A Wenjing Decoction Granule and its Preparation Method

Abstract

This invention relates to the field of traditional Chinese medicine compound preparations, specifically to a Wenjingtang granule and its preparation method. The Wenjingtang granule of this invention has the following advantages: 1. Convenience: No need for immediate decoction; simply dissolve in warm water and take one sachet three times a day, suitable for modern clinical needs; 2. Industrial adaptability: Spray drying, dry granulation, and other processes are suitable for large-scale production, reducing energy consumption and costs.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine compound preparations, specifically to a Wenjing Decoction granule and its preparation method. Background Technology

[0002] Wenjing Decoction originates from Chen Ziming's "Complete Collection of Effective Prescriptions for Women" from the Song Dynasty. It is a classic Chinese medicine formula with the effects of warming the meridians and dispelling cold, nourishing blood and removing blood stasis. Clinically, it is mainly used to treat gynecological diseases, with definite efficacy and high safety. As a traditional Chinese medicine compound preparation managed in the catalog of ancient classic prescriptions, its original formula is used in the form of a decoction, which needs to be prepared by traditional decoction method. The usage is: "Chew the herbs, take five qian each time, decoct with one and a half cups of water until eight-tenths remain, remove the dregs and take warm."

[0003] The existing Wenjing Decoction has the following main problems: 1. Significant loss of volatile components: The original formula contains volatile medicinal materials such as Angelica sinensis, Ligusticum chuanxiong, Cinnamomum cassia, Paeonia suffruticosa, and Curcuma zedoaria. However, during the concentration and drying process of traditional decoctions, volatile components such as cinnamaldehyde and paeonol are significantly lost, making these components undetectable in the dry powder and affecting the integrity of the pharmacodynamic material basis.

[0004] 2. Limitations of traditional decoctions: Inconvenient to take and carry: Decoctions need to be prepared just before use, which is time-consuming and laborious, and does not meet the needs of modern fast-paced life.

[0005] 3. Insufficient quality controllability: Traditional decoction process parameters (such as heating method, time, filtration conditions, etc.) lack standardization, which may lead to batch-to-batch quality differences. Summary of the Invention

[0006] This invention aims to provide a Wenjing Decoction granule and its preparation method, the specific scheme of which is as follows: A type of Wenjing Decoction granules includes the following ingredients: Angelica sinensis (processed with wine), Ligusticum chuanxiong, Paeonia lactiflora, Cinnamomum cassia, Paeonia suffruticosa, Curcuma zedoaria (processed with vinegar), Ginseng, Glycyrrhiza uralensis (processed with stir-fry), and Achyranthes bidentata (processed with wine).

[0007] A type of Wenjing Decoction granules, with the following ingredients in the indicated proportions: Angelica sinensis (wine-processed): Ligusticum chuanxiong: Paeonia lactiflora: Cinnamomum cassia: Paeonia suffruticosa: Curcuma zedoaria (vinegar-processed): Ginseng: Glycyrrhiza uralensis (fried): Achyranthes bidentata (wine-processed) = 0.8-1.2:0.8-1.2:0.8-1.2:0.8-1.2:0.8-1.2:1.8-2.2:1.8-2.2:1.8-2.2.

[0008] A method for preparing Wenjing Decoction granules includes the following steps: (1) Pretreatment process; (2) Extraction process: The coarse particles are boiled twice with water. The aromatic water is collected after the first boiling and is set aside. The decoction is filtered. The aromatic water is collected after the second boiling and is set aside. The aromatic water collected in the two boilings is combined and set aside. The decoction is filtered and the two filtrates are combined. The filtrate is concentrated under reduced pressure to a clear extract with a relative density of 1.10 to 1.15 and set aside. The aromatic water is redistilled to obtain the distillate. Betacyclodextrin is added and ground to form an inclusion solution for use. (3) Drying and granulation process.

[0009] The specific steps of step (3) are as follows: Add the inclusion solution to the clear paste and mix well, spray dry to obtain dry paste powder, add an appropriate amount of maltodextrin, mix well, and granulate by dry method to make granules. The drying parameters are as follows: inlet air temperature 165~175℃, atomizer speed 45~50Hz, outlet air temperature 90~100℃.

[0010] In step (2), the first time 12 times the amount of water is added and simmered for 60 minutes, and the second time 10 times the amount of water is added and simmered for 40 minutes.

[0011] In step (2), the distillate: betacyclodextrin = 9-11 ml: 1 g.

[0012] In step (2), the distillate is 1 / 9 to 1 / 11 of the total amount of aromatic water.

[0013] In step (2), after adding betacyclodextrin, the grinding time for inclusion is 30-60 minutes.

[0014] In step (2), the reduced pressure concentration is a vacuum concentration, and the concentration temperature is 60-80℃.

[0015] This invention targets medicinal materials containing volatile components, such as angelica and cinnamon, and employs a process of "aromatic water collection - redistillation enrichment - betacyclodextrin inclusion": 1. Aromatic water collection: Aromatic water from the first and second decoctions is collected throughout the process, with a total cinnamaldehyde content of 12.88–12.95 mg per dose; 2. Redistillation concentration: The volume of aromatic water is reduced to 1 / 10, increasing the cinnamaldehyde concentration and reducing the amount of inclusion excipients; 3. Optimization of inclusion process: The ratio of betacyclodextrin to aromatic water is determined to be 1:10 (g:ml), and grinding is performed for 45 minutes, achieving an inclusion rate of 58.44%–59.25% with good stability.

[0016] The process parameters of this invention are scientifically controllable: 1. By adding 12 times the amount of water for the first time and decocting for 60 minutes, and then adding 10 times the amount of water for the second time and decocting for 40 minutes, the components are fully extracted, resulting in better dry extract rate, extract content, and total amount of indicator components; 2. By using a reduced pressure concentration temperature of 60-80℃, a spray drying inlet air temperature of 165-175℃, and an outlet air temperature of 90-100℃, the loss of heat-sensitive components is reduced, and the moisture content of the dry extract powder is controlled at 3.9%-5.1%.

[0017] This invention is a granule product with the following advantages: 1. Convenience: No need for immediate decoction, simply dissolve in warm water and take one packet (10g) three times a day, which is suitable for modern clinical needs; 2. Industrial adaptability: Spray drying, dry granulation and other processes are suitable for large-scale production, reducing energy consumption and costs.

[0018] Finally, this invention strictly adheres to the "principle of respecting the ancients" and combines modern process optimization to ensure that the safety of the preparation is consistent with the efficacy of the original prescription, meeting the registration requirements for ancient classic prescription preparations. Attached Figure Description

[0019] Figure 1 The filtrate obtained from different filter cloths.

[0020] Figure 2 This is a diagram showing the critical relative humidity.

[0021] Figure 3 The present invention provides characteristic chromatograms of dry extract powder, concentrated liquid, extract, distillate, aromatic water, and reference sample.

[0022] Figure 4 This is a characteristic chromatogram of the medicinal materials and processed medicinal slices of the present invention. Detailed Implementation

[0023] I. Prescription information is summarized in Table 1 below: Table 1

[0024] II. Pretreatment Process The ingredients, including Angelica sinensis, Ligusticum chuanxiong, Paeonia lactiflora, Cinnamomum cassia, Paeonia suffruticosa, Curcuma zedoaria, Ginseng, Glycyrrhiza uralensis, and Achyranthes bidentata, were crushed using a crusher. All of these coarse particles could pass through a 5mm inner diameter sieve. However, no more than 20% of the powder could pass through a 1mm inner diameter sieve. The mixture was then stirred and set aside for later use.

[0025] III. Extraction Process 3.1 Examination of extraction time The dry extract yield, extract content, content of indicator components, total amount per dose, and characteristic chromatogram were used as evaluation indicators, and compared with the accompanying reference sample. Extraction time and water addition were also investigated. Four portions of medicinal slices (divided into two groups) were weighed, and 50 doses of the prescription were weighed from each portion (Angelica sinensis 82g, Ligusticum chuanxiong 83g, Paeonia lactiflora 82.5g, Cinnamomum cassia 85g, Paeonia suffruticosa 84.5g, Curcuma zedoaria 83.5g, Panax ginseng 168.5g, Glycyrrhiza uralensis 168.5g, Achyranthes bidentata 162.5g). The experiment was conducted according to the design in Table 2. The extract was filtered, the filtrates were combined, concentrated under reduced pressure, and spray-dried to obtain a dry extract powder. The weight of the dry extract powder was determined, the moisture content was measured, the dry extract yield was calculated, and the content of extract, indicator components, and other indicators were measured. The total amount per dose of each indicator in the extract was calculated. The results are shown in Table 3.

[0026] Table 2. Experimental Design of Extraction Time

[0027] Table 3 Summary of Extraction Time Examination Results

[0028] The experimental results show that the dry extract rate, extract, content and total amount of index components of the two processes are basically consistent with the accompanying reference sample. In order to ensure sufficient extraction and better component matching in the later scale-up production process, process 1 is selected as the best process, that is, the first decoction is decocted with 12 times the amount of water for 60 minutes, and the second decoction is decocted with 10 times the amount of water for 40 minutes.

[0029] 3.2 Investigation on Aromatic Water Extraction During the material reference study, the extract was concentrated and dried, resulting in significant loss of volatile components such as cinnamaldehyde. Therefore, in the process study of Wenjing Decoction compound preparation, cinnamaldehyde was used as the content determination indicator component and compared with the accompanying reference sample (extract) to investigate processes such as aromatic water extraction and redistillation.

[0030] (1) Investigation on the collection of aromatic water Two portions of the medicinal slices were weighed, and each portion contained the prescription amount for 40 doses (Angelica sinensis 65.8g, Ligusticum chuanxiong 63.8g, Paeonia lactiflora 68.8g, Cinnamomum cassia 67.8g, Paeonia suffruticosa 63.8g, Curcuma zedoaria 65.8g, Panax ginseng 136.2g, Glycyrrhiza uralensis 130.2g, and Achyranthes bidentata 136.2g). Using a predetermined extraction time and water addition process, during the preparation of the extract, it was found in preliminary experimental studies that the volatile components in the Wenjing Decoction prescription had low oil content and contained both heavy and light oils, making it impossible to directly collect the volatile oils. Only the aromatic water could be collected. The concentration of cinnamaldehyde in the aromatic water was low. Considering the large volume of aromatic water collected, large-scale production using beta-cyclodextrin inclusion complexation would require a large amount of excipients and be time-consuming. A secondary distillation of the aromatic water was planned for later investigation to reduce its volume. Therefore, the aromatic water was collected throughout the first and second decoctions. The amount of aromatic water collected was recorded, and the total amount of cinnamaldehyde per dose was calculated. The measurement results are shown in Tables 4 and 5.

[0031] Table 4. Investigation on the Collection Amount of Aromatic Water - 1

[0032] Table 5. Investigation on the Collection Amount of Aromatic Water - 2

[0033] The results show that when the extraction process is carried out according to the determined extraction time and water addition, aromatic water is collected throughout the first and second decoctions. The amount collected in the first decoction is about 1.2 times the amount of raw materials, and the amount collected in the second decoction is about 0.9 times the amount of raw materials. Using the total amount of cinnamaldehyde taken alone as an indicator, the process is stable among parallel batches. The content of cinnamaldehyde collected is higher than that of the accompanying reference sample. The aromatic water will be further investigated by secondary distillation to reduce the volume of aromatic water.

[0034] (2) Investigation on the double distillation of aromatic water The aromatic water prepared under the above-mentioned aromatic water collection and investigation was placed in a round-bottom flask for double distillation, and collected in fractions, with 1 / 20 of the total aromatic water volume collected from each fraction. The total amount of cinnamaldehyde in each fraction of redistilled aromatic water was measured, and the final amount of double distillation was determined based on the matching of the collection results with the reference decoction. Two samples were prepared in parallel for the experiment, and the results are shown in Table 6.

[0035] Table 6. Collection Quantity Survey

[0036] The results show that when the amount of redistilled aromatic water collected is 1 / 10 of the total amount of aromatic water, the cinnamaldehyde content is within ±30% of the accompanying reference sample, and at the same time, it can meet the qualitative requirements in the characteristic spectrum of the later formulation. Considering the actual production efficiency and cost, the amount of redistilled aromatic water collected is set to 1 / 10 of the total amount of aromatic water collected.

[0037] 3.3 Packaging Process To ensure the stability of the collected volatile components in the formulation, a grinding method was used to study the inclusion process of beta-cyclodextrin. The inclusion rate of cinnamaldehyde and the yield of the inclusion compound were used as indicators to investigate the amount of beta-cyclodextrin used and the inclusion time. The experimental results are as follows: (1) Investigation on the ratio of beta-cyclodextrin to aromatic water Following the aromatic water extraction and redistillation process, double-distilled aromatic water was prepared. Three portions, each 120 ml, were taken and beta-cyclodextrin was added at ratios of 1:8, 1:10, and 1:20 respectively. After grinding for 45 minutes, the mixture was refrigerated overnight. The mixture was then removed, filtered through filter paper, and the filtrate was discarded. The mixture was washed twice with an equal volume of petroleum ether (equal to the amount of beta-cyclodextrin), dried in an oven at 40–50°C, and pulverized to obtain the inclusion complex. Samples were weighed, and the cinnamaldehyde content was determined. The cinnamaldehyde inclusion rate and the yield of the inclusion complex were calculated. The results are shown in Table 7.

[0038] Table 7 Results of the study on the ratio of beta-cyclodextrin to aromatic water

[0039] The results show that the inclusion rates of cinnamaldehyde are basically the same for the three inclusion ratios. The inclusion yield is lower when the ratio of betacyclodextrin (g): aromatic water (ml) is 1:20. Considering all factors, the final inclusion ratio of betacyclodextrin (g): aromatic water (ml) is 1:10.

[0040] (2) Examination of the time of inclusion Take three portions (120 ml each) of double-distilled aromatic water. Add beta-cyclodextrin (g): aromatic water (ml) at a ratio of 1:10. Grind for 30 minutes, 45 minutes, and 60 minutes respectively, then refrigerate overnight. Remove from the refrigerator, filter with filter paper, discard the filtrate, wash twice with an equal amount of petroleum ether to the beta-cyclodextrin, dry in an oven at 40–50°C, and pulverize to obtain the inclusion complex. Weigh, sample, determine the cinnamaldehyde content, and calculate the cinnamaldehyde inclusion rate and the yield of the inclusion complex. The results are shown in Table 8.

[0041] Table 8 Results of the Investigation on Enclosure Time

[0042] The results show that the inclusion rate of cinnamaldehyde and the yield of inclusion complex are basically the same when grinding for 30 minutes, 45 minutes and 60 minutes. In order to ensure more complete inclusion in the later large-scale production, the inclusion time is selected as 45 minutes after comprehensive consideration.

[0043] (3) Validation of the inclusion process Following the aromatic water extraction and redistillation process, redistilled aromatic water was prepared. Three portions (120 ml each) of the double-distilled aromatic water were taken and mixed with beta-cyclodextrin at a ratio of 1:10 (g: aromatic water = 1:10). The mixture was ground for 45 minutes, refrigerated overnight, removed, filtered, and the filtrate was discarded. The mixture was then washed twice with an equal volume of petroleum ether (equal to beta-cyclodextrin), dried in an oven at 40–50°C, and pulverized to obtain the inclusion complex. The inclusion process was verified, and the inclusion rate of cinnamaldehyde and the yield of the inclusion complex were calculated. The results are shown in Table 9.

[0044] Table 9. Validation Results of Inclusion Process

[0045] The results showed that the inclusion rate of cinnamaldehyde and the yield of the inclusion complex in the aromatic water were basically consistent with the three batches of validation results, which were in good agreement with the above-mentioned process research process, indicating that the aromatic water extraction and inclusion process is stable and feasible.

[0046] (4) Determination of the encapsulation process The inclusion process was determined through experiments as follows: the inclusion ratio was betacyclodextrin: aromatic water = 1:10 (g: ml), the inclusion was carried out by grinding, and the inclusion time was 45 minutes.

[0047] 3.4 Filtration Process Extraction was performed according to the determined extraction process. While still hot, the extract was passed through 200-mesh and 300-mesh filter cloths. The state of the filtered liquid and the state of the filtrate after standing for a period of time were observed to determine the appropriate mesh size. The remaining filtrate was then filtered and set aside for later use. Results are shown below. Figure 1 .

[0048] Experimental results: By observing the state of the filtered medicine and the state of the filtrate after a period of time, it was found that the filtrate filtered by both 200 mesh and 300 mesh had good clarity, indicating that both mesh sizes of filter cloth can be used in the filtration process of Wenjing Decoction compound preparation.

[0049] 3.5 Concentration Study Weigh out 40 doses of the prescribed medicinal slices, divide into three parallel portions, and extract according to the conditions determined above. Combine the extracts, retain the samples, and divide them into three equal portions. Concentrate under reduced pressure at 60℃, 70℃, and 80℃ respectively until the relative density is 1.05-1.10 (60℃). Weigh the obtained concentrate, take samples, and determine the total amount of cinnamic acid, paeoniflorin, ginsenosides Rg1 and Re, and ginsenoside Rb1 before and after concentration. The results are shown in Table 10.

[0050] Table 10 Concentration Temperature Results

[0051] The results show that when the concentration temperature is 60℃, 70℃, and 80℃, there is no significant difference in the total amount of the measured index components before and after concentration. This indicates that the measured index components are relatively stable within the selected temperature range. Therefore, the concentration conditions for this product are determined to be: vacuum concentration at a temperature of 60~80℃.

[0052] Drying and granulation processes 4.1 Drying process Spray drying uses mechanical action to disperse the material to be dried into very fine, mist-like particles. These particles come into contact with hot air, instantly removing most of the moisture and drying the solid matter in the material into powder. It offers advantages such as rapid drying, reduced loss of heat-sensitive components during the process, high production efficiency, fewer operators, and high product quality. Therefore, this drying method was chosen.

[0053] The concentration density and spray drying temperature of the spray-dried extract were investigated based on the spray-drying state, moisture content of the spray-dried powder, content of major components, and compatibility with reference samples. The results are as follows: 4.1.1 Investigation of the relative density of the concentrate Equipment: Spray dryer, Model: OPD-8, Manufacturer: Shanghai Dachuanyuan Drying Equipment Co., Ltd. The formula contains several herbs, including Angelica sinensis, Ligusticum chuanxiong, Cinnamomum cassia, Paeonia suffruticosa, and Curcuma zedoaria, which contain volatile components. Since the aqueous decoction of the baseline sample also contained volatile components, the volatile components were extracted during the compound preparation research to ensure consistency with the baseline sample. For the extraction of aromatic water, considering the cost-effectiveness of the preparation, a beta-cyclodextrin inclusion complexation process was proposed to incorporate the volatile components. Considering that directly adding the inclusion complex to the concentrate and spray-drying it is more cost-effective and energy-efficient than refrigerating the inclusion complex, precipitating and drying it, and then adding it to the dry powder obtained by spray-drying the concentrate, the spray-drying process is more suitable for industrial production. Therefore, the inclusion complex was chosen to be mixed with the concentrate and spray-dried together. The specific research and results of this drying process are as follows: Weigh out 40 doses of the prescribed medicinal slices, divide into four parallel portions, extract according to the determined process, and then redistill the combined aromatic water. Divide the redistilled aromatic water into three equal portions, and encapsulate each portion using the determined method to obtain three encapsulation solutions. After retaining the extract sample, divide it into three equal portions and concentrate it under reduced pressure at 70℃ to obtain a relative density of 1.05–1.10 (60℃), 1.11–1.15 (60℃), and 1.16–1.20 (60℃). Filter the concentrate through an 80-mesh screen, retain the concentrate sample, and add one portion of the encapsulation solution to each portion. Mix well and spray dry (drying parameters: inlet air temperature 165–175℃, atomizer speed 45–50Hz, outlet air temperature 90–100℃) to obtain a dry powder. The feasibility of spray drying was determined by observing the phenomena, moisture content, and yield during the drying process. The results are shown in Table 11 below.

[0054] Table 11 Results of Relative Density Study

[0055] The results showed that spray drying was more effective when the relative density of the concentrate was between 1.05 and 1.15. However, during the compressibility test of the spray-dried powder, it was found that the powder obtained with a relative density of 1.05 to 1.10 was slightly less effective in terms of particle formation rate and hardness than the powder obtained with a relative density of 1.10 to 1.15. Therefore, it is recommended to control the relative density of the concentrate between 1.10 and 1.15 (at 60°C).

[0056] 4.1.2 Validation of drying process Weigh out 6 portions of the medicinal slices, each containing the amount required for 40 doses of the prescription. Combine every two portions. For the first decoction, add 12 times the amount of water and boil for 60 minutes. Collect approximately 1.2 times the amount of the medicinal slices as aromatic water. For the second decoction, add 10 times the amount of water and boil for 40 minutes. Collect approximately 0.9 times the amount of the medicinal slices as aromatic water. Filter the extract through a 200-mesh sieve and retain the sample. Concentrate the remaining extract under reduced pressure at 60–80°C to a relative density of 1.10–1.15 (60°C). Filter the concentrated extract through an 80-mesh sieve. Filter and set aside; combine the aromatic waters and redistill, collecting approximately 1 / 10 of the total aromatic water volume in the redistilled aromatic water. Take an appropriate amount as a sample, and add beta-cyclodextrin at a ratio of redistilled aromatic water to beta-cyclodextrin (10:1). Grind for 45 minutes to achieve inclusion. Mix the inclusion solution with the above concentrated solution evenly, and spray dry (drying parameters: inlet air temperature 165–175℃, atomizer speed 45–50Hz, outlet air temperature 90–100℃) to obtain a dry extract powder. Observe the drying process, weigh, and determine the moisture content (%), dry extract rate (%), total extract volume of each indicator component before and after drying, cinnamaldehyde inclusion rate, and characteristic chromatogram. The results are shown in Tables 12 and 13.

[0057] Table 12 Drying Validation Test-1

[0058] Table 13 Drying Validation Test-2

[0059] Experimental results show that the three batches of spray-dried powder were in good condition inside the tower, easily swept off, and the collected dry powder was relatively loose and light, making it easy to collect. The total loss of indicator components before and after spray drying was small. The moisture content, dry powder yield, characteristic chromatogram, and total amount of each indicator component of the three batches of spray-dried powder were basically consistent and matched the reference sample, indicating that the drying process is stable and feasible.

[0060] Based on the above process investigation and experiments, the extraction process of this product is summarized as follows: The nine ingredients in the formula are crushed into coarse particles of 1-5 mm, wrapped and decocted twice with water. For the first decoction, 12 times the amount of water is added, and the decoction is decocted for 60 minutes. The aromatic water (approximately 1.2 times the amount of the raw materials) is collected. The decoction is filtered through a 200-300 mesh filter while hot. For the second decoction, 10 times the amount of water is added, and the decoction is decocted for 40 minutes. The aromatic water (approximately 0.9 times the amount of the raw materials) is collected. The decoction is filtered through a 200-300 mesh filter while hot. The two filtrates are combined and set aside. The combined aromatic water is redistilled, and the volume of the distillate collected is approximately 1 / 10 of the volume of the aromatic water. Betacyclodextrin is added at a ratio of 10:1 (redistilled aromatic water:betacyclodextrin), and the mixture is ground for 45 minutes to form an inclusion solution, which is then set aside. The extract is concentrated under reduced pressure to a clear paste with a relative density of 1.10–1.15 (60°C). The inclusion solution is added to the concentrate and mixed evenly. The paste is then spray-dried (drying parameters: inlet air temperature 165–175°C, atomizer speed 45–50 Hz, outlet air temperature 90–100°C) to obtain the final product.

[0061] 4.2 Formulation Process Wenjing Decoction originates from Chen Ziming's *Complete Collection of Effective Prescriptions for Women* (Song Dynasty). Based on prescription verification and the *Key Information Table of Ancient Classic Prescriptions (7 Prescriptions)* published by the State Administration of Traditional Chinese Medicine, the dosage of raw herbs per dose is approximately 20g. Considering the baseline sample dry extract yield range of 27.50%–33.50% and the extract yield range of 28.50%–35.00%, the amount of dry extract powder per dose is 5.70g–7.00g. During the preparation process, because the dry extract powder contains beta-cyclodextrin, preliminary experiments investigated wet granulation. However, the mixed powder immediately clumped upon contact with the wetting agent and could not be dispersed, making granulation difficult and unsuitable for wet granulation. Dry granulation was used to preliminarily investigate the compressibility of the spray-dried powder, with better results; therefore, dry granulation was adopted.

[0062] 4.2.1 Compressibility Test Equipment: Dry granulation machine, Model: LGS20, Manufacturer: Nanjing Canaan Bison Technology.

[0063] To determine whether the dry powder could be directly granulated and to evaluate the granule formability, approximately 300g of spray-dried powder with a concentrated density of 1.10–1.15 was taken, and the granulation mesh was fixed at 14 mesh. Appropriate parameters were adjusted for dry granulation. Compressibility was investigated using granulation conditions, granule characteristics, formability, and solubility as evaluation indicators. The results are shown in Table 14.

[0064] Table 14 Compressibility Test Results

[0065] Results: The dry granulation process resulted in good granulation condition, uniform granule color, moderate hardness, good solubility, complete dissolution, and no visible foreign matter or charred debris. Therefore, dry granulation was chosen.

[0066] 4.2.2 Investigation of Auxiliary Material Types Based on a prescription dosage of 20g of raw medicinal materials, the baseline sample dry extract yield ranged from 29.00% to 34.00%, and the extract yield ranged from 28.50% to 35.00%. Therefore, the maximum dry extract powder for a single dose is approximately 7.00g. Considering that the dry extract powder obtained during the preparation of the Wenjing Decoction compound contains beta-cyclodextrin, which accounts for approximately 4% of the final product (0.40g) when the preparation specification is 10g / bag, the types of excipients for dry granulation were investigated. Based on a single dose of 7.40g dry extract powder and 2.60g excipients, dextrin, maltodextrin, and soluble starch were added in proportion to make a total mixed powder of 400g. The mixture was thoroughly mixed, granulated, and granulated to a mesh size of 14. The excipient types were screened based on granulation conditions, granule characteristics, one-time molding rate, solubility, and hygroscopicity. The results are shown in Table 15.

[0067] Table 15 Results of the Investigation on the Types of Auxiliary Materials

[0068] Results analysis: The granules prepared by dextrin as a filler had slightly worse solubility than the other two fillers. Considering the results of the molding rate and other factors, and for the sake of cost control in the later stage, maltodextrin was selected as the filler.

[0069] 4.3 Examination of the dosage of excipients Because the dry extract powder exhibits some hygroscopicity during the excipient selection process, a certain proportion of filler needs to be mixed in to improve the hygroscopic effect of the granules. Therefore, the excipient dosage was designed according to 10g / bag and 12g / bag. Maltodextrin was added in proportion to the specifications of 10g / bag (7.50g dry extract powder, 2.50g excipient) and 12g / bag (7.50g dry extract powder, 4.50g excipient), making the total mixed powder 400g. The mixture was thoroughly mixed, granulated, and the granulation mesh was 14 mesh. The excipient dosage was screened based on granulation conditions, granule characteristics, molding rate, and solubility, and the formulation specifications were determined. The results are shown in Table 16.

[0070] Table 16 Results of the Investigation on the Auxiliary Material Usage

[0071] Results analysis: When the formulation specifications were 10g / bag and 12g / bag, there was no sticking to the granulation wheel during the granulation process, the one-time molding rate was basically consistent, the granules were uniform in color, and the solubility and hygroscopicity met the requirements. Considering the principle of minimum dosage required for formulation molding and cost, the formulation specification was set at 10g / bag.

[0072] 4.4 Particle Flowability Test Take an appropriate amount of the granules obtained by the above dry granulation method and test the granule flowability. Determination of the angle of repose: The fixed conical base method was used. A 7cm diameter petri dish was used as the base. Two glass funnels were stacked alternately on an iron stand, with the outlet of the lower funnel 3.5–6.0cm from the base. A quantity of particles was taken and slowly added from the upper funnel, allowing the particles to accumulate on the base through the buffer between the two funnels, forming a cone, until the highest cone was obtained. The height H of the cone was measured. Each sample was measured three times, and the average value was taken. The angle of repose was calculated using the following formula: α = arctg(H / R), where α is the angle of repose and R is the radius of the base. The experimental results are shown in Table 17.

[0073] Table 17 Results of Particle Flowability Test

[0074] Experimental results show that the angle of repose is less than 40°, and the produced granules have good flowability, which can meet the flowability requirements in granule production.

[0075] 4.5 Critical Relative Humidity Test for Particles To investigate whether the particles are prone to moisture absorption, the critical relative humidity was determined. The specific method is as follows: Weigh an appropriate amount of particles, accurately determine the weight, spread them evenly in a pre-weighed flat weighing bottle with a thickness of about 2 mm, and place them in a desiccator containing supersaturated solutions of 7 different salts as listed in the table below (with the weighing bottle cap open). After keeping them at room temperature for 72 hours, accurately determine the weight and calculate the moisture absorption percentage. The test results are shown in Table 18.

[0076] Table 18 Relative humidity of different supersaturated salt solutions at 25℃

[0077] Plot a curve with the moisture absorption percentage (from the table) on the ordinate and relative humidity (RH%) on the abscissa. Draw two tangent lines at the curve's arc; the x-axis value corresponding to the intersection of these tangent lines is the critical relative humidity. See [link to relevant documentation]. Figure 2 .

[0078] Depend on Figure 2 It is known that the critical relative humidity of granules is about 58%. Therefore, during the preparation, dispensing and packaging of granules, the relative humidity of the environment should be controlled below 60% to reduce the impact of moisture on the properties and stability of the drug.

[0079] V. Summary Based on the above experiments, the preparation process of granules is summarized. In accordance with the requirements of the "Technical Guidelines for Research on Quality Standards of New Traditional Chinese Medicines" and the "Technical Guidelines for Research on Production Processes of Compound Traditional Chinese Medicine Preparations (Trial Implementation)," the prescription is based on 1000g of granules.

[0080] Prescription: Angelica sinensis 168g (processed with wine), Ligusticum chuanxiong 169g White peony root 168g, cinnamon 169g 163g of peony bark and 165g of vinegar-processed turmeric Ginseng 343g, stir-fried licorice root 323g 333g of Achyranthes bidentata (processed with wine) Preparation: Crush the above nine ingredients into coarse particles of 1-5mm, wrap them in a container, and decoct twice with water. For the first decoction, add 12 times the amount of water and decoct for 60 minutes. Collect the aromatic water (approximately 1.2 times the amount of ingredients) and set aside. Filter the decoction (200-300 mesh). For the second decoction, add 10 times the amount of water and decoct for 40 minutes. Collect the aromatic water (approximately 0.9 times the amount of ingredients). Combine the aromatic waters and set aside. Filter the decoction (200-300 mesh). Combine the two filtrates and concentrate the filtrate under reduced pressure to a clear extract with a relative density of 1.10-1.15 (60℃). Redistill the aromatic water to obtain the distillate (the amount of distillate collected is approximately 0.1 times the amount of aromatic water). Add beta-cyclodextrin at a ratio of 10:1 (ml:g) to the distillate and grind for 45 minutes to encapsulate the distillate. Set aside the encapsulated liquid. Add the above inclusion solution to the above clear paste and mix well. Spray dry to obtain dry paste powder. Add an appropriate amount of maltodextrin, mix well, and dry granulate to make 1000g of granules.

[0081] Specifications: 10g per bag, 1g is equivalent to 2g of medicinal slices. Dosage and administration: Dissolve one packet in warm water and drink, three times a day.

[0082] 5.1 Small-scale process verification Based on the above formulation development results and formulation quantities, three batches of small-scale formulation preparation experiments were conducted to verify the feasibility of the above process. The data and results are shown in Tables 19 to 21. Figure 3 and 4 .

[0083] Table 19 Results of Small-Scale Formulation Testing

[0084]

[0085] Note: Because the proportion of each intermediate sample retained in the three batches of the small-scale test was relatively large, the feed was based on a production yield of 1.2 kg, and the granulation of the later formulation was based on a production yield of 1 kg.

[0086] Table 20 Comparison of results from three batches of small-scale experimental samples and accompanying reference samples

[0087] Table 21 Relative retention times of characteristic spectra of three batches of small-scale experimental samples and accompanying reference samples

[0088]

[0089]

[0090] Results Analysis: During the study of the reference samples, it was found that significant losses of volatile components such as cinnamaldehyde occurred after concentration and drying of the extract. Therefore, both the aqueous extract and the lyophilized powder were used as reference samples for characterization of water-soluble and volatile components, respectively. In the study of the compound preparation, to ensure consistency in material characterization between the compound preparation and the reference samples, an aqueous extraction process was used to extract and collect aromatic water. The aromatic water was then redistilled and incorporated to prepare an inclusion solution. The inclusion solution was added to the concentrate and spray-dried before granulation. The reference samples, extract, concentrate, spray-dried powder, and granules were characterized and analyzed using the total amount of ginsenosides Rg1, Re, and Rb1, paeoniflorin, cinnamic acid, and characteristic spectra. In terms of the total amount of indicator components, the key indicators are basically consistent with the reference sample. From the characteristic chromatograms, the data in the extract, concentrated solution + inclusion solution, dry powder, and finished granules are basically consistent with the data in the reference sample. The dry powder and finished granules show the same 12 characteristic peaks as the reference sample (extract), and the relative retention times are all within the limits specified for the reference sample (extract). This process allows for better transfer of volatile components such as cinnamaldehyde, paeonol, and ligustilide, ensuring the consistency of substances between the compound preparation and the reference sample. There are no significant differences in the data of the three batches of samples. The prepared granules have good formability, good taste, and stable quality, proving that the determined preparation process is feasible and can be used as the preparation process for Wenjingtang granules.

[0091] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A type of Wenjing Decoction granules, characterized in that, It includes the following ingredients: Angelica sinensis (processed with wine), Ligusticum chuanxiong, Paeonia lactiflora, Cinnamomum cassia, Paeonia suffruticosa, Curcuma zedoaria (processed with vinegar), Ginseng, Glycyrrhiza uralensis (processed with stir-fry), and Achyranthes bidentata (processed with wine).

2. The Wenjing Decoction granules as described in claim 1, characterized in that, The composition and quality are as follows: Angelica sinensis (wine-processed): Ligusticum chuanxiong: Paeonia lactiflora: Cinnamomum cassia: Paeonia suffruticosa: Curcuma zedoaria (vinegar-processed): Ginseng: Glycyrrhiza uralensis (fried): Achyranthes bidentata (wine-processed) = 0.8-1.2:0.8-1.2:0.8-1.2:0.8-1.2:0.8-1.2:1.8-2.2:1.8-2.2:1.8-2.

2.

3. A method for preparing the Wenjing Decoction granules as described in claim 1, characterized in that, Includes the following steps: (1) Pretreatment process; (2) Extraction process: The coarse particles are boiled twice with water. The aromatic water is collected after the first boiling and is set aside. The decoction is filtered. The aromatic water is collected after the second boiling and is set aside. The aromatic water collected in the two boilings is combined and set aside. The decoction is filtered and the two filtrates are combined. The filtrate is concentrated under reduced pressure to a clear extract with a relative density of 1.10 to 1.15 and set aside. The aromatic water is redistilled to obtain the distillate. Betacyclodextrin is added and ground to form an inclusion solution for use. (3) Drying and granulation process.

4. The method for preparing Wenjingtang granules as described in claim 3, characterized in that: The specific steps of step (3) are as follows: add the inclusion solution to the clear paste and mix well, spray dry to obtain dry paste powder, add an appropriate amount of maltodextrin, mix well, dry granulate to make granules.

5. The method for preparing Wenjing Decoction granules as described in claim 4, characterized in that, The drying parameters are as follows: inlet air temperature 165~175℃, atomizer speed 45~50Hz, outlet air temperature 90~100℃.

6. The method for preparing Wenjingtang granules as described in claim 3, characterized in that: In step (2), the first time 12 times the amount of water is added and simmered for 60 minutes, and the second time 10 times the amount of water is added and simmered for 40 minutes.

7. The method for preparing Wenjingtang granules as described in claim 3, characterized in that: In step (2), the distillate: betacyclodextrin = 9-11 ml: 1 g.

8. The method for preparing Wenjingtang granules as described in claim 3, characterized in that: In step (2), the distillate is 1 / 9 to 1 / 11 of the total amount of aromatic water.

9. The method for preparing Wenjingtang granules as described in claim 3, characterized in that: In step (2), after adding betacyclodextrin, the grinding time for inclusion is 30-60 minutes.

10. The method for preparing Wenjingtang granules as described in claim 3, characterized in that: In step (2), the reduced pressure concentration is a vacuum concentration, and the concentration temperature is 60-80℃.

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