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

Pharmaceutics

Wing Man Lau²  Charles M. Heard¹ 

[1] School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF10 3NB, UK; E-Mails:;School of Pharmacy, University of Reading, Whiteknights, P.O. Box 226, Reading, RG6 6AP, UK

关键词: psoriasis;    dithranol;    naproxen;    co-drug;    pro-drug;    esterase;   

DOI  :  10.3390/pharmaceutics5020232

来源: mdpi

【 摘 要 】

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, V_max = 10.3 µM·min⁻¹ and K_m = 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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.