A granule production method for reducing loss of active ingredients

Abstract

This invention discloses a method for producing granules that reduces the loss of active ingredients, relating to the field of granule preparation technology. This method addresses the problem of active ingredient loss in traditional granule production due to high temperatures, oxidation, mechanical friction, and solvent residue. It employs a four-stage process—low-temperature pretreatment, inert gas-protected granulation, gradient drying, and nano-coating and end-capping—combined with the application of a specialized composite binder, significantly improving the retention rate of active ingredients. Experimental data shows that granules produced using this method have a higher retention rate of active ingredients than those produced by traditional methods, while also exhibiting high granule formation rate and dissolution rates that meet relevant standards. The process of this invention is highly stable and widely adaptable, and can be widely applied to granule production in the pharmaceutical, pesticide, food, and feed industries.

Description

Technical Field

[0001] This invention belongs to the field of granule preparation technology, specifically relating to a granule production method that can reduce the loss of active ingredients during the entire production process, and is particularly suitable for the preparation of granules containing heat-sensitive, easily oxidized or easily volatile active ingredients. Background Technology

[0002] Granules, as a common dosage form, are widely used in pharmaceuticals, pesticides, and food additives due to their convenient administration, rapid dissolution, and good stability. Granule production typically involves core steps such as raw material crushing, mixing, granulation, drying, and sizing. However, in existing production processes, the loss of active ingredients remains a prominent issue, becoming a key bottleneck restricting product quality. The main shortcomings of existing technologies are as follows: Firstly, in the raw material crushing stage, the mechanical friction generated by traditional high-speed crushing equipment leads to increased material temperature, causing irreversible degradation of heat-sensitive components and resulting in a high loss rate. Therefore, a granule production method that reduces the loss of active ingredients is needed.

[0003] Based on this, a search revealed that Chinese patent application number 201911315470.6 discloses a method for producing granules. In this method, the elastic mechanism adjusts the spacing until the raw material powder formed by the pulverizing device meets a predetermined threshold. The rotating platform rotates at a fourth rotational speed, the negative pressure unit draws airflow at a second pressure, the stirrer rotates at a fifth rotational speed, and the cutting blade rotates at a third rotational speed at a predetermined cutting height and angle to cut and form granules. For example, Chinese patent CN108785281A discloses a method for preparing traditional Chinese medicine granules by low-temperature pulverization, which solves the problem of degradation of heat-sensitive components in the pulverization stage. However, it still uses traditional processes in the granulation and drying stages, resulting in a low total retention rate of effective components.

[0004] It is known that the above-mentioned patents have the following shortcomings: traditional granule production methods only optimize a single process step, such as low-temperature pulverization, and lack the problem of preventing loss throughout the entire process; while granules have poor forming quality, high brittleness, and unstable content of active ingredients, the single production method has low adaptability and is difficult to meet the production needs of granules in different fields.

[0005] To address the aforementioned issues, a method for producing granules that reduces the loss of active ingredients is proposed. Summary of the Invention

[0006] The purpose of this invention is to provide a granule production method that reduces the loss of active ingredients. By using this device, the invention solves the problems of traditional granule production methods in the background art, which only optimize a single process step, such as low-temperature pulverization, and fail to prevent loss throughout the entire process. Furthermore, these methods also address the quality issues of poor granule formation, high brittleness, and unstable active ingredient content. Additionally, the invention addresses the limitations of single production methods, which have low adaptability and cannot meet the granule production needs of different fields.

[0007] To achieve the above objectives, the present invention provides the following technical solution: a method for producing granules with reduced loss of active ingredients, comprising the following steps: Step 1: Low-temperature inert gas protected pulverization, where raw materials are mixed with an inert diluent and pulverized under liquid nitrogen cooling via airflow; Step 2: Preparation of composite binder, where natural polysaccharides and functional polymers are mixed, and an antioxidant is added after stirring with warm water; Step 3: Inert gas protected granulation, where the composite binder is sprayed into ultrafine powder for granulation under a sealed nitrogen environment; Step 4: Gradient vacuum drying, where surface water is removed first at low temperature and low vacuum, and internal water is removed at high temperature and high vacuum, with periodic nitrogen purging; Step 5: Nano-coating and end-capping, where PLGA is coated by fluidized bed spray coating; Step 6: Aseptic packaging, where aluminum-plastic encapsulation is performed under inert gas protection.

[0008] Preferably, in step one, the mass ratio of raw material to inert diluent is 1:0.2-0.5, the inert diluent is sterilized diatomaceous earth or silica with a particle size of 5-10 μm; the grinding chamber temperature is -20℃ to -5℃, the airflow speed is 15-25 m / s, and the particle size of the powder after grinding is 10-50 μm.

[0009] This particle size range ensures sufficient contact between the powder and the binder, while avoiding agglomeration caused by excessively fine particles, thus improving granulation uniformity.

[0010] Preferably, in step two, the mass ratio of natural polysaccharide to functional polymer is 2:1-3:1, the natural polysaccharide is gum arabic or xanthan gum, and the functional polymer is povidone K30 or hydroxypropyl-β-cyclodextrin; the mass concentration of the composite adhesive is 5%-8%, and the amount of antioxidant is 0.1%-0.3% of the total mass of the colloid.

[0011] The ratio of natural polysaccharides to functional polymers has been optimized to ensure bonding strength while avoiding slow dissolution caused by excessive bonding. The precise dosage of antioxidants can maximize the anti-oxidation effect without affecting product safety.

[0012] Preferably, in step three, the nitrogen pressure in the granulator is 0.12-0.15 MPa, the stirring speed is 100-150 r / min, the amount of binder is 15%-25% of the total powder mass, the droplet size is 50-100 μm, and the wet particle size is 0.5-2 mm.

[0013] The matching design of droplet size and powder size can achieve uniform coverage of the binder, avoid insufficient local adhesion or excessive wetting, and improve the consistency of particle forming.

[0014] Preferably, the first stage of gradient drying in step four is characterized by a vacuum of 0.05-0.07 MPa, a temperature of 30-40°C, and a time of 15-20 minutes; the second stage is characterized by a vacuum of 0.08-0.095 MPa, a temperature of 45-55°C, and a time of 30-45 minutes; nitrogen purging is performed at 10-minute intervals, with each purging lasting 2 minutes.

[0015] The synergistic design of gradient temperature and vacuum can quickly remove moisture while avoiding the loss of active ingredients due to sudden temperature rises or moisture migration.

[0016] Preferably, in step five, the coating solution is a dichloromethane-ethanol mixed solution of PLGA, with a PLGA mass concentration of 2%-4% and a dichloromethane to ethanol volume ratio of 1:1; the coating conditions are an inlet air temperature of 35-45℃, an outlet air temperature of 25-30℃, an atomization pressure of 0.2-0.3MPa, a spray rate of 1-3mL / min, and a coating amount of 3%-5%.

[0017] This coating parameter can form a uniformly thick nanoscale coating film (50-200nm thick), which ensures the isolation effect without affecting the dissolution of effective ingredients in gastrointestinal fluid.

[0018] Preferably, in step six, the oxygen content of the packaging environment is less than 0.5%, and the packaging material is an aluminum-plastic composite film.

[0019] The barrier properties of the plastic composite film can effectively prevent the penetration of oxygen and moisture during storage. Combined with nitrogen replacement, it can further extend the shelf life of the product.

[0020] Preferably, the antioxidant is vitamin E or tea polyphenols, wherein vitamin E is selected when the active ingredient is fat-soluble, and tea polyphenols are selected when the active ingredient is water-soluble.

[0021] This selective combination can improve the compatibility of antioxidants with active ingredients and enhance the targeted nature of antioxidant protection.

[0022] Preferably, during the nitrogen purging process, the nitrogen introduction rate is 0.5-1 L / min to ensure that the residual amount of volatile components in the drying oven is less than 0.1%; the molecular weight of the PLGA is 20,000-60,000, and the molar ratio of lactic acid to glycolic acid is 50:50-75:25 to ensure that the degradation rate of the coating film matches the dissolution rate of the active ingredient; in step three, the stirring paddle of the closed granulator adopts an arc-shaped structure, and the gap between the stirring paddle and the machine wall is 2-5 mm to reduce the loss of active ingredients caused by powder sticking to the wall.

[0023] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0024] 1. The present invention provides a granule production method that reduces the loss of effective ingredients. Compared with the prior art, the present invention uses nitrogen or liquid nitrogen protection in all key steps from crushing to packaging to completely isolate oxygen, reduce the loss rate of effective ingredients caused by oxidation, and protect the entire process with inert gas.

[0025] 2. The combination of liquid nitrogen cooling in the pulverization stage and gradient low-temperature drying in the drying stage ensures that the highest temperature throughout the production process does not exceed 55℃, resulting in low degradation rate of heat-sensitive components, improved retention rate of volatile components, and synergistic low-temperature control.

[0026] 3. The inclusion effect of the composite adhesive and the physical isolation effect of the PLGA nano-coating form a dual protection, effectively preventing the active ingredients from contacting the external environment, while reducing the shedding of surface components caused by mechanical collisions. The granule production method forms a composite protection system.

[0027] 4. Granules produced using this method have a high forming rate, low brittleness, and dissolution rate that meets the relevant standards of the Chinese Pharmacopoeia. The total retention rate of active ingredients is higher than that of traditional methods, resulting in excellent product quality.

[0028] 5. The granule production method of the present invention can adjust the types and amounts of inert diluents, binders and coating materials according to the physicochemical properties of different active ingredients, and is applicable to granule production in multiple fields such as pharmaceuticals, pesticides, and food, thereby improving the flexibility of the method. Attached Figure Description

[0029] Figure 1 This is a schematic flowchart of the granule production method for reducing the loss of active ingredients according to the present invention. Detailed Implementation

[0030] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0031] To further understand the content of this invention, a detailed description of the invention will be provided in conjunction with the accompanying drawings.

[0032] Combination Figure 1A method for producing granules with reduced loss of active ingredients includes the following steps: Step 1: Low-temperature inert gas-protected pulverization, where raw materials are mixed with an inert diluent and pulverized under liquid nitrogen cooling via airflow; Step 2: Preparation of composite binder, where natural polysaccharides and functional polymers are mixed, and antioxidants are added after stirring with warm water; Step 3: Granulation under inert gas protection, where the composite binder is sprayed into ultrafine powder for granulation under a sealed nitrogen environment; Step 4: Gradient vacuum drying, where surface water is removed first at low temperature and low vacuum, and internal water is removed at high temperature and high vacuum, with periodic nitrogen purging; Step 5: Nano-coating and end-capping, where PLGA is coated using a fluidized bed spray coating; Step 6: Aseptic packaging, where aluminum-plastic packaging is performed under inert gas protection.

[0033] In step one, the mass ratio of raw material to inert diluent is 1:0.2-0.5. The inert diluent is sterilized diatomaceous earth or silica with a particle size of 5-10μm. The grinding chamber temperature is -20℃ to -5℃, the airflow speed is 15-25m / s, and the particle size of the powder after grinding is 10-50μm.

[0034] In step two, the mass ratio of natural polysaccharide to functional polymer is 2:1-3:1. The natural polysaccharide is gum arabic or xanthan gum, and the functional polymer is povidone K30 or hydroxypropyl-β-cyclodextrin. The mass concentration of the composite adhesive is 5%-8%, and the amount of antioxidant is 0.1%-0.3% of the total mass of the colloid.

[0035] In step three, the nitrogen pressure in the granulator is 0.12-0.15 MPa, the stirring speed is 100-150 r / min, the amount of binder is 15%-25% of the total powder mass, the droplet size is 50-100 μm, and the wet particle size is 0.5-2 mm.

[0036] In step four, the first stage of gradient drying is characterized by a vacuum of 0.05-0.07 MPa, a temperature of 30-40°C, and a time of 15-20 minutes; the second stage is characterized by a vacuum of 0.08-0.095 MPa, a temperature of 45-55°C, and a time of 30-45 minutes; nitrogen purging is performed at 10-minute intervals, with each purging lasting 2 minutes.

[0037] In step five, the coating solution is a PLGA dichloromethane-ethanol mixed solution with a PLGA mass concentration of 2%-4% and a dichloromethane to ethanol volume ratio of 1:1. The coating conditions are: inlet air temperature of 35-45℃, outlet air temperature of 25-30℃, atomization pressure of 0.2-0.3MPa, spray rate of 1-3mL / min, and coating amount of 3%-5%.

[0038] In step six, the oxygen content in the packaging environment is below 0.5%, and the packaging material is an aluminum-plastic composite film.

[0039] Antioxidants are vitamin E or tea polyphenols. Vitamin E is chosen when the active ingredient is fat-soluble, and tea polyphenols are chosen when the active ingredient is water-soluble.

[0040] During nitrogen purging, the nitrogen flow rate is 0.5-1 L / min to ensure that the residual amount of volatile components in the drying oven is less than 0.1%.

[0041] PLGA has a molecular weight of 20,000-60,000, with a molar ratio of lactic acid to glycolic acid of 50:50-75:25 to ensure that the degradation rate of the coating film matches the dissolution rate of the active ingredient. In step three, the stirring paddle of the closed granulator adopts an arc-shaped structure, and the gap between the stirring paddle and the machine wall is 2-5mm to reduce the loss of active ingredients caused by powder sticking to the wall.

[0042] Example 1:

[0043] The production of traditional Chinese medicine granules containing volatile oils, using honeysuckle and peppermint as raw materials (containing chlorogenic acid, menthol, and other effective components), employs the method of this invention to produce granules. The specific steps are as follows:

[0044] Step 1: Low-temperature pulverization. Honeysuckle and peppermint extract (chlorogenic acid content 12%, menthol content 8%) are mixed with sterilized diatomaceous earth at a mass ratio of 1:0.3. The mixture is then put into a low-temperature airflow pulverizer, and liquid nitrogen is introduced to control the chamber temperature at -10℃. The airflow speed is 20m / s, and the mixture is pulverized for 6 minutes to obtain 30μm ultrafine powder.

[0045] Step 2: Adhesive preparation: Gum arabic and povidone K30 are mixed at a mass ratio of 2:1, sterile water at 45℃ is added, and the mixture is stirred at 500r / min for 25 minutes to make a 6% colloid. Then, 0.2% vitamin E is added and the mixture is stirred for 8 minutes.

[0046] Step 3: Inert granulation: The powder is put into a closed granulator, nitrogen gas is introduced to 0.13MPa, and the mixture is stirred at 120r / min. The amount of spray binder is 20%, and the mixture is stirred for 8 minutes to obtain 1mm wet granules.

[0047] Step 4: Gradient drying: In a vacuum drying oven, dry at 0.06 MPa and 35°C for 18 minutes, then dry at 0.09 MPa and 50°C for 40 minutes, with nitrogen gas purging for 2 minutes every 10 minutes;

[0048] Step 5: Nanocoating: PLGA is dissolved in dichloromethane-ethanol (1:1) to prepare a 3% coating solution. The fluidized bed has an inlet air temperature of 40°C and an outlet air temperature of 28°C. The atomization pressure is 0.25MPa, and the spray rate is 2mL / min, with a coating amount of 4%.

[0049] Step Six: Packaging: After sieving, the samples are packaged in aluminum-plastic packaging under nitrogen atmosphere with an oxygen content of 0.3%.

[0050] Test results: chlorogenic acid retention rate 92.5%, menthol retention rate 91.2%, granule formation rate 93.8%, friability 1.2%, dissolution rate 90.1% (30 minutes).

[0051] Example 2:

[0052] The production of vitamin C food granules, using vitamin C as the active ingredient, employs the method of this invention, with the following steps:

[0053] Step 1: Low-temperature pulverization: Mix vitamin C powder and silicon dioxide at a ratio of 1:0.2, control the temperature with liquid nitrogen at -5℃, and pulverize for 3 minutes at an airflow speed of 15m / s to obtain 20μm powder;

[0054] Step 2: Adhesive preparation: Xanthan gum and hydroxypropyl-β-cyclodextrin are mixed at a ratio of 3:1 and stirred in water at 50°C for 30 minutes to prepare an 8% colloid. 0.3% tea polyphenols are added.

[0055] Step 3: Inert granulation: Nitrogen pressure 0.12MPa, stirring at 100r / min, binder dosage 15%, to obtain 0.8mm wet granules;

[0056] Step 4: Gradient drying: dry at 0.05MPa and 30℃ for 15 minutes, then dry at 0.08MPa and 45℃ for 30 minutes, with nitrogen purging intervals of 10 minutes;

[0057] Step 5: Nanocoating: PLGA coating solution concentration 2%, inlet air temperature 35℃, outlet air temperature 25℃, coating amount 3%;

[0058] Step Six: Packaging: Nitrogen-environmental packaging with an oxygen content of 0.4%.

[0059] Test results: Vitamin C retention rate 94.1%, molding rate 92.3%, friability 1.0%, dissolution rate 91.5% (20 minutes)

[0060] Example 3:

[0061] Using coenzyme Q10 as the core active ingredient (highly heat-sensitive, easily oxidized, melting point 49℃), this invention produces health food granules suitable for enhancing immunity. The steps are as follows:

[0062] Step 1: Low-temperature pulverization: Mix coenzyme Q10 powder (99% purity) with sterilized diatomaceous earth at a mass ratio of 1:0.4, put it into a low-temperature airflow pulverizer, and pulverize it for 6 minutes with liquid nitrogen to control the temperature of the pulverizing chamber at -12℃ and the airflow speed at 22m / s to obtain 35μm ultrafine mixed powder.

[0063] Step 2: Adhesive preparation: Gum arabic and hydroxypropyl-β-cyclodextrin are mixed at a mass ratio of 2:1, sterile deionized water at 48℃ is added, and the mixture is stirred at 450 rpm for 25 minutes to form a homogeneous colloid with a mass concentration of 7%; vitamin E is added at a mass ratio of 0.2% of the total colloid, and the mixture is stirred for another 8 minutes to prepare a composite adhesive;

[0064] Step 3: Inert Granulation: The ultrafine mixed powder is put into a closed fluidized bed granulator, and nitrogen gas is introduced into the machine to a pressure of 0.14 MPa. The stirring and airflow fluidization device is turned on, and the stirring speed is 130 r / min. The composite binder is evenly sprayed into the fluidized powder in the form of droplets with a diameter of 80 μm through a dual-fluid spray gun. The total amount of binder is 22% of the total mass of the powder. After spraying, stirring is continued for 8 minutes under a nitrogen atmosphere to obtain uniform wet granules with a diameter of 1.2 mm.

[0065] Step 4: Gradient Vacuum Drying: Transfer the wet particles to a vacuum drying oven equipped with nitrogen purging function. In the first stage, dry for 18 minutes at a vacuum of 0.065 MPa and a temperature of 38°C to remove free moisture from the particle surface. In the second stage, increase the vacuum to 0.09 MPa and the temperature to 52°C, and dry for 42 minutes to remove bound moisture from the particles. During the drying process, sterile nitrogen is introduced into the oven every 10 minutes for 2 minutes each time.

[0066] Step 5: Nanocoating: Using PLGA (molecular weight 50,000) as the coating material, it is dissolved in a mixed solvent of dichloromethane and ethanol (volume ratio 1:1) to prepare a coating solution with a mass concentration of 3.5%; the dried particles are fed into a fluidized bed coating machine, the inlet air temperature is controlled at 42℃, the outlet air temperature at 28℃, and the atomization pressure at 0.28MPa, and the coating solution is sprayed at a rate of 2.5mL / min, with a coating amount of 4.5% of the total mass of the particles, to obtain nanocoated particles;

[0067] Step Six: Packaging: After the coated granules are sieved through a 1.0-2.0mm sieve, they are sent into an automatic packaging machine under sterile nitrogen protection. Food-grade aluminum-plastic composite film is used for single-dose packaging. Before sealing, nitrogen is introduced to replace the air inside the packaging to ensure that the oxygen content inside the packaging is less than 0.4%. After packaging, light-proof markings are applied.

[0068] Test results: Coenzyme Q10 retention rate 91.5%, granule formation rate 94.3%, friability 1.0%, dissolution rate 89.7% in simulated gastrointestinal fluid at 37℃ for 30 minutes; after 12 months of storage in the dark at 25℃ and 65% relative humidity, the degradation rate of active ingredients is only 4.1%, which meets the relevant technical requirements for health food product registration.

[0069] Example 4:

[0070] Using ginsenoside Rg1 as the core active ingredient (heat-sensitive, easily degraded above 60℃, and easily oxidized), the following steps are taken to produce immune-enhancing health food granules using the method of this invention:

[0071] Step 1: Low-temperature pulverization: Ginseng total saponin extract (ginsenoside Rg1 content 15%) is mixed with sterilized diatomaceous earth at a mass ratio of 1:0.35, put into a low-temperature airflow pulverizer, and liquid nitrogen is introduced to control the temperature of the pulverization chamber at -8℃. The airflow speed is 20m / s, and pulverization is carried out for 7 minutes to obtain 40μm ultrafine mixed powder.

[0072] Step 2: Adhesive preparation: Xanthan gum and hydroxypropyl-β-cyclodextrin are mixed at a mass ratio of 2.5:1, sterile deionized water at 46℃ is added, and the mixture is stirred at 420 rpm for 26 minutes to form a homogeneous colloid with a mass concentration of 6.5%; tea polyphenols accounting for 0.25% of the total mass of the colloid are added, and stirring is continued for 7 minutes to prepare a composite adhesive;

[0073] Step 3: Inert Granulation: The ultrafine mixed powder is put into a closed fluidized bed granulator, and nitrogen gas is introduced into the machine to a pressure of 0.135 MPa. The stirring and airflow fluidization device is turned on, and the stirring speed is 125 r / min. The composite binder is evenly sprayed into the fluidized powder in the form of droplets with a diameter of 70 μm through a two-fluid spray gun. The total amount of binder is 19% of the total mass of the powder. After spraying, the mixture is stirred for 7 minutes under a nitrogen atmosphere to obtain uniform wet granules with a diameter of 0.9 mm.

[0074] Step 4: Gradient Vacuum Drying: Transfer the wet particles to a vacuum drying oven equipped with nitrogen purging function. In the first stage, dry for 17 minutes at a vacuum of 0.06 MPa and a temperature of 36°C to remove free moisture from the particle surface. In the second stage, increase the vacuum to 0.085 MPa and the temperature to 50°C, and dry for 38 minutes to remove bound moisture from the particles. During the drying process, sterile nitrogen is introduced into the oven every 10 minutes for 2 minutes each time.

[0075] Step 5: Nanocoating: Using PLGA (molecular weight 45,000) as the coating material, it is dissolved in a mixed solvent of dichloromethane and ethanol (volume ratio 1:1) to prepare a coating solution with a mass concentration of 3.2%; the dried particles are fed into a fluidized bed coating machine, the inlet air temperature is controlled at 41℃, the outlet air temperature is controlled at 27℃, the atomization pressure is 0.26MPa, and the coating solution is sprayed at a rate of 2.2mL / min, with a coating amount of 4% of the total mass of the particles, to obtain nano-coated particles;

[0076] Step Six: Packaging: After the coated granules are sieved through a 0.8-2.2mm sieve, they are sent to an automatic packaging machine under sterile nitrogen protection. Food-grade aluminum-plastic composite film is used for strip packaging, with a net content of 3g per bag. Before sealing, nitrogen is introduced to replace the air inside the packaging to ensure that the oxygen content inside the packaging is less than 0.45%. The packaging is marked with relevant labels indicating that it should be stored in a cool, dark place.

[0077] Test results: Ginsenoside Rg1 retention rate was 92.1%, granule formation rate was 93.9%, friability was 1.2%, and dissolution rate was 90.3% in simulated gastrointestinal fluid at 37℃ for 45 minutes; after 18 months of storage in the dark at 20℃ and 70% relative humidity, the degradation rate of active ingredients was only 5.3%, which meets the technical requirements for health food registration products and the relevant provisions of the national food safety standards for health foods.

[0078] This experiment used the core process step as a single-factor variable, comparing the "full-process optimization scheme" with a "comparative example lacking a single key process" to verify the impact of each innovation on the retention rate of effective ingredients, granule formation rate, friability, and dissolution. Ginsenoside Rg1 granules, containing heat-sensitive and easily oxidized effective ingredients, were selected as the research object; only one variable was changed, while all other parameters remained constant.

[0079] Comparative Example 1:

[0080] The process lacks low-temperature inert gas protection during pulverization and instead employs traditional room-temperature pulverization.

[0081] Variables: No liquid nitrogen cooling (room temperature 25℃) and no nitrogen protection were used in the pulverizing process; otherwise, the process was the same as in the previous example.

[0082] The test results are as follows: the retention rate of ginsenoside Rg1 is 78.3%, the granulation rate is 85.6%, the friability is 2.8%, the dissolution rate at 45 minutes is 86.7%, and the degradation rate at 18 months (20℃, RH 70%) is 8.9%.

[0083] Comparative Example 2:

[0084] Lacking composite adhesive and antioxidant, it uses a single gum arabic adhesive without antioxidant;

[0085] Variables: The adhesive was single gum arabic (6.5% concentration), without added tea polyphenols, otherwise the same as in the example;

[0086] The test results are as follows: ginsenoside Rg1 retention rate 83.5%, granule formation rate 82.1%, friability 3.5%, 45-minute dissolution rate 84.2%, and 18-month degradation rate (20℃, RH 70%) 10.2%.

[0087] Comparative Example 3:

[0088] Granulation without inert gas protection, granulation in ambient air environment;

[0089] Variable: The granulation process is not protected by nitrogen and is exposed to air (oxygen content 21%), otherwise the same as in the example;

[0090] The test results are as follows: ginsenoside Rg1 retention rate 81.7%, granule formation rate 90.3%, friability 1.5%, 45-minute dissolution rate 88.9%, and 18-month degradation rate (20℃, RH70%) 9.5%.

[0091] Comparative Example 4:

[0092] Lacking gradient vacuum drying, traditional single high-temperature drying was used: 0.09MPa, 50℃, 55 minutes;

[0093] Variables: The drying process involves no gradient control, direct high-temperature drying, and no nitrogen purging; otherwise, it is the same as in the example.

[0094] The test results are as follows: ginsenoside Rg1 retention rate 80.2%, granule formation rate 88.7%, friability 2.1%, 45-minute dissolution rate 85.5%, and 18-month degradation rate (20℃, RH70%) 9.1%.

[0095] Comparative Example 5:

[0096] Lacking nano-coating end-capping, and without PLGA coating treatment;

[0097] Variable: Remove the nano-coating step, and package directly after drying; otherwise, it is the same as in the example.

[0098] The test results are as follows: ginsenoside Rg1 retention rate 84.6%, granule formation rate 92.8%, friability 1.4%, 45-minute dissolution rate 91.1%, and 18-month degradation rate (20℃, RH 70%) 12.7%.

[0099] Comparative Example 6:

[0100] Lacking aseptic packaging and inert gas protection, using conventional aluminum-plastic packaging without nitrogen purging;

[0101] Variables: No nitrogen purging was performed during packaging; the oxygen content inside the packaging was 2.3%; all other parameters were the same as in the example.

[0102] The test results are as follows: ginsenoside Rg1 retention rate 90.5%, granule formation rate 93.6%, friability 1.3%, 45-minute dissolution rate 90.1%, and 18-month degradation rate (20℃, RH70%) 8.4%.

[0103] In summary: Step 1, low-temperature inert gas protected pulverization: The raw material containing the effective components is mixed with an inert diluent at a mass ratio of 1:0.2-0.5 and fed into a low-temperature airflow pulverizer; liquid nitrogen is introduced into the pulverizer, the temperature of the pulverization chamber is controlled at -20℃ to -5℃, the airflow velocity is 15-25m / s, and the pulverization time is 3-8 minutes, to obtain an ultrafine mixed powder with a particle size of 10-50μm; wherein, the inert diluent is sterilized diatomaceous earth or silica with a particle size of 5-10μm, and there are no incompatibilities with the effective components of the raw material;

[0104] This step uses liquid nitrogen cooling to prevent degradation of heat-sensitive components caused by mechanical friction heat generation, an inert gas atmosphere to isolate oxygen and prevent oxidation, and the addition of an inert diluent to reduce collision and wear between raw material particles while preventing the adsorption of active ingredients on the inner wall of the equipment. In addition, the uniform particle size of the ultrafine powder can improve the uniformity of binder coverage in the subsequent granulation process, laying the foundation for the quality of granulation.

[0105] Step 2, preparation of composite adhesive: Mix natural polysaccharides (gum arabic or xanthan gum) and functional polymers (povidone K30 or hydroxypropyl-β-cyclodextrin) at a mass ratio of 2:1-3:1, add to sterile deionized water at 40-50℃, stir at 300-500 r / min for 20-30 minutes to form a homogeneous colloid with a mass concentration of 5%-8%; then add antioxidants (vitamin E or tea polyphenols) at 0.1%-0.3% of the total mass of the colloid, and continue stirring for 5-10 minutes to obtain the composite adhesive;

[0106] In this composite adhesive, natural polysaccharides provide excellent adhesion and film-forming properties, functional polymers protect the active ingredients through inclusion, and antioxidants further enhance the anti-oxidation effect. All components also exhibit good biocompatibility. The synergistic effect of these components not only ensures high particle formation rate but also reduces adverse interactions between the adhesive and the active ingredients, thereby improving product stability.

[0107] Step 3: Inert gas protected granulation: The ultrafine mixed powder obtained in Step 1 is put into a closed granulator, and nitrogen gas is introduced into the machine to a pressure of 0.12-0.15 MPa. The stirring device is turned on and the speed is 100-150 r / min. The composite binder prepared in Step 2 is sprayed evenly into the powder in the form of droplets with a particle size of 50-100 μm through a spraying device. The amount of binder is 15%-25% of the total mass of the powder. After spraying, continue stirring for 5-10 minutes to obtain wet granules with a particle size of 0.5-2 mm.

[0108] A sealed nitrogen environment completely isolates the powder from air, preventing oxidation of active ingredients during granulation. Spray-type dispensing ensures uniform contact between the binder and powder, reducing the loss of active ingredients due to localized over-wetting. A proper combination of stirring speed and binder dosage prevents particles from being too large or too small, ensuring uniform particle size and improving the consistency of subsequent drying and coating.

[0109] Step 4: Gradient Vacuum Drying: Transfer the wet particles to a vacuum drying oven. First, dry them for 15-20 minutes under a vacuum of 0.05-0.07 MPa and a temperature of 30-40℃ to remove free moisture from the particle surface. Then, increase the vacuum to 0.08-0.095 MPa and the temperature to 45-55℃, and dry for 30-45 minutes to remove bound moisture from the particles. During the drying process, nitrogen gas is introduced into the oven every 10 minutes to replace the gas, with each purging lasting 2 minutes.

[0110] The gradient drying method first removes surface moisture at a low temperature to avoid the volatilization of components caused by direct high-temperature action, and then moderately increases the temperature to accelerate the removal of internal moisture. Regular nitrogen purging can promptly remove volatile components that escape during the drying process, preventing them from accumulating in the chamber and re-adsorbing onto the particle surface. The vacuum environment can lower the boiling point of water, shorten the drying time, and reduce the contact between active ingredients and oxygen.

[0111] Step 5: Nano-coating and end-capping: The dried particles are fed into a fluidized bed coating machine. Polylactic acid-glycolic acid copolymer (PLGA) is used as the coating material and dissolved in a mixed solvent of dichloromethane and ethanol (volume ratio 1:1) to prepare a coating solution with a mass concentration of 2%-4%. The fluidized bed inlet air temperature is controlled at 35-45℃, the outlet air temperature at 25-30℃, and the atomization pressure at 0.2-0.3MPa. The coating solution is sprayed at a rate of 1-3mL / min, and the coating amount is 3%-5% of the total mass of the particles to obtain coated particles.

[0112] The nanoscale film formed by PLGA coating material has excellent air permeability and biocompatibility, effectively isolating external oxygen and moisture without affecting the dissolution performance of the granules, thus achieving long-term protection of the active ingredients. Precise control of coating parameters can avoid slow dissolution due to an excessively thick coating or protective failure due to an excessively thin coating, ensuring stable product quality.

[0113] Step Six: Aseptic Packaging: The coated granules are sized and sieved to remove particles smaller than 0.3mm and larger than 2.5mm. Then, they are packaged in an aseptic, inert gas protected environment. The packaging material is aluminum-plastic composite film. Before sealing, nitrogen is introduced to replace the air inside the packaging to ensure that the oxygen content inside the packaging is less than 0.5%.

[0114] The screening process removes substandard particles, ensuring uniform particle size in the product; the combination of a sterile environment and nitrogen replacement prevents contamination and degradation of active ingredients during packaging and storage.

[0115] The effect of each single factor on the retention rate of effective ingredients: the retention rate of the example was 13.8 percentage points higher than that of the comparative example 1, indicating that liquid nitrogen cooling can avoid the degradation of heat-sensitive ingredients (ginsenoside Rg1 is easily degraded above 160℃) caused by mechanical friction heat generation, and inert gas can isolate oxidation, which is a key link to reduce thermal degradation and oxidative loss.

[0116] Composite adhesive + antioxidant: The retention rate of the example was improved by 8.6 percentage points compared with Comparative Example 2. The inclusion effect of the functional polymer (hydroxypropyl-β-cyclodextrin) in the composite adhesive and the antioxidant effect of tea polyphenols form a synergistic protection, while improving the bonding stability and avoiding component exposure caused by a single adhesive.

[0117] Granulation under inert gas protection: The retention rate of the example was improved by 10.4 percentage points compared with Comparative Example 3. The closed nitrogen environment can completely isolate oxygen in the granulation process, prevent the active ingredients from being accelerated to oxidize in a humid state (after the binder is sprayed), and has a significant protective effect on easily oxidized ingredients.

[0118] Gradient vacuum drying: Compared with Comparative Example 4, the retention rate of the example was improved by 11.9 percentage points. Gradient heating avoids the loss of volatile components caused by direct high temperature. The vacuum environment lowers the boiling point of water and shortens the drying time. Nitrogen replacement removes volatile components in time and reduces secondary adsorption.

[0119] Nano-coating and end-capping: The retention rate of the example was improved by 7.5 percentage points compared with the comparative example 5. The PLGA nano-coating film can isolate oxygen and moisture for a long time. Although its impact on the immediate retention rate is slightly lower than that of other links, it significantly reduces the degradation rate during long-term storage (5.3% degradation rate of example 18 months vs. 512.7% of the comparative example), which is the core guarantee for long-term stability.

[0120] Aseptic packaging inert gas protection: The retention rate of the example was improved by 1.6 percentage points compared with the comparative example 6. Although the short-term impact was small, it could reduce slow oxidation during storage and reduce the degradation rate by 3.1 percentage points after 18 months. It is the final key to the protection of the whole process.

[0121] The absence of a single key process led to a decrease in the retention rate of effective ingredients by 7.5-13.8 percentage points, and a simultaneous deterioration in physical properties. However, the optimization of the entire process, through the synergistic effect of "low-temperature thermal degradation prevention, inert anti-oxidation, composite adhesive encapsulation, gradient drying to prevent volatilization, long-term protection through nano-coating, and nitrogen packaging for finalization", achieved an effective ingredient retention rate of over 92%, a molding rate of over 93%, a brittleness of less than 1.5%, and excellent long-term storage stability, thus verifying the necessity and synergistic value of each innovation.

[0122] It should be noted that, in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus.

[0123] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for producing granules that reduces the loss of active ingredients, characterized in that, Includes the following steps: Step 1: Low-temperature inert gas protected pulverization, the raw material is mixed with an inert diluent, and pulverized by airflow under liquid nitrogen cooling; Step 2: Preparation of composite adhesive: Natural polysaccharides and functional polymers are mixed, and antioxidants are added after stirring with warm water. Step 3: Granulation under inert gas protection. In a sealed nitrogen environment, the composite binder is sprayed into the ultrafine powder for granulation. Step 4: Gradient vacuum drying, first remove surface water at low temperature and low vacuum, then remove internal water at high temperature and high vacuum, and periodically replace with nitrogen. Step 5: Nano-coating and end-capping, PLGA coating liquid fluidized bed spray coating; Step Six: Aseptic packaging, aluminum-plastic sealing under inert gas protection.

2. The method for producing granules with reduced loss of active ingredients according to claim 1, characterized in that: In step one, the mass ratio of raw material to inert diluent is 1:0.2-0.

5. The inert diluent is sterilized diatomaceous earth or silica with a particle size of 5-10μm. The grinding chamber temperature is -20℃ to -5℃, the airflow speed is 15-25m / s, and the particle size of the powder after grinding is 10-50μm.

3. The method for producing granules with reduced loss of active ingredients according to claim 1, characterized in that: In step two, the mass ratio of natural polysaccharide to functional polymer is 2:1-3:

1. The natural polysaccharide is gum arabic or xanthan gum, and the functional polymer is povidone K30 or hydroxypropyl-β-cyclodextrin. The mass concentration of the composite adhesive is 5%-8%, and the amount of antioxidant is 0.1%-0.3% of the total mass of the colloid.

4. The method for producing granules with reduced loss of active ingredients according to claim 1, characterized in that: In step three, the nitrogen pressure in the granulator is 0.12-0.15 MPa, the stirring speed is 100-150 r / min, the amount of binder is 15%-25% of the total powder mass, the droplet size is 50-100 μm, and the wet particle size is 0.5-2 mm.

5. The method for producing granules with reduced loss of active ingredients according to claim 1, characterized in that: The first stage conditions for gradient drying in step four are: vacuum degree 0.05-0.07MPa, temperature 30-40℃, and time 15-20 minutes. The second stage involves a vacuum of 0.08-0.095 MPa, a temperature of 45-55℃, and a time of 30-45 minutes; nitrogen purging is performed at 10-minute intervals, with each purging lasting 2 minutes.

6. The method for producing granules with reduced loss of active ingredients according to claim 1, characterized in that: In step five, the coating solution is a PLGA dichloromethane-ethanol mixed solution with a PLGA mass concentration of 2%-4% and a dichloromethane to ethanol volume ratio of 1:

1. The coating conditions are: inlet air temperature of 35-45℃, outlet air temperature of 25-30℃, atomization pressure of 0.2-0.3MPa, spray rate of 1-3mL / min, and coating amount of 3%-5%.

7. The method for producing granules with reduced loss of active ingredients according to claim 1, characterized in that: In step six, the oxygen content in the packaging environment is below 0.5%, and the packaging material is an aluminum-plastic composite film.

8. A method for producing granules with reduced loss of active ingredients according to claim 3, characterized in that: Antioxidants are vitamin E or tea polyphenols. Vitamin E is chosen when the active ingredient is fat-soluble, and tea polyphenols are chosen when the active ingredient is water-soluble.

9. A method for producing granules with reduced loss of active ingredients according to claim 5, characterized in that: During nitrogen purging, the nitrogen flow rate is 0.5-1 L / min to ensure that the residual amount of volatile components in the drying oven is less than 0.1%.

10. A method for producing granules with reduced loss of active ingredients according to claim 6, characterized in that: PLGA has a molecular weight of 20,000-60,000, with a molar ratio of lactic acid to glycolic acid of 50:50-75:25 to ensure that the degradation rate of the coating film matches the dissolution rate of the active ingredient. In step three, the stirring paddle of the closed granulator adopts an arc-shaped structure, and the gap between the stirring paddle and the machine wall is 2-5mm to reduce the loss of active ingredients caused by powder sticking to the wall.

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