Application of sinomenine in the preparation of drugs for the prevention and / or treatment of obesity and related metabolic syndrome

Abstract

This invention belongs to the field of drug and disease treatment technology, specifically relating to the application of sinomenine in the preparation of drugs for the prevention and / or treatment of obesity and related metabolic syndromes. The research results of this invention show that sinomenine can reduce the body weight and blood lipids in high-fat diet-induced obese mice. Through multi-target synergy of "inhibiting lipogenesis, promoting thermogenics, anti-inflammatory and hepatoprotective effects, and improving glucose and lipid metabolism," sinomenine achieves a triple breakthrough for the first time in a single natural molecule: "highly effective weight loss without rebound, comprehensive lipid regulation without liver damage, and no toxicity with long-term oral administration." This provides a safe, effective, and long-term usable new technical pathway for the preparation of drugs or functional foods for obesity, hyperlipidemia, and non-alcoholic fatty liver disease.

Description

Technical Field

[0001] This invention belongs to the field of drug and disease treatment technology, specifically relating to the application of sinomenine in the preparation of drugs for the prevention and / or treatment of obesity and related metabolic syndrome. Background Technology

[0002] Obesity is a chronic, complex disease defined as the excessive deposition of fat that can lead to health problems. Obesity increases the risk of type 2 diabetes and heart disease, affects bone health and the reproductive system, and increases the risk of certain cancers. Obesity also impacts quality of life, such as sleep and activity levels.

[0003] The primary treatment for obesity is weight loss. Currently, weight loss methods include a healthy diet, portion control, and exercise; some patients may consider bariatric surgery or medication. Medications currently used to treat obesity include orlistat capsules, lorcaserin, phenbutylbromide, topiramate (qsymia) extended-release capsules, naltrexone hydrochloride, bupropion hydrochloride combined extended-release tablets (contrave), and liraglutide injection. Although some medications are currently used clinically for the long-term treatment of obesity, the safety profile of existing drugs hinders their clinical application. Summary of the Invention

[0004] To address the problem that existing drugs for treating obesity have low safety profiles, hindering their clinical application, this invention provides the use of sinomenine in the preparation of weight-loss drugs.

[0005] To achieve the above objectives, the present invention adopts the following technical solution: This invention provides the use of sinomenine in the preparation of medicaments for the prevention and / or treatment of obesity and related metabolic syndromes. The structural formula of sinomenine is as follows:

[0006] .

[0007] The sinomenine provided by this invention integrates five differentiated advantages within a single natural molecule: "inhibition of fat synthesis + promotion of adaptive thermogenesis + zero-stimulation anti-inflammatory effect between the gut and liver + broad-spectrum lipid regulation + non-toxicity with long-term oral administration." This offers a novel intervention pathway that is "highly effective, safe, and suitable for lifelong use" for obesity, hyperlipidemia, non-alcoholic fatty liver disease, and metabolic syndrome complicated by glucose intolerance. Furthermore, sinomenine itself is a natural alkaloid; its preparation as a drug demonstrates high safety and will not hinder its clinical application.

[0008] Furthermore, the drug uses sinomenine as the active ingredient and is supplemented with pharmaceutically acceptable excipients or carriers.

[0009] Furthermore, the drug is in liquid form.

[0010] Furthermore, the drug is a solution or suspension.

[0011] Furthermore, the excipients of the solution are selected from at least one of water, physiological saline, anhydrous ethanol, sucrose, phosphate buffer, and glycerol; the excipients of the suspension are selected from at least one of water, sodium alginate, methylcellulose, sodium dodecyl sulfate, and vitamin C.

[0012] Furthermore, the solution is prepared by combining the sinomenine and physiological saline.

[0013] Furthermore, the concentration of sinomenine in the solution is 0.8 mg / mL to 20 mg / mL. The dosage concentration is 4 mg / kg to 100 mg / kg.

[0014] Furthermore, the obesity and related metabolic syndrome includes obesity-related liver complications, such as non-alcoholic steatohepatitis, liver fibrosis, or cirrhosis.

[0015] The present invention has the following beneficial effects: The purpose of this invention is to provide a use of sinomenine in the preparation of weight-loss drugs and to provide a new method for weight loss. The sinomenine provided by this invention is the first to integrate five major differentiated advantages within a single natural molecule: "inhibition of fat synthesis + promotion of adaptive thermogenesis + entero-hepatic zero-stimulation anti-inflammatory + broad-spectrum lipid regulation + long-term oral non-toxicity." This provides a novel intervention pathway that is "highly effective, safe, and can be taken for life" for obesity, hyperlipidemia, non-alcoholic fatty liver disease, and metabolic syndrome complicated with impaired glucose tolerance. Furthermore, sinomenine itself is a natural alkaloid; its preparation as a drug has high safety and will not hinder its clinical application. Attached Figure Description

[0016] Figure 1 This is the structural formula of sinomenine in this invention.

[0017] Figure 2 This is a diagram showing the weight loss results of sinosteroids in this invention; wherein: A is a schematic diagram of the mouse obesity model construction and the sinomenine administration regimen; B represents the weight loss in obese mice during administration of sinomenine, where # indicates the difference between sin-M and the model group. P <0.05, ## indicates that sin-M is compared with the model group. P <0.01, ### indicates that sin-M is compared with the model group. P <0.001, * indicates that sin-H is compared with the model group. P<0.05, ** indicates that sin-H is lower than that of the model group. P <0.01, *** indicates that sin-H is lower than that of the model group. P <0.001; C represents the change in body weight of obese mice during the administration of sinomenine; where # indicates the difference between sin-M and the model group. P <0.05, ## indicates that sin-M is compared with the model group. P <0.01, ### indicates that sin-M is compared with the model group. P <0.001, * indicates that sin-H is compared with the model group. P <0.05, ** indicates that sin-H is lower than that of the model group. P <0.01, *** indicates that sin-H is lower than that of the model group. P <0.001.

[0018] Figure 3 The figure shows the changes in blood glucose in mice after intervention with sinomenine in this invention; where * indicates the difference between each group and the model group. P <0.05, ** indicates that each group is compared to the model group. P <0.01, *** indicates that compared to the model group, each group has a lower value. P <0.001.

[0019] Figure 4 The figure shows the change in total cholesterol in mice after intervention with sinomenine in this invention; where * indicates the difference between each group and the model group. P <0.05, ** indicates that each group is compared to the model group. P <0.01, *** indicates that compared to the model group, each group has a lower value. P <0.001.

[0020] Figure 5 The changes in triglycerides in mice after intervention with sinomenine in this invention are shown; where * indicates the difference between each group and the model group. P <0.05, ** indicates that each group is compared to the model group. P <0.01, *** indicates that compared to the model group, each group has a lower value. P <0.001.

[0021] Figure 6 The changes in high-density lipoprotein in mice after intervention with sinomenine in this invention are shown; where * indicates the difference between each group and the model group. P <0.05, ** indicates that each group is compared to the model group. P <0.01, *** indicates that compared to the model group, each group has a lower value. P <0.001.

[0022] Figure 7The changes in low-density lipoprotein in mice after intervention with sinomenine in this invention are shown; where * indicates the difference between each group and the model group. P <0.05, ** indicates that each group is compared to the model group. P <0.01, *** indicates that compared to the model group, each group has a lower value. P <0.001. Detailed Implementation

[0023] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments, but this should not be construed as limiting the invention. Unless otherwise specified, the technical means used in the following embodiments are conventional means well known to those skilled in the art, and the materials, reagents, etc. used in the following embodiments are commercially available unless otherwise specified.

[0024] Example 1 I. Methods 1. Establishment of experimental animals and models Establishment of a mouse obesity model: Before the experiment, C57BL / 6 mice were housed separately in plastic cages in the experimental environment, with free access to food and water for 7 days to allow them to acclimatize. After acclimatization, they were randomly divided into two groups: a control group of 6 mice, which continued to be fed a basal diet; and a high-fat model group of 24 mice, which were fed a high-fat diet. At the same time, the model group was given high-sugar drinking water (42 g / L of carbohydrates, composed of sucrose and fructose, with a weight ratio of 45:55 for sucrose).

[0025] The model was established for 4 months. Body weight was measured weekly. Successful modeling was defined as the body weight of rats in the high-fat model group exceeding that of rats in the control group by at least 20%. Six mice were randomly assigned to each group: the model group, the high-dose model treatment group, the medium-dose model treatment group, and the low-dose model treatment group.

[0026] The specific processing methods for each of the above groups are as follows: Model group: high-fat diet + high-sugar drinking water + intraperitoneal injection of physiological saline.

[0027] High-dose treatment group in the model: high-fat diet + high-sugar drinking water + intraperitoneal injection of 100 mg / (kg·d) sinomenine.

[0028] Medium-dose administration group: high-fat diet + high-sugar drinking water + intraperitoneal injection of 20 mg / (kg·d) sinomenine.

[0029] Low-dose administration group: high-fat diet + high-sugar drinking water + intraperitoneal injection of sinomenine 4 mg / (kg·d).

[0030] The C57BL / 6 mice were purchased from Jiangsu Huachuang Xinno Pharmaceutical Technology Co., Ltd., and were raised under strict hygiene and good ventilation conditions, with free access to food and water.

[0031] The conditions for raising the animals are as follows: Specific Pathogen Free Animals (SPF), temperature of 23.5℃±2.5℃, humidity of 55%±5%, and a diurnal light cycle (12h light, 12h darkness).

[0032] All animal experiments in this invention were approved by the Animal Welfare Committee of Xi'an People's Hospital (Xi'an Fourth Hospital).

[0033] Qingteng alkaloid was purchased from Taoshu Biotechnology Co., Ltd., CAS No. 115-53-7, structural formula as follows: Figure 1 As shown.

[0034] The basic feed refers to the maintenance feed for rats and mice, which was purchased from Wuhan Wanqianjiaxing Biotechnology Co., Ltd.

[0035] The high-fat feed was purchased from Nantong Trofi Feed Technology Co., Ltd., and contains the following nutritional components by mass fraction: fat 42%, protein 14%, carbohydrates 44%, and cholesterol 0.2%.

[0036] 2. Administration method After grouping, the control group continued to be given a basal diet with free access to food daily, while the other experimental groups were given a high-fat diet daily and simultaneously began receiving the drug. The test compound groups, sino-L (low-dose model group), sino-M (medium-dose model group), and sino-H (high-dose model group), were administered intraperitoneally at doses of 4 mg / (kg·d), 20 mg / (kg·d), and 100 mg / (kg·d), respectively. Mice in the high-fat model group received an equal volume of physiological saline intraperitoneally. All groups received these injections for three consecutive weeks. Food intake was measured daily, and body weight was measured every three days. Body weight and weight gain were observed and recorded for each group.

[0037] In the high-dose model group, mice were injected intraperitoneally with sinomenine at a dose of 100 mg / (kg·d).

[0038] Mice in the model medium-dose group were intraperitoneally injected with sinomenine at a dose of 20 mg / (kg·d).

[0039] Mice in the low-dose treatment group were injected intraperitoneally with sinomenine at a dose of 4 mg / (kg·d).

[0040] 3. Experimental Data Detection and Processing Detection Indicators Blood was collected from the orbital vein of mice after anesthetizing them with isoflurane. After standing at room temperature, the blood was centrifuged at 3000 r / min for 10 min. The serum was then collected and placed in a -20℃ refrigerator for testing. After blood processing, serum total cholesterol, total triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were determined by enzyme colorimetric assay using a kit.

[0041] Serum total cholesterol: TC.

[0042] Total triglycerides: TG.

[0043] High-density lipoprotein cholesterol: HDL.

[0044] Low-density lipoprotein cholesterol: LDL.

[0045] II. Results 1. Tendrine reduces the body weight of mice with high-fat diet-induced obesity. Three weeks after administration of sinomenine, high- and medium-dose interventions with sinomenine significantly reduced the body weight of obese mice (e.g., Figure 2 As shown in the figure, low-dose intervention showed a certain trend of reducing mouse body weight. Therefore, it can be concluded that sinomenine can significantly reduce the body weight of obese mice induced by a high-fat diet.

[0046] 2. Tendrine reduces blood glucose and blood lipids in high-fat diet-induced obese mice. Three weeks after administration of sinomenine, high-dose intervention significantly improved blood glucose, total cholesterol (TC), triglycerides (TG), low-dose LDL, and high-HDL in obese mice, while medium-dose significantly improved TC, TG, and HDL. Low-dose intervention showed some improvement in TC and HDL (e.g., ...). Figures 3-7 (As shown).

[0047] As shown above, sinomenine reduces blood glucose and blood lipids in mice with high-fat diet-induced obesity.

[0048] The purpose of this invention is to provide a use of sinomenine in the preparation of weight-loss drugs and to provide a new method for weight loss. The sinomenine provided by this invention is the first to integrate five major differentiated advantages within a single natural molecule: "inhibition of fat synthesis + promotion of adaptive thermogenesis + entero-hepatic zero-stimulation anti-inflammatory + broad-spectrum lipid regulation + long-term oral non-toxicity." This provides a novel intervention pathway that is "highly effective, safe, and can be taken for life" for obesity, hyperlipidemia, non-alcoholic fatty liver disease, and metabolic syndrome complicated with impaired glucose tolerance. Furthermore, sinomenine itself is a natural alkaloid; its preparation as a drug has high safety and will not hinder its clinical application.

[0049] It should be noted that when numerical ranges are involved in this invention, it should be understood that the two endpoints of each numerical range and any value between the two endpoints can be selected. To avoid redundancy, this invention describes preferred embodiments.

[0050] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments, all of which fall within the scope of the invention.

Claims

1. The use of sinomenine in the preparation of drugs for the prevention and / or treatment of obesity and related metabolic syndrome, characterized in that, The structural formula of sinomenine is as follows: 。 2. The application according to claim 1, characterized in that, The drug uses sinomenine as its active ingredient and is supplemented with pharmaceutically acceptable excipients.

3. The application according to claim 2, characterized in that, The drug is in liquid form.

4. The application according to claim 3, characterized in that, The drug is a solution or suspension.

5. The application according to claim 4, characterized in that, The excipients of the solution are selected from at least one of water, physiological saline, anhydrous ethanol, sucrose, phosphate buffer, and glycerol; the excipients of the suspension are selected from at least one of water, sodium alginate, methylcellulose, sodium dodecyl sulfate, and vitamin C.

6. The application according to claim 5, characterized in that, The solution is prepared by combining sinomenine and physiological saline.

7. The application according to claim 6, characterized in that, The concentration of sinomenine in the solution is 0.8 mg / mL to 20 mg / mL.

8. The application according to claim 1, characterized in that, The obesity and related metabolic syndrome includes obesity-related liver complications, including non-alcoholic steatohepatitis, liver fibrosis, or cirrhosis.

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