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

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

Inkjet Printing of Pharmaceuticals

© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC), https://creativecommons.org/licenses/by-nc/4.0/Inkjet printing (IJP) is an additive manufacturing process that selectively deposits ink materials, layer-by-layer, to create 3D objects or 2D patterns with precise control over their structure and composition. This technology has emerged as an attractive and versatile approach to address the ever-evolving demands of personalized medicine in the healthcare industry. Although originally developed for nonhealthcare applications, IJP harnesses the potential of pharma-inks, which are meticulously formulated inks containing drugs and pharmaceutical excipients. Delving into the formulation and components of pharma-inks, the key to precise and adaptable material deposition enabled by IJP is unraveled. The review extends its focus to substrate materials, including paper, films, foams, lenses, and 3D-printed materials, showcasing their diverse advantages, while exploring a wide spectrum of therapeutic applications. Additionally, the potential benefits of hardware and software improvements, along with artificial intelligence integration, are discussed to enhance IJP's precision and efficiency. Embracing these advancements, IJP holds immense potential to reshape traditional medicine manufacturing processes, ushering in an era of medical precision. However, further exploration and optimization are needed to fully utilize IJP's healthcare capabilities. As researchers push the boundaries of IJP, the vision of patient-specific treatment is on the horizon of becoming a tangible reality.Peer reviewe

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

© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/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.Peer reviewe

Predicting pharmaceutical inkjet printing outcomes using machine learning

[Abstract]: Inkjet printing has been extensively explored in recent years to produce personalised medicines due to its low cost and versatility. Pharmaceutical applications have ranged from orodispersible films to complex polydrug implants. However, the multi-factorial nature of the inkjet printing process makes formulation (e.g., composition, surface tension, and viscosity) and printing parameter optimization (e.g., nozzle diameter, peak voltage, and drop spacing) an empirical and time-consuming endeavour. Instead, given the wealth of publicly available data on pharmaceutical inkjet printing, there is potential for a predictive model for inkjet printing outcomes to be developed. In this study, machine learning (ML) models (random forest, multilayer perceptron, and support vector machine) to predict printability and drug dose were developed using a dataset of 687 formulations, consolidated from in-house and literature-mined data on inkjet-printed formulations. The optimized ML models predicted the printability of formulations with an accuracy of 97.22%, and predicted the quality of the prints with an accuracy of 97.14%. This study demonstrates that ML models can feasibly provide predictive insights to inkjet printing outcomes prior to formulation preparation, affording resource- and time-savings.The research was partially supported by MCIN (PID 2020-113881RB-I00/AEI/10.13039/501100011033), Spain, Xunta de Galicia (ED431C 2020/17), and FEDER.L.R.P. acknowledges the predoctoral fellowship provided by the Ministerio de Universidades (Formación de Profesorado Universitario (FPU 2020). I.S.V. acknowledges Consellería de Cultura, Educación e Universidade for her Postdoctoral Fellowship (Xunta de Galicia, Spain; ED481B-2021-019). L.R.P. acknowledges the predoctoral fellowship provided by the Ministerio de Universidades (Formación de Profesorado Universitario (FPU 2020) .Xunta de Galicia; ED431C 2020/17Xunta de Galicia; ED481B-2021-01

Polymorphisms in genes related to the complement system and antibody-mediated cardiac allograft rejection

[Abstract] Background. Heart transplantation (HT) is a life-saving treatment for patients with end-stage heart failure. One of the main problems after HT is the humoral response termed antibody-mediated rejection (AMR). Complement activation plays a key role in AMR contributing to graft damage. The aim of this study was to analyze genetic variants in genes related to the complement pathways that could be associated with the development of AMR. Methods. Analysis of 51 genes related to the complement pathway was performed by next-generation sequencing in 46 HT recipients, 23 with and 23 without AMR. Statistical analysis was performed with SNPstats and R. Results. We identified 2 single nucleotide polymorphisms, 1 in the mannose-binding lectin 2 gene (p.Gly54Asp-MBL2) and 1 in the complement factor properdin gene (p.Asn428(p=)-CFP), that showed significant association with the absence and development of AMR, respectively. Moreover, the presence of the rare allele in p.Gly54Asp-MBL2 control patients correlated with an immunodeficiency of mannose-binding lectin (6.24 ng/ml vs 207.50 ng/ml, p < 0.01), whereas the presence of the rare allele p.Asn428(p=)-CFP in patients with AMR correlated with higher levels of properdin protein (14.65 μg/ml vs 10.77 μg/ml, p < 0.05). Conclusions. AMR is a complex phenotype affected by many recipient factors. Variants in p.Gly54Asp-MBL2 and p.Asn428(p=)-CFP genes, encoding mannose-binding lectin 2 and properdin, may influence the risk of AMR.Instituto de Salud Carlos III; PI13/0217

Circulating miR-181a-5p as a new biomarker for acute cellular rejection in heart transplantation

[Abstract] Background: Acute cellular rejection (ACR) is a major complication in heart transplantation (HTx). Endomyocardial biopsy is the reference method for early detection of ACR, but a new non-invasive approach is needed. Tentative candidates could be circulating microRNAs. This study aimed to discover and validate microRNAs in serum for ACR detection after HTx. Methods: This prospective, observational, single-center study included 121 HTx patients. ACR was graded according to International Society of Heart and Lung Transplantation classification (0R−3R). First, in the discovery phase, microRNA expression profile was carried out in serum samples from patients at pre-rejection, during, and post-rejection time (0RS1 → 2RS2 → 0RS3). Relative expression (2-ΔCq) of 179 microRNAs per sample was analyzed by reverse transcription quantitative polymerase chain reaction. Second, a microRNA with a significant rise and fall pattern during ACR was selected for the next validation phase, where it was analyzed (reverse transcription quantitative polymerase chain reaction) in serum samples from 2 groups of patients: the no-ACR group (0R grade) and the ACR group (≥2R grade). Finally, a sensitivity analysis (receiver operating characteristic curve) was done to assess microRNA accuracy for ACR detection in HTx. Results: A total of 21 ACR episodes (0RS1 → 2RS2 → 0RS3) with their respective serum samples (n = 63) were included in the discovery phase. Among the 179 microRNAs analyzed, only miR-181a-5p met the rise and fall criteria. In the validation phase, miR-181a-5p relative expression (2-ΔCq) in the ACR group (n = 45) was significantly overexpressed (p < 0.0001) vs the no-ACR group (n = 45). miR-181a-5p showed an area under the curve of 0.804 (95% confidence interval: 0.707-0.880); sensitivity and specificity of 78% and 76%, respectively; and a negative predicted value of 98%.Instituto de Salud Carlos III; PI15/0222

Galectina-3 circulante tras el trasplante cardiaco: dinámica a largo plazo y valor pronóstico

[Abstract] Introduction and objectives: Circulating galectin-3 (Gal-3) is elevated and significantly correlates with all-cause and cardiovascular mortality in patients with heart failure. However, the relationship between serum Gal-3 and heart transplant (HT) outcomes is unclear. The aim of this study was to describe the longitudinal trend and prognostic value of Gal-3 levels after HT. Methods: Banked serum samples were available from 122 HT recipients, collected before transplant and at 1, 3, 6, and 12 months posttransplant. Gal-3 levels in these serum samples were measured by enzyme immune assay. Multivariable Cox regression was performed to determine the prognostic value of 12-month posttransplant Gal-3 serum levels. The primary endpoint was the composite variable all-cause death or graft failure over long-term posttransplant follow-up. Results: Circulating Gal-3 concentration steadily decreased during the first year after HT (median values: pretransplant, 19.1 ng/mL; 1-year posttransplant, 14.6 ng/mL; P<.001). Circulating Gal-3 levels 1-year posttransplant were associated with an increased risk of all-cause death or graft failure (adjusted HR per 1 ng/mL, 1.04; 95%CI, 1.01-1.08; P=.008). The predictive accuracy of this biomarker was moderate: area under the ROC curve, 0.72 (95%CI, 0.60-0.82; P<.001). Conclusions: Circulating Gal-3 steadily decreased during the first year after HT. However, 1-year posttransplant Gal-3 serum levels that remained elevated were associated with increased long-term risk of death and graft failure.[Resumen] Introducción y objetivos. Los valores plasmáticos de galectina-3 (Gal-3) están elevados y se correlacionan con la mortalidad total y cardiovascular en pacientes con insuficiencia cardiaca, pero su correlación con el pronóstico tras el trasplante cardiaco (TxC) es desconocida. El objetivo fue describir la tendencia evolutiva y el valor pronóstico de este biomarcador tras el TxC. Métodos. Mediante enzimoinmunoensayo, se midieron las concentraciones plasmáticas de Gal-3 en muestras de suero de 122 receptores de TxC, antes y 1, 3, 6 y 12 meses después de este. Mediante regresión de Cox se analizó el valor pronóstico del valor plasmático de Gal-3 a los 12 meses del TxC. El objetivo primario del estudio fue la variable combinada muerte o disfunción del injerto. Resultados. Las concentraciones de Gal-3 disminuyeron progresivamente durante el primer año tras el TxC (medianas: pretrasplante, 19,1 ng/ml; 1 año postrasplante, 14,6 ng/ml; p < 0,001). Los valores de Gal-3 1 año tras el TxC se asociaron con mayor riesgo de muerte o disfunción del injerto (HR por 1 ng/ml: 1.04; IC95%: 1,01-1,08; p = 0,008). La capacidad predictiva del biomarcardor fue moderada: área bajo la curva ROC, 0,72 (IC95%: 0,60-0,82; p < 0,001). Conclusiones. Las concentraciones plasmáticas de Gal-3 disminuyeron progresivamente durante el primer año tras el TxC. Un valor plasmático elevado de Gal-3 1 año tras el TxC se correlacionó con un pronóstico adverso.Instituto de Salud Carlos III; PI12/0267

El colegio encantado II : Piratas del Cervantes

El trabajo obtuvo un premio de la modalidad A de los Premios Tomás García Verdejo a las buenas prácticas educativas en la Comunidad Autónoma de Extremadura para el curso académico 2012/2013Se describe una experiencia llevada a cabo en el CEP Cervantes (Moraleja, Cáceres) que tenía por objetivo principal fomentar el interés y el gusto por la lectura a través de cuentos y en la que participasen, además de los profesores y alumnos,las familias y los monitores del centro. Para cumplir el objetivo la escuela se convirtió durante una noche en una isla pirata, donde habitaban personajes que contaban historias de diferente temáticaExtremaduraES