Designing an ADME liquid formulation with matching exposures to an amorphous dosage form

Abstract

Amorphous Solid Dispersion (ASD) based formulations have been frequently used to improve the bioavailability of poorly water soluble drugs, however, common processes to produce ASDs are not feasible for Absorption, Distribution, Metabolism and Excretion (ADME) studies with radio-labeled Active Pharmaceutical Ingredients (API) due to the complications associated with radioactive material handling. Liquid formulations are routinely used to support the ADME studies, though bridging the bioperformance between a liquid formulation to the amorphous dosage form for poorly soluble compounds has not been well studied, and can be challenging due to the potentially rapid in vitro and in vivo recrystallization and precipitation. Here we report the development of a fit for purpose liquid formulation that could accommodate the radioactive API and provide comparable bioavailability relative to the amorphous formulation without the need for dose adjustment. A number of formulation approaches were explored and the prototype formulations were evaluated by dissolution and preclinical pharmacokinetic studies. A PolyEthylene Glycol 400 (PEG 400) based solution formulation impregnated with a polymer, HydroxyPropyl MethylCellulose Acetate Succinate-L (HPMCAS-L), was identified as the lead formulation. It was found that the bioavailability of the formulation can be compromised by the presence of undissolved crystalline seeds, and the inclusion of HPMCAS-L can mitigate this effect, as well as potentially facilitate the nanoparticle formation. During the study, it is also noted that although dissolution test is instrumental in the formulation development, the in vitro study over predicted the extent of in vivo precipitation for PEG 400 formulation containing no crystalline seeds.