Sarah J. Trenfield

3D Printing Pharmaceuticals: Drug Development to Frontline Care

3D printing (3DP) is forecast to be a highly revolutionary technology within the pharmaceutical sector. In particular, the main benefits of 3DP lie in the production of small batches of medicines, each with tailored dosages, shapes, sizes and release characteristics. The manufacture of medicines in this way may finally lead to the concept of personalised medicines becoming a reality. In the shorter term, 3DP could be extended throughout the drug development process, ranging from preclinical development and clinical trials, through to frontline medical care. In this review, we provide a timely perspective on the motivations and potential applications of 3DP pharmaceuticals, as well as a practical viewpoint on how 3DP could be integrated across the pharmaceutical space.

Reshaping drug development using 3D printing

The pharmaceutical industry stands on the brink of a revolution, calling for the recognition and embracement of novel techniques. 3D printing (3DP) is forecast to reshape the way in which drugs are designed, manufactured, and used. Although a clear trend towards personalised fabrication is perceived, here we accentuate the merits and shortcomings of each technology, providing insights into aspects such as the efficiency of production, global supply, and logistics. Contemporary opportunities for 3DP in drug discovery and pharmaceutical development and manufacturing are unveiled, offering a forward-looking view on its potential uses as a digitised tool for personalised dispensing of drugs.

3D printed medicines: A new branch of digital healthcare

ABSTRACT Three‐dimensional printing (3DP) is a highly disruptive technology with the potential to change the way pharmaceuticals are designed, prescribed and produced. Owing to its low cost, diversity, portability and simplicity, fused deposition modeling (FDM) is well suited to a multitude of pharmaceutical applications in digital health. Favourably, through the combination of digital and genomic technologies, FDM enables the remote fabrication of drug delivery systems from 3D models having unique shapes, sizes and dosages, enabling greater control over the release characteristics and hence bioavailability of medications. In turn, this system could accelerate the digital healthcare revolution, enabling medicines to be tailored to the individual needs of each patient on demand. To date, a variety of FDM 3D printed medical products (e.g. implants) have been commercialised for clinical use. However, within pharmaceuticals, certain regulatory hurdles still remain. This article reviews the current state‐of‐the‐art in FDM technology for medical and pharmaceutical research, including its use for personalised treatments and interconnection within digital health networks. The outstanding challenges are also discussed, with a focus on the future developments that are required to facilitate its integration within pharmacies and hospitals.

Personalisation of warfarin therapy using thermal ink-jet printing

&NA; Warfarin is a widely used anticoagulant that is critical in reducing patient morbidity and mortality associated with thromboembolic disorders. However, its narrow therapeutic index and large inter‐individual variability can lead to complex dosage regimes. Formulating warfarin as an orodispersible film (ODF) using thermal ink‐jet (TIJ) printing could enable personalisation of therapy to simplify administration. Commercial TIJ printers are currently unsuitable for printing the milligram dosages, typically required for warfarin therapy. As such, this study aimed to modify a commercial TIJ printing system to formulate personalised warfarin ODFs containing therapeutic dosages. A TIJ printer was modified successfully with the printer functionality intact; the substrate (paper) rolling mechanism of the printer was replaced by printing onto a stationary stage. Free film substrates were composed of hydroxypropyl methylcellulose (20%w/w) and glycerol (3%w/w). The resulting ODFs were characterised for morphology, disintegration, solid‐state properties and drug content. Printed film stability was assessed at 40 °C/75% relative humidity for 30 days. Therapeutic warfarin doses (1.25 and 2.5 mg) were successfully printed onto the film substrates. Excellent linearity was observed between the theoretical and measured dose by changing the warfarin feed concentration (R2 = 0.9999) and length of the print objective, i.e. the Y‐value, (R2 = 0.9998). Rapid disintegration of the ODFs was achieved. As such, this study successfully formulated personalised warfarin ODFs using a modified TIJ printer, widening the range of applications for TIJ printing to formulate narrow therapeutic index drugs. Graphical abstract Figure. No caption available.

3D printing of drug-loaded gyroid lattices using selective laser sintering

Graphical abstract Figure. No caption available. ABSTRACT Three‐dimensional printing (3DP) is gaining momentum in the field of pharmaceuticals, offering innovative opportunities for medicine manufacture. Selective laser sintering (SLS) is a novel, high resolution and single‐step printing technology that we have recently introduced to the pharmaceutical sciences. The aim of this work was to use SLS 3DP to fabricate printlets (3D printed tablets) with cylindrical, gyroid lattice and bi‐layer structures having customisable release characteristics. Paracetamol‐loaded constructs from four different pharmaceutical grade polymers including polyethylene oxide, Eudragit (L100‐55 and RL) and ethyl cellulose, were created using SLS 3DP. The novel gyroid lattice structure was able to modulate the drug release from all four polymers. This work is the first to demonstrate the feasibility of using SLS to achieve customised drug release properties of several polymers, in a swift, cost‐effective manner, avoiding the need to alter the formulation composition. By creating these constructs, it is therefore possible to modify drug release, which in practice, could enable the tailoring of drug performance to the patient simply by changing the 3D design.

Sex differences in the gastrointestinal tract of rats and the implications for oral drug delivery

Abstract Pre‐clinical research often uses rodents as animal models to guide the selection of appropriate oral drug and dose selection in humans. However, traditionally, such research fails to consider the gastrointestinal differences between the sexes of rats and the impact on oral drug delivery. This study aimed to identify and characterise the potential sex‐related differences in the gastrointestinal environment of sacrificed male and female Wistar rats. Their gastrointestinal tracts were excised and segmented into the stomach, duodenum, jejunum, ileum, caecum and colon. The respective contents and tissue sections were collected and analysed for pH, buffer capacity, surface tension, osmolality and relative P‐glycoprotein (P‐gp) expression. The pH in the stomach of females was found to be lower than in males. Female rats also exhibited a higher buffer capacity in the caecum and colon when compared with their male counterparts. Males were found to have a higher osmolality than females in the duodenum, ileum and colon. Significant sex differences (p < 0.05) in surface tension were observed in the ileum, where females exhibited a higher surface tension. Interestingly, female rats displayed significantly higher relative P‐gp expression levels (p < 0.05) when compared with male rats in the duodenum (1.24 ± 0.85 vs. 0.36 ± 0.26), jejunum (1.45 ± 0.88 vs. 0.38 ± 0.26) and ileum (0.92 ± 0.43 vs. 0.40 ± 0.18) but not in the colon (0.5 ± 0.32 vs. 0.33 ± 0.16) segments. The work reported has demonstrated the stark physiological differences between male and female rats at a physiological level, indicating how the ‘sex of the gut’ could influence oral drug delivery. These findings, therefore, are of critical importance in pre‐clinical research and drug development. Graphical abstract Figure. No caption available.

3D printed drug products: Non-destructive dose verification using a rapid point-and-shoot approach

Graphical abstract Figure. No Caption available. Abstract Three‐dimensional printing (3DP) has the potential to cause a paradigm shift in the manufacture of pharmaceuticals, enabling personalised medicines to be produced on‐demand. To facilitate integration into healthcare, non‐destructive characterisation techniques are required to ensure final product quality. Here, the use of process analytical technologies (PAT), including near infrared spectroscopy (NIR) and Raman confocal microscopy, were evaluated on paracetamol‐loaded 3D printed cylindrical tablets composed of an acrylic polymer (Eudragit L100‐55). Using a portable NIR spectrometer, a calibration model was developed, which predicted successfully drug concentration across the range of 4–40% w/w. The model demonstrated excellent linearity (R2 = 0.996) and accuracy (RMSEP = 0.63%) and results were confirmed with conventional HPLC analysis. The model maintained high accuracy for tablets of a different geometry (torus shapes), a different formulation type (oral films) and when the polymer was changed from acrylic to cellulosic (hypromellose, HPMC). Raman confocal microscopy showed a homogenous drug distribution, with paracetamol predominantly present in the amorphous form as a solid dispersion. Overall, this article is the first to report the use of a rapid ‘point‐and‐shoot’ approach as a non‐destructive quality control method, supporting the integration of 3DP for medicine production into clinical practice.

Printing T3 and T4 oral drug combinations as a novel strategy for hypothyroidism

Graphical abstract Figure. No Caption available. Abstract Hypothyroidism is a chronic and debilitating disease that is estimated to affect 3% of the general population. Clinical experience has highlighted the synergistic value of combining triiodothyronine (T3) and thyroxine (T4) for persistent or recurrent symptoms. However, thus far a platform that enables the simultaneous and independent dosing of more than one drug for oral administration has not been developed. Thermal inkjet (TIJ) 2D printing is a potential solution to enable the dual deposition of T3 and T4 onto orodispersible films (ODFs) for therapy personalisation. In this study, a two‐cartridge TIJ printer was modified such that it could print separate solutions of T3 and T4. Dose adjustments were achieved by printing solutions adjacent to each other, enabling therapeutic T3 (15–50 &mgr;g) and T4 dosages (60–180 &mgr;g) to be successfully printed. Excellent linearity was observed between the theoretical and measured dose for both T3 and T4 (R2 = 0.982 and 0.985, respectively) by changing the length of the print objective (Y‐value). Rapid disintegration of the ODFs was achieved (<45 s). As such, this study for the first time demonstrates the ability to produce personalised dose combinations by TIJ printing T3 and T4 onto the same substrate for oral administration.

The Shape of Things to Come: Emerging Applications of 3D Printing in Healthcare

We now stand on the brink of a fourth industrial revolution. By the remarkable technological advancements of the twenty-first century, manufacturing is now becoming digitalised. In the last decade, the rise of rapid prototyping has provided individual patient care, acted as an educational and training tool and contributed to research. Innovative technologies such as three-dimensional printing (3DP), have the potential to cause a paradigm shift in medicine design, manufacture and use. Instead of using conventional large batch processes, customised printlets (3D printed tablets) with a tailored dose, shape, size and release characteristics could be produced on-demand. Arguably, never before has the pharmaceutical industry experienced such a transformative technology in medicines manufacture. Indeed, this technology could be utilised throughout the drug development process, ranging from pre-clinical development and first-in-human clinical trials through to front-line medical care (personalized medicines). This chapter aims to discuss the current and future potential applications of 3DP in healthcare and, ultimately, the power of 3DP in pharmaceuticals.

3D Printing Technologies, Implementation and Regulation: An Overview

The rise in three-dimensional (3D) printing in design and manufacturing, like any other, is the product of vision and implementation, pioneered by those who were brave enough to make it happen. In this chapter, the advancements of exponential developments driven by 3D printers themselves and its application in almost all areas of manufacturing and personalisation, namely; aeronautics, engineering, architecture and pharmaceutics are discussed. This chapter further serves to provide an introduction to the different 3D printing technologies, their respective histories, potential benefits, limitations and regulatory requirements, and a thorough description of the new and exciting possibilities that can arise by simply acknowledging the capabilities of 3D printing in healthcare.