In vitro dissolution/permeation tools for amorphous solid dispersions bioavailability forecasting II: Comparison and mechanistic insights

Along with the increasing demand for complex formulations comes the need for appropriate in vitro method-ologies capable of predicting their corresponding in vivo performance and the mechanisms controlling the drug release which can impact on in vivo drug absorption. In vitro dissolution-permeation (D/P) methodologies that can account for the effects of enabling formulations on the permeability of drugs are increasingly being used in performance ranking during early development stages. This work comprised the application of two different cell -free in vitro D/P setups: BioFLUXTM and PermeaLoopTM to evaluate the dissolution-permeation interplay upon drug release from itraconazole (ITZ)-HPMCAS amorphous solid dispersions (ASDs) of different drug loads. A solvent-shift approach was employed, from a simulated gastric environment to a simulated intestinal environ-ment in the donor compartment. PermeaLoopTM was then combined with microdialysis sampling to separate the dissolved (free) drug from other species present in solution, like micelle-bound drug and drug-rich colloids, in real time. This setup was applied to clarify the mechanisms for drug release and permeation from these ASDs. In parallel, a pharmacokinetic study (dog model) was conducted to assess the drug absorption from these ASDs and to compare the in vivo results with the data obtained from each in vitro D/P setup, allowing to infer which would be the most adequate setup for ASD ranking. Even though both D/P systems resulted in the same qualitative ranking, BioFLUXTM overpredicted the difference between the in vivo AUC of two ASDs, whereas PermeaLoopTM permeation flux resulted in a good correlation with the AUC observed in pharmacokinetic studies (dog model) (R2 & AP; 0.98). Also, PermeaLoopTM combined with a microdialysis sampling probe clarified the mechanisms for drug release and permeation from these ASDs. It demonstrated that the free drug was the only driving force for permeation, while the drug-rich colloids kept permeation active for longer periods by acting as drug reservoirs and maintaining constant high levels of free drug in solution, which are then immediately able to permeate. Hence, the data obtained points BioFLUXTM and PermeaLoopTM applications to different momentums in the drug product development pipeline: while BioFLUXTM, an automated standardized method, poses as a valuable tool for initial ASD ranking during the early development stages, PermeaLoopTM combined with microdialysis sampling allows to gain mechanistic understanding of the dissolution-permeation interplay, being crucial to fine tune and identify leading ASD candidates prior to in vivo testing.

Automated summary

The increasing demand for complex formulations requires appropriate in vitro methodologies to predict their in vivo performance and the mechanisms controlling drug release. In vitro dissolution-permeation (D/P) methodologies are being used to rank the performance of enabling formulations during early development. In this study, two different cell-free in vitro D/P setups were used to evaluate the dissolution-permeation interplay of itraconazole (ITZ)-HPMCAS amorphous solid dispersions (ASDs) with different drug loads. A solvent-shift approach was employed, and microdialysis sampling was used to separate the dissolved drug from other species in solution. The results showed that BioFLUXTM and PermeaLoopTM have different applications in the drug product development pipeline.