Evaluation of amorphous and lipid-based formulation strategies to increase the in vivo cannabidiol bioavailability in piglets.

Cannabidiol (CBD) suffers from poor oral bioavailability due to poor aqueous solubility and high metabolism, and is generally administered in liquid lipid vehicles. Solid-state formulations of CBD have been developed, but their ability to increase the oral bioavailability has not yet been proven in vivo. Various approaches are investigated to increase this bioavailability. This study aimed to demonstrate the enhancement of the oral bioavailability of oral solid dosage forms of amorphous CBD and lipid-based CBD formulation compared to crystalline CBD. Six piglets received the three formulations, in a cross-over design. CBD and 7 - COOH - CBD, a secondary metabolite used as an indicator of hepatic degradation, were analyzed in plasma. A 10.9-fold and 6.8-fold increase in oral bioavailability was observed for the amorphous and lipid formulations, respectively. However, the lipid-based formulation allowed reducing the inter-variability when administered to fasted animals. An entero-hepatic cycle was confirmed for amorphous formulations. Finally, this study showed that the expected protective effect of lipids against hepatic degradation of the lipid-based formulation did not occur, since the ratio CBD/metabolite was higher than that of the amorphous one.

Feasibility study of the use of a homemade direct powder extrusion printer to manufacture printed tablets with an immediate release of a BCS II molecule.

Among the various 3D printing techniques, FDM is the most studied in pharmaceutical research. However, it requires the fabrication of filaments with suitable mechanical properties using HME, which can be laborious and time-consuming. DPE has emerged as a single-step printing technique that can overcome FDM limits as it enables the direct printing of powder blends without the need of filaments. This study demonstrated the manufacturing of cylindrical-shaped printed tablets containing CBD, a BCS II molecule, with an immediate release. Different blends of PEO/E100 and PEO/SOL, each with 10 % of CBD, were printed and tested according to the Eur. Ph. for uncoated tablets. Each printed cylinder met the Eur. Ph. specifications for friability, mass variation and mass uniformity. However, only the E100-based formulations enabled a CBD immediate release, as formulations containing SOL formed a gel once in contact with the dissolution medium, reducing the drug dissolution rate.

Influence of API physico-chemical properties on amorphization capacity of several mesoporous silica loading methods.

The objective of this work was to evaluate the impact of physico-chemical properties of pharmaceutical drugs on the optimal mesoporous silica loading methods. Indeed, a good combination between drug and loading process has to be studied to promote the deepest penetration of the drug inside the mesopores, allowing high drug amorphization. Six molecules, namely lidocaine and its hydrochloride, ibuprofen, ketoprofen, artemether and miconazole, with different physico-chemical properties (the ionized character, the acid-base character, the HBDA number, the solubility in sc-CO2 and the behavior under subcritical CO2) were used to produce drug-silica formulations. Different impregnation processes (physical mixing, melting, wetting, sc-CO2 and subcritical CO2 impregnations) have been compared for each drug, in terms of drug recovery and crystallinity. Formulations showed drug percentage close to 100% except for supercritical soluble drug formulations impregnated by using sc-CO2. However, the basic drug character provided less or no drug loss during impregnation. Processing insoluble sc-CO2 molecule under supercritical conditions led to less crystallinity than the correspondent physical mixture suggesting an interesting repulsive effect that forces the drug penetration within the mesopores. Besides, it has been also highlighted that the HBDA number is not sufficient to predict the final drug loading. Melting methods have high interest considering the drugs tested and subcritical CO2 could increase the loading, especially for drugs with high molten viscosity. This study showed that a plethora of loading methods can be used to provide high drug loaded MS formulations with a wide choice of equipment.

Impregnation of mesoporous silica with poor aqueous soluble molecule using pressurized carbon dioxide: Is the solubility in the supercritical and subcritical phase a critical parameter?

Recently, mesoporous silica (MS) has been used as a material able to maintain amorphous state of active compounds and therefore, enhance the oral bioavailability of BCSII drugs. Among impregnation methods of MS, techniques using supercritical carbon dioxide (Sc-CO2) are promising tools. Solubility of compounds in Sc-CO2 is reported as one of the most critical parameters, which usually limits its use in drug formulation. Indeed, most of compounds have poor solubility in Sc-CO2. The aim of this work is to compare different MS and to study alternative processes using pressurized CO2 for insoluble molecule in Sc-CO2. By using high pressure reactor, DSC, HPLC and in vitro dissolution tests, the crystallinity and dissolution profiles of MS with different pore size (6.6 nm, 25.0 nm and 2.5 nm) impregnated with fenofibrate (FF) under Sc-CO2 were compared to select the most appropriate carrier. Then, the selected MS has been impregnated under supercritical, subcritical and atmospheric conditions. We have shown that the MS pore size of 6.6 nm provides the higher amorphous drug loading capacity as well as the faster and higher drug dissolution. In addition, FF-MS formulations produced with pressurized CO2 as fusion medium, both in subcritical and supercritical conditions; give similar crystallinity and dissolution results compared to those produced with supercritical fluids as solvent. Through this study, we show new possibilities of using CO2 for insoluble compounds in this fluid.