(30r) The Particle Drifting Effect – Impact of Membrane, Sink Condition, Particle Size, Drug Solubility, and Colloid Type

Colloidal drug particles, such as amorphous drug aggregates, nanocrystals, and bile micelles, are known to promote oral absorption of poorly soluble drugs. As only solubilized drug can permeate through membranes freely, it remains less well understood how and to what extent these colloidal particles contribute to drug absorption. Thus, the aim of this study is to gain insights on the mechanisms and extent of enhanced absorption by colloidal particles. Various experimental setups, including artificial membranes, biphasic diffusion, cell culture models, and animal studies were used to investigate this phenomenon, and colloidal particles of different size, type, and compositions were tested. Our results suggested minimal contribution from endocytosis, whereas passive permeation is the main mechanism of enhanced absorption by drug nanoparticles. Colloidal drug particles dissolve or dissociate, and replenish the consumed free drug concentration within the diffusional boundary layer, thus leading to increased local concentration in the aqueous solution adjacent to the membrane surface. The extent of such enhancement was found to be dependent on both the particle dissolution/dissociation and membrane permeation processes, where colloidal and drug properties as well as the relative contribution of diffusional boundary layer appeared to be key factors. Mass transport analyses were performed to provide more quantitative understanding of this phenomenon. This work provides insight on the permeability advantages by drug particles and colloidal species, and may contribute to improved bioavailability prediction of colloid containing formulations.