Case study: cremophor EL-based liquid formulations as simple substitutes for amorphous solid dispersions in early preclinical in vivo studies.

Objectives: The objective of the present case study was to increase the exposure of the poorly soluble crystalline compound A.

Methods: Mice received 10 mg/kg of crystalline compound A formulated in eight different cosolvent, oil, and cyclodextrin mixtures.

Key findings: In all cases, AUC0-24h and maximum blood/plasma concentration (Cmax) were in the range of 6-16 µM × h and <1.4 µm, respectively, with a bioavailability below 18%. When 6% cremophor (CrEL) was added to three selected vehicles, AUC0-24h and Cmax increased ~5-10 times. The obtained pharmacokinetic profile of the most improved formulation using CrEL was possible to superimpose on the one obtained after administration of a CrEL-free amorphous solid dispersion (ASD, HPMC-AS:drug, 80:20) suspension of compound A.

Conclusions: It is crucial to find an optimal screen vehicle as early as possible for a poorly water-soluble lead series and then avoid time and resource-consuming vehicle testing of multiple compounds in vivo. An ASD approach is more suited for clinical development when more time and resources are allocated to the project. In this case study, some preclinical formulations were used to maximize exposure but also as preindicators for ASDs later in the development chain.