Compound bovine bone collagen peptide beverage based on guidance of biological information technology
The compound bovine bone collagen peptide beverage, guided by bioinformatics, solves the problems of significant side effects of existing drugs and limited variety of health foods, achieving safe and effective improvement of bone health, promoting osteoblast differentiation and enhancing bone density.
Patent Information
- Application Number
- CN202511947085.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-23
- Publication Date
- 2026-01-23
AI Technical Summary
Existing medications for osteoporosis have side effects, and there is a lack of effective beverage solutions. Furthermore, the health supplements available on the market are limited in variety and their effects are unproven, making it impossible to safely and effectively improve bone health through dietary therapy.
Guided by bioinformatics, a compound bovine bone collagen peptide beverage, comprising bovine bone collagen peptide powder, jujube polysaccharide, astragalus polysaccharide, calcium carbonate, chondroitin sulfate, and sodium hyaluronate, was prepared through steps such as pulverization, mixing, low-temperature drying, and granulation to ensure the uniformity and activity of the raw materials. Bioinformatics tools were used to optimize the formula during the preparation process.
This beverage is better absorbed by the body, improves bone health, promotes osteoblast differentiation, increases bone density, and has no toxic side effects, which aligns with modern health concepts.
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Figure CN121369708A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of food preparation, in particular to a compound bovine bone collagen peptide beverage based on bioinformatics technology guidance. BACKGROUND
[0002] With the aging of the population, osteoporosis is gradually becoming a serious global health problem, affecting more than 200 million people worldwide. This condition can cause lower back pain, hunched back, loss of height and fractures. Due to the decrease in bone mass, patients have an increased risk of bone fragility and fractures. If not prevented or treated, it will progress painlessly and lead to serious fractures of the wrist, hip and spine, causing disability and death in the elderly.
[0003] Most of the existing drugs for treating and improving osteoporosis are accompanied by abdominal pain, diarrhea, nausea, constipation and indigestion. At the same time, the health foods on the market for relieving osteoporosis are single and limited in number, especially lacking related drinks, and the specific effects have not been proven.
[0004] Therefore, it is the most ideal way to develop a health drink that can improve osteoporosis, improve bone health, has good safety and no toxic side effects, and regulate bone health through diet, which meets the modern health concept of "preventing disease" and has a broad market prospect. SUMMARY
[0005] The purpose of the present application is to provide a compound bovine bone collagen peptide beverage based on bioinformatics technology guidance to solve the problems raised in the background.
[0006] To achieve the above purpose, the present application provides the following technical scheme: a compound bovine bone collagen peptide beverage based on bioinformatics technology guidance, the preparation raw materials of the compound bovine bone collagen peptide beverage comprising: bovine bone collagen peptide powder, red jujube polysaccharide, astragalus polysaccharide, calcium carbonate, chondroitin sulfate and sodium hyaluronate; The specific step process of the compound bovine bone collagen peptide beverage preparation method is as follows: Step one, bioinformatics assisted formula optimization and raw material screening: using bioinformatics database to retrieve the core active ingredients of each raw material, and confirming and pretreating the specifications of various raw materials; Step two, crushing: crushing various raw materials, and detecting the particle size of the crushed particles; Step three, targeted mixing: sequentially mixing various raw materials in order, and controlling the mixing environment; Step four, low-temperature drying: drying the mixed mixture until the moisture content meets the requirements; Step five, granulation: granulating the dried beverage solids; Step six, quality detection: the prepared beverage particles are detected for safety and nutrition indicators.
[0007] Preferably, the specific amount of the preparation raw materials of the compound bovine bone collagen peptide beverage is: 60-80 parts of bovine bone collagen peptide powder, 8-10 parts of red jujube polysaccharide, 5-10 parts of astragalus polysaccharide, 3-5 parts of calcium carbonate, 3-5 parts of chondroitin sulfate, and 2-7 parts of sodium hyaluronate.
[0008] Preferably, in step one, the raw materials are weighed according to the formula, the purity of the raw materials is verified, HPLC combined with bioinformatics auxiliary data processing is used to verify that the content of active ingredients of each raw material meets the design requirements of the formula, and the impurity exceeding raw materials are removed.
[0009] Preferably, the specific steps of step two are as follows: a jet mill is used to crush the raw materials, first, the crushing pressure of the jet mill is adjusted to 0.6-0.8 MPa, the feeding speed is 10-15 kg / h, and the bovine bone collagen peptide and polysaccharide raw materials are crushed; secondly, the crushing pressure of the jet mill is adjusted to 1.0-1.2 MPa, and the feeding speed is 8-10 kg / h for crushing calcium carbonate. After complete crushing, a laser particle size analyzer is used for detection, and bioinformatics tools are used to analyze the particle size distribution data to ensure that the particle size of all crushed raw materials is ≤10 μm. The crushed raw materials are immediately sealed and stored in a dry environment.
[0010] Preferably, the specific steps of step three are as follows: the various raw materials are mixed, first, the bovine bone collagen peptide powder is added, mixed at a low speed of 150 r / min for 5 min, then the red jujube polysaccharide and astragalus polysaccharide are added, mixed at a medium speed of 300 r / min for 10 min, finally, the calcium carbonate, chondroitin sulfate, and sodium hyaluronate are added, mixed at a high speed of 500 r / min for 15 min; near-infrared spectroscopy is used to monitor the mixing process in real time to ensure that the variation coefficient (CV) of the mixing uniformity is ≤3%, avoid local component concentration deviation, and the mixing environment is guaranteed at a temperature of 20-25°C and a humidity of ≤40%.
[0011] Preferably, the specific steps of step four are as follows: the raw material mixture is dried by vacuum freeze-drying, the vacuum degree is controlled at 0.08-0.1 MPa, and the drying time is 8-12 h; after drying, the moisture content is detected by a moisture meter to ensure that the moisture content is ≤5%; if the moisture content exceeds the standard, the drying time can be extended by 2-4 h.
[0012] Preferably, the specific steps of step five are as follows: the dried mixed powder is added into a dry granulator, the pressure roller pressure is set to 5-8 MPa, the granulation rotation speed is set to 50-80 r / min, after granulation, the granules are screened through a vibrating screen, the screen mesh size is 50 μm in the lower layer and 100 μm in the upper layer, respectively, the 50-100 μm granules are collected, the large granules on the screen are returned to the granulator for re-granulation, and the fine powder under the screen is returned to the mixing step for re-mixing.
[0013] Compared with the prior art, the application has the following beneficial effects: The compound bovine bone collagen peptide beverage in the application contains a large amount of collagen in bovine bone, is rich in type I collagen, and has more abundant amino acid composition. A large number of research results show that after protein intake, the protein is not completely hydrolyzed into amino acids, but is mostly absorbed in the form of peptides. Therefore, the bovine bone collagen peptide powder can be better absorbed by the human body. Red dates have the effects of beautifying and anti-aging. In addition, the compound bovine bone collagen peptide beverage is supplemented with other traditional Chinese medicine extracts such as astragalus, thereby enhancing the functional properties and improving the original bad flavor of the animal peptide. BRIEF DESCRIPTION OF DRAWINGS
[0014] Figure 1 It is a formula chart of raw and auxiliary materials of the compound bovine bone collagen peptide beverage; Figure 2 It is an efficacy comparison chart of each component of the bovine bone collagen peptide compound solid beverage; Figure 3 It is a change in the influence of the bovine bone collagen peptide compound solid beverage on the ALP activity of osteoblasts; Figure 4 It is a change in the influence of the bovine bone collagen peptide compound solid beverage on the OCN content of osteoblasts; Figure 5 It is a change in the influence of the bovine bone collagen peptide compound solid beverage on the CO1-I content of osteoblasts; Figure 6 It is an alizarin red staining and semi-quantitative result of the bovine bone collagen peptide compound solid beverage on osteoblasts; Figure 7 It is a quantitative result of the bovine bone collagen peptide compound solid beverage on the matrix calcium content of osteoblasts.
[0015] Figure 2 In the figure, “RD” represents red date polysaccharide, “BBCP” represents bovine bone collagen peptide, “Model group” is an osteoporosis model group, “Control group” is a normal control group, and “Alendronate” is a positive control drug (alendronate sodium). DETAILED DESCRIPTION
[0016] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by a person of ordinary skill in the art without creative effort belong to the scope of protection of the present application.
[0017] Please refer to Figures 1-7 The present application provides a technical solution: a compound bovine bone collagen peptide beverage based on bioinformatics guidance, and the preparation raw materials of the compound bovine bone collagen peptide beverage include bovine bone collagen peptide powder, red date polysaccharide, astragalus polysaccharide, calcium carbonate, chondroitin sulfate and sodium hyaluronate. The specific step process of the compound bovine bone collagen peptide beverage preparation method is as follows: Step one, bioinformatics assisted formula optimization and raw material screening: the core active ingredients of each raw material are retrieved by using a bioinformatics database, and the specifications of various raw materials are confirmed and pretreated; Step two, crushing: the various raw materials are crushed, and the particle size of the crushed particles is detected; Step three, targeted mixing: the various raw materials are sequentially mixed in order, and the mixing environment is controlled; Step four, low-temperature drying: the mixture after mixing is dried until the moisture content meets the requirements; Step five, granulation: the solid of the dried beverage is granulated; Step six, quality detection: the prepared beverage particles are detected for safety and nutrition indicators.
[0018] The specific amount of the preparation raw materials of the compound bovine bone collagen peptide beverage is: 60-80 parts of bovine bone collagen peptide powder, 8-10 parts of red date polysaccharide, 5-10 parts of astragalus polysaccharide, 3-5 parts of calcium carbonate, 3-5 parts of chondroitin sulfate, and 2-7 parts of sodium hyaluronate.
[0019] In step one, the raw materials are weighed according to the formula ratio, and the purity of the raw materials is verified. HPLC combined with bioinformatics assisted data processing is used to verify that the active ingredient content of each raw material meets the formula design requirements, and the impurity exceeding raw materials are removed.
[0020] The specific steps of step two are as follows: the raw materials are crushed using an air flow crusher. First, the crushing pressure of the air flow crusher is adjusted to 0.6-0.8 MPa, and the feeding speed is 10-15 kg / h. The bovine bone collagen peptide and polysaccharide raw materials are crushed. Then, the crushing pressure of the air flow crusher is adjusted to 1.0-1.2 MPa, and the feeding speed is 8-10 kg / h. The calcium carbonate is crushed. After the complete crushing, a laser particle size analyzer is used for detection, and the particle size distribution data are analyzed by bioinformatics tools to ensure that the particle size of all raw materials is ≤10 μm after crushing. The crushed materials are immediately sealed and stored in a dry environment.
[0021] The specific steps of step three are as follows: the raw materials are mixed, the bovine bone collagen peptide powder is first added, mixed at a low speed of 150 r / min for 5 min, then the jujube polysaccharide and astragalus polysaccharide are added, mixed at a medium speed of 300 r / min for 10 min, and finally the calcium carbonate, chondroitin sulfate and sodium hyaluronate are added, mixed at a high speed of 500 r / min for 15 min; the mixing process is monitored in real time by near-infrared spectroscopy to ensure that the variation coefficient (CV) of the mixing uniformity is ≤3%, to avoid local component concentration deviation, and the mixing environment is ensured at a temperature of 20-25°C and a humidity of ≤40%.
[0022] The specific steps of step four are as follows: the raw material mixture is dried by vacuum freeze-drying, the vacuum degree is controlled at 0.08-0.1 MPa, and the drying time is 8-12 h to ensure slow evaporation of water and protect the tertiary structure of collagen peptide and the active groups of polysaccharide; after drying, the moisture content is detected by a moisture meter to ensure that the moisture content is ≤5%; if the moisture content exceeds the standard, the drying time can be extended by 2-4 h.
[0023] The specific steps of step five are as follows: the dried mixed powder is added to a dry granulator, the roller pressure is set at 5-8 MPa, and the granulation speed is set at 50-80 r / min; after granulation, the particles are screened by a vibrating screen, the screen mesh size is 50 μm at the lower layer and 100 μm at the upper layer, the 50-100 μm particles are collected, the large particles on the screen are returned to the granulator for re-granulation, and the fine powder under the screen is returned to the mixing step for re-mixing.
[0024] Based on bioinformatics technology, the raw material combination scheme is screened, and the alkaline phosphatase (ALP) activity is used as an indicator to screen and optimize the main raw materials bovine bone collagen peptide, jujube polysaccharide and astragalus polysaccharide; the specific screening method includes: screening the active ingredients of jujube polysaccharide and astragalus polysaccharide through the TCMSP database, constructing the protein interaction network of bone metabolism related targets (such as RUNX2, BMP-2, OCN) by using the STRING database, combining the molecular docking technology (AutoDock Vina software) to predict the binding energy (≤-5 kcal / mol) of the components and the targets, and screening the raw material combination with synergistic effect; the osteocalcin (OCN) and type I collagen (COL-1) contents are determined by cell experiments to evaluate the osteogenic effect of the combination scheme; The use of the beverage in preparing a solid functional food for improving osteoporosis in middle-aged and elderly women, the daily consumption of the food is 200-900 mg, and the bovine bone collagen peptide powder is 140-630 mg.
[0025] Example 1: A compound bovine bone collagen peptide beverage based on bioinformatics guidance is composed of 60 parts bovine bone collagen peptide powder, 8 parts jujube polysaccharide, 5 parts astragalus polysaccharide, 3 parts calcium carbonate, 3 parts chondroitin sulfate, and 2 parts sodium hyaluronate. Example 2: A compound bovine bone collagen peptide beverage based on bioinformatics guidance is composed of 70 parts bovine bone collagen peptide powder, 9 parts jujube polysaccharide, 7 parts astragalus polysaccharide, 4 parts calcium carbonate, 4 parts chondroitin sulfate, and 5 parts sodium hyaluronate. Example 3: A compound bovine bone collagen peptide beverage based on bioinformatics guidance is composed of 80 parts bovine bone collagen peptide powder, 10 parts jujube polysaccharide, 8 parts astragalus polysaccharide, 5 parts calcium carbonate, 5 parts chondroitin sulfate, and 7 parts sodium hyaluronate. Comparative Example 1: To further illustrate the beneficial effects of the present invention, Comparative Example 1 is provided. Compared with Example 1, the difference of Comparative Example 1 is that the ratio of the main components of the present invention, bovine bone collagen peptide powder and jujube polysaccharide, is adjusted, and the efficacy of the compound product and single bovine bone collagen peptide powder and single jujube polysaccharide are compared. The efficacy of the main components is compared to facilitate the selection of the optimal ratio. Comparative Example 2: To further illustrate the beneficial effects of the present invention, Comparative Example 2 is provided. Compared with Example 2, the difference of Comparative Example 2 is that the ratio of the main components of the present invention, bovine bone collagen peptide powder and jujube polysaccharide, is adjusted, and the efficacy of the compound product and single bovine bone collagen peptide powder and single jujube polysaccharide are compared. The efficacy of the main components is compared to facilitate the selection of the optimal ratio. Comparative Example 3: To further illustrate the beneficial effects of the present invention, Comparative Example 3 is provided. Compared with Example 3, the difference of Comparative Example 3 is that the ratio of the main components of the present invention, bovine bone collagen peptide powder and jujube polysaccharide, is adjusted, and the efficacy of the compound product and single bovine bone collagen peptide powder and single jujube polysaccharide are compared. The efficacy of the main components is compared to facilitate the selection of the optimal ratio. like Figure 2 As shown, after testing, comparative examples 1, 2, and 3 of the compound formulation of this invention were compared with the model group. The study found that the alkaline phosphatase (ALP) content in comparative examples 1 and 2 was increased, but not significantly, promoting osteoblast differentiation. Comparative example 3 showed significantly higher activity than the model group. At the same concentration, ALP values were measured for different ratios of BBCP and RD compound, single RD, and single BBCP. As shown in the figure, the ALP content of single RD and single BBCP increased, but not significantly. Functional Example 1: ALP content: The present application provides a compound bovine collagen peptide beverage based on bioinformatics guidance. Functional experiments are conducted on the anti-osteoporosis activity of the compound product. The test concentration is set to low (0.1 mg / ml), medium (0.5 mg / ml), and high (1.0 mg / ml) concentration gradients. The protection and differentiation promotion of osteoblasts MC3T3-E1 are studied. The product's effect on the alkaline phosphatase content of osteoblasts is detected. ALP is a specific enzyme secreted by osteoblasts, and its activity directly reflects the degree of osteoblast differentiation. By adding different concentrations of the formula (low, medium, and high) to the differentiation induction medium and measuring the ALP activity in osteoblasts at 3 and 7 days (3 replicates per group, n=3), the effect of the formula on osteoblast differentiation is studied.
[0026] As shown in Figure 3 , after testing, it is found that the ALP activity of the compound formula (low, medium, and high) is significantly higher than that of the model group, and shows a dose-dependent effect (P<0.01), which promotes the differentiation of osteoblasts. In Functional Example 1, the comparison with the comparative example shows that the example can increase the alkaline phosphatase content and promote the differentiation of osteoblasts, thereby improving osteoporosis. p
[0027] Functional Example 2: COL-1 content: Type I collagen is an important factor affecting the mineralization of bone matrix. The effect of different concentrations of the formula on the CoL-1 content in osteoblasts is shown in Figure 4 . The detection method is ELISA, with 3 replicates per group (n=3). Compared with the model group, the CoL-1 content of each formula experimental group increases (P<0.05), and this increase is dose-dependent. With increasing concentration, the difference between CoL-1 content and the model group becomes more significant. When the concentration is low, there is a significant difference in CoL-1 content compared with the model group (P<0.05). When the dose is medium or high, the difference is extremely significant compared with the model group (P<0.01). This indicates that the formula can increase the CoL-1 content in osteoblasts. p p p
[0028] Functional Example 3: OCN content: OCN is the main component of non-collagen proteins in bone tissue and belongs to non-collagen acidic glycoprotein. It can reflect the activity of osteoblasts or bone formation and is an important indicator of bone formation. The effect of different concentrations of the formula on the OCN content of osteoblasts is shown in Figure 5 Each group was repeated 3 times (n=3). The OCN content of the model group was significantly higher than that of the control group p <0.05). Compared with the model group, the formula could dose-dependently increase the OCN content. With the increase of concentration, the difference of OCN content with the model group was more significant. This indicates that the product formula can increase the osteocalcin in osteoblasts. This is similar to the effect of collagen hydrolysate in the literature, indicating that the formula may enhance the synthesis of cyanate, further promote the differentiation of osteoblasts, and induce bone remodeling and bone formation.
[0029] Functional Example 4: Alizarin Red Staining and Calcium Nodule Quantification: Mineralized nodules are a marker of osteoblast differentiation and maturation, and are also the main morphological feature of osteoblasts to perform osteogenesis. Observing the mineralized nodules of osteoblasts is one of the common technical methods for studying osteoblast differentiation.
[0030] Osteoblast mineralization staining experiment method: The medium was changed every 3-4 days, and the cells were induced to differentiate for 21 days. After the culture was completed, the alizarin red staining experiment was performed according to the following steps: ① After the culture solution was aspirated, it was gently washed with pre-cooled PBS for 2-3 times; ② 3%-5% paraformaldehyde fixation for 15 min, discard the fixing solution, and wash with ultrapure water for 2-3 times; ③ After the water was completely aspirated, alizarin red S staining solution was slowly added, and the cells were stained at room temperature for 20-30 min; ④ Discard the dye and wash with ultrapure water for 2-3 times; ⑤ Add appropriate ultrapure water to each well, randomly select the field of view under low magnification, and count the mineralized nodules.
[0031] Since alizarin red S can chelate with calcium in calcium carbonate or calcium phosphate to form an orange-red complex, it is used to locate calcium deposition in tissues. As shown in Figure 6 As shown, low, medium, and high concentrations can promote the mineralization ability of osteoblasts and promote calcium deposition, and medium and high concentrations are particularly obvious compared with the model group, and have a certain significance, as shown in Figure 7 As shown, the cell matrix calcium content (semi-quantitative) is consistent with the staining results.
[0032] The foregoing illustrates and describes embodiments of the present application. However, it is to be understood that the application is not limited to the above-described embodiments, and that various changes and modifications can be suggested to one skilled in the art. It is intended that the present application encompass any and all such changes and modifications without departing from the spirit or scope of the underlying principles of the application. In addition, it should be understood that the figures are not necessarily drawn to scale and that, where appropriate, reference numerals have been maintained from one figure to another and from one embodiment to another in order to illustrate similar constructions.
[0033] While the application has been illustrated and described in detail in the drawings and foregoing description, the same is to be considered as illustrative and not restrictive in character, since the scope of the application is indicated by the appended claims rather than by the foregoing description, and all changes and modifications that come within the meaning of the claims are desired to be embraced therein.
Claims
1. A compound cow bone collagen peptide beverage based on bioinformatics guidance, characterized in that, The preparation raw materials of the compound bovine bone collagen peptide beverage include: bovine bone collagen peptide powder, red jujube polysaccharide, astragalus polysaccharide, calcium carbonate, chondroitin sulfate and sodium hyaluronate; The specific step process of the compound bovine bone collagen peptide beverage preparation method is as follows: Step one, bioinformatics assisted formula optimization and raw material screening: use bioinformatics database to search the core active ingredients of each raw material, and confirm and pretreat the specifications of various raw materials; Step two, crushing: crush various raw materials, and detect the particle size of the crushed particles; Step three, targeted mixing: sequentially mix various raw materials in order, and control the mixing environment; Step four, low-temperature drying: dry the mixed mixture until the moisture content meets the requirements; Step five, granulation: granulate the dried beverage solids; Step six, quality detection: detect the safety and nutrition indicators of the prepared beverage particles.
2. The compound collagen peptide beverage based on bioinformatics according to claim 1, characterized in that: The specific amount of the preparation raw materials of the compound bovine bone collagen peptide beverage is: 60-80 parts of bovine bone collagen peptide powder, 8-10 parts of red jujube polysaccharide, 5-10 parts of astragalus polysaccharide, 3-5 parts of calcium carbonate, 3-5 parts of chondroitin sulfate, and 2-7 parts of sodium hyaluronate.
3. The compound collagen peptide beverage based on bioinformatics according to claim 1, characterized in that: In step one, the raw materials are weighed according to the formula, and the purity of the raw materials is verified. HPLC combined with bioinformatics assisted data processing is used to verify that the active ingredient content of each raw material meets the requirements of the formula design, and the impurity exceeding raw materials are removed.
4. The compound collagen peptide beverage based on bioinformatics according to claim 1, characterized in that: The specific steps of step two are as follows: use an air flow crusher to crush the raw materials. First, adjust the crushing pressure of the air flow crusher to 0.6-0.8 MPa, and the feeding speed to 10-15 kg / h to crush the bovine bone collagen peptide and polysaccharide raw materials. Then, adjust the crushing pressure of the air flow crusher to 1.0-1.2 MPa, and the feeding speed to 8-10 kg / h to crush the calcium carbonate; After complete crushing, use a laser particle size analyzer to detect the particle size distribution data, and ensure that the particle size of all crushed raw materials is ≤10 μm. The crushed raw materials are immediately sealed and stored in a dry environment.
5. The compound collagen peptide beverage based on bioinformatics according to claim 1, characterized in that: The specific steps of step three are as follows: mix the various raw materials. First, add the bovine bone collagen peptide powder and mix at a low speed of 150 r / min for 5 min. Then, add the red jujube polysaccharide and astragalus polysaccharide and mix at a medium speed of 300 r / min for 10 min. Finally, add the calcium carbonate, chondroitin sulfate and sodium hyaluronate and mix at a high speed of 500 r / min for 15 min. Use near-infrared spectroscopy to monitor the mixing process in real time to ensure that the variation coefficient (CV) of the mixing uniformity is ≤3% and avoid local component concentration deviation. The mixing environment is controlled to have a temperature of 20-25 ℃ and a humidity of ≤40%.
6. The compound collagen peptide beverage based on bioinformatics according to claim 1, characterized in that: The specific steps of step four are as follows: dry the raw material mixture by vacuum freeze-drying, control the vacuum degree to 0.08-0.1 MPa, and dry for 8-12 h. After drying, detect the moisture content by a moisture meter to ensure that the moisture content is ≤5%; If the moisture content exceeds the standard, the drying time can be extended by 2-4 h.
7. The compound collagen peptide beverage based on bioinformatics according to claim 1, characterized in that: The specific step of the step five is as follows: the dried mixed powder is added into a dry granulator, the roller pressure is set to 5-8 MPa, the granulating rotating speed is set to 50-80 r / min, after granulating, the granules are screened through a vibrating screen, the mesh size of the screen is 50 μm in the lower layer and 100 μm in the upper layer, the granules with the size of 50-100 μm are collected, the large granules on the screen are returned to the granulator for re-granulating, and the fine powder under the screen is returned to the mixing step for re-mixing.