iontophoresis and sonophoretic system

it is a novel drug delivery system.

1. Topic:IONTOPHORESIS-SONOPHORETIC SYSTEM Submitted by: Chaitrali Gijare Subject: NOVEL DRUG DELIEVERY SYSTEM 2PH801

2. Contents Introduction Iontophoretic drug delivery system Sonophoretic drug delivery system Iontophoretic Vs sonophoretic drug delivery system Reference

3. Introduction THE SKIN- Protective layer with large no. of dead cells, hence acts as barrier to penetration. The skin accounts for about 15% of adult’s wt. Penetration varies with humidity, pigmentation, age, chemical status of all layers. Stratum Corneum (SC) offers maximum resistance. SC consists of keratinocytes and lipid bilayer. Permeability can be increased by Chemicals, Electrical Fields or Ultrasound which disrupt lipid bilayer of SC and increase permeability.

4. IONTOPHORETIC DRUG DELEIVERY SYSTEM Iontophoresis can be defined as the permeation of ionized drug molecules across biological membranes under the influence of electrical current. Principles of Iontophoresis : Electrode placement is dependent on the electric charge of the ion which is to be delivered into the tissue. A positive ion will be delivered from the positive electrode and a negative ion will be delivered by the negative electrode. Electrical energy assists the movement of ions across the stratum corneum according to the basic electrical principle “like charges repel each other and opposite charges attract each other .”

5. Advantages of Iontophoresis Virtually painless when properly applied . Provides option for patients unable to receive injections. Reduced risk of infection 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 .

6. Drawback E xcessive current density usually results in pain. Burns are caused by electrolyte changes within the tissues. The high current density and 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.

7. Iontophoretic drug delivery system works by three mechanism Ion-electric field interaction provides an additional force that drives ions through the skin. The flow of electric current increases the permeability of the skin. 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.

8. C omponents Power source for generating controlled direct current . Electrodes that contain and disperse the drug. Negatively or positively charged aqueous medication. A localized treatment site

9. Movement of Ions In Solution Ionization- Soluble 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 . 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.

10. Contd … 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 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.

11. Contd … Force which acts to move ions through the tissues is determined by Strength of the electrical field Electrical impedance of tissues to current flow. 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. 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 .

12. Contd … Current density should be reduced at the cathode Alkaline reaction is more likely to produce tissue damage than acidic reaction . Thus negative electrode should be larger to reduce current density. 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. 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 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 .

13. Iontophoresis Generator Produce continuous direct current in the order as per the requirement. Assures unidirectional flow of ions. It also consist of a timer for regulating the supply of current. 11 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. Adjustable Timer for giving the duration of treatment.

14. Electrodes of iontophoresis Active pad- This electrode have a small chamber covered by a semipermeable membrane into which ionized solution may be injected. Dispersive pad- Also known as Inactive pad. Dispersive pad should be larger than active pad to reduce the current density leading to reduction of irritation. The polarity of these electrode depends on the characterictics of drugs and these electrodes self adheres to the skin .

15. Electrodes Material The electrode materials used for iontophoretic delivery are to be harmless to the body and sufficiently flexible to apply closely to the body surface. T he most common electrodes used for iontophoretic drug delivery are : Aluminum foil Platinum and Silver/ Silverchloride A better choice of electrode is silver/silver chloride because it minimizes electrolysis of water during drug delivery.

16. 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. 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. Electrode Placement • Size and shape of electrodes can cause variation in current density (smaller = higher density) • Inactive electrodes should be separated by a distance atleast the diameter of active electrode

17. Factors affecting iontophoretic drug deleivery system Operational factor Composition of the formulation Concentration of the drug solution pH of the donor solution Ionic strength Presence of co-ions Physicochemical properties Molecular size P olarity Charge Molecular weight

18. Experimental conditions current density polarity of electrodes electrode material 4) Biological factors Intra and inter variability Regional blood flow Skin pH Condition of skin

19. Iontophoresis formulation Solvent Water Co-solvent PEG glycerol Ethanol PG Matrix Hydrophillic Nonionizing polymer Drug salt Halide salt Counter reservoir Weak acid Weak base

20. Iontotrophic patch

21. SONOPHORETIC DRUG DELIEVERY SYSTEM Sonophoresis , is a process that exponentially increases the absorption of topical compounds (transdermal delivery) with high-frequency ultrasound. Sonophoresis occurs because ultrasound waves stimulate micro-vibrations within the skin epidermis and increase the overall kinetic energy of molecules making up topical agents. It is thought that high-frequency ultrasound can influence the integrity of the stratum corneum and thus affect its penetrability. Among the agents examined are hydrocortisone, lidocaine, salicylic acid

22. ADVANTAGES Avoids vagaries associated with gastrointestinal absorption due to pH, enzymatic activity, drug-food interactions etc. Substitute oral administration when the route is unsuitable as in case of vomiting, diarrhea. Avoids hepatic “first pass” effect. Avoids the risks and inconveniences of parenteral therapy. Reduces daily dosing, thus, improving patient compliance. Extends the activity of drugs having short plasma half-life through the reservoir of drug present in the therapeutic delivery system and its controlled release characteristics. Rapid termination of drug effect by removal of drug application from the surface of the skin. Rapid identification of the medication in emergencies. (e.g.. Non-responsive, unconscious, or comatose patient.

23. Contd … Elimination of the hazards and difficulties of I.V. infusions or I.M. injections. Enhance therapeutic efficacy, reduced side effects due to optimization of the blood concentration-time profile and elimination of pulse entry of drugs into the systemic circulation. Provide predictable activity over extended duration of time and ability to approximate zero-order kinetics. Improved control of the concentrations of drug with small therapeutic indices. Minimize inter and intrapatient variation. Suitability for self-administration.

24. Limitations Only limited number of potent drugs can be absorbed in therapeutic dose. Many systemically effective therapeutic drugs produce skin irritation. The drug must have some desirable physicochemical properties for penetration through stratum corneum . If the drug dosage required for therapeutic value is more than 10mg/day, the transdermal delivery will be very difficult. The barrier function of the skin changes from one site to another on the same person, from person to person and with age.

25. Understanding the drug delivery Sonophoresisor ultrasound can be used to create holes in the skin for fluids to travel into or out of the skin. By emitting sound at a particular frequency, the sound waves disrupt the lipid-bilayer of the stratus corneum (outermost layer of skin which has the most barrier properties), creating more and larger microchannels in the skin. Drugs can be administered through these channels .

26. Generation of ultrasound Ultrasound is a sound wave possessing frequencies above 20 kHz . These waves are characterized by two main parameters, frequency and amplitude. The waves used for sonophoresis which reduce the resistance offered by SC lie in the frequency range of 20 KHz to 20 MHz. Ultrasound is generated with the help of a device called sonicator which is a AC electric signal generator. It produces a AC electric signal which is applied across a piezoelectric crystal i.e. transducer. The crystal undergoes rhythmic deformation due to electric current, producing ultrasonic vibrations. In the process of ultrasonic wave generation, electric energy is converted into mechanical energy in the form of oscillations, which generates acoustic waves.

27. Ultrasound is applied by bringing the transducer in contact with the skin. For sonophoretic delivery, the desired drug is dissolved in a solvent and applied to the skin. The coupling medium can be the same as the solvent used to dissolve the drug or it can be a commercial ultrasound coupling e.g. gel. It helps to match impedence of tissue with the impedence of the transducer, so that the Ultrasound gets properly into the tissue.

28. Selection of ultrasound parameters ( 1) Ultrasound frequency : Therapeutic Frequency Ultrasound (1-3 MHz) Low Frequency Ultrasound (Below 1MHz) High Frequency Ultrasound (Above 3MHz) ( 2) Ultrasound intensity: Various ultrasound intensities in the range of 0.1 to 2 W/cm2 ( 3) Pulse length: Ultrasound can be applied in a continuous or pulse mode. The pulse mode is frequently used because it reduces severity of side effects such as thermal effects. It was also found that urea permeability of cuprophane membrane increased from 6 to 56% as pulse length increased from 100 to 400 ms.

29. VARIOUS TYPES OF MECHANISM FOR SONOPHORESIS Although considerable attention has been given to the investigation of sonophoresis in the past years, its mechanisms were not clearly understood, reflecting the fact that several phenomena may occur in the skin upon ultrasound exposure. These include: Cavitation (generation and oscillation of gas bubbLes ). Thermal effects (temperature increase). Induction of convective transport. Mechanical effects (occurrence of stresses due to pressure variation induced by ultrasound.)

30. CAVITATION EFFECTS: Cavitation is the formation of gaseous cavities in a medium ultrasound exposure. The primary cause for cavitation is ultrasound -induced pressure variation in the medium . It is further of 2 types 1. Inertial cavitation: The rapid growth and collapse of a bubble. 2. Stable cavitation: The slow oscillatory motion of a bubble in an ultrasound field. Collapse of cavitation bubbles releases a shock wave that can cause structural alteration in the surrounding tissue. The cavitational effects vary inversely with ultrasound frequency and directly with ultrasound intensity At higher frequencies it becomes difficult to generate cavitation due to the fact that the time between the positive and negative acoustic pressures becomes too short, diminishing the ability of dissolved gas within the medium to diffuse into the cavitation nuclei . For example, application of ultrasound at 20 kHz induced transdermal transport enhancements of up to 1000 times higher than those induced by therapeutic ultrasound.

31. FIGURE: CAVITATIONAL EFFECT

32. Thermal effects Ultrasound does not pass through tissues with 100% efficiency. During its propagation, the ultrasound wave is partially scattered and absorbed by the tissue medium, resulting in attenuation of the emitted wave. The lost energy is converted into heat, while the remainder of the wave penetrates into and propagates through the medium Convective transport Fluid velocities are generated in porous medium exposed to ultrasound due to interference of the incident and reflected ultrasound waves in the diffusion cell and oscillations of the cavitation bubbles. Experimental findings suggest that convective transport does not play an important role in the observed transdermal enhancement.

33. Mechanical effects Ultrasound is a longitudinal pressure wave inducing sinusoidal pressure variations in the skin, which, in turn, induce sinusoidal density variation. At frequencies greater than 1 MHz, the density variations occur so rapidly that a small gaseous nucleus cannot grow and cavitational effect cease. But other effects due to density variations, such As generation of cyclic stresses because of density changes that ultimately lead to fatigue of the medium, may continue to occur. Lipid bilayers, being self-assembled structures, can easily be disordered by ese stresses, which result in an increase in the bilayer permeability. This increase is, however, non-significant and hence mechanical effects do not play an important role in therapeutic sonophoresis . Thus, cavitation induced lipid bilayer disordering is found to be the most important cause for ultrasonic enhancement of transdermal transport.

34. DEPENDENCE OF SONOPHORETIC SKIN PERMEABILISATION ON ULTRASOUND Frequency: Attenuation of an acoustic wave is inversely proportional to its frequency, and thus as the frequency increases, the ultrasound penetrates less deeply into the skin. Low-frequency ultrasound(f~20 kHz) is significantly more potent in enhancing skin permeability compared to therapeutic ultrasound (f~1-3 MHz) Intensity: The skin conductivity increases with increasing intensity, but upto a certain point, and then drops off. This is due to the increase in the total energy put into the system with increasing ultrasound intensity. The linearity between skin conductivity and ultrasound intensity may break down at higher intensities (>15 W/cm2 ) due to other effects such as ‘acoustic decoupling’ which is a phenomena where cavitation generated near the ultrasound source results in the formation of large number of gaseous cavities, thus reducing the amount of energy delivered to the system. The intensity is directly dependent on the acoustic energy emitted and the speed of sound in the medium.

35. Mode: Ultrasound can be applied in continuous or pulsed (sequential) mode. The rise in temperature is faster and more intense with the continuous mode. Threshold energy: Skin conductivity enhancement is directly proportional to the incident ultrasound energy density. There exists a threshold ultrasound energy below which the effect of ultrasound on skin conductivity cannot be detected, and beyond the threshold value the conductivity increases with the energy density.

36. VARIATION IN ENHANCEMENT OF SONOPHORESIS FOR VARIOUS DRUGS The observed enhancement for a particular drug depends significantly on the physicochemical and pharmacokinetic properties of the permeant, and hence varies from drug to drug. Another factor of great importance in the selection of drugs is their biological half-life; the lower the half-life, the faster the rate at which steady state levels in blood are attained. The sonophoretic enhancement of transdermal drug transport can be quantitatively predicted based on knowledge of two physiochemical properties of the drug: passive skin permeability, and octanol–water partition coefficient, K o/w.

37. MARKETED PRODUCTS Microlysis : The Microlysis developed by Ekos is designed to deliver ultrasound and thrombolytic (clot-dissolving) drug directly into the area of a brain clot. The Microlysis device is a miniature catheter that is inserted into an artery in the brain until it reaches the clot. Drug is infused through the catheter to the tip, where a tiny ultrasound transmitter is located. The ultrasound and drug are designed to be administered simultaneously because it has been shown that ultrasound energy induces a temporary change in the structure of a clot that allows the drug to penetrate more efficiently into the inner reaches of the blockage .

38. SonoPrep : Sontra Medical Corporation is the pioneer of SonoPrep , a non-invasive and painless ultrasonic skin permeation technology. The medical device uses an ultrasonic method to make skin temporarily more permeable. The small, battery-powered device applies a low-frequency, ultrasonic energy to the skin for 15 seconds. The sound waves open small cavities in the skin by disorganizing the lipid bi-layer, creating tiny, reversible channels through which fluids can be extracted and delivered. The skin goes back to its normal state within 24 hours. Sontra is investigating the delivery of several large proteins and peptides by incorporating the use of the SonoPrep device in combination with transdermal patches to deliver the drug transdermally . Sontra Medical is also developing a vaccine against dengue fever .

39. Sonoderm Technology: The sonoderm is a device based on the generation of low frequency ultrasounds waves acting on a vibratory and thermal way, this technology is called ultrasonotherapy . ImaRx is now developing Sonolysis in which MRX-801 microbubbles and ultrasound waves are used to disperse the blood clots and restore blood flow. Patch-Cap and U-strip: In June 2005, Dermisonics obtained the patent for the ultrasonic Patch-Cap and a flexible patch for transdermal delivery of drugs via ultrasound.The U-Strip is a drug delivery system .

40. USES OF SONOPHORESIS Sonophoresis also used in treatment of glaucoma and corneal infection, to increase the permeability of drugs. Ultrasound can also be used for nail delivery of drugs. Ultrasound helps in treatment of wide varieties of sports injuries such as tennis elbow, tendon problems, repairing damaged ligaments, muscle spasms, stiff joints, fractured bones and cartilage. Also used in healing of wounds, skin rejuvenation, nerve stimulation, and improving the strength and elasticity of scar tissues Sonophoresis is used in the treatment of damaged skin. Process of cavitation takes place during the treatment but the cavities disappear after the treatment and histological examination has shown that the skin is normal after treatment. Hormone delivery. Low-frequency ultrasonic gene delivery. Ultrasound is used for Calcific Tendinitis of the s.houlder

41. Drug used by sonophoresis 1 ) Sonophoresis with Corticosteroid: Majority of studies on sonophoresis , ultrasound was used to enhanced the delivery of steroidal anti-inflammatory drugs (e.g. hydrocortisone. Ultrasound could carry hydrocortisone across a vascular membrane for the effective treatment of polyarthritis Also, hydrocortisone sonophoresis is useful in the treatment of numerous musculo -skeletal injuries. 2) Sonophoresis with Salicylates: In combination with ultrasound, Salicylate could be moved into deeper, subdermal tissues to help to reduce pain.

42. 3) Sonophoresis with Anesthetics: The effectiveness of sonophoresis has been explored extensively for delivery of local anesthetics. Sonophoresis with Decadron and Lidocaine results in relief from their trigger point pain. 4) Sonophoresis with other Drugs: Ultrasound as an enhancer of benzydamine hydrochloride (3%) a nonsteroidal anti-inflammatory drug. Sonophoresis of D- mannitol, a diuretic. Ultrasound with topically applied Amphotericin B.

43. Sonophoretic Vs. iontophoretic drug delivery system Sonophoresis Iontophoresis Sonophoresis is the enhancement of migration of drug molecules by ultrasonic energy. Iontophoresis is movement of ions of soluble salts across a membrane through the skin under an externally applied potential difference Sonophoresis uses acoustic energy (ultrasound) to drive molecules into tissues. Iontophoresis uses electiral current to transport ions into tissues Proper choice of ultrasound parameters including ultrasound energy dose, frequency, intensity, pulse length and distance of transducer from the skin, is critical for for efficient sonophoresis . Proper choice of electricity parameters including Current density, Current profile, Duration of treatment, Electrode material, Polarity of electrodesis critical for efficient Iontophoresis. Sonophoresis usually employs a ultrasound between 20 KHz to 20 MHz Iontophoresis usually employs a direct current between 0.5 mA to 5.0 mA

44. In sonophoresis drugs mixing with a coupling agent like gel, cream, ointment. In Iontophoresis drug is mix with solvent . The main mechanism for transport of drug is “Cavitation” The main mechanism for transport of drug is “Electroporation” Drug should be in aqueous or non aqueous and ionized or non in ionized form. Drug must be in aqueous and must be ionized form. Enhanced partitioning, Lipid bilayer disordering, Keratin denaturation etc gives the the synergetic effect of sonophoresis Electrophoresis, Lipid bilayer disordering, Electroosmosis etc. Gives synergetic effect of Iontophoresis . Ultrasound can be applied in a continuous or pulse mode. Electrical current can be applied only in continuous mode Contd ….

45. References N.K.Jain , Sonophoresis : Biophysical of Transdermal Drug Delivery, Controlled and Novel Drug Delivery, 1 st edition, 1997, page. 208-235 James Swarbrick, Transdermal Delivery: Sonophoresis , Encyclopedia of pharmaceutical technology, 3 rd edition, Volume-6, 2007, page no. 3828-3842 Mr. Ashish Pahade , Dr. Mrs. V.M.Jadhav , Dr. Mr. V.J.Kadam , Sonophoresis : an overview, International Journal of Pharmaceutical Science, 2010, Volume 3, Issue 2, page. 24-32 Wikipedia slideshare

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