Application of diosgenin in preparation of medicine for treating gout

Abstract

The invention discloses an application of diosgenin in preparation of a medicine for treating gout, and in conclusion, the invention provides the medicine for treating gout based on diosgenin and the application thereof, DIO has a remarkable gout treatment effect, not only can reduce uric acid but also can relieve gouty arthritis, has less damage to renal functions, has higher safety, and can be used for preparing medicines for treating gout. A new choice is provided for treatment of hyperuricemia and related diseases, and the medicine has wide application prospects and market potential in the field of gout treatment.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and particularly to the application of diosgenin in the preparation of drugs for treating gout. Background Art

[0002] Gout is a common metabolic disease, which is caused by the deposition of monosodium urate crystals in joints, resulting in acute arthritis. Hyperuricemia (HUA) is considered to be a precursor of gout. In China, gout has become the second most prevalent metabolic disease after diabetes, with a prevalence rate of 3% - 5%. Gouty arthritis (GA) is the first clinical manifestation of gout and is a common treatable crystalline inflammatory arthropathy, mostly seen in the first metatarsophalangeal joint, and can also occur in other larger joints. Gout can be divided into four pathophysiological stages:

[0003] ① HUA, but there is no evidence of MSU crystal deposition or gout;

[0004] ② MSU crystal deposition, but without gout symptoms;

[0005] ③ MSU crystal deposition accompanied by acute GA;

[0006] ④ Advanced gout characterized by tophus, chronic GA and radiological erosion.

[0007] Terminating acute attacks, preventing recurrent attacks and the occurrence of complications are the goals of gout treatment. These goals can be achieved through the education of gout patients and drug treatment. Under the influence of multiple factors such as physical and chemical factors, sodium ion and protein concentration, the solubility of urate may be less than 6.0 mg / dL or a lower concentration. Therefore, long-term control of serum urate concentration to sub-saturation level (6 mg / dL) or below helps to control the condition, prevent or reverse the formation and deposition of MSU, and prevent recurrence.

[0008] In the acute attack period of gout, anti-inflammatory and pain-relieving treatment should be started as soon as possible (usually within 24 hours) to terminate the acute attack. Recommended treatment regimens include the application of non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and glucocorticoids. For patients with severe symptoms and multi-joint attacks, and those with poor treatment effect with a single drug, the combined application of the above drugs can be selected. The choice of western medicine should be based on drug interactions, patient comorbidities, contraindications and patient individual differences, etc.; the combined application of non-steroidal anti-inflammatory drugs and glucocorticoids is not recommended to avoid the occurrence of synergistic toxicity (such as gastrointestinal bleeding).

[0009] In the remission period of gout, controlling blood uric acid concentration, inhibiting crystal deposition, and achieving crystal dissolution to avoid the occurrence of gout symptoms are the key to effectively managing gout. Currently, the main western medicines for reducing uric acid include allopurinol, febuxostat, and benzbromarone, etc., but they all have serious side effects, such as allergic reactions, cardiovascular risks, and hepatotoxicity, etc. Therefore, finding safe and effective drugs for reducing uric acid and treating gout has important clinical significance. Currently, the commonly used drugs for reducing uric acid in clinical practice mainly include allopurinol, benzbromarone, etc. Although these drugs can reduce the blood uric acid level to a certain extent, they have certain side effects. For example, allopurinol can cause liver and kidney function damage, and benzbromarone can cause gastrointestinal reactions, etc.

[0010] Currently, the Chinese invention patent with the publication number CN201110266508.2 discloses a uric acid-lowering active ingredient extracted from natural plants - resveratrol, which treats gout by inhibiting uric acid production and promoting uric acid excretion. However, resveratrol has poor stability and low bioavailability in the body, which limits its clinical application.

[0011] Currently, the Chinese invention patent with the publication number CN110123456A discloses a uric acid-lowering active ingredient extracted from natural plants - tengcha flavonoids, which treats gout through anti-inflammatory and antioxidant effects. However, the solubility and bioavailability of tengcha flavonoids are low, and it may cause gastrointestinal discomfort at high doses, affecting its actual application effect.

[0012] Therefore, it is urgent to develop a new type, safe, and effective drug for treating gout. Summary of the Invention

[0013] The purpose of the present invention is to overcome the deficiencies of the prior art and provide an application of diosgenin in the preparation of drugs for treating gout; it can safely and effectively reduce uric acid and relieve gouty arthritis, solve the problems of large side effects and low safety of existing uric acid-lowering drugs; and provide a safe and effective treatment plan for gout treatment.

[0014] To achieve the above purpose, the technical solution designed by the present invention is as follows:

[0015] The present invention provides an application of diosgenin in the preparation of drugs for treating gout.

[0016] The above diosgenin (DIO) is a natural sapogenin extracted from plants of the Dioscoreaceae family and has a variety of biological activities; its chemical formula is C 27 H 42 O 3 , the CAS number is 512-04-9, and its structural formula is shown as follows:

[0017]

[0018] The present invention also provides a drug for treating gout, and the active ingredient of the drug comprises diosgenin.

[0019] Furthermore, in the drug for treating gout, the content of diosgenin is 6-24 mg / mL.

[0020] Still further, in the drug for treating gout, the content of diosgenin is 6 mg / mL.

[0021] Still further, the drug may further comprise pharmaceutically acceptable excipients.

[0022] Still further, the excipient is any one or several of sodium carboxymethylcellulose, filler, disintegrant and lubricant, etc.

[0023] Still further, when the excipient is sodium carboxymethylcellulose, the concentration of sodium carboxymethylcellulose is 0.1-1.0%.

[0024] Still further, the concentration of sodium carboxymethylcellulose is 0.5%.

[0025] Still further, the drug is a tablet, capsule or injection.

[0026] The above drug for treating gout can be used to treat hyperuricemia and its related diseases, such as gout, kidney stones, etc. This drug can be administered by various administration methods, including oral administration, gavage, injection, transdermal administration, etc. The dosage of the drug for treating gout is referenced as 40-160 mg (DIO) / kg body weight; the administration frequency can be adjusted according to the specific condition and individual differences of the patient.

[0027] Advantages of the present invention:

[0028] 1. Single active ingredient: Using diosgenin (DIO) as the single active ingredient, it avoids the complexity of the interaction of multiple components in compound drugs, and improves the stability and controllability of the drug.

[0029] 2. Significant gout treatment effect: Experimental results show that DIO has a significant gout treatment effect within the dosage range of 40-160 mg / kg body weight, and has less damage to kidney function.

[0030] 3. Unique gout treatment mechanism: The gout treatment mechanism of DIO is mainly achieved by reducing the body's inflammatory response and increasing uric acid excretion, with dual effects, which is different from the mechanisms of existing drugs and has unique innovation.

[0031] 4. Safety and economy: The preparation process of DIO is relatively simple, with low cost, easy for large-scale production, and has high economy and practical application potential.

[0032] In summary, the present invention provides a drug for treating gout based on diosgenin (DIO) and its application. The gout treatment effect of DIO is remarkable. It can not only reduce uric acid but also relieve gouty arthritis, and has less damage to kidney function, with higher safety, providing a new option for the treatment of hyperuricemia and its related diseases. The drug of the present invention has broad application prospects and market potential in the field of gout treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 It is a diagram of the serum biochemical results of mice after 7 days of DIO treatment;

[0034] In the figure, A is the diagram of serum uric acid (UA) level, and B is the diagram of blood urea nitrogen (UREA) level.

[0035] C is the creatinine (CREA) level

[0036] Blank: blank control group; Model: model group;

[0037] DIO-L: low-dose DIO group, with a concentration of 6 mg / mL (drug 1);

[0038] DIO-M: medium-dose DIO group, with a concentration of 12 mg / mL (drug 2);

[0039] DIO-H: high-dose DIO group, with a concentration of 24 mg / mL (drug 3);

[0040] AP: allopurinol group, with a concentration of 12 mg / mL.

[0041] Figure 2 It is the influence of DIO on uric acid transporters;

[0042] In the figure, A and B are the diagrams of the gene expression of uric acid transporters GLUT9 and OAT1.

[0043] C is the diagram of the protein expression of GLUT9 and OAT1;

[0044] Blank: blank control group; Model: model group;

[0045] DIO-L: low-dose DIO group, with a concentration of 6 mg / mL (drug 1);

[0046] DIO-M: medium-dose DIO group, with a concentration of 12 mg / mL (drug 2);

[0047] DIO-H: high-dose DIO group, with a concentration of 24 mg / mL (drug 3);

[0048] AP: allopurinol group, with a concentration of 12 mg / mL.

[0049] Figure 3 It is the effect diagram of the improvement result of DIO on gouty arthritis;

[0050] In the figure, KB: blank control group; Model: model group;

[0051] DIO: DIO group, with a concentration of 6 mg / mL (drug 1). Specific implementation manners

[0052] The present invention will be further described in detail below in combination with specific embodiments for those skilled in the art to understand.

[0053] Embodiment 1

[0054] The anti-gout drug 1 is obtained by dissolving diosgenin in a sodium carboxymethylcellulose solution with a mass fraction of 0.5%, and in drug 1, the content of diosgenin is 6 mg / mL.

[0055] Embodiment 2

[0056] The anti-gout drug 2 is obtained by dissolving diosgenin in a sodium carboxymethylcellulose solution with a mass fraction of 0.5%, and in drug 2, the content of diosgenin is 12 mg / mL.

[0057] Embodiment 3

[0058] The anti-gout drug 3 is obtained by dissolving diosgenin in a sodium carboxymethylcellulose solution with a mass fraction of 0.5%, and in drug 3, the content of diosgenin is 24 mg / mL.

[0059] The anti-gout drugs 1-3 prepared in the above Embodiments 1-3 are used for relevant experiments

[0060] 1. Verify the uric acid-lowering effect of DIO

[0061] 1.1 Experimental animals:

[0062] Male mice (SPF grade) with a body weight of 30±5 g are selected and start the experiment after 3 days of adaptive feeding.

[0063] 1.2 Model construction:

[0064] Except for the blank control group, the other groups are all gavaged with potassium oxonate at 200 mg / kg to construct a hyperuricemia model in mice. After 1 h, then referring to the body weight of the mice (administering 40-160 mg (DIO) / kg of the active ingredient per kilogram of weight), different volumes of the drug are administered, and they are respectively:

[0065] Low-dose DIO group (DIO-L): administer the anti-gout drug 1;

[0066] Medium-dose DIO group (DIO-M): Administer drug 2 for treating gout;

[0067] High-dose DIO group (DIO-H): Administer drug 3 for treating gout;

[0068] The model group and the blank control group (Blank) were given an equal amount of distilled water.

[0069] Allopurinol group (AP): Administer allopurinol at a concentration of 12 mg / mL.

[0070] 1.3 Detection indicators:

[0071] Detect the renal serum biochemical indicators (uric acid, urea nitrogen, creatinine), renal gene and protein expression, etc. of mice.

[0072] 1.4 Result analysis:

[0073] The experimental results showed that compared with the blank control group (Blank), the levels of serum uric acid (UA), urea nitrogen (UREA) and creatinine (CERA) in the model group (Model) mice were significantly increased, while diosgenin at different concentrations had the effect of reducing serum uric acid (UA), urea nitrogen (UREA) and creatinine (CERA), and had no side effects on renal function. Among them, the low-dose diosgenin group (DIO-L, drug 1 for treating gout) had the best effect. In contrast, for the positive control drug allopurinol (AP), although it had the effect of reducing uric acid, it could not reduce the CERA level and even increased the UREA level, indicating that it was harmful to renal function ( Figure 1 ). In addition, the active ingredient DIO in the drug for treating gout could significantly inhibit the gene and protein expression of GLUT9 and increase the gene and protein expression of OAT1, which would contribute to the excretion of renal uric acid ( Figure 2 ).

[0074] 2. Verify the anti-arthritis effect of DIO

[0075] 2.1 Experimental animals:

[0076] Thirty 6- to 7-week-old SPF-grade male SD rats with a body weight of 180 g to 220 g were selected.

[0077] 2.2 Model construction:

[0078] Thirty SD rats were randomly divided into 3 groups, with 10 rats in each group. Before the experiment, a circular mark was made on the right ankle joint of each rat with a black oil-based pen. Using this circular line as a mark, the joint and toes below the mark line were all immersed in the measuring device to obtain the ankle joint volume at that moment. The rats in the Model group were gavaged with potassium oxonate (1.5 g / kg) once a day, and the rats in the KB group were gavaged with an equal amount (1.5 g / kg) of sodium carboxymethylcellulose. This was done continuously for 9 days (throughout the entire test period). On the 5th day, an acute gouty arthritis model (AGA) was constructed referring to the Coderre method. At 15 min after injection, the rats were anesthetized with 3 mL / kg of 10% chloral hydrate by intraperitoneal injection. Then, a disposable sterile syringe was inserted at 30° - 45° behind the right ankle joint of the rats to the medial side of the Achilles tendon, and 0.4 mL of sodium urate solution (50 mg / mL) was injected into the joint cavity. Successful injection could be seen as a bulge on the opposite side of the joint capsule, and the rats showed symptoms of limping and ataxia. 60 min after modeling, the rats in each group were medicated as follows:

[0079] The KB group and the Model group: gavaged with an equal amount of sodium carboxymethylcellulose,

[0080] The DIO group: gavaged with gout treatment drug 1;

[0081] This was done continuously for 5 days, and the volume of the ankle joint was recorded. After the last day of gavage, the rats were fasted. 12 h later, they were weighed and anesthetized with chloral hydrate, and blood was collected from the abdominal aorta. Tissue samples of the joint part were collected.

[0082] 2.3 Result analysis:

[0083] In the KB group, the structure of the joint synovial cells was complete, arranged neatly, and there was no infiltration of inflammatory cells in the loose connective tissue; in the Model group, the joint synovial cells showed severe hyperplasia, the connective tissue under the synovial cells became dense due to the hyperplasia of collagen fibers, there was a large amount of lymphocyte infiltration in the synovium, and fibroblast hyperplasia. The synovial structure of the DIO group was restored compared with that of the Model group, and the infiltration of inflammatory cells in the stroma was significantly reduced. This indicates that the active ingredient DIO in gout treatment drug 1 can significantly relieve gouty arthritis and has good application potential for the treatment of acute gout.

[0084] Other parts not described in detail are all prior arts. Although the above embodiments have described the present invention in detail, they are only a part of the embodiments of the present invention, not all embodiments. People can also obtain other embodiments according to this embodiment without creative work, and these embodiments all belong to the protection scope of the present invention.

Claims

1. An application of diosgenin in preparing a drug for treating gout.

2. A drug for treating gout, characterized in that: The active ingredient of the medicine comprises diosgenin.

3. The gout treatment drug according to claim 2, characterized in that: In the gout treating medicine, the content of diosgenin is 6-24 mg / mL.

4. The gout treatment drug according to claim 3, characterized in that: In the gout treating medicine, the content of diosgenin is 6 mg / mL.

5. The gout treatment drug according to any one of claims 2 to 4, characterized in that: The medicament may further comprise pharmaceutically acceptable excipients.

6. The gout treatment drug according to claim 5, characterized in that: The auxiliary materials are any one or more of sodium carboxymethyl cellulose, fillers, disintegrants and lubricants.

7. The gout treatment drug according to claim 6, characterized in that: When the auxiliary material is sodium carboxymethyl cellulose, the concentration of sodium carboxymethyl cellulose is 0.1-1.0%.

8. The gout treatment drug according to claim 7, characterized in that: The concentration of the sodium carboxymethyl cellulose is 0.5%.

9. The gout treatment drug according to claim 5, characterized in that: The medicine is in the form of tablets, capsules or injections.

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