CN111053828A - Pharmaceutical composition for treating urinary system calculus - Google Patents
Pharmaceutical composition for treating urinary system calculus Download PDFInfo
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- CN111053828A CN111053828A CN201911342832.0A CN201911342832A CN111053828A CN 111053828 A CN111053828 A CN 111053828A CN 201911342832 A CN201911342832 A CN 201911342832A CN 111053828 A CN111053828 A CN 111053828A
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Abstract
The invention discloses a pharmaceutical composition for treating urinary calculus, which is prepared by the following steps of (1) weighing traditional Chinese medicine raw materials including astragalus, poria cocos, wolfberry, dodder, endothelium corneum gigeriae galli, desmodium, rhizoma alismatis, cowherb seed, spora lygodii, liquorice, asteriscus Pseudosciaenae and cluster mallow, (2) adding water into the traditional Chinese medicine raw materials, decocting under normal pressure, filtering, collecting filtrate, concentrating the filtrate under reduced pressure to obtain concentrated solution for later use, and (3) sequentially adding a surfactant, chitosan oligosaccharide, β -cyclodextrin or β -cyclodextrin modifier into the concentrated solution, fully mixing uniformly, and drying to obtain the pharmaceutical composition for treating urinary calculus.
Description
Technical Field
The invention relates to the technical field of traditional Chinese medicine compositions, in particular to a pharmaceutical composition for treating urinary calculus.
Background
Urinary stones, a common surgical disease, occur most frequently in south China, with the incidence being the first of all urological diseases. Urinary calculi usually include kidney calculi, vesical calculi, ureteral calculi and the like, and after the occurrence of the diseases, the main clinical symptoms of the patients are severe pain at the waist and abdomen, nausea, vomiting, hematuria and the like, and the clinical signs are in the categories of 'urolithiasis', 'sand stranguria', 'bloody stranguria', 'lumbago' and 'hematuria' in the traditional Chinese medicine. At present, the main clinical treatment means of urinary calculus is external shock wave lithotripsy, although the method has small physical trauma to patients, the method still has the risk that the calculus in the body can not be effectively discharged after the treatment of the patients, and repeated lithotripsy causes damage to the ureter wall and forms inflammatory or damaged ureteral stenosis, thus causing great pain to the patients. The traditional Chinese medicine has unique curative effect on urinary calculus removal, and multiple studies prove that the traditional Chinese medicine can promote calculus removal and reduce calculus removal times, so that the traditional Chinese medicine has important clinical significance.
According to the traditional Chinese medicine, the urinary system calculus belongs to the categories of lithiasis, renal colic and the like, the formation of the urinary system calculus is related to factors such as kidney deficiency, damp heat, stasis and the like, the urinary system calculus accumulates in the day and month, turbid substances are coagulated and become stones for a long time, and the main symptoms are that the urinary system calculus is radiated to the pudendum or the urethra is painful, hematuria or urine goes out of gravels, and nausea, vomiting, abdominal distension and fever can be accompanied. Therefore, the treatment of urinary calculus by traditional Chinese medicine means mainly comprises two methods of attack and tonification, which are divided into damp-heat type, qi-stagnation type and kidney deficiency type, wherein the kidney deficiency type comprises kidney-yang deficiency and kidney-yin deficiency. For damp-heat type patients, the traditional Chinese medicine treatment takes diuresis for treating stranguria as a main treatment method; qi stagnation type is to regulate qi-flowing for patients, remove blood stasis, relieve stranguria and strengthen body resistance; the patients with kidney deficiency are mainly treated by invigorating qi and kidney, and patients with kidney-yang deficiency need to strengthen kidney and tonify deficiency, and patients with kidney-yin deficiency need to nourish and clear. The main action mechanism of clinical application of the traditional Chinese medicine is to dissolve stones, relieve stranguria, strengthen spleen and stomach, clear heat, eliminate stagnation, activate blood and promote qi circulation, soften hard lumps and dissolve stones, and although oral administration is simple and convenient, the curative effect is general.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a pharmaceutical composition for treating urinary system calculus, which comprises the following components in part by weight: the astragalus, the tuckahoe, the medlar and the dodder have stimulation effect on a hematopoietic system, can enhance the immunity function, and has the functions of adjusting trace elements and resisting aging so as to play a role in integrally regulating qi and yin deficiency of the traditional Chinese medicine nephropathy; the astragalus, the rhizoma alismatis and the poria cocos have the effects of diuresis, inflammation resistance, bacteria resistance and virus resistance, and the pharmacological effects of improving the kidney function and eliminating urine protein can be the kidney protection effect on the qi and yin deficiency syndrome of the traditional Chinese medicine nephropathy; in addition, the desmodium and the endothelium corneum gigeriae galli contain various nitrogen-containing acids, and urine can be changed into acid after oral administration, so that alkaline calculi are dissolved; the herba lysimachiae and the spora lygodii can cause the pressure in the upper end cavity of the ureter to increase, and the increase of the ureter peristalsis frequency is the pharmacological basis of the stone removing and removing effects of the prescription.
The pharmaceutical composition for treating the urinary calculus is prepared by the following steps:
(1) weighing the following traditional Chinese medicine raw materials in parts by weight: 30-35 parts of astragalus membranaceus, 10-20 parts of poria cocos, 10-30 parts of wolfberry, 8-12 parts of semen cuscutae, 10-40 parts of endothelium corneum gigeriae galli, 20-50 parts of lysimachia christinae hance, 10-30 parts of rhizoma alismatis, 20-30 parts of cowherb seed, 25-30 parts of spora lygodii, 10-20 parts of liquorice, 10-20 parts of asteriscus Pseudosciaenae and 20-25 parts of cluster mallow seeds;
(2) adding water which is 5-20 times of the total weight of the traditional Chinese medicine raw materials into the traditional Chinese medicine raw materials, decocting for 1-2 hours at 70-90 ℃ under normal pressure, filtering, and collecting filtrate; concentrating the filtrate at 50-60 deg.C under reduced pressure until the concentration reaches 0.8-1.5 g/mL of crude drug to obtain concentrated solution;
(3) and (2) sequentially adding a surfactant accounting for 0.6-1% of the mass of the concentrated solution, chitosan oligosaccharide accounting for 1.5-3% of the mass of the concentrated solution, and β -cyclodextrin or β -cyclodextrin modifier accounting for 2-3% of the mass of the concentrated solution into the concentrated solution, fully mixing uniformly, and drying to obtain the pharmaceutical composition for treating the urinary system calculus.
Further, the β -cyclodextrin modifier is obtained by introducing a long hydrophobic chain of octadecenyl succinic anhydride into β -cyclodextrin.
β -cyclodextrin is a cyclic oligosaccharide formed by connecting α -1, 4D-glucose units, is similar to a truncated cone in shape and has the characteristics of good biocompatibility, biodegradability, special nonpolar cavity structure and the like β -cyclodextrin has a hydrophilic structure due to rich hydroxyl groups, and if octadecylsuccinic anhydride hydrophobic long chains are introduced, the solubility of β -cyclodextrin in an aqueous solution can be effectively reduced to form a stable structure.
According to some technical schemes, the β -cyclodextrin modified substance is prepared by dispersing 8-15 g of β -cyclodextrin in 80-100 mL of water under stirring at 50-60 ℃, stirring for 1-3 hours, adjusting the pH value to 8-9 by using a sodium hydroxide aqueous solution with the mass fraction of 2-5%, adding 0.1-1 g of octadecenyl succinic anhydride within 1-2 hours, stirring until the pH value is kept constant, namely, completing the reaction, neutralizing the pH value of a reaction system to 6-7 by using hydrochloric acid with the mass fraction of 1-5% after the reaction is completed, then carrying out vacuum freeze drying to obtain a crude product, washing the crude product by using a mixed solution composed of n-hexane/isopropanol in a volume ratio of (2-4): 1 until no chloride ion and octadecenyl succinic anhydride exist, collecting residues, finally washing the residues by using water, and carrying out vacuum freeze drying to obtain the β -cyclodextrin modified substance.
According to some technical schemes, the β -cyclodextrin modified substance is prepared by dispersing 8-15 g β -cyclodextrin in 80-100 mL of water under stirring at 50-60 ℃, stirring for 1-3 hours, adjusting the pH value to 8-9 by using a sodium hydroxide aqueous solution with the mass fraction of 2-5%, adding 0.1-1 g octadecenyl succinic anhydride within 1-2 hours, stirring until the pH value is kept constant, namely, completing the reaction, neutralizing the pH value of a reaction system to 6-7 by using hydrochloric acid with the mass fraction of 1-5% after the reaction is completed, performing vacuum freeze drying to obtain a crude product, washing the crude product by using n-hexane/isopropanol in a volume ratio (2-4) to a mixed solution consisting of 1 until no chlorine ion and octadecenyl succinic anhydride, collecting residues, washing the residues by using water, performing vacuum freeze drying to obtain octadecenyl succinic anhydride modified substance, preparing β -cyclodextrin modified substance by using octadecenyl succinic anhydride aqueous solution with the mass fraction of 398-12% to modify β -cyclodextrin aqueous solution, stirring for 80 g, performing vacuum freeze drying at 60-30 minutes, performing vacuum precipitation to 30-30 minutes, performing vacuum precipitation to obtain a precipitate, performing a reaction, and performing centrifugal precipitation on the precipitate after washing for 50-20 minutes, after stirring for 50-20-30 minutes, and performing vacuum precipitation at room temperature, and obtaining a centrifugal precipitation reaction.
Further, the chitosan oligosaccharide is replaced by a graft of chitosan oligosaccharide and a small molecule acid.
Further, the graft of the chitosan oligosaccharide and the small molecular acid is prepared by the following steps: adding 1.2-1.6 g of carbodiimide and 0.2-0.3 g of micromolecular acid into 20-40 mL of absolute ethyl alcohol, and stirring to completely dissolve the carbodiimide and the micromolecular acid to form solution A; weighing 0.4-0.6 g of chitosan oligosaccharide, adding into 20-30 mL of water, and stirring to completely dissolve the chitosan oligosaccharide to form solution B; adding the solution B into the solution A, stirring and reacting at 20-30 ℃ for 40-60 hours, transferring the reaction solution into a dialysis bag with the molecular weight cutoff of 7000-9000, and continuously replacing the medium for dialysis for 10-20 hours by taking deionized water as the medium to remove ethanol and unreacted small molecular substances; and after dialysis, carrying out vacuum freeze drying on the dialysate to obtain the graft of the chitosan oligosaccharide and the micromolecular acid.
Further, the small molecular acid is one of salicylic acid, stearic acid and deoxycholic acid.
Further, the small molecule acid is preferably stearic acid.
Further, the surfactant is magnesium lauryl sulfate and/or polyethylene glycol 1000. Preferably, the surfactant is a mixture of magnesium lauryl sulfate and polyethylene glycol 1000 in a mass ratio of 1: 1.
Further, the drying mode of the step (3) is vacuum freeze drying or spray drying.
The pharmaceutical composition for treating the urinary system calculus can effectively improve clinical symptoms, reduce symptom integral, enhance the emergency capacity of an organism, also has the antioxidant capacity of removing free radicals and the like and can improve blood circulation by improving the qi-yin deficiency and the physical quality of a urinary system calculus patient and integrally regulating the functions of liver, spleen, kidney and other organs.
Detailed Description
The raw materials in the examples are as follows:
β -Cyclodextrin, manufactured by Hubei Xingying Galaxy chemical Co., Ltd, and is in food grade.
Octadecenylsuccinic anhydride, manufactured by Shanghai Koch Biotech, Inc.
Vitamin E, manufactured by Shandong Bi Sheng Biotech Co., Ltd.
Chitosan oligosaccharide, molecular weight 9000, Qingdao Honghai biotechnology limited company of manufacturers.
Carbodiimide, EDC, manufacturer Shouguang Lisheng chemical Co., Ltd.
Salicylic acid, Zhengzhou Guanhui chemical products Co., Ltd.
Stearic acid, manufacturer shin-weed chemical science and technology ltd.
Deoxycholic acid, manufacturer duckweed chemical science and technology ltd.
Magnesium lauryl sulfate, food grade, manufacturer Nanjing chemical reagents, Inc.
Polyethylene glycol 1000, food grade, manufacturer china medicine foreign trade limited.
In the case where the present invention is not specifically described, the specific conditions of the vacuum freeze-drying are as follows: the pre-freezing temperature is-80 ℃, the pre-freezing time is 2 hours, the freezing temperature is-70 ℃, the freezing time is 36 hours, and the absolute pressure is 100 Pa.
Example 1
The pharmaceutical composition for treating the urinary calculus is prepared by the following steps:
(1) weighing the following traditional Chinese medicine raw materials in parts by weight: 30 parts of astragalus membranaceus, 10 parts of poria cocos, 10 parts of wolfberry, 8 parts of semen cuscutae, 20 parts of endothelium corneum gigeriae galli, 20 parts of desmodium, 10 parts of rhizoma alismatis, 20 parts of cowherb seed, 25 parts of spora lygodii, 10 parts of liquorice, 10 parts of asteriscus Pseudosciaenae and 20 parts of malva seed;
(2) adding deionized water 15 times of the total weight of the Chinese medicinal materials into the Chinese medicinal materials, decocting at 70 deg.C under normal pressure for 2 hr, filtering with 200 mesh nylon cloth, and collecting filtrate; concentrating the filtrate at 50 deg.C under reduced pressure until the concentration reaches 1g/mL of crude drug to obtain concentrated solution;
(3) and adding 0.6% of magnesium lauryl sulfate, 1.5% of chitosan oligosaccharide and 2% of β -cyclodextrin into the concentrated solution in sequence, mixing, and vacuum freeze drying to obtain the pharmaceutical composition for treating urinary calculus.
Example 2
The pharmaceutical composition for treating the urinary calculus is prepared by the following steps:
(1) weighing the following traditional Chinese medicine raw materials in parts by weight: 30 parts of astragalus membranaceus, 10 parts of poria cocos, 10 parts of wolfberry, 8 parts of semen cuscutae, 20 parts of endothelium corneum gigeriae galli, 20 parts of desmodium, 10 parts of rhizoma alismatis, 20 parts of cowherb seed, 25 parts of spora lygodii, 10 parts of liquorice, 10 parts of asteriscus Pseudosciaenae and 20 parts of malva seed;
(2) adding deionized water 15 times of the total weight of the Chinese medicinal materials into the Chinese medicinal materials, decocting at 70 deg.C under normal pressure for 2 hr, filtering with 200 mesh nylon cloth, and collecting filtrate; concentrating the filtrate at 50 deg.C under reduced pressure until the concentration reaches 1g/mL of crude drug to obtain concentrated solution;
(3) and adding 0.6% of magnesium lauryl sulfate, 1.5% of chitosan oligosaccharide and 2% of β -cyclodextrin modifier into the concentrated solution in sequence, mixing, and vacuum freeze drying to obtain the pharmaceutical composition for treating urinary system calculus.
The β -cyclodextrin modified substance is prepared by the following processes of dispersing 10g of β -cyclodextrin into 90mL of deionized water under stirring at 50 ℃, stirring for 1 hour at 200 revolutions per minute, adjusting the pH value to 8.5 by using a sodium hydroxide aqueous solution with the mass fraction of 3%, adding 0.5g of octadecenyl succinic anhydride within 1.5 hours, stirring for 200 revolutions per minute until the pH value is kept constant, completing the reaction, neutralizing the pH value of a reaction system to 6.5 by using hydrochloric acid with the mass fraction of 3% after the reaction is completed, performing vacuum freeze drying to obtain a crude product, washing the crude product by using n-hexane/isopropanol with the weight of 5 times of the crude product in a mixed solution with the volume ratio of 3:1 until no chloride ions and octadecenyl succinic anhydride exist, collecting residues, finally washing the residues by using deionized water with the weight of 10 times of the residues, and performing vacuum freeze drying to obtain the β -cyclodextrin modified substance.
Example 3
The pharmaceutical composition for treating the urinary calculus is prepared by the following steps:
(1) weighing the following traditional Chinese medicine raw materials in parts by weight: 30 parts of astragalus membranaceus, 10 parts of poria cocos, 10 parts of wolfberry, 8 parts of semen cuscutae, 20 parts of endothelium corneum gigeriae galli, 20 parts of desmodium, 10 parts of rhizoma alismatis, 20 parts of cowherb seed, 25 parts of spora lygodii, 10 parts of liquorice, 10 parts of asteriscus Pseudosciaenae and 20 parts of malva seed;
(2) adding deionized water 15 times of the total weight of the Chinese medicinal materials into the Chinese medicinal materials, decocting at 70 deg.C under normal pressure for 2 hr, filtering with 200 mesh nylon cloth, and collecting filtrate; concentrating the filtrate at 50 deg.C under reduced pressure until the concentration reaches 1g/mL of crude drug to obtain concentrated solution;
(3) and adding 0.6% of magnesium lauryl sulfate, 1.5% of chitosan oligosaccharide and 2% of β -cyclodextrin modifier into the concentrated solution in sequence, mixing, and vacuum freeze drying to obtain the pharmaceutical composition for treating urinary system calculus.
The β -cyclodextrin modified substance is prepared by dispersing 10g β -cyclodextrin in 90mL deionized water under stirring at 50 ℃, stirring for 1 hour at 200 revolutions per minute, adjusting the pH value to 8.5 by using a sodium hydroxide aqueous solution with the mass fraction of 3%, adding 0.5g octadecenyl succinic anhydride within 1.5 hours, stirring for 200 revolutions per minute until the pH value is kept constant, completing the reaction, neutralizing the pH value of a reaction system to 6.5 by using hydrochloric acid with the mass fraction of 3% after the reaction is completed, performing vacuum freeze drying to obtain a crude product, washing the crude product by using n-hexane/isopropanol with the weight of 5 times of the crude product in a mixed solution with the volume ratio of 3:1 until no chloride ions and the octadecenyl succinic anhydride exist, collecting residues, finally washing the residues by using deionized water with the weight of 10 times of the residues, performing vacuum freeze drying to obtain the octadecenyl succinic anhydride 32-cyclodextrin, configuring a modified octadecenyl succinic anhydride aqueous solution with the mass fraction of 10% to 100g β -cyclodextrin, stirring for 30 minutes at 50 ℃, adding vitamin E into the modified solution, performing centrifugal precipitation at the bottom of the modified solution, performing centrifugal precipitation at 50-20 ℃ after the modified solution is washed by using 5 times of n-hexane/isopropanol with the volume ratio of 3:1, and the mixed solution is prepared, and the modified solution is stirred, and the precipitate is precipitated, and the precipitate is obtained after the precipitation is obtained, the precipitation is naturally, the precipitation is obtained.
Example 4
The pharmaceutical composition for treating the urinary calculus is prepared by the following steps:
(1) weighing the following traditional Chinese medicine raw materials in parts by weight: 30 parts of astragalus membranaceus, 10 parts of poria cocos, 10 parts of wolfberry, 8 parts of semen cuscutae, 20 parts of endothelium corneum gigeriae galli, 20 parts of desmodium, 10 parts of rhizoma alismatis, 20 parts of cowherb seed, 25 parts of spora lygodii, 10 parts of liquorice, 10 parts of asteriscus Pseudosciaenae and 20 parts of malva seed;
(2) adding deionized water 15 times of the total weight of the Chinese medicinal materials into the Chinese medicinal materials, decocting at 70 deg.C under normal pressure for 2 hr, filtering with 200 mesh nylon cloth, and collecting filtrate; concentrating the filtrate at 50 deg.C under reduced pressure until the concentration reaches 1g/mL of crude drug to obtain concentrated solution;
(3) and adding 0.6 mass percent of lauryl magnesium sulfate, 1.5 mass percent of chitosan oligosaccharide and salicylic acid graft and 2 mass percent of β -cyclodextrin modifier into the concentrated solution in sequence, fully mixing uniformly, and performing vacuum freeze drying to obtain the pharmaceutical composition for treating the urinary system calculus.
The β -cyclodextrin modified substance is prepared by dispersing 10g β -cyclodextrin in 90mL deionized water under stirring at 50 ℃, stirring for 1 hour at 200 revolutions per minute, adjusting the pH value to 8.5 by using a sodium hydroxide aqueous solution with the mass fraction of 3%, adding 0.5g octadecenyl succinic anhydride within 1.5 hours, stirring for 200 revolutions per minute until the pH value is kept constant, completing the reaction, neutralizing the pH value of a reaction system to 6.5 by using hydrochloric acid with the mass fraction of 3% after the reaction is completed, performing vacuum freeze drying to obtain a crude product, washing the crude product by using n-hexane/isopropanol with the weight of 5 times of the crude product in a mixed solution with the volume ratio of 3:1 until no chloride ions and the octadecenyl succinic anhydride exist, collecting residues, finally washing the residues by using deionized water with the weight of 10 times of the residues, performing vacuum freeze drying to obtain the octadecenyl succinic anhydride 32-cyclodextrin, configuring a modified octadecenyl succinic anhydride aqueous solution with the mass fraction of 10% to 100g β -cyclodextrin, stirring for 30 minutes at 50 ℃, adding vitamin E into the modified solution, performing centrifugal precipitation at the bottom of the modified solution, performing centrifugal precipitation at 50-20 ℃ after the modified solution is washed by using 5 times of n-hexane/isopropanol with the volume ratio of 3:1, and the mixed solution is prepared, and the modified solution is stirred, and the precipitate is precipitated, and the precipitate is obtained after the precipitation is obtained, the precipitation is naturally, the precipitation is obtained.
The graft of the chitosan oligosaccharide and the salicylic acid is prepared by the following steps: adding 1.48g of carbodiimide and 0.21g of salicylic acid into 30mL of absolute ethyl alcohol, and stirring at 100 revolutions per minute to completely dissolve the carbodiimide to form solution A; weighing 0.5g of chitosan oligosaccharide, adding the chitosan oligosaccharide into 25mL of deionized water, and stirring at 100 revolutions per minute to completely dissolve the chitosan oligosaccharide to form solution B; adding the solution B into the solution A, stirring and reacting for 50 hours at 25 ℃, transferring the reaction solution into a dialysis bag with the cut-off molecular weight of 7000, and continuously replacing the medium for dialysis for 10 hours by taking deionized water as the medium to remove ethanol and unreacted small molecular substances; after dialysis, the dialyzate is frozen and dried in vacuum to obtain the graft of the chitosan oligosaccharide and the salicylic acid.
Example 5
The pharmaceutical composition for treating the urinary calculus is prepared by the following steps:
(1) weighing the following traditional Chinese medicine raw materials in parts by weight: 30 parts of astragalus membranaceus, 10 parts of poria cocos, 10 parts of wolfberry, 8 parts of semen cuscutae, 20 parts of endothelium corneum gigeriae galli, 20 parts of desmodium, 10 parts of rhizoma alismatis, 20 parts of cowherb seed, 25 parts of spora lygodii, 10 parts of liquorice, 10 parts of asteriscus Pseudosciaenae and 20 parts of malva seed;
(2) adding deionized water 15 times of the total weight of the Chinese medicinal materials into the Chinese medicinal materials, decocting at 70 deg.C under normal pressure for 2 hr, filtering with 200 mesh nylon cloth, and collecting filtrate; concentrating the filtrate at 50 deg.C under reduced pressure until the concentration reaches 1g/mL of crude drug to obtain concentrated solution;
(3) and adding 0.6% of magnesium lauryl sulfate, 1.5% of chitosan oligosaccharide and stearic acid graft and 2% of β -cyclodextrin modifier into the concentrated solution in sequence, mixing, and vacuum freeze drying to obtain the pharmaceutical composition for treating urinary system calculus.
The β -cyclodextrin modified substance is prepared by dispersing 10g β -cyclodextrin in 90mL deionized water under stirring at 50 ℃, stirring for 1 hour at 200 revolutions per minute, adjusting the pH value to 8.5 by using a sodium hydroxide aqueous solution with the mass fraction of 3%, adding 0.5g octadecenyl succinic anhydride within 1.5 hours, stirring for 200 revolutions per minute until the pH value is kept constant, completing the reaction, neutralizing the pH value of a reaction system to 6.5 by using hydrochloric acid with the mass fraction of 3% after the reaction is completed, performing vacuum freeze drying to obtain a crude product, washing the crude product by using n-hexane/isopropanol with the weight of 5 times of the crude product in a mixed solution with the volume ratio of 3:1 until no chloride ions and the octadecenyl succinic anhydride exist, collecting residues, finally washing the residues by using deionized water with the weight of 10 times of the residues, performing vacuum freeze drying to obtain the octadecenyl succinic anhydride 32-cyclodextrin, configuring a modified octadecenyl succinic anhydride aqueous solution with the mass fraction of 10% to 100g β -cyclodextrin, stirring for 30 minutes at 50 ℃, adding vitamin E into the modified solution, performing centrifugal precipitation at the bottom of the modified solution, performing centrifugal precipitation at 50-20 ℃ after the modified solution is washed by using 5 times of n-hexane/isopropanol with the volume ratio of 3:1, and the mixed solution is prepared, and the modified solution is stirred, and the precipitate is precipitated, and the precipitate is obtained after the precipitation is obtained, the precipitation is naturally, the precipitation is obtained.
The graft of the chitosan oligosaccharide and the stearic acid is prepared by the following steps: adding 1.48g of carbodiimide and 0.21g of stearic acid into 30mL of absolute ethyl alcohol, and stirring at 100 revolutions per minute to completely dissolve the carbodiimide to form solution A; weighing 0.5g of chitosan oligosaccharide, adding the chitosan oligosaccharide into 25mL of deionized water, and stirring at 100 revolutions per minute to completely dissolve the chitosan oligosaccharide to form solution B; adding the solution B into the solution A, stirring and reacting for 50 hours at 25 ℃, transferring the reaction solution into a dialysis bag with the cut-off molecular weight of 7000, and continuously replacing the medium for dialysis for 10 hours by taking deionized water as the medium to remove ethanol and unreacted small molecular substances; and after dialysis, carrying out vacuum freeze drying on the dialysate to obtain the graft of the chitosan oligosaccharide and the stearic acid.
Example 6
The pharmaceutical composition for treating the urinary calculus is prepared by the following steps:
(1) weighing the following traditional Chinese medicine raw materials in parts by weight: 30 parts of astragalus membranaceus, 10 parts of poria cocos, 10 parts of wolfberry, 8 parts of semen cuscutae, 20 parts of endothelium corneum gigeriae galli, 20 parts of desmodium, 10 parts of rhizoma alismatis, 20 parts of cowherb seed, 25 parts of spora lygodii, 10 parts of liquorice, 10 parts of asteriscus Pseudosciaenae and 20 parts of malva seed;
(2) adding deionized water 15 times of the total weight of the Chinese medicinal materials into the Chinese medicinal materials, decocting at 70 deg.C under normal pressure for 2 hr, filtering with 200 mesh nylon cloth, and collecting filtrate; concentrating the filtrate at 50 deg.C under reduced pressure until the concentration reaches 1g/mL of crude drug to obtain concentrated solution;
(3) and adding 0.6% of magnesium lauryl sulfate, 1.5% of chitosan oligosaccharide and deoxycholic acid graft and 2% of β -cyclodextrin modifier into the concentrated solution in sequence, fully mixing, and performing vacuum freeze drying to obtain the pharmaceutical composition for treating urinary system calculus.
The β -cyclodextrin modified substance is prepared by dispersing 10g β -cyclodextrin in 90mL deionized water under stirring at 50 ℃, stirring for 1 hour at 200 revolutions per minute, adjusting the pH value to 8.5 by using a sodium hydroxide aqueous solution with the mass fraction of 3%, adding 0.5g octadecenyl succinic anhydride within 1.5 hours, stirring for 200 revolutions per minute until the pH value is kept constant, completing the reaction, neutralizing the pH value of a reaction system to 6.5 by using hydrochloric acid with the mass fraction of 3% after the reaction is completed, performing vacuum freeze drying to obtain a crude product, washing the crude product by using n-hexane/isopropanol with the weight of 5 times of the crude product in a mixed solution with the volume ratio of 3:1 until no chloride ions and the octadecenyl succinic anhydride exist, collecting residues, finally washing the residues by using deionized water with the weight of 10 times of the residues, performing vacuum freeze drying to obtain the octadecenyl succinic anhydride 32-cyclodextrin, configuring a modified octadecenyl succinic anhydride aqueous solution with the mass fraction of 10% to 100g β -cyclodextrin, stirring for 30 minutes at 50 ℃, adding vitamin E into the modified solution, performing centrifugal precipitation at the bottom of the modified solution, performing centrifugal precipitation at 50-20 ℃ after the modified solution is washed by using 5 times of n-hexane/isopropanol with the volume ratio of 3:1, and the mixed solution is prepared, and the modified solution is stirred, and the precipitate is precipitated, and the precipitate is obtained after the precipitation is obtained, the precipitation is naturally, the precipitation is obtained.
The graft of the chitosan oligosaccharide and the deoxycholic acid is prepared by the following steps: adding 1.48g of carbodiimide and 0.21g of deoxycholic acid into 30mL of absolute ethyl alcohol, and stirring at 100 revolutions per minute to completely dissolve the carbodiimide to form solution A; weighing 0.5g of chitosan oligosaccharide, adding the chitosan oligosaccharide into 25mL of deionized water, and stirring at 100 revolutions per minute to completely dissolve the chitosan oligosaccharide to form solution B; adding the solution B into the solution A, stirring and reacting for 50 hours at 25 ℃, transferring the reaction solution into a dialysis bag with the cut-off molecular weight of 7000, and continuously replacing the medium for dialysis for 10 hours by taking deionized water as the medium to remove ethanol and unreacted small molecular substances; after dialysis, the dialyzate is frozen and dried in vacuum to obtain the graft of the chitosan oligosaccharide and the deoxycholic acid.
Example 7
The pharmaceutical composition for treating the urinary calculus is prepared by the following steps:
(1) weighing the following traditional Chinese medicine raw materials in parts by weight: 30 parts of astragalus membranaceus, 10 parts of poria cocos, 10 parts of wolfberry, 8 parts of semen cuscutae, 20 parts of endothelium corneum gigeriae galli, 20 parts of desmodium, 10 parts of rhizoma alismatis, 20 parts of cowherb seed, 25 parts of spora lygodii, 10 parts of liquorice, 10 parts of asteriscus Pseudosciaenae and 20 parts of malva seed;
(2) adding deionized water 15 times of the total weight of the Chinese medicinal materials into the Chinese medicinal materials, decocting at 70 deg.C under normal pressure for 2 hr, filtering with 200 mesh nylon cloth, and collecting filtrate; concentrating the filtrate at 50 deg.C under reduced pressure until the concentration reaches 1g/mL of crude drug to obtain concentrated solution;
(3) adding polyethylene glycol 1000 accounting for 0.6 percent of the mass of the concentrated solution, chitosan oligosaccharide and stearic acid graft accounting for 1.5 percent of the mass of the concentrated solution and β -cyclodextrin modifier accounting for 2 percent of the mass of the concentrated solution into the concentrated solution in sequence, fully mixing uniformly, and carrying out vacuum freeze drying to obtain the pharmaceutical composition for treating the urinary system calculus.
The β -cyclodextrin modified substance is prepared by dispersing 10g β -cyclodextrin in 90mL deionized water under stirring at 50 ℃, stirring for 1 hour at 200 revolutions per minute, adjusting the pH value to 8.5 by using a sodium hydroxide aqueous solution with the mass fraction of 3%, adding 0.5g octadecenyl succinic anhydride within 1.5 hours, stirring for 200 revolutions per minute until the pH value is kept constant, completing the reaction, neutralizing the pH value of a reaction system to 6.5 by using hydrochloric acid with the mass fraction of 3% after the reaction is completed, performing vacuum freeze drying to obtain a crude product, washing the crude product by using n-hexane/isopropanol with the weight of 5 times of the crude product in a mixed solution with the volume ratio of 3:1 until no chloride ions and the octadecenyl succinic anhydride exist, collecting residues, finally washing the residues by using deionized water with the weight of 10 times of the residues, performing vacuum freeze drying to obtain the octadecenyl succinic anhydride 32-cyclodextrin, configuring a modified octadecenyl succinic anhydride aqueous solution with the mass fraction of 10% to 100g β -cyclodextrin, stirring for 30 minutes at 50 ℃, adding vitamin E into the modified solution, performing centrifugal precipitation at the bottom of the modified solution, performing centrifugal precipitation at 50-20 ℃ after the modified solution is washed by using 5 times of n-hexane/isopropanol with the volume ratio of 3:1, and the mixed solution is prepared, and the modified solution is stirred, and the precipitate is precipitated, and the precipitate is obtained after the precipitation is obtained, the precipitation is naturally, the precipitation is obtained.
The graft of the chitosan oligosaccharide and the stearic acid is prepared by the following steps: adding 1.48g of carbodiimide and 0.21g of stearic acid into 30mL of absolute ethyl alcohol, and stirring at 100 revolutions per minute to completely dissolve the carbodiimide to form solution A; weighing 0.5g of chitosan oligosaccharide, adding the chitosan oligosaccharide into 25mL of deionized water, and stirring at 100 revolutions per minute to completely dissolve the chitosan oligosaccharide to form solution B; adding the solution B into the solution A, stirring and reacting for 50 hours at 25 ℃, transferring the reaction solution into a dialysis bag with the cut-off molecular weight of 7000, and continuously replacing the medium for dialysis for 10 hours by taking deionized water as the medium to remove ethanol and unreacted small molecular substances; and after dialysis, carrying out vacuum freeze drying on the dialysate to obtain the graft of the chitosan oligosaccharide and the stearic acid.
Example 8
The pharmaceutical composition for treating the urinary calculus is prepared by the following steps:
(1) weighing the following traditional Chinese medicine raw materials in parts by weight: 30 parts of astragalus membranaceus, 10 parts of poria cocos, 10 parts of wolfberry, 8 parts of semen cuscutae, 20 parts of endothelium corneum gigeriae galli, 20 parts of desmodium, 10 parts of rhizoma alismatis, 20 parts of cowherb seed, 25 parts of spora lygodii, 10 parts of liquorice, 10 parts of asteriscus Pseudosciaenae and 20 parts of malva seed;
(2) adding deionized water 15 times of the total weight of the Chinese medicinal materials into the Chinese medicinal materials, decocting at 70 deg.C under normal pressure for 2 hr, filtering with 200 mesh nylon cloth, and collecting filtrate; concentrating the filtrate at 50 deg.C under reduced pressure until the concentration reaches 1g/mL of crude drug to obtain concentrated solution;
(3) and sequentially adding a surfactant accounting for 0.6 percent of the mass of the concentrated solution, a chitosan oligosaccharide and stearic acid graft accounting for 1.5 percent of the mass of the concentrated solution and an β -cyclodextrin modifier accounting for 2 percent of the mass of the concentrated solution into the concentrated solution, fully mixing uniformly, and carrying out vacuum freeze drying to obtain the pharmaceutical composition for treating the urinary system calculus.
The β -cyclodextrin modified substance is prepared by dispersing 10g β -cyclodextrin in 90mL deionized water under stirring at 50 ℃, stirring for 1 hour at 200 revolutions per minute, adjusting the pH value to 8.5 by using a sodium hydroxide aqueous solution with the mass fraction of 3%, adding 0.5g octadecenyl succinic anhydride within 1.5 hours, stirring for 200 revolutions per minute until the pH value is kept constant, completing the reaction, neutralizing the pH value of a reaction system to 6.5 by using hydrochloric acid with the mass fraction of 3% after the reaction is completed, performing vacuum freeze drying to obtain a crude product, washing the crude product by using n-hexane/isopropanol with the weight of 5 times of the crude product in a mixed solution with the volume ratio of 3:1 until no chloride ions and the octadecenyl succinic anhydride exist, collecting residues, finally washing the residues by using deionized water with the weight of 10 times of the residues, performing vacuum freeze drying to obtain the octadecenyl succinic anhydride 32-cyclodextrin, configuring a modified octadecenyl succinic anhydride aqueous solution with the mass fraction of 10% to 100g β -cyclodextrin, stirring for 30 minutes at 50 ℃, adding vitamin E into the modified solution, performing centrifugal precipitation at the bottom of the modified solution, performing centrifugal precipitation at 50-20 ℃ after the modified solution is washed by using 5 times of n-hexane/isopropanol with the volume ratio of 3:1, and the mixed solution is prepared, and the modified solution is stirred, and the precipitate is precipitated, and the precipitate is obtained after the precipitation is obtained, the precipitation is naturally, the precipitation is obtained.
The graft of the chitosan oligosaccharide and the stearic acid is prepared by the following steps: adding 1.48g of carbodiimide and 0.21g of stearic acid into 30mL of absolute ethyl alcohol, and stirring at 100 revolutions per minute to completely dissolve the carbodiimide to form solution A; weighing 0.5g of chitosan oligosaccharide, adding the chitosan oligosaccharide into 25mL of deionized water, and stirring at 100 revolutions per minute to completely dissolve the chitosan oligosaccharide to form solution B; adding the solution B into the solution A, stirring and reacting for 50 hours at 25 ℃, transferring the reaction solution into a dialysis bag with the cut-off molecular weight of 7000, and continuously replacing the medium for dialysis for 10 hours by taking deionized water as the medium to remove ethanol and unreacted small molecular substances; and after dialysis, carrying out vacuum freeze drying on the dialysate to obtain the graft of the chitosan oligosaccharide and the stearic acid.
The surfactant is a mixture of magnesium lauryl sulfate and polyethylene glycol 1000 in a mass ratio of 1: 1.
Test example 1
1.1 case selection criteria
The patients brought into the study are all from urinary system calculus patients who are treated in 1-2011 4 months in 2009, and the selection standard is carried out according to the clinical research guide principle of new traditional Chinese medicines issued by the ministry of health. The western diagnostic criteria include medical history, clinical symptoms, physical examination, urine and renal function tests, and imaging examinations. Chinese medicine symptom diagnosis standard: (1) kidney yin deficiency syndrome: the main symptoms comprise soreness and weakness of waist and knees and dysphoria with smothery sensation in chest, palms and soles. Headache, dry throat and eyes, dribbling or uncomfortable urine. The secondary symptoms are: dizziness, tinnitus, dry mouth and throat, tidal fever, night sweat, steaming bone, fever, emaciation, insomnia, amnesia, loose teeth, spermatorrhea, premature ejaculation, scanty menstruation, amenorrhea, red tongue with little fluid, little or no coating, and thready and rapid pulse. The diagnosis can be confirmed when there are at least one of the primary syndrome 2 (essential for soreness and weakness of the waist and knees) and the secondary symptoms. (2) Syndrome of qi deficiency: the main symptoms are: shortness of breath, lassitude, mental fatigue and a deficient pulse. The secondary symptoms are as follows: spontaneous sweating, laziness in speaking, pale tongue. The diagnosis can be confirmed with 2 items of the primary syndrome and l items of the secondary symptoms.
1.2 inclusion and exclusion criteria
Inclusion criteria were: (1) the Chinese and western medicine diagnosis standard is met; (2) the transverse diameter of the calculus is 0.5-1.0 cm, and the longitudinal diameter is 0.6-1.8 cm; (3) after the extracorporeal shock wave lithotripsy, the calculi can not be discharged by self; (4) the urinary tract has no deformity and scar adhesion; (5) renal function is good, and the degree of water accumulation is lower than moderate; (6) the retention time of the calculus is less than 1 year; (7) the patient generally is in good condition. Discharge criteria: (1) the age is less than 18 years old or more than 65 years old, pregnant, lactating women and those who cannot tolerate the drug; (2) combining various basal metabolic diseases, cardiovascular and cerebrovascular diseases, hematopoietic system diseases and mental disorder diseases; (3) the patients who do not take the medicine according to the study scheme and have insufficient clinical data.
1.3 technical scheme
Patients were randomized into 8 groups, with no statistical difference in sex, age, course of disease, and pre-treatment condition among the groups (P > 0.05). The patients in each group take the pharmaceutical composition for treating urinary system calculus in the embodiments 1-8 respectively, and take the pharmaceutical composition 2 times a day after breakfast and supper for 30 minutes respectively.
1.4 Observation index
(1) Clinical symptoms (hematuria, frequent micturition, urgent micturition, etc.), physical signs (tenderness in the renal area, percussion pain), tongue condition, pulse condition, etc. Observations were made once a week; (2) blood and urine routine: before treatment, 3d and 7d after treatment; (3) and (6) performing imaging examination.
1.5 therapeutic efficacy criteria
According to the clinical research guidelines of new Chinese medicines issued by the ministry of health, the evaluation criteria of curative effect include recovery, effectiveness and ineffectiveness. Symptom judgment criteria: (1) and (3) healing: the symptom and the physical sign disappear or basically disappear, and the symptom score is reduced by more than 95 percent; (2) the effect is shown: symptoms and physical signs are obviously improved, and the symptom integral is reduced by more than 70%; (3) the method has the following advantages: symptoms and physical signs are well changed, and the integral is reduced by more than 30%; (4) and (4) invalidation: symptoms and signs are not improved or aggravated, and the symptom score is reduced by less than 30%.
The specific test results are shown in tables 1 and 2.
TABLE 1 curative effect test table
TABLE 2 before and after treatment the syndrome score changes
| Before treatment | After treatment | |
| Example 1 | 13.52 | 8.36 |
| Example 2 | 13.48 | 7.95 |
| Example 3 | 13.45 | 7.78 |
| Example 4 | 13.50 | 7.45 |
| Example 5 | 13.49 | 6.91 |
| Example 6 | 13.45 | 6.63 |
| Example 7 | 13.56 | 6.57 |
| Example 8 | 13.51 | 6.34 |
In the treatment process, 3 cases of the treatment group corresponding to example 1 showed frequent urination and low back pain with mild symptoms, and were not treated with other drugs or special treatment. Besides, no other adverse reactions exist. The invention relates to a pharmaceutical composition for treating urinary calculus, which comprises the following components in part by weight: the astragalus, the tuckahoe, the medlar and the dodder have stimulation effect on a hematopoietic system, can enhance the immunity function, and has the functions of adjusting trace elements and resisting aging so as to play a role in integrally regulating qi and yin deficiency of the traditional Chinese medicine nephropathy; the astragalus, the rhizoma alismatis and the poria cocos have the effects of diuresis, inflammation resistance, bacteria resistance and virus resistance, and the pharmacological effects of improving the kidney function and eliminating urine protein can be the kidney protection effect on the qi and yin deficiency syndrome of the traditional Chinese medicine nephropathy; in addition, the desmodium and the endothelium corneum gigeriae galli contain various nitrogen-containing acids, and urine can be changed into acid after oral administration, so that alkaline calculi are dissolved; the herba lysimachiae and the spora lygodii can cause the pressure in the upper end cavity of the ureter to increase, and the increase of the ureter peristalsis frequency is the pharmacological basis of the stone removing and removing effects of the prescription.
Test example 2
The pharmaceutical compositions for treating urinary calculus of examples 1 to 8 were tested by using a FT4 model multifunctional powder flowability tester, using a 23.5mm blade, a 23.5mm gas head and a 25mm diameter container. Specific parameters are the flowability SE (specific flow energy) and the gas permeability PD (gas pressure drop value). The test refers to the research on improving the fluidity and the hygroscopicity of the traditional Chinese medicine extract powder by the surface coating modification technology (Chinese traditional medicine journal, great honor and honor, 2016,41 (12): 2245-2249).
The specific test results are shown in table 2.
TABLE 2 Effect of flowability and air permeability
As can be seen from table 2, the use of the graft of chitosan oligosaccharide and small molecular acid results in improved flowability and air permeability of the pharmaceutical composition for treating urinary system calculus.
It should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art will be able to make the description as a whole, and the embodiments may be appropriately combined to form other embodiments as will be appreciated by those skilled in the art.
Claims (10)
1. The pharmaceutical composition for treating the urinary calculus is characterized by being prepared by the following steps:
(1) weighing the following traditional Chinese medicine raw materials in parts by weight: 30-35 parts of astragalus membranaceus, 10-20 parts of poria cocos, 10-30 parts of wolfberry, 8-12 parts of semen cuscutae, 10-40 parts of endothelium corneum gigeriae galli, 20-50 parts of lysimachia christinae hance, 10-30 parts of rhizoma alismatis, 20-30 parts of cowherb seed, 25-30 parts of spora lygodii, 10-20 parts of liquorice, 10-20 parts of asteriscus Pseudosciaenae and 20-25 parts of cluster mallow seeds;
(2) adding water which is 5-20 times of the total weight of the traditional Chinese medicine raw materials into the traditional Chinese medicine raw materials, decocting for 1-2 hours at 70-90 ℃ under normal pressure, filtering, and collecting filtrate; concentrating the filtrate at 50-60 deg.C under reduced pressure until the concentration reaches 0.8-1.5 g/mL of crude drug to obtain concentrated solution;
(3) and (2) sequentially adding a surfactant accounting for 0.6-1% of the mass of the concentrated solution, chitosan oligosaccharide accounting for 1.5-3% of the mass of the concentrated solution, and β -cyclodextrin or β -cyclodextrin modifier accounting for 2-3% of the mass of the concentrated solution into the concentrated solution, fully mixing uniformly, and drying to obtain the pharmaceutical composition for treating the urinary system calculus.
2. The pharmaceutical composition for treating urinary system stones according to claim 1, wherein said β -cyclodextrin modifier is obtained by introducing a hydrophobic long chain of octadecylsuccinic anhydride into β -cyclodextrin.
3. The pharmaceutical composition for treating urinary calculus according to claim 2, wherein the β -cyclodextrin modified substance is prepared by dispersing 8-15 g of β -cyclodextrin in 80-100 mL of water at 50-60 ℃ under stirring, stirring for 1-3 hours, adjusting the pH value to 8-9 with a sodium hydroxide aqueous solution with the mass fraction of 2-5%, adding 0.1-1 g of octadecenyl succinic anhydride within 1-2 hours, stirring until the pH value is kept constant, completing the reaction, neutralizing the pH value of the reaction system to 6-7 with hydrochloric acid with the mass fraction of 1-5% after the reaction is completed, performing vacuum freeze drying to obtain a crude product, washing the crude product with a mixed solution of n-hexane/isopropanol in a volume ratio of (2-4): 1 until no chloride ions and octadecenyl succinic anhydride exist, collecting residues, washing the residues with water, and performing vacuum freeze drying to obtain the β -cyclodextrin modified substance.
4. The pharmaceutical composition for treating urinary system calculus according to claim 2, wherein the β -cyclodextrin modified substance is prepared by dispersing 8-15 g of β -cyclodextrin in 80-100 mL of water under stirring at 50-60 ℃, stirring for 1-3 hours, adjusting the pH value to 8-9 with a sodium hydroxide aqueous solution with the mass fraction of 2-5%, adding 0.1-1 g of octadecenyl succinic anhydride within 1-2 hours, stirring until the pH value is kept constant, completing the reaction, neutralizing the pH value of the reaction system to 6-7 with hydrochloric acid with the mass fraction of 1-5% after the reaction is completed, performing vacuum freeze drying to obtain a crude product, washing the crude product with a mixed solution of n-hexane/isopropanol in a volume ratio of (2-4): 1 until no chloride ion and octadecenyl succinic anhydride exist, collecting residues, washing the residues with water, performing vacuum freeze drying to obtain octadecenyl succinic anhydride modified β -cyclodextrin, preparing octadecenyl succinic anhydride modified with the mass fraction of 8-12% for 130-36-20 minutes, performing vacuum freeze drying to obtain a precipitate, performing a reaction at 30-20 minutes after the crude product is washed with n-2 minutes of n-2, and precipitating with a mixed solution of n-30-20 minutes, and precipitating the vitamin E, and precipitating the mixture after the precipitate is performed.
5. The pharmaceutical composition for treating urinary system stones according to claim 1, characterized in that said chitosan oligosaccharides are replaced by grafts of chitosan oligosaccharides and small molecule acids.
6. The pharmaceutical composition for treating urinary system calculus according to claim 5, wherein said graft of chitosan oligosaccharide and small molecule acid is prepared by the following process: adding 1.2-1.6 g of carbodiimide and 0.2-0.3 g of micromolecular acid into 20-40 mL of absolute ethyl alcohol, and stirring to completely dissolve the carbodiimide and the micromolecular acid to form solution A; weighing 0.4-0.6 g of chitosan oligosaccharide, adding into 20-30 mL of water, and stirring to completely dissolve the chitosan oligosaccharide to form solution B; adding the solution B into the solution A, stirring and reacting at 20-30 ℃ for 40-60 hours, transferring the reaction solution into a dialysis bag with the molecular weight cutoff of 7000-9000, and continuously replacing the medium for dialysis for 10-20 hours by taking deionized water as the medium to remove ethanol and unreacted small molecular substances; and after dialysis, carrying out vacuum freeze drying on the dialysate to obtain the graft of the chitosan oligosaccharide and the micromolecular acid.
7. The pharmaceutical composition for treating urinary system stones according to claim 6, wherein the small molecular acid is one of salicylic acid, stearic acid, deoxycholic acid.
8. The pharmaceutical composition for treating urinary system stones according to claim 7, wherein the small molecular acid is stearic acid.
9. The pharmaceutical composition for treating urinary system stones according to claim 1, wherein the surfactant is magnesium lauryl sulfate and/or polyethylene glycol 1000.
10. The pharmaceutical composition for treating urinary system lithiasis according to claim 1, wherein the drying manner in step (3) is vacuum freeze drying or spray drying.
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Application publication date: 20200424 |