Principal Investigator Daniel Blankschtein
Co-investigator Robert Langer
Project Website http://web.mit.edu/dbgroup/research_project10.shtml
Transdermal drug delivery (TDD) offers several advantages over traditional delivery methods including injections and oral delivery. However, only seven drugs, having similar chemical properties, are currently administered transdermally, without physical or chemical enhancement of the skin, because of the tremendous barrier properties of human skin. Chemical enhancers and the application of ultrasound (sonophoresis) can temporarily enhance the transport of drugs across the skin.
In previous work, we have shown that acoustic cavitation is the major mechanism of enhancement in sonophoresis. We have also shown that the skin permeability enhancement is greater using low-frequency sonophoresis (20 kHz) than using high-frequency sonophoresis (1 MHz), because of the increased size of the cavitation bubbles with a decrease in the ultrasound frequency. The increased skin permeability enhancement using low-frequency sonophoresis has allowed us to deliver therapeutic doses of insulin, ϒ-interferon, and erythropoietin across in vitro human skin. Similarly, in vivo studies with hairless rats have shown that the use of low-frequency sonophoresis enables the delivery of an insulin dose across hairless rat skin which is sufficient to decrease the blood glucose level of a diabetic hairless rat to that of a normal rat in 30 minutes.
We have also developed several models and techniques to advance the understanding of transdermal drug delivery with and without the application of ultrasound. Specifically, we formulated the Porous-Pathway Hypothesis to model the transport of hydrophilic permeants through aqueous pore pathways across both untreated and ultrasound-treated skin samples. We also developed a model to predict steady-state skin permeabilities based on transient transport data. The model performed well in predicting the steady-state permeabilities of hydrophilic permeants, and highlighted the importance of the effect of hydration on the transdermal transport of hydrophilic molecules. We have also been able to develop an excellent in vitro/in vivo correlation for the transdermal transport of hydrophilic permeants through the use of the constant skin electrical resistance protocol. In this experimental protocol, we can obtain similar permeability results in different ultrasound-treated model skin membranes by exposing the skin samples to ultrasound until they attain the same skin electrical resistance value.
Finally, we developed a novel application of Two-Photon Microscopy (TPM), in which TPM may be used to identify the location of, and to better understand the transdermal routes of delivery of, model hydrophilic and hydrophobic permeants in both untreated and chemically- enhanced in vitro human skin samples. From the TPM data, it is also possible to determine how the presence of chemical enhancers enhances several different key transport parameters, such as, the vehicle-to-skin partition coefficient and the skin diffusion coefficient.
Recently, we have shown that the efficacy of low-frequency sonophoresis in enhancing transdermal transport can be further increased by its combination with chemical enhancers, such as, the well-known surfactant, Sodium Lauryl Sulfate (SLS), to produce several localized regions of high transdermal transport in the skin. These localized transport regions (LTRs) can be observed with the naked eye by using a colored permeant, such as, the red hydrophilic probe sulforhodamine B (SRB), during treatment of the skin with low-frequency sonophoresis in combination with SLS.
To better understand the existence of the LTRs in low-frequency sonophoresis, we have carried out a series of low-frequency sonophoresis experiments using full-thickness pig skin, in the presence of the surfactant Sodium Lauryl Sulfate (SLS), in which we have separately measured the transport of calcein through the LTRs, which have areas ranging from 10 to 40 mm2, and the surrounding regions of the skin (the non-LTRs) by means of a novel masking technique. Our results clearly show that the calcein permeability through the LTRs is approximately 80-fold higher than the calcein permeability through the non-LTRs, suggesting that the LTRs are structurally perturbed to a greater extent than the non-LTRs from the exposure to the ultrasound/SLS system. In addition, we proposed basic models to predict the total skin transdermal permeability from the transdermal permeabilities of the LTRs and the non-LTRs, and then compared the predictions to the experimental data obtained from the masking experiments. We also demonstrated that both the LTRs and the non-LTRs exhibit significant decreases in skin electrical resistivity relative to untreated skin (~5000-fold and ~170-fold, respectively), suggesting the existence of two levels of significant skin structural perturbation due to ultrasound exposure in the presence of SLS. Finally, an analysis of the porosity/tortuosity ratio ( ε/τ) values suggests that trans-cellular transdermal transport pathways are present within the highly permeable, and highly structurally perturbed, LTRs.