Sex-specific formulations of doxazosin mesylate via direct powder extrusion 3D printing.

Abstract

Males and females are known to exhibit significant differences in drug pharmacokinetics and pharmacodynamics, which are still overlooked in pharmaceutical research and development. These disparities contribute to adverse effects and increased mortality in females, highlighting the critical need for sex-specific formulations. Extended-release formulations of doxazosin mesylate, an alpha blocker used to treat hypertension, have shown significant sex-based differences in pharmacokinetics, leading to heightened adverse effects in females and rendering current titration recommendations impractical. This study explored the potential of a 3D printing (3DP) technology, direct powder extrusion (DPE), for producing personalised, sex-specific doses of doxazosin mesylate. A simple three component formulation was made composed of hydroxypropyl cellulose (HPC) polymer Klucel JF, D-mannitol, and doxazosin mesylate. Extended-release printlets of varying doses (1, 2, and 3 mg) were manufactured from a single 1% w/w doxazosin pharma-ink batch, enabling easy dose personalisation by adjusting the printlet dimensions. The use of a single pharma-ink supports the technology's ease of use in a pharmacy setting, by eliminating frequent pharma-ink changes during the pharmaceutical compounding process. In vitro dissolution testing revealed an extended drug release profile, influenced by surface-area-to-volume (SA: V) ratios. Introducing channels in larger printlets standardized the SA: V ratios, enhancing release profile uniformity. Release kinetics followed the Hixson-Crowell and Korsmeyer-Peppas models, indicating diffusion and polymer swelling mechanisms. This work highlights the capability of DPE 3DP for creating personalized, extended-release oral dosage forms, supporting precise dose customization for patient-specific therapy. Graphical Abstract.