Formulation Strategies to Improve Oral Bioavailability of Ellagic Acid

Abstract

Featured Application: An updated description of pursued approaches for efficiently resolving the low bioavailability issue of ellagic acid. Abstract: Ellagic acid, a polyphenolic compound present in fruits and berries, has recently been object of extensive research for its antioxidant activity, which might be useful for the prevention and treatment of cancer, cardiovascular pathologies, and neurodegenerative disorders. Its protective role justifies numerous attempts to include it in functional food preparations and in dietary supplements not only to limit the unpleasant collateral effects of chemotherapy. However, ellagic acid use as chemopreventive agent has been debated because of its poor bioavailability associated to low solubility, limited permeability, first pass effect, and interindividual variability in gut microbial transformations. To overcome these drawbacks, various strategies for oral administration including solid dispersions, micro-nanoparticles, inclusion complexes, selfemulsifying systems, polymorphs have been proposed. Here, we have listed an updated description of pursued micro/nanotechnological approaches focusing on the fabrication processes and the features of the obtained products, as well as on the positive results yielded by in vitro and in vivo studies in comparison to the raw material. The micro/nano-sized formulations here described might be exploited for pharmaceutical delivery of this active, as well as for the production of nutritional supplements or for the enrichment of novel foods.

Oxidative Stress, Antioxidant Capabilities, and Bioavailability: Ellagic Acid or Urolithins?

“…EA is a chromene-dione derivative whose chemical name is 2, 3, 7, 8-tetrahydroxy-chromeno[5,4,3-cde]chromene-5,10-dione, which can also be seen as a dimeric derivative of gallic acid (GA) ( Figure 3 ) and whose physicochemical properties are summarized in Table 6 [ 40 , 58 ].…”

“…EA possesses a highly thermostable structure with a melting point of about 450 °C and a boiling point of 796.5 °C [ 34 ]. Due to the weak acidic nature of its four phenolic groups (pKa1 = 5.6 at 37 °C), around neutral pH it is mainly deprotonated on positions 8 and 8′, while above pH 9.6 lactone rings open to give a carboxyl derivative [ 40 ].…”

“…EA possesses an insignificant water solubility of about 9.3–9.7 µg/mL at pH 7.4 and 21 °C [ 8 ] and a very poor solubility in alcohol [ 33 ], which concretize in a very poor bioavailability and trivial absorption in gastrointestinal tract (GIT). EA water solubility increases with pH, as well as the antioxidant action [ 40 ]. EA is almost insoluble in acidic media and distilled water, while its water solubility is significantly improved by basic pH.…”

“…However, in basic solutions, phenolic compounds lack stability and these molecules, under ionic form, undergo extensive transformations or are converted to quinones, as a result of oxidation. A stability study on pomegranate fruit peel extract demonstrated that EA content significantly decreases in a few weeks regardless of the pH of the solution, due to the hydrolysis of the ester group with hexahydroxydiphenic acid formation, suggesting that EA should not be stored in aqueous medium [ 40 ].…”

“…In order to be able to obtain certainty about EA’s behavior in vivo, scientists have been increasingly and are incessantly focused on preparing water soluble and absorbable EA formulations, able to protect EA and to reduce or nullify EA metabolism to UROs [ 40 ]. The formulation of drug delivery systems, capable of transporting and releasing EA to the target site, represents a valid approach for bypassing the bad biopharmaceutical features of the polyphenol, thus allowing a better evaluation of its potential application as radical scavenger antioxidant therapeutic.…”