Sonophoresis intensities

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. 

There is a proportionai — aibeit not pureiy iinear — reiationship between the amount of energy deiivered by a US device and the increase in temperature of the vehicle in contact with the skin. At a 20 khlz US frequency, US intensities above 8 W/cm significantly increases the temperature of the vehicie, viz. about 10-20°C for intensities from 8.1 to 15 W/cm at the end of a 2-h treatment — interestingly, half of the temperature rise occurs within oniy 10 min of US appiication. Tests under isothermal control have revealed that about 25% of the skin permeabiiity enhancement produced by sonophoresis can be ascribed soieiy to a thermai effect [120]. 

A sonophoresis device with a flat flextensional US transducer has also been reported [121]. Vibration plates made of three different materials were simulated with the finite element method before fabrication and subsequent investigation of their properties. Compared to other types of flextensional US transducers, they have a simple structure, provide intensities at par with those of commercial sonicators and are easier and more inexpensive to produce. 

Sonophoresis has employed three distinct categories of US high-frequency or diagnostic US (2-10 MHz), mid-frequency or therapeutic US (0.7-3 MHz), and low-frequency US (5-100 kHz). It appears, from a general overview of the literature, that the efficiency of US-mediated drug delivery depends on several factors, including US frequency, intensity (i.e., power per unit area), continuous versus pulsed mode, duty cycle, duration, coupling medium, and so on. The fact that very few studies have used common values for some or any of these parameters almost certainly accounts for the different and sometimes contradictory results in the public domain. 

Proper selection of ultrasound parameters is required to ensure safe and efficacious sonophoresis. Ultrasound parameters such as frequency, intensity, duty cycle, and distance of transducer from the skin influence the efficiency of sonophoresis. Below we present a general discussion of the role played by various ultrasound parameters in sonophoresis. Note that the objective of this discussion is not to point out the exact values of ultrasound parameters to be selected, but rather to present information regarding the dependence of sonophoretic enhancement on each parameter. 

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. 

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. 

Mortimer, Trollope, and Roy " performed sonophoresis of oxygen across frog skin in vitro. They found that the sonophoretic enhancement of transdermal oxygen transport depends on ultrasound intensity, rather than pressure amplitude. Based on this observation, they hypothesized that cavitation cannot be responsible for sonophoresis. They hypothesized that... 

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... 

---