| Abstrakt: |
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 vitrocharacterization 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 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 vitrorelease 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 coencapsulate 6 nm hydrophobic Fe3O4colloids with CBD during FNP. The Fe3O4colloids were added at 33% by mass (approximately 20% by volume) to increase the density of the nanoparticles, resulting in particles with an average diameter of 160 nm (CBD–lecithin–Fe3O4) or 280 nm (CBD–HPMCAS–Fe3O4). This densification enabled the centrifugal separation of dissolved (released) CBD from unreleased CBD during the in vitroassay while avoiding the losses associated with a filtration step. The resulting nanoparticle formulations provided more rapid and complete in vitrodissolution kinetics than bulk CBD, representing a 6-fold improvement in dissolution compared to crystalline CBD. The coencapsulation of high-density Fe3O4colloids to enable the separation of nanoparticles from release media is a novel approach to measuring in vitrorelease kinetics of nanoencapsulated low-density, hydrophobic drug molecules. |
