No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
A Review of State-of-The-Art on Enabling Additive Manufacturing Processes for Precision Medicine
Abstract
Precision medicine is an emerging healthcare delivery approach that considers variability between patients, such as genetic makeups, in contrast to the current one-size-fits-all approach that are designed to treat the average patient. The White House launched the Precision Medicine Initiative in 2015, starting an endeavor to reshape healthcare delivery. To translate the concept of precision medicine from the bench to practice, advanced manufacturing will play an integral part, including fabrication of personalized drugs and drug delivery devices, and drug screening platforms. These products are highly customized and require robust yet flexible manufacturing systems. The advanced manufacturing field has rapidly evolved in the past five years. In this state-of-the-art review, products manufactured for precision medicine will be introduced, followed by a brief review on processing materials and their characteristics. A review on different manufacturing processes applicable to those aforementioned products are provided. The current status of the development of regulatory submission and quality control considerations are also discussed. Finally, this paper presents a future outlook for manufacturing processes used for precision medicine.
... In recent years, 3D printing technologies have garnered substantial attention across various industries [81,82], including medicine, owing to their capacity to create 3D objects layerby-layer from digital models [83]. Particularly within the pharmaceutical realm, 3D printing offers unique opportunities to fabricate customized pharmaceutical products [84,85], providing full design customization, flexibility, and high control over drug release, dose personalization, and the capacity to print multiple drugs [86][87][88][89]. ...
... In recent years, 3D printing technologies have garnered substantial attention across various industries [81,82], including medicine, owing to their capacity to create 3D objects layer-by-layer from digital models [83]. Particularly within the pharmaceutical realm, 3D printing offers unique opportunities to fabricate customized pharmaceutical products [84,85], providing full design customization, flexibility, and high control over drug release, dose personalization, and the capacity to print multiple drugs [86][87][88][89]. ...
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.
... Three-dimensional (3D) printing, where materials are deposited layer by layer to form solid objects, has gained much interest in the pharmaceutical field as it can deliver personalized and on-demand medications, such as tablets, to patients for better therapy [1]. 3D-printing is essentially a form of additive manufacturing (AM) that is extensively used in many different industries [2]. ...
... Several different 3D-printing techniques, such as binder jet printing, fused deposition modeling (FDM), semisolid extrusion (SSE), selective laser sintering (SLS), and stereolithography (SLA), have been employed for the manufacture of tablets [1,11]. Among these techniques, fused deposition modeling (FDM) 3D-printing is the most popular and widely used for the development of solid dosage forms like tablets and pellets. ...
Since the approval of a 3D-printed tablet by the FDA in 2015 for marketing, there has been a great interest in 3D printing in the pharmaceutical field for the development of personalized and on-demand medications. Among various 3D printing methods explored for the development of oral solid dosage form like tablet, the fused deposition modeling (FDM) 3D-printing, where the drug-polymer mixtures are first converted into filaments by hot melt extrusion (HME) and then the filaments are printed into tablets using 3D printers by applying computer-aided design principles, has emerged as the most attractive option. However, no FDM 3D-printed tablets have yet been marketed as the technology faces many challenges, such as limited availability of pharmaceutical-grade polymers that can be printed into tablets, low drug-polymer miscibility, the need for high temperature for HME and 3D-printing, and slow drug release rates from tablets. These challenges are discussed in this article with a special focus on drug release rates since FDM 3D-printing usually leads to the preparation of slow-release tablets while the rapid release from dosage forms is often desired for optimal therapeutic outcomes of new drug candidates. Pros and cons of various strategies for the development of rapidly dissolving FDM 3D-printed tablets reported in the literature are reviewed. Finally, two case studies on emerging strategies for the development of rapidly dissolving FDM 3D-printed tablets are presented, where one outlines a systematic approach for formulating rapidly dissolving tablets, and the other describes a novel strategy to increase dissolution rates of drugs from FDM 3D-printed tablets, which at the same time can also increase drug-polymer miscibility and printability of tablets and lower processing temperatures. Thus, this overview and commentary discusses various issues involving the formulation of rapidly dissolving FDM 3D-printed tablets and provides guidance for the development of commercially viable products.
... Predicting cell output enables the optimization of bioprinting parameters such as droplet size, printing speed, and bioink viscosity to achieve the desired cell density and distribution. This promotes fabrication of more consistent and reproducible tissue constructs for various applications in regenerative medicine, drug testing, and disease modeling [35]. Furthermore, costly trial-and-error experiments to optimize the printing process can be minimized, and the accuracy of expected cell output can be improved. ...
... However, these methods are labour-intensive, may present solubility challenges, and do not facilitate the preparation of formulations with a wide dosage range. Given the high failure rate in the drug development process, it is crucial to have a technology that enables the rapid production of dosage forms to identify suitable dose ranges and molecules for further advancement into FIH clinical trials [74]. 3D printing provides a flexible manufacturing platform for producing Printlets in a short timeframe, making it ideal for rapid preclinical progression at low cost. ...
... The personalization of treatments is an ever-growing need (Watson et al., 2021) and requires flexible and versatile manufacturing approaches, such as the one offered by three-dimensional (3D) printing (3DP) (Lyousoufi et al., 2023;Awad et al., 2022;Tracy et al., 2023;Karalia et al., 2021;Ilieva et al., 2023;Milliken et al., 2024;Cardoso and Araújo, 2024). 3DP allows for real-time dose adjustment and modulation of the printlet™ (3D printed tablet) to meet individual patient needs Pistone et al., 2023;Uboldi et al., 2023;Junqueira et al., 2022;Algahtani et al., 2020;Siamidi et al., 2020). ...
... The team created formulations of gelatine, hydroxypropyl methylcellulose (HPMC), syrup, water, and the antiepileptic drug lamotrigine. However, unlike FDM, SSE prints at low resolutions, proving to be one of its main limitations (Awad et al., 2022). This results in 3D objects produced that may have coarser surface finishes, thicker layers, and fewer intricate details than being produced by other methods. ...
Three-dimensional printing (3DP) is an emerging technology, offering the possibility for the development of dose-customized, effective, and safe solid oral dosage forms (SODFs). Although 3DP has great potential, it does come with certain limitations, and the traditional drug manufacturing platforms remain the industry standard. The consensus appears to be that 3DP technology is expected to benefit personalized medicine the most, but that it is unlikely to replace conventional manufacturing for mass production. The 3DP method, on the other hand, could prove well-suited for producing small batches as an adaptive manufacturing technique for enabling adaptive clinical trial design for early clinical studies. The purpose of this review is to discuss recent advancements in 3DP technologies for SODFs and to focus on the applications for SODFs in the early clinical development stages, including a discussion of current regulatory challenges and quality controls.
... 3DP has also been investigated as an alternative to pharmaceutical compounding, providing treatment at the point-of-care [12]. The use of 3DP would ultimately reduce dosing errors and contamination, improve the quality, and automate and accelerate the compounding process [13][14][15]. ...
... More recently, Goyanes et al. [44] have published an article that provides only an overview of the role of advanced production of precise medicine and the future scope for the manufacturing methods used for precision medicine; this present work focuses specifically on the use of SLS in the manufacture of pharmaceuticals. This article provides a deep discussion on the special capabilities of SLS, such as the capacity to control the porosity of printed materials and produce amorphous solid dispersions, which are difficult to do with conventional techniques. ...
Selective laser sintering (SLS) is an additive manufacturing process that has shown promise in the production of medical devices, including hip cups, knee trays, dental crowns, and hearing aids. SLS-based 3D-printed dosage forms have the potential to revolutionise the production of personalised drugs. The ability to manipulate the porosity of printed materials is a particularly exciting aspect of SLS. Porous tablet formulations produced by SLS can disintegrate orally within seconds, which is challenging to achieve with traditional methods. SLS also enables the creation of amorphous solid dispersions in a single step, rather than the multi-step process required with conventional methods. This review provides an overview of 3D printing, describes the operating mechanism and necessary materials for SLS, and highlights recent advances in SLS for biomedical and pharmaceutical applications. Furthermore, an in-depth comparison and contrast of various 3D printing technologies for their effectiveness in tissue engineering applications is also presented in this review.
... Currently, suppositories are manufactured through the fusion moulding method; however, this generally requires the use of moulds that have limited lifespan and are dose inflexible. Threedimensional (3D) printing is a relatively new manufacturing tool being investigated in the pharmaceutical sector for the preparation of customised dosages (Awad et al., 2023a;Cui et al., 2021;Lafeber et al., 2022;Xu et al., 2021). Semi-solid extrusion (SSE) is a material extrusion 3D printing technology (Awad et al., 2018) that can shape semi-solid materials (e.g., pastes, gels, and wax) into 3D objects by extruding them through a heated orifice (Domsta et al., 2022;Seoane-Viaño et al., 2021b;Sjöholm et al., 2022;Zhu et al., 2022). ...
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.
... It is possible to design personalised solid pharmaceutical forms (Krkobabic et al., 2020;Trenfield et al., 2020;Xu et al., 2021a;Xu et al., 2021c) by adjusting the dose and modifying the size or shape, which in turn can enhance therapeutic response (Dumpa et al., 2021;Goyanes et al., 2019;Trenfield et al., 2023;Wang et al., 2021). However, to be integrated into fast-paced clinical settings, 3D printers must afford high throughput and dimensional accuracy (Awad et al., 2022). Volumetric 3DP, or holographic printing, is a novel additive manufacturing technology that possess these attributes. ...
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.
Three-dimensional (3D) printing or additive manufacturing has recently gained widespread interest because of its many advantages over traditional manufacturing methods including shorter fabrication times, simpler preparation processes, and the opportunity for rapid prototyping. Advanced materials with 3D printing have a low cost, high efficiency, design flexibility, and low environmental impact for the use of cutting-edge approaches in the building industry. The user's chosen 3D product is created using this innovative new technology, which is being hailed as the next manufacturing revolution and a universal industrial strategy. When it comes to supplying medical gadgets and dealing with the crisis brought on by the COVID-19 epidemic, three-dimensional (3D) printing has proven to be a godsend and a technological breakthrough. However, there was a critical scarcity of face shields and masks for key employees as a result of the COVID-19 epidemic, which triggered a global health disaster. Nevertheless, the lack of essential one-time-use personal safety equipment (PPE) is becoming a global issue of rising concern. This chapter provides an overview of the use of 3D printing in advanced materials from used PPE during COVID-19. It compiles detailed information about freshly developed and manufactured safety gear such as face shields, field respiratory, and facemasks. 3D-printed medical gadgets and protective gear are explored, along with their benefits and limitations.
Gold nanoparticles (NPS) have emerged as promising candidates for revolutionizing electronic lens technology and advancing optics. This comprehensive review paper delves into their pivotal role in enhancing the performance of electronic lenses. Beginning with an illuminating exploration of electronic lenses and the distinctive optical properties of gold NPs, this review meticulously examines various methodologies for synthesizing gold NPs, elucidating crucial aspects such as size and shape control. The optical prowess of gold NPs, including their plasmon resonance and tunability, is intricately dissected in relation to their applicability in electronic lenses. Furthermore, the integration of gold NPs into lens structures is meticulously scrutinized, encompassing insightful discussions on design considerations and pertinent challenges. The profound impact of incorporating gold NPs on electronic lenses is underscored, showcasing notable advancements such as heightened light absorption, refined transmission characteristics, and adept control over focal length and depth of field. Moreover, the manifold applications of gold nanoparticle-enhanced electronic lenses spanning imaging, microscopy, optical sensors, and display technologies are meticulously highlighted. This review also navigates through recent research breakthroughs and outlines future directions, offering invaluable insights into the potential commercialization prospects of this transformative technology. Ultimately, this comprehensive review serves as a beacon, illuminating the transformative potential of gold NPs in electronic lens technology, while charting new avenues for exploration and innovation in the realm of optics.
The voyage towards revolutionising healthcare through digital technologies has launched, and its trajectory promises to reshape the contours of health and wellness for generations to come. The age of patient-centric medicine, enhanced accessibility and seamless healthcare experiences is upon us, propelled by the remarkable potential of 3D printing and its synergy with the digital realm. This chapter demonstrates that the future of healthcare is dynamic, personalised and readily available—an era where health is a shared aspiration and innovation is the driving force behind its realisation.
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.
Three-dimensional (3D) printing is a revolutionary additive manufacturing technology that constructs objects layer-by-layer. This versatile technology encompasses various processes and possesses unique properties. While originally not intended for this purpose, 3D printing has emerged as a promising approach for personalised pharmaceutical production, specifically Printlets™, which are customised dosage forms. The ageing population presents enduring challenges, and 3D printing offers innovative solutions tailored to this patient subgroup. These solutions encompass a wide range of dosage forms, including multi-drug formulations, orally disintegrating tablets, chewable medicines, multiparticulate systems, and formulations for visually or physically impaired patients. Moreover, besides solid oral dosage forms, 3D printing can also fabricate patient-specific devices for drug delivery via the auricular, topical, intravesical, or vaginal routes. This chapter provides an overview of different 3D printing technologies, highlights the various dosage forms suitable for older patients, and briefly discusses the integration of 3D printing with other advanced digital health technologies.
Advancements in additive manufacturing enable the fabrication of in vitro biomimetic grafts leveraging biological materials and cells for various biomedical applications. The realization of such biofabrication typically requires time from minutes to hours depending on the scale and complexity of the models. During direct biofabrication, cell sedimentation with the resultant aggregation is extensively deemed to be one of the acute problems for precise and reliable inkjet-based bioprinting. It often results in highly unstable droplet formation, nozzle clogging, and non-uniformity of post-printing cell distribution. Our previous study has implemented active bioink circulation to mitigate cell sedimentation and aggregation within the bioink reservoir. This study focuses on the comparison of post-printing cell distribution within formed microspheres and one-layer sheets with and without active circulation. The experimental results have demonstrated a significant improvement in post-printing cell distribution under implemented active circulation. Moreover, the printed sheet samples are subject to three-day incubation to investigate the effect of cell distribution on cell viability and proliferation. It shows that compared to non-uniform cell distribution, the uniform cell distribution significantly improves cell viability (92% versus 77% at Day 3) and cell proliferation (3.3 times versus 1.7 times at Day 3). The preliminary results in this paper have demonstrated not only the high effectiveness of the active bioink circulation to improve post-printing cell distribution within microspheres and one-layer sheets, but also the critical role of the uniform post-printing cell distribution in promoting cell viability and proliferation.
Three-dimensional (3D) printing is a digital manufacturing system that is transforming pharmaceutical production by empowering patients to play an active role in the treatment process. Along with its dynamic form, namely, four-dimensional (4D) printing, this technology can challenge boundaries across industries. Within healthcare, their digital features make them well suited for designing and formulating countless drug products with properties personalised to the needs and preferences of individual patients. Although not fully embraced, it has been predicted that 3D printing would work in synchronisation with other cyber technologies, giving rise to a modern healthcare era based on continuous patient care. This book chapter will summarise the history of 3D and 4D printing and provide an insight on their use for personalised medicine. This will be followed by a futuristic vision of its role in a modern digital healthcare model.KeywordsDigitised health and industry 4.0Pharmacy or Pharma 4.0Additive manufacturingTailored dosage forms and medicationsPersonalized drug productsBiomedical engineering and medical devices3D-printed formulationsTailored therapeutics and precision medicineOn-demand dispensing and drug manufacturingPatient-centred smart healthMedical care
ZET: Çalışmada, 5+1 serbestlik derecesine sahip bir robot kolunun belirli bir konumdaki ve belirli biçimdeki bir objeyi tespit edip buna göre kontrol sağlaması amaçlanmıştır. Çalışılan teorik ve algoritmik yapının gerçek ve simülasyon uygulamalarında kullanılması hedeflenmiştir. Robot kolun uygulamasında gerçek zamanlı ve akıllı uygulamalar gerçekleştirilmiştir. Tasarım aşamasında 6 adet adım motor kullanılarak robot kolun kontrolü için gerekli hesaplamalar yapılmıştır. Robota gideceği konumu alacağı objeyi belirleme yeteneği görüntü işleme ve yapay zekâ yöntemleri kullanılarak gerçekleştirilmiştir. İlk olarak tasarım programları yardımıyla robot kol tasarlanmıştır. Tasarlanan robot kol eklemeli imalat yöntemiyle Biopolimer Polilaktik Asit (PLA) malzemesi kullanılarak imal edilmiştir. Tasarlanan robot kola uygun motor ve programlama kartı (PLC) uygulanmıştır. PLC hazırlanan yazılım ile altı eksen de programlanmıştır. Robot kolun uzuv uzunlukları ve eksen hareketlerine göre D-H tablosu hesaplanmıştır. Her bir eksen için dönüşüm matrisleri elde edilerek ileri ve ters kinematik hesaplamaları yapılmıştır. Çalışmada nesnelerin tespiti ve ağırlık merkezleri hesaplamak için görüntü işleme ve U 2-Net yapay zekâ tekniği kullanılmıştır. Elde edilen RGB görüntüler üzerinde U 2-Net yapay zekâ modeli kullanılarak arka plan silme işlemi gerçekleştirilmiş ve nesnelerin renge göre tespit edebilmek için renk uzayları HSV renk uzayına dönüştürülmüştür. Gerçekleştirilen çalışma ile parçaları üretilen ve yazılımı gerçekleştirilen robot kol 5+1 serbestlik dereceli eksende hareket edebilen bir robot kolun görüntü işleme ve yapay zekâ tekniği kullanılarak toplam 20 adet deney yapılarak hata payları 0 mm ile 22 mm arasında değişen değerler aldığı belirlenmiş ve ortalama hata payı 10,5 mm olarak belirlenmiştir.
Çalışmada, 5+1 serbestlik derecesine sahip bir robot kolunun belirli bir konumdaki ve belirli biçimdeki bir objeyi tespit edip buna göre kontrol sağlaması amaçlanmıştır. Çalışılan teorik ve algoritmik yapının gerçek ve simülasyon uygulamalarında kullanılması hedeflenmiştir. Robot kolun uygulamasında gerçek zamanlı ve akıllı uygulamalar gerçekleştirilmiştir. Tasarım aşamasında 6 adet adım motor kullanılarak robot kolun kontrolü için gerekli hesaplamalar yapılmıştır. Robota gideceği konumu alacağı objeyi belirleme yeteneği görüntü işleme ve yapay zekâ yöntemleri kullanılarak gerçekleştirilmiştir. İlk olarak tasarım programları yardımıyla robot kol tasarlanmıştır. Tasarlanan robot kol eklemeli imalat yöntemiyle Biopolimer Polilaktik Asit (PLA) malzemesi kullanılarak imal edilmiştir. Tasarlanan robot kola uygun motor ve programlama kartı (PLC) uygulanmıştır. PLC hazırlanan yazılım ile altı eksen de programlanmıştır. Robot kolun uzuv uzunlukları ve eksen hareketlerine göre D-H tablosu hesaplanmıştır. Her bir eksen için dönüşüm matrisleri elde edilerek ileri ve ters kinematik hesaplamaları yapılmıştır. Çalışmada nesnelerin tespiti ve ağırlık merkezleri hesaplamak için görüntü işleme ve U2-Net yapay zekâ tekniği kullanılmıştır. Elde edilen RGB görüntüler üzerinde U2-Net yapay zekâ modeli kullanılarak arka plan silme işlemi gerçekleştirilmiş ve nesnelerin renge göre tespit edebilmek için renk uzayları HSV renk uzayına dönüştürülmüştür. Gerçekleştirilen çalışma ile parçaları üretilen ve yazılımı gerçekleştirilen robot kol 5+1 serbestlik dereceli eksende hareket edebilen bir robot kolun görüntü işleme ve yapay zekâ tekniği kullanılarak toplam 20 adet deney yapılarak hata payları 0 mm ile 22 mm arasında değişen değerler aldığı belirlenmiş ve ortalama hata payı 10,5 mm olarak belirlenmiştir.
This article describes the process of topology optimisation (TO) of three components of an electric scooter, namely the neck, platform, and suspension bracket. We use these example parts to investigate the additive manufacturing (AM) workflow, from re-design to nesting and support approach that has an impact on the total costs and time required for product development and manufacturing, with a focus on Direct Metal Laser Sintering (DMLS) technology. Due to the mathematically generated shape, components that are topology optimised and fabricated through AM have improved structural load-to-weight ratio. The article elaborates on the cost of manufacturing these new geometrical structures and re-designing existing components. Recognising topology-optimised design features for the LPBF manufacturing process like creating touch points between parts in 3D nesting orientations and lattice structure integration reduces cost in volume production. Our study shows that it is beneficial for the DMLS process to perform finite element analysis (FEA) and optimise components using TO and lattice structures, as weight reduction also translates to cheaper fabricating parts. Defining and implementing a streamlined workflow for editing the complex automatically generated support structures improves manufacturability. Such approaches encourage companies to adopt wider LPBF processes in mainstream industries.
Abbreviations: AM = additive manufacturing; DMLS = direct metal laser sintering; TO = topology optimisation; SLS = selective laser sintering; FEA = finite element analysis; CAD = computer-aided design; CAM = computer-aided manufacturing; 3D = three dimension; CAE = computer-aided engineering
Vat photopolymerisation three-dimensional (3D) printing is redefining manufacturing paradigms within the pharmaceutical and healthcare industries. Marked by its superb printing resolution and speed, this technology provides an advanced method for engineering patient-centred drug products and devices. In the future, it is foreseen that the combination of 3D printing with other digital health technologies could in fact give rise to a new healthcare model, involving transitioning from current treatment pathways towards personalised digital therapies. This chapter outlines the various vat photopolymerisation techniques, illustrating their unique applications for the fabrication of medicines and drug-laden devices. This is followed by a brief overview of the challenges and drawbacks associated with this printing system in context of its use within healthcare.KeywordsStereolithography (SLA)Digital light processing (DLP)Continuous liquid interface production (CLIP)Two-photon polymerisation (2PP)Volumetric printingDigital medicine productionCustom-made therapeutics and precision medicine3D printed formulations and systemsOn-demand dispensing and drug manufacturingCustomised dosage forms and drug-loaded medical devices
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.
Slow drug release, low drug-polymer miscibility, poor printability of polymers used, and high processing temperature are major challenges in developing FDM 3D-printed tablets. These challenges were addressed in this investigation by having a model basic drug, haloperidol (mp: 151.5°C), interact with a weak acid, malic acid (mp: 130°C), during the melt extrusion of formulations into filaments used for 3D-printing. Malic acid was selected as it was previously reported that it did not form any crystalline salt with haloperidol but its addition to aqueous media could greatly increase the solubility of haloperidol from ∼1 µg/mL to >1g per mL of water by acid-base supersolubilization. Concentrated solutions of haloperidol-malic acid mixtures produced amorphous materials upon drying. It has been observed in the present investigation that similar interaction between haloperidol and malic acid may also occur in absence of water. Upon heating, haloperidol-malic acid mixtures at 1:1 and 1:2 molar ratios turned amorphous starting at ∼50°C, which is much below the melting point of either component. When Kollidon® VA64, a brittle and non-printable polymer, was used as the polymeric carrier, the acid-base interaction greatly reduced the melt viscosity of haloperidol-malic acid-Kollidon® VA64 ternary mixtures. Consequently, melt extrusion of filaments and printing of tablets using such mixtures could be performed at much lower temperatures than those with haloperidol-Kollidon® VA64 binary mixtures. The filaments containing 15% and 30% haloperidol could be printed into tablets at relatively low temperatures of 125 and 100°C, respectively, thus making Kollidon® VA64 not only printable but at low temperatures. Up to 50% w/w drug load in filaments was achieved without any crystallization of haloperidol or malic acid. Drug release at pH 2 and 6.8 from printed tablets with 100% infill was 80% in <30 min. Thus, the acid-base interaction can successfully resolve multiple development challenges encountered with FDM 3D-printed tablets.
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.
3D printing (3DP), or additive manufacturing, has been actively investigated as one of the enabling technologies for the impending era of personalized medicines. However, existing 3DP technologies do not afford the speeds required for on-demand production of medicines in fast-paced clinical settings. Volumetric printing is a novel 3DP technology that offers rapid printing speed and overcomes the geometric and surface quality limitations of layer-based vat photopolymerization techniques. Unlike previous vat photopolymerization 3DP technologies, volumetric printing cures the entire desired 3D geometry simultaneously by exploiting the threshold behavior in the photopolymerization process that arise due to oxygen-induced polymerization inhibition. In this work, for the first time, a volumetric printer was used to fabricate drug-loaded 3D printed tablets (Printlets™) within seconds. Six resin formulations were evaluated using this printer, each composed of polyethylene glycol diacrylate (PEGDA) as the crosslinking monomer, phenyl-2,4-6-trimethyl-benzoyl-phosphinate as the photoinitiator, and paracetamol as the model drug. Water or PEG300 were included as diluents in varying concentrations to facilitate drug release. Paracetamol-loaded Printlets were successfully fabricated within 17 seconds. Drug release rates could be tuned by altering the monomer-to-diluent ratio of the photosensitive resin, with a lower ratio releasing drug faster. The present work confirms the suitability of volumetric 3DP for printing drug products in a matter of seconds. Upon further optimization, this novel technology can enable rapid, on-demand fabrication of medicines and medical devices.
Dry eye disease is a common ocular disorder that is characterised by tear deficiency or excessive tear evaporation. Current treatment involves the use of eye drops; however, therapeutic efficacy is limited because of poor ocular bioavailability of topically applied formulations. In this study, digital light processing (DLP) 3D printing was employed to develop dexamethasone-loaded punctal plugs. Punctal plugs with different drug loadings were fabricated using polyethylene glycol diacrylate (PEGDA) and polyethylene glycol 400 (PEG 400) to create a semi-interpenetrating network (semi-IPN). Drug-loaded punctal plugs were characterised in terms of physical characteristics (XRD and DSC), potential drug-photopolymer interactions (FTIR), drug release profile, and cytocompatibility. In vitro release kinetics of the punctal plugs were evaluated using an in-house flow rig model that mimics the subconjunctival space. The results showed sustained release of dexamethasone for up to 7 days from punctal plugs made with 20% w/w PEG 400 and 80% w/w PEGDA, while punctal plugs made with 100% PEGDA exhibited prolonged releases for more than 21 days. Herein, our study demonstrates that DLP 3D printing represents a potential manufacturing platform for fabricating personalised drug-loaded punctal plugs with extended release characteristics for ocular administration.
The development of personalised paediatric dosage forms using 3D printing technologies has gained significant interest over the last few years. In the current study extruded filaments of the highly bitter Diphenhydramine Hydrochloride (DPH) were fabricated by using suitable hydrophilic carries such as hydroxypropyl cellulose (Klucel ELFTM) and a non-ionic surfactant (Gelucire 48/16TM) combined with sweetener (Sucralose) and strawberry flavour grades. The thermoplastic filaments were used to print 3D fruit-chew designs by Fused Deposition Modelling (FDM) technology. Physicochemical characterisation confirmed the formation of glass solution where DPH was molecularly dispersed within the hydrophilic carriers. DPH was released rapidly from the 3D printed fruit-chew designs with >85% within the first 30 min. Trained panellists performed a full taste and sensory evaluation of the sweetener intensity and the strawberry aroma. The evaluation showed complete taste masking of the bitter DPH and revealed a synergistic effect of the sweetener and the strawberry flavour with enhanced sweet strawberry, fruity and aftertaste perception. The findings of the study can be used for the development of paediatric dosage forms with enhanced organoleptic properties, palatability and medication adherence.
For the last 40 years, praziquantel has been the standard treatment for schistosomiasis, a neglected parasitic disease affecting more than 250 million people worldwide. However, there is no suitable paediatric formulation on the market, leading to off-label use and the splitting of commercial tablets for adults. In this study, we use a recently available technology, direct powder extrusion (DPE) three-dimensional printing (3DP), to prepare paediatric Printlets™ (3D printed tablets) of amorphous solid dispersions of praziquantel with Kollidon® VA 64 and surfactants (Span™ 20 or Kolliphor® SLS). Printlets were successfully printed from both pellets and powders obtained from extrudates by hot melt extrusion (HME). In vitro dissolution studies showed a greater than four-fold increase in praziquantel release, due to the formation of amorphous solid dispersions. In vitro palatability data indicated that the printlets were in the range of praziquantel tolerability, highlighting the taste masking capabilities of this technology without the need for additional taste masking excipients. This work has demonstrated the possibility of 3D printing tablets using pellets or powder forms obtained by HME, avoiding the use of filaments in fused deposition modelling 3DP. Moreover, the main formulation hurdles of praziquantel, such as low drug solubility, inadequate taste, and high and variable dose requirements, can be overcome using this technology.
In this work, we developed a novel all-3D-printed device for the simple determination of quetiapine fumarate (QF) via voltammetric mode. The device was printed through a one-step process by a dual-extruder 3D printer and it features three thermoplastic electrodes (printed from a carbon black-loaded polylactic acid (PLA)) and an electrode holder printed from a non-conductive PLA filament. The integrated 3D-printed device can be printed on-field and it qualifies as a ready-to-use sensor, since it does not require any post-treatment (i.e., modification or activation) before use. The electrochemical parameters, which affect the performance of the sensor in QF determination, were optimized and, under the selected conditions, the quantification of QF was carried out in the concentration range of 5 × 10−7–80 × 10−7 mol × L−1. The limit of detection was 2 × 10−9 mol × L−1, which is lower than that of existing electrochemical QF sensors. The within-device and between-device reproducibility was 4.3% and 6.2% (at 50 × 10−7 mol × L−1 QF level), respectively, demonstrating the satisfactory operational and fabrication reproducibility of the device. Finally, the device was successfully applied for the determination of QF in pharmaceutical tablets and in human urine, justifying its suitability for routine and on-site analysis.
The human gut microbiome, composed of trillions of microorganisms, plays an essential role in human health. Many factors shape gut microbiome composition over the life span, including changes to diet, lifestyle, and medication use. Though not routinely tested during drug development, drugs can exert profound effects on the gut microbiome, potentially altering its functions and promoting disease. This study develops a machine learning (ML) model to predict whether drugs will impair the growth of 40 gut bacterial strains. Trained on over 18,600 drug–bacteria interactions, 13 distinct ML models are built and compared, including tree-based, ensemble, and artificial neural network techniques. Following hyperparameter tuning and multi-metric evaluation, a lead ML model is selected: a tuned extra trees algorithm with performances of AUROC: 0.857 (±0.014), recall: 0.587 (±0.063), precision: 0.800 (±0.053), and f1: 0.666 (±0.042). This model can be used by the pharmaceutical industry during drug development and could even be adapted for use in clinical settings.
3D printing (3DP) is a progressive technology capable of transforming pharmaceutical development. However, despite its promising advantages, its transition into clinical settings remains slow. To make the vital leap to mainstream clinical practice and improve patient care, 3DP must harness modern technologies. Machine learning (ML), an influential branch of artificial intelligence, may be a key partner for 3DP. Together, 3DP and ML can utilise intelligence based on human learning to accelerate drug product development, ensure stringent quality control (QC), and inspire innovative dosage-form design. With ML’s capabilities, streamlined 3DP drug delivery could mark the next era of personalised medicine. This review details how ML can be applied to elevate the 3DP of pharmaceuticals and importantly, how it can expedite 3DP’s integration into mainstream healthcare.
Acute liver failure (ALF) requiring liver transplantation is a disease that occurs due to rapid hepatocellular dysfunction. As liver transplantation has various limitations, including donor scarcity, high cost, and immuno‐incompatibility, continuous local delivery of biopharmaceuticals to the liver tissue can be a promising ALF treatment option. Here, the in vivo safety and usability of a 3D‐printed implantable drug delivery device for effective ALF treatment is evaluated. The implantable reservoir consists of a 3D‐printed container and a semipermeable membrane for repeated administrations of drugs, specifically to the liver tissue. The physical stability and function of the 3D‐printed reservoir are confirmed by the mechanical properties and in vitro drug release test, respectively. In mice implanted with the reservoir system, mortality, weight changes, clinical signs, hematological and serum biochemical changes, and organ weight changes are not observed, suggesting no foreign body reaction. The usability of the reservoir system is further evaluated using an ALF model of 70% hepatectomized mice treated with N‐acetylcysteine through the system, showing cell‐specific regeneration and significant liver injury alleviation. Overall, the 3D‐printed reservoir system is safe for studying the therapeutic potential of ALF treatment, and it can be used for the delivery of various active pharmaceutical ingredients.
Here we present a 3D-printed, wirelessly controlled microsystem for drug delivery, comprising a refillable microreservoir and a phase-change peristaltic micropump. The micropump structure was inkjet-printed on the back of a printed circuit board around a catheter microtubing. The enclosure of the microsystem was fabricated using stereolithography 3D printing, with an embedded microreservoir structure and integrated micropump. In one configuration, the microsystem was optimized for murine inner ear drug delivery with an overall size of 19 × 13 × 3 mm3. Benchtop results confirmed the performance of the device for reliable drug delivery. The suitability of the device for long-term subcutaneous implantation was confirmed with favorable results of implantation of a microsystem in a mouse for six months. The drug delivery was evaluated in vivo by implanting four different microsystems in four mice, while the outlet microtubing was implanted into the round window membrane niche for infusion of a known ototoxic compound (sodium salicylate) at 50 nL/min for 20 min. Real-time shifts in distortion product otoacoustic emission thresholds and amplitudes were measured during the infusion, demonstrating similar results with syringe pump infusion. Although demonstrated for one application, this low-cost design and fabrication methodology is scalable for use in larger animals and humans for different clinical applications/delivery sites.
Optical biosensors are low-cost, sensitive and portable devices that are poised to revolutionize the medical industry. Healthcare monitoring has already been transformed by such devices, with notable recent applications including heart rate monitoring in smartwatches and COVID-19 lateral flow diagnostic test kits. The commercial success and impact of existing optical sensors has galvanized research in expanding its application in numerous disciplines. Drug detection and monitoring seeks to benefit from the fast-approaching wave of optical biosensors, with diverse applications ranging from illicit drug testing, clinical trials, monitoring in advanced drug delivery systems and personalized drug dosing. The latter has the potential to significantly improve patients’ lives by minimizing toxicity and maximizing efficacy. To achieve this, the patient’s serum drug levels must be frequently measured. Yet, the current method of obtaining such information, namely therapeutic drug monitoring (TDM), is not routinely practiced as it is invasive, expensive, time-consuming and skilled labor-intensive. Certainly, optical sensors possess the capabilities to challenge this convention. This review explores the current state of optical biosensors in personalized dosing with special emphasis on TDM and provides an appraisal on recent strategies. The strengths and challenges of optical biosensors are critically evaluated, before concluding with perspectives on the future direction of these sensors.
Three-dimensional printing is a technology that prints the products layer-by-layer, in which materials are deposited according to the digital model designed by computer aided design (CAD) software. This technology has competitive advantages regarding product design complexity, product personalization, and on-demand manufacturing. The emergence of 3D technology provides innovative strategies and new ways to develop novel drug delivery systems. This review summarizes the application of 3D printing technologies in the pharmaceutical field, with an emphasis on the advantages of 3D printing technologies for achieving rapid drug delivery, personalized drug delivery, compound drug delivery and customized drug delivery. In addition, this article illustrates the limitations and challenges of 3D printing technologies in the field of pharmaceutical formulation development.
Three-dimensional (3D) printing is a recent technology, which gives the possibility to manufacture personalised dosage forms and it has a broad range of applications. One of the most developed, it is the manufacture of oral solid dosage and the four 3DP techniques which have been more used for their manufacture are FDM, inkjet 3DP, SLA and SLS. This systematic review is carried out to statistically analyze the current 3DP techniques employed in manufacturing oral solid formulations and assess the recent trends of this new technology. The work has been organised into four steps, (1) screening of the articles, definition of the inclusion and exclusion criteria and classification of the articles in the two main groups (included/excluded); (2) quantification and characterisation of the included articles; (3) evaluation of the validity of data and data extraction process; (4) data analysis, discussion, and conclusion to define which technique offers the best properties to be applied in the manufacture of oral solid formulations. It has been observed that with SLS 3DP technique, all the characterisation tests required by the BP (drug content, drug dissolution profile, hardness, friability, disintegration time and uniformity of weight) have been performed in the majority of articles, except for the friability test. However, it is not possible to define which of the four 3DP techniques is the most suitable for the manufacture of oral solid formulations, because the selection is affected by different parameters, such as the type of formulation, the physical-mechanical properties to achieve. Moreover, each technique has its specific advantages and disadvantages, such as for FDM the biggest challenge is the degradation of the drug, due to high printing temperature process or for SLA is the toxicity of the carcinogenic risk of the photopolymerising material.
Interest in 3D-printing technologies for pharmaceutical manufacturing of oral dosage forms is driven by the need of personalized medicines. Most research has to date focused on printing of polymeric-based drug delivery systems at high temperatures. Furthermore, oral formulation development is continuously challenged by the large number of poorly water-soluble drugs, which require more advanced enabling formulations to improve oral bioavailability. In this work, we used semi-solid extrusion (SSE) printing of emulsion gels with three types of emulsified lipid-based formulations (LBFs) to produce solid lipid tablets incorporating the poorly water-soluble drug, fenofibrate. Tablets were successfully 3D-printed from emulsion gels using SSE at room temperature, making the methodology particularly useful for thermolabile compounds. The tablets were well-defined in mass and disintegrated rapidly (< 15 minutes). Importantly, the oil droplet size reconstituted after dispersion of the tablets and subsequent lipid digestion was similar to traditional liquid LBFs. This work demonstrates the successful use of SSE for fabricating solid lipid tablets based on emulsion gels. The method is further promising for on demand production of personalized dosage forms, necessary for flexible dosage adjustment in e.g. pediatric patients, when poorly water-soluble compounds constitute the core of the therapy.
The last twenty years of seminal microbiome research has uncovered microbiota’s intrinsic relationship with human health. Studies elucidating the relationship between an unbalanced microbiome and disease are currently published daily. As such, microbiome big data have become a reality that provide a mine of information for the development of new therapeutics. Machine learning (ML), a branch of artificial intelligence, offers powerful techniques for big data analysis and prediction-making, that are out of reach of human intellect alone. This review will explore how ML can be applied for the development of microbiome-targeted therapeutics. A background on ML will be given, followed by a guide on where to find reliable microbiome big data. Existing applications and opportunities will be discussed, including the use of ML to discover, design, and characterize microbiome therapeutics. The use of ML to optimize advanced processes, such as 3D printing and in silico prediction of drug-microbiome interactions, will also be highlighted. Finally, barriers to adoption of ML in academic and industrial settings will be examined, concluded by a future outlook for the field.
Various three-dimensional printing (3DP) technologies have been investigated so far in relation to their potential to produce customizable medicines and medical devices. The aim of this study was to examine the possibility of tailoring drug release rates from immediate to prolonged release by varying the tablet thickness and the drug loading, as well as to develop artificial neural network (ANN) predictive models for atomoxetine (ATH) release rate from DLP 3D-printed tablets. Photoreactive mixtures were comprised of poly(ethylene glycol) diacrylate (PEGDA) and poly(ethylene glycol) 400 in a constant ratio of 3:1, water, photoinitiator and ATH as a model drug whose content was varied from 5% to 20% (w/w). Designed 3D models of cylindrical shape tablets were of constant diameter, but different thickness. A series of tablets with doses ranging from 2.06 mg to 37.48 mg, exhibiting immediate- and modified-release profiles were successfully fabricated, confirming the potential of this technology in manufacturing dosage forms on demand, with the possibility to adjust the dose and release behavior by varying drug loading and dimensions of tablets. DSC (differential scanning calorimetry), XRPD (X-ray powder diffraction) and microscopic analysis showed that ATH remained in a crystalline form in tablets, while FTIR spectroscopy confirmed that no interactions occurred between ATH and polymers.
The popularity of machine learning (ML) across drug discovery continues to grow, yielding impressive results. As their use increases, so do their limitations become apparent. Such limitations include their need for big data, sparsity in data, and their lack of interpretability. It has also become apparent that the techniques are not truly autonomous, requiring retraining even post deployment. In this review, we detail the use of advanced techniques to circumvent these challenges, with examples drawn from drug discovery and allied disciplines. In addition, we present emerging techniques and their potential role in drug discovery. The techniques presented herein are anticipated to expand the applicability of ML in drug discovery.
The aim of this study was to fabricate novel self-supporting tacrolimus suppositories using semisolid extrusion 3-dimensional printing (3DP) and to investigate their efficacy in an experimental model of inflammatory bowel disease. Blends of Gelucire 44/14 and coconut oil were employed as lipid excipients to obtain suppository formulations with self-emulsifying properties, which were then tested in a TNBS (2,4,6-trinitrobenzenesulfonic acid) induced rat colitis model. Disease activity was monitored using PET/CT medical imaging; maximum standardized uptake values (SUVmax), a measure of tissue radiotracer accumulation rate, together with body weight changes and histological assessments, were used as inflammatory indices to monitor treatment efficacy. Following tacrolimus treatment, a significant reduction in SUVmax was observed on days 7 and 10 in the rat colon sections compared to non-treated animals. Histological analysis using Nancy index confirmed disease remission. Moreover, statistical analysis showed a positive correlation (R2 = 71.48%) between SUVmax values and weight changes over time. Overall, this study demonstrates the effectiveness of 3D printed tacrolimus suppositories to ameliorate colitis and highlights the utility of non-invasive PET/CT imaging to evaluate new therapies in the preclinical area.
3D printing (3DP) in the pharmaceutical field is a disruptive technology that allows the preparation of personalised medicines at the point of dispensing. The paediatric population presents a variety of pharmaceutical formulation challenges such as dose flexibility, patient compliance, taste masking and the fear or difficulty to swallow tablets, all factors that could be overcome using the adaptable nature of 3DP. User acceptability studies of 3D printed formulations have been previously carried out in adults; however, feedback from children themselves is essential in establishing the quality target product profile towards the development of age-appropriate medicines. The aim of this study was to investigate the preference of children for different 3D printed tablets (Printlets™) as an important precursor to patient acceptability studies. Four different 3DP technologies; digital light processing (DLP), selective laser sintering (SLS), semi-solid extrusion (SSE) and fused deposition modeling (FDM) were used to prepare placebo printlets with similar physical attributes including size and shape. A single-site, two-part survey was completed with participants aged 4-11 years to determine their preference and opinions based on visual inspection of the printlets. A total of 368 participants completed an individual open questionnaire to visually select the best and worst printlet, and 310 participants completed further non-compulsory open questions to elaborate on their choices. Overall, the DLP printlets were the most visually appealing to the children (61.7%) followed by the SLS printlets (21.2%), and with both the FDM (5.4%) and SSE (11.7%) printlets receiving the lowest scores. However, after being informed that the SSE printlets were chewable, the majority of participants changed their selection and favoured this printlet, despite their original choice, in line with children's preference towards chewable dosage forms. Participant age and sex displayed no significant differences in printlet selection. Printlet descriptions were grouped into four distinct categories; appearance, perceived taste, texture and familiarity, and were found to be equally important when creating a quality target product profile for paediatric 3D printed formulations. This study is the first to investigate children's perceptions of printlets, and the findings aim to provide guidance for further development of paediatric-appropriate medicines using different 3DP technologies.
The simplicity of object shape and composition modification make additive manufacturing a great option for customized dosage form production. To achieve this goal, the correlation between structural and functional attributes of the printed objects needs to be analyzed. So far, it has not been deeply investigated in 3D printing-related papers. The aim of our study was to modify the functionalities of printed tablets containing liquid crystal-forming drug itraconazole by introducing polyvinylpyrrolidone-based polymers into the filament-forming matrices composed predominantly of poly(vinyl alcohol). The effect of the molecular reorganization of the drug and improved tablets' disintegration was analyzed in terms of itraconazole dissolution. Micro-computed tomography was applied to analyze how the design of a printed object (in this case, a degree of an infill) affects its reproducibility during printing. It was also used to analyze the structure of the printed dosage forms. The results indicated that the improved disintegration obtained due to the use of Kollidon ® CL-M was more beneficial for the dissolution of itraconazole than the molecular rearrangement and liquid crystal phase transitions. The lower infill density favored faster dissolution of the drug from printed tablets. However, it negatively affected the reproducibility of the 3D printed object.
Three-dimensional printing (3DP) is a transformative technology that is advancing pharmaceutical research by producing personalized drug products. However, advances made via 3DP have been slow due to the lengthy trial-and-error approach in optimization. Artificial intelligence (AI) is a technology that could revolutionize pharmaceutical 3DP through analyzing large datasets. Herein, literature-mined data for developing AI machine learning (ML) models was used to predict key aspects of the 3DP formulation pipeline and in vitro dissolution properties. A total of 968 formulations were mined and assessed from 114 articles. The ML techniques explored were able to learn and provide accuracies as high as 93% for values in the filament hot melt extrusion process. In addition, ML algorithms were able to use data from the composition of the formulations with additional input features to predict the drug release of 3D printed medicines. The best prediction was obtained by an artificial neural network that was able to predict drug release times of a formulation with a mean error of ±24.29 min. In addition, the most important variables were revealed, which could be leveraged in formulation development. Thus, it was concluded that ML proved to be a suitable approach to modelling the 3D printing workflow.
3D printing is a manufacturing technique that is transforming numerous industrial sectors. Within healthcare, it is empowering the small-scale development of personalised medicines that meet the individual needs of patients. 3D printing systems are being currently tested in specialised clinical settings by healthcare professionals, however, there is a need for integrating novel digital solutions that allow for rapid, safe and remote medical interventions directly at the point-of-care. To this end, a portable smartphone-activated 3D printer, operated with a custom mobile app is proposed for the first time to prepare personalised medicines. The printer uses the light from the smartphone’s screen to photopolymerise liquid resins and create solid structures. 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 in high resolution and dimensional precision using different photosensitive resins. The drug within the Printlets existed in the amorphous form, wherein 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.
Now more than ever, traditional healthcare models are being overhauled with digital technologies of Healthcare 4.0 being 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 currently being investigated 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 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 scopes for clinical adoption.
Pharmaceutical applications of the 3D printing process have recently matured, followed by the FDA approval of Spritam, the first commercial 3D printed dosage form. Due to being a new technology in the conventional dosage formulation field, there is still a dearth of understanding in the 3D printing process regarding the effect of the raw materials on the printed dosage forms and the plausibility of using this technology in dosage development beyond the conventional ways. In this review, the powder-based binder jet 3D printing (BJ3DP) process and its pharmaceutical applications have been discussed, along with a perspective of the formulation development step. The recent applications of BJ3DP in pharmaceutical dosage development, the advantages, and limitations have further been discussed here. A discussion of the critical formulation parameters that need to be explored for the preformulation study of the solid oral dosage development using the BJ3DP process is also presented.
A multi-material 3D printing offers nearly endless possibilities for the spatial arrangement of individual materials within the object being printed. In the case of pharmaceutical tablets, the spatial arrangement of individual material domains containing the active pharmaceutical ingredients (APIs) and excipients uniquely defines the release profiles of the APIs. However, the inverse is not necessarily true – identical or very similar dissolution profiles can potentially be obtained from different tablet internal structures, implemented as a combination of domains containing excipients with different individual dissolution rates and different local API concentration. This work presents a computational method based on an Evolutionary Algorithm for the solution of the inverse problem, i.e. finding such tablet internal structure that results in a prescribed dissolution profile of each API contained in the tablet. After testing the algorithm on cases with a known solution, the methodology is applied to a problem of finding tablet structures that result in delayed release and step-wise release profiles, respectively. When combined with patient-specific requirements on drug release profiles, the algoritm can serve as a tool for an automated design of 3D-printed tablets in the framework of personalised medicine.
Artificial intelligence (AI) is redefining how we exist in the world. In almost every sector of society, AI is performing tasks with super-human speed and intellect; from the prediction of stock market trends to driverless vehicles, diagnosis of disease, and robotic surgery. Despite this growing success, the pharmaceutical field is yet to truly harness AI. Development and manufacture of medicines remains largely in a ‘one size fits all’ paradigm, in which mass-produced, identical formulations are expected to meet individual patient needs. Recently, 3D printing (3DP) has illuminated a path for on-demand production of fully customisable medicines. Due to its flexibility, pharmaceutical 3DP presents innumerable options during formulation development that generally require expert navigation. Leveraging AI within pharmaceutical 3DP removes the need for human expertise, as optimal process parameters can be accurately predicted by machine learning. AI can also be incorporated into a pharmaceutical 3DP ‘Internet of Things’, moving the personalised production of medicines into an intelligent, streamlined, and autonomous pipeline. Supportive infrastructure, such as The Cloud and blockchain, will also play a vital role. Crucially, these technologies will expedite the use of pharmaceutical 3DP in clinical settings and drive the global movement towards personalised medicine and Industry 4.0.
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.
In this paper we report on a modular design that allows one to fabricate electrochemical sensors upon combining 3D printing and screen printing. The usefulness of the design is showcased with graphene paste electrodes (GPE) coated with magnetic microspheres used to detect the drug nimesulide (NIM), biomarkers dopamine (DOP) and uric acid (UA). Under optimized conditions, the limit of detection was 0.0023 μmol L-1 in the range from 0.5 to 9 μmol L-1, 0.01 μmol L-1 within the range from 0.8 to 6 μmol L-1, and 0.0034 μmol L-1 from 0.7 to 10 μmol L-1 for dopamine, nimesulide, and uric acid, respectively. The three analytes could also be detected in blood serum and artificial urine samples within approximately 20 s, which is promising for clinical applications. With the modular design, the paste can be prepared with a variety of nanomaterials, functionalized with biomolecules and magnetic particles, and then stored for later use. The working electrode may also be polished to allow for reuse. Furthermore, in contrast to standard sensors made with carbon pastes, the electrochemical sensor proposed here requires small volumes (20-200 μL), which is crucial for drug monitoring and other biomedical applications.
Additive manufacturing (AM) is gaining interests in drug delivery applications, offering innovative opportunities for the design and development of systems with complex geometry and programmed controlled release profile. In addition, polymer-based drug delivery systems can improve drug safety and efficacy and patient compliance and are the key materials in AM. Therefore, combining AM and polymers can be beneficial to overcome the existing limitations in the development of controlled release drug delivery systems. Considering these advantages, here we are focusing on the recent developments in the field of polymeric drug delivery systems prepared by AM. This review provides a comprehensive overview on a holistic polymer-AM perspective for drug delivery systems with discussion on the materials, properties, design and fabrication techniques and the mechanisms used to achieve a controlled release system. The current challenges and future perspectives for personalized medicine and clinical use of these systems are also briefly discussed.
Over the last two centuries, medicines have evolved from crude herbal and botanical preparations into more complex manufacturing of sophisticated drug products and dosage forms. Along with the evolution of medicines, the manufacturing practices for their production have advanced from small-scale manual processing with simple tools to large-scale production as part of a trillion-dollar pharmaceutical industry. Today’s pharmaceutical manufacturing technologies continue to evolve as the internet of things, artificial intelligence, robotics, and advanced computing begin to challenge the traditional approaches, practices, and business models for the manufacture of pharmaceuticals. The application of these technologies has the potential to dramatically increase the agility, efficiency, flexibility, and quality of the industrial production of medicines. How these technologies are deployed on the journey from data collection to the hallmark digital maturity of Industry 4.0 will define the next generation of pharmaceutical manufacturing. Acheiving the benefits of this future requires a vision for it and an understanding of the extant regulatory, technical, and logistical barriers to realizing it.
Three-dimensional (3D) printing is an innovative additive manufacturing technology, capable of fabricating unique objects in a layer-by-layer manner. Semi-solid extrusion (SSE) is a subset of material extrusion 3D printing, based on the sequential deposition of layers of gel or paste to create an object of a desired size and shape. In comparison to other extrusion-based technologies, SSE 3D printing employs low printing temperatures making it suitable for drug delivery and biomedical applications, and the use of disposable syringes provides benefits in meeting critical quality requirements for pharmaceutical use. Besides pharmaceutical manufacture, SSE 3D printing has attracted increasing attention in the field of bioelectronics, particularly in the manufacture of biosensors capable of measuring physiological parameters or as a means to trigger drug release from medical devices. This review begins by highlighting the major printing process parameters and material properties that influence the feasibility of transforming a 3D design into a 3D object, followed by a discussion of the current SSE 3D printing developments and applications in the fields of pharmaceutics, bioprinting and bioelectronics. Finally, the advantages and limitations offered by this technology are explored, focusing on its potential clinical applications and suitability for preparing personalised medicines.
Coaxial extrusion is a commonly used process to manufacture tubular structures to mimic vascular systems in 3D bioprinting. In this study, the stability of coaxial extrusion of a non-Newtonian material, Pluronic F127, is investigated. The extrusion process is considered stable when the extrudate form a core-annular structure. When it is unstable, dripping or jetting of the inner fluid is observed. In this study, the effects of the viscosity ratio, flow rate ratio, and the non-Newtonian behaviors on the stability of the coaxial extrusion process are investigated experimentally and numerically. The results show that all three factors can affect the stability of the process. When the ratio of viscosities increases, the process becomes unstable. The extrusion process tends to be stable when the flow rate of the outer fluid is much higher than that of the inner fluid. When the overall flow rate decreases, due to the non-Newtonian fluid behavior, the extrusion process can become unstable. This study shows the interconnected relationship between viscosity, flow rate, and non-Newtonian fluid behaviors and their effects on the stability of the coaxial extrusion process. The non-Newtonian flow behavior needs to be considered when studying or using coaxial extrusion. This study also provides a guiding principle on how to alter extrusion parameters in order to achieve the desired flow pattern.
Medicine should ideally be personalized as each individual has his/her own unique biological, physical, and medical dispositions. Medicine can be personalized by customizing drug tablets with the specific drug dosages, release durations, and combinations of multiple drugs. This study presents a method for fabricating drug tablets with customizable dosages, durations, and combinations of multiple drugs by using the 3D printing technology. The method focuses on fabricating customizable drug tablets with a very simple structure by first printing a template using the 3D printer and fabricating the drug tablet via the template. The tablets are customized by varying the amount of excipient used, the height of the tablet, and the number and amount of drugs used. Customizable drug tablets are fabricated for delivering the constant release profile due to its importance in treatment (i.e., the drug may produce side effects if too much is released and may not have therapeutic value is too little is released). Three different common drugs (i.e., paracetamol, phenylephrine HCl and diphenhydramine HCl) and FDA-approved excipients are studied. The simplicity of the structure of the tablet and method via templating allow the fabrication of these fully customizable drug tablets to be simple, low-cost, efficient, and safe for consumption. These features enable the customizable tablets to be made widely accessible to the public; hence, the concept of personalized medicine can be realized.
Patient-friendly medical diagnostics and treatments have been receiving a great deal of interest due to their rapid and cost-effective health care applications with minimized risk of infection, which has the potential to replace conventional hospital-based medical procedures. In particular, the integration of recently developed materials into health care devices allows the rapid development of point-of-care (POC) sensing platforms and implantable devices with special functionalities. In this review, the recent advances in biosensors for patient-friendly diagnosis and implantable devices for patient-friendly treatment are discussed. Comprehensive analysis of portable and wearable biosensing platforms for patient-friendly health monitoring and disease diagnosis is provided, including topics such as materials selection, device structure and integration, and biomarker detection strategies. Moreover, specific challenges related to each biological fluid for wearable biosensor-based POC applications are presented. Also, advances in implantable devices, including recent materials development and wireless communication strategies, are discussed. Furthermore, various patient-friendly surgical and treatment approaches are reviewed, such as minimally invasive insertion and mounting, in vivo electrical and optical modulations, and post-operation health monitoring. Finally, the challenges and future perspectives toward the development of the patient-friendly diagnosis and treatment are provided.
Precision medicine is a field with huge potential for improving a patient’s quality of life, wherein therapeutic drug monitoring (TDM) can provide actionable insights. More importantly, incorrect drug dose is a common contributor to medical errors. However, current TDM practice is time-consuming and expensive, and requires specialised technicians. One solution is to use electrochemical biosensors (ECBs), which are inexpensive, portable, and highly sensitive. In this review, we explore the potential for ECBs as a technology for on-demand drug monitoring, including microneedles, continuous monitoring, synthetic biorecognition elements, and multi-material electrodes. We also highlight emerging strategies to achieve continuous drug monitoring, and conclude by appraising recent developments and providing an outlook for the field.
The oral route represents the main pathway used to deliver drugs locally and systemically. Despite the technological advancements and rise of novel dosage forms, to date, tablets and capsules still remain the most commonly used types of medications. This is mainly due to the numerous advantages they offer, making them highly preferable over other dosage forms. Indeed, the behavior of a drug product is governed by a multitude of critical quality attributes, which should be carefully considered and defined when designing a formulation. This chapter aims to outline the different types of solid oral dosage forms, give an overview on the manufacturing techniques and excipients involved in their production, as well as discuss the characterization and validation methods recommended during processing.
The 3D printing of drug formulations is a promising method for preparing tailored medicines following the approval of 3D printed tablets by the US FDA in 2015. Appropriate dosage forms for pediatric patients are deficient because drugs have been developed for mainly adult patients. Here, we fabricated gummy drug formulations for pediatric patients using a 3D bioprinter compatible with semi-solid materials such as hydrogels and pastes. The gummy drug formulations were composed of gelatin, HPMC, reduced syrup, water and the antiepileptic drug lamotrigine. The formulations were extruded from the nozzle of the 3D bioprinter under air pressure and laminated from the bottom in a layer-by-layer process. The incorporation of HPMC aided smooth printing at room temperature, and gelatin and HPMC affected the viscosity of the drug formulation and the printability of the formulations. The strength of the gummy formulations was remarkably influenced by the gelatin concentration. Dissolution tests showed 85% drug release within 15 min from most formulations. The results suggest that 3D printing is an effective method for preparing gummy drug formulations with various shapes in different colors, and that the methodology may improve drug adherence of pediatric patients in future clinical settings.
Selective laser sintering (SLS) sinters a powder layer by layer with a laser beam to prepare 3D printlets, which are widely used in the field of tissue engineering and personalized implants. To promote the SLS printing of oral solid preparations, the printability of commonly used drugs and excipients was evaluated using a 450 nm low energy laser. It was found that yellow drugs could absorb laser energy and sinter, while white drugs and pharmaceutical excipients had SLS printability when tartrazine lake was added as a photoabsorber. The printing mechanism of non-crystalline and crystalline polymers was powder sintering and powder melting, respectively. Increasing the laser energy density was beneficial to the printing efficiency but reduced printing accuracy. To ensure the integrity of multilayer printlets, the sintered thickness of each layer should be greater than the layer thickness. Furthermore, ibuprofen immediate-release tablets and metoprolol tartrate sustained-release tablets were prepared. Using 10% carboxy methyl starch sodium as an additive, the shell tablets with a side thickness of 1.5 mm had a good appearance and fast dissolution. Based on the optimized formulation, IBU preparations with various design shown good appearance and fast release property. There was no difference in the drug’s crystalline state after SLS printing. Besides, the printed reservoir tablets with a sustained-released coating thickness of 3.5 mm had a good appearance and allowed 12 h sustained release. The results revealed that the SLS technique has great prospects in producing personalized oral preparations with immediate-release and sustained-release properties.
Microneedles as novel transdermal drug delivery systems have lately attracted extensive attention due to their distinguished properties, including improved patient compliance and self-administration, compared to tradi-tional parenteral administrations such as intravenous injection, intramuscular injection and subcutaneous in-jection. However, the great difficulties of precisely manufacturing those microneedles and patches within micro scale have strongly retarded their commercialization and clinical applications, particularly for the personalized medicine. Recently, numerous researches of utilizing 3D-priting process to fabricate transdermal drug delivery systems have been reported, not only adopting versatile printing methodologies, but also utilizing with different formulation strategies, to fabricate both artificial cargo delivery systems and sophisticated bio-inspired micro-needles. This review aims to summarize those lately reported studies and to elaborate their advantages and limitations, discussing promising potential applications as novel drug delivery systems.
In this study Fusion Deposition Modelling (FDM) was employed to design and fabricate a bilayer tablet consisting of isoniazid (INZ) and rifampicin (RFC) for the treatment of tuberculosis. INZ was formulated in hydroxypropyl cellulose (HPC) matrix to allow drug release in the stomach (acidic conditions) and RFC was formulated in hypromellose acetate succinate (HPMC-AS) matrix to allow drug release in the upper intestine (alkaline conditions). This design may offer a better clinical efficacy by minimizing the degradation of RFC in the acidic condition and potentially avoid drug-drug interaction. The bilayer tablet was prepared by fabricating drug containing filaments using hot melt extrusion (HME) coupled with the 3D printing. The HME and 3D printing processes were optimized to avoid drug degradation and assure consistent deposition of drug-containing layers in the tablet. The in-vitro drug release rate was optimized by varying drug loading, infilling density, and covering layers. Greater than 80% of INZ was released in 45 mins at pH 1.2 and approximately 76% of RFC was releases in 45 mins after the dissolution medium was changed to pH 7.4. The work illustrated the potential application of FDM technology in the development of oral fixed dose combination for personalized clinical treatment.
Intravesical instillation therapy is an alternative approach to oral medications for the treatment of severe bladder diseases, offering high drug concentrations at the site of action while minimising systemic side effects. However, therapeutic efficacy is often limited because of the short residence time of the drug in the bladder and the need for repeated instillations. This study reports, for the first time, the use of stereolithography (SLA) 3D printing to manufacture novel indwelling bladder devices using an elastic polymer to achieve extended and localised delivery of lidocaine hydrochloride. The devices were designed to be inserted into and retrieved from the bladder using a urethral catheter. Two types of bladder devices (hollow and solid) were prepared with a resilient material (Elastic Resin) incorporating three drug loads of lidocaine hydrochloride (10% w/w, 30% w/w and 50% w/w); a drug frequently used to treat interstitial cystitis and bladder pain. All of the devices showed acceptable blood compatibility, good resistance to compressive and stretching forces and were able to recover their original shape immediately once external forces were removed. In vitro drug release studies showed that a complete release of lidocaine was achieved within 4 days from the hollow devices, whereas the solid devices enabled sustained drug release for up to 14 days. SLA 3D printing therefore provides a new manufacturing route to produce bladder-retentive drug delivery devices using elastic polymers, and offers a revolutionary and personalised approach for clinical intravesical drug delivery.
Current treatment for pelvic organ prolapse (POP) and stress urinary incontinence (SUI) involves transvaginal implantation of surgical mesh, conventionally made of polypropylene (PP). However, it has recently become apparent that the mechanical properties of PP are unsuitable, resulting in serious complications such as tissue erosion. In this study, thermoplastic polyurethane (TPU) was chosen as an alternative material, and hormone-loaded meshes were produced by fused deposition modelling (FDM). Filaments containing various concentrations (0%, 0.25%, 1%) of 17-β-estradiol (E2) were prepared by hot-melt extrusion (HME) and were 3D printed into meshes with various geometries. The resulting meshes were characterised through a variety of instruments such as attenuated total reflection-Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), thermal analysis, fracture force and in vitro release studies. The results showed that E2 was homogeneously distributed throughout the TPU matrix. Moreover, the thermogravimetric analysis (TGA) showed degradation temperatures above those used during the FDM process, showing that the meshes can be produced below the degradation temperatures of the materials. The fracture force testing showed that material and mesh geometry influence mechanical properties, with TPU meshes appearing more elastic and therefore more suitable for pelvic floor repair than PP mesh. However, interestingly the mechanical properties of the TPU70 filament was not affected by the inclusion of E2. In addition, the 3D printed meshes showed a linear E2 release profile over a two weeks period, which can be modified according to the percentage of E2 added to the 3D printed construct. This proof of concept study demonstrates the potential of using FDM to create a new generation of safer mesh implants.
Hot-melt extruded (HME) filaments are an essential intermediate product for the three- dimensional (3D) printing of drug delivery systems (DDSs) by the fused deposition modelling (FDM) process. The aim of this study was to design novel polymeric 3D-printable HME filaments loaded with active pharmaceutical ingredients (APIs). The physical solid-state properties, mechanical properties, drug release and short-term storage stability of the filaments and 3D-printed DDSs were studied. Physical powder mixtures of polycaprolactone (PCL), plasticizer and API were manually blended, extruded by a single-screw extruder, and printed by a table-top FDM 3D-printing system. The composition of PCL and arabic gum (ARA) enabled the incorporation of 20%, 30% and 40% (w/w) of indomethacin (IND) and theophylline (THEO) into the HME filaments. The uneven distribution of API throughout the filaments impaired 3D printing. The HME filaments loaded with 20% IND or THEO were selected for the further analysis and printing tests (the ratio of PCL, ARA and IND or THEO was 7:1:2, respectively). The IND filaments were yellowish, mechanically strong and flexible, and they had a uniform filament diameter and smooth outer surface. The filaments containing THEO were smooth and off-white. The 3D-printed tablets fabricated from IND or THEO-loaded filaments showed sustained drug release in vitro. The drug release rate, however, significantly increased by changing the geometry of 3D-printed tablets from a conventional tablet structure to an unorthodox lattice (“honeycomb”) structure. Overall, the combination of PCL and ARA provides an interesting novel polymeric carrier system for 3D-printable HME filaments and tablets.
The three-dimensional (3D) printing technology has recently emerged in the pharmaceutical field, providing an array of applications for individualized dosing and elaborate formulation designs. However, an alternative asset of the 3D printing technology is the capability to imprint haptic identifiers directly onto the surface of the formulations. This approach can generate novel design concepts, that will serve specific populations for identifying the right treatment regimen, i.e., visually impaired people. Toward this direction, the fused deposition modelling (FDM) technique was investigated for manufacturing intraoral films and incorporating Braille characters on the available area. The films comprised a drug-loaded compartment and a backing layer, which are typical structural characteristics for buccal delivery. A hydrophilic polymer, i.e., hydroxypropyl methylcellulose, provided the polymer matrix for both compartments, whereas ketoprofen was incorporated in the study as model drug. The Braille-encoded texts were designed on top of the backing layer, complying with the Marburg Medium spacing convention for pharmaceutical Braille. Moreover, modifications on the standard spacing and dimension parameters were applied, to investigate the accuracy and repeatability of the FDM process. The fabricated films were subjected to a haptic evaluation study with the aid of visually impaired individuals, to assess the readability of the 3D-printed Braille-encoded text. The outcomes of the study highlighted the capacity of the FDM technology in combining novel manufacturing concepts for individualized therapies with customized services that can be provided to specific populations, as in the case of people with visual impairment.
Precision medicine is a field with huge potential for improving a patient’s quality of life, wherein therapeutic drug monitoring (TDM) can provide actionable insights. More importantly, incorrect drug dose is a common contributor to medical errors. However, current TDM practice is time-consuming and expensive, and requires specialised technicians. One solution is to use electrochemical biosensors (ECBs), which are inexpensive, portable, and highly sensitive. In this review, we explore the potential for ECBs as a technology for on-demand drug monitoring, including microneedles, continuous monitoring, synthetic biorecognition elements, and multi-material electrodes. We also highlight emerging strategies to achieve continuous drug monitoring, and conclude by appraising recent developments and providing an outlook for the field.
3D printing, and particularly fused deposition modeling (FDM), has rapidly brought the possibility of personalizing drug therapies to the forefront of pharmaceutical research and media attention. Applications for this technology, described in published articles, are expected to grow significantly in 2020. Where are we on this path, and what needs to be done to develop a FDM 2.0 process and make personalized medicines available to patients? Based on literature analysis, this manuscript aims to answer these questions and highlight the critical technical aspects of FDM as an emerging technology for manufacturing safe, high-quality personalized oral drug products. In this collaborative paper, experts from different fields contribute strategies for ensuring the quality of starting materials and discuss the design phase, printer hardware and software, the process, the environment and the resulting products, from the perspectives of both patients and operators.
Over 5% of the world's population has disabling hearing loss, which affects approximately one third of individuals over 65 years. Hearing aids are commonly used in this population group, but prolonged use of these devices may cause ear infections. We describe for the first time, the use of 3D printing to fabricate hearing aids loaded with two antibiotics, ciprofloxacin and fluocinolone acetonide. Digital light processing 3D printing was employed to manufacture hearing aids from two polymer resins, ENG hard and Flexible. The inclusion of the antibiotics did not affect the mechanical properties of the hearing aids. All multi-drug-loaded devices exhibited a hydrophilic surface, excellent blood compatibility and anti-biofilm activity against P. aeruginosa and S. aureus. Hearing aids loaded with ciprofloxacin (6%w/w) and fluocinolone acetonide (0.5% w/w) sustained drug release for more than two weeks and inhibited biofilm formation on the surface of the devices and bacteria growth in the surrounding medium. In summary, this work highlights the potential of vat photopolymerization 3D printing as a versatile manufacturing approach to fabricate high-fidelity patient-specific medical devices with anti-bacterial properties.
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.
Artificial intelligence (AI) has the potential to reshape pharmaceutical formulation development through its ability to analyze and continuously monitor large datasets. Fused deposition modeling (FDM) 3-dimensional printing (3DP) has made significant advancements in the field of oral drug delivery with personalized drug-loaded formulations being designed, developed and dispensed for the needs of the patient. However, the optimization of the fabrication parameters is a time-consuming, empirical trial approach, requiring expert knowledge. Here, M3DISEEN, a web-based pharmaceutical software, was developed to accelerate FDM 3D printing, which includes producing filaments by hot melt extrusion (HME), using AI machine learning techniques (MLTs). In total, 614 drug-loaded formulations were designed from a comprehensive list of 145 different pharmaceutical excipients, 3D printed and assessed in-house. To build the predictive tool, a dataset was constructed and models were trained and tested at a ratio of 75:25. Significantly, the AI models predicted key fabrication parameters with accuracies of 76% and 67% for the printability and the filament characteristics, respectively. Furthermore, the AI models predicted the HME and FDM processing temperatures with a mean absolute error of 8.9 °C and 8.3 °C, respectively. Strikingly, the AI models achieved high levels of accuracy by solely inputting the pharmaceutical excipient trade names. Therefore, AI provides an effective holistic modeling technology and software to streamline and advance 3DP as a significant technology within drug development. M3DISEEN is available at (http://m3diseen.com/predictions/).
Rheology is an indispensable tool for formulation development, which when harnessed, can both predict a material's performance and provide valuable insight regarding the material's macrostructure. However, rheological characterizations are under-utilized in 3D printing of drug formulations. In this study, viscosity measurements were used to establish a mathematical model for predicting the printability of fused deposition modelling 3D printed tablets (Printlets). The formulations were composed of polycaprolactone (PCL) with different amounts of ciprofloxacin and polyethylene glycol (PEG), and different molecular weights of PEG. With all printing parameters kept constant, both binary and ternary blends were found to extrude at nozzle temperatures of 130, 150 and 170 C. In contrast PCL was unextrudable at 130 and 150 C. Three standard rheological models were applied to the experimental viscosity measurements, which revealed an operating viscosity window of between 100-1000 Pa.s at the apparent shear rate of the nozzle. The drug profile of the printlets were experimentally measured over seven days. As a proof-of-concept, machine learning models were developed to predict the dissolution behaviour from the viscosity measurements. The machine learning models were discovered to accurately predict the dissolution profile, with the highest f2 similarity score value of 90.9 recorded. Therefore, the study demonstrated that using only the viscosity measurements can be employed for the simultaneous high-throughput screening of formulations that are printable and with the desired release profile.