Production process and application of Pediatric Cold Relief Mixture

Abstract

This invention belongs to the field of biomedical technology, specifically relating to the production process and application of a children's cold remedy. The production process includes filtration and concentration; both filtration and concentration are performed twice, with filtration and concentration sequentially using a plate and frame filter and a ceramic membrane filter, and the concentration sequentially using a reverse osmosis membrane and a reduced-pressure concentration. The method provided by this invention improves filtration efficiency, reduces energy consumption during concentration, and lowers production costs while ensuring that drug quality is not affected.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to the production process and application of Xiaor Ganmaoling Mixture. Background Technology

[0002] Children's bodies are not yet fully developed, their immune systems are relatively weak, and their resistance to disease is lower. Therefore, they often exhibit different symptoms when they have a cold compared to adults, and their condition may progress more rapidly. Pediatric Cold Relief Mixture is formulated specifically for children's constitution and can more effectively relieve symptoms of wind-heat colds in children, such as fever, cough, and sore throat. Compared to Western medicine, traditional Chinese medicine generally has a higher safety profile. Pediatric Cold Relief Mixture is composed of various Chinese medicinal herbs, scientifically formulated and carefully processed to reduce the occurrence of side effects. Furthermore, its dosage is adjusted according to the child's age and weight to ensure medication safety. Therefore, Pediatric Cold Relief Mixture plays an important role in the treatment of colds in children. Its characteristics of being tailored to children's constitution, high safety, and definite efficacy make it one of the important medications for treating colds in children.

[0003] Xiaor Ganmaoling Mixture is a product manufactured by Jiangxi Puzheng Pharmaceutical Co., Ltd. This medicine is a traditional Chinese medicine compound preparation made from peppermint, schizonepeta, bitter almond, burdock fruit, scutellaria, platycodon, angelica, angelica root, gardenia (fried), hawthorn (charred), medicated leaven (charred), malt (charred), reed rhizome, honeysuckle, and forsythia. The specific formula is as follows: peppermint 80g, schizonepeta 67g, bitter almond 80g, burdock fruit 80g, scutellaria 80g, platycodon 67g, angelica root 80g, angelica root 27g, gardenia (fried) 40g, hawthorn (charred) 27g, medicated leaven (charred) 27g, malt (charred) 27g, reed rhizome 120g, honeysuckle 120g, and forsythia 80g. The preparation method is as follows: Of the 15 ingredients listed above, except for peppermint and catnip spikes (for extracting volatile oil) and bitter almonds (for preparing bitter almond water), the remaining 12 ingredients, including burdock seed, are decocted twice with water, the first time for 2 hours and the second time for 1 hour. The decoctions are filtered, the filtrates are combined, and the mixture is allowed to stand for 48 hours. The supernatant is then concentrated to a suitable volume. 200g of sucrose, 2g of stevioside, and 5g of sodium benzoate are added and boiled to dissolve them. The almond water is then added and mixed well. The mixture is allowed to stand, and the supernatant is collected. Volatile oil and flavorings are added while stirring. Water is added to a final volume of 1000mL, stirred well, filtered, and then packaged. The original production process used traditional sieve filtration and vacuum concentration, which frequently resulted in unsatisfactory filtration effects and high energy consumption during vacuum concentration.

[0004] Therefore, there is an urgent need to provide a preparation process to improve clarity and save energy, thereby improving the overall product quality. Summary of the Invention

[0005] To address the aforementioned problems, this invention provides a manufacturing process for a children's cold remedy, which not only improves the clarity of the drug but also has the advantage of saving energy.

[0006] On one hand, the present invention provides a production process for a children's cold remedy, the production process including filtration and concentration; the filtration includes plate and frame filtration and ceramic membrane filtration; the concentration includes reverse osmosis membrane concentration and vacuum concentration.

[0007] Specifically, the pore size of the ceramic membrane filter is 5-200 nm.

[0008] More specifically, the ceramic membrane filter has a pore size of 100 nm.

[0009] Specifically, it includes the following steps:

[0010] S1. Extraction of volatile oils: Extracting volatile oils from peppermint and catnip spikes using steam distillation;

[0011] S2. Extracting bitter almond water: Extracting bitter almond water from bitter almonds using steam distillation;

[0012] S3. Decoction: Add water to burdock fruit, scutellaria, platycodon, angelica, angelica dahurica, gardenia, hawthorn, medicated leaven, malt, reed rhizome, honeysuckle and forsythia and decoct twice, the first time for 2 hours and the second time for 1 hour to obtain the decoction.

[0013] S4. Filtration: The above decoction is filtered sequentially using the aforementioned filtration method to obtain filtrate;

[0014] S5. Concentration: The above-mentioned filtrate is concentrated sequentially using the concentration method described above to obtain a thick paste;

[0015] S6. Preparation: Add sucrose, stevia and sodium benzoate to the above thick paste, boil to dissolve, add the above bitter almond water, mix well, let stand, take the supernatant, add the above volatile oil and fragrance, mix well, filter, and the product is obtained.

[0016] Specifically, the decoction steps consist of the following components: S3, Decoction: Burdock fruit, Scutellaria baicalensis, Platycodon grandiflorus, Peucedanum praeruptorum, Angelica dahurica, Gardenia jasminoides (fried), Crataegus pinnatifida (charred), Shenqu (charred), Malt (charred), Phragmites communis, Lonicera japonica, and Forsythia suspensa.

[0017] Specifically, the plate and frame filter uses a plate and frame filter.

[0018] More specifically, the plate and frame filter can have 20-35 filter layers and a water flow rate of 1500-2000 kg / h.

[0019] Preferably, the plate and frame filter is used; the plate and frame filter can have 32 filter layers and a water flow rate of 2000 kg / h.

[0020] Specifically, the ceramic membrane filtration uses a ceramic membrane filter.

[0021] More specifically, the ceramic membrane module of the ceramic membrane filter has a size of 30-60mm; the ceramic membrane filtration capacity is 1000-3000kg / h.

[0022] Preferably, the ceramic membrane module has a size of 50 mm and a filtration capacity of 2000 kg / h.

[0023] Specifically, the permeate membrane concentration uses a reverse osmosis membrane concentrator.

[0024] More specifically, the reverse osmosis membrane concentrator has a reverse osmosis membrane module size of 2540 (2.5×40 inches)-8040 (8×40 inches); and a reverse osmosis membrane filtration capacity of 1000-3000 kg / h.

[0025] Preferably, the reverse osmosis membrane module of the reverse osmosis membrane concentrator is 8040 (8×40 inches) in size; the reverse osmosis membrane filtration capacity is 2000 kg / h.

[0026] Specifically, the reduced pressure concentration includes, but is not limited to, using a double-effect concentrator, a spherical concentrator, a single-effect concentrator, or a flash concentrator.

[0027] More specifically, the reduced pressure concentration uses a double-effect concentrator.

[0028] Preferably, the double-effect concentrator has a processing capacity of 2000-3000 kg / h.

[0029] More preferably, the double-effect concentrator has a processing capacity of 2500 kg / h.

[0030] On the one hand, the present invention provides the application of the aforementioned production and preparation process in the preparation of Pediatric Cold Relief Mixture.

[0031] The technical effects achieved by this invention are as follows:

[0032] Compared to existing technologies, the preparation process provided by this invention adds filtration and concentration methods to the filtration and concentration process. It changes the traditional screen filtration and vacuum concentration to a process where screen filtration is followed by ceramic membrane filtration, and organic membrane concentration is added before vacuum concentration. Research results show that while the membrane filtration method changes, it has virtually no impact on the material composition. The membrane concentration method adds a concentration step, and research results indicate that it does not affect product quality. This preparation process not only improves filtration efficiency but also reduces energy costs associated with concentration, meeting overall formulation requirements and reducing production cost budgets. Attached Figure Description

[0033] Figure 1 The images show the total ion current chromatogram and ultraviolet chromatogram of Xiaor Ganmaoling Mixture. In the images, A represents the negative ion mode TIC; B represents the positive ion mode TIC; and C represents the 280 nm ultraviolet chromatogram.

[0034] Figure 2 This is the HPLC chromatogram of Xiaor Ganmaoling Mixture.

[0035] Figure 3 This is the HPLC chromatogram of the medicinal herb *Schizonepeta tenuifolia*.

[0036] Figure 4 This is the HPLC chromatogram of burdock seed.

[0037] Figure 5 This is the HPLC chromatogram of Scutellaria baicalensis.

[0038] Figure 6 This is the HPLC chromatogram of Platycodon grandiflorus.

[0039] Figure 7 The image shows the HPLC chromatogram of the herb *Peucedanum praeruptorum*.

[0040] Figure 8 The HPLC chromatogram of Gardenia (fried) medicinal material.

[0041] Figure 9 This is the HPLC chromatogram of Angelica dahurica.

[0042] Figure 10 The HPLC chromatogram of hawthorn (charred) medicinal material.

[0043] Figure 11 This is the HPLC chromatogram of reed rhizome.

[0044] Figure 12 This is the HPLC chromatogram of honeysuckle.

[0045] Figure 13 This is the HPLC chromatogram of Forsythia suspensa.

[0046] Figure 14The image shows the chromatogram before the ceramic membrane passes through it, where A represents a wavelength of 327 nm and B represents a wavelength of 239 nm.

[0047] Figure 15 The image shows the chromatogram after passing through the ceramic membrane, where A represents a wavelength of 327 nm and B represents a wavelength of 239 nm.

[0048] Figure 16 Stacked chromatograms of fingerprint patterns for ceramic membrane filtration.

[0049] Figure 17 This is a chromatogram showing the similarity of ceramic membrane filtration.

[0050] Figure 18 The image shows the chromatogram of the organic membrane before it passes through the membrane, where A is at a wavelength of 327 nm and B is at a wavelength of 239 nm.

[0051] Figure 19 The image shows the chromatogram after passing the organic membrane through the membrane, where A represents a wavelength of 327 nm and B represents a wavelength of 239 nm.

[0052] Figure 20 This is a stacked chromatogram of concentrated fingerprints from organic membranes.

[0053] Figure 21 This is a chromatogram showing the similarity of organic membrane concentration. Detailed Implementation

[0054] The present invention will be further described in detail below with reference to specific embodiments. The following embodiments are not intended to limit the present invention, but only to illustrate the present invention. Unless otherwise specified, the experimental methods used in the following embodiments are generally performed under conventional conditions. Unless otherwise specified, the materials and reagents used in the following embodiments are commercially available.

[0055] Example 1

[0056] This embodiment provides a production process for a children's cold remedy, the specific steps of which are shown in Table 1:

[0057] Table 1

[0058]

[0059]

[0060]

[0061] Example 2: Material Basis Research

[0062] The material basis and main component structure of the Xiaogan Ganmaoling compound were determined through mass spectrometry and other operations.

[0063] 2.1 Sample Information

[0064] The pediatric cold remedy was prepared using the method described in Example 1.

[0065] 2.2 Instruments and Equipment

[0066] Sample analysis was performed using a Thermo Fisher Scientific HPLC-Q-Exactive Orbitrap-MS high-resolution liquid chromatography-mass spectrometry system. The instrument error after calibration was <5 ppm. Data acquisition was conducted using a positive / negative ion switching mode. Xcalibur 2.1 software was used for data acquisition.

[0067] 2.3 Chromatographic conditions

[0068] Chromatographic column: BEH C18 column (2.1×150mm, 2.5μm)

[0069] Chromatographic gradient: Phase A is 0.1% formic acid aqueous solution, Phase B is 0.1% formic acid acetonitrile solution, flow rate 0.3 mL / min. -1 The column temperature was 40℃, the detection wavelength was 280nm, the injection volume was 5μL, and the gradient elution conditions are shown in Table 2.

[0070] Table 2

[0071] Time (min) Flow rate (mL / min) Phase A (%) Phase B (%) 0 0.3 95 5 20 0.3 5 95 45 0.3 5 95 60 0.3 95 5

[0072] 2.4 Mass Spectrometry Conditions

[0073] Electrospray ionization (ESI) source employed both positive and negative ion modes for data acquisition. Ordinary nitrogen was used as the auxiliary and sheath gas, and high-purity nitrogen as the collision gas. Full MS / dd-MS2 (Top3) was used for simultaneous positive and negative ion acquisition, triggering a secondary scan of the top three strongest precursor ions. The collision energies (NCE) were set to 2, 40, and 60. Specific mass spectrometry parameters are shown in Table 3.

[0074] Table 3

[0075]

[0076]

[0077] 2.5 Data Analysis Methods

[0078] The data processing software used was Xcalibur 2.1 and Compound Discoverer 3.1. High-resolution quasi-molecular ion and secondary fragment information was acquired using Xcalibur 2.1 and imported into Compound Discoverer 3.1 for analysis. Chromatographic peaks were inferred and identified using the local library mzVault (containing mass spectrometry data of over 1200 traditional Chinese medicine reference standards), the online library mz cloud, a self-built database, and online websites such as chemspider and pubchem.

[0079] 2.6 Research Results

[0080] The components of Xiaor Ganmaoling Mixture were analyzed using reversed-phase column chromatography. Total ion chromatograms and ultraviolet (UV) chromatograms (280 nm) of each component were acquired using Q-Exactive Orbitrap-MS. Positive ion mode, negative ion mode acquisition, and 280 nm UV chromatograms were obtained (see...). Figure 1 (A, B, and C in the table). Based on the obtained high-precision quasi-molecular ion and secondary fragment information, and through analysis of the fragmentation patterns combined with relevant references and comparisons with some reference standards, a total of 23 chemical components were identified or inferred. The retention time, compound name, molecular formula, high-resolution mass spectrometry parent ion, and fragment ion information of the chemical components are shown in Table 4.

[0081] Table 4. Identification and Attribution of Positive and Negative Ion Patterns in Pediatric Cold Relief Mixture Based on Q-Exactive Orbitrap-MS

[0082]

[0083]

[0084]

[0085] Example 3: Correlation Study between Pediatric Cold Relief Mixture and Herbal Materials

[0086] The correlation between medicinal materials and finished products was studied by using positive control tests of medicinal materials. The retention time and peak shape of each peak were compared and considered. The full wavelength scanning function of PDA diode array detector was used to compare and study the ultraviolet spectral characteristics of the corresponding chromatographic peaks and determine the medicinal material attribution of each major chromatographic peak.

[0087] (1) Preparation of test solution: Accurately measure 2 mL of the pediatric cold medicine prepared in Example 1, place it in a 50 mL volumetric flask, dilute with methanol to the mark, shake well, centrifuge the solution at high speed for 15 minutes at 15000 rpm, and take the supernatant to obtain the solution.

[0088] (2) Preparation of test solution of peppermint medicinal material: Weigh 2 kg of peppermint medicinal material, add 20 L of water, and extract the volatile oil to obtain the solution.

[0089] (3) Preparation of test solution of Schizonepeta tenuifolia spike: Weigh 2 kg of Schizonepeta tenuifolia spike, add 20 L of water, and extract the volatile oil to obtain the solution.

[0090] (4) Preparation of bitter almond medicinal material test solution: Weigh 80g of bitter almonds, press to remove oil, add five times the amount of water, soak at 37℃ for 3 hours, steam distill the soaking liquid, collect the distillate to 60mL with 20mL of 90% ethanol solution, filter, seal and store to obtain the solution.

[0091] (5) Preparation of burdock seed test solution: Weigh 80g of burdock seed, add 6 times the amount of water and decoct twice, the first time for 2 hours and the second time for 1 hour. Filter out the decoction, combine the filtrates, let stand for 48 hours, take the supernatant, concentrate to an appropriate amount, and that is the test solution.

[0092] (6) Preparation of Scutellaria baicalensis test solution: Weigh 80g of Scutellaria baicalensis, add 6 times the amount of water and decoct twice, the first time for 2 hours and the second time for 1 hour. Filter out the decoction, combine the filtrates, let stand for 48 hours, take the supernatant, concentrate to an appropriate amount, and that is the test solution.

[0093] (7) Preparation of Platycodon grandiflorus test solution: Weigh 67g of Platycodon grandiflorus, add 6 times the amount of water and decoct twice, the first time for 2 hours and the second time for 1 hour. Filter out the decoction, combine the filtrates, let stand for 48 hours, take the supernatant, and concentrate to an appropriate amount to obtain the test solution.

[0094] (8) Preparation of test solution of Peucedanum praeruptorum: Weigh 80g of Peucedanum praeruptorum, add 6 times the amount of water and decoct twice, the first time for 2 hours and the second time for 1 hour. Filter out the decoction, combine the filtrates, let stand for 48 hours, take the supernatant, concentrate to an appropriate amount, and that is the test solution.

[0095] (9) Preparation of Angelica dahurica test solution: Weigh 27g of Angelica dahurica, add 6 times the amount of water and decoct twice, the first time for 2 hours and the second time for 1 hour. Filter out the decoction, combine the filtrates, let stand for 48 hours, take the supernatant, concentrate to an appropriate amount, and that is the test solution.

[0096] (10) Preparation of Gardenia (fried) medicinal material test solution: Weigh 40g of Gardenia medicinal material, add 6 times the amount of water and decoct twice, the first time for 2 hours and the second time for 1 hour. Filter out the decoction, combine the filtrates, let stand for 48 hours, take the supernatant, concentrate to an appropriate amount, and that is the test solution.

[0097] (11) Preparation of hawthorn (charred) medicinal material test solution:

[0098] Weigh 27g of hawthorn, add 6 times the amount of water and decoct twice, the first time for 2 hours and the second time for 1 hour. Filter the decoction, combine the filtrates, let stand for 48 hours, take the supernatant, and concentrate to an appropriate amount.

[0099] (12) Preparation of test solution of Shenqu (charred) medicinal material: Weigh 27g of Shenqu medicinal material, add 6 times the amount of water and decoct twice, the first time for 2 hours and the second time for 1 hour. Filter out the decoction, combine the filtrates, let stand for 48 hours, take the supernatant, concentrate to an appropriate amount, and that is the test solution.

[0100] (13) Preparation of malt (charred) medicinal material test solution: Weigh 27g of malt medicinal material, add 6 times the amount of water and decoct twice, the first time for 2 hours and the second time for 1 hour. Filter out the decoction, combine the filtrates, let stand for 48 hours, take the supernatant, concentrate to an appropriate amount, and that is the test solution.

[0101] (14) Preparation of test solution of reed rhizome medicinal material: Weigh 120g of reed rhizome medicinal material, add 6 times the amount of water and decoct twice, the first time for 2 hours and the second time for 1 hour. Filter out the decoction, combine the filtrates, let stand for 48 hours, take the supernatant, concentrate to an appropriate amount, and that is the test solution.

[0102] (15) Preparation of honeysuckle medicinal material test solution: Weigh 120g of honeysuckle medicinal material, add 6 times the amount of water and decoct twice, the first time for 2 hours and the second time for 1 hour. Filter out the decoction, combine the filtrates, let stand for 48 hours, take the supernatant, concentrate to an appropriate amount, and that is the test solution.

[0103] (16) Preparation of Forsythia suspensa test solution: Weigh 80g of Forsythia suspensa, add 6 times the amount of water and decoct twice, the first time for 2 hours and the second time for 1 hour. Filter out the decoction, combine the filtrates, let stand for 48 hours, take the supernatant, concentrate to an appropriate amount, and that is the test solution.

[0104] Precisely pipette 10 μL of the following samples for testing: Peppermint, Schizonepeta tenuifolia, Bitter Almond, Arctium lappa, Scutellaria baicalensis, Platycodon grandiflorus, Peucedanum praeruptorum, Gardenia jasminoides (fried), Angelica dahurica, Crataegus pinnatifida (charred), Massa fermentata (charred), Malt (charred), Phragmites communis, Lonicera japonica, and Forsythia suspensa. Compare the samples under identical conditions to determine peak assignment.

[0105] The results showed that, by comparing retention time and peak shape UV spectral characteristics, there was no obvious peak attribution relationship between the common peaks in Xiaoganmaoling compound and the peaks of peppermint, bitter almond, shenqu (charred) and malt (charred) herbs.

[0106] The HPLC chromatogram of Pediatric Cold Relief Mixture is shown below. Figure 2 Peaks 12 and 14 in the Pediatric Cold Relief Mixture were identified as originating from the medicinal herb *Schizonepeta tenuifolia* (Nyctaginata). Figure 3 Peaks 1, 2, 3, 6, 7, 8, and 11 are derived from burdock seed medicinal material. Figure 4 Peaks 10, 12, and 13 are derived from Scutellaria baicalensis (Scutellaria baicalensis). Figure 5 Peak 10 comes from the medicinal herb Platycodon grandiflorus ( ); Figure 6Peak 5 comes from the medicinal herb Peucedanum praeruptorum ( ); Figure 7 Peaks 4 and 9 are derived from gardenia (fried) medicinal materials. Figure 8 Peaks 12 and 14 are derived from Angelica dahurica (a type of medicinal herb). Figure 9 Peak 10 comes from hawthorn (charred) medicinal materials. Figure 10 Peak 5 comes from reed rhizome medicinal material ( Figure 11 Peaks 1, 2, 6, 7, and 8 are derived from honeysuckle medicinal materials. Figure 12 Peak 5 comes from Forsythia suspensa medicinal material ( Figure 13 ).

[0107] In summary, peak 3 in the Pediatric Cold Relief Mixture comes from Arctium lappa; peaks 4 and 9 come from Gardenia jasminoides (fried); peak 13 comes from Scutellaria baicalensis; peaks 1, 2, 6, 7, and 8 come from Arctium lappa and Lonicera japonica; peak 5 comes from Peucedanum praeruptorum, Phragmites communis, and Forsythia suspensa; peak 10 comes from Scutellaria baicalensis, Platycodon grandiflorus, and Crataegus pinnatifida (fried); peak 11 comes from Arctium lappa and Angelica dahurica; peak 12 comes from Schizonepeta tenuifolia and Scutellaria baicalensis; and peak 14 comes from Schizonepeta tenuifolia and Angelica dahurica. Furthermore, there is no clear peak attribution relationship between the HPLC-shared peaks of Prunus armeniaca, Shenqu (fried), Malt (fried), and Mentha haplocalyx and the Pediatric Cold Relief Mixture.

[0108] Example 4: Effect of ceramic membrane filtration process on children's cold remedy.

[0109] 4.1 Investigation of Residual Substances in Ceramic Membranes

[0110] By sending samples to a third-party testing institution, the elemental composition analysis and heavy metal residue of the ceramic membrane were tested according to the XRF testing method and GB 31604.49-2016 to examine the migration of heavy metals during the ceramic membrane filtration process.

[0111] 4.1.1 Ceramic Membrane Elements

[0112] Ceramic membrane-30, ceramic membrane-40, and ceramic membrane-50 represent membrane tube sizes of 30mm, 40mm, and 50mm, respectively.

[0113] The analysis results are shown in Table 5:

[0114] Table 5

[0115]

[0116] 4.1.2 Investigation of Heavy Metal Migration

[0117] The migration of heavy metals was detected in ceramic membranes-30, ceramic membrane-40, and ceramic membrane-50 under 10 simulated conditions.

[0118] The testing items are shown in Table 6:

[0119] Table 6

[0120] Measurement items Method detection limit unit Arsenic (As) 0.03 mg / kg Cadmium (Cd) 0.003 mg / kg Chromium (Cr) 0.03 mg / kg Nickel(NI) 0.006 mg / kg Lead (Pb) 0.03 mg / kg Antimony (Sb) 0.01 mg / kg Zinc (Zn) 0.06 mg / kg

[0121] Simulation conditions:

[0122] (1) 1% citric acid; detection conditions: 98℃, 120min.

[0123] (2) 1% citric acid; detection conditions: 22℃, 24h.

[0124] (3) 5% citric acid; detection conditions: 98℃, 120min.

[0125] (4) 5% citric acid; detection conditions: 22℃, 24h.

[0126] (5) 10% citric acid; detection conditions: 98℃, 120min.

[0127] (6) 10% citric acid; detection conditions: 22℃, 24h.

[0128] (7) 20% citric acid; detection conditions: 98℃, 120min.

[0129] (8) 20% citric acid; detection conditions: 22℃, 24h.

[0130] (9) 95% ethanol; detection conditions: 98℃, 120min.

[0131] (10) 95% ethanol; detection conditions: 22℃, 24h.

[0132] The migration of various heavy metals in the ceramic membrane was not detected under different conditions. The results show that the risk of heavy metal contamination of raw materials during ceramic membrane filtration is controllable and does not affect product quality.

[0133] 4.2 The Influence of Ceramic Membrane Filtration Technology on the Material Basis of Pediatric Cold Relief Mixture

[0134] The concentrated and clear extracts prepared in Example 1 were used to examine indicators such as solid content, multi-component content, fingerprint spectrum, pH, turbidity, conductivity, and membrane flux.

[0135] 4.2.1 Research Materials

[0136] The extract of Xiaor Ganmaoling compound was prepared according to Example 1; sodium hydroxide, AR grade, Inner Mongolia Junzheng Energy Chemical Co., Ltd.; citric acid, AR grade, Guangzhou Keqi Biotechnology Co., Ltd.; methanol and acetonitrile, HPLC grade, Merck Chemical Technology (Shanghai) Co., Ltd.; phosphoric acid, hydrochloric acid, and acetic acid, AR grade, Jiangxi Hengxin Chemical Co., Ltd.; reference solution, prepared in the laboratory (reference standard, National Institutes for Food and Drug Control).

[0137] 4.2.2 Instruments

[0138] See Table 7:

[0139] Table 7

[0140]

[0141] 4.2.3 Investigation of Membrane Flux in Ceramic Membrane Filtration Process

[0142] The ceramic membrane filtration is 10 times more efficient, with an average membrane flux of 316.0 L / H.

[0143] 4.2.4 Investigation of Basic Parameters of Ceramic Membrane Filtration Process

[0144] The results are shown in Table 8:

[0145] Table 8. Investigation of Basic Parameters of Ceramic Membrane Filtration Process

[0146]

[0147]

[0148] 4.2.5 Investigation on the determination of multiple components in ceramic membrane filtration process

[0149] The results are shown in Table 9, where 01, 02, and 03 represent three batches; the chromatograms before and after ceramic membrane filtration are shown in Table 9. Figures 14-15 .

[0150] Table 9. Investigation of Multi-Component Content Determination in Ceramic Membrane Filtration Process

[0151]

[0152] 4.2.6 Solid content analysis of ceramic membrane filtration process

[0153] The results are shown in Table 10:

[0154] Table 10 Solid Content Analysis of Ceramic Membrane Filtration Process

[0155]

[0156] 4.2.7 Examination of fingerprint patterns in ceramic membrane filtration

[0157] The results are shown in Table 11. The stacked chromatogram of the ceramic membrane filtration fingerprint is shown in [Table 11]. Figure 16 The chromatogram of similarity for ceramic membrane filtration is shown below. Figure 17 .

[0158] Table 11. Fingerprint analysis of ceramic membrane filtration.

[0159] 01 before membrane coating 02 before membrane coating 03 before membrane coating 01 after coating After coating 02 03 after coating 01 before membrane coating 1.000 1.000 1.000 1.000 1.000 0.997 02 before membrane coating 1.000 1.000 1.000 1.000 1.000 0.997 03 before membrane coating 1.000 1.000 1.000 1.000 1.000 0.997 01 after coating 1.000 1.000 1.000 1.000 1.000 0.997 After coating 02 1.000 1.000 1.000 1.000 1.000 0.997 03 after coating 0.997 0.997 0.997 0.997 0.997 1.000

[0160] In summary, the fingerprinting and multi-component content determination results of the drug solution before and after the change in ceramic membrane filtration process (i.e., before and after using a 100nm ceramic membrane for filtration) indicate that the change in membrane filtration did not cause any change in the medicinal material basis of this product, and the component loss was very low. Meanwhile, the data on solid content and turbidity show that while maintaining the material basis, membrane filtration played a certain role in impurity removal, improving product clarity and meeting the requirements for stable quality control.

[0161] Example 5: Effect of Organic Membrane (Reverse Osmosis Membrane) Concentration Process on Pediatric Cold Relief Mixture

[0162] 5.1 Investigation of organic membrane residues

[0163] By sending samples to a third-party testing institution, the sensory properties, primary aromatic amine residues, and heavy metal residues were tested according to (EU) No. 10 / 2011 and its amendment directive (EU) 2020 / 1245, to examine the migration of aromatic amines and heavy metals during the organic membrane concentration process.

[0164] (1) The total migration is shown in Table 12:

[0165] Table 12

[0166]

[0167] (2) Sensory testing results are shown in Table 13:

[0168] Table 13

[0169]

[0170] (3) The migration amount of primary aromatic amines is shown in Table 14:

[0171] Simulation conditions: 3% acetic acid, 60℃, 240h.

[0172] Table 14

[0173]

[0174] (4) Heavy metal migration scale 15:

[0175] Simulation conditions: 3% acetic acid, 60℃, 240h.

[0176] Table 15

[0177]

[0178]

[0179] Summary: As shown in the test report, the results of tests on several indicators, including total migration of organic membrane, sensory (odor and taste), specific migration of primary aromatic amines, and specific migration of heavy metals, all met EU standards. This indicates 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.

[0180] 5.2 The Influence of Organic Membrane Concentration Process on the Material Basis of Pediatric Cold Relief Mixture

[0181] The concentrated solution and clear solution prepared in Example 1 were taken and examined for indicators such as solid content, multi-component content, fingerprint spectrum, pH, turbidity, conductivity, and membrane flux.

[0182] 5.2.1 Research Materials

[0183] The extract of Pediatric Cold Relief Compound was prepared using the method described in Example 1; sodium hydroxide, AR grade, Inner Mongolia Junzheng Energy Chemical Co., Ltd.; citric acid, AR grade, Guangzhou Keqi Biotechnology Co., Ltd.; methanol and acetonitrile, HPLC grade, Merck Chemical Technology (Shanghai) Co., Ltd.; phosphoric acid, hydrochloric acid, and acetic acid, AR grade, Jiangxi Hengxin Chemical Co., Ltd.; and reference solution, prepared in the laboratory (reference standard, National Institutes for Food and Drug Control).

[0184] 5.2.2 Instruments

[0185] See Table 16:

[0186] Table 16

[0187] category model company High Performance Liquid Chromatography Waters e2695 Waters Technology (Shanghai) Co., Ltd. Electronic balance LS220A Mettler Toledo International Trading (Shanghai) Co., Ltd. conductivity meter ST300C Ohaus International Trading (Shanghai) Co., Ltd. Turbidity meter WZB-175 Shanghai Instrument & Electronics Scientific Instruments Co., Ltd. pH meter pHB-H Shanghai Instrument & Electronics Scientific Instruments Co., Ltd. Pure water machine AZX-2100-300B4 Shenzhen Angel Industrial Co., Ltd. Organic membrane pilot plant 8040-190033 Nanjing Membrane Materials Industry Technology Research Institute Co., Ltd.

[0188] 5.2.3 Investigation of Membrane Flux in Organic Membrane Concentration Process

[0189] The organic membrane was concentrated 5 times, and the average membrane flux was 343.0 L / H.

[0190] 5.2.4 Investigation of Basic Parameters of Organic Membrane Concentration Process

[0191] The results are shown in Table 17:

[0192] Table 17 Investigation of Basic Parameters of Organic Membrane Concentration Process

[0193]

[0194]

[0195] 5.2.5 Investigation on the determination of multiple component contents in organic membrane concentration process

[0196] The results are shown in Table 18. The chromatograms of the organic membrane before and after membrane transfer are shown in Table 18. Figures 18-19 .

[0197] Table 18 Investigation of Multi-Component Content Determination in Organic Membrane Concentration Process

[0198]

[0199] 5.2.6 Solid content analysis of organic membrane concentration process

[0200] The results are shown in Table 19:

[0201] Table 19 Solid Content Analysis of Organic Membrane Concentration Process

[0202]

[0203]

[0204] 5.2.7 Examination of fingerprint patterns before and after organic membrane concentration

[0205] The results are shown in Table 20. The stacked chromatograms of organic membrane concentration fingerprints and the organic membrane concentration similarity chromatograms are shown in Table 20. Figures 20-21 .

[0206] Table 20. Fingerprint patterns of organic membranes before and after concentration.

[0207] 01 before membrane coating 02 before membrane coating 03 before membrane coating 01 after coating After coating 02 03 after coating 01 after coating 1.000 0.999 1.000 0.999 0.999 1.000 After coating 02 0.999 1.000 1.000 1.000 1.000 1.000 03 after coating 1.000 1.000 1.000 0.999 1.000 1.000 01 after coating 0.999 1.000 0.999 1.000 0.999 0.999 After coating 02 0.999 1.000 1.000 0.999 1.000 1.000 03 after coating 0.999 1.000 1.000 0.999 1.000 1.000

[0208] The addition of a reverse osmosis organic membrane before the original concentration process, along with measurements of multiple components and solids content in the concentrate, showed that the change to membrane concentration did not alter the pharmaceutical material basis of the product, and component loss was almost negligible. Furthermore, compared to traditional concentration methods, membrane concentration is more efficient and less costly, effectively alleviating the energy consumption problem of the concentration process.

[0209] Comparative Example 1

[0210] The ceramic membrane pore sizes in Example 1 were replaced with 200nm, 100nm, 15nm, 10nm, and 5nm, respectively. For the same batch of pediatric cold medicine extract, under the same experimental conditions, the average membrane flux, pH, turbidity, conductivity, and other data of the membrane filtrate with different membrane pore sizes were examined.

[0211] 1. Experimental Design

[0212] 1000L of the extracted pediatric cold medicine mixture was filtered sequentially through ceramic membranes with pore sizes of 200nm, 100nm, 15nm, 10nm, and 5nm under specific experimental parameters. Membrane flux was monitored throughout the process, the average membrane flux was calculated, and the turbidity, conductivity, pH, and other data of the extract and the filtrate were tested online.

[0213] 2. Experimental apparatus is shown in Table 21:

[0214] Table 21

[0215]

[0216]

[0217] 3. Experimental parameters

[0218] Ceramic membrane equipment frequency: 45Hz, pressure: 0.2MPa, raw solution temperature: 60℃, total amount of drug solution: 1000L, ceramic membrane pore size: 200nm / 100nm / 15nm / 10nm / 5nm.

[0219] 4. Experimental Results

[0220] The results are shown in Table 22:

[0221] Table 22

[0222]

[0223] Comparison of the above data shows that the conductivity of the filtrate decreased slightly, and some ions in the feed solution were also retained during the transfer to the supernatant. The performance of the different membrane specifications was not significantly different, and the pH was almost unaffected. The 200nm ceramic membrane had the highest average membrane flux, but the filtrate turbidity was also relatively high, indicating a weaker impurity trapping effect. The 100nm membrane balanced impurity removal with high flux, resulting in a high overall membrane filtration efficiency. Therefore, the 100nm ceramic membrane was selected as the material for the membrane filtration process.

[0224] Comparative Example 2

[0225] The reverse osmosis membrane in Example 1 was replaced with a nanofiltration membrane. For the same batch of children's cold medicine ceramic membrane filtrate, under the same experimental conditions, the average membrane flux, pH, turbidity, conductivity and other data of the membrane concentrate were examined by different types of organic membranes.

[0226] 1. Experimental Design

[0227] 1000L of pediatric cold medicine filtrate that had passed through a ceramic membrane was concentrated by passing it through a nano-membrane organic membrane and a reverse osmosis organic membrane under specific experimental parameters. The concentration was increased by a total of 5 times. Membrane flux was recorded throughout the process according to the concentration factor, and the turbidity, conductivity, pH and other data of the concentrated stock solution and the filtered solution were tested online.

[0228] 2. Experimental parameters

[0229] Organic membrane size: 8040, frequency: 45Hz, pressure: 2MPa, feed solution temperature: 30℃, total chemical solution volume: 1000L, organic membrane type: nanofiltration membrane / reverse osmosis membrane. Nanofiltration organic membrane (Nanjing Membrane Materials Industry Technology Research Institute Co., Ltd., 8040-200016); Reverse osmosis organic membrane (Nanjing Membrane Materials Industry Technology Research Institute Co., Ltd., 8040-190033).

[0230] 3. Results

[0231] The results are shown in Table 23:

[0232] Table 23

[0233]

[0234]

[0235] Based on the data above, the average membrane flux of reverse osmosis membranes is higher than that of nanofiltration membranes, indicating a higher overall membrane concentration efficiency. Regarding turbidity and conductivity, as the concentration ratio increases, the clarified solution from nanofiltration membranes also increases slightly, while the reverse osmosis membrane shows little change, indicating a higher rejection rate. In terms of pH, the difference between the two is not significant. Therefore, considering both membrane efficiency and rejection rate, reverse osmosis membranes are selected as the material for the membrane concentration process.

Claims

1. The production process of Pediatric Cold Relief Mixture, characterized in that, Includes the following steps: S1. Extraction of volatile oils: Extracting volatile oils from peppermint and catnip spikes using steam distillation; S2. Extracting bitter almond water: Extracting bitter almond water from bitter almonds using steam distillation; S3. Decoction: Add water to burdock fruit, scutellaria, platycodon, angelica, angelica dahurica, gardenia, hawthorn, medicated leaven, malt, reed rhizome, honeysuckle and forsythia and decoct twice, the first time for 2 hours and the second time for 1 hour to obtain the decoction. S4. Filtration: The above decoction is filtered sequentially using plate and frame filtration and ceramic membrane filtration to obtain filtrate; S5. Concentration: The above filtrate is concentrated sequentially using reverse osmosis membrane concentration and vacuum concentration to obtain a thick paste; S6. Preparation: Add sucrose, stevia and sodium benzoate to the above thick paste, boil to dissolve, add the above bitter almond water, mix well, let stand, take the supernatant, add the above volatile oil and fragrance, mix well, filter, and the product is obtained. The pore size of the ceramic membrane filter is 5-200 nm; The plate and frame filter uses a plate and frame filter; the plate and frame filter has 20-35 filter layers and a water flow rate of 1500-2000 kg / h; The ceramic membrane filtration uses a ceramic membrane filter; the size of the ceramic membrane module of the ceramic membrane filter is 30-60mm; the ceramic membrane filtration capacity is 1000-3000kg / h; The permeate membrane concentration uses a reverse osmosis membrane concentrator; the reverse osmosis membrane module size of the reverse osmosis membrane concentrator is 2540-8040; the 2540 is 2.5×40 inches; the 8040 is 8×40 inches; the reverse osmosis membrane filtration capacity is 1000-3000 kg / h; The permeate membrane concentration concentrates the filtrate to 10%-30% of its original volume, followed by vacuum concentration. The vacuum concentration uses a double-effect concentrator; the double-effect concentrator has a processing capacity of 2000-3000 kg / h.

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