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Targeted Skin Delivery of Topically Applied Drugs by Optimised Formulation Design

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Targeted Skin Delivery of Topically Applied Drugs by Optimised Formulation Design Targeted skin delivery of topically applied drugs by optimised formulation design Eman Abd A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2015 School of Medicine (Southern Clinical Division) I Abstract Early research concentrated on the relationship between a solute’s physicochemical properties and its skin permeation, mostly from simple solutions. Relatively less is known about how vehicles, particularly complex ones, might also affect skin permeation by altering the properties of the skin, although this is an area that has attracted much interest. Key requirements for topical delivery is understanding the relationships between drug-vehicle, drug-skin or drug –vehicle –skin interaction. In this project, understanding this relationship was crucial to designing novel formulations able to deliver drugs with different lipophilicity topically or systemically. The first aim was to explore the impact of various solution compositions on skin permeation of some model drugs. I compared in vitro maximum penetration fluxes (Jmax) and solubilities of the vehicles (Sv) and of the stratum corneum (SSC) and derived diffusivities (D*) for four drugs (caffeine, minoxidil, lidocaine and naproxen) having a range of lipophilicities. I used a range of solvent vehicles that were hypothesised to affect the skin to differing degrees to evaluate vehicle effects on permeability parameters. If neither the vehicle nor the solute alters the properties of the skin, maximum (or saturated) solute flux is independent of both the vehicle composition and the solute’s saturated solubility in that vehicle. These findings were confirmed in this study for all four drugs used. The permeation of caffeine, minoxidil, lidocaine and naproxen were found to be selectively enhanced by vehicles containing specific excipients that were hypothesised to alter the properties of the skin. The greatest effects were seen on flux and diffusivity by the eucalyptol (EU) and oleic acid (OA) vehicles on the more hydrophilic compounds, caffeine and minoxidil. We concluded that enhanced solute fluxes were mainly driven by increased diffusivity in the stratum corneum. I also examined the extent of skin permeation enhancement of the hydrophilic drug caffeine and lipophilic drug naproxen applied in nanoemulsions incorporating skin penetration enhancers. Infinite doses of fully characterised oil-in-water nanoemulsions containing the skin penetration enhancers oleic acid or eucalyptol as oil phases and caffeine (3%) or naproxen (2%) were applied to full-thickness skin and human epidermal membranes in Franz diffusion cells, along with aqueous control solutions. Caffeine and naproxen fluxes were determined over 8 h. Solute solubility in the formulations and in the stratum corneum, as well as the uptake of product components into the stratum corneum were measured. The nanoemulsions significantly enhanced the skin penetration of caffeine and naproxen compared to aqueous control solutions. The maximum flux enhancement of caffeine was II associated with a synergistic increase in both its solubility in the stratum corneum and skin diffusivity. Enhanced skin penetration in these systems is largely driven by uptake of formulation excipients containing the active compounds into the stratum corneum. Fluxes of caffeine and naproxen absorbed into the receptor from full-thickness skin compared with epidermis were similar. Therefore, the amount of caffeine permeating the dermis and hypodermis was not affected by these structures although the stratum corneum only provided the barrier against penetration. In addition to lipids, the vesicle excipients included eucalyptol or oleic acid as penetration enhancers, and decyl polyglucoside (DPGluc) as a non-ionic surfactant. Vesicle particle sizes ranged between 135 and 158 nm and caffeine encapsulation efficiencies were between 46% and 66%. Caffeine penetration and permeation was measured using high performance liquid chromatography (HPLC). We found that niosomes, which are liposomes containing a non-ionic surfactant and transferosomes (ultraflexible vesicles) showed significantly greater penetration into the skin and permeation across the stratum corneum. Significant enhancement of caffeine penetration into hair follicles was found for transferosomes and those liposomes containing oleic acid. The third aim was to investigate the effectiveness of our nanoemulsion formulations of caffeine and minoxidil for transfollicular delivery. Nanoemulsions were applied to full- thickness excised human abdominal skin in Franz diffusion cells for 24 h. Minoxidil concentrations in receptor fluid, tape strip extracts, follicular casts and homogenised skin extracts were analysed. The oleic acid formulation was the best at promoting minoxidil retention into the superficial skin compartments (stratum corneum and hair follicles). The eucalyptol formulation was the best for deeper penetration into and through the skin. In the second part, caffeine in nanoemulsion formulations containing OA or EU and in controls was topically applied and the amount of caffeine retained in the stratum corneum, hair follicles, in the skin and in the receptor was analysed. The hair follicles and the area around them were imaged by a LaVision Multiphoton Microscope. Oleic acid nanoemulsion showed the highest transfollicular delivery of caffeine. Less caffeine in skin layers and storage in hair follicles was found after blocking the hair follicles. In conclusion, this project provided information to understand the mechanisms of chemical penetration enhancers on the human skin and the results of this PhD will help to improve the design of new formulations or to develop current formulations containing model drugs. III Declaration by author This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my research higher degree candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School. I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis. IV Publications during candidature Submitted journal articles 1. Eman Abd, Sarika Namjoshi, Yousuf H. Mohammed, Michael S. Roberts, Jeffrey E. Grice, Synergistic skin penetration enhancer and nanoemulsion formulations promote the human epidermal permeation of caffeine and naproxen. Journal of Pharmaceutical Science. (Accepted in September 2015)- 2. Eman Abd, Michael S. Roberts, Jeffrey E. Grice, A comparison of the penetration and permeation of caffeine into and through human epidermis after application in various vesicle formulations. Skin Pharmacology and Physiology. (Accepted in September 2015) 3. Eman Abd, Michael S. Roberts, Jeffrey E. Grice, The human epidermal skin permeation of solutes is determined by vehicle uptake into and effects on the stratum corneum. American Association Pharmaceutical Scientists (AAPS) (Submitted in October 2015) Conference abstracts 1- Eman Abd, Gregory Medley, Yousuf Mohammed, Jeffrey E. Grice, Michael S. Roberts, Development and evaluation of microemulsion formulations for transdermal delivery of caffeine. ASCEPT Annual conference, Melbourne Dec 7-11, 2013. 2- Eman Abd, Gregory Medley, Yousuf Mohammed, Michael S. Roberts, Jeffrey E. Grice, Enhanced delivery of minoxidil into skin compartments using microemulsion formulations. TRI, 2014. 3- Eman Abd, Gregory Medley, Yousuf Mohammed, Michael S. Roberts, Jeffrey E. Grice, Development and evaluation of nanoemulsion formulations for transdermal delivery of Naproxen, ASMR, Brisbane, 2014. 4- Eman Abd, Gregory Medley, Yousuf Mohammed, Michael S. Roberts, Jeffrey E. Grice, Effect of vehicles on in vitro percutaneous penetration rates, PhD symposium, Sydney, 2014. 5- Eman Abd, Gregory Medley, Yousuf Mohammed, Michael S. Roberts, Jeffrey E. Grice, Effect of chemical enhancers on the in vitro percutaneous penetration of caffeine, ASCEPT Annual conference, Melbourne Dec 7-11, 2014. 6- Eman Abd, Michael S. Roberts, Jeffrey E. Grice, Follicular penetration and retention of the hydrophilic model compound caffeine is promoted by microemulsion formulations containing penetration enhancers, 6th International Postgraduate Symposium in Biomedical Sciences, UQ, Brisbane, 2015. V Publications included in this thesis Eman Abd, Sarika
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