Abstract :
[en] The poor aqueous solubility of many pharmaceutical molecules represents a major hurdle in drug development, as it leads to a poor bioavailability. It is therefore crucial to develop strategies to improve the solubilization of these problematic molecules, which concerns up to 40% of active molecules on the market, such as fenofibrate (FF), and at least 70% of new therapeutic candidates, such as cannabidiol (CBD). Mesoporous silica (MS) are inorganic particles composed of a network of internal pores that may be useful to increase drug aqueous solubility and bioavailability. The aim of this work is therefore to study the potential of MS to improve the performance of drugs based on active substances with a low aqueous solubility. To do so, several in vitro and in vivo assays will be used.
The first part of this work focuses on methods for incorporating active molecules into the mesoporous network. This incorporation stabilizes the amorphous state of the active molecules, leading to an increase in aqueous solubility. Among the incorporation methods described, particular attention is paid to the use of supercritical carbon dioxide (CO2). We have shown that it is possible to overcome the major obstacle to the use of this method, namely the low solubility of many active molecules in the supercritical range. We have highlighted the possibility of using pressurized CO2 in the subcritical range as a method to efficiently incorporate and stabilize active molecules, such as FF and CBD, in their amorphous form to greatly increase their aqueous solubilities. This new method does not require prior solubilization in pressurized CO2 and therefore considerably broadens the range of active molecules that can be incorporated in MS using this method.
The second part focuses on the value of MS in the development of solid forms based on lipid-based formulations of CBD. A first design of experiments allowed to select a formulation composed of CBD (20%), Gelucire® 50/13 (40%) as the lipid excipient and Syloid® XDP (40%) as the mesoporous carrier. This formulation allowed increasing the aqueous dissolution of CBD and had a free-flowing behaviour thanks to the incorporation of the mixture of CBD with lipids within the mesoporous network of MS. A second design of experiments highlighted the possibility of producing tablets with the optimal CBD lipid-based formulation.
Finally, the third section details a pharmacokinetic study of optimized CBD formulations in piglets. An effective increase in CBD bioavailability using MS-based formulations was observed. The in vivo results were then compared with a series of in vitro dissolution data, enabling the development of in vitro-in vivo correlations highlighting the ability of the FeSSIF dissolution medium to adequately predict the in vivo fate of the formulations developed.
This work has therefore demonstrated the real improvement in the aqueous solubility and bioavailability of drugs through the use of formulations incorporating MS. These suitable formulations can be produced using many production methods, including green and solvent-free methods and the development of a level A IVIVC could help to rationalize future CBD formulations development.
