How broadly can poly(urethane)-based implants be applied to drugs of varied properties?

Implants offer the opportunity to improve patient adherence and real-world outcomes. However, most polymers used today are hydrophobic and limit drug properties suitable for development. Thermoplastic poly(urethanes) (TPUs) form pores upon hydration and may facilitate the development of implants containing drugs exhibiting broadly different properties. We sought to investigate the effect of drug physicochemical properties on permeability through membranes of varying TPU mixture composition; leverage imaging to visualize microstructural changes to the membrane across the TPU mixture composition range; and quantitatively characterize the membrane microstructure using equivalent pore analysis. We observed a correlation between drug hydrophobicity and its permeability through hydrophobic-rich TPU membranes. Conversely, all compounds diffused through hydrophilic-rich TPU membranes at similar rates, regardless of drug properties. Imaging revealed significant microstructure differences between hydrophobic-rich and hydrophilic-rich TPU membranes, supporting hypotheses proposed in our previous study. The hydrated hydrophilic TPU membrane pore area was determined to be 0.583% and its equivalent pore radius was found to be 128 nm, suggesting that hydrophilic TPU membranes may be used to modify the release of small molecular weight drugs and macromolecules. These findings highlight the benefits of hydrophilic TPUs as rate-controlling membranes to modulate the release rate of drugs with varying physicochemical properties.

Discovery of Oxazolobenzimidazoles as Positive Allosteric Modulators for the mGluR2 Receptor.

Novel oxazolobenzimidazoles are described as potent and selective positive allosteric modulators of the metabotropic glutamate receptor 2. The discovery of this class and optimization of its physical and pharmacokinetic properties led to the identification of potent and orally bioavailable compounds (20 and 21) as advanced leads. Compound 20 (TBPCOB) was shown to have robust activity in a PCP-induced hyperlocomotion model in rat, an assay responsive to clinical antipsychotic treatments for schizophrenia.