Oral Formulation Development for Proof-of-Concept Animal Toxicology Studies
Business Need
A large international pharmaceutical company wanted to perform proof-of-concept animal toxicology studies on a small molecule drug candidate and was in need of a suitable solution formulation for oral administration.
The desired formulation would support a compound concentration of at least 10 mg/mL, achieve bioavailability of at least 80%, and remain stable for at least 6 hours at room temperature and 7 days when refrigerated.
To facilitate future development, all excipients were GRAS status and present at concentrations no greater than that of approved products.
The molecule contains two ionizable groups and is poorly soluble at neutral pH with an intrinsic water solubility of 1 µg/mL. Caco-2 experiments found that the molecule has moderate intestinal permeability and is passively transported. It is not a substrate for P-glycoprotein.
Technical Approach
Based on preliminary physicochemical characterization and in vitro permeability data, WLI surmised that chemical instability under the relevant physiological conditions, intestinal membrane permeability, and/or rapid metabolism were not the limiting factors for oral bioavailability. Therefore, the parameter governing the oral bioavailability was the concentration of compound in the intestinal medium that is available for partitioning across the intestinal membrane.
An initial determination of the pH solubility profile was performed such that vehicles were designed to examine compound solubility as a function of pH in conjunction with various cosolvents.
The selection of a lead formulation with the highest probability of yielding high in vivo bioavailability was informed by measuring the concentration of compound in media that simulate the relevant conditions of the GI tract using simulated fluids and dilutions based on physiological volumes.
Based on the solubility and in vitro dilution data, prototype formulations were selected for a 14-day stability evaluation to inform .
Results
All 20 vehicles tested achieved formulation concentrations greater than the 10 mg/mL goal. Several vehicles compatible were identified which supported free base concentrations of greater than 20 mg/mL.
In vitro evaluation identified several vehicles capable of maintaining over 80% of the compound in solution upon dilution into simulated gastric and intestinal fluids.
Based on the data and handling properties, four vehicles were selected for 14-day stability resulting in selection of two formulations for dosing to animals.
PK results from mice indicate that over 80% bioavailability was achieved.
