The use of polymorphic state modifiers in solid lipid microparticles: The role of structural modifications on drug release performance

This study investigates the correlation between the structural and release properties of solid lipid microparticles (MPs) of tristearin containing 5 % w/w of four different liquid additives used as crystal modifiers: isopropyl myristate (IM), ethyl oleate (EO), oleic acid (OA) and medium chain triglycerides (MCT). All additives accelerated the conversion of the unstable α-form of tristearin, formed after the MPs manufacturing, to the stable β-polymorph and the transformation was completed within 24 h (for IM and EO) or 48 h (for OA and MCT). The kinetic of polymorphic transition at 25 ◦C was investigated by simultaneous synchrotron SAXS/WAXS and DSC analysis after melting and subsequent cooling of the lipid mixture. After crystallization in the α-phase, additives accelerate the solid-solid phase transformation to β-tristearin. SAXS data showed that two types of structural modifications occurred on MPs during storage: compaction of the crystal packing (slight decrease in lamellar thickness) and crystal growth (increased number of stacked lipid lamellae). The release behavior of a model hydrophilic drug (caffeine) at two different amounts (15 % and 30 %) from MPs was studied in water and biorelevant media simulated the gastric and intestinal environment. It was particularly significant that the introduction of IM, EO and MCT were able to prolong the drug release in water, passing from a diffusion-based Higuchi kinetics to a perfect zero-order kinetic. Moreover, the overall release profiles were higher in biorelevant media, where erosion/digestion of MPs was observed. After 6 months, a moderate but statistically significant change in release profile was observed for the MPs with IM and EO, which can be correlated with the timedependent structural alterations (i.e. larger average crystallite size) of these formulations; while MPs with OA or MCT displayed stable release profiles. These findings help to understand the correlation between release behavior, polymorphism and supramolecular-level structural modification of lipid formulations containing crystal modifiers

From Bitter to Sweet: a preliminary study towards a patient-friendly Praziquantel dosage form

Praziquantel (PZQ) is an antihelmintic drug used worldwide against Schistosomiasis, despite its low solubility, bioavailability and the disgusting taste. This research represents a preliminary screening of 6 selected sweeteners in terms of their aptitude to be ground with PZQ, towards the development of a patient-friendly dosage form, capable of overcoming both dissolution and taste drawbacks. A vibrational mill was used to process equimolar mixtures of PZQ and each sweetener, and the dispersions were characterized by means of Differential Scanning Calorimetry, Powder X-ray Diffraction, Fourier Transform-Infrared Spectrometry, water solubility and Intrinsic Dissolution Rate. Physical stability of the coground systems was checked over a period of 1 year. The grinding for a short period (such as 30 min) of PZQ and selected sweeteners led to several very interesting products, with prevalent amorphous character, enhanced solubility and Intrinsic Dissolution Rate comparing to the raw drug. Peculiar behavior was found in the case of xylitol:PZQ ground mixtures where the appearance of traces of PZQ anhydrous Form B was noticed. Therefore, this research highlights the possibility of using binary premixes of PZQ and sweeteners in order to obtain an increase in the biopharmaceutical and organoleptic properties of the anthelmintic drug, underlining also the need for a careful screening of sweetener to design a PZQ patient-friendly dosage form

From Bitter to Sweet: a preliminary study towards a patient-friendly Praziquantel dosage form

Praziquantel (PZQ) is an antihelmintic drug used worldwide against Schistosomiasis, despite its low solubility, bioavailability and the disgusting taste. This research represents a preliminary screening of 6 selected sweeteners in terms of their aptitude to be ground with PZQ, towards the development of a patient-friendly dosage form, capable of overcoming both dissolution and taste drawbacks. A vibrational mill was used to process equimolar mixtures of PZQ and each sweetener, and the dispersions were characterized by means of Differential Scanning Calorimetry, Powder X-ray Diffraction, Fourier Transform-Infrared Spectrometry, water solubility and Intrinsic Dissolution Rate. Physical stability of the coground systems was checked over a period of 1 year. The grinding for a short period (such as 30 min) of PZQ and selected sweeteners led to several very interesting products, with prevalent amorphous character, enhanced solubility and Intrinsic Dissolution Rate comparing to the raw drug. Peculiar behavior was found in the case of xylitol:PZQ ground mixtures where the appearance of traces of PZQ anhydrous Form B was noticed. Therefore, this research highlights the possibility of using binary premixes of PZQ and sweeteners in order to obtain an increase in the biopharmaceutical and organoleptic properties of the anthelmintic drug, underlining also the need for a careful screening of sweetener to design a PZQ patient-friendly dosage form

Conformational polymorphic changes in the crystal structure of the chiral antiparasitic drug praziquantel and interactions with calcium carbonate

Praziquantel is an antiparasitic drug used for decades. Currently, the praziquantel commercial preparation is a racemic mixture, in which only the levo-enantiomer possesses anthelmintic activity. The knowledge of its properties in the solid state and other chemical-physical properties is necessary for improving its efficacy and applications. Drug solid dispersions were prepared with calcium carbonate at 1:5 drug to excipient weight ratio by solvent evaporation method. Then, the modification of the crystal structure of the racemic polymorph of praziquantel in presence of calcium carbonate has been studied by means of several analytical techniques (DSC,TGA, XRD, SEM, FTIR, Raman spectroscopy and chiral liquid chromatography). This study has been completed with atomistic calculations based on empirical interatomic force fields and quantum mechanics methods applied to the crystal structure of praziquantel and of intermolecular interactions. The results evidenced that calcium carbonate provoked a conformational change in the praziquantel molecule yielding the formation of different polymorphs of praziquantel crystal. These alterations were not observed replacing calcium carbonate with colloidal silica as excipient in the solid dispersion

Ground Calcium Carbonate as a Low Cost and Biosafety Excipient for Solubility and Dissolution Improvement of Praziquantel

Calcium carbonate is an abundant mineral with several advantages to be a successful carrier to improve oral bioavailability of poorly water-soluble drugs, such as praziquantel. Praziquantel is an antiparasitic drug classified in group II of the Biopharmaceutical Classification System hence characterized by high-permeability and low-solubility. Therefore, the dissolution rate is the limiting factor for the gastrointestinal absorption that contributes to the low bioavailability. Consequently, the therapeutic dose of the praziquantel must be high and big tablets and capsules are required, which are difficult to swallow, especially for pediatric and elderly patients. Mixtures of praziquantel and calcium carbonate using solid-solid physical mixtures and solid dispersions were prepared and characterized using several techniques (X-ray diffraction differential scanning calorimetry, thermogravimetric analysis, scanning electron microscopy, laser diffraction, Fourier transform infrared and Raman spectroscopies). Solubility of these formulations evidenced that the solubility of praziquantel-calcium carbonate interaction product increased in physiological media. In vitro dissolution tests showed that the interaction product increased the dissolution rate of the drug in acidic medium. Theoretical models were studied to understand this experimental behavior. Cytotoxicity and cell cycle studies were performed, showing that praziquantel-calcium carbonate physical mixture and interaction product were biocompatible with the HTC116 cells, because it did not produce a decrease in cell viability or alterations in the cell cycle.We also acknowledge for financial support the MINECO, for projects FIS2016-77692-C2-2-P and CGL2016-80833-R, and the Andalusian government, for project RNM1897

A retrospective multicentre study on dalbavancin effectiveness and cost-evaluation in sternotomic wound infection treatment: DALBA SWIT Study

To evaluate the cost-effectiveness of dalbavancin compared with standard of care (SoC) treatment as daptomycin or teicoplanin in patients with sternal wound infections (SWI)

Spray-congealed Solid Lipid Microparticles as a new tool for the controlled release of Bisphosphonates from a Calcium Phosphate Bone cement

The aim of this work was to develop an innovative drug delivery system potentially useful for the local delivery of Bisphosphonates to bone tissue. We propose the use of Solid Lipid Microparticles (MPs), up to now mainly used for oral and topical drug delivery, as carrier for bisphosphonates due to the favourable biocompatibility and lower toxicity of the lipids compared with many polymers. The delivery platform consisted of a biomimetic \u3b1-tricalcium phosphate-gelatin cement (CPC) enriched with alendronate loaded MPs (MPs-AL) produced by the spray congealing technology. Alendronate direct addition to cement composition is limited since Alendronate is able to sequester calcium from calcium phosphates, thus preventing the setting of the cements. At variance, this approach permitted to load a relatively high amount of the drug on the CPC and allowed the controlled release of the highly water soluble alendronate. A Design of Experiment (DoE) was employed for the screening of the effects of the formulation variables related to the presence of unloaded microparticle (MPs) on the cement most important mechanical properties. Then, MPs loaded with 10 % w/w of alendronate were produced using five different carriers (Stearic Acid, Stearilic Alcohol, Cutina HR, Tristearin and Precirol ATO5). All MPs-AL exhibited a spherical shape, encapsulation efficiency higher than 90% and prevalent particle size ranging from 100-150 micron. Solid state characterization (DSC, HSM and X-ray powder diffraction) demonstrated that encapsulation of alendronate into MPs did not alter its crystal structure. MPs-AL addition to the cement provoked a modest lengthening of the setting times and of the hardening reaction leading to the complete transformation of \u3b1-tricalcium phosphate into calcium-deficient hydroxyapatite, without significantly affect the cement mechanical properties. Moreover, the results of in vitro AL release study performed on cements enriched with MPs-AL showed that the system allows a controlled release of the drug over time

pH and Reactive Oxygen Species-Sequential Responsive Nano-in-Micro Composite For Targeted Therapy of Inflammatory Bowel Disease

Oxidative stress and abnormally high levels of reactive oxygen species (ROS) play an essential role in the pathogenesis and progression of inflammatory bowel disease (IBD). Oxidation‐responsive nanoparticles (NPs) are formulated from a phenylboronic esters‐modified dextran (OxiDEX) that degrades selectively in response to hydrogen peroxide (H2O2). OxiDEX NPs are coated with chitosan and encapsulated in a pH‐sensitive polymer to produce nano‐in‐micro composites. The microparticles are spherical with homogeneous particle size (53 ± 3 µm) and maintain integrity at acidic pH, preventing the premature release of the NPs in gastric conditions. The degradation of NPs is highly responsive to the level of H2O2, and the release of the drug is sustained in the presence of physiologically relevant H2O2 concentrations. The presence of chitosan on the particles surface significantly enhances NPs stability in intestinal pH and their adhesion on the intestinal mucosa. Compared to a traditional enteric formulation, this formulation shows tenfold decreased drug permeability across C2BBe1/HT29‐MTX cell monolayer, implying that lower amount of drug would be absorbed to the blood stream and, therefore, limiting the undesired systemic side effects. Based on these results, a successful nano‐in‐micro composite for targeted therapy of IBD is obtained by combination of the responsiveness to pH and ROS.Peer reviewe

Shifts of Faecal Microbiota during Sporadic Colorectal Carcinogenesis

Gut microbiota has been implicated in the etiopathogenesis of colorectal cancer. The development of colorectal cancer is a multistep process by which healthy epithelium slowly develops into preneoplastic lesions, which in turn progress into malignant carcinomas over time. In particular, sporadic colorectal cancers can arise from adenomas (about 85% of cases) or serrated polyps through the "adenoma-carcinoma" or the "serrated polyp-carcinoma" sequences, respectively. In this study, we performed 16 S rRNA gene sequencing of bacterial DNA extracted from faecal samples to compare the microbiota of healthy subjects and patients with different preneoplastic and neoplastic lesions. We identified putative microbial biomarkers associated with stage-specific progression of colorectal cancer. In particular, bacteria belonging to the Firmicutes and Actinobacteria phyla, as well as members of the Lachnospiraceae family, proved to be specific of the faecal microbiota of patients with preneoplastic lesions, including adenomas and hyperplastic polyps. On the other hand, two families of the Proteobacteria phylum, Alcaligeneaceae and Enterobacteriaceae, with Sutterella and Escherichia/Shigella being the most representative genera, appeared to be associated with malignancy. These findings, once confirmed on larger cohorts of patients, can represent an important step towards the development of more effective diagnostic strategies

Evaluation of Legionella Air Contamination in Healthcare Facilities by Different Sampling Methods: An Italian Multicenter Study

Healthcare facilities (HF) represent an at-risk environment for legionellosis transmission occurring after inhalation of contaminated aerosols. In general, the control of water is preferred to that of air because, to date, there are no standardized sampling protocols. Legionella air contamination was investigated in the bathrooms of 11 HF by active sampling (Surface Air System and Coriolis®μ) and passive sampling using settling plates. During the 8-hour sampling, hot tap water was sampled three times. All air samples were evaluated using culture-based methods, whereas liquid samples collected using the Coriolis®μ were also analyzed by real-time PCR. Legionella presence in the air and water was then compared by sequence-based typing (SBT) methods. Air contamination was found in four HF (36.4%) by at least one of the culturable methods. The culturable investigation by Coriolis®μ did not yield Legionella in any enrolled HF. However, molecular investigation using Coriolis®μ resulted in eight HF testing positive for Legionella in the air. Comparison of Legionella air and water contamination indicated that Legionella water concentration could be predictive of its presence in the air. Furthermore, a molecular study of 12 L. pneumophila strains confirmed a match between the Legionella strains from air and water samples by SBT for three out of four HF that tested positive for Legionella by at least one of the culturable methods. Overall, our study shows that Legionella air detection cannot replace water sampling because the absence of microorganisms from the air does not necessarily represent their absence from water; nevertheless, air sampling may provide useful information for risk assessment. The liquid impingement technique appears to have the greatest capacity for collecting airborne Legionella if combined with molecular investigation