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The interest in microemulsions as transdermal delivery systems have been motivated by their large surface area for mass transfer, their high solubilization capacity of hydrophobic actives, and their ability to improve skin penetration. Lecithins (mixtures of phospholipids similar to those find in the skin) have been proposed as ideal surfactants in microemulsions due to their skin compatibility. Unfortunately, their incorporation into microemulsions used to require toxic medium-chain alcohols or viscous polymeric co-surfactants. Recently, microemulsion-base “green solvents” were formulated with lecithin and linker molecules. The main objective of this dissertation was to test this concept of linker-based lecithin microemulsions in transdermal delivery. In the first part of this study, linker-based lecithin formulations were developed using soybean lecithin as main surfactant, sorbitol monooleate as lipophilic linker, and caprylic acid/sodium caprylate as hydrophilic linkers. These additives, at the suggested concentration, are safe for cosmetic and pharmaceutical applications. The low toxicity of these formulations was confirmed in cultured human skin tissues. The solubilization and permeation of a common anaesthetic, lidocaine, was evaluated. The concept of “skin” permeability was introduced to account for the differences in solvent-skin partition when comparing different delivery systems. The linker-based lecithin microemulsion produced a substantial absorption of lidocaine into the skin, when compared to a conventional pentanol-lecithin microemulsion. The second part of this study takes advantage of the lidocaine adsorbed in the skin with the linker-based lecithin microemulsion as reservoir for in situ skin patches. The in situ patches were able to release 90% of the lidocaine over 24 hours, which is comparable to the release profile obtained from conventional polymer or gel-based patches. In the third part of this work, the role of surfactant droplets on the transport of lidocaine was studied. A mass balance model that accounted for mass transfer and partition coefficients was introduced. The parameters generated from the model confirm that in most cases the transport through the skin limits the overall penetration of lidocaine. Besides the conventional diffusion mechanism, the results suggest that surfactant droplets, carrying lidocaine, also penetrate into the skin and contribute to the accumulation of the lidocaine in the skin.

The interest in microemulsions as transdermal delivery systems have been motivated by their large surface area for mass transfer, their high solubilization capacity of hydrophobic actives, and their ability to improve skin penetration. Lecithins (mixtures of phospholipids similar to those find in the skin) have been proposed as ideal surfactants in microemulsions due to their skin compatibility. Unfortunately, their incorporation into microemulsions used to require toxic medium-chain alcohols or viscous polymeric co-surfactants. Recently, microemulsion-base “green solvents” were formulated with lecithin and linker molecules. The main objective of this dissertation was to test this concept of linker-based lecithin microemulsions in transdermal delivery. In the first part of this study, linker-based lecithin formulations were developed using soybean lecithin as main surfactant, sorbitol monooleate as lipophilic linker, and caprylic acid/sodium caprylate as hydrophilic linkers. These additives, at the suggested concentration, are safe for cosmetic and pharmaceutical applications. The low toxicity of these formulations was confirmed in cultured human skin tissues. The solubilization and permeation of a common anaesthetic, lidocaine, was evaluated. The concept of “skin” permeability was introduced to account for the differences in solvent-skin partition when comparing different delivery systems. The linker-based lecithin microemulsion produced a substantial absorption of lidocaine into the skin, when compared to a conventional pentanol-lecithin microemulsion. The second part of this study takes advantage of the lidocaine adsorbed in the skin with the linker-based lecithin microemulsion as reservoir for in situ skin patches. The in situ patches were able to release 90% of the lidocaine over 24 hours, which is comparable to the release profile obtained from conventional polymer or gel-based patches. In the third part of this work, the role of surfactant droplets on the transport of lidocaine was studied. A mass balance model that accounted for mass transfer and partition coefficients was introduced. The parameters generated from the model confirm that in most cases the transport through the skin limits the overall penetration of lidocaine. Besides the conventional diffusion mechanism, the results suggest that surfactant droplets, carrying lidocaine, also penetrate into the skin and contribute to the accumulation of the lidocaine in the skin.

The skin serves as a semi-permeable barrier that protects the body from pathogens and water loss. The stratum corneum, the upper 10-15 µm layer of skin, is the primary barrier layer. Due to its structure, only drugs that are lipophilic and with a low molecular weight (<500 Da) can penetrate intact skin. This study examines the use of microdermabrasion as a method of removing the stratum corneum to increase the skin's permeability to hydrophilic molecules, proteins, and vaccines. Microdermabrasion is a FDA-approved cosmetic skin resurfacing procedure that removes the stratum by bombarding it with abrasive particles under vacuum. The aims of this thesis are focused on optimizing the microdermabrasion conditions that will selectively remove stratum corneum, evaluating the transport of different sized molecules through abraded skin in vitro, examining drug efficacy in vivo by delivering insulin to diabetic rats, and examining the rate of skin healing after treatment. Microdermabrasion can be used as a non-invasive transdermal drug technique to safely remove stratum corneum to make the skin more permeable to waters soluble drugs and proteins.

This work was performed as a preliminary transdermal drug delivery (TDD) study to investigate the diffusion characteristics and effects of skin surfactants in vitro of four active ingredients on a poly(dimethyl siloxane) polycarbonate copolymer membrane. A Franz-type diffusion cell and various receptor solutions were used. The adhesive used was comprised of a polyisobutylene-based pressure sensitive adhesive manufactured by Adhesives Research Inc. High performance liquid chromatography was used to analyze the diffusion characteristics of these systems. In addition, the effects of two skin surfactants (sodium lauryl sulfate and dimethyl sulfoxide) on the adhesive were also investigated. Results from peel testing and thermal analysis showed that the peel strength, glass transition, and softening temperature of the adhesive was greatly reduced with the addition of the surfactants. / Master of Engineering

This thesis investigated the possible use of transdermal iontophoresis in paediatric care, as an alternative strategy to the oral and intravenous routes. More specifically, the potential for non-invasive delivery of ranitidine, midazolam, and phenobarbital; and the clinical sampling of iohexol through the skin were examined. The feasibility for monitoring kidney function was assessed in vitro and in vivo using the glomerular filtration rate (GFR) marker, iohexol. Sampling of iohexol in vitro was sensitive to the changes in its subdermal concentration, and pharmacokinetic parameters estimated from skin sampling agreed well with reference subdermal values. Similar observations were confirmed in vivo in a pilot study performed in four children undergoing routine iohexol GFR test. Iontophoresis was well tolerated in all subjects and the marker was successfully extracted through the skin. In 3 of 4 subjects, the elimination rate constant estimated from skin sampling data agreed well with blood sampling results. This study demonstrated the potential of transdermal iontophoresis as a non-invasive sampling approach which could significantly improve the quality-of-life of children. Drug delivery by transdermal iontophoresis was examined in vitro for three commonly used paediatric medicaments: ranitidine, midazolam, and phenobarbital. Experiments used both intact and compromised pig skin to model the less resistant skin of premature babies. Iontophoretic delivery across intact skin was superior than passive delivery and optimised conditions were achieved by use of maximal molar fraction of the drug, higher current intensity, and appropriate vehicle pH. Pluronic® F-127 gels were suitable drug matrices for the iontophoretic delivery of ranitidine. Midazolam and phenobarbital transdermal delivery through partially compromised skin barriers was controlled by iontophoresis. Across highly compromised skin, however, passive diffusion increased drastically and iontophoretic control was lost. Overall, it was possible to deliver therapeutically meaningful fluxes of all three drugs with acceptable patch application area.

Background and Purpose. Iontophoresis is a process that uses bipolar electric fields to propel molecules across intact skin and into underlying tissue. The purpose of this study was to describe and experimentally examine an iontophoresis drug delivery model. Subjects and Methods. A mechanistic model describing delivery was studied in vitro using agarose gels and was further tested in vivo by evaluation of cutaneous vasoconstriction following iontophoresis in human volunteers. Results. In vitro cathodic iontophoresis at 4 mA and 0.1 mA each delivered dexamethasone/dexamethasone phosphate (DEX/DEX-P) from a 4-mg/mL donor solution to a depth of 12 mm following a 40 mA·minute stimulation dosage. Delivery of DEX/DEX-P to at least the depths of the vasculature in humans was confirmed by observation of cutaneous vasoconstriction. This cutaneous vasoconstriction was longer lasting and greater in magnitude when using low-current, long-duration (∼0.1 mA) iontophoresis compared with equivalent dosages delivered by higher-current, shorter-duration (1.5-4.0 mA) iontophoresis. Discussion and Conclusion. From data gathered with the gel model, the authors developed a model of a potential mechanism of drug depot formation following iontophoresis. The authors believe this drug depot formation to be due to exchange of drug ions for chloride ions as the ionic current carriers. Furthermore, diffusion, not magnitude of current, appears to govern the depth of drug penetration. Although the authors did not address the efficacy of the drug delivered, the results of human experiments suggest that current magnitude and duration should be considered as factors in treating musculoskeletal dysfunctions with iontophoresis using DEX/DEX-P at a concentration of 4 mg/mL. [Anderson CR, Morris RL, Boeh SD, et al. Effects of iontophoresis current magnitude and duration on dexamethasone deposition and localized drug retention.

Microfabricated needles have the potential for inexpensive drug delivery without pain. The ability to deliver medication painlessly to patients will someday be not just hoped for but expected by the general public. The commercialization of this technology will also lead to other valuable technologies, such as systems that continually monitor and control insulin or other drugs in diabetic patients. This research presents fabrication procedures developed to produce pyramidal-shaped microneedles with microchannels that will allow for fluid delivery. The microchannels are etched into the substrate surface of a [100] silicon wafer using inductively coupled plasma etching. After the channel etch a layer of silicon nitride is deposited onto the inner walls of the microchannels and on the surface of the substrate. The nitride on the substrate surface provides the hard mask necessary to etch the microneedles, which are wet etched in a bath of potassium hydroxide (KOH). The selectivity of the KOH on [100] silicon is such that octagonal shaped pyramids are etched into the surface of the wafer. The pyramids are aligned with the previously etched microchannels to allow for needles with channels running through them. This research presents the first needles demonstrated with drug delivery channels running through the robust pyramidal needle shape. In addition to the microchannel/microneedle fabrication procedure, microchannels were developed with inner structures as a method of creating hydrophobic surfaces on the inner walls of the channels. It was found that the channels developed had far too much variability in the diameter to accurately create a measurable reduction in flow; however, a loss coefficient was calculated showing increased flow rates in hydrophobically coated microchannels when hydrophobic structures are incorporated into the channel design. It was also discovered that a hydrophobic coating, typically used to increase flow rates through a channel, can impede flow rate. There was no evidence found to suggest that hydrophobically coated microchannels of this size, with or without structures, will yield higher flow rates than non-coated microchannels.

Study Design: Controlled laboratory study. Objectives: To determine the time course of dexamethasone sodium phosphate (Dex-P) iontophoresis delivery to underlying tissues using microdialysis. Background: The efficacy of iontophoresis at delivering Dex-P through the skin is unknown in humans because of the lack of minimally invasive measurement techniques. Methods: Sixty-four healthy male participants (age = 24.4 ± 3.3 yrs, height = 71.8 ± 2.5 in, weight = 181.8 ± 26.1 lbs) were randomly assigned into one of six groups: 1) 1 mA current, 1 mm probes depth ; 2) 1 mA current, 4 mm probes depth; 3) 2 mA current, 1 mm probes depth; 4) 2 mA current, 4 mm probes depth; 5) in vivo retrodialysis; and 6) skin perfusion flowmetry. Microdialysis probes assess the combined recovery (Dextotal) of Dex-P, dexamethasone (Dex) and its metabolite. In vivo calibration of the microdialysis probes occurred via retrodialysis. Laser Doppler flowmetry assessed skin perfusion. Results: There was no difference of Dextotal between current intensities (P = 0.99) but a greater amount of Dextotal was recovered by the 1 mm probe (P < 0.0001) compared to the 4 mm probe. Peak means for the 1 and 2 mA at 1 mm were 10.8 ± 8.1 and 7.7 ± 5.5 μg/ml and at 4mm being 2.0 ± 0.8 and 1.3 ± 0.9 μg/ml, respectively. Skin perfusion rapidly increased during both current intensity treatments, but significantly decreased before the conclusion of the 1 mA treatment (P < 0.0001). Peak skin perfusion was 741.4 ± 408.7% and 711.6 ± 260.8% baseline for 1 and 2 mA intensities, respectively. Conclusion: Iontophoresis delivery of Dex-P was successful measured in vivo through human skin. Significant concentrations of Dextotal were found regardless of current intensity. Though current induced vasodilation occurred, it did not significantly affect the tissue accumulation of Dextotal.