Adaptation of pharmaceutical excipients to FDM 3D printing for the fabrication of patient-tailored immediate release tablets

This work aims to employ fused deposition modelling 3D printing to fabricate immediate release pharmaceutical tablets with various model drugs. It investigates the addition of non-melting filler to methacrylic matrix to facilitate FDM 3D printing and explore the impact of (i) the nature of filler, (ii) compatibility with the gears of the 3D printer and, and iii) polymer: filler ratio on the 3D printing process. A specially developed filament based on pharmaceutically approved methacrylic polymer (Eudragit E) and thermally stable filler, TCP (tribasic calcium phosphate) was optimised. Four model drugs with different physicochemical properties were included into ready-to-use mechanically stable tablets with immediate release properties. Amongst the investigated fillers in this work, directly compressible lactose, spray-dried lactose and microcrystalline cellulose showed a level of degradation at 135°C whilst talc and TCP allowed consistent flow of the filament and a successful 3D printing of the tablet. Following the two thermal processes (hot melt extrusion (HME) and fused deposition modelling (FDM) 3D printing), drug contents were 94.22%, 88.53%, 96.51% and 93.04% for 5-ASA, captopril, theophylline and prednisolone respectively. XRPD indicated that a fraction of 5-ASA, theophylline and prednisolone remained in the crystalline form whilst captopril was in amorphous form. By combining the advantages of thermally stable pharmaceutically approved polymers and fillers, this unique approach provides a low cost production method for on demand manufacturing of individualised dosage forms

From 'fixed dose combinations' to 'a dynamic dose combiner': 3D printed bi-layer antihypertensive tablets

There is an increased evidence for treating hypertension by a combination of two or more drugs. Increasing the number of daily intake of tablets has been reported to negatively affect the compliance by patients. Therefore, numerous fixed dose combinations (FDCs) have been introduced to the market. However, the inherent rigid nature of FDCs does not allow titration of the dose of each single component for individual patient needs. In this work, flexible dose combinations of two anti-hypertensive drugs in a single bilayer tablet with a range of doses were fabricated using dual fused deposition modelling (FDM) 3D printer. Enalapril maleate (EM) and hydrochlorothiazide (HCT) loaded filaments were produced via hot-melt extrusion (HME). Computer software was utilized to design sets of oval bi-layer tablet of individualised doses. Thermal analysis and x-ray diffractometer (XRD) indicated that HCT remained crystalline in the polymeric matrix whilst EM appeared to be in an amorphous form. The interaction between anionic EM and cationic methacrylate polymer may have contributed to a drop in the glass transition temperature (Tg) of the filament and obviated the need for a plasticiser. Across all tablet sets, the methacrylate polymeric matrix provided immediate drug release profiles. This dynamic dosing system maintained the advantages of FDCs while providing a superior flexibility of dosing range, hence offering an optimal clinical solution to hypertension therapy in a patient-centric healthcare service. [Abstract copyright: Copyright © 2018. Published by Elsevier B.V.

Emergence of 3D Printed Dosage Forms: Opportunities and Challenges

The recent introduction of the first FDA approved 3D-printed drug has fuelled interest in 3D printing technology, which is set to revolutionize healthcare. Since its initial use, this rapid prototyping (RP) technology has evolved to such as extent that it is currently being used in a wide range of applications including in tissue engineering, dentistry, construction, automotive and aerospace. However, in the pharmaceutical industry this technology is still in its infancy and its potential yet to be fully explored. This paper presents various 3D printing technologies such as stereolithographic, powder based, selective laser sintering, fused deposition modelling and semi-solid extrusion 3D printing. It also provides a comprehensive review of previous attempts at using 3D printing technologies on the manufacturing dosage forms with a particular focus on oral tablets. Their advantages particularly with adaptability in the pharmaceutical field have been highlighted, including design flexibility and control and manufacture which enables the preparation of dosage forms with complex designs and geometries, multiple actives and tailored release profiles. An insight into the technical challenges facing the different 3D printing technologies such as the formulation and processing parameters is provided. Light is also shed on the different regulatory challenges that need to be overcome for 3D printing to fulfil its real potential in the pharmaceutical industry

Engineering immediate release tablets with customized design and drug combination via fused deposition modelling 3d printing

In respect of personalised doses, fused deposition modelling 3D printing delivers a viable alternative to the mass manufacture of pharmaceuticals. Its advantages draw from low-cost, convenient use and flexible bespoke dosages. However, few polymers are compatible with the fused deposition modelling 3D printing of pharmaceuticals out of which very little is for immediate-release. The aim of this work was to investigate the feasibility of manufacturing immediate-release dosage forms with customised designs and drug combinations, using fused deposition modelling 3D Printing. Five drugs with different physicochemical properties were investigated to ascertain the practicality of using an immediate release methacrylate polymer (Eudragit EPO) and thermally stable filler (tribasic calcium phosphate). Filaments were optimised against the constraints of thermal stability, flexibility, rheological properties and compatibility with a bench top 3D printer. For the drugs investigated, the manufacture of ready-to-use mechanically stable tablets with immediate release properties was successful. In combining thermally stable pharmaceutically approved polymers and fillers, a viable production method was demonstrated for the on-demand manufacture of customised dosages. Although fixed-dose combinations are marketed, their inherently rigid nature does not allow the titration of every component for individual patient needs, which leads to non-compliance by increasing the number of tablets taken by the patient. Using a dual 3D printer, and enalapril maleate and hydrochlorothiazide loaded filaments produced via hot melt extrusion; a range of flexible dose combinations of two anti- hypertensive drugs in a single bilayer tablet was produced by altering individual drug’s layer thickness. Across all tablet sets, the methacrylate matrix delivered comparable in vitro drug release profiles. This dynamic dosing system retained the advantages of fixed-dose combinations while providing superior flexibility in the dosing range, thereby offering an optimal clinical solution to hypertension. A large amount of polymer that is necessary for fused deposition modelling 3D tablet printing retards drug release through erosion and diffusion. In addressing that problem, we utilise a novel design of caplets with perforating square channels, which accelerate drug release from the increased surface area/volume ratio. To ascertain their stability and shelf life, filaments were stored as pre-products for six months, both at room temperature and in a refrigerator. Three polymers were used with a high melting-point drug theophylline. For Eudragit RL and Eudragit EPO the results were successful; but, by its hygroscopic nature, the experiment confirms that hydroxypropyl cellulose SSL cannot be stored for prolonged periods. Provided that the clinical work is carried out, this work has paved the way to manufacture individualised doses and bespoke designs of dosage forms in an economical way

Channelled tablets: An innovative approach to accelerating drug release from 3D printed tablets

Conventional immediate release dosage forms involve compressing the powder with a disintegrating agent that enables rapid disintegration and dissolution upon oral ingestion. Among 3D printing technologies, the fused deposition modelling (FDM) 3D printing technique has a considerable potential for patient-specific dosage forms. However, the use of FDM 3D printing in tablet manufacturing requires a large portion of polymer, which slows down drug release through erosion and diffusion mechanisms. In this study, we demonstrate for the first time the use of a novel design approach of caplets with perforated channels to accelerate drug release from 3D printed tablets. This strategy has been implemented using a caplet design with perforating channels of increasing width (0.2, 0.4, 0.6, 0.8 or 1.0 mm) and variable length, and alignment (parallel or at right angle to tablet long axis). Hydrochlorothiazide (BCS class IV drug) was chosen as the model drug as enhanced dissolution rate is vital to guarantee oral bioavailability. The inclusion of channels exhibited an increase in the surface area/volume ratio, however, the release pattern was also influenced by the width and the length of the channel. A channel width was ≥ 0.6 mm deemed critical to meet the USP criteria of immediate release products. Shorter multiple channels (8.6 mm) were more efficient at accelerating drug release than longer channels (18.2 mm) despite having comparable surface area/mass ratio. This behaviour may be linked to the reduced flow resistance within the channels and the faster fragmentation during dissolution of these tablets. In conclusion, the width and length of the channel should be carefully considered in addition to surface area/mass when optimizing drug release from 3D printed designs. The incorporation of short channels can be adopted in the designs of dosage forms, implants or stents to enhance the release rate of eluting drug from polymer-rich structures

Can Filaments be stored as a shelf-item for on-demand manufacturing of oral 3D printed tablets? An initial stability assessment

3D printing of oral solid dosage forms is a recently introduced approach for dose personalisation. Fused deposition modelling (FDM) is one of the promising and heavily researched 3D printing techniques in the pharmaceutical field. However, the successful application of this technique relies greatly on the mass manufacturing of physically and chemically stable filaments, that can be readily available as a shelf item to be 3D printed on-demand. In this work, the stability of methacrylate polymers (Eudragit EPO, RL, L100-55 and S100), hydroxypropyl cellulose (HPC SSL) and polyvinyl pyrrolidone (PVP)-based filaments over 6 months were investigated. Filaments manufactured by hot melt extrusion (HME) were stored at either 5 oC or 30 oC + 65 %RH with/without vacuuming. The effects of storage on their dimensions, visual appearance, thermal properties, and ‘printability’ were analysed. Theophylline content, as well as in vitro release from the 3D printed tablets were also investigated. The filaments were analysed before storage, then after 1, 3 and 6 months from the manufacturing Storing filaments at these conditions had a significant effect on their physical properties such as shape, dimensions, flexibility and hence compatibility with FDM 3D printing. In general, the methacrylate-based filaments were more physically stable and compatible with FDM 3D printing following storage. Owing to their hygroscopic nature, cellulose- and PVP-based filaments demonstrated a reduction in their glass transition temperature upon storage, leading to increased flexibility and incompatibility with FDM 3D printer. Theophylline contents was not significantly changed during the storage. This work provides preliminary data for the impact of polymer species on the long-term stability of the filaments. In general, storage and packaging conditions have major impact on the potential of on-demand manufacturing of 3D printed tablets using hot melt extruded filaments

A Systematic Review of Internet of Things in Clinical Laboratories: Opportunities, Advantages, and Challenges

The Internet of Things (IoT) is the network of physical objects embedded with sensors, software, electronics, and online connectivity systems. This study explores the role of IoT in clinical laboratory processes; this systematic review was conducted adhering to the PRISMA Statement 2020 guidelines. We included IoT models and applications across preanalytical, analytical, and postanalytical laboratory processes. PubMed, Cochrane Central, CINAHL Plus, Scopus, IEEE, and A.C.M. Digital library were searched between August 2015 to August 2022; the data were tabulated. Cohen’s coefficient of agreement was calculated to quantify inter-reviewer agreements; a total of 18 studies were included with Cohen’s coefficient computed to be 0.91. The included studies were divided into three classifications based on availability, including preanalytical, analytical, and postanalytical. The majority (77.8%) of the studies were real-tested. Communication-based approaches were the most common (83.3%), followed by application-based approaches (44.4%) and sensor-based approaches (33.3%) among the included studies. Open issues and challenges across the included studies included scalability, costs and energy consumption, interoperability, privacy and security, and performance issues. In this study, we identified, classified, and evaluated IoT applicability in clinical laboratory systems. This study presents pertinent findings for IoT development across clinical laboratory systems, for which it is essential that more rigorous and efficient testing and studies be conducted in the future

A systematic review of internet of things in clinical laboratories: Opportunities, advantages, and challenge

The Internet of Things (IoT) is the network of physical objects embedded with sensors, software, electronics, and online connectivity systems. This study explores the role of IoT in clinical laboratory processes; this systematic review was conducted adhering to the PRISMA Statement 2020 guidelines. We included IoT models and applications across preanalytical, analytical, and postanalytical laboratory processes. PubMed, Cochrane Central, CINAHL Plus, Scopus, IEEE, and A.C.M. Digital library were searched between August 2015 to August 2022; the data were tabulated. Cohen\u27s coefficient of agreement was calculated to quantify inter-reviewer agreements; a total of 18 studies were included with Cohen\u27s coefficient computed to be 0.91. The included studies were divided into three classifications based on availability, including preanalytical, analytical, and postanalytical. The majority (77.8%) of the studies were real-tested. Communication-based approaches were the most common (83.3%), followed by application-based approaches (44.4%) and sensor-based approaches (33.3%) among the included studies. Open issues and challenges across the included studies included scalability, costs and energy consumption, interoperability, privacy and security, and performance issues. In this study, we identified, classified, and evaluated IoT applicability in clinical laboratory systems. This study presents pertinent findings for IoT development across clinical laboratory systems, for which it is essential that more rigorous and efficient testing and studies be conducted in the future

Transdermal Delivery of Glimepiride: A Novel Approach Using Nanomicelle-Embedded Microneedles

Glimepiride (GM) is a hydrophobic drug that dissolves slowly and yields inconsistent clinical responses after oral administration. Transdermal drug delivery (TDD) is an appropriate alternative to oral administration. Microneedles (MNs) offer a promising delivery system that penetrates the skin, while polymeric micelles can enhance the solubility; hence, the combination of both results in high drug bioavailability. This study aims to improve glimepiride’s solubility, dissolution rate, and bioavailability by incorporating nanomicelles into MNs for TDD. The nanomicelles formulated with 10% Soluplus® (SP) and 40% GM had a mean particle size of 82.6 ± 0.54, PDI of 0.1 ± 0.01, −16.2 ± 0.18 zeta potential, and achieved a 250-fold increase in solubility. The fabricated pyramid shaped GM-dissolving MNs were thermally stable and had no formulation incompatibility, as confirmed by thermal and FTIR analysis. The in vitro dissolution profile revealed that the GM release from nanomicelles and nanomicelle-loaded DMN was concentration-independent following non-Fickian transport mechanism. Improved pharmacokinetic parameters were obtained with dose of 240 µg as compared to 1 mg of GM oral tablet, in healthy human volunteers. The observed Cmax, Tmax and MRT were 1.56 μg/mL ± 0.06, 4 h, and 40.04 h ± 3.37, respectively. The safety profile assessment indicated that microneedles are safe with no adverse effects on skin or health. This study provides an alternative delivery system for the administration of glimepiride, resulting in improved bioavailability, enhanced patient compliance, and reduced dosing frequency

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit