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.

Smart laser Sintering: Deep Learning-Powered powder bed fusion 3D printing in precision medicine.

Medicines remain ineffective for over 50% of patients due to conventional mass production methods with fixed drug dosages. Three-dimensional (3D) printing, specifically selective laser sintering (SLS), offers a potential solution to this challenge, allowing the manufacturing of small, personalized batches of medication. Despite its simplicity and suitability for upscaling to large-scale production, SLS was not designed for pharmaceutical manufacturing and necessitates a time-consuming, trial-and-error adaptation process. In response, this study introduces a deep learning model trained on a variety of features to identify the best feature set to represent drugs and polymeric materials for the prediction of the printability of drug-loaded formulations using SLS. The proposed model demonstrates success by achieving 90% accuracy in predicting printability. Furthermore, explainability analysis unveils materials that facilitate SLS printability, offering invaluable insights for scientists to optimize SLS formulations, which can be expanded to other disciplines. This represents the first study in the field to develop an interpretable, uncertainty-optimized deep learning model for predicting the printability of drug-loaded formulations. This paves the way for accelerating formulation development, propelling us into a future of personalized medicine with unprecedented manufacturing precision.

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.

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.

Colonic drug delivery: Formulating the next generation of colon-targeted therapeutics.

Colonic drug delivery can facilitate access to unique therapeutic targets and has the potential to enhance drug bioavailability whilst reducing off-target effects. Delivering drugs to the colon requires considered formulation development, as both oral and rectal dosage forms can encounter challenges if the colon's distinct physiological environment is not appreciated. As the therapeutic opportunities surrounding colonic drug delivery multiply, the success of novel pharmaceuticals lies in their design. This review provides a modern insight into the key parameters determining the effective design and development of colon-targeted medicines. Influential physiological features governing the release, dissolution, stability, and absorption of drugs in the colon are first discussed, followed by an overview of the most reliable colon-targeted formulation strategies. Finally, the most appropriate in vitro, in vivo, and in silico preclinical investigations are presented, with the goal of inspiring strategic development of new colon-targeted therapeutics.

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.

Machine learning using multi-modal data predicts the production of selective laser sintered 3D printed drug products.

Three-dimensional (3D) printing is drastically redefining medicine production, offering digital precision and personalized design opportunities. One emerging 3D printing technology is selective laser sintering (SLS), which is garnering attention for its high precision, and compatibility with a wide range of pharmaceutical materials, including low-solubility compounds. However, the full potential of SLS for medicines is yet to be realized, requiring expertise and considerable time-consuming and resource-intensive trial-and-error research. Machine learning (ML), a subset of artificial intelligence, is an in silico tool that is accomplishing remarkable breakthroughs in several sectors for its ability to make highly accurate predictions. Therefore, the present study harnessed ML to predict the printability of SLS formulations. Using a dataset of 170 formulations from 78 materials, ML models were developed from inputs that included the formulation composition and characterization data retrieved from Fourier-transformed infrared spectroscopy (FT-IR), X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). Multiple ML models were explored, including supervised and unsupervised approaches. The results revealed that ML can achieve high accuracies, by using the formulation composition leading to a maximum F1 score of 81.9%. Using the FT-IR, XRPD and DSC data as inputs resulted in an F1 score of 84.2%, 81.3%, and 80.1%, respectively. A subsequent ML pipeline was built to combine the predictions from FT-IR, XRPD and DSC into one consensus model, where the F1 score was found to further increase to 88.9%. Therefore, it was determined for the first time that ML predictions of 3D printability benefit from multi-modal data, combining numeric, spectral, thermogram and diffraction data. The study lays the groundwork for leveraging existing characterization data for developing high-performing computational models to accelerate formulation development.

3D Printing of Dietary Products for the Management of Inborn Errors of Intermediary Metabolism in Pediatric Populations.

The incidence of Inborn Error of Intermediary Metabolism (IEiM) diseases may be low, yet collectively, they impact approximately 6-10% of the global population, primarily affecting children. Precise treatment doses and strict adherence to prescribed diet and pharmacological treatment regimens are imperative to avert metabolic disturbances in patients. However, the existing dietary and pharmacological products suffer from poor palatability, posing challenges to patient adherence. Furthermore, frequent dose adjustments contingent on age and drug blood levels further complicate treatment. Semi-solid extrusion (SSE) 3D printing technology is currently under assessment as a pioneering method for crafting customized chewable dosage forms, surmounting the primary limitations prevalent in present therapies. This method offers a spectrum of advantages, including the flexibility to tailor patient-specific doses, excipients, and organoleptic properties. These elements are pivotal in ensuring the treatment's efficacy, safety, and adherence. This comprehensive review presents the current landscape of available dietary products, diagnostic methods, therapeutic monitoring, and the latest advancements in SSE technology. It highlights the rationale underpinning their adoption while addressing regulatory aspects imperative for their seamless integration into clinical practice.

Innovations in Chewable Formulations: The Novelty and Applications of 3D Printing in Drug Product Design.

Since their introduction, chewable dosage forms have gained traction due to their ability to facilitate swallowing, especially in paediatric, geriatric and dysphagia patients. Their benefits stretch beyond human use to also include veterinary applications, improving administration and palatability in different animal species. Despite their advantages, current chewable formulations do not account for individualised dosing and palatability preferences. In light of this, three-dimensional (3D) printing, and in particular the semi-solid extrusion technology, has been suggested as a novel manufacturing method for producing customised chewable dosage forms. This advanced approach offers flexibility for selecting patient-specific doses, excipients, and organoleptic properties, which are critical for ensuring efficacy, safety and adherence to the treatment. This review provides an overview of the latest advancements in chewable dosage forms for human and veterinary use, highlighting the motivations behind their use and covering formulation considerations, as well as regulatory aspects.

Advancing pharmacy and healthcare with virtual digital technologies.

Digitalisation of the healthcare sector promises to revolutionise patient healthcare globally. From the different technologies, virtual tools including artificial intelligence, blockchain, virtual, and augmented reality, to name but a few, are providing significant benefits to patients and the pharmaceutical sector alike, ranging from improving access to clinicians and medicines, as well as improving real-time diagnoses and treatments. Indeed, it is envisioned that such technologies will communicate together in real-time, as well as with their physical counterparts, to create a large-scale, cyber healthcare system. Despite the significant benefits that virtual-based digital health technologies can bring to patient care, a number of challenges still remain, ranging from data security to acceptance within the healthcare sector. This review provides a timely account of the benefits and challenges of virtual health interventions, as well an outlook on how such technologies can be transitioned from research-focused towards real-world healthcare and pharmaceutical applications to transform treatment pathways for patients worldwide.

Clinical translation of advanced colonic drug delivery technologies.

Targeted drug delivery to the colon offers a myriad of benefits, including treatment of local diseases, direct access to unique therapeutic targets and the potential for increasing systemic drug bioavailability and efficacy. Although a range of traditional colonic delivery technologies are available, these systems exhibit inconsistent drug release due to physiological variability between and within individuals, which may be further exacerbated by underlying disease states. In recent years, significant translational and commercial advances have been made with the introduction of new technologies that incorporate independent multi-stimuli release mechanisms (pH and/or microbiota-dependent release). Harnessing these advanced technologies offers new possibilities for drug delivery via the colon, including the delivery of biopharmaceuticals, vaccines, nutrients, and microbiome therapeutics for the treatment of both local and systemic diseases. This review details the latest advances in colonic drug delivery, with an emphasis on emerging therapeutic opportunities and clinical technology translation.

Advances in powder bed fusion 3D printing in drug delivery and healthcare.

Powder bed fusion (PBF) is a 3D printing method that selectively consolidates powders into 3D objects using a power source. PBF has various derivatives; selective laser sintering/melting, direct metal laser sintering, electron beam melting and multi-jet fusion. These technologies provide a multitude of benefits that make them well suited for the fabrication of bespoke drug-laden formulations, devices and implants. This includes their superior printing resolution and speed, and ability to produce objects without the need for secondary supports, enabling them to precisely create complex products. Herein, this review article outlines the unique applications of PBF 3D printing, including the main principles underpinning its technologies and highlighting their novel pharmaceutical and biomedical applications. The challenges and shortcomings are also considered, emphasising on their effects on the 3D printed products, whilst providing a forward-thinking view.

Vat photopolymerization 3D printing for advanced drug delivery and medical device applications.

Three-dimensional (3D) printing is transforming manufacturing paradigms within healthcare. Vat photopolymerization 3D printing technology combines the benefits of high resolution and favourable printing speed, offering a sophisticated approach to fabricate bespoke medical devices and drug delivery systems. Herein, an overview of the vat polymerization techniques, their unique applications in the fields of drug delivery and medical device fabrication, material examples and the advantages they provide within healthcare, is provided. The challenges and drawbacks presented by this technology are also discussed. It is forecast that the adoption of 3D printing could pave the way for a personalised health system, advancing from traditional treatments pathways towards digital healthcare.

Smartphone-enabled 3D printing of medicines.

3D printing is a manufacturing technique that is transforming numerous industrial sectors, particularly where it is key tool in the development and fabrication of medicinees that are personalised to the individual needs of patients. Most 3D printers are relatively large, require trained operators and must be located in a pharmaceutical setting to manufacture dosage forms. In order to realise fully the potential of point-of-care manufacturing of medicines, portable printers that are easy to operate are required. Here, we report the development of a 3D printer that operates using a mobile smartphone. The printer, operating on stereolithographic principles, uses the light from the smartphone's screen to photopolymerise liquid resins and create solid structures. The shape of the printed dosage form is determined using a custom app on the smartphone. Warfarin-loaded Printlets (3D printed tablets) of various sizes and patient-centred shapes (caplet, triangle, diamond, square, pentagon, torus, and gyroid lattices) were successfully printed to a high resolution and with excellent dimensional precision using different photosensitive resins. The drug was present in an amorphous form, and the Printlets displayed sustained release characterises. The promising proof-of-concept results support the future potential of this compact, user-friendly and interconnected smartphone-based system for point-of-care manufacturing of personalised medications.

Connected healthcare: Improving patient care using digital health technologies.

Now more than ever, traditional healthcare models are being overhauled with digital technologies of Healthcare 4.0 increasingly adopted. Worldwide, digital devices are improving every stage of the patient care pathway. For one, sensors are being used to monitor patient metrics 24/7, permitting swift diagnosis and interventions. At the treatment stage, 3D printers are under investigation for the concept of personalised medicine by allowing patients access to on-demand, customisable therapeutics. Robots are also being explored for treatment, by empowering precision surgery, rehabilitation, or targeted drug delivery. Within medical logistics, drones are being leveraged to deliver critical treatments to remote areas, collect samples, and even provide emergency aid. To enable seamless integration within healthcare, the Internet of Things technology is being exploited to form closed-loop systems that remotely communicate with one another. This review outlines the most promising healthcare technologies and devices, their strengths, drawbacks, and opportunities for clinical adoption.

3D printing: Principles and pharmaceutical applications of selective laser sintering.

Pharmaceutical three-dimensional (3D) printing is a modern fabrication process with the potential to create bespoke drug products of virtually any shape and size from a computer-aided design model. Selective laser sintering (SLS) 3D printing combines the benefits of high printing precision and capability, enabling the manufacture of medicines with unique engineering and functional properties. This article reviews the current state-of-the-art in SLS 3D printing, including the main principles underpinning this technology, and highlights the diverse selection of materials and essential parameters that influence printing. The technical challenges and processing conditions are also considered in the context of their effects on the printed product. Finally, the pharmaceutical applications of SLS 3D printing are covered, providing an emphasis on the advantages the technology offers to drug product manufacturing and personalised medicine.

3D Printed Tablets (Printlets) with Braille and Moon Patterns for Visually Impaired Patients.

Visual impairment and blindness affects 285 million people worldwide, resulting in a high public health burden. This study reports, for the first time, the use of three-dimensional (3D) printing to create orally disintegrating printlets (ODPs) suited for patients with visual impairment. Printlets were designed with Braille and Moon patterns on their surface, enabling patients to identify medications when taken out of their original packaging. Printlets with different shapes were fabricated to offer additional information, such as the medication indication or its dosing regimen. Despite the presence of the patterns, the printlets retained their original mechanical properties and dissolution characteristics, wherein all the printlets disintegrated within ~5 s, avoiding the need for water and facilitating self-administration of medications. Moreover, the readability of the printlets was verified by a blind person. Overall, this novel and practical approach should reduce medication errors and improve medication adherence in patients with visual impairment.

3D printed opioid medicines with alcohol-resistant and abuse-deterrent properties.

In the past decade, prescriptions for opioid medicines have been exponentially increasing, instigating opioid abuse as a global health crisis associated with high morbidity and mortality. In particular, diversion from the intended mode of opioid administration, such as injecting and snorting the opioid, is a major problem that contributes to this epidemic. In light of this, novel formulation strategies are needed to support efforts in reducing the prevalence and risks of opioid abuse. Here, modified release tramadol printlets (3D printed tablets) with alcohol-resistant and abuse-deterrent properties were prepared by direct powder extrusion three-dimensional (3D) printing. The printlets were fabricated using two grades of hydroxypropylcellulose (HPC). Both formulations displayed strong ethanol-resistance and had moderate abuse-deterrent properties. Polyethylene oxide (PEO) was subsequently added into the formulations, which improved the printlets' resistance to physical tampering in nasal inhalation tests and delayed their dissolution in solvent extraction tests. Overall, this article reports for the first time the use of direct powder extrusion 3D printing to prepare drug products with both alcohol-resistant and abuse-deterrent properties. These results offer a novel approach for the safe and effective use of opioids that can contribute to the advantages that 3D printing provides in terms of on-demand dose personalisation.

3D Printed Pellets (Miniprintlets): A Novel, Multi-Drug, Controlled Release Platform Technology.

Selective laser sintering (SLS) is a single-step three-dimensional printing (3DP) process that can be leveraged to engineer a wide array of drug delivery systems. The aim of this work was to utilise SLS 3DP, for the first time, to produce small oral dosage forms with modified release properties. As such, paracetamol-loaded 3D printed multiparticulates, termed miniprintlets, were fabricated in 1 mm and 2 mm diameters. Despite their large surface area compared with a conventional monolithic tablet, the ethyl cellulose-based miniprintlets exhibited prolonged drug release patterns. The possibility of producing miniprintlets combining two drugs, namely paracetamol and ibuprofen, was also investigated. By varying the polymer, the dual miniprintlets were programmed to achieve customised drug release patterns, whereby one drug was released immediately from a Kollicoat Instant Release matrix, whilst the effect of the second drug was sustained over an extended time span using ethyl cellulose. Herein, this work has highlighted the versatility of SLS 3DP to fabricate small and intricate formulations containing multiple active pharmaceutical ingredients with distinct release properties.

Shaping the future: recent advances of 3D printing in drug delivery and healthcare.

Introduction: Three-dimensional (3D) printing is a relatively new, rapid manufacturing technology that has found promising applications in the drug delivery and medical sectors. Arguably, never before has the healthcare industry experienced such a transformative technology. This review aims to discuss the state of the art of 3D printing technology in healthcare and drug delivery. Areas covered: The current and future applications of printing technologies within drug delivery and medicine have been discussed. The latest innovations in 3D printing of customized medical devices, drug-eluting implants, and printlets (3D-printed tablets) with a tailored dose, shape, size, and release characteristics have been covered. The review also covers the state of the art of 3D printing in healthcare (covering topics such as dentistry, surgical and bioprinting of patient-specific organs), as well as the potential of recent innovations, such as 4D printing, to shape the future of drug delivery and to improve treatment pathways for patients. Expert opinion: A future perspective is provided on the potential for 3D printing in healthcare, covering strategies to overcome the major barriers to integration that are faced today.