A gardenia and fermented soybean soup water extract, granules, and application and preparation method thereof

Abstract

The application relates to a water extract of Zhizi Chi Tang, granules and application and preparation method thereof. Zhizi Chi Tang dry extract powder is mixed with a diluent to obtain a base material; a wetting agent is added into the base material to obtain soft material; the soft material is sieved through a first sieve screen to obtain wet granules; the wet granules are dried to obtain dry material; and the dry material is whole-granulated through a second sieve screen to obtain dry granules. The water extract of Zhizi Chi Tang contains at least iridoid, isoflavone, organic acid, crocin and other substances, and has remarkable efficacy on the treatment of depression. The application reforms the dosage form of Zhizi Chi Tang by means of modern scientific research technology and method, adopts wet granulation as a granulation technology, and selects and optimizes the types of auxiliary materials and the proportion of medicine and auxiliary materials by taking the granulation of soft material, granule hardness, granule appearance, and granule yield as indexes, and the drying temperature of the granules is investigated to optimize the better forming process of the Zhizi Chi Tang granules.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of traditional Chinese medicine research and development, and particularly relates to a Zijizi Chishui decoction water extract for treating depression, granules, and application and preparation method thereof. BACKGROUND

[0002] Depression is a common, high recurrence rate and extremely harmful emotional mental disorder disease, which is characterized by significant and persistent low mood, slow thinking, reduced language and action, or persistent significant nervousness accompanied by excitation and excessive vigilance of autonomic nervous function. Modern medical research has proved that Zijizi Chishui decoction has significant effect on treating depression.

[0003] The dosage form is one of the traditional Chinese medicine factors affecting the quality of new traditional Chinese medicine drugs. Generally, the clinical use demand, clinical drug dosage, and patient compliance should be considered to select the administration route and determine the dosage form. However, at present, the research and application thereof are mostly limited to the ancient decoction method, which has the defects of long decoction time, large dosage, inconvenience in taking and carrying, difficulty in storage, easy moldiness and deterioration after long storage, and cannot adapt to the modern fast-paced life.

[0004] Traditional Chinese medicine granules are developed on the basis of traditional Chinese medicine decoction, which plays the advantages of modern dosage forms on the basis of retaining the characteristics and advantages of the original prescription, has the characteristics of fast absorption and fast effect of decoction, and avoids the trouble of decoction. Through modern extraction and concentration, the curative effect of the prescription can be guaranteed, the quality of the preparation can be controlled, and the stability of the preparation is enhanced.

[0005] Therefore, the technical personnel in the art are committed to developing a preparation process of Zijizi Chishui decoction with clear investigation indexes. SUMMARY

[0006] In view of the above defects of the prior art, the present application reforms the dosage form of Zijizi Chishui decoction by means of modern scientific research technology and method, adopts wet granulation as the granulation technology, and selects and optimizes the types of excipients and the ratio of medicine to excipient by taking the granulation of soft material, granule hardness, granule appearance, and granule yield as the investigation indexes, and investigates the drying temperature of the granules to optimize the better forming process of Zijizi Chishui decoction granules.

[0007] The present application provides a preparation method of Zijizi Chishui decoction granules, which comprises the following steps: mixing Zijizi Chishui decoction dry extract powder and diluent to obtain base material to increase the weight of the granules; adding wetting agent to the base material to obtain soft material, so that the solid powder is bonded and formed to facilitate granulation; screening the soft material through a first screen to obtain wet granules; drying the wet granules to obtain dry material to control the drying degree of the granules; and screening the dry material through a second screen to obtain dry granules.

[0008] In some embodiments, the soft material is further mixed with a sweetener before being sieved.

[0009] In some embodiments, the drying of the wet particles further comprises gradually increasing the drying temperature to avoid the formation of a hard film on the surface of the particles, which would hinder the evaporation of the internal moisture.

[0010] In some embodiments, the same diluent, the same sweetener, the same first sieve, the same second sieve, and different concentrations and amounts of the wetting agent are used, and the concentration and amount of the wetting agent are determined according to the particle hardness, appearance, and particle yield of the dry particles.

[0011] In some embodiments, the same diluent, the same wetting agent, the same first sieve, the same second sieve, and different concentrations and amounts of the sweetener are used, and the concentration and amount of the sweetener are determined according to the sweetness of the dry particles.

[0012] In some embodiments, the same diluent, the same wetting agent, the same first sieve, the same second sieve, and different amounts of the sweetener are used, and the amount of the sweetener is determined according to the sweetness of the dry particles.

[0013] In some embodiments, the same diluent, the same wetting agent, the same first sieve, the same second sieve, and different drying temperatures are used, and the drying temperature is determined according to the particle hardness and appearance of the dry particles.

[0014] In some embodiments, the diluent comprises one or more of the following: starch, lactose, dextrin, sugar powder, calcium sulfate, sucrose, mannitol, microcrystalline cellulose, glucose.

[0015] In some embodiments, the mass ratio of the dry paste powder to the diluent ranges from 1:1 to 1:3, preferably 1:2.

[0016] In some embodiments, the wetting agent comprises one or more of the following: distilled water, ethanol.

[0017] In some embodiments, the concentration of the wetting agent ranges from 50% to 99%, preferably 95%.

[0018] In some embodiments, the mass ratio of the dry paste powder to the wetting agent ranges from 1:0.5 to 1:2, preferably 1:1.2.

[0019] In some embodiments, the sweetener includes one or more of aspartame, steviol glycosides, sucrose, sorbitol, xylitol, monosaccharide syrup, mannitol, sodium saccharin, aspartame, sucralose, glucose, maltitol, erythritol, linumol, glucitol, lactose, etc.

[0020] In some embodiments, the sweetener is used in an amount ranging from 0.01% to 0.6% of the total amount of the pharmaceutical excipients, preferably 0.02%. The total amount of the pharmaceutical excipients refers to the total amount of the pharmaceutical materials and the pharmaceutical excipients. In the present application, the pharmaceutical materials include the dried powder of Zhizi Chishang Decoction, and the pharmaceutical excipients include diluents, wetting agents, sweeteners, etc.

[0021] In some embodiments, the drying temperature ranges from 50 degrees Celsius to 100 degrees Celsius, preferably 80 degrees Celsius.

[0022] In some embodiments, the mesh number of the first sieve is greater than that of the second sieve. The mesh number of the filter screen (also called sieve) refers to the number of mesh holes contained in 1 inch (25.4 mm) length. The greater the mesh number, the smaller the aperture, and the smaller the particles obtained by passing through the sieve.

[0023] In some embodiments, the mesh number of the first sieve is 16, and the mesh number of the second sieve is 14.

[0024] The present application also provides a water extract of Zhizi Chishang Decoction for treating depression, which includes iridoid substances, isoflavone substances, organic acid substances, and crocin substances.

[0025] In some embodiments, the iridoid substances include shanzhiside, methyl isoacetyl rutinate, hydroxyisogitoxin, mack, genipin-1-β-gentiopicroside, and gardenoside.

[0026] In some embodiments, the content of shanzhiside is not less than 0.3%, the content of methyl isoacetyl rutinate is not less than 0.2%, the content of hydroxyisogitoxin is not less than 0.4%, the content of mack is not less than 0.15%, the content of genipin-1-β-gentiopicroside is not less than 0.7%, and the content of gardenoside is not less than 6%.

[0027] In some embodiments, the isoflavone substances include daidzin, glycitin, genistin, daidzein, glycitein, and genistein.

[0028] In some embodiments, the content of daidzin is not less than 0.08%, the content of glycitin is not less than 0.02%, the content of genistin is not less than 0.3%, the content of daidzein is not less than 0.04%, the content of glycitein is not less than 0.07%, and the content of genistein is not less than 0.1%.

[0029] In some embodiments, optionally, the crocin includes crocin.

[0030] In some embodiments, optionally, the crocin content is not less than 0.05%.

[0031] In some embodiments, optionally, the crocin includes crocin.

[0032] The application also provides a use of the Zhizi Chi Tang in the preparation of a medicament for treating depression, wherein the Zhizi Chi Tang is prepared into granules for treating depression, and the Zhizi Chi Tang granules include iridoid substances, isoflavone substances, organic acid substances, and crocin.

[0033] In some embodiments, optionally, the iridoid substances include shanzhiside, methyl aescinate, methyl jasminoidin, geniposidic acid, geniposide, and forsythoside.

[0034] In some embodiments, optionally, the isoflavone substances include daidzin, glycitin, genistin, daidzein, glycitein, and genistein.

[0035] In some embodiments, optionally, the crocin includes crocin.

[0036] In some embodiments, optionally, the Zhizi Chi Tang granules further include one or more of the following substances: methyl shanzhiside, loganin, geniposidic acid, geniposide, quinic acid, and chlorogenic acid.

[0037] Some technical solutions are to prepare the Zhizi Chi Tang into a decoction, but this method has no clear control index, the obtained decoction has poor taste, and the decoction is time-consuming to prepare, not easy to store, easy to deteriorate after long storage, and inconvenient to transport, store, take, and carry.

[0038] The technical solutions provided by the application have at least the following improvements over the prior art: the Zhizi Chi Tang is prepared into granules, and the excipients used in the preparation process are step by step screened and optimized, and each process has specific investigation indexes.

[0039] Each screening process in this invention has clear evaluation indicators, which can retain the characteristics of the original formula while giving full play to the advantages of modern dosage forms. It has the characteristics of rapid absorption and fast effect of decoction, eliminating the trouble of decoction before use, and solving the problems of long decoction time and easy mold and spoilage after long storage. It is easy to control in terms of production, transportation, storage and quality, with stable quality and better taste of granules.

[0040] The technical solution of the present invention addresses the problem that existing technical solutions are too simplistic and provides a solution that is significantly different from existing technologies.

[0041] The following will further explain the concept, specific structure, and technical effects of the present invention in conjunction with the accompanying drawings, so as to fully understand the purpose, features, and effects of the present invention. Attached Figure Description

[0042] The invention will become more readily understood when read in conjunction with the accompanying drawings, in which the same reference numerals denote the same objects, wherein:

[0043] Figure 1 This is a schematic diagram illustrating the selection of diluent types and proportions in this invention.

[0044] Figure 2 This is a schematic diagram illustrating the investigation of wetting agent concentration and dosage in this invention.

[0045] Figure 3 This is a schematic diagram illustrating the investigation of the amount of sweetener used in this invention.

[0046] Figure 4 This is a schematic diagram of the particle drying temperature investigation in this invention.

[0047] Figure 5 This is a schematic diagram illustrating the change in immobility time during forced swimming in the present invention.

[0048] Figure 6 This is a schematic diagram illustrating the change in the percentage of sucrose preference of rats in this invention.

[0049] Figure 7 This is a schematic diagram illustrating the change in the immobility time of a rat's suspended tail in this invention.

[0050] Figure 8A and Figure 8B This is a schematic diagram showing the 5-HT content in rat tissues in this invention, wherein, Figure 8A This is a diagram showing the 5-HT content in brain tissue. Figure 8B Image showing 5-HT levels in blood, Mean+SEM, n=6. Detailed Implementation

[0051] The technical solutions in the embodiments of the present application will be described clearly and completely below. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. The present application can be embodied in many different forms and the protection scope of the present application is not limited to the embodiments described herein. Based on the embodiments of the present application, all other embodiments obtained by a person of ordinary skill in the art without creative effort should fall within the protection scope of the present application.

[0052] The techniques, methods, and devices known to those of ordinary skill in the relevant art can not be discussed in detail herein, but should be considered as part of the description when appropriate.

[0053] Various specific embodiments of the present application will be described below with reference to the accompanying drawings, which are incorporated in and constitute a part of this specification. It should be understood that, although terms indicating directions, such as "front", "back", "up", "down", "left", "right", "inner", "outer", "top", "bottom", "positive", "negative", "proximal", "distal", "lateral", "longitudinal", "width direction", "length direction", "height direction", "axial", "radial", "clockwise", "counterclockwise", and the like are used in the present application to describe various example structural parts and elements of the present application, these terms are used herein only for the purpose of convenience of description and are determined based on the example orientation shown in the drawings. The embodiments disclosed in the present application can be arranged in different directions, so these terms indicating directions are only for illustration and should not be considered as limitation.

[0054] For the purpose of description, the connection relationship between each module or part shown in the drawings is only an example of description, and a person of ordinary skill in the art can also use other equivalent connection relationship, as long as each module or part can also realize the function of the technical solution of the present application under such connection relationship. The embodiments disclosed in the present application can be arranged in different equivalent connection relationship, so the connection relationship shown in the drawings and the related content of the specification is only for illustration and should not be considered as limitation.

[0055] The size of each component shown in the drawings is arbitrarily shown, and the present application does not limit the specific size of each component, unless explicitly stated or described in the specification and drawings. In order to make the drawing clearer, the size of the component or the corresponding proportion relationship is appropriately exaggerated in some places in the drawings.

[0056] The ordinal numbers such as "first" and "second" used in the present application are merely used to distinguish and identify, and do not have any other meanings, and do not indicate a specific order or have a specific association unless specifically indicated. For example, the term "first component" does not imply the existence of "second component" by itself, and the term "second component" does not imply the existence of "first component" by itself.

[0057] The singular forms "a", "said", and "the" and other similar descriptions used in the present application are intended to include both singular and plural forms unless the context clearly indicates otherwise. "Plural" or "multiple" generally includes at least two or at least two. The term "and / or" used in the present application is merely a description of the association relationship of the associated objects, which means that there can be three relationships, for example, A and / or B, which means that there are three cases of A alone, A and B together, and B alone. In addition, the character " / " in the present application generally represents an "or" relationship between the front and rear associated objects.

[0058] The terms "include", "contain" or any other variants thereof are intended to cover non-exclusive inclusion, so that the process, method, article or device including a series of elements not only includes those elements, but also includes other elements not explicitly listed or inherent to such process, method, article or device. Without more limitation, the element defined by the statement "including a" does not exclude the presence of another identical element in the process, method, article or device including the element.

[0059] Granulation technology is a technology for processing materials in the state of powder, molten liquid, aqueous solution, etc. into granular materials of certain shape and size. The advantages of granulation: improve flowability, facilitate packaging and tabletting; prevent segregation of components due to differences in particle size and density; prevent dust flying and adhesion on the wall; adjust bulk density and improve dissolution performance; improve the uniformity of pressure transmission in tablet production; facilitate taking and carrying, and improve commodity value.

[0060] The present application prepares the granules on the basis of Zhizi Chisheng Tang dry granules, and the excipients are screened and optimized step by step in the granulation process, and finally a better molding process is obtained. Each step in this process has a clear investigation index to ensure that the better process is stable and feasible. Sweeteners are added to improve the taste, so that the medicine taste is not too bitter, and the drug compliance is increased.

[0061] Granules refer to dry granular preparations prepared from drugs and suitable excipients. The particle size of granules is clearly specified in the Chinese Pharmacopoeia 2020 edition: the total amount of particles that cannot pass through a No. 1 sieve and can pass through a No. 5 sieve should not exceed 15% (the general internal control standard is 10%). Granulation is required for all granules, and the one-time granulation qualification rate is required to be high. Various factors should be considered comprehensively, and the granulation prescription should be determined through tests.

[0062] The main substance components in Zhizi Chisheng Tang granules include gardenoside, daidzin, daidzein, genistin, and genistein. Zhizi Chisheng Tang is composed of two traditional Chinese medicines, gardenia and soybean, and the main component in gardenia is iridoid glycoside. Gardenoside is the main component for exerting pharmacological effects, accounting for more than 70% of iridoid glycoside. The representative component in soybean that exerts physiological activity is soybean isoflavone, and its activity mainly reflects in daidzin, daidzein, genistin, and genistein, among which daidzein and genistein have higher physiological activity. The combination of the two drugs can reduce toxicity. In some embodiments, gardenoside and daidzein can be selected as index components for evaluation. The content of gardenoside in the granules is 1.13%, and the content of daidzein is 0.0144%.

[0063] The dosage form of Zhizi Chisheng Tang is reformed in the present application. The types and proportions of diluents, the concentration of wetting agents, and the amount of sweeteners are screened and optimized. After obtaining a better molding process, the drying temperature is investigated. In some embodiments, the order of the diluent, the wetting agent, the sweetener, and the drying temperature is determined in turn. This order is the process flow of granule preparation. In this process, the single-factor control variable method is used to determine the optimal type or amount of different excipients in turn. In the process flow of granule preparation, the subsequent process is carried out on the basis of the previous process. That is, the parameters of the subsequent process are affected by the related parameters of the previous process. According to the order of the process flow of granule preparation, the corresponding parameters are investigated and determined in turn, which is conducive to improving the accuracy and stability of the investigation results.

[0064] The diluent can use one or more of the following: starch, lactose, dextrin, sugar powder, calcium sulfate, sucrose, mannitol, microcrystalline cellulose, glucose;

[0065] The wetting agent can use one or more of the following: distilled water, ethanol;

[0066] The sweetener can use one or more of the following: aspartame, stevioside, sucrose, sorbitol, xylitol, monosaccharide syrup, mannitol, sodium saccharin, aspartame, sucralose, glucose, maltitol, erythritol, linamaritol, glucose, lactose, etc.

[0067] The present application provides a preparation method of Zhizi Chisheng Tang granules, which can include the following steps:

[0068] Step 1, diluent type and amount investigation (diluent is used to increase the weight of the particles).

[0069] (1) Take multiple portions of gardenia soybean soup dry extract powder and mix with soluble starch and dextrin at a ratio of 1:1, 1:1.5, and 1:2;

[0070] (2) Use 95% ethanol as a wetting agent and use a 16-mesh sieve to granulate, and observe the granulation situation;

[0071] (3) Place the wet granules into an electric heating air drying oven at 60°C for drying, and the drying temperature should be gradually increased to avoid the formation of a hard film on the surface of the particles, which would affect the evaporation of internal moisture;

[0072] (4) After drying is complete, use a 14-mesh sieve to size the particles, observe the hardness and appearance of the particles, and calculate the particle yield, and select the preferred diluent type and ratio.

[0073] Step 2, wetting agent investigation (make the solid powder stick together to facilitate granulation).

[0074] (1) Take multiple portions of gardenia soybean soup dry extract powder and mix with dextrin at a ratio of 1:2;

[0075] (2) Add different concentrations of ethanol (50%-90%) as a wetting agent, and use a 16-mesh sieve to granulate, and observe the granulation situation;

[0076] (3) Place the wet granules into an electric heating air drying oven at 80°C for drying, and the drying temperature should be gradually increased to avoid the formation of a hard film on the surface of the particles, which would affect the evaporation of internal moisture;

[0077] (4) After drying is complete, use a 14-mesh sieve to size the particles, observe the hardness and appearance of the particles, and calculate the particle yield, and select the preferred wetting agent concentration.

[0078] Step 3, sweetener amount investigation (improve the taste of the particles).

[0079] (1) Take multiple portions of gardenia soybean soup dry extract powder and mix with dextrin at a ratio of 1:2;

[0080] (2) Add 95% ethanol as a wetting agent, and add different proportions of sweeteners (0.01%-0.50%), and use a 16-mesh sieve to granulate;

[0081] (3) Place the wet granules into an electric heating air drying oven at 60°C for drying, and the drying temperature should be gradually increased to avoid the formation of a hard film on the surface of the particles, which would affect the evaporation of internal moisture;

[0082] (4) After drying is complete, use a 14-mesh sieve to size the particles, taste the influence of different sweetener amounts on the taste, and select the preferred sweetener amount.

[0083] Step four, screening of granulation drying process (control the degree of drying of the granules).

[0084] (1) Take multiple portions of gardenia and fermented soybean soup dry extract powder and mix with dextrin in a ratio of 1:2;

[0085] (2) Add 95% ethanol as a wetting agent, and the amount of sweetener is 0.02% of the total amount of medicine and adjuvant, and granulation is carried out with a 16 mesh sieve;

[0086] (3) Put the wet granules into an electric heating air drying oven at 50-80°C for drying, and the drying temperature should be gradually increased to avoid the formation of a hard film on the surface of the granules, which affects the evaporation of internal moisture;

[0087] (4) After drying, the granules are sieved with a 14 mesh sieve, and the hardness and properties of the granules are observed to select the best drying process.

[0088] In some embodiments, gardenia and fermented soybean soup water extract (i.e. gardenia and fermented soybean soup dry extract powder) can be prepared first, and then gardenia and fermented soybean soup granules can be further prepared. The water extract is a substance obtained by mixing gardenia and fermented soybean and extracting with water, and the granules are obtained by mixing the water extract with other adjuvants. Preparing gardenia and fermented soybean soup water extract can include fermented soybean fermentation, gardenia and fermented soybean soup extraction, etc.

[0089] Fermented soybean fermentation step, this step is to obtain the gardenia and fermented soybean soup formula medicinal material fermented soybean, and to provide raw materials for the next extraction. Among them, fermented soybean can also be purchased separately by other means, but according to the technical solution provided by the present application, the quality and effect can be more stably guaranteed. As an embodiment, it can include the following steps:

[0090] Step (1) extraction: mix the chopped mulberry leaves and artemisia with a mass ratio of 1:1, add 8 times the amount of water based on the total mass of artemisia and mulberry leaves, heat and condense reflux, decoct for 1 hour, filter to obtain the filtrate and residue respectively;

[0091] Step (2) washing: take 5 times the amount of black beans based on the total mass of artemisia and mulberry leaves, and wash them clean;

[0092] Step (3) soaking: put the black beans from step 2 into the decoction obtained in step 1 and soak for 1.5 hours;

[0093] Step (4) fermentation: cover the residue obtained in step 1 on the black beans obtained in step 4, and ferment under the conditions of temperature 30°C and humidity 50% for 6 days, remove the residue, wash and continue to ferment for 15 days to obtain fermented soybeans.

[0094] The extraction step of Zhizi Chishao Decoction is to extract Zhizi Chishao Decoction. The orthogonal experiment method can be used to optimize the extraction process of Zhizi Chishao Decoction to obtain the best extraction process. As an example, the following steps can be included:

[0095] Step (1) extraction: take 15.9g of Zhizi and 47.6g of Danzhi, add 6-10 times the amount of water, reflux extraction for 60-120min, extract 1-3 times, filter to obtain the filtrate;

[0096] Step (2) concentration: concentrate the filtrate obtained by extraction into thick paste, the concentration temperature is 60-100℃;

[0097] Step (3) dry distillation: dry distillation and crush the thick paste to obtain dry paste powder, and calculate the dry paste yield.

[0098] Among them, the reflux method refers to using volatile solvent to extract medicinal material components, heating and distilling the leaching liquid, and condensing the volatile solvent after distillation, and repeating the flow back to the extractor to extract the medicinal material. This way, the effective components are extracted completely. Since the solvent can be recycled, the solvent consumption of the reflux method is less.

[0099] The present application provides an extraction process of Zhizi Chishao Decoction, which can include the following steps: mixing Zhizi and Danzhi and adding water to obtain a to-be-extracted material; reflux extraction of the to-be-extracted material to obtain an extract; filtering the extract to obtain an extraction filtrate; concentrating the extraction filtrate to obtain a thick paste; and crushing the thick paste after dry distillation to obtain a dry paste powder, wherein the dry paste powder contains geniposide and daidzein.

[0100] In some embodiments, the mixture of mulberry leaves, artemisia and water can be heated and condensed after refluxing, and then filtered to obtain preparation residue and preparation filtrate. The black beans are soaked in the preparation filtrate. The preparation residue is covered on the soaked black beans for fermentation to obtain Danzhi.

[0101] In some embodiments, the dry paste powder can be added with methanol and ultrasonic dissolved to obtain a test solution for detecting the content of geniposide and / or daidzein in the dry paste powder. Ultrasonic dissolution is to dissolve gas, liquid or solid samples in liquid by using ultrasonic energy. Through the cavitation phenomenon generated by ultrasonic waves, high pressure, high temperature and high speed local areas are formed, so that the solvent molecules and sample molecules collide, vibrate, shear and impact, etc. to speed up the dissolution speed of the sample, especially suitable for the dissolution of complex systems such as difficult solubility and high molecular weight.

[0102] In some embodiments, the method can further comprise the following steps: taking a certain amount of geniposide and daidzein, respectively, adding methanol and dissolving to obtain a control solution, which is used for comparison with the test solution.

[0103] In some embodiments, the method can further comprise the following steps: selecting water amount, extraction time and extraction times as three process factors, and performing orthogonal experiment; determining the contents of geniposide and daidzein in the dry extract powder; and taking the contents of geniposide and daidzein and the dry extract yield as evaluation indexes to optimize the extraction process.

[0104] The water extract (or extract, dry extract powder) of Zhizi Chisheng Tang contains at least iridoid, isoflavone, organic acid, crocin and other substances. Among the iridoid substances, the contents of shanzhiside, methyl deacetyl plantain leaf acid, hydroxyisoglabridin, secologanoside methyl ester, genipin-1-β-gentiodiglucoside and geniposide in the extract are not less than 0.3%, 0.2%, 0.4%, 0.15%, 0.7% and 6%, respectively. The contents of isoflavones such as daidzin, glycitin, genistin, daidzein, glycitein and genistein are not less than 0.08%, 0.02%, 0.3%, 0.04%, 0.07% and 0.1%, respectively, and the content of crocin I is not less than 0.05%. In addition, the extract also contains shanzhiside methyl ester, loganin, geniposidic acid, geniposide, quinine acid, chlorogenic acid and other substances.

[0105] Then the water extract of Zhizi Chisheng Tang can be further prepared into granules as a raw material. The excipients used in the preparation of granules are added in proportion according to the amount of water extract, and the data of various preparations and ingredients involved can be calculated from the amount of raw material and added excipients, and the final granules can be expressed according to the labeled amount.

[0106] The technical solutions of the present application are further described in more detail through several embodiments.

[0107] Example 1 (corresponding Figure 1 Chinese Patent No. 3)

[0108] (1) Take the dry extract powder of Zhizi Chisheng Tang and dextrin in a ratio of 1:1;

[0109] (2) Add 95% ethanol as a wetting agent, and granulate with a 16-mesh sieve, and the soft material is slightly sticky to the sieve;

[0110] (3) Put the wet granules into an electric heating air drying oven at 60℃ for drying, and the drying temperature should be gradually increased to avoid the formation of hard film on the surface of the granules, which affects the evaporation of internal moisture;

[0111] (4) After drying, the granules were sieved with a 14-mesh sieve. The granules were brown, with uneven particle size, moderate hardness, and a granule yield of 80.8%.

[0112] Example 2 (corresponding to Figure 1 Chinese Patent No. 1)

[0113] (1) The ginseng and aconite decoction dry extract powder was mixed with dextrin at a ratio of 1:2;

[0114] (2) 95% ethanol was added as a wetting agent, and the granules were sieved with a 16-mesh sieve. The soft material was slightly sticky to the sieve;

[0115] (3) The wet granules were placed in an electric hot air drying oven at 60°C for drying. The drying temperature should be gradually increased to avoid the formation of a hard film on the surface of the granules, which would affect the evaporation of internal moisture;

[0116] (4) After drying, the granules were sieved with a 14-mesh sieve. The granules were brown, with uneven particle size, moderate hardness, and a granule yield of 80.8%.

[0117] Example 3 (corresponding to Figure 1 Chinese Patent No. 1 and Figure 2 Chinese Patent No. 5)

[0118] (1) The ginseng and aconite decoction dry extract powder was mixed with dextrin at a ratio of 1:2;

[0119] (2) 60% ethanol was added as a wetting agent, and the granules were sieved with a 16-mesh sieve. The granules were easily sieved, and the soft material was slightly sticky to the sieve;

[0120] (3) The wet granules were placed in an electric hot air drying oven at 60°C for drying. The drying temperature should be gradually increased to avoid the formation of a hard film on the surface of the granules, which would affect the evaporation of internal moisture;

[0121] (4) After drying, the granules were sieved with a 14-mesh sieve. The granules were brown, with uneven particle size, moderate hardness, and a granule yield of 80.8%.

[0122] Example 4 (corresponding to Figure 1 Chinese Patent No. 1 and Figure 2 Chinese Patent No. 8)

[0123] (1) The ginseng and aconite decoction dry extract powder was mixed with dextrin at a ratio of 1:2;

[0124] (2) 80% ethanol was added as a wetting agent, and the granules were sieved with a 16-mesh sieve. The granules were easily sieved, and the soft material was slightly sticky to the sieve;

[0125] (3) The wet granules were placed in an electric hot air drying oven at 60°C for drying. The drying temperature should be gradually increased to avoid the formation of a hard film on the surface of the granules, which would affect the evaporation of internal moisture;

[0126] (4) After drying, the granules were sized with a 14-mesh sieve. The granules had uneven color and more fine powder, and the hardness was relatively high. The granule yield was 83.1%.

[0127] Example 5 (corresponding to Figure 1 Example 1, Figure 2 Example 10, and Figure 3 Example 5)

[0128] (1) The gardenia and black bean soup dry extract powder was mixed with dextrin at a ratio of 1:2.

[0129] (2) 95% ethanol was added as a wetting agent, and 0.45% of the total amount of the sweetener was added. The granulation was easy, and the soft material was slightly sticky to the sieve.

[0130] (3) The wet granules were placed in an electric heating air drying oven at 60°C for drying. The drying temperature should be gradually increased to avoid the formation of a hard film on the surface of the granules, which would affect the evaporation of internal moisture.

[0131] (4) After drying, the granules were sized with a 14-mesh sieve. The granules had uneven color and more fine powder, and the hardness was relatively high. The granule yield was 83.1%.

[0132] Figure 1 The results of the diluent type and ratio screening are shown. The dry extract powder was screened with soluble starch and dextrin at ratios of 1:1, 1:1.5, and 1:2, respectively. The granulation, granule hardness, granule appearance, and granule yield were used as evaluation indicators. According to the results of the diluent type and ratio screening, the diluent can be dextrin or soluble starch. However, when soluble starch is used as the diluent, the granules are brittle and the granule yield is low. Therefore, dextrin is selected as the diluent. When dextrin is used as the diluent, the larger the amount, the better the quality of the granules and the larger the granule yield. Therefore, the dry extract powder and the diluent dextrin are selected at a ratio of 1:2 for granulation.

[0133] Figure 2 The results of the investigation of the concentration and amount of the wetting agent after the diluent type and ratio are shown. The concentration of the wetting agent was set at 50%-95%. The granulation, granule hardness, granule appearance, and granule yield were used as evaluation indicators. According to the investigation results, when the amount of the wetting agent is too large, the soft material forms clumps and is severely sticky to the sieve, making it difficult to granulate. When the amount of the wetting agent is too small, the soft material is loose and the granules have more fine powder. In addition, reducing the concentration of the wetting agent cannot improve the granulation effect and the quality of the granules. Therefore, 95% ethanol is still used for granulation.

[0134] Figure 3The sweetener investigation results are shown. After tasting by many people, the aspartame dosage is 0.24 g (0.45% of the total amount of the drug), and the taste is moderate and can play a taste-correcting role. In some embodiments, more accurate investigation can also be carried out by measuring the sweetness.

[0135] In some embodiments, stevioside can be selected as a sweetener to reduce side effects. The addition amount of stevioside is not more than 0.02 kg / 100 kg.

[0136] Figure 4 The granule drying temperature investigation results are shown. When dried at 60℃, the granule hardness is moderate, and the drying time is short, so 60℃ is selected as the drying temperature for the Zhizi Chidong granules.

[0137] The application also provides a water extract of Zhizi Chidong soup, which contains at least 19 substances such as iridoid glycosides, isoflavones, organic acids, and crocin. Among the iridoid glycosides, the contents of shanzhiside, methyl acetate, hydroxyisoglabridin, secologanoside methyl ester, genipin-1-beta-gentiopicroside, and gardenoside in the extract are not less than 0.3%, 0.2%, 0.4%, 0.15%, 0.7%, and 6%, respectively. The contents of daidzin, glycitin, genistin, daidzein, glycitein, and genistein are not less than 0.08%, 0.02%, 0.3%, 0.04%, 0.07%, and 0.1%, respectively, and the content of crocin I is not less than 0.05%. In addition, the extract also contains shanzhiside methyl ester, loganin, geniposidic acid, gardenoside, quinic acid, and chlorogenic acid.

[0138] The following experiments demonstrate the antidepressant effect of Zhizi Chidong granules.

[0139] In some embodiments, the investigation can be carried out by forced swimming test (FST), sugar water preference test (SPT), tail suspension test (TST), and other behavioral evaluations.

[0140] (1) Forced swimming test (FST)

[0141] Forced swimming test (FST) is mainly used for the research of antidepressants, sedatives, and analgesics.

[0142] The experiment is suitable for rats, mice or other laboratory animals, by placing the experimental animals in a confined environment (such as water), the animals struggle to escape in the environment and cannot escape, thus providing an unavoidable oppressive environment, after a period of experiment, the animals show typical "immobility", reflecting a state called "behavioral despair", a series of parameters are recorded during the process of the animals in the environment producing despair immobility. The cumulative immobility time of the animals in the second half of the time is counted, the longer the immobility time, the more severe the depression.

[0143] The forced swimming depression animal model is a reliable experimental model for studying the pharmacology of human depression and its pathogenesis, screening and observing anti-depression drugs. Its main feature is the high specificity of drug action. The experiment can well distinguish anti-depression drugs from strong tranquilizers and anti-anxiety drugs. Moreover, the effects of most anti-depression drugs are significantly related to clinical efficacy, which has been accepted by scholars.

[0144] The height of the water in the bucket should be as high as possible to ensure that the hind limbs of the experimental animals cannot support or contact the bottom of the bucket, otherwise the animals will adapt to the whole environment and affect the experimental results.

[0145] Put tap water in the bucket and make the water depth reach 40 cm, put the rats into the water and force them to swim for 6 min, and analyze the immobility time of the rats in the last 4 min. The immobility criterion is that the rat's body does not struggle, only the head is exposed to the water surface and floats on the water surface. After the rats finish swimming, clean the feces on the water surface and dry the rat's hair to prevent cold. All rats are subjected to forced swimming test on day 0, 20, 47 and 62.

[0146] The forced swimming time results of the rats during modeling and drug administration are shown in Figure 5 , which shows the changes of the immobility time of the rats in forced swimming. Among them, CON is the blank control group; CUMS is the model group (chronic unpredictable stress model); FLU is the fluoxetine administration group; ZZCD is the zizyphi fructus et semen et fructus coffae granules administration group. The abscissa represents the day on which the monitoring is carried out; the ordinate represents the immobility time, in seconds.

[0147] As shown in Figure 5 , the period from 0 to 40 days is the modeling period, except for the CON group, the other three groups train the rats to model in the same way to make them depressed, and the relevant parameters are continuously monitored. After the modeling is completed, the three groups of rats that have completed the modeling all show obvious depressive characteristics. After the modeling is completed around day 47 (in some embodiments, it can be advanced or delayed by 1-2 weeks), different ways of administration are started for the three groups of rats that have completed the modeling, ZZCD group is administered with zizyphi fructus et semen et fructus coffae granules, CON group is administered with fluoxetine, CUMS is not administered, and the administration effect is continuously monitored and controlled.

[0148] Fluoxetine is a selective 5-HT reuptake inhibitor (SSRI) widely used in clinic, which can selectively inhibit 5-HT transporter, block the reuptake of 5-HT at the presynaptic membrane, prolong and increase the effect of 5-HT, and thus produce antidepressant effect. It has low affinity for adrenergic, histaminergic, and cholinergic receptors, and weak effect, thus producing fewer adverse reactions. It is well absorbed after oral administration, with a bioavailability of 70%, and easily passes through the blood-brain barrier, with a small amount secreted into breast milk. It is metabolized in the liver by CYP2D6 to generate nortriptyline, which also has antidepressant effect.

[0149] With the increase of time, the immobility time of the model group continued to rise, and the change trend of the Zhizi Chidou Decoction group and the fluoxetine group during modeling was basically the same as that of the model group. However, after two weeks of administration, the forced swimming immobility time decreased significantly, and there was a significant difference with the model group. The forced swimming immobility time of the blank control group was basically consistent.

[0150] The above experiments can prove that Zhizi Chidou Decoction is effective in the treatment of depression, and the efficacy is comparable to or even slightly better than that of fluoxetine.

[0151] (2) Sucrose preference test (SPT)

[0152] Depression is accompanied by a variety of behavioral phenotypes, one of which is anhedonia, i.e., individuals cannot experience pleasure from rewards or enjoyable activities. Sucrose preference test is a classic experiment for detecting anhedonia, a typical symptom of depression, which is designed to detect the preference of rodents for sweet taste. After fasting for a period of time, animals are given white water and low-concentration sucrose water at the same time, and the degree of sucrose preference is used as an indicator to detect whether the animal has anhedonia, a symptom of depression.

[0153] The principle of sucrose preference test is that rodents have a strong desire for sweets by nature, and when they are given two drinking devices that can be freely chosen, i.e., containing sucrose solution and ordinary water respectively, they will selectively drink sweet sucrose solution. However, when rodents are in a depression model caused by chronic stress, they will not tend to drink sucrose solution. Therefore, the degree of preference for sucrose solution in animals can be used as a useful means to assess the anhedonia symptoms and the degree of depression in animals. 1%-2% sucrose solution is the optimal concentration to distinguish whether mice or rats have anhedonia and depression.

[0154] This experiment is widely used in chronic stress models in rats, and sucrose test is used to detect whether the depression model animals have anhedonia symptoms. In addition, this experiment is one of the main behavioral detection methods for the onset rate of antidepressants.

[0155] Sucrose preference can be used as an evaluation index. Sucrose preference (%) = sucrose water consumption / (sucrose water consumption + drinking water consumption) × 100%. Criteria for judging depressive behavior: low sucrose preference or a significant reduction compared to the control group.

[0156] Before the experiment, each cage was placed with two bottles of water containing 1% sucrose solution for 24 hours. Afterward, each cage was placed with one bottle of 1% sucrose solution and one bottle of pure water for another 24 hours to train the rats to adapt to the sucrose solution. Before the formal experiment, the rats underwent a 23-hour fasting and water restriction period, followed by simultaneous administration of one bottle of 1% sucrose solution and one bottle of pure water. After 120 minutes, the bottles were weighed, and the rats' consumption of pure water, sucrose solution, and total fluid consumption was calculated. All rats underwent the sucrose preference test on days 0, 21, 48, and 63.

[0157] Percentage of sucrose preference during rat modeling and drug administration, as shown in the figure. Figure 6 The figure shows the changes in the percentage of sucrose preference in rats. CON represents the blank control group; CUMS represents the model group (chronic unpredictable stress model); FLU represents the fluoxetine treatment group; and ZZCD represents the Gardenia and Fermented Soybean Decoction granule treatment group. The horizontal axis represents the number of days, indicating the day of monitoring; the vertical axis represents the percentage of sucrose preference, SPT(%) = sucrose consumption / total fluid consumption × 100%.

[0158] like Figure 6 As shown, the period from 0 to 40 days was the modeling period. Except for the CON group, the other three groups were trained to induce depression in rats using the same method, and relevant parameters were continuously monitored. After modeling was completed, all three groups of rats exhibited obvious depressive characteristics. Around day 47 after modeling was completed (in some embodiments, this could be done 1-2 weeks earlier or later), the three groups of rats that had completed modeling were given different medications: the ZZCD group was given Gardenia and Fermented Soybean Decoction Granules, the CON group was given Fluoxetine, and the CUMS group was not given any medication. The effects of the medications were continuously monitored and controlled.

[0159] From day 0 to day 48 of formal modeling, the changes in the model group, the Gardenia and Fermented Soybean Decoction group, and the Fluoxetine group were basically consistent, showing a continuous downward trend. However, two weeks after administration, the percentage of sucrose preference in the Gardenia and Fermented Soybean Decoction group and the Fluoxetine group increased significantly and showed a significant difference from the model group, while the percentage of sucrose preference in the blank control group was basically consistent.

[0160] The above experiments demonstrate that Gardenia and Fermented Soybean Decoction Granules are effective in treating depression, and their efficacy is comparable to or even slightly better than that of Fluoxetine.

[0161] (3) Suspended Tail Test (TST)

[0162] Tail suspension test (TST) is a classic and rapid method for evaluating the efficacy of antidepressants, stimulants and sedatives. The principle is that after the mouse tail is suspended, the mouse tries to escape but cannot escape, and then gives up struggling and enters a unique depressed state of inactivity. The inactivity time of the animal during the experiment is recorded to reflect the depressed state, and antidepressants and stimulants can significantly shorten the state.

[0163] The tail of the experimental animal is fixed, and the head is suspended downward. The animal struggles in this environment, trying to get out of the predicament. After efforts still cannot get out, intermittent inactivity appears, showing a "behavioral despair" state. The animal struggles desperately in this environment to try to escape and cannot escape, thus providing an inescapable oppressive environment. After a period of experiment, a series of parameters during the inactivity of the animal in this environment are recorded. The animal's typical "inactivity state" reflects a state called "behavioral despair state". This behavioral despair model is similar to depression, and is sensitive to most antidepressants, and its efficacy is significantly related to clinical efficacy, so it is widely used for the initial selection of antidepressants.

[0164] Body inactivity: when the animal stops struggling, the body remains in a vertical inverted suspension state, and is motionless. This indicator can be regarded as the behavior of the experimental animal giving up struggling after learning helplessness. The longer the inactivity time of the animal in the tail suspension test, the more severe the depression of the animal.

[0165] Struggle behavior: when the animal appears to struggle and get up, the shorter the struggle time of the animal, the more severe the depression of the animal.

[0166] The tail of the rat 1-2 cm from the root is fixed on a horizontal wooden stick, and the head of the rat is suspended downward for 6 min. The tail suspension inactivity time in the last 4 min is statistically analyzed. The standard for inactivity is that the body is vertically suspended and does not struggle. If the rat falls in the middle, it needs to be comforted and suspended again. All rats are subjected to tail suspension test on day 0, 21, 48 and 63.

[0167] The tail suspension inactivity time of the rat during modeling and drug administration is shown in Figure 7 , which shows the change of the tail suspension inactivity time of the rat. Among them, CON is the blank control group; CUMS is the model group (chronic unpredictable stress model); FLU is the fluoxetine administration group; ZZCD is the Zhizi Chidou Granules administration group. The abscissa represents the number of days, representing the monitoring on which day; the ordinate is the inactivity time, in seconds.

[0168] As shown in Figure 7As shown, the period of about 0-40 days is the modeling period. Except for the CON group, the other three groups of rats are trained in the same way to model depression and the relevant parameters are continuously monitored. After the modeling is completed, the three groups of rats that are modeled all show obvious depressive characteristics. After the modeling is completed at about day 47 (in some embodiments, it can be 1-2 weeks earlier or later), different ways of administration are started for the three groups of rats that have completed modeling, the ZZCD group is administered Zhizi Chitang granules, the CON group is administered fluoxetine, and the CUMS is not administered, and the administration effect is continuously monitored.

[0169] From day 0 to day 49 of formal modeling, the change trends of the model group, the Zhizi Chitang administration group, and the fluoxetine group are basically consistent, showing a continuous upward trend. After two weeks of administration, the tail suspension immobility time of the Zhizi Chitang administration group and the fluoxetine group significantly decreases and has a significant difference with the model group, and the tail suspension immobility time of the blank control group is basically consistent.

[0170] The above experiments can prove that the Zhizi Chitang granules are effective for treating depression, and compared with fluoxetine, the efficacy is equivalent or even slightly better, especially at day 64, the performance of the ZZCD group has approached that of the CON group, that is, the depressive characteristics have basically disappeared.

[0171] In some embodiments, the effect of the Zhizi Chitang granules on the 5-HT content in the CUMS-induced depression rat model can be further investigated.

[0172] (1) Collection and preservation of samples.

[0173] After the last behavioral test, all rats are anesthetized by intraperitoneal injection of 20% urethane at a standard of 10 mL / kg, the chest is opened, and all blood is collected from the heart and put into an Ep tube containing heparin in advance, mixed uniformly, centrifuged at 3500 r / min for 10 min at 4°C, the supernatant is taken out and divided, and placed in a-80°C refrigerator for standby. At the same time, brain tissue samples are collected and placed in a-80°C refrigerator for preservation.

[0174] (2) Sample pretreatment method.

[0175] First, the brain tissue is taken out for thawing. After thawing, 100 mg of brain tissue is weighed in a clean centrifuge tube, 5 μL of 2, 6-dihydroxybenzoic acid with a concentration of 20 μg / mL and 4 times the amount of pre-cooled 80% methanol solution containing 0.1% formic acid are added, homogenized, centrifuged at 13000 r / min for 10 min at 4°C, 250 μL of supernatant is taken out, concentrated and dried, 100 μL of methanol is added, vortexed for 3 min, centrifuged at 13000 r / min for 10 min at 4°C, and 50 μL of supernatant is taken for analysis.

[0176] After the blood sample was thawed, 100 μL was taken, 5 μL of 2, 6-dihydroxybenzoic acid with a concentration of 20 μg / mL and 4 times the amount of pre-cooled 80% methanol solution containing 0.1% formic acid were added, homogenized, centrifuged at 13000 r / min for 10 min at 4°C, 200 μL of supernatant was taken, concentrated and dried, 100 μL of methanol was added, vortexed for 3 min, centrifuged at 4°C, 13000 r / min for 10 min, and 50 μL of supernatant was taken for sample analysis.

[0177] (3) LC-MS analysis conditions

[0178] The chromatographic column was Atlantis T3 (2.1 mm x 100 mm, 3 μm); the mobile phase A was 0.1% formic acid aqueous solution, and B was acetonitrile containing 0.1% formic acid; the elution program was 0-1 min, 5% B; 1-3 min, 5%-40% B; 3-3.5 min, 40%-95% B; 3.5-5.5 min, 95% B; 5.5-6 min, 95%-5% B; 6-8 min, 5% B. The flow rate was set to 0.3 mL / min; the column temperature was 30°C; the injection volume was 1 μL.

[0179] The ion source in the mass spectrometry conditions was ESI, positive ion scanning; the scanning range was 50-500 m / z; the flow rate of atomizing gas was 3 L / min; the flow rate of drying gas was 10 L / min.

[0180] (4) Effect of Zhizi Chisheng Granules on 5-HT content in brain tissue and blood of CUMS rats

[0181] The existing chromatography and mass spectrometry conditions were used to analyze the rat brain tissue and blood samples, and there was a significant difference in the 5-HT content between the model group and the Zhizi Chisheng Granules administration group and the fluoxetine administration group.

[0182] Figure 8A and Figure 8B The 5-HT content in rat tissue (Mean+SEM, n=6) is shown, wherein Figure 8A is the 5-HT content in brain tissue, Figure 8B is the 5-HT content in blood. *P<0.01, ****P<0.0001, compared with CUMS. Mean represents the average number, SEM (Standard Error of Mean) is the sampling error of the average number, reflecting the sampling accuracy of the average number, and n is the sample size. The peak area ratio is the ratio of the peak area of the measured component to the peak area of the internal standard, and the content of the measured component is calculated accordingly.

[0183] The normal content of 5-HT in the brain is relatively high, and after increasing, it will cause emotional dullness (compliment, i.e. high emotional resistance), and stable mood. After decreasing, it will be particularly sensitive to pessimistic emotions, leading to depression and anxiety.

[0184] By Figure 8A and Figure 8B It can be seen that the model group, the Zhizi Chidong group and the blank control group are obviously distinguished, which shows that the metabolic state of the model group rats is quite different from the dosing groups and the blank control group. The CUMS model makes the metabolism of the rats change greatly, and after two weeks of dosing, the state of the dosing groups gradually recovers, which is significantly different from the model group, indicating that the intragastric administration of Zhizi Chidong granules reverses the changes caused by CUMS metabolism.

[0185] The present application also provides a wet granulation method, in which a wetting agent is added to the drug powder to form a soft material, which is sieved to form wet granules, and the wet granules are dried and then sized to obtain dry granules. The wet granules have the advantages of good surface modification, attractive appearance, strong wear resistance, good compression forming property, etc.

[0186] The mechanism of wet granulation is as follows: first, the liquid in the wetting agent wets the surface of the drug powder, causing adhesion between the powder particles, and then the liquid bridges and external mechanical forces form granules of a certain shape and size, which are finally solidified in the form of solid bridges after drying.

[0187] The binding force generated by the liquid bridge mainly affects the growth process of the particles and the particle size distribution of the granulation, while the binding force of the solid bridge directly affects the strength of the granules and other properties, such as solubility.

[0188] In wet granulation, the liquid first wets the surface of the powder particles, and the moisture content is very sensitive to the growth of the granules. The moisture content is related to the particle size distribution, i.e. when the moisture content is greater than 60%, the particle size distribution is more uniform, and when the moisture content is in the range of 45% to 55%, the particle size distribution is wider.

[0189] The bridging liquid produced during wet granulation is solidified after drying, forming granules of a certain strength. The transition from liquid bridging to solid bridging mainly has the following two forms:

[0190] (1) The dissolved substances (including soluble binders and drugs) in the bridging liquid are precipitated and crystallized to form solid bridges after drying.

[0191] (2) The high-viscosity bridging agent agglomerates the powder into granules by adhesion. The solvent in the binder solution evaporates during drying, and the remaining binder solidifies into a solid bridge.

[0192] Wet granulation mainly includes the processes of soft material preparation, wet granule preparation, wet granule drying and sizing, etc.

[0193] I. Soft material preparation: mix the fine powder of the raw and auxiliary materials weighed according to the prescription with an appropriate amount of wetting agent to form a soft material. The problems that should be paid attention to in the preparation of soft materials are as follows:

[0194] (1) The kind and amount of wetting agent should be determined according to the properties of the material;

[0195] (2) The concentration of the added wetting agent and the stirring time should be flexibly controlled according to different varieties.

[0196] (3) The length of the wet stirring time has a great influence on the soft material. The longer the wet stirring time, the greater the viscosity, and the harder the prepared granules.

[0197] II. Wet granulation: The soft material is made into granules by passing through a screen. If the granules fall like long strips when passing through the screen, it indicates that the soft material is too wet, and the wetting agent is too much. On the contrary, if the soft material is powdery after passing through the screen, it indicates that the soft material is too dry, and it should be adjusted appropriately. Equipment that can be used: swinging granulator, high-speed stirring granulator Screen: there are nylon wire, galvanized iron wire, stainless steel, and plate screen.

[0198] III. Drying of wet granules: The wet granules obtained by sieving should be dried immediately to prevent clumping or deformation under pressure (stainless steel trays can be used to spread the prepared wet granules and turn them over from time to time to solve the problem of clumping and deformation of the wet granules). Drying temperature: determined by the properties of the raw materials, generally 50-60°C; for some drugs that are stable to moisture and heat, the drying temperature can be appropriately increased to 80-100°C. Drying degree: controlled by measuring the water content. The water content of granules should not exceed 2%; the water content of tablet granules should be appropriately retained according to the specific variety, generally about 3%. Drying equipment: available are box-type (such as oven, drying oven) drying, boiling drying, microwave drying, or far-infrared drying, etc.

[0199] IV. Granule sizing: After drying, the wet granules need to be sieved and sized to break up the clumped particles to meet the particle size requirements of granules or the tablet pressing requirements. (1) Granules: a screen with a smaller mesh size than that used for wet granulation can be used to break up the particles that cannot pass through the screen, and then the particles are classified according to the lower limit of the particle size specification by passing through a 60-mesh or 80-mesh (5-mesh) screen to obtain particles between 10-80 mesh. (2) Tablets: a screen with a larger mesh size than that used for wet granulation can be used for the granules.

[0200] Blank granule method: For drugs that are unstable to moisture and heat and have a small dosage, the auxiliary granules and other drugs that are stable to moisture and heat can be first granulated by wet method, dried and sized, and then the drugs that are not resistant to moisture and heat are mixed uniformly with the granules. The method of using only auxiliary granules to make dry granules and then mixing the drugs with the granules (tablet pressing or dispensing) is called blank granule method.

[0201] One-step granulation: the raw materials are mixed, the binder is sprayed and stirred to make the binder meet the raw materials in the form of mist to form granules, and the operation steps such as drying are completed in one device, so it is called one-step granulation method, also known as fluidized spray granulation. Although this method can mix, granulate and dry in one device, the operation is relatively simple, but the particle density of the prepared granules is smaller and the particle strength is smaller.

[0202] Spray granulation: the raw materials, excipients and binders are mixed and stirred to form a drug solution or suspension containing about 50%-60% solid, then the pump is used to spray the solution or suspension into the hot air flow in the drying chamber through a high-pressure sprayer to directly prepare spherical dry fine particles. This method directly obtains solid powder particles from liquid, the droplet specific surface area is large, the hot air temperature is high, the drying speed is very fast, the heating time of the particles is extremely short, and the drying material temperature is relatively low, which is suitable for the treatment of heat-sensitive materials. However, the equipment cost is high, the energy consumption is large, and the operation cost is high.

[0203] Dry granulation: the drug powder (if necessary, diluent, etc.) is mixed uniformly, and then directly compressed into blocks by a suitable device, and then broken into particles of a desired size. This method relies on the compression force to generate binding force between particles. It can be divided into heavy pressure method and rolling pressure method. Heavy pressure method: also known as large piece method, which is to first compress the solid powder into a 20-25mm diameter embryo tablet on a heavy tablet press, and then break it into particles of a desired size. Rolling pressure method: it uses a rolling machine to roll the drug powder into a tablet, and then breaks it into particles of a certain size by a granulator. Dry granulation is often used for heat-sensitive materials, water-unstable drugs and compression-easy-forming drugs. The method is simple, but it may cause crystal transformation and activity reduction.

[0204] The following are some factors that affect wet granulation

[0205] I. Properties of raw materials

[0206] (1) The powder is fine, the texture is loose, the dryness and the adhesion are poor, and the solubility in water is small, so a stronger adhesive is selected, and the amount of adhesive is more.

[0207] (2) The solubility in water is large, and the raw materials themselves have strong adhesion, so a wetting agent or a less adhesive adhesive is selected, and the amount of adhesive is relatively less.

[0208] (3) Sensitive to moisture and easy to hydrolyze, so water cannot be selected as the solvent for the adhesive, and anhydrous ethanol or other organic solvents can be selected as the solvent for the adhesive.

[0209] (4) Sensitive to heat and easy to decompose, so water cannot be selected as the solvent for the adhesive, and a certain solubility of ethanol can be selected as the solvent for the adhesive to reduce the drying time and the drying temperature of the granules.

[0210] (5) If the material is stable to moisture and heat, water, which is less expensive, can be used as the solvent of the binder.

[0211] II. Wetting agents and binders

[0212] Wetting agents are liquids that wet the material to produce sufficient adhesion to facilitate granulation. Wetting agents themselves have little or no adhesion, but they can wet the material and induce the material's own adhesion to enable it to coalesce into a soft mass and be granulated. Examples include distilled water and ethanol. Binders are adhesives that can make non-adhesive or less adhesive materials cohere into granules or be compressed into shaped solid powders or viscous liquids. Examples include povidone (PVP), hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC-Na), and sugar syrup.

[0213] Distilled water: Water itself has no adhesion, but when the material contains components that can produce adhesion when they come into contact with water, distilled water can be used to induce the adhesion of the components to produce suitable granules. However, when water is used as a wetting agent, the material often absorbs water quickly, which can cause uneven wetting, and the drying temperature is high, so drugs that are not resistant to heat or are easily degraded or dissolved in water should not be used. It is better to use low-concentration starch or ethanol instead to overcome these shortcomings.

[0214] Ethanol: If the drug itself has adhesion, but is degraded or has too strong adhesion after being wetted, which makes granulation difficult, causes uneven wetting, makes drying difficult, or makes the granules hard after drying, and the compressed tablets are difficult to disintegrate, an appropriate concentration of ethanol can be used as a wetting agent. The concentration of ethanol depends on the nature of the drug and the environmental temperature, and is generally 30%-70% or more concentrated. As the concentration of ethanol increases, the adhesion produced after wetting decreases. To some extent, ethanol is a dispersant that reduces the adhesion between granules, making it easier to granulate materials with too strong adhesion. Ethanol is often used as a wetting agent for traditional Chinese medicine extract tablets, but attention should be paid to rapid operation to prevent the formation of strong adhesion lumps due to the evaporation of ethanol.

[0215] Povidone (PVP): White or milky white powder, non-toxic, high melting point, stable to heat (color change at 150°C), chemically stable, can be dissolved in water and ethanol to form a viscous gel-like liquid, and is a good binder. PVP has different specifications and models, and PVP K30 is commonly used as a binder. PVP aqueous solution, alcoholic solution, or solid powder can be used. PVP dry powder can also be used as a dry binder for direct tablet compression. A 3%-15% (usually 3%-5%) ethanol solution of PVP is often used for granulation of water-sensitive drugs, and the resulting granules have good compressibility. It can be used for drugs with very poor compressibility, but attention should be paid to the fact that these binders have very strong adhesion, and the resulting tablets are relatively hard, and a slight excess can cause the disintegration of the tablets to exceed the limit.

[0216] Hydroxypropylmethyl cellulose (HPMC): white powder, no odor and taste, quite stable to light, heat and humidity, is a most commonly used film coating material, can be dissolved in water and some polar organic solvents, can be swelled in cold water to form a viscous solution. Insoluble in ethanol, diethyl ether and chloroform, but soluble in 10% to 80% ethanol solution or methanol and dichloromethane mixture. When preparing HPMC aqueous solution, it is best to first add HPMC to the total volume of 1 / 5 to 1 / 3 hot water (80℃ to 90℃), fully dispersed and hydrated, then under cooling conditions, continue to stir, add cold water to the total volume. HPMC as an adhesive, commonly used concentration is 2% to 5%. HPMC as an adhesive is characterized by rapid disintegration and fast dissolution rate.

[0217] Sugar syrup: aqueous solution of sucrose, which has strong viscosity, is suitable for loose texture, strong elasticity of plant medicines and loose texture and easy to lose crystalline water of chemical drugs, commonly used 50% to 70% (g / g) aqueous solution. When the concentration of sucrose is as high as 70% (g / g), it is a supersaturated solution at room temperature, can only be used when hot, otherwise it is easy to precipitate crystals. Strong acid or strong alkaline drugs can cause the conversion of sucrose to produce hygroscopicity, which is not conducive to tabletting, so granulation should not be used. Sugar powder is a dry binder. Sucrose has a certain hygroscopicity, which is related to the purity, and the lower the purity, the stronger the hygroscopicity. Sometimes it is used with starch paste to enhance the adhesion, and sometimes sucrose powder is mixed with raw materials and then wetted with water to granulate.

[0218] Carboxymethycellulose sodium (CMC-Na): is the carboxymethyl ether of cellulose, insoluble in ethanol, chloroform and other organic solvents; when dissolved in water, the surface of the particles first swells, then the water slowly penetrates into the interior to become a transparent solution, but it takes a long time, it is best to heat to 60℃ to 70℃ after initial swelling and swelling, which can greatly speed up the dissolution process. Commonly used concentration is 1% to 2%. The most commonly used in pharmaceuticals is the product with a degree of substitution of 0.7, which can be dissolved in 60% ethanol solution.

[0219] Starch paste: Commonly known as starch slurry, it is suitable as a binder for heat- and moisture-stable drugs. The concentration is generally 5%-30%, with 10% being the most common. There are two preparation methods: the pouring method and the boiling method. Pouring method: First, add a small amount (1-1.5 times) of cold water to the starch, stir, then pour in the full amount of boiling water, stirring constantly until a semi-transparent paste is formed. This method is convenient and suitable for mass production. Boiling method: Slowly add the full amount of cold water to the starch, stir well, then heat and stir constantly until a paste is formed. This method should not be used with direct heat to avoid charring at the bottom and introducing black spots that affect the appearance. This method is rarely used in production now. Starch paste can evenly wet materials, is less prone to localized over-wetting, and has good adhesive properties, making it a widely used binder. The temperature at which corn starch is completely "gelatinized" (gelatinization refers to the phenomenon of starch forming a uniform paste after heating) is 77℃.

[0220] Gelatin: Commonly used solutions include 10%-20% gelatin solution and 10%-25% gum arabic solution. Suitable for drugs that are easily dispersed and cannot be granulated with starch paste.

[0221] III. Granulation and cutting time

[0222] When preparing soft materials, the mixing and cutting time should be properly controlled. If the mixing and cutting time is too long, the viscosity will be too strong, making granulation difficult; if the mixing and cutting time is too short, the viscosity will be weak, resulting in poor granulation.

[0223] IV. Sieve

[0224] (1) Nylon filament sieve: It does not affect the stability of the drug and is elastic. It is suitable for making granules from soft materials that are "wet but not too sticky but granulate well". When the soft material is sticky, the sieve is slow. After repeated rubbing and mixing, the granules made from the soft material are harder and the nylon sieve is easy to break.

[0225] (2) Galvanized iron wire mesh: It can be used to granulate relatively sticky soft materials, but metal shavings (broken iron wires) are easily carried into the granules, which may also affect the stability of some drugs. Magnets can be installed at key locations of the equipment to attract broken iron wires, which also works well.

[0226] (3) Stainless steel screen: High-quality pure stainless steel screen has a better granulation effect, but broken stainless steel wires are easy to enter the particles, and cannot be attracted by magnets.

[0227] (4) Plate screen: This can solve the problem of metal shavings being carried into the granules, but it is expensive and the granulation speed is slow. When using a swing-type pellet mill to produce wet granules, what is the effect of the tightness of the screen installation on the granule quality? If the screen is installed loosely during granulation, the reciprocating rotation and kneading of the drum can increase the viscosity of the soft material, resulting in coarse and compact wet granules. Conversely, the resulting granules are fine and loose. Therefore, the tightness of the screen installation should be appropriate during production.

[0228] Five, drying and drying equipment Drying is the process of removing water from wet materials by vaporization.

[0229] (1) Drying process of wet granules

[0230] It refers to the diffusion of water from the inside of the wet material to the surface, so that the surface of the material is heated and vaporized. After the surface water evaporates, the internal water diffuses to the surface through the humidity difference inside the particles, and continues to evaporate on the surface to achieve the purpose of drying.

[0231] (2) Problems to be paid attention to in the drying process of wet granules:

[0232] Wet granules should be dried as soon as possible, otherwise, wet granules are prone to deformation, caking or deterioration.

[0233] Drugs that are granulated with dilute alcohol and are prone to hydrolysis should be dried as soon as possible. Because the alcohol volatilizes after being left for a long time, the water content increases accordingly, which accelerates the hydrolysis of the drug.

[0234] The drying speed of the granules should be strictly controlled. The drying speed depends on the external conditions and the ease of diffusion of the liquid inside the granules to the surface. The external conditions include the humidity, temperature, flow conditions of the air and the dispersion degree of the material.

[0235] The temperature should be gradually increased during the drying process, otherwise, the surface of the granules will dry and form a hard film, which will affect the evaporation of the internal moisture. If the granules contain sugar powder and starch, sudden temperature rise can cause sugar to melt and starch to gelatinize, affecting the disintegration of the tablets.

[0236] (3) Drying equipment

[0237] Chamber dryer: multiple shelves are arranged in the dryer, and material trays are placed on the shelves. The air is heated by a preheater and then enters the drying chamber to dry the material in a horizontal direction. Features: simple equipment, strong adaptability, but high labor intensity, slow drying speed, and high heat consumption.

[0238] Spray dryer: the equipment structure and operation are the same as spray granulation. The evaporation area is large, the drying time is very short, and it is very suitable for heat-sensitive materials. The dried products are mostly crisp hollow granules with good solubility.

[0239] Fluidized bed dryer: hot air passes through the loose granular or powdery material layer from bottom to top to form a fluidized state for drying, also known as boiling dryer. Features: simple structure, easy to operate, the relative movement between granules and hot air is intense, the contact area is large, the drying speed is fast, and it is suitable for heat-sensitive materials. Vertical fluidized bed dryer is suitable for drying tablet granules, and the relative powder is more, and the tabletting effect is good. Horizontal fluidized bed dryer is suitable for drying granules, and the effect is good.

[0240] As a specific embodiment, the present application provides a mass production method as follows:

[0241] Prescription: 40 kg of raw gardenia, 120 kg of radix sophorae tonkinensis, and 100 kg of granules.

[0242] Method one (wet granulation): the above two ingredients are decocted with water for three times, each time with 10 times the amount of water, and each time for 2 hours, and then filtered respectively; the filtrate is concentrated to a relative density of 1.04-1.06 (80℃), and then left for 10 hours; the supernatant is concentrated to a relative density of 1.27 (80℃), and then dextrin and stevioside 0.02 kg are added for granulation, and then the granules are mixed, packed, and packaged (15 g per bag, 14 bags per package).

[0243] Method two (dry granulation): the above two ingredients are decocted with water for three times, each time with 10 times the amount of water, and each time for 2 hours, and then filtered respectively; the filtrate is concentrated to a relative density of 1.04-1.06 (80℃), and then left for 10 hours; the supernatant is concentrated to a relative density of 1.08-1.10 (80℃), and then dextrin and stevioside 0.02 kg are added for spray drying, granulation, mixing, packing, and packaging (15 g per bag, 14 bags per package).

[0244] Either of the above two methods is selected. According to the current edition of the Chinese Pharmacopoeia, the water content, loading capacity, solubility, particle size, and microorganisms are tested under the item of "granules".

[0245] The above is only a preferred specific embodiment of the present application, but the protection scope of the present application is not limited thereto, and any person skilled in the art can make equivalent substitutions or changes to the technical solution and the inventive concept of the present application within the technical range disclosed by the present application, which should be covered within the protection scope of the present application. In the claims and the specification of the present application, the modules used to perform the specified functions or the modules described using functional features are intended to cover any means capable of performing the functions.

[0246] The present specification uses examples to disclose the present application, one or more examples of which are described or illustrated in the specification and drawings. Each example is provided by way of explanation of the application, and not as a limitation of the application. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made in the present application without departing from the scope or spirit of the application. For instance, features illustrated or described as part of one embodiment, can be used with another embodiment to yield a still further embodiment. Thus, it is intended that the present application encompass modifications and variations as come within the scope of the appended claims and their equivalents. It is intended, additionally, that the application encompass all of the following, or any combination thereof:

Claims

1. A preparation method of Zhizi Chisheng Tang granules, characterized by, The method comprises the following steps: mixing gardenia 15.9 g and soja 47.6 g and adding water to obtain a to-be-extracted material; refluxing extraction is performed on the to-be-extracted material to obtain an extract; filtering the extract to obtain an extract filtrate; concentrating the extract filtrate to obtain a thick paste; and pulverizing the thick paste after being evaporated dry to obtain a dry paste powder, wherein the dry paste powder contains gardenoside and daidzein; mixing the gardenia-soja decoction dry paste powder with a diluent to obtain a base material to increase the weight of the granules; wherein the diluent is dextrin, and the mass ratio of the dry paste powder to the diluent is 1:2; adding a wetting agent to the base material to obtain a soft material, so that the solid powder is bonded and shaped to facilitate granulation; wherein the wetting agent is ethanol, and the concentration of the wetting agent is 95%, and the mass ratio of the dry paste powder to the wetting agent is 1:1.2; sifting the soft material through a first screen to obtain wet granules; drying the wet granules to obtain a dry material to control the drying degree of the granules, wherein the drying temperature is 60 degrees Celsius; and sieving the dry material through a second screen to obtain dry granules. Before the soft material is sifted, it further comprises:

2. The preparation method of Zhizi Chi Tang granules according to claim 1, characterized in that, adding a sweetener to the soft material to improve the taste of the granules; wherein the sweetener is aspartame, and the amount of the sweetener is 0.02% of the total amount of the adjuvant. Drying the wet granules further comprises gradually increasing the drying temperature to avoid the formation of a hard film on the surface of the granules, which affects the evaporation of internal moisture.

3. The preparation method of Zhizi Chi Tang granules according to claim 1, characterized in that, The dry paste powder comprises iridoid substances, isoflavone substances, organic acid substances, and crocin substances.

4. The preparation method of Zhizi Chi Tang granules according to claim 1, characterized in that, The iridoid substances comprise gardenoside, methyl deacetyl plantain acid, hydroxyisogardenoside, machilus glycoside methyl, genipin-1-β-gentian bisglycoside, and gardenoside.

5. The preparation method of Zhizi Chi Tang granules according to claim 4, characterized in that, The isoflavone substances comprise daidzin, glycitin, genistin, daidzein, glycitein, and genistein.

6. The preparation method of Zhizi Chi Tang granules according to claim 4, characterized in that, The crocin substances comprise crocin.

7. The preparation method of Zhizi Chi Tang granules according to claim 4, characterized in that, The gardenia-soja decoction dry paste powder is prepared into granules for treating depression.

8. The preparation method of Zhizi Chi Tang granules according to claim 1, characterized in that: ​

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