A nano-drug preparation for treating urological diseases and a preparation method thereof

Abstract

The application belongs to the technical field of medicine preparation, and discloses a kind of nano pharmaceutical preparation for treating urological disease and its preparation method, the pharmaceutical preparation has the following content of raw material components according to 100 parts of total mass: 10-20 parts of Houttuynia cordata, 10-15 parts of Plantago, 10-12 parts of dandelion, 10-12 parts of Lysimachia christin, 5-10 parts of spade heron, 5-10 parts of Astragalus, 5-10 parts of honeysuckle, 4-8 parts of Scutellaria, 6-8 parts of capillary, 2-5 parts of giant knotweed, 1-5 parts of turtle shell, 1-5 parts of Smilax, 1-3 parts of perilla, 1-3 parts of forsythia. The application extracts the active substances of the above traditional Chinese medicine composition by a suitable method, and is compounded with a polymer carrier to form a kind of nano preparation, which can reduce the reaction probability between different traditional Chinese medicine active substances, and slowly releases in the body, continuously acts, has good curative effect on urinary tract infection.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, and more specifically, relates to a nanomedicine formulation for treating urinary diseases and its preparation method. Background Technology

[0002] Urinary tract infection (UTI) is a general term for inflammation of the urinary system, including pyelonephritis, cystitis, and urethritis. UTIs are common human diseases, with main symptoms including frequent, dark, and painful urination, and in severe cases, fever, thirst, abdominal pain, lower back pain, hematuria, purulent discharge, and constipation or loose stools. Various surveys show that women are significantly more likely to suffer from UTIs than men due to their physiological characteristics. Lower UTIs are characterized by sudden onset, frequent urination, urgency, painful urination, and sometimes mucous discharge. Urine tests show elevated levels of pus cells, red blood cells, and white blood cells. If lower UTIs are not treated promptly, they can easily ascend to other infections, such as cystitis and nephritis. Ascending infections can be very serious; therefore, timely treatment during the infection phase is crucial to prevent adverse consequences.

[0003] Currently, there are also publicly available drugs for the treatment of urinary tract infections. For example, Chinese invention patent application number 202011158818.8 discloses a traditional Chinese medicine composition for treating urinary system diseases, comprising the following raw materials in the indicated weights: Lindera leaf powder 2.0-20.0g, Alpinia oxyphylla 1.0-10.0g, Rubus idaeus 1.0-10.0g, and also including Juncus effusus, Cinnamomum cassia, Gardenia jasminoides, Mantis religiosa ootheca, Cornus officinalis, and Polyporus umbellatus; Gardenia jasminoides, Juncus effusus, and Cinnamomum cassia are mainly used for clearing heat and dampness, promoting urination and regulating qi. For example, Chinese invention patent application number 200710121722.2 discloses a pharmaceutical composition for treating urinary system diseases and its preparation method, which is composed of raw materials such as 200-400 parts by weight of Dioscorea hypoglauca, 30-90 parts by weight of Acorus tatarinowii, 100-200 parts by weight of Glycyrrhiza uralensis, 50-120 parts by weight of Lindera strychnifolia, 20-80 parts by weight of Alpinia oxyphylla (fried), 200-300 parts by weight of Cuscuta chinensis, and 80-160 parts by weight of Poria cocos.

[0004] Currently, most traditional Chinese medicine preparations are made by mixing and extracting the active ingredients from multiple herbs. This process can easily lead to potential interactions between various active substances, as well as drawbacks such as rapid metabolism, short half-life, and lack of selectivity after administration. With the development of pharmaceutical research, biomaterials science, and clinical medicine, polymeric carriers are increasingly being used in drug preparation. Polymeric carriers are polymers that themselves have no pharmacological effects and do not react with drugs. As drug carriers, they rely on weak hydrogen bonds with the drug to form a carrier, or on attaching low-molecular-weight drugs to the polymer backbone through condensation reactions. Using polymeric materials as carriers for small-molecule drugs can increase the duration of drug action, improve drug selectivity, and reduce the toxicity of small-molecule drugs. Currently, excipients used in the preparation of nanoparticle formulations are mostly biodegradable polymers. Polyesters are the most studied and widely used biodegradable polymers to date, with commonly used ones including polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-polyglycolic acid copolymer (PLGA), and polycaprolactone (PCL). Currently, polymeric drug carriers are mainly used in small molecule drugs and rarely in traditional Chinese medicine. Summary of the Invention

[0005] The purpose of this invention is to overcome the problems existing in the prior art and provide a nanomedicine formulation for treating urinary diseases and its preparation method. This invention uses a combination of various traditional Chinese medicines and a polymer carrier to create a nanomedicine formulation, which can reduce the probability of reaction between different active substances in the traditional Chinese medicines, and simultaneously allows for slow release and sustained action in the body.

[0006] The objective of this invention and the technical problem it solves are achieved by the following technical solutions.

[0007] One aspect of the present invention provides a method for preparing a nanomedicine formulation for treating urinary diseases, comprising the following steps:

[0008] S1: Based on a total mass of 100 parts, prepare the following raw material components in the following proportions: Houttuynia cordata 10-20 parts, Plantago asiatica 10-15 parts, Taraxacum mongolicum 10-12 parts, Lysimachia christinae 10-12 parts, Portulaca oleracea 5-10 parts, Astragalus membranaceus 5-10 parts, Lonicera japonica 5-10 parts, Scutellaria baicalensis 4-8 parts, Artemisia capillaris 6-8 parts, Polygonum cuspidatum 2-5 parts, Trionyx sinensis 1-5 parts, Smilax china 1-5 parts, Perilla frutescens 1-3 parts, Forsythia suspensa 1-3 parts;

[0009] S2: According to the above ratio, mix Astragalus membranaceus, Scutellaria baicalensis, Polygonum cuspidatum, Trionyx sinensis, Smilax china, Perilla frutescens, and Forsythia suspensa and grind them into a mixed powder. Then add 75-80% ethanol and heat under reflux at 75-85℃ for 60-90 minutes to extract twice. Filter the extract and keep the residue for later use. After recovering the ethanol from the filtrate, concentrate the filtrate under reduced pressure to a relative density of 1.15-1.2 at 60℃ to obtain the first clear extract. Mix Houttuynia cordata, Plantago asiatica, Taraxacum mongolicum, Lysimachia christinae, Portulaca oleracea, Lonicera japonica, and Artemisia capillaris, add water and decoct three times. Combine the decoctions and filter the decoctions. Concentrate the filtrate under reduced pressure to a relative density of 1.15-1.2 at 60℃ to obtain the second clear extract.

[0010] S3: After mixing the first and second clear extracts evenly, the clear extract mixture is heated to 40-50℃. While stirring, the polymer carrier complex powder is added. After the addition is complete, the system is cooled to room temperature and stirred at 400-600 rpm for 1-3 hours. Finally, the mixture is granulated, dried, and ground into nanoscale drug powder formulations with a particle size between 100-500 nm.

[0011] Preferably, in step S2, the ethanol is added to the mixed powder at a volume-to-mass ratio of 100 mL: 10-15 g.

[0012] Preferably, the specific process of decocting and taking the medicine three times in step S2 is as follows: First, soak the raw materials in water at 8-10 times their weight for 1-3 hours, then decoct at 95-100°C for 1-1.5 hours, filter to obtain the first filtrate and the first residue, then mix the first residue with the residue obtained in step S2 and add water at 6-8 times their weight for 95-100°C for the second decoction for 0.8-1.0 hours to obtain the second filtrate and the second residue, then add water at 6-8 times their weight for 95-100°C for the third decoction for 0.8-1.0 hours.

[0013] Preferably, in step S3, the polymer carrier complex powder is added at a mass ratio of 0.3-0.7:1 to the ointment mixture.

[0014] Preferably, the preparation method of the polymer carrier composite powder is as follows:

[0015] Polylactic acid-polyglycolic acid copolymer was dissolved in an organic solvent to form a solution. The pH of the solution was adjusted to between 3 and 5. β-cyclodextrin was added to the solution while stirring. After the addition was complete, an initiator was added to the solution, and the system was heated to 40-60°C and stirred for 2-8 hours. Then, the system was cooled to room temperature, a crosslinking agent was added, and the mixture was microwaved at 400-800W for 3-5 hours. The resulting product was then filtered, washed, and dried to obtain product I. In the above reaction process, polylactic acid-polyglycolic acid copolymer, β-cyclodextrin, initiator, and crosslinking agent were added in a mass ratio of 1:0.5-1:0.05-0.1:0.04-0.08.

[0016] After heating the silica sol to 60-80℃, add the acid anhydride and stir for 1-3 hours. Then, cool down to 40-50℃ and keep warm for 10-20 minutes. After that, keep the temperature constant, add the product I obtained above, mix well, and stir for 6-8 hours. Cool the obtained product to room temperature and freeze-dry at -40 to -20℃ for 24-36 hours. Finally, vacuum dry at 40-50℃ for 4-8 hours and grind into powder to obtain the polymer carrier composite. In the above reaction process, silica sol, acid anhydride, and product I are added in a mass ratio of 1:0.03-0.08:1-5.

[0017] Preferably, the organic solvent is selected from dichloromethane, ethyl acetate, acetone, and tetrahydrofuran.

[0018] Preferably, the initiator is selected from one or more of potassium persulfate, sodium persulfate, and ammonium persulfate.

[0019] Preferably, the crosslinking agent is selected from pentylenetetrol, ethylene glycol, 1,2-propanediol, 1,4-butanediol, 1,6-hexanediol, neopentyl glycol, trimethylolpropane, oxalic acid, divinylbenzene, diisocyanate, and N,N-methylenebisacrylamide.

[0020] Preferably, the anhydride is selected from any one of succinic anhydride, maleic anhydride, oxalic anhydride, or itaconic anhydride.

[0021] Another aspect of the present invention provides a nanomedicine formulation for treating urinary diseases, which is prepared according to any of the foregoing methods.

[0022] By employing the above technical solution, the present invention has at least the following advantages: The present invention first extracts the active substances from a traditional Chinese medicine composition used to treat urinary system diseases through reflux extraction and decoction to obtain a mixed extract. Then, a polymeric carrier complex is used as a carrier in the extract to prepare a composite drug product. This drug can effectively improve the therapeutic effect and increase the loading of active substances, and is stable and can be stored for a long time. The drug of the present invention is nano-sized, making it easier for the body to absorb. The polymeric carrier complex of the present invention uses polylactic acid-polyglycolic acid copolymer as raw material. It undergoes free radical polymerization and cross-linking reactions with β-cyclodextrin under the action of an initiator and a cross-linking agent. β-cyclodextrin is a cyclic substance whose cyclic structure opens in an acidic environment. Under certain conditions, it can polymerize with polylactic acid-polyglycolic acid copolymer. Then, under the action of a cross-linking agent, cross-linking between polymer molecules occurs, forming bridge bonds between polymer molecular chains, resulting in the precipitation of an insoluble substance with a three-dimensional structure. The silica sol was modified using acid anhydride, then reacted with the aforementioned insoluble substance (product I), and finally dried to obtain a polymeric carrier complex. The viscosity of the silica sol enhanced the stability of the bonds between the complexes, resulting in a structurally stable complex. This complex, as a carrier for active extracts of traditional Chinese medicine, allows the extracts to adhere fully to the carrier surface, increasing the contact area with the external environment and improving therapeutic efficacy. Furthermore, the drug is slowly released after acting on the body, increasing its half-life and prolonging its duration of action. The pharmaceutical formulation of this invention exhibits significant antibacterial activity and a diuretic effect in rat experiments. Clinical trials have shown that the composition of this invention can improve the cure rate of patients with urinary tract infections.

[0023] The above description is merely an overview of the technical solution of the present invention. In order to better understand the technical means of the present invention and to implement it in accordance with the contents of the specification, the preferred embodiments of the present invention are described in detail below. Detailed Implementation

[0024] To make the technical means, creative features, achieved objectives, and effects of this invention readily understandable, the technical solutions in the embodiments of this invention will be clearly and completely described below in conjunction with the embodiments of this invention. Obviously, the described embodiments are merely some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0025] Example 1:

[0026] (1) Preparation of polymer carrier composite powder:

[0027] Polylactic acid-polyglycolic acid copolymer was dissolved in dichloromethane to form a solution. The pH of the solution was adjusted to between 3 and 5. β-cyclodextrin was added to the solution while stirring. After the addition was complete, ammonium persulfate was added to the solution, and the system was heated to 50°C and stirred for 6 hours. Then, the system was cooled to room temperature, oxalic acid was added, and the mixture was microwaved at 600W for 4 hours. The resulting product was then filtered, washed, and dried to obtain product I. In the above reaction, polylactic acid-polyglycolic acid copolymer, β-cyclodextrin, ammonium persulfate, and oxalic acid were reacted in a mass ratio of 1:0.75. The silica sol was added in a mass ratio of 0.075:0.06. After heating the silica sol to 70°C, succinic anhydride was added and stirred for 2 hours. The temperature was then lowered to 45°C and kept at that temperature for 15 minutes. The temperature was then kept constant, and the product I obtained above was added and mixed evenly. The mixture was stirred for 7 hours. The product was then cooled to room temperature and freeze-dried at -30°C for 30 hours. Finally, it was vacuum-dried at 45°C for 6 hours and ground into powder to obtain the polymer carrier composite. In the above reaction process, the silica sol, succinic anhydride and product I were added in a mass ratio of 1:0.055:3.

[0028] (2) Preparation of nanomedicine formulations:

[0029] Based on a total mass of 100 parts, prepare the following raw material components: Houttuynia cordata 15 parts, Plantago asiatica 12.5 parts, Taraxacum mongolicum 11 parts, Lysimachia christinae 11 parts, Portulaca oleracea 7.5 parts, Astragalus membranaceus 7.5 parts, Lonicera japonica 9 parts, Scutellaria baicalensis 6 parts, Artemisia capillaris 7 parts, Polygonum cuspidatum 3.5 parts, Trionyx sinensis 3 parts, Smilax china 3 parts, Perilla frutescens 2 parts, Forsythia suspensa 2 parts;

[0030] According to the above proportions, Astragalus membranaceus, Scutellaria baicalensis, Polygonum cuspidatum, Carapax Trionycis, Smilax china, Perilla frutescens, and Forsythia suspensa are mixed and ground into a powder. Then, 80% ethanol is added (at a volume-to-mass ratio of 100 mL: 12.5 g to the powder). The mixture is heated under reflux at 80°C for 75 min and extracted twice. The extract is filtered, and the residue is kept for later use. The ethanol is recovered from the filtrate, and the filtrate is concentrated under reduced pressure to a relative density of 1.15-1.2 at 60°C to obtain the first clear extract. Houttuynia cordata, Plantago asiatica, Taraxacum mongolicum, Lysimachia christinae, Portulaca oleracea, Lonicera japonica, and Artemisia capillaris are mixed, decocted in water, and taken three times. The specific process is as follows: First, soak the raw materials in water equal to 9 times their weight for 2 hours, then decoct at 100°C for 1.25 hours. Filter to obtain the first filtrate and the first residue. Then, mix the first residue with the residue obtained in step S2 above, add water equal to 7 times their weight of the raw materials, and decoct at 100°C for 0.9 hours to obtain the second filtrate and the second residue. Add water equal to 7 times their weight of the raw materials to the second residue and decoct at 100°C for 0.9 hours to obtain the third filtrate. Combine the decoctions and filter the decoctions. Concentrate the filtrate under reduced pressure to a relative density of 1.15-1.2 at 60°C to obtain the second clear extract.

[0031] After the first and second clear extracts are mixed evenly, the clear extract mixture is heated to 45°C. While stirring, the polymer carrier complex powder is added (at a mass ratio of 0.5:1 to the clear extract mixture). After the addition is complete, the system is cooled to room temperature and stirred at 500 rpm for 2 hours. Finally, the mixture is granulated, dried, and ground into nanoscale drug powder formulations with a particle size between 100-500 nm.

[0032] Example 2:

[0033] (1) Preparation of polymer carrier composite powder:

[0034] Polylactic acid-polyglycolic acid copolymer was dissolved in ethyl acetate to form a solution. The pH of the solution was adjusted to between 3 and 5. β-cyclodextrin was added to the solution while stirring. After the addition was complete, sodium persulfate was added, and the system was heated to 40°C and stirred for 8 hours. Then, the system was cooled to room temperature, ethylene glycol was added, and the mixture was microwaved at 800W for 3 hours. The resulting product was then filtered, washed, and dried to obtain product I. In the above reaction, polylactic acid-polyglycolic acid copolymer, β-cyclodextrin, sodium persulfate, and ethylene glycol were mixed in a mass ratio of 1:1. The silica sol was added in a mass ratio of 0.05:0.04. After heating the silica sol to 80°C, oxalic anhydride was added and stirred for 1 hour. The temperature was then lowered to 50°C and kept at that temperature for 10 minutes. The temperature was then kept constant, and the product I obtained above was added and mixed evenly. The mixture was stirred for 6 hours. The product was cooled to room temperature and then freeze-dried at -30°C for 30 hours. Finally, it was vacuum-dried at 40°C for 8 hours and ground into powder to obtain the polymer carrier composite. In the above reaction process, the silica sol, oxalic anhydride and product I were added in a mass ratio of 1:0.03:1.

[0035] (2) Preparation of nanomedicine formulations:

[0036] Based on a total mass of 100 parts, prepare the following raw material components: 20 parts houttuynia cordata, 10 parts plantain, 12 parts dandelion, 10 parts lysimachia christinae, 5 parts purslane, 10 parts astragalus membranaceus, 5 parts honeysuckle, 8 parts scutellaria baicalensis, 8 parts artemisia capillaris, 4 parts polygonum cuspidatum, 5 parts turtle shell, 1 part smilax china, 1 part perilla seed, and 1 part forsythia suspensa.

[0037] According to the above proportions, Astragalus membranaceus, Scutellaria baicalensis, Polygonum cuspidatum, Carapax Trionycis, Smilax china, Perilla frutescens, and Forsythia suspensa are mixed and ground into a powder. Then, 80% ethanol is added (at a volume-to-mass ratio of 100 mL: 10 g to the powder). The mixture is heated under reflux at 85°C for 60 min and extracted twice. The extract is filtered, and the residue is kept for later use. The ethanol is recovered from the filtrate, and the filtrate is concentrated under reduced pressure to a relative density of 1.15-1.2 at 60°C to obtain the first clear extract. Houttuynia cordata, Plantago asiatica, Taraxacum mongolicum, Lysimachia christinae, Portulaca oleracea, Lonicera japonica, and Artemisia capillaris are mixed, decocted in water, and taken three times a day. The specific process is as follows: First, soak the raw materials in water equal to 10 times their weight for 3 hours, then decoct at 95°C for 1.5 hours. Filter to obtain the first filtrate and the first residue. Then, mix the first residue with the residue obtained in step S2 above, add water equal to 6 times the weight of the raw materials, and decoct at 95°C for 1.0 hour to obtain the second filtrate and the second residue. Add water equal to 6 times the weight of the raw materials to the second residue and decoct at 95°C for 1.0 hour to obtain the third filtrate. Combine the decoctions and filter the decoctions. Concentrate the filtrate under reduced pressure to a relative density of 1.15-1.2 at 60°C to obtain the second clear extract.

[0038] After the first and second clear extracts are mixed evenly, the clear extract mixture is heated to 40°C. While stirring, the polymer carrier complex powder is added (at a mass ratio of 0.3:1 to the clear extract mixture). After the addition is complete, the system is cooled to room temperature and stirred at 600 rpm for 1 hour. Finally, the mixture is granulated, dried, and ground into nanoscale drug powder formulations with a particle size between 100-500 nm.

[0039] Example 3:

[0040] (1) Preparation of polymer carrier composite powder:

[0041] Polylactic acid-polyglycolic acid copolymer was dissolved in tetrahydrofuran to form a solution. The pH of the solution was adjusted to between 3 and 5. β-cyclodextrin was added to the solution while stirring. After the addition was complete, potassium persulfate was added, and the system was heated to 60°C and stirred for 2 hours. Then, the system was cooled to room temperature, and N,N-methylenebisacrylamide was added. The mixture was then microwaved at 400W for 5 hours. The resulting product was then filtered, washed, and dried to obtain product I. In the above reaction process, polylactic acid-polyglycolic acid copolymer, β-cyclodextrin, potassium persulfate, and N,N-methylenebisacrylamide were involved. The silica sol, maleic anhydride, and product I were added in a mass ratio of 1:0.5:0.1:0.08. After heating the silica sol to 60°C, maleic anhydride was added and stirred for 3 hours. The mixture was then cooled to 40°C and kept at that temperature for 20 minutes. The temperature was then kept constant, and product I was added and mixed thoroughly. The mixture was stirred for 8 hours. The product was then cooled to room temperature and freeze-dried at -30°C for 30 hours. Finally, it was vacuum-dried at 50°C for 4 hours and ground into powder to obtain the polymer carrier composite. In the above reaction process, the silica sol, maleic anhydride, and product I were added in a mass ratio of 1:0.08:5.

[0042] (2) Preparation of nanomedicine formulations:

[0043] Based on a total mass of 100 parts, prepare the following raw material components: 10 parts houttuynia cordata, 15 parts plantain, 10 parts dandelion, 12 parts lysimachia christinae, 10 parts purslane, 5 parts astragalus membranaceus, 10 parts honeysuckle, 8 parts scutellaria baicalensis, 6 parts artemisia capillaris, 2 parts polygonum cuspidatum, 1 part turtle shell, 5 parts smilax china, 3 parts perilla seed, and 3 parts forsythia suspensa.

[0044] According to the above ratio, Astragalus membranaceus, Scutellaria baicalensis, Polygonum cuspidatum, Carapax Trionycis, Smilax china, Perilla frutescens, and Forsythia suspensa are mixed and ground into a powder. Then, 75% ethanol is added (at a volume-to-mass ratio of 100 mL: 15 g to the powder). The mixture is heated under reflux at 75°C for 90 min and extracted twice. The extract is filtered, and the residue is kept for later use. The ethanol is recovered from the filtrate, and the filtrate is concentrated under reduced pressure to a relative density of 1.15-1.2 at 60°C to obtain the first clear extract. Houttuynia cordata, Plantago asiatica, Taraxacum mongolicum, Lysimachia christinae, Portulaca oleracea, Lonicera japonica, and Artemisia capillaris are mixed, decocted in water, and taken three times. The specific process is as follows: First, soak the raw materials in water equal to 8 times their weight for 1 hour, then decoct at 100°C for 1 hour. Filter to obtain the first filtrate and the first residue. Then, mix the first residue with the residue obtained in step S2 above, add water equal to 8 times their weight of the raw materials, and decoct at 100°C for 0.8 hours to obtain the second filtrate and the second residue. Add water equal to 8 times their weight of the raw materials to the second residue and decoct at 100°C for 0.8 hours to obtain the third filtrate. Combine the decoctions and filter the decoctions. Concentrate the filtrate under reduced pressure to a relative density of 1.15-1.2 at 60°C to obtain the second clear extract.

[0045] After the first and second clear extracts are mixed evenly, the clear extract mixture is heated to 50°C. While stirring, the polymer carrier complex powder is added (at a mass ratio of 0.7:1 to the clear extract mixture). After the addition is complete, the system is cooled to room temperature and stirred at 400 rpm for 3 hours. Finally, the mixture is granulated, dried, and ground into nanoscale drug powder formulations with a particle size between 100-500 nm.

[0046] Comparative Example 1:

[0047] (1) Preparation of polymer carrier composite powder:

[0048] Polylactic acid-polyhydroxyacetic acid copolymer was dissolved in dichloromethane to form a solution. The pH of the solution was adjusted to between 3 and 5. β-cyclodextrin was added to the solution while stirring. After the addition was complete, ammonium persulfate was added to the solution, and the system was heated to 50°C and stirred for 6 hours. Then, the system was cooled to room temperature, oxalic acid was added, and the mixture was microwaved at 600W for 4 hours. The resulting product was then filtered, washed, dried, and ground into powder to obtain the polymer carrier composite. In the above reaction process, polylactic acid-polyhydroxyacetic acid copolymer, β-cyclodextrin, ammonium persulfate, and oxalic acid were added in a mass ratio of 1:0.75:0.075:0.06.

[0049] (2) Preparation of nanomedicine formulations:

[0050] Based on a total mass of 100 parts, prepare the following raw material components: Houttuynia cordata 15 parts, Plantago asiatica 12.5 parts, Taraxacum mongolicum 11 parts, Lysimachia christinae 11 parts, Portulaca oleracea 7.5 parts, Astragalus membranaceus 7.5 parts, Lonicera japonica 9 parts, Scutellaria baicalensis 6 parts, Artemisia capillaris 7 parts, Polygonum cuspidatum 3.5 parts, Trionyx sinensis 3 parts, Smilax china 3 parts, Perilla frutescens 2 parts, Forsythia suspensa 2 parts;

[0051] According to the above proportions, Astragalus membranaceus, Scutellaria baicalensis, Polygonum cuspidatum, Carapax Trionycis, Smilax china, Perilla frutescens, and Forsythia suspensa are mixed and ground into a powder. Then, 80% ethanol is added (at a volume-to-mass ratio of 100 mL: 12.5 g to the powder). The mixture is heated under reflux at 80°C for 75 min and extracted twice. The extract is filtered, and the residue is kept for later use. The ethanol is recovered from the filtrate, and the filtrate is concentrated under reduced pressure to a relative density of 1.15-1.2 at 60°C to obtain the first clear extract. Houttuynia cordata, Plantago asiatica, Taraxacum mongolicum, Lysimachia christinae, Portulaca oleracea, Lonicera japonica, and Artemisia capillaris are mixed, decocted in water, and taken three times. The specific process is as follows: First, soak the raw materials in water equal to 9 times their weight for 2 hours, then decoct at 100°C for 1.25 hours. Filter to obtain the first filtrate and the first residue. Then, mix the first residue with the residue obtained in step S2 above, add water equal to 7 times their weight of the raw materials, and decoct at 100°C for 0.9 hours to obtain the second filtrate and the second residue. Add water equal to 7 times their weight of the raw materials to the second residue and decoct at 100°C for 0.9 hours to obtain the third filtrate. Combine the decoctions and filter the decoctions. Concentrate the filtrate under reduced pressure to a relative density of 1.15-1.2 at 60°C to obtain the second clear extract.

[0052] After the first and second clear extracts are mixed evenly, the clear extract mixture is heated to 45°C. While stirring, the polymer carrier complex powder is added (at a mass ratio of 0.5:1 to the clear extract mixture). After the addition is complete, the system is cooled to room temperature and stirred at 500 rpm for 2 hours. Finally, the mixture is granulated, dried, and ground into nanoscale drug powder formulations with a particle size between 100-500 nm.

[0053] Comparative Example 2:

[0054] Preparation of nanomedicine formulations:

[0055] Based on a total mass of 100 parts, prepare the following raw material components: Houttuynia cordata 15 parts, Plantago asiatica 12.5 parts, Taraxacum mongolicum 11 parts, Lysimachia christinae 11 parts, Portulaca oleracea 7.5 parts, Astragalus membranaceus 7.5 parts, Lonicera japonica 9 parts, Scutellaria baicalensis 6 parts, Artemisia capillaris 7 parts, Polygonum cuspidatum 3.5 parts, Trionyx sinensis 3 parts, Smilax china 3 parts, Perilla frutescens 2 parts, Forsythia suspensa 2 parts;

[0056] According to the above proportions, Astragalus membranaceus, Scutellaria baicalensis, Polygonum cuspidatum, Carapax Trionycis, Smilax china, Perilla frutescens, and Forsythia suspensa are mixed and ground into a powder. Then, 80% ethanol is added (at a volume-to-mass ratio of 100 mL: 12.5 g to the powder). The mixture is heated under reflux at 80°C for 75 min and extracted twice. The extract is filtered, and the residue is kept for later use. The ethanol is recovered from the filtrate, and the filtrate is concentrated under reduced pressure to a relative density of 1.15-1.2 at 60°C to obtain the first clear extract. Houttuynia cordata, Plantago asiatica, Taraxacum mongolicum, Lysimachia christinae, Portulaca oleracea, Lonicera japonica, and Artemisia capillaris are mixed, decocted in water, and taken three times. The specific process is as follows: First, soak the raw materials in water equal to 9 times their weight for 2 hours, then decoct at 100°C for 1.25 hours. Filter to obtain the first filtrate and the first residue. Then, mix the first residue with the residue obtained in step S2 above, add water equal to 7 times their weight of the raw materials, and decoct at 100°C for 0.9 hours to obtain the second filtrate and the second residue. Add water equal to 7 times their weight of the raw materials to the second residue and decoct at 100°C for 0.9 hours to obtain the third filtrate. Combine the decoctions and filter the decoctions. Concentrate the filtrate under reduced pressure to a relative density of 1.15-1.2 at 60°C to obtain the second clear extract.

[0057] After the first and second clear extracts are mixed evenly, the clear extract mixture is heated to 45°C. While stirring, polylactic acid-polyhydroxyacetic acid copolymer powder is added (at a mass ratio of 0.5:1 to the clear extract mixture). After the addition is complete, the system is cooled to room temperature and stirred at 500 rpm for 2 hours. Finally, the mixture is granulated, dried, and ground into nanoscale drug powder formulations with a particle size between 100-500 nm.

[0058] Comparative Example 3:

[0059] Preparation of nanomedicine formulations:

[0060] Based on a total mass of 100 parts, prepare the following raw material components: Houttuynia cordata 15 parts, Plantago asiatica 12.5 parts, Taraxacum mongolicum 11 parts, Lysimachia christinae 11 parts, Portulaca oleracea 7.5 parts, Astragalus membranaceus 7.5 parts, Lonicera japonica 9 parts, Scutellaria baicalensis 6 parts, Artemisia capillaris 7 parts, Polygonum cuspidatum 3.5 parts, Trionyx sinensis 3 parts, Smilax china 3 parts, Perilla frutescens 2 parts, Forsythia suspensa 2 parts;

[0061] According to the above proportions, Astragalus membranaceus, Scutellaria baicalensis, Polygonum cuspidatum, Carapax Trionycis, Smilax china, Perilla frutescens, and Forsythia suspensa are mixed and ground into a powder. Then, 80% ethanol is added (at a volume-to-mass ratio of 100 mL: 12.5 g to the powder). The mixture is heated under reflux at 80°C for 75 min and extracted twice. The extract is filtered, and the residue is kept for later use. The ethanol is recovered from the filtrate, and the filtrate is concentrated under reduced pressure to a relative density of 1.15-1.2 at 60°C to obtain the first clear extract. Houttuynia cordata, Plantago asiatica, Taraxacum mongolicum, Lysimachia christinae, Portulaca oleracea, Lonicera japonica, and Artemisia capillaris are mixed, decocted in water, and taken three times. The specific process is as follows: First, soak the raw materials in water equal to 9 times their weight for 2 hours, then decoct at 100°C for 1.25 hours. Filter to obtain the first filtrate and the first residue. Then, mix the first residue with the residue obtained in step S2 above, add water equal to 7 times their weight of the raw materials, and decoct at 100°C for 0.9 hours to obtain the second filtrate and the second residue. Add water equal to 7 times their weight of the raw materials to the second residue and decoct at 100°C for 0.9 hours to obtain the third filtrate. Combine the decoctions and filter the decoctions. Concentrate the filtrate under reduced pressure to a relative density of 1.15-1.2 at 60°C to obtain the second clear extract.

[0062] After the first and second clear extracts are mixed evenly, a clear extract mixture is obtained. Finally, the mixture is granulated, dried, and ground into a nano-sized drug powder formulation with a particle size between 100-500 nm.

[0063] Experimental Example 1: Detection of In Vitro Antibacterial Efficacy of Different Drug Formulations

[0064] Experimental subjects: Examples 1-3 and Comparative Examples 1-3

[0065] Experimental Methods: Weigh 10g of sample and dilute with 100mL of sterile distilled water. Inoculate each bacterial strain onto nutrient agar plates; inoculate Neisseria gonorrhoeae onto chocolate agar plates and Candida albicans onto Sabouraud agar plates. Make 5mm wells on each agar plate, add 0.2mL of diluted reagent to each well, and incubate at 37℃ for 24 hours. Incubate Neisseria gonorrhoeae at 37℃ CO2 for 24 hours. Observe the diameter of the inhibitory drug on each agar plate. Results are shown in Table 1.

[0066] Table 1. Antibacterial effects of different drug formulations

[0067]

[0068] As can be seen from the results in Table 1, compared with Comparative Examples 1-3, the nanomedicine formulation of the present invention has different degrees of inhibitory effect on the above-mentioned bacterial species. Among them, the inhibitory effect on Staphylococcus aureus, Enterococcus faecalis, Escherichia coli and Candida albicans is the most obvious, while the inhibitory effect on Pseudomonas aeruginosa is the worst.

[0069] Experimental Example 1: Diuretic Experiments of Different Drug Formulations

[0070] Experimental subjects: Examples 1-3 and Comparative Examples 1-3

[0071] Experimental methods: Seventy SD rats (purchased from Lilai Medical Experimental Center), weighing 200±20g, half male and half female, were randomly divided into 7 groups of 10 rats each. Urine was collected 1 hour before drug administration using the metabolic cage method. Then, 20mL of the drug was administered by gavage (5g of sample diluted with 100mL of sterile distilled water for later use) or an equal amount of distilled water (blank group) was administered. Urine was collected from each rat 1, 2, 3 and 5 hours after drug administration. The results are shown in Table 2.

[0072] Table 2. Diuresis test of different drug formulations

[0073]

[0074] Note: Compared with the control group, *P<0.05, **P<0.01.

[0075] As can be seen from the results in Table 2, compared with comparative examples 1-3 and the blank group, the drug of the present invention has a significant diuretic effect.

[0076] Trial Example 3: Clinical Trial

[0077] 1. This group consisted of 80 patients, all of whom were outpatients at our hospital between May 2022 and May 2023, and all met the diagnostic criteria for urinary tract infection proposed at the National Nephrology Conference. Patients were divided into a treatment group (using the drug described in Example 1) and a control group (using commercially available Sanjin tablets). The treatment group consisted of 40 patients (16 males and 24 females, with a mean age of 42 years). The control group consisted of 40 patients (13 males and 27 females, with a mean age of 44 years). The age, gender, diagnosis, severity of illness, and course of illness were similar between the two groups, with no statistically significant differences. It is important to note that no significant abnormalities were found in the blood routine, stool routine, liver function (ALT, AST), kidney function (BUN, Scr), and electrocardiogram results of all subjects before and after the trial. During the trial, no drug-related symptoms or signs occurred in the subjects, and no adverse reactions were reported.

[0078] 2. Diagnostic criteria

[0079] a. Traditional Chinese medicine diagnosis of acute urinary tract infection is characterized by frequent urination, dribbling and painful urination, lower abdominal pain, fever and chills, red tongue with yellow coating, and rapid pulse.

[0080] b. Western medicine diagnostic criteria: Clean-crush midstream urine sediment examination: white blood cells ≥10 / HP, with symptoms of urinary tract infection, or clean-crush midstream urine bacterial quantitative culture: colony count ≥105ml.

[0081] 3. Treatment methods

[0082] Treatment group: 10g of the drug preparation from Example 1 was dissolved in an appropriate amount of boiling water and taken orally twice a day, half an hour after meals. One course of treatment lasted two weeks, with continuous observation for four weeks.

[0083] Control group: Sanjin tablets, taken according to the instructions, two weeks as one course of treatment, and observed continuously for 4 weeks.

[0084] 4. Efficacy criteria

[0085] Based on the relevant standards of the "Guiding Principles for Clinical Research of New Traditional Chinese Medicines" promulgated by the Ministry of Health of the People's Republic of China: Cured: Clinical symptoms disappear, bacterial colonies in laboratory culture <105ml, and routine urinalysis is normal; Improved: Symptoms are alleviated, urine colonies are significantly reduced, and routine urinalysis is improved; Not cured: Symptoms and laboratory tests show no significant improvement.

[0086] 5. Treatment results: There was a statistically significant difference between the two groups (P < 0.05). The results are shown in Table 3.

[0087] Table 3 Comparison of efficacy between the two groups

[0088] Group Cured / Case Improvement / Example Not cured / case Overall effectiveness / % Treatment group 27 12 1 97.5 control group 23 11 6 85

[0089] As can be seen from the results in Table 3, the overall effective rate of the drug of the present invention is significantly higher than that of the control group.

[0090] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the methods and techniques disclosed above without departing from the scope of the present invention to create equivalent embodiments. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A method for preparing a nanomedicine formulation for treating urinary tract infections, characterized in that, Includes the following steps: S1: Based on a total mass of 100 parts, prepare the following raw material components in the following proportions: Houttuynia cordata 10-20 parts, Plantago asiatica 10-15 parts, Taraxacum mongolicum 10-12 parts, Lysimachia christinae 10-12 parts, Portulaca oleracea 5-10 parts, Astragalus membranaceus 5-10 parts, Lonicera japonica 5-10 parts, Scutellaria baicalensis 4-8 parts, Artemisia capillaris 6-8 parts, Polygonum cuspidatum 2-5 parts, Trionyx sinensis 1-5 parts, Smilax china 1-5 parts, Perilla frutescens 1-3 parts, Forsythia suspensa 1-3 parts; S2: According to the above ratio, mix Astragalus membranaceus, Scutellaria baicalensis, Polygonum cuspidatum, Trionyx sinensis, Smilax china, Perilla frutescens, and Forsythia suspensa and grind them into a mixed powder. Then add 75-80% ethanol and heat under reflux at 75-85℃ for 60-90 minutes to extract twice. Filter the extract and keep the residue for later use. After recovering the ethanol from the filtrate, concentrate the filtrate under reduced pressure to a relative density of 1.15-1.2 at 60℃ to obtain the first clear extract. Mix Houttuynia cordata, Plantago asiatica, Taraxacum mongolicum, Lysimachia christinae, Portulaca oleracea, Lonicera japonica, and Artemisia capillaris, add water and decoct three times. Combine the decoctions and filter the decoctions. Concentrate the filtrate under reduced pressure to a relative density of 1.15-1.2 at 60℃ to obtain the second clear extract. S3: After mixing the first and second clear extracts evenly, the clear extract mixture is heated to 40-50℃. While stirring, the polymer carrier complex powder is added. After the addition is complete, the system is cooled to room temperature and stirred at 400-600 rpm for 1-3 hours. Finally, the mixture is granulated, dried, and ground into nanoscale drug powder formulation with a particle size between 100-500 nm. The polymer carrier composite powder is added at a mass ratio of 0.3-0.7:1 to the extract mixture; The preparation method of the polymer carrier composite powder is as follows: Polylactic acid-polyglycolic acid copolymer was dissolved in an organic solvent to form a solution. The pH of the solution was adjusted to between 3 and 5. β-cyclodextrin was added to the solution while stirring. After the addition was complete, an initiator was added to the solution, and the system was heated to 40-60°C and stirred for 2-8 hours. Then, the system was cooled to room temperature, a crosslinking agent was added, and the mixture was microwaved at 400-800W for 3-5 hours. The resulting product was then filtered, washed, and dried to obtain product I. In the above reaction process, polylactic acid-polyglycolic acid copolymer, β-cyclodextrin, initiator, and crosslinking agent were added in a mass ratio of 1:0.5-1:0.05-0.1:0.04-0.

08. After heating the silica sol to 60-80℃, add the acid anhydride and stir for 1-3 hours. Then, cool down to 40-50℃ and keep warm for 10-20 minutes. After that, keep the temperature constant, add the product I obtained above, mix well, and stir for 6-8 hours. Cool the obtained product to room temperature and freeze-dry at -40~-20℃ for 24-36 hours. Finally, vacuum dry at 40-50℃ for 4-8 hours and grind into powder to obtain the polymer carrier composite. In the above reaction process, silica sol, acid anhydride, and product I are added in a mass ratio of 1:0.03-0.08:1-5.

2. The preparation method according to claim 1, characterized in that, In step S2, the ethanol is added to the mixed powder at a volume-to-mass ratio of 100 mL: 10-15 g.

3. The preparation method according to claim 1, characterized in that, The specific process of decocting and taking the medicine three times in step S2 is as follows: First, soak the raw materials in water at 8-10 times their weight for 1-3 hours, then decoct at 95-100℃ for 1-1.5 hours. Filter to obtain the first filtrate and the first residue. Then, mix the first residue with the residue obtained in step S2 and add water at 6-8 times their weight for 95-100℃ for the second decoction for 0.8-1.0 hours to obtain the second filtrate and the second residue. Add water at 6-8 times their weight for 95-100℃ to the second residue for the third decoction for 0.8-1.0 hours.

4. The preparation method according to claim 1, characterized in that, The organic solvent is selected from any one of dichloromethane, ethyl acetate, acetone, and tetrahydrofuran.

5. The preparation method according to claim 1, characterized in that, The initiator is selected from one or more of potassium persulfate, sodium persulfate, and ammonium persulfate.

6. The preparation method according to claim 1, characterized in that, The crosslinking agent is selected from pentylenetetrol, ethylene glycol, 1,2-propanediol, 1,4-butanediol, 1,6-hexanediol, neopentyl glycol, trimethylolpropane, oxalic acid, divinylbenzene, diisocyanate, and N,N-methylenebisacrylamide.

7. The preparation method according to claim 1, characterized in that, The anhydride is selected from any one of succinic anhydride, maleic anhydride, oxalic anhydride or itaconic anhydride.

8. A nanomedicine formulation for treating urinary tract infections, characterized in that, Prepared by the method according to any one of claims 1-7.

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