Development of an In Vitro Release Assay for Low-Density Cannabidiol Nanoparticles Prepared by Flash NanoPrecipitation

Abstract

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 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 coencapsulate 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, 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 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 6-fold improvement in dissolution compared to crystalline CBD. The coencapsulation of high-density Fe3O4 colloids to enable the separation of nanoparticles from release media is a novel approach to measuring in vitro release kinetics of nanoencapsulated low-density, hydrophobic drug molecules.

Exploring the Potential of Cannabinoid Nanodelivery Systems for CNS Disorders

“…In another study, CBD was encapsulated into nanoparticles with low polydispersity and high drug loading via Flash NanoPrecipitation, using hydroxypropyl methylcellulose acetate succinate and lecithin as amphiphilic particle stabilizers. These nanoformulations showed more rapid and complete in vitro dissolution kinetics than CBD alone, representing a 6-fold improvement in dissolution compared to crystalline CBD [ 115 ].…”

Sequential Flash NanoPrecipitation for the scalable formulation of stable core-shell nanoparticles with core loadings up to 90%

“…Due to this requirement, a water-soluble stabilizing material must be used in a sequential nanoprecipitation scheme using two CIJ mixers. In this work we used hydroxypropyl methylcellulose acetate succinate (HPMCAS), a semisynthetic cellulosic polymer reported previously as appropriately amphiphilic for application as a stabilizer in FNP nanoparticle formulations ( Caggiano et al, 2022 , Feng et al, 2019b , Feng et al, 2018 , Ristroph et al, 2019 ). However, many of the polymers studied in the FNP literature are water-insoluble diblock copolymers that are not appropriate for this application.…”

Formulation and Scale-up of Delamanid Nanoparticles via Emulsification for Oral Tuberculosis Treatment

“…The dissolution of delamanid from spray-dried powders was measured using an in vitro dissolution assay in aqueous media consisting of 150 mM HEPES buffer at pH 7 with 3% w/w Tween 80 based on a previously described protocol . The solubility of delamanid was measured in various buffers and in commercially available simulated intestinal fluid media (see SI Figure 7 and SI Tables 3 and 4).…”

“…l -α-Lecithin is a soybean-derived mixture of amphiphilic phospholipids comprised of >94% phosphatidylcholine and <2% triglycerides, with a nominal molecular weight of 750 Da. These stabilizers were chosen as a starting point based on extensive prior experience using lecithin and HPMCAS as stabilizers for nanoparticles prepared by FNP. − …”