Development of a Lozenge for Oral Transmucosal Delivery of Trans-Resveratrol in Humans: Proof of Concept

Abstract

Resveratrol provides multiple physiologic benefits which promote healthspan in various model species and clinical trials support continued exploration of resveratrol treatment in humans. However, there remains concern regarding low bioavailability and wide inter-individual differences in absorption and metabolism in humans, which suggests a great need to develop novel methods for resveratrol delivery. We hypothesized that oral transmucosal delivery, using a lozenge composed of a resveratrol-excipient matrix, would allow resveratrol to be absorbed rapidly into the bloodstream. We pursued proof of concept through two experiments. In the first experiment, the solubility of trans-resveratrol (tRES) in water and 2.0 M solutions of dextrose, fructose, ribose, sucrose, and xylitol was determined using HPLC. Independent t-tests with a Bonferroni correction were used to compare the solubility of tRES in each of the solutions to that in water. tRES was significantly more soluble in the ribose solution (p = 0.0013) than in the other four solutions. Given the enhanced solubility of tRES in a ribose solution, a resveratrol-ribose matrix was developed into a lozenge suitable for human consumption. Lozenges were prepared, each containing 146±5.5 mg tRES per 2000 mg of lozenge mass. Two healthy human participants consumed one of the prepared lozenges following an overnight fast. Venipuncture was performed immediately before and 15, 30, 45, and 60 minutes following lozenge administration. Maximal plasma concentrations (C max) for tRES alone (i.e., resveratrol metabolites not included) were 325 and 332 ng⋅mL−1 for the two participants at 15 minute post-administration for both individuals. These results suggest a resveratrol-ribose matrix lozenge can achieve greater C max and enter the bloodstream faster than previously reported dosage forms for gastrointestinal absorption. While this study is limited by small sample size and only one method of resveratrol delivery, it does provide proof of concept to support further exploration of novel delivery methods for resveratrol administration.

Resveratrol promotes white adipocytes browning and improves metabolic disorders in Sirt1‐dependent manner in mice

“…45,46 Furthermore, different administration route was also studied, such as intravenous administration and oral transmucosal delivery. 47,48 Another method was inhibition of metabolism. As reported by Johnson and his colleagues, 49 combination of resveratrol with UGT inhibitor piperine gave 1000% increase of peak plasma concentration.…”

The Oral Bioavailability of Trans‐Resveratrol from a Grapevine‐Shoot Extract in Healthy Humans is Significantly Increased by Micellar Solubilization

“…Thus, only a small fraction of orally administered resveratrol escapes biotransformation in vivo, even under high‐dose supplementation, which has been proposed as a major hurdle for reaching effective systemic concentrations . Of note, in a proof‐of‐concept study with two healthy men, relatively high plasma concentrations of free resveratrol (1.4 μmol L −1 ) were achieved by delivering trans ‐resveratrol (140 mg) in lozenges through absorption via the oral mucosa, which circumvents first‐pass metabolism in the intestine and liver …”

“…[11] Of note, in a proof-of-concept study with two healthy men, relatively high plasma concentrations of free resveratrol (1.4 μmol L −1 ) were achieved by delivering trans-resveratrol (140 mg) in lozenges through absorption via the oral mucosa, which circumvents first-pass metabolism in the intestine and liver. [23] Several novel formulations have attempted to enhance the bioavailability of resveratrol, mostly by means of increasing its hydrophilicity, stability, and bioaccesibility, including: micronization, microencapsulation with polymeric nanoparticles and solid lipid nanoparticles, encapsulation into colloidal lipidand/or biopolymer-based delivery systems (liposomes, micelles, nanoemulsions and microemulsions), complexation with cyclodextrins, and encapsulation into pectinate beads, to name a few. [8,[11][12][13][14]24] Food-grade surfactant-based micelles may constitute a relatively easy and cost-effective way for the solubilization of hydrophobic molecules due to their spontaneous self-assembly intro structures with a hydrophobic core and a hydrophilic outer shell.…”

Bioavailability of resveratrol: Possibilities for enhancement

“…Oral transmucosal administration is another route being investigated (Ansari et al, 2011;Blanchard et al, 2014). A proof of concept study on the formulation of resveratrol-excipient lozenges investigated the solubility of the resveratrol-excipient matrices in water; and a bioavailability experiment with two healthy male participants was performed (Blanchard et al, 2014). The study demonstrated that the resveratrol-ribose lozenges had superior solubility compared to other resveratrol-excipient lozenges tested (Blanchard et al, 2014).…”