Sonophoretic delivery of a model macromolecular drug

The use of low frequency ultrasound as a physical enhancer for transdermal drug delivery is known as sonophoresis. This science is still in its infancy. The aim of this study was to explore how low frequency ultrasound can be used to enhance the transdermal delivery of a model macromolecular drug. Initial studies aimed to validate the output of the ultrasound generator. Hydrophone measurements showed that the actual frequency was very close to the supplier's stated 20kHz value while calorimetric measurements showed that the actual intensities were close to and proportional to that stated by the generator's amplitude dial. Interferon-gamma, with a molecular weight of 17000 Da, was chosen as a model macromolecular drug while transport studies were carried out using full-thickness porcine skins inserted in Franz cells. An ultrasound beam (10% duty cycle) of SATA intensity 3.7 W/cm² was applied for periods not exceeding 5 minutes thus keeping skin surface temperatures from exceeding control levels by more than 3°C. Whereas passive macromolecule flux was virtually zero, 5 minutes sonication allowed about 50 ng/cm² drug to permeate transdermally. Drug transport could be significantly improved by pretreating the skin with sodium lauryl sulphate solution prior to the sonication step. This allowed permeation to reach over 100 ng/cm². However, all other tested chemical enhancers - sodum octyl sulphate, sodium eicosyl sulphate, menthone, carvone, alpha terpineol, oleic acid, linoleic acid and stearic acid did not show such an additive interaction with ultrasound. Interestingly, most of the cumulative permeation profiles were not of the typical lag time followed by linear steady state type. The peculiar effectivity of sodium lauryl sulphate and the irregular permeation profiles require further investigation in order to determine the mechanisms occurring.The use of low frequency ultrasound as a physical enhancer for transdermal drug delivery is known as sonophoresis. This science is still in its infancy. The aim of this study was to explore how low frequency ultrasound can be used to enhance the transdermal delivery of a model macromolecular drug. Initial studies aimed to validate the output of the ultrasound generator. Hydrophone measurements showed that the actual frequency was very close to the supplier's stated 20kHz value while calorimetric measurements showed that the actual intensities were close to and proportional to that stated by the generator's amplitude dial. Interferon-gamma, with a molecular weight of 17000 Da, was chosen as a model macromolecular drug while transport studies were carried out using full-thickness porcine skins inserted in Franz cells. An ultrasound beam (10% duty cycle) of SATA intensity 3.7 W/cm² was applied for periods not exceeding 5 minutes thus keeping skin surface temperatures from exceeding control levels by more than 3°C. Whereas passive macromolecule flux was virtually zero, 5 minutes sonication allowed about 50 ng/cm² drug to permeate transdermally. Drug transport could be significantly improved by pretreating the skin with sodium lauryl sulphate solution prior to the sonication step. This allowed permeation to reach over 100 ng/cm². However, all other tested chemical enhancers - sodum octyl sulphate, sodium eicosyl sulphate, menthone, carvone, alpha terpineol, oleic acid, linoleic acid and stearic acid did not show such an additive interaction with ultrasound. Interestingly, most of the cumulative permeation profiles were not of the typical lag time followed by linear steady state type. The peculiar effectivity of sodium lauryl sulphate and the irregular permeation profiles require further investigation in order to determine the mechanisms occurring