IONTOPHORESISNONINVASIVE DRUG DELIVERY SYSTEM

INTRODUCTIONINTRODUCTION Iontophoretic drug delivery is now an accepted method of

drug therapy which is gaining wide popularity especially in the area of pain relief.

Non-invasive systemic administration of minute amounts of drug transdermally which is especially useful in patients who require long-term medication as in chronic pain, diabetics, hypertensive, rheumatoid etc.

It negates the need for needle sticks, the pain and anxiety involved and minimises the trauma and risks of infection associated with it.

This mode of drug delivery is simple, versatile, effective, reliable and can be tailored for individual needs.

DEFINITIONDEFINITION"Iontophoresis is a process of transportation of ionic molecules or drugs into the tissues or derma by passage of electric current (0.5 mA/cm2) through the electrolyte solution containing the ionic molecules using a suitable electrode polarity.“This means it would involve an electromotive forceIn the body, ions with a positive charge(+) are driven into the skin at the anode and those with negative charge (-) at the cathodeIontophoresis is sometimes confused with electrophoresisIP involving movement of the colloid (dispersed phase) EP involving the liquid (dispersion medium)Iontophoresis may however cause an increased transport of method of penetration of non electrolytes through tissues.

ADVANTAGESADVANTAGESVirtually painless when properly applied.

Provides option for patients unable to receive injections.

Reduced risk of injection due to non-invasive nature.

Medications delivered directly to the treatment site.

Minimizes potential for tissue trauma from an injection.

Treatments are completed in minutes.

DISADVANTAGESDISADVANTAGESAn excessive current density usually results in pain.Burns are caused by electrolyte changes within the tissues.

The high current density & time of application would generate extreme pH, resulting in a chemical burn. This change in pH may cause the sweat duct plugging perhaps precipitate protein in the ducts. Electric shocks may cause by high current density at the skin surface. Ionic form of drug in sufficient concentration is necessary for iontophoretic delivery.

Iontophoresis enhances transdermal drug delivery by three mechanisms

(a) Ion-electric field interaction provides an additional force that drives ions through the skin.

(b) Flow of electric current increases the permeability of the skin.

(c) Electro-osmosis produces bulk motion of solvent that carries ions or neutral species with the solvent stream. Electro-osmotic flow occurs in a variety of membranes and is in the same direction as the flow of counter-ions. It may assist or hinder drug transport.

COMPONENTS NEEDED FOR EFFECTIVE IONTOPHORESIS DELIVERY

Power source for generating controlled direct current.

Electrodes and disperse the drug.

Negatively or positively charged aqueous medication of relatively small molecule size (<8000 Daltons).

Localized treatment site.

PHARMACOKINETICS OF ION PHARMACOKINETICS OF ION TRANSFERTRANSFER

Transdermal Iontophoresis delivers medication at a constant rate so that the effective plasma concentration remains within a therapeutic window for an extended period of time.

Therapeutic window - the plasma concentrations of a drug which should fall between a minimum concentration necessary for a therapeutic effect and the maximum effective concentration above which adverse effects may possibly occur.

IONTOPHORETIC DEVICES

Equipment should include safety, convenience, reliability and reproducibility of the device.

Basic Components of the equipments

1.DC power supply

2.Milliammeter

3.Timer

4.Rheostat

5.2 electrodes +ve and –ve charges

MAJOR COMPONENT

COMPONENT & COMPONENT & SOURCESOURCE

Iontophoresis Generators - Produce continuous direct current. Assures unidirectional flow of ionsSource of electrical energy = battery, supplies electric current to the body through two electrodes. The first electrode, called the donor electrode, delivers the therapeutic agent into the body. The second electrode, called the counter or receptor electrode, closes the electrical circuit.Each electrode contacts an ionically conductive reservoir, normally present as a liquid or hydrogel.The reservoirs are placed on the patient’s skin and contain either the drug (for the donor electrode assembly)or a biocompatible electrolyte (for the counter electrode assembly).

CONTROLSCONTROLSCurrent 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.

• Low amperage currents appear to be more effective as a driving force than currents with higher intensities.

• Higher intensity currents tend to reduce effective penetration into the tissues

Adjustable Timer Up to 25 min.

TREATMENT TREATMENT DURATIONDURATION

Treatment duration range =10-20 min with 15 min average, increased as desiredPatient 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.

ELECTRODESELECTRODESThe electrode materials used for iontophoretic delivery are to be harmless to the body & sufficiently flexible to apply closely to the body surface.

The most common electrodes used for iontophoretic drug delivery are Aluminum foil Platinum Silver/SilverchlorideA better choice of electrode is silver/silver chloride because it minimizes electrolysis of water during drug delivery.

COMMERCIAL COMMERCIAL ELECTRODESELECTRODES

Sold with most iontophoresis systems.Electrodes have a small chamber covered by a

SPM into which ionized solution may be injected.The electrode self adheres to the skin.

IONTOPHORESIS IONTOPHORESIS CONTROLLERCONTROLLER

IONTOPHORESIS - IONTOPHORESIS - SCHEMESCHEME

DRUG TRANSPORT DRUG TRANSPORT - IP- IP

MECHANISM MECHANISM When applied topically, the current is applied through a moist electrodeIP size depending on the skin region to be treated.The drug is administered through an electrode (active) which has the same charge as the drug. This is very important; if the polarity of the electrode is not the same as the ions, then penetration through the skin may not occur. The oppositely charged electrode (return) is placed some distance away at a neutral site, the size and distance of the 2 electrodes would also affect the transport of ions.Sweat ducts are primary paths by which ions move through the skin.

MECHANISMMECHANISMCurrent intensity < pain threshold that is comfortably tolerated by the patient is passed for an appropriate length of time (< 5mA/cm2). Current intensity should be gradually increased in the beginning and slowly decreased towards the end. The current can be given in any of the different waveforms, square, sinusoidal, triangular etc. The current density is the current intensity per unit cross sectional area. In practice, the density will vary from point to point and the value calculated would be an average value at the electrode surface. The ions transferred through the skin are taken up by the micro-circulation at the epidermo-dermal junction and the current flows back through the return electrode. “like charges repel each other and “like charges repel each other and opposite charges attract each other.”opposite charges attract each other.”

If any skin irritation occurs at this stage, the current intensity should be lowered.

ADMINISTRATIONADMINISTRATIONTo 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. 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. Electrodes should be separated by at least the diameter of active electrode. Wider separation minimizes superficial current density decreasing chance for burns

Operational FactorsI. Composition of formulation:

Concentration of drug solutionpH of donor solutionIonic strengthPresence of co-ions

II. Physicochemical properties of the permeant:Molecular sizeChargePolarityMolecular weight

FACTORS AFFECTING FACTORS AFFECTING IONTOPHORESIS DRUG IONTOPHORESIS DRUG

DELIVERYDELIVERY

III. Experimental conditions:Current densityDuration of treatmentElectrode materialPolarity of electrodes

Biological Factors Regional blood flow Skin pHSite & Condition of skinLipophilicityAge

FACTORS AFFECTING FACTORS AFFECTING IONTOPHORESIS DRUG IONTOPHORESIS DRUG DELIVERYDELIVERY

FACTORS AFFECTING FACTORS AFFECTING IONTOPHORETIC DRUG IONTOPHORETIC DRUG

DELIVERYDELIVERY1. Ionised state of the drug: For eg. Lignocaine is not effective

iontophoretically at a ph range of 3.4-5.2. Iontophoresis transdermal permission is maximum at pH of 9.4 and above when it is mainly in the non-ionised state and at this pH, iontophoretic delivery is minimum.

2. Presence of extraneous ions: other ions of the some charge can decrease the iontophoretic delivery of the drug ions because these ions compete with the drug for the iontophoretic flux.

3. Ionic strength: Higher ionic strength of the solution subjected to iontophoretic current resulted in decreased iontophoretic transport of the drug into the tissues as increase in ionic strength yields higher concentration of extraneous ions which compete for the electric current.

4. Concentration : increased concentration of the charged molecule yields greater molecules in the tissues.

5. Current intensity: higher the intensity, greater then transport

Polarisation: Direct current can cause polarisation whilst pulsed current can decrease tissue polarisation.Shifts in pH in tissue and drug solutions: With metallic electrodes, shifts in pH are noted which can affect ionisation of the drug. pH changes in the tissue can use injury due to migration of hydronium and hydroxyl ions produced by electrolysis. Separate buffered electrolyte solutions can be used which can prevent flow of ions into the tissue.

FACTORS AFFECTING FACTORS AFFECTING IONTOPHORETIC DRUG IONTOPHORETIC DRUG DELIVERYDELIVERY

BIOMEDICAL BIOMEDICAL APPLICATIONAPPLICATION

Greatest advantage is in the transport of protein or peptide drugs which are very difficult to transport transdermally 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 Na & Cl in the sweat.

• In scleroderma, iontophoretic delivery of hyaluronidase.

BIOMEDICAL BIOMEDICAL APPLICATIONAPPLICATION

Ophthalmology : Iontophoretic induction of various drugs like atropine, scopolamine, sulfadiazine, fluorescein, gentamycin etcENT For providing anaesthesia 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 studiesMicro-iontophoresis can be used to study neuro muscular junction, peripheral and central nervous system and smooth muscle preparations.Delivery of drugsAntihypertensives, anti-diabetics, anti-rheumatoids, hormones, vasodilators: Metaprolol, propranolol, insulin, methylcholine, bleomycin, steroids have all been introduced iontophoretically.Cardiology Iontophoretic transmyocardial drug delivery of anti-arrhythmic drugs which would avoid high systemic toxic levels is being done in animals.

BIOMEDICAL BIOMEDICAL APPLICATIONAPPLICATION

For relief of painIontophoretic histamine delivery as counter-irritantIn painless venipunctureFor post-operative pain reliefFor iontophoretic delivery of local anaesthetics for referred painAnti-inflammatory drug delivery

Inflammation With Constant Pain (Red, Hot, and Swollen)Inflammation With Constant Pain (Red, Hot, and Swollen) Dexamethasone Sodium PhosphateDexamethasone Sodium Phosphate 0.4% (negative polarity) delivered from the cathode for 3 treatments per week for 2-4 weeks.DiclofenacDiclofenac 5% (negative polarity) delivered from the cathode for 3 treatments per week for 2-4 weeks.KetoprofenKetoprofen 10% (negative polarity) delivered from the cathode for 3-5 treatments per week for 2-6 weeks.Lidocaine HydrochlorideLidocaine Hydrochloride 4% (positive polarity) delivered from the anode for 3-5 treatments per week for 2 weeks

IONTOPATCH – BIRCH MEDICAL

Lidosite®- To deliver lidocaine, an anesthetic agent.

Phoresor® II - To deliver botulinum molecule which is used for the treatment of hyperhydrosis.

E-Trans® - To deliver fentanyl.

Phoresor® - To deliver iontocaine.

COMMERCIALLY DEVELOPED IONTOPHORETIC DELIVERY SYSTEMS

SRI VENKATESWARA COLLEGE OF PHARMACY

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