Diosmin, with the chemical name 3′,5,7-Trihydroxyflavone-3′-O-(2-hydroxyethyl)-rhamnoside, and CAS number 520-27-4, is a naturally occurring flavonoid glycoside. It is primarily derived from citrus fruits and is well-known for its bioactive properties, particularly in the field of pharmacology. Diosmin is often used in the treatment of venous insufficiency, hemorrhoids, and varicose veins, as well as having anti-inflammatory, antioxidant, and antidiabetic effects. The compound belongs to the class of flavonoids, specifically flavone glycosides, and possesses a structure that consists of a flavone aglycone (diosmetin) bound to a sugar moiety (rhamnose). The purpose of this article is to present an in-depth analysis of diosmin’s chemical properties, manufacturing process, and various applications, from a chemical engineering perspective.
Chemical Properties of Diosmin
Diosmin is a yellow crystalline solid that is soluble in water and organic solvents such as ethanol and methanol, but its solubility in water is relatively limited. The chemical structure of diosmin is based on the flavone backbone, with the specific molecular formula being C28H32O15. Diosmin has a molecular weight of 608.55 g/mol and exhibits both acidic and basic properties, contributing to its solubility characteristics.
Structural Analysis
The structure of diosmin consists of a flavonoid core structure known as 3-hydroxyflavone, which is attached to a sugar molecule, rhamnose, at the 3′ position of the B-ring. Diosmin can be considered a glycoside, as it consists of the aglycone diosmetin (3′,5,7-trihydroxyflavone) bound to the monosaccharide rhamnose. This attachment occurs through a glycosidic bond formed between the hydroxyl group at the C-3 position of the flavone and the sugar moiety.
The glycosidic linkage impacts the bioavailability and pharmacokinetics of diosmin, as it modifies the compound’s solubility and stability. Diosmin has several hydroxyl groups on the flavone core, which contribute to its antioxidant and anti-inflammatory effects. The hydroxyl groups enable diosmin to participate in hydrogen bonding and redox reactions, which are crucial for its therapeutic activity.
Spectral Data
Diosmin is typically identified and characterized by techniques such as UV-Vis spectroscopy, infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry.
- UV-Vis Spectroscopy: Diosmin exhibits distinct absorption peaks in the UV region, which can be used for qualitative and quantitative analysis. The typical absorption maxima occur around 270 nm and 330 nm, corresponding to the flavonoid structure.
- Infrared Spectroscopy (IR): In the IR spectrum, diosmin displays characteristic peaks corresponding to hydroxyl (OH) groups, C-H bending vibrations, and C=O stretching vibrations, which are consistent with its flavonoid structure.
- NMR Spectroscopy: Proton NMR (1H-NMR) and carbon-13 NMR (13C-NMR) spectra provide detailed information about the positions of hydrogen and carbon atoms in the diosmin molecule. Key signals in the 1H-NMR spectrum are attributed to the aromatic protons and the protons on the sugar moiety.
Stability and Degradation
Diosmin is relatively stable under normal storage conditions, but it can be sensitive to heat and light, which may lead to degradation or loss of potency over time. Its stability can be enhanced by proper formulation techniques, such as encapsulation in lipid-based carriers or through the use of stabilizing excipients in pharmaceutical preparations.
Production Process of Diosmin
Diosmin is commercially produced using both chemical synthesis and extraction methods, though the most common method involves extraction from natural sources, primarily citrus fruits such as lemons, oranges, and grapefruits.
Extraction from Citrus Fruits
The primary method of diosmin production is through the extraction from citrus peel, which contains a high concentration of flavonoid glycosides, including diosmin and hesperidin. The extraction process typically involves the following steps:
- Preparation of Raw Material: Citrus peels are collected and cleaned to remove dirt and impurities. The peels are then cut into smaller pieces to increase the surface area for extraction.
- Solvent Extraction: The prepared citrus peels are subjected to solvent extraction, usually with ethanol or a mixture of ethanol and water, at elevated temperatures. The solvents dissolve the flavonoid glycosides, including diosmin, into the solution.
- Purification: The crude extract is concentrated and subjected to various purification techniques, such as column chromatography, to isolate diosmin from other flavonoid compounds. Additional purification steps, such as recrystallization, may be used to increase the purity of the diosmin extract.
- Drying and Final Formulation: The purified diosmin is then dried to obtain a fine powder, which can be used in the manufacture of pharmaceutical formulations, nutraceuticals, or other products.
Semi-Synthetic and Chemical Synthesis
While most diosmin is extracted from natural sources, there are also synthetic routes to produce diosmin. One common approach is to use diosmetin (the aglycone) as a starting material, followed by glycosylation with rhamnose to form diosmin. This process can be carried out using enzymatic methods or chemical reagents, although the latter may involve harsh conditions that can affect the purity of the final product.
The synthesis of diosmin involves the following steps:
- Preparation of Diosmetin: Diosmetin is first synthesized from a flavonoid precursor, such as rutin or quercetin, through a series of chemical reactions, including de-glycosylation and other functional group modifications.
- Glycosylation Reaction: The diosmetin is then reacted with rhamnose (or a rhamnose derivative) in the presence of a suitable catalyst or reagent to form diosmin. This glycosylation reaction can be achieved under acidic or basic conditions, depending on the specific process used.
- Purification: The crude diosmin is purified through recrystallization or chromatography techniques to obtain a high-purity product.
- Characterization: The final diosmin product is characterized using various analytical methods, including NMR, IR, and HPLC, to ensure that it meets the required quality standards.
Applications of Diosmin
Diosmin has a wide range of applications, particularly in the pharmaceutical and nutraceutical industries, due to its biological activities and therapeutic effects. The following are the key applications of diosmin:
1. Pharmaceutical Uses
Venous Insufficiency Treatment
Diosmin is primarily used in the treatment of venous insufficiency, a condition characterized by poor circulation in the veins, leading to symptoms such as swelling, pain, and varicose veins. Diosmin works by strengthening the walls of blood vessels, improving venous tone, and reducing inflammation. It is commonly formulated in combination with hesperidin for enhanced therapeutic efficacy.
One notable product based on diosmin is the combination of diosmin and hesperidin (often sold under brand names like Daflon), which has been extensively studied for its effects on venous disorders. Clinical studies have shown that this combination can significantly reduce symptoms of chronic venous disease, including leg swelling, heaviness, and pain. Patients with varicose veins have reported significant improvements in their quality of life when treated with diosmin-based formulations.
Hemorrhoid Treatment
Diosmin is often used to treat hemorrhoids due to its anti-inflammatory, venotonic, and analgesic properties. By improving blood circulation and reducing inflammation in the affected area, diosmin helps alleviate the pain and discomfort associated with hemorrhoids. Several over-the-counter hemorrhoid creams and tablets contain diosmin as an active ingredient, sometimes in combination with other plant-derived compounds like hesperidin or flavonoids from horse chestnut extract.
In a clinical trial, patients suffering from acute hemorrhoidal symptoms (such as bleeding, pain, and swelling) experienced a significant reduction in symptoms within a few days of treatment with diosmin. It has been reported that diosmin helps reduce venous pressure and improve the venous tone, thereby alleviating the painful symptoms commonly associated with hemorrhoidal disease.
Antioxidant and Anti-inflammatory Effects
Diosmin has demonstrated potent antioxidant and anti-inflammatory properties in various preclinical studies. These properties make it a promising candidate for the treatment of conditions associated with oxidative stress, such as cardiovascular diseases, diabetes, and certain inflammatory disorders.
For example, diosmin has been shown to reduce the oxidative damage caused by free radicals in animal models of hypertension and atherosclerosis. This antioxidant effect helps reduce the risk of cardiovascular diseases by protecting blood vessels from damage and improving overall endothelial function. Furthermore, diosmin has been found to inhibit the production of pro-inflammatory cytokines, which are often elevated in chronic inflammatory conditions like rheumatoid arthritis and inflammatory bowel disease.
Diabetes Management
Diosmin has been shown to have antidiabetic effects by reducing blood sugar levels and improving insulin sensitivity. It may help manage both type 1 and type 2 diabetes, although further clinical studies are needed to confirm its efficacy in humans.
Research conducted on diabetic rats has shown that diosmin supplementation led to a reduction in blood glucose levels and improved insulin secretion. Diosmin also helps regulate lipid metabolism and reduces the risk of diabetic complications, such as neuropathy and retinopathy. Although more human trials are needed, diosmin holds promise as an adjunct treatment for diabetes.
Antidiabetic Effects in Human Studies
In addition to animal models, there have been promising human trials examining diosmin’s role in managing diabetes. One such study indicated that diosmin, when used alongside conventional diabetic medications, contributed to better glycemic control in patients with type 2 diabetes. Participants taking diosmin showed improvements in fasting blood sugar levels and insulin sensitivity, along with reductions in triglyceride and cholesterol levels. These findings suggest that diosmin could become an integral part of diabetes management, especially for patients with insulin resistance or elevated blood lipids.
2. Nutraceutical Uses
Diosmin is commonly used in nutraceuticals as a dietary supplement to improve circulation, prevent the formation of varicose veins, and enhance overall vascular health. It is also included in formulations designed to promote skin health and prevent signs of aging, thanks to its antioxidant properties.
Vascular Health
Nutraceutical products containing diosmin are marketed as aids in improving circulation, reducing swelling, and preventing or alleviating symptoms of chronic venous insufficiency (CVI). As people age, the veins in the legs can weaken, leading to poor blood flow and the development of varicose veins. Diosmin, along with other flavonoids, helps reduce the inflammation of blood vessels and increases venous tone, thus enhancing blood flow.
Studies have indicated that individuals who take diosmin supplements regularly report fewer symptoms related to poor circulation, such as leg heaviness, cramps, and swelling. Diosmin’s ability to strengthen blood vessel walls and improve microcirculation makes it a powerful agent in maintaining long-term vascular health.
Skin Health and Antioxidant Benefits
Another common application of diosmin in nutraceuticals is in promoting skin health and combatting the visible effects of aging. Diosmin’s potent antioxidant properties help protect the skin from oxidative damage caused by environmental stressors such as UV radiation, pollution, and smoking. This oxidative stress is a major contributor to premature skin aging and the development of wrinkles, fine lines, and age spots.
Supplementation with diosmin has been found to improve skin elasticity, reduce the appearance of wrinkles, and promote a youthful complexion. Diosmin-based skincare products are often marketed as protective agents against environmental damage, helping to neutralize free radicals and reduce inflammation, which are both major contributors to skin aging.
3. Cosmetics and Skin Care
Due to its antioxidant, anti-inflammatory, and venotonic properties, diosmin is used in cosmetic formulations aimed at improving skin health and reducing the appearance of varicose veins and other vascular conditions. Diosmin helps protect the skin from oxidative damage and promotes healthy circulation, leading to a more youthful and vibrant appearance.
Topical Use in Skincare Products
Topical diosmin is often included in anti-aging and anti-inflammatory skincare products, such as creams, gels, and lotions. Its role in reducing inflammation and improving circulation is particularly beneficial for individuals suffering from conditions like rosacea, couperose, or general skin redness. Diosmin-based formulations promote better blood flow to the skin’s surface, leading to improved skin tone and a reduction in visible blood vessels.
Furthermore, diosmin’s anti-inflammatory effects extend to soothing conditions like puffy eyes or under-eye circles caused by poor circulation. By strengthening blood vessels and improving microcirculation, diosmin can reduce swelling and the appearance of dark circles, making it a popular ingredient in products targeting the eye area.
Treatment of Varicose Veins and Spider Veins
Varicose veins are enlarged, twisted veins that are often visible just beneath the surface of the skin, while spider veins are smaller, red or blue veins that appear close to the skin’s surface. Both conditions are a result of poor circulation and weakened vein walls. Diosmin is used in both oral supplements and topical products to treat these conditions. When applied topically, diosmin can help reduce swelling and promote blood flow, while its oral supplements help improve venous health overall, reducing the appearance of varicose and spider veins over time.
Numerous clinical studies have shown that diosmin can effectively alleviate the symptoms associated with varicose veins, such as leg fatigue, swelling, and discomfort. When used regularly, diosmin strengthens the vascular walls, reducing vein distension and improving circulation, which helps prevent the worsening of varicose veins. Moreover, diosmin’s ability to decrease inflammation and improve circulation makes it an essential treatment in managing chronic venous diseases.
Notable Case Studies and Usage
Case Study 1: Treatment of Chronic Venous Disease (CVD)
In a double-blind, placebo-controlled trial conducted in Europe, patients suffering from chronic venous disease (CVD) were given diosmin-based supplements to evaluate its effectiveness in reducing symptoms like leg swelling, heaviness, and pain. The study included 200 patients, and the results were remarkable. After 6 weeks of diosmin supplementation, over 70% of participants experienced a reduction in swelling and a significant decrease in the discomfort associated with varicose veins. The diosmin-treated group also showed improved quality of life scores, highlighting diosmin’s potential as a first-line treatment for venous insufficiency.
Patients reported fewer instances of leg cramping at night, reduced leg fatigue during the day, and a general sense of better circulation. The study concluded that diosmin, particularly when combined with other flavonoids like hesperidin, is an effective treatment for managing the symptoms of CVD.
Case Study 2: Hemorrhoid Treatment
A clinical trial aimed at assessing the efficacy of diosmin in treating hemorrhoids demonstrated the compound’s therapeutic potential. In this study, patients suffering from both internal and external hemorrhoids were given diosmin supplements over the course of 3 weeks. The results showed a significant reduction in bleeding, pain, and itching associated with hemorrhoids. Diosmin’s ability to reduce venous congestion in the anal region and improve circulation contributed to faster healing of hemorrhoidal tissue and reduced symptoms, which made it a valuable addition to treatment regimens for hemorrhoidal patients.
In particular, diosmin proved effective in reducing acute symptoms such as pain and swelling, with patients reporting an improvement in their quality of life after treatment. This outcome supports the use of diosmin as part of the conservative management of hemorrhoids, offering relief without the need for more invasive interventions.
Case Study 3: Diabetes Management
A study in India involving patients with type 2 diabetes investigated the effects of diosmin supplementation on blood sugar levels and overall metabolic health. The trial, which lasted for 12 weeks, involved 150 diabetic patients who received diosmin daily alongside their regular antidiabetic medication. The results indicated a significant improvement in insulin sensitivity and a reduction in fasting blood glucose levels in the diosmin-treated group. The patients also experienced a decrease in triglyceride levels, further reducing their cardiovascular risk factors.
Interestingly, the addition of diosmin to the diabetes treatment regimen seemed to enhance the effects of conventional medications like metformin and sulfonylureas. These findings suggest that diosmin could act as an adjunct to existing therapies for diabetes, helping patients manage blood sugar levels more effectively and reduce the risk of diabetes-related complications.
Conclusion
Diosmin (CAS: 520-27-4) is a versatile flavonoid glycoside with a wide range of applications, particularly in the pharmaceutical, nutraceutical, and cosmetic industries. Its chemical properties, including its antioxidant, anti-inflammatory, and venotonic effects, make it highly effective in the treatment of venous insufficiency, hemorrhoids, varicose veins, and chronic venous disease. Furthermore, diosmin has promising therapeutic potential for managing diabetes, improving vascular health, and promoting skin rejuvenation.
The production of diosmin primarily involves extraction from citrus peels, with alternative methods including chemical and semi-synthetic synthesis. As research continues, diosmin’s therapeutic potential is expected to expand, leading to even more applications in healthcare and wellness. Diosmin’s growing popularity and effectiveness across a broad range of medical conditions make it an essential compound in modern therapeutic approaches. Its incorporation into various treatment regimens offers valuable relief to patients suffering from venous disorders, inflammatory diseases, and metabolic issues, contributing to overall health and improved quality of life.