There is a growing pharmaceutical interest in supersaturated lipid-based formulations (Super-LbF) as an innovative strategy to enhance drug loading capacities while simultaneously reducing pill burden. This approach involves increasing the drug concentration above its equilibrium solubility in a lipid solution, achieved through temperature-induced supersaturation or the dissolution of lipophilic ionic salts. However, the physical instability and potential drug precipitation upon the dispersion of LbF remain critical. The focus of this work was to assess the impact of polymer and surfactant as precipitation inhibitors (PIs) in Super-LbF and investigate whether PIs can effectively address the aforementioned challenges. Ibrutinib (Ibr) was selected as a model drug due to its limited solubility and dissolution characteristics. The optimized formulations were characterized with a focus on dispersibility, lipolysis-permeation, and physical stability during storage. The inclusion of PIs in Super-LbF significantly enhanced physical stability by increasing viscosity and reducing the degree of supersaturation through elevated equilibrium solubility. During the dispersion and digestion study, varying levels of transient supersaturation were observed for both Super-LbF and PI-loaded Super-LbF. A noteworthy 2.5 to 3-fold increase in the solubilization ratio was observed for PI-loaded Super-LbF in comparison to Super-LbF without PI. This increase indicates a significant rise in transient drug supersaturation through kinetic and thermodynamic precipitation inhibition mechanisms. Moreover, lipolysis-permeation studies revealed increased flux values with enhanced solubilization, except in the case of Pluronic® F68, which exhibited a reduced free drug concentration near the Permeapad® barrier. Further, the in vivo absorption study confirmed that prolonged supersaturation, facilitated by PIs, contributed to enhancement in drug exposure in rats. PI-loaded Super-LbFs demonstrated a significant improvement (5.1 to 8.9-fold) in the absorption profile compared to Super-LbF without PI (p<0.001). The study results indicate that incorporating PIs into Super-LbF enhances physical stability and maintains transient drug supersaturation under digestive conditions. Overall, this formulation approach shows promise for expanding the application of LbF to enable the successful oral delivery of high-dose regimen drugs.
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