Compound calculus granule for treating urinary calculus and its preparation method and application

Abstract

This invention discloses a compound stone granule for treating the urinary system, its preparation method, and its application, belonging to the field of traditional Chinese medicine preparation technology. The granules are made from Lysimachia christinae, Lygodium japonicum, Gallus gallus domesticus gizzard lining, Pyrrosia lingua, Kochia scoparia, Polygonum capitatum, Plantago asiatica, Gentiana scabra, Polygonum cuspidatum, Lysimachia christinae, Sedum sarmentosum, Zea mays silk, Epimedium brevicornu, Juncus effusus, Achyranthes bidentata, and Glycyrrhiza uralensis. Preparation involves reflux extraction with 60% ethanol three times, 2 hours each time, followed by vacuum concentration to obtain a compound stone extract. The extract is then wet-granulated with lactose at a 1:3 ratio, and dried to obtain the final product. The process of this invention has been optimized through orthogonal experiments, resulting in a stable extract yield. The particle size, moisture content, and solubility of the granules all meet the pharmacopoeia standards. A TLC-HPLC quality control method has been established. In vitro experiments have confirmed that the aqueous solution of this compound stone granules has a concentration-dependent inhibitory effect on calcium oxalate crystallization, with a high concentration inhibition rate of 39.773%. It can protect renal tubules and optimize the urinary tract microenvironment, making it suitable for the prevention and treatment of urinary system stones. The process is simple and low-cost, making it suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine preparation technology, specifically, it relates to a compound stone granule for treating urinary system stones, its preparation method and application. Background Technology

[0002] Urinary tract stones, a common disease of the urinary system, include kidney stones, ureteral stones, and bladder stones. They are characterized by high recurrence rates and long disease courses, with calcium oxalate stones accounting for the largest proportion of clinical stone cases. Currently, clinical interventions for urinary tract stones mainly include three categories: surgery, chemotherapy, and traditional Chinese medicine (TCM) preparations. Surgery is mostly used for patients with large and severe stones, but it is invasive and carries the risk of postoperative complications. Chemotherapy has a narrow range of applicable cases and limited clinical application. Therefore, TCM preparations have become the mainstream research direction in the conservative treatment of urinary tract stones at present.

[0003] Existing stone granules still have significant technical shortcomings: First, most extraction processes are relatively simple, often using pure water extraction, resulting in low dissolution of effective components such as flavonoids and sterols. The processes have not undergone multi-factor systematic optimization, leading to poor stability. Second, stone extracts are highly viscous and hygroscopic, and existing excipients have poor compatibility, easily causing problems such as loose particles, poor solubility, and clumping, making industrial production difficult. Third, the product quality control system is simple, lacking qualitative and quantitative detection methods, making it difficult to accurately control the core active ingredients. Fourth, most formulations lack in vitro crystal inhibition experiments to support their efficacy, and the study of their mechanisms of action is superficial, resulting in insufficient evidence of efficacy.

[0004] To address the aforementioned technical deficiencies, there is an urgent need in this field to optimize the preparation process of compound stone-forming granules, screen appropriate extraction parameters to improve the extraction rate of active ingredients, match special excipients and proportions for high-viscosity extracts to improve granule forming quality and reduce production difficulty, establish comprehensive and reliable quality testing methods to ensure batch-to-batch stability of the drug, and supplement in vitro crystallization experiments to clarify the anti-crystallization pharmacology. In summary, developing a compound stone-forming granule with a simple process, controllable quality, excellent anti-crystallization effect, and suitability for industrial production is a pressing technical problem that needs to be solved in this field. Summary of the Invention

[0005] This invention addresses the technical shortcomings of existing traditional Chinese medicine preparations for treating urinary system stones, such as low extraction rate, poor compatibility of excipients, difficulty in granulation, simple quality control, and unclear mechanism of action. It provides a compound stone-forming granule for treating urinary system stones, its preparation method, and its application. This invention aims to optimize the extraction and granulation processes, improve the extraction rate of active ingredients from medicinal materials, overcome the difficulties in granulating high-viscosity extracts, and obtain traditional Chinese medicine granules with uniform particle size, good solubility, and stable quality. Simultaneously, it establishes a comprehensive quality testing method and verifies its anti-crystallization activity through in vitro crystallization experiments, clarifying the drug's mechanism of action. This provides a novel compound traditional Chinese medicine granule for the prevention and treatment of urinary system stones that is easy to prepare, low-cost, safe, reliable, and suitable for industrial mass production.

[0006] This invention is achieved using the following technical solution: A compound stone granule for treating urinary system stones, the effective medicinal ingredients of which, by weight, are: 50-150 parts of Lysimachia christinae, 60-150 parts of Lygodium japonicum, 50-150 parts of chicken gizzard lining, 40-130 parts of Pyrrosia lingua, 20-100 parts of Kochia scoparia, 30-90 parts of Polygonum capitatum, 30-100 parts of Plantago asiatica, 20-100 parts of Gentiana scabra, 40-120 parts of Polygonum cuspidatum, 10-100 parts of Clematis chinensis, 10-80 parts of Sedum sarmentosum, 10-60 parts of Zea mays, 10-60 parts of Epimedium brevicornu, 10-70 parts of Juncus effusus, 20-100 parts of Achyranthes bidentata, and 10-60 parts of Glycyrrhiza uralensis.

[0007] The aforementioned compound stone granules for treating urinary system stones contain the following active ingredients by weight: 80-120 parts of Lysimachia christinae, 80-110 parts of Lygodium japonicum, 90-120 parts of chicken gizzard lining, 60-100 parts of Pyrrosia lingua, 50-80 parts of Kochia scoparia, 40-70 parts of Polygonum capitatum, 50-80 parts of Plantago asiatica, 40-80 parts of Gentiana scabra, 50-90 parts of Polygonum cuspidatum, 30-70 parts of Clematis chinensis, 40-60 parts of Sedum sarmentosum, 20-40 parts of Zea mays, 20-40 parts of Epimedium brevicornu, 20-50 parts of Juncus effusus, 50-70 parts of Achyranthes bidentata, and 20-50 parts of Glycyrrhiza uralensis.

[0008] Specifically, the aforementioned compound stone granules for treating urinary system stones contain the following active ingredients by weight: 100 parts of Lysimachia christinae, 100 parts of Lygodium japonicum, 100 parts of chicken gizzard lining, 80 parts of Pyrrosia lingua, 60 parts of Kochia scoparia, 60 parts of Polygonum capitatum, 60 parts of Plantago asiatica, 60 parts of Gentiana scabra, 70 parts of Polygonum cuspidatum, 50 parts of Clematis chinensis, 50 parts of Sedum sarmentosum, 30 parts of Zea mays, 30 parts of Epimedium brevicornu, 30 parts of Juncus effusus, 60 parts of Achyranthes bidentata, and 30 parts of Glycyrrhiza uralensis.

[0009] The aforementioned method for preparing compound stone granules for treating urinary system stones is carried out according to the following steps: (1) Weigh all the medicinal materials in the formula according to the proportion, cut all the medicinal materials into 1-2cm small pieces, put them in a round bottom flask, add 0-80% ethanol solution, the mass ratio of the total amount of medicinal materials to 0-80% ethanol is 1:10-20, stir evenly, and carry out the first reflux extraction at 40-100℃ for 1-3h. After the extraction is completed, immediately filter the residue and filtrate under vacuum pressure of 0.01MPa to -0.1MPa, collect the filtrate, add 0-80% ethanol solution to the residue, the mass ratio of the residue to 0-80% ethanol is 1:10-20, stir evenly, and carry out the second reflux extraction at 40-100℃ for 1-3h. After the extraction is completed, immediately filter the residue and filtrate, collect the filtrate, and carry out the third reflux extraction according to the second reflux extraction method. After the extraction is completed, combine the filtrates obtained from the three extractions to obtain the compound stone extract, which is ready for use. (2) Take the compound stone extract and put it into a rotary evaporator with a temperature of 40-100℃, a vacuum degree of -0.01MP to -0.1MPa, and a rotation speed of 100-300r / min for vacuum concentration. Concentrate it to 1 / 5-1 / 6 of the original filtrate volume to obtain a compound stone extract with a relative density of 0.8-1.5 for later use. (3) Take the compound stone extract and add lactose. The mass ratio of the compound stone extract to lactose is 1:1-5. Stir evenly to obtain a mixed soft material for later use. (4) The mixed soft material is put into the granulator and extruded and granulated using a 10-20 mesh screen. The wet granules are placed in a drying oven at a temperature of 40-100℃ for 1-8 hours. The dried granules are then sieved through an 8-15 mesh screen to obtain compound stone granules.

[0010] Specifically, the preparation method of the aforementioned compound stone granules for treating urinary system stones is carried out according to the following steps: (1) Weigh all the medicinal materials in the formula according to the proportion, cut all the medicinal materials into small pieces of 1-2cm, put them in a round bottom flask, add 40-70% ethanol solution, the mass ratio of the total amount of medicinal materials to 40-70% ethanol is 1:12-18, stir evenly, and carry out the first reflux extraction at 50-75℃ for 1.5-2.5h. After the extraction is completed, immediately filter the residue and filtrate under vacuum pressure of 0.04MPa to -0.08MPa, collect the filtrate, add 40-70% ethanol solution to the residue, the mass ratio of the residue to 40-70% ethanol is 1:12-18, stir evenly, and carry out the second reflux extraction at 40-75℃ for 1.5-2.5h. After the extraction is completed, immediately filter the residue and filtrate, collect the filtrate, and carry out the third reflux extraction according to the second reflux extraction method. After the extraction is completed, combine the filtrates obtained from the three extractions to obtain the compound stone extract, which is ready for use. (2) Take the compound stone extract and put it into a rotary evaporator with a temperature of 40-75℃, a vacuum degree of 0.04MPa to -0.08MPa, and a rotation speed of 150-250r / min for vacuum concentration. Concentrate it to 1 / 5-1 / 6 of the original filtrate volume to obtain a compound stone extract with a relative density of 0.9-1.2 for later use. (3) Take the compound stone extract and add lactose. The mass ratio of the compound stone extract to lactose is 1:2-4. Stir evenly to obtain a mixed soft material for later use. (4) The mixed soft material is put into the granulator and extruded and granulated using a 12-17 mesh screen. The wet granules are placed in a drying oven at a temperature of 40-75℃ for 2-6 hours. The dried granules are then sieved through a 10-14 mesh screen to obtain compound stone granules.

[0011] Specifically, the preparation method of the aforementioned compound stone granules for treating urinary system stones is carried out according to the following steps: (1) Weigh all the medicinal materials in the formula according to the proportion, cut all the medicinal materials into small pieces of 1-2 cm, put them in a round bottom flask, add 60% ethanol solution, the mass ratio of the total amount of medicinal materials to 60% ethanol is 1:15, stir evenly, and perform the first reflux extraction at 60℃ for 2 hours. After the extraction is completed, immediately separate the residue and filtrate by vacuum filtration at 0.06 MPa, collect the filtrate, add 60% ethanol solution to the residue, the mass ratio of the residue to 60% ethanol is 1:15, stir evenly, and perform the second reflux extraction at 60℃ for 2 hours. After the extraction is completed, immediately separate the residue and filtrate by vacuum filtration, collect the filtrate, and perform the third reflux extraction according to the second reflux extraction method. After the extraction is completed, combine the filtrates obtained from the three extractions to obtain the compound stone extract, which is ready for use. (2) Take the compound stone extract and put it into a rotary evaporator with a temperature of 60℃, a vacuum degree of -0.06MPa and a rotation speed of 200r / min for vacuum concentration. Concentrate it to 1 / 5-1 / 6 of the original filtrate volume to obtain a compound stone extract with a relative density of 1.09 for later use. (3) Take the compound stone extract and add lactose. The mass ratio of the compound stone extract to lactose is 1:3. Stir evenly to obtain a mixed soft material for later use. (4) The mixed soft material is put into the granulator and extruded and granulated using a 14-mesh sieve. The wet granules are placed in a drying oven at 60°C for 4 hours. The dried granules are then sieved through a 12-mesh sieve to obtain compound stone granules.

[0012] The aforementioned compound stone granules are used in the preparation of products for treating urinary system stones.

[0013] The aforementioned products for treating urinary system stones are pharmaceuticals.

[0014] The aforementioned compound stone-inhibiting granules showed an inhibition rate of 39.773% against calcium oxalate crystallization at a concentration of 3.0 g / mL, demonstrating concentration-dependent crystal inhibition, protection of renal tubules, and optimization of the urinary tract microenvironment.

[0015] Beneficial effects of this invention: 1. The compound stone granules of this invention are made from Lysimachia christinae Hance, Lygodium japonicum, Gallus gallus domesticus gizzard lining, Pyrrosia lingua, Kochia scoparia, Polygonum capitatum, Plantago asiatica, Gentiana scabra, Polygonum cuspidatum, Lysimachia christinae, Sedum sarmentosum, Zea mays silk, Epimedium, Juncus effusus, Achyranthes bidentata, and Glycyrrhiza uralensis. Lysimachia christinae Hance is the dried whole herb of the Primulaceae plant Lysimachia christinae Hance, which is sweet, salty, and slightly cold in nature; it enters the liver, gallbladder, kidney, and bladder meridians; it has the functions of promoting diuresis and relieving jaundice, promoting urination and relieving strangury, detoxifying and reducing swelling; it is used for damp-heat jaundice, gallbladder distension and hypochondriac pain, urinary stones, hot strangury, painful urination, carbuncles and boils, and snake and insect bites. Lygodium japonicum (Thunb.) Sw., a plant in the Lygodiumceae family, is a dried, mature spore. It is sweet, salty, and cold in nature; it enters the bladder and small intestine meridians; it clears heat and dampness, promotes urination and relieves pain; it is used for urinary tract infections, urinary stones, hematuria, chyluria, and painful urination. Chicken gizzard lining is the dried inner wall of the gizzard of the domestic chicken (Gallus gallus domesticus Brisson); it is sweet and neutral in nature; it enters the spleen, stomach, small intestine, and bladder meridians; it strengthens the stomach and promotes digestion, astringes essence and stops seminal emission, promotes urination and dissolves stones; it is used for indigestion, vomiting and diarrhea, infantile malnutrition, enuresis, seminal emission, painful urination due to stones, and gallbladder distension and hypochondriac pain. *Pyrrosia sheareri* (Bak.) Ching, *Pyrrosia lingua* (Thunb.) Farwell, or *Pyrrosia petiolosa* (Christ) Ching (all belonging to the Polypodiaceae family) are dried leaves. They are sweet and bitter in taste, and slightly cold in nature. They enter the lung and bladder meridians. Their functions include promoting urination and relieving strangury, clearing the lungs and relieving cough, cooling the blood and stopping bleeding. They are used for urinary tract infections, hematuria, urinary stones, difficulty urinating, painful urination, cough due to lung heat, hematemesis, epistaxis, hematuria, and metrorrhagia. *Kochia scoparia* (L.) Schrad. (all belonging to the Chenopodiaceae family) are dried, mature fruits. They are pungent and bitter in taste, and cold in nature. They enter the kidney and bladder meridians. Their functions include clearing heat and dampness, dispelling wind and relieving itching. They are used for painful urination, vaginal itching and leukorrhea, urticaria, eczema, and pruritus. Polygonum capitata (Buch.-Ham. ex D. Don) H. Gross), a perennial herb belonging to the Polygonaceae family, is used medicinally in its entirety. It has a bitter and pungent taste, and is cool in nature. It possesses the effects of clearing heat and dampness, promoting blood circulation and relieving pain; it is used to treat traumatic injuries with bruises and pain, hematuria, dribbling urination, and sores. Plantago asiatica L. or Plantago depressa Willd., belonging to the Plantaginaceae family, is the dried whole herb. It has a sweet and cold taste; it enters the liver, kidney, lung, and small intestine meridians; it has the effects of clearing heat and promoting diuresis, relieving strangury, resolving phlegm, cooling blood, and detoxifying; it is used for painful urination due to heat, edema with scanty urine, summer-heat diarrhea, cough with phlegm and heat, hematemesis, epistaxis, carbuncles, and boils.Gentian is the dried root and rhizome of Gentiana manshurica Kitag., Gentiana scabra Bge., Gentiana triflora Pall., or Gentiana rigescens Franch., all belonging to the Gentianaceae family. It is bitter and cold in nature, and enters the liver and gallbladder meridians. It has the functions of clearing heat and drying dampness, purging liver and gallbladder fire, and is used for damp-heat jaundice, swelling and itching of the genitals, leukorrhea, eczema and itching, red eyes due to liver fire, tinnitus and deafness, hypochondriac pain and bitter taste in the mouth, priapism, and infantile convulsions. Polygonum cuspidatum Sieb. et Zucc., a plant in the Polygonaceae family, is a dried rhizome and root. It has a slightly bitter and slightly cold nature; it enters the liver, gallbladder, and lung meridians. Its functions include promoting diuresis and relieving jaundice, clearing heat and detoxifying, dispersing blood stasis and relieving pain, and stopping cough and resolving phlegm. It is used for damp-heat jaundice, urinary tract infections, leukorrhea, rheumatic pain, carbuncles and boils, burns, amenorrhea, abdominal masses, traumatic injuries, and cough due to lung heat. Hypericum japonicum Thunb. ex Murray, an annual or perennial herb in the Hypericaceae family, is also used medicinally. It has a bitter-sweet taste, slightly bitter, and is cool in nature. Its functions include detoxification, anti-cancer properties, reducing swelling, and clearing blood heat. It is used to treat hepatitis, cirrhosis, lung pain, mastalgia, erysipelas, hemorrhage, snake bites, and malignant sores and boils. *Sedum sarmentosum* Bunge, a plant in the Crassulaceae family, is the dried whole herb. It is sweet, bland, and cool in nature; it enters the liver, gallbladder, and small intestine meridians. It has the functions of promoting diuresis and relieving jaundice, clearing heat and detoxifying; it is used for damp-heat jaundice, difficulty urinating, and carbuncles and sores. *Zea mays* L., a plant in the Poaceae family, is the dried style and stigma of corn silk. It is sweet, bland, and neutral in nature; it enters the bladder, liver, and gallbladder meridians. It has the functions of promoting diuresis and reducing swelling, calming the liver and gallbladder; it is used for edema with scanty urine, damp-heat jaundice, and dizziness. *Epimedium brevicornu* Maxim., *Epimedium sagittatum* (Sieb. et Zucc.) Maxim., *Epimedium pubescens* Maxim., or *Epimedium koreanum* Nakai, all plants in the Berberidaceae family. Harvested in summer and autumn when the stems and leaves are lush, then sun-dried or shade-dried; pungent, sweet, and warm in nature; enters the liver and kidney meridians; tonifies kidney yang, strengthens tendons and bones, and dispels wind and dampness; used for kidney yang deficiency, impotence, seminal emission, weakness of tendons and bones, rheumatic pain, numbness, and contracture. Juncus effusus L. (also known as rush pith) is the dried pith of the stem of Juncus effusus L. (family Juncaceae); sweet, bland, and slightly cold in nature; enters the heart, lung, and small intestine meridians; clears heart fire and promotes urination; used for irritability, insomnia, scanty and painful urination, and oral ulcers.Achyranthes bidentata is the dried root of the plant Achyranthes bidentata Bl. of the Amaranthaceae family; it tastes bitter, sweet, and sour, and is neutral in nature; it enters the liver and kidney meridians; it has the functions of removing blood stasis and promoting menstruation, tonifying the liver and kidneys, strengthening tendons and bones, promoting urination and relieving strangury, and guiding blood downward; it is used for amenorrhea, dysmenorrhea, soreness of the waist and knees, weakness of tendons and bones, strangury, edema, headache, dizziness, toothache, canker sores, hematemesis, and epistaxis. Licorice is the dried root and rhizome of Glycyrrhiza uralensis Fisch., Glycyrrhiza inflata Bat., or Glycyrrhiza glabra L., all belonging to the Fabaceae family. It is sweet and neutral in nature; it enters the heart, lung, spleen, and stomach meridians. Its functions include tonifying the spleen and replenishing qi, clearing heat and detoxifying, resolving phlegm and relieving cough, alleviating spasms and pain, and harmonizing other herbs. It is used for spleen and stomach weakness, fatigue, palpitations, shortness of breath, cough with excessive phlegm, abdominal and limb spasms and pain, carbuncles and boils, and to alleviate the toxicity and harshness of other drugs.

[0016] Solution: The formula contains three herbs: Lysimachia christinae, a "holy medicine for expelling stones," which effectively clears damp-heat in the lower burner and dissolves and expels stones; Lygodium japonicum, a diuretic and urinary tract infection remedy, especially effective in relieving urinary tract pain, making it a key medicine for treating painful urination due to heat; and Gallus gallus domesticus, which has the effect of dissolving hard stones. These three herbs work together to dissolve stones formed by damp-heat scorching body fluids, serving as the principal herbs. Pyrrosia lingua, a diuretic and urinary tract infection remedy, also cools the blood and stops bleeding, treating stones accompanied by hematuria; Polygonum multiflorum, a Guizhou herb, clears damp-heat in the lower burner and is effective in treating urinary tract infections; and Kochia scoparia, which enters the bladder meridian, effectively treats urinary difficulty, redness, and pain caused by damp-heat accumulation in the bladder. These three herbs assist the principal herbs in promoting urination and increasing urine volume to flush out stones, thus aiding in their expulsion, serving as the assistant herbs. Gentian root is extremely bitter and cold, effectively purging excess heat from the liver and gallbladder, as well as the lower burner. Polygonum cuspidatum effectively clears damp-heat from the liver and gallbladder, invigorates blood, and relieves pain. Herbs like *Gnaphalium affine* and *Sedum sarmentosum* also tend to clear damp-heat from the liver and gallbladder, and have liver-protecting properties. Since the liver meridian runs around the genitals, clearing the liver helps relieve urethral burning and pain, thus assisting the other herbs in relieving urinary frequency, urgency, pain, and hematuria caused by damp-heat accumulation. Plantago asiatica, rush pith, and corn silk all assist the other herbs in clearing heat and promoting diuresis. Long-term kidney stones easily damage the kidneys; *Epimedium* can tonify kidney qi, restore the kidney's qi transformation and propulsion abilities, and enhance the power of stone expulsion. Its warming properties can also counteract the coldness of other herbs. These herbs serve as adjuvants to assist the principal and adjuvant herbs in enhancing their diuretic, urination-clearing, and stone-expelling effects. *Achyranthes bidentata* not only promotes urination and clears the strangury but also guides the herbs downwards; licorice harmonizes the other herbs; all are guiding herbs. Together, these herbs achieve the effects of "clearing heat, clearing the strangury, dissolving stones, and expelling stones."

[0017] 2. This invention adopts L9(3) 4 Orthogonal experiments were used to optimize the extraction process, and the optimal conditions were determined to be 60% ethanol reflux extraction three times for 2 hours each time, with an average extract yield of 12.5% ​​and an RSD of 3.5%. The process is stable and reliable, and can effectively enrich active ingredients such as flavonoids and sterols, thereby improving the utilization efficiency of medicinal materials.

[0018] 3. This invention uses lactose as an excipient and performs wet granulation at a drug-excipient ratio of 1:3. The granules are then granulated through a 14-mesh screen and shaped through a 12-mesh screen. No additional binder is required, which successfully solves the problem of difficult granulation of high-viscosity extracts. The process is simple and suitable for industrial production.

[0019] 4. The physicochemical properties of the particles obtained by this invention, such as particle size, moisture content, and solubility, all meet the requirements. The proportion of impurity powder is 14%, the average moisture content is 3.31%, the particles are uniform, have good solubility, and excellent storage stability.

[0020] 5. This invention establishes a quality control method using TLC and HPLC combined, with quercetin as the indicator component. The qualitative and quantitative detection is accurate, reliable, and highly specific, which can ensure the stable and uniform quality of compound explanatory granules.

[0021] 6. The compound stone granules aqueous solution of the present invention has a concentration-dependent crystal-inhibiting effect. The crystal inhibition rate of the high concentration group of 3.0g / mL reaches 39.773%. It can exert stone-inhibiting, anti-inflammatory and kidney-protecting effects by chelating calcium ions, protecting renal tubular cells and optimizing the urinary tract microenvironment. The product is safe and controllable, and has significant clinical application and promotion value. Attached Figure Description

[0022] Figure 1: Flowchart of the preparation process of compound stone granules; Figure 2: Product image of compound stone granules; Figure 3: Solubility test results of compound stone particles; Figure 4: TLC results (1 is the test sample, 2 is the blank control solution, 3 is the medicinal material control solution, and 4 is the standard control solution). Figure 5: Chromatogram of the test sample; Figure 6: Chromatogram of the standard; Figure 7: Actual image of calcium oxalate monohydrate seed crystal suspension; Figure 8: Sample images of different treatment groups after incubation (Group A (blank control group) added 1 mL of artificial urine; Group B added 1 mL of 0.25 mol / L sodium citrate solution (positive control group); Group C added 1 mL of 1.0 g / mL compound stone granules aqueous solution; Group D added 1 mL of 2.0 g / mL compound stone granules aqueous solution; Group E added 1 mL of 3.0 g / mL compound stone granules aqueous solution). Figure 9: Line graphs showing the in vitro growth index of calcium oxalate monohydrate crystals in different treatment groups at different incubation times (Group A (blank control group) added 1 mL of artificial urine; Group B added 1 mL of 0.25 mol / L sodium citrate solution (positive control group); Group C added 1 mL of 1.0 g / mL compound stone granules aqueous solution; Group D added 1 mL of 2.0 g / mL compound stone granules aqueous solution; Group E added 1 mL of 3.0 g / mL compound stone granules aqueous solution). Figure 10: Bar chart of inhibition rate for the four groups (Group A1 was treated with 3 mL of deionized water (blank control group), Group B1 was treated with 3 mL of 0.167 mol / L sodium citrate solution (positive control group), Group C1 was treated with 3 mL of 1.0 g / mL compound stone granules aqueous solution, Group D1 was treated with 3 mL of 2.0 g / mL compound stone granules aqueous solution, and Group E1 was treated with 3 mL of 3.0 g / mL compound stone granules aqueous solution). Detailed Implementation

[0023] To enable those skilled in the art to better understand and implement the technical solutions of the present invention, the present invention will be further described below with reference to specific embodiments, but the embodiments are not intended to limit the present invention.

[0024] Example 1:

[0025] Prescription: Lysimachia christinae 10g, Lygodium japonicum 10g, Gallus gallus domesticus gizzard lining 10g, Pyrrosia lingua 8g, Kochia scoparia 6g, Polygonum capitatum 6g, Plantago asiatica 6g, Gentiana scabra 6g, Polygonum cuspidatum 7g, Clematis chinensis 5g, Sedum sarmentosum 5g, Zea mays 3g, Epimedium brevicornu 3g, Juncus effusus 3g, Achyranthes bidentata 6g, Glycyrrhiza uralensis 3g Process: (1) Weigh all the medicinal materials in the formula according to the proportion, cut all the medicinal materials into small pieces of 1-2 cm, put them in a round bottom flask, add 60% ethanol solution, the mass ratio of the total amount of medicinal materials to 60% ethanol is 1:15, stir evenly, and perform the first reflux extraction at 60℃ for 2 hours. After the extraction is completed, immediately separate the residue and filtrate by vacuum filtration at 0.06 MPa, collect the filtrate, add 60% ethanol solution to the residue, the mass ratio of the residue to 60% ethanol is 1:15, stir evenly, and perform the second reflux extraction at 60℃ for 2 hours. After the extraction is completed, immediately separate the residue and filtrate by vacuum filtration, collect the filtrate, and perform the third reflux extraction according to the second reflux extraction method. After the extraction is completed, combine the filtrates obtained from the three extractions to obtain the compound stone extract, which is ready for use. (2) Take the compound stone extract and put it into a rotary evaporator with a temperature of 60℃, a vacuum degree of -0.06MPa and a rotation speed of 200r / min for vacuum concentration. Concentrate it to 1 / 5-1 / 6 of the original filtrate volume to obtain a compound stone extract with a relative density of 1.09 for later use. (3) Take the compound stone extract and add lactose. The mass ratio of the compound stone extract to lactose is 1:3. Stir evenly to obtain a mixed soft material for later use. (4) The mixed soft material is put into the granulator and extruded and granulated using a 14-mesh sieve. The wet granules are placed in a drying oven at 60°C for 4 hours. The dried granules are then sieved through a 12-mesh sieve to obtain compound stone granules.

[0026] Example 2:

[0027] Prescription: Lysimachia christinae 5g, Lygodium japonicum 6g, Gallus gallus domesticus gizzard lining 5g, Pyrrosia lingua 4g, Kochia scoparia 2g, Polygonum capitatum 3g, Plantago asiatica 3g, Gentiana scabra 2g, Polygonum cuspidatum 4g, Lysimachia christinae 1g, Sedum sarmentosum 1g, Zea mays 1g, Epimedium brevicornu 1g, Juncus effusus 1g, Achyranthes bidentata 2g, Glycyrrhiza uralensis 1g Process: (1) Weigh all the medicinal materials in the formula according to the proportion, cut all the medicinal materials into small pieces of 1-2cm, put them in a round bottom flask, add purified water, the mass ratio of the total amount of medicinal materials to purified water is 1:10, stir evenly, and perform the first reflux extraction at 40℃ for 1h. After the extraction is completed, immediately separate the residue and filtrate by vacuum filtration at 0.01MPa, collect the filtrate, add purified water to the residue, the mass ratio of the residue to purified water is 1:10, stir evenly, and perform the second reflux extraction at 40℃ for 1h. After the extraction is completed, immediately separate the residue and filtrate by vacuum filtration, collect the filtrate, and perform the third reflux extraction according to the second reflux extraction method. After the extraction is completed, combine the filtrates obtained from the three extractions to obtain the compound stone extract, which is ready for use. (2) Take the compound stone extract and put it into a rotary evaporator with a temperature of 40℃, a vacuum degree of -0.01MPa and a rotation speed of 100r / min for vacuum concentration. Concentrate it to 1 / 5-1 / 6 of the original filtrate volume to obtain a compound stone extract with a relative density of 0.8 for later use. (3) Take the compound stone extract and add lactose, the mass ratio of the compound stone extract to lactose is 1:1, stir evenly to obtain a mixed soft material for later use; (4) The mixed soft material is put into the granulator and extruded and granulated using a 10-mesh sieve. The wet granules are placed in a drying oven at 40°C for 1 hour. The dried granules are then sieved through an 8-mesh sieve to obtain compound stone granules.

[0028] Example 3:

[0029] Prescription: Lysimachia christinae 8g, Lygodium japonicum 8g, Gallus gallus domesticus gizzard lining 9g, Pyrrosia lingua 6g, Kochia scoparia 5g, Polygonum capitatum 4g, Plantago asiatica 5g, Gentiana scabra 4g, Polygonum cuspidatum 5g, Gynostemma pentaphyllum 3g, Sedum sarmentosum 4g, Zea mays 2g, Epimedium brevicornu 2g, Juncus effusus 2g, Achyranthes bidentata 5g, Glycyrrhiza uralensis 2g Process: (1) Weigh all the medicinal materials in the formula according to the proportion, cut all the medicinal materials into small pieces of 1-2 cm, put them in a round bottom flask, add 40% ethanol solution, the mass ratio of the total amount of medicinal materials to 40% ethanol is 1:12, stir evenly, and perform the first reflux extraction at 50℃ for 1.5 h. After the extraction is completed, immediately separate the residue and filtrate by vacuum filtration at 0.04 MPa, collect the filtrate, add 40% ethanol solution to the residue, the mass ratio of the residue to 40% ethanol is 1:12, stir evenly, and perform the second reflux extraction at 40℃ for 1.5 h. After the extraction is completed, immediately separate the residue and filtrate by vacuum filtration, collect the filtrate, and perform the third reflux extraction according to the second reflux extraction method. After the extraction is completed, combine the filtrates obtained from the three extractions to obtain the compound stone extract, which is ready for use. (2) Take the compound stone extract and put it into a rotary evaporator with a temperature of 40℃, a vacuum degree of 0.04MPa and a rotation speed of 150r / min for vacuum concentration. Concentrate it to 1 / 5-1 / 6 of the original filtrate volume to obtain a compound stone extract with a relative density of 0.9 for later use. (3) Take the compound stone extract and add lactose. The mass ratio of the compound stone extract to lactose is 1:2. Stir evenly to obtain a mixed soft material for later use. (4) The mixed soft material is put into the granulator and extruded and granulated using a 12-mesh sieve. The wet granules are placed in a drying oven at 40°C for 2 hours. The dried granules are then sieved through a 10-mesh sieve to obtain compound stone granules.

[0030] Example 4:

[0031] Prescription: Lysimachia christinae 12g, Lygodium japonicum 11g, Gallus gallus domesticus gizzard lining 12g, Pyrrosia lingua 10g, Kochia scoparia 8g, Polygonum capitatum 7g, Plantago asiatica 8g, Gentiana scabra 8g, Polygonum cuspidatum 9g, Clematis chinensis 7g, Sedum sarmentosum 6g, Zea mays 4g, Epimedium brevicornu 4g, Juncus effusus 5g, Achyranthes bidentata 7g, Glycyrrhiza uralensis 5g Process: (1) Weigh all the medicinal materials in the formula according to the proportion, cut all the medicinal materials into small pieces of 1-2 cm, put them in a round bottom flask, add 70% ethanol solution, the mass ratio of the total amount of medicinal materials to 70% ethanol is 1:18, stir evenly, and perform the first reflux extraction at 75℃ for 2.5 h. After the extraction is completed, immediately separate the residue and filtrate by vacuum filtration at -0.08 MPa, collect the filtrate, add 70% ethanol solution to the residue, the mass ratio of the residue to 70% ethanol is 1:18, stir evenly, and perform the second reflux extraction at 75℃ for 2.5 h. After the extraction is completed, immediately separate the residue and filtrate by vacuum filtration, collect the filtrate, and perform the third reflux extraction according to the second reflux extraction method. After the extraction is completed, combine the filtrates obtained from the three extractions to obtain the compound stone extract, which is ready for use. (2) Take the compound stone extract and put it into a rotary evaporator with a temperature of 75℃, a vacuum degree of -0.08MPa and a rotation speed of 250r / min for vacuum concentration. Concentrate it to 1 / 5-1 / 6 of the original filtrate volume to obtain a compound stone extract with a relative density of 1.2 for later use. (3) Take the compound stone extract and add lactose. The mass ratio of the compound stone extract to lactose is 1:4. Stir evenly to obtain a mixed soft material for later use. (4) The mixed soft material is put into the granulator and extruded and granulated using a 17-mesh sieve. The wet granules are placed in a drying oven at 75°C for 6 hours. The dried granules are then sieved through a 14-mesh sieve to obtain compound stone granules.

[0032] Example 5:

[0033] Prescription: Lysimachia christinae 15g, Lygodium japonicum 15g, Gallus gallus domesticus gizzard lining 15g, Pyrrosia lingua 13g, Kochia scoparia 10g, Polygonum capitatum 9g, Plantago asiatica 10g, Gentiana scabra 10g, Polygonum cuspidatum 12g, Gentiana scabra 10g, Sedum sarmentosum 8g, Zea mays 6g, Epimedium brevicornu 6g, Juncus effusus 7g, Achyranthes bidentata 10g, Glycyrrhiza uralensis 6g Process: (1) Weigh all the medicinal materials in the formula according to the proportion, cut all the medicinal materials into small pieces of 1-2 cm, put them in a round bottom flask, add 80% ethanol solution, the mass ratio of the total amount of medicinal materials to 80% ethanol is 1:20, stir evenly, and perform the first reflux extraction at 100℃ for 3 hours. After the extraction is completed, immediately filter the residue and filtrate under vacuum of -0.1MPa, collect the filtrate, add 80% ethanol solution to the residue, the mass ratio of the residue to 80% ethanol is 1:20, stir evenly, and perform the second reflux extraction at 100℃ for 3 hours. After the extraction is completed, immediately filter the residue and filtrate, collect the filtrate, and perform the third reflux extraction according to the second reflux extraction method. After the extraction is completed, combine the filtrates obtained from the three extractions to obtain the compound stone extract, which is ready for use. (2) Take the compound stone extract and put it into a rotary evaporator with a temperature of 100℃, a vacuum degree of -0.1MPa and a rotation speed of 300r / min for vacuum concentration. Concentrate it to 1 / 5-1 / 6 of the original filtrate volume to obtain a compound stone extract with a relative density of 1.5 for later use. (3) Take the compound stone extract and add lactose. The mass ratio of the compound stone extract to lactose is 1:5. Stir evenly to obtain a mixed soft material for later use. (4) The mixed soft material is put into the granulator and extruded and granulated using a 20-mesh sieve. The wet granules are placed in a drying oven at 100°C for 8 hours. The dried granules are then sieved through a 15-mesh sieve to obtain compound stone granules.

[0034] To obtain the solution and verify the technical effects of this invention, the inventors conducted extensive experimental research, some of which is recorded below: 1. Experimental Materials and Reagents 1.1 Experimental Reagents Sixteen medicinal herbs including Lysimachia christinae, chicken gizzard lining, and Lygodium japonicum (from Xingqiao Pharmacy, Huaguoyuan Traditional Chinese Medicine Market, batch number 20250308); artificially synthesized urine (pH 6.5, Tianjin Huasheng Chemical Reagent Co., Ltd., batch number 20250401); sodium oxalate (Tianjin Zhonglian Chemical Reagent Co., Ltd., batch number K4-6-20250316); anhydrous calcium chloride (Tianjin Huasheng Chemical Reagent Co., Ltd., batch number J3-17-20250206); sodium citrate (Tianjin Zhonglian Chemical Reagent Co., Ltd., K3-5-20250205); and calcium oxalate monohydrate (Tianjin Zhonglian Chemical Reagent Co., Ltd.). Limited Company, Batch No. 20250316), Tween-80 (Feijing Biotechnology Co., Ltd., Batch No. 20250403), PBS buffer (pH 7.2-7.4, 0.01M, Feijing Biotechnology Co., Ltd., Batch No. 20250405), Calcium assay kit (o-cresolphthalein complexone method, Changchun Huili Biotechnology Co., Ltd., Batch No. 2025003), Lactose (Tianjin Zhonglian Chemical Reagent Co., Ltd.), Soluble starch (Beijing Solarbio Technology Co., Ltd.), Dextrin (Tianjin Zhonglian Chemical Reagent Co., Ltd.), Microcrystalline cellulose (Beijing Solarbio Technology Co., Ltd.).

[0035] 1.2 Experimental apparatus (see Table 1) Table 1 Experimental Instruments 2. Preparation method of compound stone granules (see...) Figure 1 ) 2.1 Medicinal Herb Prescription 10g of Lysimachia christinae, 10g of Lygodium japonicum, 10g of chicken gizzard lining, 8g of Pyrrosia lingua, 6g of Kochia scoparia, 6g of Polygonum capitatum, 6g of Plantago asiatica, 6g of Gentiana scabra, 7g of Polygonum cuspidatum, 5g of Lysimachia christinae, 5g of Sedum sarmentosum, 3g of Zea mays silk, 3g of Epimedium brevicornu, 3g of Juncus effusus, 6g of Achyranthes bidentata, and 3g of Glycyrrhiza uralensis. 2.2 Extraction Process Weigh all the medicinal materials in the formula according to the proportions, cut all the medicinal materials into small pieces of 1-2 cm, place them in a round bottom flask, add 60% ethanol solution, the mass ratio of the total amount of medicinal materials to 60% ethanol is 1:15, stir evenly, and perform the first reflux extraction at 60℃ for 2 hours. After the extraction is completed, immediately separate the residue and filtrate by vacuum filtration at 0.06 MPa, collect the filtrate, add 60% ethanol solution to the residue, the mass ratio of the residue to 60% ethanol is 1:15, stir evenly, and perform the second reflux extraction at 60℃ for 2 hours. After the extraction is completed, immediately separate the residue and filtrate by vacuum filtration, collect the filtrate, and perform the third reflux extraction according to the second reflux extraction method. After the extraction is completed, combine the filtrates obtained from the three extractions to obtain the compound stone extract. 2.3 Formulation Process (1) Take the compound stone extract and put it into a rotary evaporator with a temperature of 60℃, a vacuum degree of -0.06MPa and a rotation speed of 200r / min for vacuum concentration. Concentrate it to 1 / 5-1 / 6 of the original filtrate volume to obtain a compound stone extract with a relative density of 1.09. (2) Take the compound stone extract and add lactose, wherein the mass ratio of the compound stone extract to lactose is 1:3 and stir evenly to obtain a mixed soft material; (3) The mixed soft material is put into the granulator and extruded and granulated using a 14-mesh sieve. The wet granules are placed in a drying oven at 60°C for 4 hours. The dried granules are then sieved through a 12-mesh sieve to obtain compound stone granules.

[0036] 3. Orthogonal experimental design and results 3.1 Orthogonal Experimental Design Experimental Principle: Orthogonal experiments are a mathematical statistics method based on orthogonal arrays. By arranging experimental points in a balanced and distributed manner, the maximum amount of information can be obtained with the fewest number of experiments. This study uses L9(3) arrays. 4 An orthogonal array can cover three-level combinations of four factors (AD), requiring a total of nine experiments, which is more efficient than a full factorial design (3D model). 4 =81 times) significantly reduced workload.

[0037] This extraction process design employed orthogonal experimental design, using the yield of extract as the evaluation index. Four factors were considered: extraction times (A), extraction time (B), material-to-liquid ratio (C), and ethanol concentration (D). Each factor had three levels, and an L9(3) orthogonal experimental design was used. 4 Orthogonal arrays were used to conduct orthogonal experiments. The factor level table for the orthogonal experiment is shown in Table 2. Table 2: Factor Level Table for Orthogonal Experiment Level selection criteria: Number of extractions (A): Based on similar compound Chinese medicine studies, most effective components require 2-3 extractions to fully dissolve, so we set 1, 2, and 3 extractions.

[0038] Extraction time (B): Short time (1h) may result in insufficient extraction, while too long time (2h) may lead to degradation of heat-sensitive components. Set gradients of 1, 1.5, and 2h.

[0039] Material-to-liquid ratio (C): Too little solvent affects component diffusion, while too much increases the burden of concentration. Based on the water absorption of the medicinal materials, the ratio is set to 1:10, 1:15, and 1:20 (g / mL).

[0040] Ethanol concentration (D): Based on the polarity of the components, 0% (purified water) is suitable for polar components, while 60% or 80% ethanol can accommodate medium and low polar components (such as flavonoids and sterols). Therefore, three levels are set.

[0041] 3.2 Analysis of Orthogonal Experiment Results Nine portions of 16 medicinal materials (totaling 15.9g) were accurately weighed according to the prescription ratio. An orthogonal experiment was conducted based on the extraction process level table of effective components of medicinal materials. The compound stone extract obtained from each group was rotary evaporated to obtain compound stone extract, and then dried. The dried compound stone extract powder was weighed, and the extract yield of the medicinal materials was calculated. The maximum extract yield was used as a reference for normalization. The results are shown in Table 3, and the analysis of variance is shown in Table 4.

[0042] Table 3: Orthogonal Experiment Table Table 4: Analysis of Variance Table Based on the data in the table, the influence of the four factors can be determined in the following order: number of extractions (A) > ethanol concentration % (D) > material-liquid ratio (C) > extraction time (B). Among them, the number of extractions (A) is a significant factor. According to the orthogonal array data analysis, the optimal extraction process for compound stone granules is to use 60% ethanol, reflux extraction 3 times at a material-liquid ratio of 1:15, and extraction time 2 hours each time.

[0043] 3.3 Verification of orthogonal experimental results Validation of experimental design: Three batches of medicinal materials such as Lysimachia christinae, chicken gizzard lining, and Lygodium japonicum were selected and parallel experiments were conducted according to the optimal process (60% ethanol, material-liquid ratio 1:15, extraction 3 times × 2h) to examine the repeatability of the process.

[0044] Three portions of medicinal materials, including Lysimachia christinae, chicken gizzard lining, and Lygodium japonicum, were extracted three times with 60% ethanol at a material-to-liquid ratio of 1:15, with each extraction lasting 2 hours. The yield of the extract was measured and the results are shown in Table 5.

[0045] Table 5: Verification by Orthogonal Experiment Results analysis: The yields of the extract in the three validations were 12.5%, 12.1%, and 13.0%, respectively, with an RSD of 3.5% < 5%, indicating good process stability. This proves that the above orthogonal experimental results represent the optimal extraction process.

[0046] 4. Investigation on the granulation process of compound stone granules 4.1 Preparations before granulation The reason for choosing wet granulation is that the compound calculi extract contains various components such as polysaccharides, flavonoids, and saponins, exhibiting high viscosity and hygroscopicity. Wet granulation, by adding water-soluble excipients such as lactose, forms a homogeneous solid-liquid mixture with the compound calculi extract, utilizing the extract's own viscosity as a binder, eliminating the need for additional excipients such as ethanol or starch paste. Dry granulation, on the other hand, relies on external force (such as roller extrusion) to shape the material, requiring extremely high plasticity of the compound calculi extract. Experiments show that when the moisture content of the compound calculi extract is below 5%, dry granulation results in a fine powder rate exceeding 40% due to the material's excessive brittleness, and uneven particle hardness (RSD > 20%), severely affecting quality stability.

[0047] The reason for choosing to directly mix compound calculi extract with excipients is that dry compound calculi extract powder is highly viscous and easily clumps together during granulation, forming large agglomerates that are difficult to pass through a sieve to form uniform granules. This not only reduces granulation efficiency but may also lead to inconsistent particle size, affecting product quality. Directly mixing compound calculi extract with excipients, however, allows the viscous nature of the extract to form a soft material with good plasticity and viscosity, facilitating subsequent granulation operations and resulting in granules with regular shape and uniform size. Furthermore, the components of the compound calculi extract can be evenly distributed within the granules, which helps ensure the stability and consistency of drug quality. If the compound calculi extract is dried into powder before granulation, more binder may be needed to achieve the same granulation effect, and the flowability and compressibility of the powder may not be as good as the system of directly mixing compound calculi extract with excipients, affecting granule quality. At the same time, the strong viscosity of dry compound calculi extract powder may adversely affect subsequent drying, granulation, and other processing steps. For example, during the drying process, adhesion between particles can lead to uneven drying, making it difficult to remove moisture from some particles and affecting the product's moisture content and stability. During granulation, particle breakage or re-agglomeration can also easily occur. However, directly granulating compound calculus extract, after appropriate drying and granulation, yields granular products with good properties suitable for further processing and packaging.

[0048] 4.2 Optimal Selection of Excipients Traditional Chinese medicine granules are prone to absorbing moisture and clumping, which alters their efficacy and leads to the loss of some active ingredients during extraction. Therefore, it is necessary to select appropriate excipients for granulation. When sucrose is used as an excipient, its use is limited for many elderly patients and those on sugar-restricted diets; adding insoluble excipients can affect the solubility of the granules; the presence of excipients, compound stone extract, and microorganisms in the production environment and equipment can affect microbial limits, all of which may result in unstable granules, poor quality, and even affect efficacy. Lactose, soluble starch, dextrin, and microcrystalline cellulose were used as excipients, mixed with an equal amount of compound stone extract to form a soft mass, which was then granulated. The formability of each excipient mixed with the compound stone extract was observed and recorded. The solubility was assessed by placing the granules in a certain amount of water and observing their dissolution. The results are shown in Table 6.

[0049] Table 6: Selection Consideration Table for Auxiliary Materials The results show that lactose and soluble starch have good formability, while dextrin and microcrystalline cellulose have poor formability. Lactose and dextrin have good solubility, while soluble starch and microcrystalline cellulose have poor solubility. Considering all factors, lactose was chosen as the excipient for the compound stone granules. In the formability observation, lactose mixed with the compound stone extract only required gentle kneading to form a uniform soft mass, while microcrystalline cellulose required forceful compression to form a clump and easily crumbled upon release. In the solubility experiment, the solution after dissolving dextrin granules was a clear, slightly yellow liquid, while flocculent turbidity appeared around the soluble starch granules, which is related to the starch gelatinization characteristics.

[0050] Analysis of excipient characteristics: Lactose: Composed of galactose and glucose, it has good flowability (angle of repose < 30°) and compressibility, and low hygroscopicity (hygroscopic rate < 5% at 75% relative humidity), which can reduce clumping during granule storage. In addition, lactose has good water solubility (solubility 19.5g / 100mL, 20℃), which meets the requirements for rapid dissolution of granules.

[0051] Soluble starch: Although it is a hydrophilic excipient, its long molecular chains make it easy to form colloidal solutions, resulting in poor solubility (it takes 10 minutes of stirring in the experiment to completely disperse it), and high hygroscopicity (the moisture absorption rate reaches 12% at 80% relative humidity), which is not conducive to long-term storage.

[0052] Dextrin: It is an intermediate product of starch hydrolysis. It is quite viscous. Although it dissolves well (completely within 5 minutes), it is too sticky when used alone and is prone to clumping during granulation. It needs to be used in conjunction with a lubricant.

[0053] Microcrystalline cellulose (MCC): It has a porous structure and excellent disintegration properties, but it is also highly hydrophobic. When mixed with compound stone extract, the soft material becomes loose, and additional binders (such as ethanol solution) are required for molding, which increases the complexity of the process.

[0054] 4.3 Optimal Selection of Drug-Excipient Ratio After selecting lactose as an excipient, experiments were conducted with different ratios (1:2.5, 1:3, 1:3.5) of compound calculi extract and lactose. The compound calculi extract and lactose were thoroughly mixed in the corresponding ratios to form a soft mass, and the properties of the soft mass were observed. The soft mass was then granulated to evaluate the formability of the granules at different ratios. The results are shown in Table 7.

[0055] Table 7: Examination Table of Drug Excipient Ratio The results showed that when the ratio of compound stone extract to lactose was 1:3, the soft material properties were moderate and the resulting granules had good formability.

[0056] The properties of excipients significantly affect granule quality: Lactose has good flowability, compressibility, and hygroscopicity, effectively improving granulation properties when mixed with compound calculus extract, and its excellent solubility facilitates drug release and absorption in vivo. Soluble starch, while having good granulation properties, has poor solubility, potentially affecting the drug's onset rate; dextrin and microcrystalline cellulose have poor granulation properties, hindering granule preparation and quality control. The ratio of excipients to excipients directly affects the properties of the soft mass and granule granulation. When the ratio of compound calculus extract to lactose is 1:2.5, the soft mass is too sticky, leading to granulation difficulties and poor granule granulation, possibly due to the relatively high content of compound calculus extract and excessive viscosity. When the ratio is 1:3.5, the soft mass is too loose, also affecting granulation, because the high lactose content cannot effectively bind the compound calculus extract. A 1:3 ratio provides moderate soft mass properties, ensuring smooth granule formation.

[0057] 5. Basic quality inspection and verification of compound stone granules 5.1 Visual Inspection according to Figure 2 As can be seen, the compound calculi granules are uniformly fine granules with a dry, loose texture and no clumping. Each granule is similar in size, conforming to pharmaceutical manufacturing standards, and has a smooth surface with a natural luster. The overall color is bright and uniform, without variations in shade or color depth, and there is no discoloration or clumping due to moisture absorption. The granules have clear boundaries, good flowability, and disperse smoothly when poured, exhibiting excellent physical properties.

[0058] 5.2 Particle size inspection Method: According to the particle size test method for granules in the Chinese Pharmacopoeia, take 15g of the test sample and weigh it (record the weight in m). 样 Place the powder in the prescribed sieve, keeping the sieve horizontal, and gently sieve back and forth for 3 minutes. The total amount of particles and powder that cannot pass through sieve No. 1 and those that can pass through sieve No. 5 should not exceed 15%.

[0059] Results: A sample of compound stone granules was weighed (m). 样 =15g, after sieving, the weight of non-compliant particles and powder is 2.1g, accounting for 14%, which meets the requirements of the Chinese Pharmacopoeia (unless otherwise specified, according to the particle size and particle size distribution determination method, the total amount of particles that cannot pass through the No. 1 sieve and particles that can pass through the No. 5 sieve shall not exceed 15%), and the particle size inspection is qualified.

[0060] 5.3 Moisture content test The evaporating dish was placed in an electric heating drying oven and dried at 105℃ for 2 hours. After removal, it was placed in a desiccator to cool for 30 minutes. After cooling, m1 was weighed. Approximately 2g (m2) of the granule sample was weighed into the evaporating dish, and the total weight m3 was measured. After drying and cooling, it was weighed again. The moisture content was calculated to be no more than 8%. Three samples were measured in parallel, and the results are shown in Table 8.

[0061] Table 8: Moisture content test results of compound stone granules According to the Chinese Pharmacopoeia, the moisture content of Chinese medicine granules shall not exceed 8.0% unless otherwise specified. If 3.48% < 8.0%, it meets the requirements and the moisture content test is qualified.

[0062] 5.4 Solubility test Method: Take 10g of the test sample, add 200mL of hot water, stir for 5 minutes, and observe whether the particles are completely dissolved or slightly turbid. There should be no foreign matter.

[0063] Result: From Figure 3 Observation shows that all granules dissolved, and the solution was not cloudy. According to the Chinese Pharmacopoeia, for the soluble granule test, take 10g of the test sample (or one packet for single-dose traditional Chinese medicine), add 200mL of hot water, stir for 5 minutes, and observe immediately. The soluble granules should dissolve completely or become slightly cloudy. This meets the requirements, and the solubility test is qualified.

[0064] 6. Study on quality control of compound stone granules 6.1 Design Concept Compound stone-forming granules are compound traditional Chinese medicine preparations formulated based on clinical experience. Their quality control directly affects the stability of the drug's quality. Given the complexity of the components in compound preparations, selecting key active ingredients for targeted quality research is a core strategy to ensure consistent and stable quality. Among the various ingredients in compound stone-forming granules, Lysimachia christinae (Jinqiancao) is the main herb, possessing the effects of clearing heat and dampness, promoting urination, and expelling stones. Quercetin, contained in Lysimachia christinae, is not only one of the hallmark active ingredients of Lysimachia christinae but also possesses various pharmacological activities such as antioxidant and anti-inflammatory effects, which are closely related to the overall efficacy of the compound in treating urinary system stones. Therefore, selecting quercetin as the standard ingredient can effectively reflect the quality characteristics of compound stone-forming granules.

[0065] 6.2 Qualitative identification of quercetin in compound stone granules by thin-layer chromatography (TLC) 6.2.1 Preparation of test solution Accurately weigh 2g of the compound stone granule sample and place it in a 250mL round-bottom flask. Add 50mL of 80% methanol solution, weigh, and record the initial mass. Connect the spherical condenser and heat under reflux for 1 hour, observing the solution state during this time. After reflux, cool to room temperature and weigh again, replenishing the weight loss with 80% methanol. Filter the reflux liquid using slow-speed quantitative filter paper, transfer the filtrate to a pear-shaped flask in a rotary evaporator, and evaporate under reduced pressure until nearly dry. Add distilled water to the evaporated residue to dissolve it, then slowly add 5mL of dilute hydrochloric acid. Place the flask in a constant-temperature water bath and heat for 1 hour. After completion, remove the flask, cool to room temperature, and extract twice with ethyl acetate and shake. Wash with water, discard the washings, evaporate the remaining solution to dryness, dissolve the residue in methanol, and use this as the test solution.

[0066] 6.2.2 Preparation of reference solution Take 1g of *Lysimachia christinae* (a type of medicinal herb), add 50mL of 80% methanol solution, weigh and record the initial mass. Heat under reflux for 1 hour. After reflux, cool to room temperature and weigh again, making up the weight loss with 80% methanol. Filter the reflux liquid using slow-speed quantitative filter paper, transfer the filtrate to a pear-shaped flask in a rotary evaporator, and evaporate under reduced pressure to near dryness. Add distilled water to the evaporated residue to dissolve it, then slowly add 5mL of dilute hydrochloric acid. Place in a constant-temperature water bath and heat for 1 hour. After completion, remove and cool to room temperature. After cooling, add ethyl acetate and shake to extract twice. Wash with water, discard the washings, evaporate the remaining solution to dryness, and dissolve the residue in methanol to obtain the reference solution for the medicinal material.

[0067] 6.2.3 Preparation of Standard Solutions Take an appropriate amount of quercetin reference standard, dissolve it in methanol, and use it as a standard reference solution.

[0068] 6.2.4 Preparation of blank solution Take the excipients, dissolve them in methanol, and prepare a blank control solution.

[0069] 6.2.5 Experimental Procedure According to the thin-layer chromatography method, apply the test solution, blank control solution, medicinal material control solution, and standard control solution separately to the same silica gel G thin-layer plate. Develop the plate using toluene:ethyl acetate:formic acid (5:4:1) as the developing solvent. Remove the plate, spray with 10% sulfuric acid ethanol solution, heat and dry with a hair dryer, and examine under ultraviolet light (365nm). 6.2.6 Experimental Results The results are as follows Figure 4As shown, the spots in the test sample, control medicinal material group, and standard sample group are roughly the same and clear. The blank control group shows no spots and does not interfere with the test sample group.

[0070] 6.3 Determination of Quercetin Content in Compound Stone Granules by High Performance Liquid Chromatography (HPLC) 6.3.1 Chromatographic conditions The column was packed with octadecylsilane-bonded silica gel; the mobile phase consisted of a gradient elution of methanol (A) and 0.4% phosphoric acid aqueous solution (B); the detection wavelength was 365 nm, the column temperature was 30 °C, the flow rate was 1.0 mL / min, and the injection volume was 10 μl. 6.3.2 Mobile Phase Treatment First, accurately measure an appropriate amount of chromatographically pure methanol solution, using a high-precision graduated cylinder to ensure the volume error is within ±0.5%. Simultaneously, accurately weigh phosphoric acid using an electronic analytical balance, slowly dissolve it in ultrapure water, and stir until homogeneous to prepare a 0.4% phosphoric acid aqueous solution. Then, filter both the prepared methanol solution and the 0.4% phosphoric acid aqueous solution through 0.22μm filter membranes. Passing the solution through the filter membranes effectively removes any small particles and impurities that may be present in the solution, ensuring its purity.

[0071] After filtration, both solutions were subjected to ultrasonic degassing for 20 minutes. Ultrasonic treatment ensured that dissolved gases escaped completely, eliminating the influence of air bubbles on subsequent experiments. After degassing, the solutions were quickly transferred to clean, dry reagent bottles, sealed, and properly labeled for later use.

[0072] 6.3.3 Preparation of reference solution Accurately weigh an appropriate amount of quercetin reference standard and place it in a volumetric flask. Dilute with methanol to prepare a 3.02 mg / mL reference standard solution.

[0073] 6.3.4 Preparation of the test solution Take approximately 2g of the compound stone granule sample, grind it into powder, dissolve it in 80% methanol, heat under reflux for 1 hour, cool, weigh it, make up the weight loss with methanol, shake well, and filter. Measure 25mL of the filtrate, add hydrochloric acid, heat in a water bath for 1 hour, remove, cool, transfer to a 50mL volumetric flask, dilute to the mark with 80% methanol, shake well, and filter to obtain the final product.

[0074] 6.3.5 System Suitability Test Inject 10 μl each of the reference standard and the test sample. Figure 5 , Figure 6As shown, under these conditions, the separation effect of quercetin in the test sample was good, and the peak time was roughly the same as that of the reference sample. The elution conditions were: using methanol (A)-0.4% phosphoric acid aqueous solution (B) as the mobile phase, gradient elution (0-10 min, 30%-45% (A); 10-20 min, 45%-60% (A); 20-30 min, 60%-80% (A); 30-35 min, 80% (A)).

[0075] 6.3.6 Determination of Quercetin Content in Compound Stone Granules Samples Weigh 1.5g of compound stone granules into three portions, and prepare three portions of compound stone granule sample solutions according to the above test sample preparation method. Inject the samples for determination and calculate the content. The average content is 0.1008mg / g. The specific results are shown in Table 9.

[0076] Table 9: Determination of Quercetin Content in Compound Stone Granules Samples 6.3.7 Experimental Results This experiment used HPLC to determine the quercetin content in compound stone granules. Under the established chromatographic conditions, the quercetin peak in the sample showed good separation with no interfering peaks, and the elution time was consistent with that of the reference standard, indicating good method specificity. The quercetin contents of the three parallel samples were 0.1044 mg / g, 0.0970 mg / g, and 0.1010 mg / g, respectively, with an average content of 0.1008 mg / g and an RSD of 3.87%. The data deviation was small, indicating that the detection method has good stability and repeatability, and the data are accurate and reliable.

[0077] 7. In vitro pharmacodynamic studies 7.1. In vitro simulation experiment Artificial urine was prepared to contain 2.5 mol / L calcium chloride and 0.5 mol / L sodium oxalate.

[0078] Preparation of calcium oxalate monohydrate seed crystal suspension (5 mg / mL) (see...) Figure 7 Weigh 100 mg of calcium oxalate monohydrate crystals and add 15 mL of PBS solution (phosphate buffer) containing 0.1% Tween-80 (prepared in advance: 0.1 mL Tween-80 + 99.9 mL PBS). Mix well and transfer the mixture to an ultrasonic cleaner. Ultrasonically treat the mixture at 50 W and then treat it in an ice bath for 10 minutes to disperse the agglomerated particles. Filter the suspension through a 0.45 μm filter membrane to remove large particles that are not completely dispersed. Make up the volume to 20 mL with PBS solution.

[0079] For each group, 22 mL of pH 6.5 artificial urine was placed in an Erlenmeyer flask, and 1.0 mL each of 0.02 mol / L calcium chloride solution and 0.02 mol / L sodium oxalate solution were added. The experiment was divided into 5 groups, and the following solutions were added respectively: Group A (blank control group) added 1 mL of artificial urine; Group B added 1 mL of 0.25 mol / L sodium citrate solution (positive control group); Group C added 1 mL of 1.0 g / mL compound stone granules aqueous solution; Group D added 1 mL of 2.0 g / mL compound stone granules aqueous solution; Group E added 1 mL of 3.0 g / mL compound stone granules aqueous solution. After shaking in a 37℃ constant temperature water bath for 10 min, 1 mL of each group was sampled and filtered through a 0.45 μm microporous membrane using a syringe filter. The filtered solution was then placed in a centrifuge tube. Next, 0.5 mL of a 5 mg / mL calcium oxalate monohydrate seed crystal suspension was added to each Erlenmeyer flask, and the mixture was stirred for 30 seconds to ensure uniform dispersion of the seed crystals. The flasks were then incubated in a constant temperature water bath with shaking. During incubation, 1 mL of solution was taken from each Erlenmeyer flask at 1 hour, 2 hours, and 3 hours, filtered through a 0.45 μm microporous membrane, and collected in a new centrifuge tube. The absorbance (A) of the filtrate in each centrifuge tube before and after adding the seed crystals was measured using a UV spectrophotometer. The calcium oxalate crystal growth index of each group after adding the compound stone granules was calculated using the following formula. Figure 8 .

[0080] Calcium oxalate crystal growth index (G) = [(A0-At) / A0] × 100% In the above formula, A0 is the absorbance of the filtrate before adding the calcium oxalate monohydrate seed crystal suspension, and At is the absorbance of the filtrate after incubation with the calcium oxalate monohydrate seed crystal suspension in the control group (group A) or experimental groups (groups B, C, D, and E), respectively. Three tubes were used simultaneously for both the experimental and control groups, and the average value was used to calculate G.

[0081] Calcium ion absorbance measurement: Use disposable sterile polyethylene centrifuge tubes as color development containers. Add 2 mL of 2-amino-dimethyl-1-propanol solution and 2 mL of o-cresolphthalein complex ketone color developer to both the blank tube and the sample tube, mix well, and avoid the generation of bubbles. Add 27 μL of double-distilled water to the blank tube and 27 μL of sample solution to the measurement tube, mix well, and place the centrifuge tubes in a dark environment at room temperature for 10 minutes to ensure complete color development. Zero the instrument using the blank tube and measure the absorbance of the sample at a wavelength of 578 nm.

[0082] 7.2 Results of in vitro simulation experiments The crystal growth indices of groups A, B, C, D, and E increased rapidly over time. Compared with the blank group A, the p-values ​​of groups B, C, D, and E were all less than 0.01, indicating highly significant differences. The growth indices of groups B, C, D, and E were all lower than those of the blank group. The growth index of group E was the lowest, as shown in Tables 10 and 11.

[0083] Table 10: Absorbance data of filtrate before and after adding calcium oxalate monohydrate seed crystal suspension to different treatment groups (n=3) Table 11: Effects of different treatment groups on the in vitro growth index (%) of calcium oxalate monohydrate crystals at different incubation times Compared with the blank group A, the p-values ​​for groups B, C, D, and E are all less than 0.01; compared with group B, the p-values ​​for groups C, D, and E are all less than 0.01; and the p-values ​​for groups C and E are less than 0.01. a <0.05, the P-values ​​of groups A and B at different times within the same group are all less than 0.01, comparing P values ​​at different times within the same group. b <0.05, see Figure 9 .

[0084] 7.3 Crystallization Experiment Five parallel experiments were set up. For each group, 20 mL of 0.1 mol / L calcium chloride solution and 20 mL of 0.1 mol / L sodium oxalate solution were thoroughly mixed in a beaker, and then 7 mL of deionized water was added to each beaker. For each group, the following solutions were added: Group A1: 3 mL of deionized water (blank control); Group B1: 3 mL of 0.167 mol / L sodium citrate solution (positive control); Groups C1, D1, and E1: 3 mL of compound stone granule aqueous solution with concentrations of 1.0 g / mL, 2.0 g / mL, and 3.0 g / mL, respectively. Each group was magnetically stirred for 20 min. The beakers were sealed with plastic wrap to prevent moisture evaporation from affecting the solution concentration. The mixture was placed at room temperature (25 ± 2℃) for 3 days, filtered, and the crystals were dried in a 60℃ constant temperature drying oven for 4 hours until constant weight. The weight of the crystals was recorded. Each group was repeated three times, and the results were expressed as mean ± standard deviation. The crystallization inhibition rate for each group was calculated using the following formula.

[0085] Inhibition rate = (WA - WX) / WA × 100% In the formula, WA represents the amount of crystallization in the blank group, and WX represents the amount of crystallization in the experimental group.

[0086] 7.4 Results of Crystallization Experiment The inhibition rate of group E1 was higher than that of group B. 1、 C 1、 The inhibition rates of groups D1 and B1 were higher than those of groups C1 and D1 (see Table 12). Figure 10 .

[0087] Table 12: Inhibition rate of each group in the crystallization experiment (n=3) 7.5 Data Analysis The absorbance experimental data were analyzed using SPSS 27.0 statistical software. Quantitative data were expressed as mean ± standard deviation (x ± s). One-way ANOVA was used for comparisons between groups. P < 0.05 indicated that the difference was statistically significant and that the factor had a significant effect on the observed variable. If P > 0.05, it indicated that the difference between groups was not statistically significant, meaning that the factor had no significant effect on the observed variable.

[0088] 7.6 Conclusion The crystal growth index of the blank control group (Group A) increased rapidly over time, indicating that calcium oxalate crystals can grow rapidly in the absence of inhibitors. In the positive control group (Group B), the crystal growth index was significantly lower than that of the blank group after the addition of sodium citrate, indicating that sodium citrate inhibits the growth of calcium oxalate crystals. The P-values ​​of Group B at different time points were all less than 0.01, showing a significant change in calcium oxalate crystal growth over time in the sodium citrate group. In the experimental groups (Groups C, D, and E), the crystal growth index was lower than that of the blank group after the addition of different concentrations of compound stone granule aqueous solution. Furthermore, the growth index gradually decreased with increasing concentration of the compound stone granule aqueous solution, indicating that within a certain concentration range, the compound stone granule aqueous solution has an inhibitory effect on the growth of calcium oxalate crystals, and the effect is more pronounced at higher concentrations.

[0089] At the same time point, Group E had the lowest growth index, indicating that the compound stone granule aqueous solution had a more prominent intervention effect on the formation of calcium oxalate crystals at high concentrations, providing an important reference for subsequent clinical drug dosage exploration.

[0090] The blank control group (Group A1) showed the highest crystal weight, indicating that calcium oxalate crystals could form in large quantities without inhibitors. The positive control group (Group B1) showed a significant decrease in crystal weight after the addition of sodium citrate, with an inhibition rate of 20.02%, indicating that sodium citrate inhibits calcium oxalate crystal formation. In the experimental groups (Groups C1, D1, and E1), the crystal weight was lower than that of the blank group after adding different concentrations of the compound stone-forming granule aqueous solution, and the inhibition rate gradually increased with increasing concentration of the solution. Group E1 showed the highest inhibition rate at 39.773%, indicating that high-concentration compound stone-forming granule aqueous solution had the strongest inhibitory effect on calcium oxalate crystal formation. These results further confirm that the compound stone-forming granule aqueous solution can effectively reduce calcium oxalate crystal formation, and the high-concentration group showed stronger inhibitory ability. This suggests that the compound stone-forming granule aqueous solution may have a unique mechanism of action or the advantage of synergistic effects of multiple components, giving it greater potential in inhibiting calcium oxalate crystal formation. The effectiveness of this formula in the prevention and treatment of stones has been preliminarily verified through in vitro experiments, providing new ideas for the development of novel and highly effective drugs for the prevention and treatment of stones.

[0091] Adjusting urine pH and ionic strength. In the experiment, the pH of artificial urine was set to 6.5 (close to the range where calcium oxalate easily crystallizes). The weakly alkaline components such as mangiferin in Pyrrosia lingua and ursolic acid in Plantago asiatica can release protons through the dissociation of phenolic hydroxyl groups, thereby adjusting the pH of urine. Lygodium japonicum contains mineral components, which may inhibit the formation of COM by changing the ionic strength and altering the microenvironment for crystal formation.

[0092] It chelates free calcium ions, reducing supersaturation. The positive control group B (sodium citrate) inhibits calcium oxalate precipitation by providing citrate ions to bind with calcium ions, thus reducing the concentration of free calcium. Traditional Chinese medicines such as Lysimachia christinae and Plantago asiatica are rich in citric acid, malic acid, and other polyprotic organic acids. The carboxyl (-COOH) and hydroxyl (-OH) functional groups in their molecular structures can bind with calcium ions. 2+ Complexation reactions occur, reducing the concentration of free calcium and decreasing the supersaturation of calcium oxalate, thereby weakening the driving force for crystal nucleation and growth from the root.

[0093] Adsorption on crystal surfaces inhibits growth and aggregation. Studies have confirmed that polysaccharides and flavonoids in Alisma plantago-aquatica extract can adsorb onto the surface of calcium oxalate crystals through hydrogen bonds, electrostatic attraction, and van der Waals forces, inhibiting their growth and aggregation. Other traditional Chinese medicines (such as Lysimachia christinae) may contain similar polysaccharides or mucinous components that physically adsorb and cover active sites on the crystal surface, preventing further crystallization. It is mentioned that crystal-crystal and crystal-cell adhesion are key steps in stone formation. Traditional Chinese medicines may reduce adhesion by decreasing the surface charge of crystals or providing competitive adsorption sites (such as the fibrous components in Tetrapanax papyriferus). The hydrophilic sugar chains of saponins form a hydration film on the crystal surface, increasing steric hindrance and inhibiting crystal aggregation; their hydrophobic sterol or triterpenoid cores bind tightly to the crystal surface, altering surface energy and blocking growth sites. Furthermore, the inhibitory effect of natural polyphenols is closely related to the amount of donor hydrogen (>0.1 mmol) and pKa value (<3.5). Sufficient donor hydrogen enhances hydrogen bonding, while a lower pKa value causes polyphenols to dissociate into phenolic anions at physiological pH, which are then efficiently adsorbed onto the crystal surface through electrostatic attraction, thus blocking growth.

[0094] Altering crystal morphology promotes the formation of easily excreted forms. Studies have shown that citrate can induce the formation of COD and COT (with smooth surfaces and low adhesion). Traditional Chinese medicine components may regulate crystallization kinetics; for example, the mucilage in Malva verticillata seeds can adsorb onto crystal growth sites, interfering with directional crystal growth through steric hindrance, thus causing crystals to tend towards forming low-hazard forms such as COD. Traditional Chinese medicine may also reduce the formation of needle-like COM caused by rapid crystal deposition by breaking down mucoproteins in urine.

[0095] Antioxidant and protective effects on renal tubular epithelial cells. Damage to renal tubular epithelial cells is a key pathological step in calcium oxalate crystal adhesion and stone formation. Traditional Chinese medicines such as *Pyrrosia lingua* and *Plantago asiatica* are rich in flavonoids (e.g., mangiferin, quercetin) and polysaccharides. Flavonoids, due to their conjugated double bond 2-phenylchromone structure, exhibit broad biological activities. Studies show that flavonoids have antioxidant capabilities, scavenging reactive oxygen species such as hydroxyl radicals and superoxide anions, and increasing the activity of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), thus reducing oxidative stress damage to renal cells and indirectly inhibiting crystal retention on tissue surfaces. Flavonoids also have anti-inflammatory effects, inhibiting inflammatory signaling pathways such as NF-κB, reducing the release of pro-inflammatory factors such as IL-6 and TNF-α, alleviating urinary tract mucosal inflammation, and reducing the probability of crystal adhesion to damaged mucosa.

Claims

1. A compound stone-forming granule for treating urinary system stones, characterized in that: Its medicinal active ingredients, calculated by weight, are made from: 50-150 parts of Lysimachia christinae, 60-150 parts of Lygodium japonicum, 50-150 parts of chicken gizzard lining, 40-130 parts of Pyrrosia lingua, 20-100 parts of Kochia scoparia, 30-90 parts of Polygonum capitatum, 30-100 parts of Plantago asiatica, 20-100 parts of Gentiana scabra, 40-120 parts of Polygonum cuspidatum, 10-100 parts of Clematis chinensis, 10-80 parts of Sedum sarmentosum, 10-60 parts of Zea mays, 10-60 parts of Epimedium brevicornu, 10-70 parts of Juncus effusus, 20-100 parts of Achyranthes bidentata, and 10-60 parts of Glycyrrhiza uralensis.

2. The compound stone granules for treating urinary system stones according to claim 1, characterized in that: Its medicinal active ingredients, calculated by weight, are made from: 80-120 parts of Lysimachia christinae, 80-110 parts of Lygodium japonicum, 90-120 parts of chicken gizzard lining, 60-100 parts of Pyrrosia lingua, 50-80 parts of Kochia scoparia, 40-70 parts of Polygonum capitatum, 50-80 parts of Plantago asiatica, 40-80 parts of Gentiana scabra, 50-90 parts of Polygonum cuspidatum, 30-70 parts of Clematis chinensis, 40-60 parts of Sedum sarmentosum, 20-40 parts of Zea mays, 20-40 parts of Epimedium brevicornu, 20-50 parts of Juncus effusus, 50-70 parts of Achyranthes bidentata, and 20-50 parts of Glycyrrhiza uralensis.

3. The compound stone-forming granules for treating urinary system stones according to claim 1 or 2, characterized in that: Its medicinal active ingredients, calculated by weight, are made from: 100 parts of Lysimachia christinae, 100 parts of Lygodium japonicum, 100 parts of chicken gizzard lining, 80 parts of Pyrrosia lingua, 60 parts of Kochia scoparia, 60 parts of Polygonum capitatum, 60 parts of Plantago asiatica, 60 parts of Gentiana scabra, 70 parts of Polygonum cuspidatum, 50 parts of Lysimachia christinae, 50 parts of Sedum sarmentosum, 30 parts of Zea mays, 30 parts of Epimedium brevicornu, 30 parts of Juncus effusus, 60 parts of Achyranthes bidentata, and 30 parts of Glycyrrhiza uralensis.

4. The method for preparing compound stone granules for treating urinary system stones according to any one of claims 1-3, characterized in that: The preparation method is carried out according to the following steps: (1) Weigh all the medicinal materials in the formula according to the proportion, cut all the medicinal materials into 1-2cm small pieces, put them in a round bottom flask, add 0-80% ethanol solution, the mass ratio of the total amount of medicinal materials to 0-80% ethanol is 1:10-20, stir evenly, and carry out the first reflux extraction at 40-100℃ for 1-3h. After the extraction is completed, immediately filter the residue and filtrate under vacuum pressure of 0.01MPa to -0.1MPa, collect the filtrate, add 0-80% ethanol solution to the residue, the mass ratio of the residue to 0-80% ethanol is 1:10-20, stir evenly, and carry out the second reflux extraction at 40-100℃ for 1-3h. After the extraction is completed, immediately filter the residue and filtrate, collect the filtrate, and carry out the third reflux extraction according to the second reflux extraction method. After the extraction is completed, combine the filtrates obtained from the three extractions to obtain the compound stone extract, which is ready for use. (2) Take the compound stone extract and put it into a rotary evaporator with a temperature of 40-100℃, a vacuum degree of -0.01MP to -0.1MPa, and a rotation speed of 100-300r / min for vacuum concentration. Concentrate it to 1 / 5-1 / 6 of the original filtrate volume to obtain a compound stone extract with a relative density of 0.8-1.5 for later use. (3) Take the compound stone extract and add lactose. The mass ratio of the compound stone extract to lactose is 1:1-5. Stir evenly to obtain a mixed soft material for later use. (4) The mixed soft material is put into the granulator and extruded and granulated using a 10-20 mesh screen. The wet granules are placed in a drying oven at a temperature of 40-100℃ for 1-8 hours. The dried granules are then sieved through an 8-15 mesh screen to obtain compound stone granules.

5. The method for preparing compound stone granules for treating urinary system stones according to claim 4, characterized in that: The preparation method is carried out according to the following steps: (1) Weigh all the medicinal materials in the formula according to the proportion, cut all the medicinal materials into small pieces of 1-2cm, put them in a round bottom flask, add 40-70% ethanol solution, the mass ratio of the total amount of medicinal materials to 40-70% ethanol is 1:12-18, stir evenly, and carry out the first reflux extraction at 50-75℃ for 1.5-2.5h. After the extraction is completed, immediately filter the residue and filtrate under vacuum pressure of 0.04MPa to -0.08MPa, collect the filtrate, add 40-70% ethanol solution to the residue, the mass ratio of the residue to 40-70% ethanol is 1:12-18, stir evenly, and carry out the second reflux extraction at 40-75℃ for 1.5-2.5h. After the extraction is completed, immediately filter the residue and filtrate, collect the filtrate, and carry out the third reflux extraction according to the second reflux extraction method. After the extraction is completed, combine the filtrates obtained from the three extractions to obtain the compound stone extract, which is ready for use. (2) Take the compound stone extract and put it into a rotary evaporator with a temperature of 40-75℃, a vacuum degree of 0.04MPa to -0.08MPa, and a rotation speed of 150-250r / min for vacuum concentration. Concentrate it to 1 / 5-1 / 6 of the original filtrate volume to obtain a compound stone extract with a relative density of 0.9-1.2 for later use. (3) Take the compound stone extract and add lactose. The mass ratio of the compound stone extract to lactose is 1:2-4. Stir evenly to obtain a mixed soft material for later use. (4) The mixed soft material is put into the granulator and extruded and granulated using a 12-17 mesh screen. The wet granules are placed in a drying oven at a temperature of 40-75℃ for 2-6 hours. The dried granules are then sieved through a 10-14 mesh screen to obtain compound stone granules.

6. The method for preparing compound stone granules for treating urinary system stones according to claim 5, characterized in that: The preparation method is carried out according to the following steps: (1) Weigh all the medicinal materials in the formula according to the proportion, cut all the medicinal materials into small pieces of 1-2 cm, put them in a round bottom flask, add 60% ethanol solution, the mass ratio of the total amount of medicinal materials to 60% ethanol is 1:15, stir evenly, and perform the first reflux extraction at 60℃ for 2 hours. After the extraction is completed, immediately separate the residue and filtrate by vacuum filtration at 0.06 MPa, collect the filtrate, add 60% ethanol solution to the residue, the mass ratio of the residue to 60% ethanol is 1:15, stir evenly, and perform the second reflux extraction at 60℃ for 2 hours. After the extraction is completed, immediately separate the residue and filtrate by vacuum filtration, collect the filtrate, and perform the third reflux extraction according to the second reflux extraction method. After the extraction is completed, combine the filtrates obtained from the three extractions to obtain the compound stone extract, which is ready for use. (2) Take the compound stone extract and put it into a rotary evaporator with a temperature of 60℃, a vacuum degree of -0.06MPa and a rotation speed of 200r / min for vacuum concentration. Concentrate it to 1 / 5-1 / 6 of the original filtrate volume to obtain a compound stone extract with a relative density of 1.09 for later use. (3) Take the compound stone extract and add lactose. The mass ratio of the compound stone extract to lactose is 1:

3. Stir evenly to obtain a mixed soft material for later use. (4) The mixed soft material is put into the granulator and extruded and granulated using a 14-mesh sieve. The wet granules are placed in a drying oven at 60°C for 4 hours. The dried granules are then sieved through a 12-mesh sieve to obtain compound stone granules.

7. The use of the compound stone granules according to any one of claims 1-6 in the preparation of products for treating urinary system stones.

8. The application according to claim 7, characterized in that: The urinary system stone product is a medicine.

9. The application according to claim 8, characterized in that: The compound stone-forming granules exhibited a 39.773% inhibition rate against calcium oxalate crystallization at a concentration of 3.0 g / mL, demonstrating concentration-dependent crystal inhibition, protection of renal tubules, and optimization of the urinary tract microenvironment.

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