# 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
In this work, NLCs were prepared by hot emulsification-ultrasonication method starting from 1% almond oil, 3% glyceryl dibehenate, 0.5% L-\(\alpha\)-phosphatidylcholine phospholipid, 0.25% FLV, 0.02% EA and 0.3% ALA. The mixture was melted heating up to 50 \({}^{\circ}\)C in chloroform:ethyl acetate 1:1. To this lipid phase 1% \(\text{G}\text{e}\text{l}\text{e}\text{l}\text{e}\text{l}\text{e}\text{l} \text{e}\text{l}\text{e}\text{l}\text{e}\text{l}\text{e}\text{l}\text{e} \text{l}\text{e}\text{l}\text{e}\text{l  
size of 85 nm (PDI = 0.58) and a negative zeta potential (\(\zeta=-25\) mV). The EE was 98% for FLV, 92% for ALA, and 96% for EA. The release rate was rather slow after an initial burst effect. The formulation was evaluated for its in vitro cytoxicity against PC3 prostate carcinoma cells. The co-delivery of FLV, ALA and EA from NLCs always provided better results in comparison with free drugs both when administered individually and mixed together, with significant differences in terms of cell survival, caspase-3 expression and incidence of apoptosis. In another interesting study, [PERSON] et al. focused on the preparation of an inhalable spray dried powder for targeted co-delivery of EA and doxorubicin (DOX) to lung carcinoma [102]. This system consisted of nanocomposites comprised of drug-loaded NP and excipients like sugars just to reach the micro-range size necessary to ensure deposition in deep lung tissue. Once at the alveolar surface, the carbohydrate fraction rapidly dissolves, releasing the NP components apt to be internalized by the cancer cells. NP matrix was composed of lactoferrin (Lf), a cationic glycoprotein chosen for its ability to bind transferrin receptors overexpressed on cancer cells, and chondro sulfate (ChS), a polyanionic glycosaminoglycan able to bind hyaluronic acid CD44 receptors. The first step of this procedure was the nanocrystallization of raw EA via antisolvent precipitation in order to increase EA incorporation in the hydrophilic matrix. A methanolic EA solution was added in a 1:10 volume ratio to an aqueous phase containing 0.5% _w/v_ polyacamer F188 as a stabilizer at 4 \({}^{\circ}\)C and the mixture was stirred for 15 min. The resulting EA nanocrystals had an average size of 148 nm (PDI of 0.185) and an aqueous solubility 33.3-fold higher than raw EA. The loaded Lf-ChS NPs exploited the polyelectrolyte electrostatic complexation. DOX dissolved in distilled water was dropped gradually into 2% _w/v_ ChS solution containing lyophilized nano-sized EA; this dispersion was added by controlled dripping to 2% _w/v_ Lf solution, at a suitable pH to allow formation and stabilization of NPs. The resulting product was harvested by centrifugation. The loaded NPs showed a size of around 192 nm and a negative zeta potential (\(\zeta=-27\) mV). The EE was 91% for DOX and 96% for EA. The in vitro anticancer efficacy was tested against A495 human lung cancer cell line. Co-encapsulated DOX and EA Lf-ChS NPs enhanced the potency of the drug co-administered in mixture, as demonstrated by the significant reduction of IC50 value by 3.8-fold compared with combined free drug solution. This system was not expensive, scalable, and made of natural and highly biocompatible components, characteristics that make it potentially useful for preparation of EA-enriched foods. \begin{table}
\begin{tabular}{c c c c c c c c} \hline \hline
**Formulation Type** & **Fabrication Method** & **Exipients** & **Mean Size** & **Remarkable Features** & **Highlights** & **Ref. ** \\ \hline Micro-sized EA & Anti-solvent precipitation & - & n.a. & & Use of a syringe pump & In vitro and in vivo inhibition & [54] \\  & & & & Good dispersion & of blood parasites & \\ \hline Micro-sized EA & Supercritical anti-solvent & Endragi\({}^{\text{th}}\) L 100 & 3.73 nm & & \begin{tabular}{c} Co-precipitate product \\ EA content 49\%. \\ Residual NOT 148 ppm \\ \end{tabular}  & Increased EA dissolution rate & [55] \\ \hline Amorphous solid & \multirow{2}{*}{Freeze drying