# Formulation Strategies to Improve Oral Bioavailability of Ellagic Acid
## 4 Formulation Strategies for Improving EA Oral Bioavailability
### Lipid-Based Carriers
#### 4.8.3 Self-Emulsifying Delivery Systems (SNEDDS)  
Among the several approaches that were suggested to achieve better EA oral bioavailability, SNEDDS represent an attractive opportunity. SNEDDS are isotropic mixtures of active molecules, oils, surfactants, and coemulsifiers or solubilizers able to form an _o/w_ nanoemulsion. Once in the gastrointestinal fluid, the fine droplet dispersion enhances water solubility of lipophilic molecules, thus providing more effective absorption. Though SNEDDS are not suitable for exerting controlled release, they demonstrated high potential in increasing oral bioavailability of several therapeutic agents, such as curcumin [92]. However, the poor palatability of the components and low compatibility with other excipients might be the major drawbacks in case of oral delivery. In this context, [PERSON] et al. developed a formulation containing EA starting from a mixture of EA and soy lecithin at 1:1 molar ratio [93]. This preliminary step was necessary to facilitate the incorporation of a larger amount of EA in the lipid phase and to increase its solubility. The EE was 95% and the water and n-octanol solubilities of complexed EA at 25 \({}^{\circ}\)C increased by about 3 and 6 times, respectively. Well-formulated SNEDDS should disperse in a few seconds under gentle stirring. Therefore, after a preliminary screening, the optimized composition was selected with the help of ternary phase diagrams. The final formulation included EA PL, glyceryl triacetate 40% _v/v_ as oil, polyoxyl 40 hydrogenated castor oil 40% _v/v_ as surfactant, PEG 400 20% _v/v_ as co-surfactant. To prevent EA oxidation, ocopherol was added in the oil phase. This composition led to the smallest mean diameter (106 nm, PDI of 0.3388) and to a negative zeta potential (\(\zeta=-13\) mV). As expected, EA release from SNEDDS was very fast at pH 6.8 (nearly 95% after 1 h), and a bit slower at pH 1.2, but this largest amount of dissolved EA may strongly increase gastrointestinal absorption. To support the hypothesis of a potential enhancement of oral bioavailability, an ex vivo permeability study was also carried out, which confirmed the good permeation of the SNEDDS through rat stomach and intestine. In a more recent work by [PERSON] et al., EA was entrapped in SNEDDS made of food-grade components to prepare a highly biocompatible formulation suitable for nutraceuticalals, performing the procedure previously described [94]. Firstly, a preliminary study investigated the solubility of EA in different oils, surfactants, and co-surfactants, then ternary diagrams were constructed. The best formulation was selected on the basis of the weight of water added dropwise to the mixed ingredients without causing turbidity, and the best formula corresponded to EA 2.5 mg/mL, PEG 400 45% _v/v_ as co-surfactant, Tween 80 45% _v/v_ as surfactant, and caprylic/capric triacylglycerl glycerols 10% _v/v_ as oil. This mixture was able to load EA in a concentration 250 times higher than its aqueous solubility and to release it completely within 1 h at pH 6.8. In addition, the authors developed a pharmacokinetic study on rats to evaluate in vivo oral bioavailability of EA in SNEDDS and the AUC value of the emulsified EA was 6.6 times higher than the one of the EA suspension. An issue associated with SNEDDS is the possibility for the dissolved molecule to undergo precipitation if administered in high dose [95]. Therefore, a slight but important modification consists of adding a precipitation inhibitor, such as PVP or HPMC, capable of increasing drug loading and stability over time. On this purpose a supersaturable self-nanoemulsifying drug delivery system (S-SNEDDS) containing EA was developed by [PERSON] et al. [96]. As usual, according to the results of solubility studies, those vehicles highly mixable with EA were chosen for formulation optimization through ternary phase diagrams. The final formulation consisted of Tween 80, PEG 400 and ethyl oleate at the ratio of 67.5/22.5/10% _w/w_, which can be fully diluted with water without phase separation.