Depression, a prevalent mental health disorder with a globally rising incidence, has become a critical public health challenge [1], [2], [3]. The efficacy of antidepressant treatment is tightly linked to patient compliance and treatment continuity—yet most clinically used antidepressants rely on daily oral administration. For many patients, especially those with recurrent symptoms or medication forgetfulness, maintaining regular dosing is difficult, leading to symptom fluctuations, disease recurrence, and suboptimal therapeutic outcomes [4]. This unmet clinical need is particularly pronounced among patients with moderate-to-severe depression. Long-acting pharmaceutical formulations hold significant potential to solve key limitations of conventional treatments: they may reduce the frequency of drug administration, facilitate the maintenance of stable plasma drug concentrations, and reduce the risk of treatment discontinuity arising from missed doses—ultimately contributing to enhanced overall treatment efficacy and success rates.

Among the diverse class of antidepressants, Vortioxetine—initially developed by Lundbeck (Denmark)—has emerged as a promising option due to its unique pharmacological profile [5], [6], [7]. Clinical evidence confirms its advantages, including relatively rapid onset of action, low incidence of adverse reactions, and good patient tolerance, allowing it to occupy an increasingly important role in antidepressant therapy [6], [8]. Currently, Brintellix®/Trintellix® (Vortioxetine Hydrobromide Tablets/Oral Drops) has been commercialized globally as a first-line therapeutic option for major depressive disorder (MDD) in adults. It was first approved by the FDA in September 2013 (initially under the brand name Brintellix®, later renamed Trintellix® in 2016 to avoid confusion with other medications) and has since gained regulatory clearance in over 80 countries and regions, including the European Union (EU), Japan, and China. Its commercialized formulations primarily include film-coated immediate-release tablets (5 mg, 10 mg, and 20 mg) and an oral drop formulation (20 mg/ml, containing vortioxetine lactate) exclusively marketed in the EU to accommodate patients who may have difficulty swallowing tablets. To date, no long-acting vortioxetine formulation has been developed. Usually, specific physicochemical properties are required for an active pharmaceutical ingredient (API) to achieve long-acting intramuscular (IM) sustained release. Notably, solubility requires priority consideration: poorly water-soluble APIs are more suitable for formulating into long-acting intramuscular injections. In contrast, the highly water-soluble APIs tend to dissolve rapidly in the aqueous environment of muscular tissue and be absorbed into the bloodstream too quickly—failing to maintain the desired prolonged release profile [9]. However, the inherent physicochemical properties (e.g., solubility) and pharmacokinetic characteristics (e.g., short in vivo half-life) of Vortioxetine limit its development into long-acting formulations, restricting its ability to address the compliance challenges of current treatment regimens [10]. Prodrug technology offers a viable solution to optimize the pharmacokinetic properties of drugs: through chemical modification of the drug, it can prolong in vivo half-life, reduce clearance rate and enable sustained release [11], [12], [13]. Among insoluble salt-based prodrug strategies, pamoate has been the most extensively studied. Forming a pamoate salt with a drug significantly reduces the drug’s solubility and dissolution rate, thereby extending its in vivo duration of action [14], [15], [16], [17].

Currently, relatively limited pharmaceutical technologies are available for achieving long-acting intramuscular drug delivery. From an industrial manufacturing perspective, intramuscular injectable suspensions offer distinct advantages. Firstly, their production process is relatively straightforward and highly scalable—unlike complex long-acting delivery systems (e.g., microspheres), which often involve intricate multi-step fabrication processes (such as emulsion polymerization or lyophilization) [18], [19], [20], [21]. In contrast, suspensions are primarily entail dispersing active pharmaceutical ingredients (APIs) in a suitable dispersion medium, which significantly reduces the complexity of process control and shortens overall production cycle times [22], [23], [24]. Secondly, the composition of intramuscular injectable suspensions is inherently simple: APIs, functional stabilizers and pH adjusters [25], [26]. This compositional simplicity notably minimizes the risk of compatibility between API and excipients [23], [27]. Additionally, wet bead milling is a widely used and well-established technique for suspension manufacturing. This technique leverages high-energy collisions between grinding beads and API to reduce particle diameters to the desired range (typically 1–10 μm or sub-micrometer sizes) [28], [29], [30], [31], [32].

The objective of this study is: (i) to establish a simple, efficient laboratory-scale and pilot-scale preparation method for vortioxetine suspensions; and (ii) to evaluate their pharmacokinetic profiles to achieve long-acting intramuscular injection. Vortioxetine was first synthesized into vortioxetine pamoate (VTXP), a modification intended to reduce its aqueous solubility and thereby extend its half-life. In laboratory-scale experiments, VTXP suspensions were prepared by milling VTXP with various types of stabilizers (including small-molecule surfactants and amphiphilic polymers). Following preparation, the formulations were characterized for particle size stability during milling and storage. The optimized formulations were then subjected to a laboratory-based scale-up procedure to validate their feasibility for larger-scale production. Finally, the resulting VTXP suspensions were evaluated in rats and dogs to assess their in vivo sustained-release performance.