A simplified method to screen for in-vivo performance of oral lipid formulations

To develop a simplified in-vitro screening method for oral lipid-based formulations using intestinal biorelevant media including lipolysis, as an alternative to pH-stat lipolysis models.

Fasting state simulated intestinal fluid version 2 (FaSSIF-V2) and early fed state simulated intestinal fluid (FeSSIF) were modified for use in a simplified lipolysis screening method. This screening method consists of the following steps: dispersion of the lipid formulation in biorelevant media; incubation of dispersions on an orbital shaker for 60 min at 37°C; ultracentrifugation of dispersions and drug assay of supernatants. This method was evaluated using four lipid-based formulations containing danazol, which had previously been assessed by in-vitro pH-stat lipolysis and compared in an in-vivo study in dogs.

Biorelevant media were modified under consideration of both physiological and practical aspects, including adjustment of the pH to 6.5, the addition of calcium ions and the addition of 100 U/ml porcine pancreatin to enable lipolysis of a test formulation. Using a modified FaSSIF-V2, the same rank order in performance of four danazol formulations as previously observed in a pH-stat model was observed, and these results also reflected the in-vivo study results. The results in modified early FeSSIF suggested that there would be a change in the rank order of formulation performance in the fed state compared with the fasted state. By comparing the formulation behaviour in the presence and absence of pancreatin, it was concluded that dispersion is more important than lipolysis for precipitation from the formulation in the fasted state, but that lipolysis is predicted to increase in relevance in the fed state.

The new, simplified method for lipolysis enables a more efficient screening for the in-vivo performance of lipid formulations in the fasted state and enables a prediction of formulation behaviour in both the fed and fasted states. An additional advantage of the method is that the relative influence of lipolysis and dispersion on drug release can be directly compared.