Role of biorelevant dissolution media in the selection of optimal Salt forms of oral drugs: maximizing the gastrointestinal solubility and in vitro activity of the antimicrobial molecule, clofazimine

peer-reviewedClofazimine is an antimycobacterial agent that is routinely used for the treatment of leprosy. Clofazimine has also been shown to have high clinical potential for the treatment of many Gram-positive pathogens, including those that exhibit high levels of antibiotic resistance in the medical community. The use of clofazimine against these pathogens has largely been limited by the inherently poor water solubility of the drug substance. In this work, the possibility of repurposing and reformulating clofazimine to maximize its clinical potential is investigated. To achieve this, the potential of novel salt forms of clofazimine as supersaturating drug delivery vehicles to enhance the aqueous solubility and gastrointestinal solubility of the drug substance was explored. The solution properties of seven novel salt forms, identified during an initial screening process, were examined in water and in a gastrointestinal-like media and were compared and contrasted with those of the free base, clofazimine, and the commercial formulation of the drug, Lamprene. The stability of the most promising solid forms was tested, and their bioactivity against Staphylococcus aureus was also compared with that of the clofazimine free base and Lamprene. Salts forms which showed superior stability as well as solubility and activity to the commercial drug formulation were fully characterized using a combination of spectroscopic techniques, including X-ray diffraction, solid-state NMR, and Fourier transform infrared spectroscopy

Investigation of the particle growth of fenofibrate following antisolvent precipitation and freeze-drying

peer-reviewedSubmicron to small-micron-sized particles of the hydrophobic drug, fenofibrate, were prepared by controlled crystallization in order to influence its dissolution behavior. An antisolvent precipitation process successfully generated particles (200-300 nm) which matched the size and dissolution behavior of a commercial wet-milled formulation of the drug. Although the preparation of submicron-sized particles was straightforward, retaining their size in suspension and during isolation was a challenge. Additives were employed to temporarily stabilize the suspension, and extend the time window for isolation of the submicron particles. Precipitated particles were isolated primarily by immediate freeze-drying, but drying stresses were found to destabilize the fragile submicron system. The growth pathway of particles in suspension and during oven and freeze-drying were compared. Although the growth pathways appeared considerably different from a visual morphological perspective, an investigation of the electron diffraction patterns and the inner-particle surfaces showed that the growth pathways were the same: molecular addition by Ostwald ripening. The observed differences in the time-resolved particle morphologies were found to be a result of the freeze-drying process.ACCEPTEDpeer-reviewe

Co-reductive fabrication of carbon nanodots with high quantum yield for bioimaging of bacteria

A simple and straightforward synthetic approach for carbon nanodots (C-dots) is proposed. The strategy is based on a one-step hydrothermal chemical reduction with thiourea and urea, leading to high quantum yield C-dots. The obtained C-dots are well-dispersed with a uniform size and a graphite-like structure. A synergistic reduction mechanism was investigated using Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. The findings show that using both thiourea and urea during the one-pot synthesis enhances the luminescence of the generated C-dots. Moreover, the prepared C-dots have a high distribution of functional groups on their surface. In this work, C-dots proved to be a suitable nanomaterial for imaging of bacteria and exhibit potential for application in bioimaging thanks to their low cytotoxicity

Investigating the Solubility and Cytocompatibility of CaO-Na2O-SiO2/TiO2 Bioactive Glasses

This study aims to investigate the solubility of a series of titanium (TiO2)-containing bioactive glasses and their subsequent effect on cell viability. Five glasses were synthesized in the composition range SiO2-Na2O-CaO with 5 mol % of increments TiO2 substituted for SiO2. Glass solubility was investigated with respect to (1) exposed surface area, (2) particle size, (3) incubation time, and (4) compositional effects. Ion release profiles showed that sodium (Na+) presented high release rates after 1 day and were unchanged between 7 and 14 days. Calcium (Ca2+) release presented a significant change at each time period and was also composition dependent, where a reduction in Ca2+ release is observed with an increase in TiO2 concentration. Silica (Si4+) release did not present any clear trends while no titanium (Ti4+) was released. Cell numbers were found to increase up to 44%, compared to the growing control population, with a reduction in particle size and with the inclusion of TiO2 in the glass composition

The effects of social structure and sex-biased transmission on macroparasite infection

Mathematical models of disease dynamics tend to assume that individuals within a population mix at random and so transmission is random, and yet, in reality social structure creates heterogeneous contact patterns. We investigated the effect of heterogeneity in host contact patterns on potential macroparasite transmission by first quantifying the level of assortativity in a socially structured wild rodent population (Apodemus flavicollis) with respect to the directly-transmitted macroparasitic helminth, Heligmosomoides polygyrus. We found the population to be disassortatively mixed (i.e. male mice mixing with female mice more often than same sex mixing) at a constant level over time. The macroparasite H. polygyrus has previously been shown to exhibit male-biased transmission so we used a Susceptible-Infected (SI) mathematical model to simulate the effect of increasing strengths of male-biased transmission on the prevalence of the macroparasite using empirically-derived transmission networks. When transmission was equal between the sexes the model predicted macroparasite prevalence to be 73% and infection was male biased (82% of infection in the male mice). With a male-bias in transmission ten times that of the females, the expected macroparasite prevalence was 50% and was equally prevalent in both sexes, results that both most closely resembled empirical dynamics. As such, disassortative mixing alone did not produce macroparasite dynamics analogous to those from empirical observations; a strong male-bias in transmission was also required. We discuss the relevance of our results in the context of network models for transmission dynamics and control

Development and validation of a measure of maladaptive social-evaluative beliefs characteristic of social anxiety disorder in youth: the Report of Youth Social Cognitions (RYSC)

Recent research has started to examine the applicability of influential adult models of the maintenance of social anxiety disorder (SAD) to youth. This research is limited by the lack of psychometrically validated measures of underlying constructs that are developmentally appropriate for youth. One key construct in adult models of SAD is maladaptive social-evaluative beliefs. The current study aimed to develop and validate a measure of these beliefs in youth, known as the Report of Youth Social Cognitions (RYSC). The RYSC was developed with a clinical sample of youth with anxiety disorders (N = 180) and cross-validated in a community sample of youth (N = 305). In the clinical sample, the RYSC exhibited a three-factor structure (Negative Evaluation, Revealing Self, and Positive Impression factors), good internal consistency, and construct validity. In the community sample, the three-factor structure and the internal consistency of the RYSC were replicated, but the test of construct validity showed that the RYSC had similarly strong associations with social anxiety and depressed affect. The RYSC had good test-retest reliability overall, although the Revealing Self subscale showed lower temporal stability which improved when only older participants were considered (age ≥ 9 years). The RYSC in general was also shown to discriminate between youth with and without SAD although the Revealing Self subscale again performed suboptimally but improved when only older participants were considered. These findings provide psychometric support for the RYSC and justifies its use with youth in research and clinical settings requiring the assessment of maladaptive social-evaluative beliefs