Traditional Chinese medicine composition for treating non-alcoholic fatty liver disease

Abstract

The invention discloses a traditional Chinese medicine composition for treating non-alcoholic fatty liver disease, which comprises the following components in parts by mass: 160-200 parts of gardenia root; 160 to 200 parts of herba artemisiae scopariae; 70-80 parts of tortoise plastron; 70 to 80 parts of turtle shell; 70 to 80 parts of radix astragali seu hedysari; 70-80 parts of fingered citron; 70 to 80 parts of red sage root; 70 to 80 parts of rhizoma corydalis; 35 to 45 parts of cortex moutan; 70 to 80 parts of herba patriniae; 70 to 80 parts of radix pseudostellariae; 70 to 80 parts of radix curcumae; 35 to 45 parts of radix bupleuri; 35 to 45 parts of madder; 10 to 20 parts of pseudo-ginseng; the fifteen medicines and pseudo-ginseng are dried and crushed, and are sieved by a 100-mesh sieve to form fine powder for later use, and the rest fourteen medicines are prepared into clear paste. Weighing the clear paste and auxiliary materials according to the proportion of the clear paste to the starch to the dextrin to the pseudo-ginseng powder being 1: 1.3: 0.2: 0.024, mixing the clear paste and the auxiliary materials to prepare a soft material, and granulating with a 12-mesh sieve to obtain the pseudo-ginseng powder. The traditional Chinese medicine composition has a good treatment effect on the non-alcoholic fatty liver disease.

Description

Technical Field

[0001] The invention relates to a traditional Chinese medicine composition for treating non-alcoholic fatty liver. Background Art

[0002] Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common chronic liver disease worldwide, currently estimated to affect up to 38% of the global adult population. NAFLD is an umbrella term that covers a wide range of liver diseases, including non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis and even hepatocellular carcinoma (HCC). NASH is an advanced form of NAFLD, characterized by hepatic steatosis, inflammation, cell swelling and / or fibrosis. Once a patient develops NASH, approximately 10-29% of NASH patients may develop cirrhosis within 10 years.

[0003] Early studies proposed a "double-hit" theory to describe the pathogenesis of NASH. Hepatocytes accumulate excessive triglycerides in lipid droplets, which subsequently leads to fatty degeneration of hepatocytes. As macrophages switch from an anti-inflammatory state to a pro-inflammatory state, inflammation, insulin resistance, and elevated free fatty acid (FFA) levels result. In addition, excessive FFA intake contributes to the development of lipotoxicity. At the same time, excessive production of reactive oxygen species (ROS) induces apoptosis (and other types of cell death) and exacerbates inflammation. NAFLD is a disease name in Western medicine. There is no direct corresponding disease name in traditional Chinese medicine, but this disease has been recorded in ancient Chinese medicine books. According to its symptoms and pathogenesis, it can be classified into Chinese medicine diseases and syndromes such as "phlegm turbidity", "fat gas", "stasis syndrome", "flank pain", "swelling", "fullness", "liver distension", "liver stagnation", "liver addiction", "liver adhesion", "accumulation", and "dampness obstruction". Traditional Chinese medicine believes that the pathogenesis of NAFLD is related to spleen and stomach dysfunction, liver failure to dredge and release, qi stagnation and blood stasis, etc. The disease is located in the liver and is closely related to the spleen, stomach and kidneys.

[0004] The current management of NAFLD is mainly lifestyle intervention (including low-calorie diet, exercise and weight loss), as well as early treatment of patients' cardiometabolic risk factors, but to date, there are no FDA or EMA-approved drugs for the treatment of NAFLD or NASH due to adverse side effects of the drugs or insufficient efficacy in clinical endpoints. Current clinical trials usually measure two main outcomes: NASH is relieved without progression of fibrosis, and fibrosis is regressed without worsening of NASH. In terms of available drug treatments, monotherapy is mainly divided into several categories, such as metabolic, anti-inflammatory and anti-fibrotic, such as PPARs agonists, THR-β agonists, FGF21 analogs, SCD1 agonists, ASK1 inhibitors, FASN inhibitors, DGAT1 / 2 inhibitors, AMPK activators, MPC inhibitors, FXR agonists, etc. In addition, various combination therapies have been explored to optimize the treatment effect and / or reduce drug side effects.

[0005] The TCM treatment principle for NAFLD advocates staged treatment: initial treatment focuses on regulating the liver and qi, strengthening the spleen and stomach, while mid-term and late-stage treatment emphasizes strengthening the spleen, removing blood stasis and dispersing nodules, and clearing away heat and detoxification. TCM prescriptions are known for their personalized treatment strategies, and they show multi-component and multi-pathway pharmacological effects in the treatment of NAFLD. For example, the compound Zhenshu Tiaozhi prescription can activate the AMPK pathway, improve intestinal barrier function, and regulate the composition of intestinal flora. Given the different syndrome types of NAFLD patients, specific prescription treatments are crucial and should be prepared according to the main symptoms while considering secondary manifestations. Commonly used Chinese medicines include Gardenia, Artemisia capillaris, Salvia miltiorrhiza, Crataegus pinnatifida, Bupleurum, Coptis chinensis, Ginseng, Poria, Atractylodes macrocephala, etc. These Chinese medicines have the effects of removing turbidity and reducing lipids, clearing heat and removing dampness, promoting blood circulation and removing blood stasis, and regulating the spleen and stomach, which can improve the symptoms of NAFLD patients and promote the recovery of liver function. Summary of the invention

[0006] The main purpose of the present invention is to provide a Chinese medicine composition for treating non-alcoholic fatty liver disease.

[0007] The technical solution adopted by the present invention to solve its technical problem is:

[0008] A Chinese medicine composition for treating non-alcoholic fatty liver disease, comprising the following components by weight:

[0009] 160-200 parts of Gardenia Root; 160-200 parts of Artemisia Capillaris; 70-80 parts of Testudine Plastrum;

[0010] 70-80 parts of turtle shell; 70-80 parts of astragalus; 70-80 parts of bergamot; 70-80 parts of salvia miltiorrhiza;

[0011] 70-80 parts of Rhizoma Corydalis; 35-45 parts of Cortex Moutan; 70-80 parts of Herba Patriniae; 70-80 parts of Radix Pseudostellariae;

[0012] 70-80 parts of Curcuma Radix; 35-45 parts of Bupleurum; 35-45 parts of Rubia cordifolia; 10-20 parts of Panax notoginseng.

[0013] Furthermore, a Chinese medicine composition for treating non-alcoholic fatty liver disease comprises the following components by weight:

[0014] Gardenia root 185g Artemisia capillaris 185g Tortoise shell 74g

[0015] Turtle Shell 74g Astragalus 74g Citron 74g Salvia miltiorrhiza 74g

[0016] Yuanhu 74g Moutan bark 37g Patrinia 74g Pseudostellaria 74g

[0017] Curcuma 74g Bupleurum 37g Rubia 37g Panax notoginseng 13g

[0018] Furthermore, the preparation method of a Chinese medicine composition for treating non-alcoholic fatty liver disease comprises the following steps: weighing each component according to the above mass ratio, and washing according to the characteristics of each raw material medicine; drying and crushing Panax notoginseng, sieving through 80-100 mesh to form fine powder for standby use, adding 10-20 times of water to the remaining 14 flavors, soaking for 20 minutes to 40 minutes, decocting 2-3 times, each time for 1-2 hours, filtering, combining the filtrate, and concentrating under reduced pressure to a clear paste with a relative density of 1.25-1.30 (50°C to 60°C). Centrifuging to obtain a clear paste with a relative density of 1.21-1.24 (50°C to 60°C). Then, the clear paste with a relative density of 1.21-1.24 and Panax notoginseng powder are mixed.

[0019] Furthermore, according to the mass ratio of clear paste: starch: dextrin: Panax notoginseng powder = (0.9-1.1): (1.2-1.4): (0.1-0.3): (0.02-0.03), weigh the clear paste and auxiliary materials to mix and prepare a soft material, sieve and granulate, dry at 65°C-75°C, and granulate to obtain (sugar-free type).

[0020] Furthermore, the sieve used in the sieving granulation is 8-mesh to 15-mesh.

[0021] The present invention also provides use of the traditional Chinese medicine composition in preparing a medicine for treating non-alcoholic fatty liver disease.

[0022] Furthermore, the non-alcoholic fatty liver disease is a damp-heat accumulation type non-alcoholic fatty liver disease.

[0023] Furthermore, the dosage form of the drug is an oral preparation.

[0024] Furthermore, the oral preparation includes granules and decoctions.

[0025] All ranges recited herein include all point values ​​within the range.

[0026] Compared with the background technology, this technical solution has the following advantages:

[0027] The pharmaceutical composition of the present invention, compound gardenia root granules (also known as Kang's anti-fibrosis prescription), is an experience-based prescription for treating liver disease by Mr. Kang Liangshi, a nationally renowned liver disease expert at Xiamen Traditional Chinese Medicine Hospital. Compound gardenia root granules are composed of 15 Chinese medicinal herbs, including gardenia root, wormwood, astragalus, tortoise shell, turtle shell, madder, bupleurum, bergamot, salvia miltiorrhiza, patrinia herb, pseudostellaria, corydalis, curcuma, moutan bark, and Panax notoginseng, and have the effects of invigorating qi and activating blood circulation, soothing the liver and relieving depression, and clearing away heat and removing dampness. Traditional Chinese medicine believes that the pathological mechanism of NAFLD is related to spleen and stomach qi deficiency, endogenous phlegm turbidity, damp-heat stagnation, liver qi stagnation, qi stagnation and blood stasis, and phlegm and blood stasis, forming a pathological state of qi deficiency as the root and phlegm, dampness and blood stasis as the symptoms. In view of the essence of Qi deficiency, this prescription makes heavy use of Astragalus and Pseudostellaria baicalensis to invigorate Qi and strengthen the spleen; in view of the superficial symptoms of phlegm, dampness and blood stasis, Gardenia Root, Artemisia Capillaris, Rubia Cordata, and Patrinia Herba in the prescription can clear turbidity, reduce lipids, clear away heat and remove dampness, while Bupleurum, Citron, and Corydalis can soothe the liver and relieve depression, and regulate Qi, while Curcuma, Salvia miltiorrhiza, Cortex Moutan, Panax notoginseng, Tortoise Shell, and Turtle Shell can promote Qi and resolve blood stasis, and relieve stagnation and resolve nodules; the whole prescription has one tonifying and one purging, achieving the therapeutic effect of both tonifying and clearing. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The present invention will be further described below in conjunction with the accompanying drawings and embodiments.

[0029] Figure 1 Liver function of NASH patients before and after taking the medicine. A shows a decrease in serum ALT after the patient took Gardenia Root Granules; B shows a decrease in serum AST after the patient took Gardenia Root Granules; C shows a decrease in serum γ-GGT after the patient took Gardenia Root Granules.

[0030] Figure 2 Liver function ALT and AST of mice in each group. A is the comparison of serum ALT of mice in each group; B is the comparison of serum AST of mice in each group.

[0031] Figure 3 It is an index related to lipid metabolism in mouse liver tissue. Among them, A is the macroscopic observation of liver tissue of mice in each group, hematoxylin-eosin staining and oil red staining of liver tissue paraffin sections; B is the quantification of positive area of ​​oil red staining; C is the TG comparison of liver tissue of mice in each group; D is the TC comparison of liver tissue of mice in each group.

[0032] Figure 4 It is an inflammatory index of mouse liver tissue. Among them, A is the mRNA detection of TNF-α in the liver tissue of each group of mice; B is the mRNA detection of IL-6 in the liver tissue of each group of mice; C is the mRNA detection of IL-1β in the liver tissue of each group of mice.

[0033] Figure 5 It is an index of liver tissue fibrosis in mice. Among them, A is Sirius red staining and Masson staining of paraffin sections of liver tissue of mice in each group; B is the quantification of positive area of ​​Sirius red staining; C is the quantification of positive area of ​​Masson staining; D and E are the protein expression detection of α-SMA in liver tissue of mice in each group; F is the quantification of positive area of ​​α-SMA.

[0034] Figure 6 It is an indicator of ferroptosis in mouse liver tissue. Among them, A is the comparison of ferrous ions in the liver tissue of each group of mice; B is the comparison of MDA in the liver tissue of each group of mice; C is the comparison of GSH-Px in the liver tissue of each group of mice; D and E are the mRNA detection of GPx4 and SLC7A11 in the liver tissue of each group of mice. DETAILED DESCRIPTION

[0035] Example 1

[0036] Gardenia root 185g Artemisia capillaris 185g Tortoise shell 74g

[0037] Turtle Shell 74g Astragalus 74g Citron 74g Salvia miltiorrhiza 74g

[0038] Yuanhu 74g Moutan bark 37g Patrinia 74g Pseudostellaria 74g

[0039] Curcuma 74g Bupleurum 37g Rubia 37g Panax notoginseng 13g

[0040] For the above 15 herbs, Panax notoginseng is dried and crushed, and sieved through a 100-mesh sieve to form fine powder for later use. The remaining 14 gardenia roots are added with 15 times the amount of water, soaked for 30 minutes, decocted twice, each time for 1.5 hours, filtered, the filtrate is combined, and concentrated under reduced pressure to a clear paste with a relative density of 1.27 (50°C to 60°C). Centrifuge with a tubular centrifuge to obtain a clear paste with a relative density of 1.21 to 1.24. According to the mass ratio of clear paste: starch: dextrin: Panax notoginseng powder = 1:1.3:0.2:0.024, weigh the clear paste and auxiliary materials to mix and prepare soft materials, granulate with a 12-mesh sieve, dry at 70°C, and granulate to 1000g, that is, (sugar-free type).

[0041] Example 2

[0042] Gardenia root 160g Artemisia capillaris 200g Tortoise shell 70g

[0043] Turtle Shell 80g Astragalus 70g Citron 80g Salvia miltiorrhiza 70g

[0044] Yuanhu 80g Moutan bark 35g Patrinia 80g Pseudostellaria 70g

[0045] Curcuma 80g Bupleurum 35g Rubia 45g Panax notoginseng 10g

[0046] The preparation method is the same as Example 1.

[0047] Example 3

[0048] Gardenia root 200g, Artemisia capillaris 160g, Tortoise shell 80g

[0049] Turtle Shell 70g Astragalus 80g Citron 70g Salvia miltiorrhiza 80g

[0050] Yuanhu 70g Moutan bark 45g Patrinia 70g Pseudostellaria 80g

[0051] Curcuma 70g Bupleurum 45g Rubia 35g Panax notoginseng 20g

[0052] The preparation method is the same as Example 1.

[0053] Animal experiments

[0054] Twenty 4-week-old SPF-grade C57BL / 6 male mice were selected, and 5 mice were randomly selected and included in the normal control group (NC), HFMCD liver fibrosis model group (HFMCD), low-dose group (HFMCD+LZZG) of compound gardenia root granules (prepared in Example 1), and high-dose group (HFMCD+HZZG) of compound gardenia root granules. Oral administration of HFMCD feed to establish a non-alcoholic fatty hepatitis liver fibrosis model in mice: except for the normal control group, the remaining mice consumed sufficient HFMCD feed daily for 8 consecutive weeks. From the 5th day of modeling, the low-dose and high-dose groups of compound gardenia root granules were gavaged with 0.5g / ml / kg / d and 1g / ml / kg / d of compound gardenia root granules, respectively. At the end of the experiment, the livers of mice were removed and serum was collected. The liver tissues of mice in each group were stained with HE, Sirius red, Masson and Oil red. The Elisa method was used to detect the levels of ALT and AST in serum, and the levels of TG, TC, HYP, MDA, GSH-Px and Fe in liver tissue. 2+ The levels of α-SMA were detected by immunohistochemistry in liver tissues, RNA and protein were extracted from tissues of each group, and the expressions of mRNA and protein related to liver inflammation and fibrosis were detected by Real-time qPCR and Western blot, respectively.

[0055] result:

[0056] (1) Compound Gardenia Root Granules can improve liver function in patients with NASH

[0057] The liver function indexes of patients were improved after medication, indicating that the compound gardenia root granules can improve the liver function of NASH patients ( Figure 1 AC).

[0058] (2) Compound Gardenia Root Granules Improve Liver Damage in NASH Mice

[0059] A mouse model of NASH was established, and different doses of Compound Gardenia Root Granules were given to treat the mice. The serum ALT and AST of the mice in the model group were significantly higher than those in the normal control group; compared with the model group, the serum ALT and AST of the mice in the low-dose and high-dose drug groups were significantly lower than those in the model group ( Figure 2A -B).

[0060] (3) Compound Gardenia Root Granules Inhibit Lipid Accumulation in the Liver of NASH Mice

[0061] The liver capsule of mice in the normal control group was smooth, ruddy in color, with sharp edges and a smooth surface. The liver of mice in the model group was clay-colored, with blunt edges and a greasy surface. The liver of mice in the drug group became ruddy in color and smoother in surface than that in the model group, and the improvement degree of the high-dose group was better than that of the low-dose group ( Figure 3 A). In the NASH model group, the liver plates of mice were disordered, the liver lobule structure was destroyed, and there was more inflammation, lipid droplet infiltration and ballooning in the lobule. The drug group showed a more obvious improvement. Oil red staining of liver tissue showed that the lipid droplets in the liver tissue were dyed red. The number and size of lipid droplets in the drug group were significantly less than those in the model group ( Figure 3 AB). The TG and TC contents in the liver tissue of the drug group were significantly lower than those in the model group ( Figure 3 CD).

[0062] (4) Compound Gardenia Root Granules Improve the Inflammation Level of the Liver in NASH Mice

[0063] Compared with the model group, the drug group could significantly inhibit the gene expression of TNF-α, IL-1β and IL-6 in the liver of NASH mice ( Figure 4 AC).

[0064] (5) Compound Gardenia Root Granules Inhibit Liver Fibrosis and HSC Activation in NASH Mice

[0065] The liver of mice in the model group showed fibrosis lesions and increased collagen fibers compared with the normal control group, while the collagen fiber deposition in the drug-treated group was less than that in the model group ( Figure 5 AC). The expression level of α-SMA in the liver of the model group was significantly higher than that in the control group, and administration of the drug significantly inhibited the expression of α-SMA in the liver of NASH mice ( Figure 5 DE).

[0066] (6) Compound Gardenia Root Granules Inhibit Hepatic Ferroptosis in NASH Mice

[0067] The ferrous ion content in the NASH group was significantly higher than that in the control group, and the ferrous ion content in the medication group was lower than that in the model group ( Figure 6A). Compared with the normal control group, the liver MDA level of mice in the model group was significantly increased, and the GSH level was significantly decreased. Compared with the model group, the liver MDA level of mice in the drug administration group was decreased, and the liver GSH level was increased ( Figure 6 B-6C). The expression of GPX4 and SLC7A11 in the NASH group was significantly downregulated compared with the control group, while after medication, the expression of GPX4 and SLC7A11 was significantly upregulated, suggesting that the compound gardenia root granules improve NASH by inhibiting ferroptosis ( Figure 6 DE).

[0068] in conclusion

[0069] In the early stage, through the method of clinical retrospective study, it was found that the liver function of patients was improved after treatment with compound gardenia root granules. In addition, the present invention constructed a NASH mouse model, and after treatment with compound gardenia root granules, it was found that compound gardenia root granules could significantly improve the liver function of NASH mice and reduce fat accumulation in the liver. In addition, compound gardenia root granules can reduce the inflammation and fibrosis of the liver. Preliminary mechanism studies have found that compound gardenia root granules can inhibit the ferroptosis process of hepatocytes and the polarization of macrophages. Therefore, it is speculated that compound gardenia root granules can regulate lipid metabolism, ferroptosis and polarization of macrophages, and through the combined action of the three, the liver damage, fat accumulation, inflammation and fibrosis of NASH patients are reduced, thereby achieving the therapeutic effect of alleviating NASH.

[0070] The above description is only a preferred embodiment of the present invention, and therefore cannot be used to limit the scope of the present invention. That is, equivalent changes and modifications made according to the patent scope of the present invention and the contents of the specification should still fall within the scope of the present invention.

Claims

1. A Chinese medicine composition for treating non-alcoholic fatty liver disease, characterized in that: In parts by mass, it includes the following components: 160-200 parts of Gardenia Root; 160-200 parts of Artemisia Capillaris; 70-80 parts of Testudine Plastrum; 70-80 parts of turtle shell; Astragalus 70-80 parts; 70-80 portions of bergamot; Salvia miltiorrhiza 70-80 parts; 70-80 parts of Corydalis yanhusuo; Cortex Moutan 35-45 parts; Patrinia 70-80 parts; 70-80 portions of Pseudostellaria heterophylla; 70-80 parts of turmeric; 35-45 parts of Bupleurum Root; 35-45 parts of Rubia Cordata; 10-20 servings of Panax notoginseng.

2. A Chinese medicine composition for treating non-alcoholic fatty liver disease, characterized in that: In parts by mass, it includes the following components: Gardenia root 185g; Artemisia capillaris 185g; Tortoise shell 74g; Turtle shell 74g; Astragalus 74g; Citron 74g; Salvia miltiorrhiza 74g; Rhizoma Corydalis 74g; Cortex Moutan 37g; Patrinia scabra 74g; Radix Pseudostellariae 74g; Radix Curcumae 74g; Radix Bupleuri 37g; Radix Rubiae 37g; Radix Notoginseng 13g.

3. A method for preparing a traditional Chinese medicine composition for treating non-alcoholic fatty liver disease according to claim 1 or 2, comprising the following steps: weighing each component according to the above-mentioned mass ratio and washing according to the characteristics of each raw material medicine; drying and crushing the Panax notoginseng, sieving it through an 80-mesh to 100-mesh sieve into fine powder for later use, adding 10-20 times the amount of water to the remaining fourteen ingredients, soaking for 20 minutes to 40 minutes, decocting 2 to 3 times, each time for 1 hour to 2 hours, filtering, combining the filtrate, and concentrating under reduced pressure to a clear paste with a relative density of 1.25-1.30 at 50°C to 60°C; then centrifuging to obtain a clear paste with a relative density of 1.21 to 1.24; and then mixing the clear paste with a relative density of 1.21 to 1.24 with Panax notoginseng powder.

4. The method for preparing a Chinese medicine composition for treating non-alcoholic fatty liver disease according to claim 3, characterized in that: According to the mass ratio of clear paste: starch: dextrin: Panax notoginseng powder = (0.9-1.1): (1.2-1.4): (0.1-0.3): (0.02-0.03), weigh the clear paste and auxiliary materials, mix them to prepare a soft material, sieve and granulate, dry at 65°C-75°C, and granulate to obtain the product.

5. The method for preparing a Chinese medicine composition for treating non-alcoholic fatty liver disease according to claim 4, characterized in that: The sieve used for sieving granulation is 8-15 mesh.

6. Use of the Chinese medicine composition according to any one of claims 1 or 2 in preparing a medicament for treating non-alcoholic fatty liver disease.

7. The use according to claim 6, characterized in that The non-alcoholic fatty liver disease is a damp-heat accumulation type non-alcoholic fatty liver disease.

8. The use according to claim 7, characterized in that: The dosage form of the drug is an oral preparation.

9. The use according to claim 8, characterized in that: The oral preparations include granules and decoctions.

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