# Formulation Strategies to Improve Oral Bioavailability of Ellagic Acid
## 4 Formulation Strategies for Improving EA Oral Bioavailability
### EA Formulations in Fixed Combination with Other Bioactive Molecules  
With the aim to prevent or treat diseases associated with increased oxidative stress such as hyperglycemia, obesity, atherosclerosis, the industry of nutritional supplement has rapidly and greatly expanded over recent decades [97]. In a study by [PERSON] et al., EA was combined with Coenzyme Q10 (CoQ10) in a PLGA nanoparticulate formulation to prevent hyperlipidemia [98]. The NP were prepared by emulsion-diffusion-evaporation method, dissolving PLGA and CoQ10 in ethyl acetate, and EA in PEG 400. The two solutions were mixed and emulsified in 1% PVA aqueous solution. The mean particle size obtained was around 259 nm with EE of 70% for EA and of 72% for CoQ10. In an in vivo experiment, rats were fed with a high fat diet and daily administered with oral suspension of free drugs or once in three days with EA-CoQ10 NP. The effects on reducing glucose and triglyceride levels were similar, but only EA-CoQ10 NP exerted a prolonged control on cholesterol levels for up to 2 weeks after treatment suspension. With the aim at decreasing the risk of chemotherapy complications, further investigation concerning co-delivery systems involved EA and chemotherapy drugs, such as paclitaxel (PTX), for a combined anticancer therapy [99]. The idea of combining these actives was based on the evidence that PTX resistance relies on the NF-kB-dependent pathway, while EA hinders NF-kB. The two molecules were formulated with the temperature-sensitive amphiphilic copolymer poly (N-isopropylacrylamide-PEG acrylate), stable under physiological conditions, being its lower critical solution temperature higher than 37 \({}^{\circ}\)C. The NP were loaded directly by using the dialysis method at different temperatures. Several formulations were prepared, but the best one, in terms of EE and efficacy, contained the copolymer, PTX and EA in 20:1:1 weight ratio. The mixture was solubilized in DMF and dialyzed against deionized water, in which the copolymer self-assembled, developing core-shell nanoparticles. Since the drugs molecular weight is lower than the dialysis membrane cut-off(12 kDa), a slight loss of EA and PTX was unavoidable. To limit this phenomenon and to achieve a high EE, the loading reaction was performed at 4 \({}^{\circ}\)C and an EE of 92% for PTX and of 98% for EA were achieved. After completion of the dialysis, the solution was filtered and lyophilized. NP size was below 200 nm and the release was well-controlled, as only the 8% of both drugs was released after 2 h, while the 61% of PTX and the 88% of EA were released after 48 h. In vitro cytotoxicity tests were performed against MCF-7 breast cell line. After 48 h PTX/EA-loaded NP showed slightly higher cytotoxicity compared to free PTX, deriving from an improved cellular uptake. However, further studies would be needed to assess an eventual synergism between the two loaded drugs. In a multiple drug co-delivery study by [PERSON] et al., fluxastatin (FLV), alpha lipoic acid (ALA) and EA were chosen for their anticancer properties [100]. As dosage form, nanostructured lipid carriers (NLCs) were taken into consideration. NLCs are a relatively new generation delivery system, developed to overcome SLNs drawbacks such as low payload, crystallization of the lipid matrix, and drug expulsion during storage. In fact, NLCs, being composed of both solid and liquid lipids, do not undergo crystallization, allowing higher drug loading and consequent better bioavailability of low soluble drugs. Furthermore, NLCs are composed of highly biocompatible and biodegradable lipids, so they have a wider range of applications. As an example, NLCs are useful nutraceutical delivery systems with high drug loading, stability, capability in increasing bioavailability of bioactive compounds and consumer acceptability. In addition, they may provide controlled release of the encapsulated materials [101].