Transdermal administration of macromolecular drugs by multi-frequency sequential ultrasonic irradiation

Administration methods of macromolecular drugs with high efficacy and minimal side effects are generally limited to highly invasive injections due to their components and large molecular weight. Here, we propose a sequential ultrasonic irradiation method using multi-frequency for minimally invasive administration of macromolecular drugs. In this demonstration, low-frequency ultrasound (kHz band) and high-frequency ultrasound (MHz band) were sequentially irradiated onto the porcine skin to evaluate the dosing efficiency using fluorescence-modified ovalbumin (Mw = 45 kDa), a macromolecular drug model. Quantitative evaluation of the transdermal dosage by fluorescence intensity measurement shows that the proposed method significantly increased the transdermal dosage by almost double that of the conventional method. In particular, the distance of MHz ultrasonic irradiation is indicated to influence the dosing efficiency. In addition, the evaluation of transdermal permeability by confocal observation of skin sections shows that the macromolecular drug model penetrates through the epidermis of porcine skin, including the stratum corneum, to the dermis layer with the proposed method. The proposed method permeated the drug model with a behavior correlated to the intensity of the MHz ultrasonic beam, as opposed to the discrete penetration of the drug model in the conventional method. Our results provide a minimally invasive method of administering macromolecular drugs as an alternative to injection.