Traditional Chinese medicine composition for treating chronic renal failure as well as preparation method and application thereof

Abstract

The invention relates to the field of traditional Chinese medicines, in particular to a traditional Chinese medicine composition for treating chronic renal failure, which is prepared from the following raw material medicines in parts by weight: 6-12 parts of radix bupleuri, 9-18 parts of radix scutellariae, 6-12 parts of ginger processed pinellia, 9-18 parts of radix pseudostellariae, 3-9 parts of honey-fried licorice root, 3-9 parts of leech, 3-9 parts of fructus amomi, 9-18 parts of perilla leaf and 9-18 parts of common fenugreek seed. The traditional Chinese medicine composition aims at symptoms and pathogenesis of the chronic renal failure, adopts treatment principles of tonifying qi, warming yang, dispersing blood stasis and draining turbidity, is cheap in raw materials, simple and convenient to prepare, convenient to use and small in side effect, can be taken for a long time, and has a better curative effect and a good application prospect on the chronic renal failure through observation and analysis.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine, specifically to a traditional Chinese medicine composition for treating chronic renal failure, its preparation method, and its application. Background Technology

[0002] Chronic kidney disease (CKD) is a public health problem associated with high mortality and disability rates, imposing a heavy economic burden on patients, families, and society. Regardless of the initial cause, different types of CKD progress through the same renal fibrosis process, leading to progressive loss of kidney function and destruction of the renal parenchyma. However, to date, there are no ideal specific drugs. Traditional Chinese medicine compound formulas, due to their multi-component, multi-pathway, and multi-target pharmacological characteristics, have demonstrated unique advantages and efficacy in the prevention and treatment of CKD.

[0003] Chronic renal failure (CRF) refers to a syndrome in patients with chronic kidney disease (CKD) characterized by a decreased glomerular filtration rate, leading to the accumulation of metabolic products (such as creatinine and urea), water, electrolyte, and acid-base imbalances, and damage to various organs throughout the body. Currently, modern medicine treats CKD using drugs such as renal arteriosclerosis inhibitors (ACEIs / ARBs). These drugs primarily reduce intraglomerular pressure by blocking the renal compensatory process, thereby reducing proteinuria and providing renal protection. However, as renal function deteriorates, the application of RAS inhibitors in clinical treatment becomes limited, often proving difficult to implement. In reality, approximately 25% of CKD patients experience progressive disease progression. Therefore, clinicians urgently need to explore more effective and safer treatment options to slow the progression of CKD. Increasing clinical research seeks breakthroughs in slowing CKD progression using traditional Chinese medicine. Studies have shown that traditional Chinese medicine has rich clinical experience and unique advantages in delaying chronic renal failure, improving patients' renal function and clinical symptoms, and significantly enhancing their quality of life.

[0004] Renal fibrosis is a key pathological basis and common pathway for the progressive progression of CKD. It refers to the replacement of normal functional renal tissues (including glomeruli, tubules, interstitium, and blood vessels) with excessive extracellular matrix (mainly collagen) during kidney injury, leading to scarring, sclerosis, and progressive loss of renal function. Traditional Chinese medicine believes that the pathological basis of renal fibrosis is "micro-accumulations" occurring in the renal collaterals. The "Medical Essentials - Accumulations" states: "The formation of accumulations is due to insufficient vital energy, which then allows pathogenic factors to take hold." This disease is characterized by deficiency in the root and excess in the branch. The core deficiency is spleen and kidney deficiency (insufficient vital energy), combined with deficiency of other organs such as the lungs and stomach. The spleen loses its ability to transport and transform, the kidneys lose their ability to transform and vaporize, fluid metabolism is abnormal, and the circulation of qi and blood is restricted. Pathogenic factors such as dampness, heat, blood stasis, and toxins take advantage of this deficiency and accumulate. The branch excess is the intertwining of pathological products such as dampness, blood stasis, and toxins, which accumulate and take shape. Over time, these accumulations generate heat and obstruct the renal collaterals. Therefore, in terms of treatment, the principle should be to invigorate Qi and warm Yang, while also addressing the symptoms of damp-heat and blood stasis. Oral administration of traditional Chinese medicine such as Shenshuing capsules, Uremic Clearing granules, and Bailing capsules, or decoctions adjusted according to individual conditions, is recommended. Retention enemas and topical application of traditional Chinese medicine for clearing turbidity and detoxifying can also be used. While these medications have certain therapeutic effects, they also have some drawbacks, such as slow onset of action, inconvenience in preparation and use, less pronounced effects, long treatment duration, unstable efficacy, and a high relapse rate.

[0005] However, there are currently no reports on a traditional Chinese medicine composition for treating chronic renal failure that has few side effects and can be taken long-term. Summary of the Invention

[0006] The purpose of this invention is to provide a traditional Chinese medicine composition for treating chronic renal failure with few side effects and suitable for long-term use. This invention also provides a method for preparing the aforementioned traditional Chinese medicine composition and its application in the preparation of medicaments for treating chronic renal failure.

[0007] In a first aspect, the present invention provides a traditional Chinese medicine composition for treating chronic renal failure, the traditional Chinese medicine composition comprising the following raw materials in parts by weight: Bupleurum chinense 6-12 parts, Scutellaria baicalensis 9-18 parts, Pinellia ternata 6-12 parts, Codonopsis pilosula 9-18 parts, Glycyrrhiza uralensis (processed) 3-9 parts, Hirudo medicinalis 3-9 parts, Amomum villosum 3-9 parts, Perilla frutescens leaf 9-18 parts, and Trigonella foenum-graecum 9-18 parts.

[0008] Furthermore, the traditional Chinese medicine composition comprises the following raw materials in parts by weight: Bupleurum chinense 9 parts, Scutellaria baicalensis 12 parts, Pinellia ternata 9 parts, Codonopsis pilosula 12 parts, Glycyrrhiza uralensis (processed) 6 parts, Hirudo medicinalis 6 parts, Amomum villosum 6 parts, Perilla frutescens 12 parts, and Trigonella foenum-graecum 12 parts.

[0009] In a second aspect, the present invention provides a compound preparation using the above-described traditional Chinese medicine composition as the active ingredient, wherein the compound preparation is prepared into a commonly used dosage form in pharmaceuticals using conventional preparation methods in the art.

[0010] Further, the compound preparation is a decoction, tablet, capsule, granule, pill, oral liquid or syrup.

[0011] Furthermore, the compound preparation further comprises pharmaceutically acceptable excipients such as starch, microcrystalline cellulose, lactose, etc.

[0012] Further, the compound preparation can be prepared by the following method: (A) Weigh each of the medicinal material components, mix them to obtain a mixture; (B) Add a pharmaceutically acceptable carrier or excipient to the mixture and prepare it by a conventional preparation method.

[0013] In the third aspect of the present invention, there is provided an application of the traditional Chinese medicine composition as described above in the preparation of a drug for treating chronic renal failure. [[ID=I1]]

[0014] In the fourth aspect of the present invention, there is provided an application of the compound preparation as described above in the preparation of a drug for treating chronic renal failure.

[0015] Further, the drug for treating chronic renal failure is a drug for reducing the levels of blood uric acid, serum creatinine and blood urea nitrogen in chronic renal failure and improving renal function.

[0016] Further, the drug for treating chronic renal failure is a drug for reducing renal tubular interstitial injury and collagen deposition, down-regulating the expression of fibrosis marker proteins fibronectin, α-smooth muscle actin (α-SMA) and type I collagen (Col-I), improving the pathological damage of chronic renal failure tissues, protecting renal tubular function and reducing renal fibrosis.

[0017] The traditional Chinese medicine compound of the present invention is formulated by carefully selecting medicinal herbs under the guidance of traditional Chinese medicine theory based on many years of clinical practice. In the formula, Pseudostellaria heterophylla has a sweet and slightly bitter taste, is性平 (flat in nature), and belongs to the spleen and lung meridians. It is good at replenishing qi and strengthening the spleen, promoting the production of body fluid and moistening the lungs. Trigonella foenum-graecum has a bitter taste and a warm nature, and belongs to the kidney meridian. It warms the kidney yang and excretes turbid dampness. "Compendium of Materia Medica" states that it: "Treats cold qi hernia masses, cold and damp beriberi, benefits the right kidney, and warms the dantian." The two are used as the monarch drugs together. Bupleurum chinense has a bitter taste and a slightly cold nature, and belongs to the liver and gallbladder meridians. It soothes the liver and promotes yang. "Shennong's Herbal Classic" states that it: "Mainly treats qi stagnation in the heart, abdomen, stomach and intestines, food accumulation, cold and heat pathogens, and promotes the transformation of the old and the generation of the new." Scutellaria baicalensis has a bitter taste and a cold nature, and belongs to the lung, gallbladder, spleen, large and small intestines. It purges fire and removes dampness. Bupleurum chinense and Scutellaria baicalensis are combined to harmonize the shaoyang and dredge the triple energizer. Together with Hirudo nipponica, which has a salty, bitter and性平 (flat in nature) taste and promotes blood circulation to remove stasis and dredge collaterals, the three are used as the ministerial drugs together. Pinellia ternata has a pungent and warm taste and has the functions of descending qi and harmonizing the stomach, drying dampness and resolving phlegm. Amomum villosum has the function of regulating qi and excreting turbidity. Together with Perilla frutescens, which disperses the lung qi, detoxifies and harmonizes the stomach, they are used as the assistant drugs together. Prepared licorice has a sweet taste and a性平 (flat in nature) taste, soothes the middle and relieves spasm, and coordinates all the drugs, thus serving as the envoy drug. The whole formula together plays the role of replenishing qi and warming yang, promoting blood circulation to remove stasis and excreting turbidity, which is in line with the pathological characteristics of chronic renal failure.

[0018] Compared with the prior art, the advantages of the present invention are as follows:

[0019] This invention targets the symptoms and pathogenesis of chronic renal failure, employing the treatment principles of invigorating qi and warming yang, resolving blood stasis and eliminating turbidity. The raw materials used in the herbal composition are inexpensive, easy to prepare, convenient to use, have few side effects, and can be taken long-term. Observation and analysis show that the herbal composition of this invention has a good therapeutic effect on chronic renal failure. Given the large number of people suffering from chronic renal failure, which causes immense physical and psychological suffering, and the currently unsatisfactory effects of RAS blockade therapy, the herbal composition and compound preparation provided by this invention have promising application prospects. Attached Figure Description

[0020] Figure 1 Comparison of renal tissue pathology and fibrosis marker protein expression in different groups of rats; Note: Compared with the sham-operated group, P < 0.001, compared with the model group, # P<0.05, ## P<0.01, ### P<0.001. Detailed Implementation

[0021] The specific implementation methods provided by the present invention will be described in detail below with reference to the embodiments.

[0022] Example 1: The traditional Chinese medicine composition of the present invention

[0023] Bupleurum 6 parts, Scutellaria baicalensis 9 parts, Pinellia ternata 6 parts, Codonopsis pilosula 9 parts, Glycyrrhiza uralensis 3-9 parts, Hirudo medicinalis 3 parts, Amomum villosum 3 parts, Perilla frutescens 9 parts, Trigonella foenum-graecum 9 parts.

[0024] Example 2: The traditional Chinese medicine composition of the present invention

[0025] Bupleurum chinense 8 parts, Scutellaria baicalensis 10 parts, Pinellia ternata 8 parts, Codonopsis pilosula 10 parts, Glycyrrhiza uralensis (processed) 5 parts, Hirudo medicinalis 5 parts, Amomum villosum 5 parts, Perilla frutescens 10 parts, Trigonella foenum-graecum 10 parts.

[0026] Example 3: The traditional Chinese medicine composition of the present invention

[0027] Bupleurum chinense 9 parts, Scutellaria baicalensis 12 parts, Pinellia ternata 9 parts, Codonopsis pilosula 12 parts, Glycyrrhiza uralensis (processed) 6 parts, Hirudo medicinalis 6 parts, Amomum villosum 6 parts, Perilla frutescens 12 parts, Trigonella foenum-graecum 12 parts.

[0028] Example 4: The traditional Chinese medicine composition of the present invention

[0029] Bupleurum 10 parts, Scutellaria baicalensis 15 parts, Pinellia ternata 10 parts, Codonopsis pilosula 15 parts, Glycyrrhiza uralensis (processed) 8 parts, Hirudo medicinalis 8 parts, Amomum villosum 8 parts, Perilla frutescens 15 parts, Trigonella foenum-graecum 15 parts.

[0030] Example 5: The traditional Chinese medicine composition of the present invention

[0031] 12 parts of Bupleuri Radix, 18 parts of Scutellariae Radix, 12 parts of Pinelliae Rhizoma Praeparatum, 18 parts of Pseudostellariae Radix, 9 parts of Glycyrrhizae Radix Praeparata, 9 parts of Hirudo, 9 parts of Amomi Fructus Rotundus, 18 parts of Perillae Folium, 18 parts of Trigonellae Semen.

[0032] Example 6: Preparation of Decoction

[0033] Adopt the conventional method for preparing traditional Chinese medicine decoction, that is, weigh any one of the traditional Chinese medicine compositions described in Examples 1-5, add water and decoct to form a decoction.

[0034] Example 7: Preparation of Tablets / Capsules

[0035] Weigh any one of the traditional Chinese medicine compositions described in Examples 1-5, grind them finely, decoct, concentrate under reduced pressure to obtain an extract, dry and crush the extract to make granules, add pharmaceutical excipients, and press into tablets or fill into capsules.

[0036] Example 8: Preparation of Granules

[0037] Weigh any one of the traditional Chinese medicine compositions described in Examples 1-5, grind them finely, decoct, concentrate under reduced pressure to obtain an extract, dry and crush the extract to make granules.

[0038] Example 9: Preparation of Pills / Oral Liquids / Syrups

[0039] Weigh any one of the traditional Chinese medicine compositions described in Examples 1-5, grind them finely, decoct, take the supernatant, and concentrate to a thick extract; add appropriate pharmaceutical excipients (such as white sugar, honey, benzoic acid or ethylparaben, etc.) to make pills, mixtures, oral liquids or syrups.

[0040] Example 10: Animal Experiments of the Invention

[0041] 1. Experimental Materials:

[0042] (1) 60 SPF-grade male Wistar rats, weighing 190-210 g, were purchased from Shanghai Slac Laboratory Animal Co., Ltd. [License No. SCXK (Shanghai) 2017-0005]. After being inspected and qualified, they were raised in the Experimental Animal Center of Shanghai University of Traditional Chinese Medicine. The environmental temperature was (22±2) °C, the relative humidity was 55%±2%, and there was 12-hour lighting. They had free access to food and water.

[0043] (2) Experimental drugs: Composed of 9 g of Bupleuri Radix, 12 g of Scutellariae Radix, 9 g of Pinelliae Rhizoma Praeparatum, 12 g of Pseudostellariae Radix, 6 g of Glycyrrhizae Radix Praeparata, 6 g of Hirudo, 6 g of Amomi Fructus Rotundus, 12 g of Perillae Folium, and 12 g of Trigonellae Semen. The crude drugs were purchased from Shanghai Wanshicheng Pharmaceutical Co., Ltd., and the origin of the traced cuttings was clear. They were prepared into a water decoction with a crude drug concentration of 1.1 g / mL by the Preparation Room of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine. The positive control drug losartan potassium (Cozaar, batch number: U000470) was purchased from Hangzhou Merck Sharp & Dohme Corp.

[0044] 2. Modeling method:

[0045] A classic 5 / 6 (Ablation / Infarction, A / I) rat model of chronic renal failure was used. (Deng A, Tang T, Singh P, et al. Regulation of oxygen utilization by angiotensin II inchronic kidney disease. Kidney Int. 2009;75(2):197-204.) After one week of acclimatization, the rats were anesthetized by intraperitoneal injection of 2% sodium pentobarbital (0.2 mL / 100 g), and the local hair was shaved and routinely disinfected with 75% alcohol. The rats were placed in a right lateral decubitus position on a heated table, and a 1.5 cm incision was made perpendicular to the spine, 0.5 cm below the left costal arch and 1 cm lateral to the left of the spine. The left kidney was selected through the retroperitoneum using a sterile long cotton swab and exposed. The renal capsule and adrenal gland were gently separated to expose the left renal artery and vein. The arteries and veins were separated using forceps. Two-thirds of the branches of the left renal artery (the posterior and anterior descending branches were ligated individually) were ligated, and hemostasis was achieved by applying gelatin sponge. The rat kidney was then returned to the peritoneal cavity, sutured, and disinfected. In the sham-operated group, the left kidney was selected through the retroperitoneum and exposed. The renal capsule and adrenal gland were gently separated. The rat kidney was then returned to the peritoneal cavity, sutured, and disinfected. One week later, the rats were placed in a left lateral decubitus position on a temperature-controlled table. The kidney was exposed using the same method, the adrenal gland was separated, and the renal arteries, veins, and ureters were ligated. The right kidney was removed. In the sham-operated group, only the adrenal gland was separated, sutured, and disinfected.

[0046] 3. Grouping and Dosing

[0047] Based on previous experience, the success rate of the model was approximately 80%. Sixty rats were randomly divided into a sham-operated group (n=10) and a model group (n=50). Four weeks after modeling, serum creatinine (Scr) levels were measured by blood collection from the inner canthus of the eyes. Rats were then stratified and randomly assigned to the following groups based on Scr and rat weight: model group, low-dose traditional Chinese medicine group, high-dose traditional Chinese medicine group, and losartan potassium positive control group, with 10 rats in each group. An additional 10 rats were selected as the sham-operated group. The drug dosages administered via gavage were calculated based on the equivalent adult and rat doses. The high-dose group (containing 1.1 g / mL of raw herb) received 8 mL / kg via gavage, and the low-dose group received 4 mL / kg. The losartan potassium group (1.3 mg / mL) received 8 mL / kg via gavage. The sham-operated group and the model group received saline solution to simulate the effects. Intervention was performed once daily for 8 consecutive weeks.

[0048] 4. Sample Collection and Processing

[0049] After the intervention, the rats were deprived of water and food for 12 hours. The next day, they were anesthetized by intraperitoneal injection of 2% sodium pentobarbital, and blood was collected from the abdominal aorta. The serum was collected by centrifugation at 4000 rpm / min for 10 min and sent to the Department of Laboratory Medicine of Shuguang Hospital to measure serum uric acid (UA), serum creatinine (SCr), and serum blood urea nitrogen (BUN) using a Beckman Coulter AU analyzer. The left kidney was harvested, cut into two pieces, one piece was fixed and embedded in 4% paraformaldehyde and prepared into 4μm sections for HE and Masson staining; the other piece was frozen at -80℃ for Western blot analysis.

[0050] 5. Western blot detection

[0051] Tissue or cell samples were lysed in RIPA containing protease inhibitors, centrifuged at 13,000 rpm / min for 10 min at 4°C, and the supernatant was collected. Protein concentration was determined by the BCA method. Protein samples were electrophoresed on SDS-PAGE gels at 120V, transferred at a constant voltage of 100V for 120 min, blocked with 5% skim milk cow's milk, and incubated overnight with primary antibodies against fibronectin (1:3000), type I collagen (Col-I, 1:3000), and α-smooth muscle actin (α-SMA, 1:3000). HRP-labeled goat anti-rabbit or anti-mouse IgG was incubated at room temperature for 1 h, and developed with ECL chemiluminescence solution. The gray values ​​of the bands were quantified using ImageJ software.

[0052] 6. Statistical Methods

[0053] SPSS 25.0 and GraphPad Prism 6 software were used for data processing and statistical analysis. Quantitative data are expressed as mean ± standard deviation (SD). The test indicates that for normally distributed continuous data, the LSD-t test is used for comparisons between groups; for non-normally distributed continuous data, the K-samples Kruskal-Wallis nonparametric test is used for comparisons between groups. For categorical data, the test is... test.

[0054] 7. Experimental Results

[0055] (1) Effects of traditional Chinese medicine composition on renal function in rats with chronic renal failure:

[0056] As shown in Table 1, compared with the sham surgery group, the serum uric acid (UA), serum creatinine (SCr), and serum urea nitrogen (BUN) levels in the model group were significantly increased; compared with the model group, the levels of UA, Scr, and BUN in the drug group were decreased, especially in the high-dose traditional Chinese medicine group and the Western medicine group.

[0057] Table 1. Comparison of UA, Scr, and BUN levels in each group after intervention ( )

[0058]

[0059] Note: Compared with the sham surgery group. P < 0.001; compared with the model group, # P<0.05, ## P<0.01, ### P<0.001.

[0060] (2) Effects of traditional Chinese medicine composition on renal tissue pathology and fibrosis in rats with chronic renal failure:

[0061] like Figure 1 As shown, HE and Masson staining results indicated that the glomerular and tubulointerstitial structures in the sham-operated group were normal, without interstitial fibrosis or inflammatory cell infiltration; the model group showed damage to the tubulointerstitial structure, with interstitial fibrosis accompanied by extensive inflammatory cell infiltration; the pathological damage and degree of interstitial fibrosis in each drug group were significantly reduced compared to the model group, especially the high-dose traditional Chinese medicine group and the Western medicine group. Western blot results showed that, compared with the sham-operated group, the expression of renal fibrosis marker proteins fibronectin, α-smooth muscle actin (α-SMA), and type I collagen (Col-I) in the renal tissue of rats in the model group was significantly increased; compared with the model group, the expression of renal fibrosis marker proteins in the renal tissue of rats in the drug groups was significantly decreased, especially the high-dose traditional Chinese medicine group and the Western medicine group.

[0062] The above experiments show that the traditional Chinese medicine composition of the present invention can effectively reduce the levels of serum uric acid, serum creatinine, and blood urea nitrogen in rats with chronic renal failure, suggesting that it has a good effect on improving renal function. Simultaneously, the traditional Chinese medicine composition of the present invention can significantly reduce renal tubular interstitial damage and collagen deposition, and downregulate the expression of fibrosis marker proteins fibronectin, α-smooth muscle actin (α-SMA), and type I collagen (Col-I), suggesting that it has a significant effect on improving tissue pathological damage and resisting renal fibrosis in rats with chronic renal failure.

[0063] The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the embodiments described. Those skilled in the art can make various equivalent modifications or substitutions without departing from the spirit of the present invention, and these equivalent modifications or substitutions are all included within the scope defined by the claims of this application.

Claims

1. A traditional Chinese medicine composition for treating chronic renal failure, characterized in that, The compound preparation is prepared by adopting the conventional preparation method in the art.

2. The traditional Chinese medicine composition according to claim 1, characterized in that, The compound preparation is a decoction, a tablet, a capsule, a granule, a pill, an oral liquid or a syrup.

3. A compound preparation using the traditional Chinese medicine composition of claim 1 or 2 as an active ingredient, characterized in that, The compound preparation further comprises a pharmaceutically acceptable excipient.

4. The complex preparation according to claim 3, characterized in that, 6. Use of the traditional Chinese medicine composition according to claim 1 or 2 in the preparation of a medicament for treating chronic renal failure.

5. The complex preparation according to claim 3, characterized in that, The medicament for treating chronic renal failure is a medicament for reducing the blood uric acid, serum creatinine and blood urea nitrogen levels of chronic renal failure and improving renal function. The medicament for treating chronic renal failure is a medicament for protecting renal tubular function and reducing renal fibrosis.

7. Use according to claim 6, characterized in that, 9. Use of the compound preparation according to any one of claims 3-5 in the preparation of a medicament for treating chronic renal failure.

8. Use according to claim 6, characterized in that, ​ ​

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