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.

Introduction

Despite males and females making up roughly equal proportions of the global population, a pronounced sex bias persists in the pharmaceutical space. Historically, preclinical research and drug development studies have predominantly relied on male cells and tissues, male animal models, and male participants [1,2,3,4]. Sex-based differences in drug pharmacokinetics and pharmacodynamics are common in many pharmaceutical products today, such as diazepam where females have a higher distribution volume compared to males, which is reversed when taken with alcohol [5]. Other examples include differences in hepatic clearance, with drugs like digoxin, zolpidem, temazepam, and paracetamol having a greater hepatic clearance in males; whilst being greater in females for verapamil, cyclosporine, and erythromycin [2, 6,7,8]. Failing to account for these differences often leads to serious side effects and increased mortality in females, underscoring the urgent need for more sex-specific formulations [9].

Hypertension, one of the most prevalent chronic conditions, is defined by persistently elevated arterial blood pressure, making it a major risk factor for serious disorders such as heart disease and stroke [10]. Affecting over 1.3 billion adults worldwide [11], it is largely influenced by environmental and lifestyle factors, making it a preventable condition. However, many individuals still require antihypertensive medications despite lifestyle interventions [12]. Doxazosin mesylate, a biopharmaceutical classification system (BCS) class II drug, is an alpha-blocker used to treat hypertension [13, 14]. Approved by the FDA in 2005, doxazosin is available as immediate release (Cardura™) or controlled release (Cardura XL™) tablets, with doses of 4 mg or 8 mg per day. The controlled release formulation uses a gastrointestinal therapeutic system (GITS) for precise plasma control and simplified dosing [15, 16].

A 2005 FDA clinical pharmacology and biopharmaceutics review examined the pharmacokinetics of doxazosin, comparing young and elderly males and females to assess age- and sex- related effects [17]. Findings revealed that the 4 mg extended-release formulation demonstrated a significant sex effect, with 45% higher Cmax and 46% higher AUC values in young females compared to young males. Additionally, young females reported the highest number of adverse events (34), 48% of which occurred on the first day of treatment. As a result, the FDA recommends dose titration starting at 1 mg/day for young females; however, the lowest available dose for extended-release doxazosin is 4 mg, making titration unfeasible. Furthermore, the GITS cannot be cut or crushed without compromising its controlled release mechanism. To address these limitations, three-dimensional (3D) printing (3DP) offers a promising solution by enabling the creation of personalised doses tailored to specific populations [18,19,20,21]. Through a layer-by-layer manufacturing process, 3DP ensures precise dosing while preserving the drug’s extended-release profile, making it particularly valuable for patients like young females who require careful dose adjustments for optimal safety and efficacy.

Since the advent of pharmaceutical 3DP, extrusion-based techniques like fused deposition modelling (FDM) and semi-solid extrusion (SSE) have been widely explored due to their affordability and ease of use [22,23,24,25,26,27,28,29,30]. However, both techniques have drawbacks, limiting their use in pharmaceutical applications. SSE 3DP requires complete solvent evaporation after printing which requires extensive drying times and may complicate manufacture [31]. Additionally, the gel-like semi-solid material used carries the risk of shape loss or material collapse post-printing [32]. In contrast, FDM 3DP does not exhibit such post-processing issues but is time consuming due to the filament production process of hot melt extrusion (HME), which must meet specific mechanical and rheological properties [33, 34]. Furthermore, the dual use of thermal processes, both in HME and FDM, can lead to drug degradation, making FDM unsuitable for drugs with low melting points or temperature sensitivity [35, 36].

To overcome the limitations associated with extrusion-based techniques, a novel additive manufacturing method, direct powder extrusion (DPE), was introduced. First used in 2019 by Goyanes et al., to print itraconazole and hydroxypropyl cellulose (HPC) loaded tablets (known as Printlets™) [37], this innovative single-step manufacturing process eliminates the need for filament production, utilising powder directly. The versatility and suitability of DPE 3DP for pharmaceutical manufacture under Good Manufacturing Practice (GMP) conditions has already been demonstrated by leading companies such as FABRX Ltd. and Triastek [38, 39]. As a relatively new technology, research into pharmaceutical DPE 3DP is still in its early stages. To date, only a limited number of investigational dosage forms have been explored, including modified-release tablets of various active pharmaceutical ingredients (APIs) [38], immediate-release caffeine [40] and paracetamol tablets [41], paediatric formulations of praziquantel [42], and opioid medicines with abuse and alcohol deterrent properties [43]. The technology has also been used to manufacture minitablets (< 100 mg) with high loadings of nifedipine [44], as well as cyclodextrin based tablets of niclosamide to enhance solubility [45], and paediatric budesonide minitablets [46]. Given its advantages, this innovative technology holds significant potential for printing titrated doses on demand in a pharmacy or hospital setting, in the form of pharmaceutical compounding [47].

This study aims to leverage DPE 3DP to address the critical need for sex-specific dosing, focusing on alleviating side effects associated with antihypertensive treatments like doxazosin mesylate. The work explores the feasibility of producing tailored, extended-release oral tablets, with minimal excipients that may introduce more sex differences, that maintain comparable release profiles while enabling precise dose titration. This approach seeks to overcome the limitations of traditional drug formulations, paving the way for safer and more effective personalized medicines, particularly for females that are disproportionately affected by standard dosing practices.

Download the full article as PDF here Sex-specific formulations of doxazosin mesylate via direct powder extrusion 3D printing

or read it here

Materials

Doxazosin mesylate (547.58 g/mol) was purchased from MedChemExpress LLC (NJ, USA). Klucel HPC polymer JF (MW 140,000 g/mol) was purchased from Ashland (DE, USA). D-mannitol (MW 182.17 g/mol) and methanol puriss grade (≥99.8) were purchased from Sigma-Aldrich (Gillingham, UK). Potassium dihydrogen orthophosphate (KH2PO4) (MW 136.09 g/mol) was secured from Avantor (Leicestershire, UK). Sodium hydroxide (NaOH) 5 M was acquired from Scientific Laboratory Supplies (Nottingham, UK). Hydrochloric acid (HCl) 1 M was purchased from LP Chemicals Ltd. (Cheshire, UK). Sodium chloride (NaCl) (MW 58.44 g/mol) was obtained from Fisher Scientific (Loughborough, UK).

Januskaite, P., Goyanes, A., Orlu, M. et al. Sex-specific formulations of doxazosin mesylate via direct powder extrusion 3D printing. Drug Deliv. and Transl. Res. (2025). https://doi.org/10.1007/s13346-025-01862-4

Read also our introduction article on 3D Printing here: