Optimized infantile diarrhea relieving mixture production process, application thereof and product

Abstract

The invention belongs to the technical field of traditional Chinese medicine pharmacy, and particularly relates to an optimized infantile diarrhea Ning mixture production process, application and a product thereof. According to the production process disclosed by the invention, the production process of the infantile diarrhea relieving mixture in the prior art is optimized, and the production process is mainly embodied by adding the steps of membrane filtration, reverse osmosis membrane concentration, separation and purification and column chromatography. According to the production process provided by the invention, on the premise of ensuring that the medicine quality is not influenced, the purification effect is good, the energy consumption of concentration is reduced, and the production cost is reduced. The infantile diarrhea treating mixture prepared by the production process disclosed by the invention has good biological safety and stability.

Description

Technical Field

[0001] The invention belongs to the technical field of traditional Chinese medicine pharmaceutical preparation, and specifically relates to an optimized production process of a Xiao'er Xiexianing mixture, and an application and product thereof. Background Art

[0002] Xiaoer Xiexianing mixture is a traditional Chinese medicine compound preparation made of Codonopsis pilosula, Atractylodes macrocephala, Licorice root, Pueraria root, Poria cocos, Patchouli, 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 of loose stools, abdominal distension and pain, decreased appetite, vomiting, dry mouth, fatigue, and pale tongue with white fur.

[0003] The preparation method of Xiaoer Xiexia Ning mixture is as follows: 150g of Codonopsis pilosula, 200g of Atractylodes macrocephala, 200g of Poria cocos, 250g of Pueraria root, 50g of Licorice root, 50g of Patchouli and 50g of Costus root. The above seven ingredients, Atractylodes macrocephala, Patchouli and Costus root, are distilled with water, and the distillate is collected; the residue and the other four ingredients including Codonopsis pilosula are decocted with water twice, each time for 2 hours, the decoctions are combined, filtered, the filtrates are combined, the filtrates are concentrated to a relative density of 1.10-1.20 (70°C), cooled, ethanol is added to make the alcohol content reach 50% v / v, allowed to stand, filtered, ethanol is recovered from the filtrate, 200g of sucrose, 4g of stevioside and 3g of preservative are added, boiled to dissolve, filtered, the filtrate is the above distillate, and the total amount is adjusted to 1000ml with water, stirred evenly, and packaged.

[0004] The above production process, filtration and concentration process, adopts the traditional screen filtration and vacuum concentration, and often faces problems such as unsatisfactory filtration effect and high energy consumption of vacuum concentration. Therefore, there is an urgent need for a new production process of pediatric diarrhea Ning mixture, which can improve clarity and save energy without affecting the material basis of raw materials, thereby improving product quality, simplifying production, increasing production capacity, shortening time, optimizing the production process of pediatric diarrhea Ning mixture, and providing technical support for the large-scale production of pediatric diarrhea Ning mixture. Summary of the invention

[0005] In view of the above-mentioned shortcomings, the present invention provides an optimized production process of Xiaoer Xie Ning mixture and its application and product. The production process of the present invention optimizes the production process of Xiaoer Xie Ning mixture in the prior art, which is mainly reflected in the addition of membrane filtration, reverse osmosis membrane concentration, separation and purification and column chromatography steps. The production process provided by the present invention has a purification effect, reduces the energy consumption of concentration, and reduces production costs while ensuring that the quality of the drug is not affected. The Xiaoer Xie Ning mixture prepared by the production process of the present invention has good biosafety and stability.

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

[0007] In a first aspect, the present invention provides an optimized production process of Xiaoer Xiexuening mixture, the production process comprising the following steps:

[0008] S1, distilling Atractylodes macrocephala, Patchouli, and Aucklandia lappa with water, collecting the distillate and setting aside; collecting the drug residues, decocting with Codonopsis pilosula, Poria cocos, Pueraria root, and Licorice with water, collecting the decoction and filtering it to obtain the extract of Xiaoer Xiexianing mixture;

[0009] S2, filtering the extract of the Xiao Xie Ning mixture of children through a membrane filtration system to obtain a filtrate of the Xiao Xie Ning mixture of children;

[0010] S3, the Xiaoer Xiexianing mixture is filtered through a reverse osmosis membrane concentration system and concentrated to 5%-30% v / v of the original volume, and then concentrated under reduced pressure to obtain an extract;

[0011] S4, adding ethanol to the extract to make the ethanol content reach 30%-50% v / v, after standing, collecting the supernatant to obtain supernatant A; washing the precipitate with 30%-50% v / v ethanol, centrifuging, collecting the supernatant to obtain supernatant B; combining supernatant A and supernatant B, recovering ethanol, and obtaining a combined supernatant;

[0012] S5, adding ethanol to the combined supernatants to make the ethanol content reach 60%-70% v / v, letting it stand, filtering, collecting the filtrate, and recovering the ethanol;

[0013] S6. After the filtrate is adsorbed by a macroporous adsorption resin, it is eluted with water and 30%-50% v / v ethanol in sequence, and the 30%-50% v / v ethanol eluate is collected, and the ethanol is recovered to obtain an eluate.

[0014] Specifically, the decocting with water in step S1 is decocting with water twice, and the collecting of the decoction is collecting the decoctions twice and then combining them.

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

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

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

[0018] Further preferably, the membrane flux of the plate and frame filter 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 inlet liquid temperature is 50-65° C., and the membrane outlet pressure is 0.15-0.3 MPa.

[0022] Preferably, in the ceramic membrane filtration system described in step S2, the inlet liquid 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 area of ​​the ceramic membrane is 40-50 m 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 area of ​​the ceramic membrane is 46 m 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 inlet liquid temperature is 20-40° C., 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 inlet liquid temperature 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 m 2 .

[0030] Preferably, in the reverse osmosis membrane concentration system described in step S3, the pore size of the reverse osmosis membrane is 0.5 nm, and the area of ​​a single reverse osmosis membrane is 216 m 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 reduced pressure concentration in step S3 includes: reduced pressure distillation concentration, vacuum freeze drying concentration, reduced pressure concentrator concentration, reduced pressure evaporation crystallization concentration or more.

[0034] Preferably, the reduced pressure concentration in step S3 is concentration using a reduced pressure concentrator.

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

[0036] Further 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°C.

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

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

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

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

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

[0043] S7. Add auxiliary materials to the eluate of step S6 and boil to dissolve, collect the filtrate by filtration, combine the filtrate with the distillate of step S1, add water, stir well, and obtain the Xiao'er Xiexianing mixture.

[0044] In the second aspect, the present invention provides the application of the above production process in the preparation of Xiaoer Xiexianing mixture.

[0045] In a third aspect, the present invention provides the Xiao Er Xie Xia Ning mixture prepared by the above production process.

[0046] The beneficial effects of the present invention are:

[0047] The production process of the present invention optimizes the production process of the Xiaoer Xiexi Ning mixture in the prior art, which is mainly reflected in the addition of ceramic membrane filtration, reverse osmosis membrane concentration, separation and purification, and column chromatography steps. The production process provided by the present invention has a purification effect, reduces the energy consumption of concentration, and reduces production costs while ensuring that the quality of the drug is not affected. The Xiaoer Xiexi Ning mixture prepared by the production process of the present invention has good biosafety and stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1These are the chromatograms of the filtrate of the Children's Diarrhea Ning mixture before and after it passes through the ceramic membrane; A in the figure is the chromatogram of the filtrate of the Children's Diarrhea Ning mixture before it passes through the ceramic membrane; B is the chromatogram of the filtrate of the Children's Diarrhea Ning mixture after it passes through the ceramic membrane.

[0049] Figure 2 This is the stacked chromatogram of the fingerprint of the filtrate of Xiaoer Xiexia Ning mixture.

[0050] Figure 3 This is the similarity chromatogram of the filtrate of Xiaoer Xiexia Ning mixture before and after ceramic membrane filtration.

[0051] Figure 4 These are the chromatograms of the concentrated liquid before and after organic membrane concentration; A in the figure is the chromatogram of the concentrated liquid before organic membrane concentration; B is the chromatogram of the concentrated liquid after organic membrane concentration.

[0052] Figure 5 Stacked chromatograms for the concentrate organic membrane concentration fingerprint.

[0053] Figure 6 Similarity chromatograms of the concentrate before and after organic membrane concentration. DETAILED DESCRIPTION

[0054] The present invention is described below in conjunction with specific examples. The following examples are not intended to limit the present invention, but are only intended to illustrate the present invention so that the technical solution of the present invention is easier to understand and grasp. The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are all commercially available unless otherwise specified.

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

[0056] Chromatographic conditions and system suitability: octadecylsilane bonded silica gel as filler; 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 as specified in Table 1.

[0057] Table 1 Gradient elution

[0058]

[0059]

[0060] Preparation of reference solution: Take appropriate amount of puerarin, 3-hydroxypuerarin, puerarin apiglycoside, and daidzein reference substances, weigh accurately, add methanol to make a mixed solution containing 50 μg of puerarin, 3-hydroxypuerarin, puerarin apiglycoside, and daidzein per 1 mL.

[0061] Preparation of test solution: Accurately measure 5 mL of pediatric diarrhea mixture, place it in a 50 mL volumetric flask, add methanol to dilute to the scale, shake well and filter to obtain.

[0062] Determination method: Accurately pipette 10 μL of reference solution and test solution respectively, inject into liquid chromatograph, and determine.

[0063] Basic Experimental Example 2 Fingerprint Method

[0064] Chromatographic conditions and system suitability: octadecylsilane bonded silica gel as filler; 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 as specified 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 pediatric diarrhea mixture, place it in a 50 mL volumetric flask, add methanol to dilute to the scale, shake well and filter to obtain.

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

[0069] Example 1 Optimized production process of Xiaoer Xiexianing mixture

[0070] S1. Collect distillate: add 3 times amount of water to 200g of Atractylodes macrocephala, 50g of Patchouli and 50g of Aucklandia lappa and distill at 100℃ for 3h, collect distillate and set aside.

[0071] S2. Collecting decoction: adding water to the residue, 150 g of Codonopsis pilosula, 200 g of Poria cocos, 250 g of Pueraria root and 50 g of Licorice, and decocting twice for 2 hours each time, combining the two decoctions to obtain a combined decoction.

[0072] S3. First filtration: After the decoctions are combined, they are filtered through a Φ400-32 layer plate and frame filter at a rate of 2000kg / h, and the filtrate is collected to obtain the extract of the Xiao'er Xiexianing mixture.

[0073] S4, ceramic membrane filtration: The temperature of the extract of Xiaoer Xiexue Ning mixture is controlled at 60°C, and filtered through a ceramic membrane filtration system at a pressure of 0.2Mpa to obtain the filtrate of Xiaoer Xiexue Ning mixture; in the ceramic membrane filtration system: the pore size of the ceramic membrane is 100nm, the membrane area is 46m 2 , the filtration capacity is 2000kg / h.

[0074] S5, reverse osmosis membrane concentration: the temperature of the filtrate of Xiao Er Xie Xie Ning mixture is controlled at 30°C, and at a pressure of 2.0 MPa, it is concentrated to 15% v / v of the original volume through a reverse osmosis membrane concentration system to obtain a concentrate, which is then concentrated under reduced pressure (2500 kg / h EJZN-2500 dual-effect energy-saving concentrator) to an extract with a relative density of 1.20-1.22 (70°C); in the reverse osmosis membrane concentration system: the pore size of the reverse osmosis membrane is 0.5 nm, the area is 216 m 2 , the filtration capacity is 2000kg / h.

[0075] S6, separation and purification: After the extract is cooled, ethanol is added with stirring to make the alcohol content reach 50% v / v, and it is allowed to stand for 12 hours, and the supernatant is taken for use (recorded as supernatant A); the precipitate is washed with 50% v / v ethanol for 3 times, centrifuged at 3000 rpm for 15 minutes, and the supernatant is collected (i.e., supernatant B); supernatant A and supernatant B are combined, and ethanol is recovered to obtain a combined supernatant. Ethanol is added to the combined supernatant with stirring to make the alcohol content reach 70% v / v, and it is allowed to stand for 12 hours, filtered, and the filtrate is collected to recover ethanol.

[0076] S7. Column chromatography: The filtrate is adsorbed by D101 macroporous adsorption resin, and then eluted with water and 50% v / v ethanol solution in sequence, and the 50% v / v ethanol eluate is collected, and the ethanol is recovered to obtain an eluate.

[0077] S8. Add 200 g sucrose, 4 g stevia and 3 g preservative to the eluate, boil to dissolve, filter, add the distillate collected in step S1 to the filtrate, adjust the total amount to 1000 mL with water, stir well, and package to obtain the Xiao Er Xie Xia Ning mixture.

[0078] Example 2 Optimized production process of Xiaoer Xiexuening mixture

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

[0080] S4, ceramic membrane filtration: The temperature of the extract of the children's diarrhea Ning mixture is controlled at 50°C, and filtered through a ceramic membrane filtration system at a pressure of 0.15Mpa to obtain the filtrate of the children's diarrhea Ning mixture; in the ceramic membrane filtration system: the pore size of the ceramic membrane is 100nm, the area is 50m 2 , the filtration capacity is 2000kg / h.

[0081] S5. Reverse osmosis membrane concentration: The temperature of the filtrate of Xiaoer Xiexianing mixture is controlled at 30°C. Under a pressure of 2.0 MPa, it is concentrated to 5% v / v of the original volume through a reverse osmosis membrane concentration system to obtain a concentrate, which is then concentrated under reduced pressure (2500 kg / h EJZN-2500 dual-effect energy-saving concentrator) to an extract with a relative density of 1.20-1.22 (70°C); in the reverse osmosis membrane concentration system: the pore size of the reverse osmosis membrane is 0.5 nm, the area is 250 m 2 , the filtration capacity is 2000kg / h.

[0082] S6, separation and purification: After the extract is cooled, ethanol is added with stirring to make the alcohol content reach 30% v / v, and it is allowed to stand for 12 hours, and the supernatant is taken for use (recorded as supernatant A); the precipitate is washed with 30% v / v ethanol for 3 times, centrifuged at 3000 rpm for 15 minutes, and the supernatant is collected (i.e., supernatant B); supernatant A and supernatant B are combined, and ethanol is recovered to obtain a combined supernatant. Ethanol is added to the combined supernatant with stirring to make the alcohol content reach 60% v / v, and it is allowed to stand for 12 hours, filtered, and the filtrate is collected to recover ethanol.

[0083] S7. Column chromatography: The filtrate is adsorbed by D101 macroporous adsorption resin, and then eluted with water and 30% v / v ethanol solution in sequence, and the 30% v / v ethanol eluate is collected, and the ethanol is recovered to obtain an eluate.

[0084] Example 3 Optimized production process of Xiaoer Xiexuening mixture

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

[0086] S4, ceramic membrane filtration: The temperature of the extract of Xiao Xie Ning mixture is controlled at 65°C, and filtered through a ceramic membrane filtration system at a pressure of 0.25 MPa to obtain the filtrate of Xiao Xie Ning mixture; in the ceramic membrane filtration system: the pore size of the ceramic membrane is 100 nm, the area is 40 m 2 , the filtration capacity is 2000kg / h.

[0087] S5, reverse osmosis membrane concentration: the temperature of the filtrate of Xiao Er Xie Xie Ning mixture is controlled at 30°C, and at a pressure of 2.0 MPa, it is concentrated to 30% v / v of the original volume through a reverse osmosis membrane concentration system to obtain a concentrate, which is then concentrated under reduced pressure (2500 kg / h EJZN-2500 dual-effect energy-saving concentrator) to an extract with a relative density of 1.20-1.22 (70°C); in the reverse osmosis membrane concentration system: the pore size of the reverse osmosis membrane is 0.3 nm, the area is 200 m 2 , the filtration capacity is 2000kg / h.

[0088] Comparative Example 1 Optimized Production Process of Xiaoer Xiexue Ning Mixture

[0089] Comparative Example 1 is set with reference to Example 1. The 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 temperature of the extract of Xiaoer Xiexue Ning mixture is controlled at 60°C, and filtered through a ceramic membrane filtration system at a pressure of 0.2Mpa to obtain the filtrate of Xiaoer Xiexue Ning mixture; in the ceramic membrane filtration system: the pore size of the ceramic membrane is 200nm, the area is 46m 2 , the filtration capacity is 2000kg / h.

[0091] Comparative Example 2: Optimized production process of Xiaoer Xiexuening mixture

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

[0093] S4, ceramic membrane filtration: The temperature of the extract of the children's diarrhea Ning mixture is controlled at 60°C, and filtered through a ceramic membrane filtration system at a pressure of 0.2Mpa to obtain the filtrate of the children's diarrhea Ning mixture; in the ceramic membrane filtration system: the ceramic membrane has a pore size of 15nm and an area of ​​46m 2 , the filtration capacity is 2000kg / h.

[0094] Comparative Example 3: Optimized production process of Xiaoer Xiexuening mixture

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

[0096] S5. Nanofiltration membrane concentration: The temperature of the filtrate of Xiaoer Xiexianing mixture was controlled at 30°C. At a pressure of 2.0 MPa, it was concentrated to 15% v / v of the original volume through a nanofiltration membrane filtration system, and then concentrated under reduced pressure (2500 kg / h EJZN-2500 dual-effect energy-saving concentrator) to an extract with a relative density of 1.20-1.22 (70°C); in the nanofiltration membrane filtration system: the pore size of the nanofiltration membrane is 0.5 nm, the area is 216 m 2 , the filtration capacity is 2000kg / h.

[0097] Comparative Example 4: Optimized production process of Xiaoer Xiexuening mixture

[0098] Comparative Example 4 is set with reference to Example 1. The difference between Comparative Example 4 and Example 1 is only 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, and the extract is allowed to stand for 12 hours, and the supernatant is aspirated for use (recorded as supernatant A); the precipitated part is rinsed with 50% v / v ethanol three times, centrifuged at 3000 rpm for 15 minutes, and the supernatant is collected (i.e., supernatant B); supernatant A and supernatant B are combined, and ethanol is recovered to obtain a combined supernatant.

[0100] Comparative Example 5: Optimized production process of Xiaoer Xiexuening mixture

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

[0102] S4, ceramic membrane filtration: The temperature of the extract of Xiaoer Xiexue Ning mixture is controlled at 60°C, and filtered through a ceramic membrane filtration system at a pressure of 0.2Mpa to obtain the filtrate of Xiaoer Xiexue Ning mixture; in the ceramic membrane filtration system: the pore size of the ceramic membrane is 200nm, the area is 46m 2 , the filtration capacity is 2000kg / h.

[0103] S5. Nanofiltration membrane concentration: The temperature of the filtrate of Xiaoer Xiexianing mixture was controlled at 30°C. At a pressure of 2.0 MPa, it was concentrated to 15% v / v of the original volume through a nanofiltration membrane filtration system, and then concentrated under reduced pressure (2500 kg / h EJZN-2500 dual-effect energy-saving concentrator) to an extract with a relative density of 1.20-1.22 (70°C); in the nanofiltration membrane filtration system: the pore size of the nanofiltration membrane is 0.5 nm, the area is 216 m 2 , the filtration capacity is 2000kg / 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, and the extract is allowed to stand for 12 hours, and the supernatant is aspirated for use (recorded as supernatant A); the precipitated part is rinsed with 50% v / v ethanol three times, centrifuged at 3000 rpm for 15 minutes, and the supernatant is collected (i.e., supernatant B); supernatant A and supernatant B are combined, and ethanol is recovered to obtain a combined supernatant.

[0105] Comparative Example 6 Production Process of Xiaoer Xiexuening Mixture

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

[0107] S1. Collect distillate: add 3 times amount of water to 200g of Atractylodes macrocephala, 50g of Patchouli and 50g of Aucklandia lappa and distill at 100℃ for 3h, collect distillate and set aside.

[0108] S2. Collecting decoction: adding water to the residue, 150 g of Codonopsis pilosula, 200 g of Poria cocos, 250 g of Pueraria root and 50 g of Licorice, and decocting twice for 2 hours each time, combining the two decoctions to obtain a combined decoction.

[0109] S3, filtration: after the decoctions are combined, filter them through a Φ400-32 layer plate and frame filter at a rate of 2000kg / h, collect the filtrate, and obtain the extract of Xiaoer Xiexianing mixture.

[0110] S4. The temperature of the filtrate of the Xiaoer Xiexianing mixture is controlled at 30°C, and it is concentrated under reduced pressure (2500kg / h EJZN-2500 double-effect energy-saving concentrator) to an extract with a relative density of 1.20-1.22 (70°C).

[0111] S5. After the extract is cooled, ethanol is added to make the alcohol content reach 50% v / v, the extract is allowed to stand, filtered, and the ethanol is recovered from the filtrate to obtain a filtrate.

[0112] S6. Add 200 g sucrose, 4 g stevia and 3 g preservative to the filtrate, boil to dissolve, filter, add the distillate collected in step S1 to the filtrate, adjust the total amount to 1000 mL with water, stir well, and package to obtain.

[0113] Experimental Example 1 Determination of average membrane flux, turbidity, conductivity and pH of Xiaoer Xiexuening mixture

[0114] The extract of the pediatric diarrhea-relieving mixture prepared in step S3 of Example 1-3 and Comparative Example 1-2 (before ceramic membrane filtration, i.e., concentrated solution) and the filtrate of the pediatric diarrhea-relieving mixture after filtration (after ceramic membrane filtration, i.e., clear solution) were taken to test their membrane flux, turbidity, conductivity, and pH data. The measurement results are shown in Table 3.

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

[0116]

[0117]

[0118] The measurement results show that the conductivity of the membrane filtrate is slightly decreased, and the ions in the extract of the children's diarrhea Ning mixture are also partially retained in the process of transferring to the clear liquid, and the pH is almost unaffected. The average membrane flux of the children's diarrhea Ning mixture filtrate of Examples 1-3 and Comparative Example 1 is above 160L / H, wherein the average membrane flux of the children's diarrhea Ning mixture filtrate of Example 1 is 165.6L / H, and the average membrane flux of the children's diarrhea Ning mixture filtrate of Comparative Example 1 can also reach 174.4L / H, but its turbidity is 2.41NTU. Although the turbidity of Comparative Example 2 can reach 0.18, its membrane flux value is only 132.5L / H, which is relatively low.

[0119] (2) Determination of eluate and filtrate

[0120] Take the extract of Xiao Er Xie Xia Ning mixture prepared in step S3 of Example 1-3 and Comparative Example 1-6 (referred to as the extract); the eluate prepared in step S7 of Example 1-3 and Comparative Example 1-5; and the filtrate prepared in step S5 of Comparative Example 6.

[0121] Table 4 Turbidity, conductivity, pH data

[0122]

[0123]

[0124] From the above results, it can be seen that the turbidity of the eluate prepared in Examples 1-3 is below 0.36 NTU, which is significantly lower than the turbidity of the filtrate prepared by the traditional production process of Xiaoer Xiexuening mixture (Comparative Example 6). Among them, the lowest turbidity in Example 1 is 0.25 NTU.

[0125] Experimental Example 2 Determination of the stability of Xiaoer Xiexuening mixture

[0126] The eluates prepared in Examples 1-3 and Comparative Examples 1-5 and the filtrate prepared in Comparative Example 6 were used as test samples to perform stability tests.

[0127] 1. High temperature test

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

[0129] 2. Strong light irradiation test

[0130] The test sample is placed under an illumination of 4500lx±500lx for 10 days, and samples are taken for testing at 0, 5, and 10 days. During the test, the temperature should be controlled to be consistent with the room temperature, and samples are taken for testing of turbidity at 0, 5, and 10 days.

[0131] 3. Accelerated testing

[0132] The test was conducted at 40℃±2℃, and samples were taken at the end of the 0th, 1st, 2nd, 3rd and 6th month to test the turbidity.

[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 High temperature test and strong light irradiation test results

[0135]

[0136]

[0137] Table 6 Accelerated test results

[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 show that the turbidity of the eluent prepared in Examples 1-3 is below 0.95 NTU after the high temperature test and the strong light irradiation test; and the turbidity is below 1.1 NTU after the accelerated test for 6 months. This shows that the production process of the optimized Xiaoer Xiexie Ning mixture of the present invention can maintain the clarity of the Xiaoer Xiexie Ning 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 of 0 month. However, the turbidity of Comparative Example 1 and Comparative Examples 3-5 increased by 3.81, 2.52, 1.49 and 3.23 NTU respectively after 6 months of accelerated testing compared with that of 0 month.

[0141] The technical effect of Comparative Example 1 was reduced by 0.58 NTU (3.23-3.81) compared with that of Comparative Example 5; the technical effect of Comparative Example 3 was improved by 0.71 NTU (3.23-2.52) compared with that of Comparative Example 5; the technical effect of Comparative Example 4 was improved by 1.74 compared with that of Comparative Example 5. The technical effect of Example 1 of the present invention was improved by 2.53 NTU compared with that of Comparative Example 5. It can be seen that the technical solution of the present invention has a synergistic effect.

[0142] Experimental Example 3 Determination of the effective ingredients of Xiaoer Xiexianning mixture

[0143] 3'-Hydroxypuerarin, puerarin, puerarin apiglycoside and daidzin are the active ingredients of pediatric diarrhea-ning mixture. The effect of the optimized production process of pediatric diarrhea-ning mixture on the active ingredients was investigated by detecting the contents of 3'-hydroxypuerarin, puerarin, puerarin apiglycoside and daidzin in the extract, filtrate and extract of pediatric diarrhea-ning mixture.

[0144] (1) Determination of the active ingredients in the filtrate of Xiaoer Xiexianning mixture

[0145] Take the extract of Xiaoer Xiexue Ning mixture prepared in step S3 of Example 1-3 (before ceramic membrane filtration, i.e., concentrated solution); the filtrate of Xiaoer Xiexue Ning mixture prepared in step S4 (after ceramic membrane filtration, i.e., clear solution), prepare samples, test the content of multiple components, and calculate the transmittance (transmittance % = clear solution / concentrated solution × 100%). The test results are shown in Table 7.

[0146] Table 7 Test results of filtrate of Xiaoer Xiexue Ning mixture

[0147]

[0148] (2) Determination of the active ingredients in the concentrated solution of Xiaoer Xiexianing mixture

[0149] The filtrate of the Xiaoer Xiexianing mixture prepared in step S4 of Example 1-3 (before reverse osmosis membrane concentration, i.e., clear solution) and the concentrated solution prepared in step S5 (after reverse osmosis membrane concentration, i.e., concentrated solution) were taken for sample preparation, multi-component content was tested, and the retention rate was calculated (retention rate % = concentrated solution / clear solution × 100%). The results are shown in Table 8.

[0150] Table 8 Test results of children's diarrhea Ning mixture concentrate

[0151]

[0152]

[0153] (3) Determination of the active ingredients in the eluate of Xiaoer Xiexianning mixture

[0154] The extract of Xiaoer Xiexianing mixture prepared in step S3 of Example 1-3 (before ceramic membrane filtration, i.e., concentrated solution) and the eluate prepared in step S7 (after column chromatography, i.e., clear solution) were used for sample preparation, and the contents of multiple components were tested, and the transmittance was calculated (transmittance % = clear solution / concentrated solution × 100%). The results are shown in Table 9.

[0155] Table 9 Results of determination of eluate from children's diarrhea Ning mixture

[0156]

[0157] The results show that the filtrate, concentrate and eluate of the Xiao'er Xiexia Ning mixture of Examples 1-3 of the present invention did not cause changes in the content of effective ingredients after ceramic membrane filtration, reverse osmosis membrane concentration, separation and purification, and column chromatography, and the component loss was very low.

[0158] Experimental Example 4 Investigation of Residual Substances in Ceramic Membrane

[0159] The filtrate of the Xiao'er Xiexianing mixture prepared in step S4 of Example 1 was sent to a third-party testing agency, and the elemental composition analysis and heavy metal residues 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] By analyzing the elemental composition of the ceramic membrane and detecting the migration of various heavy metals in the ceramic membrane under different conditions, the results show that the risk of heavy metal elements contaminating the raw materials during the ceramic membrane filtration process is controllable and does not affect the product quality. Figure 1 As shown; the fingerprint stacked chromatogram of the filtrate of Xiaoer Xiexue Ning mixture is as follows Figure 2 As shown; the similarity chromatograms of the filtrate of Xiaoer Xiexue Ning mixture before and after ceramic membrane filtration are shown in Figure 3shown.

[0161] Experimental Example 5 Investigation of organic film residual substances

[0162] The concentrated liquid prepared in step S5 of Example 1 is sent to a third-party testing agency for testing of sensory, primary aromatic amine residues, heavy metal residues and other items in accordance with the standards (EU) No10 / 2011 and its amending directive (EU) 2020 / 1245, to examine the migration of aromatic amines, heavy metals, etc. during the organic membrane concentration process.

[0163] Through the testing of the total migration of organic membrane, sensory (smell and taste), specific migration of primary aromatic amines, and specific migration of heavy metals, the results all meet the EU standards, indicating that during the organic membrane concentration process, the contamination risk of heavy metal elements and aromatic amines to the raw materials is controllable and does not affect the product quality. Figure 4 As shown; organic membrane concentration fingerprint stacked chromatogram as shown Figure 5 As shown; the similarity chromatogram of organic membrane concentration is as follows Figure 6 shown.

[0164] The above detailed description is a specific description of one of the feasible embodiments of the present invention, and the embodiment is not intended to limit the scope of the present invention. It should be pointed out that any equivalent implementation or change that does not deviate from the present invention should be included in the scope of the technical solution of the present invention. Therefore, the protection scope of the patent of the present invention shall be based on the attached requirements.

Claims

1. An optimized production process of Xiaoer Xiexianing mixture, characterized in that: The production process comprises the following steps: S1, distilling Atractylodes macrocephala, Patchouli, and Aucklandia lappa with water, collecting the distillate and setting aside; collecting the drug residues, decocting with Codonopsis pilosula, Poria cocos, Pueraria root, and Licorice with water, collecting the decoction and filtering it to obtain the extract of Xiaoer Xiexianing mixture; S2, filtering the extract of the Xiao Xie Ning mixture of children through a membrane filtration system to obtain a filtrate of the Xiao Xie Ning mixture of children; S3, the Xiaoer Xiexianing mixture is filtered through a reverse osmosis membrane concentration system and concentrated to 5%-30% v / v of the original volume, and then concentrated under reduced pressure to obtain an extract; S4, adding ethanol to the extract to make the ethanol content reach 30%-50% v / v, after standing, collecting the supernatant to obtain supernatant A; washing the precipitate with 30%-50% v / v ethanol, centrifuging, collecting the supernatant to obtain supernatant B; combining supernatant A and supernatant B, recovering ethanol, and obtaining a combined supernatant; S5, adding ethanol to the combined supernatants to make the ethanol content reach 60%-70% v / v, letting it stand, filtering, collecting the filtrate, and recovering the ethanol; S6, after the filtrate is adsorbed by a macroporous adsorption resin, it is eluted with water and 30%-50% v / v ethanol in sequence, the 30%-50% v / v ethanol eluate is collected, and the ethanol is recovered to obtain an eluate; In the membrane filtration system described in step S2, the pore size of the membrane is 100 nm.

2. The production process according to claim 1, characterized in that: The membrane filtration system described in step S2 is a ceramic membrane filtration system, and the area of ​​the ceramic membrane is 40-50m 2 ; The filtration capacity of ceramic membrane is 1000-3000kg / h.

3. The production process according to claim 1, characterized in that: 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 ​​the reverse osmosis membrane is about 200-250 m 2 ; The reverse osmosis membrane filtration capacity is 1000-3000kg / h.

4. The production process according to claim 1, characterized in that: In the membrane filtration system described in step S2, the inlet liquid temperature is 50-65°C and the membrane outlet pressure is 0.15-0.3Mpa; in the reverse osmosis membrane concentration system described in step S3, the inlet liquid temperature is 20-40°C and the membrane outlet pressure is 1.5-3.0Mpa.

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

6. The production process according to claim 1, characterized in that: The reduced pressure concentration in step S3 includes one or more of reduced pressure distillation concentration, vacuum freeze drying concentration, reduced pressure concentrator concentration, and reduced pressure evaporation crystallization concentration.

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

8. The production process according to claim 1, characterized in that: The production process also includes the following steps: S7. Add auxiliary materials to the eluate of step S6 and boil to dissolve, collect the filtrate by filtration, combine the filtrate with the distillate of step S1, add water, stir well, and obtain the Xiao'er Xiexianing mixture.

9. Use of the production process according to any one of claims 1 to 8 in the preparation of Xiaoer Xiexianing mixture.

10. The Xiaoer Xiexianing mixture prepared by the production process described in any one of claims 1 to 8.

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