(136f) Preparation of Low-Density Cannabidiol-Loaded Nanoparticles and Development of an in Vitro Release Assay

Nanoparticle encapsulation is an attractive approach to improve the oral bioavailability of hydrophobic therapeutics. The high specific surface area of nanoparticle formulations, combined with the thermodynamically driven increased solubility of an amorphous drug core, promotes rapid drug dissolution. However, the physicochemical properties of the hydrophobic therapeutic can present obstacles to in vitro characterization of nanoparticle formulations. Namely, drugs with low density and high membrane binding affinity frustrate traditional analytical methods to monitor release kinetics from nanoparticles. In this work, cannabidiol (CBD) was encapsulated into nanoparticles 180 nm in diameter with low polydispersity and high drug loading via Flash NanoPrecipitation (FNP), a scalable self-assembly process. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) and lecithin were employed as amphiphilic particle stabilizers during the FNP process. However, the low density and high membrane binding affinity of the amorphous CBD nanoparticle core prevented the characterization of in vitro release kinetics by conventional methods. Released CBD could not be separated from intact nanoparticles by filtration or centrifugation. To address this challenge, an alternative approach is described to co-encapsulate 6 nm hydrophobic Fe₃O₄ colloids with CBD during FNP. The Fe₃O₄ colloids were added at 33% by mass (approximately 20% by volume) to increase the density of the nanoparticles, and the resulting particles were 160 nm (CBD-lecithin-Fe₃O₄) and 280 nm (CBD-HPMCAS-Fe₃O₄). This densification enabled centrifugal separation of dissolved (released) CBD from unreleased CBD during the in vitro assay while avoiding the losses associated with a filtration step. The resulting nanoparticle formulations provided more rapid and complete in vitro dissolution kinetics than bulk CBD, representing a six-fold improvement in dissolution compared to crystalline CBD. The co-encapsulation of high-density Fe₃O₄ colloids to enable separation of nanoparticles from release media is a novel approach to measuring in vitro release kinetics of nano-encapsulated low-density, hydrophobic drug molecules.