Examination of the relationship between solubilisation, supersaturation and drug absorption from lipid-based formulations

This thesis has explored the use of lipid-based formulations (LBF) to enhance the oral bioavailability of the cholesteryl ester transfer protein (CETP) inhibitor CP-532,623, used here as a model poorly water soluble drug (PWSD), and the impact of dispersion and digestion on formulation performance. A particular focus has been the use of the in vitro lipid digestion model as a tool to predict the oral bioavailability of PWSDs, by investigating the relationship between drug solubilisation after in vitro digestion and in vivo exposure after oral administration. Dispersion and digestion of LBFs are both events that challenge the solubilisation of a co-administered drug. The data show that the development of LBFs can be informed by the dispersion and solubilisation properties of individual excipients after in vitro digestion. Different patterns of solubilisation were observed with changes in the type of excipient employed. Lipids and lipophilic co-surfactants retained drug in an oily phase but were nonetheless resistant to drug precipitation. Hydrophilic surfactants (particularly Kolliphor RH 40) maintained higher drug solubilisation levels after digestion, a characteristic that was maintained within composite formulations containing Kolliphor and additional excipients. Conversely, co-solvents supported high initial drug loading, but provided no ongoing solubilisation when introduced to aqueous media. A series of formulations based on medium chain (MC) lipids and were initially developed to provide for effective drug loading and good dispersion properties. Assessment of these MC-LBFs using the in vitro digestion model revealed varying degrees of susceptibility to precipitation during in vitro digestion, and a broad correlation between drug solubilisation after in vitro digestion and drug absorption after oral administration in beagle dogs. Subsequent modification of the formulations to include long chain (LC) lipids rather than MC lipids generally resulted in higher levels of CP-532,623 solubilisation after in vitro digestion. In all cases the LBFs greatly enhanced in vitro solubilisation and in vivo oral bioavailability of CP-532,623 in fasted beagle dogs when compared to a simple powder formulation. Within related groups of formulations in vitro solubilisation on lipid digestion was also found to correlate with in vivo exposure. Notably, formulations based on LC-LBFs required higher levels of drug solubilisation to achieve similar levels of in vivo exposure, when compared to MC-LBFs. Re-evaluation of the in vitro data to measure drug supersaturation rather than drug solubilisation, however, resulted in improved correlations, especially for formulations containing a common surfactant. Thus, formulations containing Kolliphor RH 40 were absorbed more readily at lower supersaturation levels than formulations containing polysorbate 80 or vitamin E TPGS. The data suggest that the degree of drug solubilisation and supersaturation during in vitro lipid digestion provides some indication of formulation performance but that this alone is insufficient to completely explain patterns of drug absorption. Further investigations into the factors contributing to the high bioavailability obtained in beagle dogs also suggested that drug absorption from LBFs may vary in beagle and greyhound dogs, with drug absorption typically being higher in beagles. In summary, the studies presented here further demonstrate the utility of the in vitro digestion model in formulation development. In conjunction with solubility studies, calculation of drug supersaturation, and characterisation of the physical state of precipitated drug, in vitro lipolysis tests provide useful in vitro indicators of formulation performance. Interestingly, the current studies suggest that whilst the overall patterns of in vitro-in vivo correlation that have previously been described in the literature, may be maintained, they appear to exist in parallel with excipient specific effects on drug absorption and bioavailability. Thus, in addition to concentration or thermodynamic activity, the nature of the solubilised phases formed on lipid formulation digestion appears to be a significant driver of differences in patterns of drug absorption from LBF.