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Design, Synthesis and in Vitro Degradation of a Novel Co-Drug for the Treatment of Psoriasis
School of Pharmacy, University of Reading, Whiteknights, P.O. Box 226, Reading, RG6 6AP, UK
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF10 3NB, UK
* Author to whom correspondence should be addressed.
Received: 1 February 2013; in revised form: 1 April 2013 / Accepted: 10 April 2013 / Published: 17 April 2013
(This article belongs to the Special Issue Prodrugs
Abstract: Psoriasis is a common, chronic and relapsing inflammatory skin disease. It affects approximately 2% of the western population and has no cure. Combination therapy for psoriasis often proves more efficacious and better tolerated than monotherapy with a single drug. Combination therapy could be administered in the form of a co-drug, where two or more therapeutic compounds active against the same condition are linked by a cleavable covalent bond. Similar to the pro-drug approach, the liberation of parent moieties post-administration, by enzymatic and/or chemical mechanisms, is a pre-requisite for effective treatment. In this study, a series of co-drugs incorporating dithranol in combination with one of several non-steroidal anti-inflammatory drugs, both useful for the treatment of psoriasis, were designed, synthesized and evaluated. An ester co-drug comprising dithranol and naproxen in a 1:1 stoichiometric ratio was determined to possess the optimal physicochemical properties for topical delivery. The co-drug was fully hydrolyzed in vitro by porcine liver esterase within four hours. When incubated with homogenized porcine skin, 9.5% of the parent compounds were liberated after 24 h, suggesting in situ esterase-mediated cleavage of the co-drug would occur within the skin. The kinetics of the reaction revealed first order kinetics, Vmax = 10.3 μM·min−1 and Km = 65.1 μM. The co-drug contains a modified dithranol chromophore that was just 37% of the absorbance of dithranol at 375 nm and suggests reduced skin/clothes staining. Overall, these findings suggest that the dithranol-naproxen co-drug offers an attractive, novel approach for the treatment of psoriasis.
Keywords: psoriasis; dithranol; naproxen; co-drug; pro-drug; esterase
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MDPI and ACS Style
Lau, W.M.; Heard, C.M.; White, A.W. Design, Synthesis and in Vitro Degradation of a Novel Co-Drug for the Treatment of Psoriasis. Pharmaceutics 2013, 5, 232-245.
Lau WM, Heard CM, White AW. Design, Synthesis and in Vitro Degradation of a Novel Co-Drug for the Treatment of Psoriasis. Pharmaceutics. 2013; 5(2):232-245.
Lau, Wing M.; Heard, Charles M.; White, Alex W. 2013. "Design, Synthesis and in Vitro Degradation of a Novel Co-Drug for the Treatment of Psoriasis." Pharmaceutics 5, no. 2: 232-245.