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In the treatment of pediatric diseases, mass-produced dosage forms are often not suitable for children. Commercially available medicines are commonly manipulated and mixed with food by caregivers at home, or extemporaneous medications are routinely compounded in the hospital pharmacies to treat hospitalized children. Despite considerable efforts by regulatory agencies, the pediatric population is still exposed to questionable and potentially harmful practices. When designing medicines for children, the ability to fine-tune the dosage while ensuring the safety of the ingredients is of paramount importance. For these purposes solid formulations may represent a valid alternative to liquid formulations for their simpler formula and more stability, and, to overcome the problem of swelling ability, mini-tablets could be a practicable option. This review deals with the different approaches that may be applied to develop mini-tablets intended for pediatrics with a focus on the safety of excipients. Alongside the conventional method of compression, 3D printing appeared particularly appealing, as it allows to reduce the number of ingredients and to avoid both the mixing of powders and intermediate steps such as granulation. Therefore, this technique could be well adaptable to the daily galenic preparations of a hospital pharmacy, thus leading to a reduction of the common practice of off-label preparations.

In the original publication [...]

Water-soluble formulations of the pyrazole derivative 3-(4-chlorophenyl)-5-(4-nitrophenylamino)-1H-pyrazole-4-carbonitrile (CR232), which were proven to have in vitro antiproliferative effects on different cancer cell lines, were prepared by two diverse nanotechnological approaches. Importantly, without using harmful organic solvents or additives potentially toxic to humans, CR232 was firstly entrapped in a biodegradable fifth-generation dendrimer containing lysine (G5K). CR232-G5K nanoparticles (CR232-G5K NPs) were obtained with high loading (DL%) and encapsulation efficiency (EE%), which showed a complex but quantitative release profile governed by Weibull kinetics. Secondly, starting from hydrogenated soy phosphatidylcholine and cholesterol, we prepared biocompatible CR232-loaded liposomes (CR232-SUVs), which displayed DL% and EE% values increasing with the increase in the lipids/CR232 ratio initially adopted and showed a constant prolonged release profile ruled by zero-order kinetics. When relevant, attenuated total reflectance Fourier transformed infrared spectroscopy (ATR-FTIR) and nuclear magnetic resonance (NMR) spectroscopy, scanning electron microscopy (SEM) and dynamic light scattering (DLS) experiments, as well as potentiometric titrations completed the characterization of the prepared NPs. CR232-G5K NPs were 2311-fold more water-soluble than the pristine CR232, and the CR232-SUVs with the highest DL% were 1764-fold more soluble than the untreated CR232, thus establishing the success of both our strategies.

The growing resistance of bacteria to current chemotherapy is a global concern that urgently requires new and effective antimicrobial agents, aimed at curing untreatable infection, reducing unacceptable healthcare costs and human mortality. Cationic polymers, that mimic antimicrobial cationic peptides, represent promising broad-spectrum agents, being less susceptible to develop resistance than low molecular weight antibiotics. We, thus, designed, and herein report, the synthesis and physicochemical characterization of a water-soluble cationic copolymer (P5), obtained by copolymerizing the laboratory-made monomer 4-ammoniumbuthylstyrene hydrochloride with di-methyl-acrylamide as uncharged diluent. The antibacterial activity of P5 was assessed against several multi-drug-resistant clinical isolates of both Gram-positive and Gram-negative species. Except for strains characterized by modifications of the membrane charge, most of the tested isolates were sensible to the new molecule. P5 showed remarkable antibacterial activity against several isolates of genera Enterococcus, Staphylococcus, Pseudomonas, Klebsiella, and against Escherichia coli, Acinetobacter baumannii and Stenotrophomonas maltophilia, displaying a minimum MIC value of 3.15 µM. In time-killing and turbidimetric studies, P5 displayed a rapid non-lytic bactericidal activity. Due to its water-solubility and wide bactericidal spectrum, P5 could represent a promising novel agent capable of overcoming severe infections sustained by bacteria resistant the presently available antibiotics.

To counteract the growing bacterial resistance, we previously reported the remarkable antimicrobial activity of amino acid-conjugated cationic dendrimers (CDs) against several Gram-negative species, establishing that the cationic lysine was essential for their potency. In this paper, CDs conjugated with lysine and arginine and encapsulating ursolic and oleanolic acids (UOACDs) were assumed to be excellent candidates for developing new antibacterial agents, possibly active against Gram-positive species. Indeed, both the guanidine group of arginine and the two triterpenoid acids are items known for directing antibacterial effects, particularly against Gram-positive bacteria. The cationic dendrimers were obtained by peripheral conjugation with the selected amino acids and by entrapping a physical mixture of the commercial triterpenoid acids. The cationic compounds were characterized and successfully tested against 15 Gram-positive isolates. Interesting minimum inhibitory concentration (MIC) values were obtained for all the dendrimer-drug agents, establishing that the antibacterial activity observed for the UOACDs strongly depended on the density and on the type of the cationic groups of the cationic amino acid-conjugated dendrimers and not on the presence and the release of UOA. Particularly, lysine was critical for potency, while arginine was critical for redirecting activity against Gram-positive species. Especially, a high cationic character, associated with a balanced content of lysine/arginine, produced a remarkable antimicrobial effect (MIC = 0.5–8.7 µM).

All-trans-retinoic acid (ATRA) represents the first-choice treatment for several skin diseases, including epithelial skin cancer and acne. However, ATRA’s cutaneous side effects, like redness and peeling, and its high instability limit its efficacy. To address these drawbacks and to improve ATRA solubilization, we prepared ATRA-loaded micelles (ATRA-TPGSs), by its encapsulation in D-α-tocopheryl-polyethylene-glycol-succinate (TPGS). First, to explore the feasibility of the project, a solubility study based on the equilibrium method was performed, then, six ATRA-TPGS formulations were prepared by the solvent-casting method using different TPGS amounts. ATRA-TPGSs showed small sizes (11–20 nm), low polydispersity, slightly negative zeta potential, and proved good encapsulation efficiency, confirmed by a chemometric-assisted Fourier transform infrared spectroscopy (FTIR) investigation. ATRA-TPGS stability was also investigated to choose the most stable formulation. Using Carbopol® 980 as gelling agent, ATRA-TPGS-loaded gels were obtained and analyzed for their rheological profiles. Ex vivo release studies from ATRA-TPGSs were performed by Franz cells, demonstrating a permeation after 24 h of 22 ± 4 µ cm−2. ATRA-TPGSs showed enhanced cytotoxic effects on melanoma cells, suggesting that these formulations may represent a valid alternative to improve patient compliance and to achieve more efficacious therapeutic outcomes.

Human neuroblastoma (NB) is a pediatric tumor, which, after an initial response to therapy, usually develops resistance [...]

Human neuroblastoma (NB), a pediatric tumor inclined to relapse, after an initial response to therapy, usually develops resistance. Since several chemotherapeutics exert anticancer effect by increasing reactive oxygen species (ROS), NB cells overproduce antioxidant compounds becoming drugs-resistant. A strategy to sensitize NB cells to chemotherapy involves reducing their antioxidant defenses and inducing ROS overproduction. Concerning this, although affected by several issues that limit their clinical application, antioxidant/pro-oxidant polyphenols, such as gallic acid (GA), showed pro-oxidant anti-cancer effects and low toxicity for healthy cells, in several kind of tumors, not including NB. Herein, for the first time, free GA, two GA-dendrimers, and the dendrimer adopted as GA reservoir were tested on both sensitive and chemoresistant NB cells. The dendrimer device, administered at the dose previously found active versus sensitive NB cells, induced ROS-mediated death also in chemoresistant cells. Free GA proved a dose-dependent ROS-mediated cytotoxicity on both cell populations. Intriguingly, when administered in dendrimer formulations at a dose not cytotoxic for NB cells, GA nullified any pro-oxidant activity of dendrimer. Unfortunately, due to GA, nanoformulations were inactive on NB cells, but GA resized in nanoparticles showed considerable ability in counteracting, at low dose, ROS production and oxidative stress, herein induced by the dendrimer.