Pharmaceutics 2013, 5(2), 232-245; doi:10.3390/pharmaceutics5020232
Article

Design, Synthesis and in Vitro Degradation of a Novel Co-Drug for the Treatment of Psoriasis

1 School of Pharmacy, University of Reading, Whiteknights, P.O. Box 226, Reading, RG6 6AP, UK 2 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)
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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.

AMA Style

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.

Chicago/Turabian Style

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.

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