Flocculated Amorphous Nanoparticles for Enhanced Bioavailability of Poorly-Water Soluble Drugs: In-Vitro and in-Vivo Studies

For a poorly-water soluble drug, a key challenge in oral delivery is to create a high enough bioavailability to be therapeutically effective. Particle engineering in this area has primarily emphasized creating individual amorphous nanoparticles to maximize the surface area not only to cause rapid dissolution, but also to achieve high supersaturation of the drug. Nanoparticle dispersions are formed by mixing an organic solution containing the dissolved drug with water to precipitate the drug in the presence of a stabilizer. However, these particles are difficult to harvest. For this work, we harvest the nanoparticles by purposely flocculating and filtering them to produce a powder highly favorable for further processing. The objectives of this study were two fold; 1) to flocculate the nanoparticles and ensure that they retain their amorphous qualities after filtering and drying and 2) to examine these particles for in vitro - in vivo correlation to determine the dominant effects leading to higher bioavailability for these particles in comparison to the current marketed itraconazole formulation, Sporanox®.

Nanoparticle dispersions stabilized with hydroxypropylmethylcellulose (HPMC) were flocculated and filtered by adding sodium sulfate to recover micron sized aggregates. By adding a tri-block copolymer of poly(ethylene oxide-b-propylene oxide-b-ethylene oxide) (P407), additional steric stabilization allowed the particles to redisperse to their original nanoparticle size. A second set of particles, stabilized with a random copolymer of methyl methacrylate and methacrylic acid, Eudragit®L100-55, were flocculated by lowering the pH to 2.5 to neutralize the acid groups. In vitro testing to simulate the particles through the highly acidic stomach conditions and neutral pH of the intestines correlated well with the in vivo bioavailability measured. This demonstrates the importance of not only achieving a high degree of supersaturation but also of maintaining the supersaturation through the varying conditions in the digestive tract.