Abstract by Rui Peng

Oral administration is the preferred route for the application of drugs due to its convenience and high patient acceptance, but the low aqueous solubility of many modern drug candidates limits their oral bioavailability. Lipid-based drug delivery systems (LbDDS), particularly self-nanoemulsifying drug delivery systems (SNEDDS), have emerged as an effective approach to improve the oral absorption of poorly water-soluble drugs. To overcome the low drug-loading limitations of SNEDDS, supersaturated SNEDDS (super-SNEDDS) have been developed. These systems enable higher drug loadings, reduce pill burden, and maintain - or even improve - oral bioavailability while using less excipients. However, the rational design of super-SNEDDS is still constrained by limited mechanistic insight from characterization to in vivo absorption. Therefore, this thesis aimed to establish a mechanistic framework for super-SNEDDS and related systems through four interconnected studies addressing: (i) comparative characterization of super-SNEDDS vs. conventional SNEDDS (con-SNEDDS) (50-80% equilibrium solubility (S_eq)), (ii) mechanistic assessment of physical stability of super-SNEDDS, (iii) key determinants of oral absorption for super-SNEDDS, and (iv) integration into hybrid delivery strategies.

A Design of Experiments (DoE) approach was used to construct a medium chain triglycerides (MCT)-based SNEDDS design space from four selected excipients. The first aim was to compare super-SNEDDS with their corresponding con-SNEDDS, in terms of drug loading capacity (i.e., S_eq vs. maximum supersaturation concentration (CS_max)) and emulsion droplet size after dispersion of SNEDDS preconcentrates. Within this space, fifteen formulations were prepared, each loaded with one of three poorly water-soluble molecules, carvedilol (CVL), ritonavir (RTV) and nilotinib (NTB). The formulations were characterized by their S_eq, CS_max and the corresponding maximum degree of supersaturation (DS_max) (CS_max/S_eq). Additionally, droplet size was analyzed for two formulation types: con-SNEDDS (90% S_eq) and super-SNEDDS (90% CS_max). The results showed that S_eq and CS_max were linearly correlated for each drug across the DoE-generated formulations, resulting in drug-specific, composition-independent DS_max values that were unchanged by the inclusion of fully dissolved 4% (w/w) Polyvinylpyrrolidone-vinyl acetate copolymers 64 (PVP/VA 64). Droplet size showed minimal change after drug incorporation up to con-SNEDDS relative to the blank SNEDDS. Extending the load to super-SNEDDS similarly did not result in any size alteration, but only for systems where the initial con-SNEDDS droplets were below 60 nm. In contrast, formulations beginning with droplets larger than 60 nm exhibited significant size increase under these supersaturated conditions. Accordingly, super-SNEDDS droplet size increased quadratically with the corresponding con-SNEDDS droplet size, so larger con-SNEDDS droplets resulted in disproportionately larger super-SNEDDS droplets.

Building on this DoE platform, the second aim was to assess the effect of incorporating 4% (w/w) PVP/VA 64 on the physical stability and viscosity of super-SNEDDS at identical supersaturation levels (90% CS_max), and to evaluate the effect of viscosity on stabilizing these super-SNEDDS. Incorporation of dissolved PVP/VA 64 consistently increased both viscosity and physical stability across all three drugs, but the improvements in stability were not proportional to the rise in viscosity for any drug, suggesting additional contributions such as drug-polymer interactions could play a role in hindering nucleation and delaying crystal growth.

The third aim was to assess the effect of emulsion droplet size and lipid digestion on the oral absorption of NTB from super-SNEDDS by assessing in vitro lipolysis and in vivo pharmacokinetic (PK) studies in rats. Owing to the inclusion of a coarse emulsion in this study, the formulations are hereafter referred to as super-SEDDS within this project. Three super-SEDDS (F_S, F_M, F_L) with similar CS_max (and S_eq) but distinct droplet sizes (~40 nm, ~270 nm, >1 μm) were selected from the DoE contour plots and investigated without or with 2% (w/w) orlistat to separate digestive from non-digestive conditions. In vitro, both orlistat-free (F_S, F_M, F_L) and orlistat-containing (F_{S_orlistat} F_{M_orlistat} and F_{L_orlistat}) formulations maintained NTB in a fully solubilized state. The use of orlistat, however, completely blocked lipolysis and prevented the formation of digestion-derived colloidal structures, whereas under digestion active condition all formulations transformed into vesicular colloids. In vivo, smaller droplets were associated with higher NTB absorption, but this size effect only became statistically significant (p < 0.05) when digestion was inhibited, with F_{S_orlistat} showing significantly larger area under the curve (AUC_0-23h) and higher C_max, than F_{M_orlistat} and F_{L_orlistat}. An in vivo comparison of each orlistat-free formulation with its orlistat-containing counterpart (i.e., F_S vs. F_{S_orlistat}, F_M vs. F_{M_orlistat}, F_L vs. F_{L_orlistat}) revealed that inhibiting digestion significantly reduced NTB absorption, with a similar reduction extent observed across all droplet sizes. This demonstrates that lipid digestion and the consequent formation of digestion-derived colloidal structures were critical for efficient NTB absorption in vivo.

The final aim was to directly compare two amorphous solid dispersion (ASD)-based super-SNEDDS: a hydrophilic polymer-based combination by using PVP/VA 64 (super-SNEDDS_ASD_{PVP/VA 64}) and a lipophilic phospholipid-based combination by using soybean phosphatidyl choline (SPC) (super-SNEDDS_ASD_SPC), in terms of their physical stability, in vitro lipolysis behaviour, and in vivo performance of the model drug RTV. Pure super-SNEDDS without any additives were used as a control group. Both ASD-based super-SNEDDS improved physical stability relative to pure super-SNEDDS, with the super-SNEDDS_ASD_{PVP/VA 64} providing the greatest stabilization, primarily attributed to a viscosity-mediated prolongation of supersaturation in the system, giving the stability rank order: super-SNEDDS_ASD_{PVP/VA 64} > super-SNEDDS_ASD_SPC > pure super-SNEDDS. During in vitro lipolysis, both ASD-based super-SNEDDS increased the solubilized drug fraction to a similar extent, yet only the super-SNEDDS_ASD_{PVP/VA 64} translated this in vitro advantage into larger in vivo AUC_0-23h and higher C_max in rat, compared to pure super-SNEDDS, whereas super-SNEDDS_ASD_SPC performed similarly to their pure super-SNEDDS counterpart in vivo. These findings indicate fundamental differences in how polymer- or phospholipid-containing super-SNEDDS modulate in vitro drug solubilization and in vivo absorption. In the PVP/VA 64-based system, the polymer likely acts as polymeric precipitation inhibitor (PPI) to inhibit nucleation and crystal growth of the potential supersaturated drug concentrations, and sustains in situ drug supersaturation, thus increasing the pool of freely dissolved drug available for uptake. In contrast, SPC mainly incorporates drug within phospholipid-rich colloidal structures, as evidenced by Cryogenic Transmission Electron Microscopy (Cryo-TEM) results. These structures may raise the apparent solubilized fraction but keep much of the drug colloid-associated and does not improve systemic absorption, compared to supersaturated drugs.

Ultimately, the findings obtained in this PhD thesis strengthen the mechanistic understanding of super-SNEDDS across the entire development pathway, from fundamental characterization, through identification of potential factors during oral absorption, to evaluation of ASD-SNEDDS hybrid strategies. By showing how these aspects together shape oral uptake, this work provides a guidance for the rational design of super-SNEDDS for poorly water-soluble drugs.