▶ Previous Artlcle : #4-2. Ultrasound-Mediated Adjunct Therapy
Introduction
As much as the development of a more suitable medicine is crucial for increasing the efficacy of medical therapies, effective drug delivery is also an important topic of research. Among the existing drug delivery methods, oral administration is limited by intestinal absorption and metabolism, whereas percutaneous injection is associated with pain. Recent studies are focusing on transdermal drug delivery as a new route. One of the merits of transdermal drug delivery is that a target serum concentration can be maintained without causing pain; however, low permeability of human skin is a limitation of this method. Moreover, the stratum corneum at the outermost layer of the skin is a major rate-limiting barrier. Therefore, studies on this issue are focused on increasing transdermal permeability through chemical or physical methods to ensure deep penetration of substances of certain molecular sizes.
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Recently, many protein- or peptide-based drugs have been developed for clinical use. Much of these drugs are degraded in the course of primary metabolism in the liver within the gastrointestinal tract. Therefore, transdermal drug delivery is considered as a good route of delivery for these newly developed biopharmaceuticals and vaccines. Other merits of transdermal drug delivery include the easiness of administration compared to other routes, availability of large skin areas where the drug can be applied, and relatively lower degree of protein degradation.
One of the early attempts to increase skin permeability was applying surfactants, such as Dimethyl Sulfoxide (DMSO), Sodium Lauryl Sulfate (SLS), or other chemical substances on the skin. However, these chemical substances entailed unexpected drug activities or safety issues in the clinical setting. Current studies are more focused on physical approaches, and sonophoresis is one of them.
Mechanism of Action of Sonophoresis
Although studies have investigated transdermal drug delivery with ultrasound over the last 25 years, understanding on this topic is still lacking. In 1996, Mitragotri et al. studied the mechanism of heat generation, cavitation and non-cavitational mechanism of action in increasing skin permeability with ultrasound. The authors concluded that low frequency ultrasound increases water permeability by inducing lipid changes in the stratum corneum through cavitation. They also conjectured that an aqueous channel is produced in intercellular lipids and that permeability is increased through the stratum corneum rather than through the hair follicles.
In 2000s, many studies focused on the penetration of the stratum corneum by low frequency sonophoresis. Kushner et al. (2004) and Paliwal et al. (2006) examined skin areas where low frequency sonophrosis was applied and found that permeability was increased heterogeneously. Those regions where permeability is increased are called Localized Transport Regions (LTRs) and regions where permeability is not increased despite sonophoresis are called non-LTRs.
Observing the heterogeneity of LTRs, Paliwal et al. (2006) examined the structural changes with the use of a fluorescence electron microscope. They found that permeability was increased at intercellular lipids and corneodesmosome junctions after sonophoresis. These gaps in intercellular lipids were also sparsely located in the skin not irradiated with ultrasound, which grew in number and size after irradiation at 20kHz, 2.4W/cm². It can be concluded that these gaps are expanded and connected to each other after ultrasound irradiation, creating a passageway inside the stratum corneum.
-To be continued-
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