Using resin to generate a non-invasive intestinal bile-depleted rat model was unsuccessful.

The purpose of this study was to evaluate if a rat model, based upon co-administration of the anion-exchanging resin, cholestyramine, could replace surgery when evaluating the importance of bile on drug absorption. Two different formulations were used for the administration of halofantrine; polyethylene glycol 400 (PEG 400) and PEG 400/polysorbate 80 (50:50, w/w%), as a positive and negative control on the dependency of bile. No significant effect of the resin was detected after evaluation of three different pre-dosing regimes, but in line with previous studies the formulation containing polysorbate 80 showed a significant increase in the absorption of halofantrine. This study therefore demonstrates that the pre-dosing of rats with Cholestyramine can not replace surgical bile duct cannulation if a formulation needs to be evaluated for its bile dependency.

Precipitation of a poorly soluble model drug during in vitro lipolysis: characterization and dissolution of the precipitate.

Precipitation of cinnarizine during in vitro lipolysis of a self-microemulsifying drug delivery system (SMEDDS) was characterized to gain a better understanding of the mechanisms behind the precipitation. During in vitro lipolysis of the SMEDDS with or without cinnarizine, samples were taken at several timepoints and ultracentrifuged. Cinnarizine content in the pellet increased from 4% to 59% during lipolysis. The precipitation of cinnarizine during in vitro lipolysis correlated well with the degree of lipid digestion, determined by sodium hydroxide addition. The pellet from the endpoint of lipolysis was isolated and subjected to dissolution in biorelevant media. Dissolution rate of cinnarizine from pellets containing precipitated cinnarizine was initially 10-fold higher than dissolution from blank pellet spiked with crystalline cinnarizine, reaching more than 50% drug dissolved in the first minute. Pellets were further characterized by X-ray powder diffraction (XRPD) and polarized light microscopy (PLM). Both methods indicated the presence of liquid crystalline phases of calcium fatty acid soaps, but no presence of crystalline cinnarizine in the pellet. Overall, dissolution studies along with XRPD and PLM analysis indicate that cinnarizine precipitating during in vitro lipolysis of this SMEDDS is not crystalline, suggesting an either amorphous form or a molecular dispersion.