Sophora japonica, wolfberry and yellow cane sugar-free granules and preparation process thereof

Abstract

The invention relates to Sophora japonica, wolfberry and yellow sucrose-free granules and a preparation process thereof. The Sophora japonica, wolfberry fruit and yellow sucrose-free granules are prepared from the following components in parts by weight: 30.0 parts of Sophora japonica clear paste (in terms of bovine serum albumin); 150 to 250 parts of fructus lycii; 100 to 200 parts of rhizoma polygonati; 325 to 375 parts of dextrin; 325 to 375 parts of maltodextrin; 0 to 10 parts of sucralose; or the sucrose-free granules are prepared from the following components in parts by weight: 30.0 parts of trametes robiniophila clear paste (in terms of bovine serum albumin); 150 to 250 parts of fructus lycii; 100 to 200 parts of rhizoma polygonati; 650 to 750 parts of maltodextrin; 0 to 10 parts of sucralose; and 250 to 350 parts of water. The product disclosed by the invention is good in water solubility, good in taste and easy to take by patients.

Description

Technical Field

[0001] The invention relates to the technical field of traditional Chinese medicine preparations, and in particular to Huaiqihuang sucrose-free granules and a preparation process thereof. Background Art

[0002] Huaiqihuang Granules are a new Chinese medicine of Category 3 (original classification), approved for production in April 2002, with the approval number: National Medicine Standard B20020074. In order to better control the drug production process and ensure the quality of the drug, the National Pharmacopoeia Committee proposed to revise the quality standard of Huaiqihuang Granules in 2011. The "Huaier fungus" in the [prescription] was changed to "Huaier Qing Gao" extracted from Huaier fungus, and the quality standard of Huaier Qing Gao was added in the notes. In October 2012, the National Pharmacopoeia Committee approved the revision, with the standard number WS-5067 (B-0067) -2012Z. The current specification of Huaiqihuang Granules is 10g per bag, with a validity period of 24 months.

[0003] The existing Huaiqihuang granule prescription is Huaierqing Gao (calculated as bovine serum albumin) 30.0g, Lycium barbarum 200g, Polygonatum 150g, and the auxiliary materials are sucrose, soluble starch, and an appropriate amount of flavoring agent.

[0004] The production process is: add sucrose, soluble starch and flavoring agent to Huaiqihuangqing paste, mix evenly, wet granulate, dry at normal pressure, granulate, sieve and package (10g per bag, the dosage for adults is 10-20g at a time, twice a day).

[0005] Existing Huaiqihuang granules contain more sucrose and are not suitable for patients with high blood sugar or diabetes.

[0006] In the existing preparation process, it is difficult to add all of the Sophora japonica glutinosa paste at once during wet granulation. It is necessary to first add a portion of the Sophora japonica glutinosa paste to a portion of the auxiliary materials, mix, granulate, dry and granulate them, and then crush them into fine powder. Then, the remaining Sophora japonica glutinosa paste and auxiliary materials are added, and the above process is repeated to make the finished Sophora japonica glutinosa granules. The entire production process takes a long time, consumes a lot of energy, and has high labor intensity. At the same time, long-term drying of the wet granules is not conducive to the stability of the drug. Summary of the invention

[0007] In order to overcome the above defects, the inventor of this application made the following changes: (1) Changing the production process of Huaiqihuang granules, adopting belt vacuum continuous drying and dry extrusion granulation production process to replace the original wet granulation atmospheric pressure drying production process; (2) Changing the auxiliary materials with medicinal requirements in the drug prescription, removing auxiliary materials such as sucrose and soluble starch in the prescription. On the basis of the above changes, the present invention can still obtain a product with equivalent medicinal efficacy.

[0008] Therefore, an object of the present invention is to provide a Huaiqihuang sucrose-free granule. Another object of the present invention is to provide a preparation process for the above-mentioned Huaiqihuang sucrose-free granule. Still another object of the present invention is to provide a pharmaceutical use of the above-mentioned Huaiqihuang sucrose-free granule.

[0009] The above objects of the present invention are achieved by the following technical solutions.

[0010] On the one hand, the present invention provides a Huaiqihuang sucrose-free granule, which is made of the following components in parts by weight:

[0011] Or

[0012] The Huaiqihuang sucrose-free granule is made of the following components in parts by weight:

[0013]

[0014]

[0015] Preferably, the Huaiqihuang sucrose-free granule is made of the following components in parts by weight:

[0016] Or

[0017] The Huaiqihuang sucrose-free granule is made of the following components in parts by weight:

[0018]

[0019] More preferably, the Huaiqihuang sucrose-free granule is made of the following components in parts by weight:

[0020]

[0021] Or

[0022] The Huaiqihuang sucrose-free granule is made of the following components in parts by weight:

[0023]

[0024] The Huaiqihuang sucrose-free granule is made of the following components in parts by weight:

[0025] Or

[0026] The Huaiqihuang sucrose-free granule is made of the following components in parts by weight:

[0027]

[0028] In a specific embodiment, the present invention provides a Huaikihuang sugar-free granule, and the prescription of the granule is as follows:

[0029]

[0030]

[0031] In another specific embodiment, the present invention provides a Huaikihuang sugar-free granule, and the prescription of the granule is as follows:

[0032]

[0033] In another specific embodiment, the present invention provides a Huaikihuang sugar-free granule, and the prescription of the granule is as follows:

[0034]

[0035]

[0036] In another specific embodiment, the present invention provides a Huaikihuang sugar-free granule, and the prescription of the granule is as follows:

[0037]

[0038] The prescription of this application replaces sucrose, soluble starch, and flavoring agent in the original prescription with maltodextrin (or and sucralose and dextrin, or and dextrin). The product has good water solubility, good taste, and is easy for patients to take; the prescription of this application removes sucrose, and patients with high blood sugar or diabetes can also take it.

[0039] The Huaikihuang sugar-free granule of the present invention can replenish qi and nourish yin. It is applicable to children with weak constitution caused by qi-yin deficiency, recurrent colds, or the weakness after illness of the elderly, dizziness, vertigo, fatigue, dry mouth and shortness of breath, palpitation, easy sweating, loss of appetite, and constipation.

[0040] On the other hand, the present invention provides a preparation process of the above-mentioned Huaikihuang sugar-free granule, and the process includes the following steps:

[0041] Mix the Huaikihuang clear paste with dextrin (if any), maltodextrin, and sucralose (if any) and water, dry with a vacuum belt dryer, granulate by dry extrusion, sieve, mix uniformly, make into granules, and pack, then the product is obtained.

[0042] Preferably, the Huaikihuang clear paste is prepared by the following method:

[0043] (1) Take the Tremella fuciformis Berk. mycelium substance, decoct it with water three times. For the first time, add 1 - 15 times the amount of water, boil for 0.5 - 10 hours, filter, and reserve the filtrate. For the second and third times, add 1 - 15 times the amount of water respectively, boil for 0.5 - 10 hours, filter, combine the three filtrates, and concentrate under reduced pressure to a relative density of 1.35 - 1.40 (55 °C) to obtain the Tremella fuciformis Berk. clear extract.

[0044] (2) Take Lycium barbarum L. and Polygonatum sibiricum Redoute, soak them in 1 - 15 times the amount of water for half an hour, then decoct twice, each time for 5 - 300 minutes, combine the decoction liquids, filter, and concentrate the filtrate to a clear extract with a relative density above 1.35 (50 - 60 °C).

[0045] (3) Combine the clear extracts obtained in steps (1) and (2), and mix them evenly to obtain the Tremella fuciformis Berk., Lycium barbarum L. and Polygonatum sibiricum Redoute clear extract.

[0046] Preferably, in step (1), for the first time, add 5 - 10 times the amount of water, preferably 7 times the amount of water.

[0047] Preferably, in step (1), after adding water for the first time, boil for 0.5 - 2 hours, preferably 1.5 hours.

[0048] Preferably, in step (1), for the second and third times, add 3 - 8 times the amount of water respectively, preferably 5 times the amount of water.

[0049] Preferably, in step (1), after adding water for the second and third times, boil for 0.5 - 3 hours, preferably 1 hour.

[0050] Preferably, in step (2), take Lycium barbarum L. and Polygonatum sibiricum Redoute, soak them in 6 - 10 times the amount of water, preferably 8 times the amount of water for half an hour, then decoct twice, each time for 30 - 60 minutes, preferably 45 minutes each time.

[0051] Preferably, the drying temperature of the vacuum belt dryer is: Zone I: 30 - 150 °C; Zone II: 30 - 140 °C; Zone III: 30 - 130 °C, preferably Zone I: 100 - 120 °C; Zone II: 90 - 110 °C; Zone III: 70 - 90 °C.

[0052] Preferably, the feeding frequency is 6 - 10 Hz, the conveying frequency is 14 - 18 Hz, and the cloth - laying frequency is 10 - 14 Hz, preferably the feeding frequency is 8 Hz, the conveying frequency is 16 Hz, and the cloth - laying frequency is 12 Hz.

[0053] Preferably, the conditions for dry extrusion granulation are: the pressure of the rolling wheel is 25 - 35 kg / cm 2 , the frequency of the feeding motor is 20 Hz, the frequency of the tablet - pressing motor is 26 Hz, the frequency of the cutting motor is 15 Hz, and the frequency of the granule - shaping motor is 12 Hz.

[0054] In a specific embodiment, the preparation method of the above - mentioned Tremella fuciformis Berk., Lycium barbarum L. and Polygonatum sibiricum Redoute sucrose - free granules is as follows:

[0055] (1) Take Tremella fuciformis Berk. mycelium, decoct it with water three times. For the first time, add 7 times the amount of water, boil for 1.5 hours, filter, and reserve the filtrate. For the second and third times, add 5 times the amount of water respectively, boil for 1 hour, filter, combine the three filtrates, and concentrate under reduced pressure to a relative density of 1.35 - 1.40 (55 °C) to obtain the clear extract of Tremella fuciformis Berk.

[0056] (2) Take Lycium barbarum L. and Polygonatum sibiricum Red. Add 8 times the amount of water and soak for half an hour, then decoct twice, each time for 45 minutes, combine the decoction liquids, filter, and concentrate the filtrate to a clear extract with a relative density above 1.35 (50 - 60 °C).

[0057] (3) Combine the clear extracts from steps (1) and (2), mix well to obtain the clear extract of Tremella fuciformis Berk., Lycium barbarum L. and Polygonatum sibiricum Red.

[0058] (4) Mix the clear extract of Tremella fuciformis Berk., Lycium barbarum L. and Polygonatum sibiricum Red. from step (3) with dextrin (if any), maltodextrin, sucralose (if any) and water, dry it with a vacuum belt dryer, granulate by dry extrusion, sieve, make into granules, and package to obtain the product.

[0059] In step (4), the drying temperature of the vacuum belt dryer is: Zone I: 110 °C, Zone II: 100 °C, Zone III: 80 °C.

[0060] In step (4), the conditions for dry extrusion granulation are: roller pressure 25 - 35 kg / cm 2 , the frequency of the feeding motor is 20 Hz, the frequency of the tablet pressing motor is 26 Hz, the frequency of the cutting motor is 15 Hz, and the frequency of the sizing motor is 12 Hz.

[0061] In the process of studying the above process of the present invention, the applicant investigated different drying methods for the clear extract of Tremella fuciformis Berk., Lycium barbarum L. and Polygonatum sibiricum Red., such as microwave drying method, freeze - drying method, spray - drying method, vacuum drying method, etc., and then investigated different granulation methods for the granules of Tremella fuciformis Berk., Lycium barbarum L. and Polygonatum sibiricum Red., such as wet granulation, one - step granulation, dry extrusion granulation, etc. Through repeated experiments and comparisons, it was found that belt - type vacuum continuous drying and dry extrusion granulation are more suitable for the production of the granules of Tremella fuciformis Berk., Lycium barbarum L. and Polygonatum sibiricum Red., so it was decided to adopt the production process of belt - type vacuum continuous drying and dry extrusion granulation. The belt - type vacuum continuous drying and dry extrusion granulation have the following advantages: low drying temperature, short time, light - colored granules, increasing the product stability; reducing the production process, being easy to operate and control, effectively reducing the risk of particle contamination; greatly reducing the labor intensity of workers and production energy consumption, effectively reducing the production cost; shortening the production cycle and improving the production capacity.

[0062] Compared with the prior art, the present invention has the following beneficial technical effects:

[0063] The present invention removes sucrose, soluble starch and flavoring agents from the original prescription, and uses maltodextrin (or and sucralose and dextrin, or and dextrin) as an adjuvant. Without changing the dosage of the Huaiqihuang clear paste, the production process is simplified, the labor intensity is reduced, the energy consumption is reduced, the production cycle is shortened, and the production efficiency is greatly improved.

[0064] The fine powder obtained by the belt vacuum continuous drying adopted by the present invention is not easy to agglomerate and is easy to be extruded into granules. The 3 batches of pilot production samples are inspected through stability tests. After being placed at 40 °C and RH75% for 6 months and at 25 °C and RH60% for 24 months, inspections are carried out on various items such as appearance, identification, moisture, particle size, content and microbial limit. The experimental results show that there are no obvious changes in various physical and chemical indexes, and the product quality is stable and reliable. Description of the Drawings

[0065] Figure 1 It is the process flow diagram of the sucrose-free granules of Huaiqihuang of the present invention. Detailed Implementation Modes

[0066] The present invention will be further described in detail below in conjunction with specific embodiments.

[0067] Example 1 Sucrose-free granules of Huaiqihuang of the present application

[0068] The prescription is as follows:

[0069]

[0070]

[0071] The preparation process flow diagram is as Figure 1 shown, and the preparation method is as follows:

[0072] (1) Take Tremella fuciformis mycelium, decoct it with water three times. For the first time, add 7 times the amount of water, boil for 1.5 hours, filter, and reserve the filtrate; for the second and third times, add 5 times the amount of water respectively, boil for 1 hour, filter, combine the three filtrates, and concentrate under reduced pressure to a relative density of 1.35 - 1.40 (55 °C) to obtain Tremella fuciformis clear paste;

[0073] (2) Take Lycium barbarum and Polygonatum sibiricum, soak them in 8 times the amount of water for half an hour, then decoct them twice, each time for 45 minutes, combine the decoctions, filter, and concentrate the filtrate to a clear paste with a relative density of more than 1.35 (50 - 60 °C);

[0074] (3) Combine the clear pastes in steps (1) and (2), and mix them evenly to obtain the Huaiqihuang clear paste;

[0075] (4) First, dissolve sucralose in water. Then, mix the Huaiqihuang extract obtained in step (3) with dextrin, maltodextrin, and the sucralose aqueous solution, dry it with a vacuum belt dryer, perform dry extrusion granulation, and screen it to obtain 1000 g of granules. Package them (10 g per bag) to obtain the product.

[0076] In step (4), the vacuum belt drying temperature: Zone I: 110 °C, Zone II: 100 °C, Zone III: 80 °C;

[0077] In step (4), for dry extrusion granulation: the pressure of the rolling wheel is 25 - 35 kg / cm 2 , the frequency of the feeding motor is 20 Hz, the frequency of the tablet pressing motor is 26 Hz, the frequency of the cutting motor is 15 Hz, and the frequency of the granule sizing motor is 12 Hz.

[0078] Example 2 Huaiqihuang Sucrose-free Granules of the present application

[0079] The prescription is as follows:

[0080]

[0081]

[0082] The process flow chart for preparation is as shown in Figure 1 and the preparation method is as follows:

[0083] (1) Take Tremella fuciformis mycelium, decoct it with water three times. For the first time, add 7 times the amount of water, boil for 1.5 hours, filter, and reserve the filtrate. For the second and third times, add 5 times the amount of water respectively, boil for 1 hour, filter, combine the three filtrates, and concentrate under reduced pressure to a relative density of 1.35 - 1.40 (55 °C) to obtain the Tremella fuciformis extract.

[0084] (2) Take Lycium barbarum and Polygonatum sibiricum, soak them in 8 times the amount of water for half an hour, then decoct them twice, each time for 45 minutes, combine the decoction liquids, filter, and concentrate the filtrate to an extract with a relative density of more than 1.35 (50 - 60 °C).

[0085] (3) Combine the extracts obtained in steps (1) and (2), and mix them evenly to obtain the Huaiqihuang extract.

[0086] (4) Mix the Huaiqihuang extract with water, dextrin, and maltodextrin, dry it with a vacuum belt dryer, perform dry extrusion granulation, and screen it to obtain 1000 g of granules. Package them (10 g per bag) to obtain the product.

[0087] In step (4), the vacuum belt drying temperature: Zone I: 110 °C, Zone II: 100 °C, Zone III: 80 °C;

[0088] In step (4), for dry extrusion granulation: the pressure of the rolling wheel is 25 - 35 kg / cm 2, the frequency of the feeding motor is 20 Hz, the frequency of the tablet pressing motor is 26 Hz, the frequency of the cutting motor is 15 Hz, and the frequency of the granulating motor is 12 Hz.

[0089] Example 3 Huaqi Huang Sugar-free Granules

[0090] The prescription is as follows:

[0091]

[0092] The preparation method is as follows:

[0093] (1) Take Tremella fuciformis mycelium, decoct it with water three times. For the first time, add 7 times the amount of water, boil for 1.5 hours, filter, and reserve the filtrate; for the second and third times, add 5 times the amount of water respectively, boil for 1 hour, filter, combine the three filtrates, and concentrate under reduced pressure to a relative density of 1.35 - 1.40 (55 °C) to obtain Tremella fuciformis extract.

[0094] (2) Take Lycium barbarum and Polygonatum sibiricum, soak them in 8 times the amount of water for half an hour, then decoct them twice, each time for 45 minutes, combine the decoctions, filter, and concentrate the filtrate to an extract with a relative density of more than 1.35 (50 - 60 °C).

[0095] (3) Combine the extracts from steps (1) and (2), mix well to obtain Huaqi Huang extract.

[0096] (4) First, dissolve sucralose in water, then mix the Huaqi Huang extract from step (3) with maltodextrin and the sucralose aqueous solution, dry it with a vacuum belt dryer, granulate it by dry extrusion, sieve it to make 1000 g of granules, and pack them (10 g per bag) to obtain the product.

[0097] In step (4), the vacuum belt drying temperature: Zone I: 110 °C, Zone II: 100 °C, Zone III: 80 °C;

[0098] In step (4), for dry extrusion granulation: the pressure of the rolling wheel is 25 - 35 kg / cm 2 , the frequency of the feeding motor is 20 Hz, the frequency of the tablet pressing motor is 26 Hz, the frequency of the cutting motor is 15 Hz, and the frequency of the granulating motor is 12 Hz.

[0099] Example 4 Huaqi Huang Sugar-free Granules

[0100] The prescription is as follows:

[0101]

[0102] The preparation method is as follows:

[0103] (1) Take the Tremella fuciformis Berk. mycelium substance, decoct it with water three times. For the first time, add 7 times the amount of water, boil for 1.5 hours, filter, and reserve the filtrate. For the second and third times, add 5 times the amount of water respectively, boil for 1 hour, filter, combine the filtrates of the three times, and concentrate under reduced pressure to a relative density of 1.35 - 1.40 (55 °C) to obtain the Tremella fuciformis Berk. clear extract;

[0104] (2) Take Lycium barbarum and Polygonatum sibiricum, soak them in 8 times the amount of water for half an hour, then decoct them twice, each time for 45 minutes, combine the decoction liquids, filter, and concentrate the filtrate to a clear extract with a relative density above 1.35 (50 - 60 °C);

[0105] (3) Combine the clear extracts obtained in steps (1) and (2), mix well to obtain the Tremella fuciformis Berk., Lycium barbarum and Polygonatum sibiricum clear extract;

[0106] (4) Mix the Tremella fuciformis Berk., Lycium barbarum and Polygonatum sibiricum clear extract obtained in step (3) with maltodextrin and water, dry it with a vacuum belt dryer, granulate it by dry extrusion, sieve it to make 1000 g of granules, and pack them (10 g per bag) to obtain the product.

[0107] In step (4), the vacuum belt drying temperature: Zone I: 110 °C, Zone II: 100 °C, Zone III: 80 °C;

[0108] In step (4), for dry extrusion granulation: the pressure of the rolling wheel is 25 - 35 kg / cm 2 , the frequency of the feeding motor is 20 Hz, the frequency of the tablet pressing motor is 26 Hz, the frequency of the cutting motor is 15 Hz, and the frequency of the sizing motor is 12 Hz.

[0109] Control Example 1 Tremella fuciformis Berk., Lycium barbarum and Polygonatum sibiricum Sucrose-free Granules

[0110] The prescription is as follows:

[0111]

[0112] The preparation method is as follows:

[0113] (1) Take the Tremella fuciformis Berk. mycelium substance, decoct it with water three times. For the first time, add 7 times the amount of water, boil for 1.5 hours, filter, and reserve the filtrate. For the second and third times, add 5 times the amount of water respectively, boil for 1 hour, filter, combine the filtrates of the three times, and concentrate under reduced pressure to a relative density of 1.35 - 1.40 (55 °C) to obtain the Tremella fuciformis Berk. clear extract;

[0114] (2) Take Lycium barbarum and Polygonatum sibiricum, soak them in 8 times the amount of water for half an hour, then decoct them twice, each time for 45 minutes, combine the decoction liquids, filter, and concentrate the filtrate to a clear extract with a relative density above 1.35 (50 - 60 °C);

[0115] (3) Combine the clear extracts obtained in steps (1) and (2), mix well to obtain the Tremella fuciformis Berk., Lycium barbarum and Polygonatum sibiricum clear extract;

[0116] (4) First, dissolve sucralose in water. Then, mix the Sophora japonica, Lycium barbarum and Huangqi extract from step (3) with dextrin, soluble starch and the sucralose aqueous solution, dry it with a vacuum belt dryer, granulate it by dry extrusion, sieve it, make 1000 g of granules, and package them (10 g per bag) to obtain the product.

[0117] In step (4), the vacuum belt drying temperature: Zone I: 110°C, Zone II: 100°C, Zone III: 80°C;

[0118] In step (4), for dry extrusion granulation: the roller pressure is 25 - 35 kg / cm 2 , the feeding motor frequency is 20 Hz, the tablet pressing motor frequency is 26 Hz, the cutting motor frequency is 15 Hz, and the granule finishing motor frequency is 12 Hz.

[0119] For this comparative example, the excipients selected are dextrin: soluble starch (1:1). The moisture content of the dry powder obtained by vacuum belt drying is relatively high (6.43%), which is not conducive to the quality control of the product.

[0120] Experimental Example 1 Screening Test of Excipients

[0121] Using a vacuum drying oven as the drying equipment, investigate the effects of different excipients on the drying process and the dried product.

[0122] The excipients investigated are: dextrin, soluble starch, microcrystalline cellulose, lactose, mannitol, sorbitol, starch hydrolyzate oligosaccharide, maltodextrin.

[0123] Research method: With a specification of 6 g / bag (such as experimental serial numbers 1 - 15) and a specification of 10 g / bag (such as experimental serial numbers 16 - 17), mix different excipients with the Sophora japonica, Lycium barbarum and Huangqi extract (prepared as described in (1) - (3) of Example 1 of the present invention) respectively. For the samples that can be granulated after mixing, granulate them with a 14 - mesh sieve. For those that are too thin to be granulated, directly spread them in a container for drying. Compare the drying process and the ease of removing the dried product from the container.

[0124] Research equipment used: Vacuum drying oven VOS - 60A, Shiduokai Instrument Equipment (Shanghai) Co., Ltd.

[0125] Drying conditions: Vacuum degree 0.088 MPa, temperature 110°C

[0126] Drying time: 3 hours

[0127] The research results are shown in Table 1.

[0128] Table 1 Investigation of Vacuum Drying after Adding Different Excipients to the Sophora japonica, Lycium barbarum and Huangqi Extract

[0129]

[0130]

[0131] According to the above research (such as Experiments 1-15), combined with the solubility requirements of the granule, further drying studies (such as Experiments 16 and 17) were carried out using maltodextrin + dextrin (1:1) and maltodextrin alone as excipients and adjusting the excipient dosage (specification 10 g / bag). The results showed that the moisture content of the granules prepared with maltodextrin + dextrin and maltodextrin alone as excipients was within 4%, which could meet the quality requirements. Moreover, the granules had good formability, and their solubility could also meet the requirements of the granule in the Chinese Pharmacopoeia (2020 Edition). Microcrystalline cellulose, mannitol, etc. had a worse absorption effect on Huaiqihuang Extract than maltodextrin + dextrin (1:1) and maltodextrin. When using maltodextrin + dextrin (1:1) and maltodextrin as excipients, the resulting soft materials had appropriate hardness, which was more conducive to uniform stirring and mixing. Therefore, maltodextrin + dextrin (1:1) and maltodextrin alone were preferably selected as excipients.

[0132] Screening Test of the Drying Process in Experimental Example 2

[0133] The orthogonal test method was used to study the operating parameter values of the belt drying equipment. The parameters involved were the feeding frequency, conveying frequency, spreading frequency, and the temperatures of the three drying zones.

[0134] According to the small-scale research and preliminary test results, an orthogonal table of four factors and three levels was selected. The factor-level table is shown in Table 2. The experimental batch was 10.0 kg of Huaiqihuang Extract (prepared as described in (1)-(3) of Example 1 of the present invention). The moisture content and protein content were selected as the inspection indicators. The experimental results and intuitive analysis are shown in Table 3, and the variance analyses of the two inspection indicators are shown in Tables 4 and 5 respectively.

[0135] Table 2 Factor-Level Table for the Study of Drying Process Parameters

[0136]

[0137] Table 3 Results and Intuitive Analysis of the Orthogonal Test for Belt Drying of Huaiqihuang Extract

[0138]

[0139] Table 4 Variance Analysis Table of the Moisture Content in the Orthogonal Test for Drying Huaiqihuang Extract

[0140]

[0141] Table 5 Variance Analysis Table of the Protein Content in the Orthogonal Test for Drying Huaiqihuang Extract

[0142]

[0143] The intuitive analysis results of the two evaluation indexes of moisture content and protein content show that the values of factors A, C, and D are the same. Factor B is a significant influencing factor on protein content. When B takes levels 1 and 3, the differences in moisture results are not significant, so level 3 is selected. Thus, the parameters of the belt drying of Huaiqihuang extract are determined as A3B3C1D1, that is, the feeding frequency is 8, the conveying frequency is 10, the temperatures of the three zones are 130 / 110 / 85, and the cloth feeding frequency is 8. Since the moisture content of the dry extract powder in all 9 experiments of the orthogonal experiment is above 5%, further research on the types and dosages of excipients is required. Although the moisture content of the finished product is lower when the temperatures of the three zones are 130 / 110 / 85, the color is darker, so the temperatures of the three zones also need to be further optimized.

[0144] Therefore, the inventor further experimented by only changing the drying temperature conditions while keeping other conditions unchanged: the experimental prescription and preparation method are as shown in Example 1, and the different parameters are as shown in Table 6 below. The evaluation indexes selected are moisture content, protein content, and the color of the dry product traits. The results are shown in Table 6:

[0145] Table 6

[0146]

[0147] As can be seen from the above tests, when the drying temperatures of the three zones are 110 - 100 - 80 °C, the moisture content of the dry extract powder can be stably controlled below 5%, the protein content can also meet the quality requirements, and the color of the dry extract powder is lighter, being light brownish-yellow.

[0148] Experimental Example 3

[0149] On the basis of Experimental Example 1, the applicant further studied the types and dosages of excipients and the temperatures of the three zones. The batch was 10.0 kg of Huaiqihuang extract (prepared as described in (1)-(3) of Example 1 of the present invention) / batch, and the evaluation index was the moisture content of the dry extract powder. The research results are shown in Table 7.

[0150] Table 7 Screening of Excipients for Huaiqihuang Granules

[0151]

[0152]

[0153] It can be seen from Experiment 1 and Experiment 2 that under the same equipment parameters, when using dextrin alone as the excipient compared to using dextrin and maltodextrin together as the excipient, the viscosity of the sample is lower, the cloth feeding time is shorter, and the moisture content of the finished product is also lower. Experiments 4 and 5 and Experiment 6 also show that when dextrin and maltodextrin are mixed and used, when the proportion of dextrin is larger, the moisture content of the finished product is slightly lower. However, when using dextrin alone as the excipient, the color of the sample is darker, being dark brown, which may affect the quality of the sample.

[0154] The results of Experiment 3 and Experiment 4 show that a large transmission frequency results in a short drying time and a high moisture content in the finished product; the results of Experiment 5 and Experiment 7 show that a large feeding frequency, although resulting in a short cloth-feeding time, also leads to a high moisture content in the finished product.

[0155] Experiments 8, 9, and 10 show that the moisture content of the samples using soluble starch is on the high side after drying.

[0156] The results of Experiments 11 - 14 show that by adjusting the drying parameters, the moisture content of the finished product still cannot be reduced below 4%. Therefore, Experiments 15 and 16 were conducted. The amount of auxiliary materials was increased, and the specification per bag was adjusted from 5 g to 6 g. The results show that the moisture content of the finished product is less than 5%, but still greater than 4%.

[0157] Experiments 17 - 20 show that when the amount of auxiliary materials is increased and the specification per bag is adjusted to 10 g, using dextrin + maltodextrin or only maltodextrin as the auxiliary material under the same equipment parameters, the viscosity and cloth-feeding time of the samples are moderate. The results show that the moisture content of the finished products is all less than 4%, meeting the requirements of the production process and product quality control. The granules prepared with only maltodextrin as the auxiliary material have better solubility in water.

[0158] The scale-up test shows that the moisture content of the finished product (specification 10 g / bag) is all below 4.0%, meeting the requirements of the production process. Therefore, in the present invention, dextrin and maltodextrin (1:1) or only maltodextrin is selected as the auxiliary material. From the above tests, it can be seen that when the specification is 10 g / bag, the moisture content of the dry powder can be stably controlled below 4%. When using dextrin + maltodextrin or only maltodextrin as the auxiliary material, the granules have good solubility and taste. The temperatures of the three zones were optimized to 110 / 100 / 80 °C in the experiment, and other parameters were adjusted accordingly, namely the feeding frequency of 8 Hz, the transmission frequency of 16 Hz, and the cloth-feeding frequency of 12 Hz.

[0159] Experimental Example 4

[0160] Using a dry granulator as the granulation equipment, the effects of different granulation parameters on the granulation process and the granulated finished product were investigated.

[0161] Research method: The dry powder of Huaiqihuang Qinggao obtained by drying under the optimal conditions was granulated by dry granulation, and the friability, particle size, and solubility of the prepared granules were compared.

[0162] Research equipment: A fully automatic dry granulator for production, model GL5 - 100, manufactured by Zhangjiagang Chuangkai Machinery Manufacturing Co., Ltd.

[0163] Research conditions and results

[0164] The formula and preparation method used in this example are as shown in Example 1, and the parameters different from Example 1 are recorded in Table 8 below.

[0165] Table 8

[0166]

[0167] The research results show that the granules made under a relatively small roller pressure (15 - 25 kg / cm 2 ) are relatively loose, have a relatively high particle size, poor particle formability, and it is difficult to control the quality. The granules made under a relatively large roller pressure (35 - 45 kg / cm 2 ) have a relatively low particle size and good particle formability, but the relatively large roller pressure causes the granules to be darker in color. Under the pressure condition of 25 - 35 kg / cm 2 , the granules are lighter in color, have a relatively low particle size, and the formability meets the quality requirements. The feeding frequencies were investigated under two conditions of 20 Hz and 25 Hz. The feeding was smooth under the condition of 20 Hz, while under the condition of 25 Hz, there were more fine powders due to too fast feeding, which was not conducive to particle size control. When the tableting motor was under the condition of 30 Hz, more fine powders were recovered, resulting in a relatively low production capacity. After adjusting to 26 Hz, the fine powders decreased, the production capacity increased, and the solubility, particle size, and friability could also meet the quality requirements.

[0168] In summary, considering factors such as the product properties color, product stability, production capacity, and economic benefits, the test parameters were determined as follows: roller pressure 25 - 35 kg / cm 2 , feeding motor frequency 20 Hz, tableting motor frequency 26 Hz, cutting motor frequency 15 Hz, and granulating motor frequency 12 Hz.

[0169] Experimental Example 5 Stability Test

[0170] With reference to the Guidelines for the Stability Testing of Raw Materials and Preparations in Part Four of the Chinese Pharmacopoeia 2015 Edition and the Quality Standard of Huaiqihuang Granules WS - 5067(B - 0067)-2012Z of the National Drug Standard, the stability of the test products was investigated.

[0171] Test products:

[0172] 1. The product of Example 1;

[0173] 2. The product of Example 2;

[0174] 3. The product of Example 3;

[0175] 4. The product of Example 4;

[0176] 5. The existing sucrose - containing product: The prescription is Huai'er Extract (calculated as bovine serum albumin) 30.0 g, Lycium barbarum 200 g, Polygonatum sibiricum 150 g, and the excipients are sucrose, soluble starch, and appropriate flavoring agents. The production process is as follows: Add sucrose, soluble starch, and flavoring agents to the Huaiqihuang extract, mix evenly, granulate by wet method, dry at normal pressure, granulate, sieve, and package (10 g per bag, the adult dosage for patients is 10 - 20 g once and 2 times a day).

[0177] Test methods:

[0178] 1. Accelerated test: Three batches of pilot-scale products were placed in the market packaging at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for 6 months. Samples were taken once at the end of the 1st month, 2nd month, 3rd month, and 6th month during the test, and tested according to the key items for stability test.

[0179] 2. Long-term test: Three batches of pilot-scale products were placed in the market packaging at a temperature of 25°C ± 2°C and a relative humidity of 60% ± 5% for 24 months. Samples were taken at 0 month, 3 months, 6 months, 9 months, 12 months, 18 months, and 24 months, and tested according to the key items for stability test.

[0180] Test results: The test data of this test were presented in the form of a table to effectively evaluate the stability data of Huaqi Huang Sugar-free Granules.

[0181] (1) Results of accelerated test:

[0182] The experimental results of three batches of the product of Example 1 are as described in Table 9-11.

[0183] Table 9

[0184]

[0185] Table 10

[0186]

[0187]

[0188] Table 11

[0189]

[0190] The accelerated test results of three batches of the product of Example 2 are as described in Tables 12-14.

[0191] Table 12

[0192]

[0193] Table 13

[0194]

[0195]

[0196] Table 14

[0197]

[0198] The experimental results of three batches of the product of Example 3 are as described in Tables 15-17.

[0199] Table 15

[0200]

[0201] Table 16

[0202]

[0203]

[0204] Table 17

[0205]

[0206] The experimental results of three batches of the product of Example 4 are as described in Tables 18 - 20.

[0207] Table 18

[0208]

[0209]

[0210] Table 19

[0211]

[0212] Table 20

[0213]

[0214]

[0215] Take 3 batches of the existing Huaiqihuang sucrose - containing granules as the control group to investigate the stability of the product under accelerated test conditions. The results are shown in Tables 21 - 23.

[0216] Table 21

[0217]

[0218]

[0219] Table 22

[0220]

[0221] Table 23

[0222]

[0223]

[0224] (2) Long - term test results:

[0225] The experimental results of three batches of the product of Example 1 are as described in Tables 24 - 26.

[0226] Table 24

[0227]

[0228] Table 25

[0229]

[0230] Table 26

[0231]

[0232]

[0233] The long - term test results of three batches of the product of Example 2 are as described in Tables 27 - 29.

[0234] Table 27

[0235]

[0236]

[0237] Table 28

[0238]

[0239] Table 29

[0240]

[0241] The experimental results of three batches of the product of Example 3 are as described in Tables 30 - 32.

[0242] Table 30

[0243]

[0244]

[0245] Table 31

[0246]

[0247]

[0248] Table 32

[0249]

[0250] The experimental results of three batches of the product of Example 4 are as described in Tables 33 - 35.

[0251] Table 33

[0252]

[0253]

[0254] Table 34

[0255]

[0256]

[0257] Table 35

[0258]

[0259] At the same time, 3 batches of the existing Huaiqihuang granules containing sucrose were taken as the control group to investigate the stability of the product under long-term test conditions. The results are shown in Tables 36 - 38.

[0260] Table 36

[0261]

[0262] Table 37

[0263]

[0264]

[0265] Table 38

[0266]

[0267]

[0268] The results show that the fine powder obtained by belt vacuum continuous drying is not easy to adhere, is easy to be extruded into granules, and the quality of the finished product can meet the relevant requirements of the national drug standard WS - 5067(B - 0067)-2012Z for Huaiqihuang granules. 12 batches of pilot-scale production samples of Huaiqihuang granules without sucrose and 3 batches of Huaiqihuang granules with sucrose were investigated by stability test. After being placed at 40°C, RH75% for 6 months and 25°C, RH60% for 24 months, inspections were carried out on various items such as appearance, identification, moisture, particle size, content, and microbial limit. The experimental results show that there are no obvious changes in various physical and chemical indicators, and there is no obvious change in the quality of the product of the present invention compared with the existing sucrose-containing products, and the quality is stable and reliable.

[0269] Experimental Example 6 Study on Dry Granulation Process

[0270] 1 Pilot-scale Granulation Study

[0271] 1.1 Orthogonal Experiment

[0272] The dry paste powder obtained by belt drying has good fluidity and compressibility, and the dry granulation process can be adopted.

[0273] Five factors, namely pressure, feeding frequency, tabletting frequency, granulation frequency, and granulation mesh number, were investigated. An orthogonal experiment with five factors and four levels was selected. The factor level table is shown in Table 39. The experimental batch was 200 g of Huaiqihuang dry paste powder. The inspection indexes were the amount of granules obtained from one-time granulation and the granule breakage rate. The experimental results and intuitive analysis are shown in Table 40, and the variance analyses of the two inspection indexes are shown in Tables 41 and 42 respectively.

[0274] The detection methods for the inspection indexes are as follows:

[0275] The amount of granules obtained from one-time granulation was the weight of granules above 40 mesh obtained from one-time granulation of the mixed powder;

[0276] Method for determining the granule breakage rate: Take about 10 g of granules above 40 mesh, weigh accurately, place them in a tablet friability tester, add 200 glass beads with a diameter of 4 mm, run at a speed of 25 revolutions per minute for 8 minutes, take out the granules, sieve them through a 40-mesh sieve, and weigh accurately the part above 40 mesh.

[0277] Granule breakage rate = (weight of granules before experiment - weight of granules after experiment) / weight of granules before experiment * 100%.

[0278] Table 39 Factor level table for the study of granulation process parameters

[0279]

[0280] Table 40 Results and intuitive analysis of the orthogonal experiment on granulation parameters

[0281]

[0282]

[0283] Table 41 Variance analysis table of breakage rate

[0284]

[0285]

[0286] Table 42 Variance analysis table of yield

[0287]

[0288] The results of the orthogonal experiment showed that the optimal parameters for the granule breakage rate were A4B3C1D2E3, and factors A and B were significant influencing factors; the optimal parameters for the amount of granules obtained from one-time granulation were A4B4C1D3E1, and factors A, B, C, and E were significant influencing factors.

[0289] Combining the investigation results of the two evaluation indicators, factor A takes level 4, that is, the granulation pressure is 4 Kpa; factor C takes level 1, that is, the tabletting uses 9 HZ; factor D is not a significant influencing factor for both evaluation indicators, and the level 3 with higher efficiency, that is, 15 HZ, is taken.

[0290] The values of factors B and E are further determined through single-factor experiments.

[0291] 1.2 Single-factor experiment

[0292] First, the different values of factor E are studied. When the value of the factor is 1, the granules are flaky and the roundness is not good. Since the difference in the amount of granules between the value 2 and the value 1 is not significant, the amount of granules obtained in the first granulation under the two conditions of A4B4C1D3E2 and A4B4C1D3E3 and the breakage rate of the granules are compared to determine the value of factor E. Among them, A4B4C1D3E2 is orthogonal experiment 16. On this basis, the value of factor B is further determined, and the results are shown in Table 43.

[0293] Table 43 Results of single-factor experiment

[0294]

[0295] Based on the above experiments, the granulation parameters are determined as A4B4C1D3E2, that is, the granulation pressure is 4 KPa, the feeding frequency is 12 Hz, the tabletting frequency is 9 Hz, the granulation frequency is 15 Hz, and the granulation mesh number is 18 meshes.

[0296] 1.3 Verification experiment

[0297] Using A4B4C1D3E2, that is, the granulation pressure is 4 KPa, the feeding frequency is 12 Hz, the tabletting frequency is 9 Hz, the granulation frequency is 15 Hz, and the granulation mesh number is 18, a verification experiment is carried out. The batch is 400 g of Huaiqihuang dry extract powder, and the results are shown in Table 44.

[0298] Table 44 Results of verification test

[0299]

[0300] The verification experiment shows that the process parameters of the small-scale test are stable and feasible. Since there are certain differences between the large-scale production equipment and the small-scale laboratory test equipment, the granulation parameters used in production should be determined through experiments according to the direction given by the laboratory research and combined with past production experience.

[0301] 2 Granulation process scale-up study

[0302] On the basis of the small-scale test research, the scale-up study of the granulation process was carried out in combination with the process parameters established in Experimental Example 4, and the results are shown in Table 45.

[0303] Table 45 Results of granulation process scale-up study

[0304]

[0305] The results show that the magnified determined process is stable and feasible.

[0306] 3 Verification study

[0307] After the completion of the pilot study, three batches of production verification studies were carried out. The research data are shown in Table 46. The changed process is stable and feasible, and the quality of the samples before and after the process change is consistent, indicating that the changed process is stable and feasible and can be used in production.

[0308] Table 46 Production process verification research data

[0309]

[0310]

Claims

1. A Huaqi Huang sugar-free granule, calculated by weight, the Huaqi Huang sugar-free granule is made of the following components: Calculated by weight, the Huaqi Huang sugar-free granule is made of the following components:

2. The Huaiqihuang sugar-free granules according to claim 1, wherein, Calculated by weight, the Huaqi Huang sugar-free granule is made of the following components: Calculated by weight, the Huaqi Huang sugar-free granule is made of the following components: Preferably, calculated by weight, the Huaqi Huang sugar-free granule is made of the following components: Calculated by weight, the Huaqi Huang sugar-free granule is made of the following components: Calculated by weight, the Huaqi Huang sugar-free granule is made of the following components: Calculated by weight, the Huaqi Huang sugar-free granule is made of the following components:

3. A preparation process of the Huaqi Huang sugar-free granule according to claim 1 or 2, the process comprising the following steps: Mix the Huaqi Huang clear extract with dextrin (if any), maltodextrin and sucralose (if any) and water, dry with a vacuum belt dryer, granulate by dry extrusion, screen, mix uniformly, make into granules, and package, thus obtaining.

4. The preparation process according to claim 3, wherein, The Huaqi Huang clear extract is prepared by the following method: (1) Take Tremella fuciformis mycelium, decoct with water three times. For the first time, add 1 - 15 times the amount of water, boil for 0.5 - 10 hours, filter, and reserve the filtrate; for the second and third times, add 1 - 15 times the amount of water respectively, boil for 0.5 - 10 hours, filter, combine the three filtrates, and concentrate under reduced pressure to a relative density of 1.35 - 1.40 (55 °C) to obtain the Tremella fuciformis clear extract; (2) Take Lycium barbarum and Polygonatum sibiricum, soak them in 1 - 15 times the amount of water for half an hour, then decoct twice, each time for 5 - 300 minutes, combine the decoction liquids, filter, and concentrate the filtrate to a clear extract with a relative density above 1.35 (50 - 60 °C); (3) Combine the clear extracts in steps (1) and (2), mix uniformly to obtain the Huaqi Huang clear extract.

5. The preparation process according to claim 4, wherein, In step (1), add 5 - 10 times the amount of water for the first time, preferably 7 times the amount. Preferably, in step (1), after adding water for the first time, boil for 0.5 - 2 hours, preferably 1.5 hours.

6. The preparation process according to claim 4 or 5, wherein, In step (1), add 3 - 8 times the amount of water for the second and third times respectively, preferably 5 times the amount. Preferably, in step (1), after adding water for the second and third times, boil for 0.5 - 3 hours, preferably 1 hour; Preferably, in step (2), take Lycium barbarum and Polygonatum sibiricum, soak them in 6 - 10 times the amount of water, preferably 8 times the amount, for half an hour, then decoct twice, each time for 30 - 60 minutes, preferably 45 minutes each time.

7. The preparation process according to any one of claims 3 to 6, wherein The drying temperature of the vacuum belt dryer is: Zone I: 30 - 150 °C, Zone II: 30 - 140 °C, Zone III: 30 - 130 °C; preferably Zone I: 100 - 120 °C, Zone II: 90 - 110 °C, Zone III: 70 - 90 °C.

8. The preparation process according to any one of claims 3 to 7, wherein, The conditions for dry extrusion granulation are as follows: the pressure of the rolling wheel is 25 - 35 kg / cm 2 , the frequency of the feeding motor is 20 Hz, the frequency of the tablet pressing motor is 26 Hz, the frequency of the cutting motor is 15 Hz, and the frequency of the granule finishing motor is 12 Hz.

9. The preparation process according to any one of claims 3 to 8, wherein, The preparation method of the Huaqi Huang sugar-free granule is as follows: (1) Take Tremella fuciformis mycelium, decoct with water three times. For the first time, add 7 times the amount of water, boil for 1.5 hours, filter, and reserve the filtrate; for the second and third times, add 5 times the amount of water respectively, boil for 1 hour, filter, combine the three filtrates, and concentrate under reduced pressure to a relative density of 1.35 - 1.40 (55 °C) to obtain the Tremella fuciformis clear extract; (2) Soak wolfberry fruits and polygonatum sibiricum redoute in 8 times the amount of water for half an hour, then decoct twice, each time for 45 minutes. Combine the decoction liquids, filter, and concentrate the filtrate to a clear paste with a relative density of 1.35 or more (at 50 - 60 °C). (3) Combine the clear pastes from steps (1) and (2), and mix well to obtain the Huaiqi Huang clear paste. (4) Mix the Huaiqi Huang clear paste from step (3) with dextrin (if any), maltodextrin, sucralose (if any), and water, dry with a vacuum belt dryer, granulate by dry extrusion, sieve, make into granules, and package to obtain the product.

10. The preparation process according to claim 9, wherein, In step (4), the drying temperature of the vacuum belt dryer is: Zone I: 110 °C; Zone II: 100 °C; Zone III: 80 °C. Preferably, in step (4), the conditions for dry extrusion granulation are as follows: the pressure of the rolling wheel is 25-35 kg / cm 2 , the frequency of the feeding motor is 20 Hz, the frequency of the tablet pressing motor is 26 Hz, the frequency of the cutting motor is 15 Hz, and the frequency of the granule finishing motor is 12 Hz.

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