Urine toxin removing pellet and preparation method thereof

Abstract

The invention provides a uremia clearing pellet and a preparation method thereof, and relates to the technical field of pharmaceutical preparations. The uremia clearing pellet comprises 40-60 parts of an active component, 30-50 parts of a filler, 1-6 parts of a disintegrating agent and 5-15 parts of an adhesive, the disintegrating agent comprises polyvinylpolypyrrolidone, croscarmellose sodium and low-substituted hydroxypropyl cellulose, and the mass ratio of polyvinylpolypyrrolidone to croscarmellose sodium to low-substituted hydroxypropyl cellulose is (4-5): (8-15): (3-5). The particle size of the cross-linked povidone is 20 to 50 [mu] m. The uremia clearing pellet disclosed by the invention is high in dissolution speed, high in bioavailability, low in medicine taking frequency, good in patient compliance, high in stability and easy to store.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a Uremia Qing pellet and a preparation method thereof. Background Art

[0002] In recent years, the number of nephropathy patients has been on the rise year by year. At present, the treatment effect of chronic nephritis is a public relations project both at home and abroad, and the cure rate is very low. Most patients finally develop uremia and rely on dialysis or kidney transplantation to maintain their lives.

[0003] Chinese Patent CN1269508C discloses a drug for treating chronic renal failure. This drug is a traditional Chinese medicine composition, with rhubarb and astragalus as the main drugs, and is made with other original drugs. This product has the functions of strengthening the spleen and tonifying the kidney, purging the bowels and reducing turbidity, promoting blood circulation and removing blood stasis. It has definite curative effects on treating spleen-kidney qi deficiency with damp turbidity syndrome and spleen-kidney qi deficiency with blood stasis syndrome of chronic renal failure, is safe to use, convenient to take, and can stabilize renal function and delay the progression of chronic renal failure when taken for a long time. However, it needs to be taken four times a day with warm boiled water, taking 1 packet at 6, 8, and 12 o'clock each day, and 2 packets at 22 o'clock. The medication is frequent and complex, and the patient compliance is low.

[0004] Chinese Patent CN1562315A discloses a Uremia Qing granule for treating uremia, which can effectively enhance the glomerular filtration rate, thereby reducing the content of creatinine scr and blood urea nitrogen BUN in the patient's blood. It is a safe and effective anti-renal failure drug. However, it needs to be taken four times a day, and the elderly and children need to take it in divided doses, and the patient compliance is low. Summary of the Invention

[0005] In view of the problems existing in the prior art, the present invention provides a Uremia Qing pellet and a preparation method thereof. The Uremia Qing pellet has good stability, is easy to store, has a fast dissolution rate, high bioavailability, and at the same time, the preparation method is simple and efficient.

[0006] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0007] On the one hand, the present invention provides a Uremia Qing pellet, which includes, by mass: 40 - 60 parts of active components, 30 - 50 parts of fillers, 1 - 6 parts of disintegrants, and 5 - 15 parts of binders; the disintegrants are: cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; the mass ratio of cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose is: 4 - 5: 8 - 15: 3 - 5; the particle size of the cross-linked povidone is: 20 - 50 μm.

[0008] Preferably, the hydroxypropoxy content of the low-substituted hydroxypropyl cellulose is: 10% - 15%.

[0009] Preferably, the Uremia-Clearing Pellets, by mass, comprise: 50 - 60 parts of active components, 40 - 50 parts of filler, 3 - 6 parts of disintegrant, and 10 - 15 parts of binder.

[0010] Preferably, the mass ratio of cross-linked povidone, croscarmellose sodium, and low-substituted hydroxypropyl cellulose is: 5 : 10 - 15 : 4.

[0011] Further, the active components are obtained by: rhubarb, astragalus root, mulberry bark, lightyellow sophora root, codonopsis pilosula, atractylodes macrocephala, poria cocos, processed fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum root, and licorice root being decocted with water, filtered, and concentrated to obtain an extract, and then the extract is dried to obtain the active components.

[0012] Further, the relative density of the extract is: 1.25 - 1.40.

[0013] Further, the mass ratio of rhubarb, astragalus root, mulberry bark, lightyellow sophora root, codonopsis pilosula, atractylodes macrocephala, poria cocos, processed fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum root, and licorice root is: 3 - 30 : 9 - 30 : 6 - 12 : 4.5 - 9 : 9 - 30 : 6 - 12 : 9 - 15 : 6 - 12 : 6 - 15 : 9 - 15 : 3 - 9 : 5 - 93 - 9 : 9 - 30 : 3 - 9 : 1.5 - 9.

[0014] Further, the filler is: microcrystalline cellulose, mannitol, and calcium hydrogen phosphate.

[0015] Preferably, the mass ratio of microcrystalline cellulose, mannitol, and calcium hydrogen phosphate is: 4 - 8 : 5 - 10 : 2 - 3.

[0016] Further preferably, the mass ratio of the active components, filler, and disintegrant is: 11 - 12 : 8 - 10 : 0.8 - 1.2.

[0017] Further preferably, the mass ratio of the active components, filler, and disintegrant is: 12 : 10 : 1.2.

[0018] Further, the binder is: at least one of pregelatinized starch, polyvinylpyrrolidone, ethyl cellulose, and hydroxypropyl methylcellulose.

[0019] Preferably, the binder is: pregelatinized starch and polyvinylpyrrolidone.

[0020] Further, the particle size of the Uremia-Clearing Pellets is: 0.3 mm - 2.0 mm.

[0021] In a second aspect, the present invention provides a method for preparing Uremia-Clearing Pellets, comprising the following steps:

[0022] (1) Decoct rhubarb, astragalus root, mulberry bark, lightyellow sophora root, codonopsis pilosula, atractylodes macrocephala, poria cocos, prepared fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum root and liquorice root with water, concentrate to an extract, dry the extract to obtain an active ingredient, and pulverize the active ingredient to obtain fine powder;

[0023] (2) Take the fine powder obtained in step (1), add a filler and a disintegrant, mix evenly, add a binder, make into a soft material, granulate, round, and dry to obtain.

[0024] Further, the temperature of the concentration in step (1) is: 60 - 80 °C.

[0025] Further, the relative density of the extract in step (1) is: 1.25 - 1.40.

[0026] Further, the water content after drying in step (2) is: 3 - 5 wt%.

[0027] In a third aspect, the present invention provides a uremia-clearing pellet preparation, comprising uremia-clearing pellets and a coating material.

[0028] In a fourth aspect, the present invention provides a method for improving the stability of uremia-clearing pellets, comprising the following steps:

[0029] (1) Decoct rhubarb, astragalus root, mulberry bark, lightyellow sophora root, codonopsis pilosula, atractylodes macrocephala, poria cocos, prepared fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum root and liquorice root with water, concentrate to an extract, dry the extract to obtain an active ingredient, and pulverize the active ingredient to obtain fine powder;

[0030] (2) Take the fine powder obtained in step (1), add a filler and a disintegrant, mix evenly, add a binder, make into a soft material, granulate, round, and dry to obtain.

[0031] Further, the active ingredient, filler, disintegrant and binder are in parts by mass: 40 - 60 parts of active ingredient, 30 - 50 parts of filler, 1 - 6 parts of disintegrant and 5 - 15 parts of binder; the disintegrant is in a mass ratio of: 4 - 5:8 - 15:3 - 5 of crospovidone, croscarmellose sodium and low-substituted hydroxypropyl cellulose.

[0032] Further, the filler is: microcrystalline cellulose, mannitol and calcium hydrogen phosphate; the binder is: at least one of pregelatinized starch, polyvinylpyrrolidone, ethyl cellulose and hydroxypropyl methylcellulose.

[0033] Definitions and explanations

[0034] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indeterminate or unclear without a special definition, but should be understood in its ordinary meaning.

[0035] The term "crosslinking" refers to a network structure formed by chemically or physically connecting molecular chains to each other.

[0036] The term "low substitution" refers to a relatively low degree of substitution of hydroxypropoxy (-OCH2CHOHCH3) on the cellulose molecular chain. According to the provisions of the Chinese Pharmacopoeia 2020 Edition, the hydroxypropoxy content of low-substituted hydroxypropyl cellulose should be between 5.0% and 16.0%.

[0037] The technical effects achieved by the present invention are as follows:

[0038] (1) By adjusting the types and dosage relationships of the excipients, the present invention improves the stability of the Niandutang pellets, making its active ingredients not easily deteriorate during long-term storage.

[0039] (2) By adjusting the types and dosage relationships of the active components, fillers, and disintegrants, the Niandutang pellets of the present invention can be rapidly dissolved, improving the bioavailability of the Niandutang pellets, making the drug effect take effect quickly, thereby reducing the number of medication times and improving the patient compliance. Specific Embodiments

[0040] The following specific examples illustrate the embodiments of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0041] Before further describing the specific embodiments of the present invention, it should be understood that the protection scope of the present invention is not limited to the specific embodiments described below; it should also be understood that the terms used in the embodiments of the present invention are for describing specific embodiments, rather than for limiting the protection scope of the present invention.

[0042] When the embodiments give a numerical range, it should be understood that unless otherwise specified by the present invention, any value between the two endpoints of each numerical range and any one of the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0043] It is worth noting that the raw materials used in the present invention are all ordinary commercially available products, and no specific limitation is imposed on their sources.

[0044] The following raw material sources are for illustrative purposes:

[0045] Microcrystalline cellulose and pregelatinized starch were purchased from Shandong Xinda Biotechnology Co., Ltd.; mannitol was purchased from Xi'an Xinfengda Pharmaceutical Excipients Co., Ltd.; calcium hydrogen phosphate, croscarmellose sodium, and calcium phosphate were purchased from Hunan Jiudian Pharmaceutical Co., Ltd.; polyvinylpyrrolidone was purchased from Jiaozuo Zhongwei Special Pharmaceutical Co., Ltd.

[0046] I. Examples and Comparative Examples

[0047] Example 1 A Uremia Qing Pellet

[0048] 50 parts of filler, 6 parts of disintegrant, 15 parts of binder, and 60 parts of active ingredients, where the active ingredients are rhubarb, astragalus root, mulberry bark, lightyellow sophora root, codonopsis pilosula, atractylodes macrocephala, poria cocos, prepared fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum chinense, and licorice in a weight ratio of 1:4:3:2:3:5:5:5:3:5:3:2.5:2:5:1.5:0.9. The types and dosages of the excipients are shown in Table 1.

[0049] Table 1

[0050]

[0051] Crosslinked polyvinylpyrrolidone ZW-PVPP-B has a particle size of 20 - 40 μm, and the hydroxypropoxy content of low-substituted hydroxypropyl cellulose SH-LH21 is 10% - 12.9%.

[0052] Preparation method:

[0053] (1) Decoct rhubarb, astragalus root, mulberry bark, lightyellow sophora root, codonopsis pilosula, atractylodes macrocephala, poria cocos, prepared fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum chinense, and licorice with water, and concentrate to an extract with a relative density of 1.40. Dry and pulverize the extract to obtain fine powder.

[0054] (2) Take the fine powder, add the filler and disintegrant, mix evenly, add the binder to make a soft material, granulate, round, and dry. The water content after drying is 5 wt%, and the particle size is 2.0 mm.

[0055] Example 2

[0056] 30 parts of filler, 1 part of disintegrant, 5 parts of binder, and 40 parts of active ingredients, where the active ingredients are rhubarb, astragalus root, mulberry bark, lightyellow sophora root, codonopsis pilosula, atractylodes macrocephala, poria cocos, prepared fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum chinense, and licorice in a weight ratio of 1:4:3:2:3:5:5:5:3:5:3:2.5:2:5:1.5:0.9. The types and dosages of the excipients are shown in Table 2.

[0057] Table 2

[0058]

[0059]

[0060] Crospovidone Polyplasdone XL-10 has a particle size of 30 μm, and low-substituted hydroxypropyl cellulose ZW-LHPC-11 has a hydroxypropoxy content of 10%-12.9%.

[0061] Preparation method:

[0062] (1) Decoct rhubarb, astragalus root, mulberry bark, lightyellow sophora root, codonopsis pilosula, atractylodes macrocephala, poria cocos, prepared fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum chinense and liquorice root with water, and concentrate to an extract with a relative density of 1.25. Dry and pulverize the extract to obtain fine powder.

[0063] (2) Take the fine powder, add a filler and a disintegrant, mix evenly, add a binder to make a soft material, granulate, round, and dry. The water content after drying is: 3 wt%, and the particle size is: 0.3 mm.

[0064] Example 3 A kind of Niandutang pellets

[0065] 40 parts of filler, 3 parts of disintegrant, 10 parts of binder and 50 parts of active components, wherein the active components are rhubarb, astragalus root, mulberry bark, lightyellow sophora root, codonopsis pilosula, atractylodes macrocephala, poria cocos, prepared fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum chinense and liquorice root with a weight ratio of 1:4:3:2:3:5:5:5:3:5:3:2.5:2:5:1.5:0.9. The types and dosages of the auxiliary materials are shown in Table 3.

[0066] Table 3

[0067]

[0068] Crospovidone Kollidon CL-F has a particle size of 20-40 μm.

[0069] Preparation method:

[0070] (1) Decoct rhubarb, astragalus root, mulberry bark, lightyellow sophora root, codonopsis pilosula, atractylodes macrocephala, poria cocos, prepared fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum chinense and liquorice root with water, and concentrate to an extract with a relative density of 1.35. Dry and pulverize the extract to obtain fine powder.

[0071] (2) Take the fine powder, add a filler and a disintegrant, mix evenly, add a binder to make a soft material, granulate, round, and dry. The water content after drying is: 4 wt%, and the particle size is: 1.2 mm.

[0072] Example 4 A kind of Niandutang pellets

[0073] 50 parts of filler, 6 parts of disintegrant, 15 parts of binder and 60 parts of active ingredients, wherein the active ingredients are rhubarb, astragalus root, mulberry bark, lightyellow sophora root, pilose asiabell root, largehead atractylodes rhizome, poria cocos, prepared fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum root and liquorice root in a weight ratio of 1:4:3:2:3:5:5:5:3:5:3:2.5:2:5:1.5:0.9. The types and dosages of excipients are shown in Table 4.

[0074] Table 4

[0075]

[0076] Preparation method:

[0077] (1) Decoct rhubarb, astragalus root, mulberry bark, lightyellow sophora root, pilose asiabell root, largehead atractylodes rhizome, poria cocos, prepared fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum root and liquorice root with water, and concentrate to an extract with a relative density of 1.40. Dry and pulverize the extract to obtain fine powder.

[0078] (2) Take the fine powder, add the filler and disintegrant, mix evenly, add the binder to make soft materials, granulate and round, and dry. The water content after drying is: 5 wt%, and the particle size is: 2.0 mm.

[0079] Comparative Example 1

[0080] 60 parts of filler, 6 parts of disintegrant, 5 parts of binder and 60 parts of active ingredients, wherein the active ingredients are rhubarb, astragalus root, mulberry bark, lightyellow sophora root, pilose asiabell root, largehead atractylodes rhizome, poria cocos, prepared fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum root and liquorice root in a weight ratio of 1:4:3:2:3:5:5:5:3:5:3:2.5:2:5:1.5:0.9. The types and dosages of excipients are shown in Table 5.

[0081] Table 5

[0082]

[0083] Preparation method:

[0084] (1) Decoct rhubarb, astragalus root, mulberry bark, lightyellow sophora root, pilose asiabell root, largehead atractylodes rhizome, poria cocos, prepared fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum root and liquorice root with water, and concentrate to an extract with a relative density of 1.40. Dry and pulverize the extract to obtain fine powder.

[0085] (2) Take the fine powder, add the filler and disintegrant, mix evenly, add the binder to make soft materials, granulate and round, and dry. The water content after drying is: 5 wt%, and the particle size is: 2.0 mm.

[0086] Comparative Example 2

[0087] 50 parts of filler, 6 parts of disintegrant, 15 parts of binder and 60 parts of active ingredient, wherein the active ingredient is rhubarb, astragalus root, mulberry bark, lightyellow sophora root, pilose asiabell root, largehead atractylodes rhizome, poria cocos, prepared fleece-flower root, white peony root, danshen root, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum root and licorice root in a weight ratio of 1:4:3:2:3:5:5:5:3:5:3:2.5:2:5:1.5:0.9. The types and dosages of the excipients are shown in Table 6.

[0088] Table 6

[0089]

[0090] Preparation method:

[0091] (1) Decoct rhubarb, astragalus root, mulberry bark, lightyellow sophora root, pilose asiabell root, largehead atractylodes rhizome, poria cocos, prepared fleece-flower root, white peony root, danshen root, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum root and licorice root with water, concentrate to an extract with a relative density of 1.40, dry and pulverize the extract to obtain fine powder.

[0092] (2) Take the fine powder, add the filler and disintegrant, mix evenly, add the binder to make soft materials, granulate, round, and dry. The water content after drying is: 5 wt%, and the particle size is: 2.0 mm.

[0093] Comparative Example 3

[0094] 50 parts of filler, 6 parts of disintegrant, 15 parts of binder and 60 parts of active ingredient, wherein the active ingredient is rhubarb, astragalus root, mulberry bark, lightyellow sophora root, pilose asiabell root, largehead atractylodes rhizome, poria cocos, prepared fleece-flower root, white peony root, danshen root, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum root and licorice root in a weight ratio of 1:4:3:2:3:5:5:5:3:5:3:2.5:2:5:1.5:0.9. The types and dosages of the excipients are shown in Table 7.

[0095] Table 7

[0096]

[0097] Preparation method:

[0098] (1) Decoct rhubarb, astragalus root, mulberry bark, lightyellow sophora root, pilose asiabell root, largehead atractylodes rhizome, poria cocos, prepared fleece-flower root, white peony root, danshen root, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum root and licorice root with water, concentrate to an extract with a relative density of 1.40, dry and pulverize the extract to obtain fine powder.

[0099] (2) Take the fine powder, add the filler and disintegrant, mix evenly, add the binder to make soft materials, granulate, round, and dry. The water content after drying is: 5 wt%, and the particle size is: 2.0 mm.

[0100] Comparative Example 4

[0101] 50 parts of filler, 6 parts of disintegrant, 15 parts of binder and 60 parts of active ingredients, wherein the active ingredients are rhubarb, astragalus root, mulberry bark, lightyellow sophora root, pilose asiabell root, largehead atractylodes rhizome, poria cocos, prepared fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum root and licorice root in a weight ratio of 1:4:3:2:3:5:5:5:3:5:3:2.5:2:5:1.5:0.9. The types and dosages of the excipients are shown in Table 8.

[0102] Table 8

[0103]

[0104] Preparation method:

[0105] (1) Decoct rhubarb, astragalus root, mulberry bark, lightyellow sophora root, pilose asiabell root, largehead atractylodes rhizome, poria cocos, prepared fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum root and licorice root with water, and concentrate to an extract with a relative density of 1.40. Dry and pulverize the extract to obtain fine powder.

[0106] (2) Take the fine powder, add the filler and disintegrant, mix evenly, add the binder to make soft material, granulate and round, and dry. The water content after drying is: 5wt%, and the particle size is: 2.0mm.

[0107] Control Example 5

[0108] 50 parts of filler, 6 parts of disintegrant, 15 parts of binder and 60 parts of active ingredients, wherein the active ingredients are rhubarb, astragalus root, mulberry bark, lightyellow sophora root, pilose asiabell root, largehead atractylodes rhizome, poria cocos, prepared fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum root and licorice root in a weight ratio of 1:4:3:2:3:5:5:5:3:5:3:2.5:2:5:1.5:0.9. The types and dosages of the excipients are shown in Table 9.

[0109] Table 9

[0110]

[0111]

[0112] Preparation method:

[0113] (1) Decoct rhubarb, astragalus root, mulberry bark, lightyellow sophora root, pilose asiabell root, largehead atractylodes rhizome, poria cocos, prepared fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum root and licorice root with water, and concentrate to an extract with a relative density of 1.40. Dry and pulverize the extract to obtain fine powder.

[0114] (2) Take the fine powder, add the filler and disintegrant, mix evenly, add the binder, make into a soft material, granulate, spheronize, and dry. The water content after drying is: 5 wt%, and the particle size is: 2.0 mm.

[0115] Comparative Example 6

[0116] 50 parts of filler, 6 parts of disintegrant, 15 parts of binder and 60 parts of active components, where the active components are rhubarb, astragalus root, mulberry bark, lightyellow sophora root, codonopsis pilosula, atractylodes macrocephala, poria cocos, processed fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum chinense and licorice root with a weight ratio of 1:4:3:2:3:5:5:5:3:5:3:2.5:2:5:1.5:0.9. The types and dosages of the excipients are shown in Table 10.

[0117] Table 10

[0118]

[0119] The particle size of cross-linked polyvinylpyrrolidone Polyplasdone XL is: 75 μm.

[0120] Preparation method:

[0121] (1) Decoct rhubarb, astragalus root, mulberry bark, lightyellow sophora root, codonopsis pilosula, atractylodes macrocephala, poria cocos, processed fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum chinense and licorice root with water, and concentrate to an extract with a relative density of 1.40. Dry and pulverize the extract to obtain fine powder.

[0122] (2) Take the fine powder, add the filler and disintegrant, mix evenly, add the binder, make into a soft material, granulate, spheronize, and dry. The water content after drying is: 5 wt%, and the particle size is: 2.0 mm.

[0123] Comparative Example 7

[0124] 50 parts of filler, 6 parts of disintegrant, 15 parts of binder and 60 parts of active components, where the active components are rhubarb, astragalus root, mulberry bark, lightyellow sophora root, codonopsis pilosula, atractylodes macrocephala, poria cocos, processed fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum chinense and licorice root with a weight ratio of 1:4:3:2:3:5:5:5:3:5:3:2.5:2:5:1.5:0.9. The types and dosages of the excipients are shown in Table 11.

[0125] Table 11

[0126]

[0127]

[0128] The hydroxypropoxy content of low-substituted hydroxypropyl cellulose ZW-LHPC-22 is: 7.0 - 9.9%.

[0129] Preparation method:

[0130] (1) Decoct rhubarb, astragalus membranaceus, mulberry bark, sophora flavescens, codonopsis pilosula, atractylodes macrocephala, poria cocos, processed fleece-flower root, white peony root, salvia miltiorrhiza, ligusticum wallichii, chrysanthemum, pinellia ternata, plantain herb, bupleurum chinense and licorice root with water, and concentrate to an extract with a relative density of 1.40. Dry and pulverize the extract to obtain fine powder.

[0131] (2) Add the fine powder to a filler and a disintegrant, mix evenly, add a binder to make a soft material, granulate, round, and dry. The water content after drying is: 5 wt%, and the particle size is: 2.0 mm.

[0132] Comparative Example 8

[0133] 50 parts of filler, 6 parts of disintegrant, 15 parts of binder and 60 parts of active components, wherein the active components are rhubarb, astragalus membranaceus, mulberry bark, sophora flavescens, codonopsis pilosula, atractylodes macrocephala, poria cocos, processed fleece-flower root, white peony root, salvia miltiorrhiza, ligusticum wallichii, chrysanthemum, pinellia ternata, plantain herb, bupleurum chinense and licorice root with a weight ratio of 1:4:3:2:3:5:5:5:3:5:3:2.5:2:5:1.5:0.9. The types and dosages of the auxiliary materials are shown in Table 12.

[0134] Table 12

[0135]

[0136] Preparation method:

[0137] (1) Decoct rhubarb, astragalus membranaceus, mulberry bark, sophora flavescens, codonopsis pilosula, atractylodes macrocephala, poria cocos, processed fleece-flower root, white peony root, salvia miltiorrhiza, ligusticum wallichii, chrysanthemum, pinellia ternata, plantain herb, bupleurum chinense and licorice root with water, and concentrate to an extract with a relative density of 1.40. Dry and pulverize the extract to obtain fine powder.

[0138] (2) Add the fine powder to a filler and a disintegrant, mix evenly, add a binder to make a soft material, granulate, round, and dry. The water content after drying is: 5 wt%, and the particle size is: 2.0 mm.

[0139] Comparative Example 9

[0140] 50 parts of filler, 6 parts of disintegrant, 15 parts of binder and 60 parts of active components, wherein the active components are rhubarb, astragalus membranaceus, mulberry bark, sophora flavescens, codonopsis pilosula, atractylodes macrocephala, poria cocos, processed fleece-flower root, white peony root, salvia miltiorrhiza, ligusticum wallichii, chrysanthemum, pinellia ternata, plantain herb, bupleurum chinense and licorice root with a weight ratio of 1:4:3:2:3:5:5:5:3:5:3:2.5:2:5:1.5:0.9. The types and dosages of the auxiliary materials are shown in Table 13.

[0141] Table 13

[0142]

[0143] Preparation method:

[0144] (1) Decoct Rheum palmatum, Astragalus membranaceus, Morus alba root bark, Sophora flavescens, Codonopsis pilosula, Atractylodes macrocephala, Poria cocos, Polygonum multiflorum preparatum, Paeonia lactiflora, Salvia miltiorrhiza, Ligusticum chuanxiong, Chrysanthemum morifolium, Pinellia ternata, Plantago asiatica, Bupleurum chinense and Glycyrrhiza uralensis with water, concentrate to an extract with a relative density of 1.40, dry and pulverize the extract to obtain fine powder.

[0145] (2) Take the fine powder, add a filler and a disintegrant, mix evenly, add a binder to make a soft material, granulate, round, and dry. The water content after drying is: 5 wt%, and the particle size is: 2.0 mm.

[0146] Comparative Example 10

[0147] 50 parts of filler, 6 parts of disintegrant, 15 parts of binder and 60 parts of active ingredients, wherein the active ingredients are Rheum palmatum, Astragalus membranaceus, Morus alba root bark, Sophora flavescens, Codonopsis pilosula, Atractylodes macrocephala, Poria cocos, Polygonum multiflorum preparatum, Paeonia lactiflora, Salvia miltiorrhiza, Ligusticum chuanxiong, Chrysanthemum morifolium, Pinellia ternata, Plantago asiatica, Bupleurum chinense and Glycyrrhiza uralensis with a weight ratio of 1:4:3:2:3:5:5:5:3:5:3:2.5:2:5:1.5:0.9. The types and dosages of the excipients are shown in Table 14.

[0148] Table 14

[0149]

[0150] Preparation method:

[0151] (1) Decoct Rheum palmatum, Astragalus membranaceus, Morus alba root bark, Sophora flavescens, Codonopsis pilosula, Atractylodes macrocephala, Poria cocos, Polygonum multiflorum preparatum, Paeonia lactiflora, Salvia miltiorrhiza, Ligusticum chuanxiong, Chrysanthemum morifolium, Pinellia ternata, Plantago asiatica, Bupleurum chinense and Glycyrrhiza uralensis with water, concentrate to an extract with a relative density of 1.40, dry and pulverize the extract to obtain fine powder.

[0152] (2) Take the fine powder, add a filler and a disintegrant, mix evenly, add a binder to make a soft material, granulate, round, and dry. The water content after drying is: 5 wt%, and the particle size is: 2.0 mm.

[0153] Comparative Example 11

[0154] 50 parts of filler, 6 parts of disintegrant, 15 parts of binder and 60 parts of active ingredients, wherein the active ingredients are Rheum palmatum, Astragalus membranaceus, Morus alba root bark, Sophora flavescens, Codonopsis pilosula, Atractylodes macrocephala, Poria cocos, Polygonum multiflorum preparatum, Paeonia lactiflora, Salvia miltiorrhiza, Ligusticum chuanxiong, Chrysanthemum morifolium, Pinellia ternata, Plantago asiatica, Bupleurum chinense and Glycyrrhiza uralensis with a weight ratio of 1:4:3:2:3:5:5:5:3:5:3:2.5:2:5:1.5:0.9. The types and dosages of the excipients are shown in Table 15.

[0155] Table 15

[0156]

[0157] Preparation method:

[0158] (1) Decoct rhubarb, astragalus root, mulberry bark, lightyellow sophora root, codonopsis pilosula, atractylodes macrocephala, poria cocos, prepared fleece-flower root, white peony root, salvia miltiorrhiza, chuanxiong rhizome, chrysanthemum, pinellia ternata, plantain herb, bupleurum root and liquorice root with water, concentrate to an extract with a relative density of 1.40, dry and pulverize the extract to obtain fine powder.

[0159] (2) Add the fine powder to a filler and a disintegrant, mix evenly, add a binder to make a soft material, granulate, round, and dry. The water content after drying is: 5 wt%, and the particle size is: 2.0 mm.

[0160] II. Accelerated stability test

[0161] 2.1 Test substances:

[0162] Examples 1-4, Comparative Example 1 and Comparative Examples 8-11.

[0163] 2.2 Test method:

[0164] Based on the content of paeoniflorin, determine the change in the content of paeoniflorin in NiDuQing pellets at 0 month, 1 month, and 3 months during the accelerated test (temperature: 60±2°C, relative humidity RH: 75±5%).

[0165] 2.3 Determination method:

[0166] Reference substance solution: Accurately weigh 10 mg of paeoniflorin reference substance dried to constant weight at 80°C, place it in a 50 mL volumetric flask, dissolve it with water and make up to the mark, accurately measure 5 mL, place it in a 25 mL volumetric flask, add water to the mark, and shake well to obtain the reference substance solution.

[0167] Test sample solution: Take 3 g each of the NiDuQing pellets of Examples 1-4, Comparative Example 1 and Comparative Examples 8-11 at 0 month, 1 month and 3 months, accurately weigh, place them in a stoppered conical flask, accurately add 25 mL of water, shake well, ultrasonically treat for 30 min (power 120 W, frequency 40 kHz), cool, weigh again, make up the reduced weight with water, shake well, filter, accurately absorb 5 mL of the supernatant, add it to a polyamide column (30-60 mesh, 1 cm×20 cm), elute with water, accurately collect 25 mL of the eluate, and shake well.

[0168] Chromatographic conditions:

[0169] Chromatographic column: Phenomenex C18 (250×4.6 mm, 5 μm);

[0170] Mobile phase: Acetonitrile: 0.05 mol / L potassium dihydrogen phosphate solution = 15:85 (v / v), isocratic elution;

[0171] Detection wavelength: 230 nm;

[0172] Flow rate: 1.0 mL / min;

[0173] Column temperature: 25 °C;

[0174] Sample injection volume: 10 μL.

[0175] 2.4 Test results:

[0176] The experimental results are shown in Table 16:

[0177] Table 16

[0178]

[0179] For Examples 1-4, after being placed for 1 month, the content of paeoniflorin decreased by 0 - 0.88%, and after being placed for 3 months, the content of paeoniflorin decreased by 2.68 - 4.65%. The Niaoduqing pellets in Examples 1-4 have good stability under long-term and high-temperature conditions, and the active ingredients are not easily deteriorated.

[0180] For Comparative Example 1, the amounts of the active ingredient, filler, disintegrant, and binder were changed, which are not within the scope of protection of the present invention. After being placed for 1 month, the content of paeoniflorin decreased by 11.30%, and after being placed for 3 months, the content of paeoniflorin decreased by 27.83%. The Niaoduqing pellets in Comparative Example 1 have poor stability under long-term and high-temperature conditions.

[0181] For Comparative Examples 8-11, the types and dosage relationships of the fillers were changed, which are not within the scope of protection of the present invention. After being placed for 1 month, the content of paeoniflorin decreased by 16.22 - 19.83%, and after being placed for 3 months, the content of paeoniflorin decreased by 31.86 - 37.84%. The Niaoduqing pellets in Comparative Examples 8-11 have poor stability under long-term and high-temperature conditions.

[0182] III. Dissolution test

[0183] 3.1 Test samples: The Niaoduqing pellets in Examples 1-5 and Comparative Examples 1-3.

[0184] 3.2 Determination method: Determined by the second method (paddle method) in General Chapter 0931 of the Fourth Part of Chinese Pharmacopoeia (2020 Edition).

[0185] Specifically, it includes the following steps: Put 4 g of the test sample into 900 mL of water, stir at 100 r / min, and take 20 mL of samples at the 5th min, 10th min, 20th min, 30th min, and 60th min respectively. After filtering through a 0.45 μm membrane, discard 10 mL of the initial filtrate, and use the subsequent filtrate as the test sample solution. Measure the absorbance of each solution at 362 nm using ultraviolet-visible spectrophotometry, and calculate the dissolution rate to obtain Table 17:

[0186] Table 17

[0187]

[0188] In Examples 1-4, the dissolution rate at 5 min is >90.4%, and the dissolution plateau is reached within 10 min. The Qinggan Jiedu Tablets of the present invention have a fast dissolution rate, a quick onset of effect, and improved bioavailability.

[0189] In Comparative Example 1, the dosages of the active ingredient, filler, disintegrant, and binder were changed, which are not within the protection scope of the present invention. The dissolution rate at 5 min was only 70.3%, and the dissolution plateau was not reached until 20 min later. The dissolution rate was slow, the onset of effect was slow, and the bioavailability could not be improved.

[0190] In Comparative Examples 2-7, the types and dosage relationships of the disintegrants were changed, which are not within the protection scope of this application. The dissolution rates at 5 min were only 60.7-67.5%, and the dissolution plateau was not reached until 30 min later. The dissolution rate was slow, the onset of effect was slow, and the bioavailability could not be improved.

[0191] In Comparative Examples 8-11, the types and dosage relationships of the fillers were changed, which are not within the protection scope of the present invention. The dissolution rates at 5 min were only 74.2-77.8%, and the dissolution plateau was not reached until 30 min later. The dissolution rate was slow, the onset of effect was slow, and the bioavailability could not be improved.

[0192] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than limiting the protection scope of the present invention. Simple modifications or equivalent replacements made by those of ordinary skill 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 Urea-clearing Pill, characterized in that: The composition comprises, by weight, 40-60 parts of active ingredients, 30-50 parts of fillers, 1-6 parts of disintegrants and 5-15 parts of binders; the disintegrants are cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose; The mass ratio of the cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose is: 4-5: 8-15: 3-5; The particle size of the cross-linked polyvinylpyrrolidone is 20-50 μm.

2. The urea-clearing micro-pill according to claim 1, characterized in that: The hydroxypropoxy content of the low-substituted hydroxypropyl cellulose is: 10%-15%; The mass ratio of the cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose is 5:10-15:

4.

3. The urea pill according to claim 1, characterized in that: The active components are: rhubarb, astragalus, mulberry bark, sophora flavescens, codonopsis, atractylodes, tuckahoe, prepared shouwu, white peony root, salvia miltiorrhiza, chuanxiong, chrysanthemum, pinellia tuber, plantain, bupleurum and liquorice are decocted with water, filtered and concentrated to obtain an extract, and the extract is dried to obtain the active component; The relative density of the extract is 1.25-1.

40.

4. The urea-clearing micro-pill according to claim 1, characterized in that: The filler is microcrystalline cellulose, mannitol and calcium hydrogen phosphate in a mass ratio of 4-8:5-10:2-3.

5. The urea-clearing micro-pill according to claim 1, characterized in that: The adhesive is at least one of pregelatinized starch, polyvinyl pyrrolidone, ethyl cellulose and hydroxypropyl methyl cellulose.

6. The urea-clearing micro-pill according to claim 1, characterized in that: The particle size of the urea-clearing micro-pill is 0.3mm-2.0mm.

7. A method for preparing the urine drug-clearing micro-pill according to any one of claims 1 to 6, characterized in that: The following steps are involved: (1) boiling rhubarb, astragalus, mulberry bark, sophora flavescens, codonopsis pilosula, atractylodes macrocephala, poria, prepared shouwu, white peony root, salvia miltiorrhiza, chuanxiong, chrysanthemum, pinellia tuber, plantain, bupleurum and liquorice with water, concentrating to obtain an extract, drying the extract to obtain an active component, and crushing the active component to obtain a fine powder; (2) Add a filler and a disintegrant to the fine powder obtained in step (1), mix well, add a binder to make a soft material, granulate, spheronize, and dry to obtain the product.

8. The preparation method according to claim 7, characterized in that: The concentration temperature in step (1) is 60-80°C; The relative density of the extract in step (1) is: 1.25-1.40; The water content after drying in step (2) is 3-5wt%.

9. A Urea-clearing micro-pill preparation, comprising the Urea-clearing micro-pill according to any one of claims 1 to 6 or the Urea-clearing micro-pill prepared by the preparation method according to any one of claims 7 to 8 and a coating material.

10. A method for improving the stability of urea-clearing micro-pills, characterized in that: The following steps are involved: (1) boiling rhubarb, astragalus, mulberry bark, sophora flavescens, codonopsis pilosula, atractylodes macrocephala, poria, prepared shouwu, white peony root, salvia miltiorrhiza, chuanxiong, chrysanthemum, pinellia tuber, plantain, bupleurum and liquorice with water, concentrating to obtain an extract, drying the extract to obtain an active component, and crushing the active component to obtain a fine powder; (2) adding a filler and a disintegrant to the fine powder obtained in step (1), mixing them evenly, adding a binder to make a soft material, granulating, spheronizing, and drying to obtain the product; The active component, filler, disintegrant and binder are calculated by weight as follows: 40-60 parts of active component, 30-50 parts of filler, 1-6 parts of disintegrant and 5-15 parts of binder; The disintegrant is cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose in a mass ratio of 4-5:8-15:3-5; The fillers are: microcrystalline cellulose, mannitol and calcium hydrogen phosphate; The adhesive is at least one of pregelatinized starch, polyvinyl pyrrolidone, ethyl cellulose and hydroxypropyl methyl cellulose.

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