The production of paediatric pharmaceutical forms represents a unique challenge within the pharmaceutical industry. The primary goal of these formulations is to ensure therapeutic efficacy, safety, ...and tolerability in paediatric patients, who have specific physiological needs and characteristics. In recent years, there has been a significant increase in attention towards this area, driven by the need to improve drug administration to children and ensure optimal and specific treatments. Technological innovation has played a crucial role in meeting these requirements, opening new frontiers in the design and production of paediatric pharmaceutical forms. In particular, three emerging technologies have garnered considerable interest and attention within the scientific and industrial community: 3D printing, prilling/vibration, and microfluidics. These technologies offer advanced approaches for the design, production, and customization of paediatric pharmaceutical forms, allowing for more precise dosage modulation, improved solubility, and greater drug acceptability. In this review, we delve into these cutting-edge technologies and their impact on the production of paediatric pharmaceutical forms. We analyse their potential, associated challenges, and recent developments, providing a comprehensive overview of the opportunities that these innovative methodologies offer to the pharmaceutical sector. We examine different pharmaceutical forms generated using these techniques, evaluating their advantages and disadvantages.
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•The current pharmaceutical forms on the market, intended for the adult population, do not satisfy the needs of the paediatric population. For this reason, new technologies capable of meeting this market demand are to be investigated.•3D printing is functional to produce highly customised formulations for paediatric use due to its dimensional and dosage flexibility. Various 3D printing techniques investigated ensure the production of highly customisable pharmaceutical forms.•The prilling/vibration technique guarantees the production of multiparticulates that are easy to swallow, flexible in the dose and can be administered in a user-friendly manner, making them suitable for the paediatric population.•Microfluidics is an innovative technique that, due to its advantages, shows potential application to the production of micro-and nanocarriers for paediatric patients.
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The purpose of this study was to combine direct powder extrusion (DPE) 3D printing and fluid bed coating techniques to create a budesonide (BD) loaded solid oral formulations for the ...treatment of eosinophilic colitis (EC) in paediatric patients. The preferred medication for EC treatment is BD, which has drawbacks due to its poor water solubility and low absorption. Additionally, since commercially available medications for EC treatment are created and approved for adult patients, administering them to children sometimes requires an off-label use and an impromptu handling, which can result in therapeutic ineffectiveness. The DPE 3D approach was investigated to create Mini-Tablets (MTs) to suit the swallowing, palatability, and dose flexibility control requirements needed by paediatric patients. Additionally, DPE 3D and the inclusion of hydroxypropyl-β-cyclodextrin in the initial powder mixture allowed for an improvement in the solubility and rate of BD dissolution in aqueous medium. Then, to accomplish a site-specific drug release at the intestinal level, MTs were coated with a layer of Eudragit FS 30D, an enteric polymer responsive at pH > 7.0 values. In vitro release experiments showed that film-coated MTs were suitable in terms of size and dose, enabling potential therapeutic customization and targeted delivery of BD to the colon.
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The aim of this work is the development and production by Direct Powder Extrusion (DPE) 3D printing technique of novel oral mucoadhesive films delivering Clobetasol propionate (CBS), ...useful in paediatric treatment of Oral Lichen Planus (OLP), a rare chronic disease. The DPE 3D printing of these dosage forms can allow the reduction of frequency regimen, the therapy personalization, and reduction of oral cavity administration discomfort. To obtain suitable mucoadhesive films, different polymeric materials, namely hydroxypropylmethylcellulose or polyethylene oxide blended with chitosan (CS), were tested and hydroxypropyl-β-cyclodextrin was added to increase the CBS solubility. The formulations were tested in terms of mechanical, physico-chemical, and in vitro biopharmaceutical properties. The film showed a tenacious structure, with drug chemical-physical characteristics enhancement due to its partial amorphization during the printing stage and owing to cyclodextrins multicomponent complex formation. The presence of CS enhanced the mucoadhesive properties leading to a significant increase of drug exposure time on the mucosa. Finally, the printed films permeation and retention studies through porcine mucosae showed a marked retention of the drug inside the epithelium, avoiding drug systemic absorption. Therefore, DPE-printed films could represent a suitable technique for the preparation of mucoadhesive film potentially usable for paediatric therapy including OLP.
Niclosamide (NCS) is a drug that has been used as an anthelmintic and anti-parasitic drug for about 40 years. Recently, some studies have highlighted its potential in treating various tumors, ...allowing a repositioning of this drug. Despite its potential, NCS is a Biopharmaceutical Classification System (BCS) Class II drug and is consequently characterized by low aqueous solubility, poor dissolution rate and reduced bioavailability, which limits its applicability. In this work, we utilize a very novel technique, direct powder extrusion (DPE) 3D printing, which overcomes the limitations of previously used techniques (fused deposition modelling, FDM) to achieve direct extrusion of powder mixtures consisting of NCS, hydroxypropyl methylcellulose (HPMC, Affinisol 15 LV), hydroxypropyl-β-cyclodextrin (HP-β-CD) and polyethylene glycol (PEG) 6000. For the first time, direct printing of powder blends containing HP-β-CD was conducted. For all tablets,
in vitro
dissolution studies showed sustained drug release over 48 h, but for tablets containing HP-β-CD, the release was faster. Solid-state characterization studies showed that during extrusion, the drug lost its crystal structure and was evenly distributed within the polymer matrix. All printed tablets have exhibited good mechanical and physical features and a stability of the drug content for up to 3 months. This innovative printing technique has demonstrated the possibility to produce personalized pharmaceutical forms directly from powders, avoiding the use of filament used by FDM.
Graphical abstract
Stem cell homing, namely the recruitment of mesenchymal stem cells （MSCs） to injured tissues, is highly effective for bone regeneration in vivo. In order to explore whether the incorporation of ...mimetic peptide sequences on magnesium-doped （Mg-doped） hydroxyapatite （HA） may regulate the homing of MSCs, and thus induce cell migration to a specific site, we covalently functionalized MgHA disks with two chemotactic/haptotactic factors： either the fibronectin fragment III1-C human （FF III1-C）, or the peptide sequence Gly-Arg-Gly-Asp-Ser-Pro-Lys, a fibronectin analog that is able to bind to integrin trans- membrane receptors. Preliminary biological evaluation of MSC viability, analyzed by 3-（4,5-dimethyl- thiazol-2-yl）-2,5-diphenyltetrazolium bromide （MTT） test, suggested that stem cells migrate to the MgHA disks in resoonse to the grafted haototaxis stimuli.
Abstract
The structures of discourse used by legal and ordinary languages share differences that foster technical issues when applying or fine-tuning general-purpose language models for open-domain ...question answering on legal resources. For example, longer sentences may be preferred in European laws (i.e., Brussels I bis Regulation EU 1215/2012) to reduce potential ambiguities and improve comprehensibility, distracting a language model trained on ordinary English. In this article, we investigate some mechanisms to isolate and capture the discursive patterns of legalese in order to perform zero-shot question answering, i.e., without training on legal documents. Specifically, we use pre-trained open-domain answer retrieval systems and study what happens when changing the type of information to consider for retrieval. Indeed, by selecting only the important parts of discourse (e.g., elementary units of discourse, EDU for short, or abstract representations of meaning, AMR for short), we should be able to help the answer retriever identify the elements of interest. Hence, with this paper, we publish Q4EU, a new evaluation dataset that includes more than 70 questions and 200 answers on 6 different European norms, and study what happens to a baseline system when only EDUs or AMRs are used during information retrieval. Our results show that the versions using EDUs are overall the best, leading to state-of-the-art F1, precision, NDCG and MRR scores.
Objective
Postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) are the two main forms of functional dyspepsia (FD). Probiotics are a promising therapy for FD, but current data ...remains heterogeneous. This work aims to evaluate a probiotic combination of Lacticaseibacillus rhamnosus LR04 (DSM 16605), Lactiplantibacillus pentosus LPS01 (DSM 21980), Lactiplantibacillus plantarum LP01 (LMG P-21021), and Lactobacillus delbrueckii subsp. delbruekii LDD01 (DMS 22106), alone or together with other pharmacological therapies, for clinical improvement of symptoms associated with FD.
Methods
Patients with FD were enrolled and divided into two groups: PDS and EPS. Probiotic alone or combined with prokinetics, antacids, or proton-pump-inhibitors were administered for 30 days. A progressive-score scale was used to evaluate symptoms in all patients at the beginning of the trial and at 15 days after the end of treatment.
Results
A cohort of 2676 patients were enrolled (1 357 with PDS; 1 319 with EPS). All patients showed significant improvements in dyspeptic symptoms following treatment. In patients with PDS, probiotic alone resulted in the lowest prevalence of symptoms following treatment, while patients with EPS showed no clear between-treatment differences.
Conclusions
Dyspeptic symptoms were reduced following treatment in all patients.
New magnetic hydroxyapatite-based nanomaterials as bone-specific systems for controlled drug delivery have been synthesized. The synthesized hydroxyapatite, HA, decorated with magnetite nanoparticles ...by a deposition method (HA/Fe3O4) and the nanocomposite system obtained using magnetic multi-walled carbon nanotubes (HA/MWCNT/Fe3O4) as a filler for HA have been characterized by chemical and morphological analyses, and their biological behavior was investigated. The systems have also been doped with clodronate in order to combine the effect of bone biomineralization induced by hydroxyapatite-based composites with the decrease of osteoclast formation induced by the drug. An analysis of the preosteoclastic RAW264.7 cell proliferation by MTT assay confirmed the high biocompatibility of the three systems. TRAP staining of RAW 264.7 conditioned with sRAKL to induce osteoclastogenesis, cultured in the presence of the systems doped and undoped with clodronate, showed the inhibitory effect of clodronate after we counted the MNC TRAP(+)cells but only in the osteoclast formation; in particular, the system HA/Fe3O4-Clo exerted a high inhibitory effect compared to the drug alone. These results demonstrate that the synthesized nanocomposites are a biocompatible magnetic drug delivery system and can represent a useful multimodal platform for applications in bone tissue engineering.
Human exposure to carbon nanotubes (CNTs) can cause health issues due to their chemical-physical features and biological interactions. These nanostructures cause oxidative stress, also due to ...endogenous reactive oxygen species (ROS) production, which increases following mitochondrial impairment. The aim of this in vitro study was to assess the health effects, due to mitochondrial dysfunction, caused by a sub-chronic exposure to a non-acutely toxic dose of multi walled CNTs (raw and functionalised). The A549 cells were exposed to multi-walled carbon nanotubes (MWCNTs) (2 µg mL
) for 36 days. Periodically, cellular dehydrogenases, pyruvate dehydrogenase kinase 1 (PDK1), cytochrome c release, permeability transition pore (mPTP) opening, transmembrane potential (Δψ m), apoptotic cells, and intracellular ROS were measured. The results, compared to untreated cells and to positive control formed by cells treated with MWCNTs (20 µg mL
), highlighted the efficiency of homeostasis to counteract ROS overproduction, but a
of mitochondrial functionality was not observed. Despite the tendency to restore, the mitochondrial impairment persisted. Overall, the results underlined the tissue damage that can arise following sub-chronic exposure to MWCNTs.
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•PMWCNT and fMWCNT triggered cyto- and geno-toxic effects in neuronal-like cells.•IL-1β, IL-6 and TNFα increases underlined the neuroinflammation MWCNT-induced.•ROS overproduction ...MWCNT-driven caused neurotoxicity and neuroinflammation.•Despite the different shape, the harmful effects of p-e f MWCNT were overlapped.•Effects of MWCNTs-cells interactions was highlighted by Raman spectrometry.
Multi walled carbon nanotubes (MWCNTs) activate pathways involved in cytotoxicity, genotoxicity and inflammation. Inhaled MWCNTs are translocated to extra pulmonary organs and their hydrophobicity allows them to cross the blood–brain barrier (BBB). Further exposure of central nervous system (CNS) occurs via olfactory neurons.
Using differentiated SH-SY5Y, we studied the neurotoxicity and neuroinflammation of pristine and functionalised MWCNTs. ROS overproduction was dose- and time-dependent (P<0.01) and was related to mitochondrial impairment, DNA damage and decreased viability (P<0.05). Transcript levels of TNFα, IL-1β and IL-6 increased, as confirmed by an ELISA test. Raman spectra were acquired to assess MWCNT-cells interactions.
The almost superimposable pro-oxidant activity of both CNTs could be imputable to excessive lengths with regard to the pristine MWCNTs and to the eroded surface, causing increased reactivity, with regard to functionalised MWCNTs. Considering the ease with which lightweight MWCNTs aerosolize and the increased production, the results underlined the potential onset of neurodegenerative diseases, due to unintentional MWCNT exposure.
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