Low-frequency sonophoresis has been a topic of extensive research only in the last 10 years. Tachibana et al. [60-62] reported that application of low-frequency ultrasound (48 kHz) enhanced transdermal transport of lidocaine and insulin across hairless rat skin in vivo. They found that the blood glucose level of a hairless rat immersed in a beaker filled with insulin solution (20 U/ml) and placed in an ultrasound bath (48 kHz, 5000 Pa) decreased by 50 % in 240 minutes . They also showed that application of ultrasound under similar conditions prolonged the anesthetic effect of transdermally administrated lidocaine in hairless rats  and enhanced transdermal insulin transport in rabbits. Mitragotri et al. [8, 43] showed that application of ultrasound at even lower frequencies (20 kHz) enhances transdermal transport of various low-molecular weight drugs including corticosterone and high-molecular weight proteins such as insulin, y-interferon, and erythropoeitin across the human skin in vitro. Quantitatively, Mitragotri et al. compared the enhancement ratios (ratio of the sonophoretic and passive permeabilities measured in vitro across human cadaver skin) induced by therapeutic ultrasound (1 MHz) and low-frequency ultrasound (20 kHz) for four permeants, butanol, corticosterone, salicylic acid, and sucrose. They found that the enhancement induced by low-frequency ultrasound is up to 1000-fold higher than that induced by therapeutic ultrasound .
Low-frequency sonophoresis can be classified into two categories; simultaneous sonophoresis and pretreatment sonophoresis. Simultaneous sonophoresis corresponds to a simultaneous application of drug and ultrasound to the skin. This was the first mode in which low-frequency sonophoresis was shown to be effective. This method enhances transdermal transport in two ways: i) enhanced diffusion through structural alterations of the skin and ii) convection induced by ultrasound. Transdermal transport enhancement induced by this type of sonophoresis decreases after ultrasound is turned off . Although this method can be used to achieve a temporal control over skin permeability, it requires that the patients use a wearable ultrasound device for drug delivery. In pretreatment sonophoresis, a short application of ultrasound is used to permeabilize skin prior to drug delivery. The skin remains in a state of high permeability for several hours. Drugs can be delivered through permeabilized skin during this period. In this approach, the patient does not need to wear the ultrasound device.
13.5. LOW-FREQUENCY SONOPHORESIS: CHOICE OF PARAMETERS
The enhancement induced by low-frequency sonophoresis is determined by four main ultrasound parameters, frequency, intensity, duty cycle, and application time. A detailed investigation of the dependence of permeability enhancement on frequency and intensity in the low-frequency regime (20 kHz < f < 100 kHz) has been reported by Tezel et al. . At each frequency, there exists an intensity below which no detectable enhancement is observed. This intensity is referred to as the threshold intensity. Once the intensity exceeds this threshold, the enhancement increases strongly with the intensity until another threshold intensity, referred to as the decoupling intensity is reached. Beyond this intensity, the enhancement does not increase with further increase in the intensity due to acoustic decoupling. The threshold intensity for porcine skin increased from about 0.11 W/cm2 at 19.6 kHz to more than 2 W/cm2 at 93.4 kHz. At a given intensity, the enhancement decreased with increasing ultrasound frequency.
The dependence of enhancement on intensity, duty cycle, and application time can be combined into a single parameter, total energy density delivered from the transducer, E = It where I is the ultrasound intensity (W/cm2), t is the net exposure time (seconds). As a general trend, no significant enhancement is observed until a threshold energy dose is reached. The threshold energy doses for various frequencies were found to be 10 J/cm2 for 19.6 kHz, 63 J/cm2 at 36.9 kHz, 103 J/cm2 at 58.9 kHz, 304 J/cm2 for 76.6 kHz, and 1305 J/cm2 at 93.4 kHz. Thus, the threshold energy dose increased by about 130-fold as the frequency increased from 19.6 kHz to 93.4 kHz. The dependence of enhancement on energy density after the threshold is different for different frequencies. For extremely high-energy doses (say 104 J/cm2), the enhancement induced by all the frequencies is comparable. However, for lower energy doses, the differences between various different frequencies are significant and the choice of frequency may affect the effectiveness of sonophoresis.
In addition to frequency and energy density, sonophoretic enhancement also depends on additional parameters including the distance between the transducer and the skin, gas concentration in the coupling medium, and the transducer geometry. Detailed dependence of enhancement on these parameters has not been yet studied.
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