Enhanced oral absorption and anti-inflammatory activity of ellagic acid via a novel type of case in nanosheets constructed by simple coacervation

As a nature component, ellagic acid (EA) shows a broad array of pharmacological activities but is lost in clinical translation partly due to poor aqueous solubility. In an effort to enhance its oral absorption, novel EA-loaded casein nanosheets (EA@CAS-NSs) was constructed by simple coacervation and investigated for in vitro characterization and in vivo evaluation. The influences of factors including pH, EA concentration, and mass ratio of CAS and EA on properties of EA@CAS-NSs were also studied. The low pH value and high matrix and drug ratio were harmful to small particle size of EA@CAS-NSs. Meanwhile, the low and high concentration of EA went against the 8 h short-term stability of EA@CAS-NSs. Interestingly, EA@CAS-NSs showed a typical disk-like structure with a diameter of 100–400 nm and good long-term storage stability for 24 months. The molecular structure of EA in NSs remained unchanged, but the EA in NSs had lower crystallinity and better thermal stability than in raw state. No chemical interaction occurred between CAS and EA, although the intermolecular distance of them was less than 10 nm. In simulated intestinal fluid, the solubility of EA in NSs was nearly three times that of raw EA, and the dissolution of EA@CAS-NSs was 12 folds of raw EA at 120 min. With oral administration, EA@CAS-NSs demonstrated an improved oral absorption in rats, as evidenced by an AUC0-24 value 2.34 times higher than raw EA. Also, the EA@CAS-NSs showed a better anti-inflammatory activity than EA. Generally, EA@CAS-NSs could be a potential strategy for the further clinic use of EA.