Research Progress on the Pharmacological Effects and Dosage Forms of Rutin

Rutin, also known as rutoside, is a natural flavonoid derivative widely found in the roots, stems, leaves, flowers, fruits, and seeds of plants such as rue, tobacco leaves, buckwheat, and pagoda trees. It is particularly abundant in the flower buds of the Sophora japonica L. (a species of the Fabaceae family), commonly known as "huai mi", where its content can exceed 20%. As such, huai mi is often used as the raw material for extracting rutin. Rutin possesses a broad range of pharmacological effects, including anti-myocardial injury, anti-inflammatory, antibacterial, antiviral, and antitumor activities. Among these, its antioxidant capacity serves as the foundation for many of its pharmacological activities.

Pharmacological Effects and Mechanisms of Rutin

① Rutin possesses excellent antioxidant capabilities, exerting a protective effect against cellular and intracellular oxidative damage. It can safeguard against hepatocyte oxidative damage induced by tert-butyl hydroperoxide by modulating the phosphatidylinositol kinase/protein kinase B and nuclear factor-κB signaling pathways, thereby protecting against injury to liver cancer HepG2 cells. Furthermore, rutin reduces total cellular reactive oxygen species (ROS) levels, eliminates hydroxyl radicals, scavenges superoxide anions, and alleviates mitochondrial dysfunction caused by increased ROS content, making it useful in the treatment of age-related degenerative diseases.

② Rutin exhibits cardioprotective effects, capable of ameliorating myocardial damage induced by anticancer drugs such as cisplatin, lipopolysaccharides, pirarubicin, and carfilzomib. Additionally, it inhibits apoptosis caused by ischemia-reperfusion injury. The mechanisms underlying its cardioprotective effects encompass modulation of cytokine and oxidative kinase levels, as well as regulation of relevant gene expression through signaling pathways. For instance, in studies on lipopolysaccharide-induced myocardial damage, rutin improves myocardial morphology, protects the heart, prevents myocardial fibrosis, balances the cardiac oxidative and antioxidant systems, and inhibits cardiac inflammatory responses. Its mechanisms of action include reducing levels of myocardial markers (CK, LDH); attenuating the expression of fibrosis-related genes matrix metalloproteinase-2 and matrix metalloproteinase-9; enhancing antioxidant enzyme activities of superoxide dismutase and catalase, and managing levels of oxidative products malondialdehyde and hydrogen peroxide; and modulating the activities of tumor necrosis factor-α and interleukin-6. In research on pirarubicin-induced myocardial damage, rutin protects cardiomyocytes by regulating intracellular ROS levels, activating the JunD signaling pathway, downregulating miR-125b-1-3p expression, influencing apoptotic protein expression, upregulating miR-22-5p, and altering the RAP1-α and RAP1/ERK pathways, thereby reducing oxidative damage.

③ Rutin exerts anti-inflammatory effects by reducing inflammatory factor levels, inhibiting enzymatic activities involved in inflammatory responses, or interfering with the synthesis and expression of key enzymes in certain signaling pathways. It is used to treat neutrophil-mediated inflammation, autoimmune diseases, and intestinal inflammation. Studies have confirmed that rutin can inhibit the accumulation of neutrophils in yeast polysaccharide-induced arthritic mice and suppress the synthesis of tumor necrosis factor-α (TNF-α) within the joints, thereby alleviating joint inflammation.

④ Apoptosis is a type of programmed cell death. Rutin inhibits apoptosis induced by vancomycin by modulating oxidative kinase activity and ROS content, thereby mitigating nephrotoxicity. It can also alleviate sodium nitroprusside-induced PC12 neuronal cell damage by activating extracellular signal-regulated protein kinases, reducing apoptosis triggered by NO produced by nitric oxide synthase, and thus protecting neurons. Additionally, rutin decreases intracellular levels of NO and O2-, lowers the Bax/Bcl-2 ratio, increases the phosphorylated Akt/Akt ratio, restores superoxide dismutase activity, and inhibits apoptosis induced by Aeromonas hydrophila to alleviate muscle inflammation.

⑤ Rutin can inhibit tumor growth by modulating inflammatory states. Research has shown that rutin reduces the expression of interleukin-6 (IL-6) mRNA, IL-10 mRNA, and increases the expression of TNF mRNA (an inflammatory cytokine) in U251 and TG1 cells, promoting microglial cells towards an inflammatory phenotype. Concurrently, it increases the expression of IL-1 mRNA and IL-18 mRNA, while decreasing the expression of nitric oxide synthase 2, prostaglandin-endoperoxide synthase 2, arginase, transforming growth factor-β, and insulin-like growth factor mRNA, creating an inflammatory environment unfavorable for glioma cell growth, thereby inhibiting glioma cell proliferation.

⑥ The antiviral activity of rutin typically manifests after viral infection of cells, functioning at the replication level or during later stages of the viral lifecycle. Rutin significantly inhibits the enzymatic activity of the recombinant 3C protease protein and viral 3C protease in enterovirus-A71 (EV-A71)-infected cells, thereby suppressing EV-A71 replication and reducing the occurrence of encephalitis and pulmonary edema. Furthermore, rutin inhibits the neuraminidase activity of influenza viruses and exhibits excellent in vitro inhibitory effects against influenza virus strains such as A/Puerto Rico/8/1934 (H1N1), A/FM1/1/47 (H1N1), A/Beijing/32/92 (H3N2), and A/Human/Hubei/3/2005 (H3N2).

⑦ Rutin has been confirmed to possess antibacterial activity, although its direct antibacterial effect is weaker than that of antibacterial drugs. When combined, rutin can synergize with these drugs, as evidenced by its combined use with amphotericin B and morin, where the antibacterial effect is additive and can mitigate bacterial resistance and reduce drug toxicity. Therefore, the development of rutin in combination with antibiotics as antibacterial agents can achieve enhanced efficacy and reduced toxicity.

⑧ Rutin exhibits regulatory effects on glucose and lipid metabolism by reducing malondialdehyde levels in the heart, liver, and kidneys of diabetic mice, as well as decreasing total cholesterol and triglyceride levels in serum, thereby inhibiting glucose and lipid metabolism disorders. Its mechanism is related to activating antioxidant stress. Rutin also has therapeutic effects on diabetic complications. It can lower serum myocardial enzyme levels in diabetic cardiomyopathy mice, reduce fibrosis, and thus alleviate myocardial damage. Furthermore, rutin improves renal function in diabetic rats through antioxidant and free radical scavenging effects, inhibiting pathological changes in renal tissue.

According to the Biopharmaceutics Classification System (BCS), rutin belongs to the category of drugs with low solubility and low permeability. Its rapid metabolism in the body and low bioavailability significantly limit the clinical use of rutin. The development of rutin formulations with high bioavailability is one of the effective means to broaden the clinical application of rutin. This can be achieved by two main approaches: firstly, improving the solubility of rutin and accelerating its release rate in the biological system, such as through the use of rutin inclusion complexes, solid dispersions, submicron emulsions, nanocrystals, and polymeric micelle solutions; secondly, controlling the residence time of rutin in the biological system by preparing sustained-release or controlled-release formulations, such as rutin sustained-release tablets, microcapsules, and hydrogels.

① Rutin sustained-release tablets: Some scholars have prepared rutin sustained-release tablets using hydroxypropyl methylcellulose, sodium lauryl sulfate, polyvinylpyrrolidone, magnesium stearate, and colloidal silicon dioxide as excipients. Depending on the type and viscosity grade of hydroxypropyl methylcellulose used, the sustained-release time ranges from 6 to 14 hours. Other scholars have prepared sustained-release matrix tablets using hydroxypropyl methylcellulose, compressible starch, and microcrystalline cellulose as excipients, adopting the direct powder compression method. Experimental results show that the greater the amount of hydroxypropyl methylcellulose used, the slower the release rate of rutin. Additionally, rutin chitosan sustained-release tablets were prepared using chitosan at different concentrations as an excipient. It was found that as the chitosan concentration increased, the release rate of rutin slowed down. Rutin tablets prepared with 1.5% chitosan acetic acid solution exhibited significant sustained-release effects.

② Cyclodextrin inclusion complexes: Cyclodextrins possess the characteristic of "hydrophilic exterior and hydrophobic interior," allowing their cavities to encapsulate drugs of suitable size and shape through hydrophobic interactions and van der Waals forces. Research has shown that after complexation with β-cyclodextrin, the dissolution rate of rutin was 20% at 0 hours, reaching 60% at 20 hours, and reaching a constant level after 25 hours. Structural modifications of β-cyclodextrin can yield various cyclodextrin derivatives that improve structural properties and are more suitable for drug inclusion. To increase the dissolution of rutin oral tablets, researchers mechanically activated 2-hydroxypropyl-β-cyclodextrin (HP-βCD) and then compressed it into tablets with rutin through complexation. HP-βCD acts as a channel former, shortening the disintegration time of the tablets and enhancing drug permeability. Studies have demonstrated that HP-βCD not only improves the water solubility and dissolution rate of rutin but also enhances its stability in vivo, resulting in increased bioavailability.

③ Rutin microcapsules and microspheres: Microcapsules (microspheres) are tiny capsules formed by enclosing solid or liquid drugs within natural or synthetic polymeric materials as the membrane wall. Microcapsules can mask unpleasant odors and tastes of drugs, improve drug stability, reduce gastric irritation, solidify liquid drugs, and form sustained-release or controlled-release formulations and targeted delivery systems. Chitosan-sodium alginate microcapsules prepared by the complex coacervation method can be formulated into gastric floating microcapsules by adding a foaming agent. These microcapsules exhibit pH-responsive properties, displaying an S-shaped pulsed release profile in vitro. As the amount of foaming agent increases, the release lag time can be extended from 3 hours to 6 hours. Rutin microcapsules prepared using gelatin as the encapsulating material via the simple coacervation method are enteric-coated, protecting rutin in the acidic environment of the stomach while providing a sustained-release effect that prolongs the release time of active ingredients.

④ Solid dispersions: As a novel drug delivery system, solid dispersions can significantly enhance the dissolution of poorly soluble drugs. By utilizing different carriers and methods, solid dispersions can be formulated into either rapid-release or sustained-release formulations. Silicon dioxide (SiO2), due to its structural advantages, can bind with poorly soluble drugs through strong attractive forces, thereby increasing the stability of solid dispersions. Rutin strongly adsorbs onto SiO2 through interactions such as hydrogen bonding and electrostatic interactions, achieving a highly uniform dispersion within the pores and on the surface. The resulting rutin solid dispersion exhibits stable properties, with AUC0-∞ and Cmax values in dogs after oral administration being 12.2 and 15.46 times higher, respectively, than those of conventional tablets. This indicates that the solid dispersion significantly improves the oral bioavailability of rutin. The preparation method is simple, with a high drug loading capacity, making it suitable for industrial production.

⑤ Rutin dripping pills: The preparation of dripping pills is based on the solid dispersion method, which involves dispersing poorly soluble drugs into a molecular, colloidal, or microcrystalline state using a water-soluble solid carrier. Dripping pills prepared using solid dispersion technology also exhibit rapid absorption and high bioavailability, contributing to enhanced drug efficacy. For example, using PEG-6000 as a carrier, rutin can be formulated into water-soluble dripping pills, which improves its solubility in water and facilitates the full exertion of rutin's pharmacological effects. The resulting rutin dripping pills have a smooth, round shape with uniform size and are easy to prepare.

⑥ Nanocrystals: Nanocrystals are submicron colloidal dispersions composed of drug crystals and a small amount of stabilizer. They possess superior stability, delivery performance, high safety, and minimal adverse reactions, with a drug loading capacity of up to 100%. Rutin nanocrystals are typically prepared by freeze-drying rutin nanosuspensions. After freeze-drying, the rutin nanocrystals exist in a crystalline state, with a kinetic solubility increased to 133 g·mL^-1. In pH 1.2 and pH 6.8 buffer solutions, rutin nanocrystals dissolve completely within 15 minutes, while the dissolution rate of pure rutin microcrystals is only 70% within the same timeframe. Nanocrystals can also significantly enhance the permeability of water-insoluble drugs, allowing them to be loaded into gels for transdermal drug delivery. The release of rutin nanocrystals from the gel reaches 78.07% within 24 hours, compared to only 54.05% for crude rutin gel. Furthermore, the permeation amount of rutin nanocrystals gel within 12 hours is three times that of crude rutin gel. Simultaneously, the skin retention of rutin from the nanocrystals gel is significantly higher than that from the crude rutin gel. This system holds potential as a transdermal delivery formulation for rutin.

⑦ Rutin-loaded polymeric micelles. Polymeric micelles are thermodynamically stable systems spontaneously formed by amphiphilic polymers, which exhibit excellent solubilization effects on poorly soluble drugs. Utilizing polymeric micelles as carriers for oral drug delivery can significantly improve drug solubility, enhance drug permeation across biological membranes, and ultimately boost the efficacy of the drug. Micellar solutions of rutin were prepared using cationic, nonionic, anionic, and mixed surfactant systems, and the solubilization capacity and DPPH free radical scavenging ability of these systems were investigated. The results indicated that the order of both solubilization capacity and DPPH free radical scavenging ability was cationic > nonionic > anionic. Furthermore, a micellar solution of rutin was prepared using a copolymer of ethylene oxide-propylene oxide (E62P39E62) and ethylene oxide-styrene oxide (E137S18E137), and its dissolution capacity was studied at 25°C and 37°C. The results showed that the prepared rutin-loaded micelles exhibited superior dissolution capacity compared to previously reported rutin-β-cyclodextrin inclusion complexes.

⑧ Rutin Hydrogel. Smart nanohydrogels are a class of nanogels capable of responding to environmental changes and undergoing phase transitions. They can exhibit reversible volume changes or sol-gel transitions in response to subtle variations in temperature, pH, glucose, etc., ultimately enabling targeted, timed, and controlled drug release. A viscous thixotropic gel of sodium deoxycholate was prepared in an excess buffered solution system. By evaluating characteristics such as viscosity, appearance, and distribution, it was determined that the optimal conditions for preparing this thixotropic hydrogel involved using 0.5% sodium deoxycholate in a phosphate buffer system with the addition of 5% mannitol. The hydrogel prepared with rutin as the model drug exhibited a higher rate of permeation through artificial biomembranes compared to hydrogels made from hydroxyethyl cellulose and sodium polyacrylate. Similarly, the permeation rate through rat skin in vitro was also greater for the sodium deoxycholate hydrogel. The prepared sodium deoxycholate hydrogel possessed a lower molecular weight and excellent thixotropy, making it effective as a skin penetration enhancer.

Reference Materials

[1] Yang Shiyu, Song Jizheng, Yang Shanjing, et al. Research Progress on the Pharmacological Effects and Novel Dosage Forms of Rutin [J]. Chinese Journal of Modern Applied Pharmacy, 2022, 39(10): 1360-1370.

[2] Ai Fengwei, Li Shiying, Cheng Xiaotian, et al. Recent Advances in the Research of Rutin Preparations [J]. Chinese Traditional Patent Medicine, 2012, 34(07): 1347-1350.

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.