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

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery Systems
• Pharmacokinetics

Background:

• Complex formulations require in vitro methods to predict in vivo performance and drug release mechanisms.
• In vitro dissolution-permeation (D/P) methodologies are crucial for ranking drug formulations during early development.
• Understanding drug absorption requires evaluating the interplay between dissolution and permeation.

Purpose of the Study:

• To evaluate two cell-free in vitro D/P setups, BioFLUX™ and PermeaLoop™, for assessing itraconazole (ITZ)-HPMCAS amorphous solid dispersions (ASDs).
• To compare the in vitro D/P results with in vivo pharmacokinetic data in a dog model for formulation ranking.
• To elucidate the drug release and permeation mechanisms from ASDs using advanced in vitro techniques.

Main Methods:

• Application of BioFLUX™ and PermeaLoop™ in vitro D/P systems with a solvent-shift approach (gastric to intestinal simulation).
• Integration of PermeaLoop™ with microdialysis sampling for real-time separation of free, micelle-bound, and colloid-bound drug.
• Conducting parallel in vivo pharmacokinetic studies in a dog model to assess drug absorption.

Main Results:

• Both D/P systems provided similar qualitative ranking of ASDs.
• PermeaLoop™ permeation flux demonstrated a strong correlation (R² ≈ 0.98) with in vivo AUC, outperforming BioFLUX™ which overpredicted differences.
• PermeaLoop™ with microdialysis identified free drug as the permeation driver and drug-rich colloids as reservoirs maintaining drug availability.

Conclusions:

• BioFLUX™ is suitable for initial ASD ranking in early development due to its standardized nature.
• PermeaLoop™ combined with microdialysis offers mechanistic understanding of dissolution-permeation, vital for fine-tuning and selecting leading ASD candidates before in vivo testing.
• The study highlights the importance of advanced in vitro models for accurate prediction of in vivo drug absorption from complex formulations like ASDs.