Sonophorosis by akshay patel


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Sonophorosis by akshay patel

  2. 2. Contents1. Introduction2. Sonophoresis: a historical perspective3. Generation of ultrasound4. Biological effect of ultrasound5. Mechanism of sonophoresis6. Synergetic effect with other enhancers7. Safety8. Future trends9. Applications of sonophoresis10. Advantages11. Limitations12. Drugs used by sonophoretic drug delivery13. Conclusion14. References 2
  3. 3. 1. Introduction Definition: sonophoresis is the enhancement of migration of drug molecules through the skin by ultrasonic energy Sonophoresis occurs because ultrasound waves stimulate micro-vibrations within the skin epidermis and increase the overall kinetic energy of molecules When sound is emitted at a particular frequency, the sound waves disrupt the lipid bilayers The higher the frequency, the more dispersed the transmission 3
  4. 4. The skin Protective layer with large no. of dead cells, hence acts as barrier to penetration. 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
  5. 5. 2. Sonophoresis: a historicalperspective Sonophoresis was shown to enhance transdermal drug transport about 40 years ago by Fellinger and Schmidt who showed that application of ultrasound increases transport of hydrocortisone across the skin. ultrasound was also reported for local anesthetics Hofman and Moll who studied the percutaneous absorption of benzyl nicotinate. Bommannan et al. hypothesized that since the absorption coefficient of the skin varies directly with the ultrasound frequency 5
  6. 6. 3. 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. 6
  7. 7. Figure 1: Ultrasonic generation system Pulse generator Amplifier Gate H. F. Generator (20 KHz – 20MHz) Transducer Ultrasound gel + Drug Skin + Transducer interface Stratum cornium Skin 7
  8. 8. Conti… 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. 8
  9. 9. Selection of ultrasound parameters (1) Ultrasound frequency a) Therapeutic Frequency Ultrasound (1-3 MHz) b) Low Frequency Ultrasound (Below 1MHz) c) 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. 9
  10. 10. 4. Biological effect of ultrasound Significant attention has thus been given to investigating the effects of ultrasound on biological tissues. Ultrasound affects biological tissues via three main effects(1) Thermal effect may important when, The tissue has a high protein content A high intensity of continuous wave ultrasound is used Bone is included in the heated volume Vascularization is poor 10
  11. 11. Conti…(2) Cavitation effect may important when, Low-frequency ultrasound is used Grassy fluids are exposed Small gas filled space are exposed The tissue temperature is higher than normal(3) Acoustic streaming may important when, The medium has an acoustic impedance different from its surrounding The fluids in the biological medium is free to more Continuous wave application is used 11
  12. 12. 5. Mechanism of sonophoresis(1) Cavitation Cavitation occurs due to the nucleation of small gaseous cavities during the negative pressure cycles of ultrasound This cavitation leads to the disordering of the lipid bilayers and formation of aqueous channels in the skin through which drugs can permeate 12
  13. 13. Conti… The minimum ultrasound intensity required for the onset of cavitation, referred to as cavitation thresholda) Cavitation inside skin cavitation bubbles near the keratinocytes–lipid bilayers interfaces may, in turn cause oscillations in the lipid bilayers, thereby causing structural disorder of the SC lipidsb) Cavitation out side skin cavitation bubbles can potentially play a role in the observed transdermal transport enhancement. these bubbles cause skin erosion, due to generation of shock waves, thereby enhancing transdermal transport 13
  14. 14. Conti…(2) Convective transport Fluid velocities generated in this way may affect transdermal transport by inducing convective transport of the permeant across the skin. especially through hair follicles and sweat ducts 14
  15. 15. Conti…(3) Mechanical stress Ultrasound is a longitudinal pressure wave inducing pressure variations in the skin, which, in turn, induce density variation Due to density variations, such as generation of cyclic stresses because of density changes that ultimately lead to fatigue of the medium Lipid bilayers, being self-assembled structures, can easily be disordered by these stresses, which result in an increase in the bilayers permeability 15
  16. 16. 6. Synergistic effect with other enhancer(1) Chemical enhancer Enhanced Partitioning Lipid Bilayer Disordering Keratin Denaturatione.g. Application of SLS alone for 90 min induced about 3- fold increase in mannitol permeability, while application of ultrasound alone for 90 min induced about 8-fold enhancement. However, when combined, application of ultrasound from 1% SLS solution induced about 200-fold increase in skin permeability to mannitol 16
  17. 17. Conti…(2) Iontophoresis Electrophoresis Lipid Bilayer Disordering Electroosmosise.g. The enhancement of heparin flux due to ultrasound + iontophoresis treatment was about 56-fold. This enhancement was higher than the sum of those obtained during ultrasound alone (3-fold) and iontophoresis alone (15-fold). Thus, the effect of ultrasound and iontophoresis on transdermal heparin transport was truly synergistic. 17
  18. 18. 7.Safety The World Federation for Ultrasound in Medicine and Biology (WFUMB) has issued several publications related to safety of ultrasound bioeffects, addressing specifically thermal bioeffects and non-thermal bioeffects ultrasound affecting the structure of the skin: is it a reversible or irreversible change? What is the role of the free radicals that are generated during the cavitation process within the skin? 18
  19. 19. 8. Future trends(1) Vaccination In recent years, the potential for exploiting the skin for purposes of vaccination has received a great deal of attention One common strategy is to use an adjuvant, which is a compound used to enhance the immune response to vaccine compounds Ultrasound can be used to enhance skin permeability to both the adjuvant and the vaccine, and hence to facilitate their delivery to the target cells. 19
  20. 20. Conti…(2) Gene therapy Gene therapy is a technique for correcting defective genes that are responsible for disease development, most commonly by replacing an „abnormal‟ disease-causing gene with the „normal‟ gene The most obvious candidate diseases for cutaneous gene therapy are the severe forms of particular genodermatoses (monogenic skin disorders), such as epidermolysis bullosa Other applications might be healing of cutaneous wounds such as severe burns and skin wounds of diabetic origin 20
  21. 21. 9. Applications1) Sonophoresis is used in the treatment of damaged skin.2) Hormone Delivery.3) In surgery it helps in dissection, connection, built-up and treatment of biological tissue.4) Low-Frequency Ultrasonic Gene Delivery.5) Sonophoresis is also very useful in drug enhancement in granulomas and tumors. Most cancer therapy drugs act intracellularly.6) Ultrasound is used for Calcific Tendinitis of the Shoulder.7) The dolphin therapy and sonophoretic model.8) Ultrasound Helps in Treating Tennis Elbow and Tendon Problem. 21
  22. 22. 10. Advantages1) Avoids vagaries associated with gastrointestinal absorption due to pH, enzymatic activity, drug-food interactions etc.2) Substitute oral administration when the route is unsuitable as in case of vomiting, diarrhea.3) Avoids hepatic “first pass” effect.4) Avoids the risks and inconveniences of parenteral therapy.5) Reduces daily dosing, thus, improving patient compliance.6) 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.7) Rapid termination of drug effect by removal of drug application from the surface of the skin.8) Rapid identification of the medication in emergencies. (e.g.. Non-responsive, unconscious, or comatose patient.) 22
  23. 23. Conti…9) Elimination of the hazards and difficulties of I.V. infusions or I.M. injections.10) 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.11) Provide predictable activity over extended duration of time and ability to approximate zero-order kinetics.12) Improved control of the concentrations of drug with small therapeutic indices.13) Minimize inter and intrapatient variation.14) Suitability for self-administration. 23
  24. 24. 11. Limitations1) Only limited number of potent drugs can be absorbed in therapeutic dose.2) Many systemically effective therapeutic drugs produce skin irritation.3) The drug must have some desirable physicochemical properties for penetration through stratum corneum.4) If the drug dosage required for therapeutic value is more than 10mg/day, the transdermal delivery will be very difficult.5) The barrier function of the skin changes from one site to another on the same person, from person to person and with age 24
  25. 25. 12. 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).(a) Fellinger & Schmid (1954) showed that ultrasound could carry hydrocortisone across a vascular membrane for the effective treatment of polyarthritis(b) Newman et al. (1992) suggested that hydrocortisone sonophoresis is useful in the treatment of numerous musculo-skeletal injuries. 25
  26. 26. Conti…(2) Sonophoresis with Salicylates In combination with ultrasound it is thought that Salicylate could be moved into deeper, subdermal tissues to help to reduce pain.(a) Ciccone et al. (1991) reported on a study to evaluate ultrasound as an enhancer of topically applied Salicylates 26
  27. 27. Conti…(3) Sonophoresis with Anesthetics The effectiveness of sonophoresis has been explored extensively for delivery of local anesthetics.(a) McElnay (1985) and associates described a sonophoresis study using lignocain(b) Moll (1979) studied the enhanced effects of topically applied Lidocaine (140.7 mg) and Decadron (3.75 mg). She obtained that 88% of the patients receiving sonophoresis with Decadron and Lidocaine obtained relief from their trigger point pain. 27
  28. 28. Conti...(4) Sonophoresis with other Drugs(a) Benson and colleagues (1987, 1989) studied ultrasound as an enhancer of benzydamine hydrochloride (3%) a nonsteroidal anti-inflammatory drug.(b) Levy et al. (1989) studied the sonophoresis of D- mannitol, a diuretic.(c) Romanenko (1992) used ultrasound with topically applied Amphotericin B. 28
  29. 29. Sonophoresis vs. iontophoresis Both techniques deliver chemical to biological tissues. 29
  30. 30. Sr Sonophoresis Iontophoresisno1 Sonophoresis is the enhancement Iontophoresis is movement of ions of migration of drug molecules of soluble salts across a membrane through the skin by ultrasonic under an externally applied energy potential difference2 Sonophoresis uses acoustic energy Iontophoresis uses electiral current to (ultrasound) to drive molecules transport ions into tissues into tissues3 Proper choice of ultrasound Proper choice of electricity parameters including ultrasound parameters including Current density, energy dose, frequency, intensity, Current profile, Duration of pulse length, and distance of treatment, Electrode material, transducer from the skin is critical Polarity of electrodes, is critical for for efficient sonophoresis. efficient Iontophoresis4 Sonophoresis usually employs a Iontophoresis usually employs a ultrasound between 20 KHz to 20 direct current between 0.5 mA to 5.0 MHz mA 30
  31. 31. 5 In sonophoresis drugs mixing In Iontophoresis drug is mix with with a coupling agent like gel, solvent cream, ointment6 The main mechanism for The main mechanism for transport of transport of drug is “Cavitation” drug is “Electroporation”7 Drug should be in aqueous or Drug must be in aqueous and must be non aqueous and ionized or non in ionized form ionized form8 Enhanced partitioning, Lipid Electrophoresis, Lipid bilayer bilayer disordering, Keratin disordering, Electroosmosis etc. gives denaturation etc. gives the the synergetic effect of Iontophoresis synergetic effect of sonophoresis9 Ultrasound can be applied in a Electrical current can be applied only in continuous or pulse mode continuous mode10 Sonophoresis mostly used for Iontophoresis mostly used for delivery of corticosteroids, local hyperhydrosis diagnosis of cystic anesthetics and salicylates fibrosis, metallic and non-metallic ions 31
  32. 32. 13. Conclusion Proper choice of ultrasound parameters including ultrasound energy dose, frequency, intensity, pulse length, and distance of transducer from the skin is critical for efficient sonophoresis. Various studies have indicated that application of ultrasound under conditions used for sonophoresis does not cause any permanent damage to the skin Ultrasound also works synergistically with several other enhancers including chemicals and iontophoresis. 32
  33. 33. 14. References N.K.Jain, Sonophoresis: Biophysical of Transdermal Drug Delivery, Controlled and Novel Drug Delivery, 1st edition, 1997, page. 208-235 James Swarbrick, Transdermal Delivery: Sonophoresis, Encyclopedia of pharmaceutical technology, 3rd 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 33
  34. 34. Thank you… 34