title: The application of local hypobaric pressure - A novel means to enhance macromolecule entry into the skin.
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.
authors.affiliation: King's College London, Faculty of Life Sciences & Medicine, Institute of Pharmaceutical Science, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom.
authors.forename: R
authors.initials: R
authors.lastname: Inacio
authors.affiliation: King's College London, Division of Cancer Studies and Randall Division of Cell & Molecular Biophysics, Guy's Medical School Campus, London SE1 1UL, United Kingdom.
authors.forename: S
authors.initials: S
authors.lastname: Poland
authors.affiliation: King's College London, Faculty of Life Sciences & Medicine, Institute of Pharmaceutical Science, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom.
authors.forename: X J
authors.initials: XJ
authors.lastname: Cai
authors.affiliation: King's College London, Faculty of Life Sciences & Medicine, Institute of Pharmaceutical Science, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom.
authors.forename: S J
authors.initials: SJ
authors.lastname: Cleary
authors.affiliation: King's College London, Division of Cancer Studies and Randall Division of Cell & Molecular Biophysics, Guy's Medical School Campus, London SE1 1UL, United Kingdom.
authors.forename: S
authors.initials: S
authors.lastname: Ameer-Beg
authors.affiliation: King's College London, Faculty of Life Sciences & Medicine, Institute of Pharmaceutical Science, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom.
authors.forename: J
authors.initials: J
authors.lastname: Keeble
authors.affiliation: King's College London, Faculty of Life Sciences & Medicine, Institute of Pharmaceutical Science, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom. Electronic address: stuart.jones@kcl.ac.uk.
authors.forename: S A
authors.initials: SA
authors.lastname: Jones
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D003911:Dextrans / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods*; D018859:Hair Follicle / Q000378:metabolism / Q000648:ultrastructure; D006439:Hemodynamics; D008297:Male; D011312:Pressure; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000098:blood supply / Q000378:metabolism* / Q000648:ultrastructure; D012869:Skin Absorption; D013552:Swine
chemical_list: D003911:Dextrans
keywords: Bioavailability; Blood flow; Drug delivery; Follicle; Hypobaric pressure; In vivo; Macromolecule; Penetration enhancement; Skin
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