Protective Effects of Tocopherol and Lipol Derived Co-drugs on Porcine Skin Exposed to Ultraviolet Radiation
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Issue Date
2016
Authors
Jock, Marley Marie '16
Degree
MS in Pharmaceutical Sciences
Advisor
Hass, Martha A.
Committee Members
Voigt, Jeffrey M.
Musteata, Marcel F
Musteata, Marcel F
Journal Title
Journal ISSN
Volume Title
Abstract
Ultraviolet radiation (UVR) exposure is a major factor leading to damage of the skin. Tocopherol (TOC), lipoic acid (LA), and its derivative lipol (LOH) have been shown to effectively inhibit lipid peroxidation induced by UVR in intact skin. Combinations (1:1 molar ratio) of TOC with LA or LOH exhibit synergistic inhibition of lipid peroxidation in skin. Based on these findings, we have developed four co-drugs, derived from \316\261- and \316\264-TOC, and LA/LOH for use as topical agents to inhibit oxidative damage in the skin. The object of this project was to determine the stability, skin penetration and the ability to inhibit protein oxidation of these co-drugs in a microemulsion (ME) formulation. The stability of the formulated co-drugs was analyzed using high pressure liquid chromatography (HPLC) to quantify the amount of intact co-drug in each sample. Once stability of each co-drug was confirmed, penetration assays were conducted using Franz diffusion cells and previously frozen porcine skin as an in vitro model. HPLC analysis was used to detect and quantify the presence of co-drug and parent compounds in the stratum corneum (SC), epidermal and dermal skin layers and in the receptor chamber (indicative of transdermal delivery). To assess the inhibitory activity of the co-drugs, skin was exposed to UVR to induce protein oxidation (PO). Subsequently, PO in the skin was measured using the dinitrophenylhydrazine (DNPH) assay. Using this assay, PO was measured in UVR exposed skin, with and without pre-treatment with co-drug, to determine if the amount of co-drug penetrating into the viable layers of the skin was sufficient to inhibit protein oxidation. Stability studies revealed that \357\201\244-TOCE, \357\201\241-TOCC, and \357\201\244-TOCC were stable in the formulated ME at all of the time points evaluated, up to 24h. The stability of \357\201\241-TOCE cannot be determined due to a low extraction efficiency. No TOC was detected in the HPLC analysis in any of the stability studies, indicating that no hydrolysis of the parent compounds occurred in the ME formulations. In penetration studies, all co-drugs were detected by HPLC in the SC and ED layers and none of the parent compounds were detected, indicating no hydrolysis occurred. All co-drugs were able to penetrate the skin at levels high enough to inhibit PO. Antioxidant activity of the co-drugs is dependent on the amount of co-drug penetration into the ED layers of the skin and the amount of hydrolysis of the co-drug to the active parent compounds. While no hydrolysis of any of the co-drugs was detected in previously frozen porcine skin in the penetration studies, hydrolysis was detected in skin pre-treated with the co-drugs exposed to UVR. All four co-drugs showed almost complete hydrolysis. The pre-treatment of skin with all four formulated co-drugs resulted in a significant decrease in the generation of protein carbonyls in porcine skin that was exposed to UVR compared to untreated skin. The co-drug concentrations achieved through topical application using these ME suggest that these co-drugs are efficient vehicles for topical delivery of the co-drugs and good candidates for topical protection of the skin against damaged caused by PO.
Citation
Jock, MM. Protective effects of tocopherol and lipol derived co-drugs on porcine skin exposed to ultraviolet radiation." Ann Arbor (MI): Proquest LLC; 2016. 53 p.
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