Poly(ɛ-caprolactone) and Eudragit E blends modulate the drug release profiles from FDM printlets
Abstract
Thermoplastic polymers have been used to produce filaments by hot melt extrusion (HME), which can be applied to obtain 3D printlets by fused deposition modelling (FDM). Poly(ε-caprolactone) (PCL) is a low melting point thermoplastic polymer that provides HME filaments with excellent mechanical and printability properties. However, due to the highly hydrophobic properties of PCL, they afford printlets with slow drug release behaviour. We hypothesized that blending a less hydrophobic polymer, the Eudragit E (EudE), with PCL could be an approach to increase the drug release rate from PCL 3D printlets. PCL and EudE were blended at different proportions, 50:50, 60:40, 70:30, and 80:20 (w/w), to produce HME filaments.
They were produced with dexamethasone at 5 % (w/w) and were effectively extruded and printable by FDM, except that composed of 50:50 (w/w). Printlets had homogeneous distribution of their components. Their drug release behaviour was dependent on the ratio of the polymeric blends. The highest EudE ratio (60:40 w/w) afforded printlets showing the highest release rate. Therefore, adding up to 40 % (w/w) of EudE to PCL does not impair the mechanical and printability properties of its HME filaments. This innovative approach is proposed here to modulate the drug release behaviour from PCL printlets.
Introduction
Fused deposition modelling (FDM) is a 3D printing extrusion technique that uses thermoplastic polymers that melt at specific temperatures. Firstly, polymeric filaments are produced by hot melt extrusion (HME) and, in general, they are composed of a polymer and other adjuvants that help to improve their mechanical and rheological properties, which have been reported as essential features to provide their good printability (Arrigo and Frache, 2022). More recently, a direct powder extrusion 3D printing technique has been reported to overcome the need for a previous step for the preparation of the filament (Goyanes et al., 2019). Even so, when polymeric filaments are used, they are fed into the FDM 3D printer, passing through a heated extruder, in which melted material is continuously deposited layer by layer in a build table according to a digital file (Serrano et al., 2023). Due to its ease of access and use, FDM has been used as a technique to produce drug delivery systems such as implants (Bassand et al., 2023) and tablets (Uboldi et al., 2023). It allows the printing of forms with different sizes and infill percentages, which are directly related to the release kinetics of the drug from the delivery system.
In fact, the possibility of modulating the drug release profile attributed to 3D printing is one of the most highlighted advantages of applying this technology in pharmaceutics to customize the release from the dosage forms, according to the therapy needed. Over the last few years, systems with different drug release profiles have been developed by 3D printing, as immediate (Uboldi et al., 2023), sustained (Utomo et al., 2023), or delayed release (Kotha et al., 2023), and also for different routes of administration. Specifically focusing on oral administration, it is necessary to consider the specific absorption window of each drug (in a concept that the drug has a uniform absorption throughout the gastrointestinal tract), which corresponds to the time in which the pharmaceutical form will travel through the gastrointestinal tract and be available for absorption. In general, the ideal release of the drug from the pharmaceutical forms in this case is about 10–12 h (Thombre, 2005). In some cases, if the dosage form is not able to release the drug up to this expected transit time, or if the drug has a greater absorption in the upper gastrointestinal tract, gastro-retentive drug delivery systems have been used to increase the residence time in the stomach (Mandal et al., 2016).
According to the formulation conception and the desired properties, different polymers with more hydrophobic or hydrophilic characteristics can be considered by formulators for the FDM process of 3D printing. Poly-ε-caprolactone (PCL) is a hydrophobic biodegradable polyester, biocompatible, with good stiffness, mechanical elasticity, thermal stability, rheological, and viscoelastic properties (Agocsova et al., 2023). PCL melts at low temperatures, making it a good candidate to be used in 3D printing by FDM to reduce the risk of thermal degradation of drugs or other adjuvants. However, despite the good printability characteristics attributed to PCL, its hydrophobicity and non-swelling properties in aqueous media make PCL more suitable to delay the drug release from solid dosage forms. In our previous study, we reported the production by FDM of PCL 3D-printed solid forms loaded with dexamethasone (DEX) as a model drug and showed a drug release of about 10 % in 10 h, despite some changes in their design, such as adding a channel former or lowering their infill percentage. Thus, we reached the conclusion that these PCL printlets were more suitable for the production of intratumoral implant devices (dos Santos et al., 2021a).
The possibility of blending PCL with polymers with hydrophilic properties to produce oral dosage forms with a faster drug release rate remains unclear. Due to its solubility in the gastric environment and use in the formulation of immediate-release drug release systems (McDonagh et al., 2022, Wang et al., 2020), Eudragit E (EudE) could be a good candidate to be blended with PCL. It is a methacrylate polymer with good solubility at pH values between 1.0 and 4.0, and good thermomechanical properties (Tg around 48 °C) and is listed among the Generally Recognized as Safe (GRAS) pharmaceutical excipients.
Therefore, the main goal of this study was to evaluate the hypothesis of getting PCL oral controlled drug release FDM 3D-printed solid forms by adding EudE at different ratio, as an approach to keep the mechanical and printability properties of PCL filaments and to make faster the drug release from PCL printlets. In addition, we aimed to evaluate if this approach can produce 3D printed controlled delivery systems based on a biocompatible and biodegradable polyester showing drug release behaviour suitable for oral delivery, which is still a challenge in this area. To reach our goal, DEX, an anti-inflammatory glucocorticoid, was used as a hydrophobic model drug.
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Material
EudE (MW 47,000 g mol−1) and powder PCL (Capa™ 6506, MW 50,000 g mol−1) were kindly donated by Evonik (Darmstadt, Germany) and Perstorp (Cheshire, UK), respectively. DEX, mannitol, and microcrystalline cellulose (MCC; Avicel pH 301) were purchased from Valdequímica (São Paulo, Brazil). Triethyl citrate (TEC), PEG 6000, and HPLC-grade acetonitrile were acquired from Merck (Darmstadt, Germany).
Juliana dos Santos, Tobias Kielholz, Nadine Lysyk Funk, Gabriela de Souza Balbinot, Tales da Silva Daitx, Cesar Liberato Petzhold, Silvio Buchner, Fabrício Mezzomo Collares, Maike Windbergs, Ruy Carlos Ruver Beck, Poly(ɛ-caprolactone) and Eudragit E blends modulate the drug release profiles from FDM printlets, International Journal of Pharmaceutics, Volume 647, 2023, 123533, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2023.123533.
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