A novel sodium caseinate lipid-based auto-emulsifying delivery system to increase resveratrol intestinal permeation: characterization and in vitro assessment

Abstract

In recent years, nutraceuticals have emerged as a promising strategy for maintaining health and represent a high-growth market in Italy and across Europe. However, the lack of strict regulations regarding formulation requirements and proof of efficacy raises serious concerns about their poor bioavailability and, consequently, their uncertain health benefits. An emblematic example is t-resveratrol (RES), a cardioprotective stilbene polyphenol that undergoes extensive metabolism in the intestine and liver, resulting in a bioavailability of less than 1%.

Highlights

Sodium caseinate is a reliable enteric-coating agent even in presence of pepsine.

Sodium caseinate behaves like a delaied release matrix activated by pancreatin in the small intestine.

The disaggregation time of tablets containing resveratrol entrapped in LiBADDS is linearly correlated with the following equation: NaC /(PS80/RES)

Where NaC is sodium caseinate, PS80 is polysorbate 80 and RES is resveratrol

Resveratrol delivered with LiBADDS shows a much higher Papp and permeation rate respect to unformulated resveratrol at the same concentration.

Sodium caseinate-based LiBADDS seems to reduce resveratrol ATP-binding cassettes extrusion process in the enetrocyte.

Sodium caseinate-LiBADDS could be an effective technological tool to reducing resveratrol phase II biotransformation in the enterocyte.

This manuscript describes a novel technological matrix developed with the primary goal of improving RES oral bioavailability. This technology can be classified as a lipid-based autoemulsifying drug delivery system (LIBADDS), in which RES is thoroughly solubilized in a hot liquid phase composed of lipids and surfactants, and the mixture is further adsorbed onto a powder composed of polysaccharides and sodium caseinate (NaC), along with inert excipients, and then compressed.

In this study, NaC was used for the first time to trigger pancreatin-mediated hydrolysis of an enteric-coated tablet, allowing micellar delivery of RES to the small intestine. The RES-containing tablets were characterized via differential scanning calorimetry (DSC) and X-ray diffraction (PXRD). The digested formulation, with simulated gastric and enteric fluids, was dimensionally assessed via dynamic light scattering (DLS). Finally, calculations of the bioaccessible fraction, dissolution tests, and in vitro permeability experiments using Caco-2 cell monolayers were carried out to preliminarily define the overall efficiency and applicability of this new technology in improving RES intestinal permeability.

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Materials

Compritol 888 Ato (Glyceryl dibehenate) was purchased from Gattefossè (Milan, Italy), Veremul T 80 (Polysorbate 80) was purchased from Eigenmann-Veronelli (Milan, Italy), and Tocopherol and Tonalin A 80 (conjugated carboxylic linoleic acid) were purchased from BASF (Cesano Maderno, MB, Italy). EMUL AC (sodium caseinate), magnesium stearate and citric acid were purchased from Faravelli SPA (Milan, Italy). Resveratrol was purchased from Suissenutra (Monza, Italy). A Comprez (anhydrous calcium phosphate) and Ceolus KG 802 (microcrystalline cellulose) were purchased from Seppic SRL (Milan, Italy); amorphous silica was purchased from Brenntag (Milan, Italy). FaSSIF and FSSGF were purchased from Biorelevant (London, United Kingdom); pepsin from porcine gastric mucosa, pancreatin 4X USP, methanol and ethyl acetate were purchased from Merck (Rome, Italy).

Andrea Fratter, Andrea Cignarella, Giovanni Eugenio Ramaschi, Adele Papetti, Vanessa Pellicorio, Chiara Milanese, Luca Casettari, Chiara Bolego, A novel sodium caseinate lipid-based auto-emulsifying delivery system to increase resveratrol intestinal permeation: characterization and in vitro assessment, European Journal of Pharmaceutical Sciences, 2024, 106912, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2024.106912.