Unilateral preparation for eliminating urine protein based on ovate catalpa fruit and application of unilateral preparation

Abstract

The invention discloses a Chinese catalpa fruit-based unilateral preparation for eliminating urine protein and application thereof, and belongs to the technical field of traditional Chinese medicine, the active ingredient of the unilateral preparation is extracted from a single medicinal material of Chinese catalpa fruit, and the unilateral preparation can contain pharmaceutically acceptable auxiliary materials. The single preparation can be prepared into four dosage forms of oral liquid, tablets, dripping pills and granules so as to meet different clinical requirements. Animal experiments prove that the single preparation can effectively eliminate urine protein and improve the renal function through four synergistic mechanisms of anti-inflammation, anti-oxidation, improvement of the renal function, protection of podocyte and immunoregulation and diuresis, and is suitable for treating proteinuria accompanied by nephropathy. The preparation provided by the invention has the characteristics of single formula, easy quality control and various dosage forms, and provides a traditional Chinese medicine scheme with an exact curative effect for clinically treating related diseases.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine technology, specifically to a single-herb preparation based on *Ziziphus jujuba* (a type of orchid) for eliminating proteinuria and its application. Background Technology

[0002] Nephrotic syndrome (NS) is a glomerular disease characterized by massive proteinuria, hypoalbuminemia, hyperlipidemia, and edema. It is a key factor leading to progressive deterioration of renal function and even end-stage renal disease, posing a serious clinical threat. Proteinuria is not only the core diagnostic indicator of this syndrome but also a crucial pathological marker directly reflecting the degree of damage to the glomerular filtration barrier and the activity of the disease. Therefore, developing safe, effective, and precise treatments to eliminate proteinuria has become a critical issue urgently needing breakthroughs in the field of nephrology treatment.

[0003] Currently, clinical treatment for proteinuria associated with nephropathy mainly includes modern Western medicine and traditional Chinese medicine's syndrome differentiation and treatment methods, but both have significant limitations: On the one hand, modern medical approaches primarily rely on glucocorticoids and immunosuppressants. While effective for some patients, long-term or high-dose use often results in a range of serious side effects, including but not limited to hormone dependence or resistance, increased risk of infection, osteoporosis, and metabolic disorders (such as hypertension and hyperglycemia). In recent years, the application of renin-angiotensin system inhibitors (RASi) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) has broadened treatment options, but challenges remain, such as individual differences in efficacy, potential electrolyte disturbances, and fluctuations in renal function.

[0004] On the other hand, the principles of TCM syndrome differentiation emphasize holistic regulation. Through multiple interventions such as herbal formulas and acupuncture, it shows certain advantages in improving symptoms and reducing recurrence rates, while avoiding hormone-related adverse reactions. However, its limitations are also significant: First, syndrome differentiation and treatment are highly individualized, with efficacy closely related to the physician's experience, resulting in low standardization; second, traditional compound preparations have complex components, and their precise active material basis, systemic mechanisms of action, and in vivo processes are relatively unclear, making it difficult to strictly control product quality uniformity and resulting in poor batch-to-batch stability. This severely restricts its modern development, large-scale clinical application, and international recognition.

[0005] In conclusion, neither Western medicine nor existing traditional Chinese medicine formulas have fully met the urgent clinical need for a proteinuria treatment drug with a relatively clear mechanism, stable and controllable quality, and high safety. Therefore, identifying single medicinal materials from traditional Chinese medicine that possess both a clear pharmacodynamic material basis and multi-target therapeutic potential, and developing them into standardized formulations, has become a highly valuable research direction.

[0006] The fruit of Ovate Catalpa is the dried, ripe fruit of the catalpa tree, a plant in the Bignoniaceae family. Its diuretic, swelling-reducing, heat-clearing, and detoxifying effects have been recorded in ancient books such as the Compendium of Materia Medica. It is traditionally used for edema caused by internal retention of dampness.

[0007] However, it is worth noting that the development of a standardized single-herb formulation based on the traditional efficacy of *Citrus medica* combined with modern pharmacological evidence for the treatment of proteinuria associated with kidney disease remains a gap in this field. Therefore, this invention aims to develop a single-herb formulation based on *Citrus medica*, filling the gap in this area for targeted, well-defined single-herb formulations, and potentially providing a relatively well-defined, stable, and safe traditional Chinese medicine treatment option for clinical use. Summary of the Invention

[0008] Therefore, this invention provides a single-ingredient preparation based on Ziziphus jujuba to eliminate proteinuria, which has the effects of diuresis, swelling reduction, elimination of proteinuria, and clearing heat and detoxification, and can be used to treat edema, chronic nephritis, nephritis edema, and proteinuria.

[0009] To achieve the above objectives, the present invention provides the following technical solution: According to a first aspect of the present invention, a single-ingredient preparation for eliminating proteinuria based on *Citrus medica* is provided, wherein the active ingredient is obtained by extraction from a single medicinal herb, *Citrus medica*.

[0010] Preferably, it also contains pharmaceutically acceptable excipients.

[0011] According to a second aspect of the invention, the use of the aforementioned single-component formulation based on *Ziziphus jujuba* for eliminating proteinuria is provided in the preparation of a medicament for treating proteinuria associated with nephropathy.

[0012] Preferably, the drug includes oral liquid, tablets, pills, and granules.

[0013] Preferably, the preparation method of the oral liquid includes the following steps: Weigh 200-400g of *Catella burmannii* fruit, add 6-8 times the amount of solvent, reflux and extract 2-3 times, 1-2 hours each time. Combine the extracts, recover the solvent under reduced pressure at 60-70℃ and concentrate to a relative density of 1.10-1.15 (80℃), then cool to room temperature. Add an appropriate amount of water and 0.5-1g of preservative, stir to dissolve. After standing for 4 hours, transfer to a high-speed centrifuge for centrifugation. Take the supernatant, cool to room temperature, add water to 1000mL, and adjust the pH. Filter through a 0.45μm microporous membrane, fill into 20mL oral liquid bottles, and sterilize to obtain the oral liquid. The finished oral liquid is a brown to dark brown liquid with a slightly bitter taste and a faint odor. The oral liquid is packaged in 20mL vials, containing 4g of catalpa fruit. The oral liquid is to be taken orally, three times a day, 1 to 2 vials each time; The preservative is potassium sorbate; the pH is 5-6.5; the centrifugation parameters of the high-speed centrifuge are: rotation speed ≥8000 r / min, centrifugation time 10 min; the sterilization treatment of the oral liquid is sterilization by flowing steam at 100℃ for 30 min or sterilization by cobalt-60 irradiation, and the irradiation dose is 5-25 kGy.

[0014] Preferably, the method for preparing the tablet includes the following steps: Weigh 4000g of catalpa fruit, pulverize it and pass it through a 20-mesh sieve, and extract it by reflux with 70% ethanol; after filtration and vacuum concentration, the extract is dried to obtain dried catalpa fruit extract powder; add it together with the filler into a mixer and mix thoroughly to obtain a mixed powder, and then granulate it by dry granulation; add disintegrant, glidant and lubricant to the obtained granules in sequence, mix evenly to obtain mixed granules; send the obtained mixed granules into a tablet press to obtain the tablets; The tablets have a content of 1g per tablet; The dosage of the tablets is 1 to 2 tablets three times a day. The mass ratio of the *Citrus aurantiacus* extract powder to the filler is 12:7, and the filler is selected from at least one of dextrin, corn starch, pregelatinized starch, microcrystalline cellulose, mannitol, and lactose; the mass ratio of the disintegrant, glidant, and lubricant is 3:1:1, and the disintegrant is selected from at least one of sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and croscarmellose; the glidant is colloidal silica; and the lubricant is selected from at least one of magnesium stearate, talc, and sodium stearoyl fumarate.

[0015] Preferably, the preparation method of the droplet includes the following steps: Weigh 4000g of catalpa fruit, crush it through a 20-mesh sieve, and extract it by reflux with 70% ethanol; after filtration and vacuum concentration, the extract is dried to obtain dried catalpa fruit extract powder; heat polyethylene glycol 4000 and polyethylene glycol 6000 to melt them and use them as a matrix; add the dried catalpa fruit extract powder obtained above at 70-80℃, stir thoroughly until uniformly mixed, and add pre-cooled condensing agent dropwise at a uniform rate to condense and form droplets; collect the droplets, remove the residual condensate on the surface, and dry them to obtain the droplet preparation; The specified content of the droplet is 60 mg / pill; The dosage of the pills is 30 to 60 pills three times a day. The mass ratio of polyethylene glycol 4000 to polyethylene glycol 6000 is 3:1; the mass ratio of the matrix to the tamarisk extract powder is 2:1; the dripping rate of the pre-cooled condenser is 30-40 drops / min; the condenser is dimethyl silicone oil, and the dimethyl silicone oil is selected from at least one of dimethyl silicone oil N100, dimethyl silicone oil N200 and dimethyl silicone oil N300.

[0016] Preferably, the method for preparing the granules includes the following steps: Weigh 4000g of catalpa fruit, crush it and pass it through a 20-mesh sieve, and extract it by reflux with 70% ethanol; after filtering and concentrating under reduced pressure, the extract is dried under vacuum to obtain dried catalpa fruit extract powder; mix it evenly with filler and flavoring agent, add wetting agent to make soft material; granulate the prepared soft material through a 12-mesh sieve, collect the wet granules and dry them at a temperature not exceeding 60°C, and after drying, granulate to obtain the granules; The granules have a content of 2.4g / packet; The dosage of the granules is 1 to 2 packets three times a day. The mass ratio of the added *Citrus medica* extract powder, filler, and flavoring agent is 100:300:1; the filler is selected from at least one of starch, sucrose, microcrystalline cellulose, mannitol, and dextrin; the flavoring agent is selected from at least one of aspartame, sucralose, steviol glycosides, and edible flavorings; and the wetting agent is selected from ethanol or water.

[0017] Preferably, in the preparation methods of the oral liquid, tablets, pills and granules, water can also be used as the solvent for reflux extraction.

[0018] Compared with the prior art, the present invention has the following advantages: This invention develops four single-herb preparations (oral liquid, pills, granules, and tablets) based on the single medicinal herb *Citrus aurantium*, which have the following advantages: (1) The formulation is simple, the quality is controllable, and the efficacy is clear: Compared with traditional compound preparations, single-ingredient preparations based on *Zanthoxylum bungeanum* have clearly defined components, and the quality of raw materials and preparations is easier to control. Experiments in a rat model of doxorubicin-induced nephropathy showed that it significantly reduced urinary protein excretion and exhibited a multi-target effect.

[0019] (2) Diverse dosage forms and strong adaptability: This invention provides four dosage forms, all of which have diuretic, anti-edema, proteinuria elimination, and heat-clearing and detoxifying effects, and are suitable for treating proteinuria associated with kidney disease. Each dosage form has the following characteristics: Zishi Oral Solution: It is absorbed quickly and has a rapid effect; it has high bioavailability and accurate dosage; the liquid form is easy to swallow, making it suitable for elderly patients or patients with difficulty swallowing, and it has good convenience and safety.

[0020] Zishi Dripping Pills: Dissolve quickly and take effect rapidly, even better than oral liquids; solid dosage form has good stability, is not easily hygroscopic, and is easy to store and carry; suitable for chronic patients who need rapid onset of action and long-term treatment.

[0021] Zishi Granules: The taste has been improved through flavoring, making it easy to accept and suitable for children or those with sensitive palates; it can be taken by dissolving in water, and is also easy to dispense and adjust the dosage, taking into account both flexibility of administration and portability.

[0022] Zishi tablets: precise dosage and stable quality; easy to carry and store for a long time; mature production process, suitable for large-scale long-term treatment of chronic diseases, with controllable costs and stable supply.

[0023] (3) The synergistic mechanism of multiple targets is clear: Experiments using a rat model of doxorubicin-induced nephropathy showed that continuous administration of Zizhi oral liquid for 4 weeks significantly improved renal function, reduced structural damage, inhibited inflammatory responses, and enhanced antioxidant capacity. The specific mechanisms are as follows: Anti-inflammatory effects: The active components of *Citrus aurantium*, including flavonoids (such as apigenin and luteolin) and iridoid glycosides (such as catalpol and aucubin), can inhibit the overactivation of key inflammatory signaling pathways such as nuclear factor-κB in kidney tissue, thereby reducing the expression of pro-inflammatory factors such as TNF-α and IL-6. Animal experiments have confirmed that the serum levels of IL-1β, IL-6, and TNF-α in rats in the low, medium, and high dose groups of *Citrus aurantium* were significantly lower than those in the control group.

[0024] Antioxidant effect: Phenolic acids (such as p-coumaric acid and ferulic acid) and flavonoids in *Zanthoxylum bungeanum* possess antioxidant activity. Animal experiments have shown that low, medium, and high doses of *Zanthoxylum bungeanum* significantly increased the activity of superoxide dismutase (SOD) and catalase (CAT) in the kidney tissue of model rats, and reduced the level of malondialdehyde (MDA), a lipid peroxidation end product. This demonstrates that it can effectively alleviate oxidative stress in the kidneys by enhancing the body's own antioxidant defense capabilities.

[0025] Improve kidney function: Animal experiments have shown that low, medium, and high doses of *Citrus medica* significantly reduced 24-hour urinary protein, serum urea nitrogen (BUN), and creatinine (Scr) levels in model rats, while increasing serum albumin levels. Histopathological observations revealed reduced damage to glomerular and tubular structures and decreased collagen deposition. Furthermore, based on existing pharmacological studies, the therapeutic effects of *Citrus medica* may involve the following potential pathways: First, components such as catalpol in *Citrus medica* may maintain cytoskeleton stability and filtration barrier integrity by regulating the expression of podocyte-related proteins (such as nephrin and podocin); second, iridoid glycosides and polysaccharides in *Citrus medica* may help regulate the balance of T lymphocyte subsets, potentially reducing immune complex deposition; third, catalpol and potassium salts in *Citrus medica* may create conditions for kidney repair through mild diuresis and improved microcirculation.

[0026] In summary, Ziziphus jujuba preparations exert their therapeutic effects primarily through well-defined mechanisms such as anti-inflammatory, antioxidant, and renal function improvement. These modern pharmacological mechanisms are highly consistent with traditional Chinese medicine (TCM) theories: they align closely with the TCM theory of "deficiency of the root and excess of the branch" in the pathogenesis of kidney disease. Its "diuretic and edema-reducing" properties aim to eliminate dampness in the "excess of the branch," while its heat-clearing, detoxifying, blood-activating, and meridian-clearing effects further resolve dampness and toxins and unblock the meridians. Simultaneously, by reducing pathological damage such as inflammatory responses and oxidative stress, it helps improve renal function, thereby supporting the "deficiency of the root" in the body's vital energy. The mutual corroboration between traditional TCM understanding and modern pharmacological mechanisms reveals the scientific significance of Ziziphus jujuba in the treatment of proteinuria accompanying kidney disease.

[0027] This invention is based on a single medicinal herb, *Ziziphus jujuba*, and provides multiple dosage form options. Animal experiments have verified its clear effects in eliminating proteinuria and improving renal function. It is suitable for treating proteinuria associated with kidney disease and provides a simple and quality-controllable traditional Chinese medicine preparation for the clinical treatment of related diseases. Attached Figure Description

[0028] To more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are merely exemplary, and those skilled in the art can derive other embodiments based on the provided drawings without creative effort.

[0029] The structures, proportions, sizes, etc. illustrated in this specification are only for the purpose of assisting those skilled in the art in understanding and reading the content disclosed herein, and are not intended to limit the conditions under which the present invention can be implemented. Therefore, they have no substantial technical significance. Any modifications to the structure, changes in the proportions, or adjustments to the size, without affecting the effects and objectives that the present invention can produce, should still fall within the scope of the technical content disclosed in the present invention.

[0030] Figure 1 This is a comparison of body weight and kidney organ index of rats in the model group and the blank control group in Example 1 of the present invention; wherein, (A) is a graph showing the change in body weight of rats in the model group and the blank control group during the 8-week experiment, and (B) is a bar chart showing the kidney index of rats in the model group and the blank control group at week 8 of the experiment (n=6); statistical analysis: ### P < 0.001, compared with the blank control group; * P<0.05, ** P<0.01, *** P<0.001, compared with the model group; Figure 2 This is a comparison of urinary protein and serum albumin levels in rats of the model group and the blank control group in Example 1 of the present invention; wherein, (A) a bar chart of urinary protein levels in rats of the model group and the blank control group at week 8 of the experiment (n=6), and (B) a bar chart of serum albumin levels in rats of the model group and the blank control group at week 8 of the experiment (n=6); statistical analysis: ### P < 0.001, compared with the blank control group; * P<0.05, ** P<0.01, *** P<0.001, compared with the model group; Figure 3 This is a comparison of urea nitrogen and creatinine levels in rats of the model group and the blank control group in Example 1 of the present invention; wherein, (A) a bar chart of urea nitrogen levels in rats of the model group and the blank control group at week 8 of the experiment (n=6); (B) a bar chart of creatinine levels in rats of the model group and the blank control group at week 8 of the experiment (n=6), statistical analysis: ### P < 0.001, compared with the blank control group; * P<0.05, ** P<0.01, *** P<0.001, compared with the model group; Figure 4 This is a comparison of HE staining and Masson's trichrome staining results of kidney tissue from rats in the model group and the blank control group in Example 1 of this invention. (A) HE staining pathological micrographs of kidney tissue from rats in the model group and the blank control group at week 8 of the experiment (scale bar: 100μm, magnification: ×200); green arrows indicate protein casts, blue arrows indicate renal tubular dilation, and red arrows indicate renal tubular cell swelling, necrosis, and vacuolar lesions; (B) Masson's trichrome staining pathological micrographs of kidney tissue from rats in the model group and the blank control group at week 8 of the experiment (scale bar: 100μm, magnification: ×200); blue indicates collagen deposition. Figure 5This is a comparison of the serum levels of IL-1β, IL-6, and TNF-α in rats of the model group and the blank control group in Example 1 of this invention; wherein, (A) is a bar chart of IL-1β levels in the serum of rats of the model group and the blank control group at week 8 of the experiment, (B) is a bar chart of IL-6 levels in the serum of rats of the model group and the blank control group at week 8 of the experiment, and (C) is a bar chart of TNF-α levels in the serum of rats of the model group and the blank control group at week 8 of the experiment; statistical analysis: ### P < 0.001, compared with the blank control group; * P<0.05, ** P<0.01, *** P<0.001, compared with the model group; Figure 6 This is a comparison of CAT levels in serum and SOD and MDA levels in kidney tissue of rats in the model group and the blank control group in Example 1 of the present invention; wherein, (A) a bar chart of SOD levels in kidney tissue of rats in the model group and the blank control group at week 8 of the experiment (n=6), (B) a bar chart of CAT levels in serum of rats in the model group and the blank control group at week 8 of the experiment (n=6), (C) a bar chart of MDA levels in kidney tissue of rats in the model group and the blank control group at week 8 of the experiment (n=6); statistical analysis: ### P < 0.001, compared with the blank control group; * P<0.05, ** P<0.01, *** P<0.001, compared with the model group. Detailed Implementation

[0031] The following specific embodiments illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0032] According to a first aspect of the present invention, a single-ingredient preparation for eliminating proteinuria based on *Citrus medica* is provided, wherein the active ingredient is obtained by extraction from a single medicinal herb, *Citrus medica*.

[0033] Preferably, it also contains pharmaceutically acceptable excipients.

[0034] According to a second aspect of the invention, the use of a single-ingredient preparation of a ziziphus jujuba-based agent for eliminating proteinuria in the preparation of a medicament for treating proteinuria associated with nephropathy is provided.

[0035] Preferably, the drug includes oral liquid, tablet, pellet, and granule.

[0036] Preferably, the method for preparing the oral liquid includes the following steps: Weigh 200-400g of *Catella burmannii* fruit, add 6-8 times the amount of solvent, reflux and extract 2-3 times, 1-2 hours each time. Combine the extracts, recover the solvent under reduced pressure at 60-70℃ and concentrate to a relative density of 1.10-1.15 (80℃), then cool to room temperature. Add an appropriate amount of water and 0.5-1g of preservative, stir to dissolve. After standing for 4 hours, transfer to a high-speed centrifuge for centrifugation. Take the supernatant, cool to room temperature, add water to 1000mL, and adjust the pH. Filter through a 0.45μm microporous membrane, fill into 20mL oral liquid bottles, and sterilize to obtain the oral liquid. The finished oral liquid is a brownish-black to dark brown liquid with a slightly bitter taste and a faint odor. The oral liquid contains 4g of catalpa fruit in each 20mL vial. The oral liquid is to be taken orally, three times a day, 1 to 2 vials each time; The preservative is potassium sorbate; the pH is 5-6.5; the centrifugation parameters of the high-speed centrifuge are: speed ≥8000 r / min, centrifugation time 10 min; the sterilization treatment of the oral liquid is sterilization with flowing steam at 100℃ for 30 min or sterilization by cobalt-60 irradiation, with an irradiation dose of 5-25 kGy.

[0037] Preferably, the method for preparing tablets includes the following steps: Weigh 4000g of catalpa fruit, pulverize it and pass it through a 20-mesh sieve, and extract it by reflux with 70% ethanol; after filtration and vacuum concentration, the extract is dried to obtain dried catalpa fruit extract powder; add it together with the filler into a mixer and mix thoroughly to obtain a mixed powder, and then granulate it by dry granulation; add disintegrant, glidant and lubricant to the obtained granules in sequence, mix evenly to obtain mixed granules; send the obtained mixed granules into a tablet press to obtain tablets; The tablets contain 1g per tablet. The dosage for tablets is 1 to 2 tablets three times a day. The mass ratio of the extract powder to the filler is 12:7. The filler is selected from at least one of dextrin, corn starch, pregelatinized starch, microcrystalline cellulose, mannitol, and lactose. The mass ratio of the disintegrant, glidant, and lubricant is 3:1:1. The disintegrant is selected from at least one of sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and croscarmellose. The glidant is colloidal silica. The lubricant is selected from at least one of magnesium stearate, talc, and sodium stearoyl fumarate.

[0038] Preferably, the preparation method of the droplet includes the following steps: Weigh 4000g of catalpa fruit, crush it and pass it through a 20-mesh sieve, and extract it by reflux with 70% ethanol; after filtration and vacuum concentration, the extract is dried to obtain dried catalpa fruit extract powder; heat polyethylene glycol 4000 and polyethylene glycol 6000 to melt them and use them as a matrix; add the dried catalpa fruit extract powder obtained above at 70-80℃, stir thoroughly until uniformly mixed, and add pre-cooled condensing agent dropwise at a uniform rate to condense and form droplets; collect the droplets, remove the residual condensate on the surface, and dry them to obtain droplet preparations; The dosage of the drop pills is 60mg / pill; The dosage of the drop pills is 30 to 60 pills three times a day. The mass ratio of polyethylene glycol 4000 to polyethylene glycol 6000 is 3:1; the mass ratio of matrix to catalpa extract powder is 2:1; the dripping rate of the pre-cooled condenser is 30-40 drops / min; the condenser is dimethyl silicone oil, which is selected from at least one of dimethyl silicone oil N100, dimethyl silicone oil N200 and dimethyl silicone oil N300.

[0039] Preferably, the method for preparing granules includes the following steps: Weigh 4000g of catalpa fruit, crush it and pass it through a 20-mesh sieve, and extract it by reflux with 70% ethanol; after filtering and concentrating under reduced pressure, the extract is dried under vacuum to obtain dried catalpa fruit extract powder; mix it evenly with filler and flavoring agent, add wetting agent to make soft material; granulate the prepared soft material through a 12-mesh sieve, collect the wet particles and dry them at a temperature not exceeding 60℃, and then granulate them to obtain granules; The granules contain 2.4g per packet. The dosage for granules is 1 to 2 packets three times a day. The mass ratio of the addition of the *Citrus medica* extract powder, filler, and flavoring agent is 100:300:1; the filler is selected from at least one of starch, sucrose, microcrystalline cellulose, mannitol, and dextrin; the flavoring agent is selected from at least one of aspartame, sucralose, steviol glycosides, and edible flavoring; and the wetting agent is selected from at least one of ethanol and water.

[0040] Preferably, in the preparation methods of oral liquids, tablets, pills, and granules, water can also be used as the solvent for reflux extraction.

[0041] This experiment aims to evaluate the therapeutic effect of Zizhi monotherapy on nephrotic syndrome using an adriamycin-induced nephropathy rat model, and to preliminarily explore its mechanism of action.

[0042] Preparation Example 1 A single-ingredient oral liquid for eliminating proteinuria based on *Ziziphus jujuba* is prepared by the following steps: Weigh 400g of *Citrus aurantium* seeds, add 3200mL of 70% ethanol, reflux and extract three times, 1h each time. Combine the extracts, recover the ethanol under reduced pressure at 70℃ and concentrate to a relative density of 1.12 (80℃), then cool to room temperature. Add an appropriate amount of water and 0.8g of potassium sorbate (preservative), stir to dissolve. After standing for 4h, transfer to a high-speed centrifuge and centrifuge at 8000r / min for 10min. Take the supernatant, cool to room temperature, add water to 1000mL, and adjust the pH to 5. Filter through a 0.45μm microporous membrane, fill into 20mL oral liquid bottles, and sterilize with flowing steam at 100℃ for 30min to obtain the oral liquid. The finished product of this oral liquid is a brownish-black to dark brown liquid with a slightly bitter taste and a faint odor. The oral liquid contains 4g of catalpa fruit in each 20mL vial. The oral liquid is to be taken orally, three times a day, one to two vials each time.

[0043] Preparation Example 2 A single-ingredient tablet based on *Ziziphus jujuba* for eliminating proteinuria, prepared by the following steps: Weigh 4000g of catalpa fruit, pulverize it through a 20-mesh sieve, and extract it by reflux with 70% ethanol. After filtration and vacuum concentration, the extract is dried to obtain 600g of dried catalpa fruit extract powder. Add the dried 600g of catalpa fruit extract powder, 250g of microcrystalline cellulose (filler), and 100g of pregelatinized starch (filler) to a mixer and mix thoroughly to obtain a mixed powder. Then, granulate the mixed powder using a dry granulation machine. Add 30g of crospovidone (disintegrant), 10g of colloidal silica (flow aid), and 10g of magnesium stearate (lubricant) to the granules and mix thoroughly to obtain mixed granules. Feed the mixed granules into a tablet press to obtain tablets. The tablet contains 1g per tablet. The dosage for this tablet is 1 to 2 tablets three times a day.

[0044] Preparation Example 3 A single-ingredient drop pill for eliminating proteinuria based on *Ziziphus jujuba*, the preparation method of which includes the following steps: Weigh 4000g of catalpa fruit, pulverize it and pass it through a 20-mesh sieve, and extract it by reflux with 70% ethanol; after filtration and vacuum concentration, the extract is dried to obtain 600g of dried catalpa fruit extract powder; heat and melt 900g of polyethylene glycol 4000 and 300g of polyethylene glycol 6000 as a matrix; add the above-mentioned dried 600g of catalpa fruit extract powder at 70-80℃, stir thoroughly until uniformly mixed, and uniformly drop pre-cooled dimethyl silicone oil N100 (condenser) at a dropping rate of 30-40 drops / min, condense and form droplets; collect the droplets, remove the residual condensate on the surface, and dry to obtain the droplet preparation; The dosage of this droplet is 60mg / pill; The dosage of this pill is 30 to 60 pills three times a day.

[0045] Preparation Example 4 A single-component granule preparation for eliminating proteinuria based on *Ziziphus jujuba*, the preparation method includes the following steps: Weigh 4000g of catalpa fruit, crush it and pass it through a 20-mesh sieve, and extract it by reflux with 70% ethanol; after filtration and vacuum concentration, the extract is dried to obtain 600g of dried catalpa fruit extract powder; mix the above-mentioned 600g dried catalpa fruit extract powder, 1200g dextrin (filler), 600g sucrose (filler) and 6g aspartame (flavoring agent) evenly, add 1000mL ethanol (wetting agent) to make a soft mass; granulate the prepared soft mass through a 12-mesh sieve, collect the wet granules and dry them at a temperature not exceeding 60℃, and after drying, granulate to obtain granules; The granules contain 2.4g per packet. The dosage for this granule is 1 to 2 packets three times a day.

[0046] Example 1 1. Experimental Materials 1.1 Laboratory Animals SPF-grade male SD rats, weighing 200±20g, were purchased from Liaoning Changsheng Biotechnology Co., Ltd. [Animal License No.: SCXK(Liaoning)2020-0001]. Housing environment: All rats were housed separately in an SPF-grade environment at 20-25℃ with a 12-hour light-dark cycle, and had free access to standard feed and water. All animal experimental procedures in this application were performed in accordance with the regulations approved by the Experimental Animal Research Committee of Shenyang Pharmaceutical University.

[0047] 1.2 Experimental reagents and materials Prednisolone acetate tablets (Shanghai Jinbuhuan Lankao Pharmaceutical Co., Ltd., batch number 20220521, specification 5mg / tablet), doxorubicin hydrochloride (Shanghai Aladdin Biochemical Technology Co., Ltd., batch number H2119031, specification 100mg / bottle), Table 1 below lists the reagents used in this experiment: Table 1 Reagent Name factory Item number Anhydrous ethanol Sinopharm Chemical Reagent Co., Ltd. 100092683 xylene Sinopharm Chemical Reagent Co., Ltd. 10023418 High-efficiency sliced ​​paraffin Shanghai Huashen Rehabilitation Equipment Co., Ltd. YSQN40-91 HE staining kit SolarBio G1120-100 neutral resin SolarBio 38590 Hematoxylin staining solution servicebio G1004 Differentiation solution (using 60% ethanol as solvent) servicebio G1039 saline injection Liaoning Minkang Pharmaceutical Co., Ltd. A220936H1 4% paraformaldehyde Biosharp BL539A Catalase (CAT) kit Solarbio BC0205 Superoxide dismutase (SOD) kit Nanjing Jiancheng Biotechnology Research Institute A001-1-2 Malondialdehyde (MDA) reagent kit Nanjing Jiancheng Biotechnology Research Institute A003-1-1 Blood Urea Nitrogen (BUN) Assay Kit Solarbio BC1535 Creatinine assay kit (Scr) Nanjing Jiancheng Biotechnology Research Institute C010-2-1 IL-6 ELISA KIT Shanghai Yuanju Biotechnology Center YJ002293 IL-1β ELISA KIT Shanghai Yuanju Biotechnology Center YJ301814 TNF-α ELISA KIT Shanghai Yuanju Biotechnology Center YJ002095 Albumin Assay Kit (ALB) Nanjing Jiancheng Biotechnology Research Institute A028-1-1 Urine protein quantification test kit (CBB method) Nanjing Jiancheng Biotechnology Research Institute C035-2-1 Masson Trichrome Staining Kit Solarbio G1340 1.3 Experimental Apparatus Table 2 below lists the experimental instruments used in this experiment: Table 2 name factory model Fully automatic biological tissue dehydrator Jinhua Yidi Medical Equipment Co., Ltd. Donatello Biological tissue embedding machine Jinhua Yidi Medical Equipment Co., Ltd. YD-6D Paraffin slicer Shanghai Leica Instruments Co., Ltd. Lecia RM2235 Pathological tissue drying instrument Changzhou Zhongwei Electronic Instruments Co., Ltd. PHY-III Orthogonal optical microscope Nikon Japan Nikon Eclipse E100 Electric constant temperature drying oven Shangcheng Instrument Manufacturing Co., Ltd. 101-00A Low temperature refrigerator Meiling Biomedical BCD-202K Electronic analytical balance Ohaus Instruments Co., Ltd. CPJ1003 Multifunctional ELISA reader Thermo VARIOSKAN 2 Experimental Methods 2.1 Establishment and grouping of doxorubicin nephropathy rat model Seventy-two male SD rats were acclimatized for one week and randomly divided into a blank control group (n=12) and a model group (n=60). A renal disease model was induced using the repeated doxorubicin administration method: rats in the model group were injected via tail vein with doxorubicin hydrochloride solution (4 mg / kg and 3.5 mg / kg, respectively) on day 1 and day 15, while the blank control group was injected via tail vein with an equal volume of physiological saline. After four weeks, successful modeling was confirmed, and 60 rats with successful modeling were randomly divided into 5 groups (n=12 / group): Model group: No treatment was given; The low-dose group of Zishi (CAT-L) was treated with the oral solution from Preparation Example 1, at a dose of 0.75 g / kg. The medium-dose group of Zishi (CAT-M): The oral solution prepared in Example 1 was administered at a dose of 1.5 g / kg; The high-dose group of Zishi (CAT-H) was treated with the oral solution from Preparation Example 1, at a dose of 3 g / kg. Positive control group: Prednisolone acetate was administered at a dose of 6.3 mg / kg; Each experimental group was given the drug once daily by gavage for 4 consecutive weeks, with the dosage adjusted weekly according to body weight.

[0048] 2.2 Sample Collection and Processing Following the last administration, rats were fasted for 12 hours but allowed free access to water. Urine was collected from each experimental group over 24 hours. After urine collection, rats were euthanized, and blood was collected via the abdominal aorta, with serum separated. Kidney tissue was harvested and processed as follows: a portion of the kidney tissue was fixed in 4% paraformaldehyde for subsequent pathological examination; a small amount of kidney tissue was homogenized, and the supernatant was collected by centrifugation for biochemical analysis.

[0049] 2.3 Detection of biochemical indicators in rats The total urinary protein in rats was measured 24 hours after the last administration using a urinary protein quantification kit. Serum albumin (ALB), creatinine (Scr), and blood urea nitrogen (BUN) levels were detected using the corresponding commercially available kits. All indicators were measured according to the kit instructions, and absorbance values ​​were measured at specific wavelengths using an ELISA reader: urinary protein (595 nm), ALB (628 nm), Scr (546 nm), and BUN (640 nm).

[0050] 2.4 Histopathological examination of rat kidney tissue 2.4.1 HE staining The pathological morphology of rat kidney tissue was observed using hematoxylin-eosin (HE) staining. After thorough dewaxing twice with xylene, the tissue sections were washed with anhydrous ethanol to remove residual xylene. The sections were then immersed in a gradient of 95%, 85%, 75%, and 65% ethanol for 3 minutes each for hydration, followed by rinsing with tap water. After hematoxylin staining, the sections were differentiated using hydrochloric acid-ethanol differentiation solution, rinsed with running water for 1 minute, and then rinsed with tap water. The sections were counterstained with eosin, rinsed with running water, dehydrated with a gradient of ethanol, mounted with neutral resin, and observed under a microscope.

[0051] 2.4.2 Masson staining Masson staining was used to observe collagen fiber deposition and fibrosis in rat kidney tissue. After thorough dewaxing twice with xylene, the tissue sections were washed with anhydrous ethanol to remove residual xylene. They were then immersed in a gradient of 95%, 85%, 75%, and 65% ethanol for 3 minutes each for hydration, followed by rinsing with distilled water. Weighrt hematoxylin staining was performed for 10 minutes, followed by rinsing with distilled water. Differentiation was then performed with acidic ethanol for 15 seconds, followed by rinsing with distilled water for 30 seconds. Masson blue staining was performed for 5 minutes, followed by rinsing with distilled water for 30 seconds. Ponceau fuchsin staining was performed for 10 minutes, followed by rinsing with a weak acid working solution for 30 seconds. Treatment with phosphomolybdic acid solution was performed for 2 minutes, followed by rinsing with a weak acid working solution for 30 seconds. Aniline blue solution was treated for 2 minutes, followed by rinsing with a weak acid working solution for 30 seconds. After rinsing with running water, the sections were dehydrated with a gradient of ethanol, mounted with neutral resin, and observed under a microscope.

[0052] 2.5 Determination of serum inflammatory factors and tissue oxidative stress markers in rats 2.5.1 Measurement of inflammatory factors The levels of IL-6, IL-1β, and TNF-α in the serum of rats in each experimental group were detected by enzyme-linked immunosorbent assay (ELISA). Rat serum was collected, and the absorbance was measured at 450 nm strictly according to the kit instructions. The levels of each inflammatory factor (IL-6, IL-1β, and TNF-α) were calculated based on the standard curve.

[0053] 2.5.2 Determination of Oxidative Stress Indicators The levels of malondialdehyde (MDA) in the serum of rats in each experimental group and the activities of superoxide dismutase (SOD) and catalase (CAT) in the kidney tissue were detected using the kit. All the above indicators were performed according to the kit instructions, and the absorbance values ​​were measured at specific wavelengths using an ELISA reader: MDA (532nm), SOD (550nm) and CAT (240nm).

[0054] 2.6 Statistical Analysis All experimental data are expressed as mean ± standard error (mean ± SEM). Each sample size was 12, and experiments were independently repeated three times. Statistical analysis was performed using SPSS 25.0 software, and statistical graphs were generated using GraphPad Prism 9.0 (GraphPadPrism software, La Jolla, CA, USA). Differences among multiple samples were analyzed using one-way ANOVA. When variances were homogeneous, the LSD test was used for post-hoc testing; when variances were unequal, Dunnett's T3 test was used. A p-value < 0.05 was considered statistically significant.

[0055] 3 Experimental Results 3.1 Observation of the general condition of rats During the rearing period, the overall condition of the rats in each experimental group was observed, and the results are as follows: The rats in the blank control group were in good overall condition, showing good mental state, relatively active, with shiny fur and no hair loss; their feeding and drinking behavior was normal, their urination and defecation were normal, their feces were formed, and their bedding was relatively dry; In contrast, the rats in each model group showed varying degrees of physiological abnormalities: lethargy, huddling together, slow movements, reduced hair luster and hair loss, and skin ulceration on the tail of some individuals; decreased food and water intake, loose or unformed feces, and significantly increased bedding moisture, requiring frequent changes.

[0056] 3.2 Determination of rat body weight changes and organ indices Organ indices are important indicators for assessing the degree of organ damage. To evaluate the degree of organ damage in a rat model of doxorubicin nephropathy and the intervention effect of zishi (a traditional Chinese medicine), the changes in body weight and kidney index of the rats were measured from the start of modeling to 4 weeks after drug administration. The results are as follows: Figure 1 As shown: Depend on Figure 1 As shown in A, after the first injection of doxorubicin hydrochloride, the weight gain of rats in the blank control group was significantly higher than that of the other experimental groups, with the model group showing the slowest weight gain trend.

[0057] Depend on Figure 1As shown in Figure B, the kidney coefficient in the model group was significantly higher than that in the blank control group (P < 0.001). Compared with the model group, the kidney coefficients in the low, medium, and high dose groups of *Ziziphus jujuba* and the positive control group (prednisolone acetate) all showed varying degrees of reduction. Among them, the reduction effect in the medium and high dose groups of *Ziziphus jujuba* was very significant (P < 0.01), and the effect in the positive control group (prednisolone acetate) was extremely significant (P < 0.001). This indicates that *Ziziphus jujuba* can effectively alleviate doxorubicin-induced kidney enlargement in rats.

[0058] 3.3 Determination of urinary protein and serum albumin levels in rats Proteinuria is an important pathological marker of glomerular disease and a risk factor for podocyte injury, reflecting the disruption of the glomerular filtration barrier structure and function. To evaluate the protective effect of *Ziziphus jujuba* on renal function in a rat model of doxorubicin nephropathy, the total urinary protein and serum albumin (ALB) levels were measured 24 hours after the last administration. The results are as follows: Figure 2 As shown: Depend on Figure 2 As shown in Figure A, the 24-hour urinary protein content in the model group was significantly higher than that in the blank control group (P<0.001). Compared with the model group, the urinary protein levels in the low, medium, and high dose groups of Ziziphus jujuba and the positive control group (prednisolone acetate) were all significantly lower (P<0.001).

[0059] Depend on Figure 2 B indicates that the serum albumin level in the model group was significantly lower than that in the blank control group (P<0.001); after Zishi intervention, compared with the model group: Serum albumin levels were significantly elevated in the medium- and high-dose groups of Ziziphus jujuba and the positive control group (prednisolone acetate) (P<0.001), and the low-dose group of Ziziphus jujuba also showed a very significant increase (P<0.01).

[0060] The above results indicate that *Ziziphus jujuba* can effectively reduce proteinuria and improve hypoalbuminemia in rats with doxorubicin nephropathy. This confirms that *Ziziphus jujuba* has a certain protective effect on the glomerular filtration barrier and can alleviate damage to its structure and function.

[0061] 3.4 Determination of serum urea nitrogen and creatinine levels in rats Blood urea nitrogen (BUN) and creatinine (Scr) are key indicators for assessing renal function. BUN is primarily produced by the liver and excreted by the kidneys; elevated levels are commonly seen in pathological conditions such as renal insufficiency, glomerulonephritis, or urinary tract obstruction. Creatinine is the end product of muscle metabolism, and its blood concentration increases with declining renal function. Therefore, detecting serum BUN and Scr levels can effectively reflect renal excretory function. To investigate the effect of *Ziziphus jujuba* on renal function in rats with doxorubicin nephropathy, serum BUN and Scr levels were measured. The results are as follows: Figure 3 As shown: Depend on Figure 3 It was found that, compared with the blank control group, the serum levels of BUN and Scr in the model group rats were significantly increased (P<0.001). After Zishi intervention, compared with the model group: The serum BUN levels of rats in the low, medium, and high dose groups of Ziziphus jujuba and the positive control group (prednisolone acetate) all decreased to varying degrees. Among them, the reduction effect of the medium and high dose groups of Ziziphus jujuba was significant (P<0.05), and the effect of the positive control group (prednisolone acetate) was very significant (P<0.01). Serum Scr levels in rats in the low, medium, and high dose groups of Ziziphus jujuba and the positive control group (prednisolone acetate) all decreased to varying degrees. Among them, the reduction effect in the medium dose group of Ziziphus jujuba was significant (P<0.05), the reduction effect in the high dose group of Ziziphus jujuba was very significant (P<0.01), and the reduction effect in the positive control group (prednisolone acetate) was extremely significant (P<0.001).

[0062] The above results indicate that *Citrus medica* can effectively reduce the accumulation of BUN and Scr in rats with doxorubicin nephropathy. This confirms that *Citrus medica* can improve renal excretion and metabolic function, thereby playing a protective role in renal function.

[0063] 3.5 Histopathological morphological examination of rat kidney tissue Masson staining, based on the differences in the permeability of tissue components to dyes of different molecular weights, selectively stains to distinguish collagen fibers from muscle fibers. In this stained section, collagen fibers appear blue or green, while muscle fibers appear red, and it is commonly used to assess the degree of renal fibrosis. To further investigate the protective effect of *Ziziphus jujuba* on the kidney tissue of rats with doxorubicin nephropathy, morphological changes were observed by HE staining, and the degree of renal fibrosis was assessed using Masson staining. The results are as follows: Figure 4 As shown: HE staining results ( Figure 4 A): The kidney tissue structure of the blank control group was intact, the glomeruli were normal, the renal tubules were arranged regularly, and there was no inflammatory cell infiltration. The kidney tissue sections of the model group showed obvious pathological changes: protein cast formation, renal tubular dilation, tubular cell swelling and necrosis, vacuolar lesions in the renal tubules, and glomerular sclerosis. After intervention with Zishi, compared with the model group, the above-mentioned pathological damage in the kidney tissue of the medium- and high-dose Zishi groups and the positive control group (prednisolone acetate) were improved to varying degrees.

[0064] Masson staining results ( Figure 4 B): No significant collagen deposition was observed in the blank control group; The model group showed extensive collagen fiber proliferation, exhibiting significant fibrotic pathological changes; Compared with the model group, collagen deposition and fibrosis area were significantly reduced in kidney tissue sections of the low, medium and high dose groups of Zishi and the positive control group (prednisolone acetate).

[0065] The above results indicate that *Zanthoxylum bungeanum* can alleviate doxorubicin-induced damage to kidney tissue structure and effectively inhibit abnormal collagen fiber deposition and the progression of renal fibrosis. This confirms that *Zanthoxylum bungeanum* has a protective effect on the kidneys.

[0066] 3.6 Determination of serum inflammatory factor levels in rats Inflammation is the initial stimulus inducing renal fibrosis and persists throughout the disease progression. This response damages glomerular structure and impairs the filtration system. To evaluate the anti-inflammatory effect of *Ziziphus jujuba* on rats with doxorubicin nephropathy, the serum levels of key pro-inflammatory factors IL-6, IL-1β, and TNF-α in each experimental group were measured. The results are as follows: Figure 5 As shown: Depend on Figure 5 It was found that, compared with the blank control group, the serum levels of IL-6, IL-1β and TNF-α in the model group rats were significantly increased (P < 0.001). After Zishi's intervention, compared with the model group: Both the high-dose group of Ziziphus jujuba and the positive control group (prednisolone acetate) significantly reduced serum IL-1β levels (P < 0.001), and the low- and medium-dose groups of Ziziphus jujuba also showed significant reduction effects (P < 0.05). Figure 5 A); The positive control group (prednisolone acetate) significantly reduced serum IL-6 levels (P < 0.001), and the low, medium, and high dose groups of Ziziphus jujuba also showed very significant reduction effects (P < 0.01). Figure 5 B); The positive control group (prednisolone acetate) significantly reduced serum TNF-α levels (P < 0.001), and both the medium and high dose groups of Ziziphus jujuba showed very significant reduction effects (P < 0.01). The low dose group of Ziziphus jujuba also achieved a significant reduction (P < 0.05). Figure 5 C).

[0067] The above results indicate that *Ziziphus jujuba* can effectively inhibit the release of key pro-inflammatory factors in rats with doxorubicin nephropathy, demonstrating its anti-inflammatory effect. This confirms that *Ziziphus jujuba* can alleviate inflammation-mediated glomerular structural damage and renal fibrosis by reducing the inflammatory response, thereby exerting a nephroprotective effect.

[0068] 3.7 Determination of oxidative stress indicators in rats Studies have shown that oxidative stress induces renal interstitial fibrosis through multiple pathways. When oxidative stress occurs, fibroblasts are activated and their transformation into myofibroblasts is promoted, inducing extracellular matrix deposition and thus triggering renal fibrosis. Secondly, oxidative stress participates in the EMT process, exacerbating renal fibrosis. Oxidative stress can recruit macrophages and other monocytes, subsequently inducing various growth factors, leading to the destruction of normal kidney tissue and irreversible fibrosis. Furthermore, oxidative stress has been shown to directly participate in endothelial-mesenchymal transition, ultimately leading to renal fibrosis. To investigate the effects of *Ziziphus jujuba* on oxidative stress in doxorubicin-induced nephropathy rats, the serum levels of malondialdehyde (MDA) and the activities of superoxide dismutase (SOD) and catalase (CAT) in the kidney tissue of rats in each experimental group were measured. The results are as follows: Figure 6 As shown: Depend on Figure 6 It was found that, compared with the blank control group, the serum MDA level of rats in the model group was significantly increased (P<0.001), while the SOD and CAT activities in the kidney tissue were significantly decreased (P<0.001).

[0069] After Zishi's intervention, compared with the model group: SOD activity in the kidney tissue of rats in the low, medium, and high dose groups of *Ziziphus jujuba* and the positive control group (prednisolone acetate) all showed varying degrees of increase. Among them, the increase in the high dose group of *Ziziphus jujuba* was significant (P < 0.05), and the increase in the positive control group (prednisolone acetate) was extremely significant (P < 0.001). Figure 6 A); The activity of CAT in the kidney tissue of rats in the high-dose group of Ziziphus jujuba and the positive control group (prednisolone acetate) was significantly increased (P<0.001), and the low- and medium-dose groups of Ziziphus jujuba also showed a very significant increase (P<0.01). Figure 6 B); Serum MDA levels in rats in the high-dose group of *Ziziphus jujuba* and the positive control group (prednisolone acetate) were significantly reduced (P < 0.001), and the low- and medium-dose groups of *Ziziphus jujuba* also showed a very significant decreasing effect (P < 0.01). Figure 6 C).

[0070] The above results indicate that *Ziziphus jujuba* can significantly reduce the production of the oxidative stress end product MDA and effectively enhance the activity of endogenous renal antioxidant enzymes SOD and CAT. This confirms that *Ziziphus jujuba* can exert a nephroprotective effect by enhancing the body's antioxidant defense capacity and reducing oxidative stress damage to renal tissue.

[0071] In summary, *Ziziphus jujuba* exerts a comprehensive protective effect against doxorubicin-induced nephropathy through multiple pathways, including anti-inflammatory, antioxidant, and direct improvement of renal function. Its mechanisms mainly involve the following three aspects: Improving Kidney Function and Structural Damage: *Zanthoxylum bungeanum* significantly reduced urinary protein, serum creatinine, and blood urea nitrogen levels in model rats, increased serum albumin content, effectively alleviated protein metabolism disorders, and improved glomerular filtration function. Simultaneously, pathological observations confirmed that *Zanthoxylum bungeanum* can reduce pathological damage to kidney tissue and inhibit collagen deposition and the progression of renal fibrosis.

[0072] Exercising anti-inflammatory effects: Ziziphus jujuba can significantly reduce the levels of key pro-inflammatory factors (IL-1β, IL-6, TNF-α) in the serum of model rats, indicating that it can inhibit the inflammatory response and alleviate inflammation-mediated kidney tissue damage.

[0073] Enhanced antioxidant defense: Ziziphus jujuba can significantly increase the activity of antioxidant enzymes (SOD, CAT) in the kidney tissue of model rats and reduce the level of oxidative stress end products (MDA), thereby enhancing the body's endogenous antioxidant capacity and reducing the damage of oxidative stress to the kidneys.

[0074] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A single-ingredient preparation for eliminating proteinuria based on *Ziziphus jujuba*, characterized in that, Its active ingredients are extracted from a single medicinal herb, *Citrus aurantium*.

2. The single-agent preparation for eliminating proteinuria based on *Ziziphus jujuba* as described in claim 1, characterized in that, It also contains pharmaceutically acceptable excipients.

3. The use of the single-component preparation of the protein-eliminating agent based on Ziziphus jujuba as described in any one of claims 1 or 2 in the preparation of a drug for treating proteinuria associated with nephropathy.

4. The application as described in claim 3, characterized in that, The drugs include oral liquids, tablets, pills, and granules.

5. The application as described in claim 4, characterized in that, The preparation method of the oral liquid includes the following steps: Weigh 200-400g of *Catella burmannii* fruit, add 6-8 times the amount of solvent, reflux and extract 2-3 times, 1-2 hours each time. Combine the extracts, recover the solvent under reduced pressure at 60-70℃ and concentrate to a relative density of 1.10-1.15, then cool to room temperature. Add an appropriate amount of water and 0.5-1g of preservative, stir to dissolve. After standing for 4 hours, transfer to a high-speed centrifuge for centrifugation. Take the supernatant, cool to room temperature, add water to 1000mL, and adjust the pH. Filter through a 0.45μm microporous membrane, fill into 20mL oral liquid bottles, and sterilize to obtain the oral liquid. The preservative is potassium sorbate; the pH is 5-6.5; the centrifugation parameters of the high-speed centrifuge are: rotation speed ≥8000 r / min, centrifugation time 10 min; the sterilization treatment of the oral liquid is sterilization by flowing steam at 100℃ for 30 min or sterilization by cobalt-60 irradiation, and the irradiation dose is 5-25 kGy.

6. The application as described in claim 4, characterized in that, The method for preparing the tablet includes the following steps: Weigh 4000g of catalpa fruit, pulverize it through a 20-mesh sieve, and extract it by reflux with a solvent. After filtration and vacuum concentration, the extract is dried to obtain a dry catalpa fruit extract powder. The powder is then mixed with a filler in a mixer to obtain a mixed powder, which is then granulated by a dry granulation machine. Disintegrant, glidant, and lubricant are added to the granules in sequence and mixed evenly to obtain mixed granules. The mixed granules are then fed into a tablet press to obtain the tablets. The mass ratio of the *Citrus aurantiacus* extract powder to the filler is 12:7, and the filler is selected from at least one of dextrin, corn starch, pregelatinized starch, microcrystalline cellulose, mannitol, and lactose; the mass ratio of the disintegrant, glidant, and lubricant is 3:1:1, and the disintegrant is selected from at least one of sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and croscarmellose; the glidant is colloidal silica; and the lubricant is selected from at least one of magnesium stearate, talc, and sodium stearoyl fumarate.

7. The application as described in claim 4, characterized in that, The preparation method of the droplet includes the following steps: Weigh 4000g of catalpa fruit, pulverize it and pass it through a 20-mesh sieve, and extract it by reflux with a solvent; after filtering and concentrating under reduced pressure, the extract is dried under vacuum to obtain dried catalpa fruit extract powder; heat polyethylene glycol 4000 and polyethylene glycol 6000 to melt them and use them as a matrix; add the dried catalpa fruit extract powder obtained above at a temperature of 70-80℃, stir thoroughly until uniformly mixed, and add pre-cooled condensing agent dropwise at a uniform rate to condense and form droplets; collect the droplets, remove the residual condensate on the surface, and dry them to obtain the droplet preparation; The mass ratio of polyethylene glycol 4000 to polyethylene glycol 6000 is 3:1; the mass ratio of the matrix to the tamarisk extract powder is 2:1; the dripping rate of the pre-cooled condenser is 30-40 drops / min; the condenser is dimethyl silicone oil, and the dimethyl silicone oil is selected from at least one of dimethyl silicone oil N100, dimethyl silicone oil N200 and dimethyl silicone oil N300.

8. The application as described in claim 4, characterized in that, The method for preparing the granules includes the following steps: Weigh 4000g of catalpa fruit, crush it and pass it through a 20-mesh sieve, and extract it by reflux with a solvent; after filtering and concentrating under reduced pressure, the extract is dried under vacuum to obtain dried catalpa fruit extract powder; mix it evenly with filler and flavoring agent, add wetting agent to make soft material; granulate the prepared soft material through a 12-mesh sieve, collect the wet particles and dry them at a temperature not exceeding 60°C, and after drying, granulate to obtain the granules; The mass ratio of the added *Citrus medica* extract powder, filler, and flavoring agent is 100:300:1; the filler is selected from at least one of starch, sucrose, microcrystalline cellulose, mannitol, and dextrin; the flavoring agent is selected from at least one of aspartame, sucralose, steviol glycosides, and edible flavorings; and the wetting agent is selected from ethanol or water.

9. The application as described in any one of claims 5-8, characterized in that, In the preparation methods of the oral liquid, tablets, pills and granules, the solvent for reflux extraction is water or 70% ethanol.

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