Chinese medicine composition for treating cardiovascular diseases and kidney diseases and method for producing the same

Abstract

The present invention relates to a traditional Chinese medicine composition for treating cardiorenal syndrome and heart failure, and a method for producing the same. The constituent raw materials of the traditional Chinese medicine composition are 3 to 20 parts of Cinnamomi Ramulus, 3 to 25 parts of Atractylodis Macrocephalae Rhizoma, 3 to 25 parts of Bupleuri Radix, 6 to 45 parts of Astragali Radix, 2 to 20 parts of Panacis Majoris Rhizoma, 3 to 30 parts of Paeoniae Radix Rubra, 6 to 25 parts of Spatholobi Caulis, 6 to 25 parts of Ginkgo Folium, 6 to 35 parts of Aucklandiae Radix, 3 to 20 parts of Zingiberis Rhizoma Recens, 2 to 25 parts of Citri Reticulatae Viride Fructus, 2 to 15 parts of Nigellae Semen, 2 to 20 parts of Inulae Flos, and 3 to 25 parts of Taxilli Herba. This traditional Chinese medicine composition has the effect of regulating symptoms such as myocardial ischemia, myocardial hypertrophy, myocardial fibrosis, and renal fibrosis caused by heart failure and cardiorenal syndrome.

Description

Technical Field

[0001] This application claims priority based on a Chinese patent application filed with the China National Intellectual Property Administration on June 1, 2022, with an application number of 202210615447.4 and an invention title of "Traditional Chinese Medicine Composition for Treating Cardiovascular Diseases and Kidney Diseases and Its Manufacturing Method", and the entire content thereof is incorporated herein by reference.

[0002] The present invention relates to the field of traditional Chinese medicine, and particularly to a traditional Chinese medicine composition for treating cardiovascular diseases and kidney diseases and its manufacturing method.

Background Art

[0003] Heart failure refers to a situation where the functions of the heart and blood vessels are impaired, causing sympathetic nervous system activation, which in turn activates the renin-angiotensin-aldosterone (RAA) system, leading to a vicious cycle in which the heart function is continuously impaired. Cardiorenal syndrome refers to a disease in which acute or chronic functional abnormalities occur in the heart and / or kidneys, resulting in further acute or chronic functional abnormalities in both. In the heart, the blood ejection rate continuously decreases, blood flow continuously decreases, blood flow velocity slows down, and on top of that, the compensatory function of the heart is activated, causing myocardial ischemia, myocardial hypertrophy, and myocardial fibrosis, and thereby the symptoms of heart failure gradually progress and appear. In the kidneys, kidney damage occurs, and a pathological condition of kidney fibrosis occurs, resulting in an increase in the reabsorption of water and sodium, a decrease in urine output, and the appearance of edema. The pathogenesis of heart failure and cardiorenal syndrome based on traditional Chinese medicine is that if qi deficiency and blood stasis, and the obstruction of the communication between the heart and kidneys persist for a long time, it will lead to heart yang deficiency and the flooding of water and phlegm retention.

Summary of the Invention

Problems to be Solved by the Invention

[0004] Therefore, from the perspective of traditional Chinese medicine theory, the collaborative regulation of heart and kidney functions, warming yang and supplementing qi, activating blood circulation and removing stasis, and resolving phlegm and promoting diuresis can be said to be the main treatment methods for heart failure and the cardio-renal syndrome. Although the treatment of heart failure and the cardio-renal syndrome with traditional Chinese medicine has unique clinical advantages, no particularly effective traditional Chinese medicine composition that can effectively treat heart failure and the cardio-renal syndrome has been discovered yet. Moreover, Western medicines for treating heart failure may have insufficient efficacy and may not be sufficient to improve symptoms.

Means for Solving the Problems

[0005] In view of such circumstances, the present invention provides a traditional Chinese medicine composition for treating cardiovascular and kidney diseases and a method for producing the same.

Effects of the Invention

[0006] According to the composition of the present invention, the gene expression of B-type natriuretic peptide (NPPB), which is the gold standard for heart failure induced by oxygen deficiency / reoxygenation, can be significantly reduced, the gene expression related to myocardial fibrosis and renal fibrosis induced by TGFβ can be reduced, and the blood flow velocity and cardiac output of the zebrafish heart failure model can be significantly increased. Therefore, this composition has the effect of regulating pathological conditions such as myocardial ischemia, myocardial hypertrophy, myocardial fibrosis, and renal fibrosis caused by heart failure and the cardio-renal syndrome, can effectively improve heart function and renal function, and has the medicinal effect of realizing the treatment of the cardio-renal syndrome and heart failure by suppressing the onset and progression of heart failure and the fibrosis of the heart and kidneys.

Modes for Carrying Out the Invention

[0007] In order to achieve the above object of the invention, the present invention provides the following technical means. According to the present invention, there is provided a Chinese herbal medicine composition containing, by weight parts, 3 to 20 parts of Cinnamomi Ramulus, 3 to 25 parts of Atractylodis Rhizoma, 3 to 25 parts of Ziziphi Fructus Jujubae, 6 to 45 parts of Astragali Radix, 2 to 20 parts of Panacis Majoris Rhizoma, 3 to 30 parts of Paeoniae Radix Rubra, 6 to 25 parts of Spatholobi Caulis, 6 to 25 parts of Ginkgo Folium, 6 to 35 parts of Aucklandiae Radix, 3 to 20 parts of Zingiberis Rhizoma Recens, 2 to 25 parts of Citri Fructus, 2 to 15 parts of Nigellae Semen, 2 to 20 parts of Inulae Flos, and 3 to 25 parts of Taxilli Herba, or their processed products by processing.

[0008] In some embodiments of the present invention, the above components have the following functions. Cinnamomi Ramulus is the dried young twigs of Cinnamomum cassia Presl, a plant of the Lauraceae family, and has the functions of warming and dredging meridians and assisting yang to activate qi. Atractylodis Rhizoma is the dried rhizome of Atractylodes macrocephala Koidz., a plant of the Asteraceae family, and has the functions of strengthening the spleen and replenishing qi, drying dampness and promoting diuresis. Ziziphi Fructus Jujubae is the dried mature fruit of Ziziphus jujuba Mill., a plant of the Rhamnaceae family, and has the functions of tonifying the middle-jiao and replenishing qi, nourishing blood and calming the mind. Astragali Radix is the dried root of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao or Astragalus membranaceus (Fisch.) Bge., a plant of the Fabaceae family, and has the functions of supplementing qi and ascending yang, promoting diuresis and reducing edema, promoting fluid production and nourishing blood, promoting qi movement and dredging collaterals. Zhuzishen is the dried rhizome of Panax japonicus C.A.Mey.var.major(Burk.)C.Y.Wu et K.M.Feng or Panax japonicus C.A.Mey.var.bipinnatifidus(Seem.)C.Y.Wu et K.M.Feng, both of which are plants in the Araliaceae family. It is a traditional Bai medicine that supplements lung qi, nourishes yin qi, and removes stasis. It can be used in the treatment of heart failure with qi and yin deficiency and cardio-renal syndrome.

[0009] Chishao is the dried root of Paeonia lactiflora Pall or Paeonia veitchii Lynch, both of which are plants in the Paeoniaceae family. It has the functions of clearing heat and cooling blood, and dispersing stasis and relieving pain. Jixueteng is the dried stem of Spatholobus suberectus Dunn, which is a plant in the Fabaceae family. It has the functions of promoting blood circulation and tonifying blood, and relaxing tendons and activating collaterals. Ginkgo leaf is the dried leaf of Ginkgo biloba L., which is a plant in the Ginkgoaceae family. It has the functions of promoting blood circulation to remove stasis, dredging collaterals to relieve pain, astringing the lung to relieve asthma, and resolving turbidity to reduce lipid. Poria is the dried sclerotium of Poria cocos(Schw.)Wolf, which is a fungus in the Polyporaceae family. It has the functions of promoting diuresis and percolating dampness, strengthening the spleen and calming the mind. Ginger is the fresh rhizome of Zingiber officinale Rosc., which is a plant in the Zingiberaceae family. It has the functions of warming yang, resolving phlegm, and relieving cough. Citron is the dried mature fruit of Citrus medica L. or Citrus wilsonii Tanaka, both of which are plants in the Rutaceae family. It has the functions of regulating qi-flowing for resolving phlegm, and soothing the liver and regulating qi. Black cumin seeds are the dried mature seeds of Nigella glandulifera Freyn et Sint., which is a plant in the Ranunculaceae family. It is a traditional Uygur medicine with the efficacy of tonifying the kidney and promoting diuresis. Inula flower is the dried capitulum of Inula japonica Thunb. or Inula britanica L., which are plants of the Asteraceae family, and has the functions of descending qi, eliminating phlegm, and promoting diuresis. Alisma rhizome is the dried tuber of Alisma orientale (Sam.) Juzep., which is a plant of the Alismataceae family, and has the functions of promoting diuresis and percolating dampness, and reducing turbidity and lipid.

[0010] In some embodiments of the present invention, the traditional Chinese medicine composition comprises 9 parts of Cinnamomi Ramulus, 10 parts of Paeoniae Radix Alba, 10 parts of Bupleuri Radix, 20 parts of Astragali Radix, 9 parts of Panacis japonicus Torr. Rhizoma, 12 parts of Paeoniae Radix Rubra, 10 parts of Spatholobi Caulis, 10 parts of Ginkgo Folium, 15 parts of Aucklandiae Radix, 9 parts of Zingiberis Rhizoma, 10 parts of Citri Reticulatae Viride Fructus, 6 parts of Nigella sativa seeds, 9 parts of Inula flower, and 10 parts of Alisma rhizome as crude drug components or their processed products.

[0011] In the traditional Chinese medicine composition in some embodiments of the present invention, instead of the above-mentioned Panacis japonicus Torr. Rhizoma, Ginseng, Red Ginseng, Codonopsis pilosula, Panax Japonicus Rhizome, Panax quinquefolium and / or Pseudostellariae Radix may be used, and / or instead of the above-mentioned Paeoniae Radix Alba, stir-fried Paeoniae Radix Alba and / or bran-fried Paeoniae Radix Alba may be used, and / or instead of the above-mentioned Astragali Radix, roasted Astragali Radix may be used, and / or instead of the above-mentioned Paeoniae Radix Rubra, Paeoniae Radix Lactiflora may be used, and / or instead of the above-mentioned Zingiberis Rhizoma, dried ginger (Zingiberis Rhizoma) and / or prepared ginger (Zingiberis Rhizoma Praeparata) may be used.

[0012] According to the present invention, there is further provided a method for manufacturing the traditional Chinese medicine composition, which includes extracting the crude drug components or their processed products of the traditional Chinese medicine composition in a prescribed amount with water.

[0013] In some embodiments of the present invention, the manufacturing method further includes a concentration and / or drying step after the extraction step.

[0014] In the manufacturing method according to some embodiments of the present invention, the crude drug components of the prescription amount of the Chinese herbal medicine composition or their processed products are each pulverized to obtain fine powder, extracted with water, concentrated, and freeze-dried.

[0015] In some embodiments of the present invention, the extraction step with water in the manufacturing method includes boiling out from water.

[0016] According to the present invention, there is further provided the use of the Chinese herbal medicine composition or the Chinese herbal medicine composition produced by the manufacturing method in the manufacture of a pharmaceutical for regulating cardiac and renal functions.

[0017] According to the present invention, there is further provided the use of the Chinese herbal medicine composition or the Chinese herbal medicine composition produced by the manufacturing method in the manufacture of a pharmaceutical for preventing and / or treating heart failure, cardiorenal syndrome and / or coronary heart disease.

[0018] According to the present invention, there is further provided the use of the Chinese herbal medicine composition or the Chinese herbal medicine composition produced by the manufacturing method in the manufacture of a pharmaceutical for increasing the blood flow velocity and / or cardiac output of a zebrafish heart failure model induced by verapamil.

[0019] According to the present invention, there is further provided the use of the Chinese herbal medicine composition or the Chinese herbal medicine composition produced by the manufacturing method in the manufacture of a pharmaceutical for suppressing myocardial ischemia, myocardial hypertrophy, myocardial fibrosis and / or renal fibrosis.

[0020] According to the present invention, there is further provided the use of the Chinese herbal medicine composition or the Chinese herbal medicine composition produced by the manufacturing method in the manufacture of a pharmaceutical for improving the symptoms of patients with chronic heart failure and / or reducing the NT-proBNP expression level.

[0021] In some embodiments of the present invention, the symptoms in the use include one or more of swelling, asthma, fatigue / weakness, and / or shortness of breath.

[0022] According to the present invention, there is further provided the use of the traditional Chinese medicine composition or the traditional Chinese medicine composition produced by the production method in the manufacture of a pharmaceutical for suppressing the expression of NPPB gene, COL1A1 gene, COL5A1 gene and / or SERPINE1 gene.

[0023] According to the present invention, there is further provided the use of the traditional Chinese medicine composition in the clinical treatment of chronic heart failure for improving patient symptoms, reducing the NT-proBNP concentration in plasma, etc.

[0024] According to the present invention, there is further provided a pharmaceutical comprising the traditional Chinese medicine composition or the traditional Chinese medicine composition produced by the production method and a pharmaceutically acceptable additive.

[0025] According to the present invention, there is further provided the use of the traditional Chinese medicine composition or the traditional Chinese medicine composition produced by the production method in the treatment of any of the following diseases. (I) Heart failure (II) Cardiorenal syndrome (III) Coronary heart disease (IV) Myocardial ischemia (V) Myocardial hypertrophy (VI) Myocardial fibrosis (VII) Renal fibrosis.

[0026] According to the present invention, there is further provided a method for treating a disease, which includes taking the traditional Chinese medicine composition or the traditional Chinese medicine composition produced by the production method and / or the pharmaceutical, and the disease includes the following diseases (I) Heart failure (II) Cardiorenal syndrome (III) Coronary heart disease (IV) Myocardial ischemia (V) Myocardial hypertrophy (VI) Myocardial fibrosis (VII) Renal fibrosis.

[0027] According to the present invention, there is provided a Chinese medicinal composition containing, by weight parts, 3 to 20 parts of silica, 3 to 25 parts of Phellodendri Cortex, 3 to 25 parts of Artemisiae Scopariae Herba, 6 to 45 parts of Astragali Radix, 2 to 20 parts of Panacis Japonici Rhizoma, 3 to 30 parts of Paeoniae Rubra Radix, 6 to 25 parts of Spatholobi Caulis, 6 to 25 parts of Ginkgo Folium, 6 to 35 parts of Aucklandiae Radix, 3 to 20 parts of Zingiberis Rhizoma Recens, 2 to 25 parts of Citri Reticulatae Viride Fructus, 2 to 15 parts of Nigellae Sativae Semen, 2 to 20 parts of Inulae Flos, 3 to 25 parts of Taxilli Herba as crude drug components or their processed products.

[0028] In this traditional Chinese medicine composition, Astragalus membranaceus and Nigella sativa seeds are used as the sovereign drugs. By combining Astragalus membranaceus, which functions to replenish qi and raise yang and promote diuresis to reduce edema, and Nigella sativa seeds, which function to tonify the kidney and promote diuresis, it has the effects of replenishing qi, warming yang to transform qi, and promoting diuresis on qi deficiency, yang deficiency, and water flooding, which are the main symptoms of heart failure and cardio-renal syndrome. In the prescription, Cinnamomum cassia and Atractylodes macrocephala are used as ministerial drugs to contribute to the qi-tonifying and yang-warming effects of Astragalus membranaceus. Cinnamomum cassia is pungent, sweet, and warm, and has the effect of warming yang to transform qi. Atractylodes macrocephala functions to strengthen the spleen and dry dampness. With the help of Cinnamomum cassia, the warming and transporting effect can be improved, the spleen qi can be strengthened, and water dampness can be eliminated. By using Paeonia lactiflora and Spatholobus suberectus together as ministerial drugs, they have the effects of promoting blood circulation to nourish blood, dispelling stasis and relieving pain for the syndrome of blood stasis. In addition, by using Alisma orientale and Polyporus umbellatus together as adjuvant drugs in the prescription, the efficacy of promoting diuresis and percolating dampness can be doubled. By combining Alisma orientale, Cinnamomum cassia, and Atractylodes macrocephala, the effects of promoting yang to transform qi and strengthening the spleen to promote diuresis can be achieved, with a mild and less drying property, and the medicinal power is strong but not drastic. By using Panax japonicus Torr. var. wangianus and Ginkgo biloba leaves as adjuvant drugs, they have the functions of promoting blood circulation to dispel stasis and relieving pain, and contribute to the effect of promoting blood circulation to dispel stasis of Paeonia lactiflora and Spatholobus suberectus. In addition, Panax japonicus Torr. var. wangianus has the function of tonifying the lung and nourishing yin, and by combining with Paeonia lactiflora, the effect of reducing yin qi and moistening dryness can be achieved. When blood circulation is poor, water stagnates, and when yang is deficient and there is no warming and transporting, phlegm will appear. Therefore, Ginkgo biloba leaves and Polyporus umbellatus can enhance the efficacy of removing turbidity and reducing lipid, and promoting blood circulation and diuresis throughout the body. By using Citrus medica L. var. sarcodactylis Swingle and Inula japonica Thunb. together as adjuvant drugs, they have the function of regulating qi and resolving phlegm, and can improve the syndrome of water dampness and phlegm retention in heart failure and cardio-renal syndrome. By using Zingiber officinale Rosc. and Glycyrrhiza glabra L. together as guiding drugs, since Zingiber officinale Rosc. is pungent and slightly warm, and moves without retention, it contributes to the warming the middle and strengthening the spleen of Alisma orientale, Cinnamomum cassia, and Atractylodes macrocephala. Glycyrrhiza glabra L. not only supplements the middle and benefits qi, but also can reconcile various raw medicinal materials. According to the combined use of various raw medicinal materials, the effects of warming yang and tonifying qi, promoting blood circulation to dispel stasis, and resolving phlegm and promoting diuresis can be enhanced. Therefore, according to this traditional Chinese medicine composition, it can significantly reduce the gene expression of B-type natriuretic peptide (NPPB), which is the gold standard for oxygen deficiency / reoxygenation-induced heart failure, reduce the gene expression related to myocardial fibrosis and renal fibrosis induced by TGFβ, and significantly increase the blood flow velocity and cardiac output of the zebrafish heart failure model.Clinical trials administered to humans have shown that this traditional Chinese medicine composition has the medicinal properties of improving the symptoms of patients with chronic heart failure and reducing the expression of NT-proBNP. Therefore, this composition has the effect of regulating diseases such as myocardial ischemia, myocardial hypertrophy, myocardial fibrosis, and renal fibrosis caused by heart failure and cardio-renal syndrome, and is effective in improving cardio-renal function and renal function, suppressing the onset and progression of heart failure, and suppressing the fibrosis of the heart and kidneys. Thus, it has been shown to have the medicinal effect of treating cardio-renal syndrome and heart failure.

Brief Description of the Drawings

[0029]

Figure 1

Figure 2

Figure 3

Figure 4

Examples

[0030] The present invention discloses a traditional Chinese medicine composition for treating cardiovascular and kidney diseases and a method for manufacturing the same. Those skilled in the art can appropriately improve the process parameters and implement them with reference to the content of this specification. It should be particularly noted that all similar substitutions and modifications are considered to be included in the present invention because they are obvious to those skilled in the art. Although the methods and applications of the present invention have been described through preferred embodiments, it is obvious that those skilled in the art can implement and apply the technology of the present invention by changing, appropriately modifying, or combining the methods and applications described in this specification without departing from the content, spirit, and scope of the present invention.

[0031] In the present invention, for the compounding preparation of the composition, the expression of NPPB which is the gold standard for heart failure induced by oxygen deficiency / reoxygenation, the influence on the gene expression of type I collagen α1 (COL1A1) and type V collagen α1 (COL5A1) induced by TGFβ, the influence on the gene expression of plasminogen activator inhibitor 1 (SERPINE1) and type I collagen α1 (COL1A1), and the raw materials and reagents used in the measurement of the influence of the traditional Chinese medicine composition on blood flow velocity and cardiac output using a zebrafish heart failure model can all be purchased on the market. The present invention will be further described below with reference to examples.

[0032] [Example 1] Preparation of traditional Chinese medicine composition 9 g of Cinnamomi Ramulus, 10 g of Atractylodis Macrocephalae Rhizoma, 10 g of Paeoniae Radix Alba, 20 g of Astragali Radix, 12 g of Paeoniae Radix Rubra, 10 g of Spatholobi Caulis, 10 g of Ginkgo Folium, 15 g of Aucklandiae Radix, 9 g of Zingiberis Rhizoma Recens, 10 g of Citri Reticulatae Viride Fructus, 9 g of Inulae Flos, 10 g of Taxilli Herba, 9 g of Panacis Japonicus Rhizoma, and 6 g of Nigella Sativa seeds were prepared, ground into powders of 80 - 100 mesh respectively, added with 15 times the volume of distilled water for extraction, extracted by the standard reflux method for 2 hours, concentrated the extract for 15 minutes to a volume of 2 mL, concentrated under the conditions of reducing the pressure with a vacuum freeze dryer, with a concentration ratio of 30, a vacuum degree of 5 Pa during freeze-drying, a freezing time of 24 h, and a temperature of -55 °C, and prepared a freeze-dried powder of the extract. Next, the composition was formulated according to the prescription ratio to obtain a traditional Chinese medicine composition. Finally, the traditional Chinese medicine composition was dissolved in PBS to obtain a mother liquor.

[0033] [Example 2] Influence of the traditional Chinese medicine composition on the gene expression of B-type natriuretic peptide (NPPB) which is the gold standard for heart failure of cardiomyocyte AC16 induced by oxygen deficiency / reoxygenation 1) AC16 was seeded at 200,000 cells / well in a 12-well plate. After overnight culture, the normal control group was cultured in an ordinary incubator (oxygen concentration 20%) from the beginning to the end, and the remaining groups were placed in a tri-gas incubator and cultured under the conditions of low oxygen (oxygen concentration 1%) and sugar-free medium (glucose concentration 0 g / L) for 6 hours, and then transferred to an ordinary incubator and cultured under the conditions of ordinary medium (glucose concentration 3.15 g / L) for 24 hours. 2) The Chinese herbal medicine composition prepared in Example 1 was allowed to act on the cells at a concentration of 400 μg / mL during 30 hours of oxygen deprivation / reoxygenation, respectively. 3) The cells were washed twice with PBS, RNA was extracted using a kit (Thermo, high-performance RNA-to-cDNA), and cDNA was generated through reverse transcription. 4) The qPCR reaction was carried out with a program of 95°C, 3 min, (95°C, 3 s; 60°C, 30 s) for 40 cycles.

[0034] Here, the primer sequences are as follows. NPPB1: 5'-TGAACGTCCCGGTACAG-3' (shown in SEQ ID NO: 1) NPPB2: 5’-CTGATCCCGTCTCCT-3' (shown in SEQ ID NO: 2)

[0035] 5) Data processing: Taking the gene expression level of the blank control group as 1, those with a gene expression level of 1 or more in the drug treatment group were regarded as an increase in gene expression level, and those with a gene expression level less than 1 were regarded as a decrease in gene expression level. As shown in Figure 1 and Table 1 below, such a Chinese herbal medicine composition was able to suppress the regulation of the gene expression of B-type natriuretic peptide (NPPB) in the AC16 cell model induced by oxygen deprivation / reoxygenation, thus exerting an anti-heart failure effect.

[0036]

Table 1

[0037] [Example 3] Influence of the Chinese herbal medicine composition on the gene expression of type I collagen α1 (COL1A1) and type V collagen α1 (COL5A1) in human cardiac fibroblasts induced by TGFβ 1) HCF cells were seeded at 100,000 cells / well in a 12-well plate, and after overnight culture, TGFβ (10 ng / mL) was added to treat the cells for 48 hours. 2) Add the traditional Chinese medicine composition prepared in Example 1 (final concentration of 800 μg / mL), and set up a solvent control group (add an equal volume of PBS), and co-treat the cells for 48 hours. 3) Wash the cells twice with PBS, extract RNA using a kit (Thermo, High Performance RNA-to-cDNA), and generate cDNA through reverse transcription. 4) Perform qPCR reaction with a program of 95°C, 3 min, (95°C, 3 s; 60°C, 30 s) for 40 cycles.

[0038] Here, the primer sequences are as follows. COL1A1 - 5’-GAGGGCCAAGACGAAGACATC-3’ (shown in SEQ ID NO:3) COL1A1’ - 5’-CAGATCACGTCATCGCACAAC-3’ (shown in SEQ ID NO:4) COL5A1 - 5’-TACCCTGCGTCTGCATTTCC-3’ (shown in SEQ ID NO:5) COL5A1’ - 5’-GCTCGTTGTAGATGGAGACCA-3’ (shown in SEQ ID NO:6)

[0039] As shown in Figure 2 and Table 2 below, such a traditional Chinese medicine composition was able to suppress the gene expression of type I collagen α1 (COL1A1) and type V collagen α1 (COL5A1) in human cardiac fibroblasts induced by TGFβ, thus exerting an anti-myocardial fibrosis effect.

[0040]

Table 2

[0041] [Example 4] Effects of the traditional Chinese medicine composition on the gene expression of plasminogen activator inhibitor 1 (SERPINE1) and type I collagen α1 (COL1A1) 1) Seed HK2 cells at 80,000 cells / well in a 12-well plate, perform 24-hour serum starvation treatment after overnight culture, and then add TGFβ (10 ng / mL) to treat the cells for 48 hours. 2) The traditional Chinese medicine composition prepared in Example 1 (final concentration: 800 μg / mL) was added, and a solvent control group (adding an equal volume of PBS) was set up, and the cells were co-treated for 48 hours. 3) The cells were washed twice with PBS, RNA was extracted using a kit (Thermo, High Performance RNA-to-cDNA), and cDNA was generated through reverse transcription. 4) The qPCR reaction was performed with a program of 95°C, 3 min, (95°C, 3 s; 60°C, 30 s) for 40 cycles.

[0042] Here, the primer sequences are as follows. SERPINE1 - 5’-AGTGGACTTTTCAGAGGTGGA-3’ (shown in SEQ ID NO:7) SERPINE1’ - 5’-GCCGTTGAAGTAGAGGGCATT-3’ (shown in SEQ ID NO:8) COL1A1 - 5’-GAGGGCCAAGACGAAGACATC-3’ (shown in SEQ ID NO:3) COL1A1’ - 5’-CAGATCACGTCATCGCACAAC-3’ (shown in SEQ ID NO:4)

[0043] 5) Data processing: The gene expression level of the blank control group was set as 1. Those with a gene expression level of 1 or more in the drug treatment group were regarded as an increase in gene expression level, and those with a gene expression level less than 1 were regarded as a decrease in gene expression level. As shown in Figure 3 and Table 3 below, such a traditional Chinese medicine composition could inhibit the gene expression of fibrinogen activator inhibitor 1 (SERPINE1) and type I collagen α1 (COL1A1) in human renal tubular epithelial cells HK2 induced by TGFβ, thus exerting an anti-renal fibrosis effect.

[0044]

Table 3

[0045] [Example 5] Measurement of the effects of a traditional Chinese medicine composition on blood flow velocity and cardiac output using a zebrafish heart failure model 1) Wild-type AB strain zebrafish at 2 dpf were randomly selected and placed in a 6-well plate at 30 fish per well. 2) While adding the Chinese herbal medicine composition prepared in Example 1 (final concentration of 2000 μg / mL), a solvent control group (adding an equal volume of sterile water) was set up, and the zebrafish were treated for 4 hours. 3) Except for the normal control group (not treated with verapamil hydrochloride), the remaining groups were administered with water-soluble verapamil hydrochloride to construct a zebrafish heart failure model, and treated at 28 °C for 0.5 hour. 4) Ten zebrafish were randomly selected from each experimental group, photographed with a heartbeat blood flow analyzer, data were collected using ViewPoint Application Manager software, and the blood flow velocity and cardiac output of the zebrafish were analyzed.

[0046] As shown in FIG. 4 and Table 4 below, such Chinese herbal medicine composition could increase the blood flow velocity and cardiac output of the zebrafish heart failure model induced by verapamil, thus exerting an anti-heart failure effect.

[0047] [Table 4]

[0048] [Example 6] 3 g of Cinnamomi Ramulus, 25 g of Paeoniae Radix Alba, 3 g of Bupleuri Radix, 6 g of Astragali Radix, 20 g of Panacis japonicus Torr. Rhizoma, 3 g of Paeoniae Radix Rubra, 6 g of Spatholobi Caulis, 6 g of Ginkgo Folium, 35 g of Aucklandiae Radix, 20 g of Zingiberis Rhizoma Recens, 2 g of Citri Reticulatae Viride Fructus, 15 g of Nigella sativa seeds, 20 g of Inulae Flos, 25 g of Taxilli Herba were prepared, and a Chinese herbal medicine composition was manufactured in the same manner as in Example 1.

[0049] [Example 7] 20 g of Cinnamomi Ramulus, 3 g of Paeoniae Radix Alba, 25 g of Bupleuri Radix, 45 g of Astragali Radix, 2 g of Panacis japonicus Torr. Rhizoma, 30 g of Paeoniae Radix Rubra, 25 g of Spatholobi Caulis, 25 g of Ginkgo Folium, 6 g of Aucklandiae Radix, 3 g of Zingiberis Rhizoma Recens, 25 g of Citri Reticulatae Viride Fructus, 2 g of Nigella sativa seeds, 2 g of Inulae Flos, 3 g of Taxilli Herba were prepared, and a Chinese herbal medicine composition was manufactured in the same manner as in Example 1.

[0050] [Example 8] Preparation of Decoction of the Composition According to the blending ratio of 9 g of Cinnamomi Ramulus, 10 g of Paeoniae Radix Alba, 10 g of Artemisiae Annuae Herba, 20 g of Astragali Radix, 12 g of Paeoniae Radix Rubra, 10 g of Spatholobi Caulis, 10 g of Ginkgo Folium, 15 g of Aucklandiae Radix, 9 g of Zingiberis Rhizoma, 10 g of Citri Reticulatae Fructus, 9 g of Inulae Flos, 10 g of Taxilli Herba, 9 g of Panacis Japonici Rhizoma, and 6 g of Nigellae Sativae Semen, each crude drug was weighed for 7 days, 6 L of water was added, and it was decocted for 1 hour to obtain a decoction of the traditional Chinese medicine composition for 7 days.

[0051] [Example 9] Influence of the Decoction of the Composition on the Symptoms and NT-proBNP Values of Patients with Chronic Heart Failure Twelve cases of patients were recruited. After the patients were given Western medicine for basic treatment of heart failure (referring to the 2022 version of the heart failure management guidelines by AHA / ACC / HFSA and following the standardized Western medicine basic treatment of the guidelines, including ARNI / ACEI / ARB, β-blockers, MRA, SGLT2 inhibitors, cardiac glycosides, diuretics, antiplatelet drugs, anticoagulants, statin drugs, nitrate ester drugs, hypoglycemic drugs, antihypertensive drugs, etc.), symptoms such as wheezing, shortness of breath, swelling, fatigue, and weakness persisted (for details, refer to the statistical information in the "before" part of the symptom improvement situation in Table 5 below; for NYHA heart function classification, refer to Table 5 below). Without changing the Western medicine treatment regimen, the decoction of the traditional Chinese medicine composition prepared in Example 8 was taken for more than 2 weeks. As a result, as shown in Table 5 below, each symptom of the patients was significantly improved. Specifically, in terms of improving the patients' wheezing, the effective rate reached 100% (12 / 12); in terms of improving the patients' fatigue and weakness, the treatment effective rate reached 100% (12 / 12); in terms of improving the patients' swelling, the effective rate reached 90% (9 / 10) (swelling did not occur in the remaining 2 cases); and in terms of improving the patients' shortness of breath, the effective rate reached 66.7% (8 / 12). In addition, for 5 cases of patients, plasma NT-proBNP tests were performed before, during, or at the end of taking the decoction of the traditional Chinese medicine composition prepared in Example 8, and the results showed that the NT-proBNP value was significantly decreased (refer to Table 6 below).

[0052]

Table 5

[0053] In Table 5 above, "before" represents the state after the basic treatment of heart failure by taking Western medicine in Example 9, and "after" represents the state after the basic treatment of heart failure by taking Western medicine in Example 9 and the administration of the decoction of the traditional Chinese medicine composition prepared in Example 8.

[0054] [Table 6]

[0055] In Table 6 above, "before treatment" represents the state after the basic treatment of heart failure by taking Western medicine in Example 9, and "after treatment" refers to the state after the basic treatment of heart failure by taking Western medicine in Example 9 and the administration of the decoction of the traditional Chinese medicine composition prepared in Example 8.

[0056] [Example 10] Influence of the decoction of the composition on the liver and kidney functions of patients with chronic heart failure When 12 patients recruited in Example 9 were made to take the decoction of the traditional Chinese medicine composition prepared in Example 8 for 2 weeks or more, as shown in Table 7, alanine aminotransferase (kit, manufactured by Beckman Coulter, alanine aminotransferase kit), aspartate aminotransferase (kit, manufactured by Beckman Coulter, aspartate aminotransferase kit), serum urea nitrogen (kit, manufactured by Beckman Coulter, serum urea nitrogen kit), and serum creatinine (kit, manufactured by Beckman Coulter, serum creatinine kit) related to the liver and kidney functions of the patients were detected, and there was no significant difference in the detected values.

[0057] [Table 7]

[0058] The above has introduced in detail the traditional Chinese medicine composition for treating cardiovascular diseases and kidney diseases according to the present invention and its manufacturing method. In this specification, the principles and embodiments of the present invention have been described using specific examples. However, the description of the above examples only helps to understand the method of the present invention and its core idea. For those skilled in the art, as long as they do not deviate from the principles of the present invention, some improvements and modifications can be made to the present invention, and these improvements and modifications shall also be included within the protection scope of the claims of the present invention.

Claims

1. A traditional Chinese medicine composition, characterized by comprising crude drug components or their processed products of 3 to 20 parts by weight of silica, 3 to 25 parts by weight of white peony root, 3 to 25 parts by weight of astragalus root, 6 to 45 parts by weight of astragalus membranaceus, 2 to 20 parts by weight of pseudo-ginseng, 3 to 30 parts by weight of red peony root, 6 to 25 parts by weight of millettia reticulata, 6 to 25 parts by weight of ginkgo leaf, 6 to 35 parts by weight of atractylodes macrocephala, 3 to 20 parts by weight of ginger, 2 to 25 parts by weight of citron, 2 to 15 parts by weight of nigella sativa seeds, 2 to 20 parts by weight of inula flower, and 3 to 25 parts by weight of taxus chinensis.

2. The traditional Chinese medicine composition according to claim 1, characterized by comprising crude drug components or their processed products of 9 parts by weight of silica, 10 parts by weight of white peony root, 10 parts by weight of astragalus root, 20 parts by weight of astragalus membranaceus, 9 parts by weight of pseudo-ginseng, 12 parts by weight of red peony root, 10 parts by weight of millettia reticulata, 10 parts by weight of ginkgo leaf, 15 parts by weight of atractylodes macrocephala, 9 parts by weight of ginger, 10 parts by weight of citron, 6 parts by weight of nigella sativa seeds, 9 parts by weight of inula flower, and 10 parts by weight of taxus chinensis.

3. Ginseng, red ginseng, codonopsis pilosula, japonicus ginseng, american ginseng and / or heterophylly falsestarwort are used instead of the pseudo-ginseng, and / or Fried white peony root and / or bran-fried white peony root are used instead of the white peony root, and / or Baked astragalus root is used instead of the astragalus root, and / or White peony root is used instead of the red peony root, and / or Dried ginger and / or prepared ginger are used instead of the ginger, the traditional Chinese medicine composition according to claim 1 or 2.

4. A method for manufacturing a traditional Chinese medicine composition according to any one of claims 1 to 3, characterized by extracting the crude drug components or their processed products of the traditional Chinese medicine composition in the prescribed amount with water.

5. The manufacturing method according to claim 4, further comprising a concentration and / or drying step after the extraction step.

6. The manufacturing method according to claim 4 or 5, characterized by respectively pulverizing the crude drug components or their processed products of the traditional Chinese medicine composition in the prescribed amount into fine powders, extracting with water, concentrating, and freeze-drying.

7. The manufacturing method according to any one of claims 4 to 6, characterized in that the extraction with water includes adding water and decocting.

8. Use of the traditional Chinese medicine composition according to any one of claims 1 to 3 and / or the traditional Chinese medicine composition manufactured by the manufacturing method according to any one of claims 4 to 7 in the manufacture of a medicament for regulating heart and kidney functions.

9. Use of the traditional Chinese medicine composition according to any one of claims 1 to 3 and / or the traditional Chinese medicine composition produced by the production method according to any one of claims 4 to 7 in the manufacture of a medicament for preventing and / or treating heart failure, cardio-renal syndrome and / or coronary heart disease.

10. Use of the traditional Chinese medicine composition according to any one of claims 1 to 3 and / or the traditional Chinese medicine composition produced by the production method according to any one of claims 4 to 7 in the manufacture of a medicament for increasing the blood flow velocity and / or cardiac output of a zebrafish heart failure model induced by verapamil.

11. Use of the traditional Chinese medicine composition according to any one of claims 1 to 3 and / or the traditional Chinese medicine composition produced by the production method according to any one of claims 4 to 7 in the manufacture of a medicament for suppressing myocardial ischemia, myocardial hypertrophy, myocardial fibrosis and / or renal fibrosis.

12. Use of the traditional Chinese medicine composition according to any one of claims 1 to 3 and / or the traditional Chinese medicine composition produced by the production method according to any one of claims 4 to 7 in the manufacture of a medicament for improving the symptoms of patients with chronic heart failure and / or reducing the NT-proBNP expression level.

13. Use of the traditional Chinese medicine composition according to any one of claims 1 to 3 and / or the traditional Chinese medicine composition produced by the production method according to any one of claims 4 to 7 in the manufacture of a medicament for suppressing the expression of NPPB gene, COL1A1 gene, COL5A1 gene and / or SERPINE1 gene.

14. A medicament characterized by comprising the traditional Chinese medicine composition according to any one of claims 1 to 3 and / or the traditional Chinese medicine composition produced by the production method according to any one of claims 4 to 7 and a pharmaceutically acceptable additive.

15. (I) Heart failure (II) Cardio-renal syndrome (III) Coronary heart disease (IV) Myocardial ischemia (V) Myocardial hypertrophy (VI) Myocardial fibrosis (VII) Renal fibrosis Use of the traditional Chinese medicine composition according to any one of claims 1 to 3 and / or the traditional Chinese medicine composition produced by the production method according to any one of claims 4 to 7 in the treatment of any of the above diseases.

16. A method for treating a disease, comprising administering the herbal medicine composition according to any one of claims 1 to 3, the herbal medicine composition produced by the production method according to any one of claims 4 to 7, and / or the pharmaceutical product according to claim 14, wherein the disease includes the diseases shown in the following (I) to (VII): (I) Heart failure (II) Cardiorenal syndrome (III) Coronary heart disease (IV) Myocardial ischemia (V) Myocardial hypertrophy (VI) Myocardial fibrosis (VII) Renal fibrosis A method for treating a disease, characterized by the above.

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