Sonophoresis application

Sonophoresis is defined as the transport of drugs through intact skin under the influence of an ultrasound. Ultrasound at various frequencies in the range of 20 kHz to 16 MHz has been used to enhance skin permeability [1-3]. This chapter attempts to present sonophoresis, experimental variables, possible mechanisms of action, and clinical applications. 

Tang, H., et al. 2001. Theoretical description of transdermal transport of hydrophilic permeants Application to low-frequency sonophoresis. J Pharm Sci 90 545. 

In vitro and in vivo studies on sonophoresis have allowed the variables to be optimized in developing sonophoretic experiments to be identified. Such variables pertain mainly to the irradiation source (namely, US frequency and intensity, application time and pulse length, and also the distance of the horn to the skin) others such as the nature of the permeant should also be considered, however. 

Sonophoresis (or phonophoresis) is a technique to enhance percutaneous penetration via the application of ultrasonic energy. Review of the sonophoresis literature, however, shows that the effects of ultrasound have been variable. For example, largely unsuccessful earlier studies with various common drugs used ultrasound frequencies of 1-3 MHz at 1-3 W/cm [67,68], whereas a... 

To determine sonophoretic transport route(s) at the ultrastructural level, Bom-mannan and co-workers [72] visualized guinea pig skin with transmission electron microscopy (TEM) after the application of colloidal lanthanum hydroxide (an electron dense tracer) and treatment in vivo with 10- or 16-MHz ultrasound (0.2 W/cm ). In control samples, the tracer did not appear to penetrate into the stratum comeum. But in samples exposed to sonophoresis, the tracer was found in localized areas of the intercellular space, which may correspond to the lacunae (polar head-group domains) described by Hou and co-workers [73] as polar or head-group domains. In addition, sonophoresis for 5 minutes (at both 10 and 16 MHz) did not appear to alter the morphology of the epidermal cells, whereas damage to cells was observed after 20 minutes of treatment (16 MHz). Thus, sonophoresis appears to cause the permeation of the tracers via the intercellular route within the stratum comeum. 

Topical applications in the form of spray also have been reported as vehicles for enhanced frawi-dermal delivery of drugs such as testosterone, estradiol, progesterone, and norethindrone acetate. More effective drug penetration was reported with enhancers padimate and octyl salicylate and compared with laurocapram and oleic acid (38). Other methods reported for enhanced percutaneous drug absorption include iontophoresis (39), ultrasound or sonophoresis (40), and electroporation (41). 

Mitragotri, S. Blankschtein, D. Langer, R. Sonophoresis enhanced transdermal drug delivery by application of ultrasound. In Encyclopedia of Pharmaceutical Tech- 112. nology, 1st Ed. Swarbrick, J., Boylan, J.C., Eds. Marcel Dekker, Inc. New York, 1996 14, 103-122. 

Various ultrasound intensities in the range of 0.1-2W/cm have been used for sonophoresis. In most cases, use of higher ultrasound intensities is limited by thermal effects. Several investigations have been performed to assess the dependence of sonophoretic enhancement on ultrasound intensity. Miyazaki, Mizuoka, and Takada. foimd a relationship between the plasma concentrations of indomethacin transported across the hairless rat skin by sonophoresis (therapeutic conditions) and the ultrasoimd intensity used for this purpose. Specifically, the plasma indomethacin concentration at the end of three hours after sonophoresis (0.25 W/cm ) was about 3-fold higher than controls at the same time. However, increasing intensity by 3-fold (to 0.75 W/cm ) further increased sonophoretic enhancement only by 33%. Mortimer, Trollope, and Roy found that application of ultrasoimd at IW/cm increased transdermal oxygen transport by 40%i while that at 1.5 W/cm and 2 W/cm induced an enhancement by 50%i and 55 /o, respectively. 

Ultrasound can be applied either in a continuous or a pulsed mode. A pulsed mode of ultrasound application is used many times because it reduces the severity of adverse side effects of ultrasound, such as thermal effects. However, pulsed application of ultrasound may have a significant effect on the efficacy of sonophoresis. As will be discussed later, cavitational effects, which play a crucial role in sonophoresis,... 

In a recent systematic study of the dependence of 20 kHz sonophoresis on ultrasound parameters, Mitragotri et al. showed that the enhancement of skin permeability varies linearly with ultrasound intensity and ultrasound on-time (for pulsed ultrasound, ultrasound on-time equals the product of total ultrasound application time and duty cycle), while is independent of the ultrasound duty cycle. Based on those findings, fhe authors reported that there is a threshold energy dose for ultrasound induced transdermal drug transport. Once the threshold value is crossed, the enhancement of skin permeability varies linearly with the ultrasound energy dose (J/cm ), which is calculated as the product of ultrasound intensity and ultrasound on-time. This result indicates that ultrasound energy dose can be used as a predictor of the effect of 20 kHz sonophoresis. The authors also indicated that it is important to determine the threshold energy dose for each individual sonophoresis system, for example, the real in vivo situation, because it may vary from system to system. Specifically, it may vary between different skin models, as well as with the ultrasound frequency and the distance of the transducer from the skin surface, etc. 

The most commonly used technique of sonophoresis in these studies was to apply hydrocortisone in the form of an ointment on the skin and then apply ultrasound by keeping the transducer in contact with the ointment. In some cases, the transducer was moved in circular patterns to avoid a continuous exposure of a certain part of the skin to ultrasound. Although these studies were performed using different animal models, application techniques, hydrocortisone concentrations in the ointment, and exposure time, a measurable enhancement of hydrocortisone transport was reported in almost all cases. In contrast, most of the attempts to enhance transdermal transport of lidocaine and salicylates have been less successful. In the case of lidocaine, the sonophoretic enhancement was measured in terms of reduction of onset time for anesthesia or prolonging duration of anesthesia. In most cases, no significant effect of ultrasound application on either induction time or duration of anesthesia has been reported. Similarly sonophoresis of salicylates from ointments has not been found to induce any significant increase in plasma salicylate levels. ... 

In the first set of experiments, the known effect of static pressure on cavitation was utilized. It is known that cavitation in fluids and porous media can be suppressed at high pressures. This effect is believed to occur due to the dissolution or collapse of the gaseous nuclei under the influence of pressure. Sonophoresis experiments were performed using skin compressed at 30 atm (between two smooth glass plates soaked in water placed in a compression press for two hours prior to sonophoresis experiments). They found that while application of ultrasound (IMHz, 2W/cm continuous) enhances estradiol permeability of the normal human epidermis by 13-fold, the corresponding enhancement for compressed skin is only about 1.75-fold. 

Since cavitational effects in fluids vary inversely with ultrasound frequency, it is likely that cavitational effects should play an even more important role in low-frequency sonophoresis. Tachibana et al. hypothesized that application of low-frequency ultrasound results into acoustic streaming in the hair follicles and sweat ducts of the skin, thus leading to enhanced transdermal transport. Mitragotri et al. hypohesized that transdermal transport during low-frequency sonophoresis occurs across the keratinocytes rather than hair follicles. They provided the following hypothesis for the higher efficacy of low-frequency sonophoresis. 

Application of ultrasound enhances transdermal drug transport, a phenomenon referred to as sonophoresis. Proper choice of ultrasound parameters including ultrasound energy dose, frequency, intensity, pulse length, and distance of transducer from the skin is... 

---