Development and preclinical testing of advanced formulations containing t-resveratrol and coenzyme Q10 with increased oral bioaccessibility and bioavailability

The effectiveness of nutraceutical products is often hindered by reduced intestinal bioaccessibility and even more limited bioavailability. The reasons for this phenomenon primarily lie in the presence of plant extracts containing a phyto-complex composed of substances with low or even negligible water solubility. Additionally, there are non-plant-derived substances with lipophilic characteristics and molecular sizes that do not ensure rapid dispersion in duodenal fluids. These conditions of limited bioaccessibility are further complicated by strict regulations governing nutraceutical products composition that limit the use of excipients that could improve the solubility of these substances. Consequently, a technological approach that promotes both the aqueous dispersion of active ingredients and the reduction of pre-systemic metabolism, as well as lymphatic access, represents the most promising and viable horizon. An equally important element to consider in ensuring the effectiveness of nutraceuticals is the protection of active ingredients from the gastric environment, which, due to its pH conditions and the presence of enzymes and mucins, potentially complicates the stability and bioaccessibility of many active ingredients. Two substances in the nutraceutical sector that are paradigmatic for their poor bioaccessibility and bioavailability, even though having high pharmacological and therapeutic potential, are Coenzyme Q10 (CoQ10) and Resveratrol (RES). The former is an isoprenoid quinone that is a component of the mitochondrial respiratory chain in eukaryotic cells, playing the crucial role of electron transporter in the biochemical process that leads to ATP synthesis. The latter is a polyphenolic stilbene extracted from various plant species, particularly from the seeds and skin of Vitis vinifera and the roots of Polygonum cuspidatum, possessing estrogen-agonistic, anti-neoplastic, and cardiovascular protective properties. From this perspective, the design and testing of new technological systems such as self-emulsifying drug delivery systems (SEDDS, SNEDDS) and the more recent lipid-based self-emulsifying drug delivery systems (LiBADDS) represent the new frontier for the delivery of substances with low solubility and reduced molecular weight (small molecules). This is especially true given their potential to enhance bioaccessibility while also facilitating their targeting into the lymphatic circulation, following incorporation into lipoproteins. In this work, new lipid-based and proteo-lipid-based self-emulsifying systems were designed and developed to maximize the bioaccessibility of RES and CoQ10, starting from the unique molecular and physicochemical characteristics of the two substances and their pharmacokinetic and biotransformation pathways. Specifically, for RES sodium caseinate (NaC) was chosen as a protein capable of ensuring gastric resistance and intestinal micellar delivery of RES after activation by pancreatic enzymes. NaC demonstrated its ability to ensure the gastric resistance of the formulations even in the presence of pepsin and simulated human gastric fluid (FaSSGF), in addition to exhibiting unusual characteristics of modulability in intestinal delivery. This agent was shown to provide release times that are directly proportional to its content in the tablet and inversely proportional when combined with non-ionic emulsifying excipients. Furthermore, the presence of NaC contributes to the formation of mixed micelles in the intestine in combination with bile salts and the mono- and diglycerides of fatty acids, thereby ensuring the formation of dispersions with reduced micellar diameters on the nanometer scale.