However this system has its own limitations in which the drug that require high blood levels cannot be administered and may even cause irritation or sensitization of the skin. The adhesives may not adhere well or uncomfortable to all types of skin. Along with these limitations the high cost of the product is also a major drawback for the wide acceptance of this product5.
Iontophoresis:
It is simply “The movement of medication with electric current”. Different investigators have given different definitions because one simple definition cannot explain all the mechanisms involved. But for the sake of simplicity, "Iontophoresis is a process of transportation of ionic drug molecules into the tissues by passage of electric current through the electrolyte solution containing the ionic molecules using a suitable electrodes." This means it would involve an electromotive force. In the body, ions with a positive charge (+) are driven into the skin at the anode and those with negative charge (-) at the cathode. Iontophoresis is sometimes confused with electrophoresis and electro-osmosis, the former involving movement of the colloid (dispersed phase) and the latter involving the liquid (dispersion medium), which are quite different7.
Criteria for Iontophoresis:
There are some very important rules that have to be followed when doing Iontophoresis:
1. The selected molecule must be ionized into positive and negative components and be maintained as ions during the treatment.
2. The size of the ion is important. For example even though a complex protein like collagen may be possible to ionize, due to large size of the important ion of collagen it cannot be transported through skin.
3. There is a limit to the number of polar substances that can be used simultaneously. If there are too many charged particles then the pores may be blocked by the crowd of ions converging all at once.
4. As electricity is only conducted through water and not through lipids, the ion must be water-soluble.
5. The pH of the active gel is of fundamental importance because pH is responsible for the ionization therefore pH at which 100% ionization take place considered as a ideal pH.
6. The current used should be effective one. It is high enough to be effective that it will move the ions effectively but still safe.
7. Pulsatile current works better than continuous current because it will increase the magnitude of effective electric current by allowing skin to convert from polarized state to depolarized one periodically8.
Advantages:
· Simple, versatile, effective, reliable and can be tailored for individual needs.
· Improved onset time and also a more rapid offset time.
· Improved efficacy and/or reduction in adverse effect.
· Avoiding the hepatic first-pass effect.
· Non-invasive and less tedious.
· Self medication is possible.
· Reduce frequency of dosage.
· Prevent variation in the absorption of TDDS.
· Provide simplified therapeutic regimen, leading to better compliance9.
Limitations:
· Itching, general irritation.
· Contraindicated in patients susceptible to applied currents, broken or damaged skin surfaces.
· Long-lasting skin pigmentation after application.
· Possibility of cardiac arrest due to excessive current passing through heart.
· High molecular weight 8000-12000 results in a very uncertain rate of delivery9.
Factors Affecting Iontophoretic Drug Delivery System
The movement of drug ions across the skin is dependent not only the magnitude of apparent electric field, but also upon the concentration of solution, the molecular size of drug to be passed, as well as charge and valence of ion.
(i) pH of donor solution:
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 drugs10.
Figure 1: Optimising Transdermal Drug Delivery
(ii) Characteristics of Penetrants:
The rate of penetration of substances through the intact skin depends on the size, charge, and configuration of molecules and relative solubility of the compound in lipid, water, in the Horney layer and on the vehicle in which the compound is presented to the skin11. The iontophoresis gives uncertain drug delivery rate for an ionic solute of molecular weight 8000 to 12,000 12. For a negatively charged species, the size dependent flux enhancement neutralizes the influence of electric field. Conversely, positive charged species becomes increasingly important to effect the electric field as the size of permeant increases.
(iii) Concentration of drug solution:
The concentration dependent iontophoretic delivery has not been fully investigated, some of the authors reported that as the concentration of drugs viz. hydromorphones13 and acetate ions14 increase in reservoir system then permeation of drug also increases. The iontopheric delivery of insulin does not affected by the reservoir concentration at the current range of 0.2 – 0.8 MA15.
(iv) Ionic Strength:
The ionic strength of a drug delivery system is directly related to the iontophoretic permeation of drugs. Some authors reported that increasingly the ionic strength of the system decreases the permeation rate of drug 16, 17 and has no significant effect on penetration up to the 0.5 V18.
(i) Current:
The extent of charged molecules, which may penetrate through the skin, are theoretically proportional to the intensity of current and the duration of treatment for a transdermal iontophoretic delivery19,20.
(ii) 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 Nernst-Plank equation. It states that the flux of the ionic drug due to applied electric field is directly proportional to the voltage drop and charge of the ion21.
(iii) 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 sweat22. A slight fall in resistance occurs when electrode was inserted into the epidermis.
(iv) Frequency/ Impedance:
The frequency of the applied current charges especially in man 23, variability of frequency dependent impedance of human skin ranges from 10 KHzs to 100 Khzs. The impedance of the skin decreases at higher frequencies 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 Hzs19.
(v) On/Off Ratio:
The on/off ratio of electricity affects 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 example the on/off ration 1:1 at frequency 2000 Hzs (0.5 ms/cycle) provides 0.25 ms depolarization period and same time for the polarization19.
(vi) Wave Form:
The wave form also affects the iontophoretic delivery of drug. The insulin delivery was highest at sinusoidal waveform than square and triangular waveform 19.
(i) Duration of Application:
The transport of drug delivery depends on the duration of current applied24 in Iontophoresis drug delivery. The Iontophoresis penetration of drug linearly increased with increasing application time25. The skin permeation of arginine vasopressin26 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.
(ii) 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. But pulsed DC dosing pattern is effective for drug transport, the same time average voltage because it faces lower skin resistance in comparison to simple DC application in flux enhancement.
Iontophoretic Electrochemistry:
An iontophoretic device comprises a power source and two electrode compartments. The drug formulation (D+A-) containing the ionized molecule (D+) is placed in the electrode compartment bearing the same charge; for example, a positively charged drug such as lidocaine would be placed in the anodal compartment as shown in figure 2. The indifferent electrode compartment is placed at a distal site on the skin. Although there are many different types of electrode, the most well-suited to iontophoresis is the Ag/AgCl couple28, 29, 30. First, It avoids the sharp decreases in pH that are seen with, for example, Pt-metal electrodes: Ag/AgCl electrodes have the considerable advantage that their electrochemistry occurs at voltages lower than those necessary for the electrolysis of water, which is undesirable for two reasons: first, the protons created at the anode compete to carry charge and because of their small size and high mobility, they may significantly reduce drug delivery efficiency, and second, the low pH produced in the anodal compartment can lead to acid-induced skin burns and it may have an adverse effect on drug stability. Once the current is applied, the electric field imposes a directionality on the movements of the ions present: positive charges in the anodal compartment move towards the cathode whereas anions move in the opposite direction. The electrochemistry occurring at the Ag anode necessitates the presence of Cl- ions in the anodal compartment: this requirement usually leads to a decrease in drug delivery efficiency since the NaCl commonly used to provide Cl- also introduces significant concentrations of highly mobile Na+ ions which compete very effectively with the drug to carry current. As the Cl- ions arrive at the electrode– solution interface, they react with the metallic silver to form silver chloride, which on account of its low solubility product, is deposited at the electrode surface, simultaneously releasing an electron. In order to maintain electroneutrality in the anodal compartment, either a cation must move out of the compartment and into the skin or an anion must leave the skin and move into the anodal chamber. In the cathodal compartment, the AgCl is reduced by the arrival of electrons from the power supply and yields metallic silver together with a Cl-ion, which passes into the solution. Again, for electroneutrality, this must be compensated for by the arrival of a cation from within the skin into the cathodal chamber or by the loss of an anion. Since the electrical circuit is completed by the endogenous inorganic ions that are present in the skin, primarily Na+ and Cl-, these latter species can impact on the efficiency of drug transport27.
Figure 2: Iontophoretic Electrochemistry
Iontophoretic devices
The main manufacturing concerns as in any equipment should include safety, convenience, reliability and reproducibility of the device. The iontophoretic device mainly consists of two parts7
a. Electrodes
b. Electrical Circuit
1. DC power supply
2. A milliammeter
3. A timer
4. A rheostat
5. The 2 electrodes Cathode (+ve) and Anode ( –ve).
Biomedical application:7
Iontophoresis has wide applications in Dermatology, Ophthalmology, ENT, Allergic conditions even in Cardiac and Neurological situations, but 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.
Dermatology:
· In hyperhidrosis, especially palmar and plantar – probably by obstructing the sweat ducts. No side effects when compared to anti- cholinergics.
· Copper- iontophoresis for fungal infection and male contraception, zinc for ulcers, iodine for reduction of scar tissues, iron/titanium oxide for tattoo removal.
· Histamine in allergy testing.
· In the diagnosis of cystic fibrosis to increase sweating by pilocarpine and confirm diagnosis by the concentration of sodium and chloride in the sweat.
· In scleroderma, for iontophoretic delivery of hyaluronidase.
Ophthalmology:
· Iontophoretic induction of various drugs like atropine, scopolamine, sulfadiazine, fluorescein, gentamycin etc.
ENT:
· For providing anesthesia of the external ear canal and middle ear and in maxillo facial prosthetics surgeries.
Dentistry:
· To prevent dentin hypersensitivity and for providing local anaesthetic for multiple tooth extraction.
Neurophysiological and Neuropharmacological studies:
· As a research tool, micro-iontophoresis can be used to study neuro muscular junction, peripheral and central nervous system and smooth muscle preparations.
Delivery of drugs:
· Antihypertensives, anti-diabetics, anti-rheumatoids, hormones, vasodilators: Metaprolol, propranolol, insulin, methylcholine, bleomycin, steroids have all been introduced iontophoretically.
Musculo skeletal disorders:
· Magnesium sulphate for bursitis, Calcium for myopathy, Silver for c/c osteomyelitis, local anaesthetics and steroids into elbow, shoulder and knee joints.
Cardiology:
· Iontophoretic transmyocardial drug delivery of anti-arrhythmic drugs which would avoid high systemic toxic levels is being done in animals.
For relief of pain:
· Iontophoretic histamine delivery as counter-irritant
· In painless venipuncture
· For post-operative pain relief
· For iontophoretic delivery of local anaesthetics for referred pain
· Anti-inflammatory drug delivery
CONCLUSIONS:
Traditional transdermal patches have been available for more than 20 years, and they have a proven history of success. With these new technologies, the number and complexity of transdermal drug delivery systems will increase in the near future. Pharmacists who become familiar with these technologies will be better able to address patient questions and concerns. This review focuses that the iontophoresis transdermal drug delivery can serve as a better alternative to increase the bioavailability of drug. The major advantages of iontophoretic delivery system which makes its future use hopeful on large scale are the accurate control over drug input kinetics and optimization of drug input rates. In the future, this system might be used to deliver therapeutic proteins or vaccines transdermally. Even though iontophoresis has so many advantages, a considerable amount of research and judicious use of technology is needed to make further improvement in these microelectronics devices and to make the iontophoretic delivery products available to public on a large scale. Thus, iontophoresis may prove to be an important alternative method of drug delivery in the near future.
ACKNOWLEDGEMENT:
A pleasant job remains to sit back and reflect on the pleasure and pains and acknowledge the efforts of all who helped to make this successful. I would like to acknowledge and my obligation to our principal Mr. D. G. Baheti for providing the necessary facilities. I am one of the fortunate students whose path is enlightened by the expertise and guidance of Mr. Lahoti S. R. I would like to thank RJPT to give me opportunity for presenting review article regarding my interested topic. Lastly, I would like to express my gratitude to my parents who always supported and encouraged me. Thus I have solemnized my participation in this review with dedication to make it success.
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Received on 30.10.2011 Modified on 27.11.2011
Accepted on 05.12.2011 © RJPT All right reserved
Research J. Pharm. and Tech. 5(2): Feb. 2012; Page 175-180