Dissolution / Permeation of Amorphous Solid Dispersions of Fenofibrate & Hydrogenated Phospholipid - Spontaneous Formation of Colloids: Nanofiltration & Particle Size Analysis.

Here, various melt-extruded formulations of the poorly soluble model drug fenofibrate based on hydrogenated phospholipid (HPL), either alone or in combination with the hydrophilic copolymer Polyvinylpyrrolidone-Polyvinylacetate (VA64), are compared with respect to their solid state and in vitro performance as an enabling formulation. The specific focus is on the spontaneous formation of micron and submicron colloids from phospholipidic versus conventional polymeric amorphous solid dispersions (ASDs), their size and FEN content, during dissolution in biomimetic media, and their impact on dissolved concentration, dissolution rate, and permeation. In order to judge the ASDs' supersaturation potential, the apparently dissolved drug concentrations of the different melt-extrudates immediately after dispersion in fasted state simulated intestinal fluid (FaSSIF) were determined. For all extrudates, the initial apparently dissolved drug concentration exceeded that of crude fenofibrate, indicating that all ASDs induced supersaturation at therapeutically relevant dose levels. Major differences were seen between the formulations upon separation of the apparently dissolved drug into size fractions. With respect to the drug content within the smallest size-fraction (filtrated through 20 nm pore size), the pure VA64 formulation performed best, followed by the ASD containing 20 % of HPL and pure HPL-based ASD, despite the fact that mean colloid sizes measured by dynamic light scattering (DLS) were essentially the same for all the ASDs. It is postulated that two alternative processes occur simultaneously: the spontaneous formation of drug-rich nanoparticles and the incorporation of FEN into small bile salt and or phospholipid micelles, which are assumed to be responsible for the different drug content in the colloidal fractions. It is presumed that some of the micelles can't easily pass the 20 nm filter pores, while the drug-rich particles being formed appear to be very small at the very beginning of the dissolution process and thus also pass these pores. Differentiation between drug-rich nanoparticles and drug associated with bile salt/phospholipid micelles may be important because, based on literature data, these two colloidal species are hypothesized to have a different impact on the evolution of molecularly dissolved drug concentrations during the dissolution process and thus permeability (absorption). Interestingly, the amounts of drug accumulating in the acceptor during combined dissolution/permeation experiments were rather similar, irrespective of which of the ASDs was studied.