Pharmaceutical composition for treating gout and hyperuricemia and preparation method thereof

Abstract

The invention relates to a pharmaceutical composition for treating gout and hyperuricemia and a preparation method thereof. The pharmaceutical composition consists of a celery and sophora japonica extract, an anti-sticking agent, a disintegrating agent, a surfactant, a filling agent and a lubricating agent, and is obtained by crushing, mixing, granulating, mixing and encapsulating. The invention solves the problem of difficult crushing of the apium graveolens and sophora japonica extract, and provides a wet granulation process, and the prepared apium graveolens and sophora japonica capsule pharmaceutical composition has the characteristics of simple process, rapid disintegration, high dissolution rate, good stability and convenient medication.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a medicinal composition of celery and sophora japonica flower bud extract for treating gout and hyperuricemia and a preparation method thereof. Background Art

[0002] Celery seeds are the seeds of the celery (Apium graveolens L.) plant of the Umbelliferae family. Domestic and foreign literature reports that the ethanol extract of celery seeds has obvious pharmacological effects such as preventing and treating cardiovascular diseases, anti-cancer, anti-cerebral ischemia, reducing uric acid, and anti-inflammatory. Celery seeds have been used to treat joint pain in Australia for a hundred years and are regarded as a traditional folk remedy. According to the 1983 edition of the British Herbal Pharmacopoeia, celery seeds have the effect of treating complications such as gout.

[0003] Sophora japonica flower buds in a broad sense are the dried flower buds and flowers of the sophora japonica (Sophora japonica L.) plant of the Leguminosae family. Sophora japonica flower buds are slightly cold in nature and bitter in taste, and have the effects of cooling blood for hemostasis and clearing the liver and purging fire, and can be used for hematochezia, hemorrhoids, dysentery, metrorrhagia, hematemesis, epistaxis, liver-heat red eyes, headache and dizziness, etc. Celery seeds and sophora japonica flower buds are products that are both medicine and food, so they are basically non-toxic and have few side effects, and also show good pharmaceuticability.

[0004] Chinese Patent ZL201610313303.8 discloses a preparation method of a compound extract of celery seeds and sophora japonica flower buds (hereinafter referred to as: celery and sophora japonica flower bud extract) and the effect of the celery and sophora japonica flower bud extract in reducing uric acid and preventing or treating gout. Since the characteristic of the celery and sophora japonica flower bud extract is hydrophobicity and low solubility in water, and for the preparations recorded in this patent, in addition to the active ingredient celery and sophora japonica flower bud extract, only conventional types and amounts of disintegrants are added to the prescription. Experiments show that whether it is a tablet or a capsule, slow disintegration or even non-disintegration and low dissolution are found. The slow disintegration and low dissolution of the preparation will affect the dissolution, absorption and transformation of the effective ingredients of the drug, thereby affecting the bioavailability and efficacy of the drug.

[0005] The medicinal composition containing celery and sophora japonica flower bud extract disclosed in Chinese Patent (Application No. 202110326111.1) preliminarily solves the problem of poor dissolution of the celery and sophora japonica flower bud extract preparation caused by poor disintegration and poor water solubility of the active ingredient by using a combination of cyclodextrin solubilizers, acid-base effervescent agents, disintegrants and surfactants. However, there are many types of excipients in the prescription of this technical solution, the production process is complex, and there is a problem of difficult pulverization of the celery and sophora japonica flower bud extract during the preparation process, which is not conducive to industrial production. In particular, when celery seeds have different compositions due to different harvesting origins and seasons, the degree of difficulty in pulverizing the celery and sophora japonica flower bud extract is different. For the medicinal composition prepared according to the patent technical solution, there is a problem of large batch-to-batch dissolution differences.

[0006] Therefore, it is necessary to develop an improved composition of Sophora flavescens extract and its preparation method to solve the problem of difficult pulverization of Sophora flavescens extract, and it has the advantages of fewer types of excipients, simple process, and good quality of the finished product. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a pharmaceutical composition for preventing and treating gout with Sophora flavescens extract as an active ingredient and its preparation method. Through the formulation of the composition and its preparation method, the following technical problems of the preparation containing Sophora flavescens extract are solved:

[0008] 1. The problem of difficult pulverization of Sophora flavescens extract.

[0009] Since the characteristic of Sophora flavescens extract is hydrophobic and has low solubility in water, when preparing a pharmaceutical composition suitable for patients to take, it must be pulverized to a suitable particle size to form finer particles or powder so that the active ingredient can be effectively dispersed and dissolved after being mixed with other excipients and made into a preparation.

[0010] We have found through research that since Sophora flavescens extract is obtained from natural plants through the traditional extraction process of alcohol extraction and water precipitation, its components are complex. In addition to the active ingredients, it also contains some macromolecular components and / or other oil components. When directly pulverizing Sophora flavescens extract by conventional means, the extract gets heated and softened under mechanical force. If using the sieve mesh of an ordinary pulverizer, there will be a situation of sieve clogging or particle aggregation, and it is very difficult to complete the pulverization process smoothly; if not using the sieve mesh, the pulverization process can be completed smoothly. However, the particle size of the pulverized extract is too large and the physical state is not ideal, which brings difficulties in uneven mixing and product disintegration and dissolution in the subsequent preparation of pharmaceutical dosage forms. In addition, with different origins and harvesting seasons of the medicinal materials, the types and contents of macromolecular components or their oil components in different batches of Sophora flavescens extract also change, resulting in changes in sieve clogging or particle aggregation situations. It is necessary to frequently adjust the operating parameters of the pulverization process, which brings more difficulties to the operability and process stability of the pulverization process, and further affects the unstable quality of the pulverized product, ultimately affecting the quality of the pharmaceutical dosage form, especially the stability of the dissolution degree of the active ingredient, with significant within-batch and between-batch differences.

[0011] 2. The active ingredient, Sophora flavescens extract, has poor water solubility itself, and its solubility must be increased more effectively.

[0012] The pharmaceutical composition containing Qinhua extract disclosed in the Chinese patent (application number CN 202110326111.1) uses a variety of means such as cyclodextrin solubilizer, acid-base effervescent agent, disintegrant, glidant, and surfactant in combination, and initially solves the problems of poor water solubility and poor disintegration of the Qinhua extract preparation. However, these excipients such as cyclodextrin solubilizer, effervescent agent, disintegrant, glidant, and surfactant only act on the surface of the Qinhua extract particles and cannot penetrate deep into the particles. If there are problems such as sieve clogging or particle aggregation during the pulverization process of the Qinhua extract, resulting in an unsatisfactory physical state of the particles, the result is not only that the disintegration and dissolution of different particles themselves are different, with large differences within and between batches, but also after the preparation is made, only by the means of the existing technology, only a certain degree of improvement in solubility can be achieved, but it is difficult to fundamentally guarantee the quality of the preparation finished product, especially the stability and reproducibility of the dissolution degree of the active ingredient, as well as the existing differences within and between batches, which cannot be completely eliminated by the auxiliaries outside the particles. Therefore, only by solving the physical state of the Qinhua extract particles from the source, making the pulverized extract particles or powders have a stable and uniform physical state, can the purpose be achieved.

[0013] 3. The prescription of the existing technology is complex and the process is cumbersome, which is not conducive to large-scale industrial production.

[0014] 1) In order to solve the problems of poor water solubility and poor disintegration, the Chinese patent application CN 202110326111.1 in the existing technology uses a variety of means such as cyclodextrin solubilizer, acid-base effervescent agent, disintegrant, glidant, and surfactant in combination, and with the necessary fillers and lubricants, the prescription is very complex;

[0015] 2) The preparation process of the existing technology is complex and requires the following four steps:

[0016] (1) Dissolve the surfactant in the solvent and set aside; weigh the acid effervescent agent, filler, and disintegrant and place them in a high-speed mixing granulator, mix evenly; add the solvent solution containing the surfactant, stir to make soft materials, granulate, and dry to obtain acid particles 1;

[0017] (2) Mix the Qinhua extract, alkali effervescent disintegrant, and solubilizer evenly, add acid particles 1 and lubricant for total mixing to obtain particles 2;

[0018] (3) Add the obtained particles 2 to a dry powder granulator to obtain dry particles 3.

[0019] (4) Load the dry particles 3 into pharmaceutical capsules.

[0020] The defects of the above process are as follows:

[0021] (1) It includes four steps: wet granulation + total mixing + dry granulation + capsule filling. The process is complex. Compared with the commonly used wet granulation process, dry granulation takes a longer time and has low production efficiency, which is not conducive to large-scale industrial production.

[0022] (2) It does not include the pulverization process of Qinhuai extract, and the pulverization situation has a significant impact on the dissolution of the preparation product. Therefore, the product quality cannot be guaranteed.

[0023] (3) Since the prescription contains both acids and alkaline effervescent agents at the same time, the most commonly used wet granulation process in this industry cannot be used to prepare the granules for filling capsules (acids and alkaline effervescent agents will undergo chemical reactions). Only dry granules can be obtained through dry granulation. Dry granulation is a method of promoting the agglomeration of dry powder granules through mechanical compression (striking) or compaction (roll pressing), and then pulverizing them. The fine powder part after pulverization has to be repeatedly compressed (struck) or compacted (roll pressed). However, since Qinhuai extract contains oily components and viscous macromolecular components and has poor solubility, the repeated compression (striking) or compaction (roll pressing) during dry granulation causes the Qinhuai extract granules to be further compacted, making disintegration more difficult and having a greater negative impact on improving solubility. On the contrary, wet granulation does not have the above drawbacks.

[0024] To solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0025] The present invention provides a pharmaceutical composition for treating gout and hyperuricemia, which is characterized in that by weight percentage, the pharmaceutical composition is composed of the following components: Qinhuai extract: 20 - 80%, anti-adhesive: 0 - 20%, disintegrant: 2 - 16%, filler 0 - 75%, surfactant: 0.1 - 5.0%, alkaline effervescent agent: 0 - 10%, lubricant 0.5 - 5%.

[0026] Preferably, the present invention further provides a pharmaceutical composition for treating gout and hyperuricemia, which is characterized in that the pharmaceutical composition is composed of the following components: Qinhuai extract: 40 - 60%, anti-adhesive: 2 - 10%, disintegrant: 2 - 10%, filler 10 - 45%, surfactant: 0.2 - 3.0%, alkaline effervescent agent: 3 - 8%, lubricant 0.5 - 2.0%.

[0027] More preferably, the present invention further provides a pharmaceutical composition for treating gout and hyperuricemia, which is characterized in that the pharmaceutical composition is composed of the following components: Qinhuai extract: 50%, anti-adhesive: 3 - 7%, disintegrant: 3 - 5%, filler: 25 - 35%, surfactant: 0.3 - 1%, alkaline effervescent agent: 6 - 7%, lubricant: 0.8 - 1%.

[0028] The celery and sophora flower extract is an alcohol extract of celery seeds and sophora flower buds with a weight ratio of 2:1 - 4:1, and can be obtained, for example, by the method disclosed in Chinese Patent ZL201610313303.8.

[0029] The anti-adhesive agent is selected from silicon dioxide. Silicon dioxide has the characteristics of stable chemical properties, insoluble in water, non-toxic, odorless, non-flammable, non-explosive, non-volatile, non-corrosive, large pore volume, large specific surface area, strong surface activity, and strong adsorption and absorption capacity for macromolecules and oils.

[0030] The silicon dioxide used in the present invention is further divided into fumed silica (colloidal silica, microsilica gel) and silicon dioxide (precipitated method) according to different preparation processes. Fumed silica (colloidal silica, microsilica gel) refers to silicon dioxide prepared by the gas phase method; the commonly referred to silicon dioxide refers to silicon dioxide prepared by the precipitation method, that is, sodium silicate reacts with an acid or sodium silicate reacts with a salt to produce a silicic acid precipitate, which is washed with water, and dried after removing impurities. In order to save the cost of auxiliary materials, silicon dioxide prepared by the precipitation method is further preferably used.

[0031] The filler is selected from one or more mixtures of lactose, microcrystalline cellulose, corn starch, dextrin, mannitol, and glucose, preferably lactose, microcrystalline cellulose, corn starch, and dextrin; more preferably lactose and microcrystalline cellulose.

[0032] The disintegrant includes one or more mixtures of starch, pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, and cross-linked sodium carboxymethyl cellulose; preferably low-substituted hydroxypropyl cellulose.

[0033] The surfactant is selected from one or more mixtures of polysorbate 80, poloxamer, and lecithin; preferably polysorbate 80.

[0034] The basic effervescent agent is selected from carbonates, including one or more of sodium carbonate, sodium bicarbonate, calcium carbonate, potassium carbonate, and potassium bicarbonate; preferably sodium bicarbonate.

[0035] The lubricant is selected from one or more of magnesium stearate, stearic acid, and silicon dioxide, preferably magnesium stearate.

[0036] In other words, the technical solution of the present invention is to add an anti-adhesive, a surfactant, an effervescent agent, a disintegrant and other excipients on the basis of taking the Qinhuai extract as an active ingredient. The other excipients include a lubricant, a filler and other pharmaceutically acceptable excipients. In terms of the prescription composition, the biggest difference from the prior art is the addition of an anti-adhesive. By adding an anti-adhesive and / or a filler and a disintegrant during the pulverization process of the Qinhuai extract, the adhesion and aggregation between the particles after pulverization of the Qinhuai extract are inhibited, and problems such as sieve clogging or particle agglomeration during the pulverization process are avoided. The particle size of the pulverized Qinhuai extract can be well controlled, fine powder with a smaller particle size can be obtained, and the particle size is uniform. Then, it is mixed with a filler and a disintegrant to solve the technical problems of difficult pulverization of the Qinhuai extract and poor particle disintegration. Then, by controlling the particle size of the pulverized Qinhuai extract and the dosage of the surfactant, the problem of poor water solubility of the active ingredient is solved.

[0037] The pharmaceutical composition obtained by the present invention with the Qinhuai extract as an active ingredient has good disintegration, good dissolution of the active ingredient, good absorption by patients and good curative effect, thereby preparing a pharmaceutical preparation for preventing and / or treating gout. Through stability research, it is proved that the pharmaceutical composition of the present invention has good stability after long-term storage, good effect in treating gout, and low toxicity and small side effects.

[0038] For the composition of the present invention, the dosage form preferably adopts a capsule, the content is granules, and the capsule shell has the function of masking the taste of the Qinhuai extract.

[0039] The present invention further provides a preparation method of a pharmaceutical composition for treating gout and hyperuricemia, which is characterized in that the method comprises the following steps:

[0040] (1) Pulverize the Qinhuai extract preliminarily to obtain coarse powder particles of the Qinhuai extract; mix the coarse powder particles of the Qinhuai extract, an anti-adhesive and / or a filler and a disintegrant to obtain a mixed powder; place the mixed powder in a hammer mill for pulverization to obtain fine powder;

[0041] (2) Dissolve the surfactant in a solvent for later use; place the fine powder obtained in step (1) in a high-speed wet granulator, mix, add the solvent solution containing the surfactant, stir to make a soft material, dry, and size the particles to obtain granules;

[0042] (3) Mix the excipients (such as an alkaline effervescent agent and / or a filler and a disintegrant) other than the lubricant in the prescription of the granules obtained in step (2) evenly, and then add the lubricant for total mixing to obtain total mixed granules;

[0043] (4) Fill the total mixed granules into pharmaceutical capsules.

[0044] In the above (1), in order to mix with the auxiliary materials, the dried celery and sophora japonica extract block (for example, obtained by the method disclosed in Chinese patent ZL201610313303.8) needs to be crushed to prepare celery and sophora japonica extract coarse powder particles.

[0045] In the preparation method of the present invention, when preparing the coarse powder particles of the celery and sophora japonica extract, the pulverization is performed without a screen or with a screen having an aperture greater than 2.5 mm, preferably without a screen; the pulverization is performed once or multiple times.

[0046] When preparing the mixed powder in step (1), the mixing method is manual mixing or mechanical mixing, preferably mechanical mixing, and more preferably mixing by a mixer.

[0047] When preparing the mixed powder in the step (1), the mixing method includes the following methods: weighing the coarse powder particles of the celery and Sophora japonica extract, mixing them with an anti-adhesive agent, or mixing them with a filler and a disintegrant, or mixing them with an anti-adhesive agent, a filler and a disintegrant, and then crushing them with a hammer mill to obtain fine powder; preferably, weighing the coarse powder particles of the celery and Sophora japonica extract, mixing them with an anti-adhesive agent, or mixing them with an anti-adhesive agent, a filler and a disintegrant, and further preferably mixing them with an anti-adhesive agent, a filler and a disintegrant to obtain a mixed powder; and then crushing them with a hammer mill to obtain fine powder.

[0048] When the mixed powder of step (1) is crushed to prepare fine powder, a sieve is added, and the sieve aperture is 0.2mm, 0.3mm, 0.4mm, 0.5mm, 0.6mm, 0.7mm, 0.8mm, 0.9mm, 1.0mm, 1.1mm, 1.2mm, 1.3mm, 1.4mm, 1.5mm; one or more sieves are selected, and the sieves are crushed one or more times in descending order of aperture.

[0049] The particle size distribution of the fine powder in step (1) is as follows: the proportion under 80 mesh sieve is greater than 75%; preferably, the proportion under 80 mesh sieve is greater than 80%; preferably, the proportion under 80 mesh sieve is greater than 85%; preferably, the proportion under 80 mesh sieve is greater than 90%; preferably, the proportion under 80 mesh sieve is greater than 95%; more preferably, all of the particles pass through 80 mesh sieve.

[0050] The mixing stirring speed of step (2) is 0-500 rpm, preferably 50-200 rpm, more preferably 80-150 rpm.

[0051] The shear speed of mixing in step (2) is 0-2000 rpm.

[0052] The mixing time of step (2) is 1-30 minutes, preferably 2-20 minutes, and more preferably 3-10 minutes.

[0053] The stirring speed for preparing the soft material in step (2) is 100 - 300 revolutions per minute, the shearing speed is 0 - 1500 revolutions per minute, and the stirring time is 3 - 20 minutes.

[0054] The solvent in step (2) is selected from one of water, ethanol, and aqueous ethanol solution; water is preferred.

[0055] The drying method in step (2) is fluidized bed drying or oven drying, and fluidized bed drying is preferred.

[0056] The granulating equipment in step (2) is selected from a swing granulator and a high-speed granulator; a high-speed granulator is preferred.

[0057] The aperture of the granulating sieve in step (2) is 0.5 - 2.5 mm; preferably 1.0 mm - 2.0 mm; more preferably 1.5 mm.

[0058] The mixing equipment in step (3) is selected from a wet granulator, a hopper mixer, and a three-dimensional multi-directional mixer; a hopper mixer is preferred.

[0059] When the total mixed granules in step (4) are filled into capsules, an inserting rod type capsule filling machine is selected. The inserting rod type capsule filling machine can fill 0# capsules with materials having a bulk density of 0.4 - 0.8 g / ml to reach 450 mg per capsule.

[0060] The wet granulation process is adopted in step (3). Compared with the dry granulation process of the prior art, its advantages are as follows:

[0061] 1. The process steps are simple and large-scale production is easy.

[0062] 2. Using water as the solvent is environmentally friendly, economical, does not pollute the environment, and can uniformly disperse surfactants;

[0063] 3. As a wetting agent, water enables the granulation process to be controllable, easy to dry, and the prepared granules to have good disintegration performance when the fine powder of celery and sophora japonica extract is fully mixed with excipients.

[0064] Therefore, the present invention provides a celery and sophora japonica extract capsule with simple process, rapid disintegration, and good dissolution degree and its preparation method. Specifically, the present invention provides a medicinal composition of celery seed stir-fried sophora japonica flower extract, preferably in capsule dosage form (hereinafter referred to as celery and sophora japonica capsule) and its preparation method.

[0065] The celery seeds described are the seeds of plants in the genus Apium of the family Apiaceae. The sophora japonica flower buds described are the flower buds and flowers of plants in the genus Sophora of the family Fabaceae, preferably sophora japonica flower buds, and most preferably stir-fried sophora japonica flower buds.

[0066] The celery and sophora japonica extract of the present invention is prepared according to the preparation method of the celery seed and sophora japonica extract in Chinese Patent CN201610313303.8. Specifically, the extract is prepared by the following steps: adding the raw medicinal materials of celery seeds and stir-fried sophora japonica into a solvent for extraction, filtering and concentrating the filtrate, performing water precipitation, separating the solid, and drying to obtain it.

[0067] The anti-adhesive of the pharmaceutical composition of the present invention is selected from silica prepared by the gas phase method (colloidal silica, microcrystalline silica gel) or silica prepared by the precipitation method; the dosage of the anti-adhesive is 0%-30%, including but not limited to dosages of 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%. The preferred dosage of the anti-adhesive is 2-10%, and more preferably 3-7%. The anti-adhesive within the above dosage range can significantly improve the comminution property of the celery and sophora japonica extract, reduce its particle size, and improve its solubility and dissolution rate. The mechanism is as follows: the anti-adhesive of the pharmaceutical composition of the present invention has a strong ability to absorb water and oil. Under the strong mechanical force of comminution, it fully adsorbs the hydrophobic oil components and macromolecules in the celery and sophora japonica extract, reduces the particle size of the celery and sophora japonica extract, increases its specific surface area, improves the degree of dispersion of the celery and sophora japonica extract into the excipient, thereby improving the solubility and dissolution rate of the celery and sophora japonica extract in water and achieving the solubilization effect.

[0068] The filler described in the present invention is selected from one or more mixtures of lactose, mannitol, glucose, and microcrystalline cellulose. The preferred water-soluble excipients are lactose, microcrystalline cellulose, and mannitol; more preferably lactose. The dosage of the filler is 0-75%, preferably 10-45%, and more preferably 25-35%.

[0069] The disintegrant described in the present invention is preferably a mixture of one or more of starch, pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, and cross-linked sodium carboxymethyl cellulose; more preferably low-substituted hydroxypropyl cellulose. Low-substituted hydroxypropyl cellulose is a commonly used disintegrant in solid preparations, which can absorb water and swell, accelerating the disintegration of granules. The dosage of the disintegrant is 2-16%, preferably 2-10%, and more preferably 3-5%.

[0070] The solubilizer of the pharmaceutical composition of the present invention further includes a surfactant, and the surfactant is selected from one or more mixtures of polysorbate 80 (i.e., Tween 80), poloxamer, lecithin, etc.; the non-ionic surfactant polysorbate 80 has mature technology, low price, strong solubilization ability, wide use, non-toxic by oral administration, and strong solubilization ability. Preferably, it is polysorbate 80. The dosage of the surfactant in the composition is 0.1%-5.0%, preferably 0.2-3.0%, and more preferably 0.3-1%. The above-mentioned surfactant, especially polysorbate 80, can effectively improve the dissolution rate and dissolution degree of the active ingredient within this range. After the surfactant is dissolved in water, it forms micelles or micelles, reduces the surface tension between water and the hydrophobic Qinhuai extract, and enhances the dissolution ability. Using the surfactant alone cannot achieve or requires more surfactant to achieve the effect of rapid disintegration and solubilization.

[0071] When using a surfactant (such as polysorbate 80), directly adding it to the solid is not conducive to uniform dispersion. In the present invention, after dissolving the surfactant in a solvent, it is added to the mixed granules of a filler, an organic acid, and a disintegrant, which can not only disperse the surfactant evenly, but also facilitate the preparation of soft materials and obtain granules with a suitable particle size distribution. The solvent is selected from water or an aqueous solution containing 5-20% (V / V) of lower alcohols (preferably ethanol), and water is preferably used as the solvent.

[0072] The lubricant of the present invention can be, but is not limited to, magnesium stearate and stearic acid, and magnesium stearate is preferred.

[0073] The basic effervescent agent of the present invention is selected from carbonates, including one or more of sodium carbonate, sodium bicarbonate, calcium carbonate, potassium carbonate, and potassium bicarbonate; more preferably sodium bicarbonate. Sodium bicarbonate has the smallest molecular mass and can release more carbon dioxide with the same weight.

[0074] The basic effervescent agent used in the present invention has an accelerating disintegration effect under the action of gastric acid, can overcome the influence of the hydrophobic layer on the particle surface, and avoid particle aggregation, thereby accelerating drug dispersion and disintegration.

[0075] The mechanism of action of using the above basic effervescent agent in the preparation of the present invention is that the carbonate can undergo a chemical reaction in the gastric acid solution to generate a large amount of carbon dioxide gas. The gas can cause the particles to expand violently in volume, easily break through the hydrophobic layer on the particle surface, and destroy the gel-like surface. This not only prevents the particles from aggregating into clusters, but also greatly accelerates the disintegration and dispersion of the Qinhuai capsule particles, making the preparation quickly disintegrate and disperse into very small microparticles, with a greatly increased surface area. Then, under the action of the surfactant, the dissolution rate of the active ingredient is significantly increased.

[0076] The dosage of the alkali effervescent disintegrant in the composition is 0-10%, preferably 3-8%, and more preferably 6-7%. When the alkali effervescent agent in the composition is used in the above ratio, it can achieve the effects of rapid dispersion, disintegration, and promotion of rapid dissolution.

[0077] In summary, in the present invention, the sophora japonica and sophora flavescens extract, the anti-adhesive and / or filler, and the disintegrant are selected and mixed and then crushed together to solve the problem of difficult crushing of the sophora japonica and sophora flavescens extract. Under the strong action of mechanical force, other excipients such as the anti-adhesive and / or filler and the disintegrant adsorb the hydrophobic oil components and macromolecules in the sophora japonica and sophora flavescens extract, reduce the viscosity of the sophora japonica and sophora flavescens extract, decrease the particle size of the sophora japonica and sophora flavescens extract, increase its specific surface area, and improve the degree of dispersion of the sophora japonica and sophora flavescens extract into the excipients, thereby increasing the solubility and dissolution rate of the sophora japonica and sophora flavescens extract in water. The combined use of the surfactant, the alkaline effervescent agent, and the disintegrant can play the role of rapid disintegration and solubilization faster and better.

[0078] In the above-mentioned crushing process, it can be the sophora japonica and sophora flavescens extract + anti-adhesive mixed and then crushed, or the sophora japonica and sophora flavescens extract + filler and disintegrant mixed and then crushed, and more preferably the sophora japonica and sophora flavescens extract + anti-adhesive + filler and disintegrant mixed and then crushed.

[0079] The present invention also provides the application of the above-mentioned sophora japonica and sophora flavescens extract pharmaceutical composition in the preparation of drugs for preventing and / or treating gout and reducing hyperuricemia in mammals and / or humans.

[0080] The beneficial effects obtained by the present invention:

[0081] The present invention discloses a pharmaceutical composition for preventing and treating gout and hyperuricemia and its preparation method, which solves the problem of difficult crushing of the sophora japonica and sophora flavescens extract, and obtains a sophora japonica and sophora flavescens extract pharmaceutical composition and its preparation method with simple process, rapid disintegration, high dissolution rate, good stability, convenient medication, and long-term use, and has the following beneficial effects:

[0082] 1. Solve the technical problems of difficult crushing, poor water solubility, and poor disintegration in the preparation process of the sophora japonica and sophora flavescens extract.

[0083] Under the strong mechanical force of pulverization, anti-adhesive agents (e.g., silicon dioxide) and / or other excipients (fillers, disintegrants, e.g., microcrystalline cellulose, lactose, low-substituted hydroxypropyl cellulose) absorb hydrophobic oil components and macromolecules in the celery and Sophora japonica extract, reduce the viscosity of the celery and Sophora japonica extract, make the pulverization proceed smoothly, reduce the particle size of the celery and Sophora japonica extract, obtain fine powder with smaller particle size, increase its specific surface area, and increase the degree of dispersion of the celery and Sophora japonica extract in the excipients, thereby improving the solubility and dissolution rate of the celery and Sophora japonica extract in water; at the same time, ensure that the celery and Sophora japonica extract is mixed evenly with the excipients to ensure that the intra-batch and inter-batch differences can be controlled within a smaller range. On the basis of the above technical scheme, it is preferred to add an effervescent agent (e.g., sodium bicarbonate) and a disintegrant (e.g., low-substituted hydroxypropyl cellulose) in combination to enable the preparation of the celery and Sophora japonica composition to disintegrate and disperse rapidly; further preferably, a surfactant (e.g., polysorbate 80) is added to reduce the hydrophobicity of the celery and Sophora japonica extract, further improving the dissolution rate and dissolution capacity of the celery and Sophora japonica extract preparation composition.

[0084] 2. The preparation process is suitable for the characteristics of this product and is easy for industrial large-scale production.

[0085] The coarse powder of celery and sophora extract, anti-adhesive agent and / or filler, and disintegrant are mixed, crushed to obtain fine powder of celery and sophora extract, and then subjected to the wet granulation process of making soft material, drying, granulating, mixing, and capsule filling. Compared with the dry granulation process of the prior art, the wet granulation process has the following advantages:

[0086] 1) In the wet granulation process, water plays the role of a wetting agent. When the fine powder of the celery and sophora japonica extract is fully mixed with the auxiliary materials, the granulation process is controllable, drying is easy, and the obtained granules have good disintegration performance and high solubility. In addition, the uniformity and bulk density of the material are improved, which is suitable for mass production of the product of the present invention;

[0087] 2) Using water as solvent is environmentally friendly and economical, does not pollute the environment, and evenly disperses surfactants;

[0088] 3) The product has excellent stability, the content does not decrease after long-term storage, and the dissolution rate remains basically unchanged. Specific implementation plan

[0089] In the following specific embodiments, the solubility of the total flavonoids, the active ingredient in the pharmaceutical composition of the present invention, is determined by a method disclosed in the prior art, for example, by the "Dissolution and Release Determination Method" (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules, 0931, Method 1). Wherein:

[0090] 1. Dissolution conditions: Use 500 ml of pH 6.8 phosphate as the dissolution medium, the rotation speed is 50 revolutions per minute, and the capsules need to be added with sedimentation blue. Operate according to the law. At the specified time point, take 10 ml of the solution, filter it, and keep the filtrate for later use.

[0091] 2. Determination of the dissolution rate of total flavonoids: Take the filtrate from the first step and determine and calculate the dissolution rate at each time point according to the "Ultraviolet-Visible Spectrophotometry" (General Principles 0401, Volume IV, Chinese Pharmacopoeia 2020 Edition).

[0092] For the specific determination method and operation of total flavonoids, refer to "Determination of Total Flavonoids Content in Sophora japonica - Chinese Pharmacopoeia 2020 Edition".

[0093] Examples of the present invention are as follows:

[0094] Example 1 Preparation of celery - sophora japonica extract

[0095] It is prepared according to the preparation method of celery seed - sophora japonica extract in Chinese Patent CN107362194A (ZL201610313303.8). The ratio of celery seeds to sophora japonica in the celery - sophora japonica extract is 2:1 - 4:1.

[0096] Examples 2 - 6 Crushing of celery - sophora japonica extract

[0097] In Example 2, 14 kg of celery - sophora japonica extract was crushed using a hammer mill without a sieve to obtain a crude powder of celery - sophora japonica extract.

[0098] In Example 3, the crude powder of celery - sophora japonica extract obtained in Example 2 was crushed using a hammer mill equipped with a 0.7 mm sieve, and the situation of screen clogging occurred after crushing 0.5 kg.

[0099] In Example 4, the crude powder of celery - sophora japonica extract obtained in Example 2 was continuously crushed using a hammer mill equipped with a 1.0 mm sieve, and the situation of screen clogging occurred after crushing 2 kg.

[0100] In Example 5, the crude powder of celery - sophora japonica extract obtained in Example 2 was continuously crushed using a hammer mill equipped with a 1.5 mm sieve, and the situation of screen clogging occurred after crushing 5 kg.

[0101] In Example 6, the crude powder of celery - sophora japonica extract obtained in Example 2 was crushed using a hammer mill equipped with a 2.5 mm sieve without screen clogging. The particles in the collection bag were sieved, and the proportion passing through an 80 - mesh sieve was 2%.

[0102] Examples 2 - 6 show that when crushing celery - sophora japonica extract using a hammer mill, the finer the sieve installed, the easier it is to clog the screen and the more difficult the crushing. When using a 2.5 mm sieve or a sieve with a pore size larger than 2.5 mm for crushing, although there is no screen clogging, the obtained particles are too large, resulting in problems such as uneven mixing and difficult dissolution of the preparation.

[0103] Examples 7 - 10 Crushing of celery - sophora japonica extract with fillers and disintegrants

[0104] Example 7: 20 kg of celery sophora extract was pulverized twice using a hammer mill without a sieve to obtain a crude powder of celery sophora extract.

[0105] Example 8: After mixing 2 kg and 0.5 kg of microcrystalline cellulose (extract: filler = 4:1, excipients accounting for 20%), it was pulverized once using a 0.7 mm sieve, with slight sieve clogging, and the proportion of fine powder passing through an 80-mesh sieve was 38%.

[0106] Example 9: After mixing 2 kg of the crude powder of celery sophora extract from Example 7 and 1 kg of microcrystalline cellulose (extract: filler = 2:1, excipients accounting for 33%), it was pulverized once using a 0.7 mm sieve, and no sieve clogging occurred. The proportion of fine powder passing through an 80-mesh sieve was 50%.

[0107] Example 10: After mixing 2 kg of the crude powder of celery sophora extract from Example 7, 1 kg of microcrystalline cellulose, and 0.2 kg of low-substituted hydroxypropyl methylcellulose (extract: filler: disintegrant = 20:10:2, excipients accounting for 37.5%), it was pulverized once using a 0.7 mm sieve, and no sieve clogging occurred. The proportion of fine powder passing through an 80-mesh sieve was 54%. The collected fine powder was pulverized again using a 0.7 mm sieve, and the proportion of fine powder passing through an 80-mesh sieve was 58%.

[0108] Result analysis: Examples 8 - 10 show that after mixing the crude powder of celery sophora extract with excipients such as fillers and disintegrants, the pulverizability of celery sophora extract is improved, enabling the smooth pulverization of celery sophora extract, avoiding sieve clogging, and obtaining finer fine powder of celery sophora extract.

[0109] Examples 11 - 12: Pulverize the celery sophora extract with an anti-adhesive agent

[0110] Example 11: After mixing 2 kg of the crude powder of celery sophora extract from Example 7 and 0.1 kg of silicon dioxide (extract: anti-adhesive agent = 20:1), it was pulverized using a 1.0 mm sieve, and the proportion of fine powder passing through an 80-mesh sieve was 20% (excipients accounting for 5%).

[0111] Example 12: After mixing 2 kg of the crude powder of celery sophora extract from Example 7 and 0.2 kg of silicon dioxide (extract: anti-adhesive agent = 10:1), it was pulverized once using a 1.0 mm sieve, and the proportion of particles passing through an 80-mesh sieve was 43% (excipients accounting for 9%). It was pulverized again using a 0.7 mm sieve, and the proportion of fine powder passing through an 80-mesh sieve was 65%. It was pulverized again using a 0.5 mm sieve, and the proportion of fine powder passing through an 80-mesh sieve was 85%.

[0112] Result analysis: Examples 11 - 12 show that the anti-adhesive agent can greatly improve the pulverizability of celery sophora extract, and the greater the dosage, the better the pulverization effect.

[0113] Examples 13 - 14: Pulverize the celery sophora extract with an anti-adhesive agent, filler, and disintegrant

[0114] Example 13: 2 kg of the crude powder of Qinhai extract from Example 7, 0.2 kg of silicon dioxide, 0.25 kg of microcrystalline cellulose, and 0.2 kg of low-substituted hydroxypropyl methylcellulose were mixed (extract: anti-adhesive, filler: disintegrant = 40:4:5:4). It was pulverized once using a 1.0 mm sieve, and the proportion of particles passing through an 80-mesh sieve was 63% (auxiliary materials accounted for 25%). It was pulverized again using a 0.7 mm sieve, and the proportion of fine powder passing through an 80-mesh sieve was 83% (auxiliary materials accounted for 25%). It was pulverized again using a 0.5 mm sieve, and the proportion of fine powder passing through an 80-mesh sieve was 92% (auxiliary materials accounted for 25%).

[0115] Example 14: 2 kg of the crude powder of Qinhai extract from Example 7, 1 kg of lactose, 0.2 kg of silicon dioxide, 0.25 kg of microcrystalline cellulose, and 0.2 kg of low-substituted hydroxypropyl methylcellulose were mixed. It was pulverized once using a 1.0 mm sieve, and the proportion of particles passing through an 80-mesh sieve was 73% (auxiliary materials accounted for 45%). It was pulverized again using a 0.7 mm sieve, and the proportion of fine powder passing through an 80-mesh sieve was 93%. It was pulverized again using a 0.5 mm sieve, and the proportion of fine powder passing through an 80-mesh sieve was 97%.

[0116] Examples 13 - 14 show that after the Qinhai extract is mixed with anti-adhesives, fillers, and disintegrants, the grindability of the Qinhai extract can be significantly improved, and the pulverization effect is obvious.

[0117] Example 15

[0118] (1) Formulation 1

[0119]

[0120]

[0121] Note: Water is removed during the drying process

[0122] (2) Preparation process

[0123] The Qinhai extract obtained in Example 1 was pulverized without a sieve and reserved. Weighed and taken were the Qinhai extract, silicon dioxide, low-substituted hydroxypropyl cellulose, lactose, and microcrystalline cellulose in the amount of Formulation 1, and after mixing, they were pulverized successively using a hammer mill with 1.5 mm, 1.0 mm, and 0.5 mm sieves to obtain a powder. It was measured that the proportion of the powder passing through an 80-mesh sieve was 95%.

[0124] Weighed and taken was the prescription amount of polysorbate 80, added to an appropriate amount of water and stirred until dissolved, and reserved. The powder was placed in a wet granulator for mixing, and an aqueous solution containing polysorbate 80 was spray-added to make soft materials. The wet granules were transferred to a fluidized bed for drying, and granulation was carried out using a 1.5 mm sieve to obtain Qinhai granules.

[0125] After detection, the bulk density of the above-mentioned Qinhuai granules is 0.56 g / ml, and the particle size distribution is as follows: the proportion of particles larger than 30 mesh is 14.80%; the proportion of particles between 30 - 50 mesh is 32.10%; the proportion of particles between 50 - 80 mesh is 19.24%; the proportion of particles smaller than 80 mesh is 31.48%. The Qinhuai granules have good fluidity, and the angle of repose is 34°.

[0126] The Qinhuai granules were placed in a hopper mixer, and the prescribed amount of sodium bicarbonate was added for premixing for 20 min, and then the prescribed amount of magnesium stearate was added for total mixing for 5 min, and they were reserved for use.

[0127] The total mixed granules were placed in a capsule filling machine and filled into size 0 capsules, with each capsule containing 0.45 g, and the weight difference was ±10%, thus obtaining the product.

[0128] The experimental results of the disintegration time limit and dissolution rate: The capsules disintegrated completely within 8 min. The dissolution rates of total flavonoids at 30 minutes and 60 minutes in the aqueous medium were 92% and 95% respectively. It shows that the wet granulation process for Formulation 1 is feasible. This process is simple and easy to control, and the dissolution rate of the prepared Qinhuai capsules is very good, which is suitable for large-scale production.

[0129] Example 16

[0130] Based on the formulation of Example 15, the prescribed amount of Qinhuai extract and silicon dioxide were weighed and mixed, and then crushed successively with 1.0 mm and 0.7 mm sieves using a hammer mill to obtain powder. It was measured that the proportion of the powder passing through an 80-mesh sieve was 70%. The obtained powder, low-substituted hydroxypropyl cellulose, lactose, and microcrystalline cellulose were placed in a wet granulator for mixing, and the other preparation processes were the same as those in Example 15 to obtain Qinhuai capsules.

[0131] Example 17

[0132] Based on the formulation of Example 15, the Qinhuai extract was crushed using a 1.0 mm sieve with a hammer mill, and the fine particles that did not clog the sieve in the collection bag were collected and reserved for use. It was measured that the proportion of the fine particles passing through an 80-mesh sieve was 5%. The obtained fine particles, silicon dioxide, low-substituted hydroxypropyl cellulose, lactose, and microcrystalline cellulose were placed in a wet granulator for mixing, and the other preparation processes were the same as those in Example 15 to obtain Qinhuai capsules.

[0133] Example 18

[0134] Based on the formulation of Example 15, the prescribed amount of Qinhuai extract, silicon dioxide, low-substituted hydroxypropyl cellulose, lactose, and microcrystalline cellulose were weighed and mixed, and then crushed successively with 1.5 mm, 1.0 mm, and 0.7 mm sieves using a hammer mill to obtain powder. It was measured that the proportion of the powder passing through an 80-mesh sieve was 62%. The obtained powder was placed in a wet granulator for mixing, and the other preparation processes were the same as those in Example 15 to obtain Qinhuai capsules.

[0135] Examples 15 - 18 are based on the formulation of Example 15. The pulverization methods of the celery and sophora flower extract and excipients are changed, while other preparation processes remain unchanged. Celery and sophora flower capsules are prepared, and their total flavonoid dissolution is investigated. The results are shown in the following table:

[0136]

[0137] The dissolution results of Examples 15 - 18 show that the finer the celery and sophora flower extract is pulverized, the better the dissolution of the prepared celery and sophora flower capsules. It is difficult to pulverize the celery and sophora flower extract alone into fine powder; when the celery and sophora flower extract and excipients are mixed and pulverized together, the problem of difficult pulverization can be solved. The anti-adhesive agent (such as silicon dioxide) in the excipients has the most significant effect on pulverizing the celery and sophora flower extract, followed by the disintegrant and filler (such as microcrystalline cellulose).

[0138] Examples 19 - 26 investigate the effect of the dosage change of polysorbate 80 on the capsules of the celery and sophora flower extract pharmaceutical composition

[0139] Examples 19 - 24 are based on the formulation of Example 15. The dosage of polysorbate 80 is changed, while the feeding amounts of other raw and auxiliary materials remain unchanged. Celery and sophora flower capsules are prepared according to the formulation process of Example 16, and their total flavonoid dissolution is investigated. The results are shown in the following table:

[0140]

[0141] From the total flavonoid dissolution results of the prescription screening in the above table, it can be known that as the dosage of polysorbate 80 in the celery and sophora flower capsules increases, the total flavonoid dissolution first increases and then remains unchanged.

[0142] Examples 27 - 32 investigate the effect of the dosage change of the effervescent agent on the celery and sophora flower capsules

[0143] Examples 27 - 32 are based on the formulation of Example 15. The dosage of the alkaline effervescent disintegrant is changed, while the feeding amounts of other raw and auxiliary materials remain unchanged. Celery and sophora flower capsules are prepared according to the formulation process of Example 15, and their total flavonoid dissolution is investigated. The results are shown in the following table:

[0144]

[0145] From the prescription screening results in the above table, it can be known that as the dosage of the effervescent disintegrant in the celery and sophora flower capsules increases, the dissolution of its total flavonoid within 60 minutes is greater than 85%, and it is basically completely dissolved.

[0146] In Example 33, the silicon dioxide in Example 15 is replaced with colloidal silicon dioxide (fumed silica)

[0147] Based on the formulation of Example 15, weigh the prescription amounts of Qinhuai extract, colloidal silicon dioxide, low-substituted hydroxypropyl cellulose, lactose, and microcrystalline cellulose. After mixing, use a hammer mill to crush them successively through 1.5 mm, 1.0 mm, and 0.5 mm sieves to obtain a powder. It is measured that the proportion of the powder passing through an 80-mesh sieve is 100%.

[0148] The obtained powder is placed in a wet granulator for mixing, and other preparation processes are the same as those in Example 15 to prepare Qinhuai capsules.

[0149] In Example 34, the silicon dioxide in Example 16 is replaced with colloidal silicon dioxide.

[0150] Based on the formulation of Example 15, weigh the prescription amounts of Qinhuai extract and colloidal silicon dioxide. After mixing, use a hammer mill to crush them successively through 1.0 mm and 0.7 mm sieves to obtain a powder. It is measured that the proportion of the powder passing through an 80-mesh sieve is 85%. The obtained powder, low-substituted hydroxypropyl cellulose, lactose, and microcrystalline cellulose are placed in a wet granulator for mixing, and other preparation processes are the same as those in Example 15 to prepare Qinhuai capsules.

[0151] In Examples 33 - 34, the silicon dioxide in Examples 15 and 16 is respectively replaced with colloidal silica, and other prescriptions and processes remain unchanged. The dissolution results of the prepared Qinhuai capsules are as follows:

[0152]

[0153] From the prescription screening results in the above table, it can be seen that after replacing silicon dioxide with colloidal silicon dioxide, the crushing effect is better, and the dissolution rate of the total flavonoids in the prepared Qinhuai capsules is greater than 95% within 30 minutes, and the dissolution and release rate is faster, approaching complete dissolution.

Claims

1. A pharmaceutical composition for treating gout and hyperuricemia, characterized in that by weight percentage, the pharmaceutical composition consists of the following components: celery and sophora flower extract: 20 - 80%, anti-adhesive agent: 0 - 20%, filler: 0 - 75%, surfactant: 0.1 - 5%, disintegrant: 2 - 16%, alkaline effervescent agent: 0 - 10%, lubricant: 0.5 - 5%.

2. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition consists of the following components: celery and sophora flower extract: 40 - 60%, anti-adhesive agent: 2 - 10%, filler: 10 - 45%, surfactant: 0.2 - 3%, disintegrant: 2 - 10%, alkaline effervescent agent: 3 - 8%, lubricant: 0.5 - 2%.

3. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition consists of the following components: celery and sophora flower extract: 50%, anti-adhesive agent: 3 - 7%, filler: 25 - 35%, surfactant: 0.3 - 1%, disintegrant: 3 - 5%, alkaline effervescent agent: 6 - 7%, lubricant: 0.8 - 1%.

4. The pharmaceutical composition according to claim 1, characterized in that the anti-adhesive agent is selected from silicon dioxide or colloidal silicon dioxide; the surfactant is selected from one or more mixtures of polysorbate 80, poloxamer, and lecithin, preferably polysorbate 80; the disintegrant includes one or more mixtures of starch, pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, and cross-linked sodium carboxymethyl cellulose; preferably low-substituted hydroxypropyl cellulose.

5. The pharmaceutical composition according to claim 1, characterized in that the alkaline effervescent agent is selected from carbonates, including one or more of sodium carbonate, sodium bicarbonate, calcium carbonate, potassium carbonate, and potassium bicarbonate, preferably sodium bicarbonate; the lubricant is selected from one or more of magnesium stearate and stearic acid, preferably magnesium stearate; the filler is selected from one or more mixtures of lactose, microcrystalline cellulose, mannitol, and glucose, preferably lactose and microcrystalline cellulose.

6. The preparation method of the pharmaceutical composition according to claim 1, characterized in that the method comprises the following steps: (1) Preliminarily crush the celery and sophora flower extract to obtain coarse powder particles of the celery and sophora flower extract; weigh the coarse powder particles of the celery and sophora flower extract, anti-adhesive agent and / or filler, and disintegrant, mix them to obtain a mixed powder; place the mixed powder in a hammer mill for crushing to obtain fine powder; (2) Dissolve the surfactant in a solvent for later use; place the fine powder obtained in step (1) in a high-speed mixer granulator, mix, add the solvent solution containing the surfactant, stir to make a soft material, dry, and size the particles to obtain granules; (3) Mix the granules obtained in step (2) evenly with the excipients in the prescription except for the lubricant, and then add the lubricant for total mixing to obtain total mixed granules; (4) Fill the total mixed granules into pharmaceutical capsules.

7. The preparation method of the pharmaceutical composition according to claim 1, characterized in that When preparing the mixed powder in step (1), the mixing method includes the following: Weigh the crude powder particles of Qinhuai extract, mix them with an anti-adhesive agent, or with a filler, a disintegrant, or with an anti-adhesive agent, a filler and a disintegrant, and then use a hammer mill to crush to obtain a fine powder; preferably weigh the crude powder particles of Qinhuai extract and mix them with an anti-adhesive agent or with an anti-adhesive agent, a filler and a disintegrant, and more preferably mix them with an anti-adhesive agent, a filler and a disintegrant to obtain a mixed powder; then use a hammer mill to crush to obtain a fine powder.

8. The preparation method of the Qinhuai extract pharmaceutical composition according to claim 6, characterized in that the screen used when the hammer mill crushes the mixed powder in step (1) has a screen aperture of 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.0 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm or 1.5 mm; one or more of the screens are used for crushing once or multiple times.

9. The preparation method of the Qinhuai extract pharmaceutical composition according to claim 6, characterized in that the proportion of the powder passing through an 80-mesh sieve after crushing in step (1) is > 75%; preferably the proportion passing through an 80-mesh sieve is > 80%; more preferably the proportion passing through an 80-mesh sieve is > 85%; still more preferably the proportion passing through an 80-mesh sieve is > 90%; even more preferably the proportion passing through an 80-mesh sieve is > 95%; most preferably all pass through an 80-mesh sieve.

10. The preparation method of the Qinhuai extract pharmaceutical composition according to claim 6, characterized in that the aperture of the sieving screen in step (2) is 0.5 - 2.5 mm, preferably 1.0 - 2.0 mm, and more preferably 1.5 mm.

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