Preclinical intraperitoneal delivery: Modulating dilution-induced precipitation from aqueous cosolvent formulations

Aqueous-cosolvent formulations of celecoxib containing solubilizers or precipitation inhibitors sulfobutyl ether β-cyclodextrin (SBEβCD) and polyvinylpyrrolidone (PVPK30) were evaluated using in vitro and in vivo methods. Celecoxib is a selective inhibitor of cyclooxygenase-2 (COX-2) which exhibits adequate permeability but poor aqueous solubility (BCS class II). In vitro methods were used to quantify (UV probe monitoring turbidity, UPLC monitoring solution concentration) and characterize (polarized light microscopy) precipitation following dilution of an aqueous-cosolvent solution. Subsequently, in vivo drug plasma concentrations following intraperitoneal administration were quantified using UPLC-MS/MS methods. Both in vitro and in vivo evaluations indicated that PVPK30 performed significantly better as a precipitation inhibitor than SBEβCD as a solubilizer/precipitation inhibitor, providing a metastable supersaturated state following the dilution-induced precipitation. This difference was reflected in an enhanced bioavailability which was almost 3 times higher in the first 24 hours following administration. Additionally, varying the volume but maintaining the mass of drug dosed did not provide a significant difference in drug exposure based on a subsequent administration of PVPK30 containing formulations with varying concentrations. The rank order of in vitro results was reflected by in vivo IP dosing displaying potential for utility in development of precipitation resistant formulations of poorly soluble compounds. Development of precipitation-resistant formulations of poorly soluble compounds is valuable for the achievement of adequate in vivo blood levels for preclinical and toxicological studies during early stages of drug development.