A sodium humate preparation for treating venous thrombosis and its composition

Abstract

The present invention provides a sodium humate preparation and its composition for treating venous thrombosis, belonging to the technical field of cardiovascular treatment. Through experiments, the present invention discovers that when sodium humate is used to treat venous thrombosis, it can effectively reduce the thrombus formation rate and thrombus length of venous thrombosis. Therefore, sodium humate can be used to prepare drugs for treating venous thrombosis. Secondly, the present invention discovers that when sodium humate and rivaroxaban are used in combination, they can produce a synergistic effect on the inhibition of venous thrombosis. Therefore, sodium humate can be used to prepare an enhancer of rivaroxaban to better exert the effect of rivaroxaban.

Description

Technical Field

[0001] The present invention belongs to the technical field of cardiovascular treatment, and particularly relates to a sodium humate preparation for treating venous thrombosis and its composition. Background Art

[0002] Venous thromboembolism (VTE) has become an important thromboembolic disease after myocardial infarction and stroke. The number of affected people worldwide exceeds one million every year, and it has become a major global public health problem. At the same time, whether in Western countries or Asian countries, the annual prevalence rate of VTE shows a gradually increasing trend. Currently available drugs have characteristics such as low prevention and treatment rates and high bleeding risks. Therefore, developing new thrombus treatment targets and safe, effective, and convenient antithrombotic drugs has important clinical research significance.

[0003] Humic acid is a humic substance formed by a series of complex chemical changes such as the decay of animal and plant residues. Natural humic acid is a non-toxic, odorless, and non-corrosive organic acid, and is obtained by extraction from lignite, weathered coal, and peat together with water-soluble multifunctional polymers and compounds.

[0004] Sodium humate is a soluble sodium salt of humic acid, containing active groups such as hydroxyl groups and carboxylates, and has multiple functions such as ion exchange, adsorption, flocculation, dispersion, and adhesion. At the same time, it has good effects as a compound fertilizer, feed additive, etc. However, so far, no reports have been found on the use of sodium humate for treating venous thrombosis. Summary of the Invention

[0005] The purpose of the present invention is to provide a sodium humate preparation for treating venous thrombosis and its composition.

[0006] To achieve the above purpose, the present invention provides the following technical solutions:

[0007] The present invention provides the application of sodium humate in the preparation of drugs for inhibiting venous thrombosis.

[0008] Preferably, the preparation method of the sodium humate includes the following steps:

[0009] (1) Mix 10 parts of humic acid ore powder, 1 part of sodium hydroxide, and 10 parts of distilled water in a stirring reaction kettle, and react by passing steam for 120 minutes to obtain a crude sodium humate product;

[0010] (2) Centrifuge the crude sodium humate product at 2000 revolutions per minute for 20 minutes to obtain a centrifugate containing soluble sodium humate, and transfer the centrifugate to a stirring reaction kettle;

[0011] (3) Adjust the sodium humate content in the centrifugate to 40% in the stirring reaction kettle;

[0012] (4) Add tannin acylase hydrolase and laccase to carry out enzymatic hydrolysis according to the proportions of 0.05% and 0.01% of the weight of sodium humate respectively. The reaction temperature is 60°C, and the reaction is carried out at 200 revolutions per minute for 60 minutes to obtain a modified sodium humate reaction solution;

[0013] (5) Add 0.3%-0.5% activated carbon to the modified sodium humate reaction solution, heat up to 80°C - 85°C, and stir at a speed of 50 - 100 revolutions per minute for 30 - 45 minutes;

[0014] (6) Filter to remove the activated carbon to obtain a filtered solution of modified sodium humate;

[0015] (7) Separate and refine the filtered solution of modified sodium humate through a 50 - 200nm ceramic membrane, dry it, crush it and mix it evenly with dextrin, and press it into tablets to prepare sodium humate tablets.

[0016] Preferably, the concentration of sodium humate in the drug is 600mg / L.

[0017] Secondly, the present invention provides the use of sodium humate in the preparation of an enhancer for improving the therapeutic effect of rivaroxaban on venous thrombosis.

[0018] Preferably, the sodium humate is prepared by the above preparation method.

[0019] Preferably, the concentration of sodium humate in the enhancer is 600mg / L.

[0020] Secondly, the present invention provides a composition for treating venous thrombosis, which is characterized in that the composition includes sodium humate, rivaroxaban and a pharmaceutically acceptable carrier.

[0021] Preferably, the concentration of sodium humate in the composition is 600mg / L, and the concentration of rivaroxaban in the composition is 30mg / L.

[0022] The beneficial effects of the present invention are as follows:

[0023] The present invention discovers that sodium humate can effectively inhibit the thrombus formation rate and thrombus length of venous thrombosis; at the same time, the present invention discovers that sodium humate can cooperate with rivaroxaban to inhibit venous thrombosis, so it can be used to prepare an enhancer of rivaroxaban. Description of the Drawings

[0024] Figure 1 It is the apparent diagram and statistical chart of the venous thrombosis of mice in different treatment groups. Detailed Embodiments

[0025] The various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be construed as a limitation on the present invention, but rather as a more detailed description of certain aspects, characteristics, and implementation schemes of the present invention. It should be understood that the terms described in the present invention are only for describing specific embodiments and are not used to limit the present invention. Additionally, for the numerical ranges in the present invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any intermediate value within any stated value or stated range, as well as each smaller range between any other stated value or intermediate value within the stated range, is also included in the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0026] Example 1: Preparation of Sodium Humate Tablets

[0027] (1) Mix 10 parts of humic acid ore powder, 1 part of sodium hydroxide, and 10 parts of distilled water in a stirring reaction kettle, introduce steam and react for 120 minutes to obtain crude sodium humate;

[0028] (2) Centrifuge the crude sodium humate at 2000 revolutions per minute for 20 minutes to obtain a centrifugate containing soluble sodium humate, and transfer the centrifugate to a stirring reaction kettle;

[0029] (3) Adjust the sodium humate content in the centrifugate to 40% in the stirring reaction kettle;

[0030] (4) Add tannin acyl hydrolase and laccase for enzymatic hydrolysis according to the proportions of 0.05% and 0.01% of the weight of sodium humate respectively, react at a temperature of 60°C, 200 revolutions per minute for 60 minutes to obtain a modified sodium humate reaction solution;

[0031] (5) Add 0.3% - 0.5% activated carbon to the modified sodium humate reaction solution, raise the temperature to 80°C - 85°C, stir at a speed of 50 - 100 revolutions per minute, and maintain for 30 - 45 minutes;

[0032] (6) Filter to remove the activated carbon to obtain a modified sodium humate filtrate;

[0033] (7) Separate and refine the modified sodium humate filtrate through a 50 - 200nm ceramic membrane, dry, pulverize, mix evenly with dextrin, and press into tablets to prepare sodium humate tablets.

[0034] Example 2: Detection of the inhibitory effect of sodium humate on venous thrombosis

[0035] (1) Raise 8 - week - old C57BL / 6 mice purchased from Beijing SPF Biotechnology Co., Ltd. under controlled conditions (22°C, 12 / 12 hour light - dark cycle), and feed them sufficient water and food;

[0036] (2)Before treatment, the animals were randomly divided into five groups, with 50 mice in each group:

[0037] VTE group (n = 50): 40 days before surgery, fed normal food and water;

[0038] During the operation, the mice were anesthetized with intraperitoneal injection of sodium pentobarbital (1%, 50 mg / kg) and fixed in the supine position; then, the skin of the preoperative surgical area was disinfected. Subsequently, the abdomen was incised along the white line. The inferior vena cava was slightly separated from the aorta, and then a 30-gauge insulin needle was connected in parallel under the left renal vein and ligated with 7-0 polypropylene suture; subsequently, without damaging the endothelium, the 30-gauge insulin needle was removed to form a 90% stenosis at the ligation site; all visible collateral branches were completely ligated; finally, the intestine was replaced into the abdominal cavity, and the peritoneum and skin were sutured with 6-0 suture; 48 hours after ligation, we reopened the abdominal cavity of the mice, clamped the blood vessel 2 cm below the ligation line, and removed the thrombus after opening the lumen;

[0039] Sham operation group (n = 50): 40 days before surgery, fed normal food and water;

[0040] The surgical procedure was the same as that of the VTE group, but the inferior vena cava of the mice was not ligated;

[0041] VTE + Rivaroxaban group (n = 50): 40 days before surgery, fed normal food and water (dissolve 30 mg of rivaroxaban in 1 L of drinking water and shake until completely dissolved);

[0042] The surgical procedure was the same as that of the VTE group;

[0043] VTE + Sodium Humate group (n = 50): 40 days before surgery, fed normal food and water (dissolve 600 mg of sodium humate in 1 L of drinking water and shake until completely dissolved);

[0044] The surgical procedure was the same as that of the VTE group;

[0045] VTE + Rivaroxaban + Sodium Humate group (n = 50): 40 days before surgery, fed normal food and water (dissolve 600 mg of sodium humate and 30 mg of rivaroxaban in 1 L of drinking water and shake until completely dissolved);

[0046] (3)Calculate the thrombus formation and thrombus length in each group. The experimental results are shown in Table 1 and Figure 1 as follows.

[0047] Table 1 Comparison of venous thrombosis in mice of each group

[0048]

[0049] From Table 1 and Figure 1It can be seen that thrombosis was found in all the VTE surgery groups, while no thrombosis was found in the sham surgery group, proving that the surgical method of the flow-limiting model can successfully establish the model;

[0050] Meanwhile, it can be seen that the sodium humate provided by the present invention can effectively reduce the thrombosis rate of mice and the length of thrombus. Therefore, sodium humate can be used to prepare drugs for inhibiting venous thrombosis.

[0051] In addition, the present invention discovers that when sodium humate is combined with the anticoagulant rivaroxaban, a significant synergistic effect can be produced. Therefore, sodium humate can be used as an enhancer of rivaroxaban to enhance the therapeutic effect of rivaroxaban and reduce its dosage, thereby reducing adverse reactions while achieving better therapeutic effects.

Claims

1. Use of a composition in the preparation of a medicament for treating venous thrombosis, characterized in that, The combination includes sodium humate, rivaroxaban and a pharmaceutically acceptable carrier; In the composition, the concentration of sodium humate is 600 mg / L, and the concentration of rivaroxaban is 30 mg / L; The preparation method of the sodium humate includes the following steps: (1) Mix 10 parts of humic acid ore powder, 1 part of sodium hydroxide and 10 parts of distilled water in a stirring reactor, and introduce steam to react for 120 minutes to obtain crude sodium humate; (2) Centrifuge the crude sodium humate at 2000 revolutions per minute for 20 minutes to obtain a centrifugate containing soluble sodium humate, and transfer the centrifugate to a stirring reactor; (3) Adjust the sodium humate content in the centrifugate to 40% in the stirring reactor; (4) Add tannin acyl hydrolase and laccase for enzymatic hydrolysis according to the proportions of 0.05% and 0.01% of the weight of sodium humate respectively. The reaction temperature is 60 °C, and the reaction is carried out at 200 revolutions per minute for 60 minutes to obtain a modified sodium humate reaction solution; (5) Add 0.3%-0.5% activated carbon to the modified sodium humate reaction solution, heat up to 80 °C - 85 °C, and the stirring speed is 50 - 100 revolutions per minute, and maintain for 30 - 45 minutes; (6) Filter to remove the activated carbon to obtain a filtered solution of modified sodium humate; (7) Separate and refine the filtered solution of modified sodium humate through a 50 - 200 nm ceramic membrane, dry it, crush it and mix it evenly with dextrin, and press it into tablets to prepare sodium humate tablets.

2. A composition for treating venous thrombosis, characterized in that, The combination includes sodium humate, rivaroxaban and a pharmaceutically acceptable carrier; In the composition, the concentration of sodium humate is 600 mg / L, and the concentration of rivaroxaban is 30 mg / L; The sodium humate is prepared by the preparation method described in claim 1.

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