Production and preparation process and application of infantile Ganning mixture

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a production and preparation process and application of an infantile Ganning mixture. The production and preparation process comprises filtration and concentration. The filtration and the concentration are performed twice, the filtration and the concentration are performed through plate frame filtration and ceramic membrane filtration in sequence, and the concentration is performed through reverse osmosis membrane concentration and vacuum concentration in sequence. According to the method provided by the invention, on the premise of ensuring that the medicine quality is not influenced, the filtering effect is improved, the energy consumption of concentration is reduced, and the production cost is reduced.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and particularly relates to the production preparation process and application of Xiao'er Ganmaoning Mixture. Background Art

[0002] Children's physical development is not yet mature, their immune systems are relatively weak, and their resistance to diseases is also low. Therefore, when they catch a cold, they often show symptoms different from those of adults, and the disease may progress faster. Xiao'er Ganmaoning Mixture is developed according to the physical characteristics of children and can more effectively relieve the symptoms of children's wind-heat colds, such as fever, cough, sore throat, etc. Compared with Western medicines, traditional Chinese medicines usually have higher safety. Xiao'er Ganmaoning Mixture is composed of a variety of Chinese medicinal materials. After scientific compatibility and careful processing, it can reduce the occurrence of side effects. At the same time, its dosage has also been adjusted according to the age and weight of children to ensure the safety of medication. Therefore, Xiao'er Ganmaoning Mixture plays an important role in the treatment of children's colds. Its characteristics of being targeted at children's physical characteristics, having high safety, and definite curative effect make it one of the important drugs in the treatment of children's colds.

[0003] Xiao'er Ganmaoning Mixture is a variety produced by Jiangxi Puzheng Pharmaceutical Co., Ltd. This medicine is a traditional Chinese medicine compound preparation made from Mentha haplocalyx Briq., Schizonepeta tenuifolia Briq., Prunus armeniaca L. var. ansu Maxim., Arctium lappa L., Scutellaria baicalensis Georgi, Platycodon grandiflorus (Jacq.) A. DC., Peucedanum praeruptorum Dunn, Angelica dahurica (Fisch. ex Hoffm.) Benth. et Hook. f. ex Franch. et Sav., Gardenia jasminoides Ellis (fried), Crataegus pinnatifida Bunge (charred), Agastache rugosa (Fisch. et Mey.) O. Ktze. (charred), Hordeum vulgare L. (charred), Phragmites communis Trin., Lonicera japonica Thunb., and Forsythia suspensa (Thunb.) Vahl. The specific formula is: Mentha haplocalyx Briq. 80g, Schizonepeta tenuifolia Briq. 67g, Prunus armeniaca L. var. ansu Maxim. 80g, Arctium lappa L. 80g, Scutellaria baicalensis Georgi 80g, Platycodon grandiflorus (Jacq.) A. DC. 67g, Peucedanum praeruptorum Dunn 80g, Angelica dahurica (Fisch. ex Hoffm.) Benth. et Hook. f. ex Franch. et Sav. 27g, Gardenia jasminoides Ellis (fried) 40g, Crataegus pinnatifida Bunge (charred) 27g, Agastache rugosa (Fisch. et Mey.) O. Ktze. (charred) 27g, Hordeum vulgare L. (charred) 27g, Phragmites communis Trin. 120g, Lonicera japonica Thunb. 120g, and Forsythia suspensa (Thunb.) Vahl. 80g. Its preparation method is as follows: for the above 15 flavors, except for extracting the volatile oil from Mentha haplocalyx Briq. and Schizonepeta tenuifolia Briq., and preparing bitter almond water from Prunus armeniaca L. var. ansu Maxim., the remaining 12 flavors such as Arctium lappa L. are decocted with water twice. The first time is for 2 hours, and the second time is for 1 hour. After filtration, the filtrates are combined, allowed to stand for 48h, and the supernatant is concentrated to an appropriate amount. Then, 200g of sucrose, 2g of steviol glycoside, and 5g of sodium benzoate are added, boiled until dissolved, mixed with almond water, allowed to stand, and the supernatant is taken. The volatile oil, essence, etc. are added, and stirred while adding. Water is added to 1000 mL, stirred evenly, filtered, and then sub-packed to obtain the product. In the original production process, for the filtration and concentration processes, traditional screen filtration and vacuum concentration were used, and problems such as unsatisfactory filtration effect and high energy consumption in vacuum concentration were often faced.

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

[0005] In order to solve the above problems, the present invention provides a production and preparation process of Xiaoer Ganmao Ning mixture, which can not only improve the clarity of the medicine, but also has the advantage of saving energy consumption.

[0006] On the one hand, the present invention provides a production process for Xiaoer Ganmao Ning mixture, which includes filtration and concentration; the filtration includes plate and frame filtration and ceramic membrane filtration; the concentration includes reverse osmosis membrane concentration and reduced pressure concentration.

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

[0008] More specifically, the pore size of the ceramic membrane filtration is 100 nm.

[0009] Specifically, the steps include:

[0010] S1. Extracting volatile oil: extracting volatile oil from Mentha spicata and Nepeta tenuifolia by steam distillation;

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

[0012] S3, decoction: decocting burdock seeds, scutellaria, platycodon, peucedanum, angelica dahurica, gardenia, hawthorn, liushenqu, malt, reed root, honeysuckle and forsythia suspensa twice with water, the first time for 2 hours and the second time for 1 hour to obtain a decoction;

[0013] S4, filtering: filtering the decoction in turn by the above-mentioned filtering method to obtain a filtrate;

[0014] S5, concentration: using the above-mentioned concentration method to sequentially concentrate the above-mentioned filtrate to obtain a thick paste;

[0015] S6. Preparation: add sucrose, stevioside and sodium benzoate to the thick paste, boil and dissolve, add the bitter almond water, mix well, let stand, take the supernatant, add the volatile oil and essence, mix well, filter, and obtain.

[0016] Specifically, the components of the decoction step are: S3, decoction: burdock fruit, scutellaria baicalensis, platycodon, peucedanum, angelica dahurica, gardenia (fried), hawthorn (charred), liushenqu (charred), malt (charred), reed root, honeysuckle and forsythia.

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

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

[0019] Preferably, the plate and frame filtration uses a plate and frame filter; the number of filter mesh layers of the plate and frame filter can be 32 layers, and the water flow rate can be 2000 kg / h.

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

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

[0022] Preferably, the size of the ceramic membrane module is 50 mm; the ceramic membrane filtration volume is 2000 kg / h.

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

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

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

[0026] Specifically, the vacuum 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 vacuum concentration uses a double - effect concentrator.

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

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

[0030] On the one hand, the present invention provides the application of the foregoing production and preparation process in the preparation of Xiao'er Ganmaoning Mixture.

[0031] The technical effects achieved by the present invention:

[0032] Compared with the prior art, the preparation process provided by the present invention adds filtration and concentration methods in the filtration and concentration process flows. The traditional screen filtration and vacuum concentration are changed to continue with ceramic membrane filtration after screen filtration, and organic membrane concentration is added before vacuum concentration. Research results show that although the change in membrane filtration changes the filtration method, it has basically no impact on the material basis. The change in membrane concentration adds an additional concentration process on the original basis, and various research results indicate that it has no impact on the product quality. This preparation process not only improves the filtration effect but also reduces the energy consumption cost of concentration, overall meeting the requirements of the preparation and reducing the production cost budget. Description of the Drawings

[0033] Figure 1 They are the total ion current chromatogram and ultraviolet chromatogram of Xiao'er Ganmaoning Mixture. Among them, A is the TIC in negative ion mode; B is the TIC in positive ion mode; C is the ultraviolet chromatogram at 280 nm.

[0034] Figure 2 They are the HPLC chromatograms of Xiao'er Ganmaoning Mixture.

[0035] Figure 3 They are the HPLC chromatograms of Schizonepeta tenuifolia Briq.

[0036] Figure 4 They are the HPLC chromatograms of Arctium lappa L.

[0037] Figure 5 They are the HPLC chromatograms of Scutellaria baicalensis Georgi.

[0038] Figure 6 They are the HPLC chromatograms of Platycodon grandiflorum (Jacq.) A. DC.

[0039] Figure 7 They are the HPLC chromatograms of Peucedanum praeruptorum Dunn.

[0040] Figure 8 They are the HPLC chromatograms of Gardenia jasminoides Ellis (fried).

[0041] Figure 9 They are the HPLC chromatograms of Angelica dahurica (Fisch.) Benth. et Hook. f. ex Franch. et Sav.

[0042] Figure 10 They are the HPLC chromatograms of Crataegus pinnatifida Bunge var. major N. E. Br. (charred).

[0043] Figure 11 They are the HPLC chromatograms of Phragmites australis (Cav.) Trin. ex Steud.

[0044] Figure 12 They are the HPLC chromatograms of Lonicera japonica Thunb.

[0045] Figure 13 They are the HPLC chromatograms of Forsythia suspensa (Thunb.) Vahl.

[0046] Figure 14It is the chromatogram before the ceramic membrane filtration. Among them, A is the wavelength of 327 nm; B is the wavelength of 239 nm.

[0047] Figure 15 It is the chromatogram after the ceramic membrane filtration. Among them, A is the wavelength of 327 nm; B is the wavelength of 239 nm.

[0048] Figure 16 It is the stacked chromatogram of the fingerprint of the ceramic membrane filtration.

[0049] Figure 17 It is the similarity chromatogram of the ceramic membrane filtration.

[0050] Figure 18 It is the chromatogram before the organic membrane filtration. Among them, A is the wavelength of 327 nm; B is the wavelength of 239 nm.

[0051] Figure 19 It is the chromatogram after the organic membrane filtration. Among them, A is the wavelength of 327 nm; B is the wavelength of 239 nm.

[0052] Figure 20 It is the stacked chromatogram of the fingerprint of the organic membrane concentration.

[0053] Figure 21 It is the similarity chromatogram of the organic membrane concentration. Specific embodiments

[0054] The following combines specific embodiments to further elaborate on the present invention. The following embodiments are not used to limit the present invention, but only to illustrate the present invention. The experimental methods used in the following embodiments, unless otherwise specified, and the experimental methods without specific conditions noted in the embodiments are usually in accordance with conventional conditions. The materials, reagents, etc. used in the following embodiments, unless otherwise specified, can be obtained from commercial channels.

[0055] Example 1

[0056] This example provides a production preparation process for Xiao'er Ganmaoning Mixture. The specific steps are shown in Table 1:

[0057] Table 1

[0058]

[0059]

[0060]

[0061] Example 2 Substance basis research

[0062] Through operations such as mass spectrometry analysis, determine the substance basis of the Xiao'er Ganmaoning Mixture preparation and its main component composition structure.

[0063] 2.1 Sample Information

[0064] The Pediatric Ganmaoning Mixture obtained by the preparation method of Example 1.

[0065] 2.2 Instruments and Equipment

[0066] The samples were detected using a Thermo Fisher HPLC-Q-Exactive Orbitrap-MS high-resolution liquid chromatography-mass spectrometry instrument. The error after instrument calibration was <5 ppm, and data was collected in the positive and negative ion switching mode. The data acquisition software was Xcalibur 2.1.

[0067] 2.3 Chromatographic Conditions

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

[0069] Chromatographic gradient: Phase A was 0.1% formic acid aqueous solution, Phase B was 0.1% formic acid acetonitrile solution, the flow rate was 0.3 mL·min -1 , the column temperature was 40 °C, the detection wavelength was 280 nm, the injection volume was 5 μL, 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] The electrospray ionization source was used to collect data in positive and negative ion modes. Ordinary nitrogen was used as the auxiliary gas and sheath gas, and high-purity nitrogen was used as the collision gas. Full MS / dd-MS2 (Top3) positive and negative switching was used to collect data simultaneously, triggering the second-level scanning of the top three precursor ions, and the collision energy NCE was set to: 2, 40, 60. The specific mass spectrometry parameters are shown in Table 3:

[0074] Table 3

[0075]

[0076]

[0077] 2.5 Data Analysis Method

[0078] The data processing software is: Xcalibur 2.1 and Compound Discoverer 3.1 software. High-resolution quasi-molecular ions and secondary fragment information are collected by Xcalibur 2.1 software, and the data is imported into Compound Discoverer 3.1 software for analysis. Through the local library mzVault (containing mass spectrometry data of more than 1,200 traditional Chinese medicine reference substances), the online library mz cloud, the self-built database, and online websites such as chemspider and pubchem, each chromatographic peak is speculated and identified.

[0079] 2.6 Research Results

[0080] The components of Xiao'er Ganmaoning Mixture were analyzed using a reversed-phase chromatographic column. The total ion current chromatogram and ultraviolet chromatogram (280 nm) of each component were collected by Q-Exactive Orbitrap-MS, and the positive ion mode, negative ion mode acquisitions, and 280 nm ultraviolet chromatogram were obtained (see A, B, and C in Figure 1 . Based on the obtained high-precision quasi-molecular ions and secondary fragment information, through the analysis of the fragmentation rules in combination with relevant references and comparison with some reference substances, 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 chemical components in Xiao'er Ganmaoning Mixture based on positive and negative ion modes of Q-Exactive Orbitrap-MS

[0082]

[0083]

[0084]

[0085] Example 3 Correlation Study between Xiao'er Ganmaoning Mixture and Medicinal Materials

[0086] A correlation study between medicinal materials and finished products was carried out using a medicinal material positive control test. Considering the retention time and peak shape comparison of each peak comprehensively, and supplemented by the full-wavelength scanning function of the PDA diode array detector, a comparative study was conducted on the ultraviolet spectral characteristics of the corresponding chromatographic peaks to determine the medicinal material attribution of each main chromatographic peak.

[0087] (1) Preparation of the test solution: Accurately measure 2 mL of the Xiao'er Ganmaoning Mixture prepared in Example 1, place it in a 50 mL volumetric flask, dilute it to the mark with methanol, shake well, take the solution and centrifuge it at high speed for 15 minutes at 15,000 revolutions per minute, and take the supernatant, which is the test solution.

[0088] (2) Preparation of the test solution of Mentha haplocalyx Briq. herbs: Weigh 2 kg of Mentha haplocalyx Briq. herbs, add 20 L of water, and perform volatile oil extraction to obtain it.

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

[0090] (4) Preparation of the test solution of Armeniaca vulgaris Lam. seeds herbs: Weigh 80 g of Armeniaca vulgaris Lam. seeds, squeeze to remove oil, add five times the amount of water, soak at 37 °C for 3 hours, perform steam distillation on the soaking solution, collect the distillate with 20 mL of 90% ethanol solution until 60 mL, filter, and store in a sealed manner to obtain it.

[0091] (5) Preparation of the test solution of Arctium lappa L. fruits herbs: Weigh 80 g of Arctium lappa L. fruits, decoct with 6 times the amount of water twice, for 2 hours for the first time and 1 hour for the second time. Filter out the decoction liquid, combine the filtrates, let stand for 48 hours, take the supernatant, and concentrate to an appropriate amount to obtain it.

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

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

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

[0095] (9) Preparation of the test solution of Angelica dahurica (Fisch.) Benth. et Hook. f. ex Franch. et Sav. herbs: Weigh 27 g of Angelica dahurica (Fisch.) Benth. et Hook. f. ex Franch. et Sav. herbs, decoct with 6 times the amount of water twice, for 2 hours for the first time and 1 hour for the second time. Filter out the decoction liquid, combine the filtrates, let stand for 48 hours, take the supernatant, and concentrate to an appropriate amount to obtain it.

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

[0097] (11) Preparation of the test solution of Crataegus pinnatifida Bunge (charred) herbs:

[0098] Weigh 27 g of Crataegus pinnatifida Bunge herbs, decoct with 6 times the amount of water twice, for 2 hours for the first time and 1 hour for the second time. Filter out the decoction liquid, combine the filtrates, let stand for 48 hours, take the supernatant, and concentrate to an appropriate amount to obtain it.

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

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

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

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

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

[0104] Precisely pipette 10 μL of the test samples of Xiao'er Ganmaoning Mixture, the medicinal materials of mentha haplocalyx, schizonepeta spike, bitter apricot kernel, arctium fruit, scutellaria baicalensis, platycodon grandiflorum, peucedanum praeruptorum, gardenia (fried), angelica dahurica, hawthorn (charred), six - flavor medicated leaven (charred), germinated barley (charred), phragmites rhizome, honeysuckle flower, and forsythia fruit for injection determination, and conduct a comparison under the same conditions to determine the peak attribution.

[0105] The results show that by comparing the retention time and the UV spectral characteristics of the peak shape, there is no obvious peak attribution relationship between the common peaks in Xiao'er Ganmaoning Mixture and the medicinal materials of mentha haplocalyx, bitter apricot kernel, six - flavor medicated leaven (charred), and germinated barley (charred).

[0106] The HPLC chromatogram of Xiao'er Ganmaoning Mixture is shown in Figure 2 , and it is determined that peaks 12 and 14 in Xiao'er Ganmaoning Mixture come from the medicinal material of schizonepeta spike ( Figure 3 ); peaks 1, 2, 3, 6, 7, 8, and 11 come from the medicinal material of arctium fruit ( Figure 4 ); peaks 10, 12, and 13 come from the medicinal material of scutellaria baicalensis ( Figure 5 ); peak 10 comes from the medicinal material of platycodon grandiflorum ( Figure 6); Peak 5 comes from Peucedanum chinense ( Figure 7 ); Peaks 4 and 9 come from Gardenia (fried) ( Figure 8 ); Peaks 12 and 14 come from Angelica dahurica ( Figure 9 ); Peak 10 comes from hawthorn (charred) medicinal material ( Figure 10 ); Peak 5 comes from Phragmites australis ( Figure 11 ); Peaks 1, 2, 6, 7, and 8 come from honeysuckle ( Figure 12 ); Peak 5 comes from Forsythia suspensa ( Figure 13 ).

[0107] In summary, peak 3 in Xiaoer Ganmao Ning mixture comes from Burdock fruit; peaks 4 and 9 come from Gardenia (fried); peak 13 comes from Scutellaria baicalensis; peaks 1, 2, 6, 7, and 8 come from Burdock fruit and Honeysuckle; peak 5 comes from Peucedanum chinense, Phragmites australis, and Forsythia suspensa; peak 10 comes from Scutellaria baicalensis, Platycodon grandiflorum, and Crataegus pinnatifida (charred); peak 11 comes from Burdock fruit and Angelica dahurica; peak 12 comes from Schizonepeta spicate and Scutellaria baicalensis; peak 14 comes from Schizonepeta spicate and Angelica dahurica; in addition, there is no obvious peak attribution relationship between the common peaks of Xiaoer Ganmao Ning mixture with bitter almond, Liushenqu (charred), malt (charred), and mint and the HPLC.

[0108] Example 4 Effect of Ceramic Membrane Filtration Process on Xiaoer Ganmao Ning Mixture

[0109] 4.1 Investigation of residual substances in ceramic membrane

[0110] By sending samples to a third-party testing agency, the elemental composition analysis and heavy metal residue of the ceramic membrane are tested according to the XRF test method and GB 31604.49-2016, and the migration of heavy metals and other substances during the ceramic membrane filtration process is examined.

[0111] 4.1.1 Ceramic membrane elements

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

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

[0114] Table 5

[0115]

[0116] 4.1.2 Heavy metal migration investigation

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

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

[0119] Table 6

[0120] Determination item 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 °C, 120 min.

[0123] (2) 1% citric acid; Detection conditions: 22 °C, 24 h.

[0124] (3) 5% citric acid; Detection conditions: 98 °C, 120 min.

[0125] (4) 5% citric acid; Detection conditions: 22 °C, 24 h.

[0126] (5) 10% citric acid; Detection conditions: 98 °C, 120 min.

[0127] (6) 10% citric acid; Detection conditions: 22 °C, 24 h.

[0128] (7) 20% citric acid; Detection conditions: 98 °C, 120 min.

[0129] (8) 20% citric acid; Detection conditions: 22 °C, 24 h.

[0130] (9) 95% ethanol; Detection conditions: 98 °C, 120 min.

[0131] (10) 95% ethanol; Detection conditions: 22 °C, 24 h.

[0132] The migration amounts of various heavy metals in the ceramic membrane under different conditions were not detected. The results showed that during the ceramic membrane filtration process, the pollution risk of heavy metal elements to the raw materials was controllable and did not affect the product quality.

[0133] 4.2 Influence of the ceramic membrane filtration process on the material basis of Xiao'er Ganmaoning Mixture

[0134] Take the concentrated extract and clear liquid prepared in Example 1, and investigate indicators such as solid content, multi-component content, fingerprint, pH, turbidity, conductivity, and membrane flux.

[0135] 4.2.1 Research materials

[0136] The extract of Xiao'er Ganmaoning Mixture was prepared using Example 1; Sodium hydroxide, AR grade, Inner Mongolia Junzheng Energy Chemical Co., Ltd.; Citric acid, AR grade, Guangzhou Keqi Biotechnology Co., Ltd.; Methanol, acetonitrile, HPLC grade, Merck Chemical Technology (Shanghai) Co., Ltd.; Phosphoric acid, hydrochloric acid, acetic acid, AR grade, Jiangxi Hengxin Chemical Co., Ltd.; Reference substance solution, self-made in the laboratory (reference substance, NICPBP).

[0137] 4.2.2 Instruments

[0138] See Table 7:

[0139] Table 7

[0140]

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

[0142] The ceramic membrane was filtered 10 times, and the average membrane flux was 316.0 L / H.

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

[0144] The results are shown in Table 8:

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

[0146]

[0147]

[0148] 4.2.5 Investigation of the Determination of the Contents of Multiple Components in the Ceramic Membrane Filtration Process

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

[0150] Table 9 Investigation of the Determination of the Contents of Multiple Components in the Ceramic Membrane Filtration Process

[0151]

[0152] 4.2.6 Investigation of the Solid Content of the Ceramic Membrane Filtration Process

[0153] The results are shown in Table 10:

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

[0155]

[0156] 4.2.7 Investigation of the Fingerprint of the Ceramic Membrane Filtration

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

[0158] Table 11 Investigation of the Fingerprint of the Ceramic Membrane Filtration

[0159] Before membrane filtration 01 Before membrane filtration 02 Before membrane filtration 03 After membrane filtration 01 After membrane filtration 02 After membrane filtration 03 Before membrane filtration 01 1.000 1.000 1.000 1.000 1.000 0.997 Before membrane filtration 02 1.000 1.000 1.000 1.000 1.000 0.997 Before membrane filtration 03 1.000 1.000 1.000 1.000 1.000 0.997 After membrane filtration 01 1.000 1.000 1.000 1.000 1.000 0.997 After membrane filtration 02 1.000 1.000 1.000 1.000 1.000 0.997 After membrane filtration 03 0.997 0.997 0.997 0.997 0.997 1.000

[0160] In summary, before and after the change of the ceramic membrane filtration process, that is, before and after membrane filtration using a 100 nm ceramic membrane, the results of fingerprint maps, multi-component content determination, etc. of the medicinal liquid showed that the change of membrane filtration did not cause a change in the medicinal substance basis of this variety, and the component loss was very low. At the same time, data results such as solid content and turbidity showed that while ensuring the substance basis, membrane filtration played a certain role in impurity removal, improved the product clarity, and met the requirements of quality stable control.

[0161] Effect of Organic Membrane (Reverse Osmosis Membrane) Concentration Process on Xiao'er Ganmaoning Mixture in Example 5

[0162] 5.1 Investigation of Residual Substances in Organic Membrane

[0163] By sending samples to a third-party testing agency, according to the standards of (EU) No 10 / 2011 and its amending directive (EU) 2020 / 1245, items such as sensory, primary aromatic amine residues, and heavy metal residues were inspected to investigate the migration of aromatic amines, heavy metals, etc. during the organic membrane concentration process.

[0164] (1) Total migration amount is shown in Table 12:

[0165] Table 12

[0166]

[0167] (2) Sensory detection is shown in Table 13:

[0168] Table 13

[0169]

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

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

[0172] Table 14

[0173]

[0174] (4) Migration amount of heavy metals is shown in Table 15:

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

[0176] Table 15

[0177]

[0178]

[0179] Summary: As shown in the inspection report, through the inspection of several indicators such as the total migration amount, sensory (odor and taste), specific migration amount of primary aromatic amines, and specific migration amount of heavy metals of the organic membrane, the results all meet the EU standards, indicating that during the concentration process of the organic membrane, the pollution risks of heavy metal elements and aromatic amines to the raw materials are controllable and do not affect the product quality.

[0180] 5.2 Influence of the organic membrane concentration process on the material basis of Xiao'er Ganmaoning Mixture

[0181] Take the concentrated liquid and the clear liquid of the concentrated liquid prepared in Example 1, and investigate indicators such as the solid content, multi-component content, fingerprint, pH, turbidity, conductivity, and membrane flux.

[0182] 5.2.1 Research materials

[0183] The extraction solution of Xiao'er Ganmaoning Mixture was prepared using 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 substance solution, self-made in the laboratory (reference substances, NIFDC).

[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 Trade (Shanghai) Co., Ltd. Conductivity meter ST300C Auhaus International Trade (Shanghai) Co., Ltd. Turbidity meter WZB - 175 Shanghai Yidian Scientific Instruments Co., Ltd. pH meter pHB - H Shanghai Yidian Scientific Instruments Co., Ltd. Pure water machine AZX - 2100 - 300B4 Shenzhen Angel Industry Co., Ltd. Pilot - scale equipment for organic membrane 8040-190033 Nanjing Membrane Materials Industry Technology Research Institute Co., Ltd.

[0188] 5.2.3 Investigation of the membrane flux of the 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 the basic parameters of the organic membrane concentration process

[0191] The results are shown in Table 17:

[0192] Table 17 Investigation of the basic parameters of the organic membrane concentration process

[0193]

[0194]

[0195] 5.2.5 Investigation of the determination of multi-component content in the organic membrane concentration process

[0196] The results are shown in Table 18. The chromatograms before and after the organic membrane passed through the membrane are shown in Figure 18 - Figure 19 .

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

[0198]

[0199] 5.2.6 Investigation on the Solid Content of the Organic Membrane Concentration Process

[0200] The results are shown in Table 19:

[0201] Table 19 Investigation on the Solid Content of the Organic Membrane Concentration Process

[0202]

[0203]

[0204] 5.2.7 Investigation on the Fingerprint Chromatograms before and after Organic Membrane Concentration

[0205] The results are shown in Table 20. The stacked chromatogram of the fingerprint chromatogram of the organic membrane concentration and the similarity chromatogram of the organic membrane concentration are shown in Figure 20 - Figure 21 .

[0206] Table 20 Investigation on the Fingerprint Chromatograms before and after Organic Membrane Concentration

[0207] Before membrane filtration 01 Before membrane filtration 02 Before membrane filtration 03 After membrane filtration 01 After membrane filtration 02 After membrane filtration 03 After membrane filtration 01 1.000 0.999 1.000 0.999 0.999 1.000 After membrane filtration 02 0.999 1.000 1.000 1.000 1.000 1.000 After membrane filtration 03 1.000 1.000 1.000 0.999 1.000 1.000 After membrane filtration 01 0.999 1.000 0.999 1.000 0.999 0.999 After membrane filtration 02 0.999 1.000 1.000 0.999 1.000 1.000 After membrane filtration 03 0.999 1.000 1.000 0.999 1.000 1.000

[0208] The results of the determination of the multi-component content, solid content, etc. of the medicinal liquid before and after the reverse osmosis organic membrane concentration are added before the original concentration process. It shows that the change of the membrane concentration has not caused any change in the medicinal substance basis of this variety, and there is almost no component loss. At the same time, compared with the traditional concentration method, the membrane concentration has higher efficiency and lower cost, and the change effectively alleviates the energy consumption problem of the concentration process.

[0209] Comparative Example 1

[0210] Replace the pore sizes of the ceramic membranes in Example 1 with 200 nm, 100 nm, 15 nm, 10 nm, and 5 nm respectively. For the same batch of the extraction solution of Xiao'er Ganmaoning Mixture, under the same experimental environmental conditions, investigate the average membrane flux, pH, turbidity, conductivity and other data of the membrane filtration solution passing through the membrane under different membrane pore sizes.

[0211] 1. Experimental Scheme

[0212] Take 1000 L of the extraction solution of Xiao'er Ganmaoning Mixture that has been extracted, and under specific experimental parameter conditions, pass it through the ceramic membranes with pore sizes of 200 nm, 100 nm, 15 nm, 10 nm, and 5 nm for membrane filtration in sequence. The membrane flux is detected throughout the process, the average membrane flux is calculated, and the turbidity, conductivity, pH and other data of the original extraction solution and the membrane filtration solution passing through the membrane are inspected online.

[0213] 2. The experimental instruments are shown in Table 21:

[0214] Table 21

[0215]

[0216]

[0217] 3. Experimental Parameters

[0218] Frequency of ceramic membrane equipment: 45 Hz, pressure: 0.2 mpa, raw liquid temperature: 60 °C, total amount of liquid medicine: 1000 L, pore size of ceramic membrane: 200 nm / 100 nm / 15 nm / 10 nm / 5 nm.

[0219] 4. Experimental Results

[0220] The results are shown in Table 22:

[0221] Table 22

[0222]

[0223] By comparing the above data, it shows that the conductivity of the filtrate passing through the membrane decreases slightly, and some ions in the raw liquid are also intercepted during the transfer to the clear liquid. The performance differences of several membrane specifications are not significant, and the pH is hardly affected. The average membrane flux of the 200-nm ceramic membrane is the highest, but at the same time, the turbidity of the filtrate is relatively high, and the effect of intercepting impurities is weak. The 100-nm membrane ensures both the impurity removal effect and the membrane flux, and the overall membrane passing efficiency is at a relatively high level. Therefore, the 100-nm ceramic membrane is selected as the material for the membrane filtration process.

[0224] Comparative Example 2

[0225] Replace the reverse osmosis membrane in Example 1 with a nanofiltration membrane. For the same batch of ceramic membrane filtrate of Xiao'er Ganmaoning Mixture, under the same experimental environmental conditions, by examining different types of organic membranes, data such as the average membrane flux, pH, turbidity, and conductivity of the membrane concentrate are obtained.

[0226] 1. Experimental Scheme

[0227] The 1000 L filtrate of Xiao'er Ganmaoning Mixture after passing through the ceramic membrane is respectively passed through the nanofiltration organic membrane and the reverse osmosis organic membrane for membrane concentration under specific experimental parameter conditions, with a total concentration of 5 times. The membrane flux is recorded throughout the concentration process, and the turbidity, conductivity, pH, etc. of the concentrated raw liquid and the membrane-passed clear liquid are inspected online.

[0228] 2. Experimental Parameters

[0229] Organic membrane size: 8040, frequency: 45Hz, pressure: 2mpa, raw liquid temperature: 30°C, total amount of liquid medicine: 1000L, organic membrane category: nanofiltration membrane / reverse osmosis membrane. Nanofiltration organic membrane (Nanjing Institute of Membrane Materials Industry Technology Co., Ltd., 8040-200016); Reverse osmosis organic membrane (Nanjing Institute of Membrane Materials Industry Technology Co., Ltd., 8040-190033).

[0230] 3. Results

[0231] The results are shown in Table 23:

[0232] Table 23

[0233]

[0234]

[0235] Judging from the above data, the average membrane flux of the reverse osmosis membrane is higher than that of the nanofiltration membrane, that is, the overall membrane concentration efficiency is higher. In terms of turbidity and conductivity, with the increase of the concentration ratio, the permeate clear liquid of the nanofiltration membrane also increases slightly, while the reverse osmosis membrane changes little, indicating that the rejection rate of the membrane is higher than that of the nanofiltration membrane. In terms of pH, the difference between the two is not significant. Therefore, considering the membrane passing efficiency and rejection rate, the reverse osmosis membrane is selected as the membrane concentration process material.

Claims

1. The production and preparation process of Xiao'er Ganmaoning Mixture, characterized in that, The production and preparation process includes filtration and concentration; the filtration includes plate-and-frame filtration and ceramic membrane filtration; the concentration includes reverse osmosis membrane concentration and vacuum concentration.

2. The production and preparation process according to claim 1, wherein, The pore size of the ceramic membrane filtration is 5 - 200 nm.

3. The production and preparation process according to claim 1 or 2, characterized in that, It includes the following steps: S1. Extract volatile oil: Use steam distillation to extract the volatile oil from Mentha haplocalyx Briq. and Schizonepeta tenuifolia Briq. S2. Extract amygdalus amara water: Use steam distillation to extract the amygdalus amara water from Prunus armeniaca L. S3. Decoct: Arctium lappa L., Scutellaria baicalensis Georgi, Platycodon grandiflorus (Jacq.) A. DC., Peucedanum praeruptorum Dunn, Angelica dahurica (Fisch. ex Hoffm.) Benth. et Hook. f. ex Franch. et Sav., Gardenia jasminoides Ellis, Crataegus pinnatifida Bunge, Agastache rugosa (Fisch. et Mey.) O. Ktze., Hordeum vulgare L. var. nudum Hook. f., Phragmites communis Trin., Lonicera japonica Thunb. and Forsythia suspensa (Thunb.) Vahl are decocted with water twice, 2 hours for the first time and 1 hour for the second time, to obtain a decoction. S4. Filter: Use the filtration method described in claim 1 or 2 to filter the above-mentioned decoction in sequence to obtain a filtrate. S5. Concentrate: Use the concentration method described in claim 1 to concentrate the above-mentioned filtrate in sequence to obtain a thick paste. S6. Prepare: Add sucrose, steviol glycoside and sodium benzoate to the above-mentioned thick paste, boil and dissolve, add the above-mentioned amygdalus amara water, mix well and let stand, take the supernatant, add the above-mentioned volatile oil and essence, mix well and filter to obtain the product.

4. The production and preparation process according to claim 3, characterized in that, The plate-and-frame filtration uses a plate-and-frame filter; the number of filter mesh layers of the plate-and-frame filter is 20 - 35 layers, and the water flow rate is 1500 - 2000 kg / h.

5. The production and preparation process according to claim 3, characterized in that, The ceramic membrane filtration uses a ceramic membrane filter; the size of the ceramic membrane module of the ceramic membrane filter is 30 - 60 mm; the ceramic membrane filtration volume is 1000 - 3000 kg / h.

6. The production and preparation process according to claim 3, characterized in that, The reverse osmosis membrane concentration uses a reverse osmosis membrane concentrator; the size of the reverse osmosis membrane module 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 volume is 1000 - 3000 kg / h.

7. The production and preparation process according to claim 6, characterized in that, The reverse osmosis membrane concentration concentrates the filtrate to 10% - 30% of the original volume, and then undergoes vacuum concentration.

8. The production and preparation process according to claim 7, characterized in that, The vacuum concentration uses a double-effect concentrator, a spherical concentrator, a single-effect concentrator or a flash concentrator.

9. The production and preparation process according to claim 8, characterized in that, The vacuum concentration uses a double-effect concentrator; the processing capacity of the double-effect concentrator is 2000 - 3000 kg / h.

10. Use of the production and preparation process according to any one of claims 1 - 9 in the preparation of Xiao'er Ganmaoning Mixture.

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