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Three-dimensional (3D) printing is becoming an attractive technology for the design and development of personalized paediatric dosage forms with improved palatability. In this work micro-extrusion based printing was implemented for the fabrication of chewable paediatric ibuprofen (IBU) tablets by assessing a range of front runner polymers in taste masking. Due to the drug-polymer miscibility and the IBU plasticization effect, micro-extrusion was proved to be an ideal technology for processing the drug/polymer powder blends for the printing of paediatric dosage forms. The printed tablets presented high printing quality with reproducible layer thickness and a smooth surface. Due to the drug-polymer interactions induced during printing processing, IBU was found to form a glass solution confirmed by differential calorimetry (DSC) while H-bonding interactions were identified by confocal Raman mapping. IBU was also found to be uniformly distributed within the polymer matrices at molecular level. The tablet palatability was assessed by panellists and revealed excellent taste masking of the IBU's bitter taste. Overall micro-extrusion demonstrated promising processing capabilities of powder blends for rapid printing and development of personalised dosage forms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

To provide novel data on surfactant levels in adult COVID-19 patients, we collected bronchoalveolar lavage fluid less than 72 h after intubation and used Fourier Transform Infrared Spectroscopy to measure levels of dipalmitoylphosphatidylcholine (DPPC). A total of eleven COVID-19 patients with moderate-to-severe ARDS (CARDS) and 15 healthy controls were included. CARDS patients had lower DPPC levels than healthy controls. Moreover, a principal component analysis was able to separate patient groups into distinguishable subgroups. Our findings indicate markedly impaired pulmonary surfactant levels in COVID-19 patients, justifying further studies and clinical trials of exogenous surfactant., (© 2022. The Author(s).)

The development of printable filaments has been identified as a critical aspect for the processing of pharmaceutical grade polymers and the fabrication of oral solid dosage forms. In this study a range of plain and drug loaded polymers were investigated and assessed for their printability in comparison to commercial filaments. Physicochemical characterizations of the polymers included differential scanning calorimetry (DSC) thermogravimetric analysis (TGA) and rheology were studied prior to Hot Melt Extrusion processing for the filament fabrication. A texture analyser was used to study the filament mechanical properties in order to derive the maximum tensile strength, Young's Modulus and elongation at break. Principal component analysis was used to compare the printability of the polymer and to identify the contribution of each mechanical property. The analysis showed that maximum tensile strength with a threshold between 15 and 20 MPa is the most critical property for the prediction of the printability. Furthermore, printable filaments were processed using Fusion Deposition Modelling technology and optimal printing parameters were identified. The study demonstrated that the prediction of filament printability is feasible by evaluating the mechanical properties., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aim: To develop a fast bedside test for prediction and early targeted intervention of bronchopulmonary dysplasia (BPD) to improve the outcome., Methods: In a multicentre study of preterm infants with gestational age 24-31 weeks, clinical data present at birth were combined with spectral data of gastric aspirate samples taken at birth and analysed using artificial intelligence. The study was designed to develop an algorithm to predict development of BPD. The BPD definition used was the consensus definition of the US National Institutes of Health: Requirement of supplemental oxygen for at least 28 days with subsequent assessment at 36 weeks postmenstrual age., Results: Twenty-six (43%) of the 61 included infants developed BPD. Spectral data analysis of the gastric aspirates identified the most important wave numbers for classification and surfactant treatment, and birth weight and gestational age were the most important predictive clinical data. By combining these data, the resulting algorithm for early diagnosis of BPD had a sensitivity of 88% and a specificity of 91%., Conclusion: A point-of-care test to predict subsequent development of BPD at birth has been developed using a new software algorithm allowing early targeted intervention of BPD which could improve the outcome., (© 2020 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Aim: To develop a fast bedside lung maturity test., Methods: Gastric aspirates obtained from premature infants contain lamellar bodies, carrying lung surfactant. To estimate lung maturity, we isolated lamellar bodies from fresh gastric aspirates by centrifugation. Erythrocytes and other cells were lysed by adding water and discarded subsequently with the supernatant. Mid-infrared spectroscopy was then performed to measure the lung maturity as lecithin-sphingomyelin ratio. Lecithin was determined as dipalmitoylphosphatidylcholine, the most surface-active phospholipid. Algorithms to measure lecithin and sphingomyelin concentrations in fresh gastric aspirates were developed on aspirates from 140 premature infants. Each gastric aspirate sample was divided into two samples: one for mass spectrometry as reference and one for spectroscopy. Development of the algorithm is described in detail in Appendix S1., Results: Gastric aspirates stored at 4-5°C avoid flocculation of proteins and phospholipids in contrast to when the aspirates were frozen and thawed. Omission of freezing and concentration of the lung surfactant by centrifugation combined with diminished influence of proteins improves the spectroscopic measurement of lecithin-sphingomyelin ratio. Measurement of lecithin-sphingomyelin ratio by the new method was performed within 10-15 minutes., Conclusion: We present a new fast bedside lung maturity test on fresh gastric aspirate for early targeted surfactant treatment., (©2019 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

In this study, novel 3D printed polymeric microneedle arrays were fabricated for enhanced cisplatin delivery to A-431 epidermoid skin tumours for cancer treatment. The microneedles were built by selectively photopolymerising consecutive layers of a biocompatible photopolymer resin using stereolithography (SLA), followed by coating of cisplatin formulations using inkjet dispensing on the needle surface. The printability via SLA was optimized to improve microneedle mechanical properties and optical coherence tomography analysis showed excellent piercing capacity of 3D printed microneedles to an 80% penetration depth. Franz cell diffusion studies revealed rapid cisplatin release rates of 80-90% within 1 h and in vivo evaluation with Balb/c nude mice presented sufficient cisplatin permeabilization with high anticancer activity and tumour regression. Histopathology analysis confirmed the tumour inhibition effect, showing demarcated lesions with thin fibrous capsules and necrotic cores. The use of 3D printed microneedles demonstrates the potential for in-vivo transdermal delivery of anticancer drugs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aim: To evaluate the accuracy of our new rapid point-of-care (POC) test for lung maturity. The method as we describe in an accompanying article was developed with the purpose of improving the outcome from respiratory distress syndrome (RDS). The test enables the delivery of surfactant in infants with immature lungs already at birth and ensures that infants with mature lungs are not treated unnecessarily., Methods: Fresh gastric aspirate (GAS) was sampled at birth in a cohort of preterm infants with gestational ages ranging between 24 and 31 completed weeks for lung surfactant measurement as lecithin-sphingomyelin ratio (L/S). L/S was prospectively compared with RDS development. The clinical outcome was blinded for the investigators of L/S. The time for analysis was <15 minutes., Results: GAS was obtained from 72 infants. Forty-four (61%) developed RDS. The cut-off for L/S was 3.05; predicting RDS with a sensitivity of 91% and specificity of 79%., Conclusion: The new improved spectroscopic L/S method of lung maturity on GAS has high sensitivity. The method is designed for use as a POC test at birth, and a spectroscopic prototype has been developed for bedside use. Clinical trials with this new lung maturity test are planned., (©2019 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Recently, various additive manufacturing (3D printing) approaches have been employed to fabricate dressings such as film scaffolds that possess well defined architecture and orientation at the micro level. In this study, crosslinked chitosan (CH) based film matrices were prepared using 3D printing with genipin (GE) as a crosslinker, with glycerol (GLY) and poly ethylene glycol (PEG) as plasticizer. The 3D printed films were functionally characterized using (tensile, fluid handling, mucoadhesion, drug dissolution, morphological properties and cell viability as well physico-chemical characterization using scanning electron microscopy, Fourier transform infrared spectroscopy and X-ray diffraction. CH-GE-PEG600 3D printed films having the ratio of 1:1 polymer: plasticizer was selected due to their appropriate flexibility. Fourier transform infrared results showed intermolecular interaction between CH, GE and PEG which was confirmed by X-ray diffraction showing amorphous matrix structure. In vitro mucoadhesion studies of CH-GE-PEG600 films showed the capability of the 3D printed film to adhere to the epithelial surface. Scanning electron microscopy images showed that the surface of the plasticised films were smooth indicating content uniformity of CH, GE and PEG whilst micro cracks in unplasticised films confirmed their brittle nature. Plasticised films also showed high swelling capacity which enhanced water absorption. Cytotoxicity (MTT) assay using human skin fibroblast cell lines demonstrated that more than 90% of cells were viable after 48 h confirming non-toxic nature of the 3D printed CH-GE-PEG600 films and therefore promising dressing for chronic wound healing applications., (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)

Three-layer thin films comprising of two polymers as substrate (ethyl cellulose and, copovidone K28) and three antihypertensive agents (hydrochlorothiazide, amiloride HCl, and carvedilol) were printed using jet dispensing technology. Two film formulations with different ethyl cellulose to copovidone K28 ratio (i.e., 90/10 and 50/50 w/w) were prepared using a three-course dispensing. The films were characterized regarding surface morphology, solid-state properties, polymer-drug interactions, drug distribution in each layer, and in vitro drug release. All the components of the films were found to be in the amorphous state apart from hydrochlorothiazide which retained its crystallinity. FT-IR spectroscopy revealed hydrogen bond interactions between carvedilol and copovidone K28. Combinations of ethyl cellulose and copovidone K28 provide suitable polymeric film substrates with the ability to modify drug release. Particularly, decreased ethyl cellulose to copovidone K28 weight ratio was found to suppress the crystallization of hydrochlorothiazide and to increase the release rate of the dispensed drugs. Jet dispensing was found to be a rapid technology for the preparation of multi-layered films that can be used as personalized formulations for the delivery of combinations of drugs.

Purpose: Three- dimensional (3D) printing has received significant attention as a manufacturing process for pharmaceutical dosage forms. In this study, we used Fusion Deposition Modelling (FDM) in order to print "candy - like" formulations by imitating Starmix® sweets to prepare paediatric medicines with enhanced palatability., Methods: Hot melt extrusion processing (HME) was coupled with FDM to prepare extruded filaments of indomethacin (IND), hypromellose acetate succinate (HPMCAS) and polyethylene glycol (PEG) formulations and subsequently feed them in the 3D printer. The shapes of the Starmix® objects were printed in the form of a heart, ring, bottle, ring, bear and lion. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier Transform Infra-red Spectroscopy (FT-IR) and confocal Raman analysis were used to assess the drug - excipient interactions and the content uniformity., Results: Physicochemical analysis showed the presence of molecularly dispersed IND in the printed tablets. In vivo taste masking evaluation demonstrated excellent masking of the drug bitterness. The printed forms were evaluated for drug dissolution and showed immediate IND release independently of the printed shape, within 60 min., Conclusions: 3D printing was used successfully to process drug loaded filaments for the development of paediatric printed tablets in the form of Starmix® designs.

The purpose of this study was to evaluate the performance of Neusilin® (NEU) a synthetic magnesium aluminometasilicate as an inorganic drug carrier co-processed with the hydrophilic surfactants Labrasol and Labrafil to develop Tranilast (TLT)-based solid dispersions using continuous melt extrusion (HME) processing. Twin-screw extrusion was optimized to develop various TLT/excipient/surfactant formulations followed by continuous capsule filling in the absence of any downstream equipment. Physicochemical characterization showed the existence of TLT in partially crystalline state in the porous network of inorganic NEU for all extruded formulations. Furthermore, in-line NIR studies revealed a possible intermolecular H-bonding formation between the drug and the carrier resulting in the increase of TLT dissolution rates. The capsules containing TLT-extruded solid dispersions showed enhanced dissolution rates and compared with the marketed Rizaben ® product.

Inkjet printing is an attractive material deposition and patterning technology that has received significant attention in the recent years. It has been exploited for novel applications including high throughput screening, pharmaceutical formulations, medical devices and implants. Moreover, inkjet printing has been implemented in cutting-edge 3D-printing healthcare areas such as tissue engineering and regenerative medicine. Recent inkjet advances enabled 3D printing of artificial cartilage and skin, or cell constructs for transplantation therapies. In the coming years inkjet printing is anticipated to revolutionize personalized medicine and push the innovation portfolio by offering new paths in patient - specific treatments.

Inkjet-printing technology was used to apply biodegradable and biocompatible polymeric coatings of poly(d,l-lactide) with the antiproliferative drugs simvastatin (SMV) and paclitaxel (PCX) on coronary metal stents. A piezoelectric dispenser applied coating patterns of very fine droplets (300 pL) and inkjet printing was optimized to develop uniform, accurate and reproducible coatings of high yields on the stent strut. The drug loaded polymeric coatings were assed by scanning electron microscopy (SEM), atomic force microscopy (AFM), and transition thermal microscopy (TTM) where a phase separation was observed for SMV/PLA layers while PCX showed a uniform distribution within the polymer layers. Cytocompatibility studies of PLA coatings showed excellent cell adhesion with no decrease of cell viability and proliferation. In vivo stent implantation studies showed significant intrastent restenosis (ISR) for PCX/PLA and PLA plain coatings similar to marketed Presillion (bare metal) and Cypher (drug eluting) stents. The investigation of several cytokine levels after 7 days of stent deployment showed no inflammatory response and hence no in vivo cytotoxicity related to PLA coatings. Inkjet printing can be employed as a robust coating technology for the development of drug eluting stents compared to the current conventional approaches.

The article describes the application of a twin-screw granulation process to enhance the dissolution rate of the poorly water soluble drug, ibuprofen (IBU). A quality-by-design (QbD) approach was used to manufacture IBU loaded granules via hot-melt extrusion (HME) processing. For the purpose of the study, a design of experiment (DoE) was implemented to assess the effect of the formulation compositions and the processing parameters. This novel approach allowed the use of, polymer/inorganic excipients such as hydroxypropyl methylcellulose (HPMC) and magnesium aluminometasilicate (Neusilin(®)-MAS) with polyethylene glycol 2000 (PEG) as the binder without requiring a further drying step. IBU loaded batches were processed using a twin screw extruder to investigate the effect of MAS/polymer ratio, PEG amount (binder) and liquid to solid (L/S) ratios on the dissolution rates, mean particle size and the loss on drying (LoD) of the extruded granules. The DoE analysis showed that the defined independent variables of the twin screw granulation process have a complex effect on the measured outcomes. The solid state analysis showed the existence of partially amorphous IBU state which had a significant effect on the dissolution enhancement in acidic media. Furthermore, the analysis obtained from the surface mapping by Raman proved the homogenous distribution of the IBU in the extruded granulation formulations., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A novel inkjet printing technology is introduced as a process to coat metal microneedle arrays with three anticancer agents 5-fluororacil, curcumin and cisplatin for transdermal delivery. The hydrophilic graft copolymer Soluplus(®) was used as a drug carrier and the coating formulations consisted of drug-polymer solutions at various ratios. A piezoelectric dispenser jetted microdroplets on the microneedle surface to develop uniform, accurate and reproducible coating layers without any material losses. Inkjet printing was found to depend on the nozzle size, the applied voltage (mV) and the duration of the pulse (μs). The drug release rates were determined in vitro using Franz type diffusion cells with dermatomed porcine skin. The drug release rates depended on the drug-polymer ratio, the drug lipophilicity and the skin thickness. All drugs presented increased release profiles (750 μm skin thickness), which were retarded for 900 μm skin thickness. Soluplus assisted the drug release especially for the water insoluble curcumin and cisplatin due to its solubilizing capacity. Inkjet printing has been shown to be an effective technology for coating of metal microneedles which can then be used for further transdermal drug delivery applications., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Taste masking of bitter active substances is an emerging area in the pharmaceutical industry especially for paediatric/geriatric medications. In this study we introduce the use of jet dispensing as a taste masking technology by printing mucosal thin films of three model bitter substances, Cetirizine HCl, Diphenylhydramine HCl and Ibuprofen. The process was used to dispense aqueous drugs/polymer solutions at very high speed where eventually the drugs were embedded in the polymer matrix. The in vivo evaluation of jet-dispensed mucosal films showed excellent taste masking for drug loadings from 20 to 40%. Jet dispensing was proved to make uniform, accurate and reproducible thin films with excellent content uniformity., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The aim of the work reported herein was to implement process analytical technology (PAT) tools during hot melt extrusion (HME) in order to obtain a better understanding of the relationship between HME processing parameters and the extruded formulations. For the first time two in-line NIR probes (transmission and reflectance) have been coupled with HME to monitor the extrusion of the water insoluble drug indomethacin (IND) in the presence of Soluplus (SOL) or Kollidon VA64 hydrophilic polymers. In-line extrusion monitoring of sheets, produced via a specially designed die, was conducted at various drug/polymer ratios and processing parameters. Characterisation of the extruded transparent sheets was also undertaken by using DSC, XRPD and Raman mapping. Analysis of the experimental findings revealed the production of molecular solutions where IND is homogeneously blended (ascertained by Raman mapping) in the polymer matrices, as it acts as a plasticizer for both hydrophilic polymers. PCA analysis of the recorded NIR signals showed that the screw speed used in HME affects the recorded spectra but not the homogeneity of the embedded drug in the polymer sheets. The IND/VA64 and IND/SOL extruded sheets displayed rapid dissolution rates with 80% and 30% of the IND being released, respectively within the first 20min., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Inkjet printing technology was used to apply insulin polymeric layers on metal microneedles for transdermal delivery. A range of various polymers such as gelatin (GLN), polyvinyl caprolactame-polyvinyl acetate-polyethylene glycol (SOL), poly(2-ethyl-2-oxazoline) (POX) and trehalose (THL) were assessed for their capacity to form thin uniform and homogeneous layers that preserve insulin intact. Atomic force microscopy (AFM) showed homogeneous insulin-polymer layers without any phase separation while SOL demonstrated the best performance. Circular discroism (CD) analysis of rehydrated films showed that insulin's alpha helices and β-sheet were well preserved for THL and SOL. In contrast, GLN and POX insulin layers revealed small band shifts indicating possible conformational changes. Insulin release in Franz diffusion cells from MNs inserted into porcine skin showed rapid release rates for POX and GLN within the first 20 min. Inkjet printing was proved an effective approach for transdermal delivery of insulin in solid state.

The drug distribution on the surface of hot-melt extruded, pre-mixed hot-melt extruded and direct compressed tablet formulations was characterized by using scanning electron microscopy, energy dispersive X-ray spectroscopy (EDX) and confocal Raman spectroscopy. Formulations of paracetamol (PMOL) and Compritol(®) (C-888) were extruded using hot-melt extrusion at different processing temperatures and formulation compositions before being compressed into tablets. EDX and confocal Raman spectroscopy were employed to map the drug and excipient distribution, both qualitatively and quantitatively, on the surface of the tablets. The results from EDX and confocal Raman studies confirmed better uniformity and distribution of PMOL in the pre-mixed extruded formulations compared to both hot-melt extruded formulations and those obtained by means of direct compression. The quantification of the drug composition on the surface of the tablets by both EDX and confocal Raman was in good agreement with the theoretically expected values., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Three different formulations comprising two drugs, felodipine and hydrochlorothiazide (HCT) and two polymers, poly(vinyl pyrolidone) (PVP) and poly(lactic-co-glycolic acid) (PLGA) were inkjet printed as micro-dot arrays and analysed on an individual micro-spot basis by time-of-flight secondary ion mass spectrometry (ToF-SIMS). For the HCT/PLGA formulation, the spots showed heterogeneity of the drug and other chemical constituents. To further investigate these heterogeneities, multivariate curve resolution was applied to the ToF-SIMS hyperspectral image datasets. This approach successfully identified distinct chemical components elucidating the HCT, PLGA, substrate material, and contaminants based on sulphur, phosphorous and sodium chloride. Spots printed using either of the drugs with PVP exhibited full substrate coverage and a uniform distribution of the active ingredient along with all other constituents within the printed spot area. This represents the preferred situation in terms of stability and controlling the release of a drug from a polymer matrix.

We demonstrate the viability of using an ink-jet printer to produce a formulation capable of controlling the release of a drug. This is shown for the drug felodipine, an antihypertensive, with polyvinyl pirrolidone (PVP) as an excipient. As felodipine is a poorly water soluble drug, its molecular dispersion in a soluble polymer (ie. PVP) is a commonly used approach to improve bioavailability. Various ratios of felodipine and PVP in an ethanol-DMSO mixture (95/5) were dispensed in picoliter quantities using a piezoelectric 'ink-jet' head onto a hydrophobic substrate. The resultant formulation spots were characterized using atomic force microscopy, localized nano-thermal analysis, ATR-IR and imaging confocal Raman spectroscopy. Intimate mixing of the felodipine and PVP within the micro-dots was observed. ATR-IR confirmed the known molecular level interaction of felodipine and PVP through hydrogen bonding. Nanothermal analysis indicated a single glass transition point, indicative of an intimate polymer drug mixture, which is lowered as the drug concentration increases. Confocal Raman microscopy mapping on single micro-scale droplets allowed the visualization of the drug distribution in the spots as well as facilitating characterization of the release of the drug. The drug release can be altered through control of the drug loading. As inkjet printing is an inherently scalable technology, this proof of principal work with single deposited micro-spot formulations demonstrates the potential of this approach to print practical dosage forms (e.g. as an array of many thousands of spots with different release profiles). This, for example, raises the possibility in the future of producing dosage forms at points of care with one or more drugs which have been formulated for the needs of individual patients., (Copyright © 2011 Elsevier B.V. All rights reserved.)