Bear gall powder composition and preparation method thereof

Abstract

The invention discloses a bear gall powder composition and a preparation method thereof, and particularly relates to the technical field of medicine processing.The bear gall powder is prepared by adding an antioxidant into bear bile, performing nitrogen protection, performing moist heat sterilization, and performing freeze-drying to remove water; the bear gall powder composition comprises bear gall powder and an antioxidant, wherein the bear gall powder is obtained by freeze-drying bear bile and removing moisture; the antioxidant is selected from one or more of sodium sulfite, sodium thiosulfate and ascorbic acid; the preparation method of the bear gall powder composition adopts a conventional moist heat sterilization process, is safer and is suitable for large-scale production.

Description

Technical Field

[0001] This invention relates to pharmaceutical processing technology, specifically to a bear bile powder composition and its preparation method. Background Technology

[0002] Bear bile is a traditional Chinese medicine, bitter and cool in nature, affecting the spleen, gallbladder, and heart meridians. It is non-toxic and has the functions of clearing heat and improving eyesight, calming the liver and promoting bile secretion. Bear bile powder is made by processing bear bile to remove water. It has good therapeutic effects on infantile convulsions, sore throat, hypertension, hyperlipidemia, gallstones, and hepatitis. Currently, bear bile is mainly produced by extracting bile from live bears, which is easily contaminated by microorganisms during the production process. To remove microorganisms, the most common pharmaceutical techniques are high-temperature sterilization, filtration, and irradiation. Conventional high-temperature sterilization processes may significantly affect the appearance and content of active ingredients in bear bile powder, thus affecting its efficacy. Bear bile is a highly viscous liquid, making filtration difficult to implement in production. Since bear bile comes from animals, it may contain viruses and parasites, and filtration is not effective in removing viruses, posing a safety risk. While Co-60 irradiation can effectively kill microorganisms and parasites, residual irradiation may pose a safety risk to users.

[0003] Chinese patent CN201510650516.5 discloses a method for preparing bear bile powder. The method first mixes ethanol with bile to kill pathogenic bacteria and viruses in the bear bile without destroying its active ingredients. The bear bile powder is then prepared through vacuum concentration and freeze-drying. This patent uses 75%-85% ethanol for sterilization, but ethanol is unlikely to kill all bacteria and viruses. Furthermore, the use of a relatively large amount of organic solvent increases costs.

[0004] Chinese patent CN201811325962.9 discloses a method for preparing bear bile powder and the bear bile powder itself. The method first involves sterilization through vacuum filtration, followed by freeze-drying to prepare the bear bile powder. The patent does not describe the specific operation of vacuum filtration sterilization or the filter pore size used. Typically, in pharmaceutical processes, an effective filter pore size of 0.22 micrometers is used for sterilization. However, bear bile is a viscous liquid, making smooth filtration difficult in production. Using a large filter pore size would limit bacterial retention. Furthermore, if viruses are present in bear bile, they are difficult to remove through filtration.

[0005] Therefore, in order to address the shortcomings of existing bear bile sterilization methods, and to establish a safer, more economical, and more efficient method for sterilizing bear bile without affecting the quality of the final product, bear bile powder, and then produce bear bile powder through freeze-drying, this method is of great significance for the clinical application of bear bile powder. Summary of the Invention

[0006] The main objective of this invention is to provide a bear bile powder composition and its preparation method. In the process of moist heat sterilization, an appropriate amount of water-soluble antioxidant is added to the bear bile as a protective agent. Then, nitrogen gas is introduced into the bear bile to remove oxygen and reduce the oxidation reaction of the bear bile under high temperature conditions. Finally, the mixture is sealed and moist heat sterilized.

[0007] Sterilized bear bile is then freeze-dried to remove moisture, yielding bear bile powder. The resulting bear bile powder exhibits the same appearance, color, and content of the key component, tauroursodeoxycholic acid, as bear bile powder obtained by directly freeze-drying bear bile. This effectively addresses issues related to product quality variations (such as appearance, color, and content), the impact of traditional processes on efficacy, and large-scale industrial production.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0009] A bear bile powder composition, characterized in that the composition comprises bear bile powder obtained by freeze-drying bear bile to remove moisture and an antioxidant, wherein the total amount of antioxidant accounts for 0.01% to 5% of the total amount of the bear bile powder composition.

[0010] Preferably, in the bear bile powder composition, the antioxidant is one or more of sodium sulfite, sodium thiosulfate, and ascorbic acid.

[0011] Preferably, in the bear bile powder composition, the total amount of antioxidants accounts for 0.05% to 2% of the total amount of the bear bile powder composition.

[0012] The present invention also discloses a method for preparing the above-mentioned bear bile powder composition, the specific steps of which are as follows:

[0013] S1: First, add bear bile to the mixing tank, and while stirring, add the antioxidant;

[0014] S2: Add the bear bile obtained in S1 to a glass container, fill it with nitrogen for 30-60 minutes, stopper and seal it;

[0015] S3: Place the glass container from S2 into a moist heat sterilization device, set the temperature to 100-125℃, and the time to 5-30 minutes for moist heat sterilization;

[0016] S4: Take out the sterilized bear bile and place it in a freeze dryer for the following operations: pre-freezing, sublimation drying, and desorption drying. Take out the freeze-dried material and sieve it to obtain bear bile powder.

[0017] Preferably, in step S3, the time for filling the glass container with nitrogen is 30 minutes.

[0018] Preferably, the pre-freezing stage in S4 specifically involves: taking out 1-2 ml of sterilized bear bile and placing it in a freeze dryer, selecting a pre-freezing temperature of -40℃ to -60℃, and maintaining this temperature for 1-4 hours.

[0019] Preferably, the sublimation drying method in S4 is as follows: after pre-freezing, maintain the state of the material in the freeze dryer tray, set the freeze dryer vacuum degree to 15-35 Pa, set the temperature to 3-7°C, set the heating time to 30-50 minutes, and maintain for 4-6 hours; then set the temperature to 20-30°C, set the heating time to 1.5-2.5 hours, and maintain for 10-14 hours.

[0020] Preferably, the desorption drying method in S4 is as follows: after the sublimation drying is completed, the material in the freeze dryer is kept in a certain state, the vacuum degree is set to 5-25 Pa, the temperature is set to 35-45°C, the heating time is 1.5-2.5 hours, and the temperature is maintained for 5-7 hours.

[0021] Preferably, the sieving method in step S4 is as follows: the freeze-dried material is slowly poured into a 20-40 mesh sieve, and the material is passed through the sieve by manual or mechanical vibration to remove lumps or impurities and obtain a uniform powder. Any lumps remaining on the sieve can be gently crushed to disperse them before sieving again to ensure sufficient material passage.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] 1. This invention effectively solves the problems of changes in the appearance and color of bear bile powder, such as turning yellow or brown, and a decrease in the content of effective ingredients such as tauroursodeoxycholic acid, caused by traditional moist heat sterilization, by adding one or more antioxidants such as sodium sulfite, sodium thiosulfate, and ascorbic acid to bear bile and combining it with nitrogen protection.

[0024] 2. This invention employs a moist heat sterilization process at 100–125°C for 5–30 minutes. With the synergistic effect of antioxidants and nitrogen protection, it can thoroughly kill microorganisms, viruses, and parasites in bear bile. It also avoids the drawbacks of traditional filtration sterilization, which is difficult to achieve due to the high viscosity of bear bile and cannot remove viruses, and the fact that ethanol sterilization cannot kill all bacteria and viruses, thus increasing costs. At the same time, it avoids the residual safety risks that may be caused by Co-60 irradiation, significantly improving the safety of the product.

[0025] 3. This invention uses conventional moist heat sterilization equipment and freeze-drying equipment. The operation steps are simple, including solution preparation, nitrogen filling, sterilization, freeze-drying, and sieving. No special or complicated instruments or processes are required. The addition of antioxidants and the nitrogen protection process are easy to control and the cost is low. It can meet the needs of large-scale industrial production and is conducive to the industrial application and clinical promotion of bear bile powder. Detailed Implementation

[0026] The present invention will be further described below with reference to specific embodiments.

[0027] Moist heat sterilization is the preferred and most commonly used sterilization method in pharmaceutical technology, offering the best safety profile. Through controlled high temperatures and duration, microorganisms, parasites, and viruses are killed. However, since bear bile is not heat-resistant, directly using this method for sterilization may lead to changes in product quality, such as appearance, color, and content, thus affecting efficacy.

[0028] The inventors of this application considered that the above-mentioned quality changes may be caused by the accelerated oxidation of bear bile under high temperature conditions. Therefore, in the research, they tried to add an appropriate amount of water-soluble antioxidant to bear bile as a protective agent, then put the bear bile in a glass bottle, seal it, sterilize it with moist heat, and then remove the water from the sterilized bear bile through a freeze-drying process to obtain bear bile powder.

[0029] The inventors conducted extensive screening of commonly used water-soluble antioxidants and found that some antioxidants, such as sodium thiosulfate, sodium sulfite, and ascorbic acid, have a certain protective effect against the oxidation of bear bile under high-temperature sterilization conditions. The inventors further discovered that when the aforementioned antioxidants are added to bear bile as protective agents, and nitrogen is bubbled into the bear bile before moist heat sterilization and freeze-drying, the resulting bear bile powder exhibits the same appearance, color, and content of the key component, tauroursodeoxycholic acid, as bear bile powder obtained by directly freeze-drying bear bile.

[0030] In this application example, the bear bile powder composition is prepared according to the following steps:

[0031] S1: First, add bear bile to the mixing tank, and while stirring, add the antioxidant;

[0032] S2: Add the bear bile obtained in S1 to a glass container, fill it with nitrogen for 30-60 minutes, stopper and seal it;

[0033] S3: Place the glass container from S2 into a moist heat sterilization device, set the temperature to 100-125℃, and the time to 5-30 minutes for moist heat sterilization;

[0034] S4: Take out the sterilized bear bile and place it in a freeze dryer for the following operations: pre-freezing, sublimation drying, and desorption drying. Take out the freeze-dried material and sieve it to obtain bear bile powder.

[0035] Specifically, in step S3, nitrogen gas is introduced into the glass container for 30 minutes.

[0036] Specifically, take out 1-2 ml of sterilized bear bile and place it in a freeze dryer. Select a pre-freezing temperature of -40℃ to -60℃ and keep it at this temperature for 1-4 hours.

[0037] Specifically, after pre-freezing, maintain the state of the material in the freeze dryer tray, set the freeze dryer vacuum degree to 15-35 Pa, set the temperature to 3-7℃, set the heating time to 30-50 minutes, and maintain it for 4-6 hours; then set the temperature to 20-30℃, set the heating time to 1.5-2.5 hours, and maintain it for 10-14 hours.

[0038] Specifically, after the sublimation drying is completed, maintain the state of the material inside the freeze dryer, set the vacuum degree to 5-25 Pa, set the temperature to 35-45℃, raise the temperature for 1.5-2.5 hours, and maintain the temperature for 5-7 hours.

[0039] Specifically, the freeze-dried material is slowly poured into a 20-40 mesh sieve. The material is then forced through the sieve manually or mechanically to remove lumps or impurities, resulting in a uniform powder. Any remaining lumps on the sieve can be gently crushed to disperse them before sieving again to ensure complete material passage.

[0040] The present invention will be further disclosed below with reference to specific embodiments and comparative examples.

[0041] Example 1

[0042] Table 1: Amount and Proportion of Materials in Bear Bile Powder Composition

[0043] Composition Dosage Percentage (%) Bear bile (12% solids content) 1000g 99.90 Sodium thiosulfate 0.12g 0.10 total 120.12g 100.00

[0044] Based on the above operating steps, the following operations should be performed according to the material dosage of the bear bile powder composition in Table 1:

[0045] S1: Add bear bile to the mixing tank and, while stirring, add sodium thiosulfate to dissolve it;

[0046] S2: Divide the above bear bile into 100ml glass containers, fill each container with nitrogen for 30 minutes, stopper and seal;

[0047] S3: Place the above glass container in a moist heat sterilization device, set the temperature to 121℃, and the time to 8 minutes for moist heat sterilization. Remove the container and let it cool.

[0048] S4: Take the sterilized bear bile and place it in the freeze dryer tray, with the solution height at 1.2-1.6cm. Pre-freeze: set the temperature to -50℃ and keep it for 2 hours.

[0049] Sublimation drying: Vacuum degree 20-30pa, set temperature 5℃, heating time 40 minutes, hold for 5 hours, then set temperature 25℃, heating time 2 hours, hold for 12 hours;

[0050] Drying: Vacuum degree 10-20 Pa, set temperature 40℃, heating time 2 hours, hold for 6 hours. Remove and pass through a 30-mesh sieve to obtain the product.

[0051] Example 2

[0052] Table 2: Amount and Proportion of Materials in Bear Bile Powder Composition

[0053] Composition Dosage Percentage (%) Bear bile (12% solids content) 1000g 99.90 Sodium sulfite 0.12g 0.10 total 120.12g 100.00

[0054] In step S1, sodium thiosulfate is replaced with sodium sulfite. The rest of the preparation steps are the same as in Example 1, and will not be repeated in this example.

[0055] Example 3

[0056] Table 3: Amount and Proportion of Materials in Bear Bile Powder Composition

[0057] Composition Dosage Percentage (%) Bear bile (12% solids content) 1000g 99.90 ascorbic acid 0.12g 0.10 total 120.12g 100.00

[0058] In step S1, sodium thiosulfate is replaced with ascorbic acid. The rest of the preparation steps are the same as in Example 1, and will not be repeated in this example.

[0059] Example 4

[0060] Table 4: Amount and Proportion of Materials in Bear Bile Powder Composition

[0061] Composition Dosage Percentage (%) Bear bile (12% solids content) 1000g 95.05 ascorbic acid 6g 4.75 Sodium sulfite 0.25g 0.20 total 126.25g 100.00

[0062] In step S1, sodium thiosulfate is replaced with ascorbic acid and sodium sulfite. The rest of the preparation steps are the same as in Example 1, and will not be repeated in this example.

[0063] Example 5

[0064] Table 5: Amount and Proportion of Materials in Bear Bile Powder Composition

[0065] Composition Dosage Percentage (%) Bear bile (12% solids content) 1000g 99.90 Sodium thiosulfate 0.12g 0.10 total 120.12g 100.00

[0066] S1: Add bear bile to the mixing tank and, while stirring, add sodium thiosulfate to dissolve it;

[0067] S2: Divide the above bear bile into 100ml glass containers, fill each container with nitrogen for 30 minutes, stopper and seal;

[0068] S3: Place the above glass container in a moist heat sterilization device, set the temperature to 100℃, and the time to 30 minutes for moist heat sterilization. Remove the container and let it cool.

[0069] S4: Take the sterilized bear bile and place it in the freeze dryer tray, with the solution level at 1.2-1.6 cm. Pre-freeze: set the temperature to -50℃ and hold for 2 hours; Sublimation drying: vacuum degree 20-30 Pa, set the temperature to 5℃, raise the temperature for 40 minutes, hold for 5 hours, then set the temperature to 25℃, raise the temperature for 2 hours, and hold for 12 hours; Desorption drying: vacuum degree 10-20 Pa, set the temperature to 40℃, raise the temperature for 2 hours, and hold for 6 hours. Remove and pass through a 30-mesh sieve to obtain the product.

[0070] Comparative Example 1

[0071] Prescription: Take bear bile (12% solid content), do not sterilize, and freeze dry directly.

[0072] Process:

[0073] Take bear bile and place it in a freeze dryer tray, with the solution level at 1.2-1.6 cm. Pre-freeze: set the temperature to -50℃ and hold for 2 hours. Sublimation drying: vacuum 20-30 Pa, set the temperature to 5℃, raise the temperature for 40 minutes, hold for 5 hours, then set the temperature to 25℃, raise the temperature for 2 hours, and hold for 12 hours. Desorption drying: vacuum 10-20 Pa, set the temperature to 40℃, raise the temperature for 2 hours, and hold for 6 hours. Remove and pass through a 30-mesh sieve to obtain the final product.

[0074] Comparative Example 2

[0075] Prescription: Take bear bile (12% solid content), sterilize directly, and freeze-dry.

[0076] Process:

[0077] S1: Divide the bear bile into 100ml glass containers, fill each container with nitrogen for 30 minutes, stopper and seal;

[0078] S2: Place the above glass container in a moist heat sterilization device, set the temperature to 121°C, and the time to 8 minutes for moist heat sterilization. Remove the container and let it cool.

[0079] S3: Take the sterilized bear bile and place it in the freeze dryer tray, with the solution level at 1.2-1.6 cm. Pre-freeze: set the temperature to -50℃ and hold for 2 hours; Sublimation drying: vacuum degree 20-30 Pa, set the temperature to 5℃, raise the temperature for 40 minutes, hold for 5 hours, then set the temperature to 25℃, raise the temperature for 2 hours, and hold for 12 hours; Desorption drying: vacuum degree 10-20 Pa, set the temperature to 40℃, raise the temperature for 2 hours, and hold for 6 hours. Remove and pass through a 30-mesh sieve to obtain the product.

[0080] Comparative Examples 3 to 10

[0081] Table 6; Composition and Proportion of Bear Bile Powder Compositions in Comparative Formulations

[0082]

[0083] S1: Add bear bile to the mixing tank and add an antioxidant while stirring to dissolve it;

[0084] S2: Divide the above bear bile into 100ml glass containers, stopper and seal;

[0085] S3: Place the above glass container in a moist heat sterilization device, set the temperature to 121℃, and the time to 8 minutes for moist heat sterilization. Remove the container and let it cool.

[0086] S4: Take the sterilized bear bile and place it in the freeze dryer tray, with the solution level at 1.2-1.6 cm. Pre-freeze: set the temperature to -50℃ and hold for 2 hours; Sublimation drying: vacuum degree 20-30 Pa, set the temperature to 5℃, raise the temperature for 40 minutes, hold for 5 hours, then set the temperature to 25℃, raise the temperature for 2 hours, and hold for 12 hours; Desorption drying: vacuum degree 10-20 Pa, set the temperature to 40℃, raise the temperature for 2 hours, and hold for 6 hours. Remove and pass through a 30-mesh sieve to obtain the product.

[0087] Comparative Example 11

[0088] Prescription: Take bear bile (12% solid content), sterilize and freeze-dry after nitrogen protection.

[0089] Process: The rest of the process and preparation steps are the same as in Example 1, and will not be repeated in this example.

[0090] Example 1

[0091] The bear bile powders prepared in Examples 1 to 5 and Comparative Examples 1 to 11 were tested for appearance, color, tauroursodeoxycholic acid content, and microbial limits. The results are shown in Table 8.

[0092] The detection method is as follows:

[0093] (1) Appearance and color: visual inspection

[0094] (2) Tauroursodeoxycholic acid content: determined by high performance liquid chromatography (Appendix of Part I of Chinese Pharmacopoeia).

[0095] Octadecylsilane-bonded silica gel was used as the packing material; mobile phase A was a solution (4.68 g of sodium dihydrogen phosphate and 2.0 g of sodium heptanesulfonate were dissolved in 400 ml of water, then 600 ml of methanol was added and shaken well), and mobile phase B was methanol; the detection wavelength was 205 nm. The theoretical plate number, calculated using sodium tauroursodeoxycholate, should be no less than 3500.

[0096] Table 7: Mobile Phase Ratio - Time

[0097]

[0098] Preparation of reference solution: Accurately weigh an appropriate amount of sodium tauroursodeoxycholate, add methanol to prepare a solution containing 1 mg of sodium tauroursodeoxycholate per 1 ml, which is equivalent to 0.9578 mg of tauroursodeoxycholic acid.

[0099] Preparation of the test solution: Weigh approximately 50 mg of the fine powder of this product accurately, place it in a 10 ml volumetric flask, add an appropriate amount of methanol, dissolve by sonication, dilute with methanol to the mark, shake well, filter through a 0.45 μm microporous membrane, and collect the filtrate to obtain the test solution.

[0100] Determination method: Accurately pipette 10 μl of the reference solution and the test solution into the liquid chromatograph and determine the result.

[0101] (3) Microbial limit: determined according to the microbial limit test method in Appendix I of the Chinese Pharmacopoeia.

[0102] Table 8: Summary of Quality Test Results of Bear Bile Powder Examples and Comparative Examples

[0103]

[0104] The data results show that in Examples 1-5, sterilization under conditions of antioxidants sodium thiosulfate, sodium sulfite, ascorbic acid, and simultaneous nitrogen protection resulted in products with the same appearance, color, and content as the directly freeze-dried product in Comparative Example 1, and the microbiological indicators met the requirements. The content in Example 4 was lower because of the larger amount of antioxidant and the lower proportion of bear bile powder in the formulation, leading to a lower tauroursodeoxycholic acid content.

[0105] The bear bile powders in Examples 1-5 all had a golden-yellow appearance, consistent with the golden-yellow powder of Comparative Example 1, which was directly freeze-dried without sterilization. However, Comparative Example 2, which did not contain antioxidants but was sterilized by nitrogen purging, and Comparative Example 11, which was sterilized by nitrogen purging, had an appearance of "yellowish-brown" and "yellowish-brown". Comparative Examples 3-7, which contained other antioxidants such as sodium metabisulfite and L-cysteine, had an appearance of "yellowish-brown". This indicates that the antioxidants sodium sulfite, sodium thiosulfate, and ascorbic acid selected in this invention, combined with nitrogen protection, can effectively inhibit the darkening of color caused by high-temperature sterilization.

[0106] The tauroursodeoxycholic acid content in Examples 1-5 was 32.3%-34.2%, close to that of Comparative Example 1 (34.2%); while the content in Comparative Example 2 was only 28.1%, the content in Comparative Examples 3-7 was 29.0%-29.6%, and the content in Comparative Examples 8-11 was 32.1%-32.8%. This indicates that the antioxidant and nitrogen protection of the present invention work synergistically to reduce the loss of active ingredients caused by high-temperature sterilization. The slightly lower content in Example 4 is due to the larger amount of antioxidant used (4.95%), which diluted the proportion of active ingredients, further verifying the rationality of the preferred antioxidant dosage of 0.05%-2%.

[0107] Comparative Examples 8-10, which only added the antioxidant of this invention but did not undergo nitrogen purging, appeared as a "yellow powder" with a content of 32.2%-32.8%. Although this was better than the group without antioxidant, it was slightly worse than the golden yellow powder of Examples 1-5, with a content of 34.0%-34.2%. This indicates that antioxidants and nitrogen protection need to be used in combination. Using antioxidants alone or nitrogen purging alone cannot achieve the best results. Combining the two can minimize the impact of high temperature on the product.

[0108] When other antioxidants such as sodium metabisulfite and L-cysteine ​​were used in Comparative Examples 3-7, even when combined with sterilization processes, the product appearance and content were still inferior to those in the embodiments of the present invention. This indicates that sodium sulfite, sodium thiosulfate, and ascorbic acid are the optimal antioxidants for high-temperature sterilization of bear bile, and other antioxidants cannot replace them.

[0109] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A bear bile powder composition, characterized in that, The composition comprises bear bile powder obtained by freeze-drying bear bile to remove moisture, and antioxidants, wherein the total amount of antioxidants accounts for 0.01% to 5% of the total amount of bear bile powder composition.

2. The bear bile powder composition according to claim 1, characterized in that, The antioxidant is one or more of sodium sulfite, sodium thiosulfate, and ascorbic acid.

3. The bear bile powder composition according to claim 2, characterized in that, The total amount of antioxidants used accounts for 0.05% to 2% of the total amount of bear bile powder composition.

4. A method for preparing the bear bile powder composition according to any one of claims 1-3, characterized in that, The specific steps are as follows: S1: First, add bear bile to the mixing tank, and while stirring, add the antioxidant; S2: Add the bear bile obtained in S1 to a glass container, fill it with nitrogen for 30-60 minutes, stopper and seal it; S3: Place the glass container from S2 into a moist heat sterilization device, set the temperature to 100-125℃, and the time to 5-30 minutes for moist heat sterilization; S4: Take out the sterilized bear bile and place it in a freeze dryer for the following operations: pre-freezing, sublimation drying, and desorption drying. Take out the freeze-dried material and sieve it to obtain bear bile powder.

5. The preparation method according to claim 4, characterized in that, In step S3, the time for filling the glass container with nitrogen is 30 minutes.

6. The preparation method according to claim 4, characterized in that, The pre-freezing process in S4 is as follows: Take out 1-2 ml of sterilized bear bile and place it in a freeze dryer. Select a pre-freezing temperature of -40℃ to -60℃ and keep it at this temperature for 1-4 hours.

7. The preparation method according to claim 4, characterized in that, The sublimation drying method in S4 is as follows: After pre-freezing, maintain the state of the material in the freeze dryer tray, set the freeze dryer vacuum degree to 15-35 Pa, set the temperature to 3-7℃, set the heating time to 30-50 minutes, and maintain it for 4-6 hours; then set the temperature to 20-30℃, set the heating time to 1.5-2.5 hours, and maintain it for 10-14 hours.

8. The preparation method according to claim 4, characterized in that, The desorption drying method in S4 is as follows: after the sublimation drying is completed, the material in the freeze dryer is kept in a certain state, the vacuum degree is set to 5-25 Pa, the temperature is set to 35-45℃, the heating time is 1.5-2.5 hours, and the temperature is maintained for 5-7 hours.

9. The preparation method according to claim 4, characterized in that, The sieving method in S4 is as follows: the freeze-dried material is slowly poured into a 20-40 mesh sieve, and the material is passed through the sieve by manual or mechanical vibration to remove lumps or impurities and obtain uniform powder.

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