Preparation of parenteral nanocrystal suspensions of etoposide from the excipient free dry state of the drug to enhance in vivo antitumoral properties

Nanoparticle technology in cancer chemotherapy is a promising approach to enhance active ingredient pharmacology and pharmacodynamics. Indeed, drug nanoparticles display various assets such as extended blood lifespan, high drug loading and reduced cytotoxicity leading to better drug compliance. In this context, organic nanocrystal suspensions for pharmaceutical use have been developed in the past ten years. Nanocrystals offer new possibilities by combining the nanoformulation features with the properties of solid dispersed therapeutic ingredients including (i) high loading of the active ingredient, (ii) its bioavailability improvement, and (iii) reduced drug systemic cytotoxicity. However, surprisingly, no antitumoral drug has been marketed as a nanocrystal suspension until now. Etoposide, which is largely used as an anti-cancerous agent against testicular, ovarian, small cell lung, colon and breast cancer in its liquid dosage form, has been selected to develop injectable nanocrystal suspensions designed to be transferred to the clinic. The aim of the present work is to provide optimized formulations for nanostructured etoposide solutions and validate by means of in vitro and in vivo evaluations the efficiency of this multiphase system. Indeed, the etoposide formulated as a nanosuspension by a bottom-up approach showed higher blood life span, reduced tumor growth and higher tolerance in a murine carcinoma cancer model. The results obtained are promising for future clinical evaluation of these etoposide nanosuspensions

New Lidocaine-Based Pharmaceutical Cocrystals: Preparation, Characterization, and Influence of the Racemic vs. Enantiopure Coformer on the Physico-Chemical Properties

This study describes the preparation, characterization, and influence of the enantiopure vs. racemic coformer on the physico-chemical properties of a pharmaceutical cocrystal. For that purpose, two new 1:1 cocrystals, namely lidocaine:dl-menthol and lidocaine:d-menthol, were prepared. The menthol racemate-based cocrystal was evaluated by means of X-ray diffraction, infrared spectroscopy, Raman, thermal analysis, and solubility experiments. The results were exhaustively compared with the first menthol-based pharmaceutical cocrystal, i.e., lidocaine:l-menthol, discovered in our group 12 years ago. Furthermore, the stable lidocaine/dl-menthol phase diagram has been screened, thoroughly evaluated, and compared to the enantiopure phase diagram. Thus, it has been proven that the racemic vs. enantiopure coformer leads to increased solubility and improved dissolution of lidocaine due to the low stable form induced by menthol molecular disorder in the lidocaine:dl-menthol cocrystal. To date, the 1:1 lidocaine:dl-menthol cocrystal is the third menthol-based pharmaceutical cocrystal, after the 1:1 lidocaine:l-menthol and the 1:2 lopinavir:l-menthol cocrystals reported in 2010 and 2022, respectively. Overall, this study shows promising potential for designing new materials with both improved characteristics and functional properties in the fields of pharmaceutical sciences and crystal engineering

Asphaltene multilayer growth in porous medium probed by SANS

Presence of suspended particles such as asphaltene in crude oils could significantly affect the production by means of deposition in porous media especially near the well bore. We investigate this phenomenon using the ability of Small Angle Neutron Scattering technique to probe directly the asphaltene adsorption process in a porous medium at the nanometer length scale under flow conditions. A device based on a quartz tube filled with SiC particles constitute the porous medium in which an asphaltene solution in a mixture of good (toluene)/bad (heptane) solvent is injected under controlled flow. The contrast matching technique enables to match the porous medium scattering contributions and to measure the signal of the deposit. Such a device can be used for curves surface measurements on a setup originally designed for bulk studies and permit thus the direct comparison with measurements on flat surfaces (neutron reflectivity) and indirect adsorption measurements (adsorption isotherm). We show here that asphaltene in good solvent leads to a monolayer whereas addition of bad solvent results in a multilayer growth which is consistent with the deposition behaviour described in the literature

Solid state landscape of an Active Pharmaceutical Ingredient used for rare diseases

International audienc

Solid state landscape of an Active Pharmaceutical Ingredient used for rare diseases

International audienc

Characterization of water-solid state interactions of an active pharmaceutical ingredient

International audienc

Asphaltene adsorption mechanism under shear flow probed by in situ neutron reflectivity measurements

We propose here a method to adapt a rheometer with a cone/plate geometry to a neutron reflectometer in order to perform in situ reflectivity measurements. This study allowed us to probe the influence of the shear rate on the mechanism of asphaltenes adsorption, the heaviest and most polar compounds of crude oil, using bad solvent conditions. Such experiment aims at describing at a local scale the surface modifications induced by flowing crude oils (pipe transportation or production through porous media). Without shearing, in a 34%/66% xylene/dodecane mixture for which the asphaltenes flocculation is achieved in bulk, the nanoaggregates are able to be adsorbed on a hydrophilic surface as multilayers, with a surface excess much larger than for good solvent conditions. Moreover, the thickness of these multilayers increases almost linearly with time, in accordance with QCM experiments. In shear rate conditions, the adsorption process is however strongly limited since the surface excess of the adsorbed layers is around twice lower at 2600 s−1 than at 1200 s−1

Comprehensive determination of the solid state stability of Bethanechol Chloride using combined analytical tools

National audienc