Paediatric clinical study of 3D printed personalised medicines for rare metabolic disorders.

Rare diseases are infrequent, but together they affect up to 6-10 % of the world's population, mainly children. Patients require precise doses and strict adherence to avoid metabolic or cardiac failure in some cases, which cannot be addressed in a reliable way using pharmaceutical compounding. 3D printing (3DP) is a disruptive technology that allows the real-time personalization of the dose and the modulation of the dosage form to adapt the medicine to the therapeutic needs of each patient. 3D printed chewable medicines containing amino acids (citrulline, isoleucine, valine, and isoleucine and valine combinations) were prepared in a hospital setting, and the efficacy and acceptability were evaluated in comparison to conventional compounded medicines in six children. The inclusion of new flavours (lemon, vanilla and peach) to obtain more information on patient preferences and the implementation of a mobile app to obtain patient feedback in real-time was also used. The 3D printed medicines controlled amino acid levels within target levels as well as the conventional medicines. The deviation of citrulline levels was narrower and closer within the target concentration with the chewable formulations. According to participants' responses, the chewable formulations were well accepted and can improve adherence and quality of life. For the first time, 3DP enabled two actives to be combined in the same formulation, reducing the number of administrations. This study demonstrated the benefits of preparing 3D printed personalized treatments for children diagnosed with rare metabolic disorders using a novel technology in real clinical practice.

The colon targeting efficacies of mesalazine medications and their impacts on the gut microbiome.

Successful treatment of ulcerative colitis (UC) is highly dependent on several parameters, including dosing regimen and the ability to deliver drugs to the disease site. In this study two strategies for delivering mesalazine (5-aminosalicylic acid, 5-ASA) to the colon were compared in an advanced in vitro model of the human gastrointestinal (GI) tract, the SHIME® system. Herein, a prodrug strategy employing bacteria-mediated drug release (sulfasalazine, Azulfidine®) was evaluated alongside a formulation strategy that utilised pH and bacteria-mediated release (5-ASA, Octasa® 1600 mg). SHIME® experiments were performed simulating both the GI physiology and colonic microbiota under healthy and inflammatory bowel disease (IBD) conditions, to study the impact of the disease state and ileal pH variability on colonic 5-ASA delivery. In addition, the effects of the products on the colonic microbiome were investigated by monitoring bacterial growth and metabolites. Results demonstrated that both the prodrug and formulation approaches resulted in a similar percentage of 5-ASA recovery under healthy conditions. On the contrary, during experiments simulating the GI physiology and microbiome of IBD patients (the target population) the formulation strategy resulted in a higher proportion of 5-ASA delivery to the colonic region as compared to the prodrug approach (P < 0.0001). Interestingly, the two products had distinct effects on the synthesis of key bacterial metabolites, such as lactate and short chain fatty acids, which varied according to disease state and ileal pH variability. Further, both 5-ASA and sulfasalazine significantly reduced the growth of the faecal microbiota sourced from six healthy humans. The findings support that the approach selected for colonic drug delivery could significantly influence the effectiveness of UC treatment, and highlight that drugs licensed for UC may differentially impact the growth and functioning of the colonic microbiota.

Can in vitro/in silico tools improve colonic concentration estimations for oral extended-release formulations? A case study with upadacitinib.

Upadacitinib, classified as a highly soluble drug, is commercially marketed as RINVOQ®, a modified-release formulation incorporating hydroxypropyl methylcellulose as a matrix system to target extended release throughout the gastrointestinal (GI) tract. Our study aimed to explore how drug release will occur throughout the GI tract using a plethora of in vitro and in silico tools. We built a Physiologically-Based Pharmacokinetic (PBPK) model in GastroPlus™ to predict the systemic concentrations of the drug when administered using in vitro dissolution profiles as input to drive luminal dissolution. A series of in vitro dissolution experiments were gathered using the USP Apparatus I, III and IV in presence of biorelevant media, simulating both fasted and fed state conditions. A key outcome from the current study was to establish an in vitro-in vivo correlation (IVIVC) between (i) the dissolution profiles obtained from the USP I, III and IV methods and (ii) the fraction absorbed of drug as deconvoluted from the plasma concentration-time profile of the drug. When linking the fraction dissolved as measured in the USP IV model, a Level A IVIVC was established. Moreover, when using the different dissolution profiles as input for PBPK modeling, it was also observed that predictions for plasma Cmax and AUC were most accurate for USP IV compared to the other models (based on predicted versus observed ratios). Furthermore, the PBPK model has the utility to extract the predicted concentrations at the level of the colon which can be of utmost interest when working with specific in vitro assays.

Customizable orodispersible films: Inkjet printing and data matrix encoding for personalized hydrocortisone dosing.

The aim of this study was to exploit the versatility of inkjet printing to develop flexible doses of drug-loaded orodispersible films that encoded information in a data matrix pattern, and to introduce a specialised data matrix-generator software specifically focused on the healthcare sector. Pharma-inks (drug-loaded inks) containing hydrocortisone (HC) were developed and characterised based on their rheological properties and drug content. Different strategies were investigated to improve HC solubility: formation of ß-cyclodextrin complexes, Soluplus® based micelles, and the use of co-solvent systems. The software automatically adapted the data matrix size and identified the number of layers for printing. HC content deposited in each film layer was measured, and it was found that the proportion of co-solvent used directly affected the drug solubility and simultaneously played a role in the modification of the viscosity and surface tension of the inks. The formation of ß-cyclodextrin complexes improved the drug quantity deposited in each layer. On the contrary, micelle-based inks were not suitable for printing. Orodispersible films containing flexible and low doses of personalised HC were successfully prepared, and the development of a code generator software oriented to medical use provided an additional, innovative, and revolutionary advantage to personalised medicine safety and accessibility.

Poly(D,l-lactide-co-glycolide) particles are metabolised by the gut microbiome and elevate short chain fatty acids.

The production of short chain fatty acids (SCFAs) by the colonic microbiome has numerous benefits for human health, including maintenance of epithelial barrier function, suppression of colitis, and protection against carcinogenesis. Despite the therapeutic potential, there is currently no optimal approach for elevating the colonic microbiome's synthesis of SCFAs. In this study, poly(D,l-lactide-co-glycolide) (PLGA) was investigated for this application, as it was hypothesised that the colonic microbiota would metabolise PLGA to its lactate monomers, which would promote the resident microbiota's synthesis of SCFAs. Two grades of spray dried PLGA, alongside a lactate bolus control, were screened in an advanced model of the human colon, known as the M-SHIME® system. Whilst the high molecular weight (Mw) grade of PLGA was stable in the presence of the microbiota sourced from three healthy humans, the low Mw PLGA (PLGA 2) was found to be metabolised. This microbial degradation led to sustained release of lactate over 48 h and increased concentrations of the SCFAs propionate and butyrate. Further, microbial synthesis of harmful ammonium was significantly reduced compared to untreated controls. Interestingly, both types of PLGA were found to influence the composition of the luminal and mucosal microbiota in a donor-specific manner. An in vitro model of an inflamed colonic epithelium also showed the polymer to affect the expression of pro- and anti-inflammatory markers, such as interleukins 8 and 10. The findings of this study reveal PLGA's sensitivity to enzymatic metabolism in the gut, which could be harnessed for therapeutic elevation of colonic SCFAs.

Do probiotic interventions improve female unexplained infertility? A critical commentary.

Disruption of women's gut and cervicovaginal microbiota has been associated with multiple gynaecological diseases such as endometriosis, polycystic ovary syndrome, non-cyclic pelvic pain and infertility. Female infertility affects 12.6% of women worldwide; its aetiology is complex and multifactorial and can be underpinned by uterine pathologies, systemic diseases and age. In addition, a new perspective has emerged on the role of the gut and vaginal microbiomes in reproductive health. Research shows that the administration of precisely selected probiotics, often in combination with prior antibiotic treatment, may facilitate the restoration of symbiotic microbiota to increase successful conception and assisted reproductive technology outcomes. However, clarity on this issue from fuller research is currently hampered by a lack of consistency and harmonization in clinical studies: various lactobacilli and bifidobacteria species have been delivered through both the oral and vaginal routes, in different dosages, for different treatment durations. This commentary explores the intricate relationship between the microbiota in the cervicovaginal area and gut of women, exploring their potential contribution to infertility. It highlights ongoing research on the use of probiotic formulations in improving pregnancy outcomes, critically examining the divergent findings in these studies, which complicate a conclusive assessment of the efficacy of these interventions.

The role of artificial intelligence in generating original scientific research.

Artificial intelligence (AI) is a revolutionary technology that is finding wide application across numerous sectors. Large language models (LLMs) are an emerging subset technology of AI and have been developed to communicate using human languages. At their core, LLMs are trained with vast amounts of information extracted from the internet, including text and images. Their ability to create human-like, expert text in almost any subject means they are increasingly being used as an aid to presentation, particularly in scientific writing. However, we wondered whether LLMs could go further, generating original scientific research and preparing the results for publication. We taskedGPT-4, an LLM, to write an original pharmaceutics manuscript, on a topic that is itself novel. It was able to conceive a research hypothesis, define an experimental protocol, produce photo-realistic images of 3D printed tablets, generate believable analytical data from a range of instruments and write a convincing publication-ready manuscript with evidence of critical interpretation. The model achieved all this is less than 1 h. Moreover, the generated data were multi-modal in nature, including thermal analyses, vibrational spectroscopy and dissolution testing, demonstrating multi-disciplinary expertise in the LLM. One area in which the model failed, however, was in referencing to the literature. Since the generated experimental results appeared believable though, we suggest that LLMs could certainly play a role in scientific research but with human input, interpretation and data validation. We discuss the potential benefits and current bottlenecks for realising this ambition here.

Visualizing disintegration of 3D printed tablets in humans using MRI and comparison with in vitro data.

Three-dimensional (3D) printing is revolutionising the way that medicines are manufactured today, paving the way towards more personalised medicine. However, there is limited in vivo data on 3D printed dosage forms, and no studies to date have been performed investigating the intestinal behaviour of these drug products in humans, hindering the complete translation of 3D printed medications into clinical practice. Furthermore, it is unknown whether conventional in vitro release tests can accurately predict the in vivo performance of 3D printed formulations in humans. In this study, selective laser sintering (SLS) 3D printing technology has been used to produce two placebo torus-shaped tablets (printlets) using different laser scanning speeds. The printlets were administered to 6 human volunteers, and in vivo disintegration times were assessed using magnetic resonance imaging (MRI). In vitro disintegration tests were performed using a standard USP disintegration apparatus, as well as an alternative method based on the use of reduced media volume and minimal agitation. Printlets fabricated at a laser scanning speed of 90 mm/s exhibited an average in vitro disintegration time of 7.2 ± 1 min (measured using the USP apparatus) and 25.5 ± 4.1 min (measured using the alternative method). In contrast, printlets manufactured at a higher laser scanning speed of 130 mm/s had an in vitro disintegration time of 2.8 ± 0.8 min (USP apparatus) and 18.8 ± 1.9 min (alternative method). When tested in humans, printlets fabricated at a laser scanning speed of 90 mm/s showed an average disintegration time of 17.3 ± 7.2 min, while those manufactured at a laser scanning speed of 130 mm/s exhibited a shorter disintegration time of 12.7 ± 6.8 min. Although the disintegration times obtained using the alternative method more closely resembled those obtained in vivo, no clear correlation was observed between the in vitro and in vivo disintegration times, highlighting the need to develop better in vitro methodology for 3D printed drug products.

Inkjet Printing of Pharmaceuticals.

Inkjet printing (IJP) is an additive manufacturing process that selectively deposits ink materials, layer-by-layer, to create 3D objects or 2D patterns with precise control over their structure and composition. This technology has emerged as an attractive and versatile approach to address the ever-evolving demands of personalized medicine in the healthcare industry. Although originally developed for nonhealthcare applications, IJP harnesses the potential of pharma-inks, which are meticulously formulated inks containing drugs and pharmaceutical excipients. Delving into the formulation and components of pharma-inks, the key to precise and adaptable material deposition enabled by IJP is unraveled. The review extends its focus to substrate materials, including paper, films, foams, lenses, and 3D-printed materials, showcasing their diverse advantages, while exploring a wide spectrum of therapeutic applications. Additionally, the potential benefits of hardware and software improvements, along with artificial intelligence integration, are discussed to enhance IJP's precision and efficiency. Embracing these advancements, IJP holds immense potential to reshape traditional medicine manufacturing processes, ushering in an era of medical precision. However, further exploration and optimization are needed to fully utilize IJP's healthcare capabilities. As researchers push the boundaries of IJP, the vision of patient-specific treatment is on the horizon of becoming a tangible reality.

Electroactive Polymers for On-Demand Drug Release.

Conductive materials have played a significant role in advancing society into the digital era. Such materials are able to harness the power of electricity and are used to control many aspects of daily life. Conductive polymers (CPs) are an emerging group of polymers that possess metal-like conductivity yet retain desirable polymeric features, such as processability, mechanical properties, and biodegradability. Upon receiving an electrical stimulus, CPs can be tailored to achieve a number of responses, such as harvesting energy and stimulating tissue growth. The recent FDA approval of a CP-based material for a medical device has invigorated their research in healthcare. In drug delivery, CPs can act as electrical switches, drug release is achieved at a flick of a switch, thereby providing unprecedented control over drug release. In this review, recent developments in CP as electroactive polymers for voltage-stimuli responsive drug delivery systems are evaluated. The review demonstrates the distinct drug release profiles achieved by electroactive formulations, and both the precision and ease of stimuli response. This level of dynamism promises to yield "smart medicines" and warrants further research. The review concludes by providing an outlook on electroactive formulations in drug delivery and highlighting their integral roles in healthcare IoT.

Virtually Possible: Enhancing Quality Control of 3D-Printed Medicines with Machine Vision Trained on Photorealistic Images.

Three-dimensional (3D) printing is an advanced pharmaceutical manufacturing technology, and concerted efforts are underway to establish its applicability to various industries. However, for any technology to achieve widespread adoption, robustness and reliability are critical factors. Machine vision (MV), a subset of artificial intelligence (AI), has emerged as a powerful tool to replace human inspection with unprecedented speed and accuracy. Previous studies have demonstrated the potential of MV in pharmaceutical processes. However, training models using real images proves to be both costly and time consuming. In this study, we present an alternative approach, where synthetic images were used to train models to classify the quality of dosage forms. We generated 200 photorealistic virtual images that replicated 3D-printed dosage forms, where seven machine learning techniques (MLTs) were used to perform image classification. By exploring various MV pipelines, including image resizing and transformation, we achieved remarkable classification accuracies of 80.8%, 74.3%, and 75.5% for capsules, tablets, and films, respectively, for classifying stereolithography (SLA)-printed dosage forms. Additionally, we subjected the MLTs to rigorous stress tests, evaluating their scalability to classify over 3000 images and their ability to handle irrelevant images, where accuracies of 66.5% (capsules), 72.0% (tablets), and 70.9% (films) were obtained. Moreover, model confidence was also measured, and Brier scores ranged from 0.20 to 0.40. Our results demonstrate promising proof of concept that virtual images exhibit great potential for image classification of SLA-printed dosage forms. By using photorealistic virtual images, which are faster and cheaper to generate, we pave the way for accelerated, reliable, and sustainable AI model development to enhance the quality control of 3D-printed medicines.

Supramolecular chemistry enables vat photopolymerization 3D printing of novel water-soluble tablets.

Vat photopolymerization has garnered interest from pharmaceutical researchers for the fabrication of personalised medicines, especially for drugs that require high precision dosing or are heat labile. However, the 3D printed structures created thus far have been insoluble, limiting printable dosage forms to sustained-release systems or drug-eluting medical devices which do not require dissolution of the printed matrix. Resins that produce water-soluble structures will enable more versatile drug release profiles and expand potential applications. To achieve this, instead of employing cross-linking chemistry to fabricate matrices, supramolecular chemistry may be used to impart dynamic interaction between polymer chains. In this study, water-soluble drug-loaded printlets (3D printed tablets) are fabricated via digital light processing (DLP) 3DP for the first time. Six formulations with varying ratios of an electrolyte acrylate monomer, [2-(acryloyloxy)ethyl]trimethylammonium chloride (TMAEA), and a co-monomer, 1-vinyl-2-pyrrolidone (NVP), were prepared to produce paracetamol-loaded printlets. 1H NMR spectroscopy analysis confirmed the integration of TMAEA and NVP in the polymer, and residual TMAEA monomers were found to be present only in trace amounts (0.71 - 1.37 %w/w). The apparent molecular mass of the photopolymerised polymer was found to exceed 300,000 Da with hydrodynamic radii of 15 - 20 nm, estimated based on 1H DOSY NMR measurements The loaded paracetamol was completely released from the printlets between 45 minutes to 5 hours. In vivo single-dose acute toxicity studies in rats suggest that the printlets did not cause any tissue damage. The findings reported in this study represent a significant step towards the adoption of vat photopolymerization-based 3DP to produce personalised medicines.

A case study on decentralized manufacturing of 3D printed medicines.

Pharmaceutical 3D printing (3DP) is one of the emerging enabling technologies of personalised medicines as it affords the ability to fabricate highly versatile dosage forms. In the past 2 years, national medicines regulatory authorities have held consultations with external stakeholders to adapt regulatory frameworks to embrace point-of-care manufacturing. The proposed concept of decentralized manufacturing (DM) involves the provision of feedstock intermediates (pharma-inks) prepared by pharmaceutical companies to DM sites for manufacturing into the final medicine. In this study, we examine the feasibility of this model, with respect to both manufacturing and quality control. Efavirenz-loaded granulates (0-35%w/w) were produced by a manufacturing partner and shipped to a 3DP site in a different country. Direct powder extrusion (DPE) 3DP was subsequently used to prepare printlets (3D printed tablets), with mass ranging 266-371 mg. All printlets released more than 80% drug load within the first 60 min of the in vitro drug release test. An in-line near-infrared spectroscopy system was used as a process analytical technology (PAT) to quantify the printlets' drug load. Calibration models were developed using partial least squares regression, which showed excellent linearity (R2 = 0.9833) and accuracy (RMSE = 1.0662). Overall, this work is the first to report the use of an in-line NIR system to perform real-time analysis of printlets prepared using pharma-inks produced by a pharmaceutical company. By demonstrating the feasibility of the proposed distribution model through this proof-of-concept study, this work paves the way for investigation of further PAT tools for quality control in 3DP point-of-care manufacturing.

3D printed infliximab suppositories for rectal biologic delivery.

Infliximab is a monoclonal antibody that plays an important role in the management and treatment of chronic inflammatory bowel diseases (IBD). Due to its macromolecular structure, its delivery through the oral route is challenging, limiting its administration to only via the parenteral route. The rectal route offers an alternative way for administering infliximab, allowing it to be localised at the disease site and circumventing its passage across the alimentary canal and thus, maintaining its integrity and bioactivity. Three-dimensional (3D) printing is an advanced production technology that permits the creation of dose-flexible drug products from digital designs. The current study assessed the feasibility of utilising semi-solid extrusion 3D printing for the fabrication of infliximab-loaded suppositories for the local treatment of IBD. Various printing inks composed of Gelucire® (48/16 or 44/14) mixed with coconut oil and/or purified water were investigated. It was shown that following reconstitution in water, the infliximab solution can be directly incorporated into the printing ink of Gelucire® 48/16 and can withstand the extrusion process, resulting in well-defined suppositories. Since water content and temperature are critical for safeguarding infliximab's potency, the effect of changing the composition of the printing inks and printing parameters on infliximab's biologic efficiency was evaluated by measuring its binding capacity (i.e., the amount of infliximab that actively binds to its antigen to exert an effect). Despite drug loading assays showing that infliximab remains intact following printing, it was found that the incorporation of water in isolation results in only ∼65% binding capacity. However, when oil is added to the mixture, infliximab's binding capacity increases up to ∼85%. These promising results demonstrate that 3D printing has the potential to be exploited as a novel platform for fabricating dosage forms containing biopharmaceuticals, avoiding patients' compliance issues observed with injectables and addressing their unmet needs.

Impact of Peptide Structure on Colonic Stability and Tissue Permeability.

Most marketed peptide drugs are administered parenterally due to their inherent gastrointestinal (GI) instability and poor permeability across the GI epithelium. Several molecular design techniques, such as cyclisation and D-amino acid (D-AA) substitution, have been proposed to improve oral peptide drug bioavailability. However, very few of these techniques have been translated to the clinic. In addition, little is known about how synthetic peptide design may improve stability and permeability in the colon, a key site for the treatment of inflammatory bowel disease and colorectal cancer. In this study, we investigated the impact of various cyclisation modifications and D-AA substitutions on the enzymatic stability and colonic tissue permeability of native oxytocin and 11 oxytocin-based peptides. Results showed that the disulfide bond cyclisation present in native oxytocin provided an improved stability in a human colon model compared to a linear oxytocin derivative. Chloroacetyl cyclisation increased native oxytocin stability in the colonic model at 1.5 h by 30.0%, whereas thioether and N-terminal acetylated cyclisations offered no additional protection at 1.5 h. The site and number of D-AA substitutions were found to be critical for stability, with three D-AAs at Tyr, Ile and Leu, improving native oxytocin stability at 1.5 h in both linear and cyclic structures by 58.2% and 79.1%, respectively. Substitution of three D-AAs into native cyclic oxytocin significantly increased peptide permeability across rat colonic tissue; this may be because D-AA substitution favourably altered the peptide's secondary structure. This study is the first to show how the strategic design of peptide therapeutics could enable their delivery to the colon via the oral route.

Predicting pharmaceutical inkjet printing outcomes using machine learning.

Inkjet printing has been extensively explored in recent years to produce personalised medicines due to its low cost and versatility. Pharmaceutical applications have ranged from orodispersible films to complex polydrug implants. However, the multi-factorial nature of the inkjet printing process makes formulation (e.g., composition, surface tension, and viscosity) and printing parameter optimization (e.g., nozzle diameter, peak voltage, and drop spacing) an empirical and time-consuming endeavour. Instead, given the wealth of publicly available data on pharmaceutical inkjet printing, there is potential for a predictive model for inkjet printing outcomes to be developed. In this study, machine learning (ML) models (random forest, multilayer perceptron, and support vector machine) to predict printability and drug dose were developed using a dataset of 687 formulations, consolidated from in-house and literature-mined data on inkjet-printed formulations. The optimized ML models predicted the printability of formulations with an accuracy of 97.22%, and predicted the quality of the prints with an accuracy of 97.14%. This study demonstrates that ML models can feasibly provide predictive insights to inkjet printing outcomes prior to formulation preparation, affording resource- and time-savings.

Advancing non-destructive analysis of 3D printed medicines.

Pharmaceutical 3D printing (3DP) has attracted significant interest over the past decade for its ability to produce personalised medicines on demand. However, current quality control (QC) requirements for traditional large-scale pharmaceutical manufacturing are irreconcilable with the production offered by 3DP. The US Food and Drug Administration (FDA) and the UK Medicines and Healthcare Products Regulatory Agency (MHRA) have recently published documents supporting the implementation of 3DP for point-of-care (PoC) manufacturing along with regulatory hurdles. The importance of process analytical technology (PAT) and non-destructive analytical tools in translating pharmaceutical 3DP has experienced a surge in recognition. This review seeks to highlight the most recent research on non-destructive pharmaceutical 3DP analysis, while also proposing plausible QC systems that complement the pharmaceutical 3DP workflow. In closing, outstanding challenges in integrating these analytical tools into pharmaceutical 3DP workflows are discussed.

Energy consumption and carbon footprint of 3D printing in pharmaceutical manufacture.

Achieving carbon neutrality is seen as an important goal in order to mitigate the effects of climate change, as carbon dioxide is a major greenhouse gas that contributes to global warming. Many countries, cities and organizations have set targets to become carbon neutral. The pharmaceutical sector is no exception, being a major contributor of carbon emissions (emitting approximately 55% more than the automotive sector for instance) and hence is in need of strategies to reduce its environmental impact. Three-dimensional (3D) printing is an advanced pharmaceutical fabrication technology that has the potential to replace traditional manufacturing tools. Being a new technology, the environmental impact of 3D printed medicines has not been investigated, which is a barrier to its uptake by the pharmaceutical industry. Here, the energy consumption (and carbon emission) of 3D printers is considered, focusing on technologies that have successfully been demonstrated to produce solid dosage forms. The energy consumption of 6 benchtop 3D printers was measured during standby mode and printing. On standby, energy consumption ranged from 0.03 to 0.17 kWh. The energy required for producing 10 printlets ranged from 0.06 to 3.08 kWh, with printers using high temperatures consuming more energy. Carbon emissions ranged between 11.60 and 112.16 g CO2 (eq) per 10 printlets, comparable with traditional tableting. Further analyses revealed that decreasing printing temperature was found to reduce the energy demand considerably, suggesting that developing formulations that are printable at lower temperatures can reduce CO2 emissions. The study delivers key initial insights into the environmental impact of a potentially transformative manufacturing technology and provides encouraging results in demonstrating that 3D printing can deliver quality medicines without being environmentally detrimental.

3D printed multi-drug-loaded suppositories for acute severe ulcerative colitis.

Acute severe ulcerative colitis (ASUC) is a growing health burden that often requires treatment with multiple therapeutic agents. As inflammation is localised in the rectum and colon, local drug delivery using suppositories could improve therapeutic outcomes. Three-dimensional (3D) printing is a novel manufacturing tool that permits the combination of multiple drugs in personalised dosage forms, created based on each patient's disease condition. This study, for the first time, demonstrates the feasibility of producing 3D printed suppositories with two anti-inflammatory agents, budesonide and tofacitinib citrate, for the treatment of ASUC. As both drugs are poorly water-soluble, the suppositories' ability to self-emulsify was exploited to improve their performance. The suppositories were fabricated via semi-solid extrusion (SSE) 3D printing and contained tofacitinib citrate and budesonide in varying doses (10 or 5 mg; 4 or 2 mg, respectively). The suppositories displayed similar dissolution and disintegration behaviours irrespective of their drug content, demonstrating the flexibility of the technology. Overall, this study demonstrates the feasibility of using SSE 3D printing to create multi-drug suppositories for the treatment of ASUC, with the possibility of titrating the drug doses based on the disease progression.

Simultaneous fabrication of multiple tablets within seconds using tomographic volumetric 3D printing.

3D printing is driving a shift in patient care away from a generalised model and towards personalised treatments. To complement fast-paced clinical environments, 3D printing technologies must provide sufficiently high throughputs for them to be feasibly implemented. Volumetric printing is an emerging 3D printing technology that affords such speeds, being capable of producing entire objects within seconds. In this study, for the first time, rotatory volumetric printing was used to simultaneously produce two torus- or cylinder-shaped paracetamol-loaded Printlets (3D printed tablets). Six resin formulations comprising paracetamol as the model drug, poly(ethylene glycol) diacrylate (PEGDA) 575 or 700 as photoreactive monomers, water and PEG 300 as non-reactive diluents, and lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) as the photoinitiator were investigated. Two printlets were successfully printed in 12 to 32 s and exhibited sustained drug release profiles. These results support the use of rotary volumetric printing for efficient and effective manufacturing of various personalised medicines at the same time. With the speed and precision it affords, rotatory volumetric printing has the potential to become one of the most promising alternative manufacturing technologies in the pharmaceutical industry.