From design to 3D printing: A proof-of-concept study for multiple unit particle systems (MUPS) printed by dual extrusion fused filament fabrication

Introduction

Multiple unit particle systems (MUPS) are solid oral dosage forms in the form of tablets and hard capsules. MUPS consist of small multiparticulate units, such as pellets, either pressed into tablets with excipients or filled into hard capsules, forming a single dosage unit (Abdul et al., 2010). Pellets in MUPS preparations usually have a modified release and can be divided into coated or uncoated pellets. In the case of coated pellets, often drug-free starter cores are coated with an active pharmaceutical ingredient (API) and/or a functional coating. Uncoated pellets are typically matrix pellets in which the API is incorporated (Kallakunta et al., 2018).

MUPS are administered orally and disintegrate within a short time into their multiparticulate units (Abdul et al., 2010). There is contradictory evidence in the literature that particles smaller than 2 mm, commonly incorporated in MUPS formulations, have a faster gastric passage. It is assumed that small particles can leave the stomach through the pylorus, even in the fed state. In comparison, sustained-release monolithic tablets remain in the stomach and are only transported via the migrating motor complex in phases of highest motility (housekeeping waves) in fasted state (Newton, 2010). Another advantage of MUPS is the even distribution of small individual particles inside the gastrointestinal tract. Furthermore, products containing otherwise incompatible active ingredients or specific release kinetics can be realised by combining different pellet types in one tablet. In addition, multiple individual modified release units reduce the risk of dose dumping (Abdul et al., 2010; Bechgaard and Nielsen, 1978; Dukić-Ott et al., 2009; Kallakunta et al., 2018).

Despite all these advantages, only a limited number of MUPS preparations are on the market (Abdul et al., 2010; Kallakunta et al., 2018; Patel et al., 2017). Capsules filled with pellets are more expensive to manufacture than MUPS tablet preparations due to the reduced production throughput (Abdul et al., 2010; Clelik and Maganti, 1994). However, the production of MUPS tablets is complex and time-consuming. During the compression step, it is essential that the applied force does not damage the pellets. Cracks in functional coatings, for example, could have a negative impact on the desired release kinetics. In addition, the individual pellets may fuse irreversibly during the compression process and can no longer act as small individual particles (Abdul et al., 2010; Clelik and Maganti, 1994). To use the advantages as mentioned above, the search for alternative production methods has to be considered.
3D printing is becoming integral to pharmaceutical research for the production of various dosage forms. Especially in the field of personalised medicine, 3D printing has many potential advantages (Trenfield et al., 2018). The fused filament fabrication (FFF) method is particularly noteworthy in the case of 3D printed personalised oral dosage forms. It is a process in which a polymer in the form of a filament is melted and extruded through a nozzle before being deposited layer-wise onto a heated print bed (Jamróz et al., 2018; Zema et al., 2017). The process is very flexible, and by using computer-aided design (CAD) software, the object can be individually adapted, for example, to control the dose or release kinetics (Goyanes et al., 2014; Goyanes et al., 2017). The printing process is preceded by a hot-melt extrusion to produce filaments with the desired pharmaceutical polymers, APIs, other excipients and/or to control release kinetics (Tan et al., 2018).

Within the field of FFF printing, dual extrusion printing is a promising manufacturing technique for medicinal products with a complex design that includes the use of two filaments with different compositions. In this case, the printers are equipped with two print heads (Jamróz et al., 2018). This allows, for example, the use of polymers differing in release kinetics or incorporating different APIs while printing one object. This technology has already been used to print pharmaceutical oral dosage forms. Goyanes et al. have produced capsule-shaped multilayer and shell-core tablets (Goyanes et al., 2015). Okwuosa et al. printed core-shell tablets with the addition of a gastroretentive shell (Okwuosa et al., 2017). Kempin et al. also used this technique to print gastroresistant core-shell tablets, but with the addition of a thermolabile API at low printing temperatures (Kempin et al., 2018). Zhang et al. used this technique to print bilayer tablets (Zhang et al., 2022). Apart from oral dosage forms, individualised drug-eluting implants have also been proposed by Domsta et al. (Domsta et al., 2023), showing the versatility of this method. Dual extrusion FFF printing might, therefore, also be used to produce MUPS tablets.

One of the main challenges in printing MUPS tablets is the production of small particles with a diameter of less than 2 mm. In the past, attempts have been made to produce small particles using 3D printing. Krause et al. printed mini tablets for paediatric patients with a 1.5 to 4 mm diameter using FFF (Krause et al., 2021). Also, semi-solid extrusion has already been used by Hu et al. to print cylindrical API-loaded minitablets with a diameter and height of 3 mm for paediatric use (Hu et al., 2023). Awad et al. printed individual pellets with a 1- or 2-mm diameter using selective laser sintering (SLS) (Awad et al., 2019). Xu et al. used stereolithography (SLA) technology to print pellets in the size of 1- or 2-mm diameter (Xu et al., 2021). Most of the above-mentioned studies successfully printed particles below 2 mm. However, no studies are available so far, that show a one-step 3D printing process to manufacture MUPS. The printed particles by Awad et al. and Xu et al., for example, would need to be filled into a capsule in a subsequent step to form a MUPS. Even though SLS and SLA may offer a higher printing precision compared to FFF, the big advantage of FFF is its flexibility. As already mentioned, it is possible to print several polymers with different APIs by using FFF with multiple print heads without pausing the process. The incorporation of multiple APIs is more difficult to realise with SLS and SLA, as an intervention during the printing process may be necessary to switch/add powder materials or resin tanks (Awad et al., 2019; Robles-Martinez et al., 2019). Dual extrusion FFF could be advantageous here and add new manufacturing possibilities.

The aim of this study was to investigate the feasibility of producing multiparticulate systems with small particles of less than 2 mm in diameter using FFF dual extrusion printing. For this purpose, a modular computer design of the 3D-MUPS was created. The requirements for this model were that the highest possible particle loading should be achieved to enable future dose adjustment. A maximum tablet size of 23 × 11 × 9 mm was also defined based on marketed monolithic tablets (ASACOL® Enteric Coated Tablets: Consumer Medicine Information, 2023). In addition, the tablet should not have sharp edges to improve swallowability. The printed 3D-MUPS should have a rapidly disintegrating tablet shell and contain as many particles <2 mm as possible. The process was developed and tested with commercially available polyvinyl alcohol (PVA) and polylactic acid (PLA) filaments as part of a proof-of-concept study. Finally, the suitability and transferability of the approach were tested by printing a drug-containing MUPS. For this purpose, an API-loaded (paracetamol) hydroxypropyl methylcellulose (HPMC) filament was manufactured by hot-melt extrusion and used to print the particles.
To the best of the authors’ knowledge, this is the first report of the engineering of a complete multiple unit particle system tablet via FFF.

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Materials

Commercially available technical grade filaments with a diameter of 2.85 mm were used to establish the proof-of-concept experiments. Water-soluble PVA (Aquasolve PVA Formfutura®, Netherlands) was used for the printing of the tablet shell, and water-insoluble PLA (EasyFil PLA Formfutura®, Netherlands) was used for the drug-free particles. All filaments were stored under defined humidity conditions (relative humidity <25 %) inside a customised filament box filled with silica gel as a desiccant. The used filament box was built according to (DIY Filament Box selber bauen – die ANYBOX V1, Ingenieurbüro Dr. Janko GmbH, 2020). The relative humidity inside the box was tracked using a digital hygrometer. The filament was stored on a rotating rod in the box and was fed from the box into the gear of the 3D printer via another Bowden tube to achieve a closed system.

AFFINISOL™ HPMC HME 15LV (hydroxypropyl methylcellulose, HPMC) was kindly donated by Dow Wolff Cellulosics GmbH (Bomlitz, Germany) and was used as a polymer for hot-melt extrusion of the API-loaded filament. Aerosil® 200 (fumed silica) was used as a flowability enhancer for the powder feeding process and was purchased from Evonik Operations GmbH (Rheinfelden, Germany). The model drug paracetamol (PCM), also known as acetaminophen, was purchased from Atabay Kimya Sanayi Ticaret A.S. (Istanbul, Türkiye). Phosphate buffer pH 6.8, according to European Pharmacopoeia 5.17.1 (Ph. Eur., version: 11.1), was used for dissolution studies.

Lee Roy Oldfield, Aaron Felix Christofer Mentrup, Stefan Klinken-Uth, Tobias Auel, Anne Seidlitz, From design to 3D printing: A proof-of-concept study for multiple unit particle systems (MUPS) printed by dual extrusion fused filament fabrication, International Journal of Pharmaceutics: X, Volume 8, 2024, 100299, ISSN 2590-1567, https://doi.org/10.1016/j.ijpx.2024.100299.

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