Stability, Penetration, and Antioxidant Activity of Carbamate Co-drugs in Porcine Skin
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Issue Date
2016
Authors
Mackey, Samantha Ann '16
Degree
MS in Pharmaceutical Sciences
Advisor
Hass, Martha A
Committee Members
Zheng, HaiAn
Balaz, Stefan
Balaz, Stefan
Journal Title
Journal ISSN
Volume Title
Abstract
Exposure of skin to ultraviolet radiation (UVR) results in the generation of reactive oxygen species (ROS) and causes protein damage in the skin viable layers, which can lead to long term damage. Natural antioxidants (AO) are located within the skin to prevent oxidative damage to proteins, but UVR can deplete these levels over time. Tocopherol (TOC)/tocopherylamine (TOCA) and lipol (LOH)/lipoamine (LAM) are known AO and have previously been shown to act synergistically to inhibit lipid peroxidation in pig skin. From these results, four carbamate co-drugs, \316\261- and \316\264-TOCCAM (TOC + LAM) and \316\261- and \316\264-TOCAC (TOCA + LOH) were synthesized. This thesis project focused on evaluating theses co-drugs as topical AO to determine their stability, topical penetration and ability to inhibit protein oxidation in skin. The co-drugs are designed to stay intact until they are delivered to epidermal/dermal (ED) layers of the skin. In the ED layer, the co-drugs hydrolyze through the action of metabolic enzymes, releasing the parent compounds and allowing them to exert their AO effects to inhibit protein oxidation. The four co-drugs were formulated as microemulsions (ME) and their stability in the ME was monitored using high pressure liquid chromatography (HPLC) to prove that the co-drugs did not hydrolyze spontaneously over time. All four carbamate co-drugs were stable over a 24 hour time period. The formulated co-drugs were applied to porcine skin using Franz diffusion cells to assess the amount of each co-drug and its metabolites in the stratum corneum (SC), and ED layers of the skin, using HPLC analysis. Co-drug concentrations in the receptor phase were also monitored to evaluate transdermal delivery of the compounds. It was demonstrated that all four carbamate co-drugs successfully penetrated the ED layer at 24h. Once penetration characteristics were established, the ability of the co-drugs to limit oxidative damaged induced by UVR was examined. Co-drugs were allowed to penetrate porcine skin for 24h, and treated with UVR at a dose of 486kJ/m2. Protein oxidation of the treated skin was measured and compared to protein oxidation levels in untreated skin. Hydrolysis of the co-drugs were also measured in these experiments since release of the parent compounds (TOC/TOCA + LOH/LAM) is necessary for AO activity. Skin treated with \316\264-TOCCAM significantly inhibited protein oxidation (78.8% inhibition) that was induced by UVR compared to untreated skin. \316\264\342\200\223TOCCAM partially hydrolyzed (38%) into parent compounds (\316\264-TOC + LAM) in the skin after penetration and UVR treatment. The results from this work demonstrate that carbamate co-drugs may be effective topical agents to protect the skin against oxidative damage caused by UVR.
Citation
Mackey SA. Stability, penetration, and antioxidant activity of carbamate co-drugs in porcine skin [thesis]. Ann Arbor (MI): Proquest LLC; 2016. 57 p.
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