# Formulation Strategies to Improve Oral Bioavailability of Ellagic Acid
## 4 Formulation Strategies for Improving EA Oral Bioavailability
### EA Encapsulated in Polymeric Carriers  
#### 4.4.1 Eudragit\({}^{\circledR}\) Microspheres  
EA was proposed as a prophylactic agent for the treatment of inflammatory bowel disease. [PERSON] et al. developed microspheres for EA site-specific delivery to the ileum using Eudragit\({}^{\circledR}\) P-4135, a copolymer of methacrylic acid, methyl acrylate and methyl methacrylate able to dissolve at pH \(>\) 7.2, which corresponds to the pH of the distal part of the small intestine [70]. The adopted preparation method was a solvent evaporation process in oil phase using an acetone/light liquid paraffin system. Different polymer amounts, ranging from 0.5 to 1.5 g, were dissolved in acetone and mixed with 0.5 mg of EA, previously dispersed in the same solvent and sonicated. Then, the resultant solution was added to light liquid paraffin containing Span 80 (3% _v/v_), and the emulsion was stirred up to complete evaporation of acetone. The microspheres, harvested by filtration and washed with hexane to remove paraffin, yielded an EE ranging from 57 to 99% and a DL from 33 to 36%. Increasing polymer amounts resulted in higher EE and size increase from 98 to 168 \(\upmu\)m. As expected, EA release was pH-dependent and at pH 6.8 an initial burst effect of about 25% was followed by a sustained release, with approx. 40% of loaded drug released after 6 h. In this case, the burst effect would not be critical, as it occurred at the target site, as demonstrated by the negligible EA in vitro release at more acidic pH. For in vivo studies fluorescein was added to the preparative mixture to accurately measure microsphere dissolution rate. The obtained microspheres were orally administered to rats and blood samples were collected every hour. The comparison between collected images of microspheres in small intestine of euthanized rats and fluorescein plasma concentration evidenced that the plasmatic peak occurred 3 h after administration, when microspheres reached the ileocaecal junction. Therefore, this Eudragit\({}^{\circledR}\)-based system represents an effective vehicle to target EA release to the terminal ileum,providing enhanced absorption in the region and thus preventing the variability connected to EA conversion into urolithins. .4.2 Poly (Lactic-Co-Glycolic Acid) (PLGA) and Poly (\(\epsilon\)-Caprolactone) (PCL) Nanospheres  
Among the various encapsulating polymers, PLGA has been extensively used due to its biocompatibility, biodegradability, and ability to protect the drug from degradation and in obtaining sustained drug release [71]. To increase EA bioavailability, PLGA-based formulations suitable for oral administration were developed [72]. The particles were prepared by using the emulsion-diffusion-evaporation technique. PLGA was dissolved in ethyl acetate under stirring for 2 h, then EA, previously dissolved in PEG 400, was added, and a fine EA dispersion was obtained. The dispersion was emulsified in an aqueous phase containing a stabilizer (1% _w/v_), such as polyvinyl alcohol (PVA), PVA:chitosan (CS) in 80:20 ratio, or didodecyldimethylammonium bromide (DMAB). After with stirred the emulsion at 1000 rpm for 3 h, homogenization at 15,000 rpm for 5 min was performed to obtain a more homogeneous and smaller size distribution. Then, the addition of water caused the diffusion of the organic solvent into the aqueous phase, and the evaporation of the organic phase by heating led to EA-polymer precipitation. The use of DMAB yielded smaller particles, while the other two stabilizers led to bigger sizes and higher PDI, probably due to the increased viscosity and irregular entanglement associated with the long polymeric chains. The zeta potential was highly positive for NPs containing DMAB (about +75 mV), equal to +25 mV for the ones with PVA-CS, and slightly negative for those with PVA. The highest EE (55%) was obtained with PVA-CS, the lowest with DMAB (42%).