Sanqi Danshen tablet for preparing a medicine for non-alcoholic fatty liver disease

Abstract

The present application relates to the technical field of traditional Chinese medicine, and more particularly to application of a panax notoginseng and salvia miltiorrhiza tablet in preparation of a medicine for non-alcoholic fatty liver disease (NAFLD). Clinical research shows that the panax notoginseng and salvia miltiorrhiza tablet can significantly improve liver function biochemical indicators of NAFLD patients, significantly reduce the degree of liver fibrosis of the NAFLD patients, thereby treating NAFLD. In addition, the panax notoginseng and salvia miltiorrhiza tablet also has the advantage of high safety. The present application develops a new use of the panax notoginseng and salvia miltiorrhiza tablet, and provides a new choice for medicines for treating NAFLD.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine technology, and in particular to the application of a Panax notoginseng and Salvia miltiorrhiza tablet in the preparation of a drug for non-alcoholic fatty liver disease. Background Technology

[0002] Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. With the prevalence of obesity and metabolic syndrome (Mets), NAFLD has become the leading chronic liver disease in my country and the primary cause of abnormal liver biochemical indicators in health checkups. To date, there is no specific drug for treating NAFLD alone.

[0003] Chinese patent CN1055630C discloses a Panax notoginseng and Salvia miltiorrhiza tablet, composed of Panax notoginseng, Salvia miltiorrhiza, and Cyperus rotundus, which has the effects of promoting blood circulation and removing blood stasis, aromatic resuscitation, and regulating qi and relieving pain. Currently, the application of Panax notoginseng and Salvia miltiorrhiza tablets mainly involves the treatment of cardiovascular and cerebrovascular diseases such as coronary heart disease, angina pectoris, hypertension, hyperlipidemia, and sequelae of cerebral infarction. There are currently no clinical case studies reported indicating that Panax notoginseng and Salvia miltiorrhiza tablets can treat NAFLD.

[0004] In view of this, the present invention is hereby proposed. Summary of the Invention

[0005] With the continuous accumulation of clinical experience and the gradual deepening of modern research, significant progress has been made in developing new uses for known traditional Chinese medicines. This invention provides a new use for the known traditional Chinese medicine formula "Sanqi Danshen Tablets," as detailed below:

[0006] This invention provides the application of Panax notoginseng and Salvia miltiorrhiza tablets in the preparation of a drug for non-alcoholic fatty liver disease.

[0007] Sanqi Danshen Tablets are a traditional Chinese medicine preparation independently developed by the First Affiliated Hospital of Kunming Medical University (hereinafter referred to as "our hospital"). This medicine has been used clinically for nearly 30 years, accumulating rich clinical experience and data. The main components of Sanqi Danshen Tablets are total saponins of Panax notoginseng, tanshinone IIA, luteolin, and tanshinone acid. Current pharmacological studies show that monomers such as Panax notoginseng, tanshinone IIA, and luteolin can reduce hepatic lipid deposition and inhibit the generation of hepatic oxygen free radicals through different pathways, exerting antioxidant effects. They also achieve anti-inflammatory effects by reducing the generation and release of inflammatory mediators from macrophages. Tanshinone acid and total saponins of Panax notoginseng can act on fatty acid synthase and peroxidase to regulate blood lipid levels and reduce fat accumulation in adipose tissue and the liver.

[0008] Although there are literature reports on the effects of individual components of Panax notoginseng and Danshen tablets, such as notoginsenosides and tanshinone, on reducing hepatic lipid deposition and reducing inflammation, most of these studies are based on laboratory data obtained from basic research. Currently, there are no clinical case studies reported demonstrating that Panax notoginseng and Danshen tablets can treat NAFLD. Based on years of clinical data, this invention conducted a prospective study on the treatment of NAFLD with Panax notoginseng and Danshen tablets, finding that the tablets have a positive and significant therapeutic effect on NAFLD.

[0009] The results of this invention show that Panax notoginseng and Salvia miltiorrhiza tablets can significantly improve liver function biochemical indicators and significantly reduce the degree of liver fibrosis in NAFLD patients, thus playing a role in the treatment of NAFLD.

[0010] This invention provides the application of Panax notoginseng and Salvia miltiorrhiza tablets in the preparation of a medicament for non-alcoholic fatty liver disease. This invention does not specifically limit the source of the Panax notoginseng and Salvia miltiorrhiza tablets; they can be obtained from commercially available sources (such as Yunnan Pharmaceutical Manufacturing License Z20091965A) or prepared using methods known in the art (such as Chinese Patent CN1055630C).

[0011] In a preferred embodiment of the present invention, the Panax notoginseng and Salvia miltiorrhiza tablets are made from raw materials comprising the following parts by weight: 40-60 parts of Panax notoginseng, 250-350 parts of Salvia miltiorrhiza, and 40-60 parts of Cyperus rotundus.

[0012] In a preferred embodiment of the present invention, the Panax notoginseng and Salvia miltiorrhiza tablets are made from raw materials comprising the following parts by weight: 45-50 parts of Panax notoginseng, 275-300 parts of Salvia miltiorrhiza, and 45-50 parts of Cyperus rotundus.

[0013] In another preferred embodiment of the present invention, the Panax notoginseng and Salvia miltiorrhiza tablets are made from raw materials comprising the following parts by weight: 50-55 parts of Panax notoginseng, 300-325 parts of Salvia miltiorrhiza, and 50-55 parts of Cyperus rotundus.

[0014] Most preferably, the Panax notoginseng and Salvia miltiorrhiza tablets are made from the following raw materials in parts by weight: 50 parts Panax notoginseng, 300 parts Salvia miltiorrhiza, and 50 parts Cyperus rotundus.

[0015] The Panax notoginseng and Salvia miltiorrhiza tablets obtained under the preferred formulation ratio of this invention can achieve a better therapeutic effect on NAFLD.

[0016] Furthermore, in some specific embodiments provided by the present invention:

[0017] The non-alcoholic fatty liver disease preferably includes non-alcoholic fatty liver disease caused by dysregulation of cellular inflammatory factors. The cellular inflammatory factors preferably include HS-CRP.

[0018] And / or, the non-alcoholic fatty liver disease preferably includes non-alcoholic fatty liver disease caused by enzyme dysregulation. The enzyme indicators preferably include at least one of AST, ALT, TBIL, and GGT.

[0019] And / or, the non-alcoholic fatty liver disease preferably includes non-alcoholic fatty liver and / or non-alcoholic fatty fibrosis.

[0020] And / or, the symptoms of the non-alcoholic fatty liver disease preferably include at least one of the following: elevated CAP value, elevated LSM value, elevated BMI value, and elevated waist circumference.

[0021] And / or, the symptoms of the non-alcoholic fatty liver disease preferably include abnormal blood lipid indicators, which preferably include at least one of TG, TC, LDL-C, and HDL-C.

[0022] This invention utilizes Panax notoginseng and Salvia miltiorrhiza tablets to treat non-alcoholic fatty liver disease (NAFLD), demonstrating high safety and definite efficacy. It significantly improves liver function biochemical indicators in NAFLD patients and substantially reduces liver fibrosis.

[0023] The application of the Panax notoginseng and Salvia miltiorrhiza tablets provided by this invention in the treatment of non-alcoholic fatty liver disease mainly improves the body's overall condition and reduces pathological damage, thereby alleviating the symptoms, shortening the course of the disease, and reducing complications, thus playing a good therapeutic role objectively.

[0024] This invention opens up new applications for Panax notoginseng and Salvia miltiorrhiza tablets, providing a new option for the treatment of NAFLD. Panax notoginseng and Salvia miltiorrhiza tablets can also be further expanded into liver-protective drugs.

[0025] Beneficial effects:

[0026] This invention provides the application of Panax notoginseng and Salvia miltiorrhiza tablets in the preparation of a drug for non-alcoholic fatty liver disease (NAFLD). Clinical studies of this invention show that Panax notoginseng and Salvia miltiorrhiza tablets can significantly improve liver function biochemical indicators in NAFLD patients and significantly reduce the degree of liver fibrosis in NAFLD patients, thereby treating NAFLD. In addition, Panax notoginseng and Salvia miltiorrhiza tablets also have the advantage of high safety. This invention opens up new applications for Panax notoginseng and Salvia miltiorrhiza tablets and provides a new option for the treatment of NAFLD. Attached Figure Description

[0027] To more clearly illustrate the technical solutions in this invention or the prior art, the accompanying drawings used in the description of the embodiments or the prior art will be described below.

[0028] Figure 1 This is a comparison of liver function levels between the treatment group and the control group after treatment in Example 1 of the present invention.

[0029] Figure 2This is a comparison of HS-CRP levels between the treatment group and the control group after treatment in Example 1 of the present invention.

[0030] Figure 3 This is a comparison of CAP and LSM values ​​before and after taking Sanqi Danshen tablets in Example 2 of the present invention.

[0031] Figure 4 This is a comparison of the degree of fatty liver before and after taking Sanqi Danshen tablets in Example 2 of the present invention.

[0032] Figure 5 This is a comparison of the degree of liver fibrosis before and after taking Sanqi Danshen tablets in Example 2 of the present invention.

[0033] Figure 6 This is a comparison of liver function indicators before and after taking Sanqi Danshen tablets in a patient with abnormal liver function indicators in Example 2 of the present invention.

[0034] Figure 7 This is a comparison of blood lipid levels before and after taking Sanqi Danshen tablets in a patient with dyslipidemia in Example 2 of the present invention. Detailed Implementation

[0035] The purpose of this invention is to provide a new use for Panax notoginseng and Salvia miltiorrhiza tablets in the treatment of NAFLD.

[0036] This invention overcomes the difficulties in obtaining and collecting clinical samples. It not only conducted a retrospective analysis of 2020 cases but also included 89 NAFLD patients who visited the endocrinology outpatient and inpatient departments of our hospital between August and December 2022 and met the inclusion and exclusion criteria for this study. Statistical analysis was performed on the data before and after treatment to evaluate the efficacy and safety of Sanqi Danshen tablets in treating NAFLD. Based on these 89 valuable clinical samples, this invention provides sample data on the clinical treatment of NAFLD with Sanqi Danshen tablets and evaluates its efficacy and safety in treating NAFLD.

[0037] The research provided by this invention offers data support for the safety and efficacy of Sanqi Danshen tablets in treating NAFLD, and provides guidance for its rational use, improvement of instructions, and expansion of indications.

[0038] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention. Unless otherwise specified, the experimental methods used in the embodiments are all conventional methods; the materials and reagents used are all commercially available.

[0039] Example 1

[0040] Patients who visited and used Sanqi Danshen tablets between January 2017 and November 2022 were screened from the His system of the First Affiliated Hospital of Kunming Medical University. A total of 2020 valid cases were collected, including 974 males (48.2%) and 1046 females (51.8%), with a mean age of 44.0 ± 13.9 years. Clinical data were statistically analyzed using SPSS 24.0 and EXCEL software. No adverse reactions to Sanqi Danshen tablets were reported in any of the 2020 cases, indicating that the tablets have a good safety profile.

[0041] Further screening was conducted using the His system of the First Affiliated Hospital of Kunming Medical University to identify 733 patients diagnosed with NAFLD between January 2017 and November 2022 who met the inclusion and exclusion criteria for the study.

[0042] Inclusion and exclusion criteria (Inclusion criteria: age ≥18 years; meeting the above-mentioned Western and Traditional Chinese Medicine diagnostic criteria for NAFLD; disease duration ≥3 months; Exclusion criteria: history of long-term excessive alcohol consumption; comorbid drug-induced liver disease, autoimmune hepatitis, viral hepatitis, etc.; malignant tumors, severe liver and kidney dysfunction).

[0043] A retrospective cohort study design was adopted, and participants were divided into a control group (n=365, receiving routine treatment) and a treatment group (n=368, receiving routine treatment plus 3 tablets of Panax notoginseng and Danshen tablets, 3 tablets three times a day after meals) based on whether they took Panax notoginseng and Danshen tablets.

[0044] Propensity score matching (PSM) was used to match nearest neighbors in a 1:1 ratio to balance possible confounding factors between the two groups. Finally, 246 patients were matched in each of the treatment and control groups.

[0045] The serum liver enzyme levels (AST, ALT, TBIL, ALP, GGT) of the two groups after treatment were compared in Table 1 and 2. Figure 1 The changes in inflammatory markers (HS-CRP) after treatment in the two groups are compared in Table 2 and 3. Figure 2 .

[0046] Table 1 Comparison of liver function levels between the treatment group and the control group after treatment ( n = 246)

[0047] variable Treatment group control group t-value p-value AST 22.2±8.8 21.8±8.8 0.6 0.58 ALT 24.3±15.5 24.8±14.5 0.4 0.72 TBIL <![CDATA[10.9±5.1 * ]]> 12.1±6.3 2.3 0.02 ALP 74.7±21.7 73.4±24.4 0.6 0.52 GGT 43.0±50.0 41.6±52.3 0.3 0.77

[0048] Compared with the control group, the TBIL level in the treatment group was lower (P<0.05).

[0049] Table 2 Comparison of HS-CRP levels between the treatment group and the control group after treatment ( n = 246)

[0050] variable Treatment group control group t-value p-value HS-CRP 4.1±8.9** 10.5±20.4 4.5 <0.001

[0051] After treatment, compared with the control group, the HS-CRP level in the treatment group was significantly decreased (P<0.01).

[0052] The results of this embodiment show that: compared with the control group, the levels of hypersensitive C-reactive protein (HS-CRP) and total bilirubin (TBIl) in the treatment group were decreased (P<0.05), indicating that Panax notoginseng and Salvia miltiorrhiza tablets have a certain improvement effect on the liver function and inflammatory level of NAFLD. At the same time, the research results show that Panax notoginseng and Salvia miltiorrhiza tablets have good safety in the treatment of NAFLD.

[0053] Example 2

[0054] A total of 89 NAFLD patients who met the inclusion and exclusion criteria and visited the outpatient and inpatient departments of the Endocrinology Department of the First Affiliated Hospital of Kunming Medical University from August 2022 to December 2022 were collected, and 67 patients were followed up by the end of March 2023.

[0055] The method of self-control before and after treatment was adopted to statistically analyze the data results before and after treatment, and evaluate the effectiveness and safety of Panax notoginseng and Salvia miltiorrhiza tablets in the treatment of NAFLD (the CAP score detected by Fibroscan was used as the main efficacy evaluation index in this study to evaluate the effectiveness and safety of Panax notoginseng and Salvia miltiorrhiza tablets in the treatment of NAFLD).

[0056] Specifically, in this invention, referring to the "Expert Consensus on Traditional Chinese Medicine Diagnosis and Treatment of Non-alcoholic Fatty Liver Disease (2017)", the CAP value of transient elastography examination (Fibroscan) was divided into 4 layers: ① CAP value < 238 dB / m: normal liver (fat content < 11%); ② 238 ≤ CAP value ≤ 258 dB / m: mild liver fat (fat content 11% - 33%); ③ 259 ≤ CAP value ≤ 291 dB / m: moderate liver fat (fat content 34% - 66%); ④ CAP value ≥ 292 dB / m: severe liver fat (fat content ≥ 67%). Referring to the instruction manual of the Fibroscan transient elastography scanner, the LSM value of liver fibrosis degree was divided into 5 layers (F0 - F4): ① LSM value < 7.3 kPa: F0 no fibrosis; ② 7.3 ≤ LSM value ≤ 9.7 kPa: F1 mild fibrosis; ③ 9.7 < LSM value ≤ 12.4 kPa: F2 significant fibrosis; ④ 12.4 kPa < LSM value ≤ 17.5 kPa: F3 advanced fibrosis; ⑤ LSM value > 17.5 kPa: F4 liver cirrhosis.

[0057] Before the start of the study, the patients were instructed to try to maintain their previous living habits.

[0058] This study employed a self-matched design, administering Sanqi Danshen tablets (Yunnan Pharmaceutical Manufacturing License (Z20091965A)) three times a day after meals, for 12 consecutive weeks. Other treatment regimens were administered by the attending physician in strict accordance with relevant guidelines and hospital standards. Patients returned to the hospital for examination at weeks 0 and 12 to compare changes in fatty liver-related indicators before and after treatment.

[0059] Table 3 compares changes in BMI and waist circumference before and after treatment; Table 4 compares changes in CAP and LSM values ​​before and after treatment, with a decrease in CAP and LSM values ​​considered effective. Figure 3 Table 5 compares the changes in the degree of fatty liver and liver fibrosis before and after treatment. Figure 4 and Figure 5 Comparison of liver function indicators before and after treatment is shown in Table 6 and... Figure 6 Comparison of blood lipid levels before and after treatment is shown in Table 7 and... Figure 7 .

[0060] Table 3 Comparison of waist circumference and BMI before and after taking Sanqi Danshen tablets (n=67)

[0061]

[0062]

[0063] Before treatment, the average waist circumference of the patients was 96.3 cm, and after 12 weeks of treatment, the average waist circumference was 94.9 cm. The waist circumference after treatment was significantly reduced compared with that before treatment (P<0.05).

[0064] Table 4 Comparison of CAP and LSM values ​​before and after taking Sanqi Danshen tablets (n=67)

[0065] Evaluation indicators 0 weeks 12 weeks t-value p-value CAP (dB / m) 310.2±41.5 297.3±42.8* 2.6 0.0103 LSM (kPa) 6.8±2.8 6.0±2.0** 3.0 0.0013

[0066] Fibroscan results showed that, compared with before taking Sanqi Danshen tablets, the patients' CAP value (P<0.05) and LSM value (P<0.01) were significantly reduced after taking the tablets.

[0067] Table 5 Comparison of the degree of fatty liver and liver fibrosis after taking Sanqi Danshen tablets (n=67)

[0068] Evaluation indicators 0 weeks 12 weeks Z-value p-value Fatty liver degree / / 1.0 0.306 normal 0(0.0) 5(7.5) / / Mild 6(9.0) 10(14.9) / / moderate 23(34.3) 16(23.9) / / Severe 38(56.7) 36(53.7) / / Degree of liver fibrosis / / 1.8 0.07 normal 46(68.7) 55(82.1) / / Mild 12(17.9) 7(10.4) / / moderate 5(7.4) 4(6.0) / / Severe 4(6.0) 1(1.5) / /

[0069] After 12 weeks of treatment, one patient with mild and four patients with moderate fatty liver recovered to normal. The proportions of moderate (23, 34.3%) and severe fatty liver (38, 56.7%) decreased, while the proportion of mild fatty liver increased (10, 14.9%). The differences were not statistically significant (P>0.05) according to the rank-sum test. The proportion of patients whose liver fibrosis changed from abnormal to normal (55, 82.1%) was relatively high, and the number of cases with mild, moderate, and severe fibrosis all decreased.

[0070] Table 6 Comparison of liver function indicators before and after taking Sanqi Danshen tablets in patients with normal liver function (n=67)

[0071]

[0072]

[0073] Compared with before taking Sanqi Danshen tablets, all abnormal liver function indicators decreased significantly after taking the tablets, except for ALP, the differences in the other indicators were statistically significant (P<0.05), indicating that Sanqi Danshen tablets have a significant ameliorative effect on abnormal liver function.

[0074] Table 7 Comparison of blood lipid levels before and after taking Sanqi Danshen tablets in patients with dyslipidemia (n=67)

[0075] Evaluation indicators Number of examples 0 weeks 12 weeks t-value p-value TG 29 4.5±3.0 3.9±2.8 1.1 0.3 TC 11 7.8±3.6 5.1±1.2 1.6 0.14 LDL-C 18 3.8±0.6 3.4±0.9 1.5 0.15 HDL-C 9 0.8±0.1 0.9±0.2 2.0 0.09

[0076] After medication, TG, TC, and LDL-C levels significantly decreased, while HDL-C levels increased (P>0.05). This indicates that Sanqi Danshen tablets have a regulatory effect on abnormal blood lipids.

[0077] The results of this embodiment show that after 12 weeks of treatment with Sanqi Danshen tablets, patients can reduce their waist circumference, significantly reduce CAP and LSM values, and significantly reduce the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBI1), and gamma-glutamyltransferase (GGT) in patients with abnormal liver function, thereby improving the degree of fatty liver and liver fibrosis, while having good safety.

[0078] The embodiments described above are merely illustrative of several implementations of the present invention, designed to facilitate a detailed understanding of the technical solutions of the present invention. However, they should not be construed as limiting the scope of patent protection. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention.

Claims

1. The application of Panax notoginseng and Salvia miltiorrhiza tablets in the preparation of drugs for non-alcoholic fatty liver disease, characterized in that, The Panax notoginseng and Salvia miltiorrhiza tablets are made from the following raw materials in parts by weight: Panax notoginseng 40-60 parts, Salvia miltiorrhiza 250-350 parts, and Cyperus rotundus 40-60 parts.

2. The application according to claim 1, characterized in that, The Panax notoginseng and Salvia miltiorrhiza tablets are made from the following raw materials in parts by weight: Panax notoginseng 45-50 parts, Salvia miltiorrhiza 275-300 parts, and Cyperus rotundus 45-50 parts.

3. The application according to claim 1, characterized in that, The Panax notoginseng and Salvia miltiorrhiza tablets are made from the following raw materials in parts by weight: Panax notoginseng 50-55 parts, Salvia miltiorrhiza 300-325 parts, and Cyperus rotundus 50-55 parts.

4. The application according to claim 1, characterized in that, The Panax notoginseng and Salvia miltiorrhiza tablets are made from the following raw materials in parts by weight: 50 parts Panax notoginseng, 300 parts Salvia miltiorrhiza, and 50 parts Cyperus rotundus.

5. The application according to any one of claims 1 to 4, characterized in that, The non-alcoholic fatty liver disease is caused by an imbalance of cellular inflammatory factors, including HS-CRP.

6. The application according to any one of claims 1 to 4, characterized in that, The non-alcoholic fatty liver disease is caused by an imbalance of enzyme indicators, including at least one of AST, ALT, TBIL, and GGT.

7. The application according to any one of claims 1 to 4, characterized in that, The symptoms of non-alcoholic fatty liver disease include at least one of the following: elevated CAP value, elevated LSM value, elevated BMI value, and elevated waist circumference.

8. The application according to any one of claims 1 to 4, characterized in that, The symptoms of non-alcoholic fatty liver disease include abnormal blood lipid levels, including at least one of TG, TC, LDL-C, and HDL-C.

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