Biopredictive capability assessment of two dissolution/permeation assays, μFLUX™ and PermeaLoop™, using supersaturating formulations of Posaconazole

The majority of new drug entities exhibits poor water solubility and therefore enabling formulations are often needed to ensure sufficient in vivo bioavailability upon oral administration. Several in vitro tools have been proposed for biopredictive screening of such drug formulations to facilitate formulation development. Among these, combined dissolution/permeation (D/P) assays have gained increasing interest in recent years, since they are presumed to better predict the absorption behavior as compared to single-compartment dissolution assays. Moreover, especially for supersaturating formulations, it has been demonstrated that the presence of an absorption sink better mimics the intraluminal supersaturation performance. The present study aimed to investigate the biopredictive abilities of two in vitro D/P setups to predict intestinal supersaturation and systemic absorption of supersaturable systems. Experiments were performed with a mu FLUX (TM) and PermeaLoop (TM) apparatus, respectively, which differ primarily in their volume-to-area ratios between donor compartment and membrane as well as in the type of biomimetic barrier. A two-stage dissolution protocol was adopted to mimic the transit from acidic stomach to more neutral intestinal fluids using biomimetic media. Three formulations of the weakly basic compound Posaconazole (PCZ), namely an acidified and a neutral suspension and an amorphous solid dispersion (ASD) tablet, were tested. Under the present conditions, and for the specific set of formulations studied here, PermeaLoop (TM) showed a better biopredictive ability for intestinal supersaturation and systemic absorption for the three formulations than the mu FLUX (TM) D/P setup. Interestingly, minor modifications of the two-stage D/P protocol in terms of medium transfer rates from simulated gastric fluid (SGF) to fasted state simulated intestinal fluid (FaSSIF) had a substantial impact particularly on the permeation of the crystalline PCZ suspension (acidified suspension). The ASD tablet was less sensitive to gradual medium changes than the crystalline PCZ suspensions. The current study confirms the usefulness of D/P assays for formulation ranking of weakly basic compounds and supersaturating formulations.

Automated summary

The majority of new drugs have poor water solubility, which requires the development of enabling formulations for sufficient bioavailability upon oral administration. This study compared the biopredictive abilities of two in vitro tools for predicting intestinal supersaturation and systemic absorption of drug formulations. The PermeaLoop™ apparatus showed better predictive ability compared to the mu FLUX™ setup. The study confirms the usefulness of these tools for formulation ranking of weakly basic compounds and supersaturating formulations.