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.

Keywords: Additive manufacturing of oral drug products; Gender specific drug prescribing; Hypertension; Modified release formulations and pharmaceuticals; Personalized therapeutics; Three-dimensional printing of medications.

Graphical Abstract

Fig. 1

Various printlet sizes printed using the optimised pharma-ink: (a) From left to right: 6 × 3.6; 8 × 3.6; 10 × 3.6, (b) From left to right: 6 × 3.6; Ch 8 × 3.6; Ch 10 × 3.6

Fig. 2

SEM images of (a) side view of all deposited layers in the printlet and (b) zoomed in view of each deposited layer

Fig. 3

TGA thermogram of all pharma-ink components to assess degradation

Fig. 4

Zoomed in (200–300 °C) DSC thermogram of doxazosin mesylate and its mixture of polymorphs. All indicated temperatures are presented as T_max

Fig. 5

DSC thermogram of all pharma-ink components, as well as the 1% w/w and 10% w/w pharma-inks and printlets

Fig. 6

XRPD diffractograms of all pharma-ink components in the formulation, as well as the 1% and 10% w/w pharma-inks and printlets

Fig. 7

FTIR spectra of all pharma-ink components, as well as the 1% and 10% pharma-inks and printlets. Lines correspond to significant peaks in the crystalline doxazosin sample

Fig. 8

In vitro doxazosin release profiles of all printlets printed from the same batch with varying SA: V ratios (n = 3)

Fig. 9

Drug release profiles of all printlets printed from the same batch with the same SA: V ratio through the introduction of channels (n = 3)