# Formulation Strategies to Improve Oral Bioavailability of Ellagic Acid
## 4 Formulation Strategies for Improving EA Oral Bioavailability
### Inclusion Complexes  
#### 4.3.1 EA Inclusion in Cyclodext (CDs)  
CDs are able to form inclusion complexes with a variety of molecules by hosting a guest drug with suitable polarity and dimension inside their lipophilic cavity, thus modifying its physico-chemical behavior. Among CDs, hydroxypropyl-\(\beta\)-CD (HP-\(\beta\)-CD) is characterized by better inclusion ability and higher complex solubility. To investigate the feasibility and the stoichiometry of inclusion complex formation of EA in HP-\(\beta\)-CD, phase solubility studies were carried out in water at 30 \({}^{\circ}\)C for 72 h to reach the equilibrium [61]. The obtained solubility curve of EA showed a linear increase with HP-\(\beta\)-CD concentration up to 12 mM, followed by a negative deviation from linearity up to 24 mM. This trend belongs to AN type and was explained through the formation of a soluble 1:2 EA:HP-\(\beta\)-CD inclusion complex with stability constants K1:1 and K1:2 of 201.61 and 18.91 M-1, respectively. A 15 mM HP-\(\beta\)-CD solution allowed to solubilize 54.40 \(\mu\)g/mL of EA in water at 30 \({}^{\circ}\)C. Subsequently, the inclusion complex was prepared by freeze drying a solution of EA:HP-\(\beta\)-CD in 1:2 molar ratio upon its filtration. In a dissolution test performed at pH 6.8 and 37 \({}^{\circ}\)C, HP-\(\beta\)-CD released about 55% of the loaded drug in 15 min, more than 5-fold the amount dissolved from pure EA powder. Furthermore, the anti-inflammatory effect of complexed EA was tested in a rat model of inflammation. Oral treatment with 10 or 20 mg/kg EA-HP-\(\beta\)-CD resulted more efficacious than the administration of EA alone or of 10 mg/kg indomethacin as indicated by the measure of paw edema volume. The feasibility of using \(\beta\)-CDs as complexing agent for EA was also investigated with less satisfactory results [62]. The complex was less soluble, leading to a total EA concentration up to 39.14 \(\mu\)g/mL, lower than that obtained in the previous study with HP-\(\beta\)-CD, due to the lower \(\beta\)-CD solubility. By following a different preparative procedure, \(\beta\)-CD was again chosen as EA complexing agent in another study [63]. A saturated aqueous \(\beta\)-CD solution was slowly mixed with 125 mg/mL of EA ethanolic solution and stirred for 2 h at rt, then the mixture was filtered and finally freeze-dried. As highlighted by SEM images, the obtained powder was different from those of the pure components in terms of morphology and dimensions; EE was 35% and in vitro dissolution studies (pH from 6.8 to 7.4) showed a multiphase release profile: a little amount of EA (3%) was released in a slow initial stage during the first 4-8 h, followed by a rapid phase between 8 and 24 h with 73% of drug released, and by a final slow phase. The effect of EA-\(\beta\)-CD complexes on proliferation of human liver carcinoma cells was evaluated by MTT assay and, though the lack of data relating to the treatment of cells with EA alone do not allow a comparison, a remarkable inhibition was observed. Another study to increase EA solubility regarded EA complexation with \(\beta\)-CD nanosponges (NS) [64]. NS are hyper-cross-linked CDs obtainable either from a mixture of CDs, or CDs conjugated with relevant amounts of linear dextrin. The cross-linking leads to a cage-like structure, where CDs cavities and nanochannels are strictly connected to form a porous network. Consequently, NS are able to incorporate drugs both as inclusion and non-inclusion complexes, thus improving the overall solubilizing ability of the starting CD. In this work the \(\beta\)-CD NS were obtained using dimethyl carbonate as a cross-linker. By a solubility study the authors demonstrated that the \(\beta\)-CD NS solubilized EA in water up to 49.79 \(\mu\)g/mL. The mean particle size of EA-\(\beta\)-CD NS was about 423 nm, PDI was found of 0.409 and the zeta potential equal to \(-\)34 mV, thus sufficiently high to produce a stable suspension.