Design, synthesis and in vitro degradation of a novel co-drug for the treatment of psoriasis

Lau, Wing Man, Heard, Charles Martin ORCID: https://orcid.org/0000-0001-9703-9777 and White, Alex William ORCID: https://orcid.org/0000-0002-1539-0158 2013. Design, synthesis and in vitro degradation of a novel co-drug for the treatment of psoriasis. Pharmaceutics 5 (2) , pp. 232-245. 10.3390/pharmaceutics5020232

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Subjects:	R Medicine > RS Pharmacy and materia medica
Publisher:	MDPI
ISSN:	1999-4923
Date of First Compliant Deposit:	6 December 2018
Last Modified:	11 May 2023 14:48
URI:	https://orca.cardiff.ac.uk/id/eprint/60717

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