Display omitted
The purpose of this study was to develop a new solid paediatric formulation for propranolol hydrochloride (PR). This drug is used to treat various paediatric diseases, and recently ...received clearance to treat haemangioma. However, PR has a bitter salty taste that does not facilitate high rates of compliance among children, especially in liquid formulations. In addition, the solid formulations are designed for adults and often their dosage is not suitable for children that require a flexible dose based on their weight. Therefore, matrix microbeads of EUDRAGIT® E PO containing PR were manufactured to overcome these limitations. Nine different samples were prepared using the prilling-congealing technique with high yield. Using 2 nozzles, 300 and 450 μm (code n), the diameters obtained of microbeads (from 333 to 699 μm) were homogenous and appropriate to be swallowed by children. In this study, the ratio drug:matrix for the microbeads was also examined in detail: 1:25 (F1), 1:15 (F2) and 1:10 (F3) in aqueous and tert-butyl alcohol/aqueous (code t) media. Most of the examined microbeads were characterized by high percentage of encapsulation efficiency (22–100%) and drug loading (22–77 mg of drug per g of matrix) effective for the administration of low and high doses of PR. SEM analysis revealed a matrix with a radial or a spongy structure, with numerous pores that generated soft floating microbeads in aqueous solution. Release studies confirmed a low release and dissolution of the drug in artificial saliva, mainly F1n > F1 > F2nt, and a prompt dissolution in simulated gastric media. Finally, electronic tongue measurements revealed the ability of these formulations to mask the bitter drug taste, especially for the sample with a ratio 1:25 (F1n and F1). These samples were chemically and physically stable for six months. In conclusion, the projected microbeads F1, and F1n reached the goal of the study, and could be proposed as new solid oral formulations dedicated to use by children.
Display omitted
Indomethacin (IND) is topically administered for the treatment of the anterior segment diseases such as conjunctivitis, uveitis, and inflammation prevention for post-cataract surgery, ...as well as posterior segment diseases as macular edema. Currently IND is available as 0.1% w/v hydroxypropyl-β-cyclodextrin-based eye drop formulation and its bioavailability is limited by several drawbacks such as the nasolacrimal duct draining, the reflex blinking and the low volume of the conjunctival sac. In this study, chitosan (CS)/sulfobutylether-β-cyclodextrin (SBE-β-CD) based nanoparticles (NPs) with a mean diameter of 340 (±7) nm, a ζ-potential value of +18.3 (±0.5) mV and coated with thiolated low molecular weight hyaluronic acid were formulated to improve both the solubility and the residential time in the conjunctival sac of the loaded drug IND. The NPs were prepared through the ionotropic gelation technique, exploiting the interaction between the positively charged amino group of CS and the negatively charged sulfonic group of SBE-β-CD. The mucoadhesive properties of the NPs were evaluated on chicken trachea and esophagus tissues using a texture analyser. The irritability effects of NPs were disclaimed with Hecam test. The developed coated NPs showed increased residential time in the conjunctival sac, displayed no irritancy or toxicity for local administration, making them an optimal and innovative drug delivery system for the treatment of anterior segment inflammation diseases. On the other hand, the uncoated NPs displayed better permeating properties since they are smaller and could be further exploited for the treatment of posterior segment diseases.
Display omitted
Budesonide (BUD) is a low water soluble (S0 = 5.028·10−5 M) corticosteroid used as preferred therapy for the treatment of Eosinophilic Esophagitis (EoE), a chronic allergic-immune ...condition with an increased incidence in the paediatric population. Currently there are no commercial medicines indicated for EoE, and, therefore, in the hospital pharmacy the BUD is extemporaneously formulated as viscous oral suspension at the initial dose of 1–2 mg per day for children, highlighting the need of a mucoadhesive drug delivery system (MDDS) that adheres to the site of action and prolongs the therapeutic activity of the administered drug. Considering the ability of hydroxypropyl-β-cyclodextrin (HP-β-CD, 100 mM) to increase the water solubility of BUD (SHP-β-CD = 4.3·10−3 M; K1:1 = 861.11 M−1), a mucoadhesive thiolated HP-β-CD (HP-β-CD-SH) was synthesized and characterized by mass spectroscopy, 1H- and 13C NMR techniques. Phase-solubility studies demonstrated the capability of HP-β-CD-SH (100 mM) to form a reversible water soluble inclusion complex with BUD (SHP-β-CD-SH = 10.9·10−3 M; K1:1 = 2013.52 M−1), which increases its permanence on the target site as proved by mucoadhesive studies on porcine oesophagus mucosa. HP-β-CD-SH might be a useful MDDS for the pharmacist to prepare BUD oral liquid formulations at the recommended doses, with pH values below 5, which guarantee the chemical stability of the new mucoadhesive excipient.
Display omitted
Prilling/vibration technique to produce oral microcapsules was explored to achieve local delivery of misoprostol (MIS), a prostaglandin E1 analogue indicated for the treatment of ...gastric-duodenal ulcers, at the gastric mucosa. To improve MIS chemical stability and reduce its associated systemic side effects, drug delivery systems were designed and developed as microcapsules consisting of a core of sunflower oil and MIS (Fs6 and Fs14) or a MIS complex with hydroxypropyl-beta-cyclodextrin (HP-β-CD) (Fs18), confirmed by specific studies, and a polymeric shell. The produced microcapsules showed high encapsulation efficiencies for those with MIS solubilized in sunflower oil (>59.86 %) and for the microcapsules with MIS/HP-β-CD (97.61 %). To demonstrate the ability of these systems to deliver MIS into the stomach, swelling and drug release experiments were also conducted in simulated gastric fluid. Among the three formulations, FS18 showed gastric release within 30 min and was the most advantageous formulation because the presence of the MIS/HP-β-CD inclusion complex ensured a greater ability to stabilise MIS in the simulated gastric environment. In addition, these new systems have a small size (<540 µm), and good flow properties and the dose of the drug could be easily adapted using different amounts of microcapsules (flexibility), making them a passepartout for different age population groups.
Display omitted
Solid lipid nanoparticles (SLNs) can combine the advantages of different colloidal carriers and prevent some of their disadvantages. The production of nanoparticles by means of ...microfluidics represents a successful platform for industrial scale-up of nanoparticle manufacture in a reproducible way. The realisation of a microfluidic technique to obtain SLNs in a continuous and reproducible manner encouraged us to create surface functionalised SLNs for targeted drug release using the same procedure. A tumor homing peptide, iRGD, owning a cryptic C-end Rule (CendR) motif is responsible for neuropilin-1 (NRP-1) binding and for triggering extravasation and tumor penetration of the peptide. In this study, the Paclitaxel loaded-SLNs produced by microfluidics were functionalized with the iRGD peptide. The SLNs proved to be stable in aqueous medium andwere characterized by a Z-average under 150 nm, a polydispersity index below 0.2, a zeta-potential between −20 and −35 mV and a drug encapsulation efficiency around 40%. Moreover, in vitro cytotoxic effects and cellular uptake have been assessed using 2D and 3D tumour models of U87 glioblastoma cell lines. Overall, these results demonstrate that the surface functionalization of SLNs with iRGD allow better cellular uptake and cytotoxicity ability.
At high risk of experiencing symptoms of stress, female healthcare workers also faced the psychosocial impacts of the COVID-19 pandemic. The aims of this study are to investigate whether women are ...associated with a high level of psychological distress in comparison to men and to explore the risk factors associated with a high level of psychological distress in women. For this purpose, a multivariable logistic regression model was tested with sex, age and professional role as predictors of psychological distress in women. We found that (1)women working in the four Italian hospitals analyzed during the COVID-19 pandemic experienced more psychological distress than men, (2) being between 26 and 35 years old and being a medical doctor were associated with the risk of women developing psychological distress, (3) being a female medical doctor presents a 23% risk of developing psychological distress, (4) female nurses working in COVID-19s ward had a 50% risk and female non-healthcare personnel working in COVID-19 wards had a 69% risk of developing psychological distress. In conclusion, our results suggest that interventions for supporting and promoting mental well-being among female healthcare workers are mandatory, especially for the professional categories of nurses and non-healthcare workers.
Display omitted
P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are two transporters expressed in human neural stem/progenitor cells and at the Blood-Brain Barrier (BBB) level with ...decreased activity in the early stage of Alzheimer’s disease (AD). Both proteins, have a protective role for the embryonic stem cells in the early developmental step, maintaining them in an undifferentiated state, and limit the access of exogenous and endogenous agents to the brain. Recently, MC111 selected from a P-gp/BCRP ligands library was investigated as multitarget strategy for AD treatment, considering its ability to induce the expression and activity of both proteins. However, MC111 clinical use could be limited for the ubiquitous physiological expression of efflux transporters and its moderate toxicity towards endothelial cells. Therefore, a selective MC111 delivery system based on nanostructured lipid carriers (NLC) functionalized with transferrin were developed. The results proved the formation of NLC with average size about 120 nm and high drug encapsulation efficiency (EE% greater than 50). In vitro studies on hCMEC/D3 cells revealed that the MC111 was selectively released by NLC at BBB level and then inducing the activity and expression of BCRP and P-gp, involved in the clearance of amyloid β peptide on brain endothelial cells.
Display omitted
The purpose of this study was to synthesize and characterize a novel thiolated glycogen, so-named S-preactivated thiolated glycogen, as a mucosal drug delivery systems and the ...assessment of its mucoadhesive properties. In this regard, glycogen–cysteine and glycogen-cysteine-2-mercaptonicotinic acid conjugates were synthesized. Glycogen was activated by an oxidative ring opening with sodium periodate resulting in reactive aldehyde groups to which cysteine was bound via reductive amination. The obtained thiolated polymer displayed 2203.09±200μmol thiol groups per gram polymer. In a second step, the thiol moieties of thiolated glycogen were protected by disulfide bond formation with the thiolated aromatic residue 2-mercaptonicotinic acid (2MNA). In vitro screening of mucoadhesive properties was performed on porcine intestinal mucosa using different methods. In particular, in terms of rheology investigations of mucus/polymer mixtures, the S-preactivated thiolated glycogen showed a 4.7-fold increase in dynamic viscosity over a time period of 5h, in comparison to mucus/Simulated Intestinal Fluid control. The S-preactivated polymer remained attached on freshly excised porcine mucosa for 45h. Analogous results were obtained with tensile studies demonstrating a 2.7-fold increase in maximum detachment force and 3.1- fold increase in total work of adhesion for the S-preactivated polymer compared to unmodified glycogen. Moreover, water-uptake studies showed an over 4h continuing weight gain for the S-preactivated polymer, whereas disintegration took place for the unmodified polymer within the first hour. Furthermore, even in the highest tested concentration of 2mg/ml the new conjugates did not show any cytotoxicity on Caco-2 cell monolayer using an MTT assay. According to these results, S-preactivated glycogen represents a promising type of mucoadhesive polymers useful for the development of various mucosal drug delivery systems.
Translocator protein 18 kDa (TSPO) is a promising target for molecular imaging and for targeted drug delivery to tumors overexpressing TSPO. In our previous work, new macromolecular conjugates with a ...high affinity and selectivity for TSPO were prepared by conjugating the biodegradable poly(d,l-lactic-co-glycolic acid) (PLGA) polymer with two potent and selective TSPO ligands, namely, compounds 1 and 2. Based on this, nanoparticle delivery systems (NPs), employing TSPO ligand–PLGA conjugated (PLGA–TSPO) polymers, were prepared. Furthermore, to evaluate the ability of the new NPs to be used as a drug delivery systems for anticancer therapy, PLGA–TSPO NPs were loaded with 5-fluorouracil (5-FU), chosen as a model hydrophilic anticancer drug. The main goal of this work was to investigate the synergistic potential of using NP conjugates PLGA–TSPO, TSPO ligands being pro-apoptotic agents, to simultaneously deliver a cytotoxic anticancer drug. To better highlight the occurrence of synergistic effects, dual drug loaded PLGA NPs (PLGA NPs/5-FU/1) and dual drug loaded PLGA–TSPO NPs (PLGA–TSPO NPs/5-FU/1), with 5-FU and TSPO ligand 1 physically incorporated together, were also prepared and characterized. The particle size and size distribution, surface morphology, and drug encapsulation efficiency, as well as the drug release kinetics, were investigated. In vitro cytotoxicity studies were carried out on C6 glioma cells overexpressing TSPO, and to evaluate the potential uptake of these nanoparticulate systems, the internalization of fluorescent labeled PLGA–TSPO NPs (FITC–PLGA–TSPO NPs) was also investigated by fluorescence microscopy. Results demonstrated that PLGA–TSPO NPs/5-FU and dual drug loaded PLGA NPs/5-FU/1 and PLGA–TSPO NPs/5-FU/1 could significantly enhance toxicity against human cancer cells due to the synergistic effect of the TSPO ligand 1 with the anticancer drug 5-FU.
Display omitted
This work describes S-preactivated N-acetylcysteine (NAC)- and glutathione (GSH)-glycol chitosan (GC) polymer conjugates engineered as potential mucoadhesive platform. Preactivated ...thiomers (GC-NAC-MNA, GC-GSH-MNA) were synthesized by bond formation between GC-NAC or GC-GSH and 2-mercaptonicotinic acid (MNA) used as ligand. The presence of protected thiol moieties on this new class of thiolated GC made them not subject to oxidation. The structural modifications of the resulting derivatives were confirmed by proton Nuclear Magnetic Resonance (1H NMR) and Size Exclusion Chromatography (SEC). The conjugates displayed 91.2% and 90.1% of S-preactivation for GC-NAC-MNA and GC-GSH-MNA, respectively. The polymers were tested in ex-vivo and in vitro for their mucoadhesive properties and toxicity. The results showed that the preactivation of GC-NAC and GC-GSH increased their mucoadhesive abilities compared to their thiolated precursors by 1.4-, 4.4-fold in time of adhesion evaluated using rotating cylinder method, 1.6-, 1.5-fold in total work of adhesion (TWA) and 2.0-, 1.3-fold in maximum detachment force (MDA) determined using tensile studies, respectively. Moreover, water-uptake studies showed an improved in weight indicating water-uptake strongly dependent on derivations, before erosion occurred, whereas disintegration took place for the thiolated polymers within the first hour. The S-preactivated modification did not affect the cell viability of Caco2 cells exposed to the polymers. The release of the model drug sodium naproxen from tablets prepared with a lyophilized mixture of drug and polymer was studied via dissolution apparatus revealing that the preactivation on GC-GSH and GC-NAC involves a slowdown in the drug release rate. The results shown that the novel preactivated thiolated GC-derivatives can be considered promising excipients for the development of mucoadhesive drug delivery systems.
PDF
