Optimized production process of pediatric diarrhea mixture and its application and product

Abstract

The application belongs to the technical field of traditional Chinese medicine, and particularly relates to an optimized production process of Xiaer Xiaonian Ning mixture, application and product thereof. The production process optimizes the production process of Xiaer Xiaonian Ning mixture in the prior art, mainly in that membrane filtration, reverse osmosis membrane concentration, separation and purification and column chromatography steps are added. The production process provided by the application ensures that the drug quality is not affected, the purification effect is improved, the energy consumption of concentration is reduced, and the production cost is reduced. The Xiaer Xiaonian Ning mixture prepared by the production process has good biological safety and stability.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine pharmaceutical technology, specifically involving the optimized production process of Xiaor Diarrhea-Relieving Compound, its application, and products. Background Technology

[0002] Pediatric Diarrhea Relief Mixture is a traditional Chinese medicine compound preparation made from Codonopsis pilosula, Atractylodes macrocephala, Glycyrrhiza uralensis, Pueraria lobata, Poria cocos, Pogostemon cablin, and Aucklandia lappa. It has the effects of strengthening the spleen and stomach, promoting fluid production, and stopping diarrhea. It is used for diarrhea caused by spleen and stomach qi deficiency, with symptoms such as loose stools, abdominal distension and pain, decreased appetite, vomiting, dry mouth, fatigue, and pale tongue with a white coating.

[0003] The preparation method of Xiaor Diarrhea-Relieving Compound is as follows: Codonopsis pilosula 150g, Atractylodes macrocephala 200g, Poria cocos 200g, Pueraria lobata 250g, Glycyrrhiza uralensis 50g, Pogostemon cablin 50g, and Aucklandia lappa 50g. For the above seven herbs, Atractylodes macrocephala, Pogostemon cablin, and Aucklandia lappa are distilled with water, and the distillate is collected. The dregs are then decocted twice with the remaining four herbs (Codonopsis pilosula, Atractylodes macrocephala, and Aucklandia lappa) for 2 hours each time. The decoctions are combined, filtered, and the filtrates are concentrated to a relative density of 1.10-1.20 (70℃). After cooling, ethanol is added to achieve an alcohol content of 50% v / v. The mixture is allowed to stand, filtered, and the ethanol is recovered from the filtrate. 200g of sucrose, 4g of stevioside, and 3g of preservative are added, and the mixture is boiled to dissolve. The mixture is then filtered, and the filtrate is used as the distillate. The total volume is adjusted to 1000ml with water, stirred well, and dispensed.

[0004] The aforementioned production process, including filtration and concentration steps, utilizes traditional screen filtration and vacuum concentration, which frequently encounters problems such as unsatisfactory filtration effects and high energy consumption during vacuum concentration. Therefore, there is an urgent need for a novel production process for pediatric diarrhea-relieving compound preparations that improves clarity and saves energy without affecting the raw material composition. This would ultimately enhance product quality, simplify production, increase capacity, shorten production time, optimize the production process, and provide technical support for the large-scale production of pediatric diarrhea-relieving compound preparations. Summary of the Invention

[0005] To address the aforementioned shortcomings, this invention provides an optimized production process for a children's diarrhea-relieving compound, along with its applications and products. The production process of this invention optimizes existing processes for producing children's diarrhea-relieving compound by adding membrane filtration, reverse osmosis membrane concentration, separation and purification, and column chromatography steps. The production process provided by this invention improves purification efficiency, reduces energy consumption during concentration, and lowers production costs while ensuring that drug quality is not affected. The children's diarrhea-relieving compound prepared using the production process of this invention exhibits good biosafety and stability.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0007] In a first aspect, the present invention provides an optimized production process for a pediatric diarrhea-relieving compound, the production process comprising the following steps:

[0008] S1. Atractylodes macrocephala, Pogostemon cablin, and Aucklandia lappa are distilled with water, and the distillate is collected for later use. The dregs are collected and decocted with Codonopsis pilosula, Poria cocos, Pueraria lobata, and Glycyrrhiza uralensis. The decoction is collected and filtered to obtain the extract of Pediatric Diarrhea Relief Mixture.

[0009] S2. The extract of Pediatric Diarrhea Relief Mixture was filtered through a membrane filtration system to obtain Pediatric Diarrhea Relief Mixture filtrate.

[0010] S3. After the pediatric diarrhea-relieving mixture is concentrated to 5%-30% v / v of its original volume through a reverse osmosis membrane concentration system, it is concentrated under reduced pressure to obtain an extract.

[0011] S4. Add ethanol to the extract to make the ethanol content reach 30%-50% v / v. After standing, collect the supernatant to obtain supernatant A. Wash the precipitate with 30%-50% v / v ethanol, centrifuge, collect the supernatant to obtain supernatant B. Combine supernatant A and supernatant B, recover the ethanol, and obtain combined supernatant.

[0012] S5. Combine the supernatants, add ethanol to make the ethanol content reach 60%-70% v / v, let stand, filter, collect the filtrate, and recover the ethanol.

[0013] S6. After the filtrate is adsorbed by macroporous adsorption resin, it is eluted sequentially with water and 30%-50% v / v ethanol. The 30%-50% v / v ethanol eluent is collected, the ethanol is recovered, and the eluent is obtained.

[0014] Specifically, the step S1 of adding water and decocting refers to decocting twice, and the step of collecting the decoction refers to collecting the two decoctions and then combining them.

[0015] Specifically, the filtration described in step S1 includes one or more of the following: physical filtration, chemical filtration, and biological filtration.

[0016] Preferably, the filtration in step S1 is performed using a plate and frame filter.

[0017] More preferably, the plate and frame filter mentioned in step S1 is a Φ400-32 layer plate and frame filter.

[0018] More preferably, the membrane flux of the plate and frame filter described in step S1 is 2000 kg / h.

[0019] Specifically, in the membrane filtration system described in step S2, the pore size of the membrane is 100 nm.

[0020] Specifically, the membrane filtration system described in step S2 is a ceramic membrane filtration system.

[0021] More specifically, in the ceramic membrane filtration system described in step S2, the sample inlet temperature is 50-65℃ and the membrane outlet pressure is 0.15-0.3 MPa.

[0022] Preferably, in the ceramic membrane filtration system described in step S2, the sample inlet temperature is 60°C and the membrane outlet pressure is 0.2 MPa.

[0023] More specifically, in the ceramic membrane filtration system described in step S2, the pore size of the ceramic membrane is 50-100 nm, and the ceramic membrane area is 40-50 m². 2 ;

[0024] Preferably, in the ceramic membrane filtration system described in step S2, the pore size of the ceramic membrane is 100 nm, and the ceramic membrane area is 46 m². 2 .

[0025] Specifically, in the ceramic membrane filtration system described in step S2, the ceramic membrane filtration capacity is 1000-3000 kg / h.

[0026] Preferably, in the ceramic membrane filtration system described in step S2, the ceramic membrane filtration capacity is 2000 kg / h.

[0027] Specifically, in the reverse osmosis membrane concentration system described in step S3, the temperature of the feed solution is 20-40℃, and the membrane outlet pressure is 1.5-3.0 MPa.

[0028] Preferably, in the reverse osmosis membrane concentration system described in step S3, the temperature of the feed solution is 30°C and the membrane outlet pressure is 2.0 MPa.

[0029] Specifically, in the reverse osmosis membrane concentration system described in step S3, the pore size of the reverse osmosis membrane is 0.3-0.5 nm, and the area of ​​a single reverse osmosis membrane is 200-250 m². 2 .

[0030] Preferably, in the reverse osmosis membrane concentration system described in step S3, the reverse osmosis membrane pore size is 0.5 nm, and the area of ​​a single reverse osmosis membrane is 216 m². 2 .

[0031] Specifically, in the reverse osmosis membrane concentration system described in step S3, the reverse osmosis membrane filtration capacity is 1000-3000 kg / h.

[0032] Preferably, in the reverse osmosis membrane concentration system described in step S3, the reverse osmosis membrane filtration capacity is 2000 kg / h.

[0033] Specifically, the vacuum concentration described in step S3 includes one or more of the following: vacuum distillation concentration, vacuum freeze-drying concentration, vacuum concentrator concentration, and vacuum evaporation crystallization concentration.

[0034] Preferably, the vacuum concentration described in step S3 is vacuum concentration using a vacuum concentrator.

[0035] More preferably, the vacuum concentrator is an EJZN-2500 dual-effect energy-saving concentrator.

[0036] More preferably, the membrane flux of the vacuum concentrator is 2500 kg / h.

[0037] Preferably, the relative density of the extract in step S3 is 1.20-1.22, and the temperature is 60-80℃.

[0038] Preferably, the settling time in step S4 is 12-24 hours.

[0039] Preferably, the centrifugation in step S4 includes centrifugation at 3000-5000 rpm for 5-15 minutes.

[0040] Preferably, the settling time in step S5 is 12-24 hours.

[0041] Preferably, the macroporous adsorption resin mentioned in step S6 is D101 macroporous adsorption resin.

[0042] Specifically, the production process further includes the following steps:

[0043] S7. The eluent from step S6 is boiled and dissolved with excipients, filtered and the filtrate is collected. The filtrate is combined with the distillate from step S1, water is added, and the mixture is stirred to obtain the Pediatric Diarrhea Relief Mixture.

[0044] Secondly, the present invention provides the application of the above-mentioned production process in the preparation of Pediatric Diarrhea Relief Mixture.

[0045] Thirdly, the present invention provides a pediatric diarrhea-relieving compound prepared by the above-mentioned production process.

[0046] The beneficial effects of this invention are as follows:

[0047] The production process of this invention optimizes the existing production process of pediatric diarrhea-relieving compound, mainly by adding ceramic membrane filtration, reverse osmosis membrane concentration, separation and purification, and column chromatography steps. The production process provided by this invention improves purification efficiency, reduces energy consumption during concentration, and lowers production costs while ensuring that drug quality is not affected. The pediatric diarrhea-relieving compound prepared by the production process of this invention exhibits good biosafety and stability. Attached Figure Description

[0048] Figure 1The figures show the chromatograms of the filtrate of the Pediatric Diarrhea Relief Mixture before and after passing through a ceramic membrane; A in the figure is the chromatogram of the filtrate of the Pediatric Diarrhea Relief Mixture before passing through a ceramic membrane; B is the chromatogram of the filtrate of the Pediatric Diarrhea Relief Mixture after passing through a ceramic membrane.

[0049] Figure 2 The fingerprint chromatogram of the filtrate of Xiaor Diarrhea Ning Mixture is a stacked chromatogram.

[0050] Figure 3 Chromatograms showing the similarity of the filtrate of Xiaor Diarrhea Relief Mixture before and after ceramic membrane filtration.

[0051] Figure 4 The figures show the chromatograms of the concentrate before and after organic membrane concentration; A in the figure is the chromatogram of the concentrate before organic membrane concentration; B is the chromatogram of the concentrate after organic membrane concentration.

[0052] Figure 5 This is a stacked chromatogram of the concentrated organic membrane fingerprint of the concentrate.

[0053] Figure 6 Chromatograms showing the similarity of the organic membrane in the concentrate before and after concentration. Detailed Implementation

[0054] The present invention will be described below with reference to specific embodiments. These embodiments are not intended to limit the present invention, but only to illustrate the present invention and make the technical solution of the present invention easier to understand and master. Unless otherwise specified, the experimental methods described in the following embodiments are conventional methods; the reagents and materials described are commercially available unless otherwise specified.

[0055] Basic Experiment Example 1: Multi-component Content Determination Method

[0056] Chromatographic conditions and system suitability: Octadecylsilane-bonded silica gel was used as the stationary phase; mobile phase A: acetonitrile; mobile phase B: 0.1% phosphoric acid; detection wavelength: 230 nm; flow rate: 1.0 ml / min; column temperature: 25 °C; gradient elution was performed according to the specifications in Table 1.

[0057] Table 1 Gradient Elution

[0058]

[0059]

[0060] Preparation of reference solution: Take appropriate amounts of puerarin, 3-hydroxypuerarin, puerarin apigenin and daidzein reference standards, accurately weigh them, and add methanol to prepare a mixed solution containing 50 μg each of puerarin, 3-hydroxypuerarin, puerarin apigenin and daidzein per 1 mL.

[0061] Preparation of test solution: Accurately measure 5 mL of Xiaoxia Ning Mixture, place it in a 50 mL volumetric flask, dilute with methanol to the mark, shake well and filter to obtain the test solution.

[0062] Assay: Accurately pipette 10 μL each of the reference solution and the test solution into the liquid chromatograph and determine the result.

[0063] Basic Experiment Example 2: Fingerprint Mapping Method

[0064] Chromatographic conditions and system suitability: Octadecylsilane-bonded silica gel was used as the stationary phase; mobile phase A: acetonitrile; mobile phase B: 0.1% phosphoric acid; detection wavelength: 230 nm; flow rate: 1.0 mL / min; column temperature: 25 °C; gradient elution was performed according to the specifications in Table 2.

[0065] Table 2 Gradient Elution

[0066] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 10 90 12 10 90 39 24 76 40 10 90 45 10 90

[0067] Preparation of test solution: Accurately measure 5 mL of Xiaoxia Ning Mixture, place it in a 50 mL volumetric flask, dilute with methanol to the mark, shake well and filter to obtain the test solution.

[0068] Determination method: Accurately pipette 10 μl of each test solution, inject it into the liquid chromatograph, and determine the result.

[0069] Example 1: Optimized Production Process of Pediatric Diarrhea Relief Mixture

[0070] S1. Collect the distillate: Add 200g of Atractylodes macrocephala, 50g of Pogostemon cablin, and 50g of Aucklandia lappa to 3 times the amount of water and distill at 100℃ for 3 hours. Collect the distillate for later use.

[0071] S2. Collect the decoction: Add water to the dregs and decoct 150g of Codonopsis pilosula, 200g of Poria cocos, 250g of Pueraria lobata, and 50g of Glycyrrhiza uralensis twice, each time for 2 hours. Combine the two decoctions to obtain a combined decoction.

[0072] S3. First filtration: After combining the decoctions, filter them using a Φ400-32 layer plate and frame filter at a capacity of 2000 kg / h, collect the filtrate, and obtain the extract of Xiaor Diarrhea-Relieving Compound.

[0073] S4. Ceramic membrane filtration: The extract of the pediatric diarrhea remedy is filtered through a ceramic membrane filtration system at a temperature controlled at 60℃ and a pressure of 0.2 MPa to obtain the pediatric diarrhea remedy filtrate; the ceramic membrane filtration system has a ceramic membrane pore size of 100 nm and a membrane area of ​​46 m². 2 The filtration capacity is 2000 kg / h.

[0074] S5. Reverse osmosis membrane concentration: The filtrate of the pediatric diarrhea-relieving mixture is concentrated at 30℃ and 2.0 MPa pressure through a reverse osmosis membrane concentration system to 15% v / v of its original volume, yielding a concentrate. This concentrate is then further concentrated under reduced pressure (using a 2500 kg / h EJZN-2500 double-effect energy-saving concentrator) to a relative density of 1.20-1.22 (70℃) to obtain an extract. The reverse osmosis membrane concentration system has a pore size of 0.5 nm and an area of ​​216 m². 2 The filtration capacity is 2000 kg / h.

[0075] S6. Separation and Purification: After the extract has cooled, ethanol is added with stirring to bring the alcohol content to 50% v / v. The mixture is allowed to stand for 12 hours, and the supernatant is collected (referred to as Supernatant A). The precipitate is washed three times with 50% v / v ethanol, centrifuged at 3000 rpm for 15 minutes, and the supernatant is collected (referred to as Supernatant B). Supernatants A and B are combined, and the ethanol is recovered to obtain a combined supernatant. Ethanol is added to the combined supernatant with stirring to bring the alcohol content to 70% v / v. The mixture is allowed to stand for 12 hours, filtered, and the filtrate is collected, with the ethanol recovered.

[0076] S7. Column chromatography: After the filtrate is adsorbed by D101 macroporous adsorption resin, it is eluted sequentially with water and 50% v / v ethanol solution. The 50% v / v ethanol eluent is collected, the ethanol is recovered, and the eluent is obtained.

[0077] S8. Add 200g of sucrose, 4g of stevioside and 3g of preservative to the eluent, boil to dissolve, filter, add the distillate collected in step S1 to the filtrate, and adjust the total volume to 1000mL with water, stir well, dispense into containers, and you will get the Pediatric Diarrhea Relief Mixture.

[0078] Example 2: Optimized Production Process of Pediatric Diarrhea Relief Mixture

[0079] Example 2 is set up with reference to Example 1. The only difference between Example 2 and Example 1 is that steps S4-S7 are different. Steps S4-S7 of Example 2 are as follows:

[0080] S4. Ceramic membrane filtration: The extract of the pediatric diarrhea remedy is filtered through a ceramic membrane filtration system at a temperature controlled at 50℃ and a pressure of 0.15 MPa to obtain the pediatric diarrhea remedy filtrate; the ceramic membrane filtration system has a ceramic membrane pore size of 100 nm and an area of ​​50 m². 2 The filtration capacity is 2000 kg / h.

[0081] S5. Reverse osmosis membrane concentration: The filtrate of the pediatric diarrhea-relieving mixture is concentrated at 30℃ and 2.0 MPa pressure through a reverse osmosis membrane concentration system to 5% v / v of the original volume, yielding a concentrate. This concentrate is then further concentrated under reduced pressure (using a 2500 kg / h EJZN-2500 double-effect energy-saving concentrator) to a relative density of 1.20-1.22 (70℃) to obtain an extract. The reverse osmosis membrane concentration system has a pore size of 0.5 nm and an area of ​​250 m². 2 The filtration capacity is 2000 kg / h.

[0082] S6. Separation and Purification: After the extract has cooled, ethanol is added with stirring to bring the alcohol content to 30% v / v. The mixture is allowed to stand for 12 hours, and the supernatant is collected and reserved (referred to as Supernatant A). The precipitate is washed three times with 30% v / v ethanol, centrifuged at 3000 rpm for 15 minutes, and the supernatant is collected (referred to as Supernatant B). Supernatants A and B are combined, and the ethanol is recovered to obtain a combined supernatant. Ethanol is added to the combined supernatant with stirring to bring the alcohol content to 60% v / v. The mixture is allowed to stand for 12 hours, filtered, and the filtrate is collected to recover the ethanol.

[0083] S7. Column chromatography: After the filtrate is adsorbed by D101 macroporous adsorption resin, it is eluted sequentially with water and 30% v / v ethanol solution. The 30% v / v ethanol eluent is collected, the ethanol is recovered, and the eluent is obtained.

[0084] Example 3: Optimized Production Process of Pediatric Diarrhea Relief Mixture

[0085] Example 2 is set up with reference to Example 1. The only difference between Example 2 and Example 1 is that steps S4-S5 are different. Steps S4-S5 of Example 2 are as follows:

[0086] S4. Ceramic membrane filtration: The extract of the pediatric diarrhea remedy is filtered through a ceramic membrane filtration system at a temperature controlled at 65℃ and a pressure of 0.25 MPa to obtain the pediatric diarrhea remedy filtrate; the ceramic membrane filtration system has a ceramic membrane pore size of 100 nm and an area of ​​40 m². 2 The filtration capacity is 2000 kg / h.

[0087] S5. Reverse osmosis membrane concentration: The filtrate of the pediatric diarrhea-relieving mixture is concentrated to 30% v / v of its original volume under a pressure of 2.0 MPa via a reverse osmosis membrane concentration system. The concentrate is then further concentrated under reduced pressure (using a 2500 kg / h EJZN-2500 double-effect energy-saving concentrator) to a relative density of 1.20-1.22 (70℃). The reverse osmosis membrane in the concentration system has a pore size of 0.3 nm and an area of ​​200 m². 2 The filtration capacity is 2000 kg / h.

[0088] Comparative Example 1: Optimized Production Process of Pediatric Diarrhea Relief Mixture

[0089] Comparative Example 1 is set up with reference to Example 1. The only difference between Comparative Example 1 and Example 1 is that step S4 is different. Step S4 of Comparative Example 1 is as follows:

[0090] S4. Ceramic membrane filtration: The extract of the pediatric diarrhea remedy is filtered through a ceramic membrane filtration system at a temperature controlled at 60℃ and a pressure of 0.2 MPa to obtain the pediatric diarrhea remedy filtrate; the ceramic membrane filtration system has a ceramic membrane pore size of 200 nm and an area of ​​46 m². 2 The filtration capacity is 2000 kg / h.

[0091] Comparative Example 2: Optimized Production Process of Pediatric Diarrhea Relief Mixture

[0092] Comparative Example 2 is set up with reference to Example 1. The only difference between Comparative Example 2 and Example 1 is that step S4 is different. Step S4 of Comparative Example 2 is as follows:

[0093] S4. Ceramic membrane filtration: The extract of the pediatric diarrhea remedy is filtered through a ceramic membrane filtration system at a temperature controlled at 60℃ and a pressure of 0.2 MPa to obtain the pediatric diarrhea remedy filtrate; the ceramic membrane filtration system has a ceramic membrane pore size of 15 nm and an area of ​​46 m². 2 The filtration capacity is 2000 kg / h.

[0094] Comparative Example 3: Optimized Production Process of Pediatric Diarrhea Relief Mixture

[0095] Comparative Example 3 is set up with reference to Example 1. The only difference between Comparative Example 3 and Example 1 is that step S5 is different. Step S5 of Comparative Example 3 is as follows:

[0096] S5. Nanofiltration Concentration: The filtrate of the Pediatric Diarrhea Relief Mixture is concentrated to 15% v / v of its original volume under a nanofiltration membrane system at a pressure of 2.0 MPa, and then further concentrated under reduced pressure (using a 2500 kg / h EJZN-2500 double-effect energy-saving concentrator) to a relative density of 1.20-1.22 (70℃). The nanofiltration membrane in this system has a pore size of 0.5 nm and an area of ​​216 m². 2 The filtration capacity is 2000 kg / h.

[0097] Comparative Example 4: Optimized Production Process of Pediatric Diarrhea Relief Mixture

[0098] Comparative Example 4 is set up with reference to Example 1. The only difference between Comparative Example 4 and Example 1 is that step S6 is different. Step S6 of Comparative Example 4 is as follows:

[0099] S6. Separation and purification: After the extract is cooled, ethanol is added with stirring to make the alcohol content reach 50% v / v. After standing for 12 hours, the supernatant is collected for later use (referred to as supernatant A). The precipitate is washed 3 times with 50% v / v ethanol, centrifuged at 3000 rpm for 15 min, and the supernatant is collected (i.e., supernatant B). Supernatant A and supernatant B are combined, and the ethanol is recovered to obtain the combined supernatant.

[0100] Comparative Example 5: Optimized Production Process of Pediatric Diarrhea Relief Mixture

[0101] Comparative Example 5 is set up with reference to Example 1. The only difference between Comparative Example 5 and Example 1 is that steps S4-S6 are different. Steps S4-S6 of Comparative Example 5 are as follows:

[0102] S4. Ceramic membrane filtration: The extract of the pediatric diarrhea remedy is filtered through a ceramic membrane filtration system at a temperature controlled at 60℃ and a pressure of 0.2 MPa to obtain the pediatric diarrhea remedy filtrate; the ceramic membrane filtration system has a ceramic membrane pore size of 200 nm and an area of ​​46 m². 2 The filtration capacity is 2000 kg / h.

[0103] S5. Nanofiltration Concentration: The filtrate of the Pediatric Diarrhea Relief Mixture is concentrated to 15% v / v of its original volume under a nanofiltration membrane system at a pressure of 2.0 MPa, and then further concentrated under reduced pressure (using a 2500 kg / h EJZN-2500 double-effect energy-saving concentrator) to a relative density of 1.20-1.22 (70℃). The nanofiltration membrane in this system has a pore size of 0.5 nm and an area of ​​216 m². 2 The filtration capacity is 2000 kg / h.

[0104] S6. Separation and purification: After the extract is cooled, ethanol is added with stirring to make the alcohol content reach 50% v / v. After standing for 12 hours, the supernatant is collected for later use (referred to as supernatant A). The precipitate is washed 3 times with 50% v / v ethanol, centrifuged at 3000 rpm for 15 min, and the supernatant is collected (i.e., supernatant B). Supernatant A and supernatant B are combined, and the ethanol is recovered to obtain the combined supernatant.

[0105] Comparative Example 6: Production Process of Pediatric Diarrhea Relief Mixture

[0106] The production process steps for Comparative Example 6 are as follows:

[0107] S1. Collect the distillate: Add 200g of Atractylodes macrocephala, 50g of Pogostemon cablin, and 50g of Aucklandia lappa to 3 times the amount of water and distill at 100℃ for 3 hours. Collect the distillate for later use.

[0108] S2. Collect the decoction: Add water to the dregs and decoct 150g of Codonopsis pilosula, 200g of Poria cocos, 250g of Pueraria lobata, and 50g of Glycyrrhiza uralensis twice, each time for 2 hours. Combine the two decoctions to obtain a combined decoction.

[0109] S3. Filtration: After combining the decoctions, filter them using a Φ400-32 layer plate and frame filter at a capacity of 2000 kg / h, collect the filtrate, and obtain the extract of Xiaor Diarrhea-Relieving Compound.

[0110] S4. The filtrate temperature of the Pediatric Diarrhea Relief Mixture is controlled at 30℃, and concentrated under reduced pressure (using an EJZN-2500 double-effect energy-saving concentrator with a capacity of 2500kg / h) to obtain an extract with a relative density of 1.20-1.22 (70℃).

[0111] S5. After the extract has cooled, add ethanol to make the alcohol content reach 50% v / v, let it stand, filter, recover the ethanol from the filtrate, and obtain the filtrate.

[0112] S6. Add 200g of sucrose, 4g of stevioside and 3g of preservative to the filtrate, boil to dissolve, filter, add the distillate collected in step S1 to the filtrate, adjust the total volume to 1000mL with water, stir well, dispense into containers, and the product is ready.

[0113] Experimental Example 1: Measurement of average membrane flux, turbidity, conductivity, and pH of Pediatric Diarrhea Relief Mixture

[0114] The extracts of the Pediatric Diarrhea Relief Compound prepared in step S3 of Examples 1-3 and Comparative Examples 1-2 (before ceramic membrane filtration, i.e., concentrated liquid) and the filtrate of the Pediatric Diarrhea Relief Compound after filtration (after ceramic membrane filtration, i.e., clear liquid) were tested for membrane flux, turbidity, conductivity and pH data. The test results are shown in Table 3.

[0115] Table 3. Membrane flux, turbidity, conductivity, and pH data

[0116]

[0117]

[0118] The results showed that the conductivity of the membrane filtrate decreased slightly, and some ions in the extract of the Pediatric Diarrhea Relief Compound were retained during the transfer to the clear liquid, while the pH was almost unaffected. The average membrane flux of the filtrates from Examples 1-3 and Comparative Example 1 was all above 160 L / H, with Example 1 reaching an average membrane flux of 165.6 L / H. While Comparative Example 1 also achieved an average membrane flux of 174.4 L / H, its turbidity was 2.41 NTU. Although Comparative Example 2 achieved a turbidity of 0.18, its membrane flux was only 132.5 L / H, which was relatively low.

[0119] (2) Determination of eluent and filtrate

[0120] Take the extract of the pediatric diarrhea-relieving compound prepared in step S3 of Examples 1-3 and Comparative Examples 1-6 (hereinafter referred to as the extract); the eluent prepared in step S7 of Examples 1-3 and Comparative Examples 1-5; and the filtrate prepared in step S5 of Comparative Example 6.

[0121] Table 4. Turbidity, Conductivity, and pH Data

[0122]

[0123]

[0124] The results above show that the turbidity of the eluents prepared in Examples 1-3 is below 0.36 NTU, which is significantly lower than the turbidity of the filtrate prepared by the traditional pediatric diarrhea-relieving compound production process (Comparative Example 6). Among them, the turbidity of Example 1 is the lowest, at 0.25 NTU.

[0125] Experiment Example 2: Stability Determination of Pediatric Diarrhea Relief Mixture

[0126] The eluents prepared in Examples 1-3 and Comparative Examples 1-5, and the filtrate prepared in Comparative Example 6 were used as test samples for stability determination.

[0127] 1. High temperature test

[0128] The test sample was placed in a sealed vial and stored at 60°C for 10 days. Samples were taken at 0, 5, and 10 days to test its turbidity.

[0129] 2. Strong light irradiation test

[0130] The test sample was placed under an illumination of 4500 lx ± 500 lx for 10 days, and samples were taken for testing on days 0, 5, and 10. Temperature should be carefully controlled during the experiment to maintain a constant level with room temperature, and turbidity should be measured on days 0, 5, and 10.

[0131] 3. Accelerated testing

[0132] The experiment was conducted at 40℃±2℃, and turbidity was measured at the end of months 0, 1, 2, 3, and 6 during the experiment.

[0133] The results of the high temperature test and the strong light irradiation test are shown in Table 5, and the results of the accelerated test are shown in Table 6.

[0134] Table 5. Results of High Temperature Test and Strong Light Irradiation Test

[0135]

[0136]

[0137] Table 6. Results of accelerated test.

[0138] Time / Month 0 1 2 3 6 Example 1 0.25 0.38 0.62 0.81 0.95 Example 2 0.36 0.41 0.60 0.75 0.98 Example 3 0.31 0.44 0.71 0.83 1.02 Comparative Example 1 0.73 1.38 1.54 2.68 4.54 Comparative Example 2 0.58 0.77 1.02 1.57 2.64 Comparative Example 3 0.61 0.89 1.35 1.86 3.13 Comparative Example 4 0.39 0.68 0.97 1.12 1.88 Comparative Example 5 0.81 1.27 1.63 2.42 4.04 Comparative Example 6 0.97 1.43 1.93 3.22 4.71

[0139] The test results showed that the turbidity of the eluents prepared in Examples 1-3 was below 0.95 NTU after high-temperature and strong light irradiation tests; after 6 months of accelerated testing, the turbidity was below 1.1 NTU. This indicates that the optimized production process of the Pediatric Diarrhea Relief Mixture of the present invention can maintain the clarity of the mixture and has good stability.

[0140] It is worth noting that the turbidity of the eluent prepared in Example 1 was 0.95 NTU after 6 months of accelerated testing, which was only 0.7 NTU higher than that after 0 months. In contrast, the turbidity of Comparative Examples 1 and 3-5 increased by 3.81, 2.52, 1.49 and 3.23 NTU, respectively, after 6 months of accelerated testing compared with that after 0 months.

[0141] Compared to Comparative Example 5, Comparative Example 1 reduced the technical effect by 0.58 NTU (3.23-3.81); Comparative Example 3 improved the technical effect by 0.71 NTU (3.23-2.52); and Comparative Example 4 improved the technical effect by 1.74. However, Embodiment 1 of the present invention improved the technical effect by 2.53 NTU compared to Comparative Example 5. Therefore, the technical solution of the present invention has a synergistic effect.

[0142] Experiment Example 3: Determination of the effective components of Pediatric Diarrhea Relief Mixture

[0143] 3'-Hydroxypuerarin, puerarin, puerarin apigenin, and daidzein are the active ingredients of Pediatric Diarrhea Relief Mixture. The content of 3'-hydroxypuerarin, puerarin, puerarin apigenin, and daidzein in the extract, filtrate, and paste of Pediatric Diarrhea Relief Mixture was detected to investigate the effect of optimized production process on the active ingredients.

[0144] (1) Determination of effective components in the filtrate of Pediatric Diarrhea Relief Mixture

[0145] Take the extract of the Pediatric Diarrhea Relief Compound prepared in step S3 of Examples 1-3 (before ceramic membrane filtration, i.e., concentrated liquid); and the filtrate of the Pediatric Diarrhea Relief Compound prepared in step S4 (after ceramic membrane filtration, i.e., clear liquid). Sample preparation was carried out, the content of multiple components was tested, and the permeability was calculated (permeability % = clear liquid / concentrated liquid × 100%). The test results are shown in Table 7.

[0146] Table 7 Results of the determination of filtrate from Pediatric Diarrhea Relief Mixture

[0147]

[0148] (2) Determination of effective components in concentrated solution of Pediatric Diarrhea Relief Mixture

[0149] The filtrate of the Pediatric Diarrhea Relief Mixture prepared in step S4 of Examples 1-3 (before reverse osmosis membrane concentration, i.e., clear liquid) and the concentrate prepared in step S5 (after reverse osmosis membrane concentration, i.e., concentrated liquid) were used for sample preparation. The content of multiple components was tested, and the rejection rate was calculated (rejection rate % = concentrated liquid / clear liquid × 100%). The test results are shown in Table 8.

[0150] Table 8. Results of the test of concentrated pediatric diarrhea relief mixture.

[0151]

[0152]

[0153] (3) Determination of effective components in the eluent of Pediatric Diarrhea Relief Mixture

[0154] The extract of the pediatric diarrhea-relieving compound prepared in step S3 of Examples 1-3 (before ceramic membrane filtration, i.e., concentrated liquid) and the eluent prepared in step S7 (after column chromatography, i.e., clear liquid) were used to prepare samples. The contents of multiple components were tested, and the permeability was calculated (permeability % = clear liquid / concentrated liquid × 100%). The test results are shown in Table 9.

[0155] Table 9. Results of the determination of the eluent of Pediatric Diarrhea Relief Mixture

[0156]

[0157] The results showed that the filtrate, concentrate, and eluent of the Pediatric Diarrhea Relief Mixture in Examples 1-3 of the present invention did not cause any change in the content of effective components after ceramic membrane filtration, reverse osmosis membrane concentration, separation and purification, and column chromatography, and the component loss was very low.

[0158] Experiment Example 4: Investigation of Residual Substances in Ceramic Membranes

[0159] The filtrate of the Pediatric Diarrhea Relief Mixture prepared in step S4 of Example 1 was sent to a third-party testing institution. The elemental composition analysis and heavy metal residue of the ceramic membrane were tested according to the XRF detection method and GB 31604.49-2016 to investigate the migration of heavy metals during the ceramic membrane filtration process.

[0160] Analysis of the elemental composition of the ceramic membrane and detection of the migration of various heavy metals under different conditions showed that the risk of heavy metal contamination of raw materials during ceramic membrane filtration is controllable and does not affect product quality. Example 1: Chromatograms of the filtrate of the Pediatric Diarrhea Relief Mixture before and after ceramic membrane filtration are shown below. Figure 1 As shown; the stacked chromatogram of the fingerprint chromatogram of the filtrate of Xiaor Diarrhea Ning Mixture is as follows. Figure 2 As shown; the chromatograms of similarity between the filtrate of the Pediatric Diarrhea Relief Compound and the ceramic membrane filtration before and after filtration are shown in the figure. Figure 3As shown.

[0161] Experimental Example 5: Investigation of Organic Membrane Residues

[0162] The concentrate prepared in step S5 of Example 1 was sent to a third-party testing institution for testing of sensory properties, primary aromatic amine residues, heavy metal residues, etc., in accordance with (EU) No 10 / 2011 and its amendment directive (EU) 2020 / 1245, to examine the migration of aromatic amines, heavy metals, etc. during the organic membrane concentration process.

[0163] The total migration, sensory evaluation (odor and taste), specific migration of primary aromatic amines, and specific migration of heavy metals were all tested using the organic membrane. The results all met EU standards, indicating that the risk of contamination of raw materials by heavy metals and aromatic amines during organic membrane concentration is controllable and does not affect product quality. The chromatograms of the concentrated solution before and after organic membrane filtration in Example 1 are shown below. Figure 4 As shown; stacked chromatogram of organic membrane concentration fingerprint spectrum. Figure 5 As shown; the organic membrane concentration similarity chromatogram is as follows. Figure 6 As shown.

[0164] The above detailed description is a specific illustration of one feasible embodiment of the present invention, and this embodiment is not intended to limit the patent scope of the present invention. It should be noted that all equivalent implementations or modifications made without departing from the present invention should be included within the scope of the technical solution of the present invention. Therefore, the protection scope of the present invention should be determined by the appended claims.

Claims

1. An optimized process for the production of Paediatric Diarrhoea Syrup, characterized by, The production process includes the following steps: S1. Atractylodes macrocephala, Pogostemon cablin, and Aucklandia lappa are distilled with water, and the distillate is collected for later use. The dregs are collected and decocted with Codonopsis pilosula, Poria cocos, Pueraria lobata, and Glycyrrhiza uralensis. The decoction is collected and filtered to obtain the extract of Pediatric Diarrhea Relief Mixture. S2. The extract of Pediatric Diarrhea Relief Mixture was filtered through a membrane filtration system to obtain Pediatric Diarrhea Relief Mixture filtrate. S3. After the pediatric diarrhea-relieving mixture is concentrated to 5%-30% v / v of its original volume through a reverse osmosis membrane concentration system, it is concentrated under reduced pressure to obtain an extract. S4. Add ethanol to the extract to make the ethanol content reach 30%-50% v / v. After standing, collect the supernatant to obtain supernatant A. Wash the precipitate with 30%-50% v / v ethanol, centrifuge, collect the supernatant to obtain supernatant B. Combine supernatant A and supernatant B, recover the ethanol, and obtain combined supernatant. S5. Combine the supernatants, add ethanol to make the ethanol content reach 60%-70% v / v, let stand, filter, collect the filtrate, and recover the ethanol. S6. After the filtrate is adsorbed by macroporous adsorption resin, it is eluted sequentially with water and 30%-50% v / v ethanol. The 30%-50% v / v ethanol eluent is collected, the ethanol is recovered, and the eluent is obtained. The membrane filtration system in step S2 is a ceramic membrane filtration system, the pore size of the ceramic membrane is 100 nm, the area of the ceramic membrane is 40-50 m 2 ; the ceramic membrane filtration capacity is 1000-3000 kg / h; The reverse osmosis membrane pore size in the reverse osmosis membrane concentration system in step S3 is 0.3-0.5 nm, the reverse osmosis membrane area is about 200-250 m 2 ; the reverse osmosis membrane filtration capacity is 1000-3000 kg / h.

2. The production process according to claim 1, characterized in that, In the membrane filtration system described in step S2, the sample solution temperature is 50-65℃ and the membrane outlet pressure is 0.15-0.3 MPa; in the reverse osmosis membrane concentration system described in step S3, the sample solution temperature is 20-40℃ and the membrane outlet pressure is 1.5-3.0 MPa.

3. The production process according to claim 1, characterized in that, The filtration described in step S1 includes one or more of the following: physical filtration, chemical filtration, and biological filtration.

4. The production process according to claim 1, characterized in that, The vacuum concentration described in step S3 includes one or more of the following: vacuum distillation concentration, vacuum freeze-drying concentration, vacuum concentrator concentration, and vacuum evaporation crystallization concentration.

5. The production process according to claim 1, characterized in that, The macroporous adsorption resin in step S6 is D101 macroporous adsorption resin.

6. The production process according to claim 1, characterized in that, The production process also includes the following steps: S7. The eluent from step S6 is boiled and dissolved with excipients, filtered and the filtrate is collected. The filtrate is combined with the distillate from step S1, water is added, and the mixture is stirred to obtain the Pediatric Diarrhea Relief Mixture.

7. The application of the production process according to any one of claims 1-6 in the preparation of Pediatric Diarrhea Relief Mixture.

8. The pediatric diarrhea-relieving compound prepared by the production process according to any one of claims 1-6.

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