Application of traditional Chinese medicine composition in preparation of medicine for gout

Abstract

The invention relates to an application of a traditional Chinese medicine composition in preparation of a medicine for gout, which is characterized in that the traditional Chinese medicine composition is prepared from rehmannia root, cistanche, rhizoma cibotii, glossy privet fruit, epimedium, suberect spatholobus stem, radish seed, rhizoma drynariae and radix achyranthis bidentatae. The composition disclosed by the invention can be used for remarkably improving inflammatory response of a gout mouse model; the arthrocele of a mouse gout model caused by MSU and the level of IL-18 and caspase-1 in joint tissues can be obviously reduced. The total cell number, the percentage of neutrophil and the levels of IL-18 and IL-8 in mouse air sac lavage fluid are remarkably reduced, and it is prompted that the traditional Chinese medicine composition can remarkably inhibit the inflammatory reaction induced by MSU and has a good treatment effect on arthritis caused by gout.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine technology and relates to a new use of a traditional Chinese medicine composition, specifically the application of a traditional Chinese medicine composition in the preparation of a gout medication. Background Technology

[0002] Gout is a crystal-related arthropathy caused by the deposition of monosodium urate (MSU) in the joints. It is directly related to hyperuricemia caused by purine metabolism disorders and / or decreased uric acid excretion, and falls under the category of metabolic rheumatic diseases. In addition to joint damage, gout patients may also experience kidney disease and other manifestations of metabolic syndrome, such as hyperlipidemia, hypertension, diabetes, and coronary heart disease. Gout patients often experience sudden, severe pain in one or more joints, frequently starting at night. Symptoms may include joint redness, swelling, increased skin temperature, and a reddish-purple, tense, and shiny appearance of the skin on the joint surface. The initial attacks usually affect only one joint, lasting a few days and typically subsiding spontaneously within two weeks, with symptoms disappearing completely. However, if the condition worsens and is not treated aggressively after an attack, it can lead to more frequent attacks affecting multiple joints, with attacks lasting three weeks or longer. Repeated attacks can exacerbate gout and lead to chronic progression, causing deformities in the affected joints. Finally, the continuous deposition of urate crystals around the joints and tendons causes damage, gradually restricting joint movement.

[0003] Gout is a global disease, with varying prevalence rates across different countries and regions. my country currently lacks nationwide epidemiological survey data, but reports from different periods and regions indicate that the prevalence of gout in my country is showing an upward trend year by year. In light of these issues, the field of traditional Chinese medicine should actively participate in the prevention and treatment of gout, developing and researching appropriate prescriptions. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides an application of a traditional Chinese medicine composition in the preparation of a gout medication. This composition is derived from Rehmannia glutinosa, Cistanche deserticola, Cibotium barometz, Ligustrum lucidum, Epimedium brevicornu, Spatholobus suberectus, Raphanus sativus, Drynaria fortunei, and Achyranthes bidentata. The term "used for" can refer to any method beneficial to improving the corresponding symptoms of the patient, including treatment or prevention.

[0005] Specifically, the treatment for gout includes significantly inhibiting the inflammatory response in an MSU-induced mouse model of gouty arthritis, including reducing joint swelling, decreasing IL-18 and caspase-1 levels in joint tissues, reducing the total number of cells and the percentage of neutrophils in the lavage fluid of a mouse air sac model, and inhibiting IL-18 and IL-8 levels.

[0006] Furthermore, the traditional Chinese medicine composition comprises: 150-200 parts of Rehmannia glutinosa, 100-150 parts of Cistanche deserticola, 100-150 parts of Cibotium barometz, 50-100 parts of Ligustrum lucidum, 100-150 parts of Epimedium brevicornu, 100-150 parts of Spatholobus suberectus, 50-100 parts of Raphanus sativus, 100-150 parts of Drynaria fortunei, and 100-150 parts of Achyranthes bidentata. The composition of this invention can be directly ground into powder, or it can be an extract obtained through conventional methods in the art. The traditional Chinese medicines used in the composition of this invention can also be used by directly grinding into powder, extracting, or in other processed forms.

[0007] Furthermore, the traditional Chinese medicine composition includes: 170-180 parts of Rehmannia glutinosa, 110-120 parts of Cistanche deserticola, 110-120 parts of Cibotium barometz, 50-60 parts of Ligustrum lucidum, 110-120 parts of Epimedium brevicornu, 110-120 parts of Spatholobus suberectus, 50-60 parts of Raphanus sativus, 110-120 parts of Drynaria fortunei, and 110-120 parts of Achyranthes bidentata.

[0008] Preferably, the traditional Chinese medicine composition includes: 175 parts of Rehmannia glutinosa, 117 parts of Cistanche deserticola, 117 parts of Cibotium barometz, 58 parts of Ligustrum lucidum, 117 parts of Epimedium brevicornu, 117 parts of Spatholobus suberectus, 58 parts of Raphanus sativus, 117 parts of Drynaria fortunei, and 117 parts of Achyranthes bidentata.

[0009] In some embodiments, the aforementioned medicament further includes a medically acceptable carrier and / or excipient. Specifically, the carrier or excipient may be a commonly used carrier or excipient in the art, including fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents, preservatives, and matrices, including but not limited to starch, lactose, glucose, sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose, malt, gelatin, polyols (such as propylene glycol, glycerol, mannitol), tablets, etc., to help improve the stability or activity of the pharmaceutical composition, or to produce an acceptable taste or odor when taken orally.

[0010] In some embodiments, the composition can be prepared into granules, tablets, capsules, pills, oral solutions, oral suspensions, or oral emulsions using existing traditional Chinese medicine preparation methods. This facilitates clinical administration.

[0011] Furthermore, the preparation method of the traditional Chinese medicine composition includes taking 2 / 3 of the above-mentioned Rehmannia glutinosa, Cibotium barometz, and 1 / 2 of the above-mentioned Epimedium brevicornu and pulverizing them into fine powder. Then, the remaining 1 / 3 of the Rehmannia glutinosa, 1 / 2 of the Epimedium brevicornu, Spatholobus suberectus, steamed Cistanche deserticola, Raphanus sativus, Drynaria fortunei, Ligustrum lucidum, and Achyranthes bidentata are decocted twice with water, each time for 1.5 hours. The decoction is filtered, the filtrates are combined, concentrated to an appropriate amount, the above-mentioned fine powder is added, mixed well, dried, and pulverized.

[0012] When the composition of this invention is used as a medication for treating gout, it can be administered as an oral solution. For severe cases, one dose is given daily, divided into 2-3 oral or nasal feedings, every 6-8 hours. For critically ill cases, two doses are given daily, divided into morning and evening oral or nasal feedings, every 8-12 hours. For mild cases, one dose is given daily, orally or via nasal feeding. Each dose is 150-250 ml.

[0013] When the drug is in the form of granules or tablets, the dosage is converted to the dosage of the prepared herbal medicine and administered by dissolving in water.

[0014] Clinical trials have demonstrated that the pharmaceutical composition of this invention can significantly reduce the severity of patient deterioration, especially for severely and critically ill patients. Furthermore, it also exhibits a certain therapeutic effect on severely and critically ill patients.

[0015] The composition of this invention can significantly improve the inflammatory response in a mouse model of gout; it can significantly reduce joint swelling and the levels of IL-18 and caspase-1 in joint tissues in a mouse model of gout induced by MSU. It also significantly reduces the total cell count, neutrophil percentage, and IL-18 and IL-8 levels in the air sac lavage fluid of mice, suggesting that the traditional Chinese medicine composition can significantly inhibit the MSU-induced inflammatory response and has a good therapeutic effect on arthritis caused by gout. Detailed Implementation

[0016] As mentioned above, the present invention aims to provide an application of a traditional Chinese medicine composition in the preparation of a gout medication. The following will describe this in detail with reference to specific experiments.

[0017] Unless otherwise specified, all experiments in the following experiments were conducted under standard conditions or conditions recommended by the manufacturer. The raw materials or excipients used, as well as the reagents or instruments whose manufacturers are not specified, are all commercially available products. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight. Unless otherwise specified, the medicinal materials of this invention can be either raw or processed products, provided that the overall effect of the prescription is not significantly affected.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to this invention.

[0019] Example 1: Preparation of the Traditional Chinese Medicine Composition

[0020] Take 175 parts of Rehmannia glutinosa (processed), 117 parts of Cistanche deserticola (processed with wine), 117 parts of Cibotium barometz (processed with salt), 58 parts of Ligustrum lucidum (processed with salt), 117 parts of Epimedium brevicornu, 117 parts of Spatholobus suberectus, 58 parts of Raphanus sativus (fried), 117 parts of Drynaria fortunei, and 117 parts of Achyranthes bidentata. Take 2 / 3 of the above-mentioned Rehmannia glutinosa (processed), Cibotium barometz (processed with salt), and 1 / 2 of the above-mentioned Epimedium brevicornu and grind them into fine powder. Then, take the remaining 1 / 3 of the Rehmannia glutinosa (processed), 1 / 2 of the above-mentioned Epimedium brevicornu, Spatholobus suberectus, Cistanche deserticola (processed with wine), Raphanus sativus (fried), Drynaria fortunei, Ligustrum lucidum (processed with salt), and Achyranthes bidentata and decoct them twice with water, 1.5 hours each time. Filter the decoction, combine the filtrates, concentrate to an appropriate amount, add the above-mentioned fine powder, mix well, dry, and grind into fine powder to obtain the Chinese medicine composition. Add an appropriate amount of maltodextrin, mix well, granulate, and obtain the Chinese medicine composition granules, which are then filled into capsule shells.

[0021] Experimental Example 2: Therapeutic Effect of Traditional Chinese Medicine Composition on MSU-Induced Gouty Arthritis Model in Mice 1. Experimental Materials

[0022] 1.1 Animals

[0023] ICR mice, SPF grade, 60 mice, weighing 18-22g, male.

[0024] Rearing environment: Room temperature 20-26℃, relative humidity controlled at 40-70%. 5 animals per cage.

[0025] 1.2 Drugs

[0026] The traditional Chinese medicine composition capsules prepared in Example 1 were from Jiangsu Kangyuan Pharmaceutical Co., Ltd.; sodium monourate crystals were from Sigma-Aldrich; and celecoxib capsules were from Jiangsu Hengrui Medicine Co., Ltd.

[0027] 1.3 Instruments

[0028] Electronic balance (Sartorius Scientific Instruments, model BS224S); Electronic balance (G&G, model TC3K). Vernier calipers. Microplate reader (McGen Microplate, model Flexstation 3).

[0029] 2. Dosage design

[0030] The daily dosage of the traditional Chinese medicine composition is 5.25g of crude drug / day. Based on the body surface area reduction method, the equivalent dose for mice is 5.25g / 60kg*12.3 = 1.08g of crude drug / kg. Following a 1 / 4:1 / 2:1 dosing regimen, the low dose is 0.54g of crude drug / kg, the medium dose is 1.08g of crude drug / kg, and the high dose is 2.16g of crude drug / kg. Administration is by gavage at a dose of 0.2mL / 10g. The daily dosage of celecoxib for treating arthritis is 200mg / day. Based on the body surface area reduction method, the equivalent dose for mice is 200mg / 60kg*12.3 = 40mg / kg.

[0031] 3. Experimental Methods

[0032] ICR mice were acclimatized for 3 days with free access to food and water. They were then randomly divided into four groups according to body weight: a normal control group, a model control group, high-, medium-, and low-dose groups of the traditional Chinese medicine composition, and a positive control group, with 10 mice in each group.

[0033] Thirty minutes before modeling, mice were given drug intervention, with each treatment group receiving 0.2 mL / 10 g via gavage. The normal control and model groups received an equal volume of solvent. Joint thickness was measured and recorded in each group before modeling. Thirty minutes after drug administration, mice in the model and treatment groups were injected with 30 μl of 20 mg / mL MSU solution into the sole of their paws, while the normal control group received an equal volume of solvent. Joint thickness was measured using calipers six hours after modeling. Animals were sacrificed, and joint tissue was collected to detect IL-18 and caspase-1 activities.

[0034] Joint swelling degree (mm) = Joint thickness 6 hours after modeling (mm) - Joint thickness before modeling (mm)

[0035] 4. Statistical Methods

[0036] Quantitative indicators were first tested for homogeneity of variance using the LEVENE test. If the variances were homogeneous (P>0.05), one-way ANOVA was used for statistical analysis. If the variances were unequal (P≤0.05), the Kruskal-Wallis H rank-sum test (KW method) was used. When one-way ANOVA showed statistically significant differences (P≤0.05), Dunnett's t-test (Dunnett method) was used to compare differences between groups. When one-way ANOVA showed no statistically significant differences (P>0.05), the statistical analysis was terminated. When the Kruskal-Wallis H rank-sum test showed statistically significant differences (P≤0.05), the Mann-Whitney U test (MW method) was used to compare differences between groups. When the Kruskal-Wallis H rank-sum test showed no statistically significant differences (P>0.05), the statistical analysis was terminated.

[0037] 5. Experimental Results

[0038] Compared with the normal control group, the joint swelling of mice in the model group was significantly increased (P<0.001), and the activities of IL-18 and caspase-1 in the joint tissues of mice were significantly increased (P<0.001). Compared with the model control group, the joint swelling of the high, medium, and low dose groups was significantly reduced, with statistical differences (P<0.001). In addition, the high, medium, and low dose groups of the traditional Chinese medicine composition significantly inhibited the level of IL-18 and the activity of caspase-1 in the joint tissues. See Table 1-2.

[0039] Table 1: Effects of MSU on joint swelling in a mouse model of gouty arthritis.

[0040]

[0041] Note: Compared with the normal control group, ### P<0.001; compared with the model control group, ***P<0.001; data are expressed as mean±SD.

[0042] Table 2: Effects of MSU on IL-18 levels and caspase-1 activity in a mouse model of gouty arthritis.

[0043]

[0044] Note: Compared with the normal control group, ### P<0.001; compared with the model control group, ***P<0.001; data are expressed as mean±SD.

[0045] 6. Experimental Conclusions

[0046] The traditional Chinese medicine composition significantly inhibited joint swelling in a mouse model of MSU-induced gouty arthritis and reduced IL-18 levels and caspase-1 activity in joint tissues, suggesting that the traditional Chinese medicine composition has a certain therapeutic effect on MSU-induced gouty arthritis in mice.

[0047] Example 3: Protective effect of traditional Chinese medicine composition on MSU-induced mouse air sac model. 1. Experimental materials.

[0048] 1.1 Animals

[0049] BABL / c mice, SPF grade, 60 mice, weighing 18-20g, female.

[0050] Rearing environment: Room temperature 20-26℃, relative humidity controlled at 40-70%. 5 animals / sex / group per cage.

[0051] 1.2 Drugs

[0052] The traditional Chinese medicine composition capsules were prepared according to the method of Example 1 and were provided by Jiangsu Kangyuan Pharmaceutical Co., Ltd.; sodium monourate crystals were from Sigma-Aldrich; celecoxib capsules were from Jiangsu Hengrui Medicine Co., Ltd.; and isoflurane was from Shenzhen Ruiwode Life Technology Co., Ltd.

[0053] 1.3 Instruments

[0054] Electronic balance (Sartorius Scientific Instruments, model BS224S); Electronic balance (G&G, model TC3K); Low-temperature centrifuge (Eppendorf, Germany, model 5804R); Microplate reader (McGen, USA, model Flexstation 3); Small animal gas anesthesia machine (Shenzhen Ruiwode Life Science Technology Co., Ltd., model R500); Flow cytometer (Agilent, model NovoCyte3000).

[0055] 2. Dosage design

[0056] The daily dosage of the traditional Chinese medicine composition is 5.25g of crude drug / day. Based on the body surface area reduction method, the equivalent dose for mice is 5.25g / 60kg*12.3 = 1.08g of crude drug / kg. Following a 1 / 4:1 / 2:1 dosing regimen, the low dose is 0.54g of crude drug / kg, the medium dose is 1.08g of crude drug / kg, and the high dose is 2.16g of crude drug / kg. Administration is by gavage at a dose of 0.2mL / 10g. The daily dosage of celecoxib for treating arthritis is 200mg / day. Based on the body surface area reduction method, the equivalent dose for mice is 200mg / 60kg*12.3 = 40mg / kg.

[0057] 3. Experimental Methods

[0058] BABL / c mice were acclimatized for 3 days with free access to food and water. They were then randomly divided into four groups according to body weight: a normal control group, a model control group, high-, medium-, and low-dose groups of the traditional Chinese medicine composition, and a positive control group, with 10 mice in each group.

[0059] On days 1 and 3 before modeling, mice were anesthetized with isoflurane, and 3 mL of sterile air was injected subcutaneously into their backs to create air sacs. Drug intervention began on day 1 of modeling, administered orally to one mouse daily for 7 consecutive days. The normal control group and the model group received the same volume of solvent. One hour after the last administration on day 7 of modeling, mice in the model and drug-treated groups were injected into their air sacs with PBS solution containing 3 mg of MSU, while the normal control group received the same volume of PBS. Six hours later, the experiment concluded, and the irrigation fluid was collected for cytokine detection and cell count staining.

[0060] 4. Statistical Methods

[0061] Quantitative indicators were first tested for homogeneity of variance using the LEVENE test. If the variances were homogeneous (P>0.05), one-way ANOVA was used for statistical analysis. If the variances were unequal (P≤0.05), the Kruskal-Wallis H rank-sum test (KW method) was used. When one-way ANOVA showed statistically significant differences (P≤0.05), Dunnett's t-test (Dunnett method) was used to compare differences between groups. When one-way ANOVA showed no statistically significant differences (P>0.05), the statistical analysis was terminated. When the Kruskal-Wallis H rank-sum test showed statistically significant differences (P≤0.05), the Mann-Whitney U test (MW method) was used to compare differences between groups. When the Kruskal-Wallis H rank-sum test showed no statistically significant differences (P>0.05), the statistical analysis was terminated.

[0062] 5. Experimental Results

[0063] Compared with the normal control group, the total cell count and neutrophil percentage in the air sac lavage fluid of mice were significantly increased, with statistically significant differences (P<0.01). Furthermore, the levels of IL-18 and IL-8 in the air sac lavage fluid of the model group were significantly increased. Compared with the model control group, the total cell count and neutrophil percentage in the air lavage fluid of the high, medium, and low dose groups were significantly decreased (P<0.01). Compared with the model control group, IL-8 in the air lavage fluid of the high, medium, and low dose groups was significantly decreased (P<0.01); IL-18 in the air lavage fluid of the high and medium dose groups was significantly decreased (P<0.01).

[0064] Table 3: Effects on cell counts in lavage fluid of mouse air sac model

[0065]

[0066] Note: Compared with the normal control group, ### P<0.001; compared with the model control group, *P<0.05, ***P<0.001; data are expressed as mean±SD.

[0067] Table 4: Effects of IL-18 and IL-8 on the lavage fluid of a mouse air sac model

[0068]

[0069] 6. Experimental Conclusions

[0070] The traditional Chinese medicine composition significantly inhibited the total number of cells and the percentage of centrifuges in the lavage fluid of a mouse air sac model, and reduced the levels of IL-18 and IL-8 in the lavage fluid, suggesting that the traditional Chinese medicine composition has a certain therapeutic effect on gouty arthritis in mice.

[0071] The above embodiments of the present invention are merely examples to clearly illustrate the present invention and are not intended to limit the implementation of the present invention. Those skilled in the art can make other variations or modifications based on the above description. It is neither necessary nor possible to exhaustively describe all embodiments here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. The application of a traditional Chinese medicine composition in the preparation of a gout medication, characterized in that, The traditional Chinese medicine composition is made from the following components: 150-200 parts of Rehmannia glutinosa, 100-150 parts of Cistanche deserticola, 100-150 parts of Cibotium barometz, 50-100 parts of Ligustrum lucidum, 100-150 parts of Epimedium brevicornu, 100-150 parts of Spatholobus suberectus, 50-100 parts of Raphanus sativus, 100-150 parts of Drynaria fortunei, and 100-150 parts of Achyranthes bidentata.

2. The application according to claim 1, characterized in that, The traditional Chinese medicine composition, by weight, is made from the following components: 170-180 parts of Rehmannia glutinosa, 110-120 parts of Cistanche deserticola, 110-120 parts of Cibotium barometz, 50-60 parts of Ligustrum lucidum, 110-120 parts of Epimedium brevicornu, 110-120 parts of Spatholobus suberectus, 50-60 parts of Raphanus sativus, 110-120 parts of Drynaria fortunei, and 110-120 parts of Achyranthes bidentata.

3. The application according to claim 1, characterized in that, The traditional Chinese medicine composition, by weight, is made from the following components: 175-180 parts of Rehmannia glutinosa, 115-120 parts of Cistanche deserticola, 115-120 parts of Cibotium barometz, 55-60 parts of Ligustrum lucidum, 115-120 parts of Epimedium brevicornu, 115-120 parts of Spatholobus suberectus, 55-60 parts of Raphanus sativus, 115-120 parts of Drynaria fortunei, and 115-120 parts of Achyranthes bidentata.

4. The application according to claim 1, characterized in that, The traditional Chinese medicine composition is made from the following components: 175 parts Rehmannia glutinosa, 117 parts Cistanche deserticola, 117 parts Cibotium barometz, 58 parts Ligustrum lucidum, 117 parts Epimedium brevicornu, 117 parts Spatholobus suberectus, 58 parts Raphanus sativus, 117 parts Drynaria fortunei, and 117 parts Achyranthes bidentata.

5. The application according to any one of claims 1-4, characterized in that, Medications used for gout include pharmaceutically acceptable excipients or additives.

6. The application as described in claim 5, characterized in that, Pharmaceutically acceptable excipients or additives include fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents, preservatives, and matrices.

7. The application according to claim 6, characterized in that, The dosage forms of the gout medication include oral dosage forms, injectable dosage forms, or topical dosage forms.

8. The application according to claim 7, characterized in that, The dosage forms of the gout medication include tablets, granules, capsules, pills, or drop pills.

9. The application according to any one of claims 1-4, characterized in that, The preparation method of the traditional Chinese medicine composition includes: taking 2 / 3 of the above-mentioned Rehmannia glutinosa, Cibotium barometz, and 1 / 2 of the above-mentioned Epimedium brevicornu and pulverizing them into fine powder; then, taking the remaining 1 / 3 of the Rehmannia glutinosa, 1 / 2 of the Epimedium brevicornu, Spatholobus suberectus, steamed Cistanche deserticola, Raphanus sativus, Drynaria fortunei, Ligustrum lucidum and Achyranthes bidentata and decocting them twice with water, each time for 1.5 hours; filtering the decoction; combining the filtrates; concentrating to an appropriate amount; adding the above-mentioned fine powder; mixing well; drying; and pulverizing.

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