Microdialysis during in vitro lipolysis explains enhanced permeation of indomethacin from phospholipid-based...

Many new drugs are poorly water-soluble requiring enabling formulations like amorphous solid dispersions or lipid-based formulations for oral administration. Phospholipid-based amorphous solid dispersions (PL-based ASDs) may combine the solubility advantages of ASDs and lipid-based formulations. Like lipid-based formulations, digestion may influence the biopharmaceutical performance of PL-based ASDs. Evaluating performance in the presence of solubilizing species as vesicles and micelles, forming during dissolution of PL-based ASDs, is difficult. To mitigate this, we used a novel biopharmaceutical approach based on microdialysis sampling to assess drug release from PL-based ASDs loaded with indomethacin under non-lipolytic and lipolytic conditions. Microdialysis sampling, unlike conventional sampling, can discern between molecularly dissolved drug and drug associated with colloidal species. The free drug is the main driving force for absorption. Therefore, we conducted dissolution/permeation experiments in non-lipolytic and lipolytic conditions for comparison. Microdialysis revealed that under lipolytic conditions the free drug concentration was increased as compared to non-lipolytic conditions for all PL-based ASDs agreeing with increased permeation under lipolytic conditions. PL-based ASDs with low to intermediate PL-to-drug ratios significantly improved biopharmaceutical performance. High phospholipid content impaired the performance due to colloidal entrapment. Correspondingly, the positive effect of lipolysis was most prominent at high phospholipid content. Microdialysis provided near real- time free drug concentrations and accurately ranked the formulations based on their ability to cross an absorptive barrier independent of lipolysis. Thereby, microdialysis resolves the limitations of coupled dissolution/permeation for PL-based ASDs. In conclusion, these findings provide a deeper understanding of the mechanisms of action of this formulation. The correlation between free drug concentration and permeability under simulated intestinal conditions may provide a framework for future design of PL-based ASDs presupposing that the observed correlation will be confirmed in an appropriate animal model.