Abstract
The local application of controlled hypobaric stress represents a novel means to facilitate drug delivery into the skin. The aims of this work were to understand how hypobaric stress modified the properties of the skin and assess if this penetration enhancement strategy could improve the percutaneous penetration of a macromolecule. Measurements of skin thickness demonstrated that the topical application of hypobaric stress thinned the tissue (p<0.05), atomic force microscopy showed that it shrunk the corneocytes in the stratum corneum (p<0.001) and the imaging of the skin hair follicles using multiphoton microscopy showed that it opened the follicular infundibula (p<0.001). Together, these changes contributed to a 19.6-fold increase in in vitro percutaneous penetration of a 10,000 molecular weight dextran molecule, which was shown using fluorescence microscopy to be localized around the hair follicles, when applied to the skin using hypobaric stress. In vivo, in the rat, a local hemodynamic response (i.e. a significant increase in blood flow, p<0.001) was shown to contribute to the increase in follicular transport of the dextran to produce a systemic absorption of 7.2±2.81fg·mL−1. When hypobaric stress was not applied to the rat there was no detectable absorption of dextran and this provided evidence that this novel penetration enhancement technique can improve the percutaneous penetration of macromolecules after topical application to the skin.
Highlights
The delivery of macromolecules such as peptides, proteins and antibodies via the skin is an attractive proposal when considering the treatment and prevention of diseases
Calculating the enhancement ratios showed that the effect of hypobaric stress was more pronounced upon the transdermal delivery of the higher molecular weight dextran (10 kDa)
The application of local hypobaric stress appears to be simple yet effective method to increase the percutaneous penetration of topically applied macromolecules
Summary
The delivery of macromolecules such as peptides, proteins and antibodies via the skin is an attractive proposal when considering the treatment and prevention of diseases. Their administration via this route is a challenge due to the skin's highly stratified structure [1,2]. The only means by which macromolecules can enter the skin tissue at a rate that is suitable for therapeutic applications is by the use of a penetration enhancement strategy [5,6,7,8,9]. There remains a need to develop new technologies to facilitate the passage of high molecular weight therapeutic agents into the skin
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