Along with the increasing demand for complex formulations comes the need for appropriate in vitro methodologies 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: Bio FLUX and PermeaLoop 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 environment in the donor compartment. PermeaLoop was then combined with micro dialysis sampling to sep. 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 qual. ranking, BioFLUX overpredicted the difference between the in vivo A UC of two ASDs, whereas PermeaLoop permeation flux resulted in a good correlation with the AUC observed in pharmacokinetic studies (dog model) (R2 ≈ 0.98) . Also, PermeaLoop combined with a micro dialysis sampling probe clarified the mechanisms for drug release and permeation from these A SDs. 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 Bio FLUX and PermeaLoop applications to different momentums in the drug product development pipeline: while BioFLUX, an automated standardized method, poses as a valuable tool for initial A SD ranking during the early development stages, PermeaLoop combined with micro dialysis sampling allows to gain mechanistic understanding of the dissolution-permeation interplay, being crucial to fine tune and identify leading A SD candidates prior to in vivo testing.

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