• #5-2. Sonophoresis


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    Clinical Application of Sonophoresis


    Fellinger and Schmid reported in 1954 that they have successfully treated hand osteoarthritis with sonophoresis by delivering hydrocortisone through the skin. Since then, sonophoresis has received much attention as the most effective method of transdermal drug delivery for systemic administration.


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    Earlier studies used therapeutic ultrasound concurrently with medication. In the early days without proven safety profiles, FDA guidelines limited the range of ultrasound to that of rehabilitation therapy (0.75-3.0MHz, below 2.4W/cm²). Studies also focused more on local drug delivery, rather than systemic delivery.

    In 2003, Cagnie et al. reported that the skin’s permeability to hydrocortisone increased ten-fold when sonophorosis was applied. Recent studies found, however, that transdermal permeability significantly increased when low frequency ultrasound (≤100kHz in general) was used compared to higher frequency. It is known that cavitation contributes to the action of low frequency sonophoresis on improved permeability.

    A large number of clinical studies on ultrasound used in conjunction with drugs have investigated the efficacy of transdermal delivery of insulin through low frequency sonophoresis. In one of the most recent studies, Park et al. (2007) applied transdermal insulin delivery in pigs for 90 minutes by using adhesive circular cymbal transducers at 20kHz, 100mW/cm² and found that blood concentration was reduced by 90mg/dl in the intervention group, compared to controls whose concentration rose by 31mg/dl. With the advances in the technology of adhesive transducers, transdermal delivery of insulin progressed to the point of clinical application in the near future. It would then be possible to relieve diabetic patients of the distress of repeated insulin injection.

    Some clinical inconveniences exist with the simultaneous drug delivery by an adhesive ultrasound device. A more convenient method would be to irradiate ultrasound as a pretreatment before applying drugs. In 2004, Mitragotri et al. performed the pretreatment at 20kHz, 7W/cm² before applying 500U/ml of insulin and found that the serum concentration dropped by 80% in two hours.

    This ultrasound pretreatment followed by drug penetration was also investigated as a method for reducing the application time of local anesthetic cream EMLA. Katz et al. (2004) applied EMLA for 15 seconds, 10 minutes and 15 minutes after ultrasound pretreatment at 55kHz and evaluated pain intensity. It was found that the extent of pain reduction was similar to that measured 60 minutes after EMLA application only. Becker et al. (2005) also studied the effectiveness of sonophoresis pretreatment before EMLA application. After 15 seconds of pretreatment with a commercially available device called Sono Prep (Echo therapeutics Inc., Franklin, MA), they applied 5% liposomal lidocaine for 5 minutes before intravenous injection and reported that pain was markedly reduced. This device was later approved by FDA and is currently available in the market.

    Vaccination is one of the most actively studied area among clinical applications of sonophoresis. The biggest advantage of transcutaneous immunization is the existence of langerhans cells, prominent antigen presenting cells, in the epidermis. Gockel et al. reported in 2000 that mucosal immunity as well as systemic immune response (IgG/IgM response) followed transcutaneous immunization, whereas only systemic immunity is achieved with vaccination by injection.

    Tezel et al. (2005) applied pretreatment at 20kHz, 100J/cm² to BALB/c mice before applying tetanus toxoid and evaluated the immune response. They found that only 1.3μg of antigen was enough to induce an immune response similar to that arising from subcutaneous injection of 10μg, suggesting that vaccination with a smaller amount was just as effective.

    It is expected that further in-depth studies will be conducted on in vivo penetration and intracellular penetration of various substances (including genes) with the use of sonophoresis.


    -To be continued-

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