# Formulation Strategies to Improve Oral Bioavailability of Ellagic Acid
## 1 Introduction  
Pomegranate, _Punica granatum_, is well-known as a traditional medicinal fruit mentioned in the Old Testament of the Bible, the Qur'an, the Jewish Torah, and the Babylonian Talmud as a sacred fruit harbinger of fertility, abundance, and luck. Historically and currently, pomergnate has been used for various purposes [1]. The bioactive compound mainly responsible for the health effects of pomergnate is ellagic acid (EA), as it represents one of the most potent dietary antioxidants. EA is a polyphenol compound which derives from ellagitannins (ET), a family of molecules in which hexahydroxydphenic acid residues are esterified with glucose or quinic acid. Following a hydrolytic process, the hexahydroxydphenic acid group is released, dehydates and spontaneously lactonizes, forming EA. Punicalagin isomers are the most representative of total tannins extracted from pomergnate (Figure 1). Present also in a large variety of tropical fruit, nuts, berries (strawberries, raspberries, blackberries, cranberries, goji berries) and in a type of edible mushroom (Fistulina epatica), EA has recently attracted deep interest, since many research studies showed the role of oxidative stress in different pathologic conditions such as cancer, diabetes, cardiovascular and autoimmune diseases, obesity, and neurodegenerative disorders [2; 3; 4; 5; 6; 7]. In this regard, EA may be a useful adjunct in [PERSON]'s disease treatment, as it proved to protect dopamine from oxidation and, by reducing inflammation and oxidative stress, to exert a neuroprotective effect [8]. Besides being able to reduce the pathological levels of NF-kB, EA may play a beneficial role in diseases associated with CNS inflammation, such as multiple sclerosis. EA has also been proposed as antidepressant and anxiolytic drug for its capability to modulate the monoaminergic system and to increase the endogenous levels of brain-derived neurotrophic factors [6]. In the last decade, several studies investigated EA effects on many types of cancer, showing its ability to arrest cell cycle progression, modulate pathways linked to cell viability, and inhibit angiogenesis via inactivating metalloproteinases [9; 10; 11; 12; 13; 14; 15; 16; 17; 18]. For example, EA resulted in inducing apoptosis and modulating gene expression in different colon cancer cell lines at the concentrations achievable in the intestinal lumen from the diet, suggesting a potential role in cancer chemoprevention [19]. Moreover, EA may counterbalance the dangerous side effects of antitumoral drugs such as cisplatin, doxorubicin, and cyclosporine [20; 21; 22]. In addition, EA proved to possess antimicrobial properties inhibiting the growth of methicillin-resistant Staphylococcus aureus and Salmonella [23]. These properties were explained through the ability of EA of either coupling with proteins of the bacterial wall or inhibiting gyrase activity, which cleaves the DNA strand during bacterial replication. Furthermore, EA seemed to counteract the HIV-1 virus replication, by binding envelope proteins and inhibiting reverse transcriptase [24]. Pomegranate extract has been traditionally used for treating gastrointestinal bleeding and various types of wounds, due to EA's ability to promote blood coagulation by the activation of the Hageman factor (Factor XII) [25]. Moreover, preliminary results suggest potential anti-inflammatory properties [26; 27] and an important role in prevention of cardiovascular diseases [28; 29; 30]. Finally, EA finds application also in cosmetic and nutraceutical industries, mainly for antiaging and prophylactic purposes respectively [31; 32; 33]. An overview of EA activities is shown in Figure 2.  
However, though EA has the potential to become an efficacious agent in the prevention and therapy of several diseases, as supported by several papers present in the literature, the working efficacy of EA dietary and therapeutic formulations have been mainly examined at preclinical level.