Redispersible 3D printed nanomedicines: An original application of the semisolid extrusion technique

Abstract

Semisolid extrusion is a layer-by-layer 3D printing technique that produces objects from gels or pastes. This process can be carried out at room temperature, without using a light source, and has been explored in pharmaceutics in the last few years. In this regard, our group hypothesized its suitability for the production of three-dimensional (3D) printed nanomedicines containing drug-loaded organic nanocarriers. In this study, the original application of the semisolid extrusion was evaluated to produce redispersible 3D printed oral solid forms containing drug-loaded polymeric nanocapsules. A carboxymethyl cellulose hydrogel containing resveratrol and curcumin co-encapsulated in nanocapsules was prepared, and the nanocapsules did not change its complex viscosity and yield stress. Homogeneous and yellow cylindrical-shaped solid forms were printed, with a mean weight of 0.102 ± 0.015 g, a polyphenol content of approximately 160 μg/unit, disintegration time of <45 min, and recovery of the nanosized carriers. The polyphenols were completely released from the solid forms after 8 h, although part of them remained encapsulated in the nanocapsules. This study represents a proof of concept concerning the use of semisolid extrusion to produce 3D printed forms composed of polymeric nanocapsules in a one-step process. It proposes an original platform for the development of solid nanomedicines from liquid aqueous nanocapsule suspensions.

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Introduction

Three-dimensional (3D) printing is an emerging technology that has been explored in different areas, such as aerospace, electronics, automotive and biomedical, among others. This additive manufacturing technique creates physical objects from a digital model (Gao et al., 2021). It is able to create products with a high degree of precision and promises a revolution in the manufacturing market. 3D printed products can be composed of different materials, such as resins, polymers, metals and ceramics, and the technique can create products in just one step (Saleh Alghamdi et al., 2021).

In pharmaceutics, different 3D printing techniques have been studied in recent years, such as inkjet printing, stereolithography and extrusion techniques, like fused deposition modelling (FDM) and semisolid extrusion (SSE). Indeed, SSE has more recently been explored in the medical and pharmaceutical areas to design innovative drug dosage forms and devices. The process is characterized by the extrusion of pastes or gels onto a plate through a system similar to a syringe, where printing occurs layer by layer until the object is completely formed (dos Santos et al., 2021). It can be carried out at low or room temperatures and without using light sources.

In addition to the emerging potential of 3D printing, polymeric nanocapsules have been explored in pharmaceutics in the last decades to improve the in vitro and in vivo performance of drugs. Nanostructured systems are able of improve intrinsic solubility, control the drug delivery rate, decrease the frequency of drug doses, and improve drug oral bioavailability and stability when compared to conventional systems (Coradini et al., 2021, Khattab et al., 2020, Lima et al., 2022). In addition, they can target drugs to specific tissues or cells, reducing their adverse effects (Vinhas et al., 2017).

The alliance between these two emerging technologies has been recently applied to the development of 3D printed products containing nanometric structures (dos Santos et al., 2021). These applications comprise approaches for cell growth and tissue engineering, such as the production of 3D printed implants for bone repair using silver nanoparticles (Deng et al., 2017); drug delivery, such as the development of 3D printed scaffolds containing nanohydroxyapatite with dexamethasone for bone regeneration (Li et al., 2018); antimicrobial systems, in which discs can be printed using metal oxide nanoparticles (Horst et al., 2017); stimuli-responsive devices, such as the production of 3D printed devices containing iron oxide magnetic nanoparticles for bone repair (Lin et al., 2020); and 3D printed theranostic devices, which can be designed as mimetic structures of the hepatic lobe, composed of a hydrogel matrix containing polydiacetylene nanoparticles, able to collect and eliminate toxins releasing fluorescence (Gou et al., 2014).

However, there are still few studies devoted to the development of 3D printed pharmaceutical dosage forms containing drug nanomaterials, as nanomedicines. Some studies have reported the use of drug nanocrystals (Germini and Peltonen, 2021), drug-cyclodextrin complexes (Wang et al., 2022), drug-loaded mesoporous silica (Schmidt et al., 2022)and polymeric nanocapsules (Beck et al., 2017) in the production of 3D printed dosage forms. Indeed, Beck and co-workers (2017) proposed an innovative approach for the development of FDM 3D printed nanomedicines, which are composed of poly (ε-caprolactone) (PCL) and Eudragit RL100 printlets and drug-loaded nanocapsules. The nanocapsules were loaded by soaking the printlets in a suspension of the nanocapsules, in a two-step process, comprising the printing followed by the nanocarrier loading. The drug release profiles from these printlets were affected by the type of polymer, the infill percentage and the presence of a channelling agent. In addition, electron microscopy analyses depicted the presence of the nanostructures on the surface and in the inner compartment of the printlets (Beck et al., 2017). Up to now, this is the only study reporting the alliance of nanocapsules and 3D printing to produce pharmaceuticals.

In previous studies, our group reported the improved physicochemical, biopharmaceutical and pharmacological properties of resveratrol and curcumin co-encapsulated in polymeric nanocapsules, as their antioxidant and anti-inflammatory activities (Coradini et al., 2014, Coradini et al., 2015, Friedrich et al., 2015, Kann et al., 2016). The nanoencapsulation increased the intrinsic aqueous solubility of both natural polyphenols, making possible their formulation as an aqueous suspension. However, for future clinical translation this liquid formulation should be formulated as solid dosage forms, which have advantages concerning handling, shipping, physicochemical as well as microbiological stability (Beck et al., 2017, de Oliveira et al., 2020). We hypothesized that this step could be performed by a 3D printing process without using light or heat. In addition, this nanocapsule formulation could even be a suitable model to propose a novel process of producing 3D printed nanomedicines in a single step.

Therefore, the goal of this study was to evaluate the feasibility of producing innovative 3D printed oral solid dosage forms containing resveratrol and curcumin co-encapsulated in polymeric nanocapsules using a one-step process by the SSE technique. Carboxymethylcellulose hydrogels containing nanocapsules were prepared, and the influence of the nanoparticles on the rheological properties of the hydrogel was investigated. Afterwards, the hydrogels were used as printing inks to produce disk-shaped oral dosage forms. The recovery of the nanosized particles was evaluated after disintegration of the solid form, as well as other physicochemical and biopharmaceutical properties.

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Thayse Viana de Oliveira, Rafaela Santos de Oliveira, Juliana dos Santos, Nadine Lysyk Funk, Cesar Liberato Petzhold, Ruy Carlos Ruver Beck,
Redispersible 3D printed nanomedicines: An original application of the semisolid extrusion technique,
International Journal of Pharmaceutics, Volume 624, 2022, 122029, ISSN 0378-5173,
https://doi.org/10.1016/j.ijpharm.2022.122029.