Children often reject oral medications due to their intense bitterness, which leads to non-compliance. The use of sweeteners and other palatable foods to mask a bitter medicine has long been the dominant approach to increasing treatment compliance. However, taste masking is only partially effective. Therefore, we set out to identify and develop novel compounds to block bitterness based on our current understanding of the biology of bitter taste. It has been well established that type 2 taste receptors (TAS2Rs, class T G protein-coupled receptors) located on the surface of bitter taste receptor cells mediate bitter taste. TAS2Rs couple to heterotrimeric G proteins comprising the alpha-gustducin and beta3gamma13 subunits. The activation of the G protein signaling cascade leads subsequently to the depolarization of bitter taste receptor cells and the release of ATP as the transmitter from these cells. The released ATP then activates the purinergic receptors P2X2/P2X3 on taste nerves. At Monell, we have been developing novel bitter blockers by inhibiting TAS2Rs, disrupting the interaction between TAS2Rs and alpha-gustducin, and inhibiting the P2X2/3 purinergic receptors. Our combined approach utilizes in vitro cell-based assay, in vivo mouse behavioral testing, and human sensory testing for development of bitter blockers. This presentation highlights some of our findings such as the identification of 6-methylflavone as a blocker for TAS2R39 as well as the demonstration of AF-353 (a blocker for P2X2/P2X3) as a universal bitter blocker. This presentation also discusses the strengths and weaknesses of each targeting strategy.
Learning Objectives:
Describe the recent advances and trends in pediatric formulation development, e.g., better insights into the different dosage forms suitable for pediatric formulations.
Describe how companies could work together and share resources and list the services that NIH offers and how they may be applicable to their own development programs.
Introduce researchers to the industrial perspective on pediatric formulation development.