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

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.

Thiolated and PEGylated silica nanoparticle delivery to hair follicles

“…The stability of the fluorescent label on the nanoparticles for use in skin studies was evaluated by adding the nanoparticles to skin homogenate and dialysing against phosphate buffered saline (PBS) to assess the release of free dye. Briefly, 2 g of pig skin was cut into small pieces and homogenised in 15 mL of PBS at 6500 rpm for 1 minute in an ice bath using an Ultra Turrax T18 high speed homogenizer (Lau et al, 2013). Four different samples were prepared by mixing 1.5 mL of the labelled nanoparticles, unlabelled nanoparticles, sodium fluorescein and homogenate respectively with 1.5 mL of homogenate (total 3 mL) and dialysed against PBS.…”

Facile synthesis of drug-conjugated PHPMA core-crosslinked star polymers

“…Enzyme-catalyzed release of the drug from the HPMA-MTX conjugate was investigated using porcine liver esterase (PLE), an enzyme that readily cleaves ester bonds. [55][56][57][58][59] After incubation with PLE (150 U mg −1 ) for 96 h, 30% of MTX was cleaved to yield the free drug and HPMA (Fig. S10 †).…”

Topical delivery of fluorescence (6‐Cf) labeled and radiolabeled (99m‐Tc) cisplatin and imiquimod by a dual drug delivery system

“…Over the past decade, topical delivery of drugs has gained more and more attention of which systemic side effects can be reduced compared with parenteral or oral drug administration. Moreover, combination therapy often proves more efficacious and better tolerated than monotherapy with a single drug …”