Skin penetration enhancement techniques
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Transdermal drug delivery is an effective alternative to conventional oral and injectable drug delivery routes. It offers painless and convenient once daily or even once weekly dosing for a variety of clinical indications. The major limitation to successful transdermal drug delivery is the efficient barrier properties of the skin. Significant research efforts have been focused on developing strategies to overcome these barrier properties. These strategies include the use of physical and chemical penetration enhancers. Physical skin penetration enhancers use an external energy source to alter the barrier properties of the skin. The current research focuses on some of these physical skin penetration enhancers on a range of drug molecules and peptides.The first technology investigated was Dermaportation that utilised pulsed electromagnetic energy. This technology enhanced the epidermal permeation of naltrexone in vitro as compared to passive diffusion. A 5-fold increase in naltrexone permeation was observed during Dermaportation application when compared to passive administration. Multiphoton tomography-fluorescence life-time imaging microscopy (MPT-FLIM) analysis of the permeation of gold nanoparticles in the presence of Dermaportation revealed increased penetration across ex vivo human skin. These results demonstrated that the channels created by dermaportation must be larger than the 10 nm diameter of the applied nanoparticles.The second technology investigated was an unpowered magnetic film array technology (ETP), which utilised unpowered magnetic energy. Chapter 3 presents enhanced epidermal permeation of urea with ETP. A 4-fold increase in urea penetration was observed across human epidermis in the in vitro permeation study. Optical resonance tomography was used to visualise the changes in epidermal thickness due to urea permeation as an indication of increased hydration. The results revealed an increase in epidermal thickness at 30 min, to 16% for ETP induced urea permeation as compared to 3% with urea from occlusion. These results further substantiated our previous findings that magnetic energy creates hydrophilic diffusion channels or pores in the skin.The third technology investigated was low-frequency sonophoresis that utilises cavitation bubbles as a force to create channels for drug delivery in the skin. Chapter 4 presents enhanced human skin permeation of 5-aminolevuleninic acid in vitro and curcumin dye in vivo with low-frequency sonophoresis. Two different sources of ultrasound devices that generated low-frequency sonophoresis were investigated. MPT-FLIM analysis was utilised to investigate the effects of sonophoresis on human skin in vivo. This revealed that there was substantial disturbance in the epidermal cells due to cavitation by sonophoresis. Permeation of curcumin was found in the deeper layers of the epidermal membrane with 55 kHz sonophoresis and was confined to the more superficial layers of skin with 21 kHz sonophoresis. Permeation of 5-aminolevuleninic acid across human skin increased significantly when compared to passive permeation.The fourth technology investigated in this research was iontophoresis which utilises a small electric current to drive charged and uncharged molecules across the skin. Chapter 5 presents enhanced epidermal permeation of a range of model therapeutic and cosmetic peptides. Various key parameters such as pH, concentration and presence of counterions and co-ions that are essential for effective iontophoretic delivery of these peptides were investigated. The iontophoretic delivery of 5- aminolevulenic acid revealed a 15-fold enhancement when compared to passive diffusion. For dipeptide (Ala-Trp) the mean cumulative amount increased iontophoretic delivery from 0.4±0.4, 0.1μg/cm2 to 16.0±8.8, 3.6μg/cm2 (Mean±SD, SEM) was observed when the donor pH was reduced from 7.4 to 5.5. The corresponding current intensity (0.38mA/cm2) normalised flux was 36.1±19.5, 11.2μg/(mA.h) for iontophoretic Ala-Trp. For the tetrapeptide (Ala-Ala-Pro-Val) the mean cumulative amount that permeation with 2h iontophoresis was 350.4±45.9, 15.3μg/cm2 (Mean±SD, SEM) compared to zero passive permeation. A 4-fold increase in acetyl hexapeptide-3 delivery occurred with iontophoresis compared with passive application. In addition it was observed that lowering of donor solution pH and the presence of counterions and co-ions reduced the iontophoretic delivery of acetylhexapeptide-3. Iontophoresis provided a significant enhancement factor for the decapeptide, triptorelin acetate with a 16-fold increase in epidermal permeation compared with passive permeation. The iontophoretic permeation was concentration dependent with mean cumulative amounts of 48±28, 14 μg/cm2 (Mean±SD, SEM) achieved with 9 mM concentration of triptorelin acetate.Overall the technologies investigated in this research work presented enhanced permeation of drug molecules and peptides. In addition MPT-FLIM was demonstrated to be an efficient visualisation tool for permeation within the skin. This research demonstrates the effectiveness of physical skin permeation enhancement techniques and extends our understanding of these technologies.
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Iontophoretic skin permeation of peptides: an investigation into the influence of molecular properties, iontophoretic conditions and formulation parametersKrishnan, Gayathri; Roberts, M.; Grice, J.; Anissimov, Y.; Moghimi, H.; Benson, Heather (2014)The transdermal route offers advantages for delivery of peptides and proteins. However, these polar and large molecules do not permeate the skin barrier well. Various enhancement methods have been employed to address this ...