Abstract
This study aimed to develop an oral solid dispersion nutrient delivery system of resveratrol (RSV) and Eudragit E PO (E PO) for the prevention of rheumatoid arthritis. The RSV‐E PO solid dispersion, prepared by the solvent method at a drug—polymer ratio of 1:7 (w/w), turned resveratrol into an amorphous state, as proved by SEM, DSC, XRD, and FTIR. Over 80% of resveratrol was released in vitro, a 13‐fold increase compared to raw resveratrol. In male Sprague—Dawley rats, its oral administration (20 mg·kg−1) doubled bioavailability versus unformulated resveratrol. Evaluated in an adjuvant‐induced arthritis (AIA) model, the compound demonstrated significant anti‐arthritic effects. These protective effects were primarily mediated through the modulation of key inflammatory and oxidative stress pathways, as evidenced by a marked reduction in pro‐inflammatory cytokines (IL‐6, TNF‐α, IL‐1β) and malondialdehyde (MDA) levels, coupled with an increase in the anti‐inflammatory cytokine IL‐10 and the antioxidant enzyme superoxide dismutase (SOD). Also, its safety was confirmed by stable AST, ALT, CREA, and BUN levels. In summary, the RSV‐E PO solid dispersion, with better dissolution and bioavailability, serves as an effective oral nutrient delivery system for RSV.
Introduction
Rheumatoid arthritis (RA) is an autoimmune disease marked by progressive, symmetric joint inflammation resulting in cartilage destruction, bone erosion, and disability (Lin et al. 2020). The prevalence of RA varies across different regions, with higher incidence rates commonly found in industrialized countries (Peng et al. 2024). RA affects approximately 0.5%–1% of the adult population, with a significantly higher prevalence in women than in men (Baig et al. 2024). The initial clinical manifestations of RA include the gradual onset of joint swelling, pain, and stiffness, which may subsequently evolve into symmetrical polyarthritis (Refaat et al. 2013). If left untreated, RA can result in disability and is associated with common extra‐articular manifestations affecting the cardiovascular, pulmonary, ocular, cutaneous, and vascular systems (Zhao et al. 2021).
The development of RA is a complex and protracted process, involving a multifaceted interplay of genetic, environmental, and immunological factors that contribute to immune system dysregulation (Di Matteo et al. 2023). Present pharmacological strategies for RA, such as nonsteroidal anti‐inflammatory drugs, disease‐modifying anti‐rheumatic drugs, biological agents, and glucocorticoids, primarily manage symptoms rather than offering a cure (Zewail et al. 2019). Compounding this limitation, their use is frequently constrained by a profile of significant adverse effects, including systemic toxicity, which remains a major clinical concern (Ali et al. 2023).
Given these deficiencies, there is an urgent need for safer, more effective, and affordable nutraceutical formulation designed for the prevention and alleviation of RA. Emerging evidence and reports revealed that several extracts, monomers from plants and foods were demonstrated the promising anti‐arthritic activity. Natural products have recently gained attention for their low toxicity and minimal side effects. Resveratrol (RSV), a polyphenolic compound (3,5,4′‐trihydroxystilbene) is derived from botanical sources such as grapes, berries, and Polygonum cuspidatum and is commonly used in functional foods. It is renowned for its potential health benefits, including antioxidant and anti‐inflammatory properties, anti‐obesity, anticancer, and antibacterial properties (Tian and Liu 2020). Notably, its potential anti‐arthritic activity has also become a focal point of research. A substantial number of studies have demonstrated that resveratrol can effectively inhibit the apoptosis of fibroblast—like synovial cells in rheumatoid arthritis rats compared to arthritis control rats (Wang et al. 2019).
It also significantly reduces the levels of serum malondialdehyde (MDA), interleukin‐6 (IL‐6), tumor necrosis factor α (TNF‐α), interleukin—1β (IL‐1β), and the arthritis index score in these animals (Yang et al. 2018). Moreover, a recent randomized controlled clinical trial demonstrated that the clinical and biochemical indices of rheumatoid arthritis in the Resveratrol—treated group were considerably lower than those in the control group (Khojah et al. 2018). It is well established that for an orally administered bioactive nutrient to exert its therapeutic effect, it must first dissolve in the gastrointestinal fluids to become available for absorption across the intestinal membrane and subsequently reach the systemic circulation. However, the bioavailability of RSV is notoriously low, primarily due to its hydrophobic nature, which has been a major obstacle to its practical application. We hypothesize that improving the solubility and bioavailability of RSV via our delivery system is the key mechanism underlying its enhanced prophylactic and therapeutic effects against adjuvant‐induced arthritis. As a result, it is important to select suitable bioactive delivery within the food and pharmaceutical industries. In recent years, various delivery systems of resveratrol have been developed, such as encapsulation strategies, liposomal carriers, emulsion‐based systems, and nano‐targeted technology. However, their widespread application is hampered by complex preparation processes, high production costs, and difficulties in scaling up. Additionally, nano‐targeted formulations cannot be industrialized.
Compared to these systems, solid dispersions are more suitable for industrialization. It has been reported that a total of 48 drug products incorporating amorphous solid dispersions (ASDs) were approved by the U.S. Food and Drug Administration between 2012 and 2023 (Moseson et al. 2024). This indicated that ASD‐based formulations represented a well‐established and clinically viable strategy for enhancing the delivery of poorly water‐soluble drugs. The preparation methods for solid dispersions, such as spray drying and hot‐melt extrusion, are relatively straightforward and readily scalable. Moreover, quality control of solid dispersions is facilitated by their generally favorable stability and improved batch‐to‐batch reproducibility.
Eudragit E PO (E PO), a cationic polyelectrolyte, belongs to the family of (meth)acrylate copolymers. It is composed of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate in a molar ratio of 2:1:1 (Li et al. 2015). Widely employed in the pharmaceutical industry, E PO serves multiple functions, including taste masking, moisture protection, release modification, and use as an excipient (Hofmann et al. 2025). Furthermore, it has demonstrated significant potential as a polymeric carrier in solid dispersions for enhancing the dissolution rate of poorly water‐soluble active pharmaceutical ingredients. Therefore, this study aimed to develop a high bioavailability resveratrol delivery system for rheumatoid arthritis prevention using solid dispersion. The RSV‐E PO solid dispersion was developed through the solution method and was characterized using FTIR, DSC, XRD, and release studies at pH 1.2. The anti‐arthritic activity was evaluated using paw swelling volume measurements, histopathological analysis, cytokine level evaluation, and antioxidant biomarker assessment in an adjuvant‐induced arthritis (AIA) model. Furthermore, a preliminary safety assessment was conducted by evaluating renal and hepatic functions.
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Materials
Resveratrol (98% purity) was sourced from Wuhan Yuancheng Gongchuang Technology Co. Ltd. (Hubei, China). Carbamazepine (purity of 98%) chosen as internal standard was obtained from Shanghai Haling Biotechnology Co. Ltd. (Shanghai, China). Indomethacin was obtained from Guangdong South China Pharmaceutical Group Co. Ltd. (Guangdong, China). Eudragit E PO was supplied by Evonik Industries AG in Darmstadt, Germany. Methanol and acetonitrile were supplied from OCEANPAK (Sweden). Complete Freund’s adjuvant (CFA) was provided from Sigma Aldrich, USA. ELISA kits for rat IL‐6, IL‐10, IL‐1β and TNF‐α were sourced from Thermo Fisher Scientific Biology Science and Technology Co. Ltd. SOD and MDA kits were procured from Nanjing Jiancheng Bioengineering Institute (Nanjing, China). Rat alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea and creatinine kits were obtained from Rayto Life and Analytical Sciences Co. Ltd. (Shenzhen, China).
Yu C, Zhang C. High Bioavailability Resveratrol Delivery System: A Novel Nutritional Strategy for the Prevention and Alleviation of Rheumatoid Arthritis. Food Sci Nutr. 2026 Feb 4;14(2):e71464. doi: 10.1002/fsn3.71464. PMID: 41648641; PMCID: PMC12872117.
