Amorphous ternary nanoparticle complex of curcumin-chitosan-hypromellose exhibiting built-in solubility enhancement and physical stability of curcumin.

The low aqueous solubility of curcumin (CUR) had greatly limited the clinical efficacy of CUR therapy despite its well-known potent therapeutic activities. Previously, we developed amorphous nanoparticle complex (nanoplex) of CUR and chitosan (CHI) as a solubility enhancement strategy of CUR by electrostatically-driven drug-polyelectrolyte complexation. The CUR-CHI nanoplex, however, (1) lacked a built-in ability to produce prolonged high apparent solubility of CUR in the absence of crystallization-inhibiting agents, and (2) exhibited poor physical stability during long-term storage. For this reason, herein we developed amorphous ternary nanoplex of CUR, CHI, and hypromellose (HPMC) where HPMC functioned as the crystallization inhibitor. The effects of incorporating HPMC on the (1) physical characteristics and (2) preparation efficiency of the CUR-CHI-HPMC nanoplex produced were investigated. Compared to the CUR-CHI nanoplex, the HPMC inclusion led to larger nanoplex (≈300-500 nm) having lower zeta potential (≈1-15 mV) and lower CUR payload (≈40-80%), albeit with higher CUR utilization rates (≈100%) attributed to the CUR interactions with both CHI and HPMC. The CUR-CHI-HPMC nanoplex's physical characteristics could be controlled by varying the HPMC to CHI ratio in the feed. Subsequently, the CUR-CHI-HPMC and CUR-CHI nanoplexes were examined in terms of their (1) storage stability, (2) dissolution characteristics in simulated gastrointestinal fluids, and (3) in vitro solubility enhancement. The results showed that the CUR-CHI-HPMC nanoplex exhibited superior (i) amorphous state stability after twelve-month storage, (ii) dissolution characteristics, and (iii) solubility enhancement in simulated gastrointestinal fluids, with minimal cytotoxicity towards human gastric epithelial cells.