Design and development of supersaturated lipid-based drug delivery systems for applications in pharmaceutical industry

Purpose: The need to administer high doses of poorly water-soluble drugs in preclinical studies has guided pharmaceutical research towards evaluation of supersaturated lipid-based drug delivery systems (sLBDDS). Design and development of sLBDDS in a pharmaceutical industry setting was the main purpose of this thesis. Methods: The model drugs (celecoxib, cinnarizine, JNJ-2A) and a set of LBDDS based on excipients with different properties were investigated in solubility studies, in vitro dispersion tests and in vitro static or dynamic dispersion/digestion-permeation studies. In vivo behaviour of drugs after administration as LBDDS and/or sLBDDS was evaluated using developed plasma drug quantification methods Results: Firstly, the supersaturation propensity in eight LBDDS was shown to be different for the model drugs. High apparent supersaturation degrees (aDS) were obtained for celecoxib and cinnarizine, while low aDS were found for JNJ-2A Secondly, systematic investigation of lipid excipient influence on in vivo performance of LBDDS showed that simple one or two-component LBDDS have a positive effect on drug absorption relative to three-component systems containing triglycerides. Additionally, a statistically significantly higher drug absorption in case of celecoxib and cinnarizine was seen for some long chain (LC) compared to medium chain (MC) LBDDS. Furthermore, it was indicated that a simplified test using assembled pre- and post-digestive biorelevant media consisting of dispersed or digested lipid excipients can help screen drug solubilization and further inform choice of LC or MC lipid excipients in candidate formulations, while dispersion and dilution testing correlated well with in vivo findings. Thirdly, thermally-induced drug supersaturation in one-component LBDDS resulted in higher celecoxib bioavailability relative to LBDDS, yet the drug supersaturation effect did not result in higher drug permeation in in vitro dispersion/digestion-permeation studies under static or dynamic conditions. Nevertheless, the positive effect of LC LBDDS seen in vivo was also identified in the developed in vitro models. Finally, a negative effect of thermally-induced supersaturation was observed for the precipitation-prone drug, cinnarizine. Nevertheless, cinnarizine absorption was improved by inclusion of precipitation inhibitors (PI) in the formulation, albeit only statistically significant for one sLBDDS-PI. Conclusions: Thermally-induced supersaturation resulted in increased celecoxib bioavailability from sLBDDS relative to LBDDS consisting of mono- and di-glycerides as single lipid excipient. Compositional effects were seen both in in vivo studies and in vitro dispersion/digestion-permeation testing for celecoxib. For cinnarizine, an inherent precipitation risk from sLBDDS was observed independent of lipid system composition. In contrast to celecoxib, thermally-induced supersaturation resulted in lower drug absorption relative to LBDDS, yet a positive influence was observed after inclusion of PIs in the formulations. For JNJ-2A, modest aDS were obtained using the tested lipid systems and only a minor influence of lipid composition was observed in vivo. This thesis showed that sLBDDS can be used for poorly-water soluble drugs as means to increase drug loadings and could be potentially used in preclinical studies to maximise in vivo exposure. Formulation development guidance tools are provided at the end of this thesis to aid scientists in designing and developing sLBDDS