Compound cinnabar freeze-dried powder and preparation process thereof

Abstract

This invention provides a compound Phellodendron amurense freeze-dried powder and its preparation process, relating to the field of deep processing technology of compound Phellodendron amurense extract. The preparation process includes the following steps: 80±10 parts by weight of Forsythia suspensa, 40±5 parts by weight of Phellodendron amurense, 40±5 parts by weight of Lonicera japonica, 40±5 parts by weight of Taraxacum mongolicum, and 2.4±0.3 parts by weight of Scolopendra subspinipes. S1: Take a certain weight of the above five ingredients, add water and decoct, concentrate to a clear extract with a relative density of 1.10-1.15, add ethanol to make the alcohol content reach 70%, let stand, concentrate until there is no alcohol odor, and obtain compound Phellodendron amurense ethanol extract; S2: Take the compound Phellodendron amurense ethanol extract, add water to a certain volume, refrigerate, filter, and obtain compound Phellodendron amurense freeze-dried stock solution; S3: Take the compound Phellodendron amurense freeze-dried stock solution, fill, and freeze-dry to obtain compound Phellodendron amurense freeze-dried powder. The compound Phellodendron amurense freeze-dried powder prepared by this invention solves the problems of existing coatings being non-sterile, unstable, and inconvenient to transport.

Description

Technical Field

[0001] This invention belongs to the field of deep processing technology of compound Phellodendron amurense extract, specifically, it relates to a compound Phellodendron amurense freeze-dried powder and its preparation process. Background Technology

[0002] Compound Phellodendron Amurense Liquid Topical Solution possesses the properties of clearing heat and detoxifying, reducing swelling and removing necrotic tissue. It is used for post-ulceration sores and infected wounds, particularly those with a Yang syndrome. In clinical use, its therapeutic scope ranges from superficial skin injuries to mucosal injuries of internal visceral cavities, demonstrating high clinical value. No preservatives or other excipients are used in the production of Compound Phellodendron Amurense Liquid Topical Solution, and as a liquid preparation, its transportation is not entirely safe.

[0003] This invention is a traditional Chinese medicine preparation made by modifying the dosage form of Compound Phellodendron Amurense Liquid Topical Solution. This product is developed as a sterile preparation, which improves the safety of clinical use. Compared with the original preparation, it can improve the stability of product quality while ensuring that the material basis remains unchanged. This dosage form also improves the safety of the product during transportation. Summary of the Invention

[0004] The inventors discovered that no preservatives or excipients were used in the production of Compound Phellodendron Amurense Liquid Topical Solution, and as a liquid preparation, the finished product was not safe enough for transportation. Therefore, to ensure the safety and stability of the product during transportation, a sterile lyophilized powder formulation was developed. According to the "Classification and Application Requirements for Registration of Traditional Chinese Medicine," Compound Phellodendron Amurense Lyophilized Powder falls under "2.2 Preparations that change the dosage form of an already marketed traditional Chinese medicine, i.e., preparations that change the dosage form while keeping the route of administration unchanged," requiring that the material basis not be significantly altered (changes in indicative components within 5%). The safety, efficacy, and quality controllability of the original Compound Phellodendron Amurense Liquid Topical Solution have been verified in clinical use. This application controls the final lyophilized powder product by implementing quality control on the sterile Compound Phellodendron Amurense Lyophilized Liquid Topical Solution, ensuring that the material basis is not significantly altered compared to the Compound Phellodendron Amurense Liquid Topical Solution, thus guaranteeing the safety, efficacy, and quality controllability of the final Compound Phellodendron Amurense Lyophilized Powder product.

[0005] The first aspect of this invention provides a preparation process for compound Phellodendron amurense freeze-dried powder, the preparation process comprising the following steps:

[0006] By weight, the composition was: Forsythia suspensa 80±10 parts, Phellodendron chinense 40±5 parts, Lonicera japonica 40±5 parts, Taraxacum mongolicum 40±5 parts, and Scolopendra subspinipes 2.4±0.3 parts.

[0007] S1: Take a certain weight of the above five ingredients, add water and decoct, concentrate to a clear extract with a relative density of 1.10-1.15, add ethanol to make the alcohol content reach 70%, let stand, concentrate until there is no alcohol taste, and obtain compound berberine extract.

[0008] S2: Take the compound berberine extract from step S1, add water to a certain volume, refrigerate, filter, and obtain the compound berberine freeze-dried stock solution.

[0009] S3: Take the original liquid of compound Phellodendron bark freeze-dried from step S2, fill it, freeze-dry it to obtain compound Phellodendron bark freeze-dried powder;

[0010] In this step, the ratio of the weight component in step S1 to the water added to a certain volume in step S2 is 1 weight component: 575-1000 ml.

[0011] Specifically, in the compound pine bark extract with 1 weight component containing 80±10g of forsythia, 40±5g of phellodendron bark, 40±5g of honeysuckle, 40±5g of dandelion, and 2.4±0.3g of centipede, in step S2, take 1 weight component of the compound pine bark extract and add water to prepare 575-1000ml.

[0012] In the 20-component compound Phellodendron amurense extract alcohol precipitation, the volume of the raw materials and alcohol precipitation in component 1 is increased by 20 times when the volume of water is increased by 20 times. Forsythia suspensa 1600±200g, Phellodendron amurense 800±100g, Lonicera japonica 800±100g, Taraxacum mongolicum 800±100g, and Scolopendra subspinipes 48±6g. In step S2, the 20-component compound Phellodendron amurense extract alcohol precipitation is added to water to prepare 11500-20000ml.

[0013] Optionally, in step S1, water is added and the decoction is boiled three times, and the decoctions are combined. The first time is 1 hour, the second time is 45 minutes, and the third time is 30 minutes.

[0014] Optionally, in step S1, the content of forsythoside in the compound berberine extract is ≥1.00mg / g; the content of berberine hydrochloride is ≥0.50mg / g. Alternatively, the content of forsythoside in the compound berberine extract is ≥1.50mg / g; the content of berberine hydrochloride is ≥1.00mg / g.

[0015] Optionally, the S2 step of the compound lyophilized Phellodendron bark stock solution contains forsythoside ≥0.10mg / ml; berberine hydrochloride ≥0.01mg / ml; and solid content 2.3%-11.5%.

[0016] Optionally, the compound Phellodendron amurense freeze-dried powder is a light yellow to yellow loose lumps or powder, with a pH of 3.5-6.0, a moisture content of ≤8.0%, and a content of forsythoside ≥1.00mg / bottle; berberine hydrochloride ≥0.10mg / bottle. Optionally, the pH is 4.0-6.0, the moisture content is ≤5.0%, and the content of forsythoside ≥1.20mg / bottle; berberine hydrochloride ≥0.20mg / bottle. Optionally, the S3 step filling is 11.5-20.5ml per bottle.

[0017] This invention controls the content of each component in the compound Phellodendron amurense freeze-dried stock solution, thereby controlling the final compound Phellodendron amurense freeze-dried powder product to ensure that the material basis is not significantly changed compared to the compound Phellodendron amurense liquid coating.

[0018] Optionally, the water used in steps S1 and S2 may be purified water and / or water for injection. Water for injection refers to water obtained by distillation of purified water. The requirements for microbial limits in water for injection are higher than those for purified water, and there are also requirements for testing bacterial endotoxins, making it more suitable for use in sterile products.

[0019] Optionally, the ratio of the weight component in step S1 to the water added to a certain volume in step S2 is 1 weight component: 600ml-1000ml.

[0020] Optionally, the filtration in step S2 includes: filtration at a temperature of 28-45℃, and at least i sterilization filtrations through a filter membrane to obtain the compound Phellodendron amurense freeze-dried stock solution; where i is a natural number that iterates from 1 to n, and n is a natural number that is not less than 3; the pore size of the filter membrane in the (i+1)th filtration is not greater than the pore size of the filter membrane in the ith filtration.

[0021] Optionally, in step S2, filtration is performed at a temperature of 30-40℃, and the compound Phellodendron bark freeze-dried stock solution is obtained by at least three sterilization filtrations through a filter membrane. The pore size of the filter membrane for the first filtration is no greater than 0.5μm, the pore size of the filter membrane for the second filtration is no greater than 0.3μm, and the pore size of the filter membrane for the third filtration is no greater than 0.3μm.

[0022] Optionally, the S3 step of freeze drying includes the following steps: pre-freezing the compound Phellodendron amurense freeze-dried stock solution at a temperature of -47 to -43℃; then performing a first sublimation drying at a temperature of -5 to -5℃, followed by a second sublimation drying at a temperature of 0 to 10℃; and finally performing a first desorption drying at a temperature of 38 to 42℃, followed by a second desorption drying at a temperature of 18 to 22℃.

[0023] Optionally, the S3 step of freeze drying includes the following steps: filling the compound Phellodendron bark freeze-dried stock solution into a container no larger than 15 mm and pre-freezing it at -45°C; then performing a first sublimation drying at a pressure of 2.5-4.2 Pa and a temperature of 0°C; performing a second sublimation drying at a pressure of 0-3 Pa and a temperature of 5°C; and finally performing a first desorption drying at a pressure of 0-3 Pa and a temperature of 40°C, followed by a second desorption drying at 20°C.

[0024] Furthermore, this invention controls the content of key substances in the original solution and subsequent processes, ensuring that the final freeze-dried powder has no significant change in material basis compared to the compound Phellodendron amurense liquid coating. A higher solid content in the original solution will affect the resolubility of the final freeze-dried powder.

[0025] The second aspect of the present invention provides a compound Phellodendron amurense freeze-dried powder, which is prepared by the above-described preparation process.

[0026] Compared with the prior art, the present invention achieves at least one of the following beneficial effects:

[0027] (1) This invention controls the final freeze-dried powder product by controlling the material basis of the sterile compound Phellodendron chinense freeze-dried stock solution, ensuring that the material basis of the freeze-dried powder product does not change significantly compared to the compound Phellodendron chinense liquid coating, thereby ensuring the safety, effectiveness and quality controllability of the final compound Phellodendron chinense freeze-dried powder product.

[0028] (2) The compound Phellodendron chinense freeze-dried powder prepared by the present invention has a smooth surface, uniform color, no obvious layering and color difference, and good reconstitution effect.

[0029] (3) The compound Phellodendron chinense freeze-dried powder prepared by the present invention solves the problems of existing coatings being non-sterile, unstable, and inconvenient to transport. Attached Figure Description

[0030] The accompanying drawings, which are included to provide a further understanding of the invention and form part of this invention, illustrate exemplary embodiments of the invention and are used to explain the invention, but do not constitute an undue limitation of the invention. In the drawings:

[0031] Figure 1 An exemplary embodiment of the present invention is shown, illustrating the morphology of freeze-dried powder when using disc freeze-drying.

[0032] Figure 2 Another exemplary embodiment of the present invention, showing the morphology of freeze-dried powder when using disc freeze-drying, is illustrated.

[0033] Figure 3 An exemplary embodiment of the compound Phellodendron bark freeze-dried stock solution of the present invention is shown in the bottled freeze-dried disintegration diagram;

[0034] Figure 4 The following graph shows the results of differential scanning calorimetry detection of the compound Phellodendron bark freeze-dried stock solution of the present invention;

[0035] Figure 5 An exemplary embodiment of the morphology of freeze-dried powder when the sublimation drying conditions of the present invention are screened using bottle freeze-drying is shown;

[0036] Figure 6 An exemplary embodiment of the morphology of freeze-dried powder when the sublimation drying conditions of the present invention are screened using bottle freeze-drying is shown;

[0037] Figure 7 An exemplary embodiment of the morphology of freeze-dried powder when the sublimation drying conditions of the present invention are screened using bottle freeze-drying is shown;

[0038] Figure 8 An exemplary embodiment of the morphology of freeze-dried powder when the sublimation drying conditions of the present invention are screened using bottle freeze-drying is shown;

[0039] Figure 9 An exemplary embodiment of the morphology of freeze-dried powder when the bottle-based freeze-drying sublimation drying conditions are optimized is shown;

[0040] Figure 10 An exemplary embodiment of the morphology of freeze-dried powder when the bottle-based freeze-drying sublimation drying conditions are optimized is shown;

[0041] Figure 11 An exemplary embodiment of the morphology of freeze-dried powder when the bottle-based freeze-drying sublimation drying conditions are optimized is shown;

[0042] Figure 12 An exemplary embodiment of the morphology of freeze-dried powder when the bottle-based freeze-drying sublimation drying conditions are optimized is shown;

[0043] Figure 13 An exemplary embodiment is shown, illustrating the morphology of the freeze-dried powder during the freeze-drying process in Example 3.

[0044] Figure 14 An exemplary embodiment is shown, illustrating the morphology of the freeze-dried powder during the freeze-drying process in Example 3.

[0045] Figure 15 An exemplary embodiment is shown, illustrating the morphology of the freeze-dried powder during the freeze-drying process in Example 3.

[0046] Figure 16 An exemplary embodiment is shown, illustrating the morphology of the freeze-dried powder in two comparative bottles.

[0047] Figure 17 An exemplary embodiment is shown, illustrating the morphology of the lyophilized powder as the solid content in the original solution increases.

[0048] Figure 18 The results of the resolubility test are shown in the figure for samples with a solid content of 11.5% and 17.3%;

[0049] Figure 19 An exemplary embodiment is shown, depicting a freeze-dried powder product image after a sample has been stored for a period of time.

[0050] Figure 20 An exemplary embodiment is shown, illustrating the exit diagram of freeze-dried products at different liquid heights.

[0051] Figure 21 An exemplary embodiment is shown, illustrating the bottom surface of the freeze-dried product exiting the tray and the bottom view of the tray at different liquid heights;

[0052] Figure 22An exemplary embodiment is shown, with a side view of a freeze-dried product at different liquid heights. Detailed Implementation

[0053] To more clearly illustrate the overall concept of the present invention, a detailed description will be provided below with reference to the accompanying drawings and examples.

[0054] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and therefore the scope of protection of the invention is not limited to the specific embodiments disclosed below.

[0055] Example 1

[0056] The preparation process of compound Phellodendron bark freeze-dried powder includes the following steps:

[0057] By weight, the ingredients are: Forsythia 1400g, Phellodendron bark 700g, Honeysuckle 700g, Dandelion 700g, and Centipede 42g.

[0058] S1: Take the above five ingredients, add water and decoct three times, the first time for 1 hour, the second time for 45 minutes, and the third time for 30 minutes. Combine the decoctions, concentrate them to a clear paste with a relative density of 1.10-1.15, add ethanol to make the alcohol content reach 70%, let stand, concentrate until there is no alcohol taste, and obtain compound berberine precipitate.

[0059] S2: Take the above compound berberine extract, add water to make up to 20000ml, refrigerate, take the supernatant and sterilize it at 28℃, filter it through a 0.45μm filter membrane the first time, and through a 0.22μm filter membrane the second and third times to obtain the compound berberine freeze-dried stock solution.

[0060] S3: Take the above-mentioned compound Phellodendron bark freeze-dried stock solution, fill it into bottles of 20±0.5ml each, and freeze-dry it. The freeze-drying steps are as follows:

[0061] The compound Phellodendron bark freeze-dried stock solution was pre-frozen at -47℃ for 4 hours; then it underwent the first sublimation: sublimation drying temperature -5℃, pressure 2.5-4.0 Pa, upper pressure limit 4.2 Pa, for 54 hours.

[0062] Second sublimation: Sublimation drying temperature 0℃, pressure 0.0-3.0pa, hold for 3 hours;

[0063] First analysis: analysis drying temperature 38℃, pressure 0.0-3.0pa, maintained for 10 hours;

[0064] Second analysis: Analysis and drying temperature 18℃, pressure 0.0-3.0 Pa, maintained for 1 hour.

[0065] Example 2

[0066] The preparation process of compound Phellodendron bark freeze-dried powder includes the following steps:

[0067] By weight, the ingredients are: Forsythia 1800g, Phellodendron bark 900g, Honeysuckle 900g, Dandelion 900g, and Centipede 54g.

[0068] S1: Take the above five ingredients by weight, add purified water and decoct three times, the first time for 1 hour, the second time for 45 minutes, and the third time for 30 minutes. Combine the decoctions, concentrate them to a clear paste with a relative density of 1.10-1.15, add ethanol to make the alcohol content reach 70%, let stand, concentrate until there is no alcohol taste, and obtain compound berberine precipitate.

[0069] S2: Take the above compound berberine extract, add purified water to make 16000ml, refrigerate, take the supernatant and sterilize it at 45℃, filter it through a 0.45μm filter membrane the first time, and filter it through a 0.22μm filter membrane the second and third times to obtain the compound berberine freeze-dried stock solution.

[0070] S3: Take the above-mentioned compound Phellodendron bark freeze-dried stock solution, fill it into bottles of 16±0.5ml each, and freeze-dry it. The freeze-drying steps are as follows:

[0071] The compound Phellodendron bark freeze-dried stock solution was pre-frozen at -43℃ for 4 hours; then it underwent the first sublimation: sublimation drying temperature 5℃, pressure 2.5-4.0pa, pressure upper limit 4.2pa, for 54 hours.

[0072] Second sublimation: Sublimation drying temperature 10℃, pressure 0.0-3.0pa, hold for 3 hours;

[0073] First analysis: analysis drying temperature 42℃, pressure 0.0-3.0pa, maintained for 10 hours;

[0074] Second analysis: The analysis and drying temperature was 22℃, the pressure was 0.0-3.0pa, and the process was maintained for 1 hour.

[0075] Example 3

[0076] By weight, the ingredients are: Forsythia 1600g, Phellodendron bark 800g, Honeysuckle 800g, Dandelion 800g, and Centipede 48g.

[0077] S1: Take the above five ingredients, add purified water and decoct three times, the first time for 1 hour, the second time for 45 minutes, and the third time for 30 minutes. Combine the decoctions, concentrate them to a clear paste with a relative density of 1.10-1.15, add ethanol to make the alcohol content reach 70%, let stand, concentrate until there is no alcohol taste, and obtain compound berberine precipitate.

[0078] S2: Take the above compound berberine extract, add water for injection to prepare 12000ml, refrigerate, take the supernatant and sterilize it at 30℃, filter it through a 0.45μm filter membrane the first time, and filter it through a 0.22μm filter membrane the second and third times to obtain the compound berberine freeze-dried stock solution.

[0079] S3: Take the above-mentioned compound Phellodendron bark freeze-dried stock solution, fill it into 12±0.5ml bottles, and freeze-dry it. The freeze-drying steps are as follows:

[0080] The compound Phellodendron bark freeze-dried stock solution was pre-frozen at -45℃ for 4 hours; then it underwent the first sublimation: sublimation drying temperature 0℃, pressure 2.5-4.0pa, pressure upper limit 4.2pa, for 54 hours.

[0081] Second sublimation: Sublimation drying temperature 5℃, pressure 0.0-3.0pa, hold for 3 hours;

[0082] First analysis: analysis drying temperature 40℃, pressure 0.0-3.0pa, maintained for 10 hours;

[0083] Second analysis: The analysis and drying temperature was 20℃, the pressure was 0.0-3.0pa, and the process was maintained for 1 hour.

[0084] Example 4

[0085] By weight, the ingredients are: Forsythia 1600g, Phellodendron bark 800g, Honeysuckle 800g, Dandelion 800g, and Centipede 48g.

[0086] S1: Take the above five ingredients, add water for injection and decoct three times, the first time for 1 hour, the second time for 45 minutes, and the third time for 30 minutes. Combine the decoctions, concentrate them to a clear paste with a relative density of 1.10-1.15, add ethanol to make the alcohol content reach 70%, let stand, concentrate until there is no alcohol taste, and obtain compound berberine precipitate.

[0087] S2: Take the above compound berberine extract, add water for injection to prepare 11500ml, refrigerate, take the supernatant and sterilize it at 40℃, filter it through a 0.45μm filter membrane the first time, and filter it through a 0.22μm filter membrane the second and third times to obtain the compound berberine freeze-dried stock solution.

[0088] S3: Take the above-mentioned compound Phellodendron bark freeze-dried stock solution, fill it into 11.5±0.5ml bottles, and freeze-dry it. The freeze-drying steps are as follows:

[0089] The compound Phellodendron bark freeze-dried stock solution was pre-frozen at -45℃ for 4 hours; then it underwent the first sublimation: sublimation drying temperature 0℃, pressure 2.5-4.0pa, pressure upper limit 4.2pa, for 54 hours.

[0090] Second sublimation: Sublimation drying temperature 5℃, pressure 0.0-3.0pa, hold for 3 hours;

[0091] First analysis: analysis drying temperature 40℃, pressure 0.0-3.0pa, maintained for 10 hours;

[0092] Second analysis: The analysis and drying temperature was 20℃, the pressure was 0.0-3.0pa, and the process was maintained for 1 hour.

[0093] Comparative Example 1

[0094] Five medicinal materials were used in the compound Phellodendron amurense decoction: Forsythia suspensa 80g, Phellodendron amurense 40g, Lonicera japonica 40g, Taraxacum mongolicum 40g, and Scolopendra subspinipes 2.4g. The herbs were decocted three times with water: 1 hour for the first decoction, 45 minutes for the second, and 30 minutes for the third. The decoctions were combined, filtered, and concentrated to a clear extract with a relative density of 1.10-1.15. Ethanol was added to bring the alcohol content to 70%, and the mixture was allowed to stand for 24 hours. The extract was then filtered, and the filtrate was concentrated under reduced pressure until no alcohol odor remained, yielding the compound Phellodendron amurense decoction alcohol precipitate.

[0095] Take the compound Phellodendron amurense extract alcohol precipitation paste, add water to make up to 1000ml, stir, refrigerate and stand for 24 hours, take the supernatant, filter it with filter paper at refrigeration temperature (2~10℃) to obtain the compound Phellodendron amurense extract coating.

[0096] Comparative Example 2

[0097] Based on Example 3, the main difference is that the compound Phellodendron bark freeze-dried stock solution is pre-frozen at -50°C for 150 min; then it undergoes one sublimation: sublimation drying temperature -5°C, pressure 20 Pa, for 1500 min; then it undergoes one desorption: desorption drying temperature 30°C, pressure 20 Pa, for 180 min.

[0098] The other steps are the same as in Example 3.

[0099] Experimental Example

[0100] Investigation of key process parameters related to material basis

[0101] 1. Study on the preparation ratio of compound Phellodendron bark freeze-dried stock solution

[0102] Without altering the material basis, it is proposed to increase the concentration of the stock solution before freeze-drying and reduce the total amount prepared to increase production capacity and reduce energy consumption. The preparation ratio of the compound Phellodendron amurense liquid coating is set to 1. The changes in the content of forsythoside and berberine hydrochloride, as well as the solid content, of the solutions prepared at different ratios before and after sterilization and filtration are investigated. The optimal preparation ratio of the stock solution before freeze-drying is determined based on the fact that the change rate of the above three evaluation indicators is simultaneously less than 5%. Specific data are shown in Table 1 below:

[0103] in,

[0104] The preparation ratio 1 consists of 80g of Forsythia suspensa, 40g of Phellodendron chinense, 40g of Lonicera japonica, 40g of Taraxacum mongolicum, and 2.4g of Scolopendra subspinipes. The alcoholic extract prepared by the above formula is diluted with water to 1000ml, refrigerated, and filtered through filter paper to obtain the compound Phellodendron chinense extract coating (Comparative Example 1). The preparation ratio 0.80 is obtained by adding water to 800ml of the alcoholic extract prepared by the above formula and filtering it under sterile conditions. The preparation ratio 0.60 is obtained by adding water to 600ml of the prescribed amount of extract and filtering it under sterile conditions. The preparation ratio 0.40 is obtained by adding water to 400ml of the prescribed amount of extract and filtering it under sterile conditions. The preparation ratio 0.20 is obtained by adding water to 200ml of the prescribed amount of extract and filtering it under sterile conditions.

[0105] Table 1

[0106]

[0107] Referring to Table 1, the experimental results show that as the concentration ratio of the stock solution decreases, the content of solids and forsythosides decreases, while the content of berberine hydrochloride first decreases and then increases. Furthermore, the changes in the content of forsythosides, berberine hydrochloride, and solids at each concentration ratio are not simultaneously less than 5%. The study found that the berberine hydrochloride content in the compound Phellodendron amurense liquid coating is affected by the filtration temperature; therefore, the filtration temperature was investigated simultaneously with the concentration ratio of the stock solution.

[0108] 2. Investigation on the preparation ratio and sterilization filtration temperature of compound Phellodendron bark freeze-dried stock solution

[0109] The changes in the content of forsythoside and berberine hydrochloride, as well as the solid content, of different formulations of the drug solution before and after sterile filtration were investigated. The effect of temperature on the changes of these three evaluation indicators before and after filtration was also examined. Compared with Comparative Example 1, the optimal formulation ratio and filtration temperature of the drug solution before lyophilization were selected based on the simultaneous change rate of less than 5% for all three evaluation indicators. Specific values ​​are shown in Table 2 below.

[0110] Table 2

[0111]

[0112] Referring to Table 2, the experimental results show that when the stock solution is prepared at a ratio of 0.60-0.80, and sterilized and filtered at 30℃-40℃, the changes in the contents of forsythoside, berberine, and solids are all within 5% compared to Comparative Example 1, consistent with the material basis of the original compound Phellodendron amurense liquid coating. Therefore, the stock solution preparation ratio before freeze-drying is determined to be 0.60-0.80.

[0113] 3. Investigation into the impact of sterilization filtration on the material basis

[0114] The stock solution sample with the above-mentioned configuration ratio of 0.60 was sterilized and filtered at 30℃~40℃. The changes in the material basis of the sample before and after sterilization filtration (capsule sterile filter, 0.45um for the first time, and 0.22um for the second and third times) were examined using solid content and content as evaluation indicators. The specific values ​​are shown in Table 3 below.

[0115] Table 3

[0116]

[0117]

[0118] As shown in Table 3, there were no significant changes in the sample content and solids before and after sterilization filtration, indicating that sterilization filtration does not alter the material composition.

[0119] Investigation of freeze-drying parameters:

[0120] 4. The compound Phellodendron bark freeze-dried stock solution prepared in Example 3 was first tested using a tray freeze-drying method. The results are as follows: Two batches of tray freeze-drying tests were conducted to verify the feasibility, rationality, and stability of the process parameters. The specific results are shown in Table 4 below:

[0121] Table 4

[0122]

[0123] As shown in Table 4, all parameters are reasonable and feasible, and the process is stable. The results of the pan freeze-drying are as follows: Figure 1 and Figure 2 As shown, the powder compact has a good appearance, does not stick to the tray, does not melt, has a uniform color, and can be easily crushed.

[0124] 4.1 Examination of the liquid level

[0125] Under the above freeze-drying conditions, and considering industrial manufacturing costs, the tray freezing depth of 15mm and 20mm were examined. Freeze-drying results are for reference. Figure 20-22 As shown, Figure 20-22 The left side of the paper shows the freeze-dried product with a liquid level of 15mm, and the right side shows the freeze-dried product with a liquid level of 20mm. It can be seen that the 15mm volume freeze-dried powder cake has better overall appearance, easier removal from the tray, and easier pulverization than the 20mm volume cake. Even if there is slight melting in the rear part of the tray near the cold trap, it does not affect the removal of the powder cake. Therefore, this application sets the liquid level height to no more than 15mm.

[0126] 5. Examination of bottle freeze-drying parameters:

[0127] The aforementioned compound Phellodendron amurense freeze-dried stock solution was freeze-dried using a pan-freezing method. Two small-scale trials showed stable process performance and reasonable key process parameters. However, after pan-freezing, subsequent pulverization and packaging are required. Improper handling during this process can easily lead to bacterial contamination, and the freeze-dried powder is prone to absorbing moisture and sticking together, making packaging and pulverization difficult. Therefore, to reduce the risk of aseptic and non-compliant filling during product production and improve quality control in industrialization, the loading method was changed from pan-freezing to bottle-freezing after evaluation. Consequently, some parameters were further optimized based on the pan-freezing process.

[0128] 5.1. Pre-freezing temperature investigation, see Table 5.

[0129] Table 5

[0130] Sample Name Disintegration temperature Glass transition temperature Compound Phellodendron bark freeze-dried stock solution (bottle) -30.8℃ -36.80℃

[0131] Refer to Table 5. Figure 3 and Figure 4 As shown, it can be seen that the sample loaded in the bottle of compound Phellodendron bark freeze-dried stock solution disintegrated at -30.8℃. Based on the glass transition temperature of the sample and the previous plate freezing study, the sample loaded in the bottle can be completely frozen solid at a pre-freezing temperature of -47 to -43℃, and the surface is smooth when dried.

[0132] 5.2 Screening of Sublimation Drying Conditions

[0133] Based on the tray freezing process, the sublimation drying conditions for bottle freezing were further screened, as detailed in Table 6 below:

[0134] Table 6

[0135] batch Set temperature ℃ Pressure Pa Properties L20230508 -10 10 The appearance is good, the bottom has shrunk to a moderate degree, and there is no significant melting inside the powder compact. L20230512-1 -5 5 The freeze-dried sample had a good appearance, with slight shrinkage at the bottom. L20230515 0 3 The freeze-dried samples had a good appearance, and the powder cake was plump and showed no signs of shrinkage. L20230519 10 0 The freeze-dried samples had a good appearance, and the powder cakes were plump and did not shrink.

[0136] Refer to Table 6. Figures 5-8 As shown, a single sublimation drying temperature of -10℃ to 10℃ results in no melting of the sample, and lower pressure leads to better sample properties. While a single sublimation can also achieve a good lyophilized state, the lack of a buffer process may cause slight melting and bubbling on the surface of the final lyophilized powder, making it difficult to form a powder. (Reference) Figure 19 As shown, Figure 19 The image shows the freeze-dried product after the sample has been left for a period of time. To improve the stability of the freeze-dried product, it is proposed to increase the pressure during the initial sublimation stage and to perform a secondary sublimation using an ultimate vacuum during the later stage of the initial sublimation.

[0137] 5.3 Optimization of sublimation drying conditions

[0138] Considering that low vacuum is detrimental to heat conduction, a two-step sublimation drying process was performed to accelerate heat conduction during the drying process and thus shorten the total drying time, while ensuring the product's properties remained intact. First, most of the moisture in the sample was removed under low temperature and low vacuum to maintain a basically stable appearance. Then, the temperature and vacuum were increased to remove the remaining free water, shortening the drying time. Furthermore, after only one sublimation drying step, 70%-80% of the water in the sample was removed. Although the freeze-dried state of the sample met the requirements at this point, it would shrink and partially melt after a period of time. To ensure that the powder cake would not shrink during the product's shelf life, a second sublimation was performed to further remove moisture and improve product stability. The test results are shown in Table 7.

[0139] Table 7

[0140]

[0141] Refer to Table 7. Figure 9-12 As shown, it can be seen that when the first sublimation temperature was set at 0℃ and the pressure at 3.5±0.5Pa, and the second sublimation temperature was adjusted to 5-10℃ and the pressure was 0Pa, the sample had a good appearance and the powder cake was full without shrinkage.

[0142] 5.4 Freeze-drying verification test of three batches of products: The products of Example 3 were freeze-dried respectively.

[0143] The test results for the freeze-dried powder are referenced respectively. Figure 13-15 As shown, the three batches of freeze-dried samples from the small-scale trial showed good appearance, with the powder cakes remaining plump and without shrinkage. The experimental results indicate that the freeze-drying process is reasonable, feasible, and stable.

[0144] 5.5 Comparative Experiment of Compound Phellodendron Lyophilized Powder and Compound Phellodendron Liquid Coating

[0145] To further verify whether the material basis of the compound Phellodendron amurense freeze-dried powder has changed compared with the original product, the same batch of extract was used to prepare compound Phellodendron amurense freeze-dried powder and compound Phellodendron amurense liquid coating in parallel, and the content and solid content were used as evaluation indicators for overall evaluation. Two batches of extract were used to prepare freeze-dried powder according to the methods of Example 3 and Example 4, respectively. The specific results are shown in Table 8 below:

[0146] Table 8

[0147]

[0148] As shown in Table 8, the experimental results indicate that the material basis of the compound berberine liquid freeze-dried powder is not significantly different from that of the original compound berberine liquid coating, and the material basis of the two is basically the same as that of the solid content and the content of effective ingredients.

[0149] 5.6. Verification of four batches of compound Phellodendron chinense freeze-dried powder products in Examples 1-4. The test results are shown in Table 9.

[0150] Table 9

[0151]

[0152]

[0153] refer to Figure 16 The image shows the product of the compound Phellodendron bark freeze-dried powder prepared in Comparative Example 2. As can be seen from the image, when the freeze-drying conditions changed, the sample collapsed and shrank in the bottle, and some melted. The final product was not in good condition and did not form a loose block or powdery freeze-dried powder.

[0154] refer to Figure 17 As shown, Figure 17 From left to right, the freeze-dried powder products obtained by freeze-drying under the following conditions are shown: a formulation ratio of 0.20 (prescription amount of extract added to 200ml, resulting in a solid content of 11.5%), a formulation ratio of 0.13 (prescription amount of extract added to 133ml, resulting in a solid content of 17.3%), and a formulation ratio of 0.10 (prescription amount of extract added to 100ml, resulting in a solid content of 23%). Compared to the 11.5% solid content sample, the 17.3% and 23% samples show obvious bottom melting, and the 23% sample shows layered melting in the middle. This indicates that as the solid content in the stock solution increases, the material basis of the sample changes, which also affects the product quality and morphology of the freeze-dried powder.

[0155] In addition, a resolubility test was conducted on samples with a solid content of 11.5% and 17.3%, respectively. Water was added to each sample until the solid content reached 2.3%, and the results were as follows: Figure 18 As shown, from left to right, the solid content is 11.5% and 17.3%, respectively. It can be seen that the solution obtained by reconstitution of the sample with 11.5% solid content is clear, while the solution obtained by reconstitution of the sample with 17.3% solid content is turbid. Furthermore, it can be seen that the solid content not only affects the material basis of the sample, the quality and morphology of the lyophilized powder product, but also affects the reconstitution properties. This invention controls the final lyophilized powder product by controlling the material basis of the sterile compound Phellodendron amurense lyophilized stock solution. Combined with subsequent lyophilization processes, this ensures that the material basis of the lyophilized powder product does not change significantly compared to the compound Phellodendron amurense liquid coating. Simultaneously, the prepared compound Phellodendron amurense lyophilized powder has a smooth surface, uniform color, no obvious layering or color difference, and good reconstitution effect.

[0156] The above description is merely an embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principle of the present invention should be included within the scope of the claims of the present invention.

Claims

1. A preparation process of a compound cork tree bark freeze-dried powder, characterized in that, The preparation process comprises the following steps: The preparation process comprises the following steps: The preparation process comprises the following steps: S1: Take a certain weight component of the above five raw materials, add water to decoct, concentrate, to the relative density of 1.10-1.15 clear paste, add ethanol to make the alcohol content reach 70%, stand, concentrate to no alcohol taste, get compound cortex phellodendri alcohol precipitation paste; S2: Take the compound cortex phellodendri alcohol precipitation paste of step S1, add water to a certain volume, refrigerate, filter, get compound cortex phellodendri freeze-dried stock solution; S3: Take the compound cortex phellodendri freeze-dried stock solution of step S2, fill, freeze-drying, get compound cortex phellodendri freeze-dried powder; The ratio of the weight component of step S1 to the water added to a certain volume of step S2 is 1 weight component: 575-1000ml; The compound cortex phellodendri freeze-dried powder is a light yellow to yellow loose block or powder, pH 3.5-6.0, containing moisture ≤8.0%, containing forsythoside ≥1.00mg / bottle; Berberine hydrochloride ≥0.10mg / bottle; The filtration in step S2 comprises: filtering at a temperature of 30-40℃, and performing at least i times of sterilization filtration through filter membranes to obtain the compound cortex phellodendri freeze-dried stock solution; wherein i is a natural number and traverses from 1 to n, n is a natural number and is not less than 3; the pore size of the filter membrane for the (i+1)th filtration is not greater than the pore size of the filter membrane for the ith filtration; In the compound cortex phellodendri freeze-dried stock solution of step S2, forsythoside ≥0.10mg / ml; berberine hydrochloride ≥0.01mg / ml; solid content 2.3%-11.5%; 2. The manufacturing process according to claim 1, characterized in that, The freeze-drying of step S3 comprises the following steps: pre-freezing the compound cortex phellodendri freeze-dried stock solution at a temperature of-47~-43℃; then first sublimation drying at a temperature of-5-5℃, second sublimation drying at a temperature of 0-10℃; finally, first desorption drying at a temperature of 38-42℃, and second desorption drying at a temperature of 18-22℃.

3. The manufacturing process of claim 1, wherein, The water used in steps S1 and S2 is purified water and / or water for injection.

4. The manufacturing process of claim 1, wherein, In step S2, filtering at a temperature of 30-40℃, and performing at least 3 times of sterilization filtration through filter membranes to obtain the compound cortex phellodendri freeze-dried stock solution, the pore size of the filter membrane for the first filtration is not greater than 0.5μm, the pore size of the filter membrane for the second filtration is not greater than 0.3μm, and the pore size of the filter membrane for the third filtration is not greater than 0.3μm. The freeze-drying of step S3 comprises the following steps: pre-freezing the compound cortex phellodendri freeze-dried stock solution at a temperature of-45℃; then first sublimation drying at a pressure of 2.5-4.2pa and a temperature of 0℃; second sublimation drying at a pressure of 0-3pa and a temperature of 5℃; finally, first desorption drying at a pressure of 0-3pa and a temperature of 40℃, and second desorption drying at a temperature of 20℃.

5. A compound cortex phellodendri freeze-dried powder prepared by the preparation process of any one of claims 1 to 4.

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