Agomelatine 3D-printed microneedles as a potential drug delivery system for the treatment of depression

Abstract

Microneedles (MNs) are small devices that help to overcome the skin barrier and, thus, increase the effectiveness of transdermal drug delivery. This approach could be beneficial, especially for drugs characterised by low oral bioavailability, such as the antidepressant agomelatine (AGM), which is now only available on the market as an oral tablet. The aim of this study was to obtain agomelatine-loaded microneedle systems for potential use in the treatment of depression, using the 3D-printing methods. 3D-printing is an emerging technology enabling the manufacture of drug dosage forms or devices in a personalised, fast, and cost-efficient manner. Three 3D-printing techniques, different drug loading methods, and various shapes of microneedles were investigated along with the mechanical and physicochemical evaluation, release, stability, and toxicity studies of the obtained samples. Masked Stereolithography (MSLA) and PolyJet methods were successful in obtaining good-quality microneedle systems. Additionally, the MSLA method allowed for easy combining of the resin with the drug. The presence of the drug in the product was confirmed, and the drug release pattern depended on the loading method. Mechanical testing showed that Pyramid and Cone geometries were the most promising in puncture tests, and stability testing revealed the need for light- and moisture-resistant packaging. The formulations selected based on the obtained results will be further investigated on the way to create a transdermal alternative to agomelatine oral tablets and increase the effectiveness of depression treatment.

Introduction

Almost one in five people experiences one episode of depression at some point in their life, and about 80% of them would also experience a relapse of the illness. Typical treatment of depressive disorders includes pharmacotherapy, psychological therapy, or both of these methods combined (Malhi and Mann, 2018). However, the effective treatment of depression still remains a challenge. The first reason for therapy failure is associated with medication non-adherence. While depression usually requires long-term treatment, it has been reported that almost 50% of patients stop their antidepressant therapy prematurely (Sansone and Sansone, 2012). The reasons could be forgetfulness, side effects, or polypharmacy. Another reason is the side effects, e.g., gastric problems, dizziness, or sexual dysfunction. Also, the individual response to treatment is important. “One size fits all” treatment does not apply to depression, and patients often require an individualized approach regarding the doses or dose regimen (Singh and Thase, 2025). These criteria are difficult to meet, given that antidepressants are usually administered in the form of a conventional oral tablet. An effective solution to the therapy challenges could be a drug delivery system that would ensure dose personalization, a simple method of administration, and a reduction of the risk of side effects. The above criteria are met by an innovative drug delivery system – microneedles (MNs).

Microneedles are tiny needles, usually up to 2500 µm (Tamez-Tamez et al., 2023) in length, used individually or grouped on the basis in the form of a patch. MNs aim to create small holes in the skin and facilitate skin permeation, while the appropriate design can ensure no irritation of nerve endings and no bleeding. Among the overall advantages of MNs is minimizing pain and fear of a conventional injection, creating less of dangerous medical waste, and decreasing the risk of accidental needle-stick injury (Le et al., 2023). Moreover, it is possible to obtain systems connected to a drug reservoir or providing prolonged release of the cargo, which is helpful in chronic diseases and long-term therapy, like in the case of depression. Also, MNs address typical problems related to such therapy, for instance, dose skipping and fluctuations in drug plasma levels, which may in turn intensify side effects (Vora et al., 2023). Additionally, MNs help avoid the first-pass metabolism and enable high drug bioavailability (Jung and Jin, 2021). Also, loading MNs with a smaller, personalized dose of the appropriate drug can potentially increase the effectiveness of therapy with fewer side effects.

MNs were patented in the 1970s by Martin S. Gerstel and Virgil A. Place. The idea was presented as a drug delivery device for percutaneous administration of the active substance for local or systemic effect (Gerstel and Virgil, 1976). In 1998, Henry et al. (1998) presented the first study, where microfabricated MNs were employed to enhance the transdermal delivery of a model drug through the human skin. Since then, the number of papers published in that field has increased over the years as the topic has been investigated more intensively. However, to this day, not many MN products have been marketed. Interestingly, not every MN product is an MN device according to the FDA. To be categorized as a device, the MN product should affect the structure or function of skin or meet another FDA’s criteria for this classification (Regulatory Considerations for Microneedling Products, 2020). SkinPen® Precision System was classified by the FDA as a Microneedling device for the aesthetic use, not for the transdermal delivery of topical products such as cosmetics, drugs, or biologics (De novo classification request for skinpen precision system, 2016). Another example is Collagen P.I.N.® (Percutaneous Induction Needling) System (Tamez-Tamez et al., 2023), and ExceedTM Microneedling device for the improvement of the appearance of facial acne scars (Le et al., 2023). In the medical field, BD Soluvia™ (Becton Dickinson, NJ, USA) was the first commercialized MN product and the first FDA-approved MN system for vaccine delivery. It consists of a single, steel hollow MN and was intended to deliver the loading intradermally. Soluvia™ was used as an MN system to deliver the flu vaccine – Sanofi Pasteur’s Intanza®. Another FDA-approved hollow MN product is MicronJet® from NanoPass Technologies. It consists of four hollow MN made of silicone, and attached to a plastic element compatible with a standard syringe (Le et al., 2023, Mahato, 2017, Nguyen, 2025). Also, Clearside Biomedicals’ Xipere®, equipped with SCS Microinjector® for drug delivery into the suprachoroidal space, was approved in 2021 (Clearside Biomedical, Inc., 2021).

Different types of MNs have been presented, such as solid, hollow, coated, dissolving, hydrogel-forming, and porous MNs. The role of solid MNs is to create holes in the skin before drug application, while hollow MNs have channels through which the drug can be administered. Dissolvable MNs, on the other hand, are typically made of materials that allow the needles to dissolve in the skin, releasing the preloaded drug. Coated MNs are also designed to deliver the drug to the skin, but they do not dissolve; they merely act as a carrier. Newer types include hydrogel-forming MNs, which are made of swellable polymers that gradually release the drug into the skin or can collect samples of interstitial fluid for diagnostic purposes (Oliveira et al., 2024, Mohite et al., 2024). Also, porous MNs can be used for interstitial fluid collection and for drug delivery, thanks to the porous channels or capillaries in their structure (Bao et al., 2022). Considering years 2000–2021, MNs gained more attention in research, with solid and dissolvable MN types as leaders in the field. Moreover, applications such as vaccine delivery, diagnosis, cancer, pain management, and diabetes appeared to be the most popular. In addition, MN technology is being investigated for use in the broad field of cosmetics. Among the products undergoing clinical trials, the most common are solid MNs, followed by hollow MNs. However, there is an increase in investigations using dissolvable MNs (Sartawi et al., 2022).

One method of producing MNs is 3D printing (3DP) (Loh et al., 2024), which is still an emerging technology. In medicine, it has been investigated for creating pre-surgery models of organs (Silberstein et al., 2014), personalised limb prostheses (Ten Kate et al., 2017), in prosthodontics (Tian et al., 2021), and for the manufacture of drug dosage forms such as Spritam® (West et al., 2019). There are currently attempts to implement printing in hospital and community pharmacies, particularly due to the possibility of dose personalization and small-batch production for patients with special needs. In addition, production is relatively fast, and the cost can be decreased (Huanbutta et al., 2023). All the above-mentioned advantages suggest that 3DP could be an innovative, flexible, and cost-effective method for obtaining MNs in this study, while the challenges would be, among others, the printing precision, method selection, and drug loading. When compared to the other methods of MNs fabrication, such as micromoulding, laser ablation, and microelectromechanical system (MEMS)-based techniques, 3DP offers a number of benefits. For instance, it enables the creation of complex geometries of MNs and the precise printing of the designed shape. This is difficult to achieve in the case of micromoulding and MEMS-based methods, while possible with laser ablation; however, the process is expensive. In the case of MEMS-based methods and laser ablation, the scalability would also be challenging due to the time-consuming and cost-ineffective process. The next limitation is fast product customization. In MEMS-based methods, changing the geometry requires a new photolithographic mask. Also, micromoulding requires creating a new mould, which is time-consuming. However, with 3DP, changing the design in the software is simple, fast, and offers extensive possibilities for personalizing MNs to the patient’s needs (Oliveira et al., 2024, Babu et al., 2024).

The aim of this study is to obtain agomelatine (AGM)-loaded MN systems for potential use in the treatment of depression. AGM, which has so far only been available in the form of oral tablets, has very low bioavailability after oral administration (approx. 5%) (Green, 2011). Transdermal administration could improve bioavailability due to the absence of the first-pass effect via this route, and the MN form itself could further improve the passage of the substance through the stratum corneum (SC). The clinical value of microneedles has been assessed in several animal and clinical studies, aiming to prove their efficacy and safety, particularly in the delivery of vaccines, insulin, and other macromolecules (Jung and Jin, 2021, Bhatnagar et al., 2017, Queiroz et al., 2020). Moreover, the use of 3DP is an opportunity to obtain precise MN systems, with the potential for further personalization. To the best of our knowledge, this is the first attempt at using 3D-printed MNs to deliver an antidepressant with poor bioavailability, and thus, to improve the treatment of

This study focuses on obtaining MN systems using various 3DP techniques, drug loading methods, and evaluating basic parameters such as MN penetration ability and optimal shape, drug release, stability, and toxicity. The study also aims to identify the best formulations for further research, which will include testing skin permeability using full-thickness human skin ex vivo and in vivo bioavailability studies on animal models.

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Monika Wojtyłko, Tomasz Osmałek, Wiesław Kuczko, Radosław Wichniarek, Ariadna B. Nowicka, Mirosław Szybowicz, Dariusz T. Mlynarczyk, Anna Froelich, Barbara Jadach, Oliwia Kordyl, Irena Budnik, Antoni Białek, Julia Krysztofiak, Bozena Michniak-Kohn, Joanna Budna-Tukan, Andrzej Miklaszewski, Dimitrios A. Lamprou, Agomelatine 3D-printed microneedles as a potential drug delivery system for the treatment of depression, International Journal of Pharmaceutics, Volume 690, 2026, 126572, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2026.126572.

Read also our introduction article on 3D Printing here: