Evaluation of oral bioavailability enhancement of a BCS class II compound formulated with a supercritical CO2 process

Currently, it is considered that about 70% of new drug candidates show poor aqueous solubility and that approximately 40% of the active substances marketed as IR oral dosage forms can be categorized as BCS class II compounds. These compounds are characterized by a good permeability but also by a low and erratic oral bioavailability due to an insufficient dissolution throughout the GIT. This work was initiated in order to evaluate the interest of a supercritical CO2 process namely PGSS among all the current strategies used to form SD for improving the solubility of BCS class II compounds. Fenofibrate was selected as the BCS class II model drug and Gelucire® 50/13 was chosen as carrier because of its self-emulsifying properties. The first step of this work was to develop an in vitro response able to evaluate the improvement of the oral bioavailability produced by the formulation. Three different fenofibrate formulations, for which in vivo data were available in the literature, were tested using different dissolution tests to find the most suitable. The simplest in vitro dissolution tests (single phase) were first tested before more complex tests (biphasic systems). The biphasic dissolution system combining USP apparatuses II and IV was selected for the in vitro evaluation of the new fenofibrate lipid-based self-emulsifying formulation. During the next step of this work, the PGSS process was developed and then optimized according to the in vitro drug dissolution profile. This optimization was performed using a design of experiments approach. Firstly, the effects of 9 experimental parameters were investigated by a screening study in order to select parameters that have a significant influence on the dissolution profile of fenofibrate. The three most relevant parameters were optimized using a central composite design to produce the particles with the best dissolution profile. The dissolution profile obtained with this optimal PGSS formulation was compared to the dissolution profile of an equivalent micronized solid dispersion in order to evaluate the interest of the supercritical fluid technology. These in vitro results suggested that the improvement of the oral bioavailability of fenofibrate should be more pronounced with the PGSS formulation in view of its higher supersaturation extent and duration. This hypothesis was confirmed by a pharmacokinetic in vivo study on pigs. At the end of this work, the possibility of establishing IVIVC was considered. Based on FDA recommendations, a level A correlation was successfully established for the PGSS formulations and the dissolution profiles obtained with the biphasic dissolution system (sum of 2 phases). This level A IVIVC could be very useful for future formulation development. In conclusion, this work demonstrated the interest of a SCF technology to produce a LBF containing Gelucire® to enhance the oral bioavailability of the BCS class II compound fenofibrate.