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  1. 1. IONTOPHORESIS(drug delivery system) By, Dr. Shreeraj Shah Associate Professor, Dept. of Pharmaceutical Technology, L. J. Institute of Pharmacy, Ahmedabad 1
  2. 2. contentIntroductionAdvantages and disadvantagesElectrical property of skinRoute and mechanism of systemFactor affecting iontophoresisEquipments and devicesEvaluation Application 2
  3. 3. IntroductionDefinition:-Iontophoresis can be defined as thepermeation of ionized drug moleculesacross biological membranes underthe influence of electrical current. 3
  4. 4. HISTORICAL DEVELOPMENT:-The idea of applying electric current to increase the penetration of electrically charged drugs into surface tissues was probably originated by varatti in 1747.Ledus demonstrated the introduction of strychnine and cyanide ions in to the rabbits at the beginning of the 20th century , placing two rabbits in series with a direct current generator.Today, the treatment of hyperhidrosis is the most successful and popular application of iontophoresis in dermatologic medication. 4
  5. 5. AdvantagesEnhanced drug penetration (of selected drugs) over passive transport .Allows strict control of transdermal penetration rates.Permits rapid termination of drug delivery through termination of current or ultrasound.Skin remains intact, therefore low risk of introducing infection .Not immunologically sensitizing.In many cases, greater patient satisfaction.Home units available for iontophoresis. 5
  6. 6. Advantages over other delivery systemIontophoresis enlarges the range of drug candidates for transdermal administration.Fast skin recovery than parentral route.Less risk of systemic absorption than injection. Less anxiety provoking or painful than injectionIncreases therapeutic efficacy by bypassing hepatic “first pass” metabolism.Inter and intra subject variability is considerably reduced in contras to oral route. 6
  7. 7. DisadvantagesCan be time-consuming to administerDrugs must be in aqueous solution and must be in ionized.Minor tingling, irritation, and burning can occur. (these effects can often be minimized or eradicated with proper technique or current adjustment ). The skin itself imposes a barrier to the delivery of some medication. Additional ions act as charged carriers or active competitors for the drug applied. 7
  8. 8. Electrical property of the skinStratum corneum is composed of layers of horny cells which are a good insulator and forms the principal barrier of the body to electrical conductivity.In addition to electrical resistance, skin tissue also have a capacitance because of their ability to store electrons, and are thus electrically capacitors, so skin layer is said to be reactive. A reactive circuit is said to be present impedance rather than resistance.The human skin reportedly shows a high impedance to alternating current of low frequency, but the impedance was found to decrease from 130 to 30 kilo ohm as the A.C input was increased from 1 to 1000 Hz. 8
  9. 9. 9
  10. 10. Route and mechanism of systemThe greatest concentration of ionized species is expected to move into some regions of the skin where either the skin is damaged ,or along the sweat glands and hair follicles, as the diffusional resistance on the skin to permeation is lowest in these regions. 10
  11. 11. Pathway of ion transport Percutaneous absorption may take place simultaneously by any combination of the three main pathways that include; the intercellular (paracellular) pathway between the conneocytes along the lamellar lipids, the intracellular (transcellular) pathway through the cells or the appendageal (shunt) pathway via hair follicles, sweat ducts and secretary glands. 11
  12. 12. T.S. of SKINFig. 1. A diagrammatical representation of human skin:(a) appendageal pathway; (b) intercellular pathway. 12
  13. 13. Mechanism:-In iontophoretic treatment electric potential may alter the molecular arrangement of the skin components hence change in skin permeability.The “flip-flop gating mechanism” could be responsible for pore formation in the stratum corneum which is rich in keratin, an alpha- helical polypeptide. 13
  14. 14. Pores are thus opened up as a result of repulsion between neighboring dipoles, and water molecule and ions will flow in the pore channels to neutralize the dipole moments. The phenomenon should lead to an enhancement in skin permeability for peptide and protein molecules, and other charged molecules.The isoelectric point of the skin is between 3 and 4,means pores have positive charge below pH 3 and negative charge below pH 4 ,so it is easy to introduce basic drug. 14
  15. 15. Movement of Ions In SolutionIonization- Soluable compounds dissolve into ions suspended in solutions that are called electrolytesElectrophoresis- Movement of ions in solution according to the electrically charged currents acting on them.To understand this….Understanding of Cathode and Anode 15
  16. 16. Movement of Ions In SolutionCathode = Negatively charged electrode ♦Highest concentration of electrons ♦Repels negatively charged ions ♦Attracts positively charged ions ♦Accumulation of positively charged ions in a small area creates an alkaline reaction 16
  17. 17. Movement of Ions In SolutionAnode = Positively charged electrode ♦Lower concentration of electrons ♦Repels positively charged ions ♦Attracts negatively charged ions ♦Accumulation of negatively charged ions in a small area creates an acidic reaction 17
  18. 18. Movement of Ions In SolutionPositively charged ions are driven into tissues from positive poleNegatively charged ions are driven into tissues from negative poleKnowing correct ion polarity is essential 18
  19. 19. Movement of Ions In TissueForce which acts to move ions through the tissues is determined by ♦Strength of the electrical field ♦Electrical impedance of tissues to current flow 19
  20. 20. Movement of Ions In TissueStrength of the electrical field is determined by the current density ♦Difference in current density between the active (Active electrode- the one being used to drive the ion into the tissue)and inactive electrodes establishes a gradient of potential difference which produces ion migration within the electrical field. 20
  21. 21. Movement of Ions In TissueCurrent density may be altered by ♦Increasing or decreasing current intensity ♦Changing the size of the electrode  Increasing the size of the electrode will decrease current density under that electrode. 21
  22. 22. Movement of Ions In TissueCurrent density should be reduced at the cathode (negative electrode)  Alkaline reaction (+ions) is more likely to produce tissue damage than acidic reaction(- ions)  Thus negative electrode should be larger (2x) to reduce current density. 22
  23. 23. Movement of Ions In TissueHigher current intensities necessary to create ion movement in areas where skin and fat layers are thick further increasing chance of burns around negative electrodeSweat ducts are primary paths by which ions move through the skin and act to decrease impedance facilitating the flow of direct current as well as ions 23
  24. 24. Movement of Ions In TissueThe quantity of ions transferred into the tissues through iontophoresis is directly proportional to ♦Current density at the active electrode ♦Duration of the current flow ♦Concentration of ions in solution 24
  25. 25. Movement of Ions In TissueOnce the ions pass through skin they recombine with existing ions and free radicals in the blood thus forming the necessary new compounds for favorable therapeutic interactions 25
  26. 26. ELECTROCHEMISTRY OF IONTOPHORETIC CIRCUIT [ ELECTROREPULSION ] v Anode + Cathode - Drug + Neutral Drug – Na + drug Cl - Neutral Analyte – analyte Analyte + Cl - Na + BLOOD VESSELThe number of electrons flowing through the external circuit is a direct reflection of theamount of ionic charges flowing through the skin.The transport number and the intensity of current are the two main parameterscontrolling the iontophoretic flux. 26
  27. 27. Factors affecting iontophoresisOperational Factors:-I. Composition of formulation: Concentration of drug solution pH of donor solution Ionic strength Presence of co-ionsII. Physicochemical properties of the permeant: Molecular size and Molecular weight Charge PolarityIII. Experimental conditions: Current density Current profile Duration of treatment Electrode material Polarity of electrodes 27
  28. 28. Biological Factors:- Intra and inter subject variability Regional blood flow Skin pH Condition of skin 28
  29. 29. equipments and devicesIontophoresis GeneratorsProduce continuous direct currentAssures unidirectional flow of ions 29
  30. 30. Iontophoresis Generator♦Intensity control ♦1 to 5 mA ♦Constant voltage output that adjusts to normal variations in tissue impedance thus reducing the likelihood of burns ♦Automatic shutdown if skin impedance reduces to preset limit 30
  31. 31. Iontophoresis Generator ♦Adjustable Timer ♦Up to 25 min 31
  32. 32. Iontophoresis Generator ♦Lead wires ♦ Active electrode ♦ Inactive electrode 32
  33. 33. Current IntensityIncrease intensity slowly until patient reports tingling or prickly sensation.If pain or a burning sensation occur intensity is too great and should be decreased.When terminating treatment intensity should be slowly decreased to zero before electrodes are disconnected. 33
  34. 34. Current IntensityMaximum current intensity should be determined by size of the active electrode.Current amplitude usually set so that current density falls between 0.1-0.5 mA/cm2 of the active electrode surface. 34
  35. 35. Treatment DurationTreatment duration ranges between 10-20 minutes with 15 minutes being an average.Patient should be comfortable with no reported or visible signs of pain or burning.Check skin every 3-5 minutes looking for signs of skin irritation.Decrease intensity during treatment to accommodate decrease in skin impedance to avoid pain or burning. 35
  36. 36. Commercial Electrodes Sold with most iontophoresis systems. Electrodes have a small chamber covered by a semipermiable membrane into which ionized solution may be injected . The electrode self adheres to the skin. 36
  37. 37. Electrode Preparation To ensure maximum contact of electrodes skin should be shaved and cleaned prior to attachment of the electrodes. Do not excessively abrade skin during cleaning since damaged skin has lowered resistance to current and a burn might occur more easily. 37
  38. 38. ElectrodePreparationAttach self-adhering active electrode to skin 38
  39. 39. ElectrodePreparationAttach self-adhering active electrode to skinInject ionized solution into the chamber 39
  40. 40. ElectrodePreparationAttach self-adhering active electrode to skinInject ionized solution into the chamberAttach self-adhering inactive electrode to the skin and attach lead wires from generator to each 40
  41. 41. Electrode Placement Size and shape of electrodes can cause variation in current density (smaller = higher density) Electrodes should be separated by at least the diameter of active electrode ♦ Wider separation minimizes superficial current density decreasing chance for burns 41
  42. 42. Selecting the Appropriate IonNegative ions accumulating at the positive pole or anode ♦Produce an acidic reaction through the formation of hydrochloric acid ♦Produce softening of the tissues by decreasing protein density-useful in treating scars or adhesions ♦Some negative ions can also produce an analgesic effect (salicylates) 42
  43. 43. Selecting the Appropriate IonPositive ions that accumulate at the negative pole ♦Produce an alkaline reaction with the formation of sodium hydroxide ♦Produce hardening of the tissues by increasing protein density 43
  44. 44. Selecting the Appropriate Ion Inflammation  Edema ♦ Dexamethasone (-) ♦ Hyaluronidase(+) ♦ Hydrocortisone (-) ♦ Salicylate (-) ♦ Salicylate (-) ♦ Mecholyl(+) Spasm  Open Skin Lesions ♦ Calcium (+) ♦ Zinc(+) ♦ Magnesium(+)  Scar Tissue Analgesia ♦ Chlorine(-) ♦ Lidocaine (+) ♦ Iodine(-) ♦ Magnesium (+) ♦ Salicylate(-) 44
  45. 45. Evaluation:-In-vitro evaluation:-In this experiment , the glassware is assembled, sandwiching the excised skin. The drug formulation is placed in donor reservoir and normal saline is placed in the receptor resevoir. The electrode are connected.Periodically, solution is withdrawn from the receptor reservoir and assayed for the drug. In-vivo evaluation:-The system is evaluated in rats for transdermal iontophoretic delivery of vasopressin and analogue in rats. 45
  46. 46. Treatment PrecautionsProblems which might potentially arise from treating a patient using iontophoresis may for the most part be avoided if the athletic trainer ♦Has a good understanding of the existing condition which is to be treated ♦Uses the most appropriate ions to accomplish the treatment goal ♦Uses appropriate treatment parameters and equipment set-up 46
  47. 47. Chemical Treatment BurnsMost common problem is a chemical burn which occurs as a result of direct current itself and not because of the ion being used ♦Continuous direct current creates migration of ions which alters the normal pH of the skin ♦Chemical burns typically result from accumulation of sodium hydroxide at cathode ♦Alkaline reaction causes sclerolysis of local tissues ♦Decreasing current density by increasing size of cathode can minimize potential for chemical burn 47
  48. 48. Thermal Treatment BurnsThermal burns may occur due to high resistance to current flow created by poor contact of the electrodes with the skin ♦Electrodes are not moist enough ♦Wrinkles in the gauze or paper towels impregnated with the ionic solution ♦Space between the skin and electrode around the perimeter of the electrode ♦Body weight resting on top of electrode 48
  49. 49. ApplicationTreatment of hyperhydrosis, diagnosis of cystic fibrosis, other therapeutic uses.Delivery of metallic and non-metallic ions.Delivery of vasodilators.Delivery of local anesthetics.Delivery of steroids.Uses of iontophoresis in neurosciences. 49
  50. 50. List of Drugs Investigated Recently for Iontophoretic Delivery 50
  51. 51. 51