ABSTRACT
Advances in combinatorial chemistry and high-throughput screen-
ing in the past couple of decades has enabled discovery of new
chemical entities (NCEs) for a variety of complex and diverse
biological targets. As the majority of biological targets are highly
lipophilic or hydrophobic in nature, there has been a significant
increase in the number of NCEs with poor aqueous solubility. While
oral delivery continues to be the most commonly used route of
administration for NCEs, poor aqueous solubility can result in signif-
icant development challenges such as incomplete absorption, highly
variable bioavailability, and highly variable pharmacokinetic profiles
in preclinical species and humans. A number of conventional and
enabling formulation technologies are now available to tackle poor
solubility and the resulting poor biopharmaceutical performance
of NCEs. However, a systematic evaluation and proactive selection
of the optimal formulation technology is typically not available
during discovery and early development stages due to limitations
in both time and material. As a consequence, a number of promising
NCEs are either terminated due to poor biopharmaceutics and lack
of adequate exposure for preclinical safety assessment, or remain
in the candidate selection phase for several years, resulting in
significant delays for advancing new treatments into the clinic.
The goal of this chapter is to describe a systematic approach
for generating a cross-functional package of data comprised of
physicochemical, biopharmaceutical, ADME, PK/PD, and delivery
technology evaluations to enable oral delivery of poorly water-
soluble NCEs.
