Localised and sustained intradermal delivery of methotrexate using nanocrystal-loaded microneedle arrays: Potential for enhanced treatment of psoriasis

Abstract

Methotrexate (MTX), typically used as its sodium salt (MTX Na), is a first-line treatments for moderate to severe psoriasis, showing good efficacy. However, its systemic administration is associated with many side effects. Intradermal delivery into psoriatic tissue could offer an alternative approach. However, successful intradermal administration of MTX Na is currently precluded by its physicochemical properties. Moreover, due to its hydrophilic nature, MTX Na is swiftly cleared from the target tissue, necessitating frequent dosing which may affect patient compliance. To address these limitations, we investigated the combination of nanocrystal (NC) and dissolving microneedle (MN) technologies as an alternative approach for localised and sustained intradermal delivery of MTX Na. Poorly water-soluble MTX nanocrystals (MTX NC) were produced by a bottom-up technique with a mean particle size of 678 ± 15 nm. Sustained in vitro drug release was observed over 72 h. The MTX NC were then incorporated into the shafts of dissolving MN arrays with a drug loading of 2.48 mg/array. The MTX NC-loaded MN arrays exhibited satisfactory mechanical strength and insertion capabilities in the skin-simulant Parafilm M® and their shafts dissolved entirely in less than 20 min after insertion into excised neonatal porcine skin. Importantly, in vivo studies in Sprague Dawley rats revealed that the MN arrays were able to deposit approximately 25.1% of the loaded MTX NC in the skin, which acted, in turn, as a drug depot and released the MTX in a sustained manner over 72 h, while minimising MTX systemic exposure. Indeed, 24 h from MN application, 312.70 ± 161.95 µg/g of MTX was retained in the skin at the application site. This was approximately 322-fold higher than the amount of MTX (0.942 ± 0.59 µg/g) retained in the skin after oral administration of MTX Na. Interestingly, even after 72 h after MN application, around 12.5% of the MTX NC deposited in the skin by the MN was retained. In contrast, the maximal blood concentration of MTX achieved following MN application, was only 40% of that measured after oral administration of MTX Na. Accordingly, MTX NC-loaded dissolving MN arrays could be a promising approach for effective localised and sustained intradermal delivery of MTX as a potential enhanced treatment for psoriasis.

Keywords: Dissolving microneedles; Intradermal drug delivery; Methotrexate; Nanocrystals; Psoriasis; Sustained release.