Nephrotoxicity-reducing method for administering aminoglycoside antibiotics

Abstract

The application belongs to the technical field of traditional Chinese medicines, and relates to a uremia clearing tablet and a preparation method thereof. The uremia clearing tablet comprises the following raw materials in parts by mass: 40 parts of rhubarb, 36 parts of licorice, 160 parts of astragalus, 120 parts of mulberry bark, 80 parts of sophora, 120 parts of codonopsis, 200 parts of atractylodes, 200 parts of poria, 120 parts of white peony root, 1000 parts of chrysanthemum, 200 parts of prepared rehmannia, 120 parts of chuanxiong, 200 parts of salvia, 80 parts of pinellia, 200 parts of plantain, 60 parts of bupleurum, 400-600 parts of pregelatinized starch, 100-200 parts of hydroxypropyl-beta-cyclodextrin, 80-150 parts of co-processed material, 70-100 parts of low-substituted hydroxypropyl cellulose, 10-15 parts of anhydrous calcium hydrogen phosphate, 5-8 parts of fumaric acid and 22-32 parts of lubricant. The uremia clearing tablet provided by the application has good formability, short disintegration time and good stability without coating.

Description

Technical Field

[0001] The present invention belongs to the technical field of traditional Chinese medicine, and relates to a Uremiaqing tablet and a preparation method thereof. Background Art

[0002] Chronic renal failure (CRF) is a common kidney disease, characterized by gradually decreasing renal function, ultimately leading to uremia.

[0003] In the field of traditional Chinese medicine, Uremiaqing is a commonly used proprietary Chinese medicine, composed of 16 herbs including rhubarb, astragalus membranaceus, atractylodes macrocephala, morus alba root bark, poria cocos, ligusticum wallichii, salvia miltiorrhiza, etc. It has the effects of purging the bowels to reduce turbidity, strengthening the spleen to promote diuresis, and activating blood circulation to remove stasis. It is used for chronic renal failure, azotemia stage and early uremia, and those with syndrome differentiation of spleen deficiency and turbidity and spleen deficiency and blood stasis in traditional Chinese medicine. It can reduce creatinine, urea nitrogen, stabilize renal function, and delay dialysis time. It also has a certain effect on improving renal anemia, increasing blood calcium, and reducing blood phosphorus.

[0004] However, currently the main dosage form of Uremiaqing in clinical practice is granules, which need to be taken by冲服 with water. For some patients, especially the elderly and children, it is inconvenient to take, affecting the compliance of patients. Tablets are more convenient to take than granules, so it is very necessary to develop Uremiaqing tablets.

[0005] Chinese Patent No. CN1672709A in the prior art discloses a Uremiaqing tablet, whose main ingredients are: rhubarb, licorice, astragalus membranaceus, morus alba root bark, sophora flavescens, codonopsis pilosula, atractylodes macrocephala, poria cocos, white peony root, chrysanthemum, processed fleece-flower root, ligusticum wallichii, salvia miltiorrhiza, pinellia ternata processed with ginger, plantago asiatica, bupleurum chinense. Appropriate excipients. The preparation method is: take rhubarb, licorice, and bupleurum chinense at 2 - 3% by weight percentage, astragalus membranaceus, morus alba root bark, codonopsis pilosula, white peony root, and ligusticum wallichii at 6 - 8% each, sophora flavescens, chrysanthemum, and pinellia ternata processed with ginger at 2 - 5% each, atractylodes macrocephala, poria cocos, processed fleece-flower root, salvia miltiorrhiza, and plantago asiatica at 8 - 11% each. Decoct the above herbs with water for 3 times, 3 hours for the first time, and 2 hours for the second and third times each. Combine the decoction, concentrate it into a clear paste with a relative density of 1.25 (measured at 80 °C), dry it into a dry paste, crush it into fine powder, and pass through a 120-mesh sieve for standby. Mix the dry paste powder with appropriate excipients, granulate, and dry. Press the granules into plain tablets or film-coated tablets to obtain the product. The Uremiaqing tablet is composed of drugs and fillers, which is convenient to carry, has a small dosage, and is convenient to take.

[0006] However, compared with granules, tablets have defects such as poor solubility and long disintegration time limit, and the above technical solution does not address this problem. Summary of the Invention

[0007] The purpose of the present invention is to provide a Uremiaqing tablet and a preparation method thereof. The Uremiaqing tablet provided by the present invention has good formability, short disintegration time limit, and good long-term stability without film coating.

[0008] The first aspect of this invention provides a uremic toxin-clearing tablet, comprising, by weight, the following raw materials: 40 parts rhubarb, 36 parts licorice, 160 parts astragalus, 120 parts mulberry bark, 80 parts sophora flavescens, 120 parts codonopsis, 200 parts atractylodes macrocephala, 200 parts poria cocos, 120 parts white peony root, 1000 parts chrysanthemum, 200 parts prepared polygonum multiflorum, 120 parts chuanxiong rhizome, 200 parts salvia miltiorrhiza, 80 parts ginger-processed pinellia, 200 parts plantain, 60 parts bupleurum, 400-600 parts pregelatinized starch, 100-200 parts hydroxypropyl-β-cyclodextrin, 80-150 parts co-processed product, 70-100 parts low-substituted hydroxypropyl cellulose, 10-15 parts anhydrous dicalcium phosphate, 5-8 parts fumaric acid, and 22-32 parts lubricant.

[0009] In some preferred embodiments, the co-treated material is a mixture of microcrystalline cellulose colloidal silica co-treated material and microcrystalline cellulose lactose co-treated material, wherein the mass ratio of the two is 1-3:4-8, preferably 1.5-2.5:5-7, and more preferably 2:6.

[0010] During the research and development process, the inventors unexpectedly discovered that mixing a mixture of microcrystalline cellulose colloidal silica co-treated material and microcrystalline cellulose lactose co-treated material with a clear extract, then drying, pulverizing, and making it into a dry powder, and directly compressing it into tablets, improves the tableting effect of uremic clear tablets. The resulting uremic clear tablets have low brittleness and no tablet cracking; and have a good disintegration rate, especially after long-term storage, they still have a good disintegration rate.

[0011] In some preferred embodiments, the microcrystalline cellulose colloidal silica co-treated product is produced by Zhuhai Dongchen Pharmaceutical Co., Ltd. TMS series products, preferred TMS 635.

[0012] In some preferred embodiments, the microcrystalline cellulose lactose co-treated product is produced by Zhuhai Dongchen Pharmaceutical Co., Ltd. TMC series products, preferred TMC 935.

[0013] In some preferred embodiments, the mass ratio of the pregelatinized starch, hydroxypropyl-β-cyclodextrin, co-treated product and low-substituted hydroxypropyl cellulose is 23-27:6-9:5-7:4-5, preferably 24-26:7-8:5.5-6.5:4.2-4.7, and more preferably 25:8:6:4.5.

[0014] Traditional Chinese medicine preparations with herbal extracts as active ingredients are limited in their application as tablets due to the poor flowability and compressibility of these extracts. Through inventive research, the inventors discovered that by adding pregelatinized starch, hydroxypropyl-β-cyclodextrin, a co-treated compound, and low-substituted hydroxypropyl cellulose in a controlled mass ratio of 23-27:6-9:5-7:4-5, the pregelatinized starch, hydroxypropyl-β-cyclodextrin, co-treated compound, and low-substituted hydroxypropyl cellulose work synergistically to achieve good tableting results. The resulting uremic-clearing tablets exhibit low friability and no cracking; furthermore, disintegration and stability are improved. Unexpectedly, it was also found that the effect is even better when the hydroxypropoxy content of the low-substituted hydroxypropyl cellulose is 10-12.9% and the average particle size is 40-45 μm.

[0015] In some preferred embodiments, the low-substituted hydroxypropyl cellulose has a hydroxypropoxy content of 10-12.9% and an average particle size of 40-45 μm.

[0016] In some preferred embodiments, the mass ratio of anhydrous dicalcium phosphate to fumaric acid is 12-14:6-7, preferably 12.5-13.5:6.5, and more preferably 13:6.5.

[0017] During the research and development process, the inventors discovered that uremic tablets obtained without coating have good tableting effect and disintegration speed, but their water content and microbial content increase rapidly after long-term storage. To solve this technical problem, the present invention creatively adds anhydrous dicalcium phosphate and fumaric acid. Under a specific ratio, the two work together to not only avoid the increase in water content and microbial content after long-term storage, but also further improve the tableting effect.

[0018] In a preferred embodiment, the uremic toxin-clearing tablets, by weight, comprise the following ingredients: 40 parts rhubarb, 36 parts licorice, 160 parts astragalus, 120 parts mulberry bark, 80 parts sophora flavescens, 120 parts codonopsis, 200 parts atractylodes macrocephala, 200 parts poria cocos, 120 parts white peony root, 1000 parts chrysanthemum, 200 parts prepared polygonum multiflorum, 120 parts chuanxiong rhizome, 200 parts salvia miltiorrhiza, 80 parts ginger-processed pinellia, 200 parts plantain, 60 parts bupleurum, 500 parts pregelatinized starch, 160 parts hydroxypropyl-β-cyclodextrin, 120 parts co-processed product, 90 parts low-substituted hydroxypropyl cellulose, 13 parts anhydrous dicalcium phosphate, 6.5 parts fumaric acid, and 28 parts lubricant.

[0019] In some preferred embodiments, the lubricant includes at least one of magnesium stearate, calcium stearate, sodium stearate, colloidal silica, and talc, preferably magnesium stearate.

[0020] A second aspect of the present invention provides a method for preparing the above-mentioned uremic toxin-clearing tablets, comprising the following steps:

[0021] S1. Boil rhubarb, licorice, astragalus, mulberry bark, sophora flavescens, codonopsis, atractylodes macrocephala, poria cocos, white peony root, chrysanthemum, prepared fleeceflower root, chuanxiong rhizome, salvia miltiorrhiza, ginger-processed pinellia, plantain, and bupleurum in water three times, combine the filtrates, filter, concentrate the filtrate into a clear paste, mix the clear paste with the co-processed material evenly, dry, pulverize, and obtain dry powder;

[0022] S2. Mix the dry powder, pregelatinized starch, hydroxypropyl-β-cyclodextrin, low-substituted hydroxypropyl cellulose, anhydrous dicalcium phosphate, fumaric acid, and lubricant evenly, and compress into tablets.

[0023] Preferably, the first and second decoction times are 1.5-2.5 hours, and the third decoction time is 0.5-1.5 hours.

[0024] The preferred method is to decoct for 2 hours for the first and second times, and for 1 hour for the third time.

[0025] Preferably, the filtrate is concentrated to a clear paste with a relative density of 1.25 (80°C).

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] 1. This invention uses a specific ratio of pregelatinized starch, hydroxypropyl-β-cyclodextrin, co-treated material, and low-substituted hydroxypropyl cellulose (hydroxypropoxy content of 10-12.9%, average particle size of 40-45μm). Through their combined action, the tableting effect is good, and the resulting uremic tablets have low brittleness and no cracking phenomenon; moreover, disintegration and stability are also improved.

[0028] 2. The combined effect of the microcrystalline cellulose colloidal silica co-treated product and the microcrystalline cellulose lactose co-treated product of the present invention improves the tableting effect of Uremic Clearing Tablets while the resulting Uremic Clearing Tablets have a good disintegration rate, especially after long-term storage, which ensures the disintegration stability of Uremic Clearing Tablets during long-term storage.

[0029] 3. This invention utilizes a specific ratio of anhydrous dicalcium phosphate, fumaric acid, pregelatinized starch, hydroxypropyl-β-cyclodextrin, co-treated material, and low-substituted hydroxypropyl cellulose to improve the tableting effect and the long-term stability of uremic tablets without coating (low hygroscopicity and microbial content meeting standards). Detailed Implementation

[0030] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following description is merely an exemplary illustration of the scope of protection of the present invention, and those skilled in the art can make various changes and modifications to the invention based on the disclosed content, which should also fall within the scope of protection of the present invention.

[0031] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in the present invention, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. In addition to the specific methods, apparatus, and materials used in the embodiments, based on the knowledge of the prior art possessed by one of ordinary skill in the art and the description of this invention, any prior art methods, apparatus, and materials similar to or equivalent to those described, apparatus, and materials in the embodiments of this invention may be used to implement the present invention.

[0032] The present invention will be further described below by way of specific embodiments.

[0033] The source information of the raw materials involved in the preparation of the following examples or comparative examples is shown in Table 1:

[0034] Table 1

[0035]

[0036]

[0037] Example 1

[0038] A type of uremic toxin-clearing tablet, by weight, comprises the following raw materials: 40 parts rhubarb, 36 parts licorice, 160 parts astragalus, 120 parts mulberry bark, 80 parts sophora flavescens, 120 parts codonopsis, 200 parts atractylodes macrocephala, 200 parts poria cocos, 120 parts white peony root, 1000 parts chrysanthemum, 200 parts prepared polygonum multiflorum, 120 parts chuanxiong rhizome, 200 parts salvia miltiorrhiza, 80 parts ginger-processed pinellia, 200 parts plantain, 60 parts bupleurum, 400 parts pregelatinized starch, 100 parts hydroxypropyl-β-cyclodextrin, 80 parts co-processed product, 70 parts low-substituted hydroxypropyl cellulose, 10 parts anhydrous calcium hydrogen phosphate, 5 parts fumaric acid, and 22 parts magnesium stearate.

[0039] The co-treated material is a mixture of microcrystalline cellulose colloidal silica co-treated material and microcrystalline cellulose lactose co-treated material, with a mass ratio of 1:4.

[0040] The low-substituted hydroxypropyl cellulose has a hydroxypropoxy content of 10-12.9% and an average particle size of 40 μm.

[0041] The specific preparation method of the above-mentioned Uremic Clearing Tablets is as follows:

[0042] S1. Add water to rhubarb, licorice, astragalus, mulberry bark, sophora flavescens, codonopsis, atractylodes macrocephala, poria cocos, white peony root, chrysanthemum, prepared fleeceflower root, chuanxiong rhizome, salvia miltiorrhiza, ginger-processed pinellia, plantain, and bupleurum and decoct three times. The first and second decoction times are 2 hours, and the third decoction time is 1 hour. Combine the filtrates, filter, and concentrate the filtrate to a clear extract with a relative density of 1.25 (80℃). Mix the clear extract with the co-treated material evenly, dry, and pulverize to obtain dry powder.

[0043] S2. Mix the dry powder, pregelatinized starch, hydroxypropyl-β-cyclodextrin, low-substituted hydroxypropyl cellulose, anhydrous dicalcium phosphate, fumaric acid, and lubricant evenly, and compress into tablets.

[0044] Example 2

[0045] A type of uremic toxin-clearing tablet, by weight, comprises the following raw materials: 40 parts rhubarb, 36 parts licorice, 160 parts astragalus, 120 parts mulberry bark, 80 parts sophora flavescens, 120 parts codonopsis, 200 parts atractylodes macrocephala, 200 parts poria cocos, 120 parts white peony root, 1000 parts chrysanthemum, 200 parts prepared polygonum multiflorum, 120 parts chuanxiong rhizome, 200 parts salvia miltiorrhiza, 80 parts ginger-processed pinellia, 200 parts plantain, 60 parts bupleurum, 600 parts pregelatinized starch, 200 parts hydroxypropyl-β-cyclodextrin, 150 parts co-processed product, 100 parts low-substituted hydroxypropyl cellulose, 15 parts anhydrous calcium hydrogen phosphate, 8 parts fumaric acid, and 32 parts magnesium stearate.

[0046] The co-treated material is a mixture of microcrystalline cellulose colloidal silica co-treated material and microcrystalline cellulose lactose co-treated material, with a mass ratio of 3:8.

[0047] The low-substituted hydroxypropyl cellulose has a hydroxypropoxy content of 10-12.9% and an average particle size of 40 μm.

[0048] The preparation method of the above-mentioned uremic tablets is the same as that in Example 1.

[0049] Example 3

[0050] A type of uremic toxin-clearing tablet, by weight, comprises the following raw materials: 40 parts rhubarb, 36 parts licorice, 160 parts astragalus, 120 parts mulberry bark, 80 parts sophora flavescens, 120 parts codonopsis, 200 parts atractylodes macrocephala, 200 parts poria cocos, 120 parts white peony root, 1000 parts chrysanthemum, 200 parts prepared polygonum multiflorum, 120 parts chuanxiong rhizome, 200 parts salvia miltiorrhiza, 80 parts ginger-processed pinellia, 200 parts plantain, 60 parts bupleurum, 500 parts pregelatinized starch, 160 parts hydroxypropyl-β-cyclodextrin, 120 parts co-processed product, 90 parts low-substituted hydroxypropyl cellulose, 13 parts anhydrous calcium hydrogen phosphate, 6.5 parts fumaric acid, and 28 parts magnesium stearate.

[0051] The co-treated material is a mixture of microcrystalline cellulose colloidal silica co-treated material and microcrystalline cellulose lactose co-treated material, with a mass ratio of 2:6.

[0052] The low-substituted hydroxypropyl cellulose has a hydroxypropoxy content of 10-12.9% and an average particle size of 40 μm.

[0053] The preparation method of the above-mentioned uremic tablets is the same as that in Example 1.

[0054] Comparative Example 1

[0055] The difference from Example 3 is that the microcrystalline cellulose colloidal silica co-treated material is replaced with an equal mass of microcrystalline cellulose lactose co-treated material, otherwise they are the same.

[0056] Comparative Example 2

[0057] The only difference from Example 3 is that the microcrystalline cellulose lactose co-treated product is replaced with an equal mass of microcrystalline cellulose mannitol co-treated product; all other aspects are the same.

[0058] Comparative Example 3

[0059] The only difference from Example 3 is that the pregelatinized starch is replaced with an equal mass of microcrystalline cellulose; otherwise, they are the same.

[0060] Comparative Example 4

[0061] The only difference from Example 3 is that the low-substituted hydroxypropyl cellulose has a hydroxypropoxy content of 10-12.9% and an average particle size of 50 μm; all other aspects are the same.

[0062] Comparative Example 5

[0063] The only difference from Example 3 is that the mass ratio of the pregelatinized starch, hydroxypropyl-β-cyclodextrin, co-treated product and low-substituted hydroxypropyl cellulose is 30:5:8:3;

[0064] That is: Uremic Clearing Tablets, by weight, the raw materials are: rhubarb 40 parts, licorice 36 parts, astragalus 160 parts, mulberry bark 120 parts, sophora flavescens 80 parts, codonopsis pilosula 120 parts, atractylodes macrocephala 200 parts, poria cocos 200 parts, white peony root 120 parts, chrysanthemum 1000 parts, prepared polygonum multiflorum 200 parts, chuanxiong rhizome 120 parts, salvia miltiorrhiza 200 parts, ginger-processed pinellia 80 parts, plantain 200 parts, bupleurum 60 parts, pregelatinized starch 600 parts, hydroxypropyl-β-cyclodextrin 100 parts, co-processed product 160 parts, low-substituted hydroxypropyl cellulose 60 parts, anhydrous calcium hydrogen phosphate 13 parts, fumaric acid 6.5 parts, magnesium stearate 28 parts.

[0065] Comparative Example 6

[0066] The only difference from Example 3 is that anhydrous dicalcium phosphate is replaced with an equal mass of calcium phosphate; all other aspects are the same.

[0067] Comparative Example 7

[0068] The only difference from Example 3 is that fumaric acid is replaced with an equal mass of tartaric acid; all other aspects are the same.

[0069] Comparative Example 8

[0070] The only difference from Example 3 is that the mass ratio of anhydrous dicalcium phosphate to fumaric acid is 10:10.

[0071] That is: Uremic Clearing Tablets, by weight, the raw materials are: rhubarb 40 parts, licorice 36 parts, astragalus 160 parts, mulberry bark 120 parts, sophora flavescens 80 parts, codonopsis pilosula 120 parts, atractylodes macrocephala 200 parts, poria cocos 200 parts, white peony root 120 parts, chrysanthemum 1000 parts, prepared polygonum multiflorum 200 parts, chuanxiong rhizome 120 parts, salvia miltiorrhiza 200 parts, ginger-processed pinellia 80 parts, plantain 200 parts, bupleurum 60 parts, pregelatinized starch 500 parts, hydroxypropyl-β-cyclodextrin 160 parts, co-processed product 120 parts, low-substituted hydroxypropyl cellulose 90 parts, anhydrous calcium hydrogen phosphate 10 parts, fumaric acid 10 parts, magnesium stearate 28 parts.

[0072] Experimental Example 1: Quality Testing of Uremic Clearing Tablets

[0073] Appearance: Visual inspection;

[0074] Hardness: The tablet hardness tester is used to test the tablet. The tablet is placed in the clamp of the hardness tester and pressure is gradually applied until the tablet breaks.

[0075] Friability: Tested according to the 2020 edition of the Chinese Pharmacopoeia, Part III (General Chapter 0923);

[0076] Method for detecting tablet weight variation: Take 20 tablets of Uremic Clearance Tablets, accurately weigh the total weight, calculate the average tablet weight, and then accurately weigh each tablet separately. Compare the weight of each tablet with the average tablet weight. The results are shown in Table 2.

[0077] Table 2

[0078] Appearance Hardness / N Friability / % Tablet weight difference / % Example 1 Smooth and free of cracks 98 0.3 ±1.2 Example 2 Smooth and free of cracks 97 0.4 ±1.1 Example 3 Smooth and free of cracks 98 0.2 ±0.9 Comparative Example 1 Basically smooth, with cracks 75 1.1 ±2.6 Comparative Example 2 Basically smooth, with cracks 72 1.3 ±4.1 Comparative Example 3 It has a rough surface and cracks. 60 2.8 ±8.5 Comparative Example 4 Basically smooth, with cracks 70 1.5 ±5.2 Comparative Example 5 Occasionally, there are pitted surfaces and cracks. 66 2.0 ±6.8 Comparative Example 6 Occasionally, there are pitted surfaces and cracks. 68 1.8 ±6.5 Comparative Example 7 Smooth and free of cracks 96 0.4 ±1.0 Comparative Example 8 Smooth and free of cracks 90 1.0 ±2.2

[0079] As can be seen from Table 2, the uremic tablets obtained in Examples 1-3 of the present invention have good tableting effect, smooth appearance, no cracks, high hardness, and low brittleness and weight difference.

[0080] Comparative Examples 1 and 2 had altered compositions of the co-treated material; Comparative Example 3 had pregelatinized starch replaced with an equal mass of microcrystalline cellulose; Comparative Example 4 had its average particle size of low-substituted hydroxypropyl cellulose changed; Comparative Example 5 had a mass ratio of pregelatinized starch, hydroxypropyl-β-cyclodextrin, co-treated material, and low-substituted hydroxypropyl cellulose that was not within the range of 23-27:6-9:5-7:4-5; and Comparative Example 6 had anhydrous dicalcium phosphate replaced with an equal mass of calcium phosphate. As a result, the tableting effect of the uremic tablets decreased, tablet cracking occurred, hardness decreased, and friability and tablet weight differences increased.

[0081] Example 2: Disintegration time limit test of Uremic Clearing Tablets. Test method: according to the 2020 edition of the Chinese Pharmacopoeia, Part III (General Chapter 0921). The results are shown in Table 3.

[0082] Table 3

[0083]

[0084]

[0085] Experiment 3: Disintegration time limit test of Uremic Clearing Tablets after 12 months of storage at 25℃. Test method: according to the 2020 edition of the Chinese Pharmacopoeia, Part III (General Chapter 0921). The results are shown in Table 4.

[0086] Table 4

[0087] Disintegration time / min Example 1 30 Example 2 29 Example 3 26 Comparative Example 1 48 Comparative Example 2 55 Comparative Example 3 38 Comparative Example 4 32 Comparative Example 5 35 Comparative Example 6 31 Comparative Example 7 28 Comparative Example 8 30

[0088] As can be seen from Tables 3 and 4, the uremic tablets obtained in Examples 1-3 of the present invention have good disintegration effects and still have a relatively fast disintegration rate even after long-term storage. The disintegration performance of the uremic tablets obtained in Comparative Examples 1 and 2 decreased significantly due to changes in the composition of the co-treated material. The disintegration performance of the uremic tablets obtained in Comparative Example 3 decreased because the pregelatinized starch was replaced with an equal mass of microcrystalline cellulose, and the disintegration performance of the uremic tablets obtained in Comparative Example 5 decreased because the mass ratio of pregelatinized starch, hydroxypropyl-β-cyclodextrin, co-treated material and low-substituted hydroxypropyl cellulose was not within the range of 23-27:6-9:5-7:4-5.

[0089] Long-term stability of Uremic Clearance Tablets (25±2℃, 60±10%RH) in Experiment Example 4:

[0090] Moisture content: The moisture content of Uremic Clearing Tablets after long-term storage was determined according to the 2020 edition of the Chinese Pharmacopoeia, Part III (General Chapter 0832).

[0091] Microbial limits: The number of microorganisms in Uremic Clearing Tablets after long-term storage was tested according to the 2020 edition of the Chinese Pharmacopoeia, Part III (General Chapter 1105).

[0092] Rhubarb content: The rhubarb content of Uremic Clearing Tablets after long-term storage was determined according to the high performance liquid chromatography method (General Chapter 0512) of the 2020 edition of the Chinese Pharmacopoeia; the rhubarb content was calculated as the total anthraquinone content of rhubarb.

[0093] Astragalus content: The astragalus content of Uremic Clearing Tablets after long-term storage was determined according to the high performance liquid chromatography method (General Chapter 0512) of the 2020 edition of the Chinese Pharmacopoeia; the astragalus content was calculated as the total amount of astragaloside A.

[0094] The results are shown in Tables 5 and 6.

[0095] Table 5

[0096]

[0097]

[0098] Table 6

[0099]

[0100]

[0101] As can be seen from Tables 5 and 6, the uremic tablets obtained in Examples 1-3 of the present invention have good long-term stability without coating (low hygroscopicity, microbial content meets the standard, rhubarb content decreases by 1.21-1.64%, and astragalus content decreases by 0.77-1%).

[0102] Comparative Example 2, due to replacing the microcrystalline cellulose lactose co-treatment product with an equal mass of microcrystalline cellulose mannitol co-treatment product; Comparative Example 3, due to replacing pregelatinized starch with an equal mass of microcrystalline cellulose; and Comparative Example 5, due to the mass ratio of pregelatinized starch, hydroxypropyl-β-cyclodextrin, co-treatment product, and low-substituted hydroxypropyl cellulose not falling within the range of 23-27:6-9:5-7:4-5, resulted in a slight decrease in the stability of the uremic tablets, but the change was not particularly significant. Comparative Example 6, due to replacing anhydrous dicalcium phosphate with an equal mass of calcium phosphate; Comparative Example 7, due to replacing fumaric acid with an equal mass of tartaric acid; and Comparative Example 8, due to the mass ratio of anhydrous dicalcium phosphate and fumaric acid not falling within the range of 1-3:4-8, resulted in a significant decrease in the stability of the uremic tablets (the water content increased significantly after 12 months, the total number of aerobic bacteria, molds, and yeasts also increased significantly, and the decrease rates of rhubarb and astragalus content also increased).

[0103] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A tablet of ureaform, characterized in that, The following raw materials are used in parts by mass: rhubarb 40 parts, licorice 36 parts, astragalus 160 parts, mulberry bark 120 parts, sophora 80 parts, codonopsis 120 parts, atractylodes 200 parts, poria 200 parts, white peony root 120 parts, chrysanthemum 1000 parts, prepared rehmannia 200 parts, chuanxiong 120 parts, salvia 200 parts, ginger pinellia 80 parts, plantain 200 parts, bupleurum 60 parts, pregelatinized starch 400-600 parts, hydroxypropyl-beta-cyclodextrin 100-200 parts, co-processed substance 80-150 parts, low-substituted hydroxypropyl cellulose 70-100 parts, anhydrous calcium hydrogen phosphate 10-15 parts, fumaric acid 5-8 parts, lubricant 22-32 parts; The co-processed substance is a mixture of microcrystalline cellulose colloidal silicon dioxide co-processed substance and microcrystalline cellulose lactose co-processed substance, and the mass ratio of the two is 1-3:4-8; The mass ratio of the pregelatinized starch, hydroxypropyl-beta-cyclodextrin, co-processed substance and low-substituted hydroxypropyl cellulose is 23-27:6-9:5-7:4-5; The mass ratio of the anhydrous calcium hydrogen phosphate and fumaric acid is 12-14:6-7; The hydroxypropoxy content of the low-substituted hydroxypropyl cellulose is 10-12.9%, and the average particle size is 40 μm.

2. The tablet according to claim 1, wherein The mass ratio of the microcrystalline cellulose colloidal silicon dioxide co-processed substance and microcrystalline cellulose lactose co-processed substance is 2:

6.

3. The tablet according to claim 1, wherein The mass ratio of the pregelatinized starch, hydroxypropyl-beta-cyclodextrin, co-processed substance and low-substituted hydroxypropyl cellulose is 25:8:6:4.

5.

4. The tablet according to claim 1, wherein The mass ratio of the anhydrous calcium hydrogen phosphate and fumaric acid is 13:6.

5.

5. The tablet according to claim 1, wherein The raw materials include, in parts by mass: rhubarb 40 parts, licorice 36 parts, astragalus 160 parts, mulberry bark 120 parts, sophora 80 parts, codonopsis 120 parts, atractylodes 200 parts, poria 200 parts, white peony root 120 parts, chrysanthemum 1000 parts, prepared rehmannia 200 parts, chuanxiong 120 parts, salvia 200 parts, ginger pinellia 80 parts, plantain 200 parts, bupleurum 60 parts, pregelatinized starch 500 parts, hydroxypropyl-beta-cyclodextrin 160 parts, co-processed substance 120 parts, low-substituted hydroxypropyl cellulose 90 parts, anhydrous calcium hydrogen phosphate 13 parts, fumaric acid 6.5 parts, lubricant 28 parts.

6. A process for the preparation of the urea tablets according to any one of claims 1 to 5, characterized in that, The following steps are included: S1. Rhubarb, licorice, astragalus, mulberry bark, sophora, codonopsis, atractylodes, poria, white peony root, chrysanthemum, prepared rehmannia, chuanxiong, salvia, ginger pinellia, plantain, bupleurum are decocted with water three times, the filtrates are combined and filtered, the filtrate is concentrated into a clear extract, the clear extract is mixed with the co-processed substance, dried, pulverized, and a dry powder is obtained; S2. The dry powder, pregelatinized starch, hydroxypropyl-beta-cyclodextrin, low-substituted hydroxypropyl cellulose, anhydrous calcium hydrogen phosphate, fumaric acid, and lubricant are mixed uniformly, and tablets are pressed.

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