Karl Box delivered a presentation on solubility-limited absorption and its impact on particle drift and oral fraction absorbed. His presentation covered a range of topics including solubility limits on oral absorption, the concept of particle drift, in vitro tools and evidence, and translating these findings to in vivo performance.
Box explained that in an ideal scenario, a completely soluble drug would be fully absorbed and exhibit dose proportionality. However, for BCS Class 2 molecules, solubility-limited absorption often occurred, leading to a plateau in the area under the oral absorption curve at higher doses. He noted that this effect was more pronounced with micro and nano-sized particles, especially at high doses in toxicology and first-in-human studies.
Box introduced the theory of particle drift, suggesting that very tiny particles, such as nano suspensions, could diffuse into the unstirred water layer barrier, providing a reservoir for additional absorption. He referenced Kiyohiko Sagano's work on this concept and discussed how Pion's combined solution permeation tools could study these effects.
He described various tools, including the μFlux for early development and the MiniFlux for larger volumes, which allowed for dynamic combined dissolution and absorption studies. Box highlighted the Rainbow Dynamic Dissolution Monitor, a fibre optic spectrometer platform, which enabled real-time data collection and detailed profiling of dissolution and permeation characteristics.
Box presented a case study on celecoxib, a poorly soluble BCS Class 2 drug, demonstrating how the particle drift effect influenced absorption. He explained that in vitro flux assays could isolate the impact of particle drift and that Pion's Predictor software could scale these findings to in vivo outcomes. By accounting for factors such as membrane surface area, intestinal transit time, and drug clearance, the software provided a more accurate prediction of in vivo absorption.
Particle drift is particularly important to consider in drug development and so is its potential to improve bioavailability through enabling formulation technology. Box concluded by encouraging further research in this area to enhance the mechanistic understanding of oral absorption and the development of effective drug formulations.
